mazams.weebly.com...Foreword I don't have my name on anything that I don't really do. –Heidi Klum Can the organic chemists associated with so-called “Named Reactions” make the

Name Reactions

Fourth Expanded Edition

Jie Jack Li

Name Reactions

A Collection of Detailed Mechanismsand Synthetic Applications

Fourth Expanded Edition

123

Jie Jack Li, Ph.D.Discovery ChemistryBristol-Myers Squibb Company5 Research ParkwayWallingford, CT [email protected]

ISBN 978-3-642-01052-1 e-ISBN 978-3-642-01053-8DOI 10.1007/978-3-642-01053-8Springer Dordrecht Heidelberg London New York

c© Springer-Verlag Berlin Heidelberg 2009This work is subject to copyright. All rights are reserved, whether the whole or part of the material isconcerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting,reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publicationor parts thereof is permitted only under the provisions of the German Copyright Law of September 9,1965, in its current version, and permission for use must always be obtained from Springer. Violationsare liable to prosecution under the German Copyright Law.The use of general descriptive names, registered names, trademarks, etc. in this publication does notimply, even in the absence of a specific statement, that such names are exempt from the relevant protectivelaws and regulations and therefore free for general use.

Cover design: KunkelLopka GmbH

Printed on acid-free paper

Springer is part of Springer Science+Business Media (www.springer.com)

Library of Congress Control Number: 2009931220

To Vivien

Foreword

I don't have my name on anything that I don't really do. –Heidi Klum

Can the organic chemists associated with so-called “Named Reactions” make the same claim as supermodel Heidi Klum? Many scholars of chemistry do not hesitate to point out that the names associated with “name reactions” are often not the actual inventors. For instance, the Arndt–Eistert reaction has nothing to do with either Arndt or Eistert, Pummerer did not discover the “Pummerer” rearrangement, and even the famous Birch reduction owes its initial discovery to someone named Charles Wooster (first reported in a DuPont patent). The list goes on and on…

But does that mean we should ignore, boycott, or outlaw “named reactions”? Absolutely not. The above examples are merely exceptions to the rule. In fact, the chemists associated with name reactions are typically the original discoverers, contribute greatly to its general use, and/or are the first to popularize the transformation. Regardless of the controversial history underlying certain named reactions, it is the students of organic chemistry who benefit the most from the cataloging of reactions by name. Indeed, it is with education in mind that Dr. Jack Li has masterfully brought the chemical community the latest edition of Name Reactions.

It is clear why this beautiful treatise has rapidly become a bestseller within the chemical community. The quintessence of hundreds of named reactions is encapsulated in a concise format that is ideal for students and seasoned chemists alike. Detailed mechanistic and occasionally even historical details are given for hundreds of reactions along with key references. This “must-have” book will undoubtedly find a place on the bookshelves of all serious practitioners and students of the art and science of synthesis.

Phil S. Baran May 2009

La Jolla, California

Preface

The first three editions of this book have been warmly embraced by the organic chemistry community. Many readers have indicated that while they like the detailed mechanisms, they prefer to have more real case applications in synthesis. For this edition, we have revolutionized the format, which finally liberated more space to accomodate many more synthetic examples. As a consequence, the subtitle of the book has been changed to A Collection of Detailed Mechanisms and Synthetic Applications. When putting together the 4th edition, I also strived to cap-ture the latest references, up to 2009 whenever possible. Coincidentally, my daughter Vivien, a sophomore at the University of Michigan, will take soon Or-ganic Chemistry. I hope she finds this book useful in preparing for her exams.

I am very much indebted to the readers who have kindly written to me with suggestions, which helped transform this book into a useful reference book for senior undergrate and graduate students around the world—the second edition was translated to both Chinese and Russian. I am grateful to my good friend Derek A. Pflum at Ash Stevens Inc. who kindly proofead the entire manuscript and provided many invaluable suggestions. Prof. Derrick L. J. Clive at University of Alberta also proofread the first half of the manuscript and offered helpful comments. I also wish to thank Prof. Phil S. Baran at Scripps Research Institute and his students, Tanja Gulder, Yoshi Ishihara, Chad A. Lewis, Jonathan Lockner, Jun Cindy Shi, and Ian B. Seiple for proofreading the final draft of the manuscript. Their knowledge and time have tremendously enhanced the quality of this book. Any remaining errors are, of course, solely my own responsibility.

As always, I welcome your critique!

Jie Jack Li May 2009

Killingworth, Connecticut

Alder ene reaction ..................................................................................................... 1 Aldol condensation.................................................................................................... 3 Algar–Flynn–Oyamada reaction ............................................................................... 6 Allan–Robinson reaction........................................................................................... 8 Arndt–Eistert homologation.................................................................................... 10 Baeyer–Villiger oxidation....................................................................................... 12 Baker–Venkataraman rearrangement...................................................................... 14 Bamford–Stevens reaction ...................................................................................... 16 Barbier coupling reaction ........................................................................................ 18 Bartoli indole synthesis ........................................................................................... 20 Barton radical decarboxylation ............................................................................... 22 Barton–McCombie deoxygenation ......................................................................... 24 Barton nitrite photolysis .......................................................................................... 26 Batcho–Leimgruber indole synthesis...................................................................... 28 Baylis–Hillman reaction.......................................................................................... 30 Beckmann rearrangement........................................................................................ 33 Abnormal Beckmann rearrangement ............................................................ 34 Benzilic acid rearrangement.................................................................................... 36 Benzoin condensation.............................................................................................. 38 Bergman cyclization................................................................................................ 40 Biginelli pyrimidone synthesis................................................................................ 42 Birch reduction ........................................................................................................ 44 Bischler–Möhlau indole synthesis .......................................................................... 46 Bischler–Napieralski reaction ................................................................................. 48 Blaise reaction ........................................................................................................ 50 Blum–Ittah aziridine synthesis ............................................................................... 52 Boekelheide reaction ............................................................................................... 54 Boger pyridine synthesis ......................................................................................... 56 Borch reductive amination ...................................................................................... 58 Borsche–Drechsel cyclization................................................................................. 60 Boulton–Katritzky rearrangement........................................................................... 62 Bouveault aldehyde synthesis ................................................................................. 64 Bouveault–Blanc reduction..................................................................................... 65 Bradsher reaction..................................................................................................... 66 Brook rearrangement............................................................................................... 68 Brown hydroboration .............................................................................................. 70 Bucherer carbazole synthesis .................................................................................. 72

Table of Contents

Foreword............................................................................................................... VIIPreface ................................................................................................................Abbreviations .......................................................................................................XIX

IX..

XII

Buchwald–Hartwig amination ................................................................................ 80 Burgess dehydrating reagent................................................................................... 84 Burke boronates....................................................................................................... 87 Cadiot–Chodkiewicz coupling................................................................................ 90 Camps quinoline synthesis...................................................................................... 92 Cannizzaro reaction................................................................................................. 94 Carroll rearrangement ............................................................................................. 96 Castro–Stephens coupling....................................................................................... 98 Chan alkyne reduction........................................................................................... 100 Chan–Lam C–X coupling reaction ....................................................................... 102 Chapman rearrangement ....................................................................................... 105 Chichibabin pyridine synthesis ............................................................................. 107 Chugaev reaction................................................................................................... 110 Ciamician–Dennsted rearrangement..................................................................... 112 Claisen condensation............................................................................................. 113 Claisen isoxazole synthesis................................................................................... 115 Claisen rearrangement........................................................................................... 117 para-Claisen rearrangement ....................................................................... 119 Abnormal Claisen rearrangement ................................................................ 121 Eschenmoser–Claisen amide acetal rearrangement .................................... 123 Ireland–Claisen (silyl ketene acetal) rearrangement ................................... 125 Johnson–Claisen (orthoester) rearrangement .............................................. 127 Clemmensen reduction.......................................................................................... 129 Combes quinoline synthesis.................................................................................. 131 Conrad–Limpach reaction..................................................................................... 133 Cope elimination reaction ..................................................................................... 135 Cope rearrangement .............................................................................................. 137 Anionic oxy-Cope rearrangement................................................................. 138 Oxy-Cope rearrangement.............................................................................. 140 Siloxy-Cope rearrangement .......................................................................... 141 Corey–Bakshi–Shibata (CBS) reagent ................................................................. 143 Corey−Chaykovsky reaction................................................................................. 146 Corey–Fuchs reaction............................................................................................ 148 Corey–Kim oxidation............................................................................................ 150 Corey–Nicolaou macrolactonization .................................................................... 152 Corey–Seebach reaction........................................................................................ 154 Corey–Winter olefin synthesis.............................................................................. 156 Criegee glycol cleavage ........................................................................................ 159 Criegee mechanism of ozonolysis ........................................................................ 161 Curtius rearrangement........................................................................................... 162 Dakin oxidation ..................................................................................................... 165 Dakin–West reaction............................................................................................. 167 Darzens condensation............................................................................................ 169

Bucherer reaction..................................................................................................... 74 Bucherer–Bergs reaction ......................................................................................... 76 Büchner ring expansion........................................................................................... 78

XIII

Tiffeneau–Demjanov rearrangement ............................................................ 177 Dess–Martin periodinane oxidation ...................................................................... 179 Dieckmann condensation ...................................................................................... 182 Diels–Alder reaction.............................................................................................. 184 Inverse electronic demand Diels–Alder reaction ......................................... 186 Hetero-Diels–Alder reaction ........................................................................ 187 Dienone–phenol rearrangement ............................................................................ 190 Di-π-methane rearrangement ................................................................................ 192 Doebner quinoline synthesis ................................................................................. 194 Doebner–von Miller reaction ................................................................................ 196 Dötz reaction.......................................................................................................... 198 Dowd–Beckwith ring expansion........................................................................... 200 Dudley reagent....................................................................................................... 202 Erlenmeyer−Plöchl azlactone synthesis................................................................ 204 Eschenmoser’s salt ................................................................................................ 206 Eschenmoser–Tanabe fragmentation .................................................................... 208 Eschweiler–Clarke reductive alkylation of amines .............................................. 210 Evans aldol reaction .............................................................................................. 212 Favorskii rearrangement........................................................................................ 214 Quasi-Favorskii rearrangement..................................................................... 217 Feist–Bénary furan synthesis ................................................................................ 218 Ferrier carbocyclization......................................................................................... 220 Ferrier glycal allylic rearrangement...................................................................... 222 Fiesselmann thiophene synthesis .......................................................................... 225 Fischer indole synthesis ........................................................................................ 227 Fischer oxazole synthesis ...................................................................................... 229 Fleming–Kumada oxidation ................................................................................. 231 Tamao−Kumada oxidation............................................................................ 233 Friedel–Crafts reaction.......................................................................................... 234 Friedel–Crafts acylation reaction.................................................................. 234 Friedel–Crafts alkylation reaction................................................................. 236 Friedländer quinoline synthesis ............................................................................ 238 Fries rearrangement............................................................................................... 240 Fukuyama amine synthesis ................................................................................... 243 Fukuyama reduction .............................................................................................. 245 Gabriel synthesis ................................................................................................... 246 Ing–Manske procedure.................................................................................. 249 Gabriel–Colman rearrangement ............................................................................ 250 Gassman indole synthesis...................................................................................... 251 Gattermann–Koch reaction ................................................................................... 253 Gewald aminothiophene synthesis........................................................................ 254 Glaser coupling...................................................................................................... 257 Eglinton coupling .......................................................................................... 259

Delépine amine synthesis...................................................................................... 171 de Mayo reaction................................................................................................... 173 Demjanov rearrangement ...................................................................................... 175

XIV

Grob fragmentation ............................................................................................... 268 Guareschi–Thorpe condensation........................................................................... 270 Hajos–Wiechert reaction....................................................................................... 271 Haller–Bauer reaction ........................................................................................... 273 Hantzsch dihydropyridine synthesis ..................................................................... 274 Hantzsch pyrrole synthesis.................................................................................... 276 Heck reaction......................................................................................................... 277 Heteroaryl Heck reaction .............................................................................. 280 Hegedus indole synthesis ...................................................................................... 281 Hell–Volhard–Zelinsky reaction........................................................................... 282 Henry nitroaldol reaction ...................................................................................... 284 Hinsberg synthesis of thiophene derivatives ........................................................ 286 Hiyama cross-coupling reaction ........................................................................... 288 Hofmann rearrangement ....................................................................................... 290 Hofmann–Löffler–Freytag reaction...................................................................... 292 Horner–Wadsworth–Emmons reaction ................................................................ 294 Houben–Hoesch synthesis .................................................................................... 296 Hunsdiecker–Borodin reaction ............................................................................. 298 Jacobsen–Katsuki epoxidation.............................................................................. 300 Japp–Klingemann hydrazone synthesis................................................................ 302 Jones oxidation...................................................................................................... 304 Collins–Sarett oxidation................................................................................ 305 PCC oxidation ............................................................................................... 306 PDC oxidation............................................................................................... 307 Julia–Kocienski olefination................................................................................... 309 Julia–Lythgoe olefination ..................................................................................... 311 Kahne glycosidation.............................................................................................. 313 Knoevenagel condensation ................................................................................... 315 Knorr pyrazole synthesis....................................................................................... 317 Koch–Haaf carbonylation ..................................................................................... 319 Koenig–Knorr glycosidation................................................................................. 320 Kostanecki reaction............................................................................................... 322 Kröhnke pyridine synthesis................................................................................... 323 Kumada cross-coupling reaction........................................................................... 325 Lawesson’s reagent ............................................................................................... 328 Leuckart–Wallach reaction ................................................................................... 330 Lossen rearrangement ........................................................................................... 332 McFadyen–Stevens reduction............................................................................... 334 McMurry coupling ................................................................................................ 335 Mannich reaction................................................................................................... 337 Martin’s sulfurane dehydrating reagent................................................................ 339 Masamune–Roush conditions ............................................................................... 341 Meerwein’s salt ..................................................................................................... 343

Gomberg–Bachmann reaction............................................................................... 262 Gould–Jacobs reaction .......................................................................................... 263 Grignard reaction................................................................................................... 266

XV

[2,3]-Meisenheimer rearrangement....................................................................... 350 Meyers oxazoline method ..................................................................................... 351 Meyer–Schuster rearrangement ............................................................................ 353 Michael addition.................................................................................................... 355 Michaelis–Arbuzov phosphonate synthesis.......................................................... 357 Midland reduction ................................................................................................. 359 Minisci reaction ..................................................................................................... 361 Mislow–Evans rearrangement............................................................................... 363 Mitsunobu reaction................................................................................................ 365 Miyaura borylation ................................................................................................ 368 Moffatt oxidation................................................................................................... 370 Morgan–Walls reaction ........................................................................................ 371 Mori–Ban indole synthesis.................................................................................... 373 Mukaiyama aldol reaction..................................................................................... 375 Mukaiyama Michael addition ............................................................................... 377 Mukaiyama reagent ............................................................................................... 379 Myers−Saito cyclization........................................................................................ 382 Nazarov cyclization............................................................................................... 383 Neber rearrangement ............................................................................................. 385 Nef reaction ........................................................................................................... 387 Negishi cross-coupling reaction............................................................................ 389 Nenitzescu indole synthesis .................................................................................. 391 Newman−Kwart reaction ...................................................................................... 393 Nicholas reaction................................................................................................... 395 Nicolaou dehydrogenation .................................................................................... 397 Noyori asymmetric hydrogenation........................................................................ 399 Nozaki–Hiyama–Kishi reaction............................................................................ 401 Nysted reagent ....................................................................................................... 403 Oppenauer oxidation ............................................................................................. 404 Overman rearrangement........................................................................................ 406 Paal thiophene synthesis........................................................................................ 408 Paal–Knorr furan synthesis ................................................................................... 409 Paal–Knorr pyrrole synthesis ................................................................................ 411 Parham cyclization ................................................................................................ 413 Passerini reaction................................................................................................... 415 Paternò–Büchi reaction ......................................................................................... 417 Pauson–Khand reaction......................................................................................... 419 Payne rearrangement ............................................................................................. 421 Pechmann coumarin synthesis .............................................................................. 423 Perkin reaction....................................................................................................... 424 Petasis reaction ...................................................................................................... 426 Petasis reagent ....................................................................................................... 428 Peterson olefination............................................................................................... 430

Meerwein–Ponndorf–Verley reduction ................................................................ 345 Meisenheimer complex ......................................................................................... 347 [1,2]-Meisenheimer rearrangement ...................................................................... 349

XVI

Pinner reaction....................................................................................................... 438 Polonovski reaction............................................................................................... 440 Polonovski–Potier rearrangement......................................................................... 442 Pomeranz–Fritsch reaction.................................................................................... 444 Schlittler–Müller modification ..................................................................... 446 Prévost trans-dihydroxylation .............................................................................. 447 Prins reaction......................................................................................................... 448 Pschorr cyclization ................................................................................................ 450 Pummerer rearrangement ...................................................................................... 452 Ramberg–Bäcklund reaction................................................................................. 454 Reformatsky reaction ............................................................................................ 456 Regitz diazo synthesis ........................................................................................... 458 Reimer–Tiemann reaction..................................................................................... 460 Reissert reaction.................................................................................................... 461 Reissert indole synthesis ....................................................................................... 463 Ring-closing metathesis (RCM)........................................................................... 465 Ritter reaction ........................................................................................................ 468 Robinson annulation.............................................................................................. 470 Robinson–Gabriel synthesis.................................................................................. 472 Robinson–Schöpf reaction .................................................................................... 474 Rosenmund reduction............................................................................................ 476 Rubottom oxidation............................................................................................... 478 Rupe rearrangement .............................................................................................. 480 Saegusa oxidation.................................................................................................. 482 Sakurai allylation reaction .................................................................................... 484 Sandmeyer reaction............................................................................................... 486 Schiemann reaction ............................................................................................... 488 Schmidt rearrangement ......................................................................................... 490 Schmidt’s trichloroacetimidate glycosidation reaction ........................................ 492 Shapiro reaction..................................................................................................... 494 Sharpless asymmetric amino hydroxylation......................................................... 496 Sharpless asymmetric dihydroxylation................................................................. 499 Sharpless asymmetric epoxidation ....................................................................... 502 Sharpless olefin synthesis ..................................................................................... 505 Simmons–Smith reaction ..................................................................................... 507 Skraup quinoline synthesis.................................................................................... 509 Smiles rearrangement............................................................................................ 511

Truce−Smile rearrangement ......................................................................... 513 Sommelet reaction................................................................................................. 515 Sommelet–Hauser rearrangement......................................................................... 517 Sonogashira reaction ............................................................................................. 519 Staudinger ketene cycloaddition ........................................................................... 521 Staudinger reduction ............................................................................................. 523

Pictet–Gams isoquinoline synthesis...................................................................... 432 Pictet–Spengler tetrahydroisoquinoline synthesis ................................................ 434 Pinacol rearrangement........................................................................................... 436

XVII

Stille–Kelly reaction.............................................................................................. 531 Stobbe condensation.............................................................................................. 532 Strecker amino acid synthesis ............................................................................... 534 Suzuki–Miyaura coupling ..................................................................................... 536 Swern oxidation..................................................................................................... 538 Takai reaction ........................................................................................................ 540 Tebbe olefination................................................................................................... 542 TEMPO oxidation ................................................................................................. 544 Thorpe−Ziegler reaction........................................................................................ 546 Tsuji–Trost allylation ............................................................................................ 548 Ugi reaction ........................................................................................................... 551 Ullmann coupling .................................................................................................. 554 van Leusen oxazole synthesis ............................................................................... 556 Vilsmeier–Haack reaction..................................................................................... 558 Vinylcyclopropane−cyclopentene rearrangement ................................................ 560 von Braun reaction ................................................................................................ 562 Wacker oxidation .................................................................................................. 564 Wagner–Meerwein rearrangement........................................................................ 566 Weiss–Cook reaction............................................................................................. 568 Wharton reaction ................................................................................................... 570 White reagent......................................................................................................... 572 Willgerodt–Kindler reaction ................................................................................. 576 Wittig reaction ....................................................................................................... 578 Schlosser modification of the Wittig reaction ............................................. 580 [1,2]-Wittig rearrangement ................................................................................... 582 [2,3]-Wittig rearrangement ................................................................................... 584 Wohl–Ziegler reaction........................................................................................... 586 Wolff rearrangement ............................................................................................. 588 Wolff–Kishner reduction....................................................................................... 590 Woodward cis-dihydroxylation............................................................................. 592 Yamaguchi esterification....................................................................................... 594 Zincke reaction ...................................................................................................... 596

Subject Index ......................................................................................................... 599

Stetter reaction....................................................................................................... 525 Still–Gennari phosphonate reaction...................................................................... 527 Stille coupling........................................................................................................ 529

Abbreviations and Acronyms

polymer support 3CC three-component condensation 4CC four-component condensation 9-BBN 9-borabicyclo[3.3.1]nonane A adenosine Ac acetyl ADDP 1,1'-(azodicarbonyl)dipiperidine AIBN 2,2 -azobisisobutyronitrile Alpine-borane® B-isopinocampheyl-9-borabicyclo[3.3.1]-nonane AOM p-Anisyloxymethyl = p-MeOC6H4OCH2- Ar aryl B: generic base [bimim]Cl•2AlCl3 1-butyl-3-methylimidazolium chloroaluminuminate BINAP 2,2 -bis(diphenylphosphino)-1,1 -binaphthyl Bn benzyl Boc tert-butyloxycarbonyl BT benzothiazole Bz benzoyl Cbz benzyloxycarbonyl CuTC copper thiophene-2-carboxylate DABCO 1,4-diazabicyclo[2.2.2]octane dba dibenzylideneacetone DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCC 1,3-dicyclohexylcarbodiimide DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone de diastereoselctive excess DEAD diethyl azodicarboxylate (DHQ)2-PHAL 1,4-bis(9-O-dihydroquinine)-phthalazine (DHQD)2-PHAL 1,4-bis(9-O-dihydroquinidine)-phthalazine DIAD diisopropyl azodidicarboxylate DIBAL diisobutylaluminum hydride DIPEA diisopropylethylamine DMA N,N-dimethylacetamide DMAP 4-N,N-dimethylaminopyridine DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMFDMA N,N-dimethylformamide dimethyl acetal DMS dimethylsulfide DMSO dimethylsulfoxide DMSY dimethylsulfoxonium methylide DMT dimethoxytrityl DPPA diphenylphosphoryl azide dppb 1,4-bis(diphenylphosphino)butane

XX

dppe 1,2-bis(diphenylphosphino)ethane dppf 1,1 -bis(diphenylphosphino)ferrocene dppp 1,3-bis(diphenylphosphino)propane dr diastereoselctive ratio DTBAD di-tert-butylazodicarbonate DTBMP 2,6-di-tert-butyl-4-methylpyridine E1 unimolecular elimination E1cB 2-step, base-induced β-elimination via carbanion E2 bimolecular elimination EAN ethylammonium nitrate EDDA ethylenediamine diacetate ee enantiomeric excess Ei two groups leave at about the same time and bond to

each other as they are doing so. Eq equivalent Et ethyl EtOAc ethyl acetate HMDS hexamethyldisilazane HMPA hexamethylphosphoramide HMTTA 1,1,4,7,10,10-hexamethyltriethylenetetramine IBX o-iodoxybenzoic acid Imd imidazole KHMDS potassium hexamethyldisilazide LAH lithium aluminum hydride LDA lithium diisopropylamide LHMDS lithium hexamethyldisilazide LTMP lithium 2,2,6,6-tetramethylpiperidide M metal m-CPBA m-chloroperoxybenzoic acid MCRs multicomponent reactions Mes mesityl MPS morpholine-polysulfide Ms methanesulfonyl MWI microwave irradiation MVK methyl vinyl ketone NBS N-bromosuccinimide NCS N-chlorosuccinimide NIS N-iodosuccinimide NMP 1-methyl-2-pyrrolidinone Nos nosylate (4-nitrobenzenesulfonyl) N-PSP N-phenylselenophthalimide N-PSS N-phenylselenosuccinimide Nu nucleophile PCC pyridinium chlorochromate PDC pyridinium dichromate Piv pivaloyl

XXI

PMB para-methoxybenzyl PPA polyphosphoric acid PPTS pyridinium p-toluenesulfonate PT phenyltetrazolyl PyPh2P diphenyl 2-pyridylphosphine Pyr pyridine Red-Al sodium bis(methoxy-ethoxy)aluminum hydride Red-Al sodium bis(methoxy-ethoxy)aluminum hydride (SMEAH) Salen N,N´-disalicylidene-ethylenediamine SET single electron transfer SIBX Stabilized IBX SM starting material SMEAH sodium bis(methoxy-ethoxy)aluminum hydride SN1 unimolecular nucleophilic substitution SN2 bimolecular nucleophilic substitution SNAr nucleophilic substitution on an aromatic ring TBABB tetra-n-butylammonium bibenzoate TBAF tetra-n-butylammonium fluoride TBAO 1,3,3-trimethyl-6-azabicyclo[3.2.1]octane TBDMS tert-butyldimethylsilyl TBDPS tert-butyldiphenylsilyl TBS tert-butyldimethylsilyl t-Bu tert-butyl TDS thexyldimethylsilyl TEA triethylamine TEOC trimethysilylethoxycarbonyl Tf trifluoromethanesulfonyl (triflyl) TFA trifluoroacetic acid TFAA trifluoroacetic anhydride TFP tri-2-furylphosphine THF tetrahydrofuran TIPS triisopropylsilyl TMEDA N,N,N ,N -tetramethylethylenediamine TMG 1,1,3,3-tetramethylguanidine TMP tetramethylpiperidine TMS trimethylsilyl TMSCl trimethylsilyl chloride TMSCN trimethylsilyl cyanide TMSI trimethylsilyl iodide TMSOTf trimethylsilyl triflate Tol toluene or tolyl Tol-BINAP 2,2 -bis(di-p-tolylphosphino)-1,1 -binaphthyl TosMIC (p-tolylsulfonyl)methyl isocyanide Ts tosyl TsO tosylate

XXII

UHP urea-hydrogen peroxide Δ solvent heated under reflux

Alder ene reaction The Alder ene reaction, also known as the hydro-allyl addition, is addition of an enophile to an alkene (ene) via allylic transposition. The four-electron system in-cluding an alkene -bond and an allylic C–H -bond can participate in a pericyclic reaction in which the double bond shifts and new C–H and C–C -bonds are formed.

H

XY

ene enophile

Δ, or

Lewis acid HYX

HYX‡ HOMO

LUMOH

‡

X=Y: C=C, C C, C=O, C=N, N=N, N=O, S=O, etc.

Example 15

O

O

O

OO

O 6-membered

transition stateH

xylene

reflux, 31%

‡

ene enophile

O

O

O

Alder ene

reaction

OO

O

H

‡

Example 27

OH

NH2NKOH, Pt/Clay, 35%

(Kishner reduction)

O

H

OH

O

O

0 oC, CH2Cl2, 89%(Alder ene reaction)

O

OOH

O

Example 3, Intramolecular Alder-ene reaction8

NO

O

NO H

toluene, reflux

5 h, 95%O

H

1

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_1, © Springer-Verlag Berlin Heidelberg 2009

Example 4, Cobalt-catalyzed Alder-ene reaction9

Et

Ph

OTMS[Co(dppp)Br2], Zn, ZnI2, CH2Cl2

25 oC, 8 h, 95% (GC yield)Ph OTMS

Et

Example 5, Nitrile-Alder-ene reaction10

CN

CH3 sealed ampule

120−130 oC, 5 h70%

CN

CH3

NC

H3C

CN

CH3

CH3NC

CH3

H

CN

CH3

CH3NC

H

HCN

H3CCN

Example 611

C6H13

OAc

SiEt3

CpRu(CH3CN)3•PF6

acetone, rt, 81%SiEt3

C6H13OAc

References 1. Alder, K.; Pascher, F.; Schmitz, A. Ber. 1943, 76, 27−53. Kurt Alder (Germany,

1902−1958) shared the Nobel Prize in Chemistry in 1950 with his teacher Otto Diels (Germany, 1876−1954) for the development of the diene synthesis.

2. Oppolzer, W. Pure Appl. Chem. 1981, 53, 1181−1201. (Review). 3. Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325−335. (Review). 4. Mikami, K.; Nakai, T. In Catalytic Asymmetric Synthesis; 2nd edn.; Ojima, I., ed.;

Wiley−VCH: New York, 2000, 543−568. (Review). 5. Sulikowski, G. A.; Sulikowski, M. M. e-EROS Encyclopedia of Reagents for Organic

Synthesis (2001), John Wiley & Sons, Ltd., Chichester, UK. 6. Brummond, K. M.; McCabe, J. M. The Rhodium(I)-Catalyzed Alder-ene Reaction. In

Modern Rhodium-Catalyzed Organic Reactions 2005, 151−172. (Review). 7. Miles, W. H.; Dethoff, E. A.; Tuson, H. H.; Ulas, G. J. Org. Chem. 2005, 70,

2862−2865. 8. Pedrosa, R.; Andres, C.; Martin, L.; Nieto, J.; Roson, C. J. Org. Chem. 2005, 70,

4332−4337. 9. Hilt, G.; Treutwein, J. Angew. Chem., Int. Ed. 2007, 46, 8500−8502. 10. Ashirov, R. V.; Shamov, G. A.; Lodochnikova, O. A.; Litvynov, I. A.; Appolonova, S.

A.; Plemenkov, V. V. J. Org. Chem. 2008, 73, 5985−5988. 11. Cho, E. J.; Lee, D. Org. Lett. 2008, 10, 257−259. 12. Curran, T. T. Alder ene reaction. In Name Reactions for Homologations-Part II; Li, J.

J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 2−32. (Review).

2

Aldol condensation The Aldol condensation is the coupling of an enolate ion with a carbonyl compound to form a -hydroxycarbonyl, and sometimes, followed by dehydration to give a conjugated enone. A simple case is addition of an enolate to an aldehyde to afford an alcohol, thus the name aldol.

R2 R3

OR1

OR

1. Base

R1

O

RR3

OHR2

2.

ΔR1

O

RR3

R2

R2R3

O

R1

OR R1

OR

H

B:

deprotonation condensation

R1

O

RR3

OR2

R1

O

RR3

OHR2acidic

workup

Example 13

OTMSO

LDA, THF, thenMgBr2, −110 oC, then

CHOOBnO

BnO OOTMS

OH O

85% yield

Example 28

CO2HO OTBS

LDA, THF, −78 to −40 oC, then aldehyde, 1 h, 43%, 3:2 dr

H

O

CO2HO OTBS

HO

22% of of 6S,7R-diastereomerand 10% recovered SM

6

7

3


Example 3, Enantioselective Mukaiyama-aldol reaction10

Ph

OTMS

CO2CHPh2

O

Sc(OTf)3, 4 Å MS, CH2Cl2, −40 oCPh CO2CHPh2

O OH

NO

N N

OPh

OSii-Pr3

Ph

OSii-Pr3

83% yield, 98% ee

cat.

Example 4, Intermolecular aldol reaction using organocatalyst12

H

OO

Cl

NH

O NH

O

N

H

DMSO, 10 equiv H2O, rt72 h, 57%, 46% ee, 95% de

OHO

Cl

Example 5, Transannular aldol reaction13

MeOMeO

OMe

OMe O

O

OMeO

OMeO

1. LiN(SiMe2Ph)2, THF −105 oC, 74%, 10:1, dr

2. MgI2, Et2O, 57%

MeOMeO

OH

OH O

O

OMe

OMe

CH3

O

OHCH3

References 1. Wurtz, C. A. Bull. Soc. Chim. Fr. 1872, 17, 436−442. Charles Adolphe Wurtz

(1817−1884) was born in Strasbourg, France. After his doctoral training, he spent a year under Liebig in 1843. In 1874, Wurtz became the Chair of Organic Chemistry at the Sorbonne, where he educated many illustrous chemists such as Crafts, Fittig, Friedel, and van’t Hoff. The Wurtz reaction, where two alkyl halides are treacted with sodium to form a new carbon−carbon bond, is no longer considered synthetically useful, although the Aldol reaction that Wurtz discovered in 1872 has become a staple in organic synthesis. Alexander P. Borodin is also credited with the discovery of the Aldol reaction together with Wurtz. In 1872 he announced to the Russian Chemical Society the discovery of a new byproduct in aldehyde reactions with properties like that of an alcohol, and he noted similarities with compounds already discussed in publications by Wurtz from the same year.

2. Nielsen, A. T.; Houlihan, W. J. Org. React. 1968, 16, 1−438. (Review). 3. Still, W. C.; McDonald, J. H., III. Tetrahedron Lett. 1980, 21, 1031−1034.

4

4. Mukaiyama, T. Org. React. 1982, 28, 203−331. (Review). 5. Mukaiyama, T.; Kobayashi, S. Org. React. 1994, 46, 1−103. (Review on Tin(II)

enolates). 6. Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325−335. (Review). 7. Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432−440. (Review). 8. (a) Borzilleri, R. M.; Zheng, X.; Schmidt, R. J.; Johnson, J. A.; Kim, S.-H.; DiMarco,

J. D.; Fairchild, C. R.; Gougoutas, J. Z.; Lee, F. Y. F.; Long, B. H.; Vite, G. D. J. Am. Chem. Soc. 2000, 122, 8890–8897. (b) Yang, Z.; He, Y.; Vourloumis, D.; Vallberg, H.; Nicolaou, K. C. Angew. Chem., Int. Ed. 1997, 36, 166−168. (c) Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, H.; Roschangar, F.; Sarabia, F.; Ninkovic, S.; Yang, Z.; Trujillo, J. I. J. Am. Chem. Soc. 1997, 119, 7960–7973.

9. Mahrwald, R. (ed.) Modern Aldol Reactions, Wiley−VCH: Weinheim, Germany, 2004. (Book).

10. Desimoni, G.; Faita, G.; Piccinini, F.; Toscanini, M. Eur. J. Org. Chem. 2006, 5228−5230.

11. Guillena, G.; Najera, C.; Ramon, D. J. Tetrahedron: Asymmetry 2007, 18, 2249−2293. (Review on enantioselective direct aldol reaction using organocatalysis.)

12. Doherty, S.; Knight, J. G.; McRae, A.; Harrington, R. W.; Clegg, W. Eur. J. Org. Chem. 2008, 1759−1766.

13. O’Brien, E. M.; Morgan, B. J.; Kozlowski, M. C. Angew. Chem., Int. Ed. 2008, 47, 6877−6880.

14. Trost, B. M.; Maulide, N.; Rudd, M. T. J. Am. Chem. Soc. 2009, 131, 420−421.

5

Algar−Flynn−Oyamada Reaction Conversion of 2 -hydroxychalcones to 2-aryl-3-hydroxy-4H-1benzopyran-4-ones (flavonols) by an oxidative cyclization.

OH

O

ArR1

R2

H2O2, NaOHO

O

R1

R2

Ar

OH

O

O

R1

R2

Ar

OH

OH

O

HO

H2O2

O

OO

αβ

O OH

OH

O OOH

β-attackO

OHO

O O

OHO

flavonol A side reaction:

O

OO

α-attack

then dehydration

O

O aurone

α β

Example 15

O

1. PhCHO, NaOH, EtOH, rt

2. H2O2, 15 to 50 oC, 54%

O Ph

OOH

OH

Example 25

OH

O

O

1.

OMe

CHO

, aq. NaOH, EtOH

2. aq. NaOH, 30% H2O2 47% for two steps

O O

OOH

OMe

6


Example 3, The side reaction dominated to give the aurone derivative:9

OHMeO

OMe OOMe

Phaq. NaOH

H2O2, 80%

O

O

MeO

OMe

OMePh

OHH

Example 412

O

OHBnO NaOH

EtOH, 54%

CHO

OMeO

OHBnO OMe

O

OOH

OMe

BnOH2O2, NaOH

EtOH, dioxane76%

References 1. Algar, J.; Flynn, J. P. Proc. Roy. Irish. Acad. 1934, B42, 1−8. 2. Oyamada, T. J. Chem. Soc. Jpn 1934, 55, 1256−1261. 3. Oyamada, T. Bull. Chem. Soc. Jpn. 1935, 10, 182−186. 4. Wheeler, T. S. Record Chem. Progr. 1957, 18, 133−161. (Review) 5. Smith, M. A.; Neumann, R. M.; Webb, R. A. J. Heterocycl. Chem. 1968, 5, 425−426. 6. Wagner, H.; Farkas, L. In The Flavonoids; Harborne, J. B.; Mabry, T. J.; Mabry H.,

Eds.; Academic Press: New York, 1975, 1, pp 127−213. (Review). 7. Wollenweber, E. In The Flavonoids: Advances in Research; Harborne, J. B.; Mabry,

T. J., Eds; Chapman and Hall: New York, 1982; pp 189−259. (Review). 8. Wollenweber, E. In The Flavonoids: Advances in Research Since 1986; Harborne, J.

B., Ed.; Chapman and Hall: New York, 1994, pp 259−335. (Review). 9. Bennett, M.; Burke, A. J.; O’Sullivan, W. I. Tetrahedron 1996, 52, 7163−7178. 10. Bohm, B. A.; Stuessy, T. F. Flavonoids of the Sunflower Family (Asteraceae);

Springer-Verlag: New York, 2000. (Review). 11. Limberakis, C. Algar−Flynn−Oyamada Reaction. In Name Reactions in Heterocyclic

Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 496−503. (Review).

12. Li, Z.; Ngojeh, G.; DeWitt, P.; Zheng, Z.; Chen, M.; Lainhart, B.; Li, V.; Felpo, P. Tetrahedron Lett. 2008, 49, 7243−7245.

7

Allan–Robinson reaction Synthesis of flavones or isoflavones by the treatment of of o-hydroxyaryl ketones with aromatic aldehydes. Cf. Kostanecki reaction on page 322.

R1 O R1

O O

R1CO2Na, Δ

O

OR

R1OH

OR

OH

OR

enolization

OH

OR

H

R1

O

R1

O

O acylation

R1CO2

OR

OHR1

OCOR1

O− O2CR1

OH

OHR1

O

RO2CR1

enolization

O

OR

OHR1

OHR

O: R1O

H

H

O2CR1

O

OR

R1

Example 16

OH

OOMe

OMeHO

OMe

O

O O

MeO OMe

O

OOMe

OMeHO

OMe

OMe

PhCO2Na, 170−180 oC

8 h, 45%

Example 29

OH

O pyr., 40 oC, 72 h, 85%N

S

Me

O OO O

O N

S

Me

CO2H

8


Example 310

O

O

OH

O O

OMe

O

OMeO

O O

Et3N, reflux, 12 h, 87%

References 1. Allan, J.; Robinson, R. J. Chem. Soc. 1924, 125, 2192–2195. Robert Robinson

(United Kingdom, 1886−1975) won the Nobel Prize in Chemistry in 1947 for his stud-ies on alkaloids. However, Robinson himself considered his greatest contribution to science was that he founded the qualitative theory of electronic mechanisms in organic chemistry. Robinson, along with Lapworth (a friend) and Ingold (a rival), pioneered the arrow pushing approach to organic reaction mechanism. Robinson was also an ac-complished pianist. James Allan, his student, also coauthored another important paper with Robinson on the relative directive powers of groups for aromatic substitution.

2. Széll, T.; Dózsai, L.; Zarándy, M.; Menyhárth, K. Tetrahedron 1969, 25, 715–724. 3. Wagner, H.; Maurer, I.; Farkas, L.; Strelisky, J. Tetrahedron 1977, 33, 1405–1409. 4. Dutta, P. K.; Bagchi, D.; Pakrashi, S. C. Indian J. Chem., Sect. B 1982, 21B, 1037–

1038. 5. Patwardhan, S. A.; Gupta, A. S. J. Chem. Res., (S) 1984, 395. 6. Horie, T.; Tsukayama, M.; Kawamura, Y.; Seno, M. J. Org. Chem. 1987, 52, 4702–

4709. 7. Horie, T.; Tsukayama, M.; Kawamura, Y.; Yamamoto, S. Chem. Pharm. Bull. 1987,

35, 4465–4472. 8. Horie, T.; Kawamura, Y.; Tsukayama, M.; Yoshizaki, S. Chem. Pharm. Bull. 1989,

37, 1216–1220. 9. Poyarkov, A. A.; Frasinyuk, M. S.; Kibirev, V. K.; Poyarkova, S. A. Russ. J. Bioorg.

Chem. 2006, 32, 277–279. 10. Peng, C.-C.; Rushmore, T.; Crouch, G. J.; Jones, J. P. Bioorg. Med. Chem. Lett. 2008,

16, 4064–4074.

9

Arndt–Eistert homologation One-carbon homologation of carboxylic acids using diazomethane.

R OH

O SOCl2

R Cl

O 1. CH2N2

OH

OR

2. Ag+, H2O, hv

R Cl

OR Cl

O

NN

R

ON

N

H H

ClH2C N N

R

ON

NR

ON

N

H H

− CH3N2 − N2↑

hv

CH

R OH

OH

OH

OR

:OH2

C C OH

RR

O

:H

α-ketocarbene intermediate ketene intermediate Example 17

CO2HBnO

BnOHN

Boc

1. ClCO2Et, Et3N, THF, −10 oC, 15 min

2. CH2N2, Et2O, 0 oC to rt, 18 h, 78%

BnO

BnOHN

Boc

ON2

PhCO2Ag, Et3N, MeOH/THF, dark

−25 oC to rt, 3 h, 61%

BnO

BnOHN

Boc

CO2Me

Example 2, An interesting variation9

PhCO2H

OH

1. Fmoc-Cl, pyridine, 0 oC2. isobutylchloroformate, Et3N

then CH2N2, 0 oC, 39%Ph

OFmoc

ON2

Ph

CONH2

NH2

PhCO2Ag, dioxane15 min., 50 oC, 72%

PhHN

OCONH2

Ph

10


Example 310

NOTBDPS

CbzMeO2C

H

H H

1. LiOH, MeOH/H2O, reflux2. ClCO2Et, Et3N, THF, 0 oC

3. CH2N2, Et2O4. PhCO2Ag, Et3N, MeOH, rt 69% for 4 steps

NOTBDPS

Cbz

H

H HMeO2C

References 1. Arndt, F.; Eistert, B. Ber. 1935, 68, 200−208. Fritz Arndt (1885−1969) was born in

Hamburg, Germany. He discovered the Arndt−Eistert homologation at the University of Breslau where he extensively investigated the synthesis of diazomethane and its re-actions with aldehydes, ketones, and acid chlorides. Fritz Arndt’s chain-smoking of cigars ensured that his presence in the laboratories was always well advertised. Bernd Eistert (1902−1978), born in Ohlau, Silesia, was Arndt’s Ph.D. student. Eistert later joined I. G. Farbenindustrie, which became BASF after the Allies broke up the con-glomerate after WWII.

2. Podlech, J.; Seebach, D. Angew. Chem., Int. Ed. 1995, 34, 471−472. 3. Matthews, J. L.; Braun, C.; Guibourdenche, C.; Overhand, M.; Seebach, D. In Enanti-

oselective Synthesis of β-Amino Acids Juaristi, E. ed.; Wiley-VCH: New York, N. Y. 1997, pp 105−126. (Review).

4. Katritzky, A. R.; Zhang, S.; Fang, Y. Org. Lett. 2000, 2, 3789−3791. 5. Vasanthakumar, G.-R.; Babu, V. V. S. Synth. Commun. 2002, 32, 651−657. 6. Chakravarty, P. K.; Shih, T. L.; Colletti, S. L.; Ayer, M. B.; Snedden, C.; Kuo, H.;

Tyagarajan, S.; Gregory, L.; Zakson-Aiken, M.; Shoop, W. L.; Schmatz, D. M.; Wy-vratt, M. J.; Fisher, M. H.; Meinke, P. T. Bioorg. Med. Chem. Lett. 2003, 13, 147−150.

7. Gaucher, A.; Dutot, L.; Barbeau, O.; Hamchaoui, W.; Wakselman, M.; Mazaleyrat, J.-P. Tetrahedron: Asymmetry 2005, 16, 857−864.

8. Podlech, J. In Enantioselective Synthesis of β-Amino Acids (2nd Edn.) John Wiley & Sons: Hoboken, NJ, 2005, pp 93−106. (Review).

9. Spengler, J.; Ruiz-Rodriguez, J.; Burger, K.; Albericio, F. Tetrahedron Lett. 2006, 47, 4557−4560.

10. Toyooka, N.; Kobayashi, S.; Zhou, D.; Tsuneki, H.; Wada, T.; Sakai, H.; Nemoto, H.; Sasaoka, T.; Garraffo, H. M.; Spande, T. F.; Daly, J. W. Bioorg. Med. Chem. Lett. 2007, 17, 5872−5875.

11. Fuchter, M. J. Arndt–Eistert Homologation. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 336−349. (Review).

11

Baeyer–Villiger oxidation General scheme:

R1 R2

O HO

O R3

O

R1 O

OR2

HO R3

O

or H2O2

The most electron-rich alkyl group (more substituted carbon) migrates first. The general migration order: tertiary alkyl > cyclohexyl > secondary alkyl > benzyl > phenyl > primary alkyl > methyl >> H.

For substituted aryls: p-MeO-Ar > p-Me-Ar > p-Cl-Ar > p-Br-Ar > p-MeOAr > p-O2N-Ar

Example 1:

O

O

OCl

O

OH

H

:HOAc

AcO

HO

OClalkyl

migration

O

OO

OH O

O

Cl

Example 24

O

Ph N N

O OPhPh

Zr

Zr-salen:UHP,

Zr-salen (5 mol%)

CH2Cl2, rt68%, 87% ee

O

O

Ph

OUHP,

Zr-salen (5 mol%)

PhCl, rt

OO O

O

normal product26%, 82% ee

abnormal product12%, > 99% ee

Y

Y

UHP = Urea-hydrogen peroxide complex

Example 35

NH

OH O

O

m-CPBA

CH2Cl2, rtquant.

NHO

OH O

O 100% 0%NH

OH

O

O

O

12


Example 46

H

O

O

O

O

m-CPBA, NaHCO3

CH2Cl2, 0 °C, 4 h60%

H

O

O

O

AcO

Example 58

OOAc m-CPBA, CF3SO3H

CH2Cl2, 45 min., 90%

O

OAcO

References 1. v. Baeyer, A.; Villiger, V. Ber. 1899, 32, 3625−3633. Adolf von Baeyer (1835−1917)

was one of the most illustrious organic chemists in history. He contributed to many areas of the field. The Baeyer−Drewson indigo synthesis made possible the commer-cialization of synthetic indigo. Another Baeyer’s claim of fame is his synthesis of barbituric acid, named after his then girlfriend, Barbara. Baeyer’s real joy was in his laboratory and he deplored any outside work that took him away from his bench. When a visitor expressed envy that fortune had blessed so much of Baeyer’s work with success, Baeyer retorted dryly: “Herr Kollege, I experiment more than you.” As a scientist, Baeyer was free of vanity. Unlike other scholastic masters of his time (Liebig for instance), he was always ready to acknowledge ungrudgingly the merits of others. Baeyer’s famous greenish-black hat was a part of his perpetual wardrobe and he had a ritual of tipping his hat when he admired novel compounds. Adolf von Baeyer received the Nobel Prize in Chemistry in 1905 at age seventy. His apprentice, Emil Fischer, won it in 1902 when he was fifty, three years before his teacher. Victor Villiger (1868−1934), born in Switzerland, went to Munich and worked with Adolf von Baeyer for eleven years.

2. Krow, G. R. Org. React. 1993, 43, 251−798. (Review). 3. Renz, M.; Meunier, B. Eur. J. Org. Chem. 1999, 4, 737−750. (Review). 4. Wantanabe, A.; Uchida, T.; Ito, K.; Katsuki, T. Tetrahedron Lett. 2002, 43,

4481−4485. 5. Laurent, M.; Ceresiat, M.; Marchand-Brynaert, J. J. Org. Chem. 2004, 69, 3194−3197. 6. Brady, T. P.; Kim, S. H.; Wen, K.; Kim, C.; Theodorakis, E. A. Chem. Eur. J. 2005,

11, 7175−7190. 7. Curran, T. T. Baeye−Villiger oxidation. In Name Reactions for Functional Group

Transformations; Li, J. J., Corey, E. J., eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 160−182. (Review).

8. Demir, A. S.; Aybey, A. Tetrahedron 2008, 64, 11256−11261. 9. Baj, S.; Chrobok, A. Synth. Commun. 2008, 38, 2385−2391. 10. Malkov, A. V.; Friscourt, F.; Bell, M.; Swarbrick, M. E.; Kocovsky, P. J. Org. Chem.

2008, 73, 3996−4003.

13

Baker–Venkataraman rearrangement Base-catalyzed acyl transfer reaction that converts α-acyloxyketones to β-diketones.

OOPh

O

baseOOH

Ph

O

OOPh

O

H

:B

O

OO

Ph

O

O

OPh

OO

Ph

O OOH

Ph

Oacyl

transfer

H3O

workup

Example 1, Carbamoyl Baker−Venkataraman rearrangement5

NaH, THF

reflux, 2 h, 84%

O

O

NEt2OOH

O

NEt2

O

Example 2, Carbamoyl Baker−Venkataraman rearrangement6

2.5 eq. NaH, PhMe, reflux, 2 h

then 6 equiv TFA, reflux, 1 h, 93%

O

MeOO

NEt2OO O

MeOOH

14


Example 3, Ester Baker−Venkataraman rearrangement9

O

O

O

CH3

O

CH3

OO

O

OH

CH3

O

LiH, THF

reflux, 12 h, 50%

O

Example 4, Ester Baker−Venkataraman rearrangement10

OOH O

OH

O Cl

Cl

Cl

O2 equiv DBU

pyridine, 80 oC90% OH

Cl

Cl References 1. Baker, W. J. Chem. Soc. 1933, 1381−1389. Wilson Baker (1900−2002) was born in

Runcorn, England. He studied chemistry at Manchester under Arthur Lapworth and at Oxford under Robinson. In 1943, Baker was the first one who confirmed that penicil-lin contained sulfur, of which Robinson commented: “This is a feather in your cap, Baker.” Baker began his independent academic career at University of Bristol. He re-tired in 1965 as the Head of the School of Chemistry. Baker was a well-known chem-ist centenarian, spending 47 years in retirement!

2. Mahal, H. S.; Venkataraman, K. J. Chem. Soc. 1934, 1767−1771. K. Venkataraman studied under Robert Robinson Manchester. He returned to India and later arose to be the Director of the National Chemical Laboratory at Poona.

3. Kraus, G. A.; Fulton, B. S.; Wood, S. H. J. Org. Chem. 1984, 49, 3212−3214. 4. Reddy, B. P.; Krupadanam, G. L. D. J. Heterocycl. Chem. 1996, 33, 1561−1565. 5. Kalinin, A. V.; da Silva, A. J. M.; Lopes, C. C.; Lopes, R. S. C.; Snieckus, V. Tetrahe-

dron Lett. 1998, 39, 4995−4998. 6. Kalinin, A. V.; Snieckus, V. Tetrahedron Lett. 1998, 39, 4999−5002. 7. Thasana, N.; Ruchirawat, S. Tetrahedron Lett. 2002, 43, 4515−4517. 8. Santos, C. M. M.; Silva, A. M. S.; Cavaleiro, J. A. S. Eur. J. Org. Chem. 2003, 4575–

4585. 9. Krohn, K.; Vidal, A.; Vitz, J.; Westermann, B.; Abbas, M.; Green, I. Tetrahedron:

Asymmetry 2006, 17, 3051–3057. 10. Abdel Ghani, S. B.; Weaver, L.; Zidan, Z. H.; Ali, H. M.; Keevil, C. W.; Brown, R. C.

D. Bioorg. Med. Chem. Lett. 2008, 18, 518–522.

15

Bamford–Stevens reaction The Bamford−Stevens reaction and the Shapiro reaction share a similar mechanis-tic pathway. The former uses a base such as Na, NaOMe, LiH, NaH, NaNH2, heat, etc., whereas the latter employs bases such as alkyllithiums and Grignard re-agents. As a result, the Bamford−Stevens reaction furnishes more-substituted ole-fins as the thermodynamic products, while the Shapiro reaction generally affords less-substituted olefins as the kinetic products.

R2N

HN

TsR3

R1

R2

R3

R1

H

NaOMe

R2N

NTs

R3

R1 H

H

MeO

R2N

NTs

R3

R1

H :

R2N

R3

R1

H N

In protic solvent (S–H):

− N2R2N

R3

R1

H NR2

NR3

R1

H N

HHS

R2

R3

R1

HR2H

R3

R1

H

S

SHR3

R2

R1

H

In aprotic solvent:

− N2R2N

R3

R1

H NR2

NR3

R1

H N

R2

R3

R1

HR3

R2

R1

HR2

R3

R1

H:

1,2-hydride

shift

Example 1, Tandem Bamford–Stevens/thermal aliphatic Claisen rearrangement sequence2

Ph

NO Ph

N

Ph Rh2(OAc)4ClCH2CH2Cl

130 oC87% (> 20:1)

H

O

Ph

Ph

The starting material N-aziridinyl imine is also known as Eschenmoser hydrazone.

16


Example 2, Thermal Bamford–Stevens6

Me3Si Ph

NN Ph Tol., 145 oC

sealed tube, 65%

Me3Si Ph

E : Z = 90 : 10

Example 37

ON NHTs t-BuOK, t-BuOH

reflux, 83% OOt-Bu

Example 48

R2

O

H

O

R2

R1

R1 NN

Ts

NaRh2(OAc)4

tetrahydrothiophene

BnEt3N+Cl−, MeCN, 40 oC, 3 h, 59−97%

References 1. Bamford, W. R.; Stevens, T. S. M. J. Chem. Soc. 1952, 4735−4740. Thomas Stevens

(1900−2000), another chemist centenarian, was born in Renfrew, Scotland. He and his student W. R. Bamford published this paper at the University of Sheffield, UK. Ste-vens also contributed to another name reaction, the McFadyen−Stevens reaction (page 334).

2. Felix, D.; Müller, R. K.; Horn, U.; Joos, R.; Schreiber, J.; Eschenmoser, A. Helv. Chim. Acta 1972, 55, 1276−1319.

3. Shapiro, R. H. Org. React. 1976, 23, 405−507. (Review). 4. Adlington, R. M.; Barrett, A. G. M. Acc. Chem. Res. 1983, 16, 55−59. (Review on the

Shapiro reaction). 5. Chamberlin, A. R.; Bloom, S. H. Org. React. 1990, 39, 1−83. (Review). 6. Sarkar, T. K.; Ghorai, B. K. J. Chem. Soc., Chem. Commun. 1992, 17, 1184−1185. 7. Chandrasekhar, S.; Rajaiah, G.; Chandraiah, L.; Swamy, D. N. Synlett 2001,

1779−1780. 8. Aggarwal, V. K.; Alonso, E.; Hynd, G.; Lydon, K. M.; Palmer, M. J.; Porcelloni, M.;

Studley, J. R. Angew. Chem., Int. Ed. 2001, 40, 1430−1433. 9. May, J. A.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124, 12426−12427. 10. Zhu, S.; Liao, Y.; Zhu, S. Org. Lett. 2004, 6, 377−380. 11. Baldwin, J. E.; Bogdan, A. R.; Leber, P. A.; Powers, D. C. Org. Lett. 2005, 7,

5195−5197. 12. Paul Humphries, P. Bamford−Stevens reaction. In Name Reactions for Homologa-

tions-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 642−652. (Review).

17

Barbier coupling reaction In essence, the Barbier coupling reaction is a Grignard reaction carried out in situ although its discovery preceded that of the Grignard reaction by a year. Cf. Grig-nard reaction (Page 266).

R1 R2

O R3X, MR1 R2

OH

RR M

According to conventional wisdom,3 the organometallic intermediate (M = Mg, Li, Sm, Zn, La, etc.) is generated in situ, which is intermediately trapped by the carbonyl compound. However, recent experimental and theoretical studies seem to suggest that the Barbier coupling reaction goes through a single electron trans-fer pathway. Generation of the Grignard reagent,

R3 XSET-1

R X MMX

R R MSET-2

R M

Ionic mechanism,

R MgX

O

R OMgX

R2R1R2

R1δ δ

δδ

R OH

R2R1H3O

Single electron transfer mechanism,

H3O

R MgX

OR2

R1 OR2

R1MgX

R R OMgX

R2R1

R OH

R2R1

Example 16

O

O BrSm, THF, rt

20 min., 70%

OHO

18


Example 29

MePh

NHCO2Et

O

BrZn, THF, aq. NH4Cl

0 oC, 82%, 95% de

Me

NHCO2Et

OHPh

Example 310

n-C4H9Br H3C Cl

Mg20 mol% CuCN

THF, rt, 1.5 h, 86%H3C n-C4H9 H3C

n-C4H9

10 : 90

Example 411

O

MeO

I

H OOBn

n-BuLi, THF

−78 oC, 96%

O

MeOH OH

OBn

References 1. Barbier, P. C. R. Hebd. Séances Acad. Sci. 1899, 128, 110–111. Phillippe Barbier

(1848−1922) was born in Luzy, Nièvre, France. He studied terpenoids using zinc and magnesium. Barbier suggested the use of magnesium to his student, Victor Grignard, who later discovered the Grignard reagent and won the Nobel Prize in 1912.

2. Grignard, V. C. R. Hebd. Seanes Acad. Sci. 1900, 130, 1322–1324. 3. Moyano, A.; Pericás, M. A.; Riera, A.; Luche, J.-L. Tetrahedron Lett. 1990, 31, 7619–

7622. (Theoretical study). 4. Alonso, F.; Yus, M. Rec. Res. Dev. Org. Chem. 1997, 1, 397–436. (Review). 5. Russo, D. A. Chem. Ind. 1996, 64, 405–409. (Review). 6. Basu, M. K.; Banik, B. Tetrahedron Lett. 2001, 42, 187–189. 7. Sinha, P.; Roy, S. Chem. Commun. 2001, 1798–1799. 8. Lombardo, M.; Gianotti, K.; Licciulli, S.; Trombini, C. Tetrahedron 2004, 60, 11725–

11732. 9. Resende, G. O.; Aguiar, L. C. S.; Antunes, O. A. C. Synlett 2005, 119–120. 10. Erdik, E.; Kocoglu, M. Tetrahedron Lett. 2007, 48, 4211–4214. 11. Takeuchi, T.; Matsuhashi, M.; Nakata, T. Tetrahedron Lett. 2008, 49, 6462–6465.

19

Bartoli indole synthesis 7-Substituted indoles from the reaction of ortho-substituted nitroarenes and vinyl Grignard reagents.

NH

RNO2

1.

2. H2O

MgBr

R

RN

O

O

BrMg

RN

O

OMgBr

OMgBr

RN

O

BrMg

nitroso intermediate

[3,3]-sigmatropic

rearrangementR

NO

MgBr RNMgBr

O

H

N

R

OMgBrH3O

workup

H

BrMg

NH

RNH

R

OH2

H

Example 13

NO2NH

1.

2. aq. NH4Cl, 67%

−40 oC, THFMgBr (3 eq)

Example 26

BrNO2

Me

MgCl

THF, −40 oC67%

NH

Me

Br

20


Example 310

BrNO2

MgCl

THF, 66%NH

Br

MeO

MeO

4 equivMeO

MeO

BrNO2

MgCl

THF, 38%NH

Br

MeO

MeO

4 equivMeO

MeO

Br Br

Example 411

BrNO2

MgCl

THF, −40 oC52%

NH

Br

2 equiv

Br Br

References 1. Bartoli, G.; Leardini, R.; Medici, A.; Rosini, G. J. Chem. Soc., Perkin Trans. 1 1978,

692−696. Giuseppe Bartoli is a professor at the Università di Bologna, Italy. 2. Bartoli, G.; Bosco, M.; Dalpozzo, R.; Todesco, P. E. J. Chem. Soc., Chem. Commun.

1988, 807−805. 3. Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. Tetrahedron Lett. 1989, 30,

2129−2132. 4. Bosco, M.; Dalpozzo, R.; Bartoli, G.; Palmieri, G.; Petrini, M. J. Chem. Soc., Perkin

Trans. 2 1991, 657−663. Mechanistic studies. 5. Bartoli, G.; Bosco, M.; Dalpozzo, R.; Palmieri, G.; Marcantoni, E. J. Chem. Soc.,

Perkin Trans. 1 1991, 2757−2761. 6. Dobbs, A. J. Org. Chem. 2001, 66, 638−641. 7. Garg, N. K.; Sarpong, R.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124, 13179−13184. 8. Li, J.; Cook, J. M. Bartoli indole synthesis. In Name Reactions in Heterocyclic Chem-

istry; Li, J. J., Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 100−103. (Re-view).

9. Dalpozzo, R.; Bartoli, G. Current Org. Chem. 2005, 9, 163−178. (Review). 10. Huleatt, P. B.; Choo, S. S.; Chua, S.; Chai, C. L. L. Tetrahedron Lett. 2008, 49,

5309−5311. 11. Buszek, K. R.; Brown, N.; Luo, D. Org. Lett. 2009, 11, 201−204.

21

Barton radical decarboxylation Radical decarboxylation via the corresponding thiocarbonyl derivatives of the car-boxylic acids.

R Cl

ON

HOS

R O

ON

SAIBN, Δ R

Hn-Bu3SnH

Barton ester

N N CNNCΔ

CNN2↑ 2homolyticcleavage

AIBN = 2,2 -azobisisobutyronitrile

n-Bu3Sn H CN n-Bu3Sn CNH

R O

ON

S

SnBu3

N

SBu3Sn

R O

O

Bu3SnR HCO2↑ SnBu3HR

Example 13

CO2H

OAc

OAc

1. (COCl)2

2.

NNaO

S

OO

NS

H

H

Δ

S

OAc

N98%

1. m-CPBA, −78 oC

2. 100 oC, 78%

OAc

HH

22


Example 26

HO2C OTBDPS

Ph N

S

O

2

Bu3P, THF, PhH

OTBDPS

Ph

OO

N

SOTBDPS

Me3SiH, AIBN

PhH, 80 oC, 75% Ph

Example 39

NHO

S

O

ON

SMeO2C

CO2HDCC, CH2Cl2

rt, 2 hMeO2C

PhNO O

hv15 oC, 30 min, 82%

5 equiv

MeO2C

NPh

S

O

O

N

1. m-CPBA, CH2Cl2, 0 oC

2. toluene, 110 oC, 1 h, 90%

MeO2C

NPhO

O

References 1. Barton, D. H. R.; Crich, D.; Motherwell, W. B. J. Chem. Soc., Chem. Commun. 1983,

939−941. Derek Barton (United Kingdom, 1918−1998) studied under Ian Heilbron at Imperial College in his youth. He taught in England, France and the US. Barton won the Nobel Prize in Chemistry in 1969 for development of the concept of conformation. He passed away in his office at the University of Texas A&M in 1998.

2. Barton, D. H. R.; Zard, S. Z. Pure Appl. Chem. 1986, 58, 675−684. (Review). 3. Cochane, E. J.; Lazer, S. W.; Pinhey, J. T.; Whitby, J. D. Tetrahedron Lett. 1989, 30,

7111−7114. 4. Barton, D. H. R. Aldrichimica Acta 1990, 23, 3. (Review). 5. Crich, D.; Hwang, J.-T.; Yuan, H. J. Org. Chem. 1996, 61, 6189−6198. 6. Yamaguchi, K.; Kazuta, Y.; Abe, H.; Matsuda, A.; Shuto, S. J. Org. Chem. 2003, 68,

9255−9262. 7. Zard, S. Z. Radical Reactions in Organic Synthesis Oxford University Press: Oxford,

UK, 2003. (Book). 8. Carry, J.-C.; Evers, M.; Barriere, J.-C.; Bashiardes, G.; Bensoussan, C.; Gueguen, J.-

C.; Dereu, N.; Filoche, B.; Sable, S.; Vuilhorgne, M.; Mignani, S. Synlett 2004, 316−320.

9. Brault, L.; Denance, M.; Banaszak, E.; El Maadidi, S.; Battaglia, E.; Bagrel, D.; Samadi, M. Eur. J. Org. Chem. 2007, 42, 243−247.

10. Guthrie, D. B.; Curran, D. P. Org. Lett. 2009, 11, 249−251.

23

Barton–McCombie deoxygenation Deoxygenation of alcohols by means of radical scission of their corresponding thiocarbonyl derivatives.

O S

S n-Bu3SnH, AIBN

PhH, refluxR2

R1

HR2

R1

n-Bu3SnSMe C S↑O

N N CNNCΔ


AIBN = 2,2 -azobisisobutyronitrile

n-Bu3Sn CN n-Bu3Sn CNHH

O S

S

n-Bu3Sn

O S

S

R2

R1

R2

SnBu3R1

O S

Sn-Bu3Snβ-scission

R2

R1

HR2

R1

n-Bu3Sn H n-Bu3Snhydrogen atom

abstractionR2

R1

n-Bu3SnSMeO S

Sn-Bu3Sn

C S↑O

Example 12

OH

SiH2

H2Si

10 mol% AIBNnonane, 80 °C

2 h, 85%

S

PhO

(1.5 equiv)

H

24


Example 26

OO

O

O

O

O

AIBN, Δ, 74%

(CH2)4Bu2SnH

SOPh

OO

O

O

O

Example 310

O

O

O O

OH

OBn 1. NaH, CS2, MeI, 80%

2. Bu3SnH, AIBN, 70%

O

O

O O

OBn

Example 411

N

ONBoc

MeO2C

Ts OHH NaH, CS2

MeI, THFrt

N

ONBoc

MeO2C

Ts OH

SS

N

ONBoc

MeO2C

TsHBu3SnH, AIBN

Toluene, reflux72% 2 steps

References 1. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574–1585.

Stuart McCombie, a Barton student, now works at Schering−Plough. 2. Gimisis, T.; Ballestri, M.; Ferreri, C.; Chatgilialoglu, C.; Boukherroub, R.; Manuel, G.

Tetrahedron Lett. 1995, 36, 3897–3900. 3. Zard, S. Z. Angew. Chem., Int. Ed. 1997, 36, 673–685. 4. Lopez, R. M.; Hays, D. S.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 6949–6950. 5. Hansen, H. I.; Kehler, J. Synthesis 1999, 1925–1930. 6. Boussaguet, P.; Delmond, B.; Dumartin, G.; Pereyre, M. Tetrahedron Lett. 2000, 41,

3377–3380. 7. Cai, Y.; Roberts, B. P. Tetrahedron Lett. 2001, 42, 763–766. 8. Clive, D. L. J.; Wang, J. J. Org. Chem. 2002, 67, 1192–1198. 9. Rhee, J. U.; Bliss, B. I.; RajanBabu, T. V. J. Am. Chem. Soc. 2003, 125, 1492–1493. 10. Gómez, A. M.; Moreno, E.; Valverde, S.; López, J. C. Eur. J. Org. Chem. 2004, 1830–

1840. 11. Deng, H.; Yang, X.; Tong, Z.; Li, Z.; Zhai, H. Org. Lett. 2008, 10, 1791–1793. 12. Mancuso, J. Barton–McCombie deoxygenation. In Name Reactions for Homologa-

tions-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 614−632. (Review).

25

Barton nitrite photolysis Photolysis of a nitrite ester to a γ-oximino alcohol.

O

OO

OAc

NOCl

O

HOO

OAcNO

hν

O

O

OAc

NHO OH

H

O N Cl

O

HOO

OAc

− HCl

O

OO

OAcNO

hν

homolyticcleavage

− ON•

1,5-hydrogen

abstraction

O

OO

OAc

H

O N

O

HOO

OAc

Nitric oxide radical is a stable and therefore, long-lived radical

O

O

OAc

NO OHH

O

O

OAc

NHO OHH

tautomerization

nitroso intermediate

Example 12

H O

NO

H OHNOH

hυPyrex, 250-W Hg lamp

PhH, reflux, 2 h, 67%

26


Example 26

HO

NO

H

HO

H

H

NOH

hν

PhH, 6 oC46%

Example 37

O

OAcH

HO1. NOCl, CH2Cl2, −20 oC, 100%

2. Irradiation at 350 nM 5 h, PhH, 0 oC, 50%

O

OAcH

NHO HO

References 1. (a) Barton, D. H. R.; Beaton, J. M.; Geller, L. E.; Pechet, M. M. J. Am. Chem. Soc.

1960, 82, 2640−2641. In 1960, Derek Barton took a “vacation” in Cambridge, Massa-chusetts; he worked in a small research institute called the Research Institute for Medicine and Chemistry. In order to make the adrenocortical hormone aldosterol, Barton invented the Barton nitrite photolysis by simply writing down on a piece of pa-per what he thought would be an ideal process. His skilled collaborator, Dr. John Bea-ton, was able to reduce it to practice. They were able to make 40 to 50 g of aldosterol at a time when the total world supply was only about 10 mg. Barton considered it his most satisfying piece of work. (b) Barton, D. H. R.; Beaton, J. M. J. Am. Chem. Soc. 1960, 82, 2641−2641. (c) Barton, D. H. R.; Beaton, J. M. J. Am. Chem. Soc. 1961, 83, 4083−4089. (d) Barton, D. H. R.; Lier, E. F.; McGhie, J. M. J. Chem. Soc., (C) 1968, 1031−1040.

2. Nickon, A; Iwadare, T.; McGuire, F. J.; Mahajan, J. R; Narang, S. A.; Umezawa, B. J. Am. Chem. Soc. 1970 92, 1688–1696.

3. Barton, D. H. R.; Hesse, R. H.; Pechet, M. M.; Smith, L. C. J. Chem. Soc., Perkin Trans. 1 1979, 1159−1165.

4. Barton, D. H. R. Aldrichimica Acta 1990, 23, 3−10. (Review). 5. Majetich, G.; Wheless, K. Tetrahedron 1995, 51, 7095−7129. (Review). 6. Sicinski, R. R.; Perlman, K. L.; Prahl, J.; Smith, C.; DeLuca, H. F. J. Med. Chem.

1996, 22, 4497–4506. 7. Anikin, A.; Maslov, M.; Sieler, J.; Blaurock, S.; Baldamus, J.; Hennig, L.; Findeisen,

M.; Reinhardt, G.; Oehme, R.; Welzel, P. Tetrahedron 2003, 59, 5295−5305. 8. Suginome, H. CRC Handbook of Organic Photochemistry and Photobiology 2nd edn.;

2004, 102/1−102/16. (Review). 9. Hagan, T. J. Barton nitrite photolysis. In Name Reactions for Homologations-Part I;

Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 633−647. (Review).

27

Batcho–Leimgruber indole synthesis Condensation of o-nitrotoluene derivatives with formamide acetals, followed by reduction of the trans-β-dimethylamino-2-nitrostyrene to furnish indole deriva-tives.

NO2

R

DMF, 130 oC, 86% NO2

RN

NR1

R2CH

OR3OR3

R1R2 1. Pd/C, H2

2. 5% HCl 82% N

H

R

Example 14

NO2 DMF, Δ NO2

NMe2DMFDMA Pd/C, H2

NH

DMFDMA = N,N-dimethylformamide dimethyl acetal, Me2NCH(OMe)2

NMeO

MeON

MeOOMe

CH2

N

HCH2

NO

OO

O

NMeO

OMe

NO2

NMe2MeO

H

NO2

NMe2MeOH

NH2

NMe2[H]

reduction

:

NH

NMe2

NH

NH

H

NMe2

− NHMe2

Example 24

NO2 NO2

NMe2

CO2H CO2Me1. MeI, NaHCO3

2. Me2NCH(OMe)2 DMF, Δ 80%, 2 steps

NH

CO2Me

Pd/C, H2

PhH, 82%

28


Example 35

NO2NO2

NMe2

OBn OBnMe2NCH(OMe)2pyrrolidine

DMF, 110 oC3 h, 95%

NO2

OBn

15 : 1

NH

OBn

Ra-Ni, NH2NH2

THF, MeOH96%NO2

NMe2

OBn

Example 410

NO2 NO2

NMe2

NO2 NO2

MeO2C

Me2NCH(OMe)2, CuI, DMF

microwave, 180 oC, 10 min.76%

MeO2C

NH

NH2Pd/C, H2

MeOH, 3 d89% MeO2C

References 1. Leimgruber, W.; Batcho, A. D. Third International Congress of Heterocyclic Chemis-

try: Japan, 1971. Andrew D. Batcho and Willy Leimgruber were both chemists at HoffmannLa Roche in Nutley, NJ, USA.

2. Leimgruber, W.; Batcho, A. D. USP 3732245 1973. 3. Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York & London,

1970. (Review). 4. Kozikowski, A. P.; Ishida, H.; Chen, Y.-Y. J. Org. Chem. 1980, 45, 3350–3352. 5. Batcho, A. D.; Leimgruber, W. Org. Synth. 1985, 63, 214–225. 6. Clark, R. D.; Repke, D. B. Heterocycles 1984, 22, 195–221. (Review). 7. Moyer, M. P.; Shiurba, J. F.; Rapoport, H. J. Org. Chem. 1986, 51, 5106–5110. 8. Siu, J.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem. 2004, 2, 160–167. 9. Li, J.; Cook, J. M. Batcho–Leimgruber Indole Synthesis. In Name Reactions in Het-

erocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 104–109. (Review).

10. Braun, H. A.; Zall, A.; Brockhaus, M.; Schütz, M.; Meusinger, R.; Schmidt, B. Tetra-hedron Lett. 2007, 48, 7990–7993.

11. Leze, M.-P.; Palusczak, A.; Hartmann, R. W.; Le Borgne, M. Bioorg. Med. Chem. Lett. 2008, 18, 4713–4715.

29

Baylis–Hillman reaction

30


Also known as Morita–Baylis–Hillman reaction. It is a carbon−carbon bond-forming transformation of an electron-poor alkene with a carbon electrophile. Electron-poor alkenes include acrylic esters, acrylonitriles, vinyl ketones, vinyl sulfones, and acroleins. On the other hand, carbon electrophiles may be alde-hydes, α-alkoxycarbonyl ketones, aldimines, and Michael acceptors. General scheme:

R1 R2

X EWG catalytic

tertiary amineR2 EWG

XHR1

X = O, NR2, EWG = CO2R, COR, CHO, CN, SO2R, SO3R, PO(OEt)2, CONR2, CH2=CHCO2Me Alternative catalytic tertiary amines:

NN

N N

Example 1:

PhPh H

O ON

N OOH

Ph H

OO

NN

:N

N

Oconjugate

addition

aldol

NN

O

Ph

O

H

NN

O

Ph

OH

Ph

OOHN

N

E2 (bimolecular elimination) mechanism is also operative here:

NN

O

PhE2

OH

HPh

OOHN

NN

N

:

2

Example 2, Intramolecular Baylis–Hillman reaction6

CO2Me

O

NOPMB

OBn

N

DME, 0 oC, 7 d90% (dr = 9:1)

CO2Me

OBnN

O

PMB

OHmajor

CO2Me

OBnN

O

PMB

OH

minor

Example 37

CHO

OO O

OEt

DABCO

dioxane:water (1:1)24 h, 72%, de 80%

OO

HO

OOEt

Example 48

OO

OCH(CH3)2

O TiCl4, TBAIOO

OCH(CH3)2

O

HHO

O O O2NO

H ,

CH2Cl2, −78 to −30 oC85%, dr > 99:1

NO2

O O

Example 59

H

O O

OMeCl

NN

OMe

OOH

ClMeOH, rt, 8 h, 79%

31

Example 610

O

H R

NTs

OHOH

NN

(10 mol%)

cyclopentyl methyl ether/toluene, −15 oC

R

O NHTs

87−100%, 88−95% ee

R = p-Cl-C6H5R = p-OMe-C6H5R = p-NO2-C6H5R = 2-furylR = 2-naphthyl

References 1. Baylis, A. B.; Hillman, M. E. D. Ger. Pat. 2,155,113, (1972). Both Anthony B. Baylis

and Melville E. D. Hillman were chemists at Celanese Corp. USA. 2. Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001−8062. (Review). 3. Ciganek, E. Org. React. 1997, 51, 201−350. (Review). 4. Wang, L.-C.; Luis, A. L.; Agapiou, K.; Jang, H.-Y.; Krische, M. J. J. Am. Chem. Soc.

2002, 124, 2402−2403. 5. Frank, S. A.; Mergott, D. J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 2404−2405. 6. Reddy, L. R.; Saravanan, P.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 6230−6231. 7. Krishna, P. R.; Narsingam, M.; Kannan, V. Tetrahedron Lett. 2004, 45, 4773−4775. 8. Sagar, R,; Pant, C. S.; Pathak, R.; Shaw, A. K. Tetrahedron 2004, 60, 11399−11406. 9. Mi, X.; Luo, S.; Cheng, J.-P. J. Org. Chem. 2005, 70, 2338−2341. 10. Matsui, K.; Takizawa, S.; Sasai, H. J. Am. Chem. Soc. 2005, 127, 3680−3681. 11. Price, K. E.; Broadwater, S. J.; Jung, H. M.; McQuade, D. T. Org. Lett. 2005, 7,

147−150. A novel mechanism involving a hemiacetal intermediate is proposed. 12. Limberakis, C. Morita–Baylis–Hillman reaction. In Name Reactions for Homologa-


32

Beckmann rearrangement Acid-mediated isomerization of oximes to amides. In protic acid:

R1 R2

NOH

NH

R2

OR1

H3O

H3O

R1 R2

NOH

R1 R2

NOH2

:OH2

N

R2

R1

NR1

R2

:

the substituent trans to the leaving group migrates

N

R2 O

R1

H

H

N

R2 OH

R1HN

R2 O

R1− H tautomerization

With PCl5:

R1 R2

NOH

NH

R2

OR1PCl5

R1 R2

NO

H

PCl4Cl

R1 R2

NOPCl4− HCl:

:OH2

N

R2

R1

NR1

R2

:

Again, the substituent trans to the leaving group migrates

N

R2 O

R1

H

H

N

R2 OH

R1

HN

R2 O

R1− H tautomerization

Example 1, Microwave (MW) reaction3

NOH

NH

OBiCl3

MW, 90%

33


Example 24

NOH HN

OFeCl3

Solvent free81%

Example 36

NHO

NOH

PPA

21%PPA

72%

HN O

NH

O

PPA = polyphosphoric acid

Example 48

N

OEt

OH

syn

HN

O

OEt

p-TsCl/Et3N

THF, 10% K2CO380%

Abnormal Beckmann rearrangement is when the migrating substituent fragment (e.g., R1) departs from the intermediate, leaving a nitrile as a stable product.

NR2 R1 NR2 R1

R1 R2

NOH

H

Example 19

NOHH3C

H

H

H

AcO

HC(OMe)3F3CCOOH

THF, 60 oC40 min., 79%

NH3C

H

H

H

AcO

OH2

34

H

H

H

AcO

CN

H

H

H

AcO

CN

H HH

References 1. Beckmann, E. Chem. Ber. 1886, 89, 988. Ernst Otto Beckmann (1853−1923) was

born in Solingen, Germany. He studied chemistry and pharmacy at Leipzig. In addi-tion to the Beckmann rearrangement of oximes to amides, his name is associated with the Beckmann thermometer, used to measure freezing and boiling point depressions to determine the molecular weights.

2. Gawley, R. E. Org. React. 1988, 35, 1−420. (Review). 3. Thakur, A. J.; Boruah, A.; Prajapati, D.; Sandhu, J. S. Synth. Commun. 2000, 30,

2105−2011. 4. Khodaei, M. M.; Meybodi, F. A.; Rezai, N.; Salehi, P. Synth. Commun. 2001, 31,

2047−2050. 5. Torisawa, Y.; Nishi, T.; Minamikawa, J.-i. Bioorg. Med. Chem. Lett. 2002, 12,

387−390. 6. Hilmey, D. G.; Paquette, L. A. Org. Lett. 2005, 7, 2067−2069. 7. Fernández, A. B.; Boronat, M.; Blasco, T.; Corma, A. Angew. Chem., Int. Ed. 2005,

44, 2370−2373. 8. Collison, C. G.; Chen, J.; Walvoord, R. Synthesis 2006, 2319−2322. 9. Wang, C.; Rath, N. P.; Covey, D. F. Tetrahedron 2007, 63, 7977−7984. 10. Kumar, R. R.; Vanitha, K. A.; Balasubramanian, M. Beckmann rearrangement. In

Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 274−292. (Review).

35

Benzilic acid rearrangement Rearrangement of benzil to benzylic acid via aryl migration.

ArAr

O

O KOHAr

OHOH

O

Ar

benzil benzylic acid

ArAr

O

O

OH

ArO

O

ArOH Ar

OHO

O

Armigration

ArOH

OH

O

Ar

ArO

OH

O

ArH

workup

benzilate anionOH

Final deprotonation of the carboxylic acid drives the reaction forward.

Example 13

O

H3C

H3C

H

H

H

OO

KOH, MeOH/H2O

130−140 oC, 3 h, 32%O

H3C

H3C

H

H

H

CO2HOH

Example 26

OO

HO COOH

KOH, dioxane

30 min., rt, 74%

Example 3, Retro-benzilic acid rearrangement7

NH

O

O OMe

OTBS

NBoc

Boc

H

K2CO3, MeOH

rt, 2 h, 98%

NH

O

O OMe

O

NBoc

Boc

H

NH

O

NBoc

Boc

H

O OH

36


References 1. Liebig, J. Justus Liebigs Ann. Chem. 1838, 27. Justus von Liebig (1803−1873) pur-

sued his Ph.D. In organic chemistry in Paris under the tutelage of Joseph Louis Gay-Lussac (1778−1850). He was appointed the Chair of Chemistry at Giessen University, which incited a furious jealousy amongst several of the professors already working there because he was so young. Fortunately, time would prove the choice was a wise one for the department. Liebig would soon transform Giessen from a sleepy university to the Mecca of organic chemistry in Europe. Liebig is now considered the father of organic chemistry. Many classic name reactions were published in the journal that still bears his name, Justus Liebigs Annalen der Chemie.2

2. Zinin, N. Justus Liebigs Ann. Chem. 1839, 31, 329. 3. Georgian, V.; Kundu, N. Tetrahedron 1963, 19, 1037−1049. 4. Robinson, J. M.; Flynn, E. T.; McMahan, T. L.; Simpson, S. L.; Trisler, J. C.; Conn,

K. B. J. Org. Chem. 1991, 56, 6709−6712. 5. Fohlisch, B.; Radl, A.; Schwetzler-Raschke, R.; Henkel, S. Eur. J. Org. Chem. 2001,

4357−4365. 6. Patra, A.; Ghorai, S. K.; De, S. R.; Mal, D. Synthesis 2006, 15, 2556−2562. 7. Selig, P.; Bach, T. Angew. Chem., Int. Ed. 2008, 47, 5082−5084. 8. Kumar, R. R.; Balasubramanian, M. Benzilic Acid Rearrangement. In Name Reactions

for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 395−405. (Review).

37

Benzoin condensation Cyanide-catalyzed condensation of aryl aldehyde to benzoin. Now cyanide is mostly replaced by a thiazolium salt. Cf. Stetter reaction.

Ar H

O

CN ArAr

O

OHcat.

Ar H

O

Ar H

O

CNAr

OH

CN

Ar

H Oproton

transfer

CN

NCO

OH

Ar

Ar

HNC

OHO

Ar

Ar

HAr

ArO

OHproton

transferCN

Example 12

H

OCl

H

OEtO

MeO

OEtO

MeOOH Cl

NaCN, EtOH

81%

Example 27

CHO

CH3

O

N

S

CH3

HO Br

Et3N, t-BuOH, 60 oC, 24 h, 40%

O

OHCH3

Example 37

OO

Et3N, DMF, 60 oC, 96 h, 69%

OO

OOH

O2

(air)

N

S

CH3

HO Br

H3C

38


Example 49

SiEt3

O O

H

O

OSiEt3

87% yield; 91% ee

OMe

OMe

20% n-BuLiTHF

O

OP

O

H

O

O

ArAr

ArAr

MeMe5%

Ar = 2-FPh Example 510

CHO

N

NN Ph

OTMSPh Ph

BF4

10 mol%

10 mol% KHMDStoluene, rt, 16 h

O

OH

66% yield, 95% ee References 1. Lapworth, A. J. J. Chem. Soc. 1903, 83, 995−1005. Arthur Lapworth (1872−1941)

was born in Scotland. He was one of the great figures in the development of the mod-ern view of the mechanism of organic reactions. Lapworth investigated the benzoin condensation at the Chemical Department, The Goldsmiths’ Institute, New Cross, UK.

2. Buck, J. S.; Ide, W. S. J. Am. Chem. Soc. 1932, 54, 3302−3309. 3. Ide, W. S.; Buck, J. S. Org. React. 1948, 4, 269−304. (Review). 4. Stetter, H.; Kuhlmann, H. Org. React. 1991, 40, 407−496. (Review). 5. White, M. J.; Leeper, F. J. J. Org. Chem. 2001, 66, 5124−5131. 6. Hachisu, Y.; Bode, J. W.; Suzuki, K. J. Am. Chem. Soc. 2003, 125, 8432−8433. 7. Enders, D.; Niemeier, O. Synlett 2004, 2111−2114. 8. Johnson, J. S. Angew. Chem., Int. Ed. 2004, 43, 1326−1328. (Review). 9. Linghu, X.; Potnick, J. R.; Johnson, J. S. J. Am. Chem. Soc. 2004, 126, 3070−3071. 10. Enders, D.; Han, J. Tetrahedron: Asymmetry 2008, 19, 1367−1371. 11. Cee, V. J. Benzoin condensation. In Name Reactions for Homologations-Part I; Li, J.

J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp381−392. (Review).

39

Bergman cyclization 1,4-Benzenediyl diradical formation from enediyne via electrocyclization.

hydrogen donor

Δ or

hv2

Helectrocyclization

reversibleH

enediyne 1,4-benzenediyl diradical

Example 16

S

S

DMSO, 180 oC, 24 h, 60% S

SS

S Ph

Ph S

S Ph

Ph

Example 27

N

N

H3Chv

THF, 45%

N

N

H3C

Example 3, Wolff rearrangement followed by the Bergman cyclization8

O

N2

Ohv or Δ, ROH

OHCO2R

CO2ROH

7 : 4

40


Example 410

O

TMS

142 oC, t1/2 = 14.4 h

OTMS

References 1. Jones, R. R.; Bergman, R. G. J. Am. Chem. Soc. 1972, 94, 660−661. Robert G. Berg-

man (1942−) is a professor at the University of California, Berkeley. His discovery of the Bergman cyclization was completed far in advance of the discovery of ene-diyne’s anti-cancer properties.

2. Bergman, R. G. Acc. Chem. Res. 1973, 6, 25−31. (Review). 3. Myers, A. G.; Proteau, P. J.; Handel, T. M. J. Am. Chem. Soc. 1988, 110, 7212−7214. 4. Yus, M.; Foubelo, F. Rec. Res. Dev. Org. Chem. 2002, 6, 205−280. (Review). 5. Basak, A.; Mandal, S.; Bag, S. S. Chem. Rev. 2003, 103, 4077−4094. (Review). 6. Bhattacharyya, S.; Pink, M.; Baik, M.-H.; Zaleski, J. M. Angew. Chem., Int. Ed. 2005,

44, 592−595. 7. Zhao, Z.; Peacock, J. G.; Gubler, D. A.; Peterson, M. A. Tetrahedron Lett. 2005, 46,

1373−1375. 8. Karpov, G. V.; Popik, V. V. J. Am. Chem. Soc. 2007, 129, 3792−3793. 9. Kar, M.; Basak, A. Chem. Rev. 2007, 107, 2861−2890. (Review). 10. Lavy, S.; Pérez-Luna, A.; Kündig, E. P. Synlett 2008, 2621−2624. 11. Pandithavidana, D. R.; Poloukhtine, A.; Popik, V. V. J. Am. Chem. Soc. 2009, 131,

351−356.

41

Biginelli pyrimidone synthesis One-pot condensation of an aromatic aldehyde, urea, and β-dicarbonyl compound in the acidic ethanolic solution and expansion of such a condensation thereof. It belongs to a class of transformations called multicomponent reactions (MCRs).

Ar CHOO

O O

H2N NH2

O Δ

NHHN

OO

O

Ar

HCl, EtOH

ArO

O O

HO

aldol

addition

H

O

O OH

H

enolization

H

O

O O

Ar OH

HH

O

O O

Ar OH

H

O

O O

Ar OH2

H

conjugate

additionNH2H2N

O

O

O O

Ar :

H

H

OH

O

O

HN Ar

O NH2

:

O

O

O

NH

ArO

H2N

H

HN NH

O

HO Ar

O OH

H

HN NH

O

H2O Ar

O OH

− H2O

NHHN

OO

O

ArH

42


Example 14

O

OF CHO

H2N NH2

S

NH

NH

O

S

F

HCl

EtOH, Δ81%

Example 25

O O

O H

H2N

O

NH2MeO

OMe

NH

NH

O

OMe

MeOOCCeCl3 •7H2O

EtOH, Δ, 2.5 h95%

Example 3, Microwave-induced Biginelli condensation (MWI = microwave irra-diation)9

O O

O H

H2N

O

NH2EtO

OMe

NH

NH

O

OMe

EtOOCBi(NO3)3, MWI

EtOH, Δ, 5 h80%

References 1. Biginelli, P. Ber. 1891, 24, 1317. Pietro Biginelli was at Lab. chim. della Sanita

pubbl. In Roma, Italy. 2. Kappe, C. O. Tetrahedron 1993, 49, 6937−6963. (Review). 3. Kappe, C. O. Acc. Chem. Res. 2000, 33, 879−888. (Review). 4. Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043−1052. (Review). 5. Ghorab, M. M.; Abdel-Gawad, S. M.; El-Gaby, M. S. A. Farmaco 2000, 55, 249−255. 6. Bose, D. S.; Fatima, L.; Mereyala, H. B. J. Org. Chem. 2003, 68, 587−590. 7. Kappe, C. O.; Stadler, A. Org. React. 2004, 68, 1−116. (Review). 8. Limberakis, C. Biginelli Pyrimidone Synthesis. In Name Reactions in Heterocyclic


9. Banik, B. K.; Reddy, A. T.; Datta, A.; Mukhopadhyay, C. Tetrahedron Lett. 2007, 48, 7392−7394.

43

Birch reduction The Birch reduction is the 1,4-reduction of aromatics to their corresponding cyclohexadienes by alkali metals (Li, K, Na) dissolved in liquid ammonia in the presence of an alcohol. Benzene ring bearing an electron-donating substituent:

ONa, liq. NH3

ROH

O

O O

H

H

H OR

single electron

transfer (SET)

O

radical anion

OO

H

HH e

O

H

HH

H OR

Benzene ring with an electron-withdrawing substituent:

CO2HNa, liq. NH3

CO2H

H

CO2CO2H CO2e e

radical anion

H NH2H

CO2 CO2HCO2

H H

H

44


Example 14

ON

O

OMe

OMe

1. Na, NH3, THF, −78 oC

2. MeI, 98%, 30:1 dr ON

O

OMe

OMe Example 27

N

Na, NH3, THF

−78 oC, quant.N

Example 38

Ph

PhPh

Na, NH3THF, EtOH

−33 oC, 1 h16.3% H

Ph

H

H

H

H

Ph

H

H

Ph

H

H

HPh

H

H

H

Ph

H

H

H

Ph

H

H

References 1. Birch, A. J. J. Chem. Soc. 1944, 430−436. Arthur Birch (1915−1995), an Australian,

developed the “Birch reduction” at Oxford University during WWII in Robert Robin-son’s laboratory. The Birch reduction was instrumental to the discovery of the birth control pill and many other drugs.

2. Rabideau, P. W.; Marcinow, Z. Org. React. 1992, 42, 1−334. (Review). 3. Birch, A. J. Pure Appl. Chem. 1996, 68, 553−556. (Review). 4. Donohoe, T. J.; Guillermin, J.-B.; Calabrese, A. A.; Walter, D. S. Tetrahedron Lett.

2001, 42, 5841−5844. 5. Pellissier, H.; Santelli, M. Org. Prep. Proced. Int. 2002, 34, 611−642. (Review). 6. Subba Rao, G. S. R. Pure Appl. Chem. 2003, 75, 1443−1451. (Review). 7. Kim, J. T.; Gevorgyan, V. J. Org. Chem. 2005, 70, 2054−2059. 8. Gealis, J. P.; Müller-Bunz, H.; Ortin, Y.; Condell, M.; Casey, M.; McGlinchey, M. J.

Chem. Eur. J. 2008, 14, 1552−1560.

45

Bischler–Möhlau indole synthesis The Bischler–Möhlau indole synthesis, also known as the Bischler indole synthesis, refers to the synthesis of 3-arylindoles from the cyclization of -arylamino-ketones and excess anilines.

OH2NBr

Δ

ONH N

H

O

H2N

BrO

NH

: :

H

SN2

NHO

H

H

H

dehydration

N

H

HNH

Example 15

NH2

OO

BrNaHCO3, EtOH

reflux, 4 h

NH O

O230−250 oC

silicone oil, 10−15 min35−80%

NH

O

Example 29

N

OTBS

O

F

NH2N NH2

OMe

DME, H2SO4

reflux, 53%NH2N

OMe

NH

N

F

46


Example 310

OH2NBr N

H

LiBr, NaHCO3

EtOH, reflux6 h, 74%

OMe

OMe

MeO

OMe

Example 4, Microwave-assisted, solvent-free Bischler indole synthesis11

OH2NBr

Cl

ONH

ClneatNaHCO3

rt, 3 h

NH

Cl

H3NBr

cat. DMF, microwave, 540 W60 s, 52%

References 1. Möhlau, R. Ber. 1881, 14, 171–175. 2. Bischler, A.; Fireman, P. Ber. 1893, 26, 1346–1349. 3. Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York, 1970, pp 164.

(Book). 4. Buu-Hoï, N. P.; Saint-Ruf, G.; Deschamps, D.; Bigot, P. J. Chem. Soc. (C) 1971,

2606–2609. 5. Houlihan, W. J., Ed.; The Chemistry of Heterocyclic Compounds, Indoles (Part 1),

Wiley & Sons: New York, 1972. (Book). 6. Bigot, P.; Saint-Ruf, G.; Buu-Hoï, N. P. J. Chem. Soc., Perkin 1 1972, 2573–2576. 7. Bancroft, K. C. C.; Ward, T. J. J. Chem. Soc., Perkin 1 1974, 1852–1858. 8. Coïc, J. P.; Saint-Ruf, G.; Brown, K. J. Heterocycl. Chem. 1978, 15, 1367–1371. 9. Henry, J. R.; Dodd, J. H. Tetrahedron Lett. 1998, 39, 8763–8764. 10. Pchalek, K.; Jones, A. W.; Wekking, M. M. T.; Black, D. S. C. Tetrahedron 2005, 61,

77–82. 11. Sridharan, V.; Perumal, S.; Avendaño, C.; Menéndez, J. C. Synlett 2006, 91–95.

47

Bischler–Napieralski reaction Dihydroisoquinolines from β-phenethylamides in refluxing phosphorus oxychlo-ride.

HN O

R

POCl3N

R

HN O

R

PCl

OClCl

HN O

RPOCl2

− ClNH

OPOCl2R

N

R OPOCl2

HH

Cl

N

R OH NH

RPOCl

Cl

POCl

OHCl HCl

Example 12

NH

NO

CO2Me

NH

N1. POCl3

2. NaBH4

H

H

CO2Me

NH

N

CO2MeH

H

H

H

H

H60% 23%

Example 24

NCO2Me

BnMeO N

OBn

MeOPOCl3, P2O5

96%

Example 36

O

O N

H

H

H

MeO2C

O

O N

H

H

H

O

POCl3

80 oC, 81%

48


Example 47

O

OHN O

MeOOMe

OMe

O

ON

MeOOMe

OMe

POCl3

toluene, 95%

Example 59

NH

NO

H H

AcO OAc

H H

HO OH

NH

NH

POCl3, PhH, reflux, 3 h

then LiAlH4, THF, 1.5 h 64%

References 1. Bischler, A.; Napieralski, B. Ber. 1893, 26, 1903–1908. Augustus Bischler

(1865−1957) was born in Southern Russia. He studied in Zurich with Arthur Hantzsch. He discovered the Bischler–Napieralski reaction while studying alkaloids at Basel Chemical Works, Switzerland with his coworker, B. Napieralski.

2. Aubé, J.; Ghosh, S.; Tanol, M. J. Am. Chem. Soc. 1994, 116, 9009–9018. 3. Sotomayor, N.; Domínguez, E.; Lete, E. J. Org. Chem. 1996, 61, 4062–4072. 4. Wang, X.-j.; Tan, J.; Grozinger, K. Tetrahedron Lett. 1998, 39, 6609–6612. 5. Ishikawa, T.; Shimooka, K.; Narioka, T.; Noguchi, S.; Saito, T.; Ishikawa, A.; Yama-

zaki, E.; Harayama, T.; Seki, H.; Yamaguchi, K. J. Org. Chem. 2000, 65, 9143–9151. 6. Banwell, M. G.; Harvey, J. E.; Hockless, D. C. R., Wu, A. W. J. Org. Chem. 2000, 65,

4241–4250. 7. Capilla, A. S.; Romero, M.; Pujol, M. D.; Caignard, D. H.; Renard, P. Tetrahedron

2001, 57, 8297–8303. 8. Wolfe, J. P. Bischler–Napieralski Reaction. In Name Reactions in Heterocyclic Chem-

istry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 376−385. (Review).

9. Ho, T.-L.; Lin, Q.-x. Tetrahedron 2008, 64, 10401–10405. 10. Csomós, P.; Fodor, L.; Bernáth, G.; Csámpai, A.; Sohár, P. Tetrahedron 2009, 65,

1475–1480.

49

Blaise reaction β-Ketoesters from nitriles, α-haloesters and Zn. Cf. Reformatsky reaction.

R CNBr CO2R2

R1

1. Zn, THF, reflux

2. H3O+CO2R2

R1R

O

R

Br CO2R2

R1

Zn(0)

R1

N

nucleophilic

addition

OR2

O

workupCO2R2

R1R

NZnBr

H2O H

BrZn

The Zn enolate itself is a C-enolate (in the crystal form), but for the reaction to oc-cur, it equilibrates back into an O-enolate

CO2R2

R1R

NHH

H2O:

CO2R2

R1R

O

CO2R2

R1R

OH2N HH2O H

Example 1, Preparation of the statin side chain5

Cl CNOTMS

Br CO2t-Bu1. cat. Zn, THF, reflux

2. H3O+, 85%Cl

OH OCO2t-Bu

Example 26

Zn, MeSO3H

THF, reflux, 2.5 hN

F CN

Cl ClBr CO2Et

HCl, 72%

N

F

Cl Cl

HN

OEt

OZnBr

N

F

Cl Cl

O

OEt

O

50


Example 37

NC OBnOH

MeOMe

O

Br

3 equiv Zn, 1 mol% MeSO3HTHF, reflux, 78%

OBnOHO

MeO2C

Example 4, The first chemoselective tandem acylation of the Blaise reaction in-termediate9

Ph CN

Zn*

BrCH2CO2Et

THF, reflux, 1 h

ZnHN O

OEtPh

Br

n-BuLi, Ac2O

rt, 3 h, 82%

NH2 O

OEtPh

O CH3

References 1. (a) Blaise, E. E. C. R. Hebd. Seances Acad. Sci. 1901, 132, 478–480. (b) Blaise, E. E.

C. R. Hebd. Seances Acad. Sci. 1901, 132, 978–980. Blaise was at Institut Chimique de Nancy, France.

2. Beard, R. L.; Meyers, A. I. J. Org. Chem. 1991, 56, 2091–2096. 3. Deutsch, H. M.; Ye, X.; Shi, Q.; Liu, Z.; Schweri, M. M. Eur. J. Med. Chem. 2001, 36,

303–311. 4. Creemers, A. F. L.; Lugtenburg, J. J. Am. Chem. Soc. 2002, 124, 6324–6334. 5. Shin, H.; Choi, B. S.; Lee, K. K.; Choi, H.-w.; Chang, J. H.; Lee, K. W.; Nam, D. H.;

Kim, N.-S. Synthesis 2004, 2629–2632. 6. Choi, B. S.; Chang, J. H.; Choi, H.-w.; Kim, Y. K.; Lee, K. K.; Lee, K. W.; Lee, J. H.;

Heo, T.; Nam, D. H.; Shin, H. Org. Proc. Res. Dev. 2005, 9, 311–313. 7. Pospíšil, J.; Markó, I. E. J. Am. Chem. Soc. 2007, 129, 3516–3517. 8. Rao, H. S. P.; Rafi, S.; Padmavathy, K. Tetrahedron 2008, 64, 8037–8043. (Review). 9. Chun, Y. S.; Lee, S.-g.; Ko, Y. O.; Shin, H. Chem. Commun. 2008, 5098–5100.

51

Blum–Ittah aziridine synthesis Ring opening of oxiranes using azide followed by PPh3-reduction of the interme-diate azido-alcohol to give the corresponding aziridines.

R2R1

O NaN3 R1R2

N3

OH R2R1

HNPPh3

R2R1

OSN2 R1

R2

N3

OHN3 Regardless of the regioselectivity of the SN2 reaction of the azide, the ultimate stereochemical outcome for the aziridine is the same.

R1

R2

HON N N :PPh3

R1

R2

HON N N PPh3 N N N PR3

R1

R2

HO

PR3NN N

X

N2

NPR3

R1R2

OH

NPR3

HOR2

R1

NHR3P:O

R1

R2

R2R1

HNproton

transfer R2O

NHR1

PPh3 Example 13

OTrO

1. NaN3, NH4Cl, MeOH, reflux, 4 h

2. Ph3P, CH3CN, reflux, 30 min. 60−75%

HN OTr

Example 25

OTBSO NaN3, NH4Cl, MeOH

reflux, 4 h, 50%

52


OTBSOH

N3

OTBSN3

OH

Ph3P, CH3CN

reflux, 99% OTBSNH

Example 37

OHN

Cbz 1. NaN3, NH4Cl, MeOH, 3 h, 64 oC

2. PPh3, MeCN, 1 h, reflux 66%

HNH

NCbz

Example 48

O NaN3, NH4Cl

microwave, 15 min.93%

OHN3

PPh3

CH3CN, reflux2 h, 95%

HN

References 1. Ittah, Y.; Sasson, Y.; Shahak, I.; Tsaroom, S.; Blum, J. J. Org. Chem. 1978, 43, 4271–

4273. Jochanan Blum is a professor at The Hebrew University in Jerusalem, Israel. 2. Tanner, D.; Somfai, P. Tetrahedron Lett. 1987, 28, 1211–1214. 3. Wipf, P.; Venkatraman, S.; Miller, C. P. Tetrahedron Lett. 1995, 36, 3639–3642. 4. Fürmeier, S.; Metzger, J. O. Eur. J. Org. Chem. 2003, 649–659. 5. Oh, K.; Parsons, P. J.; Cheshire, D. Synlett 2004, 2771–2775. 6. Serafin, S. V.; Zhang, K.; Aurelio, L.; Hughes, A. B.; Morton, T. H. Org. Lett. 2004,

6, 1561–1564. 7. Torrado, A. Tetrahedron Lett. 2006, 47, 7097–7100. 8. Pulipaka, A. B.; Bergmeier, S. C. J. Org. Chem. 2008, 73, 1462–1467.

53

Boekelheide reaction Treatment of 2-methylpyridine N-oxide with trifluoroacetic anhydride, or acetic, anhydride gives rise to 2-hydroxymethylpyridine.

NO

TFAA

NOH

TFAA, trifluoroacetic anhydride

NO

F3C O CF3

O O

acyl

transferNO

CF3

O

H

O2CCF3

NO

CF3

O

NOHN

O CF3

O

hydrolysis

Example 14

NN

Ac2O, CH2Cl2

reflux, 1 h, 90% NNOAcO

Example 26

NO

Ot-Bu

N

Ot-Bu

OH

1. TFAA, CH2Cl2

2. Na2CO3, 3 h 89%

Example 38

N N

OTBDPS1. Ac2O, 100 oC, 18 h

2. K2CO3, MeOH−H2O, rt, 2 h 63%

N N

OTBDPS

HO OHO O

54


Example 49

N

NO2

O

N

NO2

OH

Ac2O, HOAc, 90 oC, 3 h

then HCl, 79%

References 1. Boekelheide, V.; Linn, W. J. J. Am. Chem. Soc. 1954, 76, 1286−1291. Virgil Boekel-

heide (1919−2003) was a professor at the University of Oregon. 2. Boekelheide, V.; Harrington, D. L. Chem. Ind. 1955, 1423−1424. 3. Katritzky, A. R.; Lagowski, J. M. Chemistry of the Heterocylic N-Oxides, Academic

Press: NY, 1971. (Review). 4. Newkome, G. R.; Theriot, K. J.; Gupta, V. K.; Fronczek, F. R.; Baker, G. R. J. Org.

Chem. 1989, 54, 1766−1769. 5. Katritzky, A. R.; Lam, J. N. Heterocycles 1992, 33, 1011−1049. (Review). 6. Fontenas, C.; Bejan, E.; Haddou, H. A.; Balavoine, G. G. A. Synth. Commun. 1995,

25, 629−633. 7. Galatsis, P. Boekelheide Reaction. In Name Reactions in Heterocyclic Chemistry; Li,

J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 340−349. (Review). 8. Havas, F.; Danel, M.; Galaup, C.; Tisnès, P.; Picard, C. Tetrahedron Lett. 2007, 48,

999−1002. 9. Dai, L.; Fan, D.; Wang, X.; Chen, Y. Synth. Commun. 2008, 38, 576−582.

55

Boger pyridine synthesis Pyridine synthesis via hetero-Diels−Alder reaction of 1,2,4-triazines and dieno-philes (e.g., enamine) followed by extrusion of N2.

O

NHN N

N

N

O

HN

: NOH

HH2O

NNN

N

hetero-Diels-Alder

reaction

enamine

NN

NN

:B

N

retro-Diels-Alder

reaction, − N2 NNH

Example 13

NN

NEtO2C

EtO2C

CO2EtN O

NEtO2C

EtO2C

CO2EtCHCl3, 60 oC

26 h, 92%

Example 2, Intramolecular Boger pyridine synthesis8

triisopropylbenzene

232 oC, 36 h

NN N

CH3

N

N

Ph

PhPh N

NCH3

Ph

Ph

70%

N

N

Ph

Ph

27%

56


Example 310

OH3C

HO

H

H H

NNN

1. pyrrolidine, xylene, Δ 10 h, sealed tube2. silica, 5 h, 67%

H3C

HO

H

H H

N

N

N

Example 411

NN

N NN

N

S SN N

S Sp-cumene, 30 h, 150 oC67%

References 1. Boger, D. L.; Panek, J. S. J. Org. Chem. 1981, 46, 2179−2182. Dale Boger obtained

his Ph.D. under Elias J. Corey at Harvard University in 1980. He started his independent career at the University of Kansas, moving onto Purdue University, and currently he is a professor at The Scripps Research Institute.

2. Boger, D. L. Tetrahedron 1983, 39, 2869−2939. (Review). 3. Boger, D. L.; Panek, J. S.; Yasuda, M. Org. Synth. 1988, 66, 142−150. 4. Boger, D. L. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.;

Pergamon, 1991, Vol. 5, 451−512. (Review). 5. Behforouz, M.; Ahmadian, M.Tetrahedron 2000, 56, 5259−5288. (Review). 6. Buonora, P.; Olsen, J.-C.; Oh, T. Tetrahedron 2001, 57, 6099−6138. (Review). 7. Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P. Tetrahedron 2002, 58, 379−471.

(Review). 8. Lahue, B. R.; Lo, S.-M.; Wan, Z.-K.; Woo, G. H. C.; Snyder, J. K. J. Org. Chem.

2006, 69, 7171−7182. 9. Galatsis, P. Boger Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J.,

Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 323−339. (Review). 10. Catozzi, N.; Bromley, W. J.; Wasnaire, P.; Gibson, M.; Taylor, R. J. K. Synlett 2007,

2217−2221. 11. Lawecka, J.; Bujnicki, B.; Drabowicz, J.; Rykowski, A. Tetrahedron Lett. 2008, 49,

719−722.

57

Borch reductive amination Reduction (often using NaCNBH3) of the imine, formed by an amine and a car-bonyl, to afford the corresponding amine—basically, reductive amination.

H

R1 R2

O

R3

HN

R4 N

R1 R2

R4R3

H

HR1 R2

O

R3

HN

R4

R1 R2

OH

N:R4

R3N

R1 R2

R4R3N

R1 R2

R4R3

H

Example 14

CH3

O

NH2

1. TiCl4, Et3N, CH2Cl2, rt, 18 h

2. NaCNBH3, MeOH, rt, 15 min. 94% CH3

HN

Example 25

5 N HCl, NaCNBH3

MeOH, rt, 72 h, 75%O O

NH2N

Example 38

H

O

NH •HCl

0.3 equiv InCl3

2 equiv Et3SiHMeOH, rt, 48 h, 66%

N

58


Example 49

OHOH

NO

O

O

OBn

1. NaIO4, 8:2 acetone−H2O, rt

2. BnNH2, MeOH, HOAc NaCNBH3, 3 Å MS, −78 oC to rt 64%

NO

O

O

OBn

NBn

References 1. Borch, R. F., Durst, H. D. J. Am. Chem. Soc. 1969, 91, 3996–3997. Richard F. Borch,

born in Cleveland, Ohio, was a professor at the University of Minnesota. 2. Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc. 1971, 93, 2897–2904. 3. Borch, R. F.; Ho, B. C. J. Org. Chem. 1977, 42, 1225–1227. 4. Barney, C. L.; Huber, E. W.; McCarthy, J. R. Tetrahedron Lett. 1990, 31, 5547–5550. 5. Mehta, G.; Prabhakar, C. J. Org. Chem. 1995, 60, 4638–4640. 6. Lewin, G.; Schaeffer, C. Heterocycles 1998, 48, 171–174. 7. Lewin, G.; Schaeffer, C.; Hocquemiller, R.; Jacoby, E.; Léonce, S.; Pierré, A.; Atassi,

G. Heterocycles 2000, 53, 2353–2356. 8. Lee, O.-Y.; Law, K.-L.; Ho, C.-Y.; Yang, D. J. Org. Chem. 2008, 73, 8829–8837. 9. Sullivan, B.; Hudlicky, T. Tetrahedron Lett. 2008, 49, 5211–5213. 10. Koszelewski, D.; Lavandera, I.; Clay, D.; Guebitz, G. M.; Rozzell, D.; Kroutil, W.

Angew. Chem., Int. Ed. 2008, 47, 9337–9340.

59

Borsche–Drechsel cyclization Tetrahydrocarbazole synthesis from cyclohexanone phenylhydrazone. Cf. Fischer indole synthesis.

NH

N

HCl

NH

[3,3]-sigmatropic

rearrangementNH

N

H

HNH

NHNH

NH

H

NHNH2

H

NH

NH2

H

NH

H

Example 16

NH2

H3CO

O

HO

CH3HCl, NaNO2, NaOAc

H2O, MeOH, 54%

NH

NH

N

H3COO

CH3

HOAc, HCl, reflux

10 min., 44% O

CH3

H3CO

Example 210

OCO2Et

NO

NN

KOAc, H2O

− 4 oC to rt

retro-Claisen condensation

followed by Japp-Klingemann hydrazone synthesis

60


NO

NHN

CO2H

EtO2C

H3O , 100 oC

68% 2 steps NH

NO

CO2Et

CO2H

Example 310

NH

N

CO2Et

CO2H

conc. HCl, EtOH

reflux, 85% NH

CO2Et

CO2Et

References 1. Drechsel, E. J. Prakt. Chem. 1858, 38, 69. 2. Borsche, W.; Feise, M. Ann. 1908, 359, 49–80. Walther Borsche was a professor at

Chemischen Institut, Universität Göttingen, Germany when this paper was published. Borsche was completely devoid of the arrogance shown by many of his contemporar-ies. Both Borsche and his colleague at Frankfurt, Julius von Braun, suffered under the Nazi regime for their independent minds.

3. Bruck, P. J. Org. Chem. 1970, 35, 2222–2227. 4. Gazengel, J.-M.; Lancelot, J.-C.; Rault, S.; Robba, M. J. Heterocycl. Chem. 1990, 27,

1947–1951. 5. Abramovitch, R. A.; Bulman, A. Synlett 1992, 795–796. 6. Lin, G.; Zhang, A. Tetrahedron 2000, 56, 7163–7171. 7. Ergun, Y.; Bayraktar, N.; Patir, S.; Okay, G. J. Heterocycl. Chem. 2000, 37, 11–14. 8. Rebeiro, G. L.; Khadilkar, B. M. Synthesis 2001, 370–372. 9. Takahashi, K.; Kasai, M.; Ohta, M.; Shoji, Y.; Kunishiro, K.; Kanda, M.; Kurahashi,

K.; Shirahase, H. J. Med. Chem. 2008, 51, 4823–4833. 10. Pete, B. Tetrahedron Lett. 2008, 49, 2835–2838.

61

Boulton–Katritzky rearrangement Rearrangement of one five-membered heterocycle into another under thermolysis.

NA

BD

XY

ZH

YX

NZ

ABD

H

Example 14

N:H

NO

N

Ph

N

NO

N

Ph

150 oC H HN

N NH Ph

O

Example 2, Hydrazinolysis7

NN

OF3C

Ph

ONH2NH2, DMF

rt, 1 h NN

OF3C

N

Ph

NH2

NNNH

PhNHF3C

O

5%

N

NH

NF3C

PhN

HO

92%

Example 43

NN

O

NHN

NH

CH3H3C

CF3

Ot-BuOK, DMF

reflux, 2 h, 75%CF3

ONH

O

62


References 1. Boulton, A. J.; Katritzky, A. R.; Majid Hamid, A. J. Chem. Soc. (C) 1967, 2005–2007.

Alan Katritzky, a professor at the University of Florida, is best known for his series Advances of Heterocyclic Chemistry, now in its 93rd volume.

2. Ruccia, M.; Vivona, N.; Spinelli, D. Adv. Heterocycl. Chem. 1981, 29, 141–169. (Re-view).

3. Vivona, N.; Buscemi, S.; Frenna, V.; Gusmano, C. Adv. Heterocyl. Chem. 1993, 56, 49–154. (Review).

4. Katayama, H.; Takatsu, N.; Sakurada, M.; Kawada, Y. Heterocycles 1993, 35, 453–459.

5. Rauhut, G. J. Org. Chem. 2001, 66, 5444–5448. 6. Crampton, M. R.; Pearce, L. M.; Rabbitt, L. C. J. Chem. Soc., Perkin Trans. 2 2002,

257–261. 7. Buscemi, S.; Pace, A.; Piccionello, A. P.; Macaluso, G.; Vivona, N.; Spinelli, D.;

Giorgi, G. J. Org. Chem. 2005, 70, 3288–3291. 8. Pace, A.; Pibiri, I.; Piccionello, A. P.; Buscemi, S.; Vivona, N.; Barone, G. J. Org.

Chem. 2007, 64, 7656–7666. 9. Piccionello, A. P.; Pace, A.; Buscemi, S.; Vivona, N.; Pani, M. Tetrahedron 2008, 64,

4004–4010. 10. Pace, A.; Pierro, P.; Buscemi, S.; Vivona, N.; Barone, G. J. Org. Chem. 2009, 74,

351–358.

63

Bouveault aldehyde synthesis Formylation of an alkyl or aryl halide to the homologous aldehyde by transformation to the corresponding organometallic reagent then addition of DMF (M = Li, Mg, Na, and K).

R X

1. M2. DMF

3. HR CHO

R XM

R MMe2N

R

O MH

R CHOMe2N H

O

Comins modification:4

H

ON NLi LiO N

H

N

n-BuLi

ortho-lithiation

N

LiO

N

1. RX, X = Br, I

2. H3OH

O

R

Example3

BrLi, DMF, THF, 10 oC

ultrasound 5 min., 85%

CHO

References 1. Bouveault, L. Bull. Soc. Chim. Fr. 1904, 31, 1306−1322, 1322−1327. Louis Bou-

veault (1864−1909) was born in Nevers, France. He devoted his short yet very pro-ductive life to teaching and to working in science.

2. Sicé, J. J. Am. Chem. Soc. 1953, 75, 3697−3700. 3. Pétrier, C.; Gemal, A. L.; Luche, J.-L. Tetrahedron Lett. 1982, 23, 3361−3364. 4. Comins, D. L.; Brown, J. D. J. Org. Chem. 1984, 49, 1078−1083. 5. Einhorn, J.; Luche, J. L. Tetrahedron Lett. 1986, 27, 1793−1796. 6. Meier, H.; Aust, H. J. Prakt. Chem. 1999, 341, 466−471.

64


Bouveault–Blanc reduction Reduction of esters to the corresponding alcohols using sodium in an alcoholic solvent.

R OEt

O Na, EtOHR OH

R OEt

OOEtsingle-electron

transfer (SET) R OEt

O HR OEt

OH

e ketyl (radical anion)

R OEt

OH

R OEt

OH

OEtH

OEt

eR H

O e

OEt

R H

O H

R H

OHR H

OH

OEtHR OH

e

Example2

OEt

OOH

Na, Al2O3t-BuOH, Tol.

reflux, 6 h, 66%

References 1. Bouveault, L.; Blanc, G. Compt. Rend. Hebd. Seances Acad. Sci. 1903, 136,

1676−1678. 2. Bouveault, L.; Blanc, G. Bull. Soc. Chim. 1904, 31, 666−672. 3. Rühlmann, K.; Seefluth, H.; Kiriakidis, T.; Michael, G.; Jancke, H.; Kriegsmann, H. J.

Organomet. Chem. 1971, 27, 327−332. 4. Seo, B.-I.; Wall, L. K.; Lee, H.; Buttrum, J. W.; Lewis, D. E. Synth. Commun. 1993,

23, 15−22. 5. Singh, S.; Dev, S. Tetrahedron 1993, 49, 10959−10964. 6. Schopohl, M. C.; Bergander, K.; Kataeva, O.; Föehlich, R.; Waldvogel, S. R. Synthesis

2003, 2689−2694.

65


Bradsher reaction The intramolecular Bradsher cyclization refers to the acid-catalyzed aromatic cyclodehydration of ortho-acyl diarylmethanes to form anthracenes. On the other hand, the intermolecular Bradsher cycloaddition often involves the Diels–Alder reaction of a pyridium with a vinyl ether or vinyl sulfide.

R

O R

HBr

CH3CO2H

anthracene

R

O

H R

OH

R HO

H

R

− H

OH RR OH2

H

H

Example 1, Intramolecular Bradsher reaction2

Br

O

Br

HBr, CH3CO2H

150 oC, 7 h, 21%

Example 2, Intramolecular Bradsher reaction5

S SClCl

AcOH

PPA S SClCl

O

H3C

S SClCl

CH3

CH3O

66


Example 3, Intermolecular Bradsher cycloaddition (DNP = dinitrophenyl)8

NDNP

OCO2Et

Cl

H OEt CaCO3, MeOH

rt, 2 d

CHO

NHDNP

EtO2COOEt

66%19%N

O

DNP

EtO

Example 4, Intermolecular Bradsher cycloaddition10

H SPh CaCO3, MeOHNDNP

NHAc NHAc

DNPN

PhS

Cl

Cl

H3O

DNPHN SPh

NOH

Ac

80%

References 1. (a) Bradsher, C. K. J. Am. Chem. Soc. 1940, 62, 486–488. Charles K. Bradsher was

born in Petersburg, VA in 1912. After his Ph.D. under Louis F. Fieser at Harvard and postdoctoral training with R. C. Fuson, he became a professor at Duke University. (b) Bradsher, C. K.; Smith, E. S. J. Am. Chem. Soc. 1943, 65, 451–452. (c) Bradsher, C. K.; Vingiello, F. A. J. Org. Chem. 1948, 13, 786–789. (d) Bradsher, C. K.; Sinclair, E. F. J. Org. Chem. 1957, 22, 79–81.

2. Vingiello, F. A.; Spangler, M. O. L.; Bondurant, J. E. J. Org. Chem. 1960, 25, 2091–2094.

3. Brice, L. K.; Katstra, R. D. J. Am. Chem. Soc. 1960, 82, 2669–2670. 4. Saraf, S. D.; Vingiello, F. A. Synthesis 1970, 655. 5. Ahmed, M.; Ashby, J.; Meth-Cohn, O. J. Chem. Soc., Chem. Commun. 1970, 1094–

1095. 6. Ashby, J.; Ayad, M.; Meth-Cohn, O. J. Chem. Soc., Perkin Trans. 1 1974, 1744–1747. 7. Bradsher, C. K. Chem. Rev. 1987, 87, 1277–1297. (Review). 8. Nicolas, T. E.; Franck, R. W. J. Org. Chem. 1995, 60, 6904–6911. 9. Magnier, E.; Langlois, Y. Tetrahedron Lett. 1998, 39, 837–840. 10. Soll, C. E.; Franck, R. W. Heterocycles 2006, 70, 531–540.

67

Brook rearrangement Rearrangement of α-silyl oxyanions to α-silyloxy carbanions via a reversible process involving a pentacoordinate silicon intermediate is known as the [1,2]-Brook rearrangement, or [1,2]-silyl migration.

[1,2]-Brook rearrangement

SiR3

OHR1

R2

RLi

Li

OR1

R2

SiR3

SiR3

OR1

R2

R

HSiR3

OR1

R2

R1R2

SiR3

O

pentacoordinate silicon intermediate

H

OPh

Ph

SiPh3OPh

Ph

SiPh3

H OH

workup


OLi

R1

O

R1

SiR3

R2

SiR3OSiR3

R2R1

Li

R2


OLi

R1 R1

O

R2

SiR3OSiR3

R2R1

Li

R2

R3Si

Example 16

t-BuMe2SiCN

O

Ph

1. 4 eq. NaHMDS, −30 to 15 oC

2. PhCH2Br, −10 oC, 75%t-BuMe2SiO

CN

Ph Ph

68


Example 2, [1,2]-Brook rearrangement followed by a retro-[1,5]-Brook rear-rangement8

PhBrt-BuLi, Et2O

−78 oCPhLi

Me3Si Ph

O

−78 oC to rt, 30 min.then NH4Cl, H2O, 44%

Ph

OPh

SiMe3

Example 3, [1,5]-Brook rearrangement9

TMSBu

SS

OH

KHMDS, THF

− 78 oC, 1 h, 93%H

BuSS

OTMS

Example 4, Retro-[1,4]-Brook rearrangement10

Me SnBu3

TESO OTMSn-BuLi, THF

− 78 oC, 30 min.91%

Me TMS

TESO OH

11% [1,2]-BrookMe TES

OH OTMS

89% [1,4]-Brook

References 1. Brook, A. G. J. Am. Chem. Soc. 1958, 80, 1886−1889. Adrian G. Brook (1924−) was

born in Toronto, Canada. He was a professor in Lash Miller Chemical Laboratories, University of Toronto, Canada.

2. Brook, A. G. Acc. Chem. Res. 1974, 7, 77−84. (Review). 3. Bulman Page, P. C.; Klair, S. S.; Rosenthal, S. Chem. Soc. Rev. 1990, 19, 147−195.

(Review). 4. Fleming, I.; Ghosh, U. J. Chem. Soc., Perkin Trans. 1 1994, 257−262. 5. Moser, W. H. Tetrahedron 2001, 57, 2065−2084. (Review). 6. Okugawa, S.; Takeda, K. Org. Lett. 2004, 6, 2973−2975. 7. Matsumoto, T.; Masu, H.; Yamaguchi, K.; Takeda, K. Org. Lett. 2004, 6, 4367−4369. 8. Clayden, J.; Watson, D. W.; Chambers, M. Tetrahedron 2005, 61, 3195−3203. 9. Smith, A. B., III; Xian, M.; Kim, W.-S.; Kim, D.-S. J. Am. Chem. Soc. 2006, 128,

12368–12369. 10. Mori, Y.; Futamura, Y.; Horisaki, K. Angew. Chem., Int. Ed. 2008, 47, 1091–1093. 11. Greszler, S. N.; Johnson, J. S. Org. Lett. 2009, 11, 827–830.

69

Brown hydroboration Addition of boranes to olefins followed by alkalinic oxidation of the organoborane adducts to afford alcohols.

R1. R'2BH

2. H2O2, NaOHR

OH

RB

HR'

R' syn-

addition RB

H

R'

R'

O OHR

BH

R'R'

RB

H

O

R'OH

R'

alkyl migrationR

OB

R'

R'

O OHR

OB

OR'

OR'

ROHOH B(OH)3

Example 12

H

H

H

H

1. BH3•SMe2, LiAlH4, Et2O

2. NaOOH

H

H

H

H 35% 40%

H

H

H

H

OH HO

Example 27

OMe

OMeNO2

MeO

OBn

HO

Me

BH3•SMe2, NaOOH

THF, 85%, dr 8:1~11:1

OMe

OMeNO2

MeO

OBn

HO

Me

HO

70


Example 38

Ph1. Pyridine•BH3, I2, CH2Cl2, 2 h

2. H2O2, NaOH, MeOH, 92% Ph

OH PhOH

15:1

Example 4, Asymmetric hydroboration10

PhNH

CH3

O

PhNH

O

CH3

O

OP N

Ph

CH3

0.5 mol% Rh(nbd)2•BF41.1% cat., 2 equiv PinBH

THF, 40 oC, 2 h

cat. =

PhNH

CH3

O B(OCMe2)2 H2O2, aq. NaOH

80%

PhNH

CH3

O OH

99% ee

Example 511

NHSi

Ph

HPh

H

t-But-Bu

BH3•SM2, THF;

NaOH, H2O285%

HPh

(t-Bu)2Si

Ph

NH2

OH

OH

References 1. Brown, H. C.; Tierney, P. A. J. Am. Chem. Soc. 1958, 80, 1552−1558. Herbert C.

Brown (USA, 1912−2004) began his academic career at Wayne State University and moved on to Purdue University where he shared the Nobel Prize in Chemistry in 1981 with Georg Wittig (Germany, 1897−1987) for their development of organic boron and phosphorous compounds.

2. Nussim, M.; Mazur, Y.; Sondheimer, F. J. Org. Chem. 1964, 29, 1120−1131. 3. Pelter, A.; Smith, K.; Brown, H. C. Borane Reagents, Academic Press: New York,

1972. (Book). 4. Brewster, J. H.; Negishi, E. Science 1980, 207, 44−46. (Review). 5. Fu, G. C.; Evans, D. A.; Muci, A. R. Advances in Catalytic Processes 1995, 1,

95−121. (Review). 6. Hayashi, T. Comprehensive Asymmetric Catalysis I−III 1995, 1, 351−364. (Review). 7. Carter K. D.; Panek J. S. Org. Lett. 2004, 6, 55−57. 8. Clay, J. M.; Vedejs, E. J. Am. Chem. Soc. 2005, 127, 5766−5767. 9. Clay, J. M. Brown hydroboration reaction. In Name Reactions for Functional Group

Transformations; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2007; pp 183−188. (Review).

10. Smith, S. M.; Thacker, N. C.; Takacs, J. M. J. Am. Chem. Soc. 2008, 130, 3734−3735. 11. Anderson, L. L.; Woerpel, K. A. Org. Lett. 2009, 11, 425−428.

71

Bucherer carbazole synthesis Carbazole formation from naphthols and aryl hydrazines promoted by sodium bi-sulfite. Another variant of the Fischer indole synthesis.

OH

NHNH2

NaHSO3

NH

OHH O

HH

OSO2H

OHHH

OSO2H

OHH

OSO2H

:NH2NHPh

H H

OSO2H

NHNHPh

H:B

HH

OSO2H

NHNHPhOH

NHNH

H

[3,3]-sigmatropicrearrangement

thenNHNH2H NH

NH2HNH

H

H

Example 12

OH

NHNH2CO2H NH

NaHSO3, NaOHΔ, 130 oC

several days, 46%

Example 23

H2NHN

1. aq. NaHSO3, ΔOH

NH

2. H

72


Example 37

H2NHN NH

Na2S2O5BrOH

Br

HCl, Δ

Example 34

H2NHN

OHHO HNNH

1. NaHSO3, Δ

2. H0.5% yield!

References 1. Bucherer, H. T. J. Prakt. Chem. 1904, 69, 49−91. Hans Th. Bucherer (1869−1949)

was born in Ehrenfeld, Germany. He shuttled between industry and academia all through his career.

2. Bucherer, H. T.; Schmidt, M. J. Prakt. Chem. 1909, 79, 369−417. 3. Bucherer, H. T.; Sonnenburg, E. F. J. Prakt. Chem. 1909, 81, 1−48. 4. Drake, N. L. Org. React. 1942, 1, 105−128. (Review). 5. Seeboth, H. Angew. Chem., Int. Ed. 1967, 6, 307−317. (Review). 6. Robinson, B. The Fischer Indole Synthesis, Wiley-Interscience, New York, 1982.

(Book). 7. Hill, J. A.; Eaddy, J. F. J. Labelled Compd. Radiopharm. 1994, 34, 697−706. 8. Pischel, I.; Grimme, S.; Kotila, S.; Nieger, M.; Vögtle, F. Tetrahedron: Asymmetry

1996, 7, 109−116. 9. Moore, A. J. Bucherer carbazole synthesis. In Name Reactions in Heterocyclic Chem-


73

Bucherer reaction Transformation of β-naphthols to β-naphthylamines using ammonium sulfite.

OH NH2(NH4)2SO3•NH3

H2O, 150 oC

OH O

HH

OSO2NH4

OHH

OSO2NH4

HH

H

O

OSO2NH4

:NH3

OSO2NH4

NH2

OHtautomerization H

OSO2NH4

NH2

H

NH2

OSO2NH4

NH2

OH2

:

H

Example 1, Although the classic Bucherer reaction requires high temperatures, it may be carried out at room temperature with the aid of microwave (150 watts):7

OH NH2NH3, (NH4)2SO3, H2O, rt

microwave 30 min. 93% Example 2, Retro-Bucherer reaction7

N

N

OOMe

OH

5 mol% Na2S2O5H2O, reflux, 4 h;

10 mol% NaOHreflux, 24 h

46%N

N

OOMe

NH2

74


Example 38

(NH4)2SO3NH3, H2O

200 oC, 5 d, 91%OHOH

OHNH2

References 1. Bucherer, H. T. J. Prakt. Chem. 1904, 69, 49−91. 2. Drake, N. L. Org. React. 1942, 1, 105−128. (Review). 3. Gilbert, E. E. Sulfonation and Related Reactions Wiley: New York, 1965, p 166. (Re-

view). 4. Seeboth, H. Angew. Chem., Int. Ed. 1967, 6, 307−317. 5. Gruszecka, E.; Shine, H. J. J. Labelled Compd. Radiopharm. 1983, 20, 1257–1264. 6. Belica, P. S.; Manchand, P. S. Synthesis 1990, 539−540. 7. Deady, L. W.; Devine, S. M. Tetrahedron 2006, 62, 2313−2320. 8. Körber, K.; Tang, W.; Hu, X.; Zhang, X. Tetrahedron Lett. 2002, 43, 7163–7165. 9. Budzikiewicz, H. Mini-Reviews Org. Chem. 2006, 3, 93–97. (Review).

75

Bucherer–Bergs reaction Formation of hydantoins from carbonyl compounds with potassium cyanide (KCN) and ammonium carbonate [(NH4)2CO3] or from cyanohydrins and ammo-nium carbonate. It belongs to the category of multiple component reactions (MCRs).

R1

R2O

KCN

(NH4)2CO3NH

HNR1

R2

O

O

(NH4)2CO3 = 2 NH3 + CO2 + H2O

NC

R2H2NOH

R1H3N

R1

R2O :

R1NH2

R2N

C O

:

O

:

R1 R2

NH2

O

NR1

R2

O

HN

H

NH

HNR1

R2

O

O

:

NH2

NR1

R2

O

COOHRH

NR1

R2

OH

O

N

:

isocyanate intermediate

Example 15

N

CH3O

CH3O

O

KCN, (NH4)2CO3

48 h, 60 oC, 83%

N

CH3O

CH3ON

CH3O

CH3OH H

HNNH HN

NHO

O

O

O

Example 26

O

O

O

H

HHCO2Et

KCN, (NH4)2CO3

EtOH/H2O, 70 oC, 50%O

O

H

HHCO2Et

NHHN

O

O

76


Example 37

B(OH)2

CH3

O

KCN, (NH4)2CO3

EtOH/H2O (1:1)60 oC, 4 h, 83%

B(OH)2

CH3

NHHN

O

O

Example 49

EtO2C

F

H

O

O 1. 1 M NaOH, EtOH, rt, 30 min.

2. KCN, (NH4)2CO3, 60 oC, 5 days 77%

HO2CF

H OHN

NH

OO

References 1. Bergs, H. Ger. Pat. 566, 094, 1929. Hermann Bergs worked at I. G. Farben in Ger-

many. 2. Bucherer, H. T., Steiner, W. J. Prakt. Chem. 1934, 140, 291–316. (Mechanism). 3. Ware, E. Chem. Rev. 1950, 46, 403–470. (Review). 4. Wieland, H. In Houben−Weyl’s Methoden der organischen Chemie, Vol. XI/2, 1958, p

371. (Review). 5. Menéndez, J. C.; Díaz, M. P.; Bellver, C.; Söllhuber, M. M. Eur. J. Med. Chem. 1992,

27, 61–66. 6. Domínguez, C.; Ezquerra, A.; Prieto, L.; Espada, M.; Pedregal, C. Tetrahedron:

Asymmetry 1997, 8, 511–514. 7. Zaidlewicz, M.; Cytarska, J.; Dzielendziak, A.; Ziegler-Borowska, M. ARKIVOC

2004, iii, 11−21. 8. Li, J. J. Bucherer–Bergs Reaction. In Name Reactions in Heterocyclic Chemistry, Li,

J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 266−274. (Review). 9. Sakagami, K.; Yasuhara, A.; Chaki, S.; Yoshikawa, R.; Kawakita, Y.; Saito, A.; Ta-

guchi, T.; Nakazato, A. Bioorg. Med. Chem. 2008, 16, 4359–4366. 10. Wuts, P. G. M.; Ashford, S. W.; Conway, B.; Havens, J. L.; Taylor, B.; Hritzko, B.;

Xiang, Y.; Zakarias, P. S. Org. Proc. Res. Dev. 2009, 13, 331–335.

77

Büchner ring expansion Reaction of a phenyl ring with diazoacetic esters to give cyclohepta-2,4,6-trienecarboxylic acid esters. Intramolecular Büchner reaction is more useful in synthesis. Cf. Pfau−Platter azulene synthesis.

N2 CO2CH3

[Rh]CO2CH3

N2 CO2CH3[Rh]

[Rh] CO2CH3N2↑ rhodium carbenoid

[Rh]

CO2CH3

[Rh]

CO2CH3[2 + 2]

cycloaddition

reductive

elimination

CO2CH3electrocyclic

ring openingCO2CH3

Example 1, Intramolecular Büchner reaction7

H O

Rh2(OAc)4

CH2Cl2

ON2

Example 2, Intramolecular Büchner reaction8

Br

ON2

Icat. Rh2(OCOt-Bu)4, DMAP

Ac2O, CH2Cl2, 73%

I

OAc

Example 3, An intramolecular Büchner reaction within the Grubbs’ catalyst!9

NN

RuPh

PCy3

Cl

Cl

1 atm CO

CH2Cl2, 90%

NN

Ru CO

PCy3

Cl

Cl

PhOC

78


Example 410

Ar0.5 mol%

CH2Cl2, −78 oC, 49−66%

ORh Rh

O

CPh3

4

EtO2C

N2

[Rh]CO2Et

Ar

[Rh]

CO2EtAr CO2EtAr

CO2Et

Ar

References 1. Büchner, E. Ber. 1896, 29, 106–109. 2. von E. Doering, W.; Knox, L. H. J. Am. Chem. Soc. 1957, 79, 352–356. 3. Marchard, A. P.; Brockway, N. M. Chem. Rev. 1974, 74, 431–469. (Review). 4. Anciaux, A. J.; Demoncean, A.; Noels, A. F.; Hubert, A. J.; Warin, R.; Teyssié, P. J.

Org. Chem. 1981, 46, 873–876. 5. Duddeck, H.; Ferguson, G.; Kaitner, B.; Kennedy, M.; McKervey, M. A.; Maguire, A.

R. J. Chem. Soc., Perkin Trans. 1 1990, 1055–1063. 6. Doyle, M. P.; Hu, W.; Timmons, D. J. Org. Lett. 2001, 3, 933–935. 7. Manitto, P.; Monti, D.; Speranza, G. J. Org. Chem. 1995, 60, 484–485. 8. Crombie, A. L; Kane, J. L., Jr.; Shea, K. M.; Danheiser, R. L. J. Org. Chem. 2004, 69,

8652–8667. 9. Galan, B. R.; Gembicky, M.; Dominiak, P. M.; Keister, J. B.; Diver, S. T. J. Am.

Chem. Soc. 2005, 127, 15702–15703. 10. Panne, P.; Fox, J. M. J. Am. Chem. Soc. 2007, 129, 22–23. 11. Gomes, A. T. P. C.; Leão, R. A. C.; Alonso, C. M. A.; Neves, M. G. P. M. S.;

Faustino, M. A. F.; Tomé, A. C.; Silva, A.M. S.; Pinheiro, S.; de Souza, M. C. B. V.; Ferreira, V. F.; Cavaleiro, J. A. S. Helv. Chim. Acta 2008, 91, 2270–2283.

79

Buchwald–Hartwig amination The Buchwald–Hartwig amination is an exceedingly general method for generat-ing an aromatic amine from an aryl halide or an aryl sulfonates. The key feature of this methodology is the use of catalytic palladium modulated by various electron-rich ligands. Strong bases, such as sodium tert-butoxide, are essential for catalyst turnover.

R1X+ HN

R2

R3

X = I, Br, Cl, OSO2R

cat. LnPd(0)

NaOt-Bu R1NR2

R3

Mechanism:

Br

NH

NPd(OAc)2, dppf

NaOt-Bu, Tol., Δ

BrPd(0)

oxidative addition

Pd(II) Br NH

ligandexchange

− HBr

NPd(II) N reductive

elimination− Pd(0)

The catalytic cycle is shown on the next page.

Example 13

R1I+ HN

R2

R3

0.5 mol% Pd2(dba)32 mol% P(o-tol)3

NaOt-Bu, dioxane65–100 °C, 2–24 h

18–79% yield

R1NR2

R3

R1 = EWG or EDGamine = 2° cyclic or acyclicamine = 1° aliphatic: low yield, unless R1 ortho

80


Catalytic cycle:

LnPd(0)

LnPdX

Ar

HNR2

R3+ NaOt-Bu+ HOt-BuNaX

LnPdNR2(R3)

Ar

NR2

R3Ar ArX

Ln+1Pd(0)

k1k-1

k2

k3

k4

NR2

R3' H

LnPdH

Ar

Ar H

Ln-1Pd(0)

–d[ArX]

dt=

k1k2

k–1[L][ArX][Pd]

Pd(BINAP)2 catalyzed

Example 24

R1X+ HN

R2

R3

5 mol% (DPPF)PdCl215 mol% DPPF

NaOt-Bu, THF100 °C (sealed), 3 h

80–96% yield(11 examples)

R1NR2

R3

X = Br or IR1 = EWG or EDGamine = 2° acyclic (one example)amine = 1° aliphatic or aromatic

FePPh2

PPh2

DPPF

Example 3, Room temperature Buchwald–Hartwig amination9

R1Br+

1–2 mol% Pd(dba)2(t-Bu)3P (P/Pd = 0.8/1)

NaOt-Bu, tol.22 °C, 1–6 h81–99% yield

R1 = EDG or EWGamine = 2° cyclic or acyclic: aromatic, aliphatic, or azolesamine = 1° anilines: no aliphatic

HNR2

R3R1

NR2

R3

81

Example 410

BrMe

MeOn-HexNH2

0.25 mol% Pd2(dba)30.75 mol% rac-BINAP

NaOt-Bu (1.4 equiv)tol., 80 °C, 18–23 h

94%

HN

Me

MeO

n-Hex

Example 511

O Cl HN O

0.5 mol% Pd2(dba)21 mol% ligand

1.4 eq. NaOt-Bu, Tol.100 oC, 24 h, 92%

O N O

ligand =P

N

N

Ni-Bu

i-Bu

Ni-Bu

Example 612

CO2MeI

NH2Pd(OAc)2, Cs2CO3

DPE-Phos, Tol., 95 oC95%

OCF3

MeO2C HN

OCF3

DPE-Phos =O

PPh2 PPh2

Example 7, Amination of volatile amines14

NXNO

O

X = N, CH2

Br

5 equiv R1NHR25 mol% Pd(OAc)2

10 mol% dppp2 equiv NaOt-Bu

80 oC, 14 h, sealed tube55−98%

NXNO

O

NR2

R1

Example 815

MeO NH2 NCl Cl

O Ot-Bu1 mol% Pd(OAc)2

2 mol% XPhos

1.4 equiv NaOt-Butoluene, rt, 4 d, 67% NN

HCl

O Ot-Bu

MeO

82

PXPhos =

References 1. (a) Paul, F.; Patt, J.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116, 5969−5970. John

Hartwig earned his Ph.D. at the University of California-Berkeley in 1990 under the guidance of Robert Bergman and Richard Anderson. He moved from Yale University to the University of Illinois at Urbana-Champaign in 2006. Hartwig and Buchwald in-dependently discovered this chemistry. (b) Mann, G.; Hartwig, J. F. J. Org. Chem. 1997, 62, 5413−5418. (c) Mann, G.; Hartwig, J. F. Tetrahedron Lett. 1997, 38, 8005−8008.

2. (a) Guram, A. S.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 7901−7902. Stephen Buchwald received his Ph.D. in 1982 under Jeremy Knowles at Harvard University. He is currently a professor at MIT. (b) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 10333−10334.

3. Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1996, 61, 1133−1135. 4. Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 7217−7218. 5. Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31,

805−818. (Review). 6. Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852−860. (Review). 7. Frost, C. G.; Mendonça, P. J. Chem. Soc., Perkin Trans. 1 1998, 2615−2624. (Re-

view). 8. Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125−146. (Review). 9. Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman, L.

M. J. Org. Chem. 1999, 64, 5575−5580. 10. Wolfe, J. P.; Buchwald, S. L. Org. Syn. 2002, 78, 23−30. 11. Urgaonkar, S.; Verkade, J. G. J. Org. Chem. 2004, 69, 9135−9142. 12. Csuk, R.; Barthel, A.; Raschke, C. Tetrahedron 2004, 60, 5737−5750. 13. Janey, J. M. Buchwald–Hartwig amination, In Name Reactions for Functional Group

Transformations; Li, J. J., Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2007; pp 564−609. (Review).

14. Li, J. J.; Wang, Z.; Mitchell, L. H. J. Org. Chem. 2007, 72, 3606−3607. 15. Lorimer, A. V.; O’Connor, P. D.; Brimble, M. A. Synthesis 2008, 2764−2770. 16. Nodwell, M.; Pereira, A.; Riffell, J. L.; Zimmerman, C.; Patrick, B. O.; Roberge, M.;

Andersen, R. J. J. Org. Chem. 2009, 74, 995−1006.

83

Burgess reagent

CH3O2C N S NEt3O

O

The Burgess reagent [(methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt], a neutral, white crystalline solid, is efficient at generating olefins from secondary and tertiary alcohols where the first-order thermolytic Ei (during the elimination takes place—the two groups leave at about the same time and bond to each other concurrently) mechanism prevails. Preparation2

N S ClO

OO

H3C OH

MeOH, PhH

rt, 88−92%

CH3O2CN S Cl

O

O

H

NEt3, PhH

rt, 84−86%

CH3O2C N S NEt3O

O:NEt3

CH3O2CN S Cl

O

O

H

:NEt3

Mechanism5

MeO2C N S NEt3O

O

Ph

HO DH Ph

Ph

O D

HH

S NCO2Me

OO

HNEt3slow

SN2

H

Ph

Ph

O D

HH

S NCO2Me

OO

HNEt3Ph

fast

Ei Ph H

H Ph OD

S NCO2Me

O

O

HNEt3

84


Example 1, On primary alcohols, the hydroxyl group does not eliminate but rather undergoes substitution3

O NH

OHOMe

H

H

Burgess reagent

THF, 21 oC, 9 h, 71%

O N

OMe

H

H Example 26

OSi

NOH

1.5 eq. Burgess, THF

reflux, 1 h, 97% OSi

N

Example 37

OHO

OBn

NCH O

OBn

NCHBurgess reagent

toluene, 50 oC, 60%

Example 48

2.5 equiv Burgess reagent

THF/CH2Cl2 (4:1)reflux, 6 h, 86%

O OH

OHBnOOBn

OBnO

BnOOBn

OBn

OS

N OO

CO2Me

α/β = (8:1)

Example 510

O

NNHBoc 2.5 equiv Burgess reagent

THF, reflux, 30 min., 86% N NHBoc

O

OHN

O2S

85

References 1 (a) Atkins, G. M., Jr.; Burgess, E. M. J. Am. Chem. Soc. 1968, 90, 4744–4745. (b)

Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A., Jr. J. Am. Chem. Soc. 1970, 92, 5224–5226. (c) Atkins, G. M., Jr.; Burgess, E. M. J. Am. Chem. Soc. 1972, 94, 6135–6141. (d) Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A. J. Org. Chem. 1973, 38, 26–31.

2 (a) Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A.; Williams, W. M. Org. Synth. Coll. Edn. 1987, 6, 788–791. (b) Duncan, J. A.; Hendricks, R. T.; Kwong, K. S. J. Am. Chem. Soc. 1990, 112, 8433–8442.

3 Wipf, P.; Xu, W. J. Org. Chem. 1996, 61, 6556–6562. 4 Lamberth, C. J. Prakt. Chem. 2000, 342, 518–522. (Review). 5 Khapli, S.; Dey, S.; Mal, D. J. Indian Inst. Sci. 2001, 81, 461–476. (Review). 6 Miller, C. P.; Kaufman, D. H. Synlett 2000, 8, 1169–1171. 7 Keller, L.; Dumas, F.; D’Angelo, J. Eur. J. Org. Chem. 2003, 2488–2497. 8 Nicolaou, K. C.; Snyder, S. A.; Longbottom, D. A.; Nalbandian, A. Z.; Huang, X.

Chem. Eur. J. 2004, 10, 5581–5606. 9 Holsworth, D. D. The Burgess Dehydrating Reagent. In Name Reactions for Func-

tional Group Transformations; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2007; pp 189−206. (Review).

10 Li, J. J.; Li, J. J.; Li, J.; Trehan, A. K.; Wong, H. S.; Krishnananthan, S.; Kennedy, L. J.; Gao, Q.; Ng, A.; Robl, J. A.; Balasubramanian, B.; Chen, B.-C. Org. Lett. 2008, 10, 2897−2900.

86

Burke boronates

MeN

OOB

OO

Br

MeN

OOB

OO

B-protected haloboronic acids

HO

MeN

OOB

OO

MeN

OOB

OO

Stable boronic acid surrogates

SBr

Burke boronates can serve as B-protected haloboronic acids for a wide variety of applications in iterative cross-coupling.1–6 The corresponding boronic acids can be liberated using mild aqueous bases such as NaOH or NaHCO3.1–4 Burke boronates are also compatible with many synthetic reagents, enabling the synthesis of complex boronic acids from simple B-containing starting materials.3,6 They can also serve as stable building blocks for cross-coupling, i.e., under aqueous basic conditions, the corresponding boronic acid is released and coupled in situ.2,3,7 Moreover, Burke boronates are highly crystalline, monomeric, free-flowing solids that are indefinitely stable to benchtop storage under air and compatible with silica gel chromatography.1–3,6 Preparation:1,2,4,6

MeN

OOB

OOSBr

B(OH)2SBrHO2C CO2H

NMe

PhH:DMSO 10:1Dean-Stark

99%Burke boronate

MeN

OOB

OOTMS

BBr3 BBr2NaO2C CO2Na

NMe

CH2Cl2 CH3CN86%

30 mmol scale Burke boronate

Burke boronates can be conveniently prepared from the corresponding boronic ac-ids via complexation with N-methyliminodiacetic acid (MIDA)1,4 or from dibromoboranes via complexation with MIDA2−Na+

22,6 Alternatively, many of

these building blocks are now commercially available.

87


Example 12

A wide range of selective couplings can be performed at the halide terminus of a B-protected haloboronic acid.

Pd(OAc)2, PPh3Et3N, DMF, 45 °C

90%

Pd2dba3, Fur3PDMF, 45 °C, 91%

piperidineTHF

23 °C, 73%

Pd(PPh3)4, CuI

MeN

OOB

OO

Br

MeN

OOB

OO

BO

O

MeMeMe

Me

MeN

OOB

OO

Ph

MeN

OOB

OO

Bu3Sn

MeN

OOB

OO

MeN

OOB

OO

TMS

MeN

OOB

OOMeO

O

SnBu3

ZnClBu3Sn

MeO

O

TMSB(OH)2Ph

Pd(OAc)2, SPhosTHF, 0 °C

66%

PdCl2(CH3CN)2SPhos, KOAc

PhMe45 °C, 71%

Pd(OAc)2

OB

OMe

Me

MeMe

2

SPhos, KFPhMe, 23°C

92 %Suzuki coupling Sonogashira coupling

Miyaura coupling

Negishi coupling

Stille coupling

Heck reaction

Example 22 Small molecule natural products can be prepared via iterative cross-coupling with B-protected haloboronic acids.

Me Me

Me

MeB(OH)2

MeN

OOB

OO

BrMe Me

Me

Me MeN

OOB

OO

Pd(OAc)2, SPhosK3PO4,Toluene

23 °C, 78%

Br

Me

O

H

1. aq. NaOH, THF, 23 °C2.

Me Me

Me

Me Me

O

H

all-trans-retinalK3PO4, THF, 23 °C66% over two steps

Pd(OAc)2 SPhos

88

Example 33

Burke boronates are stable to a wide range of synthetic reagents, including acids, non-aqueous bases, oxidants, reductants, electrophiles, and soft nucleophiles. This reagent compatibility enables multistep synthesis of complex boranes from simple boron-containing starting materials.

HO

MeN

OOB

OO

MeN

OOB

OO

PMBO

TfOH, THF0→23 °C , 5 h, 64%

PMBOC(NH)CCl3

23 °C, 1.5 h, 79%DDQ, DCM

TBSCl, Imid, THF

HF•Py, THF23 °C, 20 min

83%

23 °C, 9 h, 98%

CrO3, H2SO4Acetone

23 °C, 30 min90%

MeN

OOB

OO

TBSO

MeN

OOB

OO

O

HO

MeN

OOB

OO

OH

Me

O

NO

Bn

O

MeN

OOB

OO

O

EtO

MeN

OOB

OO

NO

morpholine NaBH(OAc)3

DCE, 23 °C, 8 h, 76%

O(EtO)2P

OEt

O

NaH, DMF23 °C, 30 min, 71%

Me

O

N O

Bn

O

H2O2, MeOHpH 6.0 buffer, 79%

n-BuOTf Et3N, DCM−78→0 °C, 2 h;

Swern and then

Example 42 Burke boronates can be hydrolyzed in situ under aqueous basic coupling condi-tions, as evidenced by this synthesis of the complex polyene skeleton of ampho-tericin B.

OAcMe

ClMe

TESOMe OAc

Me

Me

Me

TESONMe

OO B

OO

Me

Pd(OAc)2, XPhos1 N aq. NaOH

THF, 45 °C, 48%

Me

5

References

1. Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2007, 129, 6716–6717. 2. Lee, S. J., Gray, K. C., Paek, J. S., Burke, M. D. J. Am. Chem. Soc. 2008, 130, 466–

468. 3. Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2008, 130, 14084–14085. 4. Ballmer, S. G.; Gillis, E. P.; Burke, M. D. Org. Synth. 2009, in press. 5. Gillis, E. P.; Burke, M. D. Aldrichimica Acta 2009, in press. 6. Uno, B. E.; Gillis, E. P.; Burke, M. D. Tetrahedron 2009, 65, 3130–3138. 7. Knapp, D. M.; Gillis, E. P., Burke, M. D. J. Am. Chem. Soc. 2009, 131, ASAP.

89

Cadiot–Chodkiewicz coupling Bis-acetylene synthesis from alkynyl halides and alkynyl copper reagents. Cf. Castro−Stephens reaction.

X Cu R2R1 R1 R2

X Cu R2oxidative

addition

XCu R2R1 R1

Cu(III) intermediate

reductive

eliminationCuX R1 R2

Example 13

OHBr

OH

cat. CuCl, NH2OH•HCl

EtNH2, MeOH30−40 oC, 70−80%

Example 27

TBS Br OH TBS OHcat. CuCl, NH2OH•HCl

30% n-BuNH2, H2O, 92%

Example 39

OMeMeO

HH

MeO OMe

Br Br

CuBr, NH2OH•HCl

piperidine, MeOHrt, 3.5 h, 80%

OMeMeO

MeO OMe n

n = 1 to 7

n = 1, 8%n = 2, 11%n = 3, 32%n = 4, 8%n = 5, 13%n = 6, 3%n = 7, 8%

Example 4, Cadiot–Chodkiewicz active template synthesis of rotaxanes and switchable molecular shuttles with weak intercomponent interactions10

90


OH

1

1. 1 equiv n-BuLi THF, −78 oC

2. 1 equiv CuI, 0 oC3. 1 equiv 3 1 equiv 2

OO

N N

O O

O O

N N

O O

O O

trapping molecule 3 =O Br

2

References 1. Chodkiewicz, W.; Cadiot, P. C. R. Hebd. Seances Acad. Sci. 1955, 241, 1055−1057.

Both Paul Cadiot (1923−) and Wladyslav Chodkiewicz (1921−) are French chemists. 2. Cadiot, P.; Chodkiewicz, W. In Chemistry of Acetylenes; Viehe, H. G., ed.; Dekker:

New York, 1969, 597−647. (Review). 3. Gotteland, J.-P.; Brunel, I.; Gendre, F.; Désiré, J.; Delhon, A.; Junquéro, A.; Oms, P.;

Halazy, S. J. Med. Chem. 1995, 38, 3207−3216. 4. Bartik, B.; Dembinski, R.; Bartik, T.; Arif, A. M.; Gladysz, J. A. New J. Chem. 1997,

21, 739−750. 5. Montierth, J. M.; DeMario, D. R.; Kurth, M. J.; Schore, N. E. Tetrahedron 1998, 54,

11741−11748. 6. Negishi, E.-i.; Hata, M.; Xu, C. Org. Lett. 2000, 2, 3687−3689. 7. Marino, J. P.; Nguyen, H. N. J. Org. Chem. 2002, 67, 6841−6844. 8. Utesch, N. F.; Diederich, F.; Boudon, C.; Gisselbrecht, J.-P.; Gross, M. Helv. Chim.

Acta 2004, 87, 698−718. 9. Bandyopadhyay, A.; Varghese, B.; Sankararaman, S. J. Org. Chem. 2006, 71, 4544–

4548−4548. 10. Berna, J.; Goldup, S. M.; Lee, A.-L.; Leigh, D. A.; Symes, M. D.; Teobaldi, G.; Zer-

betto, F. Angew. Chem., Int. Ed. 2008, 47, 4392−4396.

91

Camps quinoline synthesis Base-catalyzed intramolecular condensation of a 2-acetamido acetophenone (1) to a 2-(and possibly 3)-substituted-quinolin-4-ol (2), a 4-(and possibly 3)-substituted-quinolin-2-ol (3), or a mixture.

R1O

NH

OR2

R1

N

1 2

OH

R2NaOR

ROH

R2

N

3

OH

R1

Pathway A:

R1O

NH

OR2

1

R1

NH

O

O

R2H

OR

2R1

NH

O

R2

OH

H

H2O

Pathway B:

OR

R1O

NH

OR2

1

R2

NH

O

OR1

H

3R2

NH

O

R1

HOH

H2O

Example 11

69%

N OH

20%

N

OH

NH

O

NaOH, H2O

104 °C

O

92


Example 26

HN

O

O

N

Me

MeN

NOH

Me

MeNaOH

H2O, 90%

References 1. (a) Camps, R. Chem. Ber. 1899, 32, 3228−3234. Rudolf Camps worked under Profes-

sor Engler from 1899 to 1902 at the Technische Hochschule in Karlsruhe, Germany. (b) Camps, R. Arch. Pharm. 1899, 237, 659−691.

2. Elderfield, R. C.; Todd, W. H.; Gerber, S. Heterocyclic Compounds Vol. 6, Elderfield, R. C., ed.; Wiley and Sons, New York, 1957, 576. (Review).

3. Clemence, F.; LeMartret, O.; Collard, J. J. Heterocycl. Chem. 1984, 21, 1345−1353. 4. Hino, K.; Kawashima, K.; Oka, M.; Nagai, Y.; Uno, H.; Matsumoto, J. Chem. Pharm.

Bull. 1989, 37, 110−115. 5. Witkop, B.; Patrick, J. B.; Rosenblum, M. J. Am. Chem. Soc. 1951, 73, 2641−2647. 6. Barret, R.; Ortillon, S.; Mulamba, M.; Laronze, J. Y.; Trentesaux, C.; Lévy, J. J. Hete-

rocycl. Chem. 2000, 37, 241−244. 7. Pflum, D. A. Camps Quinolinol Synthesis. In Name Reactions in Heterocyclic Chemis-

try; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 386−389. (Re-view).

93

Cannizzaro reaction Redox reaction between aromatic aldehydes, formaldehyde or other aliphatic al-dehydes without α-hydrogen. Base is used to afford the corresponding alcohols and carboxylic acids.

R H

O OH

R OH

OR OH2

R H

O

OH

OH

R H

OHO

R H

OO

Pathway A:

hydride

transfer R O

OR OR H

O

R OH

OH H R OH R O

O

Final deprotonation of the carboxylic acid drives the reaction forward.

Pathway B:

hydride

transfer R O

OR O

R H

O

R O

OH R OH

OR OH

acidic

workup

Example 14

CHO KOH powder

100 oC, 5 minsolvent-free

CO2HOH

41% 38%

Example 26

CHOOH

NNa

H

THF, 0 oC, 5 h, 76%

OHN

81% 76%

94


Example 38

CHO 1 equiv TMG

H2O, rt, 10 h

CO2HOH

42% 43%

O2N O2N O2N

TMG = 1,1,3,3-tetramethylguanidine

Example 4, Desymmetrization by intramolecular Cannizzaro reaction9

CHO

O

O

O

CHO

2

1 M BaCl2

H2O, refluxquant.

CH2OH

O

O

O

CO2H

2

References 1. Cannizzaro, S. Ann. 1853, 88, 129−130. Stanislao Cannizzaro (1826−1910) was born

in Palermo, Sicily, Italy. In 1847, he had to escape to Paris for participating in the Si-cilian Rebellion. Upon his return to Italy, he discovered benzyl alcohol synthesis by the action of potassium hydroxide on benzaldehyde. Political interests brought Can-nizzaro to the Italian Senate and he later became its vice president.

2. Geissman, T. A. Org. React. 1944, 1, 94−113. (Review). 3. Russell, A. E.; Miller, S. P.; Morken, J. P. J. Org. Chem. 2000, 65, 8381−8383. 4. Yoshizawa, K.; Toyota, S.; Toda, F. Tetrahedron Lett. 2001, 42, 7983−7985. 5. Reddy, B. V. S.; Srinvas, R.; Yadav, J. S.; Ramalingam, T. Synth. Commun. 2002, 32,

219−223. 6. Ishihara, K.; Yano, T. Org. Lett. 2004, 6, 1983−1986. 7. Curini, M.; Epifano, F.; Genovese, S.; Marcotullio, M. C.; Rosati, O. Org. Lett. 2005,

7, 1331−1333. 8. Basavaiah, D.; Sharada, D. S.; Veerendhar, A. Tetrahedron Lett. 2006, 47,

5771−5774. 9. Ruiz-Sanchez, A. J.; Vida, Y.; Suau, R.; Perez-Inestrosa, E. Tetrahedron 2008, 64,

11661−11665. 10. Yamabe, S.; Yamazaki, S. Org. Biomol. Chem. 2009, 7, 951−961.

95

Carroll rearrangement Thermal rearrangement of β-ketoesters followed by decarboxylation to yield γ-unsaturated ketones via anion-assisted Claisen rearrangement. It is a variant of the Claisen rearrangement (page 117).

O

O O OΔ

O

O O

O

O OH

O

O OH

Δ [3,3]-sigmatropic

rearrangement

O O

– CO2 α

βδ

γ

H

keto–enol

tautomerization

Example 1, Asymmetric Carroll rearrangement4,5

NN

OMe

O

ON

O

OLiOMe

LiN

N

OMe

CO2H

2.4 equiv LiTMP

toluene–100 °C to rt

de > 96%

Example 2, Hetero-Carroll rearrangement6

N

CH3

OH3C

OO

CH3

O 110 °Ctoluene

NH

CH3

H3C

O

O

CH3

N

CH3

H3C

O

CH3

O

OHO

82%

Example 37

H

H3C

HTESO

H3C

O

OS

OPh

OH NaH, xylenes, 140 °C, 82%H3C

HTESO

H3C

SO2PhTESO

H3C

H O

Me HSO2Ph

H

ONa

96


Example 4, Similar to Example 37

TESOH

O

O O2 eq. NaH, xylene

reflux, 96%

TESOH

O O

O

Carroll

rearrangement

TESOH

O

CO2H

CO2

TESOH

O

Example 58

O

OO

OMeMeO

LDA, THF

−78 oC to rt

CCl4

reflux, 86%

OMeMeO

Me

O

HO2C

OMeMeO

Me

O

References 1. (a) Carroll, M. F. J. Chem. Soc. 1940, 704−706. Michael F. Carroll worked at A.

Boake, Roberts and Co. Ltd., in London, UK. (b) Carroll, M. F. J. Chem. Soc. 1941, 507−511.

2. Ziegler, F. E. Chem. Rev. 1988, 88, 1423−1452. (Review). 3. Echavarren, A. M.; Mendosa, J.; Prados, P.; Zapata, A. Tetrahedron Lett. 1991, 32,

6421–6424. 4. Enders, D.; Knopp, M.; Runsink, J.; Raabe, G. Angew. Chem., Int. Ed. 1995, 34,

2278−2280. 5. Enders, D.; Knopp, M. Tetrahedron 1996, 52, 5805–5818. 6. Coates, R. M.; Said, I. M. J. Am. Chem. Soc. 1977, 99, 2355−2357. 7. Hatcher, M. A.; Posner, G. H. Tetrahedron Lett. 2002, 43, 5009−5012. 8. Jung, M. E.; Duclos, B. A. Tetrahedron Lett. 2004, 45, 107−109. 9. Defosseux, M.; Blanchard, N.; Meyer, C.; Cossy, J. J. Org. Chem. 2004, 69,

4626−4647. 10. Williams, D. R.; Nag, P. P. Claisen and Related Rearrangements. In Name Reactions


97

Castro–Stephens coupling Aryl–acetylene synthesis, Cf. Cadiot–Chodkiewicz coupling and Sonogashira coupling. The Castro–Stephens coupling uses stoichiometric copper, whereas the Sonogashira variant uses catalytic palladium and copper.

+CuR1

1: copper acetylide

pyridine, Δ

3: disubstituted alkyne

R1 R2

R2 = aryl, vinyl, X = I, Br

R2X

2: sp2 halideor:

DMF, base, Δ

R1 = alkyl or aryl

CuII

Cu

LL

L

CC

R1

Cu

IL

L

C C R1

R2

I

CCR1

R2

Cu

LL

I

CC

R1

R1 C C Cu

+ ligands (solvent)

R2

R2

An alternative mechanism similar to that of the Cadiot–Chodkiewicz coupling:

Ar X Cu Roxidative

additionAr

XCu R Ar R

reductive

eliminationCuX

Cu(III) intermediate

Example 1, A variant, also known as the Rosenmund–von Braun synthesis of aryl nitriles2

N N

OBr CuCN

1-methyl-2-pyrrolininone

170 oC, 3 h, 55% N N

ONC

Example 24

H

CuSO4, NH2OH•HClaq. NH3, EtOH

ca. 95%Cu

N

OH

I

N

O

pyridine, Δ75%

98


Example 35

N

N

OMeI

MeO

OO

Cu

pyridine, Δ

87% N

N

OMe

MeO

O

O

Example 48

O

I

Ocat. CuI, Ph3P, K2CO3

DMF, 120 oC, 37%

O

O

Example 5, In situ Castro–Stephens reaction10

MeO2C

O

MeO2C I

OH

MeO2C

OO

CO2Me

Cu2O, pyridine

100 oC, 43% References 1. (a) Castro, C. E.; Stephens, R. D. J. Org. Chem. 1963, 28, 2163. Castro and Stephens

worked in the Department of Nematology and Chemistry at University of California, Riverside. (b) Stephens, R. D.; Castro, C. E. J. Org. Chem. 1963, 28, 3313–3315.

2. Clark, R. L.; Pessolano, A. A.; Witzel, B.; Lanza, T.; Shen, T. Y.; Van Arman, C. G.; Risley, E. A. J. Med. Chem. 1978, 21, 1158–1162.

3. Staab, H. A.; Neunhoeffer, K. Synthesis 1974, 424. 4. Owsley, D.; Castro, C. Org. Synth. 1988, 52, 128–131. 5. Kundu, N. G.; Chaudhuri, L. N. J. Chem. Soc., Perkin Trans 1 1991, 1677–1682. 6. Kabbara, J.; Hoffmann, C.; Schinzer, D. Synthesis 1995, 299–302. 7. White, J. D.; Carter, R. G.; Sundermann, K. F.; Wartmann, M. J. Am. Chem. Soc.

2001, 123, 5407–5413. 8. Coleman, R. S.; Garg, R. Org. Lett. 2001, 3, 3487–3490. 9. Rawat, D. S.; Zaleski, J. M. Synth. Commun. 2002, 32, 1489–1494. 10. Bakunova, A.; Bakunov, S.; Wenzler, T.; Barszcz, T.; Werbovetz, K.; Brun, R.; Hall,

J.; Tidwell, R. J. Med. Chem. 2007, 50, 5807–5823. 11. Gray, D. L. Castro–Stephens coupling. In Name Reactions for Homologations-Part I;


99

Chan alkyne reduction Stereoselective reduction of acetylenic alcohols to E-allylic alcohols using sodium bis(2-methoxyethoxy)aluminum hydride (SMEAH, also known as Red-Al) or Li-AlH4.

R1R

OHNaAlH2(OCH2CH2OCH3)2 in PhH

Et2O, heat R R1

OH

R1R

OHAlH2R2

R1

R

OH2↑

AlRR

H

R1

OAl

RR

R

Hworkup

R R1

OH

Example 13

OHLiAlH4

77%

OH

Example 24

Ph

OH

CO2Me

1.5 eq. Red-Al, −72 oC, 25 min.

then 5 eq. I2, −72 to −10 oC, THF, 2 h78%

Ph

OH

CO2Me

I

Example 36

OH

OTBDPS

OHOTBDPS

Cl

1. Red-Al, THF/PhMe −78 oC to rt, 4 h

2. NCS, −78 oC to rt 65%

Example 47

OO

O

OMeOMeMeO

Me

BnOOH

Me

Red-Al, Et2O

0 oC, 80%

OO

O

OMeOMeMeO

Me

BnOOH

Me

100


References 1. Chan, K.-K.; Cohen, N.; De Noble, J. P.; Specian, A. C., Jr.; Saucy, G. J. Org. Chem.

1976, 41, 3497−3505. Ka-Kong Chan was a chemist at Hoffmann−La Roche, Inc. in Nutley, NJ, USA.

2. Blunt, J. W.; Hartshorn, M. P.; Munro, M. H. G.; Soong, L. T.; Thompson, R. S.; Vaughan, J. J. Chem. Soc., Chem. Commun. 1980, 820−821.

3. Midland, M. M.; Gabriel, J. J. Org. Chem. 1985, 50, 1143−1144. 4. Meta, C. T.; Koide, K. Org. Lett. 2004, 6, 1785−1787. 5. Yamazaki, T.; Ichige, T.; Kitazume, T. Org. Lett. 2004, 6, 4073−4076. 6. Xu, S.; Arimoto, H.; Uemura, D. Angew. Chem., Int. Ed. 2007, 46, 5746−5749. 7. Chakraborty, T. K.; Reddy, V. R.; Gajula, P. K. Tetrahedron 2008, 64, 5162−5167.

101

Chan–Lam C–X coupling reaction Arylation of a wide range of NH/OH/SH substrates by oxidative cross-coupling with boronic acids in the presence of catalytic cupric acetate and either triethyl-amine or pyridine at room temperature in air. The reaction works for amides, amines, anilines, azides, hydantoins, hydrazines, imides, imines, nitroso, pyrazi-nones, pyridones, purines, pyrimidines, sulfonamides, sulfinates, sulfoximines, ureas, alcohols, phenols, and thiols. It is also the mildest method for N/O-vinylation. The boronic acids can be replaced with siloxanes or stannanes. The mild condition of this reaction is an advantage over Buchwald–Hartwig’s Pd-catalyzed cross-coupling. The Chan–Lam C–X bond cross-coupling reaction is complementary to Suzuki–Miyaura’s C–C bond cross-coupling reaction.

M = B(OH)2, B(OR)2, B(OR)3−, BF3

−, SnMe3, Si(OMe)3.X = N, O, S, Se, Te.

Ar M H XRcat. Cu(AcO)2

airAr XR

N

NR

cat. Cu(AcO)2

air, > 90%

N

HNB(OH)2

R

Example 11a,d

NH

B(OH)2

Cu(OAc)2, pyridinert, 48 h, air

74%

H3C

N CH3

Mechanism:1c,d,17

NHCu(OAc)2, pyridine

coordination anddeprotonation

CuIIL L

N OAc

Ph

pyridinium acetate

B(OH)2H3C

transmetallation

CuIIL L

N

PhCH3

AcOB(OH)2+ [CuII]

– [CuI]

N CH3reductive

elimination

CuIIIL L

N

PhCH3

102


Example 24

OH B(OH)2

1.1 eq Cu(OAc)2, TEArt, 24 h, air

52%

O

Example 35

t-BuO2C NH

CO2Me

O

B(OH)2OMe

Cu(OAc)2TEA, air

54%

OH

t-BuO2C NH

CO2Me

OMe

O

O

Example 413

BnO

ONH

O

O N(HO)2B

Cu(OAc)2/Et3N/Py93% (α-ester assistance, acetal lower yield,e.g., dimethyl acetal, 23%)

BnO

ON

O

O

N

1eq/3 eq/ 3 eq4 Å MS, air

Example 514

NH

CO2Me

N

CO2MeB(OH)2

NaHMDS, Cu(AcO)2DMAP, air, 95 oC

93% Example 615

B(OH)2NH2

0.1 eq Cu2OMeOH, air, rt

92%NH4OH

References 1. (a) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Lett.

1998, 39, 2933–2936. (b) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Win-ters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941–2949. Dominic Chan is a chemist at DuPont Crop Protection, Wilmington, DE, USA. He did his PhD research with Prof. Barry Trost at the University of Wisconson, Madison. Pat-rick Lam is a research director at Bristol–Myers Squibb, Princeton, NJ, USA. He was formerly with DuPont Pharmaceuticals Company. He did his PhD research with Prof. Louis Friedrich at the Univeristy of Rochester and Postdoc research with Prof. Mi-

103

chael Jung and the late Prof. Donald Cram at UCLA. (c) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39, 2937–2940. Prof. Evans’ group found out about the discovery of this reaction on a National Organic Symposium poster and be-came interested in the O-arylation because of his long interest in vancomycin total synthesis. (d) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Averill, K. M.; Chan, D. M. T.; Combs, A. Synlett 2000, 674–676. (e) Lam, P. Y. S.; Bonne, D.; Vin-cent, G.; Clark, C. G.; Combs, A. P. Tetrahedron Lett. 2003, 44, 1691–1694.

2. Reviews: (a) Chan, D. M. T.; Lam, P. Y. S., Book chapter in Boronic Acids Hall, ed. 2005, Wiley–VCH, 205–240. (b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400–5449.

3. Catalytic copper: (a) Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P. K. Tetrahedron Lett. 2001, 42, 3415–3418. (b) Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077–2079. (c) Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 4397–4400. (d) Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233–1236. (e) Lan, J.-B.; Zhang, G.-L.; Yu, X.-Q.; You, J.-S.; Chen, L.; Yan, M.; Xie, R.-G. Synlett 2004, 1095–1097.

4. Vinyl boronic acids: Lam, P. Y. S.; Vincent, G.; Bonne, D.; Clark, C. G. Tetrahedron Lett. 2003, 44, 4927–4931.

5. Intramolecular: Decicco, C. P.; Song, Y.; Evans, D.A. Org. Lett. 2001, 3, 1029–1032. 6. Solid phase: (a) Combs, A. P.; Saubern, S.; Rafalski, M.; Lam, P. Y. S. Tetrahedron

Lett. 1999, 40, 1623–1626. (b) Combs, A. P.; Tadesse, S.; Rafalski, M.; Haque, T. S.; Lam, P. Y. S. J. Comb. Chem. 2002, 4, 179–182.

7. Boronates/borates: (a) Chan, D. M. T.; Monaco, K. L.; Li, R.; Bonne, D.; Clark, C. G.; Lam, P. Y. S. Tetrahedron Lett. 2003, 44, 3863–3865. (b) Yu, X. Q.; Yamamoto, Y.; Miyuara, N. Chem. Asian J. 2008, 3, 1517–1522.

8. Siloxanes: (a) Lam, P. Y. S.; Deudon, S.; Averill, K. M.; Li, R.; He, M. Y.; DeShong, P.; Clark, C. G. J. Am. Chem. Soc. 2000, 122, 7600–7601. (b) Lam, P. Y. S.; Deudon, S.; Hauptman, E.; Clark, C. G. Tetrahedron Lett. 2001, 42, 2427–2429.

9. Stannanes: Lam, P. Y. S.; Vincent, G.; Bonne, D.; Clark, C. G. Tetrahedron Lett. 2002, 43, 3091–3094.

10. Thiols: (a) Herradura, P. S.; Pendola, K. A.; Guy, R. K. Org. Lett. 2000, 2, 2019–2022. (b) Savarin, C.; Srogl, J.; Liebeskind, L. S. . Org. Lett. 2002, 4, 4309–4312.

11. Sulfinates: (a) Beaulieu, C.; Guay. D.; Wang, C.; Evans, D. A. Tetrahedron Lett. 2004, 45, 3233–3236. (b) Huang, H.; Batey, R. A. Tetrahedron. 2007, 63, 7667–7672. (c) Kar, A.; Sayyed, L. A.; Lo, W. F.; Kaiser, H. M.; Beller, M.; Tse, M. K. Org. Lett. 2007, 9, 3405–3408.

12. Sulfoximines: Moessner, C.; Bolm, C. Org. Lett. 2005, 7, 2667–2669. 13. β-Lactam: Wang, W.; Devsathale, P.; et al. Bio. Med. Chem. Lett. 2008, 18, 1939–

1944. 14. Cyclopropyl boronic acid: Tsuritani, T.; Strotman, N. A.; Yamamoto, Y.; Kawasaki,

M.; Yasuda, N.; Mase, T. Org. Lett. 2008, 10, 1653–1655. 15. Ammonia: Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. Ang. Chem., Int. Ed. 2009, 48, 1114–

1116. 16. Alcohol: Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 1381–1384. 17. Mechanism: (a) Huffman, L. M.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 9196–

9197. (b) King, A. E.; Brunold, T. C.; Stahl, S. S. J. Am. Chem. Soc. 2009, 131, 5044–5045

104

Chapman rearrangement Thermal aryl rearrangement of O-aryliminoethers to amides.

Ar OPh

NAr1 Δ

Ar NAr1

O

Ph

Ar O

N:Ar1

Ar NAr1

O

Ph

NO

Ar1

Ar

SNAr

oxazete intermediate

Example 12

ClMeO2C

NaO

MeO

N Ph

ClNaOEt, EtOH/Et2O

0 oC to rt, 48 hMeO

N Ph

O

MeO2CCl

210−215 oC, 70 min

28% for 2 steps

MeO

N

PhO

ClMeO2C

MeO

NH

ClHO2C

Example 24

Ph

O

N

Ph

Ph

300 oC

30 min., 87%

PhN

Ph

Ph O

105


Example 3, Double Chapman rearrangement10

OO

MeO2C CO2MeNMe2

N

Me2N

N

C12H25 C12H25

110−140 oC

70−74%

MeO2C CO2Me

NN

C12H25 C12H25

O

NMe2

O

Me2N

Example 4, Chapman-like thermal rearrangement11

SN

OR

OO

Δ

SNR

O

OO

References 1. Chapman, A. W. J. Chem. Soc. 1925, 127, 1992−1998. Arthur William Chapman was

born in 1898 in London, England. He was a Lecturer in Organic Chemistry and later became Registrar of the University of Sheffield from 1944 to 1963.

2. Dauben, W. G.; Hodgson, R. L. J. Am. Chem. Soc. 1950, 72, 3479−3480. 3. Schulenberg, J. W.; Archer, S. Org. React. 1965, 14, 1−51. (Review). 4. Relles, H. M. J. Org. Chem. 1968, 33, 2245−2253. 5. Shawali, A. S.; Hassaneen, H. M. Tetrahedron 1972, 28, 5903−5909. 6. Kimura, M.; Okabayashi, I.; Isogai, K. J. Heterocycl. Chem. 1988, 25, 315−320. 7. Farouz, F.; Miller, M. J. Tetrahedron Lett. 1991, 32, 3305−3308. 8. Dessolin, M.; Eisenstein, O.; Golfier, M.; Prange, T.; Sautet, P. J. Chem. Soc., Chem.

Commun. 1992, 132−134. 9. Shohda, K.-I.; Wada, T.; Sekine, M. Nucleosides Nucleotides 1998, 17, 2199−2210. 10. Marsh, A.; Nolen, E. G.; Gardinier, K. M.; Lehn, J. M. Tetrahedron Lett. 1994, 35,

397−400. 11. Almeida, R.; Gomez-Zavaglia, A.; Kaczor, A.; Cristiano, M. L. S.; Eusebio, M. E. S.;

Maria, T. M. R.; Fausto, R. Tetrahedron 2008, 64, 3296−3305.

106

Chichibabin pyridine synthesis Condensation of aldehydes with ammonia to afford pyridines.

3 R CHO NH3N

RR

R

H3N:

RO

HR

NH2

H

H3N:

ROH

NH2

HR

NH

H

enamine imine

:NH3

RO

H

RO

H

HR

O

H

Aldol

condensation

RO

H

RH

OH

H− H2O R

O

H

R

HN

R

:

Michael

addition

RO

RN

RH

RH

O

RN

R: N

RR

R

OHH

H

H3N H

H

N

RR

R

OHH

HN

RR

R

H

H

autoxidation

[O] N

RR

R

Example 14

CHOO

NH4OAc, HOAc

reflux, 1 h, 68%N

107


Example 28

N

HO

MeTroc

CH2 CHO N

1. AcOH, rt, 1 d, 49%

2. Zn, HCl, MeOH, 65 oC, 72%

N

HO

MeTroc

CH2N

Cl10

CH210

N

HO

MeTroc

Example 39

OO2NO

CF3OHCCH3CO2NH4, MeOH

reflux, 4 h, 45%

OO2NN

O NO2

CF3

Example 4, An abnormal Chichibabin reaction10

H

OBr 1 equiv BnNH3Cl

0.5 equiv Yb(OTf)3

H2O/dioxane, rt, 65%

N

ArAr

ArBn

N

Ar Ar

Bn

dehydration

6πN

Ar Ar

Bn Ar

[O]benzaldehyde

TfO

References 1. Chichibabin, A. E. J. Russ. Phys. Chem. Soc. 1906, 37, 1229. Alexei E. Chichibabin

(1871−1945) was born in Kuzemino, Russia. He was Markovnikov’s favorite student. Markovnikov’s successor, Zelinsky (of Hell–Volhard–Zelinsky reaction fame) did not

108

want to cooperate with the pupil and gave Chichibabin a negative judgment on his Ph.D. work, earning Chichibabin the nickname “the self-educated man.”

2. Sprung, M. M. Chem. Rev. 1940, 40, 297−338. (Review). 3. Frank, R. L.; Riener, E. F. J. Am. Chem. Soc. 1950, 72, 4182−4183. 4. Weiss, M. J. Am. Chem. Soc. 1952, 74, 200−202. 5. Kessar, S. V.; Nadir, U. K.; Singh, M. Indian J. Chem. 1973, 11, 825−826. 6. Shimizu, S.; Abe, N.; Iguchi, A.; Dohba, M.; Sato, H.; Hirose, K.-I. Microporous

Mesoporous Materials 1998, 21, 447−451. 7. Galatasis, P. Chichibabin (Tschitschibabin) Pyridine Synthesis. In Name Reactions in

Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 308−309. (Review).

8. Snider, B. B.; Neubert, B. J. Org. Lett. 2005, 7, 2715−2718. 9. Wang, X.-L.; Li, Y.-F.; Gong, C.-L.; Ma, T.; Yang, F.-C. J. Fluorine Chem. 2008,

129, 56−63. 10. Burns, N. Z.; Baran, P. S. Angew. Chem., Int. Ed. 2008, 47, 205−208. 11. Liaw, D.-J.; Wang, K.-L.; Kang, E.-T.; Pujari, S. Pu.; Chen, M.-H.; Huang, Y.-C.;

Tao, B.-C.; Lee, K.-R.; Lai, J.-Y. J. Polymer Sci., A: Polymer Chem. 2009, 47, 991−1002.

109

Chugaev elimination Thermal elimination of xanthates to olefins.

ROH R

O S

S

1. CS2, NaOH

2. CH3I

ΔR OCS CH3SH

xanthate

RO S

S

Δ HS

O

S

R

CH3SH↑R SO

SC S↑O

H

Example 14

OH

OH OH

1. NaH, CS2; MeI, 90%

2. HMPA, 230 oC, 90%

Example 25

OOHO

H

O

OHH

CS2, MeI, NaH

THF, rt, 2 h, 51%

OOO

H

O

OHH

S

S

dodecane

reflux (216 oC)48 h, 74%

OO

H

O

OHH

Example 3, Chugaev syn-elimination is followed by an intramolecular ene reac-tion6

O

O N

OH

Cbz

CS2, MeI, NaH

THF, 92%

O

O N

O

Cbz

S

S

110


NaHCO3, Ph2O

280 oC, 25 minChugaev

NCbz

OOH N

CbzO

O72%

Alder ene

References 1. Chugaev, L. Ber. 1899, 32, 3332. Lev A. Chugaev (1873−1922) was born in Moscow,

Russia. He was a Professor of Chemistry at Petrograd, a position once held by Dimitri Mendeleyev and Paul Walden. In addition to terpenoids, Chugaev also investigated nickel and platinum chemistry. He completely devoted his life to science. The light in Chugaev’s study would invariably burn until 4 or 5 a.m.

2. Harano, K.; Taguchi, T. Chem. Pharm. Bull. 1975, 23, 467−472. 3. Ho, T.-L.; Liu, S.-H. J. Chem. Soc., Perkin Trans. 1 1984, 615−617. 4. Fu, X.; Cook, J. M. Tetrahedron Lett. 1990, 31, 3409−3412. 5. Meulemans, T. M.; Stork, G. A.; Macaev, F. Z.; Jansen, B. J. M.; de Groot, A. J. Org.

Chem. 1999, 64, 9178−9188. 6. Nakagawa, H.; Sugahara, T.; Ogasawara, K. Org. Lett. 2000, 2, 3181−3183. 7. Nakagawa, H.; Sugahara, T.; Ogasawara, K. Tetrahedron Lett. 2001, 42, 4523−4526. 8. Fuchter, M. J. Chugaev elimination. In Name Reactions for Functional Group Trans-

formations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 334−342. (Review).

9. Ahmed, S.; Baker, L. A.; Grainger, R. S.; Innocenti, P.; Quevedo, C. E. J. Org. Chem. 2008, 73, 8116−8119.

111

Ciamician–Dennsted rearrangement Cyclopropanation of a pyrrole with dichlorocarbene generated from CHCl3 and NaOH. Subsequent rearrangement takes place to give 3-chloropyridine.

NH N

ClCHCl3

NaOH

Cl3C HOH

CCl2H2OCl

− Cl:CCl2

carbene

NH N

ClCCl2 NCl

Cl

H

HO Example 14

N

Cl2 eq. PhHgCCl3

PhH, Δ, 54%N

H Example 25

NH

NH

HNHN

N

N

N

N

Cla Clb

Cla

Clb

ClaClb

Cla

Clb

NaO2CCl3

26%

References 1. Ciamician, G. L.; Dennsted, M. Ber. 1881, 14, 1153. Giacomo Luigi Ciamician

(1857−1922) was born in Trieste, Italy. Ciamician is considered the father of modern organic photochemistry.

2. Wynberg, H. Chem. Rev. 1960, 60, 169−184. (Review). 3. Wynberg, H. and Meijer, E. W. Org. React. 1982, 28, 1−36. (Review). 4. Parham, W. E.; Davenport, R. W.; Biasotti, J. B. J. Org. Chem. 1970, 35, 3775−3779. 5. Král, V.; Gale, P. A.; Anzenbacher, P. Jr.; K. Jursíková; Lynch, V.; Sessler, J. L. J.

Chem. Soc., Chem. Comm. 1998, 9−10. 6. Pflum, D. A. Ciamician–Dennsted Rearrangement. In Name Reactions in Heterocyclic


112


Claisen condensation Base-catalyzed condensation of esters to afford β-keto esters.

OR1

OR

base OR1

O

RR2R2 OR3

OO

OR3R2

O

OR1

OR

OR1

OR

H

B:

deprotonation condensation

OR1

O

RR3O

OR2

OR1

O

RR2

O

Example 14

O Ph

O t-BuOK, solvent-free

90 oC, 20 min., 84%O Ph

OPh

O

Ph

Ph

Example 26

CbzHN CO2Me

PhO

t-BuO

CbzHN

Ph

O

O

Ot-Bu

3.5 eq. LDA, THF −45 to −50 oC

then H+, 97%

Example 3, Retro-Claisen condensation9

O O5 equiv H2O

5 mol% In(OTf)3

neat, 80 oC, 24 h85%

OH

O O

O OIn HH2O:

O OHO

In

113


Example 4, Solvent-free Claisen condensation10

OBn

O= 13CKOt-Bu, 100 oC, 30 min.

solvent-free, 51%

O

OBn

O

References 1 Claisen, R. L.; Lowman, O. Ber. 1887, 20, 651. Rainer Ludwig Claisen (1851−1930),

born in Cologne, Germany, probably had the best pedigree in the history of organic chemistry. He apprenticed under Kekulé, Wöhler, von Baeyer, and Fischer before embarking on his own independent research.

2 Hauser, C. R.; Hudson, B. E. Org. React. 1942, 1, 266−302. (Review). 3 Schäfer, J. P.; Bloomfield, J. J. Org. React. 1967, 15, 1−203. (Review). 4 Yoshizawa, K.; Toyota, S.; Toda, F. Tetrahedron Lett. 2001, 42, 7983−7985. 5 Heath, R. J.; Rock, C. O. Nat. Prod. Rep. 2002, 19, 581−596. (Review). 6 Honda, Y.; Katayama, S.; Kojima, M.; Suzuki, T.; Izawa, K. Org. Lett. 2002, 4,

447−449. 7 Mogilaiah, K.; Reddy, N. V. Synth. Commun. 2003, 33, 73−78. 8 Linderberg, M. T.; Moge, M.; Sivadasan, S. Org. Pro. Res. Dev. 2004, 8, 838−845. 9 Kawata, A.; Takata, K.; Kuninobu, Y.; Takai, K. Angew. Chem., Int. Ed. 2007, 46,

7793−7795. 10 Iida, K.; Ohtaka, K.; Komatsu, T.; Makino, T.; Kajiwara, M. J. Labelled Compd. Ra-

diopharm. 2008, 51, 167−169.

114

Claisen isoxazole synthesis Cyclization of β-keto esters with hydroxylamine to provide 3-hydroxy-isoxazoles (3-isoxazolols).

O O

R1R2

OR

ON

R2 OH

R1

NH2OH

− H2O

O O

R1R2

OR

:NH2OH

O O

R1R2

NH

OH

O

R1R2

NH

OHORO

ON

R2 OH

R1ONH

R2 O

R1

HO ONH

R2 O

R1

− H2O

3-isoxazolol

A side reaction:

HON O

R1R2

OR

OHO O

R1R2

OR NH2OH

:NH2OH

H

− H2O:

N O

R1R2

OR

ON

R2

R1 O

O:H

ON

R1

R2

ORO H

5-isoxazolone

Example 1, A thio-analog6

SH O

NH2NMeO

O

1. aqueous NH3, 67%

2. H2S, HCl, EtOH, 53%

O O

OEtNMeO

O

115


SN

R OH

I2, K2CO3, 59%

NMeO

O Example 27

O

OO

O

HO

RO

OO

O53−91%

HN OBoc

Boc

O

ClR , pyr., 0 oC

74−100%For R = Ph:(PhCO)2O, DMF

Meldrum’s acid

O O

R NO

N

OH

ROBoc

Boc

HCl

76−99%

R = Me, Et, i-Pr, cyclopropyl,cyclohexyl, Ph, Bn, neopentyl

Example 38

O O

OMe

ON

OHNH2OH•HCl, NaOH

MeOH, −50 oC, 2 hthen 85 oC, 1 h, 65%

References 1. (a) Claisen, L; Lowman, O. E. Ber. 1888, 21, 784. (b) Claisen, L.; Zedel, W. Ber.

1891, 24, 140. (c) Hantzsch, A. Ber. 1891, 24, 495−506. 2. Barnes, R. A. In Heterocyclic Compounds; Elderfield, R. C., Ed.; Wiley: New York,

1957; Vol. 5, p 474ff. (Review). 3. Loudon, J. D. In Chemistry of Carbon Compounds; Rodd, E. H., Ed.; Elsevier: Am-

sterdam, 1957; Vol. 4a, p. 345ff. (Review). 4. McNab, H. Chem. Soc. Rev. 1978, 7, 345−358. (Review). 5. Chen, B.-C. Heterocycles 1991, 32, 529−597. (Review). 6. Frølund, B.; Kristiansen, U.; Brehm, L.; Hansen, A. B.; Krogsgaard-Larsen, K.; Falch,

E. J. Med. Chem. 1995, 38, 3287−3296. 7. Sorensen, U. S.; Falch, E.; Krogsgaard-Larsen, K. J. Org. Chem. 2000, 65,

1003−1007. 8. Madsen, U.; Bräuner-Osborne, H.; Frydenvang, K.; Hvene, L.; Johansen, T.N.; Niel-

sen, B.; Sánchez, C.; Stensbøl, T.B.; Bischoff, F.; Krogsgaard-Larsen, K. J. Med. Chem. 2001, 44, 1051−1059.

9. Brooks, D. A. Claisen Isoxazole Synthesis. In Name Reactions in Heterocyclic Chem-istry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 220−224. (Review).

116

Claisen rearrangements The Claisen, para-Claisen rearrangements, Belluš–Claisen rearrangement; Corey–Claisen, Eschenmoser–Claisen rearrangement, Ireland–Claisen, Kazmaier–Claisen, Saucy–Claisen; orthoester Johnson–Claisen, along with the Carroll rear-rangement, belong to the category of [3,3]-sigmatropic rearrangements. The Claisen rearrangement is a concerted process and the arrow pushing here is merely illustrative.

O

R

O

R

O

RΔ, [3,3]-sigmatropic

rearrangement

1 23

1 23

1 23

1 23

π2S

π2S

σ2S3

4

σ2S

π2S

π2S 4

O O O1 1 12

45

6

2 2

4 45

66

5

3

chair-like boat-like

Example 17

O

BnO

BnO O

BnO

BnOO

O O

n-decane/toluene 5:1

180 oC, 70%

O

OBn

BnOO

OBnBnO

O

O

O

Example 28

O

O

Et2AlCl, hexanes

−78 oC, 81%

O

OH

Example 39

O

Et Ph

SiMe3OHC

Et Ph

SiMe31 mol% Ir(PCy3)3

+

PPh3, Δ, 50% yieldsyn:anti 95:85, 91% ee

117


Example 4, Asymmetric Claisen rearrangement10

MeO CH3

O

O

OBn

N N

OO

t-Bu t-BuCu

H2O OH2

2+

2 SbF6−

CH2Cl2, rt, 12 hOMe

CH3

O

O

BnO

98%, > 90% de, 99% eecat. =

CF3CH2OHcat, 7.5 mol%

Example 5, Asymmetric Claisen rearrangement11

MeO CH3

O

O

H3C

MeO

O

O

CH3 CH3

73%, 96% eeNH

NH

NH2

N NPh PhB

CF3

CF3

4

–

20 mol%, hexane, 8 days, 35 °C

References 1. Claisen, L. Ber. 1912, 45, 3157−3166. 2. Rhoads, S. J.; Raulins, N. R. Org. React. 1975, 22, 1−252. (Review). 3. Wipf, P. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Perga-

mon, 1991, Vol. 5, 827−873. (Review). 4. Ganem, B. Angew. Chem., Int. Ed. 1996, 35, 937−945. (Review). 5. Ito, H.; Taguchi, T. Chem. Soc. Rev. 1999, 28, 43−50. (Review). 6. Castro, A. M. M. Chem. Rev. 2004, 104, 2939−3002. (Review). 7. Jürs, S.; Thiem, J. Tetrahedron: Asymmetry 2005, 16, 1631−1638. 8. Vyvyan, J. R.; Oaksmith, J. M.; Parks, B. W.; Peterson, E. M. Tetrahedron Lett. 2005,

46, 2457−2460. 9. Nelson, S. G.; Wang, K. J. Am. Chem. Soc. 2006, 128, 4232–4233. 10. Körner, M.; Hiersemann, M. Org. Lett. 2007, 9, 4979–4982. 11. Uyeda, C.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 9228–9229. 12. Williams, D. R.; Nag, P. P. Claisen and Related Rearrangements. In Name Reactions


118

para-Claisen rearrangement Further rearrangement of the normal ortho-Claisen rearrangement product gives the para-Claisen rearrangement product.

ORR

OHRR

Δ

Mechanism 1:

ORR

OHRR

ortho-

Claisen

ORR

dienone

Cope

rearrangement

Mechanism 2:

ORR

OHRR

ORR

Dewar intermediate

H2C CH2

Mechanism 3:

ORR

OHRRO

RR[3,3]-sigmatropic

rearrangement

ORR

H

119

Example 16

OHO CHO

160−170 oC

OHHO CHO

58%

OHHO

25.5%CHO

OHHO CHO

4.6%

Example 27

HO O

MeMe

CO2Me

PhNEt2

reflux O OHO

Me

Me

80%O OHO

12%

Me

Me

Example 38

O

OTBSO220 oC

xylene, 70%O

O

OTBSO

OH Example 410

OO

MOMO OMOMPhNMe2, reflux

200 oC, 64%

OOH

MOMO OMOM

References 1. Alexander, E. R.; Kluiber, R. W. J. Am. Chem. Soc. 1951, 73, 4304–4306. 2. Rhoads, S. J.; Raulins, R.; Reynolds, R. D. J. Am. Chem. Soc. 1953, 75, 2531–2532. 3. Dyer, A.; Jefferson, A.; Scheinmann, F. J. Org. Chem. 1968, 33, 1259–1261. 4. Murray, R. D. H.; Lawrie, K. W. M. Tetrahedron 1979, 35, 697–699. 5. Cairns, N.; Harwood, L. M.; Astles, D. P. J. Chem. Soc., Chem. Commun. 1986, 1264–

1266. 6. Kilényi, S. N.; Mahaux, J.-M.; van Durme, E. J. Org. Chem. 1991, 56, 2591–2594. 7. Cairns, N.; Harwood, L. M.; Astles, D. P. J. Chem. Soc., Perkin Trans. 1 1994, 3101–

3107. 8. Pettus, T. R. R.; Inoue, M.; Chen, X.-T.; Danishefsky, S. J. J. Am. Chem. Soc. 2000,

122, 6160–6168. 9. Al-Maharik, N.; Botting, N. P. Tetrahedron 2003, 59, 4177–4181. 10. Khupse, R. S.; Erhardt, P. W. J. Nat. Prod. 2007, 70, 1507–1509.

120

Abnormal Claisen rearrangement Further rearrangement of the normal Claisen rearrangement product with the β-carbon becoming attached to the ring.

OHα

β δ

α

β δ

O

δ

αβ

Δ

O [3,3]-sigmatropicrearrangement

"normal Claisen"

O

H

tautomerization δ

αβ

δ

βα

OHOH

OH

ene

reaction

[1,5]-H-atom

shift δ

βα

δ α

βα

β δ

Example 13

O

Me

PhNEt2, 230 oC

5.5 h, 63%

OH

Menormal, 58%

OH

Meabnormal, 42%

O

Me

10 equiv HSi(NMe2)2PhNEt2, 230 oC

8.0 h, 70%

OH

Menormal, > 99%

OH

Meabnormal, < 1%

Example 2, Enantioselective aromatic Claisen rearrangement4

OHO

Et3N, −23 oC, 2 d 92%, 95% ee

OHOH

NB

N

Ph Ph

Br

SO2

SO2

121

Example 35

OMeMeO

O

CHOMeOPhNEt2

180 oC40%

OMeO

MeO

CHO

OMe

kodsurenin M Example 46

OO

O

Tol., 180 oC

24 h, 65%

OO

O

= 13C

Example 57

OAlM3, CH2Cl2

OH

OH50% 50%

References 1. Hansen, H.-J. In Mechanisms of Molecular Migrations; vol. 3, Thyagarajan, B.

S., ed.; Wiley-Interscience: New York, 1971, pp 177−236. (Review). 2. Kilényi, S. N.; Mahaux, J.-M.; van Durme, E. J. Org. Chem. 1991, 56,

2591−2594. 3. Fukuyama, T.; Li, T.; Peng, G. Tetrahedron Lett. 1994, 35, 2145−2148. 4. Ito, H.; Sato, A.; Taguchi, T. Tetrahedron Lett. 1997, 38, 4815−4818. 5. Yi, W. M.; Xin, W. A.; Fu, P. X. J. Chem. Soc., (S), 1998, 168. 6. Schobert, R.; Siegfried, S.; Gordon, G.; Mulholland, D.; Nieuwenhuyzen, M. Tet-

rahedron Lett. 2001, 42, 4561−4564. 7. Wipf, P.; Rodriguez, S. Ad. Synth. Catal. 2002, 344, 434−440. 8. Puranik, R.; Rao, Y. J.; Krupadanam, G. L. D. Indian J. Chem., Sect. B 2002,

41B, 868−870. 9. Williams, D. R.; Nag, P. P. Claisen and Related Rearrangements. In Name Reac-

tions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Ho-boken, NJ, 2009, pp 33−87. (Review).

122

Eschenmoser–Claisen amide acetal rearrangement [3,3]-Sigmatropic rearrangement of N,O-ketene acetals to yield γ,δ-unsaturated amides. Since Eschenmoser was inspired by Meerwein’s observations on the interchange of amide, the Eschenmoser–Claisen rearrangement is sometimes known as the Meerwein–Eschenmoser–Claisen rearrangement.

NMe2

OMeMeO

R R1

OH

R R1

CONMe2Δ

NMe2

OMeMeO

NMe2

OMeOMe

:

R R1

O:

R R1

OH

OMeMe2NH

R R1

OH

NMe2: OMeH NMe2

OMe

R R1

O

NMe2

R R1

[3,3]-sigmatropic

rearrangement

CONMe2

Example 14

O PhF3C

OH

CH3C(OMe)2NMe2

PhH, 100 oC, 2 h, 75%O

NMe2Ph

CF3 O

Example 25

O

H3C CH3

N

HH

OLi

CH3

O

N

CH3

CH3

OMe CH3

CH3

*ArHN

O

LiNEt2, THF

–78 °C to rt5 h, 78 %

(dr 97:3)

123

Example 36

HO

H OTBS

O

OTBS

TBS

H OTBS

O

OTBS

TBS

HH

NMe2

O

NMe2

MeO OMe

xylene, 150 °C18 h, 91%

OPMB OPMB

Example 48

HO CO2Me

5 eq. CH3C(OMe)2NMe2

xylene, reflux, 48 h, 50%

CO2Me

NMe2

O

References 1. Meerwein, H.; Florian, W.; Schön, N.; Stopp, G. Ann. 1961, 641, 1−39. 2. Wick, A. E.; Felix, D.; Steen, K.; Eschenmoser, A. Helv. Chim. Acta 1964, 47,

2425−2429. Albert Eschenmoser (Switzerland, 1925−) is known for his work on, among many others, the monumental total synthesis of Vitamin B12 with R. B. Wood-ward in 1973. He now holds dual appointments at both ETH Zürich and the Scripps Research Institute in La Jolla, CA.

3. Wipf, P. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Perga-mon, 1991, Vol. 5, 827−873. (Review).

4. Konno, T.; Nakano, H.; Kitazume, T. J. Fluorine Chem. 1997, 86, 81−87. 5. Metz, P.; Hungerhoff, B. J. Org. Chem.1997, 62, 4442–4448. 6. Kwon, O. Y.; Su, D. S.; Meng, D. F.; Deng, W.; D’Amico, D. C.; Danishefsky, S. J.

Angew. Chem., Int. Ed. 1998, 37, 1877–1880. 7. Ito, H.; Taguchi, T. Chem. Soc. Rev. 1999, 28, 43−50. (Review). 8. Loh, T.-P.; Hu, Q.-Y. Org. Lett. 2001, 3, 279−281. 9. Castro, A. M. M. Chem. Rev. 2004, 104, 2939−3002. (Review). 10. Williams, D. R.; Nag, P. P. Claisen and Related Rearrangements. In Name Reactions


124

Ireland–Claisen (silyl ketene acetal) rearrangement Rearrangement of allyl trimethylsilyl ketene acetal, prepared by reaction of allylic ester enolates with trimethylsilyl chloride, to yield γ,δ-unsaturated carboxylic acids. The Ireland–Claisen rearrangement seems to be advantageous to the other variants of the Claisen rearrangement in terms of E/Z geometry control and mild conditions.

O

OLDA, then

Me3SiCl

CO2H

O

OLDA, then

Me3SiClO

OSiMe3

O

OSiMe3H CO2HΔ, [3,3]-sigmatropic

rearrangement

Example 12

O

O

OO

SS SS

OO

CO2TBS

S

SH O

HOTBSH

OO

LDA, TBSCl

THF, reflux77%

Example 23

O

N

O

Bn

TIPSOTf, Et3N

PhH, rt, 62%NBn

CO2TIPS

Example 3, Enantioselective ester enolate-Claisen Rearrangement6

O

CH3

O

H3C

CO2H

H3CNB

N

PhPh

Br

SO2

SO2

CF3

CF3

F3C

F3C

pentaisopropylguanidine, –94 to 4 °C86%, dr > 98:2, > 98% ee

110 mol%

125

Example 4, A modified Ireland–Claisen rearrangement8

O

F

FO

F

HOF

F

O

F

BBr3, Et3N, PhMechiral ligand

−78 to rt, 63%, > 99% ee

Example 59

O

OO

OPMP

KHMDS, TMSCl, THF

−78 to 25 oC, 1 h, 81% O

CO2HPMPO

References 1. Ireland, R. E.; Mueller, R. H. J. Am. Chem. Soc. 1972, 94, 5897−5898. Also J. Am.

Chem. Soc. 1976, 98, 2868−2877. Robert E. Ireland obtained his Ph.D. from William S. Johnson before becoming a professor at the University of Virginia and later at the California Institute of Technology. He is now retired.

2. Begley, M. J.; Cameron, A. G.; Knight, D. W. J. Chem. Soc., Perkin Trans. 1 1986, 1933–1938.

3. Angle, S. R.; Breitenbucher, J. G. Tetrahedron Lett. 1993, 34, 3985−3988. 4. Pereira, S.; Srebnik, M. Aldrichimica Acta 1993, 26, 17−29. (Review). 5. Ganem, B. Angew. Chem., Int. Ed. 1996, 35, 936−945. (Review). 6. Corey, E.; Kania, R. S. J. Am. Chem. Soc. 1996, 118, 1229−1230. 7. Chai, Y.; Hong, S.-p.; Lindsay, H. A.; McFarland, C.; McIntosh, M. C. Tetrahedron

2002, 58, 2905−2928. (Review). 8. Churcher, I.; Williams, S.; Kerrad, S.; Harrison, T.; Castro, J. L.; Shearman, M. S.;

Lewis, H. D.; Clarke, E. E.; Wrigley, J. D. J.; Beher, D.; Tang, Y. S.; Liu, W. J. Med. Chem. 2003, 46, 2275−2278.

9. Fujiwara, K.; Goto, A.; Sato, D.; Kawai, H.; Suzuki, T. Tetrahedron Lett. 2005, 46, 3465−3468.

10. Williams, D. R.; Nag, P. P. Claisen and Related Rearrangements. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 45−51. (Review).

126

Johnson–Claisen orthoester rearrangement Heating of an allylic alcohol with an excess of trialkyl orthoacetate in the presence of trace amounts of a weak acid gives a mixed orthoester. Mechanistically, the or-thoester loses alcohol to generate the ketene acetal, which undergoes [3,3]-sigmatropic rearrangement to give a γ,δ-unsaturated ester.

R R1

OH CH(OR2)3

H+ R R1

CO2R2

R R1

OH CH(OR2)3

H+

R R1

OH

OR2R2OH

R R1

OH

OR2:B:

R R1

O

OR2

[3,3]-sigmatropic

rearrangement R R1

CO2R2

Example 12

OH

CH3

CO2Et

OOEt

H

H3C

CH3C(OEt)3EtCO2H (cat.)

xylene, Δ, 3 h 72%

Example 23

TBSO

THPO

H

OPh

HO

THPO

TBSO

THPO

OPhTHPO

•H

CO2EtMeCO2H (cat.)CH3C(OEt)3

170 °C, 30 min 77%

Example 34

ClOH

ClOTBS

CH3C(OCH3)3, TsOH

170 oC, 55%OMe

Cl

OTBS

ClO

127

Example 49

N

OMe

OH

CH3C(OCH3)3cat. CH3CH2CO2H

reflux, 77%

N

OMe

OMe

O

Example 510

O

OOTBS

OOO

OHH

(EtO)3CCH3

pivalic acidxylene, 140 °C

54%, E:Z > 95:5

O

TBSOOTBS

OOO

OHH

EtO2C

E

TBSOH

References 1. Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.; Li, T.-t.; Faulkner,

D. J.; Peterson, M. R. J. Am. Chem. Soc. 1970, 92, 741–743. William S. Johnson (1913−1995) was born in New Rochelle, New York. He earned his Ph.D. in only two years at Harvard under Louis Fieser. He was a professor at the University of Wiscon-sin for 20 years before moving to Stanford University, where he was credited with building the modern-day Stanford Chemistry Department.

2. Paquette, L.; Ham, W. H. J. Am. Chem. Soc. 1987, 109, 3025–3036. 3. Cooper, G. F.; Wren, D. L.; Jackson, D. Y.; Beard, C. C.; Galeazzi, E.; Van Horn, A.

R.; Li, T. T. J. Org. Chem. 1993, 58, 4280–4286. 4. Schlama, T.; Baati, R.; Gouverneur, V.; Valleix, A.; Falck, J. R.; Mioskowski, C.

Angew. Chem., Int. Ed. 1998, 37, 2085–2087. 5. Giardiná, A.; Marcantoni, E.; Mecozzi, T.; Petrini, M. Eur. J. Org. Chem. 2001, 713–

718. 6. Funabiki, K.; Hara, N.; Nagamori, M.; Shibata, K.; Matsui, M. J. Fluorine Chem.

2003, 122, 237–242. 7. Montero, A.; Mann, E.; Herradón, B. Eur. J. Org. Chem. 2004, 3063–3073. 8. Scaglione, J. B.; Rath, N. P.; Covey, D. F. J. Org. Chem. 2005, 70, 1089–1092. 9. Zartman, A. E.; Duong, L. T.; Fernandez-Metzler, C.; Hartman, G. D.; Leu, C.-T.;

Prueksaritanont, T.; Rodan, G. A.; Rodan, S. B.; Duggan, M. E.; Meissner, R. S. Bio-org. Med. Chem. Lett. 2005, 15, 1647–1650.

10. Hicks, J. D.; Roush, W. R. Org. Lett. 2008, 10, 681–684. 11. Williams, D. R.; Nag, P. P. Claisen and Related Rearrangements. In Name Reactions


128

Clemmensen reduction Reduction of aldehydes and ketones to the corresponding methylene compounds using amalgamated zinc in hydrochloric acid.

R R1

O Zn(Hg)

HCl R R1

HH

The zinc-carbenoid mechanism:3

Ph CH3

O Zn(Hg), HCl

SET Ph CH3

O ZnCl

radical anion

Ph CH3

Zn

Ph CH3

OZnCl

ZnPh CH3

HH

H zinc-carbenoid

The radical anion mechanism:

Ph CH3

O e ; HPh CH3

OZnCl

H

Zn(Hg), HCl

SET Ph CH3

O ZnCl H Ph CH3

OZnCl

H

H

Cl radical anion

Ph CH3

H

Cl

SN2Ph CH3

H

Ph CH3

HHe ; He

Example 15

Zn(Hg), HCl

MeOH, reflux, 1 hOH

OHO OH

O

OH18% 67%

129


Example 26

Zn(Hg), HCl

Et2O, −5 oC, 57%N

OH

HPh

N

H

HPhO O

Example 38

H3CH3C

CH3

HO

H3C H

H H

HOH

OH

H3C

HO

H3C H

H H

O

OZn dust

37% HCl, EtOH

reflux, 15 min.50%diosgenin

References 1. Clemmensen, E. Ber. 1913, 46, 1837−1843. Erik C. Clemmensen (1876−1941) was

born in Odense, Denmark. He received the M.S. degree from the Royal Polytechnic Institute in Copenhagen. In 1900, Clemmensen immigrated to the United States, and worked at Parke, Davis and Company in Detroit as a research chemist for 14 years, where he discovered the reduction of carbonyl compounds with amalgamated zinc. Clemmensen later founded a few chemical companies and was the president of one of them, the Clemmensen Chemical Corporation in Newark, New Jersey.

2. Martin, E. L. Org. React. 1942, 1, 155−209. (Review). 3. Vedejs, E. Org. React. 1975, 22, 401−422. (Review). 4. Talpatra, S. K.; Chakrabarti, S.; Mallik, A. K.; Talapatra, B. Tetrahedron 1990, 46,

6047−6052. 5. Martins, F. J. C.; Viljoen, A. M.; Coetzee, M.; Fourie, L.; Wessels, P. L. Tetrahedron

1991, 47, 9215−9224. 6. Naruse, M.; Aoyagi, S.; Kibayashi, C. J. Chem. Soc., Perkin Trans. 1 1996,

1113−1124. 7. Kappe, T.; Aigner, R.; Roschger, P.; Schnell, B.; Stadlbauer, W. Tetrahedron 1995,

51, 12923−12928. 8. Alessandrini, L.; Ciuffreda, P.; Santaniello, E.; Terraneo, G. Steroids 2004, 69,

789−794. 9. Dey, S. P.; Dey, D. K.; Dhara, M. G.; Mallik, A. K. J. Indian Chem. Soc. 2008, 85,

717−720.

130

Combes quinoline synthesis Acid-catalyzed condensation of anilines and β-diketones to assemble quinolines. Cf. Conrad–Limpach reaction.

NH2 R1 R2

O O H

ΔN R1

R2

NH2:

O

R1

HR2

ONH2

OHR1

O

R2 proton

transfer NH

OH2

:

R1

O

R2

N R1

O

R2

NH

R1

O

R2 H

NH

R1

R2

OH

imine enamine

NH

R1

R2

OH

:

NH

R1

R2OH

N R1

H R2OH

H

H

H

N R1

R2

NH

R1

R2OH H

:

HN R1

R2

H

An electrocyclization mechanism is also possible:

:

NH

R1

R2

OH

N R1

R2

OH

6π-electrocyclization

H

131


N R1

R2HO

N R1

R2

H

proton

transferN R1

HOH2

R2 H2O

Example 16

NH

NH2

MeOO O

PPA, 110 °C

NH

MeO

N

35%

Example 27

NH

NH2

CO2Et

O

Ph

O

cat. p-TsOH, 220 °Cneat, 38%

NH

CO2Et

N

Ph

References 1. Combes, A. Bull. Soc. Chim. Fr. 1888, 49, 89. Alphonse-Edmond Combes

(1858−1896) was born in St. Hippolyte-du-Fort, France. He apprenticed with Wurtz at Paris. He also collaborated with Charles Friedel of the Friedel−Crafts reaction fame. He became the president of the French Chemical Society in 1893 at the age of 35. His sudden death shortly after his 38th birthday was a great loss to organic chemistry.

2. Roberts, E. and Turner, E. J. Chem Soc. 1927, 1832−1857. (Review). 3. Elderfield, R. C. In Heterocyclic Compounds, Elderfield, R. C., ed.; Wiley & Sons:

New York, 1952, vol. 4, 36–38. (Review). 4. Popp, F. D. and McEwen, W. E. Chem. Rev. 1958, 58, 321–401. (Review). 5. Jones, G. In Chemistry of Heterocyclic Compounds, Jones, G., ed.; Wiley & Sons,

New York, 1977, Quinolines Vol. 32, pp 119–125. (Review). 6. Alunni-Bistocchi, G.; Orvietani, P., Bittoun, P., Ricci, A.; Lescot, E. Pharmazie 1993,

48, 817−820. 7. El Ouar, M.; Knouzi, N.; Hamelin, J. J. Chem. Res. (S) 1998, 92−93. 8. Curran, T. T. Combes Quinoline Synthesis. In Name Reactions in Heterocyclic Chem-


132

Conrad–Limpach reaction Thermal or acid-catalyzed condensation of anilines with β-ketoesters leads to qui-nolin-4-ones. Cf. Combes quinoline synthesis.

NH2 NH

OEt

O O Ph2O

260 oC

O

NH2

EtO2C

O

NH

CO2Et

OH

: :

H2Oproton

transfer

N

CO2Et

N

OEtHO 6π electron

electrocyclizationtautomerize

N

H OEtO

H

Schiff base

− HOEt

N

HO

H OEtNH

Oproton

transfer N

OH

Example 13

N

NH2 CHCl3, HCl (cat.)

60%OEt

O O

N

HNCO2Et

N

N

OH

Ph2O, reflux

60%

133


Example 27

N NH2

EtO2CO

CO2Et3

PPA,

120 °C25%

N N

OCO2Et3

+

paraffin,

280 °C75% N N

HCO2Et3

O

Example 38

NH2

NO2

CO2MeHO

OMeO2C

2 HCl, MeOH

64%

O2N

NH

CO2Me

NHPhNO2MeO2C

Dowtherm A

250 °C, 55% NH

HN

CO2Me

O2NO

NO2

References 1. Conrad, M.; Limpach, L. Ber. 1887, 20, 944. Max Conrad (1848−1920), born in Mu-

nich, Germany, was a professor of the University of Würzburg, where he collaborated with Leonhard Limpach (1852−1933) on the synthesis of quinoline derivatives.

2. Manske, R. F. Chem Rev. 1942, 30, 113–114. (Review). 3. Misani, F.; Bogert, M. T. J. Org. Chem. 1945, 10, 347–365 4. Reitsema, R. H. Chem. Rev. 1948, 43, 43–68. (Review). 5. Elderfield, R. C. In Chemistry of Heterocyclic Compounds, Elderfield, R. C., Wiley &

Sons, New York, 1952, vol. 4, 31–36. (Review). 6. Jones, G. In Heterocyclic Compounds, Jones, G., ed.; John Wiley & Sons, New York,

1977, Quinolines, Vol 32, 137–151. (Review). 7. Deady, L. W.; Werden, D. M. Synth. Commun. 1987, 17, 319−328. 8. Kemp, D. S.; Bowen, B. R. Tetrahedron Lett. 1988, 29, 5077−5080. 9. Curran, T. T. Conrad–Limpach Reaction. In Name Reactions in Heterocyclic Chemis-


10. Chan, B. K.; Ciufolini, M. A. J. Org. Chem. 2008, 72, 8489−8495.

134

Cope elimination reaction Thermal elimination of N-oxides to olefins and N-hydroxyl amines.

NO

H

R2R3RR1

Δ

R2

R3

R1

R

NOH

Ei

Example 1, Solid-phase Cope elimination5

OO

N

OH

m-CPBA, CHCl3

rt, 67%

OO

N

OH

OH

OO

HON

OH

Example 26

OBn

BnO

BnO

N(CH3)2

OTBDPS

O

OBn

BnO

BnO

N(CH3)2

OTBDPSm-CPBA

CH2Cl2, 0 oC83%

OBn

BnO

BnOOTBDPS

145 oC

63%

Example 38

N

CN

O m-CPBA, CH2Cl2

rt, 100%

NOO

NC H

NOH O

CN

135


Example 4, Retro-Cope elimination9

OMe

PhN

MeOHNC

Cope

elimination

OTBDPSO

MePh

NMe

HNC

OTBDPS m-CPBA, K2CO3

−78 oC, 3 h, then rt

OMe

PhN

MeHO

OTBDPS

MeOH, Δ, 5 d 67%, 2 steps

retro-Copeelimination

O

N

Ph

MeMe

OOTBDPS

O

N

Ph

MeMe

OOTBDPS

5 : 2

References 1. Cope, A. C.; Foster, T. T.; Towle, P. H. J. Am. Chem. Soc. 1949, 71, 3929−3934. Ar-

thur Clay Cope (1909−1966) was born in Dunreith, Indiana. He was a professor at MIT when he discovered the Cope elimination reaction and the Cope rearrangement. The Arthur Cope Award is a prestigious award in organic chemistry from the Ameri-can Chemical Society.

2. Cope, A. C.; Trumbull, E. R. Org. React. 1960, 11, 317−493. (Review). 3. DePuy, C. H.; King, R. W. Chem. Rev. 1960, 60, 431−457. (Review). 4. Gallagher, B. M.; Pearson, W. H. Chemtracts: Org. Chem. 1996, 9, 126−130. (Re-

view). 5. Sammelson, R. E.; Kurth, M. J. Tetrahedron Lett. 2001, 42, 3419−3422. 6. Vasella, A.; Remen, L. Helv. Chim. Acta. 2002, 85, 1118−1127. 7. Garcia Martinez, A.; Teso Vilar, E.; Garcia Fraile, A.; de la Moya Cerero, S.; Lora

Maroto, B. Tetrahedron: Asymmetry 2002, 13, 17−19. 8. O’Neil, I. A.; Ramos, V. E.; Ellis, G. L.; Cleator, E.; Chorlton, A. P.; Tapolczay, D. J.;

Kalindjian, S. B. Tetrahedron Lett. 2004, 45, 3659−3661. 9. Henry, N.; O’Meil, I. A. Tetrahedron Lett. 2007, 48, 1691−1694. 10. Fuchter, M. J. Cope elimination reaction. In Name Reactions for Functional Group

Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 342−353. (Review).

11. Bourgeois, J.; Dion, I.; Cebrowski, P. H.; Loiseau, F.; Bedard, A.-C.; Beauchemin, A. M. J. Am. Chem. Soc. 2009, 131, 874−875.

136

Cope rearrangement The Cope, oxy-Cope, and anionic oxy-Cope rearrangements belong to the cate-gory of [3,3]-sigmatropic rearrangements. Since it is a concerted process, the ar-row pushing here is only illustrative. This reaction is an equilibrium process. Cf. Claisen rearrangement.

R R RΔ, [3,3]-sigmatropic

rearrangement

Example 14

CO2CH3

OTMS

BrCO2CH3

OTMS

H

BrO

H

Br

160 °C

tolueneCope

NaCl

wet DMSOreflux

Krapcho 71%

Example 26

O OTMS

CO2Me 100 oC, 12 h

84%

CO2Me

TMS

Example 39

CO2Me

CO2MeO

dioxane, Et3N, 60 oC

22 h, 1 bar, 92%O

CO2Me

CO2Me

Example 410

140 °C

benzene

OH

OH

HH

H

H3CO

H

OH

OH

OH

H3COH

94%OH

Example 511

O

OMOMO

OMOMOTBDPS

1,2-dichlorobenzene

reflux, 95% O

O OMOM

OMOMTBDPSO

137


Example 612

H3CO1. HCl, MeOH

2. 1,2-dichlorobenzene reflux, 80%

N

O

OCH3

OCH3H3CO H3CO

N

O

O

OCH3H3CO

References 1. Cope, A. C.; Hardy, E. M. J. Am. Chem. Soc. 1940, 62, 441−444. 2. Frey, H. M.; Walsh, R. Chem. Rev. 1969, 69, 103−124. (Review). 3. Rhoads, S. J.; Raulins, N. R. Org. React. 1975, 22, 1−252. (Review). 4. Wender, P. A.; Schaus, J. M. White, A. W. J. Am. Chem. Soc. 1980, 102, 6159–6161. 5. Hill, R. K. In Comprehensive Organic Synthesis Trost, B. M.; Fleming, I., Eds.; Per-

gamon, 1991, Vol. 5, 785−826. (Review). 6. Chou, W.-N.; White, J. B.; Smith, W. B. J. Am. Chem. Soc. 1992, 114, 4658−4667. 7. Davies, H. M. L. Tetrahedron 1993, 49, 5203−5223. (Review). 8. Miyashi, T.; Ikeda, H.; Takahashi, Y. Acc. Chem. Res. 1999, 32, 815−824. (Review). 9. Von Zezschwitz, P.; Voigt, K.; Lansky, A.; Noltemeyer, M.; De Meijere, A. J. Org.

Chem. 1999, 64, 3806–3812. 10. Lo, P. C.-K.; Snapper, M. L. Org. Lett. 2001, 3, 2819–2821. 11. Clive, D. L. J.; Ou, L. Tetrahedron Lett. 2002, 43, 4559–4563. 12. Malachowski, W. P.; Paul, T.; Phounsavath, S. J. Org. Chem. 2007, 72, 6792–6796. 13. Mullins, R. J.; McCracken, K. W. Cope and Related Rearrangements. In Name Reac-

tions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 88−135. (Review).

Anionic oxy-Cope rearrangement

ROH KH

THF R

O

ROH

ROKKH

THF

Δ, [3,3]-sigmatropic

rearrangementR

OK

ROK H2O

ROH

R

Otautomerize

Example 11

OH KH, THF, rt

then H2O, 88%

O

138

Example 24

OH

CH3

OHKH, THF

70% OH

H3C

H

H3COHC

Example 35

OH

H3CCH3

H3CCH3

O

X = OCH2CH2TMS 0 °C; 71%

OMOM

X

BnOOPMB

OPMB

OTBS

OMOM

X

OTBS

OPMB

OPMBBnO

H

H

KHMDS18-crown-6, THF

temperature;

then NH4Cl, H2O

−78 °C; 85%X = SPh

Example 48

OHNaH, THF, reflux

22 h, 88%

O

Example 59

MeO

MeO

OMeMeO OMe

HO

MeO

MeO

OMeMeO OMe

O

KOt-Bu18-crown-6

THF, −10°C74%

References 1. Wender, P. A.; Sieburth, S. M.; Petraitis, J. J.; Singh, S. K. Tetrahedron 1981, 37,

3967–3975. 2. Wender, P. A.; Ternansky, R. J.; Sieburth, S. M. Tetrahedron Lett. 1985, 26, 4319–

4322. 3. Paquette, L. A. Tetrahedron 1997, 53, 13971−14020. (Review). 4. Corey, E. J.; Kania, R. S. Tetrahedron Lett. 1998, 39, 741–744. 5. Paquette, L. A.; Reddy, Y. R.; Haeffner, F.; Houk, K. N. J. Am. Chem. Soc. 2000, 122,

740–741. 6. Voigt, B.; Wartchow, R.; Butenschon, H. Eur. J. Org. Chem. 2001, 2519–2527.

139

7. Hashimoto, H.; Jin, T.; Karikomi, M.; Seki, K.; Haga, K.; Uyehara, T. Tetrahedron Lett. 2002, 43, 3633–3636.

8. Gentric, L.; Hanna, I.; Huboux, A.; Zaghdoudi, R. Org. Lett. 2003, 5, 3631–3634. 9. Jones, S. B.; He, L.; Castle, S. L. Org. Lett. 2006, 8, 3757–3760. 10. Mullins, R. J.; McCracken, K. W. Cope and Related Rearrangements. In Name Reac-


Oxy-Cope rearrangement

While the anionic oxy-Cope rearrangements work at low temperature, the oxy-Cope rearrangements require high temperature but provide a thermodynamic sink.

ROH

ROHΔ, [3,3]-sigmatropic

rearrangement ROH

R

Otautomerize

Example 12

H

Me

Me HO

TMSH

O

Me

Me

OPMBH

Me

Me

Me

OPMBO

H

HO H

OMe

1. 230−240 °C DMF, 19 h

2. CsF, DMF 210 °C, 65%

Example 23

OH

CO2Et reflux

o-dichloro-benzene

O H

EtO2C

ene

EtO2C

OH90%

H

Example 34

PhMe2Si

PhMe2SiO O

O

t-Bu

O

1. 170 oC

2. p-TsOH•H2O 65−75%

O

O

t-Bu

O

PhMe2SiOOHC

Example 46

OH Oxylene, Ace® tube

225 oC, 24 h, 49%

140

References 1. Paquette, L. A. Angew. Chem., Int. Ed. 1990, 29, 609−626. (Review). 2. Paquette, L. A.; Backhaus, D.; Braun, R. J. Am. Chem. Soc. 1996, 118, 11990–11991. 3. Srinivasan, R.; Rajagopalan, K. Tetrahedron Lett. 1998, 39, 4133–4136. 4. Schneider, C.; Rehfeuter, M. Chem. Eur. J. 1999, 5, 2850−2858. 5. Schneider, C. Synlett 2001, 1079−1091. (Review on siloxy-Cope rearrangement). 6. DiMartino, G.; Hursthouse, M. B.; Light, M. E.; Percy, J. M.; Spencer, N. S.; Tolley,

M. Org. Biomol. Chem. 2003, 1, 4423−4434. 7. Mullins, R. J.; McCracken, K. W. Cope and Related Rearrangements. In Name Reac-


Siloxy-Cope rearrangement

R'OSiR3 Δ, [3,3]-sigmatropic

rearrangement R'

OSiR3

Example 11

OTMSCH3

H

OTMSOTBS

HH3C

OTMS

OTMSOTBSHsealed tube

high vacuum

310 °C, 1 h> 79%

Example 22

O

N

O

BnTDSO

O

180 °C

toluene, 3 h63%

O

N

O

Bn

O

TDSO

> 97:3 dr TDS = thexyldimethylsilyl

Example 33

Et3SiO

AOM

OO

OTBDPS OSiEt3O

OOAOMTBDPSO

chlorobenzene

reflux, 3 h, 99%

AOM = p-Anisyloxymethyl = p-MeOC6H4OCH2-

141

Example 44

OHH3C

4H3C

TESO

OO O

OH

4H3C

TESO

OO O115 °C

toluene, reflux95%

OTBDPS TBDPSO

H3C

References 1. Askin, D.; Angst, C.; Danishefsky, D. J. J. Org. Chem. 1987, 52, 622–635. 2. Schneider, C. Eur. J. Org. Chem. 1998, 1661–1663. 3. Clive, D. L. J.; Sun, S.; Gagliardini, V.; Sano, M. K. Tetrahedron Lett. 2000, 41,

6259–6263. 4. Bio, M. M.; Leighton, J. L. J. Org. Chem. 2003, 68, 1693–1700. 5. Mullins, R. J.; McCracken, K. W. Cope and Related Rearrangements. In Name Reac-


142

Corey–Bakshi–Shibata (CBS) reagent

N BO

PhPhH

Me

The CBS (Corey–Bakshi–Shibata) reagent is a chiral catalyst derived from proline. Also known as Corey’s oxazaborolidine, it is used in enantioselective bo-rane reduction of ketones, asymmetric Diels–Alder reactions and [3 + 2] cycloadditions. Preparation1,3

NH

O

OH

H

O

MeOH

H3ONH

O

O

H

O

1. PhMgCl2. BH3•THF

50% 3 steps

N BO

PhPhH

MeNH

OH

PhPhH MeB(OH)2, toluene

reflux, 3 h, 86%

The mechanism and catalytic cycle:1,3

O OHcat.

BH3, THF, rt, 97% ee

N BO

PhPhH

Me

CH3

O

N BO

PhPhH

R

N BO

PhPhH

R

BH3•THF

H3B

N BO

PhPhH

OH2B R

B Ph

CH3

::

HHH H

ON B

Ph

Ph H2B OCH3

PhH

RON B

Ph

Ph BH2

OCH3

Ph

R

H

CH3

HH2BO

HCl, MeOH

CH3

HHO

BH3

143


Example 16

SO2C6H4CH3-pO

O

0.1 eq. (S)-CBS1.0 eq. i-Pr(Et)NPh•BH3

THF, rt, syringe pump1.5 h, 98%, 97% ee

SO2C6H4CH3-pOH

O

N BO

PhPhH

CH3

(S)-Me-CBS =

Example 29

O

O

OO BH3•SMe2

cat. (R)-Me-CBS

CH2Cl2, 30 oC84%, > 99% ee

HO

O

OO

Example 311

> 97% eeCO2CH2CF3

NB

O

H

H

PhPh

o-Tol

10 mol%, neat23 oC, 30 h, 97%

OCH2CF3

OTf2N

CO2Et

O

H3N

HN

Ac

H2PO4

oseltamivir (Tamiflu®)

Example 4, Asymmetric [3 + 2]-cycloaddition10

NB

O

H

H

PhPh

o-Tol

Tf2NOMeO

O

O CH3CN−CH2Cl265%

OH

OO

MeO

H

H92% ee99% ee recryst.

References 1. (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551–5553.

(b) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K. J. Am. Chem. Soc. 1987, 109, 7925–7926. (c) Corey, E. J.; Shibata, S.; Bakshi, R. K. J. Org. Chem. 1988, 53, 2861–2863.

2. Reviews: (a) Corey, E. J. Pure Appl. Chem. 1990, 62, 1209–1216. (b) Wallbaum, S.; Martens, J. Tetrahedron: Asymm. 1992, 3, 1475–1504. (c) Singh, V. K. Synthesis

144

1992, 605–617. (d) Deloux, L.; Srebnik, M. Chem. Rev. 1993, 93, 763–784. (e) Taraba, M.; Palecek, J. Chem. Listy 1997, 91, 9–22. (f) Corey, E. J.; Helal, C. J. Angew. Chem. Int. Ed. 1998, 37, 1986–2012. g) Corey, E. J. Angew. Chem. Int. Ed. 2002, 41, 1650–1667. (h) Itsuno, S. Org. React. 1998, 52, 395–576. (i) Cho, B. T. Aldrichimica Acta 2002, 35, 3–16. (j) Glushkov, V. A.; Tolstikov, A. G. Russ. Chem. Rev. 2004, 73, 581–608. (k) Cho, B .T. Tetrahedron 2006, 62, 7621–7643.

3. (a) Mathre, D. J.; Thompson, A. S.; Douglas, A. W.; Hoogsteen, K.; Carroll, J. D.; Corley, E. G.; Grabowski, E. J. J. J. Org. Chem. 1993, 58, 2880–2888. (b) Xavier, L. C.; Mohan, J. J.; Mathre, D. J.; Thompson, A. S.; Carroll, J. D.; Corley, E. G.; Des-mond, R. Org. Synth. 1997, 74, 50–71.

4. Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1996, 37, 4837–4840. 5. Clark, W. M.; Tickner-Eldridge, A. M.; Huang, G. K.; Pridgen, L. N.; Olsen, M. A.;

Mills, R. J.; Lantos, I.; Baine, N. H. J. Am. Chem. Soc. 1998, 120, 4550–4551. 6. Cho, B. T.; Kim, D. J. Tetrahedron: Asymmetry 2001, 12, 2043–2047. 7. Price, M. D.; Sui, J. K.; Kurth, M. J.; Schore, N. E. J. Org. Chem. 2002, 67, 8086–

8089. 8. Degni, S.; Wilen, C.-E.; Rosling, A. Tetrahedron: Asymmetry 2004, 15, 1495–1499. 9. Watanabe, H.; Iwamoto, M.; Nakada, M. J. Org. Chem. 2005, 70, 4652–4658. 10. Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2005, 127, 11958–11959. 11. Yeung, Y.-Y.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 6310–6311. 12. Patti, A.; Pedotti, S. Tetrahedron: Asymmetry 2008, 19, 1891–1897.

145

Corey−Chaykovsky reaction

The Corey−Chaykovsky reaction entails the reaction of a sulfur ylide, either di-methylsulfoxonium methylide 1 (Corey’s ylide) or dimethylsulfonium methylide 2, with electrophile 3 such as carbonyl, olefin, imine, or thiocarbonyl, to offer 4 as the corresponding epoxide, cyclopropane, aziridine, or thiirane.

R R1

X

R R1

X

X = O, CH2, NR2, S, CHCOR3,CHCO2R3, CHCONR2, CHCN

3H3C

SCH3

CH2

1 2

H3CSCH3

CH2

O

4

1 or 2

Preparation1

H3CS

CH3CH3

O

INaH

DMSO H3CSCH3

CH2

O

Mechanism1

H3CS

CH2CH3

O R R1

O

H3CS

H3C

O R

OR1

H3CS

CH3

O

O R1

R

Example 111

N

O

O

ClF

N

O

O

ClF

Me3S(O)+I−

NaH, DMSO

60 oC, 3.5 h79%

Example 29

OOEt

OAcMe2S CO2Et O

OEt

OAc

CO2Et

PhH, rt, 8 h, 62%

Example 310

H

N

Me3SCl50% aq. NaOH

Bu4NHSO4

CH2Cl2, 84%

O

O

H

N

O

O

146


Example 414

Me2S

H

SiEt3BrCHO

2.5 equiv t-Bu3Ga

PhCl, rt, 3 h, 66%Z:E = 94:6

O

SiEt3 Example 515

O

Ph

OH

4 equiv(CH3)3SOI

n-BuLi, THF60 oC, 4 h

O

O

PhS

OO

Ph

OHO

Ph

50% 20%

References 1 (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84, 867−868. (b) Corey, E.

J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84, 3782. (c) Corey, E. J.; Chaykovsky, M. Tetrahedron Lett. 1963, 169−171. (d) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1964, 86, 1639−1640. (e) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353−1364.

2 Okazaki, R.; Tokitoh, N. In Encyclopedia of Reagents in Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995, pp 2139−2141. (Review).

3 Ng, J. S.; Liu, C. In Encyclopedia of Reagents in Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995, pp 2159−2165. (Review).

4 Trost, B. M.; Melvin, L. S., Jr. Sulfur Ylides; Academic Press: New York, 1975. (Re-view).

5 Block, E. Reactions of Organosulfur Compounds Academic Press: New York, 1978. (Review).

6 Gololobov, Y. G.; Nesmeyanov, A. N. Tetrahedron 1987, 43, 2609−2651. (Review). 7 Aubé, J. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Ed.; Perga-

mon: Oxford, 1991, Vol. 1, pp 820−825. (Review). 8 Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem. Rev. 1997, 97, 2341−2372. (Review). 9 Rosenberger, M.; Jackson, W.; Saucy, G. Helv. Chim. Acta 1980, 63, 1665−1674. 10 Tewari, R. S.; Awatsthi, A. K.; Awasthi, A. Synthesis 1983, 330−331. 11 Vacher, B.; Bonnaud, B. Funes, P.; Jubault, N.; Koek, W.; Assie, M.-B.; Cosi, C.;

Kleven, M. J. Med. Chem. 1999, 42, 1648−1660. 12 Chandrasekhar, S.; Narasihmulu, Ch.; Jagadeshwar, V.; Reddy, K. V. Tetrahedron

Lett. 2003, 44, 3629−3630. 13 Li, J. J. Corey−Chaykovsky Reaction. In Name Reactions in Heterocyclic Chemistry;

Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 1−14. (Review). 14 Nishimura, Y.; Shiraishi, T.; Yamaguchi, M. Tetrahedron Lett. 2008, 49, 3492−3495. 15 Chittimalla, S. K.; Chang, T.-C.; Liu, T.-C.; Hsieh, H.-P.; Liao, C.-C. Tetrahedron

2008, 64, 2586−2595.

147

Corey−Fuchs reaction One-carbon homologation of an aldehyde to dibromoolefin, which is then treated with n-BuLi to produce a terminal alkyne.

R CHOCBr4, PPh3

Zn Br

Br

H

R n-BuLiR H

:PPh3Br3C Br CBr3 Br PPh3

SN2

CBr3

Br PPh3

Br

PPh3

BrBr

Br

SN2SN2

Br

Br

H

RO PPh3

R H

O

Br2 PPh3

Br

Br Wittig reaction (see page 578 for the mechanism)

Br2 Zn ZnBr2

Br

Br

H

R

Bu

R Br

BuR HR

acidic

workup

Example 13

OHC

OMe

OTBS

OO

CBr4, Ph3P, CH2Cl2

rt, 35 min., 90%

OMe

OTBS

OO

Br

Br

3.0 eq. n-BuLi/hexanes, THF

−78 oC, 1 h; rt, 1 h, 99%

OMe

OTBS

OO

OH

148


Example 27

Fe

O

HFe H

BrBr

CBr4, Zn

PPh3, quant.

n-BuLi

75%Fe

H

Example 38

CHOOTBS

1. CBr4, Ph3P, Zn, CH2Cl2

2. n-BuLi, then NH4Cl, 90% OTBS

Example 410

CHO

CHO

4 equiv CBr48 equiv PPh3

8 equiv Zn

CH2Cl2, 0 oC to rt3 h, 94%

HH

Br Br

Br Br

n-BuLi, n-hexane

−78 oC to rt, 1 h, 96%

H

H

References 1 Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769−3772. Phil Fuchs is a pro-

fessor at Purdue University. 2 For the synthesis of 1-bromalkynes see Grandjean, D.; Pale, P.; Chuche, J. Tetrahe-

dron Lett. 1994, 35, 3529−3530. 3 Gilbert, A. M.; Miller, R.; Wulff, W. D. Tetrahedron 1999, 55, 1607−1630. 4 Muller, T. J. J. Tetrahedron Lett. 1999, 40, 6563−6566. 5 Serrat, X.; Cabarrocas, G.; Rafel, S.; Ventura, M.; Linden, A.; Villalgordo, J. M.

Tetrahedron: Asymmetry 1999, 10, 3417−3430. 6 Okamura, W. H.; Zhu, G.-D.; Hill, D. K.; Thomas, R. J.; Ringe, K.; Borchardt, D. B.;

Norman, A. W.; Mueller, L. J. J. Org. Chem. 2002, 67, 1637−1650. 7 Tsuboya, N.; Hamasaki, R.; Ito, M.; Mitsuishi, M.; Miyashita, T. Yamamoto, Y. J.

Mater. Chem. 2003, 13, 511–513 8 Zeng, X.; Zeng, F.; Negishi, E.-i. Org. Lett. 2004, 6, 3245−3248. 9 Quéron, E.; Lett, R. Tetrahedron Lett. 2004, 45, 4527−4531. 10 Sahu, B.; Muruganantham, R.; Namboothiri, I. N. N. Eur. J. Org. Chem. 2007, 2477–

2489. 11 Han, X. Corey−Fuchs reaction. In Name Reactions for Homologations-Part I; Li, J. J.,

Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 393−403. (Review).

149

Corey–Kim oxidation Oxidation of alcohol to the corresponding aldehyde or ketone using NCS/DMS, followed by treatment with a base. Cf. Swern oxidation.

R1 R2

OH

R1 R2

ONCS, DMS

then NEt3

NCS = N-Chlorosuccinimide; DMS = Dimethylsulfide.

SN

O

O

Cl:

ClSN

O

O R1 R2

:OHN

O

O

S

Cl

NH

O

O

R1 R2

OS H

H:NEt3

Cl

R1 R2

O

R1

OS

(CH3)2S↑

HR2

Et3N·HCl

Example 1, Fluorous Corey−Kim reaction5

NO2

OHC6F13

S

NCS, toluene, −25 oC, 2 hthen Et3N, 86%

NO2CHO

Example 2, Odorless Corey−Kim reaction7

NO

0.5 eq. NCS, CH2Cl2, −40 oC, 2 hthen Et3N, −40 oC to rt, 8 h

OH

D

S

O

NO

S D

45%86%

150


Example 39

NH

OH

HH

HH

NCS, Me2S

Et3N, CH2Cl2−78 oC to rt, 90%

NH

CHOHH

HH

Example 410

O

O

O

OH

O

OOBzO

N

N

HN

OO

NCS, DMS

Et3N, CH2Cl2> 300 Kg scale

O

O

O

O

O

OOBzO

N

N

HN

OO

References 1 Corey, E. J.; Kim, C. U. J. Am. Chem. Soc. 1972, 94, 7586−7587. Choung U. Kim

now works at Gilead Sciences Inc., a company specialized in antiviral drugs in Foster City, California, where he co-discovered oseltamivir (Tamiflu).

2 Katayama, S.; Fukuda, K.; Watanabe, T.; Yamauchi, M. Synthesis 1988, 178−183. 3 Shapiro, G.; Lavi, Y. Heterocycles 1990, 31, 2099−2102. 4 Pulkkinen, J. T.; Vepsäläinen, J. J. J. Org. Chem. 1996, 61, 8604−8609. 5 Crich, D.; Neelamkavil, S. Tetrahedron 2002, 58, 3865−3870. 6 Ohsugi, S.-I.; Nishide, K.; Oono, K.; Okuyama, K.; Fudesaka, M.; Kodama, S.; Node,

M. Tetrahedron 2003, 59, 8393−8398. 7 Nishide, K.; Patra, P. K.; Matoba, M.; Shanmugasundaram, K.; Node, M. Green

Chem. 2004, 6, 142−146. 8 Iula, D. M. Corey−Kim Oxidation. In Name Reactions for Functional Group Trans-

formations; Li, J. J., Corey, E. J. (eds), John Wiley & Sons: Hoboken, NJ, 2007, pp 207−217. (Review).

9 Yin, W.; Ma, J.; Rivas, F. M.; Cook, M. Org. Lett. 2007, 9, 295−298. 10 Cink, R. D.; Chambournier, G.; Surjono, H.; Xiao, Z.; Richter, S.; Naris, M.; Bhatia,

A. V. Org. Pro. Res. Dev. 2007, 11, 270−274.

151

Corey–Nicolaou macrolactonization Macrolactonization of ω-hydroxyl-acid using 2,2 -dipyridyl disulfide. Also known as the Corey–Nicolaou double activation method.

OH

OH

O

n

SS

NN

Ph3P On

O

SS

NN

Ph3P:

H

OH

O

O

n

SPPh3

N

HNH

S

S

OH

O

O

n

PPh3

NH

OH

O

O

n

PPh3

S

N

O PPh3NH

S

O n

OH

NH

S

ONH

S

O

On

O

n

2-pyridinethione

Example 13

N

OHOO

HO2C

PhPh H (2-pyr-S)2, PPh3

CHCl3, Δ, 75%

N

HOO

O

O

PhPh

152


Example 26

OH

OH OMOM

O

O O(2-pyr-S)2, PPh3

AgClO4, Δ, 33%

O

O

HOO

O

Example 39

(PyS)2, PPh3

toluene, reflux7 d, 69%

O

HO OH

O

BnO

O

O O

OC5H11

HO2C

O

HO O

O

BnO

O

O O

OC5H11

O

O

O OH

O

BnO

O

O O

OC5H11

O 58% 11%

References 1. Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96, 5614–5616. 2. Nicolaou, K. C. Tetrahedron 1977, 33, 683–710. (Review). 3. Devlin, J. A.; Robins, D. J.; Sakdarat, S. J. Chem. Soc., Perkin Trans. 1 1982, 1117–

1121. 4. Barbour, R. H.; Robins, D. J. J. Chem. Soc., Perkin Trans. 1 1985, 2475–2478. 5. Barbour, R. H.; Robins, D. J. J. Chem. Soc., Perkin Trans. 1 1988, 1169–1172. 6. Andrus, M. B.; Shih, T.-L. J. Org. Chem. 1996, 61, 8780–8785. 7. Lu, S.-F.; O’yang, Q. Q.; Guo, Z.-W.; Yu, B.; Hui, Y.-Z. J. Org. Chem. 1997, 62,

8400–8405. 8. Sasaki, T.; Inoue, M.; Hirama, M. Tetrahedron Lett. 2001, 42, 5299–5303. 9. Zhu, X.-M.; He, L.-L.; Yang, G.-L.; Lei, M.; Chen, S.-S.; Yang, J.-S. Synlett 2006,

3510–3512.

153

Corey–Seebach reaction Dithiane as a nucleophile, serving as a masked carbonyl equivalent. This is an ex-ample of umpolung.

SH

SH

CH2(OMe)2

Et2O•BF3 S

S 1. BuLi

2. Cl-(CH2)4-I 80%

S

S

Cl

HgCl2, 50 oC

50%

OHC

Cl

S

S

HH

Bu

S

S

ClI

S

S

Cl

Example 12

CHOS

S

Ph

n-BuLi, THF

0 oC, 30 min., 99%

S S

PhHOPh

PhI(O2CCCl3)2

CH3CN, H2O, rt, 5 min., 95% Ph Ph

HO O

Example 24

O CHO SSPh

n-BuLi, THF, −78 to 0 oC

OOH

SS

Ph

Example 3, Ethyl is infinitely different from methyl6

OMeOS

SLi

MeOH

S

SS

SMe Me

OMeO S

S

Et

CO2H

n-BuLi, THFrt, overnight

80−90%

HO2C

S SO

Et S

SEt

154


HO2C

O

S

SEt

SS

EtSET

HO2C

O

S

SEt

HO2C

S SO

Et S

SEt

S S

Et

HO2C

S SO

Et

Example 48

SO

OBn

OBn

OBn

NHTfa

S n-BuLi, THF

−10 oC, 78%

SSNHTfa

BnOOBn

OBn

HO

54%

S

S

BnO NHTfa

HO

BnO

BnO

23% Tfa = Trifluoroacetyl

S

S

BnO NHTfa

HO

BnO

BnO

Ra-Ni, EtOH

reflux, 71%BnO NHTfa

HO

BnO

BnO

References 1. (a) Corey, E. J.; Seebach, D. Angew. Chem., Int. Ed. 1965, 4, 1075–1077. Dieter See-

bach is a professor at ETH in Zürich, Switzerland. (b) Corey, E. J.; Seebach, D. J. Org. Chem. 1966, 31, 4097–4099. (c) Seebach, D.; Jones, N. R.; Corey, E. J. J. Org. Chem. 1968, 33, 300–305. (d) Seebach, D.; Corey, E. J. Org. Synth. 1968, 50, 72. (e) Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231–237.

2. Stowell, M. H. B.; Rock, R. S.; Rees, D. C.; Chan, S. I. Tetrahedron Lett. 1996, 37, 307–310.

3. Hassan, H. H. A. M.; Tamm, C. Helv. Chim. Acta 1996, 79, 518–526. 4. Lee, H. B.; Balasubramanian, S. J. Org. Chem. 1999, 64, 3454–3460. 5. Bräuer, M.; Weston, J.; Anders, E. J. Org. Chem. 2000, 65, 1193–1199. 6. Valiulin, R. A.; Kottani, R.; Kutateladze, A. G. J. Org. Chem. 2006, 71, 5047–5049. 7. Chen, Y.-L.; Leguijt, R.; Redlich, H. J. Carbohydrate Chem. 2007, 26, 279–303. 8. Chen, Y.-L.; Redlich, H.; Bergander, K.; Froehlich, R. Org. Biomol. Chem. 2007, 5,

3330–3339.

155

Corey–Winter olefin synthesis Transformation of diols to the corresponding olefins by sequential treatment with 1,1 -thiocarbonyldiimidazole (TCDI) and trimethylphosphite. Also known as Corey–Winter reductive elimination, or Corey–Winter reductive olefination.

R

R1

OH

OHN N

S

NN

R

R1 O

OS

P(OMe)3 R

R1

H

H

TCDI = Thiocarbonyldiimidazole

R

R1

OH

OH

N N

S

NN

: R

R1

O

OH

NS

N

NN

H R

R1 OH

OImd

S R

R1 O

O

ImdS H

R

R1 O

OS

:P(OMe)3R

R1 O

OS

P(OMe)3

1,3-dioxolane-2-thione (cyclic thiocarbonate)

S P(OMe)3

R

R1 O

OP(OMe)3

R

R1 O

O

P(OMe)3S

:P(OMe)3

R

R1

H

H O

OP(OMe)3 C O↑O P(OMe)3

A mechanism involving a carbene intermediate can also be drawn and is supported by pyrolysis studies:

:P(OMe)3R

R1 O

OS

R

R1 O

OS P(OMe)3

S P(OMe)3R

R1 O

O:P(OMe)3

R

R1 O

OP(OMe)3

156


R

R1

H

H O

OP(OMe)3 :P(OMe)3 C O↑O

Example 12

OO

O

OOH

OH

Cl Cl

S

CH2Cl2, DMAP0 oC, 1 h, 93%

O

O

OO

OO

S

NP

N

Ph

H3C CH3

OO

O

O

40 °C, 88%

Example 24

O

OMOM

HO

HO CF3

N OMe Imd2CS, toluene

reflux, 79%

O

OMOMCF3

N OMeO

OS

P(OMe)3

92%

O

OMOM

N OMeF3C

Single olefin isomer

Example 38

HO

HO

TBSOH

H

OMe

OAc CSCl2, DMAP

CH2Cl2, rt, 96%O

O

TBSOH

H

OMe

OAcS

P(OEt)3, reflux

76%

TBSOH

H

OMe

OAc

157

Example 49

N

OO

CH3O

O

O

CH3H3CO

SO

CH3

P(OMe)3

120 °C, 66%N

OO

CH3

CH3O

O

H3C OCH3

Example 510

AcO OH

OHOAc

Cl

S

OAr(F)5

AcO

OAc

O

O

S

NP

N

PhH3C CH3

AcO

OAc

pyridine, DMAP23 °C, 5 h, 78%

THF, 40 °C 4 h, 65%

Example 611

CbzHNNHCbz

OH

OHPh

PhTCDI, THF

70 oCCbzHN

NHCbz

O

OPh

PhS

CbzHNNHCbz

Ph

Ph

P(OEt)3, 160 oC

77%, 2 steps References 1. Corey, E. J.; Winter, R. A. E. J. Am. Chem. Soc. 1963, 85, 2677−2678. Roland A. E.

Winter works at Ciba Specialty Chemicals Corporation, USA. 2. Corey, E. J.; Carey, F. A.; Winter, R. A. E. J. Am. Chem. Soc. 1965, 87, 934−935. 3. Block, E. Org. React. 1984, 30, 457−566. (Review). 4. Kaneko, S.; Nakajima, N.; Shikano, M.; Katoh, T.; Terashima, S. Tetrahedron 1998,

54, 5485−5506. 5. Crich, D.; Pavlovic, A. B.; Wink, D. J. Synth. Commun. 1999, 29, 359−377. 6. Palomo, C.; Oiarbide, M.; Landa, A.; Esnal, A.; Linden, A. J. Org. Chem. 2001, 66,

4180−4186. 7. Saito, Y.; Zevaco, T. A.; Agrofoglio, L. A. Tetrahedron 2002, 58, 9593−9603. 8. Araki, H.; Inoue, M.; Katoh, T. Synlett 2003, 2401−2403. 9. Brüggermann, M.; McDonald, A. I.; Overman, L. E.; Rosen, M. D.; Schwink, L.;

Scott, J. P. J. Am. Chem. Soc. 2003, 125, 15284−15285. 10. Freiría, M.; Whitehead, A. J.; Motherwell, W. B. Synthesis 2005, 3079−3084. 11. Mergott, D. J. Corey−Winter olefin synthesis. In Name Reactions for Functional

Group Transformations; Li, J. J., Corey, E. J., eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 354−362. (Review).

12. Xu, L.; Desai, M. C.; Liu, H. Tetrahedron Lett. 2009, 50, 552−554.

158

Criegee glycol cleavage Vicinal diol is oxidized to the two corresponding carbonyl compounds using Pb(OAc)4, (lead tetraacetate, LTA).

R2 R4

OHHOR1 R3 Pb(OAc)4

R1 R2

O

R3 R4

OPb(OAc)2 2 HOAc

Pb(OAc)3AcO

R2 R4

OHHOR1 R3

HOAc

R2 R4

OHOR1 R3

(AcO)2PbOAc

R2 R4R1 R3

OPb

O

OAcAcO

R1 R2

O

R3 R4

OPb(OAc)2HOAc

An acyclic mechanism is possible as well. It is much slower than the cyclic mechanism, but is operative when the cyclic intermediate can not form:3

O:

OH

H Pb(OAc)3O

O HOAc

O

O

Pb(OAc)2

O

O

AcO

H

H

PbII(OAc)2

O

O

HOAc

Example 17

N

OPh

CO2Et

OH

OH Pb(OAc)4, K2CO3

PhH, 0 oC, 80%

N

O

CO2Et

O

H

159


Example 29

HPhO2S

OHHOH Pb(OAc)4, CH2Cl2, K2CO3

−15 oC to rt, 1 h, then

Ph3P=CHCO2Me, CH3CN, 80% HPhO2S

CO2MeH

E:Z = 10:1

Example 310

OO

ArAr

HO

HO

Pb(OAc)4, PhH

rt, 1.5 h, quant. OHC O ArH H

Example 411

HOMe

Me

OMe

Me Me

OH

Me

OH

Me OHHO

Me

OMe

Me Me

OH

MeH

OPb(OAc)4, EtOAc

0 oC, 5 min., 99%

References 1 Criegee, R. Ber. 1931, 64, 260–266. Rudolf Criegee (1902−1975) was born in Düssel-

dorf, Germany. He earned his Ph.D. at age 23 under K. Dimroth at Würzburg. Criegee became a professor at Technical Institute at Karlsruhe in 1937, a chair in 1947. He was known for his modesty, mater-of-factness, and his breadth of interests.

2 Mihailovici, M. L.; Cekovik, Z. Synthesis 1970, 209–224. (Review). 3 March, J. Advanced Organic Chemistry, 5th ed., Wiley & Sons: Hoboken, NJ, 2003.

(Review). 4 Danielmeier, K.; Steckhan, E. Tetrahedron: Asymmetry 1995, 6, 1181–1190. 5 Masuda, T.; Osako, K.; Shimizu, T.; Nakata, T. Org. Lett. 1999, 1, 941–944. 6 Lautens, M.; Stammers, T. A. Synthesis 2002, 1993–2012. 7 Hartung, I. V.; Eggert, U.; Haustedt, L. O.; Niess, B.; Schäfer, P. M.; Hoffmann, H. M.

R. Synthesis 2003, 1844–1850. 8 Gaul, C.; Njardarson, J. T.; Danishefsky, S. J. J. Am. Chem. Soc. 2003, 125, 6042–

6043. 9 Gorobets, E.; Stepanenko, V.; Wicha, J. Eur. J. Org. Chem. 2004, 783–799. 10 Prasad, K. R.; Anbarasan, P. Tetrahedron 2006, 63, 1089–1092. 11 Perez, L. J.; Micalizio, G. C. Synthesis 2008, 627–648.

160

Criegee mechanism of ozonolysis

O3OO

O

OO

O OO

O:1,3-dipolar

cycloaddition

primary ozonide (1,2,3-trioxolane)

OO

O

OO

O

1,3-dipolar

cycloaddition

zwitterionic peroxide secondary ozonide (1,2,4-trioxolane) (Criegee zwitterion)

also known as “carbonyl oxide” Example 17

HO

HO

O3, EtOAc, −78 oC, then

Ac2O, Et3N, DMAP, −78 oC to rt, 75%

O

OH

H

O OAc

Example 28

O3, CH2Cl2

−70 oC

OO

O

O

MeOH

quant. CO2Me

CO2Me

OMe

H References 1. (a) Criegee, R.; Wenner, G. Ann. 1949, 564, 9−15. (b) Criegee, R. Rec. Chem. Prog.

1957, 18, 111−120. (c) Criegee, R. Angew. Chem. 1975, 87, 765−771. 2. Bunnelle, W. H. Chem. Rev. 1991, 91, 335−362. (Review). 3. Kuczkowski, R. L. Chem. Soc. Rev. 1992, 21, 79−83. (Review). 4. Marshall, J. A.; Garofalo, A. W. J. Org. Chem. 1993, 58, 3675−3680. 5. Ponec, R.; Yuzhakov, G.; Haas, Y.; Samuni, U. J. Org. Chem. 1997, 62, 2757−2762. 6. Dussault, P. H.; Raible, J. M. Org. Lett. 2000, 2, 3377−3379. 7. Jiang, L.; Martinelli, J. R.; Burke, S. D. J. Org. Chem. 2003, 68, 1150−1153. 8. Schank, K.; Beck, H.; Pistorius, S. Helv. Chim. Acta 2004, 87, 2025−2049.

161


Curtius rearrangement Alkyl-, vinyl-, and aryl-substituted acyl azides undergo thermal 1,2-carbon-to-nitrogen migration with extrusion of dinitrogen — the Curtius rearrangement — producing isocyantes. Reaction of the isocyanate products with nucleophiles, of-ten in situ, provides carbamates, ureas, and other N-acyl derivatives. Alterna-tively, hydrolysis of the isocyanates leads to primary amines.

R N3

O Heat

R

Nu–H NH

Nu

O

R

NH2RCurtius

RearrangementN

CO

H2O–CO2

The thermal rearrangement:

R Cl

O NaN3

R N3

O ΔR N C ON2↑

H2OR NH3 CO2↑

R Cl

O

R N

O

N3N NR N3

O

R Cl

N3O

R N

O

N N

Δ N2↑ R N C O

:OH2

H

R NH2 CO2↑RHN O

OH

:B


The photochemical rearrangement:

R N

O

N NN2↑

hν

R N:

O

Nitrene

R N C O R NH2 CO2↑R N:

O

162


Example 1, The Shioiri–Ninomiya–Yamada modification2

NO2H

HO

O

O

NO2H

O21

NH

OMe

O

21

DPPA, Et3NPhH, Δ

then MeOH, Δ89%

DPPA = diphenylphosphoryl azide

Example 23

O

O O

CO2MeHO2C DPPA, Et3N, t-BuOH

80 oC, 16 h, 64%

O

O O

CO2MeBocHN

Example 34

OOCO2H EtO(CO)Cl, then NaN3

EtOH, PhH, reflux, 55% OONHCO2Et

Example 4, The Weinstock variant of the Curtius rearrangement6

NMe

NH

NCOOH

H

H

Cl OEt

O

i-PrNEt2, acetone, 0 °C

then NaN3, rt, 12 h75% N

Me

NH

NHN

H

H

OEt

O

Example 57

PhO

Cl

1. n-Bu3SnN3 PhBr, 0 °C to RT 30 min., 97%

2. t-BuOH/o-xylene Δ, 6 h, 77%

Ph NHBoc

163

Example 6, The Lebel modification8

O

BnOOBn

OBn

CO2HOMPM 2 equiv DPPA

0.1 equiv Ag2CO32 equivK2CO3

PhH, Δ, 16 h, 81%(2 equiv)

O

BnOOBn

OBn

OMeHO O

BnOOBn

OBn

HN

OMPMO

BnOOBn

OBn

OMeO

O

References 1. Curtius, T. Ber. 1890, 23, 3033−3041. Theodor Curtius (1857−1928) was born in Du-

isburg, Germany. He studied music before switching to chemistry under Bunsen, Kolbe, and von Baeyer before succeeding Victor Meyer as a Professor of Chemistry at Heidelberg. He discovered diazoacetic ester, hydrazine, pyrazoline derivatives, and many nitrogen-heterocycles. Curtius also sang in concerts and composed music.

2. Ng, F. W.; Lin, H.; Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 9812–9824. 3. van Well, R. M.; Overkleeft, H. S.; van Boom, J. H.; Coop, A.; Wang, J. B.; Wang, H.;

van der Marel, G. A.; Overhand, M. Eur. J. Org. Chem. 2003, 1704–1710. 4. Dussault, P. H.; Xu, C. Tetrahedron Lett. 2004, 45, 7455–7457. 5. Holt, J.; Andreassen, T.; Bakke, J. M.; Fiksdahl, A. J. Heterocycl. Chem. 2005, 42,

259–264. 6. Crawley, S. L.; Funk, R. L. Org. Lett. 2006, 8, 3995–3998. 7. Tada, T.; Ishida, Y.; Saigo, K. Synlett 2007, 235–238. 8. Sawada, D.; Sasayama, S.; Takahashi, H.; Ikegami, S. Eur. J. Org. Chem. 2007, 1064–

1068. 9. Rojas, C. M. Curtius Rearrangements. In Name Reactions for Homologations-Part II;


164

Dakin oxidation Oxidation of aryl aldehydes or aryl ketones to phenols using basic hydrogen per-oxide conditions. Cf. A variant of Baeyer–Villiger oxidation.

HCO2HO CHOH2O2, NaOH

45−50 oCHO OH

OO

H

HOH

OHO

OH

O

HO

aryl

migration

OHO

H OHOhydrolysisHO O

HO

OH

HO OHHO O

H workup

Example 16

OBn

CHO

NHCO2t-Bu

CO2H

2.5 eq. 30% H2O2

4% (PhSe)2CH2Cl2, 18 h

OBnO

NHCO2t-Bu

CO2H

CHONH3, MeOH

1 h, 78%

OBnOH

NHCO2t-Bu

CO2H

Example 27

HO

CHO urea-hydrogen peroxide (UHP)

solvent-free, 55 oC, 3 h, 83% HO

OH

Example 3, Improved solvent-free Dakin oxidation protocol9

MeO

BnO

CHO 1.5 equiv m-CPBA, neat, 5 min.

then10% aq. NaOH 85%

MeO

BnO

OH

165


Example 410

NH

OMe

MeOCHO

H2O2, HCl

MeOH, THF50%

NH

O

MeOO

References: 1. Dakin, H. D. Am. Chem. J. 1909, 42, 477−498. Henry D. Dakin (1880−1952) was

born in London, England. During WWI, he invented his hypochlorite solution (Da-kin’s solution), which became a popular antiseptic for the treatment of wounds. After the Great War, he emmigrated to New York, where he investigated the B vitamins.

2. Hocking, M. B.; Bhandari, K.; Shell, B.; Smyth, T. A. J. Org. Chem. 1982, 47, 4208−4215.

3. Matsumoto, M.; Kobayashi, H.; Hotta, Y. J. Org. Chem. 1984, 49, 4740−4741. 4. Zhu, J.; Beugelmans, R.; Bigot, A.; Singh, G. P.; Bois-Choussy, M. Tetrahedron Lett.

1993, 34, 7401−7404. 5. Guzmán, J. A.; Mendoza, V.; García, E.; Garibay, C. F.; Olivares, L. Z.; Maldonado,

L. A. Synth. Commun. 1995, 25, 2121−2133. 6. Jung, M. E.; Lazarova, T. I. J. Org. Chem. 1997, 62, 1553−1555. 7. Varma, R. S.; Naicker, K. P. Org. Lett. 1999, 1, 189−191. 8. Lawrence, N. J.; Rennison, D.; Woo, M.; McGown, A. T.; Hadfield, J. A. Bioorg.

Med. Chem. Lett. 2001, 11, 51−54. 9. Teixeira da Silva, E.; Camara, C. A.; Antunes, O. A. C.; Barreiro, E. J.; Fraga, C. A.

M. Synth. Commun. 2008, 38, 784−788. 10. Alamgir, M.; Mitchell, P. S. R.; Bowyer, P. K.; Kumar, N.; Black, D. St. C. Tetrahe-

dron 2008, 64, 7136−7142.

166

Dakin−West reaction

The direct conversion of an α-amino acid into the corresponding α-acetylamino-alkyl methyl ketone, via oxazoline (azalactone) intermediates. The reaction pro-ceeds in the presence of acetic anhydride and a base, such as pyridine, with the evolution of CO2.

R CO2H

NH2

Ac2O R

NHAc

O

CO2↑

R CO2H

NH2

O

OO

R

HN

O

OH

O

OO

AcO

R

NH

OOH

OH

:

H

NO

R OHO

H

NO

RO OH

O

NO

RO

H

O

OH

AcO H

H

oxazolone (azalactone) intermediate

HN O

RO

O

O

H N OH

RO

H

R

NHAc

O− CO2 tautomerization

Example 16

Me CO2H

NH2

Me

NHAcMe

OAc2O, AcOH, Et3N

DMAP, 50 oC, 14 h, > 90%

Example 27

NH

OBn

O OOHO

Ac2O, pyr.

90 oC, 2 h, 58% NH

OBn

O OO Me

167


Example 3, Green Dakin–West reaction using the heteropoly acid catalyst, ace-tonitrile is a reactant9

CHO

NC

OPh

CH3CN, H3PW12O40

CH3COClrt, 60 min., 75% NHAc

Ph

O

CN

Example 4, Acetonitrile is a reactant10

CHO

R1

O

R2

CH3CN10 mol% Ln(OTf)3

CH3COCl, reflux78−87% NHAc O

R2R1

References: 1. Dakin, H. D.; West, R. J. Biol. Chem. 1928, 78, 91, 745, and 757. In 1928, Henry Da-

kin and Rudolf West, a clinician, reported on the reaction of α-amino acids with acetic anhydride to give α-acetamido ketones via azalactone intermediates. Interestingly, one year before this paper by Dakin and West, Levene and Steiger had observed both tyrosine and α-phenylananine gave “abnormal” products when acetylated under these conditions.2,3 Unfortunately, they were slow to identify the products and lost an op-portunity to be immortalized by a name reaction.

2. Buchanan, G. L. Chem. Soc. Rev. 1988, 17, 91–109. (Review). 3. Jung, M. E.; Lazarova, T. I. J. Org. Chem. 1997, 62, 1553–1555. 4. Kawase, M.; Hirabayashi, M.; Koiwai, H.; Yamamoto, K.; Miyamae, H. Chem. Com-

mun. 1998, 641–642. 5. Kawase, M.; Hirabayashi, M.; Saito, S. Recent Res. Dev. Org. Chem. 2001, 4,

283−293. (Review). 6. Fischer, R. W.; Misun, M. Org. Proc. Res. Dev. 2001, 5, 581–588. 7. Godfrey, A. G.; Brooks, D. A.; Hay, L. A.; Peters, M.; McCarthy, J. R.; Mitchell, D. J.

Org. Chem. 2003, 68, 2623–2632. 8. Khodaei, M. M.; Khosropour, A. R.; Fattahpour, P. Tetrahedron Lett. 2005, 46, 2105–

2108. 9. Rafiee, E.; Tork, F.; Joshaghani, M. Bioorg. Med. Chem. Lett. 2006, 16, 1221–1226. 10. Tiwari, A. K.; Kumbhare, R. M.; Agawane, S. B.; Ali, A. Z.; Kumar, K. V. Bioorg.

Med. Chem. Lett. 2008, 18, 4130–4132.

168

Darzens condensation α,β-Epoxy esters (glycidic esters) from base-catalyzed condensation of α-haloesters with carbonyl compounds.

R CO2Et

X

R1 R2

O OEt OR1

R2 CO2EtR

R

XH

OEt

R

X R1 R2

O

OEt

OOEt

O

R2 RO

R1

XCO2Et

OR1

R2 CO2EtR

intramolecular

SN2

Example 14

O

Cl CO2EtO

CO2Ett-BuOK, t-BuOH

10 °C, 85–95% Example 26

H3C Br

t-BuMe2Si

O LDA, THF, –78 °C then H3C

t-BuMe2Si

O OPh

H

H

66%, 90% dePhCHO, –90 °C

Example 39

XNPh2

X = Cl, Br, I

O

Ar H

O

Solid MOH, M = Na, K, RbCH2Cl2, 4−24 h, rt

O

Ar CONPh2

O

Ar CONPh2

N

O O

NCo

OMeMeO 2 mol%

ee up to 50%

ee up to 43%

169


Example 4, the phenyl ring substituting for the carbonyl to acidify the protons10

Br PO(OMe)2

OBr

MeODBU, CH3CN

6 h, 48%

O PO(OMe)2

BrOMe

References 1 Darzens, G. A. Compt. Rend. Acad. Sci. 1904, 139, 1214–1217. George Auguste Dar-

zens (1867−1954), born in Moscow, Russia, studied at École Polytechnique in Paris and stayed there as a professor.

2 Newman, M. S.; Magerlein, B. J. Org. React. 1949, 5, 413–441. (Review). 3 Ballester, M. Chem. Rev. 1955, 55, 283–300. (Review). 4 Hunt, R. H.; Chinn, L. J.; Johnson, W. S. Org. Syn. Coll. IV, 1963, 459. 5 Rosen, T. Darzens Glycidic Ester Condensation In Comprehensive Organic Synthesis;

Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991, Vol. 2, pp 409–439. (Re-view).

6 Enders, D.; Hett, R. Synlett 1998, 961−962. 7 Davis, F. A.; Wu, Y.; Yan, H.; McCoull, W.; Prasad, K. R. J. Org. Chem. 2003, 68,

2410−2419. 8 Myers, B. J. Darzens Glycidic Ester Condensation. In Name Reactions in Heterocyclic


9 Achard, T. J. R.; Belokon, Y. N.; Ilyin, M.; Moskalenko, M.; North, M.; Pizzato, F. Tetrahedron Lett. 2007, 48, 2965−2969.

10 Demir, A. S.; Emrullahoglu, M.; Pirkin, E.; Akca, N. J. Org. Chem. 2008, 73, 8992−8997.

170

Delépine amine synthesis The reaction between alkyl halides and hexamethylenetetramine, followed by cleavage of the resulting salt with ethanolic HCl to yield primary amines. Cf. Gabriel synthesis, where the product is also an amine and Sommelet reaction, where the product is an aldehyde. The Delépine works well for active halides such as benzyl, allyl halides, and α-halo-ketones.

Ar X NN

N

N

NN

N

NAr

XAr NH3 X

hexamethylenetetramine

[ArCH2C6H12N4]+X− + 3 HCl + 6 H2O

ArCH2NH2•HX + 6 CH2O + 3 NH4Cl

NN

N:

N

NN

N

NAr

Ar X

SN2

X

:

NN

N

NAr

H2O:

NN

N

NAr

HO H

OCH2

NN

N

NAr

H

Ar NH3

X

Example 13

Br OH

O1. (CH2)6N4, NaHCO3 15 h, EtOH, H2O

2. HCl, EtOH, reflux, 15 h, 85% H2N OH

O

Example 27

NN

BrBr


CH2Cl2, refux, 5 h, then−30 oC

171


NN

BrN4C6H12

+Br−

conc. HCl, EtOH

reflux, 1 d78%, 2 steps

NN

BrNH2

Example 38

1. hexamethylenetetramine CHCl3, reflux, 6 h

2. 2 N HCl, EtOH, 100 oC, 15 min.

O O

Br

O

OO O O

OOO

O

O O

NH2

O

OO O O

OOO

O

Example 49

BrO

NO2


CHCl3, rt, 18 h

O

NO2

NN

N

N

Br

NH3O

NO2

Br48% HBr

CH3OH, rt, 5 d

89% 2 steps

References 1. (a) Delépine, M. Bull. Soc. Chim. Paris 1895, 13, 352−355; (b) Delépine, M. Bull.

Soc. Chim. Paris 1897, 17, 292−295. Stephe Marcel Delépine (1871−1965) was born in St. Martin le Gaillard, France. He was a professor at the Collège de France after working for M. Bertholet at that institute. Delépine’s long and fruitful career in sci-ence encompassed organic chemistry, inorganic chemistry, and pharmacy.

2. Galat, A.; Elion, G. J. Am. Chem. Soc. 1939, 61, 3585−3586. 3. Wendler, N. L. J. Am. Chem. Soc. 1949, 71, 375−384. 4. Quessy, S. N.; Williams, L. R.; Baddeley, V. G. J. Chem. Soc., Perkin Trans. 1 1979,

512−516. 5. Blažzevi , N.; Kolnah, D.; Belin, B.; Šunji , V.; Kafjež, F. Synthesis 1979, 161−176.

(Review). 6. Henry, R. A.; Hollins, R. A.; Lowe-Ma, C.; Moore, D. W.; Nissan, R. A. J. Org.

Chem. 1990, 55, 1796−1801. 7. Charbonnière, L. J.; Weibel, N.; Ziessel, R. Synthesis 2002, 1101−1109. 8. Xie, L.; Yu, D.; Wild, C.; Allaway, G.; Turpin, J.; Smith, P. C.; Lee, K.-H. J. Med.

Chem. 2004, 47, 756−760. 9. Loughlin, W. A.; Henderson, L. C.; Elson, K. E.; Murphy, M. E. Synthesis 2006,

1975−1980.

172

de Mayo reaction [2 + 2]-Photochemical cyclization of enones with olefins is followed by a retro-aldol reaction to give 1,5-diketones.

O

OH

CO2Me hνO

OH

O

O CO2MeCO2Me

Head-to-tail alignment gives the major product:

O

OH

hν, [2 + 2]

cycloadditionCO2Me

O

OHCO2Meδ

δ

δ

δ

retro-aldol

cyclobutane cleavage

O

O CO2Me

H O

O CO2Me

O

OH

CO2Me

Head-to-head alignment gives the minor regioisomer:

OCO2Me

OH

hν, [2 + 2]

cycloaddition

O

OH

CO2Me

retro-aldol

cyclobutane cleavage

O

O

H O

O

CO2Me CO2Me

O

O

CO2Me

H

Example 13

OPh

O

O

1. hν, cyclohexane, 83%

2. H2 (3 atm), Pd/C (10%) HOAc, rt, 18 h, 83%

O

O

173


Example 26

O

OH

hν, MeOH

> 90%

O

HO

O

O

H

H

H

H

Example 39

N

O

O

HO

hv, Pyrex filter

CH3CN, rt, 1.5 h, 72% N

O

OH

O

N

O

O

O

HH

Example 410

O

R

O

O hv

Et2O

O

O

H

OR

H

H

O

O

H

OR

H

H

R = H 70% 100 : 0R = Me 58% 50 : 50R = t-Bu 72% 0 : 100

References 1. (a) de Mayo, P.; Takeshita, H.; Sattar, A. B. M. A. Proc. Chem. Soc., London 1962,

119. Paul de Mayo received his doctorate from Sir Derek Barton at Birkbeck College, University of London. He later became a professor at the University of Western On-tario in London, Ontario, Canada, where he discovered the de Mayo reaction. (b) Challand, B. D.; Hikino, H.; Kornis, G.; Lange, G.; de Mayo, P. J. Org. Chem. 1969, 34, 794−806.

2. de Mayo, P. Acc. Chem. Res. 1971, 4, 41−48. (Review). 3. Oppolzer, W.; Godel, T. J. Am. Chem. Soc. 1978, 100, 2583−2584. 4. Oppolzer, W. Pure Appl. Chem. 1981, 53, 1181−1201. (Review). 5. Kaczmarek, R.; Blechert, S. Tetrahedron Lett. 1986, 27, 2845−2848. 6. Disanayaka, B. W.; Weedon, A. C. J. Org. Chem. 1987, 52, 2905−2910. 7. Crimmins, M. T.; Reinhold, T. L. Org. React. 1993, 44, 297−588. (Review). 8. Quevillon, T. M.; Weedon, A. C. Tetrahedron Lett. 1996, 37, 3939−3942. 9. Minter, D. E.; Winslow, C. D. J. Org. Chem. 2004, 69, 1603−1606. 10. Kemmler, M.; Herdtweck, E.; Bach, T. Eur. J. Org. Chem. 2004, 4582−4595.

174

Demjanov rearrangement Carbocation rearrangement of primary amines via diazotization to give alcohols through C−C bond migration.

NH2

HNO2

OHOH

2 HON

OH

H2ON

O

− H2OON

OH

ON

ON

O

ON

ON

O

N N O− HNO2

NH2

:

H

N N OH2

H

:

− H2ON NN N OH

− N2

N OH

N

OH

H

: − H

− N2

OH

OH

H

NN

:

− Hor

Example 13

NPh

NH2 NOH

Ph NPh

NaNO2, HOAc

100 oC, 2 h30% 16%

Example 26

HNH2 NaNO2, AcOH/H2O

100−110 oC, 2 h, 61%

H OH

175


Example 37

O

NH2

NaNO2, 0−4 oC

0.25 M H2SO4/H2O

O

HO

O

OH

Example 48

MeO

OO

H

H

H2N

5 equiv NaNO25 equiv AcOH

H2O/THF (1:1)0 oC, 2 h, 61%

O

O

H

HO

MeOH

References 1. Demjanov, N. J.; Lushnikov, M. J. Russ. Phys. Chem. Soc. 1903, 35, 26−42. Nikolai

J. Demjanov (1861−1938) was a Russian chemist. 2. Smith, P. A. S.; Baer, D. R. Org. React. 1960, 11, 157−188. (Review). 3. Diamond, J.; Bruce, W. F.; Tyson, F. T. J. Org. Chem. 1965, 30, 1840−184. 4. Kotani, R. J. Org. Chem. 1965, 30, 350−354. 5. Diamond, J.; Bruce, W. F.; Tyson, F. T. J. Org. Chem. 1965, 30, 1840−1844. 6. Nakazaki, M.; Naemura, K.; Hashimoto, M. J. Org. Chem. 1983, 48, 2289−2291. 7. Fattori, D.; Henry, S.; Vogel, P. Tetrahedron 1993, 49, 1649−1664. 8. Kürti, L.; Czakó, B.; Corey, E. J. Org. Lett. 2008, 10, 5247−5250. 9. Curran, T. T. Demjanov and Tiffeneau–Demjanov Rearrangement. In Name Reactions


176

Tiffeneau–Demjanov rearrangement Carbocation rearrangement of β-aminoalcohols via diazotization to afford car-bonyl compounds through C−C bond migration.

OH

NH2

NaNO2

H

O

Step 1, Generation of N2O3

HON

OH

H2ON

O

− H2OON

OH

ON

ON

O− H

Step 2, Transformation of amine to diazonium salt

ON

ON

OOH

NH2

OH

N:

HN OHONO

HOH

N N OH2:

− H2O OH

NN

OH

N N OH

Step 3, Ring-expansion via rearrangement

O

− N2OH − H

ON

N H:

Example 15

HO

H2NO

ONaNO2, H2O

AcOH, 0 oC,then rt−60 oC 76% yield 90 : 6

177

Example 26

NOMe

OH

AcOH•H2N CONEt2

NaNO2, AcOH

H2O, 0−5 oC60%

O N2

ONEt2H

NOMe

OCONEt2

Example 37

NH2

OHNaNO2, AcOH/H2O, 0 oC, 1 h

then reflux 1 h, 98%O

Example 49

SiMe3

HO NH2 NaNO2

AcOH

O O

SiMe3

SiMe3

72% 28% References 1. Tiffeneau, M.; Weill, P.; Tehoubar, B. Compt. Rend. 1937, 205, 54−56. 2. Smith, P. A. S.; Baer, D. R. Org. React. 1960, 11, 157−188. (Review). 3. Parham, W. E.; Roosevelt, C. S. J. Org. Chem. 1972, 37, 1975−1979. 4. Jones, J. B.; Price, P. Tetrahedron 1973, 29, 1941−1947. 5. Miyashita, M.; Yoshikoshi, A. J. Am. Chem Soc. 1974, 96, 1917–1925. 6. Steinberg, N. G.; Rasmusson, G. H.; Reynolds, G. F.; Hirshfield, J. H.; Arison, B. H.

J. Org. Chem. 1984, 49, 4731–4733. 7. Stern, A. G.; Nickon, A. J. Org. Chem. 1992, 57, 5342−5352. 8. Fattori, D.; Henry, S.; Vogel, P. Tetrahedron 1993, 49, 1649–1664. 9. Chow, L.; McClure, M.; White, J. Org. Biomol. Chem. 2004, 2, 648−650. 10. Curran, T. T. Demjanov and Tiffeneau–Demjanov Rearrangement. In Name Reactions


178

Dess−Martin periodinane oxidation Oxidation of alcohols to the corresponding carbonyl compounds using triace-toxyperiodinane. The Dess–Martin periodinane, 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, is one of the most useful oxidant for the conversion of primary and secondary alcohols to their corresponding aldehyde or ketone prod-ucts, respectively.

R1 R2

OHO

I

O

AcO OAcOAc

R1 R2

O

Preparation,1,2 The oxone preparation is much safer and easier than KBrO3. The IBX intermediate that comes out of it has proven to be far less explosive12

ICO2H

KBrO3, H2SO4, 93%

or 1.3 equiv OxoneH2O, 70 oC, 3 h

79-81%

OI

O

HO O Ac2O, 0.5% TsOH

80 oC, 2 h, 91%O

I

O

AcOOAc

OAc

IBX

However, The Dess–Martin periodinane is hydrolyzed by moisture to o-iodoxybenzoic acid (IBX), which is a more powerful oxidating agent3

OI

O

HO O

OI

O

AcOOAc

OAc

IBX

H2O

CH2Cl2

Mechanism1

OI

O

AcOO

OAc

OI

O

AcOOAc

OAc:O

H

R1

H

R1R2

R2 OAcSN2

OI

O

OAc

R1 R2

OAcOH

179


Example 16

OI

O

AcO OAcOAc

O

OOOH

OCH2Cl2, 2 h, 67% O

OOO

O

Example 2, An atypical Dess–Martin periodinane reactivity7

OI

O

AcO OAcOAc

NaN3, CH2Cl20 oC, 3 h, 86%

N

CHO

N

N3

O

Example 310

t-BuO2CNH

NH

HN

NHBoc

O

O CO2t-Bu

SS N

HOH

O

Dess−Martin periodinane

CH2Cl2, rt, 1 h, 70%

t-BuO2CNH

NH

HN

NHBoc

O

O CO2t-Bu

SS N

HO

O

Example 411

O

OHBnO

BnO OBnO

O

NHAcAllO OTDS

PMBO Dess−Martin periodinane

CH2Cl2, rt, 2 h, 90%

O

OBnO

BnO OBnO

O

NHAcAllO OTDS

PMBO

TDS = Thexyldimethylsilyl

180

References 1. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155−4156. James Cullen (J.

C.) Martin (1928−1999) had a distinguished career spanning 36 years both at the Uni-versity of Illinois at Urbana-Champaign and Vanderbilt University. J. C.’s formal training in physical organic chemistry with Don Pearson at Vanderbilt and P. D. Bart-lett at Harvard prepared him well for his early studies on carbocations and radicals. However, it was his interest in understanding the limits of chemical bonding that lead to his landmark investigations into hypervalent compounds of the main group ele-ments. Over a 20-year period the Martin laboratories successfully prepared unprece-dented chemical structures from sulfur, phosphorus, silicon and bromine while the ul-timate “Holy Grail” of stable pentacoordinate carbon remained elusive. Although most of these studies were driven by J. C.’s fascination with unusual bonding schemes, they were not without practical value. Two hypervalent compounds, Martin’s sulfu-rane (for dehydration, page 365) and the Dess−Martin periodinane have found wide-spread application in synthetic organic chemistry. J. C. Martin and his student Daniel Dess developed this methodology at the University of Illinois at Urbana. (Martin’s bi-ography was kindly supplied by Prof. Scott E. Denmark). (b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277−7287.

2. Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899. 3. Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549−7552. 4. Speicher, A.; Bomm, V.; Eicher, T. J. Prakt. Chem. 1996, 338, 588−590. (Review). 5. Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. Angew. Chem., Int. Ed. 2000, 39,

622−625. 6. Bach, T.; Kirsch, S. Synlett 2001, 1974−1976. 7. Bose, D. S.; Reddy, A. V. N. Tetrahedron 2003, 44, 3543−3545. 8. Tohma, H.; Kita, Y. Adv. Synth. Cat. 2004, 346, 111−124. (Review). 9. Holsworth, D. D. Dess−Martin oxidation. In Name Reactions for Functional Group

Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ; 2007, pp 218−236. (Review).

10. More, S. S.; Vince, R. J. Med. Chem. 2008, 51, 4581−4588. 11. Crich, D.; Li, M.; Jayalath, P. Carbohydrate Res. 2009, 344, 140−144. 12. Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537−4538.

181

Dieckmann condensation The Dieckmann condensation is the intramolecular version of the Claisen conden-sation.

CO2EtCO2Et NaOEt O

CO2Et

CO2Et O

OEtH O OEt

OOEt

enolate

formation

5-exo-trig

ring closure

OEt

CO2Et

OEtO O

CO2Et

Example 16

N

H OBn

OTBSO

MeO2CNMeO2C

H OBn

OTBS

MeO2C

NaHMDS, THF

−78 oC, 58%

Example 28

O

ON

1. t-BuOK, Tol., reflux, 5 min.

2. 18 N H2SO4, THF, 4 h 61% for two steps

MeO2C

ON

EtO2C

Example 39

Ar1 OCH2CF3O

OAr2

O

3 equiv KOt-Bu, DMF

0 oC, 30−90 min., 75−88%

Ar1O

O

Ar2

OH

182


Example 410

HN

CO2MeO

NCO2Me

1. K2CO3, DMSO, 24 h2. 60 oC, 48 h

3. 5 oC, 2 M HCl, 1 h 63%

NH

O N

CO2Me

O

OMe

HN

N

O

O CO2Me

HN

N

O

HO CO2Me

References 1. Dieckmann, W. Ber. 1894, 27, 102. Walter Dieckman (1869−1925), born in Ham-

burg, Germany, studied with E. Bamberger at Munich. After serving as an assistant to von Baeyer in his private laboratory, he became a professor at Munich. At age 56, he died while working in his chemical laboratory at the Barvarian Academy of Science.

2. Davis, B. R.; Garratt, P. J. Comp. Org. Synth. 1991, 2, 795−863. (Review). 3. Shindo, M.; Sato, Y.; Shishido, K. J. Am. Chem. Soc. 1999, 121, 6507−6508. 4. Balo, C.; Fernández, F.; García-Mera, X.; López, C. Org. Prep. Proced. Int. 2000, 32,

563−566. 5. Deville, J. P.; Behar, V. Org. Lett. 2002, 4, 1403−1405. 6. Rabiczko, J.; Urba czyk-Lipkowska, Z.; Chmielewski, M. Tetrahedron 2002, 58,

1433−1441. 7. Ho, J. Z.; Mohareb, R. M.; Ahn, J. H.; Sim, T. B.; Rapoport, H. J. Org. Chem. 2003,

68, 109-114. 8. de Sousa, A. L.; Pilli, R. A. Org. Lett. 2005, 7, 1617−1617. 9. Bernier, D.; Brueckner, R. Synthesis 2007, 2249−2272. 10. Koriatopoulou, K.; Karousis, N.; Varvounis, G. Tetrahedron 2008, 64, 10009−10013. 11. Takao, K.-i.; Kojima, Y.; Miyashita, T.; Yashiro, K.; Yamada, T.; Tadano, K.-i.

Heterocycles 2009, 77, 167−172.

183

Diels–Alder reaction The Diels–Alder reaction, inverse electronic demand Diels–Alder reaction, as well as the hetero-Diels–Alder reaction, belong to the category of [4+2]-cycloaddition reactions, which are concerted processes. The arrow pushing here is merely illus-trative.

HOMO‡

EDGEWG Δ

EDGEWG

EDGEWG

LUMO

‡

diene dienophile adduct

EDG = electron-donating group; EWG = electron-withdrawing group

Example 16

OMeCO2Et

Me3SiO

OMe

CO2EtH

Me3SiO

AcO

OAc

hydroquinone

180 oC, 1.5 h, 62%

‡

The Danishefsky diene Alder’s endo rule

OMe

AcO

OMe

CO2Et

Me3SiO AcOOSiMe3

EtO2C

4:1 α-OMe : β-OMe

Example 2, Intramolecular Diels–Alder reaction7

O

O

FBr4-BIPOL, AlMe3

CH2Cl2, rt, 8 h, 65%

O

OF

H

184


Example 3, Asymmetric Diels–Alder reaction5,8

94% ee90:10 endo:exo

CO2CH2CF3

NB

O

H

Br3Al

PhPh

4 mol%, CH2Cl2−78 oC, 12 h, 99%

OCH2CF3

OCH3O

O

Example 4, Retro-Diels–Alder reaction4,9

MeO2C

OH

H

MeAlCl2, maleic anhydride

CH2Cl2, μ-wave, 110 oC1 min., 74−84%

MeO2C

O

Example 5, Intramolecular Diels–Alder reaction11

O

OH

Me

HO

OOO

Me

Me2AlCl, CH2Cl2

−78 to −30 oC, 71%

References 1. Diels, O.; Alder, K. Ann. 1928, 460, 98−122. Otto Diels (Germany, 1876−1954) and

his student, Kurt Alder (Germany, 1902−1958), shared the Nobel Prize in Chemistry in 1950 for development of the diene synthesis. In this article they claimed their terri-tory in applying the Diels–Alder reaction in total synthesis: “We explicitly reserve for ourselves the application of the reaction developed by us to the solution of such prob-lems.”

2. Oppolzer, W. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 5, 315−399. (Review).

3. Weinreb, S. M. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 5, 401−449. (Review).

4. (a) Rickborn, B. The retro-Diels−Alder reaction. Part I. C−C dienophiles in Org. Re-act. John Wiley & Sons, 1998, 52. (b) Rickborn, B. The retro-Diels−Alder reaction. Part II. Dienophiles with one or more heteroatom in Org. React. John Wiley & Sons, 1998, 53.

5. Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650−1667. (Review).

185

6. Wang, J.; Morral, J.; Hendrix, C.; Herdewijn, P. J. Org. Chem. 2001, 66, 8478−8482. 7. Saito, A.; Yanai, H.; Sakamoto, W.; Takahashi, K.; Taguchi, T. J. Fluorine Chem.

2005, 126, 709−714. 8. Liu, D.; Canales, E.; Corey, E. J. J. Am. Chem. Soc. 2007, 129, 1498−1499. 9. Iqbal, M.; Duffy, P.; Evans, P.; Cloughley, G.; Allan, B.; Lledo, A.; Verdaguer, X.;

Riera, A. Org. Biomol. Chem. 2008, 6, 4649−4661. 10. Ibrahim-Ouali, M. Steroids 2009, 74, 133−162. 11. Gao, S.; Wang, Q.; Chen, C. J. Am. Chem. Soc. 2009, 131, 1410−1412.

Inverse electronic demand Diels–Alder reaction

HOMO

‡EWG

EDG

LUMOEWGEDG Δ

EWGEDG

‡

Diene dienophile adduct

Example 12

O

BOO

EtO

3 mol% Cat., BaO, rt, 5 h

O

BOO

OEt

Me

NCr

OClO

Cat. =

OHCCO2Et

O OEtOH

HEtO2C

110 oC, 48 h76% 2 steps 98% dr, 95% ee

Example 23

H R1

O

ClR2 R3

O

N

O

NN

Mes

Cl

5 mol%

1.5 equiv NEt3, EtOAc, rt, 6 h

O

O

R1

R3R2

70−90% yield95−99% ee

186

Example 3, Catalytic asymmetric inverse-electron-demand Diels–Alder reaction4

NO2S

N

Ph

Ph5 equiv10 mol% Ni(ClO4)2•6H2O10 mol% DBFOX-Ph

CH2Cl2, rt, 73% yield

OEtOEt

Ph

SO2ArPh

97:3 endo/exo88% ee

DBFOX-Ph =O

ON N

O

Ph Ph

Example 45

O

OEWG

EWG = CONEt2, CO2Et,COR, SO2Ph, CN, Aryl

OMe

MeO OMe

MeO

1.solvent, 135 oC

2. Et2O•BF3, CH2Cl2, rt

O

OEWG

OMeOMe

O

OEWG

EWG = CONEt2, CO2Et,COR, SO2Ph, CN, Aryl

MeO NR2

MeO

PhH, Δ O

OEWG

OMe

References 1. Boger, D. L.; Patel, M. Prog. Heterocycl. Chem. 1989, 1, 30–64. (Review). 2. Gao, X.; Hall, D. G. J. Am. Chem. Soc. 2005, 127, 1628–1629. 3. He, M.; Uc, G. J.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 15088–15089. 4. Esquivias, J.; Gomez Arrayas, R.; Carretero, J. C. J. Am. Chem. Soc. 2007, 129, 1480–

1481. 5. Dang, A.-T.; Miller, D. O.; Dawe, L. N.; Bodwell, G. J. Org. Lett. 2008, 10, 233–236.

Hetero-Diels–Alder reaction Heterodiene addition to dienophile or heterodienophile addition to diene. Typical hetero-Diels–Alder reactions are aza-Diels–Alder reaction and oxo-Diels–Alder reaction.

187

YYX X

X XXYY

X

e.g.:

NSO2Ph

OEt

Ph

NSO2Ph

Ph OEtH

EtO2CEtO2C

NSO2Ph

Ph

EtO2C OEt

‡

Example 1, Heterodienophile addition to diene1

CO2Et

O

MeO

O

CO2EtMeOtoluene

110 oC, 60%

Example 2, Similar to the Boger pyridine synthesis (see page 59)2

MeO

OMe

OMeMeO N

N NN

CO2Me

CO2Me

CHCl3, reflux

5 days, 65%

NN

N N

CO2Me

MeO2C

MeOMeO

MeO2C CO2Me

Example 3, Using the Rawal diene4

OTBS

O

CO2MeMe

NMe2 CHCl3, −40 oC

71%

O

OMe

MeO2C

Rawal diene Example 4, Also similar to the Boger pyridine synthesis6

N

N

N

OSCH3

N

n

Δ or MW

NO

SCH3

n n = 1, 75%n = 2, 65%n = 3, 54%n = 4, 30%

188

Example 57

EtO

Me

OEt

OO

NCu

N

OOMeMe

Me3C CMe3

OTfH2O OH2

OTf

2 mol%

3 Å MS, THF, 0 oC, 87%

OEtOOEt

O

Me24:1 endo/exo97% ee

References 1. Wender, P. A.; Keenan, R. M.; Lee, H. Y. J. Am. Chem. Soc. 1987, 109, 4390–4392. 2. Boger, D. L. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.;

Pergamon, 1991, Vol. 5, 451−512. (Review). 3. Boger, D. L.; Baldino, C. M. J. Am. Chem. Soc. 1993, 115, 11418−11425. 4. Huang, Y.; Rawal, V. H. Org. Lett. 2000, 2, 3321−3323. 5. Jørgensen, K. A. Eur. J. Org. Chem. 2004, 2093−2102. (Review). 6. Lipi ska, T. M. Tetrahedron 2006, 62, 5736−5747. 7. Evans, D. A.; Kvaerno, L.; Dunn, T. B.; Beauchemin, A.; Raymer, B.; Mulder, J. A.;

Olhava, E. J.; Juhl, M.; Kagechika, K.; Favor, D. A. J. Am. Chem. Soc. 2008, 130, 16295−16309.

189

Dienone–phenol rearrangement Acid-promoted rearrangement of 4,4-disubstituted cyclohexadienones to 3,4-disubstituted phenols.

O

R R

H

OH

RR

H

O

R R

OH

R

O

R R

H OH

RRH R

H−

:1,2-alkyl

shift

H

Example 14

O

O

O

50% aq. H2SO4

reflux, 80%

O

O

OH

Example 25

O OH

HO conc. H2SO4

Et2O, 95%

HO

Example 39

O

NBoc

O

O

conc. HCl, CH3CN

1.5 h, rt, 73%

OH

NHO

O

190


Example 410

O

O

Ac2OH2SO4

0 oC to rt62%

AcO

OAc

OAc(1:1)

References 1. Shine, H. J. In Aromatic Rearrangements; Elsevier: New York, 1967, pp 55−68. (Re-

view). 2. Schultz, A. G.; Hardinger, S. A. J. Org. Chem. 1991, 56, 1105−1111. 3. Schultz, A. G.; Green, N. J. J. Am. Chem. Soc. 1992, 114, 1824−1829. 4. Hart, D. J.; Kim, A.; Krishnamurthy, R.; Merriman, G. H.; Waltos, A.-M. Tetrahedron

1992, 48, 8179−8188. 5. Frimer, A. A.; Marks, V.; Sprecher, M.; Gilinsky-Sharon, P. J. Org. Chem. 1994, 59,

1831−1834. 6. Oshima, T.; Nakajima, Y.-i.; Nagai, T. Heterocycles 1996, 43, 619−624. 7. Draper, R. W.; Puar, M. S.; Vater, E. J.; Mcphail, A. T. Steroids 1998, 63, 135−140. 8. Kodama, S.; Takita, H.; Kajimoto, T.; Nishide, K.; Node, M. Tetrahedron 2004, 60,

4901−4907. 9. Bru, C.; Guillou, C. Tetrahedron 2006, 62, 9043−9048. 10. Sauer, A. M.; Crowe, W. E.; Henderson, G.; Laine, R. A. Tetrahedron Lett. 2007, 48,

6590−6593.

191

Di-π-methane rearrangement Conversion of 1,4-dienes to vinylcyclopropanes under photolysis. Also known as the Zimmerman rearrangement.

R1R

R4 R3

R2 hν R1RR2

R4R3

1,4-diene vinylcyclopropane

R1R

R4 R3

R2 hνR1R

R4 R3

R2R1R

R2

R4R3

R1R

R4 R3

R2

diradical diradical

Example 1, Aza-π-methane rearrangement2

hν, acetophenone

benzene, 86%Ph

N OAcPh

Ph

PhN

OAc

Example 24

CN

CNhν, acetone

90%

CN

CN

Example 38

SO2 X S

O2

X

X = CH3, CH2Ph, COCMe3, CO2CH2Ph SiMe3, SnBu3, SePh,

hv, 300 nMCH3COCH3

23−64%

(CH2)3CH3

192


Example 4, Oxa-π-methane rearrangement8

MeO Me

hv, acetone

Pyrex, 76% OMe

Me H

H

References 1. (a) Zimmerman, H. E.; Grunewald, G. L. J. Am. Chem. Soc. 1966, 88, 183–184.

Known for the Traxler–Zimmerman trasition state for the asymmetric synthesis, How-ard E. Zimmerman is a professor at the University of Wisconsin at Madison. (b) Zimmerman, H. E.; Armesto, D. Chem. Rev. 1996, 96, 3065–3112. (Review). (c) Zimmerman, H. E.; Církva, V. Org. Lett. 2000, 2, 2365–2367.

2. Armesto, D.; Horspool, W. M.; Langa, F.; Ramos, A. J. Chem. Soc., Perkin Trans. I 1991, 223–228.

3. Jiménez, M. C.; Miranda, M. A.; Tormos, R. Chem. Commun. 2000, 2341–2342. 4. Ünaldi, N. S.; Balci, M. Tetrahedron Lett. 2001, 42, 8365–8367. 5. Altundas, R.; Dastan, A.; Ünaldi, N. S.; Güven, K.; Uzun, O.; Balci, M. Eur. J. Org.

Chem. 2002, 526–533. 6. Zimmerman, H. E.; Chen, W. Org. Lett. 2002, 4, 1155–1158. 7. Tanifuji, N.; Huang, H.; Shinagawa, Y.; Kobayashi, K. Tetrahedron Lett. 2003, 44,

751–754. 8. Dura, R. D.; Paquette, L. A. J. Org. Chem. 2006, 71, 2456–2459. 9. Singh, V.; Chandra, G.; Mobin, S. M. Synlett 2008, 2267–2270.

193

Doebner quinoline synthesis Three-component coupling of an aniline, pyruvic acid, and an aldehyde to provide a quinoline-4-carboxylic acid.

NH2 OHC N

CO2H

CO2H

O

NH2:

NH

OH2O

HH

:− H2O CO2H

OH

NH

H

NH

O CO2H

N

CO2HHOH

HNH

CO2HH2OH

B:

H

N

CO2H

NH

CO2H

air oxidation

− 2 H

− H2O

Example 12

MeO

NH2

O

HO

CO2H

NO2MeO

N

CO2H

NO2

EtOH

Δ, 95%

Example 26

NH2 CO2H

OH

ON

CO2H

EtOH, reflux

3 h, 20%

194


Example 3, Combinatorial Doebner reaction7

NH

HN

O

R3 O

O

NH2R1 OHC

R2 PhH

reflux, 8 h

R1

N

R2

O NH O

HN

R3

References 1. Doebner, O. G. Ann. 1887, 242, 265. Oscar Gustav Doebner (1850−1907) was born in

Meininggen, Germany. After studying under Liebig, he actively took part in the Franco-Prussian War. He apprenticed with Otto and Hofmann for a few years after the war, then began his independent researches at the University at Halle.

2. Mathur, F. C.; Robinson, R. J. Chem. Soc. 1934, 1520−1523. 3. Elderfield, R. C. Heterocyclic Compounds; Elderfield, R. C., Ed.; John Wiley & Sons,

Inc.: New York, 1952, Vol. 4, Quinoline, Isoquinoline and Their Benzo Derivatives, pp. 25−29. (Review).

4. Jones, G. In Chemistry of Heterocyclic Compounds, Jones, G., ed.; John Wiley & Sons, Inc.: New York, 1977, Vol. 32; Quinolines, pp. 125−131. (Review).

5. Atwell, G. J.; Baguley, B. C.; Denny, W. A. J. Med. Chem. 1989, 32, 396−401. 6. Herbert, R. B.; Kattah, A. E.; Knagg, E. Tetrahedron 1990, 46, 7119−7138. 7. Gopalsamy, A.; Pallai, P. V. Tetrahedron Lett. 1997, 38, 907−910. 8. Pflum, D. A. Doebner quinoline synthesis. In Name Reactions in Heterocyclic Chemis-


195

Doebner–von Miller reaction Doebner–von Miller reaction is a variant of the Skraup quinoline synthesis (page 509). Therefore, the mechanism for the Skraup reaction is also operative for the Doebner–von Miller reaction. The following mechanism is favored by Denmark’s mechnistic study using 13C-labelled α,β-unsaturated ketones.9

NH2

O

NH

HCl or

ZnCl2

NH2

Oreversible

conjugate additionNH

O

irreversible

fragmentationN

Ocondensation

N

NH2

conjugate additionN

NH

cyclization

rearomatization NH NH2

Example 15

N CO2Me

NH2

MeO2C CO2Me

O TsOH, CH2Cl2

reflux, 24 h

CO2Me

Example 26

NHAc

FH

ON

FF F

Me

6 N HCl, Tol.

100 °C, 2 h, 70%

196


Example 3, A novel variant10

B(OH)2

NH22 equiv

R3 OR2

R1

3% [RhCl(cod)]2KOH, rt, 24 h

then 10% Pd/Cair, reflux, 4 h

42−96%N

R3R2

R1

References 1. Doebner, O.; von Miller, W. Ber. 1883, 16, 2464. 2. Corey, E. J.; Tramontano, A. J. Am. Chem. Soc. 1981, 103, 5599−5600. 3. Eisch, J. J.; Dluzniewski, T. J. Org. Chem. 1989, 54, 1269−1274. 4. Zhang, Z. P.; Tillekeratne, L. M. V.; Hudson, R. A. Tetrahedron Lett. 1998, 39,

5133−5134. 5. Carrigan, C. N.; Esslinger, C. S.; Bartlett, R. D.; Bridges, R. J. Bioorg. Med. Chem.

Lett. 1999, 9, 2607−2712. 6. Sprecher, A.-v.; Gerspacher, M.; Beck, A.; Kimmel, S.; Wiestner, H.; Anderson, G. P.;

Niederhauser, U.; Subramanian, N.; Bray, M. A. Bioorg. Med. Chem. Lett. 1998, 8, 965−970.

7. Fürstner, A.; Thiel, O. R.; Blanda, G. Org. Lett. 2000, 2, 3731−3734. 8. Moore, A. Skraup Doebner–von Miller Reaction. In Name Reactions in Heterocyclic

Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 488−494. (Review).

9. Denmark, S. E.; Venkatraman, S. J. Org. Chem. 2006, 71, 1668−1676. Mechanistic study using 13C-labelled α,β-unsaturated ketones.

10. Horn, J.; Marsden, S. P.; Nelson, A.; House, D.; Weingarten, G. G. Org. Lett. 2008, 10, 4117−4120.

197

Dötz reaction Cr(CO)3-coordinated hydroquinone from vinylic alkoxy pentacarbonyl chromium carbene (Fischer carbene) complex and alkynes.

R1 R2

(OC)5CrOR

RL RS

Δ RL

RSOR

R1

OH

Cr(CO)3

R2

R1 R2

(OC)5CrOR

−COOR

R1 R2

(OC)4Cr alkyne

coordination

RL RS

R1 R2

(OC)4CrOR

R3

RSRL

OR

COOCOC CO

Cr

R2R1

alkyne insertion

Cr

R2R1

RSRL

OR

COOC CO

COCO insertion

electrocyclic

ring closureCr(CO)3

ORL

RSOR

R1

RL

RSOR

R1

OH

Cr(CO)3

tautomerizationR2

R2

Example 15

SeNO2

(OC)5CrOMe

1. THF, reflux

2. CAN, 22%

O

O

SeNO2

Example 38

MOMO

MOMO

OMe

Cr(CO)5

O O

H

MOMO OH

MOMO OMe

OO

ClCH2CH2Cl

70 oC, 1 h, 76%

198


Example 38

BnO

MOMO MeO

Cr(CO)5

OMe

THF, 50 oC, 61%OH

MeOOMe

OMOM

BnO

Example 39

O

OMeFMeO

MeO

1. 1.5 equiv t-BuLi, THF, −78 oC2. 1.02 equiv Cr(CO)6, THF −78 oC to rt

3. 1.02 equiv Et3O•FB4, rt 29%

O

OMeFMeO

MeO OEt

Cr(CO)5

5 equiv

THF, 80 oC

Ph H CAN−HNO3

84%, 2 steps

O

MeOMeO

MeO

F

OEt

Ph

Cr(CO)n O

MeOMeO

MeO

O

Ph

O O

References 1. Dötz, K. H. Angew. Chem., Int. Ed. 1975, 14, 644−645. Karl H. Dötz (1943−) was a

professor at the University of Munich in Germany. 2. Wulff, W. D. In Advances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI

Press, Greenwich, CT; 1989; Vol. 1. (Review). 3. Wulff, W. D. In Comprehensive Organometallic Chemistry II; Abel, E. W., Stone, F.

G. A., Wilkinson, G., Eds.; Pergamon Press: Oxford, 1995; Vol. 12. (Review). 4. Torrent, M.; Solá, M.; Frenking, G. Chem. Rev. 2000, 100, 439−494. (Review). 5. Caldwell, J. J.; Colman, R.; Kerr, W. J.; Magennis, E. J. Synlett 2001, 1428−1430. 6. Solá, M.; Duran, M.; Torrent, M. The Dötz reaction: A chromium Fischer carbene-

mediated benzannulation reaction. In Computational Modeling of Homogeneous Ca-talysis Maseras, F.; Lledós, eds.; Kluwer Academic: Boston; 2002, 269−287. (Re-view).

7. Pulley, S. R.; Czakó, B. Tetrahedron Lett. 2004, 45, 5511−5514. 8. White, J. D.; Smits, H. Org. Lett. 2005, 7, 235−238. 9. Boyd, E.; Jones, R. V. H.; Quayle, P.; Waring, A. J. Tetrahedron Lett. 2005, 47,

7983−7986.

199

Dowd−Beckwith ring expansion Radical-mediated ring expansion of 2-halomethyl cycloalkanones.

OBr

CO2CH3

Bu3SnH, AIBN

PhH, reflux

O

CO2CH3

N N CNNCΔ


2,2 -azobisisobutyronitrile (AIBN)

n-Bu3Sn H CN n-Bu3Sn CNH

SnBu3

OBr

CO2CH3

O

CO2CH3Bu3SnBr

O

CO2CH3

O

CHO2CH3

SnBu3H Bu3Sn

O

CO2CH3

Example 14

1.2 eq. Bu3SnHcat. AIBN

Tol., reflux, 23 h

H

CO2EtH

I

O

H

H

H

CO2EtH

H

O

CO2Et86% 13%

O

Example 29

OCO2Me

I

AIBN, Bu3SnD

PhH, 80 oC

O

CO2MeD77%

OCO2Me

H

D

OCO2Me

D

8% 15%

200


References 1. Dowd, P.; Choi, S.-C. J. Am. Chem. Soc. 1987, 109, 3493−3494. Paul Dowd

(1936−1996) was a professor at the University of Pittsburgh. 2. (a) Beckwith, A. L. J.; O’Shea, D. M.; Gerba, S.; Westwood, S. W. J. Chem. Soc.,

Chem. Commun. 1987, 666−667. Athelstan L. J. Beckwith is a professor at University of Adelaide, Adelaide, Australia. (b) Beckwith, A. L. J.; O’Shea, D. M.; Westwood, S. W. J. Am. Chem. Soc. 1988, 110, 2565−2575. (c) Dowd, P.; Choi, S.-C. Tetrahedron 1989, 45, 77−90. (d) Dowd, P.; Choi, S.-C. Tetrahedron Lett. 1989, 30, 6129−6132. (e) Dowd, P.; Choi, S.-C. Tetrahedron 1991, 47, 4847−4860.

3. Dowd, P.; Zhang, W. Chem. Rev. 1993, 93, 2091−2115. (Review). 4. Banwell, M. G.; Cameron, J. M. Tetrahedron Lett. 1996, 37, 525−526. 5. Studer, A.; Amrein, S. Angew. Chem., Int. Ed. 2000, 39, 3080−3082. 6. Kantorowski, E. J.; Kurth, M. J. Tetrahedron 2000, 56, 4317−4353. (Review). 7. Sugi, M.; Togo, H. Tetrahedron 2002, 58, 3171−3177. 8. Ardura, D.; Sordo, T. L. Tetrahedron Lett. 2004, 45, 8691−8694. 9. Ardura, D.; Sordo, T. L. J. Org. Chem. 2005, 70, 9417−9423.

201

Dudley reagent

NCH3

OOTf

Dudley benzyl reagent

NO

Dudley PMB reagentH3CO

CH3

The Dudley reagents are employed for the protection of alcohols as benzyl1 or PMB2 ethers, respectively, under mild conditions. Carboxylic acids are readily protected as well.3 Activation of the appropriate Dudley reagent in the presence of an alcohol furnishes the desired arylmethyl ether. The benzyl reagent is activated upon warming to approximately 80–85 °C, whereas activation of the PMB reagent occurs at room temperature upon treatment with methyl triflate (CH3OTf) or protic acid.4 Aromatic solvents, most commonly trifluorotoluene, often provide the best results. Magnesium oxide (MgO) is typically included in the reaction mixture as an acid scavenger.5 For benzylation of carboxylic acids, triethylamine (Et3N) is used in place of MgO.3 Preparation:1–3

NO

CH3OTf, toluene

0 °C to rt, 1 h, 99%NCH3

OOTf

Dudley benzyl reagent

NO

Dudley PMB reagentH3CO

CH3

OH

H3CONCl

CH3KOH, 18-crown-6

toluene, reflux (–H2O)90–93%

The Dudley reagents are conveniently prepared from readily available starting ma-terials and are indefinitely stable to storage and handling under standard laboratory conditions. Alternatively, both reagents are commercially available.

Example 16

OHOAc

Dudley benzyl reagent, MgO

PhCF3, 85 °C, 24 h, 96%

OBnOAc

202


Benzylation of a monoacetylated diol is shown in Example 1.6 The Dudley benzyl reagent was uniquely effective for protection of the free alcohol without loss and/or migration of the labile acetyl group. Example 22

PhSi(CH3)3

OHDudley PMB reagent

CH3OTf, MgO

PhCF3, rt, 1 h, 80% PhSi(CH3)3

OPMB

PMB-protection of a β-hydroxysilane can be accomplished without competition from the Peterson elimination (Example 2),2 which would occur under the basic or acidic conditions required for many other alkylation reactions.

Example 34

O

O OOH

O

O

O OOPMB

O

Dudley PMB reagent, CSA

CH2Cl2, rt, 72 h, 85%

The Dudley PMB reagent can also be activated under mildly acidic conditions us-ing catalytic camphorsulfonic acid (CSA) in lieu of CH3OTf (Example 3).4

Example 4, In situ-formation of the Dudley benzyl reagent is achieved by treating a mixture of an alcohol and 2-benzyloxypyridine with CH3OTf 7

O NH

OCH3

O

O

OHCH3OTf, MgO, toluene

0 to 85 °C, 24 h, 84% O NH

OCH3

O

O

OBn

O N

References 1. Poon, K. W. C.; Dudley, G. B. J. Org. Chem. 2006, 71, 3923–3927. 2. Nwoye, E. O.; Dudley, G. B. Chem. Commun. 2007, 1436–1437. 3. Tummatorn, J.; Albiniak, P. A.; Dudley, G. B. J. Org. Chem. 2007, 72, 8962–8964. 4. Stewart, C. A.; Peng, X.; Paquette, L. A. Synthesis 2008, 433–437. 5. Poon, K. W. C.; Albiniak, P. A.; Dudley, G. B. Org. Synth. 2007, 84, 295–305. 6. Schmidt, J. P.; Beltrân-Rodil, S.; Cox, R. J.; McAllister, G. D.; Reid, M.; Taylor, R. J.

K. Org. Lett. 2007, 9, 4041–4044. 7. Lopez, S. S.; Dudley, G. B. Beilstein J. Org. Chem. 2008, 4, No. 44.

203

Erlenmeyer−Plöchl azlactone synthesis Formation of 5-oxazolones (or “azlactones”) by intramolecular condensation of acylglycines in the presence of acetic anhydride.

O

HN

R1 O

NOR1

Ac2OCO2H

O

HN

R1

OO

H

O

O O

O

N

R1

OO

H

O

mixed anhydride

AcO

O

NOR1

2 AcOH

Example 12

O

HN

PhCO2H

OO

H

O

O

NOPh

O

O

NaOAc, Ac2O

110 oC, 69−73%

Example 28

O

HN

PhCO2H

OH

OH

OO

OO

Pb(OAc)4, Ac2O

THF, reflux, 15 h

NO

O

Ph

BuNH2

67%

OO

H

HNNH-Bu

O

Ph

OO

H

O

5.5:1 Z/E

Example 39

O

HN

PhCO2H H

O

FF

OBnN

O

O

Ph

BnONaOAc, Ac2O

95%

204


References 1. (a) Plöchl, J. Ber. 1884, 17, 1616−1624. (b) Erlenmeyer, E., Jr. Ann. 1893, 275, 1−3.

Emil Erlenmeyer, Jr. (1864−1921) was born in Heidelberg, Germany to Emil Erlen-meyer (1825−1909), a famous chemistry professor at the University of Heidelberg. He investigated the Erlenmeyer−Plöchl azlactone synthesis while he was a Professor of Chemistry at Strasburg. The Erlenmeyer flasks “ ” are ubiquitous in organic chemistry laboratories.

2. Buck, J. S.; Ide, W.S. Org. Synth. Coll. II, 1943, 55. 3. Carter, H. E. Org. React. 1946, 3, 198−239. (Review). 4. Baltazzi, E. Quart. Rev. Chem. Soc. 1955, 9, 150−173. (Review). 5. Filler, R.; Rao, Y. S. New Development in the Chemistry of Oxazolines, In Adv. Het-

erocyclic Chem; Katritzky, A. R.; Boulton, A. J., Eds; Academic Press, Inc: New York, 1977, Vol. 21, pp 175−206. (Review).

6. Mukerjee, A. K.; Kumar, P. Heterocycles 1981, 16, 1995−2034. (Review). 7. Mukerjee, A. K. Heterocycles 1987, 26, 1077−1097. (Review). 8. Combs, A. P.; Armstrong, R. W. Tetrahedron Lett. 1992, 33, 6419−6422. 9. Konkel, J. T.; Fan, J.; Jayachandran, B.; Kirk, K. L. J. Fluorine Chem. 2002, 115,

27−32. 10. Brooks, D. A. Erlenmeyer−Plöchl Azlactone Synthesis. In Name Reactions in Hetero-

cyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 229−233. (Review).

205

Eschenmoser’s salt

NCH2

H3C CH3

I

Eschenmoser’s salt, dimethylmethylideneammonium iodide, is a strong dimethylaminomethylating agent, used to prepare derivatives of the type RCH2N(CH3)2. Enolates, enolsilylethers, and even more acidic ketones undergo efficient dimethylaminomethylation—employed in the Mannich reaction.

Mechanism

LDA

THFR1R2

O

R1R2

OLi NCH2

H3C CH3

I

R1R2

O

NCH2

H3C CH3

R1

O

R2

NCH3

CH3

Li

Example 13 Once prepared, the resulting tertiary amines can be further methylated and then

subjected to base-induced elimination to afford methylenated ketones.

OH

CH3TBSO

O

O

O

H3C H

HH H

OTBS

CO2Me

1. 15 equiv NaN(SiMe3)2, THF −78 oC, 45 min. then 15 equiv of Me2(CH2)N+I−

0 oC, 15 min.

2. 20 equiv MeI, MeOH, 0.5 h3. 10 equiv DBU, PhH, rt, 1 h 51% 3 steps

OH

CH3TBSO

O

O

O

H3C H

HH H

OTBS

CO2Me

206


Example 24

NCH2

H3C CH3

IHN

NH

NO S

OO

OEt3NH Et3N, DMF, rt

12 h, 64%

HN

NN

O SO

OO

NCH3

CH3

: Et3NH

HN

NH

NO S

OO

OEt3NH

HN

NNN

CH3

CH3

HN

NH

NO S

OO

O

Example 35

O

O

NH

OO

NCH2

H3C CH3

I

DMF, 90 oC, 62% N

O

O H

O

O

References 1. Schreiber, J.; Maag, H.; Hashimoto, N.; Eschenmoser, A. Angew. Chem., Int. Ed.

1971, 10, 330–331. 2. Kleinman, E. F. Dimethylmethyleneammonium Iodide and Chloride. In Encyclopedia

of Reagents for Organic Synthesis (Ed: Paquette, L. A.) 2004, John Wiley & Sons, New York. (Review).

3. Nicolaou, K. C.; Reddy, K. R.; Skokotas, G.; Sato, F.; Xiao, X. Y.; Hwang, C. K. J. Am. Chem. Soc. 1993, 115, 3558–3575.

4. Saczewski, J.; Gdaniec, M. Tetrahedron Lett. 2007, 48, 7624–7627. 5. Hong, A.-W.; Cheng, T.-H.; Raghukumar, V.; Sha, C.-K. J. Org. Chem. 2008, 73,

7580–7585. 6. Cesario, C.; Miller, M. J. Org. Lett. 2009, 11, 449–452.

207

Eschenmoser−Tanabe fragmentation

Fragmentation of α,β-epoxyketones via the intermediacy of α,β-epoxy sulfonyl-hydrazones.

O

1. H2O2, −OH

2. H2NNHSO2Ar, H+

3. −OH

O

O

O OH

O

OOH

O

O

N

O

NH

SO2Ar

H2NNHSO2Ar

H

NN SO2Ar

O

SO2Ar N2↑

O

OH

N

O

N SHO2Ar

Example 14

O

OAcO

Tol-SO2NHNH2CHCl3-AcOH (1:1)

rt, 5 h, 73%AcO

O

Example 27

Me

MeOO

1. TsNHNH2, rt

2. 55 oC, 2 h, 50% O

Me

Me

208


Example 39

OO

OAcOMe

H

O

NNs

1. NsNHNH2, AcOH, THF; evaporation, 60 oC, NaBH4, AcOH, THF, 0 oC

2. TESOTf, 2,6-lutidine CH2Cl2, rt 60%, 2 steps

O

OAcOMe

H

NNsTESO

References 1. Eschenmoser, A.; Felix, D.; Ohloff, G. Helv. Chim. Acta 1967, 50, 708−713. Albert

Eschenmoser (Switzerland, 1925−) is best known for his work on, among many others, the monumental total synthesis of Vitamin B12 with R. B. Woodward in 1973. He now holds appointments at ETH Zürich and Scripps Research Institute, La Jolla.

2. Tanabe, M.; Crowe, D. F.; Dehn, R. L. Tetrahedron Lett. 1967, 3943−3946. 3. Felix, D.; Müller, R. K.; Horn, U.; Joos, R.; Schreiber, J.; Eschenmoser, A. Helv.

Chim. Acta 1972, 55, 1276−1319. 4. Batzold, F. H.; Robinson, C. H. J. Org. Chem. 1976, 41, 313−317. 5. Covey, D. F.; Parikh, V. D. J. Org. Chem. 1982, 47, 5315−5318. 6. Chinn, L. J.; Lenz, G. R.; Choudary, J. B.; Nutting, E. F.; Papaioannou, S. E.; Metcalf,

L. E.; Yang, P. C.; Federici, C.; Gauthier, M. Eur. J. Med. Chem. 1985, 20, 235−240. 7. Dai, W.; Katzenellenbogen, J. A. J. Org. Chem. 1993, 58, 1900−1908. 8. Mück-Lichtenfeld, C. J. Org. Chem. 2000, 65, 1366−1375. 9. Kita, Y.; Toma, T.; Kan, T.; Fukuyama, T. Org. Lett. 2008, 10, 3251−3253.

209

Eschweiler–Clarke reductive alkylation of amines Reductive methylation of primary or secondary amines using formaldehyde and formic acid. Cf. Leuckart–Wallach reaction.

R NH2 CH2O HCO2H R N

formic acid is the hydride source as a reducing agent

R NH2

O

: R NOH2

H

H

HH

R NOH

H

H

R NH O

HO C O↑O

R NH

:

OH

HH

R NOH2:H

R NH O

HO R NC O↑O H R N

− H

Example 17

H3C

ONHCH3

DCOD, DCO2D, DMSO

microwave (120 W)1−3 min.

d3-tamoxifen

H3C

ON

CD3

CH3

Example 29

HN

OH

1.2 equiv 37% CH2O in H2O5 equiv 85% HCO2H in H2O

steam bath, 84%

N

OH

CH3

210


Example 310

N

NNH

CHO

varenicline (Chantix)

N

NN

OH

:

N

NN

H O

ON

NN

References 1 (a) Eschweiler, W. Chem. Ber. 1905, 38, 880–892. Wilhelm Eschweiler (1860−1936)

was born in Euskirchen, Germany. (b) Clarke, H. T.; Gillespie, H. B.; Weisshaus, S. Z. J. Am. Chem. Soc. 1933, 55, 4571–4587. Hans T. Clarke (1887−1927) was born in Harrow, England.

2 Moore, M. L. Org. React. 1949, 5, 301–330. (Review). 3 Pine, S. H.; Sanchez, B. L. J. Org. Chem. 1971, 36, 829–832. 4 Bobowski, G. J. Org. Chem. 1985, 50, 929–931. 5 Alder, R. W.; Colclough, D.; Mowlam, R. W. Tetrahedron Lett. 1991, 32, 7755–7758. 6 Bulman Page, P. C.; Heaney, H.; Rassias, G. A.; Reignier, S.; Sampler, E. P.; Talib, S.

Synlett 2000, 104–106. 7 Harding, J. R.; Jones, J. R.; Lu, S.-Y.; Wood, R. Tetrahedron Lett. 2002, 43, 9487–

9488. 8 Brewer, A. R. E. Eschweiler–Clarke reductive alkylation of amine. In Name Reactions

for Functional Group Transformations; Li, J. J., Corey, E. J., eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 86−111. (Review).

9 Weis, R.; Faist, J.; di Vora, U.; Schweiger, K.; Brandner, B.; Kungl, A. J.; Seebacher, W. Eur. J. Med. Chem. 2008, 43, 872–879.

10 Waterman, K. C.; Arikpo, W. B.; Fergione, M. B.; Graul, T. W.; Johnson, B. A.; Mac-donald, B. C.; Roy, M. C.; Timpano, R. J. J. Pharm. Sci. 2008, 97, 1499–1507.

211

Evans aldol reaction Asymmetric aldol condensation of aldehyde and chiral acyl oxazolidinone, the Evans chiral auxiliary.

O

R* +H

O

R' base

chiral auxiliary

R*

O

MeMeR'

OH

R* = NO

O

Bn

NO

O

Me

NO

O

Ph Ph

Evans syn

Lewis acid

NO

O

t-Bu

NO

O

i-Pr

Example 12

ON

OO1. Bu2BOTf, R3N

2. PhCHO, − 78 oC79%, 80:20 de

ON

OO

Ph

OH

ON

OO

HR3N:

Bu2B OTf

Z-(O)-boron enolate

formationON

OOB

BuBu

PhCHO

OBO Bu

Bu

Ph

HN

O

OH

H

ON

OO

Ph

Oaldol

condensation

BBuBu

ON

OO

Ph

OHworkup

Example 25

ON

OOMeO

N OMeCO2Me

TiCl4, DIPEACH2Cl2, −78 oC, 1.5 h

then rt, overnight, 52%

ON

OO

NMeO2C

OMe

212


Example 39

OTES

ONO

S

Bn

O

OBn

1 eq. Bu2BOTf1.1 eq. Et3N

PhMe, 0.15 M− 50 to − 30 oC

2 h, 72%

NO

S

Bn

O

OBn

OTESOH

Example 4, Crimmins procedure10

N O

Bn

OO

TBDPSOCHO

TiCl4(−)-sparteine

96%, 96% deN O

Bn

OOOH

TBDPSO

References 1. (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127−2129.

David Evans is a professor at Harvard University. (b) Evans, D. A.; McGee, L. R. J. Am. Chem. Soc. 1981, 103, 2876−2878.

2. Danda, H.; Hansen, M. M.; Heathcock, C. H. J. Org. Chem. 1990, 55, 173−181. 3. Ager, D. J.; Prakash, I.; Schaad, D. R. Aldrichimica Acta 1997, 30, 3−12. (Review). 4. Braddock, D. C.; Brown, J. M. Tetrahedron: Asymmetry 2000, 11, 3591−3607. 5. Matsumura, Y.; Kanda, Y.; Shirai, K.; Onomura, O.; Maki, T. Tetrahedron 2000, 56,

7411−7422. 6. Williams, D. R.; Patnaik, S.; Clark, M. P. J. Org. Chem. 2001, 66, 8463−8469. 7. Guerlavais, V.; Carroll, P. J.; Joullié, M. M. Tetrahedron: Asymmetry 2002, 13,

675−680. 8. Li, G.; Xu, X.; Chen, D.; Timmons, C.; Carducci, M. D.; Headley, A. D. Org. Lett.

2003, 5, 329−331. 9. Zhang, W.; Carter, R. G.; Yokochi, A. F. T. J. Org. Chem. 2004, 69, 2569−2572. 10. Ghosh, S.; Kumar, S. U.; Shashidhar, J. J. Org. Chem. 2008, 73, 1582−1585. 11. Zhang, J. Evans aldol reaction. In Name Reactions for Homologations-Part II; Li, J.


213

Favorskii rearrangement Transformation of enolizable α-haloketones to esters, carboxylic acids, or amides via alkoxide-, hydroxide-, or amine-catalyzed rearrangements, respectively.

O

R2 R4

R3R1X H

X = Cl, Br, INuc-HNuc = OH, OR, NRR'

O

Nuc

H

R2

R1

R4R3base

The intramolecular Favorskii Rearrangement:

OR2R1

X HNuc-H

( )n

O

NucR1

HR2

( )n

n = 0−5base

ORO

Cl

O OR

enolizable α-haloketone

ORO

ClO

ClHHOR

O

Cl

OR

cyclopropanone intermediate

ORO O ORH OR HOR

O OR

OR

Example 12

O O

Br Br

CO2HHBr2, CH3CO2H

50 oC, 1 h, 97%

KOH, DMSO

100 oC, 1 h47%

214


Example 2, Homo-Favorskii rearrangement3

OTsO 1.96 eq. NaOH

dioxane/H2O90 oC, 3 h, 86%

H

O

51 : 40 : 9

O O

Example 36

OCO2Me

OCO2Me

BrBrBr2

Et2O

O

MeO

O

MeO

NaOMe, MeOH

37% 2 steps

Example 4, Photo-Favorskii Rearrangement7

O

H H

Cl electron

transfer

hν

homolysis

OCl

300 nm light

5% aq. CH3CNpropylene oxide

4 h, 81%

O

H H

ClH H

1,2-aryl

migration O

OH

OH2O

Cl

Example 58

Br

O

Br

Br

O

BrNC

KCN, α-cyclodextrin

MeCN, H2O10−15 oC, 12 h

80%

Br

O

NC

NC

215

HH

NC O

NCH

H

HO O

NC HH

HO O

NC

9 : 1Ratio

Example 610

O

ClTHPO

OMeO

THPO

NaOMe

MeOH0 oC, 15 min.

96%

References 1. (a) Favorskii, A. E. J. Prakt. Chem. 1895, 51, 533−563. Aleksei E. Favorskii

(1860−1945), born in Selo Pavlova, Russia, studied at St. Petersburg State University, where he became a professor since 1900. (b) Favorskii, A. E. J. Prakt. Chem. 1913, 88, 658.

2. Wagner, R. B.; Moore, J. A. J. Am. Chem. Soc. 1950, 72, 3655−3658. 3. Wenkert, E.; Bakuzis, P.; Baumgarten, R. J.; Leicht, C. L.; Schenk, H. P. J. Am. Chem.

Soc. 1971, 93, 3208−3216. 4. Chenier, P. J. J. Chem. Ed. 1978, 55, 286−291. (Review). 5. Barreta, A.; Waegell, B. In Reactive Intermediates; Abramovitch, R. A., ed.; Plenum

Press: New York, 1982, 2, pp 527−585. (Review). 6. White, J. D.; Dillon, M. P.; Butlin, R. J. J. Am. Chem. Soc. 1992, 114, 9673−9674. 7. Dhavale, D. D.; Mali, V. P.; Sudrik, S. G.; Sonawane, H. R. Tetrahedron 1997, 53,

16789−16794. 8. Kitayama, T.; Okamoto, T. J. Org. Chem. 1999, 64, 2667−2672. 9. Mamedov, V. A.; Tsuboi, S.; Mustakimova, L. V.; Hamamoto, H.; Gubaidullin, A. T.;

Litvinov, I. A.; Levin, Y. A. Chem. Heterocyclic Compd. 2001, 36, 911. (Review). 10. Pogrebnoi, S.; Saraber, F. C. E.; Jansen, B. J. M.; de Groot, A. Tetrahedron 2006, 62,

1743−1748. 11. Filipski, K.J.; Pfefferkorn, J. A. Favorskii rearrangement. In Name Reactions for Ho-

mologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 238−252. (Review).

216

Quasi-Favorskii rearrangement

If there are no enolizable hydrogens present, the classical Favorskii rearrange-ment is not possible. Instead, a semi-benzylic mechanism can lead to a rear-rangement referred to as quasi-Favorskii.

O

R2 R5

R3R1X R4

X = Cl, Br, INuc

Nuc = OH, OR, NRR'

O

Nuc

R5

R3

R4

R1R2 R3,4,5 = H

Example 1, Arthur C. Cope’s initial discovery1

Br

O OEt

Br

OEtO

CO2Et

Hg(OAc)2

EtOH, reflux4 h, 71%

non-enolizable ketone

Example 25

O

Br

NHLi O

NH

Et2O, hexane25 oC, 67%

Example 36

Br

O

Li

THF, −78 to −30 oC, 90% O

References 1. Cope, A. C.; Graham, E. S. J. Am. Chem. Soc. 1951, 73, 4702−4706. 2. Smissman, E. E.; Diebold, J. L. J. Org. Chem. 1965, 30, 4005−4007. 3. Sasaki, T.; Eguchi, S.; Toru, T. J. Am. Chem. Soc. 1969, 91, 3390−3391. 4. Baudry, D.; Begue, J. P.; Charpentier-Morize, M. Tetrahedron Lett. 1970, 2147−2150. 5. Stevens, C. L.; Pillai, P. M.; Taylor, K. G. J. Org. Chem. 1974, 39, 3158−3161. 6. Harmata, M.; Wacharasindhu, S. Org. Lett. 2005, 7, 2563−2565. 7. Harmata, M.; Wacharasindhu, S. J. Org. Chem. 2005, 70, 725−728. 8. Filipski, K.J.; Pfefferkorn, J. A. Favorskii rearrangement. In Name Reactions for Ho-


9. Harmata, M.; Wacharasindhu, S. Synthesis 2007, 2365−2369.

217

Feist–Bénary furan synthesis α-Haloketones react with β-ketoesters in the presence of base to fashion furans.

OEt

O OCl

OO

CO2Et

Et3N, 0 °C, 52 h

54−57%

ClOCO2Et

O

HCO2Et

O

Et3N Hrate-determining

step

Et3N:

O

OHCl

HCO2Et

:NEt3

O

CO2EtHOEt3N H

O

CO2EtH2O

:

O

CO2Et

O

CO2Et

H

Et3N:

Example 12,3

O

OOEt

O O

ClOCH3

OH3CO2C

O H3CO

KOH, MeOH

57%

Example 24

OEt

O O

HCl

O O

CO2Et

pyridine, rt to 50 °C, 4 h

then rt, overnight, 86%

Example 3, Ionic liquid-promoted interrupted Feist–Benary reaction10

R1 R2

O OR3 OEt

Br O

O

[bmim]OH

rt O

R1OC

R1

HOCO2Et

R3

interrupted Feist−Benary

products

[pmim]Br

70−75 oC O

R1OC

R1

CO2Et

R3

Feist−Benary products

R1 = CH3, Et, Ph, n-Pr, etc.R2 = CH3, OCH3, PEtR3 = H, n-Bu, CO2Et [bmim]OH = N N C4H9

OH[pmim]Br = N N C4H9

Br

218


References 1. (a) Feist, F. Ber. 1902, 35, 1537−1544. (b) Bénary, E. Ber. 1911, 44, 489−492. 2. Gopalan, A.; Magnus, P. J. Am. Chem. Soc. 1980, 102, 1756−1757. 3. Gopalan, A.; Magnus, P. J. Org. Chem. 1984, 49, 2317−2321. 4. Padwa, A.; Gasdaska, J. R. Tetrahedron 1988, 44, 4147−4160. 5. Dean, F. M. Recent Advances in Furan Chemistry. Part I. In Advances in Heterocyclic

Chemistry, Katritzky, A. R., Ed.; Academic Press: New York, 1982; Vol. 30, 167−238. (Review).

6. Cambie, R. C.; Moratti, S. C.; Rutledge, P. S.; Woodgate, P. D. Synth. Commun. 1990, 20, 1923−1929.

7. Friedrichsen, W. Furans and Their Benzo Derivatives: Synthesis. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V.; Bird, C. V. Eds.; Pergamon: New York, 1996; Vol. 2, 351−393. (Review).

8. König, B. Product Class 9: Furans. In Science of Synthesis: Houben−Weyl Methods of Molecular Transformations; Maas, G., Ed.; Georg Thieme Verlag: New York, 2001; Cat. 2, Vol. 9, 183−278. (Review).

9. Shea, K. M. Feist–Bénary Furan Synthesis. In Name Reactions in Heterocyclic Chem-istry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 160−167. (Review).

10. Ranu, B. C.; Adak, L.; Banerjee, S. Tetrahedron Lett. 2008, 49, 4613−4617.

219

Ferrier carbocyclization This process (also known as the “Ferrier II Reaction”) has proved to be of consid-erable value for the efficient, one-step conversion of 5,6-unsaturated hexopyranose derivatives into functionalized cyclohexanones useful for the preparation of such enantiomerically pure compounds as inositols and their amino, deoxy, unsaturated and selectively O-substituted derivatives, notably phosphate esters. In addition, the products of the carbocyclization have been incorporated into many complex com-pounds of interest in biological and medicinal chemistry.1,2

General examples:3

O

OMe

BzOBzO

TsO

O

OMe

BzOBzO

TsO

HgCl

OBzOBzO

HgCl

HO

1

2

HgCl2, Me2CO, H2O

reflux, 4.5 h, 83%

OMeOTs

BzOBzO

O

HgCl

OTs O OH

BzOBzO

TsO

O

43

BzOBzO

O

BzO OH

OBzO

BzOO

OBzBzO

BzO OBzOBz

OMe

BzOBzO

O

OH

OBz

OBzO

OMeBzOBzO

BzOO

OHOBz83%6

93%480%6

More complex products:

O

OMe

BzO

OBzO

O

OMe

BzO

AcOAcO

OH

OBzO

AcOAcO

75%7

O

OMeO

OC6H4OMe(p)O

OC6H4OMe(p)

OH

86% (2:1)8

OAcOAc

OH

AcOAcO

83%7

O

O

O

Complex bioactive compounds made following the application of the reaction:

O

OH

O NH

O

O

OH O

HOH

OHHOH

OH

NHHOHO

HOHO

Paniculide A9 Pancratistatin10 Calystegine B211

O

220


Modified hex-5-enopyranosides and reactions

OH

BnOBnO

BnO

HOOAca,b

85%14

O

OMe

BnOBnO

BnO

OAc

O

OMe

BnOBnO

BnO

OMe

BnOBnO

OMe

BnOBnO

BnO

HO OBn

O

Hc

d

79%13

98%13

a, Hg(OCOCF3)2, Me2CO, H2O, 0 oC; b, NaBH(OAc)3, AcOH, MeCN, rt; c, i-Bu3Al, PhMe, 40 °C; d, Ti(Oi-Pr)Cl3, CH2Cl2, –78 °C, 15 min. (Note: The aglycon is retained in the Al- and Ti-induced reactions). References 1. Ferrier, R. J.; Middleton, S. Chem. Rev. 1993, 93, 2779−2831. (Review). 2. Ferrier, R. J. Top. Curr. Chem. 2001, 215, 277−291 (Review). 3. Ferrier, R. J. J. Chem. Soc., Perkin Trans. 1 1979, 1455−1458. The discovery (1977)

was made in the Pharmacology Department, University of Edinburgh, while R. J. Fer-rier was on leave from Victoria University of Wellington, New Zealand where he was Professor of Organic Chemistry. He is now a consultant with Industrial Research Ltd., Lower Hutt, New Zealand.

4. Blattner, R.; Ferrier, R. J.; Haines, S. R. J. Chem. Soc., Perkin Trans. 1, 1985, 2413−2416.

5. Chida, N.; Ohtsuka, M.; Ogura, K.; Ogawa, S. Bull. Chem. Soc. Jpn. 1991, 64, 2118−2121.

6. Machado, A. S.; Olesker, A.; Lukacs, G. Carbohydr. Res. 1985, 135, 231−239. 7. Sato, K.-i.; Sakuma, S.; Nakamura, Y.; Yoshimura, J.; Hashimoto, H. Chem. Lett.

1991, 17−20. 8. Ermolenko, M. S.; Olesker, A.; Lukacs, G. Tetrahedron Lett. 1994, 35, 711−714. 9. Amano, S.; Takemura, N.; Ohtsuka, M.; Ogawa, S.; Chida, N. Tetrahedron 1999, 55,

3855−3870. 10. Park, T. K.; Danishefsky, S. J. Tetrahedron Lett. 1995, 36, 195−196. 11. Boyer, F.-D.; Lallemand, J.-Y. Tetrahedron 1994, 50, 10443−10458. 12. Das, S. K.; Mallet, J.-M.; Sinaÿ, P. Angew. Chem., Int. Ed. 1997, 36, 493−496. 13. Sollogoub, M.; Mallet, J.-M.; Sinaÿ, P. Tetrahedron Lett. 1998, 39, 3471−3472. 14. Bender, S. L.; Budhu, R. J. J. Am. Chem. Soc. 1991, 113, 9883−9884. 15. Estevez, V. A.; Prestwich, E. D. J. Am. Chem. Soc. 1991, 113, 9885−9887. 16. Yadav, J. S.; Reddy, B. V. S.; Narasimha Chary, D.; Madavi, C.; Kunwar, A. C.

Tetrahedron Lett. 2009, 50, 81−84.

221

Ferrier glycal allylic rearrangement In the presence of Lewis acid catalysts O-substituted glycal derivatives can react with O-, S-, C- and, less frequently, N-, P- and halide nucleophiles to give 2,3-unsaturated glycosyl products.1,2 This allylic transformation has been termed the “Ferrier Reaction” or, to avoid complications, the “Ferrier I Reaction” or the “Fer-rier Rearrangement”. However, the reaction was first noted by Emil Fischer when he heated tri-O-acetyl-D-glucal in water.3 When carbon nucleophiles are involved, the term “Carbon Ferrier Reaction” has been used,4 although the only contribution the Ferrier group made in this area was to find that tri-O-acetyl-D-glucal dimerizes under acid catalysis to give a C-glycosidic product.5 The general reaction is illus-trated by the separate conversions of tri-O-acetyl-D-glucal with O-, S- and C-nucleophiles to the corresponding 2,3-unsaturated glycosyl derivatives. Normally, Lewis acids are used as catalysts, boron trifluoride etherate being the most com-mon. Allyloxycarbenium ions are involved as intermediates, high yields of prod-ucts are obtained, and glycosidic compounds with quasi-axial bonds (as illus-trated) predominate (commonly in the , -ratio of about 7:1). The examples illustrated4,6,7 are typical of a very large number of literature reports.1

OAcO

AcO

AcOO

OAc

AcO

i) HOCH2CCH6

ii) HSPh7

iii)

+ Lewis acid

4

O

RAcO

R = i) OCH2CCH6

ii) SPh7

iii) 4

OAc

General examples4

OAcOAcO

OAc SnBr4, C6H14, EtOAc

rt, 5 min, 94%

OAcO

OAc

H

More complex products made directly from the corresponding glycols:

OH

O

O

OH

OH O

O

O

AcO

O

Ph

AcOOAc

EtOO O

O

OMe

In PhCOCH2CO2Et,BF3.OEt2,

rt, 15 min, (81% α-anomer).9

OO NHC(O)CCl3

In benzene, BF3•OEt2,5 oC, 10 min, (67%, α-anomer).8

By spontaneous sigmatropic rearrangement of the glycal3-trichloroacetimidate made with NaH, Cl3CCN, (78% α-anomer).10

222


Products formed without acid catalysts

OHO O OMe OAcO O

DDQ DEAD, Ph3P(80%, α-anomer)11 (88%, mainly α)12

C-3 leaving group of glycal:

Promoter:

hydroxy acetoxy

OO

O

O

OO

OO

O

N-iodonium dicollidine perchlorate

(65%, mainly α)13

pent-4-enoyloxy

Modified glycals and their reactions:

OOBn

BnOOAc

OBn

OOBn

BnOO

O

O

O

Ph

O

O

O

PhN

NH N

N

ClI

N

NH N

N

Me

, reflux MeNO2,AgNO3, Na2CO36 h (58%, α,β 1:1).15

++

OH

BF3•OEt2, CH2Cl2, 0 oC

(70%, mainly α)14

References 1. Ferrier, R. J.; Zubkov, O. A. Transformation of glycals into 2,3-unsaturated glycosyl

derivatives, In Org. React. 2003, 62, 569−736. (Review). It was almost 50 years after Fischer’s seminal finding that water took part in the reaction3 that Ann Ryan, working in George Overend’s Department in Birkbeck College, University of London, found, by chance, that p-nitrophenol likewise participates.16 Robin Ferrier, her immediate su-pervisor, who suggested her experiment, then found that simple alcohols at high tem-peratures also take part,17 and with other students, notably Nagendra Prasad and George Sankey, he explored the reaction extensively. They did not apply it to make the very important C-glycosides.

2. Ferrier, R. J. Top. Curr. Chem. 2001, 215, 153−175. (Review). 3. Fischer, E. Chem. Ber. 1914, 47, 196−210. 4. Herscovici, J.; Muleka, K.; Boumaïza, L.; Antonakis, K. J. Chem. Soc., Perkin Trans.

1 1990, 1995−2009. 5. Ferrier, R. J.; Prasad, N. J. Chem. Soc. (C) 1969, 581−586. 6. Moufid, N.; Chapleur, Y.; Mayon, P. J. Chem. Soc., Perkin Trans. 1 1992, 999−1007. 7. Whittman, M. D.; Halcomb, R. L.; Danishefsky, S. J.; Golik, J.; Vyas, D. J. Org.

Chem. 1990, 55, 1979−1981. 8. Klaffke, W.; Pudlo, P.; Springer, D.; Thiem, J. Ann. 1991, 509−512. 9. Yougai, S.; Miwa, T. J. Chem. Soc., Chem. Commun. 1983, 68−69. 10. Armstrong, P. L.; Coull, I. C.; Hewson, A. T.; Slater, M. J. Tetrahedron Lett. 1995, 36,

4311−4314.

223

11. Sobti, A.; Sulikowski, G. A. Tetrahedron Lett. 1994, 35, 3661−3664. 12. Toshima, K.; Ishizuka, T.; Matsuo, G.; Nakata, M.; Kinoshita, M. J. Chem. Soc.,

Chem. Commun. 1993, 704−705. 13. López, J. C.; Gómez, A. M.; Valverde, S.; Fraser-Reid, B. J. Org. Chem. 1995, 60,

3851−3858. 14. Booma, C.; Balasubramanian, K. K. Tetrahedron Lett. 1993, 34, 6757−6760. 15. Tam, S. Y.-K.; Fraser-Reid, B. Can. J. Chem. 1977, 55, 3996−4001. 16. Ferrier, R. J.; Overend, W. G.; Ryan, A. E. J. Chem. Soc. (C) 1962, 3667−3670. 17. Ferrier, R. J. J. Chem. Soc. 1964, 5443−5449. 18. De, K.; Legros, J.; Crousse, Be.; Bonnet-Delpon, D. Tetrahedron 2008, 64,

10497−10500.

224

Fiesselmann thiophene synthesis Condensation reaction of thioglycolic acid derivatives with , -acetylenic esters, which upon treatment with base result in the formation of 3-hydroxy-2-thiophenecarboxylic acid derivatives.

CO2MeO

OMeHSMeO2C S

CO2Me

OH

MeO2C

NaOMe

MeO2C

O

OMeS

OCH3

O

O

OMeS

OH3CO

O

OMeSH

S

MeO2C

MeO2C O

OMeS

OOMe

SS

CO2Me

MeO2C

MeO2C

OMe

O

O

OMeSH

SS

CO2MeMeO2C

OMe

O NaOMe

O

MeOH

OMe

SS

CO2Me

O

OMe

MeO2C

OMe

OS

MeO2C

OMe

CO2MeO

SCO2Me

S

MeO2C

CO2Me

SCO2Me

H

H

O HOMe

OMeS

MeO2C

CO2Me

OHS

MeO2C

CO2MeH

O

MeO

Example 15

O

CO2R3

12 equiv HSCH2CO2H

R3OH, HCl (g), −10 oC, 1 h

S

CO2R3

CO2R3 NaOR3, R3OH

rt, 24 h, 46−98%

SCO2R3

OH

225


Example 26

OO

NCH3 CH3

O

OS

NCH3 CH3

O

CO2CH3O

NCH3

S

CH3

O

OCH3HSCH2CO2H

HCl, MeOH

NaOMe

MeOH

Example 37

N Cl

CN

O

OEtHS N S

NH2

CO2Et

NaH, DMSO, 89%

Example 49

CN

S CO2Me

NH2

HSCH2CO2Me

NaOMe, 68%

References 1. Fiesselmann, H.; Schipprak, P. Ber. 1954, 87, 835−841; Fiesselmann, H.; Schipprak,

P.; Zeitler, L. Ber. 1954, 87, 841−848; Fiesselmann, H.; Pfeiffer, G. Ber. 1954, 87, 848; Fiesselmann, H.; Thoma, F. Ber. 1956, 89, 1907−1912; Fiesselmann, H.; Schip-prak, P. Ber. 1956, 89, 1897−1902.

2. Gronowitz, S. In Thiophene and Its Derivatives, Part 1, Gronowitz, S., Ed.; Wiley & Sons: New York, 1985, 88−125. (Review).

3. Nicolaou, K. C.; Skokotas, G.; Furuya, S.; Suemune, H.; Nicolaou, D. C. Angew. Chem., Int. Ed. 1990, 29, 1064−1068.

4. Mullican, M. D.; Sorenson, R. J.; Connor, D. T.; Thueson, D. O.; Kennedy, J. A.; Con-roy, M. C. J. Med. Chem. 1991, 34, 2186−2194.

5. Donoso, R.; Jordan de Urries, P.; Lissavetzky, J. Synthesis 1992, 526−528. 6. Ram, V. J.; Goel, A.; Shukla, P. K.; Kapil, A. Bioorg. Med. Chem. Lett. 1997, 7,

3101−3106. 7. Showalter, H. D. H.; Bridges, A. J.; Zhou, H.; Sercel, A. D.; McMichael, A.; Fry, D.

W. J. Med. Chem. 1999, 42, 5464−5474. 8. Shkinyova, T. K.; Dalinger, I. L.; Molotov, S. I.; Shevelev, S. A. Tetrahedron Lett.

2000, 41, 4973−4975. 9. Redman, A. M.; Johnson, J. S.; Dally, R.; Swartz, S.; Wild, H.; Paulsen, H.; Caringal,

Y.; Gunn, D.; Renick, J.; Osterhout, M. Bioorg. Med. Chem. Lett. 2001, 11, 9−12. 10. Migianu, E.; Kirsch, G. Synthesis, 2002, 1096. 11. Mullins, R. J.; Williams, D. R. Fiesselmann Thiophene Synthesis. In Name Reactions

in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 184−192. (Review).

226

Fischer indole synthesis Cyclization of arylhydrazones to indoles.

NH

N

R2R1

NH

NH3

O

R2R1

NH

R2

R1

NH3

H

phenylhydrazine phenylhydrazone

NH

N

R2R1

H

HNH

NH2

R2R1

[3,3]-sigmatropic

rearrangement N H

NH2

R2R1

H

H

tautomerization

protonation ene-hydrazine double imine

N H2

NH2

R2R1

N

H

H H

R2R1

NH2 NH

R2

R1

NH3

NH

H

R2R1

NH3

Example 13

NH

N

OPh

ON N

HNH2

NH

N

HN

N

1. neat, 160 oC, 24 h

2. NH2NH2, 120 oC, 12 h 71%

Example 213

NHNH2

O

CNCO2Et

AcOH, Δ, 5 h

57%NH

CNCO2Et

Example 4 (Severe racemization)9

O N

H

H

CO2Me

PhO N

H

H

CO2Me

Ph

or1. PhNHNH2

2. AcOH

227


N

H

H

CO2Me

PhNH

22%NH

NPh

H

H

CO2Me

16%NH

NPh

H

H

CO2Me

6%

N

H

H

CO2Me

PhNH

4%

N

H

H

CO2Me

PhNH

5%

N

H

H

CO2Me

PhNH

4%

References 1. (a) Fischer, E.; Jourdan, F. Ber. 1883, 16, 2241−2245. H. Emil Fischer (1852−1919)

is arguably the greatest organic chemist ever. He was born in Euskirchen, near Bonn, Germany. When he was a boy, his father, Lorenz, said about him: “The boy is too stupid to go in to business; so in God’s name, let him study.” Fischer studied at Bonn and then Strassburg under Adolf von Baeyer. Fischer won the Nobel Prize in Chemis-try in 1902 (three years ahead of his master, von Baeyer) for his synthetic studies in the area of sugar and purine groups. (b) Fischer, E.; Hess, O. Ber. 1884, 17, 559.

2. Robinson, B. The Fisher Indole Synthesis, John Wiley & Sons: New York, NY, 1982. (Book).

3. Martin, M. J.; Trudell, M. L.; Arauzo, H. D.; Allen, M. S.; LaLoggia, A. J.; Deng, L.; Schultz, C. A.; Tan, Y.; Bi, Y.; Narayanan, K.; Dorn, L. J.; Koehler, K. F.; Skolnick, P.; Cook, J. M. J. Med. Chem. 1992, 35, 4105−4117.

4. Hughes, D. L. Org. Prep. Proc. Int. 1993, 25, 607−632. (Review). 5. Bosch, J.; Roca, T.; Armengol, M.; Fernández-Forner, D. Tetrahedron 2001, 57,

1041−1048. 6. Ergün, Y.; Patir, S.; Okay, G. J. Heterocycl. Chem. 2002, 39, 315−317. 7. Pete, B.; Parlagh, G. Tetrahedron Lett. 2003, 44, 2537−2539. 8. Li, J.; Cook, J. M. Fischer Indole Synthesis. In Name Reactions in Heterocyclic Chem-


9. Borregán, M.; Bradshaw, B.; Valls, N.; Bonjoch, J. Tetrahedron: Asymmetry 2008, 19, 2130−2134.

10. Donald, J. R.; Taylor, R. J. K. Synlett 2009, 59−62.

228

Fischer oxazole synthesis Oxazoles from the condensation of equimolar amounts of aldehyde cyanohydrins and aromatic aldehydes in dry ether in the presence of dry hydrochloric acid.

N

OR2

R1

etherH2O HCl

HClR1 CN

OHR2CHO

O R2

H

:NH

Cl

R1

OH

NHR1

OH

Cl

NHO

R1

Cl

R2OH

NH2O

R1

Cl

R2OH

HCl

ON

Cl

R2

R1

HSN2 isomerization

ON

Cl

R2

R1

H elimination ON

R2

R1HCl

Example 14

H3CNH2

OH

O CHO

TsOH, Tol.

reflux

N

OCH3HN

OCH3

O

POCl3, 80−85 oC

15 min., 40%

Example 28

SOCl2, ether

dry HCl gas

HO

CN

OH

HO

ClNH

Cl

229


N

O

dry HCl gas, 16.5%

N

OH

N

CHO

halfordinal

References 1. Fischer, E. Ber. 1896, 29, 205. 2. Ladenburg, K.; Folkers, K.; Major, R. T. J. Am. Chem. Soc. 1936, 58, 1292−1294. 3. Wiley, R. H. Chem. Rev. 1945, 37, 401−442. (Review). 4. Cornforth, J. W.; Cornforth, R. H. J. Chem. Soc. 1949, 1028-1030. 5. Cornforth, J. W. In Heterocyclic Compounds 5; Elderfield, R. C. Ed.; Wiley & Sons:

New York, 1957, 5, 309−312. (Review). 6. Crow, W. D.; Hodgkin, J. H. Tetrahedron Lett. 1963, 2, 85−89. 7. Brossi, A.; Wenis, E. J. Heterocycl. Chem. 1965, 2, 310−312. 8. Onaka, T. Tetrahedron Lett. 1971, 4393−4394. 9. Brooks, D. A. Fisher Oxazole Synthesis. In Name Reactions in Heterocyclic Chemis-


230

Fleming−Kumada oxidation Stereoselective oxidation of alkyl-silanes into the corresponding alkyl-alcohols us-ing peracids.

R R1

SiMe2Ph1. HX2. ArCO3H, base

3. hydrolysis R R1

OH

retention of configuration

R R1

SiH

R R1

SiX

Hipso

substitution R R1

SiX H

:OO

Ar

O

the β-carbocation is stabilized by the silicon group

R R1

SiO

O

Ar

OHX ArCO2

R R1

OSiO

O Ar

O

R R1

OSi

HO

O Ar

O

:

R R1

OSiO

HO

O Ar

O

:− ArCO2

R R1

OSi

O

OO

O

Ar

R R1

OSiO

O Ar

OO

R R1

OSiO

OO

Ar

OHO

R R1

OSiO

OO

O

Ar hydrolysis

OH R R1

OR R1

OHHO

O

Ar

Example 14

NBoc

OO O

HO

OH

OTBS

C8H18

NBoc

OO O

(EtO)2PhSi

OH

OTBS

C8H18 m-CPBA, KHF2, DMF

0 to 25 oC, 55−70%

231


Example 25

O NO

OSii-Pri-Pr

H

O

TBSO

HTsO

PhH2O2, KHCO3

THF, H2O55 oC, 90%

O NO

OHOH

O

TBSO

HTsO

PhH

Example 38

O

H3CCH3

CH3H

H3C

H3C

BnO

Si

H2O2, KF, KHCO3

DMF, 93%

HO

H3CCH3

CH3H

H3C

H3C

BnO

HOH3C CH3

Example 49

SiMe2(OMe)MeO2C

CO2Me

KF, KHCO3THF/MeOH

30% H2O2, 77%

OHMeO2C

CO2Me

References 1. (a) Fleming, I.; Henning, R.; Plaut, H. J. Chem. Soc., Chem. Commun. 1984, 29−31.

(b) Fleming, I.; Sanderson, P. E. J. Tetrahedron Lett. 1987, 28, 4229−4232. (c) Flem-ing, I.; Dunoguès, J.; Smithers, R. Org. React. 1989, 37, 57−576. (Review).

2. Hunt, J. A.; Roush, W. R. J. Org. Chem. 1997, 62, 1112−1124. 3. Knölker, H.-J.; Jones, P. G.; Wanzl, G. Synlett 1997, 613−616. 4. Barrett, A. G. M.; Head, J.; Smith, M. L.; Stock, N. S.; White, A. J. P.; Williams, D. J.

J. Org. Chem. 1999, 64, 6005−6018. 5. Denmark, S.; Cottell, J. J. Org. Chem. 2001, 66, 4276−4284. 6. Lee, T. W.; Corey, E. J. Org. Lett. 2001, 3, 3337−3339. 7. Jung, M. E.; Piizzi, G. J. Org. Chem. 2003, 68, 2572−2582. 8. Paquette, L. A.; Yang, J.; Long, Y. O. J. Am. Chem. Soc. 2003, 125, 1567−1574. 9. Clive, D. L. J.; Cheng, H.; Gangopadhyay, P.; Huang, X.; Prabhudas, B. Tetrahedron

2004, 60, 4205−4221. 10. Mullins, R. J.; Jolley, S. L.; and Knapp, A. R. Tamao–Kumada–Fleming Oxidation. In

Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 237−247. (Review).

232

Tamao−Kumada oxidation Oxidation of alkyl fluorosilanes to the corresponding alcohols. A variant of the Fleming−Kumada oxidation.

RSi

R

FF KF, H2O2

KHCO3, DMF2 ROH

RSi

R

FF

F

R SiR

FF

F

HO

OH

R SiR

FF

FO

HOH

SiR

FF

FO

HOH

R

:

O SiR

FF

FRO Si

OF

F

FRR

2 ROH

Example 13

O

Me2FSi

O

CO2Me

NaCO3, CH3CO3H

3 h, 64%O

HO

O

CO2Me

Example 24

SiO

R

EtEt

OSiMe3

H2O2, KF, KHCO3

THF−MeOH51−85%

R

OH SiEt2F

OHR

OH OH

OH

References 1. Tamao, K.; Ishida, N.; Kumada, M. J. Org. Chem. 1983, 48, 2120−2122. 2. Fleming, I.; Dunoguès, J.; Smithers, R. Org. React. 1989, 37, 57−576. (Review). 3. Kim, S.; Emeric, G.; Fuchs, P. L. J. Org. Chem. 1992, 57, 7362−7364. 4. Mullins, R. J.; Jolley, S. L.; Knapp, A. R. Tamao–Kumada–Fleming Oxidation. In

Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 237−247. (Review).

5. Beignet, J.; Jervis, P. J.; Cox, L. R. J. Org. Chem. 2008, 73, 5462−5475. 6. Cardona, F.; Parmeggiani, C.; Faggi, E.; Bonaccini, C.; Gratteri, P.; Sim, L.; Gloster,

T. M.; Roberts, S.; Davies, G. J.; Rose, D. R.; Goti, A. Chem. Eur. J. 2009, 15, 1627–1636.

233

Friedel–Crafts reaction

Friedel–Crafts acylation reaction Introduction of an acyl group onto an aromatic substrate by treating the substrate with an acyl halide or anhydride in the presence of a Lewis acid.

R Cl

O

AlCl3R

O

HCl

AlCl3complexation

R Cl:

O

R Cl

O:AlCl3 AlCl4

OR

R

O

acylium ion

electrophilic

substitutionR

OH

aromatizationR

OClAlClCl

ClAlCl3HCl

Example 1, Intermolecular Friedel–Crafts acylation6

F

AlCl3, CH2Cl288%

OF

FN NCl

OF

CHOCHO

Example 2, Intramolecular Friedel–Crafts acylation7

OHO

OMeOMe (COCl)2, DMF

then AlCl3, 84%O

OMeOMe

234



HN

CO2CH3

CO2HPPSE, CH3NO2

reflux, 10 min., 44% NH

CO2CH3

O

PPSE = Trimethylsilyl polyphosphate


NH

CONMe2POCl3, K2CO3

CH3CN, 60 oC74%

NH

O

NH

MeOCO2H

PPA, 80 oC

35% NH

O

MeO

N

20 mol% BF3OEt2

MeNO2, 100 oC15 min., 98%

Ns

O

O

O

O

NNs

O

References 1. Friedel, C.; Crafts, J. M. Compt. Rend. 1877, 84, 1392−1395. Charles Friedel

(1832−1899) was born in Strasbourg, France. He earned his Ph.D. In 1869 under Wurtz at Sorbonne and became a professor and later chair (1884) of organic chemistry at Sorbonne. Friedel was one of the founders of the French Chemical Society and served as its president for four terms. James Mason Crafts (1839−1917) was born in Boston, Massachusetts. He studied under Bunsen and Wurtz in his youth and became a professor at Cornell and MIT. From 1874 to 1891, Crafts collaborated with Friedel at École de Mines in Paris, where they discovered the Friedel–Crafts reaction. He re-turned to MIT in 1892 and later served as its president. The discovery of the Friedel–Crafts reaction was the fruit of serendipity and keen observation. In 1877, both Friedel and Crafts were working in Charles A. Wurtz’s laboratory. In order to prepare amyl iodide, they treated amyl chloride with aluminum and iodide using benzene as the solvent. Instead of amyl iodide, they ended up with amylbenzene! Unlike others before them who may have simply discarded the reaction, they thoroughly investigated

235

the Lewis acid-catalyzed alkylations and acylations and published more than 50 papers and patents on the Friedel–Crafts reaction, which has become one of the most useful organic reactions.

2. Pearson, D. E.; Buehler, C. A. Synthesis 1972, 533−542. (Review). 3. Hermecz, I.; Mészáros, Z. Adv. Heterocyclic Chem. 1983, 33, 241−330. (Review). 4. Metivier, P. Friedel-Crafts Acylation. In Friedel-Crafts Reaction Sheldon, R. A.; Bek-

kum, H., eds.; Wiley-VCH: New York. 2001, pp 161−172. (Review). 5. Basappa; Mantelingu, K.; Sadashira, M. P.; Rangappa, K. S. Indian J. Chem. B. 2004,

43B, 1954−1957. 6. Olah, G. A.; Reddy, V. P.; Prakash, G. K. S. Chem. Rev. 2006, 106, 1077−1104. (Re-

view). 7. Simmons, E.M.; Sarpong, R. Org. Lett. 2006, 8, 2883−2886. 8. Bourderioux, A.; Routier, S.; Beneteau, V.; Merour, J.-Y. Tetrahedron 2007, 63,

9465−9475. 9. Fillion, E.; Dumas, A. M. J. Org. Chem. 2008, 73, 2920−2923. 10. de Noronha, R. G.; Fernandes, A. C.; Romao, C. C. Tetrahedron Lett. 2009, 50,

1407−1410.

Friedel–Crafts alkylation reaction Introduction of an alkyl group onto an aromatic substrate by treating the substrate with an alkylating agent such as alkyl halide, alkene, alkyne and alcohol in the presence of a Lewis acid.

AlCl3RCl:

RCl

AlCl3 AlCl4 R

R

RH

aromatization

ClAlClCl

Cl

HCl

alkyl cation

Example 11

O O

O Br

OSnCl4, CH2Cl2

0 oC, 1 h, 84%

O

OO

O

Example 24

NR

R1

R2 R3

O

OH

R3 = aryl, alkyl

NCu

N

OOMeMe

Me3C CMe3TfO OTf10 mol%

NR

R1

R2

R3

O OHH

32−96% yield, 83−98% ee

236

NMe

R3

O

OH

R3 = aryl, alkyl

NCu

N

OOMeMe

Me3C CMe3TfO OTf10 mol%

R3

O

OH

H

80−95% yield, 68−97% ee

NMe

Example 35

OB(OH)2 Me O 20 mol%

DME, rt, 36 h1 equiv HF

O O

Me51% yield, 92% ee

N

NH•HCl

O Me

Me

MeMe

NBu

References 1. Patil, M. L.; Borate, H. B.; Ponde, D. E.; Bhawal, B. M.; Deshpande, V. H. Tetrahe-

dron Lett. 1999, 40, 4437−4438. 2. Meima, G. R.; Lee, G. S.; Garces, J. M. Friedel-Crafts Alkylation. In Friedel−Crafts

Reaction Sheldon, R. A.; Bekkum, H., eds.; Wiley-VCH: New York. 2001, pp 550−556. (Review).

3. Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int. Ed. 2004, 43, 550−556. (Review).

4. Palomo, C.; Oiarbide, M.; Kardak, B. G.; Garcia, J. M.; Linden, A. J. Am. Chem. Soc. 2005, 127, 4154−4155.

5. Lee, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129, 15438−15439. 6. Poulsen, T. B.; Jorgensen, K. A. Chem. Rev. 2008, 108, 2903−2915. (Review). 7. Silvanus, A. C.; Heffernan, S. J.; Liptrot, D. J.; Kociok-Kohn, G.; Andrews, B. I.; Car-

bery, D. R. Org. Lett. 2009, 11, 1175−1178.

237

Friedländer quinoline synthesis The Friedländer quinoline synthesis combines an α-amino aldehyde or ketone with another aldehyde or ketone with at least one methylene α adjacent to the car-bonyl to furnish a substituted quinoline. The reaction can be promoted by acid, base, or heat.

CHO

NH2R

R1

O OH

N

R

R1

NH2

RR1

O

H

HO

RR1

O

H

O Aldol

condensation NH2

R

COR1

OH

HOH

R

NH2

R1

O

:

N

R

N

R

R1R1OH

H

HO

Example 15

CHO

NH2 O N

NBn NBnNaOMe, EtOH

reflux, 3 h, 90%

Example 27

NHBoc

O

HO N

N O

OBn

N

OBn

OAcOH, 100 °C

88%

238


Example 38

N

CHO

NH2 O N N

Me

Me Me N N Me

Me

ConditionsNaOH, rt

pyrrolidine, 5% H2SO4, rtTBAO, 5% H2SO4, rt

TBAO, 5% H2SO4, slow addition, 65 °C

Conversion> 99%97%

> 99%> 99%

Ratio37:6386:1487:1394:6

TBAO = 1,3,3-trimethyl-6-azabicyclo[3.2.1]octane

HN

Me

Me

Me

Example 410

OH

NH2

R2 R1

O 1 mol%

KOH, 1,4-dioxane80 oC, 1 h

N

R2

R1

N NMes Mes

RuClCl PhPCy3

References 1. Friedländer, P. Ber. 1882, 15, 2572−2575. Paul Friedländer (1857−1923), born in

Königsberg, Prussia, apprenticed under Carl Graebe and Adolf von Baeyer. He was interested in music and was an accomplished pianist.

2. Elderfield, R. C. In Heterocyclic Compounds, Elderfield, R. C., ed.; Wiley & Sons,: New York, 1952, 4, Quinoline, Isoquinoline and Their Benzo Derivatives, 45–47. (Review).

3. Jones, G. In Heterocyclic Compounds, Quinolines, vol. 32, 1977; Wiley & Sons: New York, pp 181–191. (Review).

4. Cheng, C.-C.; Yan, S.-J. Org. React. 1982, 28, 37−201. (Review). 5. Shiozawa, A.; Ichikawa, Y.-I.; Komuro, C.; Kurashige, S.; Miyazaki, H.; Yamanaka,

H.; Sakamoto, T. Chem. Pharm. Bull. 1984, 32, 2522−2529. 6. Gladiali, S.; Chelucci, G.; Mudadu, M. S.; Gastaut, M.-A.; Thummel, R. P. J. Org.

Chem. 2001, 66, 400−405. 7. Henegar, K. E.; Baughman, T. A. J. Heterocycl. Chem. 2003, 40, 601−605. 8. Dormer, P. G.; Eng, K. K.; Farr, R. N.; Humphrey, G. R.; McWilliams, J. C.; Reider,

P. J.; Sager, J. W.; and Volante, R. P. J. Org. Chem. 2003, 68, 467−477. 9. Pflum, D. A. Friedländer Quinoline Synthesis. In Name Reactions in Heterocyclic


10. Vander Mierde, H.; Van Der Voot, P.; De Vos, D.; Verpoort, F. Eur. J. Org. Chem. 2008, 1625−1631.

239

Fries rearrangement Lewis acid-catalyzed rearrangement of phenol esters and lactams to 2- or 4-ketophenols. Also known as the Fries−Finck rearrangement.

O R

O

AlCl3

OHOH

O R

R

O

and/or

O R

O:

AlCl3

complexation O R

OCl3Al

OAlCl3

C−O bond

fragmentation

O

R

aluminum phenolate, acylium ion

O

R

OOAlCl3

O

R

HH OH

R

O

OAlCl3

O R

OH

O R

O

HR

O

H

Example 15

OMe

O

O

Br

Br

ZrCl4, PhCl

160 oC, 3 h, 63%

OH O OH

Br Br

240


Example 26

OAc

O

O

10% Bi(OTf)3, PhMe

110 oC, 15 h, 64%

OAc

OH O

Example 3, Photo-Fries rearrangement7

HN

OPh

Low-pressure Hg lamp

254 nM, MeCN, 36 h, 65%

NH2 OPh

Example 4, ortho-Fries rearrangement8

MeO OMe

OCONEt2

O 2.1 equiv LTMP

−78 oC to rt, 97%

MeO OMe

O

OCONEt2

Example 5, Thia-Fries rearrangement9

Cl

H

OSO

OCF3

LDA, THF, −78 oC

then H3O+, 80%Cl

OH

SO

O

CF3

References 1. Fries, K.; Finck, G. Ber. 1908, 41, 4271−4284. Karl Theophil Fries (1875−1962) was

born in Kiedrich near Wiesbaden on the Rhine. He earned his doctorate under Theo-dor Zincke. Although G. Finck co-discovered the rearrangement of phenolic esters, somehow his name has been forgotten by history. In all fairness, the Fries rearrange-ment should really be the Fries−Finck rearrangement.

2. Martin, R. Org. Prep. Proced. Int. 1992, 24, 369−435. (Review). 3. Boyer, J. L.; Krum, J. E.; Myers, M. C.; Fazal, A. N.; Wigal, C. T. J. Org. Chem.

2000, 65, 4712−4714. 4. Guisnet, M.; Perot, G. The Fries rearrangement. In Fine Chemicals through Hetero-

geneous Catalysis 2001, 211−216. (Review). 5. Tisserand, S.; Baati, R.; Nicolas, M.; Mioskowski, C. J. Org. Chem. 2004, 69,

8982−8983. 6. Ollevier, T.; Desyroy, V.; Asim, M.; Brochu, M.-C. Synlett 2004, 2794−2796.

241

7. Ferrini, Serena; Ponticelli, Fabio; Taddei, Maurizio. Org. Lett. 2007, 9, 69−72. 8. Macklin, T. K.; Panteleev, J.; Snieckus, V. Angew. Chem., Int. Ed. 2008, 47,

2097−2101. 9. Dyke, A. M.; Gill, D. M.; Harvey, J. N.; Hester, A. J.; Lloyd-Jones, G.C.; Munoz, M.

P.; Shepperson, I. R. Angew. Chem., Int. Ed. 2008, 47, 5067−5070.

242

Fukuyama amine synthesis Transformation of a primary amine to a secondary amine using 2,4-dinitro-benzenesulfonyl chloride and an alcohol. Also known as the Fuku-yama−Mitsunobu procedure.

SO2Cl

NO2

NO2

R1HN

R2

S

NO2

NO2

CO2H1. R1NH2, pyr.2. R2OH, PPh3, DEAD

3. HSCH2CO2HSO2

R1NH2

SO2

NO2

NO2

ClSO2NHR1

NO2

NO2 R2OH, PPh3

DEAD

:

HSO2NR1R2

NO2

NO2

S CO2HH

:

See page 365 for mechanism of the Mitsunobu reaction.

SNAr

NO2

NO2

SO2SHO2C

H

NR1R2

R1HN

R2

S

NO2

NO2

CO2H

SO2

Meisenheimer complex Example 16

Ns NH2

DEAD, PPh3

NsHNBr

Cs2CO3

n-Bu4NI

NsN

n nfor n = 1–367–74% 62–66%

HOBr

n

Example 27

NBocMsO

OH

NsNH2

DEAD, PPh3

O Et

NBocMsO

NsHNO Et

CO2MeOTBDPS

243


K2CO3

DMF NBocMsO

NsNOH

Et

CO2MeOTBDPS

Example 38

OHSO2

NO2

H2NPyPh2P, DTBAD

CH2Cl2, 84%

SO2NO2

HN K2CO3, PhSH

CH3CN, 80% NH2

PyPh2P = diphenyl 2-pyridylphosphine; DTBAD = di-tert-butylazodicarbonate References 1. (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373−6374.

Tohru Fukuyama moved to the University of Tokyo from Rice University in 1995. (b) Fukuyama, T.; Cheung, M.; Jow, C.-K.; Hidai, Y.; Kan, T. Tetrahedron Lett. 1997, 38, 5831−5834.

2. Piscopio, A. D.; Miller, J. F.; Koch, K. Tetrahedron Lett. 1998, 39, 2667−2670. 3. Bolton, G. L.; Hodges, J. C. J. Comb. Chem. 1999, 1, 130−133. 4. Lin, X.; Dorr, H.; Nuss, J. M. Tetrahedron Lett. 2000, 41, 3309−3313. 5. Olsen, C. A.; JØrgensen, M. R.; Witt, M.; Mellor, I. R.; Usherwood, P. N. R.;

Jaroszewski, J. W.; Franzyk, H. Eur. J. Org. Chem. 2003, 3288-3299. 6. Kan, T.; Fujiwara, A.; Kobayashi, H.; Fukuyama, T. Tetrahedron 2002, 58,

6267−6276. 7. Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama, T.; Tokuyama, H.; Fu-

kuyama, T. Pure Appl. Chem. 2003, 75, 29−38. 8. Guisado, C.; Waterhouse, J. E.; Price, W. S.; JØrgensen, M. R.; Miller, A. D. Org.

Biomol. Chem. 2005, 3, 1049−1057. 9. Olsen, C. A.; Witt, M.; Hansen, S. H.; Jaroszewski, J. W.; Franzyk, H. Tetrahedron

2005, 61, 6046−6055. 10. Janey, J. M. Fukuyama amine synthesis. In Name Reactions for Functional Group

Transformations; Li, J. J., Corey, E. J., eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 424−437. (Review).

244

Fukuyama reduction Aldehyde synthesis through reduction of thiol esters with Et3SiH in the presence of Pd/C catalyst.

R SEt

O Et3SiH, Pd/C

THF, rt R H

O

Path A:

Pd(0)

oxidativeaddition

R PdSEt

O

R SEt

O Et3SiH

Et3Si SEtR H

Oreductive

eliminationPd(0)

R PdH

O

Path B: Et3SiH Pd(0) Et3SiPdH

R SEt

O Et3SiPdHR SEt

OSiEt3

PdH Pd(0) R H

O

Et3Si SEtR SEt

OSiEt3

Example 11

CO2Me

COSEtO O

OEt3SiH, 10% Pd/C

acetone, rt, 92%

CO2Me

CHOO O

O

Example 23

HO2C CO2MeNHBoc

EtSH, DCC, DMAP

CH3CN, rt, 1 h, > 70%CO2Me

NHBoc

EtS

O

Et3SiH, 10% Pd/C

acetone, rt, 30 min., >74%CO2Me

NHBoc

H

O Example 38

MeO

COSEt 0.5 mol% Pd/C

2 equiv Et3SiHrt, 2 h, 92% MeO

CHO

245


References 1. Fukuyama, T.; Lin, S.-C.; Li, L. J. Am. Chem. Soc. 1990, 112, 7050–7051. 2. Kanda, Y.; Fukuyama, T. J. Am. Chem. Soc. 1993, 115, 8451–8452. 3. Fujiwara, A.; Kan, T.; Fukuyama, T. Synlett 2000, 1667–1673. 4. Tokuyama, H.; Yokoshima, S.; Lin, S.-C.; Li, L.; Fukuyama, T. Synthesis 2002, 1121–

1123. 5. Evans, D. A.; Rajapakse, H. A.; Stenkamp, D. Angew. Chem., Int. Ed. 2002, 41, 4569–

4573. 6. Shimada, K.; Kaburagi, Y.; Fukuyama, T. J. Am. Chem. Soc. 2003, 125, 4048–4049. 7. Kimura, M.; Seki, M. Tetrahedron Lett. 2004, 45, 3219–3223. (Possible mechanisms

were proposed in this paper). 8. Miyazaki, T.; Han-ya, Y.; Tokuyama, H.; Fukuyama, T. Synlett 2004, 477–480.

246

Gabriel synthesis Synthesis of primary amines using potassium phthalimide and alkyl halides.

N

O

O

K1. R⎯X

2. Nu or R'OHH2N R

CO2H

CO2H

R X

SN2 N

O

O

Rhydrolysis

OH

N

O

R

OHO

N

O

O

K

HN

OR

OO

H

CO2HN

RO OH

H2N RCO2

CO2

OH

OH

Example 12

O

O

Br

BrO

OO

O

NPhth

NPhthO

OKNPhth, DMF

90 oC, 40 min.90%

O

O

NH2

NH2

O

OH2NNH2, CH3OH

reflux, 1 h, 80%

Example 26

R1

R2 OHR3

R1

R2 NPhthR3

DIAD, PPh3phthalimide

THF, rt, 4 h76−98%

R1

R2 NH2R3

NH2H2 or CH3NH2CH3OH

76−88%

247


Example 38

NK

O

O

Br CO2Et

DMF, 90 oC, 3 h, 77%N

O

O

CO2Et

N

O

O

O OO

6 M HCl, reflux

14 h, 93% HCl•H2N

O OHO

= 13C

Example 49

OH

OH

phthalimide, PPh3

DEAD, THF

NPht

NPht54%

NH2

NH2

1. NH2NH2•H2O, THF, reflux, 8 h

2. Pd/C, H2, THF, 95%, 2 steps

References 1. Gabriel, S. Ber. 1887, 20, 2224−2226. Siegmund Gabriel (1851−1924), born in Ber-

lin, Germany, studied under Hofmann at Berlin and Bunsen in Heidelberg. He taught at Berlin, where he discovered the Gabriel synthesis of amines. Gabriel, a good friend of Emil Fischer, often substituted for Fischer in his lectures.

2. Sheehan, J. C.; Bolhofer, V. A. J. Am. Chem. Soc. 1950, 72, 2786−2788. 3. Han, Y.; Hu, H. Synthesis 1990, 122−124. 4. Ragnarsson, U.; Grehn, L. Acc. Chem. Res. 1991, 24, 285–289. (Review). 5. Toda, F.; Soda, S.; Goldberg, I. J. Chem. Soc., Perkin Trans. 1 1993, 2357−2361. 6. Sen, S. E.; Roach, S. L. Synthesis, 1995, 756−758. 7. Khan, M. N. J. Org. Chem. 1996, 61, 8063−8068. 8. Iida, K.; Tokiwa, S.; Ishii, T.; Kajiwara, M. J. Labelled. Compd. Radiopharm. 2002,

45, 569−570. 9. Tanyeli, C.; Özçubukçu, S. Tetrahedron Asymmetry 2003, 14, 1167−1170. 10. Ahmad, N. M. Gabriel synthesis. In Name Reactions for Functional Group Transfor-

mations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 438−450. (Review).

11. Al-Mousawi, S. M.; El-Apasery, M. A.; Al-Kanderi, N. H. ARKIVOC 2008, (16), 268−278.

248

Ing–Manske procedure A variant of Gabriel amine synthesis where hydrazine is used to release the amine from the corresponding phthalimide:

N

O

O

K1. RX

2. NH2NH2H2N R NH

NH

O

O

R X

N

O

O

K SN2N

O

O

R

:NH2NH2

N

O

R

NHNH2O

NHNH2

O

NHRO

:NHNH

O

O NH

H2N R NHNH

O

OR

Example 16

N

O

O

Br P(OEt)3

ΔN

O

O

PO(OEt)2H2NNH2, EtOH

rt, 18 h, 97% H2NPO(OEt)2

References 1. Ing, H. R.; Manske, R. H. F. J. Chem. Soc. 1926, 2348–2351. H. R. Ing was a profes-

sor of pharmacological chemistry at Oxford. R. H. F. Manske, Ing’s collaborator at Oxford, was of German origin but trained in Canada before studying at Oxford. Man-ske left England to return to Canada, eventually to become Director of Research in the Union Rubber Company, Guelph, Ontario, Canada.

2. Ueda, T.; Ishizaki, K. Chem. Pharm. Bull. 1967, 15, 228–237. 3. Khan, M. N. J. Org. Chem. 1995, 60, 4536–4541. 4. Hearn, M. J.; Lucas, L. E. J. Heterocycl. Chem. 1984, 21, 615–622. 5. Khan, M. N. J. Org. Chem. 1996, 61, 8063–8063. 6. Tanyeli, C.; Özçubukçu, S. Tetrahedron: Asymmetry 2003, 14, 1167–1170. 7. Ariffin, A.; Khan, M. N.; Lan, L. C.; May, F. Y.; Yun, C. S. Synth. Commun. 2004, 34,

4439–4445. 8. Ali, M. M.; Woods, M.; Caravan, P.; Opina, A. C. L.; Spiller, M.; Fettinger, J. C.;

Sherry, A. D. Chem. Eur. J. 2008, 14, 7250–7258.

249

Gabriel–Colman rearrangement

250


Reaction of the enolate of a maleimidyl acetate to provide isoquinoline 1,4-diol.

GN

ROO

G = CO, SO2

ArNaOR

ROHG

NH

OH O

RAr

N

O

O

OMe

N

OOR

OR

OMeO

NOMe

O

OR

O

HN

O

OO

OMe

NH

O

O

R

O

N

OH

OH

R

O

NH

O

R

OOOMe

Example 16

SN

Oi-PrOO

OO S

NH

OO

OH O

Oi-Pr4 equiv i-PrONa

i-PrOH, reflux5 min., 85%

Example 29

N

O

OCO2Et NH

OH

O

CO2EtNaOMe, MeOH

reflux, 24 h91%

References 1. (a) Gabriel, S.; Colman, J. Ber. 1900, 33, 980−995. (b) Gabriel, S.; Colman, J. Ber.

1900, 33, 2630−2634. (c) Gabriel, S.; Colman, J. Ber. 1902, 35, 1358−1368. 2. Allen, C. F. H. Chem. Rev. 1950, 47, 275−305. (Review). 3. Gensler, W. J. Heterocyclic Compounds, Vol. 4, R. C. Elderfield, Ed., Wiley & Sons.,

New York, N.Y., 1952, 378. (Review). 4. Hill, J. H. M. J. Org. Chem. 1965, 30, 620−622. (Mechanism). 5. Lombardino, J. G.; Wiseman, E. H.; McLamore, W. M. J. Med. Chem. 1971, 14,

1171−1175. 6. Schapira, C. B.; Perillo, I. A.; Lamdan, S. J. Heterocycl. Chem. 1980, 17, 1281−1288. 7. Lazer, E. S.; Miao, C. K.; Cywin, C. L.; et al. J. Med. Chem. 1997, 40, 980−989. 8. Pflum, D. A. Gabriel−Colman Rearrangement. In Name Reactions in Heterocyclic


9. Kapatsina, E.; Lordon, M.; Baro, A.; Laschat, S. Synthesis 2008, 2551−2560.

Gassman indole synthesis The Gassman indole synthesis involves a one-pot process in which a hypohalite, a

-carbonyl sulfide derivative, and a base are added sequentially to an aniline or a substituted aniline to provide 3-thioalkoxyindoles. The sulfur can be easily re-moved by hydrogenolysis or Raney nickel.

NHCl

SR

O

Et3N

NH

R

S

NH2

t-BuOCl

NHCl

SR

OSN2

Et3N

NH

S

O

RH

:

:

sulfonium ion

NH

OS

R

HEt3N:

H

NH

S

O

R[2,3]-sigmatropic

rearrangement(Sommelet−Hauser)

NEt3

NH

S

NH

R

S

OHR

N

SHEt3N:

: R

H Example 11

NH2

1. t-BuOCl

S CH3

O3. Et3N, 69%

NH

Me

S

2.

NH2

1. t-BuOCl

3. Et3N

N2.

SCH3

OSCH3

LiAlH4, Et2O

NH

0 oC, 48% overall

251


Example 22

O

OO

MeSt-BuOCl, PhNH2

Et3N, 93%

O

OO

MeS

NH2

Ra-Ni

EtOH

O

OONH2

p-TsOH, PhH, reflux

71% 2 steps

O

ONH

References 1. (a) Gassman, P. G.; van Bergen, T. J.; Gilbert, D. P.; Cue, B. W., Jr. J. Am. Chem. Soc.

1974, 96, 5495−5508. Paul G. Gassman (1935−1993) was a professor at the Univer-sity of Minnesota (1974−1993). (b) Gassman, P. G.; van Bergen, T. J. J. Am. Chem. Soc. 1974, 96, 5508−5512. (c) Gassman, P. G.; Gruetzmacher, G.; van Bergen, T. J. J. Am. Chem. Soc. 1974, 96, 5512−5517.

2. Wierenga, W. J. Am. Chem. Soc. 1981, 103, 5621−5623. 3. Ishikawa, H.; Uno, T.; Miyamoto, H.; Ueda, H.; Tamaoka, H.; Tominaga, M.; Naka-

gawa, K. Chem. Pharm. Bull. 1990, 38, 2459−2462. 4. Smith, A. B., III; Sunazuka, T.; Leenay, T. L.; Kingery-Wood, J. J. Am. Chem. Soc.

1990, 112, 8197−8198. 5. Smith, A. B., III; Kingery-Wood, J.; Leenay, T. L.; Nolen, E. G.; Sunazuka, T. J. Am.

Chem. Soc. 1992, 114, 1438−1449. 6. Savall, B. M.; McWhorter, W. W.; Walker, E. A. J. Org. Chem. 1996, 61, 8696−8697. 7. Li, J.; Cook, J. M. Gassman Indole Synthesis. In Name Reactions in Heterocyclic


252

Gattermann–Koch reaction Formylation of arenes using carbon monoxide and hydrogen chloride in the pres-ence of aluminum chloride under high pressure.

HClCOAlCl3

Cu2Cl2

CHO

:C O

:::C O:

AlCl3 :C OAlCl3

:

HCl Cl:C O

AlCl3

: C OAlCl3

:Cl

H

Cl H

OAlCl3 O

HAlCl4

Cl H

OCl3Al

: :O

H

acylium ion

CHOHCHO CHO

HCl AlCl3

Cl

AlCl4 AlCl4

Example, A more practical variant4

OH

HO

Zn(CN)2, AlCl3

HCl (g), 0 oC

OH

HO

NH2

Clorcinol

H2O0 to 100 oC

95%

OH

HO

CHO

References 1. Gattermann, L.; Koch, J. A. Ber.1897, 30, 1622−1624. Ludwig Gattermann

(1860−1920) was born in Freiburg, Germany. His textbook, “Die Praxis de or-ganischen Chemie” (1894) was one of his major contributions to organic chemistry.

2. Crounse, N. N. Org. React. 1949, 5, 290−300. (Review). 3. Truce, W. E. Org. React. 1957, 9, 37−72. (Review). 4. Solladié, G.; Rubio, A.; Carreño, M. C.; García Ruano, J. L. Tetrahedron: Asymmetry

1990, 1, 187−198. 5. (a) Tanaka, M.; Fujiwara, M.; Ando, H. J. Org. Chem. 1995, 60, 2106−2111. (b)

Tanaka, M.; Fujiwara, M.; Ando, H.; Souma, Y. Chem. Commun. 1996, 159−160. (c) Tanaka, M.; Fujiwara, M.; Xu, Q.; Souma, Y.; Ando, H.; Laali, K. K. J. Am. Chem. Soc. 1997, 119, 5100−5105. (d) Tanaka, M.; Fujiwara, M.; Xu, Q.; Ando, H.; Raeker, T. J. J. Org. Chem. 1998, 63, 4408−4412.

6. Kantlehner, W.; Vettel, M.; Gissel, A; Haug, E.; Ziegler, G.; Ciesielski, M.; Scherr, O.; Haas, R. J. Prakt. Chem. 2000, 342, 297−310.

253


Gewald aminothiophene synthesis Base-promoted aminothiophene formation from ketone, α-active methylene nitrile and elemental sulfur.

R

R1

O CO2R2

CNS8

Base

S

CO2R2

NH2R1

R

O

R1

R

CN

OOR2

HB: CN

OOR2 Knoevenagel

condensationBH NC

O

OR2

RR1

HO

H

:B

R

R1

CN

O OR2

H

:B

BH

NC

O

OR2

RR1

HO

R

R1

CN

O OR2

SSS

S SSS

S

R

R1

O OR2

S S S

N

6

:

BHH

S

CO2R2

NH2R1

RS7S

R2O2CNH

R1

R

HSS

S SS

SSB

Ylidene-sulfur adduct

Example 14

N

NH3C CH3

CO2Et

CNS

CO2Et

NH2

N

S8

morpholine

82%

Example 27

O

O O CO2Et

CN St-BuO2C NH2

CO2EtMeS8, EtOH, morpholine

60 oC, 5 h, 74%

254


Example 39

Me

O

O2N

NC CN

HN(TMS)3, HOActoluene, 65 oC, 90%

Knoevenagelcondensation

Me

O2N

NC CN 1.2 atom equiv S81 equiv NaHCO3

THF, H2O, 80−85%O2N

NC

S

NH2

Example 410

O

OO

OO

S

NH2

O O3 equiv morpholine

1 equiv S8, 55 oC, 24 h

85% conversion64% yield

NCO

O

Example 511

ON

NO

O

S

OO

NH2

N

3 equiv morpholine2 equiv S8, MeOH

20−45 oC, 24 h72%

S

OO

NH2

N

Condensation

MPS = morpholine-polysulfide

OO

NN

Addition

of sulfurS

OO

NN

SxS

Cyclization

NH2NC

CN

CO2CH3

CN

dimer

Re-cyclization

Dimerization

ylidene ylidene-sulfuradduct

255

References 1. (a) Gewald, K. Z. Chem. 1962, 2, 305−306. (b) Gewald, K.; Schinke, E.; Böttcher, H.

Chem. Ber. 1966, 99, 94−100. (c) Gewald, K.; Neumann, G.; Böttcher, H. Z. Chem. 1966, 6, 261. (d) Gewald, K.; Schinke, E. Chem. Ber. 1966, 99, 271−275.

2. Mayer, R.; Gewald, K. Angew. Chem., Int. Ed. 1967, 6, 294−306. (Review). 3. Gewald, K. Chimia 1980, 34, 101−110. (Review). 4. Bacon, E. R.; Daum, S. J. J. Heterocycl. Chem. 1991, 28, 1953-1955. 5. Sabnis, R. W. Sulfur Reports 1994, 16, 1−17. (Review). 6. Sabnis, R. W.; Rangnekar, D. W.; Sonawane, N. D. J. Heterocycl. Chem. 1999, 36,

333−345. (Review). 7. Gütschow, M.; Kuerschner, L.; Neumann, U.; Pietsch, M.; Löser, R.; Koglin, N.; Eger,

K. J. Med. Chem. 1999, 42, 5437. 8. Tinsley, J. M. Gewald Aminothiophene Synthesis. In Name Reactions in Heterocyclic


9. Barnes, D. M.; Haight, A. R.; Hameury, T.; McLaughlin, M. A.; Mei, J.; Tedrow, J. S.; Dalla Riva Toma, J. Tetrahedron 2006, 62, 11311−11319.

10. Tormyshev, V. M.; Trukhin, D. V.; Rogozhnikova, O. Yu.; Mikhalina, T. V.; Troit-skaya, T. I.; Flinn, A. Synlett 2006, 2559−2564.

11. Puterová, Z.; Andicsová, A.; Végh, D. Tetrahedron 2008, 64, 11262−11269.

256

Glaser coupling Oxidative homo-coupling of terminal alkynes using copper catalyst in the pres-ence of oxygen.

CuCl

NH4OH, EtOHC CHR C CR C C R

Cu

Cu+

Cu

XCu

X

L L

L L

+2

L = AmineX = Cl, OAc

Cu+2

2 Cu

Cu

Cu

L L

L L

+2

R

R

Cu

Cu

L L

L L

+2

XR

R R

R

R :

or

Cu

R

Alternatively, the radical mechanism is also operative:

H CuClBase

Cu(I)

O2

Cu(II) Cu(I)

dimerization

Example 11

Cu2O2

NH4OH, EtOH90%

257


Example 2, Homo-coupling2

HO

Cu, NH4Cl

O2, 90% HO OH Example 37

S

SS

SR

R CuCl

TMEDA

O2, CH2Cl2, 0°C

47%

S

S

S

S

SS

S

SS

S

SS

R

R R

R

R R

R = n-Hexyl

References 1. Glaser, C. Ber. 1869, 2, 422–424. 2. Bowden, K.; Heilbron, I.; Jones, E. R. H.; Sondheimer, F. J. Chem. Soc. 1947, 1583–

1590. 3. Hoeger, S.; Meckenstock, A.-D.; Pellen, H. J. Org. Chem. 1997, 62, 4556–4557. 4. Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed. 2000, 39, 2632–

2657. (Review). 5. Youngblood, W. J.; Gryko, D. T.; Lammi, R. K.; Bocian, D. F.; Holten, D.; Lindsey, J.

S. J. Org. Chem. 2002, 67, 2111–2117. 6. Moriarty, R. M.; Pavlovic, D. J. Org. Chem. 2004, 69, 5501–5504. 7. Andersson, A. S.; Kilsa, K.; Hassenkam, T.; Gisselbrecht, J.-P.; Boudon, C.; Gross,

M.; Nielsen, M. B.; Diederich, F. Chem. Eur. J. 2006, 12, 8451–8459. 8. Gribble, G. W. Glaser Coupling. In Name Reactions for Homologations-Part I; Li, J.


258

Eglinton coupling Oxidative homo-coupling of terminal alkynes mediated by stoichiometric (or often excess) Cu(OAc)2. A variant of the Glaser coupling reaction.

R HCu(OAc)2

pyridine/MeOHR R

RR Hpyridine

NH

CuAcO OAc

R Cu OAc

R RR

dimerizationR

Example 12

Cu(OAc)2

pyr., 25 °C

20%

Example 2, Cross-coupling3

Ph

SPh

CO2Me

Cu(OAc)2pyridine/MeOH (1:1)

rt, 72%Ph

SPh

CO2Me

Example 3, Homo-coupling4

Cu(OAc)2, pyridine

MeOH, 1.5 h, 68%

NNC

Cl

NNC

Cl

NCN

Cl

259

Example 45

TMS

TIPSR = H, t-Bu

Cu(OAc)2

K2CO3pyr., MeOH

61–70%

R

TIPS

TIPS

R

1. TBAF

2. CuCl, Cu(OAc)2 pyr.

R

R

R

51–64%R

R

Example 511

Fe

CNO

2 equiv Cu(OAc)2•H2O

1 : 1 Pyr : MeOH 70 oC, 12 h, 41%

Fe

CNO Fe

CNO

Example 612

Cu(OAc)2

Pyr./MeOH/Et2O62%

260

References 1. (a) Eglinton, G.; Galbraith, A. R. Chem. Ind. 1956, 737−738. Geoffrey Eglinton

(1927−) was born in Cardiff, Wales. (b) Behr, O. M.; Eglinton, G.; Galbraith, A. R.; Raphael, R. A. J. Chem. Soc. 1960, 3614−3625. (c) Eglinton, G.; McRae, W. Adv. Org. Chem. 1963, 4, 225−328. (Review).

2. McQuilkin, R. M.; Garratt, P. J.; Sondheimer, F. J. Am. Chem. Soc. 1970, 92, 6682–6683.

3. Nicolaou, K. C.; Petasis, N. A.; Zipkin, R. E.; Uenishi, J. J. Am. Chem. Soc. 1982, 104, 5558−5560.

4. Srinivasan, R.; Devan, B.; Shanmugam, P.; Rajagopalan, K. Indian J. Chem., Sect. B 1997, 36B, 123−125.

5. Haley, M. M.; Bell, M. L.; Brand, S. C.; Kimball, D. B.; Pak, J. J.; Wan, W. B. Tetra-hedron Lett. 1997, 38, 7483–7486.

6. Nakanishi, H.; Sumi, N.; Aso, Y.; Otsubo, T. J. Org. Chem. 1998, 63, 8632-8633. 7. Kaigtti-Fabian, K. H. H.; Lindner, H.-J.; Nimmerfroh, N.; Hafner, K. Angew. Chem.,

Int. Ed. 2001, 40, 3402−3405. 8. Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed. 2000, 39,

2632−2657. (Review). 9. Inouchi, K.; Kabashi, S.; Takimiya, K.; Aso, Y.; Otsubo, T. Org. Lett. 2002, 4,

2533−2536. 10. Xu, G.-L.; Zou, G.; Ni, Y.-H.; DeRosa, M. C.; Crutchley, R. J.; Ren, T. J. Am. Chem.

Soc. 2003, 125, 10057−10065. 11. Shanmugam, P.; Vaithiyananthan, V.; Viswambharan, B.; Madhavan, S. Tetrahedron

Lett. 2007, 48, 9190−9194. 12. Miljanic, O. S.; Dichtel, W. R.; Khan, S. I.; Mortezaei, S.; Heath, J. R.; Stoddart, J. F.

J. Am. Chem. Soc. 2007, 129, 8236−8246.

261

Gomberg–Bachmann reaction Base-promoted radical coupling between an aryl diazonium salt and an arene to form a diaryl compound.

N2O

O

OH

OHN N

N N

N NOH

Ph

: N NPh

ONN

PhN2↑

ONN

Ph

O

O

OH

ONN

Ph

OHNN

Ph

Example 14

N2O

O

O

O

BF4 KOAc, 18-C-6

rt, 55%O

O Example 25

N

N N

N

NH2

MeOONO

PhH, TFAA, reflux2 d, 33%

N

N N

N

MeO

References 1. Gomberg, M.; Bachmann, W. E. J. Am. Chem. Soc. 1924, 46, 2339−2343. Moses

Gomberg (1866−1947) was born in Elizabetgrad, Russia. He discovered the triphenyl-methyl stable radical at the University of Michigan in Ann Arbor, Michigan. In this article, Gomberg declared that he had reserved the field of radical chemistry for him-self! Werner Bachmann (1901−1951), Gomberg’s Ph.D. student, was born in Detroit, Michigan. After his postdoctoral trainings in Europe Bachmann returned to the Uni-versity of Michigan as the Moses Gomberg Professor of Chemistry.

2. Beadle, J. R.; Korzeniowski, S. H.; Rosenberg, D. E.; Garcia-Slanga, B. J.; Gokel, G. W. J. Org. Chem. 1984, 49, 1594−1603.

3. McKenzie, T. C.; Rolfes, S. M. J. Heterocycl. Chem. 1987, 24, 859−861. 4. Lai, Y.-H.; Jiang, J. J. Org. Chem. 1997, 62, 4412−4417.

262


Gould–Jacobs reaction The Gould–Jacobs reaction is a sequence of the following reactions: a. Substitution of an aniline with either alkoxy methylenemalonic ester or acyl malonic ester providing the anilinomethylenemalonic ester; b. Cyclization of to the 4-hydroxy-3-carboalkoxyquinoline (4-hydroxyquinolines exist predominantly in 4-oxoform); c. Saponification to form acid; d. Decarboxylation to give the 4-hydroxyquinoline. Extension could lead to unsubstituted parent heterocycles with fused pyridine ring of Skraup type.

NH2

CO2RRO2C

OR''R' NH

R'

CO2Rheat

− R''OH

ΔRO2C

N

CO2ROH

R' N

CO2HOH

R'

HO− Δ

NH

O

R'

R = alkyl; R' = alkyl, aryl, or H; R'' = alkyl or H

NH2

EtO2C

OEt NH2

substitutionEtO2C

OEt

O

OEt

OEt

O

− EtOH

NH

CO2EtOEtO

:

N

CO2EtO

Hcyclization tautomerization

N

CO2EtOH

NH

CO2EtO

Example 13

O

NH

EtO2C CO2EtPh2O, reflux

75%, 10:1NH N

H

OO CO2EtO

OCO2Et

263


Example 28

EtO2C CO2Et

EtO H

N

H2N

RN

HN

R

H

CO2EtEtO2CEtOH, reflux

PhOPh

250 oC

N R

NH

OEtO2C N R

N

ClEtO2CPOCl3

70 oC

Example 3, Microwave-assisted Gould–Jacobs reaction9

N

N CO2EtEtO2C

OEtHNR1

R NH2

Ph−O−Ph

130−140 oC N

N

NR1

R HNCO2Et

CO2Et

Ph−O−Ph250 oC

N

N

NR1

R N

O

CO2Et

Microwave, neat

10−12 min., 64−75%

Example 410

CO2EtEtO2C

OEtH

Ph-O-Ph

heat

NNPh

NH2

Ar

NNPh

NH

ArEtOH

reflux H

EtO2C CO2Et

NN

PhNH

ArCO2Et

O

NN

PhN

ArCO2Et

Cl

POCl3

reflux

POCl3reflux

References 1. Gould, R. G.; Jacobs, W. A. J. Am. Chem. Soc. 1939, 61, 2890−2895. R. Gordon

Gould was born in Chicago in 1909. He earned his Ph.D. at Harvard University in 1933. After serving as an instructor at Harvard and Iowa, Gould worked at Rockefel-

264

ler Institute for Medical Research where he discovered the Gould–Jacobs reaction with his colleague Walter A. Jacobs.

2. Reitsema, R. H. Chem. Rev. 1948, 53, 43−68. (Review). 3. Cruickshank, P. A., Lee, F. T., Lupichuk, A. J. Med. Chem. 1970, 13, 1110−1114. 4. Elguero J., Marzin C., Katritzky A. R., Linda P., The Tautomerism of Heterocycles,

Academic Press, New York, 1976, pp 87−102. (Review). 5. Wang, C. G., Langer, T., Kiamath, P. G., Gu, Z. Q., Skolnick, P., Fryer, R. I. J. Med.

Chem. 1995, 38, 950−957. 6. Milata, V.; Claramunt, R. M.; Elguero, J.; Zálupský, P. Targets in Heterocyclic Sys-

tems 2000, 4, 167–203. (Review). 7. Curran, T. T. Gould–Jacobs Reaction. In Name Reactions in Heterocyclic Chemistry;

Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 423−436. (Review). 8. Ferlin, M. G.; Chiarelotto, G.; Dall’Acqua, S.; Maciocco, E.; Mascia, M. P.; Pisu, M.

G.; Biggio, G. Bioorg. Med. Chem. 2005, 13, 3531−3541. 9. Desai, N. D. J. Heterocycl. Chem. 2006, 43, 1343−1348. 10. Kendre, D. B.; Toche, R. B.; Jachak, M. N. J. Heterocycl. Chem. 2008, 45,

1281−1286.

265

Grignard reaction Addition of organomagnesium compounds (Grignard reagents), generated from organohalides and magnesium metal, to electrophiles.

R XMg(0)

R MgX R1 R2

O

R OH

R2R1

Formation of the Grignard reagent:

Mg Mg

R X

Mg Mg

R X

single electron

transfer

Mg Mg

R MgXR MgX

Grignard reaction, ionic mechanism:

R OMgX

R2R1R2

R1

R MgX

OR2

R1δ δ

δδ

R MgXO

‡

Radical mechanism,

R MgX

OR2

R1

OR2

R1MgX

R

R OMgX

R2R1

R OH

R2R1H

Example 14

EtMgBr

reflux, tol./ether, 76%NOH

NH

H

This reaction is known as the Hoch–Campbell aziridine synthesis, which entails treatment of ketoximes with excess Grignard reagents and subsequent hydrolysis of the organometallic complex to produce aziridines.

266


Example 25

OMeMeO

MeOOMe

N

OPh

OMe

OO

Br

OO

MeO

MeOOMe

N

O Ph

MeO

OO

OOMg

65%

Example 510

Garner's aldehydeCHO

OO MgBr

THF

0 oC to rt, 91% OO

OH

Example 611

O

OH

HO

OH

HO

HOO

O

52% 28% 5%

3 equiv BrMg

THF, 55 oC, 1 h, 85%

References 1. Grignard, V. C. R. Acad. Sci. 1900, 130, 1322−1324. Victor Grignard (France,

1871−1935) won the Nobel Prize in Chemistry in 1912 for his discovery of the Grig-nard reagent.

2. Ashby, E. C.; Laemmle, J. T.; Neumann, H. M. Acc. Chem. Res. 1974, 7, 272−280. (Review).

3. Ashby, E. C.; Laemmle, J. T. Chem. Rev. 1975, 75, 521−546. (Review). 4. Sasaki, T.; Eguchi, S.; Hattori, S. Heterocycles 1978, 11, 235−242. 5. Meyers, A. I.; Flisak, J. R.; Aitken, R. A. J. Am. Chem. Soc. 1987, 109, 5446−5452. 6. Grignard Reagents Richey, H. G., Jr., Ed.; Wiley: New York, 2000. (Book). 7. Holm, T.; Crossland, I. In Grignard Reagents Richey, H. G., Jr., Ed.; Wiley: New

York, 2000, Chapter 1, pp 1−26. (Review). 8. Shinokubo, H.; Oshima, K. Eur. J. Org. Chem. 2004, 2081−2091. (Review). 9. Graden, H.; Kann, N. Cur. Org. Chem. 2005, 9, 733−763. (Review). 10. Babu, B. N.; Chauhan, K. R. Tetrahedron Lett. 2008, 50, 66−67. 11. Mlinaric-Majerski, K.; Kragol, G.; Ramljak, T. S. Synlett 2008, 405−409. 12. Chen, D.; Yang, C.; Xie, Y.; Ding, J. Heterocycles 2009, 77, 273−277.

267

Grob fragmentation The C−C bond cleavage primarily via a concerted process involving a five atom system. General scheme:

D L

:

D L

D = O−, NR2; L = OH2

+, OTs, I, Br, Cl

Example 12

OMOM

OH

MsO

OMOM

O

MsONaH

15-crown-5

0 oC to rt, 95%O

OMOM

Example 2, Aza-Grob fragmentation3

N O

S

15 eq. NaBH4, THF

70 oC, 31 h, 53% NH

OHSH

Example 37

OH

OTs

NaH, DMSO, 40 oC, 1 h;

then tosylate, 40 oC, 1 h52%MeO

OMeO

Example 48

OH

H

OMsH

H H1.1 equiv KHMDS

THF, 0 oC, 15 min.93%

OH H

H

268


References 1. (a) Grob, C. A.; Baumann, W. Helv. Chim. Acta 1955, 38, 594−603. (b) Grob, C. A.;

Schiess, P. W. Angew. Chem., Int. Ed. 1967, 6, 1−15. Cyril A. Grob (1917−2003) was born in London (UK) to Swiss parents, studied chemistry at ETH Zürich and com-pleted his PhD in 1943 under the guidance of Leopold Ruzicka (A Nobel laureate) on artificial steroidal antigens. He then moved to Basel to work with Taddeus Reichstein (another Nobel laureate) first at the pharmaceutical institute and from 1947 at the or-ganic chemistry institute of the university, where he moved up the academic career ladder to become the director of the institute and holder of the chair there as Reich-stein’s successor in 1960. An investigation of the reductive elimination of bromine from 1,4-dibromides in the presence of zinc led in 1955 to the recognition of hetero-lytic fragmentation as a general reaction principle. The heterolytic fragmentation has now entered textbooks under his name. Experimental evidence for vinyl cations as dis-crete reactive intermediates was also first provided by Grob. Cyril Grob never acted impulsively, but always calmly and deliberately. He never sought attention in public, but fulfilled his social duties efficiently, reliably, and without a fuss. He died in his home in Basel (Switzerland) on December 15, 2003 at the age of 86. (Schiess, P. Angew. Chem., Int. Ed. 2004, 43, 4392.)

2. Yoshimitsu, T.; Yanagiya, M.; Nagaoka, H. Tetrahedron Lett. 1999, 40, 5215−5218. 3. Hu, W.-P.; Wang, J.-J.; Tsai, P.-C. J. Org. Chem. 2000, 65, 4208−4029. 4. Molander, G. A.; Le Huerou, Y.; Brown, G. A. J. Org. Chem. 2001, 66, 4511−4516. 5. Paquette, L. A.; Yang, J.; Long, Y. O. J. Am. Chem. Soc. 2002, 124, 6542−6543. 6. Barluenga, J.; Alvarez-Perez, M.; Wuerth, K.; Rodriguez, F.; Fananas, F. J. Org. Lett.

2003, 5, 905−908. 7. Khripach, V. A.; Zhabinskii, V. N.; Fando, G. P.; et al. Steroids 2004, 69, 495−499. 8. Maimone, T. J.; Voica, A.-F.; Baran, P. S. Angew. Chem., Int. Ed. 2008, 47,

3054−3056. 9. Yuan, D.-Y.; Tu, Y.-Q.; Fan, C.-A. J. Org. Chem. 2008, 73, 7797−7799. 10. Barbe, G.; St-Onge, M.; Charette, A. B. Org. Lett. 2008, 10, 5497−5499.

269

Guareschi–Thorpe condensation 2-Pyridone formation from the condensation of cyanoacetic ester with diketone in the presence of ammonia.

O

O

R

R

CN

OR1O

NH3

NH

RCN

R O

CN

OR1O

H3N: CN

OR1O

H2NCN

OH2N

HH3N:

H

R1OHCN

OH2NO

R

O

R

H3N H

CN

R ONH2O

OHR

H :NH3OH

NH

RCN

R O

CN

R ONH2O

R

: NH

RCN

R OOH

HH3N:

H3N H

H2O

Example6

O CO2Et

CN NH3

NH

CNNC

O O

Guareschi imide

75%

References 1. (a) Guareschi, I. Mem. R. Accad. Sci. Torino 1896, II, 7, 11, 25. (b) Baron, H.; Renfry,

F. G. P.; Thorpe, J. F. J. Chem. Soc. 1904, 85, 1726−1961. Jocelyn F. Thorpe spent two years in Germany where he worked in the laboratory of a dyestuff manufacturer before taking a post as a lecturer at Manchester. Thorpe later became FRS (Fellow of the Royal Society) and professor of organic chemistry at Imperial College.

2. Vogel, A. I. J. Chem. Soc. 1934, 1758−1765. 3. McElvain, S. M.; Lyle, R. E. Jr. J. Am. Chem. Soc. 1950, 72, 384−389. 4. Brunskill, J. S. A. J. Chem. Soc. (C) 1968, 960−966. 5. Brunskill, J. S. A. J. Chem. Soc., Perkin Trans. 1 1972, 2946−2950. 6. Holder, R. W.; Daub, J. P.; Baker, W. E.; Gilbert, R. H. III; Graf, N. A. J. Org. Chem.

1982, 47, 1445−1451. 7. Krstic, V.; Misic-Vukovic, M.; Radojkovic-Velickovic, M. J. Chem. Res. (S) 1991, 82. 8. Galatsis, P. Guareschi−Thorpe Pyridine Synthesis. In Name Reactions in Heterocyclic


270


Hajos–Wiechert reaction Asymmetric Robinson annulation catalyzed by (S)-(−)-proline.

O

OO

cat. NH

HO2CH

O

O CH3CN

O

O

O

H

Michael

addition

O

OO

NH

HO2CH

enamine formation

O

ON

HCO2

catalyticasymmetric

enamine aldol

O

ON

CO2 NH H

CO2

:

O

NOH

CO2

H2O: hydrolysis

of iminium salt

O

NOH

CO2

HO

:

O

O

O

OOH

H

B:

O

OOH

E1cB

Example 11a

O

OO

3 mol% (S)-proline

CH3CN, 100%, 93.4% ee

O

O

Example 23

O

1 equiv L−phenylalanine

D-CSA, DMF, rt, 24 h,then increase temperature

10 oC every 24 h for 5 days.79%, 91% ee

OO

O

O

271


Example 38

O

OO

O

O

L-phenylalanine, PPTS

DMSO, 50 oC, 24 hsonication, 94%, 73% ee

OBn OBn

Example 49

O

1 equiv L-phenylalanine0.5 equiv 1 N HClO4

DMSO, 90 oC86%, 48% ee

O

O

OO

References 1. (a) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615−1621. Hajos and Parrish

were chemists at Hoffmann−La Roche. (b) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. 1971, 10, 496−497.

2. Brown, K. L.; Dann, L.; Duntz, J. D.; Eschenmoser, A.; Hobi, R.; Kratky, C. Helv. Chim. Acta 1978, 61, 3108−3135.

3. Hagiwara, H.; Uda, H. J. Org.Chem. 1998, 53, 2308–2311. 4. Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357−389. 5. List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395−2396. 6. List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573−576. 7. Hoang, L.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125, 16−17. 8. Shigehisa, H.; Mizutani, T.; Tosaki, S.-y.; Ohshima, T.; Shibasaki, M. Tetrahedron

2005, 61, 5057−5065. 9. Nagamine, T.; Inomata, K.; Endo, Y.; Paquette, L. A. J. Org. Chem. 2007, 72, 123–

131. 10. Kennedy, J. W. J.; Vietrich, S.; Weinmann, H.; Brittain, D. E. A. J. Org. Chem. 2009,

73, 5151−5154. 11. Christen, D. P. Hajos–Wiechert Reaction. In Name Reactions for Homologations-Part

II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 554−582. (Re-view).

12. Zhu, H.; Clemente, F. R.; Houk, K. N.; Meyer, M. P. J. Am. Chem. Soc. 2009, 131, 1632−1633.

272

Haller–Bauer reaction Base-induced cleavage of non-enolizable ketones leading to carboxylic amide de-rivative and a neutral fragment in which the carbonyl group is replaced by a hy-drogen.

R R5O

R2 R3R1 R4

NaNH2

PhH, reflux

RNH2

O

R2R1

H R5

R3 R4

non-enolizable ketone

R R5O

R2 R3R1 R4

NH2

R R5

R2 R3R1 R4

NH2OR

NH3

O

R2R1

R5

R3R4H R5

R3R4

Example 14

O

t-BuOK, t-BuOH

43%

CO2H

Example 29

O

OOMe

OMe

1. KOH, dioxane

2. CH2N2 77% 2 steps

OO

OMeOMe

OMe

Example 3, Racemization10

H

H

OLiNHC6H11

PhH, 80 oC46%

H

H

O NHC6H11

References 1. Haller, A.; Bauer, E. Compt. Rend. 1908, 147, 824−829. 2. Gilday, J. P.; Gallucci, J. C.; Paquette, L. A. J. Org. Chem. 1989, 54, 1399−1408. 3. Paquette, L. A.; Gilday, J. P.; Maynard, G. D. J. Org. Chem. 1989, 54, 5044−5053. 4. Paquette, L. A.; Gilday, J. P. Org. Prep. Proc. Int. 1990, 22, 167−201. 5. Mehta, G.; Praveen, M. J. Org. Chem. 1995, 60, 279−280. 6. Mehta, G.; Venkateswaran, R. V. Tetrahedron 2000, 56, 1399−1422. (Review). 7. Arjona, O.; Medel, R.; Plumet, J. Tetrahedron Lett. 2001, 42, 1287−1288. 8. Ishihara, K.; Yano, T. Org. Lett. 2004, 6, 1983−1986. 9. Patra, A.; Ghorai, S. K.; De, S. R.; Mal, D. Synthesis 2006, 2556−2562. 10. Braun, I.; Rudroff, F.; Mihovilovic, M. D.; Bach, T. Synthesis 2007, 24, 3896−3906.

273


Hantzsch dihydropyridine synthesis 1,4-Dihydropyridine from the condensation of aldehyde, β-ketoester and ammo-nia. Hantzsch 1,4-dihydropyridines are popular reducing reagents in organocata-lysis.

R H

O CO2Et

R1O

NH3

NH

RCO2EtEtO2C

R1 R1

R H

O

CO2Et

R1O

enolate

formationCO2Et

R1OHH3N:

HH3N:

aldol

condensation

R1O

R

OH

CO2EtR1O

RCO2Et

R1O

R

OH

CO2EtH

:NH3

CO2Et

R1O

:NH3enamine

formation

CO2Et

R1HOH2N :

− H2O

H3N:CO2Et

R1

H

H2N

CO2Et

R1H2N

:

Michael

addition

EtO2C

R1

R

O

CO2Et

R1N

REtO2C

OR1

H

H2N HH

:NH3

tautomerizationCO2Et

R1NH2

REtO2C

O R1H2N H N

RCO2EtEtO2C

R1HOR1

H

H

H3N:

NH

RCO2EtEtO2C

R1 R1

Example 12

H

OCO2Et

O

NH3

NH

CO2EtEtO2C

NO2

NO2

nifedipine

274


Example 29

R' H

O O

NH

RCO2R2R1O2C

CO2R2 NH4OAc

SiO2O

OOHO3S

(SiO2-SO3H), solvent-free60 oC, 83−95%

H

Example 3, Hantzsch 1,4-dihydropyridine as a hydrogen donor10

N R

O

OP

O

OH

NH

CO2EtEtO2C

NH

R

84−99% ee

References 1. Hantzsch, A. Ann. 1882, 215, 1−83. 2. Bossert, F.; Vater, W. Naturwissinschaften 1971, 58, 578−585. 3. Balogh, M.; Hermecz, I.; Naray-Szabo, G.; Simon, K.; Meszaros, Z. J. Chem. Soc.,

Perkin Trans. 1 1986, 753−757. 4. Katritzky, A. R.; Ostercamp, D. L.; Yousaf, T. I. Tetrahedron 1987, 43, 5171−5187. 5. Menconi, I.; Angeles, E.; Martinez, L.; Posada, M. E.; Toscano, R. A.; Martinez, R. J.

Heterocycl. Chem. 1995, 32, 831−833. 6. Raboin, J.-C.; Kirsch, G.; Beley, M. J. Heterocycl. Chem. 2000, 37, 1077−1080. 7. Sambongi, Y.; Nitta, H.; Ichihashi, K.; Futai, M.; Ueda, I. J. Org. Chem. 2002, 67,

3499−3501. 8. Galatsis, P. Hantzsch Dihydro-Pyridine Synthesis. In Name Reactions in Heterocyclic


9. Gupta, R.; Gupta, R.; Paul, S.; Loupy, A. Synthesis 2007, 2835−2838. 10. Metallinos, C.; Barrett, F. B.; Xu, S. Synlett 2008, 720−724.

275

Hantzsch pyrrole synthesis Reaction of α-chloromethyl ketones with β-ketoesters and ammonia to assemble pyrroles.

O

Cl

CO2Et

O NH

CO2EtNH3

CO2Et

O:NH3

enamine

formation

CO2Et

HOH2N:

H3N:CO2EtH

H2N

CO2Et

H2N

− H2O

CO2Et

H2N

ClO

HN

OHCl

HCO2Et

:NH:

− H2OH3N H

N

CO2Et

HN

Cl CO2Et:

H

HH3N: NH

CO2Et

Example 14

O

Br

F3C

CO2MeH2N NH

CO2Me

DME, 87−140 oC

2.5 h, 60% F3C

Example 27

OCl

CO2Et

O NH

CO2EtNH3, EtOH

48 h, 48%

References 1. Hantzsch, A. Ber. 1890, 23, 1474−1483. 2. Katritzky, A. R.; Ostercamp, D. L.; Yousaf, T. I. Tetrahedron 1987, 43, 5171−5186. 3. Kirschke, K.; Costisella, B.; Ramm, M.; Schulz, B. J. Prakt. Chem. 1990, 332,

143−147. 4. Kameswaran, V.; Jiang, B. Synthesis 1997, 530−532. 5. Trautwein, A. W.; Sü muth, R. D.; Jung, G. Bioorg. Med. Chem. Lett. 1998, 8,

2381−2384. 6. Ferreira, V. F.; De Souza, M. C. B. V.; Cunha, A. C.; Pereira, L. O. R.; Ferreira, M. L.

G. Org. Prep. Proced. Int. 2001, 33, 411−454. (Review). 7. Matiychuk, V. S.; Martyak, R. L.; Obushak, N. D.; Ostapiuk, Yu. V.; Pidlypnyi, N. I.

Chem. Heterocycl. Compounds 2004, 40, 1218−1219.

276


Heck reaction The palladium-catalyzed alkenylation or arylation of olefins.

R1 XR3

H R2

R4 R3

R1 R2

R4

Pd(0) (catalytic)

base

R1 = aryl, alkenyl, alkyl (with no β-hydrogen)X = Cl, Br, I, OTf, OTs, N2

+

The catalytic cycle:

A

R1 X

R3

H R2

R4

R3

R1 R2

R4

LnPd(II)R1

X

LnPd(0)

Pd(II)LnXR1

H R4R3 R2

Pd(II)LnXH

R3 R4R1 R2

LnPd(II)H

X

base

base•HX

Pd(0) or Pd(II) precatalysts

B

C

D

E

A: Oxidative additionB: Migratory insertion (syn)C: C−C bond rotation

D: syn-β-eliminationE: Reductive elimination

Example 1, Asymmetric intermolecular Heck reaction6

NCO2Me

CO2Et

OTfNCO2Me

EtO2C

*

Pd[(R)-BINAP]23 mol%

proton spongePhH, 60 oC

95%, > 99% ee

277


Example 2, Intramolecular Heck7

N

N

HO

I

OTBS

HN

N

OH

OTBS

0.3 eq. Pd(OAc)2

Bu4NCl, DMF, K2CO370 oC, 3 h, 74%

Example 38

Cl

MeO

O

O

MeO

O

O

1.5% Pd2(dba)3, 6% P(t-Bu)31.1. eq. Cs2CO3, dioxane

120 oC, 24 h, 82%


N

N Cl

NH N

N

NH

10 mol% Pd(OAc)2

Bu4NCl, K2CO3DMF, 100 oC, 67%


HN

MeNH

NMeNH H

NBn

ONTsMe

TfO

TsNMe

BnN

O

OTf Pd(OAc)2(R)-Tol-BINAPMeCN, 80 oC

(62%, 90% ee)

NMe

MeMe

MeMe

HN

MeNH

NMeNH H

BnN

NBn

TsNMe

NTsMe

O

O

Example 6, Reductive Heck reaction17

HMe

O

NH

Me

Br

H Me

NH

MeMe

O

5 mol% Pd(P(o-tol)3(OAc)2

NaOCHO, TBAB, Et3NDMF, 80 oC, 65%

278

References 1. Heck, R. F.; Nolley, J. P., Jr. J. Am. Chem. Soc. 1968, 90, 5518−5526. Richard Heck

discovered the Heck reaction when he was an assistant professor at the University of Delaware. Despite having discovered a novel methodology that would see ubiquitous utility in organic chemistry and having published a popular book,4 Heck had difficul-ties in securing funding for his research, he left chemistry and moved to Asia. Now he is retired in Florida.

2. Heck, R. F. Acc. Chem. Res. 1979, 12, 146−151. (Review). 3. Heck, R. F. Org. React. 1982, 27, 345−390. (Review). 4. Heck, R. F. Palladium Reagents in Organic Synthesis, Academic Press, London, 1985.

(Book). 5. Hegedus, L. S. Transition Metals in the Synthesis of Complex Organic Molecule 1994,

University Science Books: Mill Valley, CA, pp 103−113. (Book). 6. Ozawa, F.; Kobatake, Y.; Hayashi, T. Tetrahedron Lett. 1993, 34, 2505−2508. 7. Rawal V. H.; Iwasa, H. J. Org. Chem. 1994, 59, 2685−2686. 8. Littke, A. F.; Fu, G. C. J. Org. Chem. 1999, 64, 10−11. 9. Li, J. J. J. Org. Chem. 1999, 64, 8425−8427. 10. Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009−3066. (Review). 11. Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314−321. (Review). 12. Link, J. T. Org. React. 2002, 60, 157−534. (Review). 13. Lebsack, A. D.; Link, J. T.; Overman, L. E.; Stearns, B. A. J. Am. Chem. Soc. 2002,

124, 9008−9009. 14. Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945−2963. (Review). 15. Beller, M.; Zapf, A.; Riermeier, T. H. Transition Metals for Organic Synthesis (2nd

edn.) 2004, 1, 271−305. (Review). 16. Oestreich, M. Eur. J. Org. Chem. 2005, 783−792. (Review). 17. Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature 2007, 446, 404−406. 18. Fuchter, M. J. Heck Reaction. In Name Reactions for Homologations-Part I; Li, J. J.,

Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 2−32. (Review). 19. The Mizoroki-Heck Reaction; Oestreich, M., Ed.; Wiley & Sons: Hoboken, NJ, 2009.

279

Heteroaryl Heck reaction Intermolecular or intramolecular Heck reaction that occurs onto a heteroaryl re-cipient.

N

SI

Pd(Ph3P)4, Ph3P, CuI

Cs2CO3, DMF, 140 oCN

S

N

SI

Pd(0)

oxidative additionPd(II)I

insertion

NS

Pd(II)H

B:I

NSCs2CO3

CsI CsCHO3Pd(0)

Example 12

O

Br

NN

N

BuN

NN

BuO

Pd(OAc)2, NaHCO3

n-Bu4NCl, DMA 150 oC, 24 h, 83%

Example 23

N

N Cl

N

O

N

NN

OPd(Ph3P)4, KOAcDMA, reflux, 65%

References 1. Ohta, A.; Akita, Y.; Ohkuwa, T.; Chiba, M.; Fukunaka, R.; Miyafuji, A.; Nakata, T.;

Tani, N. Aoyagi, Y. Heterocycles 1990, 31, 1951−1958. 2. Kuroda, T.; Suzuki, F. Tetrahedron Lett. 1991, 32, 6915−6918. 3. Aoyagi, Y.; Inoue, A.; Koizumi, I.; Hashimoto, R.; Tokunaga, K.; Gohma, K.; Koma-

tsu, J.; Sekine, K.; Miyafuji, A.; Kunoh, J. Honma, R. Akita, Y.; Ohta, A. Heterocy-cles 1992, 33, 257−272.

4. Proudfoot, J. R.; Patel, U. R.; Kapadia, S. R.; Hargrave, K. D. J. Med. Chem. 1995, 38, 1406−1410.

5. Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 467−473.

6. Li, J. J.; Gribble, G. W. In Palladium in Heterocyclic Chemistry; 2nd ed.; 2007, El-sevier: Oxford, UK. (Review).

280

Hegedus indole synthesis Stoichiometric Pd(II)-mediated oxidative cyclization of alkenyl anilines to in-doles. Cf. Wacker oxidation.

NH2

PdCl2(CH3CN)2, THF

then, Et3N, 84%MeO2C NHMeO2C

CH3

NH2MeO2C PdNH2MeO2C Cl

ClPdCl2(CH3CN)2

palladation

Et3N

precipitate

NH2MeO2C

PdCl

Et3NCl

:

NH2

PdEt3N

Cl

Cl

MeO2C

– HCl

– "PdH"

H

NHMeO2C

"PdH"

NHMeO2C

PdLn

H

NHMeO2C

CH3β-elimination

CH3

Example 11a

NH2

10 mol% (CH3CN)2PdCl2100 mol% benzoquinone

10 eq. Et3N, THF, reflux, 84% NH

CH3

Example 21d

10 mol % (CH3CN)2PdCl2100 mol% benzoquinone

10 eq. LiCl, THF, reflux, 77%NHTs N

Br

Ts

Br

References 1. (a) Hegedus, L. S.; Allen, G. F.; Waterman, E. L. J. Am. Chem. Soc. 1976, 98,

2674−2676. Lou Hegedus is a professor at Colorado State University. (b) Hegedus, L. S.; Allen, G. F.; Bozell, J. J.; Waterman, E. L. J. Am. Chem. Soc. 1978, 100, 5800−5807. (c) Hegedus, L. S.; Winton, P. M.; Varaprath, S. J. Org. Chem. 1981, 46, 2215−2221. (d) Harrington, P. J.; Hegedus, L. S. J. Org. Chem. 1984, 49, 2657−2662. (e) Hegedus, L. S. Angew. Chem., Int. Ed. 1988, 27, 1113−1126. (Review).

2. Brenner, M.; Mayer, G.; Terpin, A.; Steglich, W. Chem. Eur. J. 1997, 3, 70−74. 3. Osanai, Y. Y.; Kondo, K.; Murakami, Y. Chem. Pharm. Bull. 1999, 47, 1587−1590. 4. Kondo, T.; Okada, T.; Mitsudo, T. J. Am. Chem. Soc. 2002, 124, 186−187. A ruthe-

nium variant. 5. Johnston, J. N. Hegedus Indole Synthesis. In Name Reactions in Heterocyclic Chemis-


281


Hell–Volhard–Zelinsky reaction α-Halogenation of carboxylic acids using X2/PBr3.

ROH

OR

Br

O

Br

H2OR

OH

O

Br

PBr3

Br2

α-bromoacid

RO

O

P BrBr

Br

RO

OP

Br

Br

Br

RO

OP

Br

Br

BrH

RBr

O

O P Br H

Br

enolization RBr

O

Br Br

H

:OH2

ROH

O

BrR

Br

O

Br

RBr

O

OH

H

Br

HB:

hydrolysis

Example 15

CO2H Cl2, cat. PCl3

97 oC, 6 h, 77%

CO2HCl

Example 26

CO2H

PBr3

Br2, 57%Br

CO2H

CO2HBr

H

References 1. (a) Hell, C. Ber. 1881, 14, 891−893. Carl M. von Hell (1849−1926) was born in Stutt-

gart, Germany. He studied under Fehling and Erlenmeyer. After serving in the war of 1870, he became very ill. Hell became a professor at Stuttgart in 1883 where he dis-covered the Hell–Volhard–Zelinsky reaction. (b) Volhard, J. Ann. 1887, 242, 141−163. Jacob Volhard (1849−1909) was born in Darmstadt, Germany. He appren-ticed under Liebig, Will, Bunsen, Hofmann, Kolbe, and von Baeyer. He improved Hell’s original procedure in preparing α-bromo-acid during his research in thiophenes. (c) Zelinsky, N. D. Ber. 1887, 20, 2026. Nikolai D. Zelinsky (1861−1953) was born in

282


Tyaspol, Russia. He studied at Göttingen under Victor Meyer, receiving his Ph.D. In 1889. Zelinsky returned to Russia and became a professor at the University of Mos-cow. On his ninetieth birthday in 1951, he was awarded the Order of Lenin.

2. Watson, H. B. Chem. Rev. 1930, 7, 173−201. (Review). 3. Sonntag, N. O. V. Chem. Rev. 1953, 52, 237−246. (Review). 4. Harwood, H. J. Chem. Rev. 1962, 62, 99−154. (Review). 5. Jason, E. F.; Fields, E. K. US Patent 3,148,209 (1964). 6. Chow, A. W.; Jakas, D. R.; Hoover, J. R. E. Tetrahedron Lett. 1966, 5427−5431. 7. Liu, H.-J.; Luo, W. Synth. Commun. 1991, 21, 2097−2102. 8. Zhang, L. H.; Duan, J.; Xu, Y.; Dolbier, W. R., Jr. Tetrahedron Lett. 1998, 39,

9621−9622. 9. Sharma, A.; Chattopadhyay, S. J. Org. Chem. 1999, 64, 8059−8062. 10. Stack, D. E.; Hill, A. L.; Diffendaffer, C. B.; Burns, N. M. Org. Lett. 2002, 4,

4487−4490.

283

Henry nitroaldol reaction The nitroaldol condensation reaction involving aldehydes and nitronates, derived from deprotonation of nitroalkanes by bases.

R1 R2

O

R4 NO2

BaseR3

R4R2

R1HOR3 H NO2

2-nitroalcohols

NO2

HR1

R2

B

HBnitroalkanes

NO2R2

R1N

R2

R1 O

O

HB

BN

R2

R1

OH

nitronic acidsor aci-nitroalkanes

R3

O

H

NO2

R2

R1

R3

O

NO2

R2

R1

R3

OHHBB

2-nitroalcohols

O

nitronates

Example 14

NO2

CHO

Amberlyst A-21 (basic)rt, 62%

NO2HO

Example 2, Retro-Henry reaction5

OHNO2 NO2

OCuSO4, SiO2

PhH, reflux67%

Example 3, Aza-Henry reaction8

N

Ph

PO

PhPh

NO2Ph

5 mol% TMG, 100 oC

0.1 mBar, 26 h95%, anti:syn = 98:2

HN

Ph

PO

PhPh

NO2

Ph

284


Example 4, Intramolecular Henry reaction10

N O

NO2

ON

O

H

O2N

HODBU, MeCN

62%

References 1. Henry, L. Compt. Rend. 1895, 120, 1265–1268. 2. Barrett, A. G. M.; Robyr, C.; Spilling, C. D. J. Org. Chem. 1989, 54, 1233–1234. 3. Rosini, G. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Per-

gamon, 1991, 2, 321−340. (Review). 4. Chen, Y.-J.; Lin, W.-Y. Tetrahedron Lett. 1992, 33, 1749–1750. 5. Saikia, A. K.; Hazarika, M. J.; Barua, N. C.; Bezbarua, M. S.; Sharma, R. P.; Ghosh,

A. C. Synthesis 1996, 981–985. 6. Luzzio, F. A. Tetrahedron 2001, 57, 915–945. (Review). 7. Westermann, B. Angew. Chem., Int. Ed. 2003, 42, 151–153. (Review on aza-Henry re-

action). 8. Bernardi, L.; Bonini, B. F.; Capito, E.; Dessole, G.; Comes-Franchini, M.; Fochi, M.;

Ricci, A. J. Org. Chem. 2004, 69, 8168–8171. 9. Palomo, C.; Oiarbide, M.; Laso, A. Angew. Chem., Int. Ed. 2005, 44, 3881–3884. 10. Kamimura, A.; Nagata, Y.; Kadowaki, A.; Uchidaa, K.; Uno, H. Tetrahedron 2007,

63, 11856–11861. 11. Wang, A. X. Henry Reaction. In Name Reactions for Homologations-Part I; Li, J. J.,


285

Hinsberg synthesis of thiophene derivatives Condensation of diethyl thiodiglycolate and α-diketones under basic conditions, which provides 3,4-disubstituted thiophene-2,5-dicarbonyls upon hydrolysis of the crude ester product with aqueous acid.

O

O SO

EtO

O

OEt S

PhPh

O

OH

HO

O1.

NaOEt, EtOH2. H3O+

O

Ph

O

Ph

S

CO2Et

CO2Et

O

Ph

O

CO2EtS

EtO

O

Ph S

OO

CO2Et

Ph

O

H

Ph

EtO

O2C

S CO2Et

Ph

OPh

S

Ph Ph

CO2EtHO2C S

Ph Ph

HO2C CO2H

H+, H2O

reflux

Example 12

O

S

O

CH3

CH3

O

H3CO

CH3

O

PhO

Ph

NaOMe

NaOMe

O

ArS

O

Ar

O

ArS

O

Ar

HO OH

HO OH

H3C CH3

Ph Ph

90%

81%

SOCl2, pyr.

SOCl2, pyr.

O

ArS

O

Ar

O

ArS

O

Ar

Ph Ph

H3C CH3

95%

89%

Example 24

S

O

O

S

O

O

(CHO)3, NaOMe

MeOH, 42%

286


Example 35

O

Ph SO

Ph1.

KOH

2. SOCl2, pyr.9% yield, 2 steps

O

OS

O

Ph

OPh Example 46

S CNNCO

H3C

O

CH3

S

CH3H3C

NH2

ONC

NaOH, MeOH

94%

Example 5, Polymer-support Hinsberg thiophene synthesis9

OS R1

O

R2 R2

OO KOt-Bu

R1 = CO2i-Pr CONEt2 PPh3

+

O SR1

O

R2 R2

10% TFA

CH2Cl2

HO SR1

O

R2 R2

References 1. Hinsberg, O. Ber. 1910, 43, 901−906. 2. Miyahara, Y.; Inazu, T.; Yoshino, T. Bull. Chem. Soc. Jpn. 1980, 53, 1187−1188. 3. Gronowitz, S. In Thiophene and Its Derivatives, Part 1, Gronowitz, S., ed.; Wiley-

Interscience: New York, 1985, pp 34−41. (Review). 4. Miyahara, Y.; Inazu, T.; Yoshino, T. J. Org. Chem. 1984, 49, 1177−1182. 5. Christl, M.; Krimm, S.; Kraft, A. Angew. Chem., Int. Ed. 1990, 29, 675−677. 6. Beye, N.; Cava, M. P. J. Org. Chem. 1994, 59, 2223−2226. 7. Vogel, E.; Pohl, M.; Herrmann, A.; Wiss, T.; König, C.; Lex, J.; Gross, M.; Gissel-

brecht, J. P. Angew. Chem., Int. Ed. 1996, 35, 1520−1525. 8. Mullins, R. J.; Williams, D. R. Hinsberg Synthesis of Thiophene Derivatives. In Name

Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Ho-boken, NJ, 2005, pp 199−206. (Review).

9. Traversone, A.; Brill, W. K.-D. Tetrahedron Lett. 2007, 48, 3535−3538.

287

Hiyama cross-coupling reaction Palladium-catalyzed cross-coupling reaction of organosilicons with organic hal-ides, triflates, etc. In the presence of an activating agent such as fluoride or hy-droxide (transmetallation is reluctant to occur without the effect of an activating agent). For the catalytic cycle, see the Kumada coupling on page 325.

R1 SiY R2 XPd catalystactivator

R1 R2

R1 = alkenyl, aryl, alkynyl, alkylR2 = aryl, alkyl, alkenylY = (OR)3, Me3, Me2OH, Me(3-n)F(n+3)X = Cl, Br, I, OTfactivator = TBAF, base

Pd(0)

Ar1 Pd(II) XAr1 Pd(II) Ar2

Ar1 Ar2

R3SiF X

SiR

Ar2

F

R

RBu4N

Ar1 Xoxidativeaddition

trans"metal"lation

reductiveelimination

Example 11a

S Si(Et)F2

S

I

MeO2C S

SMeO2C(η3-C3H5PdCl)2

DMF, KF, 100 oC82%

Example 22

C5H11 Si(OMe)3N

Br

Bu4NF, Pd(OAc)2, Ph3P DMF, reflux, 72%

C5H11N

288


Example 37

SiO

O

OPMB

IMe

Me

CH3

[allylPdCl]2 (7.5 mol%)

TBAF, THF, 25 °C, 60 h61%

OHO

PMBOMe

Example 49

I

CO2Me

OMe

Me

MOMO

Me

O O

H3CO

Ph

Me3Si H

O O

Ph

HMe

Me

CO2Me

O

MOMO

MeMe

O

[allylPdCl]2 TBAF (12 mol%)

THF, 60 °C, 20 h20%

References 1. (a) Hatanaka, Y.; Fukushima, S.; Hiyama, T. Heterocycles 1990, 30, 303−306. (b)

Hiyama, T.; Hatanaka, Y. Pure Appl. Chem. 1994, 66, 1471−1478. (c) Matsuhashi, H.; Kuroboshi, M.; Hatanaka, Y.; Hiyama, T. Tetrahedron Lett. 1994, 35, 6507−6510.

2. Shibata, K.; Miyazawa, K.; Goto, Y. Chem. Commun. 1997, 1309−1310. 3. Hiyama, T. In Metal-Catalyzed Cross-Coupling Reactions; 1998, Diederich, F.; Stang,

P. J., Eds.; Wiley–VCH: Weinheim, Germany, pp 421–53. (Review). 4. Denmark, S. E.; Wang, Z. J. Organomet. Chem. 2001, 624, 372−375. 5. Hiyama, T. J. Organomet. Chem. 2002, 653, 58−61. 6. Pierrat, P.; Gros, P.; Fort, Y. Org. Lett. 2005, 7, 697−700. 7. Denmark, S. E.; Yang, S.-M. J. Am. Chem. Soc. 2004, 126, 12432−12440. 8. Domin, D.; Benito-Garagorri, D.; Mereiter, K.; Froehlich, J.; Kirchner, K. Or-

ganometallics 2005, 24, 3957−3965. 9. Anzo, T.; Suzuki, A.; Sawamura, K.; Motozaki, T.; Hatta, M.; Takao, K.-i.; Tadano,

K.-i. Tetrahedron Lett. 2007, 48, 8442−8448. 10. Yet L. Hiyama Cross-Coupling Reaction. In Name Reactions for Homologations-Part

I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 33−416. (Re-view).

289

Hofmann rearrangement Upon treatment of primary amides with hypohalites, primary amines with one less carbon are obtained via the intermediacy of isocyanate. Also know as the Hof-mann degradation reaction.

R NH2

OR N C O

H2OR NH2 CO2↑

Br2

NaOH

R NH

O

OH

Br BrH

R NH

O R N

O

H

Br

R N

OBr

OH

R NH2 CO2↑N C O

RHN O

OH

R

OH OH isocyanate intermediate Example 1, NBS variant2

NH2

O2N

ONBS, DBU, MeOH

reflux, 25 min., 70%

HN

O2N

O

O

Example 2, Iodosobenzene diacetate5

NH2

O

OH

IOCOCF3

OCOCF3

CH3CN/H2O, 4.5 h, 100%NH

O

OH

IO CF3

OPh

:

N

OH

CO

:

H

O

HN

O

Example 3, Bromine and alkoxide6

NH

AcOH

H H HOH

H H

HN

O

O

O

Br2, NaOMe

MeOH, rt → reflux75%

290


Example 4, Sodium hypochlorite7

O

CONH2

OHHO

HOO

NH2

OHHO

HO

NaOCl

aq. NaOH50 °C, 81%

Example 5, The original conditions, bromine and hydroxide9

NN

NN

NNPh Ph

Me

CONH2N

NN

N

NNPh Ph

Me

NH2

Br2, aq. KOH

0 °C to reflux80%

Example 6, Lead tetraacetate10

NO2

O

CONH2

NO2

O

NHBocPb(OAc)4

t-BuOH, Et3Nreflux, 75%

References 1. Hofmann, A. W. Ber. 1881, 14, 2725–2736. 2. Jew, S.-s.; Kang, M.-h. Arch. Pharmacol Res. 1994, 17, 490–491. 3. Huang, X.; Seid, M.; Keillor, J. W. J. Org. Chem. 1997, 62, 7495–7496. 4. Togo, H.; Nabana, T.; Yamaguchi, K. J. Org. Chem. 2000, 65, 8391–8394. 5. Yu, C.; Jiang, Y.; Liu, B.; Hu, L. Tetrahedron Lett. 2001, 42, 1449–1452. 6. Jiang, X.; Wang, J.; Hu, J.; Ge, Z.; Hu, Y.; Hu, H.; Covey, D. F. Steroids 2001, 66,

655–662. 7. Stick, R. V.; Stubbs, K. A. J. Carbohydr. Chem. 2005, 24, 529–547. 8. Moriarty, R. M. J. Org. Chem. 2005, 70, 2893−2903. (Review). 9. El-Mariah, F.; Hosney, M.; Deeb, A. Phosphorus, Sulfur Silicon Relat. Elem. 2006,

181, 2505–2517. 10. Jia, Y.-M.; Liang, X.-M.; Chang, L.; Wang, D.-Q. Synthesis 2007, 744–748. 11. Gribble, G. W. Hofmann rearrangement. In Name Reactions for Homologations-Part


291

Hofmann–Löffler–Freytag reaction Formation of pyrrolidines or piperidines by thermal or photochemical decomposi-tion of protonated N-haloamines.

R1 NR2

Cl 1. H+, ΔNR1

R22. −OH

R1 NR2

Cl H

R1 NR2

ClH

Δ

homolyticcleavage

R1 NR2

HClH

chloroammonium salt nitrogen radical cation

HN

R1R2

H1,5-hydrogen

atom transfer

NH2R1

R1 NR2

ClH

R1N

R2H

R2

NH2R1 ClR2

NR1

R2NH

Cl R2R1:

SN2NR1

R2H

OH OH

Example 12

HO

H

H H

NH1. NaOCl, 95%

2. TFA, hv, 87%3. NaOH, MeOH, 76%

HO

H

H H

N

O O

Example 24

84% H2SO465 oC, 30 min.

25% N

N Ph

N

N PhBr

N

O

Example 35

N NNH N

NCS, ether, Et3Nthen hv, (Hg0 lamp)

0 oC, 3.5 h in N2100%

292


Example 47

AcOH

HN P(O)(OEt)2

PhI(OAc)2or Pb(OAc)4

I2, hv, 99%

AcOH

N P(O)(OEt)2

Example 512

Me Me

Me NBr

O

Me

O CF3 1.0 equiv CBr4, hv0.05 M PhCF3

100 W flood lamprt, 7 min. Me Me

Me NH

O

Me

O CF3

Br

1.25 equiv Ag2CO3

CH2Cl2, rt, 1 h

then AcOH, 15 min.> 69% overall

Me Me

Me OO

Me

O

References 1. (a) Hofmann, A. W. Ber. 1883, 16, 558−560. (b) Löffler, K.; Freytag, C. Ber. 1909,

42, 3727. 2. Wolff, M. E.; Kerwin, J. F.; Owings, F. F.; Lewis, B. B.; Blank, B.; Magnani, A.;

Karash, C.; Georgian, V. J. Am. Chem. Soc. 1960, 82, 4117−4118. 3. Wolff, M. E. Chem. Rev. 1963, 63, 55−64. (Review). 4. Dupeyre, R.-M.; Rassat, A. Tetrahedron Lett. 1973, 2699−2701. 5. Kimura, M.; Ban, Y. Synthesis 1976, 201−202. 6. Stella, L. Angew. Chem., Int. Ed. 1983, 22, 337−422. (Review). 7. Betancor, C.; Concepcion, J. I.; Hernandez, R.; Salazar, J. A.; Suarez, E. J. Org.

Chem. 1983, 48, 4430−4432. 8. Majetich, G.; Wheless, K. Tetrahedron 1995, 51, 7095−7129. (Review). 9. Togo, H.; Katohgi, M. Synlett 2001, 565−581. (Review). 10. Pellissier, H.; Santelli, M. Org. Prep. Proced. Int. 2001, 33, 455−476. (Review). 11. Li, J. J. Hofmann–Löffler–Freytag Reaction. In Name Reactions in Heterocyclic


12. Chen, K.; Richter, J. M.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 17247−17249.

293

Horner–Wadsworth–Emmons reaction Olefin formation from aldehydes and phosphonates. Workup is more advanta-geous than the corresponding Wittig reaction because the phosphate by-product can be washed away with water. Typically gives the trans- rather than the cis-olefins.

EtOP

OEt

OEtO

O NaH, then

RCHO

CO2Et

R EtOP

ONa

OEtO

EtOP

OEt

OEtO

O

H

HO R

HEtOP

OEt

OEtO

O

EtOP

OEt

OEtO

O

O R

The stereochemical outcome: erythro (kinetic) or threo (thermodynamic)

PO

HR CO2Et

H

O

OEtOEt

HR CO2Et

HPO OEt

OEtO

R CO2Et

erythro, kinetic adduct

PO

HR H

CO2Et

O

OEtOEt CO2Et

RHR H

CO2EtPO OEt

OEtO

threo, thermodynamic adduct Example 13

OCHO

OMe

EtOP

OEt

OEtO

O

NaH, THF, 95%

O

OMe

CO2Et

Example 24

CHOEtO

POEt

OEtO

O

KOH, THF, 95%

CO2Et

BnO BnO Example 37

OH

OTBDPS

OMOMO

NaH, THF92%

N

O

OMe

PEtO

OEtO O

H

OTBDPS

OMOMN

O

OMe

294


Example 4, Intramolecular Horner–Wadsworth–Emmons9

O O

O

ON

N

O

O

OMe

Br

O

O POEtO

OEt

OTBS

MeO

MeOOTIPS

K2CO318-crown-6

Toluene −20 oC

67%Z/E = 5:1

2

3

O

OO

N

N

OO

MeO

Br

O

TBSO

MeO

MeO

OTIPS

O

23

References 1. (a) Horner, L.; Hoffmann, H.; Wippel, H. G.; Klahre, G. Chem. Ber. 1959, 92, 2499–

2505. (b) Wadsworth, W. S., Jr.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83, 1733–1738. (c) Wadsworth, D. H.; Schupp, O. E.; Seus, E. J.; Ford, J. A., Jr. J. Org. Chem. 1965, 30, 680–685.

2. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863−927. (Review). 3. Shair, M. D.; Yoon, T. Y.; Mosny, K. K.; Chou, T. C.; Danishefsky, S. J. J. Am. Chem.

Soc. 1996, 118, 9509–9525. 4. Nicolaou, K. C.; Boddy, C. N. C.; Li, H.; Koumbis, A. E.; Hughes, R. J.; Natarajan, S.;

Jain, N. F.; Ramanjulu, J. M.; Bräse, S.; Solomon, M. E. Chem. Eur. J. 1999, 5, 2602–2621.

5. Comins, D. L.; Ollinger, C. G. Tetrahedron Lett. 2001, 42, 4115–4118. 6. Lattanzi, A.; Orelli, L. R.; Barone, P.; Massa, A.; Iannece, P.; Scettri, A. Tetrahedron

Lett. 2003, 44, 1333–1337. 7. Ahmed, A.; Hoegenauer. E. K.; Enev, V. S.; Hanbauer, M.; Kaehlig, H.; Öhler, E.;

Mulzer, J. J. Org. Chem. 2003, 68, 3026–3042. 8. Blasdel, L. K.; Myers, A. G. Org. Lett. 2005, 7, 4281–4283. 9. Li, D.-R.; Zhang, D.-H.; Sun, C.-Y.; Zhang, J.-W.; Yang, L.; Chen, J.; Liu, B.; Su, C.;

Zhou, W.-S.; Lin, G.-Q. Chem. Eur. J. 2006, 12, 1185–1204. 10. Rong, F. Horner–Wadsworth–Emmons reaction in. In Name Reactions for Homologa-


295

Houben−Hoesch reaction Acid-catalyzed acylation of phenols as well as phenolic ethers using nitriles.

OH

OH

RCN

HCl, AlCl3

OH

OH

R NH•HCl

OH

OH

R O

H2O

OH

OHR N:AlCl3 complexation

R N AlCl3

:

electrophilic

substitution

O

OH

R NHH

H

OH

OH

R NH•HCl

H2O:

OH

OH

R O

hydrolysis

OH

OH

R ONH2

H

H

Example 1, Intramolecular Houben−Hoesch reaction3

O

CN

OMe

OMe

1. ZnCl2, HCl(g), Et2O

2. H2O, reflux, 89%

O OMe

OMeO Example 26

FPivO CN

OMe

OH

MeO

CO2Me

OH

SbCl5, 2-chloropropane

CH2Cl2, rt, 2 h, 95%

OPiv

MeO FOMe

OCO2Me

OH

NH

Example 38

NH2•HCl14Cu

NC ClBCl3•CH2Cl2, ZnCl2

then aq. HCl

NH214Cu

OCl

14Cu = 14C-labelled

296


Example 49

NH

OMe

MeO

ClNC

NH

OMe

MeO

Cl

O

HCl (g), THF, overnight

then 2% aq. HClreflux, 3 h, 43%

References 1. (a) Hoesch, K. Ber. 1915, 48, 1122−1133. Kurt Hoesch (1882−1932) was born in

Krezau, Germany. He studied at Berlin under Emil Fischer. During WWI, Hoesch was Professor of Chemistry at the University of Istanbul, Turkey. After the war he gave up his scientific activities to devote himself to the management of a family busi-ness. (b) Houben, J. Ber. 1926, 59, 2878−2891.

2. Yato, M.; Ohwada, T.; Shudo, K. J. Am. Chem. Soc. 1991, 113, 691−692. 3. Rao, A. V. R.; Gaitonde, A. S.; Prakash, K. R. C.; Rao, S. P. Tetrahedron Lett. 1994,

35, 6347−6350. 4. Sato, Y.; Yato, M.; Ohwada, T.; Saito, S.; Shudo, K. J. Am. Chem. Soc. 1995, 117,

3037−3043. 5. Kawecki, R.; Mazurek, A. P.; Kozerski, L.; Maurin, J. K. Synthesis 1999, 751−753. 6. Udwary, D. W.; Casillas, L. K.; Townsend, C. A. J. Am. Chem. Soc. 2002, 124,

5294−5303. 7. Sanchez-Viesca, F.; Gomez, M. R.; Berros, M. Org. Prep. Proc. Int. 2004, 36,

135−140. 8. Wager, C. A. B.; Miller, S. A. J. Labelled Compd. Radiopharm. 2006, 49, 615−622. 9. Black, D. St. C.; Kumar, N.; Wahyuningsih, T. D. ARKIVOC 2008, (6), 42−51.

297

Hunsdiecker−Borodin reaction Conversion of silver carboxylate to halide by treatment with halogen.

R O

OAg

X2R X CO2↑ AgX

R O

OAg

X X

AgX R O

OX

homolytic

cleavage

R XCO2↑XR O

OR

R O

OX

R O

O

Example 15

Cl CO2H Cl BrHgO, Br2, Δ

CCl4, dark, 35−46% Example 26

NBS, n-Bu4N+CF3CO2−

ClCH2CH2Cl, 96%

CO2H

MeO

Br

MeO

Example 38

CO2H

HO

N

N

Cl

2 BF4

KBr, CH3CN, 82%

Br

HO

F"Select fluor"

Example 4, One-pot microwave-Hunsdiecker−Borodin followed by Suzuki10

BnOOMe

CO2HNBS, LiOAc

CH3CN−H2O 9:1MW 1 min.

BnOOMe

Br

298


BnOOMe

PhB(OH)2, K2CO3Pd(PPh3)4

CH3CN/H2O 2:1microwave, 5 min.

64% 2 steps

References 1. (a) Borodin, A. Ann. 1861, 119, 121−123. Aleksandr Porfirevi Borodin (1833−1887)

was born in St Petersburg, the illegitimate son of a prince. He prepared methyl bro-mide from silver acetate in 1861, but another eighty years elapsed before Heinz and Cläre Hunsdiecker converted Borodin’s synthesis into a general method, the Huns-diecker or Hunsdiecker−Borodin reaction. Borodin was also an accomplished com-poser and is now best known for his musical masterpiece, opera Prince Egor. He kept a piano outside his laboratory. (b) Hunsdiecker, H.; Hunsdiecker, C. Ber. 1942, 75, 291−297. Cläre Hunsdiecker was born in 1903 and educated in Cologne. She devel-oped the bromination of silver carboxylate alongside her husband, Heinz.

2. Sheldon, R. A.; Kochi, J. K. Org. React. 1972, 19, 326−421. (Review). 3. Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron Lett. 1983, 24,

4979−4982. 4. Crich, D. In Comprehensive Organic Synthesis; Trost, B. M.; Steven, V. L., Eds.; Per-

gamon, 1991, Vol. 7, pp 723−734. (Review). 5. Lampman, G. M.; Aumiller, J. C. Org. Synth. 1988, Coll. Vol. 6, 179. 6. Naskar, D.; Chowdhury, S.; Roy, S. Tetrahedron Lett. 1998, 39, 699−702. 7. Das, J. P.; Roy, S. J. Org. Chem. 2002, 67, 7861−7864. 8. Ye, C.; Shreeve, J. M. J. Org. Chem. 2004, 69, 8561−8563. 9. Li, J. J. Hunsdiecker reaction. In Name Reactions for Functional Group Transforma-

tions; Li, J. J., Corey, E. J., Eds., John Wiley & Sons: Hoboken, NJ, 2007, pp 623−629. (Review).

10. Bazin, M.-A.; El Kihel, L.; Lancelot, J.-C.; Rault, S. Tetrahedron Lett. 2007, 48, 4347−4351.

299

Jacobsen–Katsuki epoxidation Mn(III)salen-catalyzed asymmetric epoxidation of (Z)-olefins.

O

N

O

N

R1

R2 R2

R1Mn

R R

Cl

terminal oxidant, solvent

R3

R4

R5

R6

R3

R4

R5

R6

O

* *

1. Concerted oxygen transfer (cis-epoxide):

R1R OMn(V)

R1R

OMn(V)

R1R

OMn(V)

R1R

O

2. Oxygen transfer via radical intermediate (trans-epoxide):

R1R OMn(V)

R1R

OMn(V)

R1R

O

R1R

OMn(V)

3. Oxygen transfer via manganaoxetane intermediate (cis-epoxide):

R1R OMn(V)

R1

R

OMn(V)

R1R

O

[2 + 2]

cycloaddition

R1

RMn(V)O

Example 12

cat, 4-phenylpyridine-N-oxide

NaOCl, CH2Cl2, 4 oC, 12 h56%, 95−97% ee

CO2EtCO2Et

O

O

N

O

N

t-Bu

t-Bu t-Bu

t-BuMn

Clcat. =

H H

300


Example 25

Ph

OOMe

N

Ph

OOMe

NO

cat., NaOCl

58% yield, 89% ee

Example 26

O88% ee

N

NN

HN

OHOHPh

O NHt-BuCrixivan

cat. NaOCl

88%

References 1. (a) Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. N. J. Am. Chem. Soc. 1990,

112, 2801–2903. (b) Irie, R.; Noda, K.; Ito, Y.; Matsumoto, N.; Katsuki, T. Tetrahe-dron Lett. 1990, 31, 7345–7348. (c) Irie, R.; Noda, K.; Ito, Y.; Katsuki, T. Tetrahe-dron Lett. 1991, 32, 1055–1058. (d) Deng, L.; Jacobsen, E. N. J. Org. Chem. 1992, 57, 4320–4323. (e) Palucki, M.; McCormick, G. J.; Jacobsen, E. N. Tetrahedron Lett. 1995, 36, 5457–5460.

2. Zhang, W.; Jacobsen, E. N. J. Org. Chem. 1991, 56, 2296–2298. 3. Jacobsen, E. N. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: Weinheim,

New York, 1993, Ch. 4.2. (Review). 4. Jacobsen, E. N. In Comprehensive Organometallic Chemistry II, Eds. G. W. Wilkin-

son, G. W.; Stone, F. G. A.; Abel, E. W.; Hegedus, L. S., Pergamon, New York, 1995, vol 12, Chapter 11.1. (Review).

5. Lynch, J. E.; Choi, W.-B.; Churchill, H. R. O.; Volante, R. P.; Reamer, R. A.; Ball, R. G. J. Org. Chem. 1997, 62, 9223–9228.

6. Senananyake, C. H. Aldrichimica Acta 1998, 31, 3–15. (Review). 7. Jacobsen, E. N.; Wu, M. H. In Comprehensive Asymmetric Catalysis, Jacobsen, E. N.;

Pfaltz, A.; Yamamoto, H. Eds.; Springer: New York; 1999, Chapter 18.2. (Review). 8. Katsuki, T. In Catalytic Asymmetric Synthesis; 2nd edn.; Ojima, I., Ed.; Wiley-VCH:

New York, 2000, 287. (Review). 9. Katsuki, T. Synlett 2003, 281–297. (Review). 10. Palucki, M. Jacobsen–Katsuki epoxidation. In Name Reactions in Heterocyclic Chem-

istry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 29−43. (Re-view).

11. Engelhardt, U.; Linker, T. Chem. Commun. 2005, 1152–1154. 12. Fernandez de la Pradilla, R.; Castellanos, A.; Osante, I.; Colomer, I.; Sanchez, M. I. J.

Org. Chem. 2009, 74, 170–181.

301

Japp–Klingemann hydrazone synthesis Hydrazones from β-ketoesters and diazonium salts with the acid or base.

KOHArN2 Cl CO2R

O N CO2RHN

Ar OH

O

Diazonium salt β-keto-ester hydrazone

CO2RO

HCO2R

O

OHdeprotonation

N N Arcoupling

CO2RO

NN

Ar

HO

CO2RNN

Ar

O OH

N CO2RHN

ArOH

O

N CO2RN

Ar

H

Example 14

SN

OONH2

Me

CO2Et

SN

OON

Me

CO2Et

N

ClNaNO2

conc. HCl, H2O0 oC

SN

OONH

N

CO2Et

NMe2Me NMe2

O

CO2Et

NaOAc (pH 3−4)0 to 50 oC

72%

Me

CO2Et

Example 26

OBnN2

+Cl

NH

OHO2C

0.5 N KOH, THF, rt, 1 h

thenNH

ON

HN

OBn

62% yield

302


Example 310

O

OEt

O

NR1R2

NN

KOAc, H2O

−4 oC to rt60−85%

NR1R2

HNN

O

OEt

H+, 100 oC

70−85%NH

NR1R2

CO2EtHO2C

CO2H

References 1. (a) Japp, F. R.; Klingemann, F. Ber. 1887, 20, 2942−2944. (b) Japp, F. R.; Klinge-

mann, F. Ber. 1887, 21, 2934−2936. (c) Japp, F. R.; Klingemann, F. Ber. 1887, 20, 3398−3401. (d) Japp, F. R.; Klingemann, F. Ann. 1888, 247, 190−225. (e) Japp, F. R.; Klingemann, F. J. Chem. Soc. 1888, 53, 519−544.

2. Phillips, R. R. Org. React. 1959; 10, 143−178. (Review). 3. Loubinoux, B.; Sinnes, J.-L.; O’Sullivan, A. C.; Winkler, T. J. Org. Chem. 1995, 60,

953−959. 4. Pete, B.; Bitter, I.; Harsanyi, K.; Toke, L. Heterocycles 2000, 53, 665−673. 5. Atlan, V.; Kaim, L. E.; Supiot, C. Chem. Commun. 2000, 1385−1386. 6. Dubash, N. P.; Mangu, N. K.; Satyam, A. Synth. Commun. 2004, 34, 1791−1799. 7. He, W.; Zhang, B.-L.; Li, Z.-J.; Zhang, S.-Y. Synth. Commun. 2005, 35, 1359−1368. 8. Li, J. Japp–Klingemann hydrazone synthesis. In Name Reactions for Functional

Group Transformations; Li, J. J., Corey, E. J., eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 630−634. (Review).

9. Chen, Y.; Shibata, M.; Rajeswaran, M.; Srikrishnan, T.; Dugar, S.; Pandey, R. K. Tet-rahedron Lett. 2007, 48, 2353−2356.

10. Pete, B. Tetrahedron Lett. 2008, 49, 2835−2838.

303

Jones oxidation The Collins/Sarett oxidation (chromium trioxide-pyridine complex), and Corey´s PCC (pyridinium chlorochromate) and PDC (pyridinium dichromate) oxidations follow a similar pathway as the Jones oxidation (chromium trioxide and sulfuric acid in acetone). All these oxidants have a chromium (VI), normally black or yellow, which is reduced to Cr(IV), often green.

N 2CrO3

Collins/Sarett

N 2Cr2O7

H

CrO3ClNH

PCC PDC

CrO3/H2SO4

Jones

Jones oxidation By the Jones oxidation, the primary alcohols are oxidized to the corresponding aldehyde or carboxylic acids, whereas the secondary alcohols are oxidized to the corresponding ketones.

R1 R2

OH CrO3

H2SO4, acetone R1 R2

O

CrO3 + H2O H2CrO4

R1 R2

OH :

CrO O

R1

OCr

R2H

OH

OH2O

H

:BR1 R2

OCr

O OHCr(VI)

black

Cr(III)

green

O

The intramolecular mechanism is also operative:

R1

OCr

R2H

O

OHO

R1 R2

OCr

O OH

OH

Example 16

CO2t-Bu

OO

O

OO

OH

OH

1. Jones reagent acetone, 20 min.

2. HCO2H, rt, 1 h 96% 2 steps

CO2H

OO

O

OO

OH

O

(−)-CP-263114

304


Example 27

HHO

OCO2Me

H

CrO3, H2SO4acetone/H2O

rt, 74%

HO

OCO2Me

H Example 319

HO

CrO3, H2SO4

acetone, 0 oC1−2 h, 86%

OO

References 1. Bowden, K.; Heilbron, I. M., Jones, E. R. H.; Weedon, B. C. L. J. Chem. Soc. 1946,

39−45. Ewart R. H. (Tim) Jones worked with Ian M. Heilbron at Imperial College. Jones later succeeded Robert Robinson to become the prestigious Chair of Organic Chemistry at Manchester. The recipe for the Jones reagent: 25 g CrO3, 25 mL conc. H2SO4, and 70 mL H2O.

2. Ratcliffe, R. W. Org. Synth. 1973, 53, 1852. 3. Vanmaele, L.; De Clerq, P.; Vandewalle, M. Tetrahedron Lett. 1982, 23, 995−998. 4. Luzzio, F. A. Org. React. 1998, 53, 1−222. (Review). 5. Zhao, M.; Li, J.; Song, Z.; Desmond, R. J.; Tschaen, D. M.; Grabowski, E. J. J.; Rei-

der, P. J. Tetrahedron Lett. 1998, 39, 5323−5326. (Catalytic CrO3 oxidation). 6. Waizumi, N.; Itoh, T.; Fukuyama, T. J. Am. Chem. Soc. 2000, 122, 7825−7826. 7. Hagiwara, H.; Kobayashi, K.; Miya, S.; Hoshi, T.; Suzuki, T.; Ando, M. Org. Lett.

2001, 3, 251−254. 8. Fernandes, R. A.; Kumar, P. Tetrahedron Lett. 2003, 44, 1275−1278. 9. Hunter, A. C.; Priest, S.-M. Steroids 2006, 71, 30−33. 10. Dong, J.; Chen, W.; Wang, S.; Zhang, J. J. Chromatogr., B 2007, 858, 239−246.

Collins–Sarett oxidation

Different from the Jones oxidation, the Collins–Sarett oxidation converts primary alcohols to the corresponding aldehydes.

Example 15

O

O

OH

Ph

O

O8 eq CrO3•2Pyr

CH2Cl2, 15 min., 86%

O

O

CHO

Ph

O

O

305

Example 27

MeO2C

Me

OMe

OHMe

7 equiv CrO3•Py2

CH2Cl2, 30 min., 75%

MeO2C

Me

OMe

CHO

Me

Example 39

NPhO2S

R1 R2 R3

R4

CrO3, Pyr.

50−60 oC, 48 h50−65%

NPhO2S

R1 R2 R3

R4O

References 1. Poos, G. I.; Arth, G. E.; Beyler, R. E.; Sarett, L. H. J. Am. Chem. Soc. 1953, 75, 422–

429. 2. Collins, J. C; Hess, W. W.; Frank, F. J. Tetrahedron Lett. 1968, 3363–3366. J. C.

Collins was a chemist at Sterling-Winthrop in Resselaer, New York. 3. Collins, J. C; Hess, W. W. Org. Synth. 1972, Coll. Vol. V, 310. 4. Hill, R. K.; Fracheboud, M. G.; Sawada, S.; Carlson, R. M.; Yan, S.-J. Tetrahedron

Lett. 1978, 945–948. 5. Krow, G. R.; Shaw, D. A.; Szczepanski, S.; Ramjit, H. Synth. Commun. 1984, 14,

429–433. 6. Li, M.; Johnson, M. E. Synth. Commun. 1995, 25, 533–537. 7. Harris, P. W. R.; Woodgate, P. D. Tetrahedron 2000, 56, 4001–4015. 8. Nguyen-Trung, N. Q.; Botta, O.; Terenzi, S.; Strazewski, P. J. Org. Chem. 2003, 68,

2038–2041. 9. Arumugam, N.; Srinivasan, P. C. Synth. Commun. 2003, 33, 2313–2320.

PCC oxidation

Example 1, One-pot PCC–Wittig reactions2

SiOH

t-Bu PCC, Celite, CH2Cl2, rt, 3 h

then Ph3P=CHCO2CH380%

Sit-Bu

O

O

95 : 5 E : Z

306

Example 23

NEtO2C

OH 1.5 eq PCC, CH2Cl2

rt, 3 h, 75%N

EtO2CO

Example 34

O

OAcPh

OAc

OAc

PCC, pyr.

CH2Cl2, reflux8 h, 64%

O

OAcPh

OAc

OAc

O

Example 45

O

HO

Cl

PCC, CH2Cl2

75%, 93:7 er

O

O

Cl

References 1. Corey, E. J.; Suggs, W. Tetrahedron Lett. 1975, 16, 2647–2650. 2. Bressette, A. R.; Glover, L. C., IV Synlett 2004, 738–740. 3. Breining, S. R.; Bhatti, B. S.; Hawkins, G. D.; Miao, L.; Mazurov, A.; Phillips, T. Y.;

Miller, C. H. WO2005037832 (2005). 4. Srikanth, G. S. C.; Krishna, U. M.; Trivedi, G. K.; Cannon, J. F. Tetrahedron 2006,

62, 11165–11171. 5. Kim, S.-G. Tetrahedron Lett. 2008, 49, 6148–6151.

PDC oxidation

Example 12

S

S

OH

O

PDC, CH2Cl2

24 h, 68%

SCHO

SO

307

Example 2, Cleavage of primary carbon–boron bond3

B(OH)2PDC, DMF

rt, 24 h75%

CO2H

Example 34

OH

OH OTBDMS

PDC, DMF

rt, 24 h, 56%O

OTBDMS

O References 1 Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 399–402. 2 Terpstra, J. W.; Van Leusen, A. M. J. Org. Chem. 1986, 51, 230–208. 3 Brown, H. C.; Kulkarni, S. V.; Khanna, V. V.; Patil, V. D.; Racherla, U. S. J. Org.

Chem. 1992, 57, 6173–6177. 4 Chênevert, R. Courchene, G.; Caron, D. Tetrahedron: Asymmmetry 2003, 2567–2571. 5 Jordão, A. K Synlett 2006, 3364–3365. (Review).

308

Julia–Kocienski olefination Modified one-pot Julia olefination to give predominantly (E)-olefins from het-eroarylsulfones and aldehydes. A sulfone reduction step is not required.

NNN N

SO2R1

Ph

1. KHMDS

2. R2CHOR1

R2

NNN N

Ph

OH SO2

NNN N

SO2R1

Ph

HNN

N NSO2

R1

Ph

R2 H

O

NNN N

SO2R1

Ph

R2O

N(TMS)2

NNN N

Ph

K

SO2

OR2

R1

NN

N NPh

O R2

SR1O

O

R1R2

NNN N

Ph

OH SO2

Alternatives to tetrazole:

S

N NNN

N

N NN N

N F3C

F3Ct-BuPh

PYRBTPT TBT BTFP

The use of larger counterion (such as K+) and polar solvents (such as DME) favors an open transition state (PT = phenyltetrazolyl):

R1R2

SO2PT

OK

O

R2H

HR1

SO2PT Example 1, (BT = benzothiazole)2

SO2BT OHC OTIPSOTIPSNaHMDS, DMF

−78 oC to rt, 90% E:Z (78:22) Example 23

O

O

OPiv

S S

N

O O

OOMe

OTBS

KHMDS, THF, −78 oC, 85%

309


O

O

OPiv

OMe

OTBS

Example 37

CHO

KHMDS, toluene

25 oC, 64%SO

O

NOTIPS

88 : 12

OTIPS TIPSO

Example 48

S

F3C

F3CO

OOMe

MeO

MeO

CHO

MeO

1) P4−t-Bu, THF, −78 oC

2)74%, yieldE/Z = 98/2

OMe

OMe

References 1. (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron Lett. 1991, 32,

1175−1178. (b) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Bull. Soc. Chim. Fr. 1993, 130, 336−357. (c) Baudin, J. B.; Hareau, G.; Julia, S. A.; Loene, R.; Ruel, O. Bull. Soc. Chim. Fr. 1993, 130, 856−878. (d) Blakemore, P. R.; Cole, W. J.; Kocien-ski, P. J.; Morely, A. Synlett 1998, 26−28.

2. Charette, A. B.; Lebel, H. J. Am. Chem. Soc. 1996, 118, 10327−10328. 3. Blakemore, P. R.; Kocienski, P. J.; Morley, A.; Muir, K. J. Chem. Soc., Perkin Trans.

1 1999, 955−968. 4. Williams, D. R.; Brooks, D. A.; Berliner, M. A. J. Am. Chem. Soc. 1999, 121,

4924−4925. 5. Kocienski, P. J.; Bell, A.; Blakemore, P. R. Synlett 2000, 365−366. 6. Liu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 10772−10773. 7. Charette, A. B.; Berthelette, C.; St-Martin, D. Tetrahedron Lett. 2001, 42, 5149–5153. 8. Alonso, D. A.; Najera, C.; Varea, M. Tetrahedron Lett. 2004, 45, 573–577. 9. Alonso, D. A.; Fuensanta, M.; Najera, C.; Varea, M. J. Org. Chem. 2005, 70, 6404. 10. Rong, F. Julia–Lythgoe olefination. In Name Reactions for Homologations-Part I; Li,

J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 447−473. (Review).

310

Julia–Lythgoe olefination (E)-Olefins from sulfones and aldehydes.

R SAr

OO

1. n-BuLi2. R1CHO

RR1

SO2Ar

OAc

Na(Hg)

CH3OHR

R1

3. Ac2O

R SAr

OO

H

n-Buα-deprotonation

R

SO2Ar

H O

R1 coupling

RR1

SO2Ar

O

O

O O

acetylation

RR1

SO2Ar

OAc

RR1

SO2Ar

O O

O O

Na(Hg)

single electrontransfer (SET)

RR1

SO2ArOAc

4 possible diastereomers

Na(Hg)

single electrontransfer (SET)

RR1R

R1

OAcOAc

Example 12

SO2Ph

OHC

1. n-BuLi, THF, −78 oC

2.

3. Ac2O

4. Na(Hg) 43% E:Z (99:1)

Example 23

NTEOC H

CHO

OTBSO

SO2PhLi

1. THF, −78 oC2. Ac2O3. 5% Na(Hg), 77%

NTEOC H

OTBSO

Example 37

S

HO

Ph

CH3S

Ph

OHC CH3

n-BuLi, THF, 0 oC to rt61−75% SO2

OH

Ph CH3m-CPBA, CH2Cl2

0 oC, 80−98%

311


SO2

OAc

Ph CH3

H3C

Na/HgTHF, MeOH

−20 oC, 53%

Ac2O, DMPA, CH2Cl2

0 oC to rt, 60−95%

Example 48

1. LDA, THF, −78 oC 2. BzCl, −78 oC to rt3. Me2N(CH2)3OH

Ph SPh

PhCHO

O

PhPh

PhPh

SmI2, THFHMPA, −78 oC

67%, E/Z = > 95:1S

OBzO

Ph

References 1. (a) Julia, M.; Paris, J. M. Tetrahedron. Lett. 1973, 4833–4836. (b) Lythgoe, B. J.

Chem. Soc., Perkin Trans. 1 1978, 834–837. 2. Kocienski, P. J.; Lythgoe, B.; Waterhause, I. J. Chem. Soc., Perkin Trans. 1 1980,

1045–1050. 3. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003–

2005. 4. Keck, G. E.; Savin, K. A.; Weglarz, M. A. J. Org. Chem. 1995, 60, 3194–3204. 5. Breit, B. Angew. Chem., Int. Ed. 1998, 37, 453–456. 6. Marino, J. P.; McClure, M. S.; Holub, D. P.; Comasseto, J. V.; Tucci, F. C. J. Am.

Chem. Soc. 2002, 124, 1664–1668. 7. Bernard, A. M.; Frongia, A.; Piras, P. P.; Secci, F. Synlett 2004, 6, 1064–1068. 8. Pospíšil, J.; Pospíšil, T, Markó, I. E. Org. Lett. 2005, 7, 2373–2376. 9. Gollner, A.; Mulzer, J. Org. Lett. 2008, 10, 4701−4704. 10. Rong, F. Julia–Lythgoe olefination. In Name Reactions for Homologations-Part I; Li,


312

Kahne glycosidation Diastereoselective glycosidation of a sulfoxide at the anomeric center as the gly-cosyl acceptor. The sulfoxide activation is achieved using Tf2O.

OPivO

PivOPivO

S

OPiv

Ph

OO

HOO

OPh

SPhN3

N

CH3

t-But-Bu

Tf2O, CH2Cl2, −78 to −30 oC

OOOPh

SPhN3

OPivO

PivOPivO

OPiv

O

OPivO

PivOPivO

S

OPiv

Ph

O

S O SF

F F

FFF

O

O

O

OTfO O:

PivO

PivOPivO

S

OPiv

Ph

OTfSN1

PhS

OTf OHO

OOPh

SPhN3

OPivO

PivOPivO

OPiv

OOOPh

SPhN3

OPivO

PivOPivO

OPiv

O

oxonium ion

Example 11d

O OMOMOMOM

OMe OHBzO

O S(O)PhOBn

OBnOBn

Tf2O, DTBMP, CH2Cl2

−70 to −50 oC, 38% OOBn

OBnOBn

O OMOMOMOM

OMe OBzO

Example 24

OO

O OTBS

SPh

OPMBPh

OO

MeO

OTIPS

OHOTBS

313


Tf2O, DTBMP, CH2Cl2

−78 to 0 oC, 67%O

O

O

O

O

Ph

PMBOOTBS

MeO

OTIPSOTBS

Example 3, Reverse Kahne-type glycosylation6

O

OO

S

O

MeO OMeOCbz

O Et

Tf2O, CH2Cl2

−78 oC, NuH

O

OO

Nu

O

MeO OMeOCbz

NuH = ROH, ArOH, ArNH2, CH2=CHCH2TMS

References 1. (a) Kahne, D.; Walker, S.; Cheng, Y.; Van Engen, D. J. Am. Chem. Soc. 1989, 111,

6881−6882. (b) Yan, L.; Taylor, C. M.; Goodnow, R., Jr.; Kahne, D. J. Am. Chem. Soc. 1994, 116, 6953−6954. (c) Yan, L.; Kahne, D. J. Am. Chem. Soc. 1996, 118, 9239−9248. (d) Gildersleeve, J.; Pascal, R. A.; Kahne, D. J. Am. Chem. Soc. 1998, 120, 5961−5969. Daniel Kahne now teaches at Harvard University.

2. Boeckman, R. K., Jr.; Liu, Y. J. Org. Chem. 1996, 61, 7984−7985. 3. Crich, D.; Sun, S. J. Am. Chem. Soc. 1998, 120, 435−436. 4. Crich, D.; Li, H. J. Org. Chem. 2000, 65, 801−805. 5. Nicolaou, K. C.; Rodríguez, R. M.; Mitchell, H. J.; Suzuki, H.; Fylaktakidou, K. C.;

Baudoin, O.; van Delft, F. L. Chem. Eur. J. 2000, 6, 3095−3115. 6. Berkowitz, D. B.; Choi, S.; Bhuniya, D.; Shoemaker, R. K. Org. Lett. 2000, 2,

1149−1152. 7. Crich, D.; Li, H.; Yao, Q.; Wink, D. J.; Sommer, R. D.; Rheingold, A. L. J. Am. Chem.

Soc. 2001, 123, 5826−5828. 8. Crich, D.; Lim, L. B. L. Org. React. 2004, 64, 115−251. (Review).

314

Knoevenagel condensation Condensation between carbonyl compounds and activated methylene compounds catalyzed by amines.

R CHO CH2(CO2R1)2NH R

CO2R1

CO2R1

OHR

CO2H

CH(CO2R1)2

NHH deprotonation

NH2 CH(CO2R1)2:

NH

(CO2R1)2CH

R O

H iminium ion

formationR

H

NOH

:R N

H:

NH2

R

OHN

R

CO2R1

HCO2R1

NH

O OR1

hydrolysisO

OR1

OH:

HR

O O

O

O

R

OR1O

HO

OR1

OHO

R

O O

O

OH

HHworkup

decarboxylationR

CO2HCO2↑ R • O

OHH

H

Example 13

N NO

H

O

NH

S

OO

piperidine, AcOH

toluene, refluxDean−Stark trap

95%

N NO N

H

S

OO

Example 2, EDDA = Ethylenediamine diacetate5

NBoc

NCbzH

CHO O O

O OEDDA, PhH, 60 oC

12 h, 84%

NBoc

NCbzHO O

O O

Meldrum's acid

315


Example 3, Using ionic liquid ethylammonium nitrate (EAN) as solvent8

CHO

CO2Et

CN ethylammonium nitrate

rt, 10 h, 87%

CN

CO2Et

Example 49

N

SO2Me

O

H

NN

O

MeO2S

piperidineN

SO2Me

H

NN

O

MeO2S

2-propanol, reflux89%

References 1. Knoevenagel, E. Ber. 1898, 31, 2596−2619. Emil Knoevenagel (1865−1921) was

born in Hannover, Germany. He studied at Göttingen under Victor Meyer and Gat-termann, receiving a Ph.D. In 1889. He became a full professor at Heidelberg in 1900. When WWI broke out in 1914, Knoevenagel was one of the first to enlist and rose to the rank of staff officer. After the war, he returned to his academic work until his sud-den death during an appendectomy.

2. Jones, G. Org. React. 1967, 15, 204−599. (Review). 3. Cantello, B. C. C.; Cawthornre, M. A.; Cottam, G. P.; Duff, P. T.; Haigh, D.; Hindley,

R. M.; Lister, C. A.; Smith, S. A. Thurlby, P. L. J. Med. Chem. 1994, 37, 3977−3985. 4. Paquette, L. A.; Kern, B. E.; Mendez-Andino, J. Tetrahedron Lett. 1999, 40,

4129−4132. 5. Tietze, L. F.; Zhou, Y. Angew. Chem., Int. Ed. 1999, 38, 2045−2047. 6. Pearson, A. J.; Mesaros, E. F. Org. Lett. 2002, 4, 2001−2004. 7. Kourouli, T.; Kefalas, P.; Ragoussis, N.; Ragoussis, V. J. Org. Chem. 2002, 67,

4615−4618. 8. Hu, Y.; Chen, J.; Le, Z.-G.; Zheng, Q.-G. Synth. Commun. 2005, 35, 739−744. 9. Conlon, D. A.; Drahus-Paone, A.; Ho, G.-J.; Pipik, B.; Helmy, R.; McNamara, J. M.;

Shi, Y.-J.; Williams, J. M.; MacDonald, D. Org. Process Res. Dev. 2006, 10, 36−45. 10. Rong, F. Julia–Lythgoe olefination. In Name Reactions for Homologations-Part I; Li,


316

Knorr pyrazole synthesis Reaction of hydrazine or substituted hydrazine with 1,3-dicarbonyl compounds to provide the pyrazole or pyrazolone ring system. Cf. Paal–Knorr pyrrole synthesis (page 411).

NHNH3

O

R1

R NN

R2

OR3

R

R1 R3

R2

NN

R1 R3

R2R

R = H, Alkyl, Aryl, Het-aryl, Acyl, etc.

NHNH2

O

R1

R NN

OR2

OR3

R

R1 R3

OH NN

R

R1 R3

O

RO

RO NH

NH

R

R

OH

OH

NH2NH2

NHN

R

RNHN

R

ROH

Alternatively,

RO

RO

NR

R

NH2O

NH2NH2

NHN

R

RNHN

R

ROH

Example 12

MeO Me

OMe O MeNHNH2 NN

Me

MeHCl, H2O

68%

Example 28

Me

O

Me

EtO2CCF3, NaH, THF

−5 to 0 oC, 30 min.,rt, 5 h, 95%

O

Me

CF3

O

317


HNSH2N

O

ONH2•HCl N N

SH2N O

O

Me

CF3

EtOH, reflux, 46%

Celebrex

References 1 (a) Knorr, L. Ber 1883, 16, 2597. Ludwig Knorr (1859−1921) was born near Munich,

Germany. After studying under Volhard, Emil Fischer, and Bunsen, he was appointed professor of chemistry at Jena. Knorr made tremendous contributions in the synthesis of heterocycles in addition to discovering the important pyrazolone drug, pyrine. (b) Knorr, L. Ber 1884, 17, 546, 2032. (c) Knorr, L. Ber. 1885, 18, 311. (d) Knorr, L. Ann. 1887, 238, 137.

2 Burness, D. M. J. Org. Chem. 1956, 21, 97−101. 3 Jacobs, T. L. in Heterocyclic Compounds, Elderfield, R. C., Ed.; Wiley: New York,

1957, 5, 45. (Review). 4 Houben−Weyl, 1967, 10/2, 539, 587, 589, 590. (Review). 5 Elguero, J., In Comprehensive Heterocyclic Chemistry II, Katrizky, A. R.; Rees, C.

W.: Scriven, E. F. V., Eds; Elsevier: Oxford, 1996, 3, 1. (Review). 6 Stanovnik, E.; Svete, J. In Science of Synthesis, 2002, 12, 15; Neier, R., Ed.; Thieme.

(Review). 7 Sakya, S. M. Knorr Pyrazole Synthesis. In Name Reactions in Heterocyclic Chemistry;

Li, J. J., Corey, E. J., Eds, Wiley & Sons: Hoboken, NJ, 2005, pp 292−300. (Review). 8 Ahlstroem, M. M.; Ridderstroem, M.; Zamora, I.; Luthman, K. J. Med. Chem. 2007,

50, 4444−4452.

318

Koch–Haaf carbonylation

319


Strong acid-catalyzed tertiary carboxylic acid formation from alcohols or olefins and CO.

R OHCO, H2O

H

CO2HR

R O:H

protonationR O

H

HH

CH2R

alkyl

migration

R :C O: RO

The tertiary carbocation is thermodynamically favored

R OH2

OR

O

:OH2

R OH

O

H

acylium ion Example 13

OHHCO2H, H2SO4

rt, 66%

CO2H

Example 25

HCO2H, H2SO4

CCl4, 5 oC, 95%

OH CO2H

References

1. Koch, H.; Haaf, W. Ann. 1958, 618, 251–266. 2. Hiraoka, K.; Kebarle, P. J. Am. Chem. Soc. 1977, 99, 366–370. 3. Langhals, H.; Mergelsberg, I.; Rüchardt, C. Tetrahedron Lett. 1981, 22, 2365–2366. 4. Takeuchi, K.; Akiyama, F.; Miyazaki, T.; Kitagawa, I.; Okamoto, K. Tetrahedron

1987, 43, 701–709. 5. Takahashi, Y.; Yoneda, N. Synth. Commun. 1989, 19, 1945–1954. 6. Stepanov, A. G.; Luzgin, M. V.; Romannikov, V. N.; Zamaraev, K. I. J. Am. Chem.

Soc. 1995, 117, 3615–3616. 7. Olah, G. A.; Prakash, G. K. S.; Mathew, T.; Marinez, E. R. Angew. Chem., Int. Ed.

2000, 39, 2547–2548. 8. Li, T.; Tsumori, N.; Souma, Y.; Xu, Q. Chem. Commun. 2003, 2070–2071. 9. Davis, M. C.; Liu, S. Synth. Commun. 2006, 36, 3509–3514.

Koenig–Knorr glycosidation Formation of the β-glycoside from α-halocarbohydrate under the influence of sil-ver salt.

O

HAcO Br

OHH

AcO

Ac

AcO ROH

Ag2CO3

O

HAcO H

OHOR

AcO

Ac

AcO AgBr CO2↑ H2O

O:

HAcO Br

OHH

AcO

Ac

AcO

Ag

O

HAcO OH

AcO

AcOO:

oxonium ion

O

HAcO H

OHOR

AcO

Ac

AcOβ-anomer is

favored

HO

R

:

O

HAcO OH

AcO

AcOO

β-anomer

Example 17

OMeO2C

PivO

Br

OPivOPiv

NO2HO

NN CF3

Ag2O, 10 eq. HMTTA

CH3CN, rt, 6 h, 41%

OMeO2C

PivO

O

OPivOPiv

NO2

NN CF3

Example 28

O

HAcO Br

OHH

AcO

Ac

AcO

OMe

OH

OMe

Cd2CO3, Tol.

reflux, 6 h, 84%O

HAcO OH

O

AcO

Ac

AcO

320


Example 39

HOH

H

Hcholesterol

HO

HPivO Br

OHH

PivO

Piv

PivO

AgOTf, TMU, CH2Cl2

4 Å MS, −20 oC to rt16 h, 58%

OH

H

H

H

O

HPivO OH

PivO

Piv

PivO

References 1. Koenig, W.; Knorr, E. Ber. 1901, 34, 957−981. 2. Igarashi, K. Adv. Carbohydr. Chem. Biochem. 1977, 34, 243−83. (Review). 3. Schmidt, R. R. Angew. Chem. 1986, 98, 213−236. 4. Smith, A. B., III; Rivero, R. A.; Hale, K. J.; Vaccaro, H. A. J. Am. Chem. Soc. 1991,

113, 2092−2112. 5. Fürstner, A.; Radkowski, K.; Grabowski, J.; Wirtz, C.; Mynott, R. J. Org. Chem. 2000,

65, 8758−8762. 6. Yashunsky, D. V.; Tsvetkov, Y. E.; Ferguson, M. A. J.; Nikolaev, A. V. J. Chem. Soc.,

Perkin Trans. 1 2002, 242−256. 7. Stazi, F.; Palmisano, G.; Turconi, M.; Clini, S.; Santagostino, M. J. Org. Chem. 2004,

69, 1097−1103. 8. Wimmer, Z.; Pechova, L.; Saman, D. Molecules 2004, 9, 902−912. 9. Presser, A.; Kunert, O.; Pötschger, I. Monat. Chem. 2006, 137, 365−374. 10. Steinmann, A.; Thimm, J.; Thiem, J. Eur. J. Org. Chem. 2007, 5506−5513. 11. Schoettner, E.; Simon, K.; Friedel, M.; Jones, P. G.; Lindel, T. Tetrahedron Lett. 2008,

49, 5580−5582.

321

Kostanecki reaction Also known as Kostanecki−Robinson reaction. Transformation 1→2 represents an Allan−Robinson reaction (see page 8), whereas 1→3 is a Kostanecki (acyla-tion) reaction:

O

O OOH

O

O

O

R R R O O

R1 2 3

O

O

O

O

O

O

O

R

R

OO

R

OR H

acyl

transferH

: O

O

O

R enolization

O

O

O

R

H

6-exo-trig

ring closure

O O

R

O O

OH

− H2OO O

OHHR

:BR

Example 12

H O

O OOH

O O

OEt

O

O O

OEtHCO2Na, rt, 15 h, 76%

Example 23

O O

O

HO

O

O O

O

O

O

NaOAc, Ac2O, reflux

62 %

References 1. von Kostanecki, S.; Rozycki, A. Ber. 1901, 34, 102−109. 2. Pardanani, N. H.; Trivedi, K. N. J. Indian Chem. Soc. 1972, 49, 599−604. 3. Flavin, M. T.; Rizzo, J. D.; Khilevich, A.; et al. J. Med. Chem. 1996, 39, 1303−1313. 4. Mamedov, V. A.; Kalinin, A. A.; Gubaidullin, A. T.; Litvinov, I. A.; Levin, Y. A.

Chemistry of Heterocyclic Compounds 2003, 39, 96−100. 5. Limberakis, C. Kostanecki−Robinson Reaction. In Name Reactions in Heterocyclic


322


Kröhnke pyridine synthesis Pyridines from α-pyridinium methyl ketone salts and α,β-unsaturated ketones.

RN

O BrR1 R2

O

NH4OAc, HOAc NR R2

R1

RN

O

R1 R2

OH

H

enolizationR

NO

HMichael

additionO

NR

R2

O R1

H

Br

Br

Br

AcOH

ON

RBr

R2

O HR1

O

R

R2

O R1

:NH3

O

R

R2

R1HOH2N:

The ketone is more reactive than the enone

O

R

R2

HN R1

HOAc

NR2

R1

OHR

H H

AcO

NR2 R

R1

Example 11b

N

Ph O O

Ph

Ph NPh Ph

PhNH4OAcAcOH

90%

Example 24

N

N

N

N

NN

N

N

N

N

N

O

O

O

N

NH4OAcAcOH

81%

323


Example 36

NH4OAc, AcOH

115 oC, overnightO

N

OX

NX

X = H, 65%X = F, 83%X = Br, 82%X = OMe, 40%

References 1. (a) Zecher, W.; Kröhnke, F. Ber. 1961, 94, 690−697. (b) Kröhnke, F.; Zecher, W.

Angew. Chem. 1962, 74, 811−817. (c) Kröhnke, F. Synthesis 1976, 1−24. (Review). 2. Potts, K. T.; Cipullo, M. J.; Ralli, P.; Theodoridis, G. J. Am. Chem. Soc. 1981, 103,

3584−3585, 3585−3586. 3. Newkome, G. R.; Hager, D. C.; Kiefer, G. E. J. Org. Chem. 1986, 51, 850−853. 4. Kelly, T. R.; Lee, Y.-J.; Mears, R. J. J. Org. Chem. 1997, 62, 2774−2781. 5. Bark, T.; Von Zelewsky, A. Chimia 2000, 54, 589−592. 6. Malkov, A. V.; Bella, M.; Stara, I. G.; Kocovsky, P. Tetrahedron Lett. 2001, 42,

3045−3048. 7. Cave, G. W. V.; Raston, C. L. J. Chem. Soc., Perkin Trans. 1 2001, 3258−3264. 8. Malkov, A. V.; Bell, M.; Vassieu, M.; Bugatti, V.; Kocovsky, P. J. Mol. Cat. A: Chem.

2003, 196, 179−186. 9. Galatsis, P. Kröhnke Pyridine Synthesis. In Name Reactions in Heterocyclic Chemis-

try; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 311−313. (Re-view).

10. Yan, C.-G.; Wang, Q.-F.; Cai, X.-M.; Sun, J. Central Eur. J. Chem. 2008, 6, 188−198.

324

Kumada cross-coupling reaction

325


The Kumada cross-coupling reaction (also occasionally known as the Kharasch cross-coupling reaction) was originally reported as the nickel-catalyzed cross-coupling of Grignard reagents with aryl- or alkenyl halides. It has subsequently been developed to encompass the coupling of organolithium or organomagnesium compounds with aryl-, alkenyl or alkyl halides, catalyzed by nickel or palladium. The Kumada cross-coupling reaction, as well as the Negishi, Stille, Hiyama, and Suzuki cross-coupling reactions, belong to the same category of Pd-catalyzed cross-coupling reactions of organic halides, triflates and other electrophiles with organometallic reagents. These reactions follow a general mechanistic catalytic cycle as shown below. There are slight variations for the Hiyama and Suzuki re-actions, for which an additional activation step is required for the transmetallation to occur.

R XPd(0)

R R1R1 MgX MgX2

PdL

L X

R R1 MgXR X L2Pd(0)

transmetallationisomerization

oxidative

addition

MgX2 PdL

R R1

LR1R

reductive

eliminationL2Pd(0)


LnPd(II) R1Mtransmetallation

R1

LnPd(II)R1

LnPd(0)R1R1reductive

elimination

L2Pd(0)

PdL

L X

PdL

R R1

R

L

XR

R1R

transmetallation and isomerization


oxidativeaddition

R1M

MX

Example 12

O SBr MgBr

Pd(dppf)Cl2, Et2O

–30 oC to rt, 5 h, 98%O

S Example 23

MgBrMe

BrMe

MeMe

FePh2PMeO

H Me

Ligand

Ni/Ligand

(2−5 mol%)69%

95% ee

Example 35

N Br PdCl2•(dppb)THF, rt, 87%

Br N MgBrN

NBr

S MgBr

PdCl2•(dppb)THF, reflux, 98%

NN

S Example 48

OTBS

I

S

NOTBS

S

N

23 mol% PdCl2(dppf)Et2O, rt, 12 h, 75%

MgBr3 equiv

Example 59

MeO

MeO

C5H11

TESO

OPO

EtOEtO

MeO

MeO

C5H11

TESO

Me

2.5 equiv MeMgCl

10 mol% Ni(acac)2THF, 0 oC, 10 min.

90%

326

1. Tamao, K.; Sumitani, K.; Kiso, Y.; Zembayashi, M.; Fujioka, A.; Kodma, S.-i.; Naka-jima, I.; Minato, A.; Kumada, M. Bull. Chem. Soc. Jpn. 1976, 49, 1958−1969.

2. Carpita, A.; Rossi, R.; Veracini, C. A. Tetrahedron 1985, 41, 1919−1929. 3. Hayashi, T.; Hayashizaki, K.; Kiyoi, T.; Ito, Y. J. Am. Chem. Soc. 1988, 110,

8153−8156. 4. Kalinin, V. N. Synthesis 1992, 413−432. (Review). 5. Meth-Cohn, O.; Jiang, H. J. Chem. Soc., Perkin Trans. 1 1998, 3737−3746. 6. Stanforth, S. P. Tetrahedron 1998, 54, 263−303. (Review). 7. Huang, J.; Nolan, S. P. J. Am. Chem. Soc. 1999, 121, 9889−9890. 8. Rivkin, A.; Njardarson, J. T.; Biswas, K.; Chou, T.-C.; Danishefsky, S. J. J. Org.

Chem. 2002, 67, 7737−7740. 9. William, A. D.; Kobayashi, Y. J. Org. Chem. 2002, 67, 8771−8782. 10. Fuchter, M. J. Kumada cross-coupling reaction. In Name Reactions for Homologa-


327

References

Lawesson’s reagent 2,4-Bis(4-methoxyphenyl)-1,3-dithiadiphosphetane-2,4-disulfide transforms the carbonyl groups of aldehydes, ketones, amides, lactams, esters and lactones into the corresponding thiocarbonyl compounds. Cf. Knorr thiophene synthesis.

R1 R2

O

SPS P

OO

S

S

Lawesson's reagent R1 R2

S

R1,R2 = H, R, OR, NHR

NH

O

SPS P

OO

S

SNH

SLawesson's reagent

NHO

SPS P

OO

S

S

2 O PS

S

:

O PO

S

NHS

NH

SO PO

SS H

N O PS

O

Example 14

Lawesson's reagent(Me2N)2C=S

xylene, 160 oC, 47%O

OH

HO

OMe

OO

OH

HS

OMe

S

Example 25

NO

MeO2C H Lawesson's

reagent, quant.

NS

MeO2C H

328


Example 3, Thiophene from dione8

Lawesson's reagent

toluene, reflux88−99%

N N

O O

SO2Ph SO2Ph

R R

N NSO2Ph SO2Ph

SR R R = H

R = MeR = OMeR = ClR = Br

Example 410

N

O

O

O

Me

Me

MeO

O N

O

O

O

Me

Me

MeO

S

Lawesson's reagent

toluene, reflux, 100%

References 1. Scheibye, S.; Shabana, R.; Lawesson, S. O.; Rømming, C. Tetrahedron 1982, 38, 993–

1001. 2. Navech, J.; Majoral, J. P.; Kraemer, R. Tetrahedron Lett. 1983, 24, 5885–5886. 3. Cava, M. P.; Levinson, M. I. Tetrahedron 1985, 41, 5061–5087. (Review). 4. Nicolaou, K. C.; Hwang, C.-K.; Duggan, M. E.; Nugiel, D. A.; Abe, Y.; Bal Reddy,

K.; DeFrees, S. A.; Reddy, D. R.; Awartani, R. A.; Conley, S. R.; Rutjes, F. P. J. T.; Theodorakis, E. A. J. Am. Chem. Soc. 1995, 117, 10227–10238.

5. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003–2005.

6. Luheshi, A.-B. N.; Smalley, R. K.; Kennewell, P. D.; Westwood, R. Tetrahedron Lett. 1990, 31, 123–127.

7. Ishii, A.; Yamashita, R.; Saito, M.; Nakayama, J. J. Org. Chem. 2003, 68, 1555–1558. 8. Diana, P.; Carbone, A.; Barraja, P.; Montalbano, A.; Martorana, A.; Dattolo, G.; Gia,

O.; Dalla Via, L.; Cirrincione, G. Bioorg. Med. Chem. Lett. 2007, 17, 2342–2346. 9. Ozturk, T.; Ertas, E.; Mert, O. Chem. Rev. 2007, 107, 5210–5278. (Review). 10. Taniguchi, T.; Ishibashi, H. Tetrahedron 2008, 64, 8773–8779. 11. de Moreira, D. R. M. Synlett 2008, 463–464. (Review).

329

Leuckart–Wallach reaction Amine synthesis from reductive amination of a ketone and an amine in the pres-ence of excess formic acid, which serves as the reducing reagent by delivering a hydride. When the ketone is replaced by formaldehyde, it becomes the Eschweiler–Clarke reductive alkylation of amines on page 210.

R1

R2O

R4HN

R3HCO2H

NR2

R1

R4

R3

CO2↑ H2O

R1

R2O:N

R3H

NHO

R1

R2R3

R4

R4

H NHO

R1

R2R3

R4

:

HH

NR2

R1

R4

R3− H2O

gem-aminoalcohol; iminium ion intermediate

HCO2H NR1 R3

HHO

R4

O

R2 NR2

R1

R4

R3

NH

R1

H

R3

R4R2− CO2 H

reduction

Example 14

HCO2H

60 oC, 57%CHO

HN

ON

O

Example 26

O

OHCN

HCO2H, H2O190 oC, autoclave

16 h, 75%

N

Example 37

HCO2H, reflux

7 h, 45%S

O

H

N

NH2N S

HNN

N

330


Example 48

O NHCOCH3 OHCHN NHCOCH3

H2NCHO

HCO2H150oC

An unexpected intramolecular transamidation via a Wagner–Meerwein shift after the Leuckart–Wallach reaction

O NHCOCH3CH3COHN NHCHO

H2NCHO, HCO2H

150 oC

References 1. Leuckart, R. Ber. 1885, 18, 2341−2344. Carl L. R. A. Leuckart (1854−1889) was born

in Giessen, Germany. After studying under Bunsen, Kolbe, and von Baeyer, he be-came an assistant professor at Göttingen. Unfortunately, chemistry lost a brilliant con-tributor by his sudden death at age 35 as a result of a fall in his parent’s house.

2. Wallach, O. Ann. 1892, 272, 99. Otto Wallach (1847−1931), born in Königsberg, Prussia, studied under Wöhler and Hofmann. He was the director of the Chemical In-stitute at Göttingen from 1889 to 1915. His book “Terpene und Kampfer” served as the foundation for future work in terpene chemistry. Wallach was awarded the Nobel Prize in Chemistry in 1910 for his work on alicyclic compounds.

3. Moore, M. L. Org. React. 1949, 5, 301−330. (Review). 4. DeBenneville, P. L.; Macartney, J. H. J. Am. Chem. Soc. 1950, 72, 3073−3075. 5. Lukasiewicz, A. Tetrahedron 1963, 19, 1789−1799. (Mechanism). 6. Bach, R. D. J. Org. Chem. 1968, 33, 1647−1649. 7. Musumarra, G.; Sergi, C. Heterocycles 1994, 37, 1033−1039. 8. Martínez, A. G.; Vilar, E. T.; Fraile, A. G.; Ruiz, P. M.; San Antonio, R. M.; Alcazar,

M. P. M. Tetrahedron: Asymmetry 1999, 10, 1499−1505. 9. Kitamura, M.; Lee, D.; Hayashi, S.; Tanaka, S.; Yoshimura, M. J. Org. Chem. 2002,

67, 8685−8687. 10. Brewer, A. R. E. Leuckart–Wallach reaction. In Name Reactions for Functional

Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 451−455. (Review).

11. Muzalevskiy, V. M.; Nenajdenko, V. G.; Shastin, A. V.; Balenkova, E. S.; Haufe, G. J. Fluorine Chem. 2008, 129, 1052−1055.

331

Lossen rearrangement The Lossen rearrangement involves the generation of an isocyanate via thermal or base-mediated rearrangement of an activated hydroxamate which can be generated from the corresponding hydroxamic acid. Activation of the hydroxamic acid can be achieved through O-acylation, O-arylation, chlorination, or O-sulfonylation. Such hydroxamic acids can also be activated using polyphosphoric acid, car-bodiimide, Mitsunobu conditions, or silyation. The product of the Lossen rear-rangement, an isocyanate can be subsequently converted to an urea or an amine resulting in the net loss of one carbon atom relative to the starting hydroxamic acid.

R1 NH

O R2O

O

OHR1 N C O

H2OR1 NH2 CO2↑

R1 NO R2

O

O

OH

R1 NO R2

O

OH

R1 N C O

:OH2

R2CO2

HO H


R1 NH2CO2↑R1

HN O

OH

:B

decarboxylation

Example 16

O

NMsO

O

O

N

NHO

O

BnOH, CH3CN, 85 oC, 78%

Example 27

Br

Cl

OEtO2C

HN

OCO2Et

Et3N, H2OBr

NC

OEtOH, H2O

50% Br

NH2

332


Example 38

N

O

O

OS

OO

H3C NH2

PhH, rt, 6 h, 54%

NHCONHAr

CONHArArNH2:

N

O

OSO2Ph

O NH2

Ar

O

HN

O Ar

N OSO2Ph N

HN

O Ar

C OLossen

ArNH2

Example 49

N

NHN

OAcO

OOMeMeO

DBU, THF, H2O

reflux, 1 h

N

NN

OOMeMeO

CO

N

NH2N

OOMeMeO

References 1. Lossen, W. Ann. 1872, 161, 347. Wilhelm C. Lossen (1838−1906) was born in

Kreuznach, Germany. After his Ph.D. studies at Göttingen in 1862, he embarked on his independent academic career, and his interests centered on hydroxyamines.

2. Bauer, L.; Exner, O. Angew. Chem., Int. Ed. 1974, 13, 376. 3. Lipczynska-Kochany, E. Wiad. Chem. 1982, 36, 735−756. 4. Casteel, D. A.; Gephart, R. S.; Morgan, T. Heterocycles 1993, 36, 485−495. 5. Zalipsky, S. Chem. Commun. 1998, 69−70. 6. Stafford, J. A.; Gonzales, S. S.; Barrett, D. G.; Suh, E. M.; Feldman, P. L. J. Org

Chem. 1998, 63, 10040–10044. 7. Anilkumar, R.; Chandrasekhar, S.; Sridhar, M. Tetrahedron Lett. 2000, 41,

5291−5293. 8. Abbady, M. S.; Kandeel, M. M.; Youssef, M. S. K. Phosphorous, Sulfur and Silicon

2000, 163, 55–64. 9. Ohmoto, K.; Yamamoto, T.; Horiuchi, T.; Kojima, T.; Hachiya, K.; Hashimoto, S.;

Kawamura, M.; Nakai, H.; Toda, M. Synlett 2001, 299−301. 10. Choi, C.; Pfefferkorn, J. A. Lossen rearrangement. In Name Reactions for Homologa-


333

McFadyen–Stevens reduction Treatment of acylbenzenesulfonylhydrazines with base delivers the corresponding aldehydes.

R NH

HN

SO2Ar

OBase

R H

O

R NHN

SO2Ar

O

R NN

O

H

B:

H N2↑ R

Ohomolytic

cleavage R H

O

H

Example 18

K2CO3, MeOH

reflux, 1 h, 75%H

OO2N

NHHN

SO2

OO2N

Example 210

NH

NO

NHNHTs

ONa2CO3, glass powder

ethylene glycol

microwave (450 W)90% N

H

NO

H

O

References 1. McFadyen, J. S.; Stevens, T. S. J. Chem. Soc. 1936, 584−587. Thomas S. Stevens

(1900−2000) was born in Renfrew, Scotland. After earning his Ph.D. under W. H. Perkin at Oxford University, he became a reader at the University of Sheffield. J. S. McFadyen (1908−?) was born in Toronto, Canada. After studying under Stevens at the University of Glasgow, he worked for ICI for 15 years before returning to Canada where he worked for the Canadian Industries, Ltd., Montreal.

2. Newman, M. S.; Caflisch, E. G., Jr. J. Am. Chem. Soc. 1958, 80, 862−864. 3. Sprecher, M.; Feldkimel, M.; Wilchek, M. J. Org. Chem. 1961, 26, 3664−3666. 4. Babad, H.; Herbert, W.; Stiles, A. W. Tetrahedron Lett. 1966, 7, 2927−2931. 5. Graboyes, H.; Anderson, E. L.; Levinson, S. H.; Resnick, T. M. J. Heterocycl. Chem.

1975, 12, 1225−1231. 6. Eichler, E.; Rooney, C. S.; Williams, H. W. R. J. Heterocycl. Chem. 1976, 13,

841−844. 7. Nair, M.; Shechter, H. J. Chem. Soc., Chem. Commun. 1978, 793−796. 8. Dudman, C. C.; Grice, P.; Reese, C. B. Tetrahedron Lett. 1980, 21, 4645−4648. 9. Manna, R. K.; Jaisankar, P.; Giri, V. S. Synth. Commun. 1998, 28, 9−16. 10. Jaisankar, P.; Pal, B.; Giri, V. S. Synth. Commun. 2002, 32, 2569−2573.

334


McMurry coupling Olefination of carbonyls with low-valent titanium such as Ti(0) derived from TiCl3/LiAlH4. A single-electron process.

R1

R2O

R2

R1

R2

R11. TiCl3, LiAlH4

2. H2OTiO

Ti(III)Cl3 LiAlH4 Ti(0)

R1

R2O :Ti(0)

single electron

transfer

homocouplingR1

R2 R2R1

O OTi Ti

radical anion intermediate

R2

R1

R2

R1

O OTi Ti

R1

R2 R2R1

O OTi Ti

R1

R2 R2R1

O OTi Ti

oxide-coated titanium surface

Example 1, Cross-McMurry coupling7

MeO2S

O

OZn, TiCl4, reflux

4.5 h, 75%, > 99% Z

OH OHMeO2S

Example 2, Homo-McMurry coupling8

CHOSZn, TiCl4, THF,110 oC

microwave (10 W), 10 min.87%

SS

335



OMe

NOO

N

O O

N

Zn, TiCl4

THF, 78%

N

N

OON

OMe


CHO

OHBnO

OHC

MeO O

OZn−TiCl4, THF

−5 to 0 oC thenreflux, 2.5 h, 77% BnO

O

O

OH

MeO

References 1. (a) McMurry, J. E.; Fleming, M. P. J. Am. Chem. Soc. 1974, 96, 4708−4712. (b)

McMurry, J. E. Chem. Rev. 1989, 89, 1513−1524. (Review). 2. Hirao, T. Synlett 1999, 175−181. 3. Sabelle, S.; Hydrio, J.; Leclerc, E.; Mioskowski, C.; Renard, P.-Y. Tetrahedron Lett.

2002, 43, 3645−3648. 4. Williams, D. R.; Heidebrecht, R. W., Jr. J. Am. Chem. Soc. 2003, 125, 1843−1850. 5. Honda, T.; Namiki, H.; Nagase, H.; Mizutani, H. Tetrahedron Lett. 2003, 44,

3035−3038. 6. Ephritikhine, M.; Villiers, C. In Modern Carbonyl Olefination Takeda, T., Ed.; Wiley-

VCH: Weinheim, Germany, 2004, 223−285. (Review). 7. Uddin, M. J.; Rao, P. N. P.; Knaus, E. E. Synlett 2004, 1513−1516. 8. Stuhr-Hansen, N. Tetrahedron Lett. 2005, 46, 5491−5494. 9. Zeng, D. X.; Chen, Y. Synlett 2006, 490−492. 10. Duan, X.-F.; Zeng, J.; Zhang, Z.-B.; Zi, G.-F. J. Org. Chem. 2007, 72, 10283−10286. 11. Debroy, P.; Lindeman, S. V.; Rathore, R. J. Org. Chem. 2009, 74, 2080−2087.

336

Mannich reaction Three-component aminomethylation from amine, aldehyde and a compound with an acidic methylene moiety.

H H

O

RNHR

R1R2

O HN R2R

R R1

O

H H

O

RHN

R

N HR

R

OH

N HR

R

OH2:N

R

R

H

:

H

When R = Me, the +Me2N=CH2 salt is known as Eschenmoser’s salt (page 206)

R1R2

O

enolization N R2R

R R1

O

NR

R

R1R2

OH

H

The Mannich reaction can also operate under basic conditions:

R1R2

O

H

B:

enolate

formationN R2R

R R1

O

NR

R

R1R2

O

Mannich Base

Example 1, Asymmetric Mannich reaction2

O

NH2

O

OHC

NO2

35 mol% L-proline

DMSO, rt, 50%, 94% ee

HN

O

O

NO2

Example 2, Asymmetric Mannich-type reaction9

No-Ts

OHN

O

O

In(Oi-Pr)3, ligand

5 Å MS, THF, rt, 80%

NHo-Ts

OHN

O

O

337


Example 3, Asymmetric Mannich reaction10

R1

O

R2 O

R3

O

NH

ArO2S R4

10 mol %

Na2CO3, NaCl, −15 ºC 72−98%, 99:1 er

R1

O

R2 O

HN

R4

O

R3N

H

H

HO

N

Example 411

EtO2C H

NPMP

OL-proline, DMSO

rt, 81%EtO2C

NHPMP

O

syn

ON

PhPh

O

OL-proline, DMSO

rt, 81%

NH OO

PhPh

O

References 1. Mannich, C.; Krösche, W. Arch. Pharm. 1912, 250, 647–667. Carl U. F. Mannich

(1877−1947) was born in Breslau, Germany. After receiving a Ph.D. at Basel in 1903, he served on the faculties of Göttingen, Frankfurt and Berlin. Mannich synthesized many esters of p-aminobenzoic acid as local anesthetics.

2. List, B. J. Am. Chem. Soc. 2000, 122, 9336–9337. 3. Schlienger, N.; Bryce, M. R.; Hansen, T. K. Tetrahedron 2000, 56, 10023–10030. 4. Bur, S. K.; Martin, S. F. Tetrahedron 2001, 57, 3221–3242. (Review). 5. Martin, S. F. Acc. Chem. Res. 2002, 35, 895−904. (Review). 6. Padwa, A.; Bur, S. K.; Danca, D. M.; Ginn, J. D.; Lynch, S. M. Synlett 2002, 851−862.

(Review). 7. Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580−591. (Re-

view). 8. Córdova, A. Acc. Chem. Res. 2004, 37, 102−112. (Review). 9. Harada, S.; Handa, S.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2005, 44,

4365–4368. 10. Lou, S.; Dai, P.; Schaus, S. E. J. Org. Chem. 2007, 72, 9998–10008. 11. Hahn, B. T.; Fröhlich, R.; Harms, K.; Glorius, F. Angew. Chem., Int. Ed. 2008, 47,

9985−9988. 12. Galatsis, P. Mannich reaction. In Name Reactions for Homologations-Part II; Li, J. J.,


338

Martin’s sulfurane dehydrating reagent Dehydrates secondary and tertiary alcohols to give olefins, but forms ethers with primary alcohols. Cf. Burgess dehydrating reagent.

OHHOC(CF3)2PhPh2S[OC(CF3)2Ph]2 Ph2S O

Ph2SOC(CF3)2Ph

OC(CF3)2Ph

H Ot-Bu

HOC(CF3)2Ph O

Ph2SO−C(CF3)2Ph

:

The alcohol is acidic

OPh2S

OC(CF3)2Ph protonation

:

H OC(CF3)2Ph

OC(CF3)2Ph OPh2S

O−C(CF3)2PhH

OH

Ph2S OC(CF3)2Ph β-elimination

E1cBHOC(CF3)2PhPh2S O

Example 15

O

OMeO

O

O

O

O

OMe

BzOOBn

OBn OH

OPMB

Martin's sulfurane

Et3N, CHCl3, 50 oC85%

O

OMeO

O

O

O

O

OMe

BzOOBn

OBn

OPMB

Example 26

Martin'ssulfurane

PhH, reflux88%

OBnOH

OBnOO

OBn

OBn

OBnOO

BnO

339


Example 37

OO

OMe

MeO

CO2MeHO

TBSO

1.5 eq. Martin's sulfurane

CH2Cl2, rt, 24 h, 84%O

OOMe

MeO

TBSO

CO2Me

Example 49

HN

O

OMOMi-PrO

H3COOCH3

O

ON

OOH

Cl

TESO O

OTIPS

HN

O

OMOMi-PrO

H3COOCH3

O

ON

O

Cl

TESO O

OTIPS

Martin'ssulfurane

PhH, rt83%

References 1. (a) Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 2339–2341; (b0 Martin, J.

C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 2341–2342; (c) Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 4327–4329. (d) Martin, J. C.; Arhart, R. J.; Franz, J. A.; Perozzi, E. F.; Kaplan, L. J. Org. Synth. 1977, 57, 22–26.

2. Gallagher, T. F.; Adams, J. L. J. Org. Chem. 1992, 57, 3347–3353. 3. Tse, B.; Kishi, Y. J. Org. Chem. 1994, 59, 7807–7814. 4. Winkler, J. D.; Stelmach, J. E.; Axten, J. Tetrahedron Lett. 1996, 37, 4317–4320. 5. Nicolaou, K. C.; Rodríguez, R. M.; Fylaktakidou, K. C.; Suzuki, H.; Mitchell, H. J.

Angew. Chem., Int. Ed. 1999, 38, 3340–3345. 6. Kok, S. H. L.; Lee, C. C.; Shing, T. K. M. J. Org. Chem. 2001, 66, 7184–7190. 7. Box, J. M.; Harwood, L. M.; Humphreys, J. L.; Morris, G. A.; Redon, P. M.; White-

head, R. C. Synlett 2002, 358–360. 8. Myers, A. G.; Glatthar, R.; Hammond, M.; Harrington, P. M.; Kuo, E. Y.; Liang, J.;

Schaus, S. E.; Wu, Y.; Xiang, J.-N. J. Am. Chem. Soc. 2002, 124, 5380–5401. 9. Myers, A. G.; Hogan, P. C.; Hurd, A. R.; Goldberg, S. D. Angew. Chem., Int. Ed.

2002, 41, 1062–1067. 10. Shea, K. M. Martin’s sulfurane dehydrating reagent. In Name Reactions for Func-

tional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hobo-ken, NJ, 2007, pp 248−264. (Review).

11. Sparling, B. A.; Moslin, R. M.; Jamison, T. F. Org. Lett. 2008, 10, 1291−1294.

340

Masamune–Roush conditions for the Horner–Emmons reaction Applicable to base-sensitive aldehydes and phosphonates for the Horner–Wadsworth–Emmons reaction. α-Keto or α-alkoxycarbonyl phosphonate re-quired.

(EtO)2POEt

O OCHO

AcO

N

N

LiCl, CH3CN, 70%AcO

CO2EtDBU

DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene

(EtO)2POEt

O O

N

N

H

:

deprotonation(EtO)2P

OEt

O O LiCl

chelation

AcO

(EtO)2POEt

O OLi

O

HAcO O

EtO2C PO

OEtOEt

AcOCO2Et

AcO

EtO2C

OP(OEt)2

O

Example 15

NH

P(OEt)2

OORCHO

LiBr, Et3NNH

R

O TFAH2N R

O

75−95%

Example 26

OOOMe

MeO

MOMO

OHOO

7

(EtO)2(O)POO

OMe

MeO

MOMO

OO7

LiCl, Hunig base

MeCN, rt, 14 h, 58%

341


Example 37

CHOBocNO

PhN

O

O

O

Ph

(EtO)2(O)P

LiBr, DBU, CH3CN, rt, 67%

NBocN

O

Ph

O

O

O

Ph

Example 48

OP

(EtO)2CO2Et Ph

O NH

N

N

THF, 92%

CO2EtPh

Example 510

(MeO)2PNH

CO2Me

O O Ph MeO CHO

DBU, LiCl, THF, rt90%

NH

CO2Me

O Ph

NH

CO2Me

O Ph

MeO

OMe

98 : 2

References 1. Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune, S.; Roush, W.

R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183–2186. 2. Rathke, M. W.; Nowak, M. J. Org. Chem. 1985, 50, 2624–2636. 3. Tius, M. A.; Fauq, A. H. J. Am. Chem. Soc. 1986, 108, 1035–1039, and 6389–6391. 4. Marshall, J. A.; DuBay, W. J. J. Org. Chem. 1994, 59, 1703–1708. 5. Johnson, C. R.; Zhang, B. Tetrahedron Lett. 1995, 36, 9253–9256. 6. Rychnovsky, S. D.; Khire, U. R.; Yang, G. J. Am. Chem. Soc. 1997, 119, 2058–2059. 7. Dixon, D. J.; Foster, A. C.; Ley, S. V. Org. Lett. 2000, 2, 123–125. 8. Simoni, D.; Rossi, M.; Rondannin, R.; Mazzali, A.; Baruchello, R.; Malagutti, C.;

Roberti, M.; Invidiata, F. P. Org. Lett. 2000, 2, 3765–3768. 9. Crackett, P.; Demont, E.; Eatherton, A.; Frampton, C. S.; Gilbert, J.; Kahn, I.; Red-

shaw, S.; Watson, W. Synlett 2004, 679–683. 10. Ordonez, M.; Hernandez-Fernandez, E.; Montiel-Perez, M.; Bautista, R.; Bustos, P.;

Rojas-Cabrera, H.; Fernandez-Zertuche, M.; Garcia-Barradas, O. Tetrahedron: Asymmetry 2007, 18, 2427–2436.

11. Zanato, C.; Pignataro, L.; Hao, Z.; Gennari, C. Synthesis 2008, 2158–2162.

342

Meerwein’s salt

343


Meerwein’s salts, also known as the Meerwein reagent, refer to trimethyloxonium tetrafluoroborate (Me3O+BF4

−) and triethyloxonium tetrafluoroborate (Et3O+BF4−).

Named after the inventor Hans Meerwein,1 these trialkyloxonium salts are power-ful alkylating agents.

O

BFF

F F

O

BFF

F F

Preparation:2

4 BF3•OEt2 + 6 Me2O

ClO

+ 3

3 Me3O+BF4− + 4 Et2O

+

Cl

OO Me

3

B

4 BF3•OEt2 + 2 Et2O

ClO

+ 3

3 Et3O+BF4−

+

Cl

OO Et

3

B

Example 1, The Meerwein reagent is an excellent O-alkylating agent:5

Cl

NH

OEt3O•BF4, NaHPO4

CH3CN, rt, 6 h Cl

O

OEt

Cl

N

OEt

H3O

81%

Transforming an amide into its corresponding ethyl or methyl esters

Example 2, Metal-methylation4

Co(CO)6

1. PhLi, Et2O, 0 oC

2. Me3O•BF4

t-Bu, t-BuOMe

45 oC, 79%Dötz reaction

OHt-Bu

OMe

OMe

PhCo(OC)5

Example 3, N-Alkylation, the product is an ionic liquid8

Me3O•BF4

Et2O, 94%N N N N CH3

H3CBF4

Example 4, N-Methylation9

N N

I

SO2NMe2

SPh1. Me3O•BF4, slow addition CH2Cl2, rt

2. BuMeNH, CH3CN, Δ, quant.

N N

I

SPhMe

References 1. (a) Meerwein, H.; Hinz, G.; Hofmann, P.; Kroning, E.; Pfeil, E. J. Prakt. Chem. 1937,

147, 257–285. (b) Meerwein, H.; Bettenberg, E.; Pfeil, E.; Willfang, G. J. Prakt. Chem. 1939, 154, 83–156.

2. (a) Meerwein, H. Org. Synth.; Coll. Vol. V, 1973, 1080. Triethyloxonium tetra-fluoroborate. (b) Curphey, T. J. Org. Synth.; Coll. Vol. VI, 1988, 1019. Trimethy-loxonium tetrafluoroborate.

3. Chen, F. M. F.; Benoiton, N. L. Can. J. Chem. 1977, 55, 1433–1534. 4. Dötz, K. H.; Möhlemeier, J.; Schubert, U.; Orama, O. J. Organomet. Chem. 1983, 247,

187–201. 5. Downie, I. M.; Heaney, H.; Kemp, G.; King, D.; Wosley, M. Tetrahedron 1992, 48,

4005–4016. 6. Kiessling, A. J.; McClure, C. K. Synth. Commun. 1997, 27, 923–937. 7. Pichlmair, S. Synlett 2004, 195−196. (Review). 8. Egashira, M.; Yamamoto, Y.; Fukutake, T.; Yoshimoto, N.; Morita, M. J. Fluorine

Chem. 2006, 127, 1261–1264. 9. Delest, B.; Nshimyumukiza, P.; Fasbender, O.; Tinant, B.; Marchand-Brynaert, J.;

Darro, F.; Robiette, R. J. Org. Chem. 2008, 73, 6816–6823. 10. Perst, H.; Seapy, D. G. Triethyloxonium Tetrafluoroborate In Encyclopedia of

Reagents for Organic Synthesis John Wiley & Sons, New York, 2008, (Review).

344

Meerwein–Ponndorf–Verley reduction Reduction of ketones to the corresponding alcohols using Al(Oi-Pr)3 in isopropanol. Reverse of the Oppernauer oxidation.

R1 R2

O

R1 R2

OH OAl(Oi-Pr)3

HOi-Pr

R1 R2

O

Al(Oi-Pr)3

coordination

H OAlO

Oi-Pr

Oi-Pr

R1

R2

: O

R1R2 H

OAl

Oi-Pri-PrO‡‡

cyclic transition state

hydride

transfer

H

R1 R2

OO Al(Oi-Pr)2

R1 R2

OH

Example 12

O

OH

H

MeO2CH

Al(Oi-Pr)3

HOi-Pr, 90%

OHH

O

O H

H

H

Example 24

O

R R

OH

*43−99% yield30−80% ee

(R)-BINOL (0.1 eq)AlMe3 (0.1 eq)

i-PrOH (4 eq)toluene

Example 37

O

MeO O

OTBDPS

MeMe

4 equiv Me3Al, i-PrOH

0 oC to rt, 24 hO

MeO OH

OTBDPS

MeMe

84%

O

MeO OH

OTBDPS

MeMe

15%

345


Example 49

O OMeO OMe

O O

3 equiv AlMe39 equiv HOCH(Ph)2

CH2Cl2

O OMeO OMe

OH OH

O OMeO OMe

OH OH73% 12%

References 1. Meerwein, H.; Schmidt, R. Ann. 1925, 444, 221−238. Hans L. Meerwein, born in

Hamburg Germany in 1879, received his Ph.D. at Bonn in 1903. In his long and pro-ductive academic career, Meerwein made many notable contributions in organic chem-istry.

2. Woodward, R. B.; Bader, F. E.; Bickel, H.; Frey, A. J.; Kierstead, R. W. Tetrahedron 1958, 2, 1−57.

3. de Graauw, C. F.; Peters, J. A.; van Bekkum, H.; Huskens, J. Synthesis 1994, 1007−1017. (Review).

4. Campbell, E. J.; Zhou, H.; Nguyen, S. T. Angew. Chem., Int. Ed. 2002, 41, 1020−1022.

5. Sominsky, L.; Rozental, E.; Gottlieb, H.; Gedanken, A.; Hoz, S. J. Org. Chem. 2004, 69, 1492−1496.

6. Cha, J. S. Org. Proc. Res. Dev. 2006, 10, 1032−1053. 7. Manaviazar, S.; Frigerio, M.; Bhatia, G. S.; Hummersone, M. G.; Aliev, A. E.; Hale,

K. J. Org. Lett. 2006, 8, 4477−4480. 8. Clay, J. M. Meerwein–Ponndorf–Verley reduction. In Name Reactions for Functional


9. Dilger, A. K.; Gopalsamuthiram, V.; Burke, S. D. J. Am. Chem. Soc. 2007, 129, 16273−16277.

346

Meisenheimer complex Also known as the Meisenheimer−Jackson salt, the stable intermediate for cer-tain SNAr reactions.

FNO2

NO2

:R NH2

NO2

NO2SNAr, slow,

rate-determining step

FHNR

NHNO2

NO2

R

NO2

NO2

Ffast

FNHR

Meisenheimer complex

Sanger’s reagent, ipso attack ipso substitution

Example 17

Ph CN

NO2CO2Et

t-BuOK, DMF/THF

−70 oC, argon

NCO2Et

O O

HNC

Phnitronate

Example 29

OH

NO2O2N

NO2

N C NCH2Cl2

argon, rt, 3 h2

NOO

O2N NO2N

N

N

O Ni-Pri-Pr

H

15.5%

NO2N

NO2

NH

O

15.8%

NO2

The reaction using Sanger’s reagent is faster than using the corresponding chloro-, bromo-, and iododinitrobenzene—the fluoro-Meisenheimer complex is the most stabilized because F is the most electron-withdrawing. The reaction rate does not depend upon the capacity of the leaving group.

347


Example 310

FNO2

NO2

NHNO2

NO2

R

HNR'

R

NO2

NO2FNHR

R'R'

NNO2

NO2

R R'

F

H

NO2

NO2FNR

R'

H

F

References 1. Meisenheimer, J. Ann. 1902, 323, 205–214. 2. Strauss, M. J. Acc. Chem. Res. 1974, 7, 181–188. (Review). 3. Bernasconi, C. F. Acc. Chem. Res. 1978, 11, 147–152. (Review). 4. Terrier, F. Chem. Rev. 1982, 82, 77–152. (Review). 5. Manderville, R. A.; Buncel, E. J. Org. Chem. 1997, 62, 7614–7620. 6. Hoshino, K.; Ozawa, N.; Kokado, H.; Seki, H.; Tokunaga, T.; Ishikawa, T. J. Org.

Chem. 1999, 64, 4572–4573. 7. Adam, W.; Makosza, M.; Zhao, C.-G.; Surowiec, M. J. Org. Chem. 2000, 65, 1099–

1101. 8. Gallardo, I.; Guirado, G.; Marquet, J. J. Org. Chem. 2002, 67, 2548–2555. 9. Al-Kaysi, R. O.; Guirado, G.; Valente, E. J. Eur. J. Org. Chem. 2004, 3408–3411. 10. Um, I.-H.; Min, S.-W.; Dust, J. M. J. Org. Chem. 2007, 72, 8797–8803. 11. Han, T. Y.-J.; Pagoria, P. F.; Gash, A. E.; Maiti, A.; Orme, C. A.; Mitchell, A. R.;

Fried, L. E. New J. Chem. 2009, 33, 50–56.

348

[1,2]-Meisenheimer rearrangement [1,2]-Sigmatropic rearrangement of tertiary amine N-oxides to substituted hy-droxylamines.

R2N

OR1 Δ

R2N

OR

R1RR2

NO

RR1

Example 17

O

O N35% H2O2, CHCl3/MeOH, rt, 15 h

then PtO2, rt, 4.5 h

O

O NO

O

O

NO

THF, reflux, 1 h

64%, 2 steps

References 1. Meisenheimer, J. Ber. 1919, 52, 1667–1677. 2. Castagnoli, N., Jr.; Craig, J. C.; Melikian, A. P.; Roy, S. K. Tetrahedron 1970, 26,

4319–4327. 3. Johnstone, R. A. W. Mech. Mol. Migr. 1969, 2, 249–266. (Review). 4. Kurihara, T.; Sakamoto, Y.; Tsukamoto, K.; Ohishi, H.; Harusawa, S.; Yoneda, R. J.

Chem. Soc., Perkin Trans. 1, 1993, 81–87. 5. Yoneda, R.; Sakamoto, Y.; Oketo, Y.; Minami, K.; Harusawa, S.; Kurihara, T. Tetra-

hedron Lett. 1994, 35, 3749–3752. 6. Kurihara, T.; Sakamoto, Y.; Takai, M.; Ohishi, H.; Harusawa, S.; Yoneda, R. Chem.

Pharm. Bull. 1995, 43, 1089–1095. 7. Yoneda, R.; Sakamoto, Y.; Oketo, Y.; Harusawa, S.; Kurihara, T. Tetrahedron 1996,

52, 14563–14576. 8. Yoneda, R.; Araki, L.; Harusawa, S.; Kurihara, T. Chem. Pharm. Bull. 1998, 46, 853–

856.

349


[2,3]-Meisenheimer rearrangement [2,3]-Sigmatropic rearrangement of allylic tertiary amine-N-oxides to give O-allyl hydroxylamines:

ΔN

O

RR R

NO

R1

23

1'2'

1'

2'

1

23

Example 17

N

ON

PhSO2

Ph

Et2O, rt, 48 h48%, 61% de

NO

*

Example 28

NO

OHO

Bn

m-CPBA

CH2Cl2, 100%

NO

OHO

BnHO Al2O3 (alumina)

MeOH

NO

OHO

BnO CDCl3, rt

67%, 65% deN

OO*

OHO

Bn

References 1. Meisenheimer, J. Ber. 1919, 52, 1667–1677. 2. Yamamoto, Y.; Oda, J.; Inouye, Y. J. Org. Chem. 1976, 41, 303–306. 3. Johnstone, R. A. W. Mech. Mol. Migr. 1969, 2, 249–266. (Review). 4. Kurihara, T.; Sakamoto, Y.; Matsumoto, H.; Kawabata, N.; Harusawa, S.; Yoneda, R.

Chem. Pharm. Bull. 1994, 42, 475–480. 5. Blanchet, J.; Bonin, M.; Micouin, L.; Husson, H.-P. Tetrahedron Lett. 2000, 41, 8279–

8283. 6. Enders, D.; Kempen, H. Synlett 1994, 969–971. 7. Buston, J. E. H.; Coldham, I.; Mulholland, K. R. Synlett 1997, 322–324. 8. Guarna, A.; Occhiato, E. G.; Pizzetti, M.; Scarpi, D.; Sisi, S.; van Sterkenburg, M. Tet-

rahedron: Asymmetry 2000, 11, 4227–4238. 9. Mucsi, Z.; Szabó, A.; Hermecz, I.; Kucsman, Á.; Csizmadia, I. G. J. Am. Chem. Soc.

2005, 127, 7615–7621. 10. Bourgeois, J.; Dion, I.; Cebrowski, P. H.; Loiseau, F.; Bedard, A.-C.; Beauchemin, A.

M. J. Am. Chem. Soc. 2009, 131, 874–875.

350


Meyers oxazoline method Chiral oxazolines employed as activating groups and/or chiral auxiliaries in nu-cleophilic addition and substitution reactions that lead to the asymmetric construc-tion of carbon–carbon bonds.

N

O Ph

OMe N

O Ph

OMeR

1. LDA

2. R-X

N

O Ph

OMe

H

N(i-Pr)2

ONLi

Ph

OMe

H3C

H ONLi

Ph

OMe

H

H3C

XR

ON

Ph

OMe

H

H3C

R

Example 12

N

O Ph

OMe

TMSO Br1. LDA2.

3. LDA 4. Me2SO4

N

O Ph

OMe

H

TMSO

H3OO

O

66% yield70% ee

Example 25

NO

PhOMe

Li

IOO

NO

Ph OMeOO

1.

2.

99% yield

Example 39

NO 3 equiv n-BuLi3 equiv (−)-sparteine

Et2O, −78 oC, 4 h

NO

n-BuLi MeOH

79%

NO

n-Bu

er (S:R) = 86:14

351


References 1. (a) Meyers, A. I.; Knaus, G.; Kamata, K. J. Am. Chem. Soc. 1974, 96, 268–270. While

Albert I. Meyers was an assistant professor at Wayne State University, neighboring pharmaceutical firm Parke–Davis (Drs. George Moersch and Harry Crooks) donated several kilograms of (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol (Meyers referred to it as the Parke–Davis diol), from which his chemistry with chiral oxazolines began. He taught at Colorado State University since 1972. Meyers passed away in 2007. (b) Meyers, A. I.; Knaus, G. J. Am. Chem. Soc. 1974, 96, 6508–6510. (c) Meyers, A. I.; Knaus, G. Tetrahedron Lett. 1974, 15, 1333–1336. (d) Meyers, A. I.; Whitten, C. E. J. Am. Chem. Soc. 1975, 97, 6266–6267. (e) Meyers, A. I.; Mihelich, E. D. J. Org. Chem. 1975, 40, 1186–1187. (f) Meyers, A. I.; Mihelich, E. D. Angew. Chem., Int. Ed. 1976, 15, 270–271. (Review). (g) Meyers, A. I. Acc. Chem. Res. 1978, 11, 375–381. (Review).

2. Meyers, A. I.; Yamamoto, Y.; Mihelich, E. D.; Bell, R. A. J. Org. Chem. 1980, 45, 2792–2796.

3. Meyers, A. I., Lutomski, K. A. In Asymmetric Synthesis, Morrison, J. D. Ed.; Vol III, Part B, Chapter 3, Academic Press, 1983. (Review).

4. Reuman, M.; Meyers, A. I. Tetrahedron 1985, 41, 837–860. (Review). 5. Robichaud, A. J.; Meyers, A. I. J. Org. Chem. 1991, 56, 2607–2609. 6. Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297–2360. (Review). 7. Meyers, A. I. J. Heterocycl. Chem. 1998, 35, 991–1002. (Review). 8. Wolfe, J. P. Meyers Oxazoline Method. In Name Reactions in Heterocycl. Chemistry;

Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 237–248. (Review). 9. Hogan, A.-M. L.; Tricotet, T.; Meek, A.; Khokhar, S. S.; O’Shea, D. F. J. Org. Chem.

2008, 73, 6041–6044.

352

Meyer–Schuster rearrangement The isomerization of secondary and tertiary α-acetylenic alcohols to α,β-unsaturated carbonyl compounds via 1,3-shift. When the acetylenic group is ter-minal, the products are aldehydes, whereas the internal acetylenes give ketones. Cf. Rupe rearrangement.

R

OHR

R1

H , H2OR R1

R O

R

OHR

R1

HR

OH2R

R1

RR

R1

:OH2

R •

R

R1 R •

R

R1

OHR R1

R OtautomerizationH

Example 16

O

NOH

Br 98% H2SO4

50% N

H H

OBr

O

Example 27

POP

OPO

O

TMSO

O O

O PO

OTMSOTMS

PhSOH

ClCH2CH2Cl, 83 oC, 30 min.PhS

6%

PhS

O

54%

Example 38

OO

O

HOOEt

10% H2SO4

THF, rt, 1.5 h

OO

O

CO2Et

OO

O

CO2EtHO

70%21%

353


Example 49

EtO2C

CO2EtPMBN

OH

BF3·Et2O

TFA, 89% EtO2C

CO2EtPMBN

O

OMe

OMeOMe

OMe

References 1. Meyer, K. H.; Schuster, K. Ber. 1922, 55, 819–823. 2. Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 429–438. (Review). 3. Edens, M.; Boerner, D.; Chase, C. R.; Nass, D.; Schiavelli, M. D. J. Org. Chem. 1977,

42, 3403–3408. 4. Andres, J.; Cardenas, R.; Silla, E.; Tapia, O. J. Am. Chem. Soc. 1988, 110, 666–674. 5. Tapia, O.; Lluch, J. M.; Cardenas, R.; Andres, J. J. Am. Chem. Soc. 1989, 111, 829–

835. 6. Brown, G. R.; Hollinshead, D. M.; Stokes, E. S.; Clarke, D. S.; Eakin, M. A.; Foubis-

ter, A. J.; Glossop, S. C.; Griffiths, D.; Johnson, M. C.; McTaggart, F.; Mirrlees, D. J.; Smith, G. J.; Wood, R. J. Med. Chem. 1999, 42, 1306–1311.

7. Yoshimatsu, M.; Naito, M.; Kawahigashi, M.; Shimizu, H.; Kataoka, T. J. Org. Chem. 1995, 60, 4798–4802.

8. Crich, D.; Natarajan, S.; Crich, J. Z. Tetrahedron 1997, 53, 7139–7158. 9. Williams, C. M.; Heim, R.; Bernhardt, P. V. Tetrahedron 2005, 61, 3771–3779. 10. Mullins, R. J.; Collins, N. R. Meyer–Schuster Rearrangement. In Name Reactions for

Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 305−318. (Review).

354

Michael addition Also known as conjugate addition, Michael addition is the 1,4-addition of a nu-cleophile to an α,β-unsaturated system.

R2 Y

OR1

R3

Nuc:R2 Y

OR1

R3

Nuc

H

R2 Y

OR1

R3

Nuc:R2 Y

OR1

R3

Nuc

H

conjugate

additionR2 Y

OR1

R3

Nuc

H

enolate

workup

Example 1, Asymmetric Michael addition2

N Si(Me)2Ph

O

OCPh3

O

N Si(Me)2Ph

O

OCPh3

O PhPhMgBr, CuBr•DMS

ether, THF, −55 oC92%, 92% de

Example 2, Thia-Michael addition3

ON

OH2S, NaOMe

MeOH, 75%O

N

OHS

Example 3, Phospha-Michael addition7

MeO R

O (EtO)2P(O)H

MeO P

O ROEt

O OEt

R = H, 71%R = Me, 51%cat.

Me2N NMe2

NH

Example 4, Asymmetric aza-Michael addition9

MeO2CCl

Ph NH2

NaI, Na2CO3, Bu4NBrCH3CN, 82%

NMeO2C

Ph

NMeO2C

Ph2 : 1

355


Example 5, Intramolecular Michael addition10

O OMeBocN

CO2Me

LiHMDS, DMF

−60 oC, 20 min.95%

OO

NBoc

CO2MeMe

H H

H

H

References

1. Michael, A. J. Prakt. Chem. 1887, 35, 349. Arthur Michael (1853−1942) was born in

Buffalo, New York. He studied under Robert Bunsen, August Hofmann, Adolphe Wurtz, and Dimitri Mendeleev, but never bothered to take a degree. Back to the United States, Michael became a Professor of Chemistry at Tufts University, where he married one of his most brilliant students, Helen Abbott, one of the few female organic chemists in this period. Since he failed miserably as an administrator, Michael and his wife set up their own private laboratory at Newton Center, Massachusetts, where the Michael addition was discovered.

2. Hunt, D. A. Org. Prep. Proced. Int. 1989, 21, 705−749. 3. D’Angelo, J.; Desmaële, D.; Dumas, F.; Guingant, A. Tetrahedron: Asymmetry 1992,

3, 459−505. 4. Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135−631. (Review). 5. Hoz, S. Acc. Chem. Res. 1993, 26, 69−73. (Review). 6. Ihara, M.; Fukumoto, K. Angew. Chem., Int. Ed. 1993, 32, 1010−1022. (Review). 7. Simoni, D.; Invidiata, F. P.; Manferdini, M.; Lampronti, I.; Rondanin, R.; Roberti, M.;

Pollini, G. P. Tetrahedron Lett. 1998, 39, 7615−7618. 8. Enders, D.; Saint-Dizier, A.; Lannou, M.-I.; Lenzen, A. Eur. J. Org. Chem. 2006,

29−49. (Review on the phospha-Michael addition). 9. Chen, L.-J.; Hou, D.-R. Tetrahedron: Asymmetry 2008, 19, 715−720. 10. Sakaguchi, H.; Tokuyama, H.; Fukuyama, T. Org. Lett. 2008, 10, 1711−1714. 11. Thaler, T.; Knochel, P. Angew. Chem., Int. Ed. 2009, 48, 645−648.

356

Michaelis−Arbuzov phosphonate synthesis Phosphonate synthesis from the reaction of alkyl halides with phosphites. General scheme:

(R1O)3P R2 XΔ

R2 PO

OR1

OR1R1 X

R1 = alkyl, etc.; R2 = alkyl, acyl, etc.; X = Cl, Br, I

For instance:

ΔBr

O

O(CH3O)3P

BrO

CH3

O

(CH3O)3P:

SN2

Br

PO

CH3OCH3O

O

OCH3

CH3

PO

CH3OCH3O

O

OCH3Br↑

SN2

Example 12

Br

Br (EtO)3P, Tol.

145 oC, 4 h, 70%

P(OEt)2O

Example 26

PO

BnOBnO

Cl (BnO)3P140 oC

8 h, 92%PO

BnOBnO

PO

OBn

OBn

Example 37

O

FF

F Br (EtO)3P, NiCl2

100 oC, 72 h, 10%

O

FF

F PO

OEtOEt

Example 49

BrN Ph

O

Bn

Me (MeO)3P

105−110 oC92−98%

(MeO)2PN Ph

O

Bn

MeO

357


Example 510

O

BnO OSCN

BnO

Bn

BnO

TMSO−P(OEt)2

50 oC, 1 h, 82%

O

BnO OS

BnO

Bn

BnO P(OEt)2O

References 1. (a) Michaelis, A.; Kaehne, R. Ber. 1898, 31, 1048−1055. (b) Arbuzov, A. E. J. Russ.

Phys. Chem. Soc. 1906, 38, 687. 2. Surmatis, J. D.; Thommen, R. J. Org. Chem. 1969, 34, 559−560. 3. Gillespie, P.; Ramirez, F.; Ugi, I.; Marquarding, D. Angew. Chem., Int. Ed. 1973, 12,

91−119. (Review). 4. Waschb sch, R.; Carran, J.; Marinetti, A.; Savignac, P. Synthesis 1997, 727−743. 5. Bhattacharya, A. K.; Stolz, F.; Schmidt, R. R. Tetrahedron Lett. 2001, 42, 5393−5395. 6. Erker, T.; Handler, N. Synthesis 2004, 668−670. 7. Souzy, R.; Ameduri, B.; Boutevin, B.; Virieux, D. J. Fluorine Chem. 2004, 125,

1317−1324. 8. Kadyrov, A. A.; Silaev, D. V.; Makarov, K. N.; Gervits, L. L.; Röschenthaler, G.-V. J.

Fluorine Chem. 2004, 125, 1407−1410. 9. Ordonez, M.; Hernandez-Fernandez, E.; Montiel-Perez, M.; Bautista, R.; Bustos, P.;

Rojas-Cabrera, H.; Fernandez-Zertuche, M.; Garcia-Barradas, O. Tetrahedron: Asymmetry 2007, 18, 2427−2436.

10. Piekutowska, M.; Pakulski, Z. Carbohydrate Res. 2008, 343, 785−792.

358

Midland reduction Asymmetric reduction of ketones using Alpine-borane®. Alpine-borane® = B-isopinocampheyl-9-borabicyclo[3.3.1]nonane.

R1

O

R

Alpine-borane

neat R1

OH

R

BH

THF

reflux

B

(1R)-(+)-α-pinene 9-BBN (R)-Alpine-borane

9-BBN = 9-borabicyclo[3.3.1]nonane

R1

O

R

BH

OR1

R

B

R1

O

R

B H2O2, NaOH

workupR1

OH

R

hydride

transfer

Example 16

BnOO

H

(R)-Alpine-borane, THF

−10 oC to rt, 95%, 88% ee

BnOOH

H

Example 27

TBSO

O

OPMB(R)-Alpine-borane

22 oC, 6 kbar, 82%80% de

TBSO

OH

OPMB

359


Example 38

TBSO

O

TBSO

OH

(R)-Alpine-borane (neat)

rt, 74%, 93% ee

References 1. Midland, M. M.; Greer, S.; Tramontano, A.; Zderic, S. A. J. Am. Chem. Soc. 1979,

101, 2352−2355. M. Mark Midland was a professor at the University of California, Riverside.

2. Midland, M. M.; McDowell, D. C.; Hatch, R. L.; Tramontano, A. J. Am. Chem. Soc. 1980, 102, 867−869.

3. Brown, H. C.; Pai, G. G. J. Org. Chem. 1982, 47, 1606−1608. 4. Brown, H. C.; Pai, G. G.; Jadhav, P. K. J. Am. Chem. Soc. 1984, 106, 1531−1533. 5. Singh, V. K. Synthesis 1992, 605−617. (Review). 6. Williams, D. R.; Fromhold, M. G.; Earley, J. D. Org. Lett. 2001, 3, 2721−2724. 7. Mulzer, J.; Berger, M. J. Org. Chem. 2004, 69, 891−898. 8. Kiewel, K.; Luo, Z.; Sulikowski, G. A. Org. Lett. 2005, 7, 5163−5165. 9. Clay, J. M. Midland reduction. In Name Reactions for Functional Group Transforma-

tions; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2007, pp 40−45. (Re-view).

360

Minisci reaction Radical-based carbon–carbon bond formation with electron-deficient heteroaro-matics. The reaction entails an intermolecular addition of a nucleophilic radical to protonated heteroaromatic nucleus.

R CO2HN RN

2 AgNO3(NH4)2S2O8

H2SO4

R CO2H

N2 AgNO3, (NH4)2S2O8, H2SO4

silver-catalyzed oxidative decarboxylation

CO2 R HH2SO4

NH

R

Example 14

S2O8 CH3OH •CH2OH H+ SO4 SO4•

N

CN

OCH3

BF4(NH4)2S2O8MeOH, H2O

reflux, 1 h, 40% N

CN

OH

Example 25

N

1.6 equiv m-CPBA

acetone, rt, 1.5 h75%

NO

(CH3)3O•BF4

CH2Cl2, rt90 min.

Meerwein’s reagent

NOCH3

BF4

(NH4)2S2O8MeOH, H2O

reflux, 1 h40%, 2 steps

NOH

N

1.6 equiv m-CPBA

acetone, rt, 1.5 h78%

NO

361


NOCH3

BF4(CH3)3O•BF4

CH2Cl2, rt90 min., 85%

(NH4)2S2O8MeOH, H2O

reflux, 1 h, 41%N

OH

Example 3, Intramolecular Minisci reaction6

NH

O

O

OHN

EtO2C

AgNO3, (NH4)2S2O8

CH2Cl2, H2O, AcOH, TFArt, 1 h, 46%

NH

ON

CO2Et

Example 47

NN

Me

Cl

(NH4)2S2O8, AgNO3

TFA, H2O, 75 °C53%

NN

Me

Cl

BzNH

NN

Me

Cl

BzNH

90 : 10

CO2HBzNH

Example 510

CO2H

CO2HHO2C1 equiv

N

N 10 equiv FeSO4•7H2OH2O2, H2O, H2SO4

CH2Cl2, 0 oC, 15 min.24%10 equiv

NN

N

NN

N References 1. Minisci, F, Bernardi. R, Bertini, F, Galli, R, Perchinummo, M. Tetrahedron 1971, 27,

3575–3579. 2. Minisci, F. Synthesis 1973, 1–24. (Review). 3. Minisci, F. Acc. Chem. Res. 1983, 16, 27–32. (Review). 4. Katz, R. B.; Mistry, J.; Mitchell, M. B. Synth. Commun. 1989, 19, 317–325. 5. Biyouki, M. A. A.; Smith, R. A. J.; Bedford, J. J.; Leader, J. P. Synth. Commun. 1998,

28, 3817–3825. 6. Doll, M. K. H. J. Org. Chem. 1999, 64, 1372–1374. 7. Cowden, C. J. Org. Lett. 2003, 5, 4497–4499. 8. Kast, O.; Bracher, F. Synth. Commun. 2003, 33, 3843–3850. 9. Benaglia, M.; Puglisi, A.; Holczknecht, O.; Quici, S.; Pozzi, G. Tetrahedron 2005, 61,

12058–12064. 10. Palde, P. B.; McNaughton, B. R.; Ross, N. T.; Gareiss, P. C.; Mace, C. R.; Spitale, R.

C.; Miller, B. L. Synthesis 2007, 2287–2290. 11. Brebion, F.; Nàjera, F.; Delouvrié, B.; Lacôte, E.; Fensterbank, L.; Malacria, M. J.

Heterocycl. Chem. 2008, 45, 527–532.

362

Mislow–Evans rearrangement [2,3]-Sigmatropic rearrangement of allylic sulfoxide to allylic alcohol.

R SAr

O Δ ArS

O

R

P(OCH3)3 HO

R

SAr

OAr

SO

R

:P(OCH3)3

R [2,3]-sigmatropic

rearrangement1

2

31

21

12

2

3

O

R

SN2Ar

SP(OCH3)3

H HO

R

Example 12

O

TBSOCHO

O

TBSOOMePhS

NaIO4dioxane/H2O

50%

Example 27

OO

OMe

MeOOTBS

SPh

O

(EtO)3P, EtOH

reflux, 16 h, 98%

OO

OMe

MeOOTBS

OH

Example 3, Seleno-Mislow-Evans8

OHH

HO

OTBSPMBO

TBDPSO

1. PhSeCN, Bu3P, THF

2. H2O2, pyr., THF, −30 oC 62%

O

OH

HH

OTBSPMBO

TBDPSO

363


References 1. (a) Tang, R.; Mislow, K. J. Am. Chem. Soc. 1970, 92, 2100–2104. (b) Evans, D. A.;

Andrews, G. C.; Sims, C. L. J. Am. Chem. Soc. 1971, 93, 4956–4957. (c) Evans, D. A.; Andrews, G. C. J. Am. Chem. Soc. 1972, 94, 3672–3674. (d) Evans, D. A.; An-drews, G. C. Acc. Chem. Res. 1974, 7, 147–155. (Review).

2. Sato, T.; Shima, H.; Otera, J. J. Org. Chem. 1995, 60, 3936–3937. 3. Jones-Hertzog, D. K.; Jorgensen, W. L. J. Am. Chem. Soc. 1995, 117, 9077–9078. 4. Jones-Hertzog, D. K.; Jorgensen, W. L. J. Org. Chem. 1995, 60, 6682–6683. 5. Mapp, A. K.; Heathcock, C. H. J. Org. Chem. 1999, 64, 23–27. 6. Zhou, Z. S.; Flohr, A.; Hilvert, D. J. Org. Chem. 1999, 64, 8334–8341. 7. Shinada, T.; Fuji, T.; Ohtani, Y.; Yoshida, Y.; Ohfune, Y. Synlett 2002, 1341–1343. 8. Aubele, D. L.; Wan, S.; Floreancig, P. E. Angew. Chem., Int. Ed. 2005, 44, 3485–

3499. 9. Albert, B. J.; Sivaramakrishnan, A.; Naka, T.; Koide, K. J. Am. Chem. Soc. 2006, 128,

2792–2793. 10. Pelc, M. J.; Zakarian, A. Tetrahedron Lett. 2006, 47, 7519–7523. 11. Brebion, F.; Najera, F.; Delouvrie, B.; Lacote, E.; Fensterbank, L.; Malacria, M. Syn-

thesis 2007, 2273–2278.

364

Mitsunobu reaction SN2 inversion of an alcohol by a nucleophile using disubstituted azodicarboxylates (originally, diethyl diazodicarboxylate, or DEAD) and trisubstituted phosphines (originally, triphenylphosphine).

R1 R2

OH

HNuc

1o or 20 alcohol

NNEtO2C

CO2Et

PPh3R1 R2

NucPPh3O N

EtO2C

CO2EtHN

H

:PPh3

N NCO2Et

EtO2C N NEtO2C

CO2Et

Ph3P

adduct

formation

H Nuc

R1 R2

:OH

N NEtO2C

CO2Et

Ph3P

H

Diethyl azodicarboxylate (DEAD)

N NCO2Et

HEtO2C

H

alcohol

activation R1 R2

O PPh3

R1 R2

NucO PPh3

Nuc

SN2

reaction

Example 12

O

OAcOAc

OAc

CH2OAc

OH

PhCO2HDIAD, PPh3, THF

−50 oC to rt, 2 h, 80%

O

OAcOAc

OAc

CH2OAc

O2CPh

2:1 β:α

Example 23

OHO

O CO2HO2NDEAD, PPh3, Tol.

−30 to 0 oC, 1 h, 90%

4-O2NPhCOOO

O

365


Example 3, Ether formation6

PBu3, ADDP, THF,0 oC to rt, overnight

100%

NO

OMe

OHOBnO2C

OBn

OH

BnO OBn

NO

OMe

OO

OBn

CO2Bn

OBn

BnO

ADDP = 1,1'-(azodicarbonyl)dipiperidine

Example 47

TMSHN

OOH

PhN

TMSPh

OPPh3, DIAD, PhCH3

reflux, 60%

Example 58

N

H

H

CH3

HO

H3CCH3

n-BuLi

then Ph2PClN

H

H

CH3

Ph2PO

H3CCH3

N

H

H

CH3

H3CCH3

O

O

O2NOH

O

O2N

OO

80%

Example 6, Intramolecular Mitsunobu reaction9

DEAD, PPh3

PhH, 92 %NBocMeO

OMe

NHNs

R CO2Et

OH

R=CH(OMe)2NBocMeO

OMe

NsHN

R CO2Et

366

References 1. (a) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380−2382. (b) Mit-

sunobu, O. Synthesis 1981, 1−28. (Review). 2. Smith, A. B., III; Hale, K. J.; Rivero, R. A. Tetrahedron Lett. 1986, 27, 5813−5816. 3. Kocie ski, P. J.; Yeates, C.; Street, D. A.; Campbell, S. F. J. Chem. Soc., Perkin

Trans. 1, 1987, 2183−2187. 4. Hughes, D. L. Org. React. 1992, 42, 335−656. (Review). 5. Hughes, D. L. Org. Prep. Proc. Int. 1996, 28, 127−164. (Review). 6. Vaccaro, W. D.; Sher, R.; Davis, H. R., Jr. Bioorg. Med. Chem. Lett. 1998, 8, 35–40. 7. Cevallos, A.; Rios, R.; Moyano, A.; Pericàs, M. A.; Riera, A. Tetrahedron: Asymmetry

2000, 11, 4407–4416. 8. Mukaiyama, T.; Shintou, T.; Fukumoto, K. J. Am. Chem. Soc. 2003, 125, 10538–

10539. 9. Sumi, S.; Matsumoto, K.; Tokuyama, H.; Fukuyama, T. Tetrahedron 2003, 59, 8571–

8587. 10. Christen, D. P. Mitsunobu reaction. In Name Reactions for Homologations-Part II; Li,


367

Miyaura borylation Palladium-catalyzed reaction of aryl halides with diboron reagents to produce arylboronates. Also known as Hosomi−Miyaura borylation.

Ar XO

BOO

BO Pd(0)

base

OB

OAr

X = I, Br, Cl, OTf.

Ar X L2Pd(0)oxidative

additionPd

L

L X

Ar

O

BOO

BO base O

BOO

BO

base

PdL

L I

transmetallation

Ar

OB

OI

reductive

elimination

PdL

Ar B

L

O

O OB

OAr L2Pd(0)

Example 17

OB

OOB

OPh

BO

OPh

OAc O

CuCl, LiCl, KOAc, DMF, 92%

O

Example 28

O

BOO

BO

NCbz

3% (Ph3P)2PdCl2, 6% Ph3P1.5 eq. K2CO3, dioxane, 90 oC

85%

NCbzOTf

BO

O

368


Example 39

I

BnO

CO2BnCbzHN

B

BnO

CO2BnCbzHNO

O

OB

OOB

O

Pd(dppf)Cl2, KOAcDMSO, 80 oC, 24 h

85%

I

BnO

CO2BnCbzHN

OBn

BnO2C NHCbz

BnO

CO2BnCbzHN

Pd(dppf)Cl2, K2CO3DMSO, 80 oC, 24 h

85%

Example 4, One-pot synthesis of biindolyl10

NH

MeO

MeOBr

1. 1 mol% Pd2(dba)3, 4 mol% XPhos 3 equiv HB(pin), 3 equiv Et3N dioxane, 100 oC

2. 1 mol% Pd2(dba)3, 3 equiv K3PO4•H2O dioxane/H2O (10 : 1), 100 oC

NH

MeO

MeO

Br NH

MeO

MeO

NH

MeO

MeO

References 1. Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508−7510. 2. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457−2483. (Review). 3. Suzuki, A. J. Organomet. Chem. 1995, 576, 147−168. (Review). 4. Carbonnelle, A.-C.; Zhu, J. Org. Lett. 2000, 2, 3477−3480. 5. Giroux, A. Tetrahedron Lett. 2003, 44, 233−235. 6. Kabalka, G. W.; Yao, M.-L. Tetrahedron Lett. 2003, 44, 7885−7887. 7. Ramachandran, P. V.; Pratihar, D.; Biswas, D.; Srivastava, A.; Reddy, M. V. R. Org.

Lett. 2004, 6, 481−484. 8. Occhiato, E. G.; Lo Galbo, F.; Guarna, A. J. Org. Chem. 2005, 70, 7324−7330. 9. Skaff, O.; Jolliffe, K. A.; Hutton, C. A. J. Org. Chem. 2005, 70, 7353−7363. 10. Duong, H. A.; Chua, S.; Huleatt, P. B.; Chai, C. L. L. J. Org. Chem. 2008, 73,

9177−9180. 11. Jo, T. S.; Kim, S. H.; Shin, J.; Bae, C. J. Am. Chem. Soc. 2009, 131, 1656−1657.

369

Moffatt oxidation Oxidation of alcohols using DCC and DMSO, aka “Pfitzner−Moffatt oxidation”.

R1 R2

OH

R1 R2

ODCC

DMSO, HX

DCC, 1,3-dicyclohexylcarbodiimide

N C N N C N

OS

HH

R1 R2

:OH

HN C NO

S

H

NH

NH

O

R1 R2

OS H

HH X

R1 R2

OS

H R1 R2

O

(CH3)2S

1,3-dicyclohexylurea Example 12

OH

OH

DCC, DMSO, C5H5NH+CF3CO2

PhH, rt, 70%

O

O Example 28

O

O O

A OH

DCC, DMSO, Cl2CHCO2H

rt, 90 min., 90%

O

O O

A CHO

A = adenosine

References 1. Pfitzner, K. E.; Moffatt, J. G. J. Am. Chem. Soc. 1963, 85, 3027−3028. 2. Schobert, R. Synthesis 1987, 741−742. 3. Liu, H. J.; Nyangulu, J. M. Tetrahedron Lett. 1988, 29, 3167–3170. 4. Tidwell, T. T. Org. React. 1990, 39, 297−572. (Review). 5. Gordon, J. F.; Hanson, J. R.; Jarvis, A. G.; Ratcliffe, A. H. J. Chem. Soc., Perkin

Trans. 1, 1992, 3019−3022. 6. Krysan, D. J.; Haight, A. R.; Lallaman, J. E. Org. Prep. Proced. Int. 1993, 25,

437−443. 7. Adak, A. K. Synlett 2004, 1651−1652. 8. Wang, M.; Zhang, J.; Andrei, D.; Kuczera, K.; Borchardt, R. T.; Wnuk, S. F. J. Med.

Chem. 2005, 48, 3649−3653. 9. van der Linden, J. J. M.; Hilberink, P. W.; Kronenburg, C. M. P.; Kemperman, G. J.

Org. Proc. Res. Dev. 2008, 12, 911–920.

370


Personal

Highlight

Personal

Highlight

Morgan–Walls reaction Phenanthridine cyclization by dehydrative ring closure of acyl-o-aminobiphenyls with phosphorus oxychloride in boiling nitrobenzene.

R1

NHRO

POCl3

R1

NR

R1

NHOR

PCl ClCl

O

:

R1

NHOR

POCl2

R1

NHOPOCl2R

:

R1

NR

H HOPOCl2

Example 16

O2N NO2

HNO

CN

nitrobenzene, POCl3

SnCl4, 98%

O2N NO2

N

CN

Pictet–Hubert reaction

The Morgan-Walls reaction is a variant of the Pictet-Hubert reaction where the phenanthridine cyclization was accomplished by dehydrative ring closure of acyl-o-aminobiphenyls on heating with zinc chloride at 250−300 °C.

R1

NHRO

R1

NR

ZnCl2

250−300 oC

Example 24

N

OH

N

ZnCl2, 250−300 oC

80%

371


References 1. (a) Pictet, A.; Hubert, A. Ber. 1896, 29, 1182−1189. (b) Morgan, C. T.; Walls, L. P. J.

Chem. Soc. 1931, 2447−2456. (c) Morgan, C. T.; Walls, L. P. J. Chem. Soc. 1932, 2225−2231.

2. Gilman, H.; Eisch, J. J. Am. Chem. Soc. 1957, 79, 4423−4426. 3. Hollingsworth, B. L.; Petrow, V. J. Chem. Soc. 1961, 3664−3667. 4. Fodor, G.; Nagubandi, S. Tetrahedron 1980, 36, 1279−1300. 5. Atwell, G. J.; Baguley, B. C.; Denny, W. A. J. Med. Chem. 1988, 31, 774−779. 6. Peytou, V.; Condom, R.; Patino, N.; Guedj, R.; Aubertin, A.-M.; Gelus, N.; Bailly, C.;

Terreux, R.; Cabrol-Bass, D. J. Med. Chem. 1999, 42, 4042−4043. 7. Holsworth, D. D. Pictet–Hubert Reaction. In Name Reactions in Heterocyclic Chemis-


372

Mori−Ban indole synthesis Intramolecular Heck reaction of o-halo-aniline with pendant olefin to prepare in-dole.

N

Br

Ac

CO2MePd(OAc)2, Ph3P

NaHCO3, DMF, 130 oC N

CO2Me

Ac

Reduction of Pd(OAc)2 to Pd(0) using Ph3P:

Pd OAcAcOPd OAcPh3P

:PPh3AcO

Pd(0) O PPh3

OO PPh3

O

O O

AcO Mori−Ban indole synthesis:

N

Br

Ac

CO2MePd(0)

NAc

CO2MePdLn

Br

oxidativeaddition

insertion

N

PdBrLn

Ac

MeO2C

H

PdBrLnHNAc

CO2Meβ-hydride

eliminationaddition

of PdH

HNAc

CO2MePdBrLn

N

CO2Me

Ac

β-hydride

elimination N

CO2Me

Ac

Regeneration of Pd(0):

H PdBrLn NaHCO3 Pd(0) NaBr H2O CO2↑ Example 11a

I

NH

NH

MePd(OAc)2

Et3N, MeCNsealed tube

110 °C, 87%

373


Example 24

N

N Cl

NN

N

N

10 mol% Pd(OAc)2

Bu4NBr, K2CO3,DMF, 100 oC

67%

Example 37

Br

NCOCF3

SO2NHMe

Br

NCbz N

HBr

NSO2NHMe

Cbz

Pd(OAc)2, Bu4NCl

Et3N, DMF heat, DME, 76%

References 1. Mori−Ban indole synthesis, (a) Mori, M.; Chiba, K.; Ban, Y. Tetrahedron Lett. 1977,

18, 1037−1040; (b) Ban, Y.; Wakamatsu, T.; Mori, M. Heterocycles 1977, 6, 1711−1715.

2. Reduction of Pd(OAc)2 to Pd(0), (a) Amatore, C.; Carre, E.; Jutand, A.; M’Barki, M. A.; Meyer, G. Organometallics 1995, 14, 5605−5614; (b) Amatore, C.; Carre, E.; M’Barki, M. A. Organometallics 1995, 14, 1818−1826; (c) Amatore, C.; Jutand, A.; M’Barki, M. A. Organometallics 1992, 11, 3009−3013; (d) Amatore, C.; Azzabi, M.; Jutand, A. J. Am. Chem. Soc. 1991, 113, 8375−8384.

3. Macor, J. E.; Ogilvie, R. J.; Wythes, M. J. Tetrahedron Lett. 1996, 37, 4289−4293. 4. Li, J. J. J. Org. Chem. 1999, 64, 8425−8427. 5. Gelpke, A. E. S.; Veerman, J. J. N.; Goedheijt, M. S.; Kamer, P. C. J.; van Leuwen, P.

W. N. M.; Hiemstra, H. Tetrahedron 1999, 55, 6657−6670. 6. Sparks, S. M.; Shea, K. J. Tetrahedron Lett. 2000, 41, 6721−6724. 7. Bosch, J.; Roca, T.; Armengol, M.; Fernandez-Forner, D. Tetrahedron 2001, 57,

1041−1048. 8. Ma, J.; Yin, W.; Zhou, H.; Liao, X.; Cook, J. M. J. Org. Chem. 2009, 74, 264−273.

374

Mukaiyama aldol reaction Lewis acid-catalyzed aldol condensation of aldehyde and silyl enol ether.

R CHO R1OSiMe3

R2 Lewis

acidR R2

OH

R1

O

R1O

R2 R R2

OH

R1

O

R H

O

SiMe3

X SiMe3

LAX

R R2

Me3SiO

R1

O

Example 1, Intramolecular Mukaiyama aldol reaction3

O

CH(OMe)2

EtO2CEtO2C

1. LDA, THF, −78 oC, 10 min.

2. 1.8 equiv TMSCl, −78 oC, 4 h 92%

OTMS

CH(OMe)2

EtO2CEtO2C

TiCl4, CH2Cl2

−78 oC to rt, 15 h

HOMe

12%

CO2EtEtO2C

OOMe

H

40%

CO2EtEtO2C

O

Example 2, Mukaiyama aldol reaction7

N

O

Bn

OTBDMS

N

O

OHCBoc

BF3•OEt2, DTBMP

CH2Cl2, −78 to −50 oC, 73%NBn

OH

N

O

BocO

O

Example 3, Vinylogous Mukaiyama aldol reaction8

OSiMe3

OO

CHO

CN

1. PhCO2H, rt

2. TFA, 60% O

OO

NC

OH

375


Example 4, Asymmetric Mukaiyama aldol reaction10

Bu3SnCHO

cat. NBH

O

O

TsOTMS

OMe

Bu3Sn

OTMS

Bu3Sn

HO OMe

O

38% 50%

Example 5, Mukaiyama aldol reaction12

MeBr

CHO

OTBS

O OTIPS

MeMe

Br

OTBS

OH

OO

Me10 mol% Bi(OTf)3CH2Cl2, −40 oC76% out of 56%

conversion

References 1. (a) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011−1014. (b) Mu-

kaiyama, T.; Narasaka, K.; Banno, K. J. Am. Chem. Soc. 1974, 96, 7503−7509. 2. Ishihara, K.; Kondo, S.; Yamamoto, H. J. Org. Chem. 2000, 65, 9125−9128. 3. Armstrong, A.; Critchley, T. J.; Gourdel-Martin, M.-E.; Kelsey, R. D.; Mortlock, A.

A. J. Chem. Soc., Perkin Trans. 1 2002, 1344−1350. 4. Clézio, I. L.; Escudier, J.-M.; Vigroux, A. Org. Lett. 2003, 5, 161−164. 5. Ishihara, K.; Yamamoto, H. Boron and Silicon Lewis Acids for Mukaiyama Aldol Re-

actions. In Modern Aldol Reactions Mahrwald, R., Ed.; 2004, 25−68. (Review). 6. Mukaiyama, T. Angew. Chem., Int. Ed. 2004, 43, 5590−5614. (Review). 7. Adhikari, S.; Caille, S.; Hanbauer, M.; Ngo, V. X.; Overman, L. E. Org. Lett. 2005, 7,

2795−2797. 8. Acocella, M. R.; Massa, A.; Palombi, L.; Villano, R.; Scettri, A. Tetrahedron Lett.

2005, 46, 6141−6144. 9. Jiang, X.; Liu, B.; Lebreton, S.; De Brabander, J. K. J. Am. Chem. Soc. 2007, 129,

6386−6387. 10. Webb, M. R.; Addie, M. S.; Crawforth, C. M.; Dale, J. W.; Franci, X.; Pizzonero, M.;

Donald, C.; Taylor, R. J. K. Tetrahedron 2008, 64, 4778−4791. 11. Frings, M.; Atodiresei, I.; Runsink, J.; Raabe, G.; Bolm, C. Chem. Eur. J. 2009, 15,

1566−1569. 12. Gao, S.; Wang, Q.; Chen, C. J. Am. Chem. Soc. 2009, 131, 1410−1412.

376

Mukaiyama Michael addition Lewis acid-catalyzed Michael addition of silyl enol ether to an α,β-unsaturated system.

R1OSiMe3

R2 Lewis

acidR

O

R

OR1

R2

O

Example 12

OOMe

OSiMe3 1. 0.1 mol% TBABB, THF, 3 h

2. 1 N HCl, THF, 0 oC, 0.5 h 87%

O

O

O

TBABB = tetra-n-butylammonium bibenzoate

Example 25

OMe

OSiMe3O1. neat DBU, rt, 24 h

2. 1 N HCl, THF, 68%

O

O

O

Example 38

TBSOOMe

OMeO

O

OMeOMe 10 mol% Sc(OTf)3

CH2Cl2, −78 oC to rt

10% HF/CH3CN quench85%, 20 : 1 (syn/anti)

O

O

OMeOMe

MeOOMe

O

H

Example 49

R3

R1

O

R2

CO2Me

N2

OTBS 0.5 mol% Zn(OTf)2

CH2Cl2, 0−25 oC78−81%

CO2Me

N2

O

OTBS

R1R2

R3

CO2Me

N2

O

O

R1R2

R3

4 N HCl

THF

377


References 1. (a) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011−1014. (b)

Mukaiyama, T.; Narasaka, K.; Banno, K. J. Am. Chem. Soc. 1974, 96, 7503−7509. (c) Mukaiyama, T. Angew. Chem., Int. Ed. 2004, 43, 5590−5614. (Review).

2. Gnaneshwar, R.; Wadgaonkar, P. P.; Sivaram, S. Tetrahedron Lett. 2003, 44, 6047−6049.

3. Wang, X.; Adachi, S.; Iwai, H.; Takatsuki, H.; Fujita, K.; Kubo, M.; Oku, A.; Harada, T. J. Org. Chem. 2003, 68, 10046−10057.

4. Jaber, N.; Assie, M.; Fiaud, J.-C.; Collin, J. Tetrahedron 2004, 60, 3075−3083. 5. Shen, Z.-L.; Ji, S.-J.; Loh, T.-P. Tetrahedron Lett. 2005, 46, 507−508. 6. Wang, W.; Li, H.; Wang, J. Org. Lett. 2005, 7, 1637−1639. 7. Ishihara, K.; Fushimi, M. Org. Lett. 2006, 8, 1921−1924. 8. Jewett, J. C.; Rawal, V. H. Angew. Chem., Int. Ed. 2007, 46, 6502−6504. 9. Liu, Y.; Zhang, Y.; Jee, N.; Doyle, M. P. Org. Lett. 2008, 10, 1605−1608. 10. Takahashi, A.; Yanai, H.; Taguchi, T. Chem. Commun. 2008, 2385−2387.

378

Mukaiyama reagent Mukaiyama reagent such as 2-chloro-1-methyl-pyridinium iodide for esterification or amide formation. General scheme:

R1CO2H R2OH

NXR3

Y

R1 OR2

O

NOR3base

X = F, Cl, Br

Example 11c

O CO2HHO BF4

N Br

O

OOBu3N, CH2Cl2

NON

BF4BrO

O BrO

O

O

:

H

SNAr

− H

NBu3

− Br

HO

NO

O

O

Bn

: BF4

NO

O

O OBn

NOBn

OO O

:

H

NHO

BF4

BF4

Amide formation using the Mukaiyama reagent follows a similar mechanistic pathway.1d

Example 2, Polymer-supported Mukaiyama reagent5

OOH

N Cl

Tf2O, CH2Cl2, 16 h, rt

ON

Cl

1.25 mmol/g

TfO

379


NH

CO2H

NHBoc ONH2

O

polymer-supportedMukaiyama reagent

Et3N, CH2Cl2, rt16 h, 88%

NH

NHBoc

OO

NH

O

Example 39

NS

N S

O

HO

NHBoc

St-BuS

O

NHFmoc

CO2TMSE

Mukaiyama reagent

DIPEA, CH2Cl2, 91% St-BuS

O

NH

CO2TMSE

NS

N S

O

NHBoc

Example 4, Fluorous Mukaiyama reagent10

RCO2H R1NH2 or R2OH

1. Fluorous Mukaiyama reagent 1 equiv DMAP, 3 equiv Et3N dry DMF, rt, 1h

2. H2O, rt, 5 min., 87−100%RCONHR1 or RCO2R2

N

C10F21

ClFluorous Mukaiyama reagent

TfO

References 1. (a) Mukaiyama, T.; Usui, M.; Shimada, E.; Saigo, K. Chem. Lett. 1975, 1045–1048.

(b) Hojo, K.; Kobayashi, S.; Soai, K.; Ikeda, S.; Mukaiyama, T. Chem. Lett. 1977, 635–636. (c) Mukaiyama, T. Angew. Chem., Int. Ed. 1979, 18, 707–708. (d) For am-ide formation, see: Huang, H.; Iwasawa, N.; Mukaiyama, T. Chem. Lett. 1984, 1465–1466.

2. Nicolaou, K. C.; Bunnage, M. E.; Koide, K. J. Am. Chem. Soc. 1994, 116, 8402–8403. 3. Yong, Y. F.; Kowalski, J. A.; Lipton, M. A. J. Org. Chem. 1997, 62, 1540–1542. 4. Folmer, J. J.; Acero, C.; Thai, D. L.; Rapoport, H. J. Org. Chem. 1998, 63, 8170–8182. 5. Crosignani, S.; Gonzalez, J.; Swinnen, D. Org. Lett. 2004, 6, 4579–4582.

380

6. Mashraqui, S. H.; Vashi, D.; Mistry, H. D. Synth. Commun. 2004, 34, 3129–3134. 7. Donati, D.; Morelli, C.; Taddei, M. Tetrahedron Lett. 2005, 46, 2817–2819. 8. Vandromme, L.; Monchaud, D.; Teulade-Fichou, M.-P. Synlett 2006, 3423–3426. 9. Ren, Q.; Dai, L.; Zhang, H.; Tan, W.; Xu, Z.; Ye, T. Synlett 2008, 2379–2383. 10. Matsugi, M.; Suganuma, M.; Yoshida, S.; Hasebe, S.; Kunda, Y.; Hagihara, K.; Oka,

S. Tetrahedron Lett. 2008, 49, 6573–6574.

381

Myers−Saito cyclization Cf. Bergman cyclization and Schmittel cyclization.

hydrogen atom donor

Δ or

hv•

•

HreversibleH

allenyl enyne diradical

Example 13

Ph

Ph

H

PhH, reflux

96 h, 40%

Ph Ph

Example 2, Aza-Myers−Saito reaction8

Ph

N CDCl3

10 oC, 12 h

NCHO

Ph

N

Ph

MeOH

0 oC, 14 h

OMe

References 1. (a) Myers, A. G.; Proteau, P. J.; Handel, T. M. J. Am. Chem. Soc. 1988, 110, 7212–

7214. (b) Myers, A. G.; Dragovich, P. S.; Kuo, E. Y. J. Am. Chem. Soc. 1992, 114, 9369–9386.

2. Schmittel, M.; Strittmatter, M.; Kiau, S. Tetrahedron Lett. 1995, 36, 4975–4978. 3. Schmittel, M.; Steffen, J.-P.; Auer, D.; Maywald, M. Tetrahedron Lett. 1997, 38,

6177–6180. 4. Bruckner, R; Suffert, J. Synlett 1999, 657−679. (Review). 5. Stahl, F.; Moran, D.; Schleyer, P. von R.; Prall, M.; Schreiner, P. R. J. Org. Chem.

2002, 67, 1453–1461. 6. Musch, P. W; Remenyi, C.; Helten, H.; Engels, B. J. Am. Chem. Soc. 2002, 124,

1823–1828. 7. Bui, B. H.; Schreiner, P. R. Org. Lett. 2003, 5, 4871–4874. 8. Feng, L.; Kumar, D.; Birney, D. M.; Kerwin, S. M. Org. Lett. 2004, 6, 2059–2062. 9. Schmittel, M.; Mahajan, A. A.; Bucher, G. J. Am. Chem. Soc. 2005, 127, 5324–5325. 10. Karpov, G.; Kuzmin, A.; Popik, V. V. J. Am. Chem. Soc. 2008, 130, 11771–11777.

382


Nazarov cyclization Acid-catalyzed electrocyclic formation of cyclopentenone from di-vinyl ketone.

O

HO

H

OO

protonation

H HO

H

Otautomerization

OH

Example 12

NCO2Me

O

SiMe3

ZrCl4, (CH2Cl)2

60 oC, 36 h, 76% NCO2Me

H O

H

Example 26

O

O

PhHClO4 (10−2 M)

Ac2O (1 M)

EtOAc, 9 h, 75%

OAc

O

Ph

H

Example 39

OTIPS

OTIPSO

MeO2C

MePh

5 mol% Cu(ClO4)2

DCE, 45 oC, 8 h, 80%

OTIPS

OTIPSO

MeO2CMe Ph

383


Example 410

NTs

OAc

MeOO

O

NTs

OAc

MeO

OO

10 mol% Sc(OTf)3LiClO4, 80 oC

ClCH2CH2Cl (0.3 M)65%

Example 511

1. hν (350 nm), CH3CN, rt

2. i-Pr2NH, MeOH, 50 oC 60%, 2 steps

MeCl

OMe

Br

O OO

Me

OTBS

ClO

O

Me

Me

O Me

HH

Me

Br

OO

OMeMe

ClCl

OTBS

OO

Me9

References 1. Nazarov, I. N.; Torgov, I. B.; Terekhova, L. N. Bull. Acad. Sci. (USSR) 1942, 200. I.

N. Nazarov (1900−1957), a Soviet Union Scientist, discovered this reaction in 1942. It was said that almost as many young synthetic chemists have been lost in the pursuit of an asymmetric Nazarov cyclization as of the Bayliss−Hillman reaction.

2. Denmark, S. E.; Habermas, K. L.; Hite, G. A. Helv. Chim. Acta 1988, 71, 168−194; 195−208.

3. Habermas, K. L.; Denmark, S. E.; Jones, T. K. Org. React. 1994, 45, 1−158. (Review). 4. Kim, S.-H.; Cha, J. K. Synthesis 2000, 2113−2116. 5. Giese, S.; West, F. G. Tetrahedron 2000, 56, 10221−10228. 6. Mateos, A. F.; de la Nava, E. M. M.; González, R. R. Tetrahedron 2001, 57,

1049−1057. 7. Harmata, M.; Lee, D. R. J. Am. Chem. Soc. 2002, 124, 14328−14329. 8. Leclerc, E.; Tius, M. A. Org. Lett. 2003, 5, 1171−1174. 9. Marcus, A. P.; Lee, A. S.; Davis, R. L.; Tantillo, D. J.; Sarpong, R. Angew. Chem., Int.

Ed. 2008, 47, 6379−6383. 10. Bitar, A. Y.; Frontier, A. J. Org. Lett. 2009, 11, 49−52. 11. Gao, S.; Wang, Q.; Chen, C. J. Am. Chem. Soc. 2009, 131, 1410−1412.

384

Neber rearrangement α-Aminoketone from tosyl ketoxime and base. The net conversion of a ketone into an α-aminoketone via the oxime.

R1R2

NOTs 1. KOEt

2. H2OR1 R2

NH2

O

TsOH

ketoxime α-aminoketone

deprotonation

R2

NOTs

cyclizationH

R2

NOTs

R1EtOR1

TsO N

R2R1

:OH2 hydrolysisHR1 R2

NH2

O

HN

R2R1

O H

azirine intermediate Example 13

N

Me

O1. NH2OH•HCl

2. TsCl, Pyr. 93%

N

Me

NOTs

1. KOEt

2. HCl 82% N

NH2

EtO OEt

Example 2, A variant using iminochloride5

Ph

OEt

NH•HCl

PhOEt

NCl

PhOH

O

NH2HOCl

100%

1. KOt-Bu

2. HCl 71%

Example 38

N

N

N

TsON

MeO

OSEM

OMe

N

Br

Ts

1. KOH, H2O, EtOH, 0 oC, 3 h

2. 6 N HCl, 60 oC, 10 h3. K2CO3, THF, H2O, 10 min. 96%

385


N

N

HN

O

MeO

O

OMe

N

Br

Ts

H2N

Example 49

R1

O

R 1. H2NOH

2. MsCl, Et3N; DBU, Bu3P 70–91%

R1N N

H

R1R

Rheat

41–89%

References 1. Neber, P. W.; v. Friedolsheim, A. Ann. 1926, 449, 109–134. 2. O’Brien, C. Chem. Rev. 1964, 64, 81–89. (Review). 3. LaMattina, J. L.; Suleske, R. T. Synthesis 1980, 329–330. 4. Verstappen, M. M. H.; Ariaans, G. J. A.; Zwanenburg, B. J. Am. Chem. Soc. 1996,

118, 8491–8492. 5. Oldfield, M. F.; Botting, N. P. J. Labelled Cpd. Radiopharm. 1998, 16, 29–36. 6. Palacios, F.; Ochoa de Retana, A. M.; Gil, J. I. Tetrahedron Lett. 2002, 41, 5363-–

5366. 7. Ooi, T.; Takahashi, M.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2002, 124, 7640–

7641. 8. Garg, N. K.; Caspi, D. D.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5970–5978. 9. Taber, D. F.; Tian, W. J. Am. Chem. Soc. 2006, 128, 1058–1059. 10. Richter, J. M. Neber rearrangement. In Name Reactions for Homologations-Part I; Li,


386

Nef reaction Conversion of a primary or secondary nitroalkane into the corresponding carbonyl compound.

R1 R2

NO2

R1 R2

O1/2 N2O 1/2 H2O

1. NaOH

2. H2SO4

R1 R2

NO O

H R1 R2

NO O

HO

H2O

nitronate

R1 R2

NHO O

OH

H− H2O

R1 R2

NHO OH

:OH2

nitronic acid

H H

R1 R2

O1/2 N2O 1/2 H2O

R1 R2

NO

OH

H

R1 R2

OHNO

R1 R2

NHO

OH

Example 14

O

NO2

1. NaOH, EtOH, 0 oC, 30 min.

2. 3 M HCl, 0 to 20 oC, 12 h, 68%

O

O

Example 27

H

HONO2

1. 2 M NaOH, MeOH

2. ice-cooled KMnO4 45% H

HOO

Example 39

OTBS

NO2

OO

SSt-Bu

t-Bu

2.2 equiv PMe3, THF, rt, 30 min.

OTBS

NH

OO H2O, rt, 5 min.

94%, 2 steps

OTBS

O

OO

387


Example 410

*

NO2

CO2HR *

CO2HCO2H

RHOAc, HCl

reflux, 2 h

References 1. Nef, J. U. Ann. 1894, 280, 263−342. John Ulrich Nef (1862−1915) was born in Swit-

zerland and emigrated to the US at the age of four with his parents. He went to Mu-nich, Germany to study with Adolf von Baeyer, earning a Ph.D. In 1886. Back to the States, he served as a professor at Purdue University, Clark University, and the Uni-versity of Chicago. The Nef reaction was discovered at Clark University in Worcester, Massachusetts. Nef was temperamental and impulsive, suffering from a couple of mental breakdowns. He was also highly individualistic, and had never published with a coworker save for three early articles.

2. Pinnick, H. W. Org. React. 1990, 38, 655−792. (Review). 3. Adam, W.; Makosza, M.; Saha-Moeller, C. R.; Zhao, C.-G. Synlett 1998, 1335–1336. 4. Thominiaux, C.; Rousse, S.; Desmaele, D.; d’Angelo, J.; Riche, C. Tetrahedron:

Asymmetry 1999, 10, 2015–2021. 5. Capecchi, T.; de Koning, C. B.; Michael, J. P. J. Chem. Soc., Perkin Trans. 1 2000,

2681–2688. 6. Ballini, R.; Bosica, G.; Fiorini, D.; Petrini, M. Tetrahedron Lett. 2002, 43, 5233–5235. 7. Chung, W. K.; Chiu, P. Synlett 2005, 55–58. 8. Wolfe, J. P. Nef reaction. In Name Reactions for Functional Group Transformations;

Li, J. J., Corey, E. J., Eds; John Wiley & Sons: Hoboken, NJ, 2007, pp 645−652. (Re-view).

9. Burés, J.; Vilarrasa, J. Tetrahedron Lett. 2008, 49, 441–444. 10. Felluga, F.; Pitacco, G.; Valentin, E.; Venneri, C. D. Tetrahedron: Asymmetry 2008,

19, 945–955.

388

Negishi cross-coupling reaction The Negishi cross-coupling reaction is the nickel- or palladium-catalyzed coupling of organozinc compounds with various halides or triflates (aryl, alkenyl, alkynyl, and acyl).

R1 X

R1 = aryl, alkenyl, alkynyl, acylR2 = aryl, heteroaryl, alkenyl, allyl, Bn, homoallyl, homopropargylX = Cl, Br, I, OTfY = Cl, Br, ILn = PPh3, dba, dppe

+ R2Zn Y R2R1NiLn or PdLn

solvent

Pd(0)Ln

R2ZnXZnX2

R1 R2

Pd(II)

R1

Ln

XZnX

R2

Pd(II)R2

Pd(0) or Pd(II) complexes (precatalysts)

R1 X

oxidative addition

LnPd(II)R1

X

reductive elimination

transmetallation/trans/cis isomerization

1

2

3Ln

R1

Example 13

N

I

OHO

OOO

Ph

Ph

N

CH2CO2Et

OHO

OOO

Ph

Ph

BrZnCH2CO2Et, Pd(Ph3P)4

HMPA/(CH2OCH3)2 (1:1)3.5 h, 40%

Example 24

BnOZnI

O

NHTrBnO

IO

NHTr

activated

Zn/Cu couple

389


N

N

I

Boc

CO2t-Bu

NHBoc

NHTrN

NBoc

CO2t-Bu

NHBoc

BnO

O

PdCl2(Ph3P)2, DMA40 oC, 79%

Example 38

NBoc I1. Zn, DMA, TMSCl, BrCH2CH2Br, 65 °C

2. ArX (X = Br, OTf), PdCl2(dppf) (3 mol%) CuI (6 mol%), DMA, 80 °C 41–97%

NBoc Ar

Example 49

I OTBSMe Me

1. t-BuLi, ZnCl2, Et2O, –78 °C2.

Pd(PPh3)4, THF, 0 °C 85%

PivO I

Me Me

OTBSMe Me

PivO

MeMe

References 1. (a) Negishi, E.-I.; Baba, S. J. Chem. Soc., Chem. Commun. 1976, 596−597. (b) Negi-

shi, E.-I.; King, A. O.; Okukado, N. J. Org. Chem. 1977, 42, 1821−1823. (c) Negishi, E.-I. Acc. Chem. Res. 1982, 15, 340−348. (Review).

2. Erdik, E. Tetrahedron 1992, 48, 9577−9648. (Review). 3. De Vos, E.; Esmans, E. L.; Alderweireldt, F. C.; Balzarini, J.; De Clercq, E. J. Hetero-

cycl. Chem. 1993, 30, 1245−1252. 4. Evans, D. A.; Bach, T. Angew. Chem., Int. Ed. 1993, 32, 1326−1327. 5. Negishi, E.-I.; Liu, F. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.;

Stang, P. J., Eds.; Wiley–VCH: Weinheim, Germany, 1998, pp 1–47. (Review). 6. Arvanitis, A. G.; Arnold, C. R.; Fitzgerald, L. W.; Frietze, W. E.; Olson, R. E.; Gilli-

gan, P. J.; Robertson, D. W. Bioorg. Med. Chem. Lett. 2003, 13, 289−291. 7. Ma, S.; Ren, H.; Wei, Q. J. Am. Chem. Soc. 2003, 125, 4817−4830. 8. Corley, E. G.; Conrad, K.; Murry, J. A.; Savarin, C.; Holko, J.; Boice, G. J. Org.

Chem. 2004, 69, 5120−5123. 9. Inoue, M.; Yokota, W.; Katoh, T. Synthesis 2007, 622−637. 10. Yet, L. Negishi cross-coupling reaction. In Name Reactions for Homologations-Part I;


390

Nenitzescu indole synthesis 5-Hydroxylindole from condensation of p-benzoquinone and β-aminocrotonate.

N

CO2R3

O

O

H

HN

CO2R3

R2R2

R1

HO

R1

Δ

O

O

H

HN

CO2R3

R2R1

:

HO

OR1

conjugate

addition NR2

CO2R3

H

H

N

CO2R3

R2

HO

R1 N

CO2R3

R2

HO

R1

H

OH

H

Example 15

NH

HNBn

O

O

O1. acetone, rt, 48 h2. 20% TFA, CH2Cl2 86%

N

ONH2

Bn

HO

Example 26

N

CO2CH3

O

O

H

HN

CO2CH3 HOCH3NO2, rt

95%

Example 37

R2R1

O R4-NH2

rt R2R1

NHR4 O O

HOAc, rt

391


N

HO

R4

R2

R1HCHO, HNMe2

ethanol, 50 oC N

HO

R4

R2

R1

NMe

Me

Example 410

O

O

OEt

ONH

NH

OEt

O

ZnCl2, CH2Cl2

reflux, 80%

N

N

HOO

OEt

HOO

OEt

References 1. Nenitzescu, C. D. Bull. Soc. Chim. Romania 1929, 11, 37−43. 2. Allen, G. R., Jr. Org. React. 1973, 20, 337−454. (Review). 3. Kinugawa, M.; Arai, H.; Nishikawa, H.; Sakaguchi, A.; Ogasa, T.; Tomioka, S.; Kasai,

M. J. Chem. Soc., Perkin Trans. 1 1995, 2677−2681. 4. Mukhanova, T. I.; Panisheva, E. K.; Lyubchanskaya, V. M.; Alekseeva, L. M.;

Sheinker, Y. N.; Granik, V. G. Tetrahedron 1997, 53, 177−184. 5. Ketcha, D. M.; Wilson, L. J.; Portlock, D. E. Tetrahedron Lett. 2000, 41, 6253−6257. 6. Brase, S.; Gil, C.; Knepper, K. Bioorg. Med. Chem. 2002, 10, 2415−2418. 7. Böhme, T. M.; Augelli-Szafran, C. E.; Hallak, H.; Pugsley, T.; Serpa, K.; Schwarz, R.

D. J. Med. Chem. 2002, 45, 3094−3102. 8. Schenck, L. W.; Sippel, A.; Kuna, K.; Frank, W.; Albert, A.; Kucklaender, U. Tetra-

hedron 2005, 61, 9129−9139. 9. Li, J.; Cook, J. M. Nenitzescu indole synthesis. In Name Reactions in Heterocyclic


10. Velezheva, V. S.; Sokolov, A. I.; Kornienko, A. G.; Lyssenko, K. A.; Nelyubina, Y. V.; Godovikov, I. A.; Peregudov, A. S.; Mironov, A. F. Tetrahedron Lett. 2008, 49, 7106−7109.

392

Newman−Kwart rearrangement Transformation of phenol to the corresponding thiophenol, a variant of the Smile reaction (page 513).

OHCl NMe2

S

O NMe2

S

Δ

SHS NMe2

O

hydrolysis

O S

NMe2

S NMe2

O

O

SMe2N

The Newman−Kwart rearrangement is a member of a series of related rearrange-ments, such as the Schönberg rearrangement and the Chapman rearrangement (page 105), in which aryl groups migrate intramolecularly between nonadjacent atoms. The Schönberg rearrangement is the most similar and involves the 1,3-migration of an aryl group from oxygen to sulfur in a diarylthioncarbonate. The Chapman rearrangement involves an analogous migration but to nitrogen.

O OAr

S

Δ S OAr

O

O Ar

NAr

Δ N Ar

OAr

Schönberg rearrangement Chapman rearrangement

Example 15

OH

NaH, DMF, 78%

N Cl

SO NMe2

SPh2O, 208 oC

50 h, 55% S NMe2

O

393


Example 26

OHOH

Cl NMe2

S

NaH, DMF85 oC, 1 h, 45%

OOH

NMe2

S275 oC

0.8 mmHg

55%

SOH

NMe2

O

Example 37

O

OH

1. Br2, CH2Cl2, 5 to 20 oC, 90 min.

2. CH2Cl2, 20 oC, 16 h, 37.4%

Cl NMe2

S

O

OBr

Me2N

S

dimethylaniline

218 oC, 7 h, 65.7%

O

SBr

Me2N

O

1. KOH, MeOH, reflux, 2 h

2. MeI, K2CO3, 90%

O

SBr

References 1. (a) Kwart, H.; Evans, E. R. J. Org. Chem. 1966, 31, 410–413. (b) Newman, M. S.;

Karnes, H. A. J. Org. Chem. 1966, 31, 3980–3984. (c) Newman, M. S.; Hetzel, F. W. J. Org. Chem. 1969, 34, 3604–3606.

2. Cossu, S.; De Lucchi, O.; Fabbri, D.; Valle, G.; Painter, G. F.; Smith, R. A. J. Tetra-hedron 1997, 53, 6073–6084.

3. Lin, S.; Moon, B.; Porter, K. T.; Rossman, C. A.; Zennie, T.; Wemple, J. Org. Prep. Proc. Int. 2000, 32, 547–555.

4. Ponaras, A. A.; Zain, Ö. In Encyclopedia of Reagents for Organic Synthesis, Paquette, L. A., Ed.; Wiley & Sons: New York, 1995, 2174–2176. (Review).

5. Kane, V. V.; Gerdes, A.; Grahn, W.; Ernst, L.; Dix, I.; Jones, P. G.; Hopf, H. Tetrahe-dron Lett. 2001, 42, 373–376.

6. Albrow, V.; Biswas, K.; Crane, A.; Chaplin, N.; Easun, T.; Gladiali, S.; Lygo, B.; Woodward, S. Tetrahedron: Asymmetry 2003, 14, 2813–2819.

7. Bowden, S. A.; Burke, J. N.; Gray, F.; McKown, S.; Moseley, J. D.; Moss, W. O.; Murray, P. M.; Welham, M. J.; Young, M. J. Org. Proc. Res. Dev. 2004, 8, 33–44.

8. Nicholson, G.; Silversides, J. D.; Archibald, S. J. Tetrahedron Lett. 2006, 47, 6541–6544.

9. Gilday, J. P.; Lenden, P.; Moseley, J. D.; Cox, B. G. J. Org. Chem. 2008, 73, 3130–3134.

10. Lloyd-Jones, G. C.; Moseley, J. D.; Renny, J. S. Synthesis 2008, 661–689. 11. Tilstam, U.; Defrance, T.; Giard, T.; Johnson, M. D. Org. Proc. Res. Dev. 2009, 13,

321–323.

394

Nicholas reaction Hexacarbonyldicobalt-stabilized propargyl cation is captured by a nucleophile. Subsequent oxidative demetallation then gives the propargylated product.

R1

R4

OR2

R31. Co2(CO)8

2. H+ or Lewis acid

1. NuH

2. [O]R1

R4

NuR3

R1

R4

OR2

R3

(CO)4Co Co(CO)3

CO

− CO

R1

R3OR2

Co(CO)3(CO)3CoCO

R4

− COR1

R3OR2

Co(CO)3(CO)3Co

R4

+ H

R1

R3O

Co(CO)3(CO)3Co

R4 R2H SN1

R1

R3

Co(CO)3(CO)3Co

R4R1

R3

Co(CO)3(CO)3Co

R4Nu

NuH

propargyl cation intermediate (stabilized by the hexacarbonyldicobalt com-

plex).

[O]

demetallationC O↑O R1

R3

Co(CO)2(CO)3Co

R4Nu R1

R4

NuR3

Example 1, A chromium variant of the Nicholas reaction3

1. HBF4·Et2O, CH2Cl2, −60 oC2. 5 eq. X, CH2Cl2, −60 oC, 86%

HN NO

CO2n-Bu

OH

ClCr(CO)3

X =

N N

Cl

OCO2n-Bu

Cr(CO)3

N N

Cl

OCO2H

2HCl

Zyrtec

Example 2, A Nicholas-Pauson–Khand sequence4

Me3Si

OEt

O

H

HO

Co(CO)3

(CO)3CoH

H

1. Co2(CO)8

2. Et2AlCl, 82% O

O

H

H

H

H

NMO

70%

395


Example 3, Intramolecular Nicholas reaction using chromium7

OAc

Cr(CO)3BF3•OEt2, CH2Cl2

0 oC, 3.5 h, 49% Cr(CO)3

Example 49

R

OH OH

O

O

O O

H HMe

H

OHMe

HOH H H

Me

OTIPS

1. Co2(CO)8, 100%

2. BF3•OEt2, 75%

O

O

O O

H HMe

H

OHMeH H H

Me

OTIPS

OR

OH

H

(OC)3Co

(OC)3Co

References 1. Nicholas, K. M.; Pettit, R. J. Organomet. Chem. 1972, 44, C21–C24. 2. Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207–214. (Review). 3. Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1996, 37, 4837–4840. 4. Jamison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber, S. L. J. Am. Chem. Soc.

1997, 119, 4353–4363. 5. Teobald, B. J. Tetrahedron 2002, 58, 4133−4170. (Review). 6. Takase, M.; Morikawa, T.; Abe, H.; Inouye, M. Org. Lett. 2003, 5, 625–628. 7. Ding, Y.; Green, J. R. Synlett 2005, 271–274. 8. Pinacho Crisóstomo, F. R.; Carrillo, R.; Martin, T.; Martin, V. S. Tetrahedron Lett.

2005, 46, 2829–2832. 9. Hamajima, A.; Isobe, M. Org. Lett. 2006, 8, 1205–1208. 10. Shea, K. M. Nicholas reaction. In Name Reactions for Homologations-Part I; Li, J. J.,


396

Nicolaou IBX dehydrogenation α,β-Unsaturation of aldehydes and ketones mediated by stoichiometric amounts of o-iodoxybenzoic acid (IBX), alternative to the Saegusa oxidation (page 482).

R1

O

R3

R2

IO

O

OHO

IBX = o-iodoxybenzoic acid R1

O

R3

R2

A SET mechanism has also been proposed. Additionally, silyl enol ethers are also viable substrates.

R1

O

R3

R2

R1

HO

R3

R2 IO

O

O

HOtautomerization

R1

O

R3

R2IOHO

O OH

H

R1

O

R3

R2

Example 11a

H

OH

H H

H

OH

H H

IBXfluorobenzene

DMSO

65 °C, 24 h80%

Example 23

O

OH

H

TBSO

MeO2C CO2Me

O

OH

H

TBSO

MeO2C CO2Me

IBX

DMSO, Tol.80 °C, 3 h, 52%

397


Example 37

NMe

NO

MeO

H

H

H

HO

IBX

Tol., DMSO70 °C

NMe

NO

MeO

H

H

H

HO

Example 4, o-Methyl-IBX (Me-IBX)9

OI

OMeO

Me OHO

R1S

R2CH3CN, reflux

40−90%

R1S

R2

O

Example 5, Stabilized IBX (SIBX)10

OH

MeO OMe

O

O

MeO OMe

O

OHO

MeO OMe

O

OH

1 : 1

SIBX, THF

rt, 98%

References 1. (a) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000, 122, 7596–

7597. (b) Nicolaou, K. C.; Montagnon, T.; Baran, P. S. Angew. Chem., Int. Ed. 2002, 41, 993–996. (c) Nicolaou, K. C.; Gray, D. L.; Montagnon, T.; Harrison, S. T. Angew. Chem., Int. Ed. 2002, 41, 996–1000.

2. Nagata, H.; Miyazawa, N.; Ogasawara, K. Org. Lett. 2001, 3, 1737–1740. 3. Ohmori, N. J. Chem. Soc., Perkin Trans. 1 2002, 755–767. 4. Hayashi, Y.; Yamaguchi, J.; Shoji, M. Tetrahedron 2002, 58, 9839–9846. 5. Shimokawa, J.; Shirai, K.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K. Angew. Chem.,

Int. Ed. 2004, 43, 1559–1562. 6. Smith, N. D.; Hayashida. J.; Rawal, V. H. Org. Lett. 2005, 7, 4309–4312. 7. Liu, X.; Deschamp, J. R.; Cook, J. M. Org. Lett. 2002, 4, 3339–3342. 8. Herzon, S. B.; Myers, A. G. J. Am. Chem. Soc. 2005, 127, 5342–5344. 9. Moorthy, J. N.; Singhal, N.; Senapati, K. Tetrahedron Lett. 2008, 49, 80–84. 10. Pouységu, L.; Marguerit, M.; Gagnepain, J.; Lyvinec, G.; Eatherton, A. J.; Quideau, S.

Org. Lett. 2008, 10, 5211–5214.

398

Noyori asymmetric hydrogenation Asymmetric reduction of carbonyls and alkenes via hydrogenation, catalyzed by a ruthenium(II) BINAP complex.

O

R R1

R3 R4

R2 R3

OH

R R1

R4 R5

R2 R3

*

*

*

H2, (R)- or (S)-BINAP

Metal [Ru(II) or Rh(I)]

PPh2

PPh2

RuCl2L2(R)-BINAP-Ru =

[RuCl2(binap)(solv)2]

H2

− HCl[RuHCl(binap)(solv)2]


R

OR1

O

O

[RuHCl(binap)(solv)2]

(binap)ClHRu

R

OR1

O

O(binap)ClRu

H+

[RuCl(binap)(solv)2]+

R OR1

OH O

solv

R OR1

O O

solv

H2

H+, solv

HH

Example 11b

OH

Ru[(S)-BINAP](CF3CO2)2

30 atm H2, rt, 96% ee OH

399


Example 21c

O

Br

Ru[(R)-BINAP]Cl2

100 atm H2, rt, 92% eeOH

Br Example 39

OO

H HOMe8

O O5 bar H2

3.2 mol% Ru(II)-(+)-(R)-BINAP

MeOH, 70 oC, 24 h, 90%

OO

H HOMe8

OH O

Example 410

C5H11 OMe

O O100 atm H2

Ru[(S)-BINAP]Cl2

EtOH, rt, 75%98% ee

C5H11 OMe

OH O

References

1. (a) Noyori, R.; Ohta, M.; Hsiao, Y.; Kitamura, M.; Ohta, T.; Takaya, H. J. Am. Chem. Soc. 1986, 108, 7117−7119. Ryoji Noyori (Japan, 1938−) and William S. Knowles (USA, 1917−) shared half of the Nobel Prize in Chemistry in 2001 for their work on chirally catalyzed hydrogenation reactions. K. Barry Sharpless (USA, 1941−) shared the other half for his work on chirally catalyzed oxidation reactions. (b) Takaya, H.; Ohta, T.; Sayo, N.; Kumobayashi, H.; Akutagawa, S.; Inoue, S.; Kasahara, I.; Noyori, R.; J. Am. Chem. Soc. 1987, 109, 1596−1598. (c) Kitamura, M.; Ohkuma, T.; Inoue, S.; Sayo, N.; Kumobayashi, H.; Akutagawa, S.; Ohta, T.; Takaya, H.; Noyori, R. J. Am. Chem. Soc. 1988, 110, 629−631. (d) Noyori, R.; Ohkuma, T.; Kitamura, H.; Ta-kaya, H.; Sayo, H.; Kumobayashi, S.; Akutagawa, S. J. Am. Chem. Soc. 1987, 109, 5856−5858. (e) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40−73. (Review). (f) Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008−2022. (Review, No-bel Prize Address).

2. Noyori, R. In Asymmetric Catalysis in Organic Synthesis; Ojima, I., ed.; Wiley: New York, 1994, Chapter 2. (Review).

3. Chung, J. Y. L.; Zhao, D.; Hughes, D. L.; McNamara, J. M.; Grabowski, E. J. J.; Rei-der, P. J. Tetrahedron Lett. 1995, 36, 7379−7382.

4. Bayston, D. J.; Travers, C. B.; Polywka, M. E. C. Tetrahedron: Asymmetry 1998, 9, 2015−2018.

5. Berkessel, A.; Schubert, T. J. S.; Mueller, T. N. J. Am. Chem. Soc. 2002, 124, 8693−8698.

6. Fujii, K.; Maki, K.; Kanai, M.; Shibasaki, M. Org. Lett. 2003, 5, 733−736. 7. Ishibashi, Y.; Bessho, Y.; Yoshimura, M.; Tsukamoto, M.; Kitamura, M. Angew.

Chem., Int. Ed. 2005, 44, 7287−7290. 8. Lall, M. S. Noyori asymmetric hydrogenation. In Name Reactions for Functional


9. Bouillon, M. E.; Meyer, H. H. Tetrahedron 2007, 63, 2712−2723. 10. Case-Green, S. C.; Davies, S. G.; Roberts, P. M.; Russell, A. J.; Thomson, J. E. Tetra-

hedron: Asymmetry 2008, 19, 2620−2631.

400

Nozaki–Hiyama–Kishi reaction Cr−Ni bimetallic catalyst-promoted redox addition of vinyl halides to aldehydes.

R1 X

R1 = alkenyl, aryl, allyl, vinyl, propargyl, alkynyl, allenylR2 = R3 = aryl, alkyl, alkenyl, HX = Cl, Br, I, OTfSolvent = DMF, DMSO, THF

Cr(II)Cl2aprotic solvent R1 Cr(III)ClX

organochromium(III)reagent

R2 R3

O

allylic orhomoallylic

alcohols

R1 R3

OH

R2

The catalytic cycle:2

R1 X

R1 R3

OCr(III)X2

R2

R2 R3

O

R1 Ni(II) X

Ni(II)Cl2

Ni(0)

R1 Cr(III)Cl2

Cr(III)Cl3

oxidativeadditiontransmetallation

2Cr(II)Cl2

2Cr(III)Cl3

Example 13

AcOCHO

OTHPI OTBDPS

AcOOTBDPS

OTHP

OH

10 eq CrCl2, cat. NiCl2

DMSO, 25 oC, 12 h, 80%

Example 25

4 eq CrCl20.008 eq NiCl2

DMF, rt, 15 h35%

O

OOHC

O

OTf

O

O

OOH

401


Example 3, Intramolecular Nozaki–Hiyama–Kishi reaction8

I

CHOOTBDMS

5 equiv CrCl2, NiCl2

THF, 84%

OH

OTBDMS

Example 4, Intramolecular Nozaki–Hiyama–Kishi reaction9

I

O

O

1. HCl, THF, 0.003 M dark

2. CrCl2, NiCl2, DMSO 0.0025 M, 50 oC 37%, 2 steps

HO

References 1. (a) Okude, C. T.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am. Chem. Soc. 1977, 99,

3179−3181. Hitosi Nozaki and T. Hiyama are professors at the Japanese Academy. (b) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H. Tetrahedron Lett. 1983, 24, 5281−5284. Kazuhiko Takai was Prof. Nozaki’s student during the discovery of the reaction and is a professor at Okayama University. (c) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644−5646. Yoshito Kishi at Harvard independently discovered the catalytic effect of nickel during his total synthesis of polytoxin. (d) Takai, K.; Tagahira, M.; Kuroda, T.; Oshima, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048−6050. (e) Kress, M. H.; Ruel, R.; Miller, L. W. H.; Kishi, Y. Tetrahedron Lett. 1993, 34, 5999−6002.

2. Fürstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349−12357. (The catalytic cy-cle).

3. Chakraborty, T. K.; Suresh, V. R. Chem. Lett. 1997, 565−566. 4. Fürstner, A. Chem. Rev. 1999, 99, 991−1046. (Review). 5. Blaauw, R. H.; Benningshof, J. C. J.; van Ginkel, A. E.; van Maarseveen, J. H.; Hiem-

stra, H. J. Chem. Soc., Perkin Trans. 1 2001, 2250−2256. 6. Berkessel, A.; Menche, D.; Sklorz, C. A.; Schroder, M.; Paterson, I. Angew. Chem.,

Int. Ed. 2003, 42, 1032−1035. 7. Takai, K. Org. React. 2004, 64, 253−612. (Review). 8. Karpov, G. V.; Popik, V. V. J. Am. Chem. Soc. 2007, 129, 3792−3793. 9. Valente, C.; Organ, M. G. Chem. Eur. J. 2008, 14, 8239−8245. 10. Yet, L. Nozaki–Hiyama–Kishi reaction. In Name Reactions for Homologations-Part I;


402

Nysted reagent

403


The Nysted reagent, cyclo-dibromodi- -methylene( -tetrahydrofuran)trizinc, is used for the olefination of ketones and aldehydes.

OZn

Zn

ZnBrBr

Example 1, The Wittig reagent opened the lactone:6

O

OMOMTBDPSO

O

O

O

O

OMOMTBDPSO

O

CH2

O

excessZn(CH2ZnBr)2•THF

TiCl4, THFreflux, 64%

Example 28

1.5 equivZn(CH2ZnBr)2•THF

1.5 equiv TiCl4THF, reflux

O

OH

OTBS

CH2

OH

OTBS

OH

CH2

OTBS

42% 14%

Example 39

2 equivZn(CH2ZnBr)2•THF

2 equiv TiCl4THF, 0 oC to rt

1 h, 74%

O

OHTBDPSO

BnO

H

CH2

OHTBDPSO

BnO

H

References 1. Nysted, L. N. US Patent 3,865,848 (1975). 2. Tochtermann, W.; Bruhn, S.; Meints, M.; Wolff, C.; Peters, E.-M.; Peters, K.;

von Schnering, H. G. Tetrahedron 1995, 51, 1623 1630. 3. Matsubara, S.; Sugihara, M.; Utimoto, K. Synlett 1998, 313 315. 4. Tanaka, M.; Imai, M.; Fujio, M.; Sakamoto, E.; Takahashi, M.; Eto-Kato, Y.;

Wu, X. M.; Funakoshi, K.; Sakai, K.; Suemune, H. J. Org. Chem. 2000, 65, 5806 5816.

5. Tarraga, A.; Molina, P.; Lopez, J. L.; Velasco, M. D. Tetrahedron Lett. 2001, 42, 8989 8992.

6. Aïssa, C.; Riveiros, R.; Ragot, J.; Fürstner, A. J. Am. Chem. Soc. 2003, 125, 15512 15520.

7. Clark, J. S.; Marlin, F.; Nay, B.; Wilson, C. Org. Lett. 2003, 5, 89 92. 8. Paquette, L. A. Hartung, R. E., Hofferberth, J. E., Vilotijevic, I., Yang, J. J. Org.

Chem. 2004, 69, 2454 2460. 9. Hanessian, S.; Mainetti, E.; Lecomte, F. Org. Lett. 2006, 8, 4047 4049.

Oppenauer oxidation Alkoxide-catalyzed oxidation of secondary alcohols. Reverse of the Meerwein–Ponndorf–Verley reduction.

OR1 R2

OH Al(Oi-Pr)3

R1 R2

O OH

O

R1 R2

OH

Al(Oi-Pr)2

coordinationR1 R2

OOHAl(Oi-Pr)2

Oi-Pr

:

O

H

OAl

R1R2

Oi-Pri-PrO

H OAlO

Oi-Pr

Oi-PrR1

R2

hydride

transfer R1 R2

O OH

cyclic transition state

Example 1, Mg-Oppenauer oxidation3

OOH 1. EtMgBr, i-Pr2O

2. PhCHO, 60%

Example 26

(i-PrO)2AlO2CCF3p-O2N-Ph-CHO

PhH, rt, 24 h, 70%

OH

OH

O

OH

Example 3, Mg-Oppenauer oxidation8

RMgCl•LiCl

−20 oC R'CHO

OMgClR

R'

PhCHO

0 oC to rtO

R

R'PhCH2OMgCl

H O

MgO

H

Ph

R

R'

ClH O

MgO

H

Ph

R

R'

Cl

404


Example 410

O

CF3H3C

AlOR

R1 H

H

R

OH

R1

O

CF3H3C2 equiv

EtOAlEt2

CH2Cl2, rt, 1 h

O

R1R

H

H2C

OH

CF3

References 1. Oppenauer, R. V. Rec. Trav. Chim. 1937, 56, 137−144. Rupert V. Oppenauer

(1910−), born in Burgstall, Italy, studied at ETH in Zurich under Ruzicka and Reich-stei, both Nobel laureates. After a string of academic appointments around Europe and a stint at Hoffman−La Roche, Oppenauer worked for the Ministry of Public Health in Buenos Aires, Argentina.

2. Djerassi, C. Org. React. 1951, 6, 207−235. (Review). 3. Byrne, B.; Karras, M. Tetrahedron Lett. 1987, 28, 769−772. 4. Ooi, T.; Otsuka, H.; Miura, T.; Ichikawa, H.; Maruoka, K. Org. Lett. 2002, 4,

2669−2672. 5. Suzuki, T.; Morita, K.; Tsuchida, M.; Hiroi, K. J. Org. Chem. 2003, 68, 1601−1602. 6. Auge, J.; Lubin-Germain, N.; Seghrouchni, L. Tetrahedron Lett. 2003, 44, 819−822. 7. Hon, Y.-S.; Chang, C.-P.; Wong, Y.-C. Byrne, B.; Karras, M. Tetrahedron Lett. 2004,

45, 3313−3315. 8. Kloetzing, R. J.; Krasovskiy, A.; Knochel, P. Chem. Eur. J. 2006, 13, 215−227. 9. Fuchter, M. J. Oppenauer oxidation. In Name Reactions for Functional Group Trans-

formations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 265−373. (Review).

10. Mello, R.; Martinez-Ferrer, J.; Asensio, G.; Gonzalez-Nunez, M. E. J. Org. Chem. 2008, 72, 9376−9378.

11. Borzatta, V.; Capparella, E.; Chiappino, R.; Impala, D.; Poluzzi, E.; Vaccari, A. Cat. Today 2009, 140, 112−116.

405

Overman rearrangement Stereoselective transformation of allylic alcohol to allylic trichloroacetamide via trichloroacetimidate intermediate.

R R1

OH cat. NaH

Cl3CCNR R1

O

CCl3

HNΔ

R R1

HN O

CCl3

or Hg(II) or Pd(II)

trichloroacetimidate

R R1

OH

HH2↑

R R1

O

N CCl3

R R1

OH

R R1

O

CCl3

N

OHN

CCl3

R

R1

H

R R1

O

CCl3

HNR R1

HN O

CCl3Δ, [3,3]-sigmatropic

rearrangement

Example 15

O

O

O

O

OH

HO

Cl3CCN, DBU

CH2Cl2, −78 oC

O

O

O

O

OH

OCl3C

HN

K2CO3, p-xylene

reflux, 90%, 2 steps

O

O

O

O

OH

HN

O

Cl3C

Example 26

K2CO3, p-xylene

reflux, 77%

O

TBDMSO

OCl3C

NHO

O

TBDMSO

ONHCl3C

O

406


Example 37

O

OO

OOBn

OHO

OO

OOBn

HN CF3

O

CF3CN, n-BuLi;toluene, 120 °C

30%

Example 49

DBU, CCl3CN

toluene, reflux51%

NMe F

(CH2)3OTBDPS

O O OH

Bn

NMe F

(CH2)3OTBDPS

O O

Bn

NHC(O)CCl3

References 1. (a) Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597−599. (b) Overman, L. E. J. Am.

Chem. Soc. 1976, 98, 2901−2910. (c) Overman, L. E. Acc. Chem. Res. 1980, 13, 218–224. (Review).

2. Demay, S.; Kotschy, A.; Knochel, P. Synthesis 2001, 863−866. 3. Oishi, T.; Ando, K.; Inomiya, K.; Sato, H.; Iida, M.; Chida, N. Org. Lett. 2002, 4,

151−154. 4. Reilly, M.; Anthony, D. R.; Gallagher, C. Tetrahedron Lett. 2003, 44, 2927−2930. 5. Tsujimoto, T.; Nishikawa, T.; Urabe, D.; Isobe, M. Synlett 2005, 433−436. 6. Montero, A.; Mann, E.; Herradon, B. Tetrahedron Lett. 2005, 46, 401−405. 7. Hakansson, A. E.; Palmelund, A.; Holm, H.; Madsen, R. Chem. Eur. J. 2006, 12,

3243−3253. 8. Bøjstrup, M.; Fanejord, M.; Lundt, I. Org. Biomol. Chem. 2007, 5, 3164−3171. 9. Lamy, C.; Hifmann, J.; Parrot-Lopez, H.; Goekjian, P. Tetrahedron Lett. 2007, 48,

6177−6180. 10. Wu, Y.-J. Overman rearrangement. In Name Reactions for Homologations-Part II; Li,


407

Paal thiophene synthesis Thiophene synthesis from addition of a sulfur atom to 1,4-diketones and subse-quent dehydration.

H3C CH3

O O SH3CCH3

P2S5, tetralin

reflux

The reaction now is frequently carried out using the Lawesson’s reagent. For the mechanism of carbonyl to thiocarbonyl transformation, see Lawesson’s reagent on page 328.

O

H3CCH3

O

S

H3CCH3

XX = O or S

P2S5 tautomerization

SH

H3CCH3

X

S

CH3

XHH3C

H

SCH3

H3C− H2X

Example 12

O

PhO

NLawesson's reagent

110 ºC, 10 min, 82%

S NPh

Example 23

PhO

O

PhPh

O Ph

O

SS

Ph

Ph Ph

Ph

Lawesson's reagentchlorobenzene, reflux, 36 h

69%

References 1. (a) Paal, C. Ber. 1885, 18, 2251−2254. (b) Paal, C. Ber. 1885, 18, 367−371. 2. Thomsen, I.; Pedersen, U.; Rasmussen, P. B.; Yde, B.; Andersen, T. P.; Lawesson, S.-

O. Chem. Lett. 1983, 809−810. 3. Parakka, J. P.; Sadannandan, E. V.; Cava, M. P. J. Org. Chem. 1994, 59, 4308−4310. 4. Kikuchi, K.; Hibi, S.; Yoshimura, H.; Tokuhara, N.; Tai, K.; Hida, T.; Yamauchi, T.;

Nagai, M. J. Med. Chem. 2000, 43, 409−423. 5. Sonpatki, V. M.; Herbert, M. R.; Sandvoss, L. M.; Seed, A. J. J. Org. Chem. 2001, 66,

7283−7286. 6. Kiryanov, A. A.; Sampson, P.; Seed, A. J. J. Org. Chem. 2001, 66, 7925−7929. 7. Mullins, R. J.; Williams, D. R. Paal Thiophene Synthesis. In Name Reactions in Het-

erocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 207−217. (Review).

8. Kaniskan, N.; Elmali, D.; Civcir, P. U. ARKIVOC 2008, xii, 17−29.

408


Paal–Knorr furan synthesis Acid-catalyzed cyclization of 1,4-diketones to form furans.

RR3

O

O OR R3

cat. HR2

R1

R1 R2

or P2O5

RR3

O

OR1

H

:

R2

O R3

R1 R2

RHO

: H3O

OR R3

R1 R2

OR R3

R2R1H

H

Example 13

O

O

OTsOH

toluene, reflux

Cl

N

F

ClF

N

Example 26

O

n-Bu98%

n-Bu

O

O

OMe

MeO

OMe

p-TsOH

toluene

MeO OMe

MeO

Example 39

CH3O

O

NH

phosphoric acid

130−140 oC, 4−6 hNH

O CH3

409


Example 410

RO

CH CSMe

OR

SnCl2, H

72−89% O

SMe

R R O

SMe

R R

BrBr2, CHCl3

88−92%

30% HBr−HOAc, CHCl3, 58−64%

References 1. (a) Paal, C. Ber. 1884, 17, 2756−2767. (b) Knorr, L. Ber. 1885, 17, 2863−2870. (c)

Paal, C. Ber. 1885, 18, 367−371. 2. Friedrichsen, W. Furans and Their Benzo Derivatives: Synthesis. In Comprehensive

Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Per-gamon: New York, 1996; Vol. 2, 351−393. (Review).

3. de Laszlo, S. E.; Visco, D.; Agarwal, L.; et al. Bioorg. Med. Chem. Lett. 1998, 8, 2689−2694.

4. Gupta, R. R.; Kumar, M.; Gupta, V. Heterocyclic Chemistry, Springer: New York, 1999; Vol. 2, 83−84. (Review).

5. Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell Science: Cambridge, 2000; 308−309. (Review).

6. Mortensen, D. S.; Rodriguez, A. L.; Carlson, K. E.; Sun, J.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med. Chem. 2001, 44, 3838−3848.

7. König, B. Product Class 9: Furans. In Science of Synthesis: Houben−Weyl Methods of Molecular Transformations; Maas, G., Ed.; Georg Thieme Verlag: New York, 2001; Cat. 2, Vol. 9, 183−278. (Review).

8. Shea, K. M. Paal–Knorr Furan Synthesis. In Name Reactions in Heterocyclic Chemis-try; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 168−181. (Re-view).

9. Kaniskan, N.; Elmali, D.; Civcir, P. U. ARKIVOC 2008, xii, 17−29. 10. Yin, G.; Wang, Z.; Chen, A.; Gao, M.; Wu, A.; Pan, Y. J. Org. Chem. 2008, 73,

3377−3383.

410

Paal–Knorr pyrrole synthesis Reaction between 1,4-diketones and primary amines (or ammonia) to give pyr-roles. A variation of the Knorr pyrazole synthesis (page 317).

RR1

O

O

R2 NH2

NR2

R R1

RR1

O

OHHNRR1

O

O

R2H2N:

R2

slowN

HO

R

OH

R1

R2

:

NR2

R1HO

R

H H

NR2

R R1

NR2

R1

H H

NR2

R1HO

R

H

:

R

Example 14

NF

CONHPh

OEtEtO

O

OF

CONHPh

H2N OEt

OEt

1 eq. pivalic acidTHF, reflux, 43%

N

CO2

F

HO

HO

Ca2+

2

O

HN

Lipitor

411


Example 25

O

N

OCl

F

NH4OAc

NH

N

F Cl

HOAc110 °C

90%

Example 39

OOOMeOOMeO

NH

NH4OAc, CSA

MeOH, 50 oC93%

Example 410

HO

O

NH

NH

NR

RNH2, AcOH, MeOH, 40 oC; orRNH2, AcOH, NaOAc, toluene, 60 oC; or

NH4OAc, 28% NH4OH, EtOH, 40 oC30−96%

References 1. (a) Paal, C. Ber. 1885, 18, 367−371. (b) Paal, C. Ber. 1885, 18, 2251−2254. (c) Knorr,

L. Ber. 1885, 18, 299−311. 2. Corwin, A. H. Heterocyclic Compounds Vol. 1, Wiley, NY, 1950; Chapter 6. (Re-

view). 3. Jones, R. A.; Bean, G. P. The Chemistry of Pyrroles, Academic Press, London, 1977,

pp 51−57, 74−79. (Review). 4. (a) Brower, P. L.; Butler, D. E.; Deering, C. F.; Le, T. V.; Millar, A.; Nanninga, T. N.;

Roth, B. D. Tetrahedron Lett. 1992, 33, 2279-2282. (b) Baumann, K. L.; Butler, D. E.; Deering, C. F.; Mennen, K. E.; Millar, A.; Nanninga, T. N.; Palmer, C. W.; Roth, B. D. Tetrahedron Lett. 1992, 33, 2279, 2283−2284.

5. de Laszlo, S. E.; Visco, D.; Agarwal, L.; et al. Bioorg. Med. Chem. Lett. 1998, 8, 2689−2694.

6. Braun, R. U.; Zeitler, K.; Müller, T. J. J. Org. Lett. 2001, 3, 3297−3300. 7. Quiclet-Sire, B.; Quintero, L.; Sanchez-Jimenez, G.; Zard, Z. Synlett 2003, 75−78. 8. Gribble, G. W. Knorr and Paal−Knorr Pyrrole Syntheses. In Name Reactions in Het-

erocyclic Chemistry; Li, J. J., Corey, E. J., Eds, Wiley & Sons: Hoboken, NJ, 2005, 77−88. (Review).

9. Salamone, S. G.; Dudley, G. B. Org. Lett. 2005, 7, 4443−4445. 10. Fu, L.; Gribble, G. W. Tetrahedron Lett. 2008, 49, 7352−7354.

412

Parham cyclization The Parham cyclization is the generation by halogen–lithium exchange of aryllith-iums and heteroaryllithiums, and their subsequent intramolecular cyclization onto an electrophilic site.

E

X

E

LiRLi

E.g.

ICH3O

CH3ON

ONEt2

2.2 eq. t-BuLi

THF, −78 oC→rt

ICH3O

CH3ON

ONEt2

halogen-metal

exchange I

LiCH3O

CH3ON

Et2N OCH3O

CH3ON

CH3O

CH3ON

OOEt2N

cyclization

The fate of the second equivalent of t-BuLi:

I

H I

Example 12

O O

OBr

MeO

MeO OMe MeO OMe

O

MeOO NMe2

Ot-BuLi

THF, –95 °C92%

Example 24

O

O Br

O

O

O

OPMB

O

n-BuLi

Et2O, –78 °C64%

O

O

OPMBO

OO

OHH

413


Example 35

2 eq. n-BuLi

THF, −78 oC2.5 h, 83%

I

MeOOMe

N

O

ON

MeO

MeOO

Example 49

O Br

N OMe

O

PMB

t-BuLi, THF, −100 oC

Ar, 30 min., 55%

ON

O

PMB

References 1. (a) Parham, W. E.; Jones, L. D.; Sayed, Y. J. Org. Chem. 1975, 40, 2394−2399. Wil-

liam E. Parham was a professor at Duke University. (b) Parham, W. E.; Jones, L. D.; Sayed, Y. J. Org. Chem. 1976, 41, 1184−1186. (c) Parham, W. E.; Bradsher, C. K. Acc. Chem. Res. 1982, 15, 300−305. (Review).

2. Paleo, M. R.; Lamas, C.; Castedo, L.; Domínguez, D. J. Org. Chem. 1992, 57, 2029–2033.

3. Gray, M.; Tinkl, M.; Snieckus, V. In Comprehensive Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: Exeter, 1995; Vol. 11; p 66. (Review).

4. Gauthier, D. R., Jr.; Bender, S. L. Tetrahedron Lett. 1996, 37, 13–16. 5. Collado, M. I.; Manteca, I.; Sotomayor, N.; Villa, M.-J.; Lete, E. J. Org. Chem. 1997,

62, 2080−2092. 6. Mealy, M. M.; Bailey, W. F. J. Organomet. Chem. 2002, 646, 59−67. (Review). 7. Sotomayor, N.; Lete, E. Current Org. Chem. 2003, 7, 275−300. (Review). 8. González-Temprano, I.; Osante, I.; Lete, E.; Sotomayor, N. J. Org. Chem. 2004, 69,

3875−3885. 9. Moreau, A.; Couture, A.; Deniau, E.; Grandclaudon, P.; Lebrun, S. Org. Biomol.

Chem. 2005, 3, 2305−2309. 10. Gribble, G. W. Parham cyclization. In Name Reactions for Homologations-Part II; Li,


414

Passerini reaction Three-component condensation (3CC) of carboxylic acids, C-isocyanides, and carbonyl compounds to afford α-acyloxycarboxamides. Cf. Ugi reaction.

R1 N CR2 R3

OR4 CO2H R1

HN

O R4O

R3R2 O

isocyanide

O

R4 O

OH

CN

R1

OO

ON

R1

R4R3R2

HR2

R3

R2 R3

OR4 CO2H

R1

HN

O R4

O

R3R2 OO

ON

R1

R3R2O

R4

H

H

acyl

transfer

Example 13

MeO

MeO

OMe

OMe

OMeOMe

Ts

CNTFA, PhH

rt, 2 h, 93%

MeO

MeO

OMe HN

O

Ts

OMe

OMe Example 25

CHO

CN

HOAc, THF

rt, 93% HNO

EtAcO

Example 36

BocNH CO2HCN CO2Bn

Me

Me

FmocNH

Me

CHO

CbzNH

415


FmocNH

Me

O

O

NH

CO2Bn

Me

Me

O

NHBocCbzNH

CH2Cl2, 0 °C → rt

3–5 days, 80%

Example 47

CNNH

O

CO2Me

Ph

OBn(Cl2)

BocHN CHO

NH

NH2NNO2

NAlloc

OH

O

CH2Cl2, 0 °C → rt

2 days, 59% BocHNO

O

NH

HN

CO2MeO

Ph

O

NAlloc

OBn(Cl2)NH

NH2NNO2

References 1. Passerini, M. Gazz. Chim. Ital. 1921, 51, 126−129. (b) Passerini, M. Gazz. Chim. Ital.

1921, 51, 181−188. Mario Passerini (b, 1891) was born in Scandicci, Italy. He obtained his Ph.D. In chemistry and pharmacy at the University of Florence, where he was a professor for most of his career.

2. Ferosie, I. Aldrichimica Acta 1971, 4, 21. (Review). 3. Barrett, A. G. M.; Barton, D. H. R.; Falck, J. R.; Papaioannou, D.; Widdowson, D. A.

J. Chem. Soc., Perkin Trans. 1 1979, 652−661. 4. Ugi, I.; Lohberger, S.; Karl, R. In Comprehensive Organic Synthesis; Trost, B. M.;

Fleming, I., Eds.; Pergamon: Oxford, 1991, Vol. 2, p.1083. (Review). 5. Bock, H.; Ugi, I. J. Prakt. Chem. 1997, 339, 385−389. 6. Banfi, L.; Guanti, G.; Riva, R. Chem. Commun. 2000, 985–986. 7. Owens, T. D.; Semple, J. E. Org. Lett. 2001, 3, 3301–3304. 8. Xia, Q.; Ganem, B. Org. Lett. 2002, 4, 1631−1634. 9. Banfi, L.; Riva, R. Org. React. 2005, 65, 1−140. (Review). 10. Klein, J. C.; Williams, D. R. Passerini reaction. In Name Reactions for Homologa-


416

Paternó–Büchi reaction Photoinduced electrocyclization of a carbonyl with an alkene to form polysubsti-tuted oxetane ring systems

R R1

O hv O

RR1

oxetane

R R1

O hv

R R1

O

n, π* triplet

O

RR1

O

RR1

O

RR1

triplet diradical singlet diradical Example 12

Me

PhO

O

O

PhMe

O

O

O

O

OH

*ROOChν, C6H6, 99%Ph H

Example 24

O

Ph Ph

i-Pr

SMe

(E/Z = 6/1)

hν, C6H6

73%

OPh

Ph

i-Pr

SMe

Example 36

H

O

hv, MeCN

82%H

O

417


Example 48

OH

OO

solvent

hv

100%O

O

PhPh

HO

References 1. (a) Paternó, E.; Chieffi, G. Gazz. Chim. Ital. 1909, 39, 341−361. Emaubuele Paternó

(1847−1935) was born in Palermo, Sicily, Italy. (b) Büchi, G.; Inman, C. G.; Lipin-sky, E. S. J. Am. Chem. Soc. 1954, 76, 4327−4331. George H. Büchi (1921−1998) was born in Baden, Switzerland. He was a professor at MIT when he elucidated the structure of oxetanes, the products from the light-catalyzed addition of carbonyl com-pounds to olefins, which had been observed by E. Paternó in 1909. Büchi died of heart failure while hiking with his wife in his native Switzerland.

2. Koch, H.; Runsink, J.; Scharf, H.-D. Tetrahedron Lett. 1983, 24, 3217−3220. 3. Carless, H. A. J. In Synthetic Organic Photochemistry; Horspool, W. M., Ed.; Plenum

Press: New York, 1984, 425. (Review). 4. Morris, T. H.; Smith, E. H.; Walsh, R. J. Chem. Soc., Chem. Commun. 1987, 964−965. 5. Porco, J. A., Jr.; Schreiber, S. L. In Comprehensive Organic Synthesis; Trost, B. M.;

Fleming, I., Eds.; Pergamon: Oxford, 1991, Vol. 5, 151−192. (Review). 6. de la Torre, M. C.; Garcia, I.; Sierra, M. A. J. Org. Chem. 2003, 68, 6611−6618. 7. Griesbeck, A. G.; Mauder, H.; Stadtmüller, S. Acc. Chem. Res. 1994, 27, 70−75. (Re-

view). 8. D’Auria, M.; Emanuele, L.; Racioppi, R. Tetrahedron Lett. 2004, 45, 3877−3880. 9. Liu, C. M. Paternó–Büchi Reaction. In Name Reactions in Heterocyclic Chemistry; Li,

J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 44−49. (Review). 10. Cho, D. W.; Lee, H.-Y.; Oh, S. W.; Choi, J. H.; Park, H. J.; Mariano, P. S.; Yoon, U.

C. J. Org. Chem. 2008, 73, 4539−4547.

418

Pauson−Khand reaction Formal [2 + 2 +1] cycloaddition of an alkene, alkyne, and carbon monoxide medi-ated by octacarbonyl dicobalt to form cyclopentenones.

O

toluene, 60−80 oC4−6 d, 60%

O

O

Co(CO)3Co(CO)3

HCo2(CO)8

Co(CO)3Co(CO)3

H

H(CO)4Co Co(CO)3

CO

− COCo(CO)3

Co(CO)3

H

OC

− COO

hexacarbonyldicobalt complex

Co(CO)3Co(CO)2

H

− CO OO+ CO

insertiontoward CH (CO)3Co

(CO)3Co H

HH

+ CO

insertion

exo complex sterically-favored isomer

O(CO)3Co H

(CO)3Co

OO

(CO)3Co HO

(CO)3Co

reductive elimination

− Co2(CO)6

O

O

reductive

elimination

Example 13

benzene, 65 oC16 h, 23%

Co2(CO)8OO

O

O

O

Example 2, A catalytic version6

NTs

5 mol% Co2(CO)820 mol% P(OPh)3

3 atm CO, DME120 oC, 48 h, 94%

NTs O

419


Example 3, Intramolecular Pauson−Khand reaction9

NH

N CbzCo2(CO)8, DMSO

THF, 65 oC, 94% NH

NCbz

O

H

Example 4, Intramolecular Pauson−Khand reaction10

Co2(CO)8

5 equiv Me3NO•2H2O

THF/H2O (3:1), 0 oC to rt7 h, 71%

NS

NO2O ON

SNH2O O

O

H

References 1. (a) Pauson, P. L.; Khand, I. U.; Knox, G. R.; Watts, W. E. J. Chem. Soc., Chem. Com-

mun. 1971, 36. Ihsan U. Khand and Peter L. Pauson were at the University of Strath-clyde, Glasgow in Scotland. (b) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.; Foreman, M. I. J. Chem. Soc., Perkin Trans. 1 1973, 975−977. (c) Bladon, P.; Khand, I. U.; Pauson, P. L. J. Chem. Res. (S), 1977, 9. (d) Pauson, P. L. Tetrahedron 1985, 41, 5855−5860. (Review).

2. Schore, N. E. Chem. Rev. 1988, 88, 1081−1119. (Review). 3. Billington, D. C.; Kerr, W. J.; Pauson, P. L.; Farnocchi, C. F. J. Organomet. Chem.

1988, 356, 213−219. 4. Schore, N. E. In Comprehensive Organic Synthesis; Paquette, L. A.; Fleming, I.; Trost,

B. M., Eds.; Pergamon: Oxford, 1991, Vol. 5, p.1037. (Review). 5. Schore, N. E. Org. React. 1991, 40, 1−90. (Review). 6. Jeong, N.; Hwang, S. H.; Lee, Y.; Chung, J. J. Am. Chem. Soc. 1994, 116, 3159−3160. 7. Brummond, K. M.; Kent, J. L. Tetrahedron 2000, 56, 3263−3283. (Review). 8. Tsujimoto, T.; Nishikawa, T.; Urabe, D.; Isobe, M. Synlett 2005, 433−436. 9. Miller, K. A.; Martin, S. F. Org. Lett. 2007, 9, 1113−1116. 10. Kaneda, K.; Honda, T. Tetrahedron 2008, 64, 11589−11593. 11. Gao, P.; Xu, P.-F.; Zhai, H. J. Org. Chem. 2009, 74, 2592−2593.

420

Payne rearrangement The isomerization of 2,3-epoxy alcohol under the influence of a base to 1,2-epoxy-3-ol is referred to as the Payne rearrangement. Also known as epoxide mi-gration.

OHO

aq. NaOHR

OH

O

R

OO

HOH

OOR R

R

O

O

SN2 H

workup R

OH

O Example 12

TrOHO

O

HOOTr

NaOMe, MeOH

reflux, 1 h, 84%TrO

HOOTr

OOH

Example 23

BzOCO2Me

OBzOTs K2CO3, MeOH

rt, 2 h, 98% CO2Me

OH

O

Example 3, Aza-Payne rearrangement8

N

HO H

H

Ts

NaOH, t-BuOH/H2O

rt, 4 h, 98%

O

HTsHN

H

Example 4, Aza-Payne rearrangement9

N

H

Me

H

OHBoc

0.28 M NaOH, t-BuOH/H2O/THF (4:5:1),

rt, 30%, or

NaH, THF/HMPA (10:1),

rt, 80%

OCH3

OCH3

OH

NHBoc

MeOCH3

OCH3

421


References 1. Payne, G. B. J. Org. Chem. 1962, 27, 3819−3822. George B. Payne was a chemist at

Shell Development Co. in Emeryville, CA. 2. Buchanan, J. G.; Edgar, A. R. Carbohydr. Res. 1970, 10, 295−302. 3. Corey, E. J.; Clark, D. A.; Goto, G.; Marfat, A.; Mioskowski, C.; Samuelsson, B.;

Hammerstrom, S. J. Am. Chem. Soc. 1980, 102, 1436−1439, and 3663−3665. 4. Ibuka, T. Chem. Soc. Rev. 1998, 27, 145−154. (Review). 5. Hanson, R. M. Org. React. 2002, 60, 1−156. (Review). 6. Yamazaki, T.; Ichige, T.; Kitazume, T. Org. Lett. 2004, 6, 4073−4076. 7. Bilke, J. L.; Dzuganova, M.; Froehlich, R.; Wuerthwein, E.-U. Org. Lett. 2005, 7,

3267−3270. 8. Feng, X.; Qiu, G.; Liang, S.; Su, J.; Teng, H.; Wu, L.; Hu, X. Russ. J. Org. Chem.

2006, 42, 514−500. 9. Feng, X.; Qiu, G.; Liang, S.; Teng, H.; Wu, L.; Hu, X. Tetrahedron: Asymmetry 2006,

17, 1394−1401. 10. Kumar, R. R.; Perumal, S. Payne rearrangement. In Name Reactions for Homologa-


422

Pechmann coumarin synthesis Lewis acid-mediated condensation of phenol with β-ketoester to produce cou-marin.

OH

R OEt

O O AlCl3O

R

O

O:H EtO

R

O

OAlCl3 O O

ROH

:

O O

O

RH

H

EtO

R

O

O

AlCl3

O

Michael

addition

O OO

R

O

R OH2

HO O

R OH

H

H

Example 16

OH

OEt

O O

[bimim]Cl•2AlCl3130 oC, 35 min., 90% O OHO HO

Example 28

OH

OH

OEt

O O

BiCl3, 75 oC, 2 h, 66%

OH

O O

O O

References 1. von Pechmann, H.; Duisberg, C. Ber. 1883, 16, 2119. Hans von Pechmann

(1850−1902) was born in Nürnberg, Germany. After his doctorate, he worked with Frankland and von Baeyer. Pechmann taught at Munich and Tübingen. He committed suicide by taking cyanide.

2. Corrie, J. E. T. J. Chem. Soc., Perkin Trans. 1 1990, 2151–2997. 3. Hua, D. H.; Saha, S.; Roche, D.; Maeng, J. C.; Iguchi, S.; Baldwin, C. J. Org. Chem.

1992, 57, 399–403. 4. Li, T.-S.; Zhang, Z.-H.; Yang, F.; Fu, C.-G. J. Chem. Res., (S) 1998, 38–39. 5. Potdar, M. K.; Mohile, S. S.; Salunkhe, M. M. Tetrahedron Lett. 2001, 42, 9285–9287. 6. Khandekar, A. C.; Khandilkar, B. M. Synlett. 2002, 152–154. 7. Smitha, G.; Sanjeeva Reddy, C. Synth. Commun. 2004, 34, 3997–4003. 8. De, S. K.; Gibbs, R. A. Synthesis 2005, 1231–1233. 9. Manhas, M. S.; Ganguly, S. N.; Mukherjee, S.; Jain, A. K.; Bose, A. K. Tetrahedron

Lett. 2006, 47, 2423–2425. 10. Rodriguez-Dominguez, J. C.; Kirsch, G. Synthesis 2006, 1895–1897.

423


Perkin reaction Cinnamic acid synthesis from aryl aldehyde and acetic anhydride.

Ar CHO Ac2OAcONa

Ar O

OAc O O OH

H2O Ar OH

O

cinnamic acid

O

O OH

OAcenolate

formationO

O O

H Ar

O

aldol

condensation Ar O

O O

O

intramolecular

acyl transfer Ar O

O O

O

Ar O

O O

O

H

O

O O

Ar O

O O O

O

H

OH

acyl

transferAr O

OE2

elimination

O

OH

AcOH

Ar O

O

O

OHOO

Ar Ar OH

OHOAc

Example 17

CHO

MeO

MeO

MeOCO2H

Ac2O, Et3N, 90 oC

5 h, 66%

MeO

MeO

H

CO2H

MeO

Example 29

ClF2C

PhO

Ac2O, Δ

AcONa, 46%

ClF2C

Ph CO2H

424


References 1. Perkin, W. H. J. Chem. Soc. 1868, 21, 53. William Henry Perkin (1838−1907), born

in London, England, studied under A. W. von Hofmann at the Royal College of Chem-istry. In an attempt to synthesize quinine in his home laboratory in 1856, Perkin syn-thesized mauve, the purple dye. He then started a factory to manufacture mauve and later other dyes including alizarin. Perkin was the first person to show that organic chemistry was not just mere intellectual curiosity but could be profitable, which cata-pulted the discipline into a higher level. In addition, Perkin was also an exceptionally talented pianist.

2. Gaset, A.; Gorrichon, J. P. Synth. Commun. 1982, 12, 71−79. 3. Kinastowski, S.; Nowacki, A. Tetrahedron Lett. 1982, 23, 3723−3724. 4. Koepp, E.; Vögtle, F. Synthesis 1987, 177−179. 5. Brady, W. T.; Gu, Y.-Q. J. Heterocycl. Chem. 1988, 25, 969−971. 6. Pálinkó, I.; Kukovecz, A.; Török, B.; Körtvélyesi, T. Monatsh. Chem. 2001, 131,

1097−1104. 7. Gaukroger, K.; Hadfield, J. A.; Hepworth, L. A.; Lawrence, N. J.; McGown, A. T. J.

Org. Chem. 2001, 66, 8135−8138. 8. Solladié, G.; Pasturel-Jacopé, Y.; Maignan, J. Tetrahedron 2003, 59, 3315−3321. 9. Sevenard, D. V. Tetrahedron Lett. 2003, 44, 7119−7126. 10. Chandrasekhar, S.; Karri, P. Tetrahedron Lett. 2006, 47, 2249−2251. 11. Lacova, M.; Stankovicova, H.; Bohac, A.; Kotzianova, B. Tetrahedron 2008, 64,

9646−9653.

425

Petasis reaction Allylic amine from the three-component reaction of a vinyl boronic acid, a car-bonyl and an amine. Also known as boronic acid-Mannich or Petasis boronic acid-Mannich reaction. Cf. Mannich reaction.

H

OR1 B(OH)2

R2 NH

R3

OH R1OH

NR2 R3

R3

NHR2

H

O

R1 B(OH)2

OH R1OH

NR2 R3N

R2 R3

:OH

NR2 R3

OB

HOR1

OH

Example 12

PhB

OH

OHO

C5H11

OHPh N

H

EtOH, rt

84%, 99% de PhC5H11

NPh

OH

Example 24

HO

HO

CHO

OMe

(HO)2BMeNHBn, EtOH, rt

24 h, 72%, 99% de

HO N

OMe

HO

MeBn

Example 39

N

NBnS R1

HN

R2

R3OHC−CO2H, PhB(OH)2

50−94% N

NBnS R1

N

R2

R3

Ph CO2H

Example 4, Asymmetric Petasis reaction10

H CO2Et

O

R2

HN

R3B(OEt)2R1 15 mol% (S)-VAPOL

3 A MS, −15 oC, Tol.R1 CO2Et

NR3R2

R1 = aryl, alkyl R2 = Bn, allylR3 = alkyl

70−92% yield89:11 to 98:2 er

426


References 1. (a) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34, 583–586. (b) Petasis,

N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445–446. (c) Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997, 53, 16463–16470. (d) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798–11799.

2. Koolmeister, T.; Södergren, M.; Scobie, M. Tetrahedron Lett. 2002, 43, 5969–5970. 3. Orru, R. V. A.; deGreef, M. Synthesis 2003, 1471–1499. (Review). 4. Sugiyama, S.; Arai, S.; Ishii, K. Tetrahedron: Asymmetry 2004, 15, 3149–3153. 5. Chang, Y. M.; Lee, S. H.; Nam, M. H.; Cho, M. Y.; Park, Y. S.; Yoon, C. M. Tetrahe-

dron Lett. 2005, 46, 3053–3056. 6. Follmann, M.; Graul, F.; Schaefer, T.; Kopec, S.; Hamley, P. Synlett 2005, 1009–

1011. 7. Danieli, E.; Trabocchi, A.; Menchi, G.; Guarna, A. Eur. J. Org. Chem. 2007, 1659–

1668. 8. Konev, A. S.; Stas, S.; Novikov, M. S.; Khlebnikov, A. F.; Abbaspour Tehrani, K. Tet-

rahedron 2007, 64, 117–123. 9. Font, D.; Heras, M.; Villalgordo, J. M. Tetrahedron 2007, 64, 5226–5235. 10. Lou, S.; Schaus, S. E. J. Am. Chem. Soc. 2008, 130, 6922–6923. 11. Abbaspour Tehrani, K.; Stas, S.; Lucas, B.; De Kimpe, N. Tetrahedron 2009, 65,

1957–1966.

427

Petasis reagent

428


The Petasis reagent (Cp2TiMe2, dimethyltitanocene) undergoes similar olefination reactions with ketones and aldehydes as does the Tebbe’s reagent. The originally proposed mechanism5 was very different from that of Tebbe olefination. How-ever, later experimental data seem to suggest that both Petasis and Tebbe olefina-tion share the same mechanism, i.e., the carbene mechanism involving a four-membered titanium oxide ring intermediate.9 Petasis reagent is easier to make than the Tebbe reagent.

TiCl

ClCp

Cp

MeLi or

MeMgCl

heat TiC

CHH

H

HH H

TiCH3

CH3Ti

Cp

CpCH2

− CH4

OR2

R1Ti

H

H

OR2

R1

− Cp2Ti=O

R2

R1Ti

H2C

O R2

R1

Example 12

Cp2TiMe2

THF, 65 °C 8 h, 52%

O

NO Ph

MeO2CCHO

CH3

O

NO Ph

MeO2C CH3

Example 23

TiCp Cp

O O OPhMe, 50 °C, 67%

Example 35

CF3

CF3O

O

O

N

F

2.4 eq MeLi

6 mol% Cp2TiCl2PhMe, 80 °C, 6.5 h

91%

CF3

CF3OO

N

F250 kg(474 mol) 227 kg

O

O Ph0.75 eq

Example 48

R2 N

R3 R1 1.8 equiv Cp2TiMe2

Tol., THF, microwave, 65 oC3−10 min., ~ 50−60%

O

OMe

R2 N

R3 R1 OMe

References 1. Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392−6394. 2. Colson, P. J.; Hegedus, L. S. J. Org. Chem. 1993, 58, 5918−5924. 3. Petasis, N. A.; Bzowej, E. I. Tetrahedron Lett. 1993, 34, 943–946. 4. Payack, J. F.; Hughes, D. L.; Cai, D.; Cottrell, I. F.; Verhoeven, T. R. Org. Synth.

2002, 79, 19. 5. Payack, J. F.; Huffman, M. A.; Cai, D. W.; Hughes, D. L.; Collins, P. C.; Johnson, B.

K.; Cottrell, I. F.; Tuma, L. D. Org. Pro. Res. Dev. 2004, 8, 256−259. 6. Cook, M. J.; Fleming, E. I. Tetrahedron Lett. 2005, 46, 297−300. 7. Morency, L.; Barriault, L. J. Org. Chem. 2005, 70, 8841−8853. 8. Adriaenssens, L. V.; Hartley, R. C. J. Org. Chem. 2007, 72, 10287−10290. 9. Naskar, D.; Neogi, S.; Roy, A.; Mandal, A. B. Tetrahedron Lett. 2008, 49, 6762−6764. 10. Zhang, J. Tebbe reagent. In Name Reactions for Homologations-Part I, Li, J. J. Ed.,

Wiley & Sons: Hoboken, NJ, 2009, pp 319−333. (Review).

429

Peterson olefination Alkenes from α-silyl carbanions and carbonyl compounds. Also known as the sila-Wittig reaction.

R1 R2

O

R3

HSiR3M

R1

HO

R3

SiR3R2 H

acid or

base R2

R1

R3

H

Basic conditions:

R3

HSiR3

M

R1 R2

O

R2

O

R3

SiR3R1 H

R2 R3R1 H

SiR3O

R2

R1

R3

Hsyn-

elimination

β-silylalkoxide intermediate

Acidic conditions:

R2

HO

R3

SiR3R1 H

rotation

R2

HO

SiR3

R3

R1 HH

R2

R1

H

R3

R2

H2O

SiR3

R3

R1 H E2 anti-

elimination:OH2

β-hydroxysilane

Example 16

OBnHO

HOSiMe2Ph

OH

OBn

OBnHO

HO

OBn

KHMDS,18-C-6, THF

−78 oC, 1 h99%, > 20:1 dr

OBnHO

OH

OBn

H2SO4, THF

23 oC, 24 h95%

Example 27

PhO2S TBS

F 1. n-BuLi, Et2O, −78 oC

2. benzophenone, 63%PhO2S

FPh

Ph

Example 38

N

(t-BuO)Ph2Si CN1. KHMDS, THF, −78 oC

2. N88% yield92:8 Z:ECHO

CN

430


Example 410

O

OMe

OMOM O

OMe

OMOM

1. LiCH2TMS, THF 0 oC, 15 min.2. KHMDS, 0 oC to rt, 1.5 h

3. HCl, MeOH/Et2O, 5 min. 74%

References 1. Peterson, D. J. J. Org. Chem. 1968, 33, 780−784. 2. Ager, D. J. Org. React. 1990, 38, 1−223. (Review). 3. Barrett, A. G. M.; Hill, J. M.; Wallace, E. M.; Flygare, J. A. Synlett 1991, 764−770.

(Review). 4. van Staden, L. F.; Gravestock, D.; Ager, D. J. Chem. Soc. Rev. 2002, 31, 195−200.

(Review). 5. Ager, D. J. Science of Synthesis 2002, 4, 789−809. (Review). 6. Heo, J.-N.; Holson, E. B.; Roush, W. R. Org. Lett. 2003, 5, 1697−1700. 7. Asakura, N.; Usuki, Y.; Iio, H. J. Fluorine Chem. 2003, 124, 81−84. 8. Kojima, S.; Fukuzaki, T.; Yamakawa, A.; Murai, Y. Org. Lett. 2004, 6, 3917−3920. 9. Kano, N.; Kawashima, T. The Peterson and Related Reactions in Modern Carbonyl

Olefination; Takeda, T., Ed.; Wiley-VCH: Weinheim, Germany, 2004, 18−103. (Re-view).

10. Huang, J.; Wu, C.; Wulff, W. D. J. Am. Chem. Soc. 2007, 129, 13366. 11. Ahmad, N. M. Peterson olefination. In Name Reactions for Homologations-Part I; Li,

J. J., Corey, E. J., Eds., Wiley & Sons: Hoboken, NJ, 2009, pp 521−538. (Review).

431

Pictet–Gams isoquinoline synthesis The isoquinoline framework is derived from the corresponding acyl derivatives of β-hydroxy-β-phenylethylamines. Upon exposure to a dehydrating agent such as phosphorus pentoxide, or phosphorus oxychloride, under reflux and in an inert solvent such as decalin, isoquinoline frameworks are formed.

P2O5, decalin

reflux4

3

1HN

OH

O

RN

R

1

34

P2O5 actually exists as P4O10, an adamantane-like structure.

HN

OH

R

O

P O PO

O O

O

: HN

OH

R

OP

O

O

NH

R OPO2

OH

:H

N

R

OH : P O P

O

O O

O

N

RN

R

OPO2H

Example 14

O NH

O

HN

O

HN

HO

OHOH

POCl3, P4O10, decalin

180 oC, 6 h, 14%

N

N

N

Example 27

N O

OH

ClH

P2O5

o-dichlorobenzene 80%

N

Cl

432


Reference 1. (a) Pictet, A.; Kay, F. W. Ber. 1909, 42, 1973−1979. (b) Pictet, A.; Gams, A. Ber.

1909, 42, 2943−2952. Amé Pictet (1857−1937), born in Geneva, Switzerland, carried out a tremendous amount of work on alkaloids.

2. Ardabilchi, N.; Fitton, A. O.; Frost, J. R.; Oppong-Boachie, F. Tetrahedron Lett. 1977, 18, 4107−4110.

3. Ardabilchi, N.; Fitton, A. O.; Frost, J. R.; Oppong-Boachie, F. K.; Hadi, A. H. A.; Sharif, A. M. J. Chem. Soc., Perkin Trans. 1 1979, 539−543.

4. Dyker, G.; Gabler, M.; Nouroozian, M.; Schulz, P. Tetrahedron Lett. 1994, 35, 9697−9700.

5. Poszávácz, L.; Simig, G. J. Heterocycl. Chem. 2000, 37, 343−348. 6. Poszávácz, L.; Simig, G. Tetrahedron 2001, 57, 8573−8580. 7. Manning, H. C.; Goebel, T.; Marx, J. N.; Bornhop, D. J. Org. Lett. 2002, 4,

1075−1081. 8. Holsworth, D. D. Pictet–Gams Isoquinoline Synthesis. In Name Reactions in Hetero-

cyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 457−465. (Review).

433

Pictet–Spengler tetrahydroisoquinoline synthesis Tetrahydroisoquinolines from condensation of β-arylethylamines and carbonyl compounds followed by cyclization.

NH2NHR2 H

O HCl

R2

R1O

R1O

R1O

R1O

NH2H

R2

OR1O

R1O : N

R1O

R1O HOH

R2

+ HH

N

R1O

R1O HR2

N:

R1O

R1O HOH2

R2

− H2O

NH

R2

R1O

R1OH

NH

R2

R1O

R1OH

NH

R2

R1O

R1O

Example 14

NO

O

S

O

O

OAcOMe

HO

MeONH2

NO

O

S

O

OAcOMe

NH

HO

MeOsilica gel

dry EtOH80%

Example 27

NHMe

i-PrO

i-PrOMeO

i-PrO

i-PrOMeO

NMe

(CH2O)n

aq. HCl, EtOH

75%

434


Example 3, Asymmetric acyl Pictet–Spengler9

NH

NH2

OHCOTBDPS

CH2Cl2/Et2O (3 : 1)Na2SO4, 23 oC, 2 h

NH

N

OTBDPS

i-Bu2NNH

NHO

t-Bu S

N Ph

AcCl, 2,6-lutidine, Et2O−78 oC to −60 oC, 23 h

NH

NAc

OTBDPS81% 2 steps

94% ee

Example 4, Oxa-Pictet–Spengler10

O

O O

OH

O

CHO

BF3•OEt2, CH2Cl20 oC to rt, 88%, 88% de

O

O O

O

O

References 1. Pictet, A.; Spengler, T. Ber. 1911, 44, 2030−2036. 2. Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797−1842. (Review). 3. Corey, E. J.; Gin, D. Y.; Kania, R. S. J. Am. Chem. Soc. 1996, 118, 9202−9203. 4. Zhou, B.; Guo, J.; Danishefsky, S. J. Org. Lett. 2002, 4, 43−46. 5. Yu, J.; Wearing, X. Z.; Cook, J. M. Tetrahedron Lett. 2003, 44, 543−547. 6. Tsuji, R.; Nakagawa, M.; Nishida, A. Tetrahedron: Asymmetry 2003, 14, 177−180. 7. Couture, A.; Deniau, E.; Grandclaudon, P.; Lebrun, S. Tetrahedron: Asymmetry 2003,

14, 1309−1320. 8. Tinsley, J. M. Pictet–Spengler Isoquinoline Synthesis. In Name Reactions in Hetero-

cyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 469−479. (Review).

9. Mergott, D. J.; Zuend, S. J.; Jacobsen, E. N. Org. Lett. 2008, 10, 745−748. 10. Eid, C. N.; Shim, J.; Bikker, J.; Lin, M. J. Org. Chem. 2009, 74, 423−426.

435

Pinacol rearrangement Acid-catalyzed rearrangement of vicinal diols (pinacols) to carbonyl compounds.

R1

HO

R3

OHR R2 H

RR2

O

R1R3

The most electron-rich alkyl group (more substituted carbon) migrates first. The general migration order:

tertiary alkyl > cyclohexyl > secondary alkyl > benzyl > phenyl > primary alkyl > methyl >> H.

For substituted aryls: p-MeO-Ar > p-Me-Ar > p-Cl-Ar > p-Br-Ar > p-MeOAr > p-O2N-Ar

R1

HO

R3

OHR R2

R1

HO

R3

OH2R R2

− H2OH

H RR2

O

R1R3RR2

O

R1R3

Halkyl

migration

HO

R3R R2

R1

Example 14

OH

OH

OMeMeO

MeO

OTBDMSOTBDMS

OMe

BF3•OEt2

THF, 68%

OMeMeO

MeOOTBDMS

OTBDMSOMe

CHOH

Example 25

Ph

OH

OH

NSO2Ph

1. MsCl, Et3N, CH2Cl2 0 oC, 10 min.

2. Et3Al, CH2Cl2, −78 oC 10 min., 90% N

SO2Ph

OPh

436


Example 37

Ph OHOHPh

cat. TsOH

CDCl3

Ph PhO O

PhPh

3 : 1 Example 49

N O

OHR

HO

OBnBF3•OEt2

CH2Cl2, 0 oC

N O

RO

OBn R = vinyl, 92%R = allyl, 95%R = furyl, 90%R = prenyl, 94%

98% ee

References 1. Fittig, R. Ann. 1860, 114, 54−63. 2. Magnus, P.; Diorazio, L.; Donohoe, T. J.; Giles, M.; Pye, P.; Tarrant, J.; Thom, S. Tet-

rahedron 1996, 52, 14147−14176. 3. Razavi, H.; Polt, R. J. Org. Chem. 2000, 65, 5693−5706. 4. Pettit, G. R.; Lippert III, J. W.; Herald, D. L. J. Org. Chem. 2000, 65, 7438–7444. 5. Shinohara, T.; Suzuki, K. Tetrahedron Lett. 2002, 43, 6937−6940. 6. Overman, L. E.; Pennington, L. D. J. Org. Chem. 2003, 68, 7143−7157. (Review). 7. Mladenova, G.; Singh, G.; Acton, A.; Chen, L.; Rinco, O.; Johnston, L. J.; Lee-Ruff,

E. J. Org. Chem. 2004, 69, 2017−2023. 8. Birsa, M. L.; Jones, P. G.; Hopf, H. Eur. J. Org. Chem. 2005, 3263−3270. 9. Suzuki, K.; Takikawa, H.; Hachisu, Y.; Bode, J. W. Angew. Chem., Int. Ed. 2007, 46,

3252–3254. 10. Goes, B. Pinacol rearrangement. In Name Reactions for Homologations-Part I; Li, J.

J., Corey, E. J., Eds., Wiley & Sons: Hoboken, NJ, 2009, pp 319−333. (Review).

437

Pinner reaction Transformation of a nitrile into an imino ether, which can be converted to either an ester or an amidine.

R CN R1 OHHCl (g)

R OR1

NH2 ClH+, H2O

NH3, EtOH

R OR1

O

R NH2•HCl

NH2

R1 O R OR1

NH2 ClR N:

HR NH nucleophilic

addition

protonation

H

:

common intermediate

R OR1

NH2 Cl

R OR1

Ohydrolysis

H2O: R OR1

OH2N HH

R OR1

NH2 Cl

R NH2•HCl

NH2

H3N:R NH2

OR1HCl•H2Nnucleophilic

addition

H

H

Example 12

Ph NH

O Ph

N

EtSH, HCl, CH2Cl2

0 oC, 10 min., 95%N O

NHPh

Ph

pyr., H2S

4 h, 0 oC, 42%N O

NH2Ph

Ph Example 22

Ph NH

O

N

EtSH, HCl, CH2Cl2

0 oC, 1 h, 85%

pyr., H2S

2 h, 0 oC, 40%Ph N

H

OSEt

NHPh N

H

OSEt

S Example 36

O2S

OPh

N

MeOH, HCl

Et2O, 0 oC90%

O2S

OPh

HCl•HN OMe

NaHCO3, Et2O

−5 oC, 87−92%

O2S

OPh

HN OMe

438


O2S

OPh

H2N OMe

O2S

OPh

MeO NH2

Ph

NH2

Me

EtOH, rt36 h, 78%

O2S

OPh

HN NH2

Me Ph Example 410

S

N

NC

HCl

EtOH95%

S

N

H2N

OEt

Cl

NaHCO3S

N

HN

OEt

NH4Cl

65%S

N

H2N

NH2Cl

References 1. (a) Pinner, A.; Klein, F. Ber. 1877, 10, 1889–1897. (b) Pinner, A.; Klein, F. Ber.

1878, 11, 1825. 2. Poupaert, J.; Bruylants, A.; Crooy, P. Synthesis 1972, 622–624. 3. Lee, Y. B.; Goo, Y. M.; Lee, Y. Y.; Lee, J. K. Tetrahedron Lett. 1990, 31, 1169–1170. 4. Cheng, C. C. Org. Prep. Proced. Int. 1990, 22, 643–645. 5. Siskos, A. P.; Hill, A. M. Tetrahedron Lett. 2003, 44, 789–794. 6. Fischer, M.; Troschuetz, R. Synthesis 2003, 1603–1609. 7. Fringuelli, F.; Piermatti, O.; Pizzo, F. Synthesis 2003, 2331–2334. 8. Cushion, M. T.; Walzer, P. D.; Collins, M. S.; Rebholz, S.; Vanden Eynde, J. J.; May-

ence, A.; Huang, T. L. Antimicrob. Agents Chemoth. 2004, 48, 4209–4216. 9. Li, J.; Zhang, L.; Shi, D.; Li, Q.; Wang, D.; Wang, C.; Zhang, Q.; Zhang, L.; Fan, Y.

Synlett 2008, 233–236. 10. Racané, L.; Tralic-Kulenovic, V.; Mihalic, Z.; Pavlovic, G.; Karminski-Zamola, G.

Tetrahedron 2008, 64, 11594–11602.

439

Polonovski reaction Treatment of a tertiary N-oxide with an activating agent such as acetic anhydride, resulting in rearrangement where an N,N-disubstituted acetamide and an aldehyde are generated.

(CH3CO)2O

pyr., CH2Cl2R2 N

O

R1

RR

NR1

OR2 H

O

R2 NO

R1

R

O

O O

acylationR2 N

O

R1

RH

O

CH3CO2

R2 NR1

R HOAc

CH3CO2 iminium ion

R2 N:R1

RO O

O

O O

RNR1

OR2 H

OR2 NR

O

OR1

O

OAc

Ac2O

The intramolecular pathway is also operative:

R2 NR

O O

R1

:

RNR1

OR2 H

O

ON

R2

R

R1

O

Example 11

N(CH3CO)2O

100 oCN

OO

Example 22

(CH3CO)2O

< 30 oC, 98%

N N

OO

440


Example 3, Iron salt-mediated Polonovski reaction9

OMe

O

HO H

codeine

NMe

H2O2 then

2 M HCl

OMe

O

HO H NMe

OH

ClFeSO4

87%, 2 steps

OMe

O

HO H NH

References 1. Polonovski, M.; Polonovski, M. Bull. Soc. Chim. Fr. 1927, 41, 1190–1208. 2. Michelot, R. Bull. Soc. Chim. Fr. 1969, 4377–4385. 3. Lounasmaa, M.; Karvinen, E.; Koskinen, A.; Jokela, R. Tetrahedron 1987, 43, 2135–

2146. 4. Tamminen, T.; Jokela, R.; Tirkkonen, B.; Lounasmaa, M. Tetrahedron 1989, 45,

2683–2692. 5. Grierson, D. Org. React. 1990, 39, 85–295. (Review). 6. Morita, H.; Kobayashi, J. J. Org. Chem. 2002, 67, 5378–5381. 7. McCamley, K.; Ripper, J. A.; Singer, R. D.; Scammells, P. J. J. Org. Chem. 2003, 68,

9847–9850. 8. Nakahara, S.; Kubo, A. Heterocycles 2004, 63, 1849–1854. 9. Thavaneswaran, S.; Scammells, P. J. Bioorg. Med. Chem. Lett. 2006, 16, 2868–2871. 10. Volz, H.; Gartner, H. Eur. J. Org. Chem. 2007, 2791–2801.

441

Polonovski–Potier reaction A modification of the Polonovski reaction where trifluoroacetic anhydride is used in place of acetic anhydride. Because the reaction conditions for the Polonovski–Potier reaction are mild, it has largely replaced the Polonovski reaction.

N O (CF3CO)2O

pyr., CH2Cl2

N

O CF3

tertiary N-oxide

N O

F3C O CF3

O O

acylationN O

CF3OH

CF3CO2

N

H

CF3CO2 iminium ion

N:

CF3OF3C

OO

N

O CF3

N

O CF3

HCF3CO2

enamine

Example 12

NH

NNH

NH

(CF3CO)2O, CH2Cl2, 0 oC

then, HCl, heat, 30%HOHO

O

Example 25

N

HN O

O

H

H

OH

N

HN O

O

H

H

OH

OF3C

(CF3CO)2O, pyr.

CH2Cl2, 0 oC, 65%O

442


Example 38

NBoc

N

OHH

Me 1.3 equiv m-CPBA

CH2Cl2, 0 oC, 94% NBoc

N

OHH

Me

O

1. TFAA, CH2Cl2, rt, 3 h

2. KCN, H2O, pH 4 0 oC, 30 min., then rt, 3 h

NBoc

N

OHH

Me

NBoc

N

H

CN O

OHH

HO

25%22% Example 410

HN

HN

CH3

O OH

H

HN

HN

CH3

O H

H 1. m-CPBA, DMF, 0 oC, 0.5 h, 80%

2. Ac2O, Et3N, DMF, 0 oC, 1 h

References 1. Ahond, A.; Cavé, A.; Kan-Fan, C.; Husson, H.-P.; de Rostolan, J.; Potier, P. J. Am.

Chem. Soc. 1968, 90, 5622–5623. 2. Husson, H.-P.; Chevolot, L.; Langlois, Y.; Thal, C.; Potier, P. J. Chem. Soc., Chem.

Commun. 1972, 930–931. 3. Grierson, D. Org. React. 1990, 39, 85–295. (Review). 4. Sundberg, R. J.; Gadamasetti, K. G.; Hunt, P. J. Tetrahedron 1992, 48, 277–296. 5. Kende, A. S.; Liu, K.; Brands, J. K. M. J. Am. Chem. Soc. 1995, 117, 10597–10598. 6. Renko, D.; Mary, A.; Guillou, C.; Potier, P.; Thal, C. Tetrahedron Lett. 1998, 39,

4251–4254. 7. Suau, R.; Nájera, F.; Rico, R. Tetrahedron 2000, 56, 9713–9720. 8. Thomas, O. P.; Zaparucha, A.; Husson, H.-P. Tetrahedron Lett. 2001, 42, 3291–3293. 9. Lim, K.-H.; Low, Y.-Y.; Kam, T.-S. Tetrahedron Lett. 2006, 47, 5037–5039. 10. Gazak, R.; Kren, V.; Sedmera, P.; Passarella, D.; Novotna, M.; Danieli, B.

Tetrahedron 2007, 63, 10466–10478. 11. Nishikawa, Y.; Kitajima, M.; Kogure, N.; Takayama, H. Tetrahedron 2009, 65, 1608–

1617.

443

Pomeranz–Fritsch reaction Isoquinoline synthesis via acid-mediated cyclization of the appropriate ami-noacetal intermediate.

CHOH2N

OEt

OEt

NOEt

OEtH

N

H2NOEt

OEt

H

O

:

NOEt

OEt

OH2

H

condensation:

imine

formation

H

NOEt

OEtH

:

NOEt

OEt:

N

OEtHOEt

N

OEt

NN

OEtH

H

H

Example 13

N

EtO OEt

N

MeO

MeO

MeO

MeO

BF3•AcOH, (CF3CO)2O

60−82 %

Example 24

N

O

OMeH

Me

TiCl4, CH2Cl2

N

O Me

MeO OMe

−78 oC, 69 %

444


Example 39

N

OMe

OMe

Ns

MeO

MeON

Ns

MeO

MeO6 N HCl, EtOH, dioxane

reflux, 30 min., 68%

Example 4, Bobbitt modification10

MeO

MeOHN

H

BrOEt

OEt

NaH, DMF

MeO

MeON

H

OEtEtO

MeO

MeON

H1. 5 M HCl, 12 h, rt

2. NaBH4, TFA, CH2Cl2 38% overall

References 1. (a) Pomeranz, C. Monatsh. 1893, 14, 116−119. Cesar Pomeranz (1860−1926) re-

ceived his Ph.D. degree at Vienna, where he was employed as an associate professor of chemistry. (b) Fritsch, P. Ber. 1893, 26, 419−422. Paul Fritsch (1859−1913) was born in Oels, Silesia. He studied at Munich where he received his doctorate in 1884. Fritsch eventually became a professor at Marburg after several junior positions.

2. Gensler, W. J. Org. React. 1951, 6, 191−206. (Review). 3. Bevis, M. J.; Forbes, E. J.; Naik, N. N.; Uff, B. C. Tetrahedron 1971, 27, 1253−1259. 4. Ishii, H.; Ishida, T. Chem. Pharm. Bull. 1984, 32, 3248−3251. 5. Bobbitt, J. M.; Bourque, A. J. Heterocycles 1987, 25, 601−616. (Review). 6. Gluszy ska, A.; Rozwadowska, M. D. Tetrahedron: Asymmetry 2000, 11, 2359−2368. 7. Capilla, A. S.; Romero, M.; Pujol, M. D.; Caignard, D. H.; Renard, P. Tetrahedron

2001, 57, 8297−8303. 8. Hudson, A. Pomeranz–Fritsch Reaction. In Name Reactions in Heterocyclic Chemis-


9. Bracca, A. B. J.; Kaufman, T. S. Eur. J. Org. Chem. 2007, 5284−5293. 10. Grajewska, A.; Rozwadowska, M. D. Tetrahedron: Asymmetry 2007, 18, 2910−2914.

445

Schlittler–Müller modification Simple permutation where the amine and the aldehyde switch places for the two reactants in comparison to the Pomeranz–Fritsch reaction.

OHC OEt

OEtNH2

R

NOEt

OEt

HN

R R

Example 13

X

R

HN

OMe

OMe

TsR

NTs

OMe

OMe

RN

Ts

H

Example 24

NH2H2N

EtOO

H

OEt

1.

2. oleum, 30%NN

References 1. Schlittler, E.; Müller, J. Helv. Chim. Acta 1948, 31, 914−924, 1119−1132. 2. Guthrie, D. A.; Frank, A. W.; Purves, C. B. Can. J. Chem. 1955, 33, 729−742. 3. Boger, D. L.; Brotherton, C. E.; Kelley, M. D. Tetrahedron 1981, 37, 3977−3980. 4. Gill, E. W.; Bracher, A. W. J. Heterocycl. Chem. 1983, 20, 1107−1109. 5. Hudson, A. Pomeranz–Fritsch Reaction. In Name Reactions in Heterocyclic Chemis-


446

Prévost trans-dihydroxylation Cf. Woodward cis-dihydroxylation.

I2

AgO2CPh

O2CPh

O2CPh

hydrolysisOH

OH

I I I

O2CHPh

SN2I

O

SN2

O

Ph cyclic iodonium ion intermediate neighboring group assistance

O O

Ph

O2CPh

SN2O2CPh

O2CPh

hydrolysis OH

OH

Example 15

FFO

OO

Ph

AgOCOPh, I2

PhH, rt, 2 h, reflux, 10 h, 46%

Ph

O

Example 29

AgOCOPh, I2

CCl4, 74%

O2C-C6H4-p-OMe

O

O2C-C6H4-p-OMe

O

OHI 1. KOH, H2O

2. Ac2O, pyr.

OAc

O

OAcAcO

References 1. Prévost, C. Compt. Rend. 1933, 196, 1129–1131. 2. Campbell, M. M.; Sainsbury, M.; Yavarzadeh, R. Tetrahedron 1984, 40, 5063–5070. 3. Ciganek, E.; Calabrese, J. C. J. Org. Chem. 1995, 60, 4439–4443. 4. Brimble, M. A.; Nairn, M. R. J. Org. Chem. 1996, 61, 4801–4805. 5. Zajc, B. J. Org. Chem. 1999, 64, 1902–1907. 6. Hamm, S.; Hennig, L.; Findeisen, M.; Muller, D. Tetrahedron 2000, 56, 1345–1348. 7. Ray, J. K.; Gupta, S.; Kar, G. K.; Roy, B. C.; Lin, J.-M. J. Org. Chem. 2000, 65,

8134–8138. 8. Sabat, M.; Johnson, C. R. Tetrahedron Lett. 2001, 42, 1209–1212. 9. Hodgson, R.; Nelson, A. Org. Biomol. Chem. 2004, 2, 373–386.

447


Prins reaction The Prins reaction is the acid-catalyzed addition of aldehydes to alkenes and gives different products depending on the reaction conditions.

HR

H H

O

H2O R OH

OH

R OHor or

O O

R

H

RH H

O H2O

R OH

OHH H

OH

R OH

the common intermediate

R OHR OH

H

:B

H

O O

RH H

O

R O

OR OH

H

H

H

H

Example 15

O

TsO

OAc

OBn

SnBr4, CH2Cl2

−78 oC, 84%O

TsO

Br

OBn

Example 27

AcO

(CH2O)n, Bi(OTf)3

CH3CN, rt, 10 h, 77% AcO

OO

448


Example 39

TMSEO2CO

OBn OTBS

O HO

O

O

O

TMSEO2CO

OBn OH

O

O

O

O

In(OTf)3, TMSCl, CH2Cl2

−78 to −40 ºC, 4 h, 42%

Cl

Example 410

OH

O

OHC

PhO2SO OCH3

AcOH, BF3•OEt2

0 oC, CH2Cl2X = OAc, 33%

X = F, 48%

O O

OOCH3

X

PhO2S

References 1. Prins, H. J. Chem. Weekblad 1919, 16, 1072−1023. Born in Zaandam, The Nether-

lands, Hendrik J. Prins (1889−1958) was not even an organic chemist per se. After obtaining a doctorate in chemical engineering, Prins worked for an essential oil com-pany and then a company dealing with the rendering of condemned meats and car-casses. But he had a small laboratory near his house where he carried out his experi-ments in his spare time, which obviously was not a big distraction—for he rose to be the president-director of the firm he worked for.

2. Adam, D. R.; Bhatnagar, S. P. Synthesis 1977, 661−672. (Review). 3. Hanaki, N.; Link, J. T.; MacMillan, D. W. C.; Overman, L. E.; Trankle, W. G.;

Wurster, J. A. Org. Lett. 2000, 2, 223−226. 4. Davis, C. E.; Coates, R. M. Angew. Chem., Int. Ed. 2002, 41, 491−493. 5. Marumoto, S.; Jaber, J. J.; Vitale, J. P.; Rychnovsky, S. D. Org. Lett. 2002, 4,

3919−3922. 6. Braddock, D. C.; Badine, D. M.; Gottschalk, T.; Matsuno, A.; Rodriguez-Lens, M.

Synlett 2003, 345−348. 7. Sreedhar, B.; Swapna, V.; Sridhar, Ch.; Saileela, D.; Sunitha, A. Synth. Commun.

2005, 35, 1177−1182. 8. Aubele, D. L.; Wan, S.; Floreancig, P. E. Angew. Chem., Int. Ed. 2005, 44,

3485−3488. 9. Chan, K.-P.; Ling, Y. H.; Loh, T.-P. Chem. Commun. 2007, 939−941. 10. Bahnck, K. B.; Rychnovsky, S. D. J. Am. Chem. Soc. 2008, 130, 13177−13181.

449

Pschorr cyclization The intramolecular version of the Gomberg−Bachmann reaction.

NH2

CO2HNaNO2, HCl

Cu

CO2H

HON

OH2O

NO

ON

OH

− H2O

ON

ON

O

− NO2NH2

CO2H

:H

NH

CO2H

N O

N:

CO2H

NOH2

N

CO2H

NOH

H HH

− H2O

N2

CO2HCu(0)

CO2H

Cu(I)

H

N2↑

CO2H

6-exo-trig

radical cyclization H

Cu(I)Cu(0)

CO2H

H

Example 17

O

NH2S

OO

1. NaNO2, HCl−H2O−HOAc 0 to 5 oC, 2 h

2. CuSO4, HOAc, reflux 2 h, 86%

O

S

OOO

S

OO

6 : 1

450


Example 28

NN

O

NH2 NaNO2, HCl

5 to 20 oC, 64%

NN

O

Example 310

O

Br

hv (350 nM)

MeCN, N2

O

OO

34% 62%

References

1. Pschorr, R. Ber. 1896, 29, 496−501. Robert Pschorr (1868−1930), born in Munich,

Germany, studied under von Baeyer, Bamberger, Knorr, and Fischer. He became an assistant professor in 1899 at Berlin where he discovered the phenanthrene synthesis. During WWI, Pschorr served as a major in the German Army.

2. Kupchan, S. M.; Kameswaran, V.; Findlay, J. W. A. J. Org. Chem. 1973, 38, 405−406. 3. Wassmundt, F. W.; Kiesman, W. F. J. Org. Chem. 1995, 60, 196−201. 4. Qian, X.; Cui, J.; Zhang, R. Chem. Commun. 2001, 2656−2657. 5. Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102,

1359−1469. (Review). 6. Karady, S.; Cummins, J. M.; Dannenberg, J. J.; del Rio, E.; Dormer, P. G.; Marcune,

B. F.; Reamer, R. A.; Sordo, T. L. Org. Lett. 2003, 5, 1175−1178. 7. Xu, Y.; Qian, X.; Yao, W.; Mao, P.; Cui, J. Bioorg. Med. Chem. 2003, 11, 5427−5433. 8. Tapolcsányi, P.; Maes, B. U. W.; Monsieurs, K.; Lemière, G. L. F.; Riedl, Z.; Hajós,

G.; Van der Driessche, B.; Dommisse, R. A.; Mátyus, P. Tetrahedron 2003, 59, 5919−5926.

9. Mátyus, P.; Maes, B. U. W.; Riedl, Z.; Hajós, G.; Lemière, G. L. F.; Tapolc anyi, P.; Monsieurs, K.; Éliás, O.; Dommisse, R. A.; Krajsovszky, G. Synlett 2004, 1123−1139. (Review).

10. Moorthy, J. N.; Samanta, S. J. Org. Chem. 2007, 72, 9786−9789.

451

Pummerer rearrangement The transformation of sulfoxides into α-acyloxythioethers using acetic anhydride.

R1 S R2O Ac2O R1 S R2

OAc

R1 S R2O

O

OO

R1 S R2O

O

HR1 S R2

O

OOO

acyl

transfer

AcO

AcO

R1 S R2

OAcR1 S R2 R1 S R2

AcO

HOAc

Example 12

BnOSPh

OH

OH

1. Me2C(OMe)2, H+

2. m-CPBA, CH2Cl2, −20 oC

3. Ac2O, NaOAc, reflux, 6 h 81%

BnOSPh

O

O

OAc

Example 27

MeO

MeO

N

N N

CO2Et

SOPh O

N

NN

CO2EtPhS

MeO

MeO

OBn Bn

TMSOTf, DIPEA

CH2Cl2, −20 oC88%, dr = 2:1

Example 38

N

OSEtO

MeO

MeOCO2Me

Br

N

MeO2CSEt

HO

Br

MeO

MeOCSA, PhMe

reflux, 88%

452


Example 49

BnN SBn

Ph

O OAc2O, pyr., DMAP

CH2Cl2, rt, 91%Bn

N SBn O

OAcPh

References 1. Pummerer, R. Ber. 1910, 43, 1401−1412. Rudolf Pummerer, born in Austria in 1882,

studied under von Baeyer, Willstätter, and Wieland. He worked for BASF for a few years and in 1921 he was appointed head of the organic division of the Munich Labo-ratory, fulfilling his long-desired ambition.

2. Katsuki, T.; Lee, A. W. M.; Ma, P.; Martin, V. S.; Masamune, S.; Sharpless, K. B.; Tuddenham, D.; Walker, F. J. J. Org. Chem. 1982, 47, 1373−1378.

3. De Lucchi, O.; Miotti, U.; Modena, G. Org. React. 1991, 40, 157−406. (Review). 4. Padwa, A.; Gunn, D. E., Jr.; Osterhout, M. H. Synthesis 1997, 1353−1378. (Review). 5. Padwa, A.; Waterson, A. G. Curr. Org. Chem. 2000, 4, 175−203. (Review). 6. Padwa, A.; Bur, S. K.; Danca, D. M.; Ginn, J. D.; Lynch, S. M. Synlett 2002, 851−862.

(Review). 7. Gámez Montaño, R.; Zhu, J. Chem. Commun. 2002, 2448−2449. 8. Padwa, A.; Danca, M. D.; Hardcastle, K.; McClure, M. J. Org. Chem. 2003, 68, 929. 9. Suzuki, T.; Honda, Y.; Izawa, K.; Williams, R. M. J. Org. Chem. 2005, 70, 7317. 10. Ahmad, N. M. Pummerer rearrangement. In Name Reactions for Homologations-Part


453

Ramberg–Bäcklund reaction Olefin synthesis via α-halosulfone extrusion.

SO O

R R1

X Base

R

R1

S O↑O

SO O

R R1

X HS

O OX R1

Rbackside

displacement

:B

R

R1

S O↑OS

O O

SO2

extrusion

R R1

episulfone intermediate Example 14

SO2

H

HBr

KOt-Bu, THF

−15 oC to rt, 71%

H

Example 25

HSO2CH2Br

Br KOt-Bu, THF/HOt-Bu

0 oC to rt, 0.5 h, 65%

Example 36

OO

O

O

O

O2S

Cl

H

1. 2.2 eq. KOt-Bu, 10 eq. HMPADME, 70 oC, 5 min., 82%

2. 6 N HCl/THF (1:10, v/v), rt, 4 h, 85%

O O

O

O

O

OH

H

454


Example 4, in situ chlorination7

O2S O

TMSO

TMSO

1. t-BuOK, t-BuOH CCl4, rt, 65%

2. TsOH, H2O, EtOH rt, 95%

O

HO

HO

References 1. Ramberg, L.; Bäcklund, B. Arkiv. Kemi, Mineral Geol. 1940, 13A, 1−50. 2. Paquette, L. A. Acc. Chem. Res. 1968, 1, 209−216. (Review). 3. Paquette, L. A. Org. React. 1977, 25, 1−71. (Review). 4. Becker, K. B.; Labhart, M. P. Helv. Chim. Acta 1983, 66, 1090−1100. 5. Block, E.; Aslam, M.; Eswarakrishnan, V.; Gebreyes, K.; Hutchinson, J.; Iyer, R.; Laf-

fitte, J. A.; Wall, A. J. Am. Chem. Soc. 1986, 108, 4568−4580. 6. Boeckman, R. K., Jr.; Yoon, S. K.; Heckendorn, D. K. J. Am. Chem. Soc. 1991, 113,

9682−9784. 7. Trost, B. M.; Shi, Z. J. Am. Chem. Soc. 1994, 116, 7459−7460. 8. Taylor, R. J. K. Chem. Commun. 1999, 217−227. (Review). 9. Taylor, R. J. K.; Casy, G. Org. React. 2003, 62, 357−475. (Review). 10. Li, J. J. Ramberg–Bäcklund olefin synthesis. In Name Reactions for Functional Group


11. Pal, T. K.; Pathak, T. Carbohydrate Res. 2008, 343, 2826−2829. 12. Baird, L. J.; Timmer, M. S. M.; Teesdale-Spittle, P. H.; Harvey, J. E. J. Org. Chem.

2009, 74, 2271−2277.

455

Reformatsky reaction Nucleophilic addition of organozinc reagents generated from α-haloesters to car-bonyls.

R R1

OBr

OR2

O

Zn OR2

O

HO

R1R

R R1

OBr

OR2

O

Zn(0)

oxidative addition orelectron transfer

OR2

O

nucleophilic

additionZnBr

OR2

O

BrZnO

R1R

H2O, hydrolysis

during workup

OR2

O

HO

R1R

Example 14

NS

Boc

Ph

OTBDMSBrCH2CO2Me

Zn, THF, reflux, 71% NBoc

Ph

OTBDMS

MeO2C

Example 26

MeO

O

OBr

OZn, THF

60 oC

MeO

HO O

OMeO

O

OHCl

THF, rt, 10 h92%

456


Example 3, Boron-mediated Reformatsky reaction8

O

I

OO

OP

P = TBS

Me

H

H

OBEt3, tol.

−78 oC, quant.

O

OO

OP

Me

H

H

OH

single diastereomer

H

Example 4, SmI2-mediated Reformatsky reaction9

O

BrOSiEt3

OTBDPS

OH

Me

MeO

n-Bu CHOOSiEt3

1. SmI2, THF, −78 oC

2. Martin sulfurane, CH2Cl2 72%, 2 steps

O

O

OSiEt3

OTBDPS

OH

Me

n-Bu

Me

OSiEt3

References 1. Reformatsky, S. Ber. 1887, 20, 1210−1211. Sergei Reformatsky (1860−1934) was

born in Russia. He studied at the University of Kazan in Russia, the cradle of Russian chemistry professors, where he found competent guidance of a distinguished chemist, Alexander M. Za tsev. Reformatsky then studied at Göttingen, Heidelberg, and Leip-zig in Germany. After returning to Russia, Reformatsky became the Chair of Organic Chemistry at the University of Kiev.

2. Rathke, M. W. Org. React. 1975, 22, 423−460. (Review). 3. Fürstner, A. Synthesis 1989, 571−590. (Review). 4. Lee, H. K.; Kim, J.; Pak, C. S. Tetrahedron Lett. 1999, 40, 2173−2174. 5. Fürstner, A. In Organozinc Reagents Knochel, P., Jones, P., Eds.; Oxford University

Press: New York, 1999, pp 287−305. (Review). 6. Zhang, M.; Zhu, L.; Ma, X. Tetrahedron: Asymmetry 2003, 14, 3447−3453. 7. Ocampo, R.; Dolbier, W. R., Jr. Tetrahedron 2004, 60, 9325−9374. (Review). 8. Lambert, T. H.; Danishefsky, S. J. J. Am. Chem. Soc. 2006, 128, 426−427. 9. Moslin, R. M.; Jamison, T. F. J. Am. Chem. Soc. 2006, 128, 15106−15107. 10. Cozzi, P. G. Angew. Chem., Int. Ed. 2007, 46, 2568−2571. (Review). 11. Ke, Y.-Y.; Li, Y.-J.; Jia, J.-H.; Sheng, W.-J.; Han, L.; Gao, J.-R. Tetrahedron Lett.

2009, 50, 1389−1391.

457

Regitz diazo synthesis Synthesis of 2-diazo-1,3-diketones or 2-diazo-3-oxoesters using sulfonyl azides.

R OR1

O O

TsN3, Et3N

MeCNR OR1

O O

N2

Ts NH2

R OR1

O O

H enolate

formation R OR1

O O

SNNNO

O

:NEt3

R OR1

O O

HNN

NSO2Tol

proton

transferSH2NO

OR OR1

O O

NN

R OR1

O O

NN

HN

SO2Tol:

tosyl amide is the by-product

When only one carbonyl is present, ethylformate can be used as an activating aux-iliary:6−9

O

NaH, HCO2Et

Et2O

O

OHMsN3

Et2O

ON2

:NEt3O

OH

O

O

MeSNNNO

OO

NN

NSO2Me

H

O

ON2MeSHN

O

OOH

ON

NO

NNN

SO2Me

H O

Alternatively, the triazole intermediate may be assembled via a 1,3-dipolar cycloaddition of the enol and mesyl azide:

458


O

NNN

SO2Me

H OH

O

OH

MeSNNNO

O1,3-dipolar

cycloaddition

ON2MeSHN

O

OOH

Example 15

O H

N

OSO2N3O

Ot-Bu

O

Et3N, CH3CN

0 oC, 5 h, 45%

O

O

Ot-Bu

O

N2

Example 210

N NH

OTIPSO O O O

N

CH3SO2N3

CH3CN, 84%

N NH

OTIPSO O O O

NN2

References 1. (a) Regitz, M. Angew. Chem., Int. Ed. 1967, 6, 733–741. (b) Regitz, M.; Anschütz,

W.; Bartz, W.; Liedhegener, A. Tetrahedron Lett. 1968, 9, 3171–3174. (c) Regitz, M. Synthesis 1972, 351–373. (Review).

2. Pudleiner, H.; Laatsch, H. Ann. 1990, 423–426. 3. Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am. Chem. Soc. 1990, 112,

4011–4030. 4. Charette, A. B.; Wurz, R. P.; Ollevier, T. J. Org. Chem. 2000, 65, 9252–9254. 5. Hodgson, D. M.; Labande, A. H.; Pierard, F. Y. T. M.; Expésito Castro, M. A. J. Org.

Chem. 2003, 68, 6153–6159. 6. Sarpong, R.; Su, J. T.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 13624–13628. 7. Mejía-Oneto, J. M.; Padwa, A. Org. Lett. 2004, 6, 3241–3244. 8. Muroni, D.; Saba, A.; Culeddu, N. Tetrahedron: Asymmetry 2004, 15, 2609–2614. 9. Davies, J. R.; Kane, P. D.; Moody, C. J. Tetrahedron 2004, 60, 3967–3977. 10. Oguri, H.; Schreiber, S. L. Org. Lett. 2005, 7, 47–50.

459

Reimer–Tiemann reaction Synthesis of o-formylphenol from phenols and chloroform in alkaline medium.

OH

CHCl3

OH

3 KClCHO3 KOH 2 H2O

a. Carbene generation:

Cl3C HOH

CCl2H2OCl α-elimination

− Cl−, slow:CCl2

fast

b. Addition of dichlorocarbene and hydrolysis:

OH

H2O CCl2

KOHO O

CCl2

HO

CHClCl

OHO Cl

H

O Cl

HOH

OHCHO

O O

H

H

Example 1, Photo-Reimer–Tiemann reaction without base7

CN

OH

hv (Hg lamp)

CHCl3, 5 h, 48%CN

OCHCl2

Example 28

OH

NHBoc

CO2H

CHCl3, 6 eq. NaOH

2 eq. H2O, reflux4 h, 64%

OH

NHBoc

CO2H

CHO

References 1. Reimer, K.; Tiemann, F. Ber. 1876, 9, 824–828. 2. Wynberg, H.; Meijer, E. W. Org. React. 1982, 28, 1–36. (Review). 3. Bird, C. W.; Brown, A. L.; Chan, C. C. Tetrahedron 1985, 41, 4685–4690. 4. Neumann, R.; Sasson, Y. Synthesis 1986, 569–570. 5. Cochran, J. C.; Melville, M. G. Synth. Commun. 1990, 20, 609–616. 6. Langlois, B. R. Tetrahedron Lett. 1991, 32, 3691–3694. 7. Jiménez, M. C.; Miranda, M. A.; Tormos, R. Tetrahedron 1995, 51, 5825–5828. 8. Jung, M. E.; Lazarova, T. I. J. Org. Chem. 1997, 62, 1553–1555.

460


Reissert reaction Treatment of quinoline or isoquinoline with acid chloride and KCN gives qui-naldic acid, aldehyde, and KCN.

R Cl

O N

KCN

N

O RCN

H H2SO4

R H

O

N CO2HNH3

Reissert Compound

N N

O RCN

H

:

R O

Cl N

O R

H

CN

N

R O

H

NH

H

Reissert compound

N:O

R

NHH

:

HNO

R

NH

H

HO

H

NO

R

NHH

H

NO

R H

NH2

OHN

OR H

NH2

O HR H

ON

O

NH2

H

NO

NH2

H

H2O:

NH3N CO2H

NO

NH2HO

H

Example 13

Cl

O

MeO

MeO

OMeN

NaCN, H2O, CH2Cl2

4.5 h, 95%

461


H

O

MeO

MeO

OMe

N CN

OMeO

OMeMeO

30% H2SO4

reflux, 1 h, 95%

Example 2, Reissert compound from isoquinoline7

N

Br

chiral Al catalystTMSCN, CH2=CHOCOCl

CH2Cl2, −40 oC, 72 h, 53%

N

Br

CN

O

O

73% ee

Example 3, Reissert compound fron isoquinoline10

N

OCl

O

TMS-CN, CH2Cl248 h, rt, 96%

N

CN O

O N

CN O

O

1 : 1

Reissert compounds References 1. (a) Reissert, A. Ber. 1905, 38, 1603–1614. (b) Reissert, A. Ber. 1905, 38, 3415–3435.

Carl Arnold Reissert was born in 1860 in Powayen, Germany. He received his Ph.D. In 1884 at Berlin, where he became an assistant professor. He collaborated with Tie-mann. Reissert later joined the faculty at Marburg in 1902.

2. Popp, F. D. Adv. Heterocycl. Chem. 1979, 24, 187–214. (Review). 3. Schwartz, A. J. Org. Chem. 1982, 47, 2213–2215. 4. Lorsbach, B. A.; Bagdanoff, J. T.; Miller, R. B.; Kurth, M. J. J. Org. Chem. 1998, 63,

2244–2250. 5. Perrin, S.; Monnier, K.; Laude, B.; Kubicki, M.; Blacque, O. Eur. J. Org. Chem. 1999,

297–303. 6. Takamura, M.; Funabashi, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123,

6801–6808. 7. Shibasaki, M.; Kanai, M.; Funabashi, K. Chem. Commun. 2002, 1989–1999. 8. Sieck, O.; Schaller, S.; Grimme, S.; Liebscher, J. Synlett 2003, 337–340. 9. Kanai, M.; Kato, N.; Ichikawa, E.; Shibasaki, M. Synlett 2005, 1491–1508. (Review). 10. Gibson, H. W.; Berg, M. A. G.; Clifton Dickson, J.; Lecavalier, P. R.; Wang, H.; Mer-

ola, J. S. J. Org. Chem. 2007, 72, 5759–5770. 11. Fuchs, C.; Bender, C.; Ziemer, B.; Liebscher, J. J. Heterocycl. Chem. 2008, 45, 1651–

1658.

462

Reissert indole synthesis The Reissert indole synthesis involves base-catalyzed condensation of an o-nitrotoluene derivative with an ethyl oxalate, which is followed by reductive cy-clization to an indole-2-carboxylic acid derivative.

NO2

CO2EtCO2Et

NO2

CO2Et

O

BR R

NH

CO2HHR H

CH2

NO2

EtO

OEtO

OCH3

NO2 NO2

OHOEt

CO2Et

B H

NO2CO2Et

Ohydrolysis

NO2CO2H

O H

NH2CO2H

O

NH

CO2H

H

NH

CO2H H

NH

CO2H

OH

Example 12

N

MeO

NO2

CO2EtCO2Et

KOEt

93% N

MeO

NO2

N

MeO

NH

CO2EtH2, Pd/C

EtOH, 85%

CO2EtO

Example 23

NO2

CO2EtCO2Et

KOEt, EtOH

Et2O NO2

CO2Et

OKH2 (30 psi), PtO2

HOAc, 41−44% NH

CO2Et

463


Example 3, Furan ring as the masked carbonyl10

O

O

NHMs

PhO

HCl, EtOH

reflux, 84%

O

O

N

Ph

Ms

O

References 1. Reissert, A. Ber. 1897, 30, 1030−1053. 2. Frydman, B.; Despuy, M. E.; Rapoport, H. J. Am. Chem. Soc. 1965, 87, 3530−3531. 3. Noland, W. E.; Baude, F. J. Org. Synth. 1973; Coll. Vol. 567−571. 4. Leadbetter, G.; Fost, D. L.; Ekwuribe, N. N.; Remers, W. A. J. Org. Chem. 1974, 39,

3580−3583. 5. Cannon, J. G.; Lee, T.; Ilhan, M.; Koons, J.; Long, J. P. J. Med. Chem. 1984, 27,

386−389. 6. Suzuki, H.; Gyoutoku, H.; Yokoo, H.; Shinba, M.; Sato, Y.; Yamada, H.; Murakami,

Y. Synlett 2000, 1196−1198. 7. Butin, A. V.; Stroganova, T. A.; Lodina, I. V.; Krapivin, G. D. Tetrahedron Lett. 2001,

42, 2031−2036. 8. Katayama, S.; Ae, N.; Nagata, R. J. Org. Chem. 2001, 66, 3474−3483. 9. Li, J.; Cook, J. M. Reissert Indole Synthesis. In Name Reactions in Heterocyclic


10. Butin, A. V.; Smirnov, S. K.; Stroganova, T. A.; Bender, W.; Krapivin, G. D. Tetrahe-dron 2006, 63, 474−491.

464

Ring-closing metathesis (RCM)

NMoO

O Ph

F3CF3C

F3CF3C

PhRu

ClCl

Cy3P

N NMes Mes

PhRu

ClCl

Cy3P

PCy3

Grubbs’ catalysts Schrock’s catalyst Mes = mesityl All three catalysts are illustrated as “LnM=CHR” in the mechanism below.

Generation of the real catalyst from the precatalysts:

CHRLnM LnMR

the active catalyst

CHRLnM

[2 + 2]

cycloaddition

LnM CHRcycloreversion

CHRMLn

[2 + 2]

cycloadditionMLn

cycloreversionLnM

Catalytic cycle:

LnM

LnM[2 + 2]

cycloaddition

LnMcycloreversion MLn

[2 + 2]

cycloaddition

MLn cycloreversionLnM

465


Example 13

OO C11H23OO C11H23

10 mol% (PCy3)2Cl2Ru=CHPh

0.3 eq. Ti(Oi-Pr)4CH2Cl2, 40 oC, 93%

Example 25

PhRu

ClCl

Cy3P

N NMes MesEE

45 oC, 60 min., 100%

EE

E = CO2Et

Example 37

O

OO

OBn

1. cat. PhH (0.07 mM) 80 oC, then air

2. 10% Pd/C, H2, EtOAc, rt 80−85%

O

OO

OBn

MesN NMes

Ru

OCl

Clcat. =

Example 49

O

OBzO

H

HCH2Cl2, rt, 73%

5.4 mol%

PhRu

ClCl

Cy3P

N NMes Mes

O

OH

OBz

CH2Cl2, rt, 93%, > 10:1 E:Z

5 mol%

PhRu

ClCl

Cy3P

N NMes Mes

O

OH

OBz

466

Example 510

O

O O O

OTBSO

TES

15 mol% Grubbs II

toluene, 110 oC, 78%

O OTES

OO

TBSO O

singleisomer

Example 612

NH

N

NH

N

NMo

O

N Ph

Cl

TBSO

Cl

1. 1 mol%

PhH, rt, 1 h

2. H2, Pd/C, 81%, 96% ee

References 1. Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; DiMare, M.; O’Regan, M. J.

Am. Chem. Soc. 1990, 112, 3875–3886. Richard Schrock is a professor at MIT. He shared the 2005 Nobel Prize in Chemistry with Robert Grubbs of Caltech and Yves Chauvin of Institut Français du Pétrole in France for their contributions to metathesis.

2. Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446–452. (Review). 3. Scholl, M.; Tunka, T. M.; Morgan, J. P.; Grubbs, R. H. Tetrahedron Lett. 1999, 40,

2247–2250. 4. Fellows, I. M.; Kaelin, D. E., Jr.; Martin, S. F. J. Am. Chem. Soc. 2000, 122, 10781–

10787. 5. Timmer, M. S. M.; Ovaa, H.; Filippov, D. V.; van der Marel, G. A.; van Boom, J. H.

Tetrahedron Lett. 2000, 41, 8635–8638. 6. Thiel, O. R. Alkene and alkyne metathesis in organic synthesis. In Transition Metals

for Organic Synthesis (2nd Edn.), 2004, 1, pp 321–333. (Review). 7. Smith, A. B., III; Basu, K.; Bosanac, T. J. Am. Chem. Soc. 2007, 129, 14872–14874. 8. Hoveyda, A.H.; Zhugralin, A. R. Nature 2007, 450, 243–251. (Review). 9. Marvin, C. C.; Clemens, A. J. L.; Burke, S. D. Org. Lett. 2007, 9, 5353–5356. 10. Keck, G. E.; Giles, R. L.; Cee, V. J.; Wager, C. A.; Yu, T.; Kraft, M. B. J. Org. Chem.

2008, 73, 9675–9691. 11. Donohoe, T. J.; Fishlock, L. P.; Procopiou, P. A. Chem. Eur. J. 2008, 14, 5716–5726.

(Review). 12. Sattely, E. S.; Meek, S. J.; Malcolmson, S. J.; Schrock, R. R.; Hoveyda, A. H. J. Am.

Chem. Soc. 2009, 131, 943–953.

467

Ritter reaction Amides from nitriles and alcohols in strong acids. General scheme:

R1 OH R2 CNH

R1NH

R2

O

e.g.:

H3C CNOHH2SO4

H2ONH

O

HOH OH2

:NH2OE1

N

nitrilium ion

N

:OH2

NH

O

N

OH2

N

OHH

Similarly:

H3C CNH2SO4

H2O NH

O

Example 13

CrCO

COOC

HOH

CrCO

COOC

MeOCHNH

H2SO4

MeCN89%

Example 24

N

CH3

CN

t-BuOH, conc. H2SO4

70−75 oC, 75 min., 97%N

CH3

O

HN

468


Example 35

OO2N

NO2

O2N

NO2

OHNH

OPt electrode, E = 2.5 V

CH3CN, LiClO4

H2O, 56%, dr 8:2

Example 46

O

fuming H2SO4, CH3CN, rt, 30 min.,

then H2O, 100 oC, 2 h, 77%

OH

NH2

References 1. (a) Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70, 4045−4048. (b) Ritter, J. J.;

Kalish, J. J. Am. Chem. Soc. 1948, 70, 4048−4050. 2. Krimen, L. I.; Cota, D. J. Org. React. 1969, 17, 213–329. (Review). 3. Top, S.; Jaouen, G. J. Org. Chem. 1981, 46, 78−82. 4. Schumacher, D. P.; Murphy, B. L.; Clark, J. E.; Tahbaz, P.; Mann, T. A. J. Org. Chem.

1989, 54, 2242−2244. 5. Le Goanvic, D; Lallemond, M.-C.; Tillequin, F.; Martens, T. Tetrahedron Lett. 2001,

42, 5175−5176. 6. Tanaka, K.; Kobayashi, T.; Mori, H.; Katsumura, S. J. Org. Chem. 2004, 69,

5906−5925. 7. Nair, V.; Rajan, R.; Rath, N. P. Org. Lett. 2002, 4, 1575−1577. 8. Concellón, J. M.; Riego, E.; Suárez, J. R.; García-Granda, S.; Díaz, M. R. Org. Lett.

2004, 6, 4499−4501. 9. Penner, M.; Taylor, D.; Desautels, D.; Marat, K.; Schweizer, F. Synlett 2005,

212−216. 10. Brewer, A. R. E. Ritter reaction. In Name Reactions for Functional Group Transfor-


11. Baum, J. C.; Milne, J. E.; Murry, J. A.; Thiel, O. R. J. Org. Chem. 2009, 74, 2207−2209.

469

Robinson annulation Michael addition of cyclohexanones to methyl vinyl ketone followed by in-tramolecular aldol condensation to afford six-membered α,β-unsaturated ketones.

O

R

O baseO

R

methyl vinyl ketone (MVK)

O

R

O

H

B:

O

R

enolate

formation

Michael

additionisomerization

O

RO

O

RO

aldol

addition

H B O

R

− H2O

dehydrationO

R

HOH

:B

Example 1, Homo-Robinson7

TMSOO

MVK, AcOH, BF3•OEt2

−20 oC, 97% OO

NaOMe

98%

2.5 equiv LDA, TMSCl

THF, −78 oC TMSO

1.5 equiv Et2Zn1.1 equiv CH2I2

Et2O, 0 oC

TMSO

1. 2.5 equiv FeCl3, 0 oC2. NaOAc, reflux

40% for 4 steps O Example 28

O O 3 equiv TfOH, P4O10

CH2Cl2, microwave40 oC, 8 h, 57%

O

470


Example 3, Double Robinson-type cyclopentene annulation9

CO2R

RO2C

OH

OH

O10 equiv

0.1 equiv FeCl3•6H2OCH2Cl2, 60 oC, 2 d

O

O

O

O

CO2RRO2C

conc. H2SO40 oC, 1 h

then rt, 16 h

O

O

CO2R

RO2C

Example 410

O

CN

O

DBU, tol., reflux, 20 h,16% NC

O

References 1. Rapson, W. S.; Robinson, R. J. Chem. Soc. 1935, 1285–1288. Robert Robinson used

the Robinson annulaton in his total synthesis of cholesterol. Here is a story told by Derek Barton about Robinson and Woodward: “By pure chance, the two great men met early in a Monday morning on an Oxford train station platform in 1951. Robinson politely asked Woodward what kind of research he was doing these days; Woodward replied that he thought that Robinson would be interested in his recent total synthesis of cholesterol. Robinson, incensed and shouting ‘Why do you always steal my re-search topic?’, hit Woodward with his umbrella.”—An excerpt from Barton, Derek, H. R. Some Recollections of Gap Jumping, American Chemical Society, Washington, D.C., 1991.

2. Gawley, R. E. Synthesis 1976, 777–794. (Review). 3. Guarna, A.; Lombardi, E.; Machetti, F.; Occhiato, E. G.; Scarpi, D. J. Org. Chem.

2000, 65, 8093–8096. 4. Tai, C.-L.; Ly, T. W.; Wu, J.-D.; Shia, K.-S.; Liu, H.-J. Synlett 2001, 214–217. 5. Jung, M. E.; Piizzi, G. Org. Lett. 2003, 5, 137–140. 6. Singletary, J. A.; Lam, H.; Dudley, G. B. J. Org. Chem. 2005, 70, 739–741. 7. Yun, H.; Danishefsky, S. J. Tetrahedron Lett. 2005, 46, 3879–3882. 8. Jung, M. E.; Maderna, A. Tetrahedron Lett. 2005, 46, 5057–5061. 9. Zhang, Y.; Christoffers, J. Synthesis 2007, 3061–3067. 10. Jahnke, A.; Burschka, C.; Tacke, R.; Kraft, P. Synthesis 2009, 62–68.

471

Robinson–Gabriel synthesis Cyclodehydration of 2-acylamidoketones to give 2,5-di- and 2,4,5-trialkyl, aryl, heteroaryl-, and aralkyloxazoles.

HNR3R1

R2

O

NR3R1

R2

O O

− H2O

R1, R2, R3 = alkyl, aryl, heteroaryl

O

N R3

R1

R2

OH

NR3R1

R2

O O

H H

O

NR3R1

R2− H2O

Example 13

O

N

O

O

CbzHN

H

O

HN

O

O

O

CbzHN

HH

Ph3P, I2, Et3N

55%

Example 24

O

OTIPS

MeO

H

HN

OMe

HOO

N

O

O

OH

OMe H

NOMe

N

OR

O

1. Dess−Martin, CH2Cl22. Ph3P, BrCCl2CCl2Br

3. DBU, CH3CN4. TBAF, THF 42% (+)-hennoxazole A

Example 3, Halogen effect9

HN

NHO

O 2 equiv PPh3

CCl4, MeCNreflux, 97% N N

O

472


HN

NHO

O 2 equiv PPh3

CBr4, MeCNreflux, 68% N N

OBr

Example 410

NH

OTBSN

OTBDPSO

O CHO

1. PPh3, C2Br2Cl4, CH2Cl2 2,6-di-tert-butylpyridine NaHCO3, CH2Cl2, 0 oC

2. Et3N, MeCN, 0 oC to rt 89% for 2 steps

N

OTBDPSO

N

OOTBS

References 1. (a) Robinson, R. J. Chem. Soc. 1909, 95, 2167−2174. (b) Gabriel, S. Ber. 1910, 43,

134−138. (c) Gabriel, S. Ber. 1910, 43, 1283−1287. 2. Turchi, I. J. In The Chemistry of Heterocyclic Compounds, 45; Wiley: New York,

1986; pp 1−342. (Review). 3. Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604−3606. 4. Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 117, 558−559. 5. Morwick, T.; Hrapchak, M.; DeTuri, M.; Campbell, S. Org. Lett. 2002, 4, 2665−2668. 6. Nicolaou, K. C.; Rao, P. B.; Hao, J.; Reddy, M. V.; Rassias, G.; Huang, X.; Chen, D.

Y.-K.; Snyder, S. A. Angew. Chem., Int. Ed. 2003, 42, 1753−1758. 7. Godfrey, A. G.; Brooks, D. A.; Hay, L. A.; Peters, M.; McCarthy, J. R.; Mitchell, D. J.

Org. Chem. 2003, 68, 2623−2632. 8. Brooks, D. A. Robinson–Gabriel Synthesis. In Name Reactions in Heterocyclic Chem-

istry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 249−253. (Re-view).

9. Yang, Y.-H.; Shi, M. Tetrahedron Lett. 2005, 46, 6285–6288. 10. Bull, J. A.; Balskus, E. P.; Horan, R. A. J.; Langner, Martin; Ley, Steven V. Angew.

Chem., Int. Ed. 2006, 45, 6714−6718.

473

Robinson−Schöpf reaction 1,4-Diketone condensations with primary amines to give tropinones.

CHO

CHONH2

CO2H

CO2H

O

N

O

2 CO2↑ 2 H2O

CHO

O

HNH2:

CHO

OH

HN:

CHO

N

HO2C CO2HO

H

imine

formation

− H2O

HO2C CO2HO

NHH

O

:

HO2C CO2HO

N

OH

:

HO2C CO2HO

N

H

− H2O

hemiaminal

CO2↑

N

OHHO2C

decarboxylationN

OHO2C

OO

H

N

OOO

H

N

OH

N

O

CO2↑

Example 15

OHNH2

HPh O OMeMeO

KCN, citric acid, H2O, rt, 24−48 h

then EtOH, reflux, 96 h

N O

Ph

NC

474


Example 29

CO2H

CO2H

ONH2

CHO

OH

CHOTHF, rt

72 h, 51%

OH

O

N

References 1. Robinson, R. J. Chem. Soc. 1917, 111, 762–768. 2. Paquette, L. A.; Heimaster, J. W. J. Am. Chem. Soc. 1966, 88, 763–768. 3. Büchi, G.; Fliri, H.; Shapiro, R. J. Org. Chem. 1978, 43, 4765–4769. 4. Guerrier, L.; Royer, J.; Grierson, D. S.; Husson, H. P. J. Am. Chem. Soc. 1983, 105,

7754–7755. 5. Royer, J.; Husson, H. P. Tetrahedron Lett. 1987, 28, 6175–6178. 6. Villacampa, M.; Martínez, M.; González-Trigo, G.; Söllhuber, M. M. J. Heterocycl.

Chem. 1992, 29, 1541–1544. 7. Bermudez, J.; Gregory, J. A.; King, F. D.; Starr, S.; Summersell, R. J. Bioorg. Med.

Chem. Lett. 1992, 2, 519–522. 8. Langlois, M.; Yang, D.; Soulier, J. L.; Florac, C. Synth. Commun. 1992, 22, 3115–

3116. 9. Jarevång, T.; Anke, H.; Anke, T.; Erkel, G.; Sterner, O. Acta Chem. Scand. 1998, 52,

1350–1352. 10. Amedjkouh, M.; Westerlund, K. Tetrahedron Lett. 2004, 45, 5175–5177.

475

Rosenmund reduction Hydrogenation reduction of acid chloride to aldehyde using BaSO4-poisoned pal-ladium catalyst. Without this poisoning, the resulting aldehyde may be further re-duced to the corresponding alcohol.

R Cl

O H2

Pd−BaSO4 R H

O

Pd Pd

H HH HPd Pd

H HPd Pd

Pd HH

R Cl

O Pd(0)

oxidativeaddition

R Pd

OCl

Pd HH

ligand exchange

R H

OPd(0)R Pd

OH

reductive

elimination

Example 14

R Cl

O

R H

OH2/Pd or Pd/BaSO42,6-dimethylpyridine, THF

or H2/Pd−C/quinoline−S, PhH74−97%

Example 26

HOCO2t-Bu

O

NBoc2

Cl

Me2NCl

CO2t-BuO

NBoc2

H2, 5% Pd/C2,6-lutidine

THF, 2 h, 78%

HCO2t-Bu

O

NBoc2

Example 39

OH

O 1. SOCl2, cat. DMF, reflux, 4 h

2. H2, 5% Pd/C, EtOAc, 53%

476


H

O

References 1. Rosenmund, K. W. Ber. 1918, 51, 585–594. Karl Wilhelm Rosenmund was born in

Berlin, Germany in 1884. He was a student of Otto Diels and received his Ph.D. In 1906. Rosenmund became professor and director of the Pharmaceutical Institute in Kiel in 1925.

2. Mosettig, E.; Mozingo, R. Org. React. 1948, 4, 362–377. (Review). 3. Tsuji, J.; Ono, K.; Kajimoto, T. Tetrahedron Lett. 1965, 6, 4565–4568. 4. Burgstahler, A. W.; Weigel, L. O.; Schäfer, C. G. Synthesis 1976, 767–768. 5. McEwen, A. B.; Guttieri, M. J.; Maier, W. F.; Laine, R. M.; Shvo, Y. J. Org. Chem.

1983, 48, 4436–4438. 6. Bold, V. G.; Steiner, H.; Moesch, L.; Walliser, B. Helv. Chim. Acta 1990, 73, 405–

410. 7. Yadav, V. G.; Chandalia, S. B. Org. Proc. Res. Dev. 1997, 1, 226–232. 8. Chandnani, K. H.; Chandalia, S. B. Org. Proc. Res. Dev. 1999, 3, 416–424. 9. Chimichi, S.; Boccalini, M.; Cosimelli, B. Tetrahedron 2002, 58, 4851–4858. 10. Ancliff, R. A.; Russell, A. T.; Sanderson, A. J. Chem. Commun. 2006, 3243–3245.

477

Rubottom oxidation α-Hydroxylation of enolsilanes.

OSiR31. m-CPBA

2. K2CO3, H2O

OOH

R3SiO O HOO

Ar

Prilezhaev

epoxidationO

R3SiOH

OO

ArO

OR3Si

H

‡

The “butterfly” transition state

OO

R3Si H OOH

SiR3 OOHK2CO3, H2O

hydrolysis

:

Example 12

N

OSiMe3CO2Me

2.5 eq m-CPBAClCH2CH2Cl

0 oC to rt, 1 h, 80%

N

OOH

CO2Me

Example 23

O

TMSCl, NaI

Et3N, rt, 91%OTMS

1. m-CPBA, NaHCO3, pentane, 0 oC

2. aq. K2CO3, 0 oC, 20 h, 80%O

OH

Example 34

TMSO

TMSO

OTBSO

TMSO

OTBS

TMSO SiO2

O

TMSO

OTBS

HOm-CPBA

63%

478


Example 45

Me

H

H

H

Me

MeO

Me

H

H

H

Me

MeO

HO

1. LDA, TMSCl2. m-CPBA, NaHCO3

3. K2CO3, MeOH 72%

References 1. Rubottom, G. M.; Vazquez, M. A.; Pelegrina, D. R. Tetrahedron Lett. 1974, 15,

4319−4322. George Rubottom discovered the Rubottom oxidation when he was an assistant professor at the University of Puerto Rico. He is now a grant officer at the National Science Foundation.

2. Andriamialisoa, R. Z.; Langlois, N.; Langlois, Y. Tetrahedron Lett. 1985, 26, 3563−2366.

3. Jauch, J. Tetrahedron 1994, 50, 12903−12912. 4. Crimmins, M. T.; Al-awar, R. S.; Vallin, I. M.; Hollis, W. G., Jr.; O’Mahoney, R.;

Lever, J. G.; Bankaitis-Davis, D. M. J. Am. Chem. Soc. 1996, 118, 7513–7528. 5. Paquette, L. A.; Sun, L.-Q.; Friedrich, D.; Savage, P. B. Tetrahedron Lett. 1997, 38,

195–198. 6. Paquette, L. A.; Hartung, R. E.; Hofferberth, J. E.; Vilotijevic, I.; Yang, J. J. Org.

Chem. 2004, 69, 2454−2460. 7. Christoffers, J.; Baro, A.; Werner, T. Adv. Synth. Cat. 2004, 346, 143−151. (Review). 8. He, J.; Tchabanenko, K.; Adlington, R. M.; Cowley, A. R.; Baldwin, J. E. Eur. J. Org.

Chem. 2006, 4003−4013. 9. Wolfe, J. P. Rubottom oxidation. In Name Reactions for Functional Group Transfor-


10. Wang, H.; Andemichael, Y. W.; Vogt, F. G. J. Org. Chem. 2009, 74, 478−481.

479

Rupe rearrangement Acid-catalyzed rearrangement of tertiary α-acetylenic (terminal) alcohols, leading to the formation of α,β-unsaturated ketones rather than the corresponding α,β-unsaturated aldehydes. Cf. Meyer−Schuster rearrangement.

H+, H2OOH O

HOH OH2 − H2O

dehydration H

− H

H

protonation H

H

H2O:

tautomerizationO

H

H

OH:

H

Example 14

OH

conc. H2SO4

CHCl3, HOAc, reflux, 1 h

O

Example 28

Me

OH

MeCH3

O

HCO2H, reflux

15 min., 42%

Example 39

O

H3C

H

H

H

OHA-252C H+ resin

EtOAc, reflux

4 h, 78%O

H3C

H

H

O

480


References 1. Rupe, H.; Kambli, E. Helv. Chim. Acta 1926, 9, 672. 2. Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 429−438. (Review). 3. Hasbrouck, R. W.; Anderson Kiessling, A. D. J. Org. Chem. 1973, 38, 2103−2106. 4. Baran, J.; Klein, H.; Schade, C.; Will, E.; Koschinsky, R.; Bäuml, E.; Mayr, H. Tetra-

hedron 1988, 44, 2181−2184. 5. Barre, V.; Massias, F.; Uguen, D. Tetrahedron Lett. 1989, 30, 7389–7392. 6. An, J.; Bagnell, L.; Cablewski, T.; Strauss, C. R.; Trainor, R. W. J. Org. Chem. 1997,

62, 2505–2511. 7. Yadav, J. S.; Prahlad, V.; Muralidhar, B. Synth. Commun. 1997, 27, 3415−3418. 8. Takeda, K.; Nakane, D.; Takeda, M. Org. Lett. 2000, 2, 1903–1905. 9. Weinmann, H.; Harre, M.; Neh, H.; Nickisch, K.; Skötsch, C.; Tilstam, U. Org. Proc.

Res. Dev. 2002, 6, 216−219. 10. Mullins, R. J.; Collins, N. R. Meyer–Schuster Rearrangement. In Name Reactions for


481

Saegusa oxidation Palladium-catalyzed conversion of enol silanes to enones, also known as the Saegusa enone synthesis.

O

Me

O

Me

Me3Si0.5 Pd(OAc)2

0.5 p-benzoquinonebenzene, rt, 3 h, 91%

The mechanism is similar to that of the Wacker oxidation (page 564).

O:

Me

Me3Si O

Me

Me3Si

Pd(II)

AcO

Me OSiMe3

OPd(II)AcO OAc

OAc

O

MeH

Pd(II) β-hydride

elimination

O

Me

Pd

H

OAc

O

Me

Pd(0) HOAcOAc

Regenerating the Pd(II) oxidant:

Pd(0) 2 HOAc

O

O

OH

OH

Pd(OAc)2

Larock reported regeneration of the Pd(II) oxidant using oxygen:4

Pd(0) O2O

PdO

HOAcHOOPdOAc

OSiMe3

O

HOOSiMe3 Pd(II)(OAc)2 Example 13

OMeO

OO

H

HO O

Me3SiCl, Et3N

CH3OCH2CH2OCH3rt, 3 h, 74%

OMeO

OTMSO

H

HO O

482


Pd(OAc)2, p-benzoquinone

CH3CN, rt, 60 oC, 53%

OMeO

OO

H

HO O

Example 28

O

O

O

O

O

OTBS

LDA, TBSCl

HMPA−THF−78 to 0 oC, 93%

O

O

O

Pd(OAc)2, O2

DMSO, 80 oC48 h, 77%

Example 310

H

OTES

MeO

MeO

MeO

MePd(OAc)2, DMSO

0 oC to rt, 12 h, 81%

References 1. Ito, Y.; Hirao, T.; Saegusa, T.; J. Org. Chem. 1978, 43, 1011–1013. 2. Dickson, J. K., Jr.; Tsang, R.; Llera, J. M.; Fraser-Reid, B. J. Org. Chem. 1989, 54,

5350–5356. 3. Kim, M.; Applegate, L. A.; Park, O.-S.; Vasudevan, S.; Watt, D. S. Synth. Commun.

1990, 20, 989–997. 4. Larock, R. C.; Hightower, T. R.; Kraus, G. A.; Hahn, P.; Zheng, D. Tetrahedron Lett.

1995, 36, 2423–2426. 5. Porth, S.; Bats, J. W.; Trauner, D.; Giester, G.; Mulzer, J. Angew. Chem., Int. Ed.

1999, 38, 2015–2016. The authors proposed a sandwiched Pd(II) as a possible alterna-tive pathway.

6. Williams, D. R.; Turske, R. A. Org. Lett. 2000, 2, 3217–3220. 7. Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000, 122, 7596–7597. 8. Kadota, K.; Kurusu, T.; Taniguchi, T.; Ogasawara, K. Adv. Synth. Catal. 2001, 343,

618–623. 9. Sha, C.-K.; Huang, S.-J.; Zhan, Z.-P. J. Org. Chem. 2002, 67, 831–836. 10. Angeles A. R; Waters, S. P.; Danishefsky S. J. J. Am. Chem. Soc. 2008, 130, 13765–

13770.

483

Sakurai allylation reaction Lewis acid-mediated addition of allylsilanes to carbon nucleophiles. Also known as the Hosomi–Sakurai reaction. The allylsilane will add to the carbonyl com-pound directly if the electrophile (carbonyl group) is not part of an α,β-unsaturated system (Example 2), giving rise to an alcohol.

OSiMe3

TiCl4O

O

SiMe3

TiCl4

complexation OTiCl3:

Cl

SiMe3

OTiCl3

Cl

Michael

addition

The β-carbocation is stabilized by the β-silicon effect

silicon

cleavage

OOTiCl3

H2O

workupMe3Si Cl

Example 12

O

EtAlCl2, Tol.

0 oC, 50%O

TMS

Example 26

OBr

OTIPS

CHOSiMe3

TiCl4, CH2Cl2

rt, 10 min., 67%

OBr

OTIPS

OH

9:1 dr

484


Example 39

SiMe3

H3C OPMB

OHC

H

OC(O)CO2Me

CO2Et

BF3•OEt2

−78 oC, 4 h

Ba(OH)2•8H2O

0 oC, 2 h, 62%CO2Et

H

H

H OH

OC(O)CO2Me

HOPMB

Me

OO

Me OPMB

HH CHO

H

Example 410

BnN NBn

O

OHO

HHO HSiMe3

BF3•OEt2, CH2Cl2rt, 64%

BnN NBn

O

O

HH

References 1. Hosomi, A.; Sakurai, H. Tetrahedron Lett. 1976, 1295–1298. 2. Majetich, G.; Behnke, M.; Hull, K. J. Org. Chem. 1985, 50, 3615–3618. 3. Tori, M.; Makino, C.; Hisazumi, K.; Sono, M.; Nakashima, K. Tetrahedron: Asymme-

try 2001, 12, 301–307. 4. Leroy, B.; Markó, I. E. J. Org. Chem. 2002, 67, 8744–8752. 5. Itsuno, S.; Kumagai, T. Helv. Chim. Acta 2002, 85, 3185–3196. 6. Trost, B. M.; Thiel, O. R.; Tsui, H.-C. J. Am. Chem. Soc. 2003, 125, 13155–13164. 7. Knepper, K.; Ziegert, R. E.; Bräse, S. Tetrahedron 2004, 60, 8591–8603. 8. Rikimaru, K.; Mori, K.; Kan, T.; Fukuyama, T. Chem. Commun. 2005, 394–396. 9. Kalidindi, S.; Jeong, W. B.; Schall, A.; Bandichhor, R.; Nosse, B.; Reiser, O. Angew.

Chem., Int. Ed. 2007, 46, 6361–6363. 10. Norcross, N. R.; Melbardis, J. P.; Solera, M. F.; Sephton, M. A.; Kilner, C.; Zakharov,

L. N.; Astles, P. C.; Warriner, S. L.; Blakemore, P. R. J. Org. Chem. 2008, 73, 7939–7951.

485

Sandmeyer reaction Haloarenes from the reaction of a diazonium salt with CuX.

ArN2 YCuX

Ar X

X = Cl, Br, CN

e.g.:

ArN2 ClCuCl

Ar ClCuCl2ArN2↑ CuCl

Example 14

N2

Cl

Cl1. FeCl3

2. CuCl2 81%

N2

Cl

CuCl4

2

DMSO, rt

97%Cl

Cl

Cl Cl Cl

Example 27

CF3

ClNH2

1. H2SO4

2. NaNO2

CF3

ClN

NCuCN, NaCN

Na2CO3, 50%

CF3

ClCN

Example 38

OH

OMe

H2N

NaNO2, CuBr

55%

OH

OMe

Br

Example 49

N

O

O

NO2

NH

O

1. HOAc, H2O, H2SO4 reflux, 2 h

2. NaNO2, 0 oC3. CuCN, 50 oC 50−58%

N

O

O

NO2

NC

486


References 1. Sandmeyer, T. Ber. 1884, 17, 1633. Traugott Sandmeyer (1854−1922) was born in

Wettingen, Switzerland. He apprenticed under Victor Meyer and Arthur Hantzsch al-though he never took a doctorate. He later spent 31 years at the company J. R. Geigy, which is now part of Novartis.

2. Suzuki, N.; Azuma, T.; Kaneko, Y.; Izawa, Y.; Tomioka, H.; Nomoto, T. J. Chem. Soc., Perkin Trans. 1 1987, 645–647.

3. Merkushev, E. B. Synthesis 1988, 923–937. (Review). 4. Obushak, M. D.; Lyakhovych, M. B.; Ganushchak, M. I. Tetrahedron Lett. 1998, 39,

9567–9570. 5. Hanson, P.; Jones, J. R.; Taylor, A. B.; Walton, P. H.; Timms, A. W. J. Chem. Soc.,

Perkin Trans. 2 2002, 1135–1150. 6. Daab, J. C.; Bracher, F. Monatsh. Chem. 2003, 134, 573–583. 7. Nielsen, M. A.; Nielsen, M. K.; Pittelkow, T. Org. Proc. Res. Dev. 2004, 8, 1059–

1064. 8. Kim, S.-G.; Kim, J.; Jung, H. Tetrahedron Lett. 2005, 46, 2437–2439. 9. LaBarbera, D. V.; Bugni, T. S.; Ireland, C. M. J. Org. Chem. 2007, 72, 8501–8505. 10. Gehanne, K.; Lancelot, J.-C.; Lemaitre, S.; El-Kashef, H.; Rault, S. Heterocycles

2008, 75, 3015–3024.

487

Schiemann reaction Fluoroarene formation from arylamines. Also known as the Balz−Schiemann re-action.

ArN2 BF4

Ar NH2 HNO2 HBF4

ΔAr F N2↑ BF3

HBF4HO

NO H2O

NO: H2O N O

HON

OO

NO

NO

ArNH2

ArHN

NO Ar

NN

OH:ON

ON

O: ArN

NOH2

H :

H2O Ar N N ArN2 BF4ArN2↑

Δ Ar F BF3F BF3

Example 14

N

N N

N

F

NH2NaNO2, HBF4, H2O

−10 to 0 oC, 25%

N

N N

N

F

F

R R

R = 2,3-5-tri-O-acetyl-β-D-ribofuranose

Example 2, Photo-Schiemann reaction6

HN N

F NHBoc 1. HBF42. NaNO2

3. hvHN N

F F

HN N

F

36% 8%

Example 3, Photo-Schiemann reaction8

HN N

CO2EtH2N NO+BF4−

[bmim][BF4] HN N

CO2EtBF4−N2

+ hv

[bmim][BF4]0 oC, 24 h, 56%

HN N

CO2EtF

488


Example 410

S

NH2

CO2Me

NaNO2

HBF493% S

N2+BF4

−

CO2Me

160−200 oC

sand, 67% S

F

CO2Me

References 1. Balz, G.; Schiemann. G. Ber. 1927, 60, 1186−1190. Günther Schiemann was born in

Breslau, Germany in 1899. In 1925, he received his doctorate at Breslau, where he became an assistant professor. In 1950, he became the Chair of Technical Chemistry at Istanbul, where he extensively studied aromatic fluorine compounds.

2. Roe, A. Org. React. 1949, 5, 193−228. (Review). 3. Sharts, C. M. J. Chem. Educ. 1968, 45, 185−192. (Review). 4. Montgomery, J. A.; Hewson, K. J. Org. Chem. 1969, 34, 1396−1399. 5. Laali, K. K.; Gettwert, V. J. J. Fluorine Chem. 2001, 107, 31−34. 6. Dolensky, B.; Takeuchi, Y.; Cohen, L. A.; Kirk, K. L. J. Fluorine Chem. 2001, 107,

147−152. 7. Gronheid, R.; Lodder, G.; Okuyama, T. J. Org. Chem. 2002, 67, 693−720. 8. Heredia-Moya, J.; Kirk, K. L. J. Fluorine Chem. 2007, 128, 674−678. 9. Gribble, G. W. Balz-Schiemann reaction. In Name Reactions for Functional Group


10. Pomerantz, M.; Turkman, N. Synthesis 2008, 2333−2336.

489

Schmidt rearrangement The Schmidt reactions refer to the acid-catalyzed reactions of hydrazoic acid with electrophiles, such as carbonyl compounds, tertiary alcohols and alkenes. These substrates undergo rearrangement and extrusion of nitrogen to furnish amines, ni-triles, amides or imines.

R1 R2

ON2↑

R2 NH

OR1

HN3

H+

R1 R2

O H

R1 R2

OH HN3

R1 R2

N3HO

R1 R2

NHON

N

R1 R2

NH2ON

N

H

azido-alcohol

NR2

R1

N N− H2O

migration

:

R1 NR1

N2↑

H2O

:

R2

nitrilium ion intermediate (Cf. Ritter intermediate)

NR2

R1HO

R2 NH

OR1tautomerization

H

Example 1, A classic example3

CO2EtO

NaN3

MeSO3H21%

HN CO2Et

O

Example 25

O H

NO

NaN3, H2SO4

CHCl3, 92%

490


Example 3, Intramolecular Schmidt rearrangement6

OH

O

N3

TfOH, CH2Cl2

0 oC, 79%N

O

OH

Example 4, Intramolecular Schmidt rearrangement8

H

Et

TiCl482%

OO

N3

Et

O N OH

H

Example 5, Intermolecular Schmidt rearrangement9

OMe

N

ONC

NaN3, CHCl3

conc. H2SO4

OMe

N

NH

OHO2C

OMe

N

HNHO2C O

84%0%

References 1. (a) Schmidt, K. F. Angew. Chem. 1923, 36, 511. Karl Friedrich Schmidt (1887−1971)

collaborated with Curtius at the University of Heidelberg, where Schmidt became a Professor of Chemistry after 1923. (b) Schmidt, K. F. Ber. 1924, 57, 704−706.

2. Wolff, H. Org. React. 1946, 3, 307−336. (Review). 3. Tanaka, M.; Oba, M.; Tamai, K.; Suemune, H. J. Org. Chem. 2001, 66, 2667−2573. 4. Golden, J. E.; Aubé, J. Angew. Chem., Int. Ed. 2002, 41, 4316−4318. 5. Johnson, P. D.; Aristoff, P. A.; Zurenko, G. E.; Schaadt, R. D.; Yagi, B. H.; Ford, C.

W.; Hamel, J. C.; Stapert, D.; Moerman, J. K. Bioorg. Med. Chem. Lett. 2003, 13, 4197−4200.

6. Wrobleski, A.; Sahasrabudhe, K.; Aubé, J. J. Am. Chem. Soc. 2004, 126, 5475−5481. 7. Gorin, D. J.; Davis, N. R.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260−11261. 8. Iyengar, R.; Schidknegt, K.; Morton, M..; Aubé, J. J. Org. Chem. 2005, 70,

10645−10652. 9. Amer, F. A.; Hammouda, M.; El-Ahl, A. A. S.; Abdel-Wahab, B. F. Synth. Commun.

2009, 39, 416−425. 10. Wu, Y.-J. Schmidt reactions. In Name Reactions for Homologations-Part II; Li, J. J.,


491

Schmidt’s trichloroacetimidate glycosidation reaction Lewis acid-promoted glycosidation of trichloroacetimidates with alcohols or phe-nols.

O

OAcOCH3

AcO

OHO

OAcOCH3

AcO

O

HN CCl3

cat. NaH

Cl3CCN

HO Ar

BF3•OEt2

O

OAcOCH3

AcO

OAr

trichloroacetimidate

O

OAcOCH3

AcO

OH

HO

OAcOCH3

AcO

O

N CCl3

H2↑deprotonation BF3•OEt2

O

OCH3O

AcO

O

HN CCl3

BF3•OEt2

Oneighboring

group assistance

O

NH2Cl3C

O

CH3OAcO O

OO

OAcOCH3

AcO

OArO Ar

H:

Example 15

O

OAcOCH3

AcO

O

HN CCl3

I CO2Me

OMeOMe

HO

O

OAcOCH3

AcO

OBF3•OEt2, 4 Å MS

CH2Cl2, −50 oC, 95%

I CO2Me

OMeOMe

492


Example 27

O

BnO AcO

BnO

BnOO

CCl3

NH

OH

BF3•OEt2CH2Cl2/hexane

−20 oC, 68%

OO

BnO AcO

BnO

BnO

Example 39

O

AcO

AcO

AcOO

CCl3

NH

OAc

0.2 equiv TMSOTf, CH2Cl2, −15 oC, 5 min.

HONH2

PF6

O

AcO

AcO

AcO

ONH2

t-BuPF6

O

AcO

AcO

AcOO

OAc

NH2

t-BuPF6

40%

O

O

30%

References 1. (a) Grundler, G.; Schmidt, R. R. Carbohydr. Res. 1985, 135, 203−218. (b) Schmidt,

R. R. Angew. Chem., Int. Ed. 1986, 25, 212−235. (Review). 2. Smith, A. L.; Hwang, C.-K.; Pitsinos, E.; Scarlato, G. R.; Nicolaou, K. C. J. Am.

Chem. Soc. 1992, 114, 3134−3136. 3. Toshima, K.; Tatsuta, K. Chem. Rev. 1993, 93, 1503−1531. (Review). 4. Nicolaou, K. C. Angew. Chem., Int. Ed. 1993, 32, 1377−1385. (Review). 5. Groneberg, R. D.; Miyazaki, T.; Stylianides, N. A.; Schulze, T. J.; Stahl, W.;

Schreiner, E. P.; Suzuki, T.; Iwabuchi, Y.; Smith, A. L.; Nicolaou, K. C. J. Am. Chem. Soc. 1993, 115, 7593−611.

6. Fürstner, A.; Jeanjean, F.; Razon, P. Angew. Chem., Int. Ed. 2002, 41, 2097−2101. 7. Yan, L. Z.; Mayer, J. P. J. Org. Chem. 2003, 68, 1161−1162. 8. Harding, J. R.; King, C. D.; Perrie, J. A.; Sinnott, D.; Stachulski, A. V. Org. Biomol.

Chem. 2005, 3, 1501−1507. 9. Steinmann, A.; Thimm, J.; Thiem, J. Eur. J. Org. Chem. 2007, 66, 5506−5513. 10. Coutrot, F.; Busseron, E.; Montero, J.-L. Org. Lett. 2008, 10, 753−756.

493

Shapiro reaction The Shapiro reaction is a variant of the Bamford−Stevens reaction. The former uses bases such as alkyl lithium and Grignard reagents whereas the latter employs bases such as Na, NaOMe, LiH, NaH, NaNH2, etc. Consequently, the Shapiro re-action generally affords the less-substituted olefins (the kinetic products), while the Bamford−Stevens reaction delivers the more-substituted olefins (the thermo-dynamic products).

R2

R3

R1

ER2N

HN

TsR3

R12 n-BuLi

then E

R2N

NTs

R3

R1 H

H

BuR2

NN

TsR3

R1

H

Bu

R2

R3

R1

R2N

N

R3

R1− N2 E

R2

R3

R1

E

Example 12

NNHTs MeLi, Et2O

98% 2%

Example 23

NNHTsMeLi, Et2O−PhH

75−80%

Example 37

O

O

MeO

HOMe

H

H H

OTBDPS 1. TsNHNH2, MeOH, THF

2. n-BuLi, THF, –78 °C to rtO

MeO

HOMe

H

H H

OTBDPS

3. aqueous workup69%

494


Example 48

Me

H

Me

NNHTris

1. n-BuLi

2. MgBr2•OEt2

3.

PhO

Me

Me

O

O

Me

H

Me HO PhO

Me

Me

O

55% yieldone diastereomer

References

1. Shapiro, R. H.; Duncan, J. H.; Clopton, J. C. J. Am. Chem. Soc. 1967, 89, 471–472.

Robert H. Shapiro was an assistant professor at the University of Colorado. He was not given tenure despite getting a reaction named after him.

2. Shapiro, R. H.; Heath, M. J. J. Am. Chem. Soc. 1967, 89, 5734–5735. 3. Dauben, W. G.; Lorber, M. E.; Vietmeyer, N. D.; Shapiro, R. H.; Duncan, J. H.;

Tomer, K. J. Am. Chem. Soc. 1968, 90, 4762−4763. 4. Shapiro, R. H. Org. React. 1976, 23, 405−507. (Review). 5. Adlington, R. M.; Barrett, A. G. M. Acc. Chem. Res. 1983, 16, 55–59. (Review). 6. Chamberlin, A. R.; Bloom, S. H. Org. React. 1990, 39, 1−83. (Review). 7. Grieco, P. A.; Collins, J. L.; Moher, E. D.; Fleck, T. J.; Gross, R. S. J. Am. Chem. Soc.

1993, 115, 6078–6093. 8. Tamiya, J.; Sorensen, E. J. Tetrahedron 2003, 59, 6921–6932. 9. Wolfe, J. P. Shapiro reaction. In Name Reactions for Functional Group Transforma-

tions; Li, J. J., Corey, E. J., eds, John Wiley & Sons: Hoboken, NJ, 2007, pp 405−413. 10. Bettinger, H. F.; Mondal, R.; Toenshoff, C. Org. Biomol. Chem. 2008, 6, 3000–3004.

495

Sharpless asymmetric amino-hydroxylation Osmium-mediated cis-addition of nitrogen and oxygen to olefins. Regioselectiv-ity may be controlled by ligand. Nitrogen sources (X−NClNa) include:

SNClNa

R O

O

R = p-Tol; MeEtO NClNa

OBnO NClNa

O

NClNa

OTMS NBrLi

O

R1

R

chiral ligandK2OsO2(OH)4

ClNaN−Xt-BuOH, H2O

R1

HO

R

NHX


R1

R

R1

HO

R

NHX

OsO4 ClN−X

OsO

OO

N X

OsO

OO

N XL*

OsO

OO

NL*

X

R

R1OsO

OO

NL*

X

R

R1

OsO

OO

NN X

R

R1

X

L*

ClN−X

L*

H2O

Example 11b

5 mol% (DHQD)2PHAL4 mol% K2OsO2(OH)4

n-PrOH/H2O (1:1), 63% ee51%

BnO NClNa

O NH OHBnO

O

496


(DHQD)2-PHAL = 1,4-bis(9-O-dihydroquinidine)phthalazine:

N

HO

N

O

NNO

N

N

O

Example 22

CO2Et

BnO

CO2Et

BnO

OH

NHCbz

BnOCONH2NaOH, t-BuOCl(DHQD)2AQN

K2OsO2(OH)4n-PrOH/H2O (1:1)

rt, 12 h, 45%, 87% ee

Example 36

NaOH, urethaneK2OsO2(OH)4(DHQD)2PHAL

1,3-dichloro-5,5-di-methyl hydantoin

n-PrOH/H2O

F

Me

F

OH

Me

HNOEt

O

F

NH

Me

HO

OEtO

1. Cs2CO2, MeOH

2. H2SO4

F

HN O

O

References 1. (a) Herranz, E.; Sharpless, K. B. J. Org. Chem. 1978, 43, 2544−2548. K. Barry Shar-

pless (USA, 1941−) shared the Nobel Prize in Chemistry in 2001 with Herbert Wil-liam S. Knowles (USA, 1917−) and Ryoji Noyori (Japan, 1938−) for his work on chirally catalyzed oxidation reactions. (b) Li, G.; Angert, H. H.; Sharpless, K. B. Angew. Chem., Int. Ed. 1996, 35, 2813−2817. (c) Rubin, A. E.; Sharpless, K. B. Angew. Chem., Int. Ed. 1997, 36, 2637−2640. (d) Kolb, H. C.; Sharpless, K. B. Tran-sition Met. Org. Synth. 1998, 2, 243−260. (Review). (e) Thomas, A.; Sharpless, K. B. J. Org. Chem. 1999, 64, 8379−8385. (f) Gontcharov, A. V.; Liu, H.; Sharpless, K. B. Org. Lett. 1999, 1, 783−786.

497

2. Nicolaou, K. C.; Boddy, C. N. C.; Li, H.; Koumbis, A. E.; Hughes, R.; Natarajan, S.; Jain, N. F.; Ramanjulu, J. M.; Braese, S.; Solomon, M. E. Chem. Eur. J. 1999, 5, 2602−2621.

3. Lohr, B.; Orlich, S.; Kunz, H. Synlett 1999, 1139−1141. 4. Boger, D. L.; Lee, R. J.; Bounaud, P.-Y.; Meier, P. J. Org. Chem. 2000, 65,

6770−6772. 5. Demko, Z. P.; Bartsch, M.; Sharpless, K. B. Org. Lett. 2000, 2, 2221−2223. 6. Barta, N. S.; Sidler, D. R.; Somerville, K. B.; Weissman, S. A.; Larsen, R. D.; Reider,

P. J. Org. Lett. 2000, 2, 2821−2824. 7. Bolm, C.; Hildebrand, J. P.; Muñiz, K. In Catalytic Asymmetric Synthesis; 2nd edn.,

Ojima, I., Ed.; Wiley−VCH: New York, 2000, 399. (Review). 8. Bodkin, J. A.; McLeod, M. D. J. Chem. Soc., Perkin 1 2002, 2733−2746. (Review). 9. Rahman, N. A.; Landais, Y. Cur. Org. Chem. 2000, 6, 1369−1395. (Review). 10. Nilov, D.; Reiser, O. Recent Advances on the Sharpless Asymmetric Aminohydroxyla-

tion. In Organic Synthesis Highlights Schmalz, H.-G.; Wirth, T., eds.; Wiley−VCH: Weinheim, Germany 2003, 118−124. (Review).

11. Bodkin, J. A.; Bacskay, G. B.; McLeod, M. D. Org. Biomol. Chem. 2008, 2544−2553. 12. Wong, D.; Taylor, C. M. Tetrahedron Lett. 2009, 50, 1273−1275.

498

Sharpless asymmetric dihydroxylation Enantioselective cis-dihydroxylation of olefins using osmium catalyst in the pres-ence of cinchona alkaloid ligands.

RL

RMRS

H

AD-mix-β

AD-mix-α

K2OsO2(OH)4

K2CO3, K3Fe(CN)6

(DHQD)2-PHAL

(DHQ)2-PHAL

OHHO

RS RL HRM

HO OH

HRMRSRL

(DHQ)2-PHAL = 1,4-bis(9-O-dihydroquinine)phthalazine:

NO

N

O

NNO

N

N

O

The concerted [3 + 2] cycloaddition mechanism:5

LOs

O

OO

OOsO

OO

LO

OsO

OO

LO

[3 + 2]-like

cycloadditionOsO

OO

LO

hydrolysis HO

HO

Example 12

EtO2CO

OH

N3

K2OsO2(OH)4(DHQD)2PHAL

K2CO3, MeSO2NH2t-BuOH/H2O (1:1)rt, 12 h, 90% de

EtO2CO

OH

N3

OH

OH

Example 24

CO2Et

BnO

1. AD-mix-β, MeSO2NH2 t-BuOH/H2O (1:1), rt, 12 h

2. NosCl, Et3N, CH2Cl2 0 oC, 54%, 92% ee

CO2Et

BnO

OH

ONos

Nos = nosylate = 4-nitrobenzenesulfonyl

499


The catalytic cycle: (the secondary cycle is shut off by maintaining a low concen-tration of olefin):

R

R

LH2O

OHR

OHR

low ee

OsO

OR

R

LO O

LR

R

OsOO

OO

OsOO

OO O

RR

H2O

OHR

OHR

high ee

OsOO

OO O

RR

R R

NMONMM

L

Secondary cyclelow ee

Primary cyclehigh ee

Example 39

CO2EtOMe

Me

OO

CO2EtOMe

Me

OO

OH

OHAD-mix-α

t-BuOH/H2O (1:1)93%, 97% ee

500

Example 410

K2OsO2(OH)4(DHQD)2PHAL

NMOacetone/H2O

89%

OH

OH 70% ee

References 1. (a) Jacobsen, E. N.; Markó, I.; Mungall, W. S.; Schröder, G.; Sharpless, K. B. J. Am.

Chem. Soc. 1988, 110, 1968−1970. (b) Wai, J. S. M.; Markó, I.; Svenden, J. S.; Finn, M. G.; Jacobsen, E. N.; Sharpless, K. B. J. Am. Chem. Soc. 1989, 111, 1123−1125.

2. Kim, N.-S.; Choi, J.-R.; Cha, J. K. J. Org. Chem. 1993, 58, 7096−7699. 3. Kolb, H. C.; VanNiewenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94,

2483−2547. (Review). 4. Rao, A. V. R.; Chakraborty, T. K.; Reddy, K. L.; Rao, A. S. Tetrahedron Lett. 1994,

35, 5043−5046. 5. Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1996, 118, 319−329. (Mechanism). 6. DelMonte, A. J.; Haller, J.; Houk, K. N.; Sharpless, K. B.; Singleton, D. A.; Strassner,

T.; Thomas, A. A. J. Am. Chem. Soc. 1997, 119, 9907−9908. (Mechanism). 7. Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2024−2032. (Review, Nobel Prize

Address). 8. Zhang, Y.; O’Doherty, G. A. Tetrahedron 2005, 61, 6337−6351. 9. Chandrasekhar, S.; Reddy, N. R.; Rao, Y. S. Tetrahedron 2006, 62, 12098−12107. 10. Ferreira, F. C.; Branco, L. C.; Verma, K. K.; Crespo, J. G.; Afonso, C. A. M.

Tetrahedron: Asymmetry 2007, 18, 1637−1641. 11. Ramon, R.; Alonso, M.; Riera, A. Tetrahedron: Asymmetry 2007, 18, 2797−2802. 12. Krishna, P. R.; Reddy, P. S. Synlett 2009, 209−212.

501

Sharpless asymmetric epoxidation Enantioselective epoxidation of allylic alcohols using t-butyl peroxide, titanium tetra-iso-propoxide, and optically pure diethyl tartrate.

R1 R

R2OH

t-Bu−O−OH, Ti(Oi--Pr)4

L-(+)-diethyl tartrate

R1 R

R2OH

O

R1 R

R2OH

t-Bu−O−OH, Ti(Oi-Pr)4

D-(−)-diethyl tartrate

R1 R

R2OH

O


LnTiOi-Pr

Oi-Pr

OH t-Bu−O−OH

LnTiO

O

Ot-Bu

LnTiO *

t-Bu

O

LnTi OO

Ot-Bu

LnTi OO

Ot-Bu

*

**

***

LnTiO

O

t-Bu

O

*

*

OHO

502


The putative active catalyst and the transition state:

O

Ti

O

Tii-PrO

i-PrO

Oi-PrO

OEt

O

EtO2C

O

CO2EtOEtO

Oi-Pr

OOTi

OO

EtO2C CO2Et

t-Bu

O

Example 13

OHMeTi(Oi-Pr)4, 4 Å MS, (+)-DET

t-BuOOH, CH2Cl2 −20 °C

OHO

Mecrude: 88% yield, 92.3 % ee

recrystallization: 73% yield, > 98% ee

Example 23

OH(−)-DIPT, Ti(Oi-Pr)4

TBHP, 3 Å MS50−60%, 88−92% ee

OHO

Example 311

L-(+)-DIPT, Ti(Oi-Pr)4

TBHP, EtOAc89%, 98% ee

OH OHO

(R,R)O

NHH

HOEt

(S,S)-reboxetine

Example 412

O

BnO BnO

BnO

BnO

OH

D-(−)-DIPT, Ti(Oi-Pr)4

TBHP, 4 Å MS70%, > 95% ee

O

BnO BnO

BnO

BnO

OHO

503

References 1. (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974−5976. (b) Wil-

liams, I. D.; Pedersen, S. F.; Sharpless, K. B.; Lippard, S. J. J. Am. Chem. Soc. 1984, 106, 6430−6433. (c) Woodard, S. S.; Finn, M. G.; Sharpless, K. B. J. Am. Chem. Soc. 1991, 113, 106−113.

2. Pfenninger, A. Synthesis 1986, 89−116. (Review). 3. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J.

Am. Chem. Soc. 1987, 109, 5765−5780. 4. Corey, E. J. J. Org. Chem. 1990, 55, 1693−1694. (Review). 5. Johnson, R. A.; Sharpless, K. B. In Comprehensive Organic Synthesis; Trost, B. M.,

Ed,; Pergamon Press: New York, 1991; Vol. 7, Chapter 3.2. (Review). 6. Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; Ojima, I., ed,;

VCH: New York, 1993; Chapter 4.1, pp 103−158. (Review). 7. Schinzer, D. Org. Synth. Highlights II 1995, 3. (Review). 8. Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1−299. (Review). 9. Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; 2nd ed., Ojima, I.,

ed.; Wiley-VCH: New York, 2000, 231−285. (Review). 10. Palucki, M. Sharpless−Katsuki Epoxidation. In Name Reactions in Heterocyclic


11. Henegar, K. E.; Cebula, M. Org. Proc. Res. Dev. 2007, 11, 354−358. 12. Pu, J.; Franck, R. W. Tetrahedron 2008, 64, 8618−8629. 13. Knight, D. W.; Morgan, I. R. Tetrahedron Lett. 2009, 50, 35−38.

504

Sharpless olefin synthesis Olefin synthesis from the syn-oxidative elimination of o-nitrophenyl selenides, which may be prepared using o-nitrophenyl selenocyanate and Bu3P, among other methods.

OHR

SeCNNO2

Bu3P, THF, rtSe

R

NO2

OR

O

R

SeNO2

CN

H

:

SeNO2

PBu3CN

Bu3P:

SN2

SeR

NO2

SeNO2

OR PBu3 O PBu3

OSe

R

NO2H OR

SeNO2

syn-elimination OH

Example 13

OHOH H

H

N

MeO

1. Bu3P, o-O2NPhSeCN, THF, rt2. CSA, PhH, rt to 70 oC

3. m-CPBA, 2,4,6-collidine CH2Cl2, 0 oC, 42%

OH

H

NH

Example 26

1. Bu3P, o-O2NPhSeCN THF, rt, 6 h, 97%

2. m-CPBA, Et3N, CH2Cl2, −78 oC 86%

OOO

MeO

OH

OH

OH OOO

MeO

OH

OH

505


Example 39

O

H

OH

O

H

OO

HOOMe

OH

SeCNNO2

n-Bu3P, THF, rt, 78%

2. aq. H2O2, THF, pyr. −40 oC to rt, 90%

1.

O

HO

H

OO

HOOMe

Example 410

OH

H O

HOSeCN

NO2

n-Bu3P, THF, rt

2. aq. H2O2, THF, 40 oC 90% 2 steps

1.

OH

H O

References 1. (a) Sharpless, K. B.; Young, M. Y.; Lauer, R. F. Tetrahedron Lett. 1973, 1979−1982.

(b) Sharpless, K. B.; Young, M. Y. J. Org. Chem. 1975, 40, 947−949. 2. (a) Grieco, P. A.; Miyashita, M. J. Org. Chem. 1974, 39, 120−122. (b) Grieco, P. A.;

Miyashita, M. Tetrahedron Lett. 1974, 1869−1871. (c) Grieco, P. A.; Masaki, Y.; Boxler, D. J. Am. Chem. Soc. 1977, 97, 1597−1599. (d) Grieco, P. A.; Gilman, S.; Ni-shizawa, M. J. Org. Chem. 1976, 41, 1485−1486. (e) Grieco, P. A.; Yokoyama, Y. J. Am. Chem. Soc. 1977, 99, 5210−5219.

3. Smith, A. B., III; Haseltine, J. N.; Visnick, M. Tetrahedron 1989, 45, 2431−2449. 4. Reich, H. J.; Wollowitz, S. Org. React. 1993, 44, 1−296. (Review). 5. Hsu, D.-S.; Liao, C.-C. Org. Lett. 2003, 5, 4741−4743. 6. Meilert, K.; Pettit, G. R.; Vogel, P. Helv. Chim. Acta 2004, 87, 1493−1507. 7. Siebum, A. H. G.; Woo, W. S.; Raap, J.; Lugtenburg, J. Eur. J. Org. Chem. 2004,

2905−2916. 8. Blay, G.; Cardona, L.; Collado, A. M.; Garcia, B.; Morcillo, V.; Pedro, J. R. J. Org.

Chem. 2004, 69, 7294−7302. The authors observed the concurrent epoxidation of a tri-subsituted olefin, possibly by the o-nitrophenylselenic acid via an intramolecular process.

9. Paquette, L. A.; Dong, S.; Parker, G. D. J. Org. Chem. 2007, 72, 7135−7147. 10. Yokoe, H.; Yoshida, M.; Shishido, K. Tetrahedron Lett. 2008, 49, 3504−3506.

506

Simmons–Smith reaction Cyclopropanation of olefins using CH2I2 and Zn(Cu).

CH2I2 Zn(Cu) ICH2ZnI

CH2 ICH2ZnII IZn

Oxidativeaddition

Simmons−Smith reagent

2 ICH2ZnI (ICH2)2Zn ZnI2

ZnI2CH2

ZnII ZnII

Example 12

O

Zn/Cu [from Zn and Cu(SO4)2]

CH2I2, Et2O, reflux, 36 h, 90%

O

Example 2, An asymmetric version3

MeO

OH

CONEt2

OHOH

CONEt2

(1 eq)

6 eq Zn/Cu, 3 eq CH2I2 CH2Cl2, 0 oC, 15 h

78%, 94% ee

MeO

OH

Example 3, Diastereoselective Simmons−Smith cyclopropanations of allylic amines and carbamates9

NBn2Et2Zn, CH2I2, TFA

CH2Cl2, rt, 1 h92%, > 98% de

NBn2

N

Ph

ZnI

Ph

I

507


Example 410

O

OO

1. PhMe2SiH, RhCl(PPh3)3, 60 oC2. Et2Zn, CH2I2, 0 oC

3. TsOH, MeOH 83%, 3 steps

OO

HOH

OO

HOH

References 1. Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1958, 80, 5323−5324. Howard E.

Simmons (1929−1997) was born in Norfolk, Virginia. He carried out his graduate studies at MIT under John D. Roberts and Arthur Cope. After obtaining his Ph.D. In 1954, he joined the Chemical Department of the DuPont Company, where he discov-ered the Simmons–Smith reaction with his colleague, R. D. Smith. Simmons rose to be the vice president of the Central Research at DuPont in 1979. His views on physi-cal exercise were the same as those of Alexander Woollcot’s: “If I think about exer-cise, I know if I wait long enough, the thought will go away.”

2. Limasset, J.-C.; Amice, P.; Conia, J.-M. Bull. Soc. Chim. Fr. 1969, 3981−3990. 3. Kitajima, H.; Ito, K.; Aoki, Y.; Katsuki, T. Bull. Chem. Soc. Jpn. 1997, 70, 207−217. 4. Nakamura, E.; Hirai, A.; Nakamura, M. J. Am. Chem. Soc. 1998, 120, 5844−5845. 5. Loeppky, R. N.; Elomari, S. J. Org. Chem. 2000, 65, 96−103. 6. Charette, A. B.; Beauchemin, A. Org. React. 2001, 58, 1−415. (Review). 7. Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem. Soc. 2003, 125, 2341−2350. 8. Long, J.; Du, H.; Li, K.; Shi, Y. Tetrahedron Lett. 2005, 46, 2737−2740. 9. Davies, S. G.; Ling, K. B.; Roberts, P. M.; Russell, A. J.; Thomson, J. E. Chem. Com-

mun. 2007, 4029−4031. 10. Shan, M.; O’Doherty, G. A. Synthesis 2008, 3171−3179. 11. Kim, H. Y.; Salvi, L.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2009, 131,

954−962.

508

Skraup quinoline synthesis Quinoline from aniline, glycerol, sulfuric acid and oxidizing agent (e.g. PhNO2).

NH2

HO OHOH

H2SO4

PhNO2 N

HO OHOH

H HO OHOH2

Hdehydration

HO OH HOCHO

glycerol

H2OCHO

H

dehydration

H2N

:

O

Hconjugate

additionNH

OH

H

HH

acrolein

NH

O

NH

OH

intramolecular

additionNH

OHH

NH

OH

:

Htautomerization

N

dehydration

NH

OH2H

NH

oxidation by

PhNO2, − H2

H

For an alternative mechanism, see that of the Doebner−von Miller reaction (page 196). Example 15

OHHO OH

F

F

F

NH2

F

F

F

N

NO2

SO3H

H2SO4, FeSO4H3BO3, 80 %

509


Example 26

N O

O

NH2

OHHO OH

N O

O

N

H2SO4, H3BO3FeSO4•7H2O

75 %

Example 3, A modified Skraup quinoline synthesis8

H

MeS

O

SMe

H

NH2MeONMeO SMe

HOAc, reflux

8−10 h, 78%

References 1. (a) Skraup, Z. H. Monatsh. Chem. 1880, 1, 316. Zdenko Hans Skraup (1850−1910)

was born in Prague, Czechoslovakia. He apprenticed under Lieben at the University of Vienna. (b) Skraup, Z. H. Ber. 1880, 13, 2086.

2. Manske, R. H. F.; Kulka, M. Org. React. 1953, 7, 80−99. (Review). 3. Bergstrom, F. W. Chem. Rev. 1944, 35, 77−277. (Review). 4. Eisch, J. J.; Dluzniewski, T. J. Org. Chem. 1989, 54, 1269−1274. 5. Oleynik, I. I.; Shteingarts, V. D. J. Fluorine Chem. 1998, 91, 25−26. 6. Fujiwara, H.; Kitagawa, K. Heterocycles 2000, 53, 409−418. 7. Ranu, B. C.; Hajra, A.; Dey, S. S.; Jana, U. Tetrahedron 2003, 59, 813−819. 8. Panda, K.; Siddiqui, I.; Mahata, P. K.; Ila, H.; Junjappa, H. Synlett 2004, 449−452. 9. Moore, A. Skraup Doebner–von Miller Reaction. In Name Reactions in Heterocyclic


10. Denmark, S. E.; Venkatraman, S. J. Org. Chem. 2006, 71, 1668−1676. Mechanistic study using 13C-labelled α,β-unsaturated ketones.

11. Vora, J. J.; Vasava, S. B.; Patel, Asha D.; Parmar, K. C.; Chauhan, S. K.; Sharma, S. S. E-J. Chem. 2009, 6, 201−206.

510

Smiles rearrangement Intramolecular nucleophilic aromatic rearrangement. General scheme:

X

YH

Z

Y

XZ

strong

base

X = S, SO, SO2, O, CO2 YH = OH, NHR, SH, CH2R, CONHR Z = NO2, SO2R e.g.:

O2S

OH

OHNO2 O2

S

O

NO2

SNAr

O

NO2O2S

O

O2S

NO2

spirocyclic anion intermediate (Meisenheimer complex)

Example 17

O

HO NaOH, DMA

BrNH2

O O

OH2N

O

NaOH, H2O

50 oC

O

NH

HO

O

H2O, reflux

59%, 3 steps

O

H2N

Example 2, Microwave Smiles rearrangement9

N

N O

NH2

K2CO3, 200 oC

μW, NMP, 30 min.90%

N

HN O

NH

511


Example 310

OMOMO

OHOMe

OI(OAc)2

BnO

2 equiv Na2CO3H2O, rt, 2 h

OMOMO

OHOMe

O

I

OBn

AcO

DMF, 150 oC

87% overall

OMOMO

OOMe

O

OBnI

References 1. Evans, W. J.; Smiles, S. J. Chem. Soc. 1935, 181−188. Samuel Smiles began his ca-

reer at King’s College London as an assistant professor. He later became professor and chair there. He was elected Fellow of the Royal Society (FRS) in 1918.

2. Truce, W. E.; Kreider, E. M.; Brand, W. W. Org. React. 1970, 18, 99−215. (Review). 3. Gerasimova, T. N.; Kolchina, E. F. J. Fluorine Chem. 1994, 66, 69−74. (Review). 4. Boschi, D.; Sorba, G.; Bertinaria, M.; Fruttero, R.; Calvino, R.; Gasco, A. J. Chem.

Soc., Perkin Trans. 1 2001, 1751−1757. 5. Hirota, T.; Tomita, K.-I.; Sasaki, K.; Okuda, K.; Yoshida, M.; Kashino, S.

Heterocycles 2001, 55, 741−752. 6. Selvakumar, N.; Srinivas, D.; Azhagan, A. M. Synthesis 2002, 2421−2425. 7. Mizuno, M.; Yamano, M. Org. Lett. 2005, 7, 3629−3631. 8. Bacque, E.; El Qacemi, M.; Zard, S. Z. Org. Lett. 2005, 7, 3817−3820. 9. Bi, C. F.; Aspnes, G. E.; Guzman-Perez, A.; Walker, D. P. Tetrahedron Lett. 2008, 49,

1832−1835. 10. Jin, Y. L.; Kim, S.; Kim, Y. S.; Kim, S.-A.; Kim, H. S. Tetrahedron Lett. 2008, 49,

6835−6837.

512

Truce−Smile rearrangement A variant of the Smiles rearrangement where Y is carbon:

XL

Zbase

YH

YL

Z

XH

Example 16

N

O

CF3

CO2Me

KH or NaH

N

O

CF3

OMeMO

N

CF3

OM

O

OMe

OO

N

CF3

OOH

N

CF3

Example 27

N

O2S

ONO2

NaOH, H2O

EtOH, reflux

N

O2SNO2

O2S H

N

NO2

41% 46%

Example 38

F

O2N K2CO3, DMF

reflux, 73%HO

O

O

O2NO OH

O2N O

513

Example 410

HOO

OF

NO21. K2CO3, DMSO, rt, 85%

2. PTSA, acetone/H2O 50 oC, 98%

O2NO

O

K2CO3, DMSO

rt, 93% O2NO

OHO O

NO2

References 1. Truce, W. E.; Ray, W. J. Jr.; Norman, O. L.; Eickemeyer, D. B. J. Am. Chem. Soc.

1958, 80, 3625–3629. 2. Truce, W. E.; Hampton, D. C. J. Org. Chem. 1963, 28, 2276–2279. 3. Bayne, D. W; Nicol, A. J.; Tennant, G. J. Chem. Soc., Chem. Comm. 1975, 19, 782–

783. 4. Fukazawa, Y.; Kato, N.; Ito, S.; Tetrahedron Lett. 1982, 23, 437–438. 5. Hoffman, R. V.; Jankowski, B. C.; Carr, C. S.; Düsler, E. N J. Org. Chem. 1986, 51,

130–135. 6. Erickson, W. R.; McKennon, M. J. Tetrahedron Lett. 2000, 41, 4541–4544. 7. Kimbaris, A.; Cobb, J.; Tsakonas, G.; Varvounis, G. Tetrahedron 2004, 60, 8807–

8815. 8. Mitchell, L. H.; Barvian, N. C. Tetrahedron Lett. 2004, 45, 5669–5672. 9. Snape, T. J. Chem. Soc. Rev. 2008, 37, 2452–2458. (Review). 10. Snape, T. J. Synlett 2008, 2689–2691.

514

Sommelet reaction Transformation of benzyl halides to the corresponding benzaldehydes with the aide of hexamethylenetetramine. Cf. Delépine amine synthesis (page 171).

Ar X NN

N

N

NN

N

NAr

XAr

CHOΔ

H2O

Δ

CHCl3


NN

N:

N

NN

N

NAr

X

Ar X

SN2N

NN

N CH2 H

Ar

: hydride

transfer

NN

N

N CH3 Ar

:OH2

NN

N

N CH3 Ar

O H

H ArCHO

NN

NH

N CH3

hemiaminal The hydride transfer and the ring-opening of hexamethylenetetramine may occur in a synchronized fashion:

NN

N

NH

X

Ar

NN

N

N CH3 Ar

Example 13

S

BrBnO 1. HMTA, CHCl3, reflux, 6 h

2. 50% HOAc/H2O, reflux, 3 h 40%

S

CHOBnO

Example 24

NH2

OH

HMTA, HOAc/H2O (11:3)reflux, 4 h

then 4.5 HCl, reflux, 1.5 h68%

CHO

OH

515


Example 37

NN

N

NCl

F

F

HOAc, H2O

Δ, 62%

CHOF

F

Example 48

NBS, BPO

CCl4, reflux, 15 h

38% 62%

Br Br Br

CHO

HMTA, H2O/EtOH (1:1)

reflux, 4 h, 75%

References 1. Sommelet, M. Compt. Rend. 1913, 157, 852−854. Marcel Sommelet (1877−1952) was

born in Langes, France. He received his Ph.D. In 1906 at Paris where he joined the Faculté de Pharmacie after WWI and became the chair of organic chemistry in 1934.

2. Angyal, S. J. Org. React. 1954, 8, 197–217. (Review). 3. Campaigne, E.; Bosin, T.; Neiss, E. S. J. Med. Chem. 1967, 10, 270−271. 4. Stokker, G. E.; Schultz, E. M. Synth. Commun. 1982, 12, 847−853. 5. Armesto, D.; Horspool, W. M.; Martin, J. A. F.; Perez-Ossorio, R. Tetrahedron Lett.

1985, 26, 5217−5220. 6. Kilenyi, S. N., in Encyclopedia of Reagents of Organic Synthesis, ed. Paquette, L. A.,

Wiley: Hoboken, NJ, 1995, Vol. 3, p. 2666. (Review). 7. Malykhin, E. V.; Shteingart, V. D. J. Fluorine Chem. 1998, 91, 19−20. 8. Karamé, I.; Jahjah, M.; Messaoudi, A.; Tommasino, M. L.; Lemaire, M. Tetrahedron:

Asymmetry 2004, 15, 1569−1581. 9. Göker, H.; Boykin, D. W.; Yildiz, S. Bioorg. Med. Chem. 2005, 13, 1707−1714. 10. Li, J. J. Sommelet reaction. In Name Reactions for Functional Group Transformations;

Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 689−695. (Re-view).

516

Sommelet–Hauser rearrangement [2,3]-Wittig rearrangement of benzylic quaternary ammonium salts upon treatment with alkali metal amides via the ammonium ylide intermediates.

NNH2

NH3N

NNH3

H

N [2,3]-sigmatropic

rearrangement

NH2 ammonium ylide

NNH

aromatization

H NH2

Example 13

Ph N SiMe3 IDMF, reflux

18 h, 94%N SiMe3

ICsF, HMPA

rt, 23 h, 86% N

Example 24

N SiMe3

Br CsF, HMPA

10 oC, 0.5 h, 32%AcO

NAcOAcO

N

46:54

Example 38

N

Br

t-BuOK, THF

−15 oC, 50% N

517


Example 410

N CO2R*

CO2Me R* = (−)-8-phenylmenthyl

Br

t-BuOK, THF

−60 oC, 4 h57%, > 20:1 de

CO2Me

N CO2R*

References 1. Sommelet, M. Compt. Rend. 1937, 205, 56–58. 2. Shirai, N.; Sato, Y. J. Org. Chem. 1988, 53, 194–196. 3. Shirai, N.; Watanabe, Y.; Sato, Y. J. Org. Chem. 1990, 55, 2767–2770. 4. Tanaka, T.; Shirai, N.; Sugimori, J.; Sato, Y. J. Org. Chem. 1992, 57, 5034–5036. 5. Klunder, J. M. J. Heterocycl. Chem. 1995, 32, 1687–1691. 6. Maeda, Y.; Sato, Y. J. Org. Chem. 1996, 61, 5188–5190. 7. Endo, Y.; Uchida, T.; Shudo, K. Tetrahedron Lett. 1997, 38, 2113–2116. 8. Hanessian, S.; Talbot, C.; Saravanan, P. Synthesis 2006, 723–734. 9. Liao, M.; Peng, L.; Wang, J. Org. Lett. 2008, 10, 693–696. 10. Tayama, E.; Orihara, K.; Kimura, H. Org. Biomol. Chem. 2008, 6, 3673–3680.

518

Sonogashira reaction Pd/Cu-catalyzed cross-coupling of organohalides with terminal alkynes. Cf. Cadiot–Chodkiewicz coupling and Castro−Stephens reaction. The Castro–Stephens coupling uses stoichiometric copper, whereas the Sonogashira variant uses catalytic palladium and copper.

R X R'PdCl2•(PPh3)2

CuI, Et3N, rtR R'

II

PdPh3P

Ph3P

Cl

Cl

R'C CCuII

R'C CH

PdPh3P

Ph3P

X

RRX

CuXCuX R'C CH

IIIIPd

Ph3P

Ph3P

C

C

CR'

CR' PdPh3P

Ph3P

C

R

CR'

R'C CC CR'

RC CR'

HX-amine

Pd0(PPh3)2

HX-amine

Cycle A

Cycle BCycle B'ii

iii

iii

iiii. oxidative additionii. transmetallationiii. reductive elimination

CuC CR'

Note that Et3N may reduce Pd(II) to Pd(0) as well, where Et3N is oxidized to the iminium ion at the same time:

NEt3PdCl2

NEt2HH

PdCl2

NEt2

PdH Cl

Cl

NEt2 ClCl Pd H

reductive

eliminationHCl Pd(0)

Example 12

NH

I

CO2Et

PdCl2•(Ph3P)2

CuI, Et3N60 oC, 89% N

HCO2Et

519


Example 23

N Br

SiMe3

NSiMe3

BrBr

PdCl2•(Ph3P)2, CuIEt3N, rt, 65–74%

Example 38

OMeOMe

I

Pd(PPh3)4, CuI, [bmim][BF4] Et3N, 80 °C, 12 h, 11%

N N

[bmim][BF4]MeO

OMeMeO

MeOOMe

OMe

OMe

OMeOMe

MeO

BF4

Example 49

OTf

OO TMSCl

MeOOMOM

OTBDPS

OO

PMPO

OTBS

OHO

OPMPO

OTBS

OH OO TMSCl

MeOOMOM

OTBDPSPd(PPh3)4, CuI,

i-PrNEt2:DMF (1:1)> 83%

References 1. (a) Sonogashira K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467−4470.

Richard Heck also discovered the same transformation using palladium but without the use of copper: J. Organomet. Chem. 1975, 93, 259−263.

2. Sakamoto, T.; Nagano, T.; Kondo, Y.; Yamanaka, H. Chem. Pharm. Bull. 1988, 36, 2248−2252.

3. Ernst, A.; Gobbi, L.; Vasella, A. Tetrahedron Lett. 1996, 37, 7959−7962. 4. Hundermark, T.; Littke, A.; Buchwald, S. L.; Fu, G. C. Org. Lett. 2000, 2, 1729−1731. 5. Batey, R. A.; Shen, M.; Lough, A. J. Org. Lett. 2002, 4, 1411−1414. 6. Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.; de Mei-

jere, A., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 1, 319. (Review). 7. Lemhadri, M.; Doucet, H.; Santelli, M. Tetrahedron 2005, 61, 9839−9847. 8. Li, Y.; Zhang, J.; Wang, W.; Miao, Q.; She, X.; Pan, X. J. Org. Chem. 2005, 70,

3285−3287. 9. Komano, K.; Shimamura, S.; Inoue, M.; Hirama, M. J. Am. Chem. Soc. 2007, 129,

14184−11186. 10. Gray, D. L. Sonogashira Reaction. In Name Reactions for Homologations-Part II; Li,


520

Staudinger ketene cycloaddition [2 + 2]-Cycloaddition of ketene and imine to form β-lactam. Other coupling part-ners for ketenes include: olefin to give cyclobutanone and carbonyl to give β-lactone.

O

R1 R2

X

R4R3

XO

R1R2R3

R4

X = NR; O; CHR

O

R1 R2

XO

R1R2R3

R4

XR4

R3

puckered transition state:

Example 16

p-TolN

NOt-Bu

OPhO

Cl

O

Et3N, CH2Cl210 oC to rt, 24 h

88%

N

PhOO Ot-Bu

O N p-Tol

Example 27

AcOCl

O

Et3N, CH2Cl2−78 oC to rt, 60%

N N

AcO

O

Example 39

O

O

CO2Et

COCl

PMPN CHPMP

Et3N, CH2Cl2−40 oC to rt15 h, 70%

O

OCO2Et

N

O

PMPH

PMPO

OCO2Et

NPMP

O

PMP H

major minor

521


Example 410

S

NCO2H

CO2t-BuMeO2C NMe

Cl I

CH2Cl2, Et3N S

NC

CO2t-BuMeO2C

O

CH

N CH2Ph PMP

62% SN

CO2t-BuMeO2C

NO CH2PMP

PhH S

NCO2t-Bu

MeO2C

NCH2PMP

O

PhH

56 : 44

References 1. Staudinger, H. Ber. 1907, 40, 1145−1146. Hermann Staudinger (Germany,

1881−1965) won the Nobel Prize in Chemistry in 1953 for his discoveries in the area of macromolecular chemistry.

2. Cooper, R. D. G.; Daugherty, B. W.; Boyd, D. B. Pure Appl. Chem. 1987, 59, 485−492. (Review).

3. Snider, B. B. Chem. Rev. 1988, 88, 793−811. (Review). 4. Hyatt, J. A.; Raynolds, P. W. Org. React. 1994, 45, 159−646. (Review). 5. Orr, R. K.; Calter, M. A. Tetrahedron 2003, 59, 3545−3565. (Review). 6. Bianchi, L.; Dell’Erba, C.; Maccagno, M.; Mugnoli, A.; Novi, M.; Petrillo, G.; San-

cassan, F.; Tavani, C. Tetrahedron 2003, 59, 10195−10201. 7. Banik, I.; Becker, F. F.; Banik, B. K. J. Med. Chem. 2003, 46, 12−15. 8. Banik, B. K.; Banik, I.; Becker, F. F. Bioorg. Med. Chem. Lett. 2005, 13, 3611−3622. 9. Chincholkar, P. M.; Puranik, V. G.; Rakeeb, A.; Deshmukh, A. S. Synlett 2007,

2242−2246. 10. Cremonesi, G.; Dalla Croce, P.; Fontana, F.; La Rosa, C. Tetrahedron: Asymmetry

2008, 19, 554−561.

522

Staudinger reduction Phosphazo compounds (e.g., iminophosphoranes) from the reaction of tertiary phosphine (e.g., Ph3P) with organic azides.

N3XPR3

X N N N PR3N2 X N PR3

phosphazide

NX N N :PR3X N N N PR3X N N N PH2R3

PR3NN N

X phosphazide

PR3NN N

X

PR3NN N

XN2 X N PR3

H2O X NH2 O PR3

‡

4-membered ring transition state

Example 12

N

OMeO

OTBDMS

N3Ph3P, THF

Δ, 81%

N

OMe

OTBDMS

N

Example 23

N3

CO2CH3

O

MeOO

H

H

O

1. PPh3, THF

2. NaBH4, MeOH

60%

CO2CH3OO

H

NHMeO

H

Example 34

NBr NH

Br

HN

O

O

N3

Ts

523


NBr

N

HN O

NH

BrTs

PBu3, toluene

reflux, 20 h, 82%

Example 48

O

N3

BnOBnO

N3O

N3

AcOOAc

N3

1.1 eq. PMe3, 2.4 eq. Boc-ON

Tol., −78 to 10 oC

O

N3

BnOBnO

N3O

N3

AcOOAc

NHBoc

37% O

N3

BnOBnO

N3O

NHBoc

AcOOAc

N3

42%

Example 59

PPh3, H2O

THF, 45 °C78%

NN

F

R2NC

O

O

N3NN

F

R2NC

O

O

NH2

References 1. Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635−646. 2. Stork, G.; Niu, D.; Fujimoto, R. A.; Koft, E. R.; Bakovec, J. M.; Tata, J. R.; Dake, G.

R. J. Am. Chem. Soc. 2001, 123, 3239−3242. 3. Williams, D. R.; Fromhold, M. G.; Earley, J. D. Org. Lett. 2001, 3, 2721−2722. 4. Jiang, B.; Yang, C.-G.; Wang, J. J. Org. Chem. 2002, 67, 1369−1371. 5. Venturini, A.; Gonzalez, J. J. Org. Chem. 2002, 67, 9089−9092. 6. Chen, J.; Forsyth, C. J. Org. Lett. 2003, 5, 1281−1283. 7. Fresneda, P. M.; Castaneda, M.; Sanz, M. A.; Molina, P. Tetrahedron Lett. 2004, 45,

1655−1657. 8. Li, J.; Chen, H.-N.; Chang, H.; Wang, J.; Chang, C.-W. T. Org. Lett. 2005, 7,

3061−3064. 9. Takhi, M.; Murugan, C.; Munikumar, M.; Bhaskarreddy, K. M.; Singh, G.; Sreenivas,

K.; Sitaramkumar, M.; Selvakumar, N.; Das, J.; Trehan, S.; Iqbal, J. Bioorg. Med. Chem. Lett. 2006, 16, 2391−2395.

10. Iula, D. M. Staudinger reaction. In Name Reactions for Functional Group Transfor-mations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 129−151. (Review).

524

Stetter reaction 1,4-Dicarbonyl derivatives from aldehydes and α,β-unsaturated ketones and es-ters. The thiazolium catalyst serves as a safe surrogate for −CN. Also known as the Michael−Stetter reaction. Cf. Benzoin condensation.

R CHOO

N

S

PhHO

NH3

R

O

O

Cl

N

S

PhHO

H

:NH3

deprotonation N

S

Bn

R1

R

OHR1 = HOCH2CH2CH2-

O

N

S

Bn

R1 OH

RH

N

S

Bn

R1 OH

R

Michael

addition

:NH3

N

S

Bn

R1

R

OH

O

tautomerization N

S

Bn

R1

R

O

O

R

O

O

N

S

PhHO N

S

PhHO

NH4

Example 1, Intramolecular Stetter reaction2

CN

MeO2C

O

CN

MeO2C

OHC

S

NMe

MeI

HO2.3 equiv

TEA, i-PrOH, 80 oC67%

Example 23

O CHOOHC O

(cat.)

Et3N, EtOH, 80 oC, 56%O

OO

OOS

NMe

MeI

HO

525


Example 35

N

NO

H

O

CO2Me

N

S

Ph

HOCl

Et3N, DMF, 100 ºC, 75%

(cat.)

N

NO

O

CO2Me

Example 4, Sila-Stetter reaction9

Ph

OPh

O

Ph Si

O

PhPh

OPh

S

NEt

MeBr

HOMe

MeMe

30 mol%

4 equiv i-PrOH, DBU, THF, 77%

References 1. (a) Stetter, H.; Schreckenberg, H. Angew. Chem. 1973, 85, 89. Hermann Stetter

(1917−1993), born in Bonn, Germany, was a chemist at Technische Hochschule Aachen in West Germany. (b) Stetter, H. Angew. Chem. 1976, 88, 695−704. (Re-view). (c) Stetter, H.; Kuhlmann, H.; Haese, W. Org. Synth. 1987, 65, 26.

2. Trost, B. M.; Shuey, C. D.; DiNinno, F., Jr.; McElvain, S. S. J. Am. Chem. Soc. 1979, 101, 1284−1285.

3. El-Haji, T.; Martin, J. C.; Descotes, G. J. Heterocycl. Chem. 1983, 20, 233−235. 4. Harrington, P. E.; Tius, M. A. Org. Lett. 1999, 1, 649−651. 5. Kikuchi, K.; Hibi, S.; Yoshimura, H.; Tokuhara, N.; Tai, K.; Hida, T.; Yamauchi, T.;

Nagai, M. J. Med. Chem. 2000, 43, 409−419. 6. Kobayashi, N.; Kaku, Y.; Higurashi, K. Bioorg. Med. Chem. Lett. 2002, 12,

1747−1750. 7. Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2005, 127, 6284−6289. 8. Reynolds, N. T.; Rovis, T. Tetrahedron 2005, 61, 6368−6378. 9. Mattson, A. E.; Bharadwaj, A. R.; Zuhl, A. M.; Scheidt, K. A. J. Org. Chem. 2006, 71,

5715−5724. 10. Cee, V. J. Stetter Reaction. In Name Reactions for Homologations-Part I; Li, J. J.,


526

Still–Gennari phosphonate reaction A variant of the Horner−Emmons reaction using bis(trifluoroethyl)phosphonate to give Z-olefins.

(CF3CH2O)2P CO2CH3

O KN(SiMe3)2, 18-Crown-6

then PhCH2CHOCO2CH3Ph

CF3CH2OP

OMe

OCF3CH2O

O

H CF3CH2OP

OMe

OCF3CH2O

O

O

H

NSiMe3

SiMe3 Ph

PO

HCO2CH3

H

O

OCH2CF3

OCH2CF3

PhH

CO2CH3

HPO OCH2CF3

OCH2CF3O

Ph

CO2CH3Ph

erythro isomer, kinetic adduct

Example 12

(CF3CH2O)2P CO2CH3

OKN(SiMe3)2, 18-Crown-6

−78 oC, THF, 30 min.

then PhCH2CHO, 87%

CO2CH3Ph

Example 23

F3CH2COP

OEt

OF3CH2COO

F Sn(OSO2CF3)2, N-methylpiperidineCH2Cl2, 70%, E:Z = 96:4

CO2Et

MeF

NNMe

NNO

Example 34

S

NCH3

O

OTBS

F3CH2COP

OEt

OF3CH2COO

527


KHMDS, THF18-crown-6, −78 oC, 1 h

89%, (Z)-isomer onlyS

NCH3EtO

O

OTBS

Example 49

MeOP(OCH2CF3)2

O O OTBS TBS

O O

OTBS

CHOOTBS

OPMB

NaH, THF

73%, Z:E 5:1

OTBS

OTBS

OPMB

MeO

O O OTBS TBS

O

References 1. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405−4408. W. Clark Still

(1946−) was born in Augusta, Georgia. He was a professor at Columbia University. 2. Nicolaou, K. C.; Nadin, A.; Leresche, J. E.; LaGreca, S.; Tsuri, T.; Yue, E. W.; Yang,

Z. Chem. Eur. J. 1995, 1, 467−494. 3. Sano, S. Yokoyama, K.; Shiro, M.; Nagao, Y. Chem. Pharm. Bull. 2002, 50, 706–709. 4. Mulzer, J.; Mantoulidis, A.; Öhler, E. Tetrahedron Lett. 1998, 39, 8633–8636. 5. Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N. J. Am. Chem. Soc.

2001, 123, 9535−9544. 6. Mulzer, J.; Ohler, E. Angew. Chem., Int. Ed. 2001, 40, 3842−3846. 7. Beaudry, C. M.; Trauner, D. Org. Lett. 2002, 4, 2221−2224. 8. Dakin, L. A.; Langille, N. F.; Panek, J. S. J. Org. Chem. 2002, 67, 6812−6815. 9. Paterson, I.; Lyothier, I. J. Org. Chem. 2005, 70, 5494−5507. 10. Rong, F. Horner–Wadsworth–Emmons reaction. In Name Reactions for Homologa-

tions-Part I; Li, J. J., Corey, E. J.; Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 420−466. (Review).

528

Stille coupling Palladium-catalyzed cross-coupling reaction of organostannanes with organic hal-ides, triflates, etc. For the catalytic cycle, see Kumada coupling on page 325.

R X R1 Sn(R2)3Pd(0)

R R1 X Sn(R2)3

R XR1 Sn(R2)3

L2Pd(0) transmetallationisomerization

oxidative

additionPd

L

L X

R

X Sn(R2)3 PdL

R R1

LR1R

reductive

eliminationL2Pd(0)

Example 14

N

N

NH2

Cl

ClN

N

NH2

BrCl

Cl PdCl2•(Ph3P)2, CuITHF, reflux, 92%

NSnBu3

SO2Ph

NPhO2S

Example 25

TBDPSO Br

(MeCN)2PdCl2

AsPh3, NMP80 oC, 1.5 h, 55%

Me3Sn Cl

Cl

TBDPSO Cl

Cl HCl

HN Cl

Cl

Zoloft

Example 3, π-Allyl Stille coupling8

OTBDPSSnMe3

OAc

Me

MeO

MeMe

Me

MeO

MeMe

OTBDPSPd2(dba)3, LiCli-Pr2NEt, NMP

35 °C, 1.5 h, 96%

529


Example 49

I

OH

O

Me

OMe

NS

OMeHN

O

MeOMe

OTBS SnMe3

Pd(PPh3)4, CuTC

DMF, 32%

OH

O

Me

OMe

NS

OMeHN

O

MeOMe

OTBS

18

References 1. (a) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636−3638. John Kenneth

Stille (1930−1989) was born in Tucson, Arizona. He developed the reaction bearing his name at Colorado State University. At the height of his career, Stille unfortunately died of an airplane accident returning from an ACS meeting. (b) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1979, 101, 4992−4998. (c) Stille, J. K. Angew. Chem., Int. Ed. 1986, 25, 508−524.

2. Farina, V.; Krishnamurphy, V.; Scott, W. J. Org. React. 1997, 50, 1–652. (Review). 3. Duncton, M. A. J.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1999, 1235−1249.

(Review on the intramolecular Stille reaction). 4. Li, J. J.; Yue, W. S. Tetrahedron Lett. 1999, 40, 4507−4510. 5. Lautens, M.; Rovis, T. Tetrahedron, 1999, 55, 8967−8976. 6. Mitchell, T. N. Organotin Reagents in Cross-Coupling Reactions. In Metal-Catalyzed

Cross-Coupling Reactions (2nd edn.) De Meijere, A.; Diederich, F. eds., 2004, 1, 125−161. Wiley-VCH: Weinheim, Germany. (Review).

7. Schröter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61, 2245−2267. (Review). 8. Snyder, S. A.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 740−742. 9. Roethle, P. A.; Chen, I. T.; Trauner, D. J. Am. Chem. Soc. 2007, 129, 8960−8961. 10. Mascitti, V. Stille Coupling. In Name Reactions for Homologations-Part I; Li, J. J.,


530

Stille− Kelly reaction Palladium-catalyzed intramolecular cross-coupling reaction of bis-aryl halides us-ing ditin reagents.

OHOH

Br

Br Me3Sn SnMe3

Pd(Ph3P)4OH

OH

OHOH

Br

Br

OHOH

Br

BrPd

Me3Sn SnMe3Pd(0)

oxidativeaddition

transmetalation

OHOH

Br

PdMe3Sn

OHOH

Br

Me3Sn

reductive

eliminationPd(0)

Pd(0)

oxidativeaddition

OHOH

PdBr

Me3Sn

transmetallation

OHOH

OHOH

Pdreductive

eliminationPd(0)

Example 16

N

Cl

I HO

I

N

O

I I

NaH, DMF, reflux, 89%

Me3Sn SnMe3

PdCl2•(Ph3P)2xylene, reflux, 92%

N

O

References 1. Kelly, T. R.; Li, Q.; Bhushan, V. Tetrahedron Lett. 1990, 31, 161−164. 2. Grigg, R.; Teasdale, A.; Sridharan, V. Tetrahedron Lett. 1991, 32, 3859−3862. 3. Iyoda, M.; Miura, M.; Sasaki, S.; Kabir, S. M. H.; Kuwatani, Y.; Yoshida, M. Hetero-

cycles 1997, 38, 4581−4582. 4. Fukuyama, Y.; Yaso, H.; Nakamura, K.; Kodama, M. Tetrahedron Lett. 1999, 40,

105−108. 5. Iwaki, T.; Yasuhara, A.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1999,

1505−1510. 6. Yue, W. S.; Li, J. J. Org. Lett. 2002, 4, 2201−2203. 7. Olivera, R.; SanMartin, R.; Tellitu, I.; Dominguez, E. Tetrahedron 2002, 58,

3021−3037. 8. Mascitti, V. Stille Coupling. In Name Reactions for Homologations-Part I; Li, J. J.,


531


Stobbe condensation Condensation of diethyl succinate and its derivatives with carbonyl compounds in the presence of bases.

R R1

O

CO2Et

CO2Et R

R1

CO2EtCO2HKOt-Bu

HOt-Bu

R

R1

OCO2Et

enolate

formation

aldol

addition

O

OEtH

t-BuO

CO2Et

O

OEt O

CO2EtRR1

OEtO

lactonization

O

RR1

EtO O

CO2Et

O

RR1 CO2Et

O

H

Ot-Bu

R

R1

CO2EtCO2

H R

R1

CO2EtCO2H

ring

opening

Example 1, Stobbe condensation and cyclization5

CO2Me

CO2Me

1. t-BuOK, t-BuOH, reflux

2. Ac2O, NaOAc, reflux 84%

OCHO

OO

O

OO

CO2Me

OAc

Example 2, Stobbe condensation6

O

O

CHOO

O

O

aq. NaOH, EtOH

−10 oC, 5 h, 80−95%

O

O

O

O

OH

Example 3, Cyclization of the Stobbe product7

BnO2C

CO2Et

CO2H

BnO2C

CO2Et

OAc

NaOAc, Ac2O

reflux, 57%

532


Example 4, Two sequential Stobbe condensations9

F CHO

1. (CH2CO2Et)2, NaOMe, MeOH then aq. NaOH, 36%

2. MeOH, H2O4, 94% FCO2Me

CO2Me

NaOMe, MeOH, 74%

CHO

IO

O

F CO2H

CO2Me

IO

O

References 1. Stobbe, H. Ber. 1893, 26, 2312. Hans Stobbe (1860−1938) was born in Tiehenhof,

Germany. He earned his Ph.D. In 1889 at the University of Leipzig where he became a professor in 1894.

2. Zerrer, R.; Simchen, G. Synthesis 1992, 922–924. 3. Yvon, B. L.; Datta, P. K.; Le, T. N.; Charlton, J. L. Synthesis 2001, 1556–1560. 4. Liu, J.; Brooks, N. R. Org. Lett. 2002, 4, 3521–3524. 5. Giles, R. G. F.; Green, I. R.; van Eeden, N. Eur. J. Org. Chem. 2004, 4416–4423. 6. Mahajan, V. A.; Shinde, P. D.; Borate, H. B.; Wakharkar, R. D. Tetrahedron Lett.

2005, 46, 1009–1012. 7. Sato, A.; Scott, A.; Asao, T.; Lee, M. J. Org. Chem. 2006, 71, 4692–4695. 8. Kapferer, T.; Brückner, R. Eur. J. Org. Chem. 2006, 2119–2133. 9. Mizufune, H.; Nakamura, M.; Mitsudera, H. Tetrahedron 2006, 62, 8539–8549. 10. Lowell, A. N.; Fennie, M. W.; Kozlowski, M. C. J. Org. Chem. 2008, 73, 1911–1918.

533

Strecker amino acid synthesis Sodium cyanide-promoted condensation of aldehyde, or ketone, with amine to af-ford α-amino nitrile, which may be hydrolyzed to α-amino acid.

R1 H

OH2N

R2

R1 CN

HNR2

H

R1 CO2H

HNR2

NaCN

AcOH

:

R1 H

O

H2NR2 NC

:

R1

HNH

R1 NH

H

R2O

R2

HH

H2O:

R1

HNR2

N R1

HNR2

NH

OHH

iminium ion

R1

HNR2

NH2

O

:OH2

acidic amide

hydrolysis R1

HNR2

NH2

HO OHR1

HNR2

NH3

HO OH

R1 CO2H

HNR2

H

H

Example 1, Soluble cyanide source2

C8H17

H

H

HO

C8H17

H

H

HN

NC

(EtO)2P CNO

pyrrolidine, THF, 62%

Example 23

NH

S acetone cyanohydrinMgSO4, 45 oCtoluene, 31%

OHCCl

N

S

ClCN

N

S

ClO O

Plavix

Example 38

Ph

O NaCN, NH4Cl

i-PrOH, NH4OH

PhNH2

CNH

PhCN

NH2H34% 35%

534


Example 49

O

O

Ph

CF3

F3C OPh

CF3

F3CCN

HN Bn

NaCN, BnNH2AcOH, MeOH

98%

References 1. Strecker, A. Ann. 1850, 75, 27−45. 2. Harusawa, S.; Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1979, 20, 4663–4666. 3. Burgos, A.; Herbert, J. M.; Simpson, I. J. Labelled. Compd. Radiopharm. 2000, 43,

891–898. 4. Ishitani, H.; Komiyama, S.; Hasegawa, Y.; Kobayashi, S. J. Am. Chem. Soc. 2000,

122, 762–766. 5. Yet, L. Recent Developments in Catalytic Asymmetric Strecker-Type Reactions, in Or-

ganic Synthesis Highlights V, Schmalz, H.-G.; Wirth, T. eds.; Wiley−VCH: Wein-heim, Germany, 2003, pp 187−193. (Review).

6. Meyer, U.; Breitling, E.; Bisel, P.; Frahm, A. W. Tetrahedron: Asymmetry 2004, 15, 2029–2037.

7. Huang, J.; Corey, E. J. Org. Lett. 2004, 6, 5027–5029. 8. Cativiela, C.; Lasa, M.; Lopez, P. Tetrahedron: Asymmetry 2005, 16, 2613–2523. 9. Wrobleski, M. L.; Reichard, G. A.; Paliwal, S.; Shah, S.; Tsui, H-C.; Duffy, R. A.; La-

chowicz, J. E.; Morgan, C. A.; Varty, G. B.; Shih, N-Y. Bioorg. Med. Chem. Lett. 2006, 16, 3859–3863.

10. Galatsis, P. Strecker amino acid synthesis. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 477−499. (Review).

11. Belokon, Y. N.; Hunt, J.; North, M. Tetrahedron: Asymmetry 2008, 19, 2804−2815.

535

Suzuki–Miyaura coupling Palladium-catalyzed cross-coupling reaction of organoboranes with organic hal-ides, triflates, etc. In the presence of a base (transmetallation is reluctant to occur without the activating effect of a base). For the catalytic cycle, see Kumada cou-pling on page 325.

R X R1 B(R2)2 R1RL2Pd(0)

NaOR3

R X L2Pd(0)oxidative

additionPd

L

L X

R NaOR3

baseR1 B(R2)2 R1 B(R2)2

OR3

PdL

L X

R

transmetallation

isomerizationPd

L

R R1

LR1R

reductive

eliminationL2Pd(0)R3O B(R2)2

Example 12

N

CO2Me

CO2Me

I

CO2Et

OB

O

Pd(OAc)2Ph3P, K2CO3

THF, MeOH70 °C, 15 h, 80% N

CO2Me

CO2Me

CO2Et

Example 24

N

N

I

ISEM

NTBS

N

N

I

I

SEM

I

N

B(OH)2

TBS

Pd(Ph3P)4, Na2CO3, 45%

Example 3, Intramolecular Suzuki–Miyaura coupling8

TBDMSO

O

O

OBn

Br

OMOM

1.BH

2

2. H2O, CH2O3. KHF2

99%

TBDMSO

O

O

OBn

Br

OMOM

BF3K

536


O

O OMOM

BnO

OHcat. Pd(PPh3)4, Cs2CO3

THF/H2O, reflux, 42%

Example 49

SnBu3BO

OBO

Ocat. Pd2(dba)3, Ph3AsDMF, 84%

3

O

NH

OMeI

3NH

OOMe

cat. PdCl2(dppf), Ph3AsK3PO4 (aq), DMF, 71%

OHI O

NH

OMeHO

References 1. (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 36, 3437−3440. (b)

Miyaura, N.; Suzuki, A. Chem. Commun. 1979, 866–867. 2. Tidwell, J. H.; Peat, A. J.; Buchwald, S. L. J. Org. Chem. 1994, 59, 7164–7168. 3. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457−2483. (Review). 4. (a) Kawasaki, I.; Katsuma, H.; Nakayama, Y.; Yamashita, M.; Ohta, S. Heterocycles

1998, 48, 1887–1901. (b) Kawaski, I.; Yamashita, M.; Ohta, S. Chem. Pharm. Bull. 1996, 44, 1831–1839.

5. Suzuki, A. In Metal-catalyzed Cross-coupling Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley−VCH: Weinhein, Germany, 1998, 49–97. (Review).

6. Stanforth, S. P. Tetrahedron 1998, 54, 263−303. (Review). 7. Zapf, A. Coupling of Aryl and Alkyl Halides with Organoboron Reagents (Suzuki Re-

action). In Transition Metals for Organic Synthesis (2nd edn.); Beller, M.; Bolm, C. eds., 2004, 1, 211−229. Wiley−VCH: Weinheim, Germany. (Review).

8. Molander, G. A.; Dehmel, F. J. Am. Chem. Soc. 2004, 126, 10313–10318. 9. Coleman, R. S.; Lu, X.; Modolo, I. J. Am. Chem. Soc. 2007, 129, 3826–3827. 10. Wolfe, J. P.; Nakhla, J. S. Suzuki coupling. In Name Reactions for Homologations-

Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 163−184. (Review).

537

Swern oxidation Oxidation of alcohols to the corresponding carbonyl compounds using (COCl)2, DMSO, and quenching with Et3N.

R1 R2

OH

R1 R2

O(COCl)2, DMSOCH2Cl2, −78 oC

then Et3N

ClCl

O

O

OS

ClO

O

OS

ClCl

OO

SCl O

CO2↑ CO↑

SCl

R1 R2

:OH

Cl

R1 R2

OS H

H

:NEt3

R1 R2

OEt3N•HCl↓ (CH3)2S↑

OHCH2

S

R1

R2

sulfur ylide

Example 12

OMe

OMeOMe OHOH

HOH 1. (COCl)2, DMSO, −60 oC, 45 min

2. Et3N, −60 oC, 15 min. then rt 81%

OMe

OMeOMe OOH

HO

Example 23

O

OHO

TMSCH2CH2O2C

NC

Swernconditions

80%O

OO

TMSCH2CH2O2C

NC

Cl

Example 35

C6H13

OSiMe2t-Bu

OHC11H23 (COCl)2, DMSO

then Et3N, 89%

C6H13

OSiMe2t-Bu

OC11H23

538


Example 47

N

OMeO

OTBDPS

N3

N

OMeHO

OTBDPS

N3 (COCl)2, DMSO

then Et3N, 85%

References 1. (a) Huang, S. L.; Omura, K.; Swern, D. J. Org. Chem. 1976, 41, 3329−3331. (b)

Huang, S. L.; Omura, K.; Swern, D. Synthesis 1978, 4, 297−299. (c) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43, 2480−2482.

2. Ghera, E.; Ben-David, Y. J. Org. Chem. 1988, 53, 2972−2979. 3. Smith, A. B., III; Leenay, T. L.; Liu, H. J.; Nelson, L. A. K.; Ball, R. G. Tetrahedron

Lett. 1988, 29, 49−52. 4. Tidwell, T. T. Org. React. 1990, 39, 297−572. (Review). 5. Chadka, N. K.; Batcho, A. D.; Tang P. C.; Courtney, L. F.; Cook C. M.; Wovliulich, P.

M.; Uskovi , M. R. J. Org. Chem. 1991, 56, 4714−4718. 6. Harris, J. M.; Liu, Y.; Chai, S.; Andrews, M. D.; Vederas, J. C. J. Org. Chem. 1998,

63, 2407−2409. (Odorless protocols). 7. Stork, G.; Niu, D.; Fujimoto, R. A.; Koft, E. R.; Bakovec, J. M.; Tata, J. R.; Dake, G.

R. J. Am. Chem. Soc. 2001, 123, 3239−3242. 8. Nishide, K.; Ohsugi, S.-i.; Fudesaka, M.; Kodama, S.; Node, M. Tetrahedron Lett.

2002, 43, 5177−5179. (Another odorless protocols). 9. Kawaguchi, T.; Miyata, H.; Ataka, K.; Mae, K.; Yoshida, J.-i. Angew. Chem., Int. Ed.

2005, 44, 2413−2416. 10. Ahmad, N. M. Swern oxidation. In Name Reactions for Functional Group Transfor-


11. Lopez-Alvarado, P; Steinhoff, J; Miranda, S; Avendano, C; Menendez, J. C. Tetrahedron 2009, 65, 1660−1672.

539

Takai reaction Stereoselective conversion of an aldehyde to the corresponding E-vinyl iodide us-ing CHI3 and CrCl2.

R H

OR

ICHI3, CrCl2

THF

CrCl2HI

II H

I

CrIIICl2I CrCl2

R

HO

HCrIIICl2

CrIIICl2I

Cl2CrIII

I

ROCrIIICl2 R

I

A radical mechanism was recently proposed10

I

I

H

I

CrIICrIIII

I

H

I

CrII

R H

O

HI

CrIIII

RI

OCrIII

I

CrII

H RIR

IOCrIII

CrII

HR

IOCrIII

CrIII

Example 12

CHI3, CrCl2

THF, 70%Ph

OTBSCHO Ph

OTBSI

20: 1 E:Z

Example 23

N

N N

NEt

EtEt

Et

Et

Et Et

Et

CHONiN

N N

NEt

EtEt

Et

Et

Et Et

Et

Ni25 equiv CrCl26 equiv CHI3

THF, rt, 3 h75%

I

540


Example 34

CO2MeOHC

OTES CHI3, CrCl2, 0 oC

THF, 50% CO2Me

OTES

I

Example 4, A Br/Cl variant9

OOTHP

6 equiv CrCl2, 2 equiv CHBr3

THF, 0 oC, 2.5 h, 67%

OTHPBr OTHPCl

1 : 1

Example 510

CO2Me

CHOMOMO

H

H CO2MeMOMO

H

H

I

5.8 equiv anhydrous CrCl22 equiv CHI3

1,4-dioxane−THF (6:1)20 oC, 72 h, 88%

References 1. Takai, K.; Nitta, Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408–7410. 2. Andrus, M. B.; Lepore, S. D.; Turner, T. M. J. Am. Chem. Soc. 1997, 119, 12159–

12169. 3. Arnold, D. P.; Hartnell, R. D. Tetrahedron 2001, 57, 1335–1345. 4. Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2004, 45, 8717–8724. 5. Dineen, T. A.; Roush, W. R. Org. Lett. 2004, 6, 2043–2046. 6. Lipomi, D. J.; Langille, N. F.; Panek, J. S. Org. Lett. 2004, 6, 3533–3536. 7. Paterson, I.; Mackay, A. C. Synlett 2004, 1359–1362. 8. Concellón, J. M.; Bernad, P. L.; Méjica, C. Tetrahedron Lett. 2005, 46, 569–571. 9. Gung, B. W.; Gibeau, C.; Jones, A. Tetrahedron: Asymmetry 2005, 16, 3107–3114. 10. Legrand, F.; Archambaud, S.; Collet, S.; Aphecetche-Julienne, K.; Guingant, A.;

Evain, M. Synlett 2008, 389–393.

541

Tebbe’s reagent The Tebbe’s reagent, -chlorobis(cyclopentadienyl)(dimethylaluminium)- -methylenetitanium, transforms a carbonyl compound to the corresponding exo-olefin.

Ti

H2C

Cl

AlCH3

CH3

Preparation:2,6

Cp2TiCl2 + 2 Al(CH3)3 Cp2TiCl

Al(CH3)2CH4↑ + Al(CH3)2Cl +

Mechanism:3

Cp2Ti CH2

Cl Al(CH3)2Cp2Ti

ClAl(CH3)2

O

dissociation

RR1

R R1Cp2Ti O

[2 + 2]

cycloaddition

Cp2Ti CH2

OR

R1retro-[2 + 2]

cycloaddition

oxatitanacyclobutane formation of the strong Ti=O is the driving force.

Example 1, Ketone2

Tebbe's reagent, Tol.

then the ketone substrate,THF, 0 oC to rt, 30 min., 67%

O

CO2Et CO2Et

Example 2, Double Tebbe4

O

H2.5 eq

O

H

O THF, CH2Cl2−40 to 25 °C, 69%HO

Ti

Cl

AlCp

Cp

542


Example 3, Double Tebbe5

OHC

TBSO

O

OBn

OBn

OTBS

OTBS

CHO

3 equiv Tebbe's reagent in Tol.pyr., Tol./THF

−78 oC to −15 oC, 2 h86%

TBSO

O

OBn

OBn

OTBS

OTBS

TBSTBS

Example 4, N-Oxide6

NO

Ti

Cl

AlCp

Cp

NTHF, 0 oC to rt, 90%

Example 5, Amide11

N O

N

O

CF3CF3

O

N O

N

O

CF3CF3

OH1. Tebbe's reagent

2. BH3, THF, H2O2, NaOH 75−95%

References 1. Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc. 1978, 100, 3611−3613. 2. Pine, S. H.; Pettit, R. J.; Geib, G. D.; Cruz, S. G.; Gallego, C. H.; Tijerina, T.; Pine, R.

D. J. Org. Chem. 1985, 50, 1212–1216. 3. Cannizzo, L. F.; Grubbs, R. H. J. Org. Chem. 1985, 50, 2386–2387. 4. Philippo, C. M. G.; Vo, N. H.; Paquette, L. A. J. Am. Chem. Soc. 1991, 113,

2762−2764. 5. Ikemoto, N.; Schreiber, L. S. J. Am. Chem. Soc. 1992, 114, 2524–2536. 6. Pine, S. H. Org. React. 1993, 43, 1−98. (Review). 7. Nicolaou, K. C.; Koumbis, A. E.; Snyder, S. A.; Simonsen, K. B. Angew. Chem., Int.

Ed. 2000, 39, 2529–2533. 8. Straus, D. A. Encyclopedia of Reagents for Organic Synthesis; John Wiley & Sons,

2000. (Review). 9. Payack, J. F.; Hughes, D. L.; Cai, D.; Cottrell, I. F.; Verhoeven, T. R. Org. Syn., Coll.

Vol. 10, 2004, p 355. 10. Beadham, I.; Micklefield, J. Curr. Org. Synth. 2005, 2, 231−250. (Review). 11. Long, Y. O.; Higuchi, R. I.; Caferro, T.s R.; Lau, T. L. S.; Wu, M.; Cummings, M. L.;

Martinborough, E. A.; Marschke, K. B.; Chang, W. Y.; Lopez, F. J.; Karanewsky, D. S.; Zhi, L. Bioorg. Med. Chem. Lett. 2008, 18, 2967−2971.

12. Zhang, J. Tebbe reagent. In Name Reactions for Homolotions-Part I; Li, J. J., Corey, E. J., Eds., Wiley & Sons: Hoboken, NJ, 2009, pp 319−333. (Review).

543

TEMPO oxidation TEMPO = Tetramethyl pentahydropyridine oxide. 2,2,6,6-Tetramethylpiperi-dinyloxy is a stable nitroxyl radical, which serves in oxidations as catalyst

R OHNaOCl, cat. TEMPO

KBr, NaHCO3, CH2Cl2 R OH

O

1/2 NaOClNO

NO

OCl

::

:

NO

HO R

:

NO O

H RH

N O

N

NHAc

OH

R H

O

OCl

:B

R

OH

OCl R O

O

R O

OH

Example 14

NaOCl, cat. TEMPO

KBr, NaHCO3, CH2Cl255%

HO OHO

OHOMe

OH

HOO

HOOH

OMe

HO2C

544


Example 2, Trichloroisocyanuric/TEMPO Oxidation5

R OH0.01 mol equiv TEMPO

0.05 mol equiv NaBracetone, aq. NaHCO3, rt

1−24 h, 75−100%

N

N N

OO

OCl

Cl

Cl

R OH

O

Example 38

cat. TEMPO, 2 eq. 2,6-lutidine

electrolysis in CH3CN/H2O (95:5)95%

O

Example 410

Ormosil-TEMPO, NaOCl

CH3CN, NaHCO3, 5%0 oC, 80%Cl

OHOH

Cl

CO2H

OH

“Ormosil-TEMPO” is a sol-gel hydrophobized nanostructured silica matrix

doped with TEMPO

References 1. Garapon, J.; Sillion, B.; Bonnier, J. M. Tetrahedron Lett. 1970, 11, 4905–4908. 2. de Nooy, A. E.; Besemer, A. C.; van Bekkum, H. Synthesis 1996, 1153–1174. (Re-

view). 3. Rychnovsky, S. D.; Vaidyanathan, R. J. Org. Chem. 1999, 64, 310–312. 4. Fabbrini, M.; Galli, C.; Gentili, P.; Macchitella, D. Tetrahedron Lett. 2001, 42, 7551–

7553. 5. De Luca, L.; Giacomelli, G.; Masala, S.; Porcheddu, A. J. Org. Chem. 2003, 45, 4999–

5001. 6. Ciriminna, R.; Pagliaro, M. Tetrahedron Lett. 2004, 45, 6381–6383. 7. Tashino, Y.; Togo, H. Synlett 2004, 2010–2012. 8. Breton, T.; Liaigre, D.; Belgsir, E. M. Tetrahedron Lett. 2005, 46, 2487–2490. 9. Chauvin, A.-L.; Nepogodiev, S. A.; Field, R. A. J. Org. Chem. 2005, 47, 960–966. 10. Gancitano, P.; Ciriminna, R.; Testa, M. L.; Fidalgo, A.; Ilharco, L. M.; Pagliaro, M.

Org. Biomol. Chem. 2005, 3, 2389–2392. 11. Zhang, M.; Chen, C.; Ma, W.; Zhao, J. Angew. Chem., Int. Ed. 2008, 47, 9730–9733.

545

Thorpe−Ziegler reaction The intramolecular version of the Thorpe reaction, which is base-catalyzed self-condensation of nitriles to yield imines that tautomerize to enamine.

CNCN OEt

CN

NH2HOEt

N

HEtO

N

N

NH OEt H

H OEt

OEt

CN

NH

CN

NH2

H

H OEt

EtO

Example 1, A radical Thorpe−Ziegler reaction2

Br

CN

NC

Bu3SnH, AIBNsyringe pump

PhH, 80 oC, 56%

CNH2N

Example 25

N CNPh

CNLDA, THF

−78 oC to rt

2 h, 80%NPh

CNNH2

Example 38

NH

O

N

SHN

O

PhKOH, EtOH

reflux, 5 min., 80% NH

O

NH2

S

HN

O

Ph

546


Example 49

OMe

NH

NC CN

OMe

N

NC CN

CN

OMe

N

NC

CNCl CN

NH2

Et3N, reflux15 min., 91%

References 1. (a) Baron, H.; Remfry, F. G. P.; Thorpe, Y. F. J. Chem. Soc. 1904, 85, 1726–1761. (b)

Ziegler, K. et al. Ann. 1933, 504, 94–130. Karl Ziegler (1898−1973), born in Helsa, Germany, received his Ph.D. In 1920 from von Auwers at the University of Marburg. He became the director of the Max-Planck-Institut für Kohlenforschung at Mül-heim/Ruhr in 1943. He shared the Nobel Prize in Chemistry in 1963 with Giulio Natta (1903−1979) for their work in polymer chemistry. The Ziegler−Natta catalyst is widely used in polymerization.

2. Curran, D. P.; Liu, W. Synlett 1999, 117–119. 3. Dansou, B.; Pichon, C.; Dhal, R.; Brown, E.; Mille, S. Eur. J. Org. Chem. 2000, 1527–

1531. 4. Keller, L.; Dumas, F.; Pizzonero, M.; d’Angelo, J.; Morgant, G.; Nguyen-Huy, D. Tet-

rahedron Lett. 2002, 43, 3225–3228. 5. Malassene, R.; Toupet, L.; Hurvois, J.-P.; Moinet, C. Synlett 2002, 895–898. 6. Satoh, T.; Wakasugi, D. Tetrahedron Lett. 2003, 44, 7517–7520. 7. Wakasugi, D.; Satoh, T. Tetrahedron 2005, 61, 1245–1256. 8. Dotsenko, V. V.; Krivokolysko, S. G.; Litvinov, V. P. Monatsh. Chem. 2008, 139,

271–275. 9. Salaheldin, A. M.; Oliveira-Campos, A. M. F.; Rodrigues, L. M. ARKIVOC 2008,

180–190. 10. Miszke, A.; Foks, H.; Brozewicz, K.; Kedzia, A.; Kwapisz, E.; Zwolska, Z.

Heterocycles 2008, 75, 2723–2734.

547

Tsuji−Trost reaction The Tsuji–Trost reaction is the palladium-catalyzed substitution of allylic leaving groups by carbon nucleophiles. These reactions proceed via π-allylpalladium in-termediates.

XR1 NuR1R1

Pd(II)

X

Pd(0) (catalytic)

base

Nu

π-allyl complex2

R2R1

X

R2R1

X

R2R1

NuOR

R1 >> R2

Hard Nu

Pd(0)

Inversion ofconfiguration

Retention ofconfiguration

Soft Nu

Pd(0)

X = OCOR, OCO2R, OCONHR, OP(O)(OR)2, OPh, Cl, NO2, SO2Ph, NR3X, SR2X, OH

R2R1

Nu


A

LnPd(0)

Pd(0) or Pd(II) precatalysts

B

C

D

A: CoordinationB: Oxidative addition (Ionization)

C: Ligand exchangeD: Substitution then reductive elimination

R1 X

R1 Nu

Nu

R1 X

LnPd(0)

R1

Pd(II)X

+ L

− XL

R1

Pd(II)LL

R1 Nu

LnPd(0)

π-allyl complex

548


Example 1, Allylic ether3

O

BnO OPh

BnON

NH

O

BnO N

BnO

N

Pd2(dba)3, dppb

THF, 60–70 oC72%

α:β = 90:10

Example 2, Allylic acetate3

OAcAcO

N

NH

NaH, Pd(Ph3P)4, DMF60 oC, 18 h, 79%

NAcO

NN

N

NH2

NN

NH2

Example 3, Allylic epoxide5

N

NHO NHO

N

Pd(Ph3P)4, THFrt, 64 h, 35%

Example 4, Intramolecular Tsuji–Trost reaction6

S

N OCO2Me

CO2Me

Bn

ONH2

SCO2Me

NHBnN

O10 mol% Pd(OAc)210 mol% n-Bu4NCl

P(OEt)3, NaHCO3DMF, 100 oC, 77%

Example 5, Intramolecular Tsuji–Trost reaction7

t-BuO

O

Me

O

O

OMe

TMSO

Me

O O

Ot-Bu

TESO OTESMe

Me

TESO

OTES

Me

O

OTMSMe

10 mol% Pd2(dba)3

THF (0.005 M)40 oC, 80%

549

Example 6, Asymmetric Tsuji–Trost reaction8

2.5 mol% (dba)3Pd2•CHCl37.5 mol% ent-cat

30 mol% Bu4NClCH2Cl2

O

O

EtO2CI

OHMeO

O

O

EtO2CI

OMeO OH

O

89% yield, 95% ee

O OBocO

NH HNO O

PPh2 Ph2Pent-cat =

References 1. (a) Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett. 1965, 6, 4387−4388. (b)

Tsuji, J. Acc. Chem. Res. 1969, 2, 144−152. (Review). 2. Godleski, S. A. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., eds.;

Vol. 4. Chapter 3.3. Pergamon: Oxford, 1991. (Review). 3. Bolitt, V.; Chaguir, B.; Sinou, D. Tetrahedron Lett. 1992, 33, 2481–2484. 4. Moreno-Mañas, M.; Pleixats, R. In Advances in Heterocyclic Chemistry; Katritzky, A.

R., ed.; Academic Press: San Diego, 1996, 66, 73. (Review). 5. Arnau, N.; Cortes, J.; Moreno-Mañas, M.; Pleixats, R.; Villarroya, M. J. Heterocycl.

Chem. 1997, 34, 233−239. 6. Seki, M.; Mori, Y.; Hatsuda, M.; Yamada, S. J. Org. Chem. 2002, 67, 5527−5536. 7. Vanderwal, C. D.; Vosburg, D. A.; Weiler, S.; Sorenson, E. J. J. Am. Chem. Soc. 2003,

125, 5393−5407. 8. Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 3090−3100. 9. Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044−15045. 10. Fuchter, M. J. Tsuji–Trost Reaction. In Name Reactions for Homologations-Part I; Li,


550

Ugi reaction Four-component condensation (4CC) of carboxylic acids, C-isocyanides, amines, and carbonyl compounds to afford diamides. Cf. Passerini reaction.

R3 N CR CO2H R1 NH2 R2 CHO R NHN

O

R1

R2

OR3

isocyanide

R1 NH2

R2

H

O

: R2

H

HN

HOR1:

R2

H

N R1 R CO2H R

OO

R3

NC

R2

H

N R1H

imine

R OHN

O N

R1

R3

:

R2

R NHN

O

R1

R2

OR3

O

NO

R

NR3

R2

R1

H

Example 12

OO

NH2

OTBDPS

OMOMOMe

BnO

IBocHN

CO2H

H

O

O

NC

OO

N

OMOM NHPMP

ONHBoc

OMe

OBnI

MeOH, Δ

1 h, 90%

TBDPSOO

551


Example 25

HN

OCO2H

OTBS

N

CHO

O2SO2N NH2

OMe

NC

HN

O

OTBS

NO2SO2N

ON

NHt-Bu

OMeOH, Δ

61%

OMe

Example 37

O

OO

HO

O CH3

CH3

CH3H3CO

N

OCH3

OCH3C

NH2

O

ON

H3C H

O

PMB O NHOCH3

OCH3

CH3

CH3

TFE, rt

78%

Example 48

TBSO

OTBSH

TBSO

HH3C

CH3

H3CH

OHO

H2NO

NH2N

O

OH

C(CH2O)n2

552

HO

OHH

HO

HH3C

CH3

H3CH

NO

NO

O

O

HN

O

Cy

1. MeOH, rt.

2. TBAF, THF 54%, 2 Steps

ONH

Cy

References 1. (a) Ugi, I. Angew. Chem., Int. Ed. 1962, 1, 8 21; (b) Ugi, I.; Offermann, K.; Herlin-

ger, H.; Marquarding, D. Liebigs Ann. Chem. 1967, 709, 1–10.; (c) Ugi, I.; Kaufhold, G. Ann. 1967, 709, 11–28; (d) Ugi, I.; Lohberger, S.; Karl, R. In Comprehensive Or-ganic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991, Vol. 2, 1083. (Review); (e) Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168. (Re-view); (f) Ugi, I. Pure Appl. Chem. 2001, 73, 187 191. (Review).

2. Endo, A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 6552−6554.

3. Hebach, C.; Kazmaier, U. Chem. Commun. 2003, 596 597. 4. Multicomponent Reactions J. Zhu, H. Bienaymé, Eds.; Wiley-VCH, Weinheim, 2005. 5. Oguri, H.; Schreiber, S. L. Org. Lett. 2005, 7, 47 50. 6. Dömling, A. Chem. Rev. 2006, 106, 17 89. 7. Gilley, C. B.; Buller, M. J.; Kobayashi, Y. Org. Lett. 2007, 9, 3631 3634. 8. Rivera, D. G.; Pando, O.; Bosch, R.; Wessjohann, L. A. J. Org. Chem. 2008, 73,

6229 6238. 9. Bonger, K. M.; Wennekes, T.; Filippov, D. V.; Lodder, G.; van der Marel, G. A.;

Overkleeft, H. S. Eur. J. Org. Chem. 2008, 3678 3688. 10. Williams, D. R.; Walsh, M. J. Ugi Reaction. In Name Reactions for Homologations-

Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 786−805. (Review).

553

Ullmann coupling Homocoupling of aryl halides in the presence of Cu or Ni or Pd to afford biaryls.

I2Cu

CuI2

I Cu(I)ICu(II)ICu, single

electron transfer SET

Cu(II)II

CuI2

The overall transformation of PhI to PhCuI is an oxidative addition process.

Example 13

N

NO2

Cl

Cu powder, DMF

100−105 oC, 4 h, 63%N

NO2

N

O2N

Example 2, CuTC-catalyzed Ullmann coupling4

I

N

I

OSCu

O

NMP, rt, 88%

N

Example 35

OMe

OEt

OI

MeO

OMe

O

OEt

MeO OMeMeO

O

OEt

Cu-bronze210−220 οC

72%

554


Example 48

IO

OI

P(O)Ph2

P(O)Ph2

O P(O)Ph2

O P(O)Ph2

O P(O)Ph2

O P(O)Ph2

Cu, DMF

140 οC, 88%

70% 18%

Example 59

MeO

MOMOI NCy

MeO

MOMOO

N

PhHNOCN

IO

PhHNCu0, Pd(PPh3)4

DMF, 100 οC39%

References 1. (a) Ullmann, F.; Bielecki, J. Ber. 1901, 34, 2174−2185. Fritz Ullmann (1875−1939),

born in Fürth, Bavaria, studied under Graebe at Geneva. He taught at the Technische Hochschule in Berlin and the University of Geneva. (b) Ullmann, F. Ann. 1904, 332, 38−81.

2. Fanta, P. E. Synthesis 1974, 9−21. (Review). 3. Kaczmarek, L.; Nowak, B.; Zukowski, J.; Borowicz, P.; Sepiol, J.; Grabowska, A. J.

Mol. Struct. 1991, 248, 189−200. 4. Zhang, S.; Zhang, D.; Liebskind, L. S. J. Org. Chem. 1997, 62, 2312−2313. 5. Hauser, F. M.; Gauuan, P. J. F. Org. Lett. 1999, 1, 671−672. 6. Buck, E.; Song, Z. J.; Tschaen, D.; Dormer, P. G.; Volante, R. P.; Reider, P. J. Org.

Lett. 2002, 4, 1623−1626. 7. Nelson, T. D.; Crouch, R. D. Org. React. 2004, 63, 265−556. (Review). 8. Qui, L.; Kwong, F. Y.; Wu, J.; Wai, H. L.; Chan, S.; Yu, W.-Y.; Li, Y.-M.; Guo, R.;

Zhou, Z.; Chan, A. S. C. J Am. Chem. Soc. 2006, 128, 5955−5965. 9. Markey, M. D.; Fu, Y.; Kelly, T. R. Org. Lett. 2007, 9, 3255−3257. 10. Ahmad, N. M. Ullman coupling. In Name Reactions for Homologations-Part I; Li, J.


555

van Leusen oxazole synthesis 5-Substituted oxazoles through the reaction of p-tolylsulfonylmethyl isocyanide (TosMIC, also known as the van Leusen reagent) with aldehydes in protic solvents at refluxing temperatures.

H

O

MeOH, refluxO

NS NC

O OK2CO3

S NO O

CH

B

S NO O

C

O R

S NO O

C

OR

O

NTos

R

+ HO

NH H

RO

NTos H

R H

H

B

− TosH

Example 13

S NCO O

HO

HN

NPr

PrH

MeOH, reflux81%

HN

NPr

PrH

NO

NaOMe

Example 25

OH

OEtO

O N

OEtOS

NCO OK2CO3

DMF, 80%

556


Example 39

CHO

CHOOHC

TosMIC, K2CO3

MeOH, reflux81%

NO

N

ON

O

Example 410

TosMIC, K2CO3

MeOH, reflux4 h, 91%

N

OCHOO

O

O

O

References 1. (a) van Leusen, A. M.; Hoogenboom, B. E.; Siderius, H. Tetrahedron Lett. 1972, 13,

2369–2381. (b) Possel, O.; van Leusen, A. M. Heterocycles 1977, 7, 77–80. (c) Sai-kachi, H.; Kitagawa, T.; Sasaki, H.; van Leusen, A. M. Chem. Pharm. Bull. 1979, 27, 793–796. (d) van Nispen, S. P. J. M.; Mensink, C.; van Leusen, A. M. Tetrahedron Lett. 1980, 21, 3723–3726.

2. van Leusen, A. M.; van Leusen, D. In Encyclopedia of Reagents of Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 7, 4973−4979. (Review).

3. Anderson, B. A.; Becke, L. M.; Booher, R. N.; Flaugh, M. E.; Harn, N. K.; Kress, T. J.; Varie, D. L.; Wepsiec, J. P. J. Org. Chem. 1997, 62, 8634–8639.

4. Kulkarni, B. A.; Ganesan, A. Tetrahedron Lett. 1999, 40, 5633–5636. 5. Sisko, J.; Kassick, A. J.; Mellinger, M.; Filan, J. J.; Allen, A.; Olsen, M. A. J. Org.

Chem. 2000, 65, 1516–1524. 6. Barrett, A. G. M.; Cramp, S. M.; Hennessy, A. J.; Procopiou, P. A.; Roberts, R. S.

Org. Lett. 2001, 3, 271–273. 7. Herr, R. J.; Fairfax, D. J., Meckler, H.; Wilson, J. D. Org. Process Res. Dev. 2002, 6,

677–681. 8. Brooks, D. A. van Leusen Oxazole Synthesis. In Name Reactions in Heterocyclic

Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 254–259. (Review).

9. Kotha, S.; Shah, V. R. Synthesis 2007, 3653–3658. 10. Besselièvre, F.; Mahuteau-Betzer, F.; Grierson, D. S.; Piguel, S. J. Org. Chem. 2008,

73, 3278–3280.

557

Vilsmeier−Haack reaction The Vilsmeier–Haack reagent, a chloroiminium salt, is a weak electrophile. There-fore, the Vilsmeier–Haack reaction works better with electron-rich carbocycles and heterocycles.

O DMF, POCl3

100 oC, 24 h

OO

CHO

CHO

34% 4%

N O

H

PO

ClClCl:

N O

H

PCl2

O

Cl

N O

Cl

PCl2

O

H

: N H

Cl O PCl2

O

Vilsmeier–Haack reagent

O:

N H

Cl

O

Cl HN

H

O

Cl HN:

B

:

aqueous

workup

O

HO HN

O

CHO

O

H N

HO

H

:

H

Example 12

DMF, POCl3

100 oC, 14 h, 98%OH

OMeMeO

OMeMeO

OHC

Example 23

N

NDMF, POCl3

100 oC, 83%N

N

CHOCl Cl

558


Example 39

POCl3/DMF

100 oC, 20 hN

CH3

CH3

CH3

OH

N

CH3

CH3

ClCHO

N

CH3

CH3

CH3

Cl

N

CH3

CH3

CH3

OHCHO

OH65% 10%

15%

Example 410

OR

12 equiv POCl3/DMF

80−100 oC, 31−71%R

O

OCl

OR

12 equiv POCl3/DMF

120−135 oC, 39−78%R

CHOCl

Cl

References 1. Vilsmeier, A.; Haack, A. Ber. 1927, 60, 119–122. 2. Reddy, M. P.; Rao, G. S. K. J. Chem. Soc., Perkin Trans. 1 1981, 2662–2665. 3. Lancelot, J.-C.; Ladureé, D.; Robba, M. Chem. Pharm. Bull. 1985, 33, 3122–3128. 4. Marson, C. M.; Giles, P. R. Synthesis Using Vilsmeier Reagents CRC Press, 1994.

(Book). 5. Seybold, G. J. Prakt. Chem. 1996, 338, 392−396 (Review). 6. Jones, G.; Stanforth, S. P. Org. React. 1997, 49, 1–330. (Review). 7. Jones, G.; Stanforth, S. P. Org. React. 2000, 56, 355–659. (Review). 8. Tasneem, Synlett 2003, 138–139. (Review of the Vilsmeier–Haack reagent). 9. Nandhakumar, R.; Suresh, T.; Jude, A. L. C.; Kannan, V. R.; Mohan, P. S. Eur. J.

Med. Chem. 2007, 42, 1128–1136. 10. Tang, X.-Y.; Shi, M. J. Org. Chem. 2008, 73, 8317–8320. 11. Pundeer, R.; Ranjan, P.; Pannu, K.; Prakash, O. Synth. Commun. 2009, 39, 316–324.

559

Vinylcyclopropane−cyclopentene rearrangement Transformation of vinylcyclopropane to cyclopentene via a diradical intermediate.

R1

R2

R1

R2Δ

R1

R2

R1

R2

R1

R2

R1

R2

Example 11

O

CO2Me

340 oC, 2 h

50%

O CO2Me

Example 22

SO2Ph

1. n-BuLi, THF−HMPT −78 to −30 oC2. PhCH2Br

3. desulfonylation 77% overall yield

Ph

Example 39

O

HH

H

N

NOMOM

OMOM

O

HH

H

NN

O

MOMO

MOM

AlCl3, CH2Cl2

0 oC, 88%

N

NOMOM

OMOM O

O

N

NO

MOM

OMOM

H

H

560


Example 410

O

MeMe

CO2MeMe

H

150 mol% MgI2 (0.2 M)

CH3CN, 40 oC, 6 h, 75%

OMe

MeCO2Me

H

Me

References 1. Brule, D.; Chalchat, J. C.; Garry, R. P.; Lacroix, B.; Michet, A.; Vessier, R. Bull. Soc.

Chim. Fr. 1981, 1−2, 57−64. 2. Danheiser, R. L.; Bronson, J. J.; Okano, K. J. Am. Chem. Soc. 1985, 107, 4579−4581. 3. Hudlický, T.; Kutchan, T. M.; Naqvi, S. M. Org. React. 1985, 33, 247−335. (Review). 4. Goldschmidt, Z.; Crammer, B. Chem. Soc. Rev. 1988, 17, 229−267. (Review). 5. Sonawane, H. R.; Bellur, N. S.; Kulkarni, D. G.; Ahuja, J. R. Synlett 1993, 875−884.

(Review). 6. Hiroi, K.; Arinaga, Y. Tetrahedron Lett. 1994, 35, 153−156. 7. Baldwin, J. E. Chem. Rev. 2003, 103, 1197−1212. (Review). 8. Wang, S. C.; Tantillo, D. J. J. Organomet. Chem. 2006, 691, 4386−4392. 9. Zhang, F.; Kulesza, A.; Rani, S.; Bernet, B.; Vasella, A. Helv. Chim. Acta 2008, 91,

1201−1218. 10. Coscia, R. W.; Lambert, T. H. J. Am. Chem. Soc. 2009, 131, 2496−2498.

561

von Braun reaction Different from the von Braun degradation reaction (amide to nitrile), the von Braun reaction refers to the treatment of tertiary amines with cyanogen bromide, resulting in a substituted cyanamide.

R1 NR2

R Br CNR1 N

R2

CNBr R

R1N

R2

RNC Br

:R1

NR2

RCN

BrSN2

R1N

R2

CNBr R

Example 14

O

CF3

N CNO

CF3

N

Br-CN

Tol.

O

CF3

NH

KOH

MeOH/H2O

Prozac

Example 25

N

CO2Me

CO2Me

Br-CN, THF, H2O

75% NCN

CO2Me

CO2Me

Br

Example 39

N

OTBS

Ph

BrCN, CH2Cl2

reflux, 98% N

OTBS

PhCN

Br NCN

TBSO

Ph

Br

References 1. von Braun, J. Ber. 1907, 40, 3914−3933. Julius von Braun (1875−1940) was born in

Warsaw, Poland. He was a Professor of Chemistry at Frankfurt.

562


2. Hageman, H. A. Org. React. 1953, 7, 198−262. (Review). 3. Fodor, G.; Nagubandi, S. Tetrahedron 1980, 36, 1279−1300. (Review). 4. Mody, S. B.; Mehta, B. P.; Udani, K. L.; Patel, M. V.; Mahajan, Rajendra N.. Indian

Patent IN177159 (1996). 5. McLean, S.; Reynolds, W. F.; Zhu, X. Can. J. Chem. 1987, 65, 200−204. 6. Chambert, S.; Thomasson, F.; Décout, J.-L. J. Org. Chem. 2002, 67, 1898−1904. 7. Hatsuda, M.; Seki, M. Tetrahedron 2005, 61, 9908−9917. 8. Thavaneswaran, S.; McCamley, K.; Scammells, P. J. Nat. Prod. Commun. 2006, 1,

885−897. (Review). 9. McCall, W. S.; Abad Grillo, T.; Comins, D. L. Org. Lett. 2008, 10, 3255−3257.

563

Wacker oxidation Palladium-catalyzed oxidation of olefins to ketones, and aldehydes in certain cases.

R

OR

cat. PdCl2, H2O

CuCl2, O2

LnPdCl2


complexation

R

O

R

RLnClPdCl

HO

H: :

HCl

L = ligand or solvent

LnClPd

HR

OH

::

hydride shift

LnPdHCl

HClLnPd

2 CuCl

2 CuCl2

2 HCl+

0.5 O2

H2O

hydroxypalladation

Example 15

CO2HO2, 5% Pd(OAc)2

NaOAc, DMSO, 80%

O

O

Example 27

O

H

H H

O

H 10% Pd(OAc)2, HClO4

0.5 equiv benzoquinoneCH3CN

O

H

H H

O

H

45%

O

H

H H

CHOO

H

35%

O

564


Example 39

O2, 20 mol% Cu(OAc)210 mol% PdCl2

DMA/H2O (7:1)

84%O O O O O

Example 410

O

O

HOO

O

O O 5 eq. PdCl2, air

DMF/H2O (7:1)81%

O

O

HOO

O

O O

O

O

HOO

O CHO

O O

O

12 : 1

References 1. Smidt, J.; Sieber, R. Angew. Chem., Int. Ed. 1962, 1, 80−88. 2. Tsuji, J. Synthesis 1984, 369−384. (Review). 3. Hegedus, L. S. In Comp. Org. Syn. Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991,

Vol. 4, 552. (Review). 4. Tsuji, J. In Comp. Org. Syn. Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 7,

449. (Review). 5. Larock, R. C.; Hightower, T. R. J. Org. Chem. 1993, 58, 5298−5300. 6. Hegedus, L. S. Transition Metals in the Synthesis of Complex Organic Molecule 1994,

University Science Books: Mill Valley, CA, pp 199−208. (Review). 7. Pellissier, H.; Michellys, P.-Y.; Santelli, M. Tetrahedron 1997, 53, 10733−10742. 8. Feringa, B. L. Wacker oxidation. In Transition Met. Org. Synth. Beller, M.; Bolm, C.,

eds.; Wiley−VCH: Weinheim, Germany. 1998, 2, 307−315. (Review). 9. Smith, A. B.; Friestad, G. K.; Barbosa, J.; Bertounesque, E.; Hull, K. G.; Iwashima,

M.; Qiu, Y.; Salvatore, B. A.; Spoors, P. G.; Duan, J. J.-W. J. Am. Chem. Soc. 1999, 121, 10468−10477.

10. Kobayashi, Y.; Wang, Y.-G. Tetrahedron Lett. 2002, 43, 4381−4384. 11. Hintermann, L. Wacker-type Oxidations in Transition Met. Org. Synth. (2nd edn.) Bel-

ler, M.; Bolm, C., eds., Wiley−VCH: Weinheim, Germany. 2004, 2, pp 379−388. (Re-view).

12. Li, J. J. Wacker−Tsuji oxidation. In Name Reactions for Functional Group Transfor-mations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 309−326. (Review).

13. Okamoto, M.; Taniguchi, Y. J. Cat. 2009, 261, 195−200.

565

Wagner–Meerwein rearrangement Acid-catalyzed alkyl group migration of alcohols to give more substituted olefins.

R2 HR

R3

R1

OH H

R3

R

R2

R1

HR2 H

R

R3

R1

OHR2 H

R

R3

R1

OH2

− H2OR2 H

R

R3

R1

1,2-shift

−R2 H

R1

R3R R3

R

R2

R1 H

Example 13

H3CNN O

OHN

N

H3C OH

Br

HNO

OCH3

OCH3H3CO

H3CO2C

CH3SO3H

ClCH2CH2Cl50 oC, 86%

H3CNN O

OHN

N

H3C CO2CH3

Br

HNO

OCH3

OCH3H3CO

Example 2, Double Wagner–Meerwein rearrangement6

O

OEt

O

HOTFA, CH2Cl2

72 h, 76%

O

OEt

O

566


Example 37

HO

OH

CH3 OTBSO

MsOBzO H

O

OH

CH3 OTBS

O

BzO HH

Et2AlCl,CH2Cl2

−78 oC → rt52%

Example 49

O

H

OBzH3C

CH3

H

O

H

OBzCH3

H

H3C H

BzOBzO

BF3•Et2O

benzene, 40%

References 1. Wagner, G. J. Russ. Phys. Chem. Soc. 1899, 31, 690. 2. Hogeveen, H.; Van Kruchten, E. M. G. A. Top. Curr. Chem. 1979, 80, 89–124. (Re-

view). 3. Kinugawa, M.; Nagamura, S.; Sakaguchi, A.; Masuda, Y.; Saito, H.; Ogasa, T.; Kasai,

M. Org. Proc. Res. Dev. 1998, 2, 344–350. 4. Trost, B. M.; Yasukata, T. J. Am. Chem. Soc. 2001, 123, 7162–7163. 5. Guizzardi, B.; Mella, M.; Fagnoni, M.; Albini, A. J. Org. Chem. 2003, 68, 1067–1074. 6. Bose, G.; Ullah, E.; Langer, P. Chem. Eur. J. 2004, 10, 6015–6028. 7. Guo, X.; Paquette, L. A. J. Org. Chem. 2005, 70, 315–320. 8. Li, W.-D. Z.; Yang, Y.-R. Org. Lett. 2005, 7, 3107–3110. 9. Michalak, K.; Michalak, M.; Wicha, J. Molecules 2005, 10, 1084–1100. 10. Mullins, R. J.; Grote, A. L. Wagner–Meerwein rearrangement. In Name Reactions for


567

Weiss–Cook reaction Synthesis of cis-bicyclo[3.3.0]octane-3,7-dione. The product is frequently decar-boxylated.

EtO2C

EtO2C

OR1

RO

O

aq. bufferR

R1

OO

EtO2C

EtO2C

CO2Et

CO2Et

EtO2C

EtO2C

O O

OR

R1

EtO2C

EtO2C

OH

EtO2C

EtO2C

O OR1

OHR

HEtO2C

EtO2C

O OR1

OHR

H

OO

EtO2C

EtO2C

CO2Et

CO2Et

OOH

R

R1OH

EtO2CH

HEtO2C

H

R

R1HHO

EtO2C

EtO2C R1

R CO2Et

O

CO2Et

O

EtO2C

EtO2CR1

R CO2Et

O

CO2Et

HH

R

R1

OHO

EtO2C

EtO2C

CO2Et

CO2Et

R

R1

OHHO

EtO2C

EtO2C

CO2Et

CO2Et

Example 12

MeO2C

MeO2C

O

O O

pH 5.6

86%

O

CO2MeMeO2C O

MeO2C CO2Me

Example 23

O CHO

1. pH = 8.32. HOAc/HCl, Δ

90% O O

H

CO2CH3

CO2CH3

O

568


Example 34

O

O

CO2CH3

CO2CH3

O

1. pH = 6.82. HOAc/HCl

80%O O

Example 49

EtO2C

EtO2C

OEt

Me O

O NaHCO3

H2O/MeOHrt, 24 h, 86%

CO2Et

CO2Et

O

Et

Me

OO

EtO2C

EtO2C

CO2Et

CO2Et

Et

Me

OHHO

EtO2C

EtO2C

CO2Et

CO2Et

Et

Me

OHHO

EtO2C

EtO2C

CO2Et

CO2Et

References 1. Weiss, U.; Edwards, J. M. Tetrahedron Lett. 1968, 9, 4885–4887. 2. Bertz, S. H.; Cook, J. M.; Gawish, A.; Weiss, U. Orga. Synth. 1986, 64, 27–38. 3. Kubiak, G.; Fu, X.; Gupta, A. K.; Cook, J. M. Tetrahedron Lett. 1990, 31, 4285–4288. 4. Wrobel, J.; Takahashi, K.; Honkan, V.; Lannoye, G.; Bertz, S. H.; Cook, J. M. J. Org

Chem. 1983, 48, 139–141. 5. Gupta, A. K.; Fu, X.; Snyder, J. P.; Cook, J. M. Tetrahedron 1991, 47, 3665–3710. 6. Paquette, L. A.; Kesselmayer, M. A.; Underiner, G. E.; House, S. D.; Rogers, R. D.;

Meerholz, K.; Heinze, J. J. Am. Chem. Soc. 1992, 114, 2644–2652. 7. Fu, X.; Cook, J. M. Aldrichimica Acta 1992, 25, 43–54. (Review). 8. Fu, X.; Kubiak, G.; Zhang, W.; Han, W.; Gupta, A. K.; Cook, J. M. Tetrahedron 1993,

49, 1511–1518. 9. Williams, R. V.; Gadgil, V. R.; Vij, As.; Cook, J. M.; Kubiak, G.; Huang, Q. J. Chem.

Soc., Perkin Trans. 1 1997, 1425–1428. 10. van Ornum, S. G.; Li, J.; Kubiak, G. G.; Cook, J. M. J. Chem. Soc., Perkin Trans. 1

1997, 3471–3478.

569

Wharton reaction Reduction of α,β-epoxy ketones by hydrazine to allylic alcohols.

R1

R2

OO

NH2NH2

Δ HO

R2 N2↑ H2OR1

R1

R2

OO:NH2NH2

R1

R2

O NHOH

NH2:

H2OHR1

R2

ON

NH

H

hydrazone

tautomerizationR1

R2

ON

N

H:OH2

H

diazene

N2↑HO

R2R1

Example 15

O

NTEOC

O

H

NH2NH2•H2O, MeOH

HOAc, rt, 52%N

TEOC H

OH

Example 26

CO2CH3TBDMSO

OO

NH2NH2•HCl, Et3N

(dimethylamino)ethanol32%

CO2CH3TBDMSO

OH

Example 37

O

O

NH2NH2, KOH

THF, reflux, 64%HO

OH

570


HOOH

OH

HOOH

OH

91 : 9

Example 48

NH2NH2•H2O, MeOH

HOAc, rt, 59%

O

OTESO

O

O

OTESO

O

OH

References 1. (a) Wharton, P. S.; Bohlen, D. H. J. Org. Chem. 1961, 26, 3615−3616. (b) Wharton,

P. S. J. Org. Chem. 1961, 26, 4781−4782. 2. Caine, D. Org. Prep. Proced. Int. 1988, 20, 1−51. (Review). 3. Dupuy, C.; Luche, J. L. Tetrahedron 1989, 45, 3437−3444. (Review). 4. Thomas, A. F.; Di Giorgio, R.; Guntern, O. Helv. Chim. Acta 1989, 72, 767−773. 5. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112,

2003−2004. 6. Yamada, K.-i.; Arai, T.; Sasai, H.; Shibasaki, M. J. Org. Chem. 1998, 63, 3666−3672. 7. Di Filippo, M.; Fezza, F.; Izzo, I.; De Riccardis, F.; Sodano, G. Eur. J. Org. Chem.

2000, 3247−3249. 8. Takagi, R.; Tojo, K.; Iwata, M.; Ohkata, K. Org. Biomol. Chem. 2005, 3, 2031−2036. 9. Li, J. J. Wharton reaction. In Name Reactions for Functional Group Transformations;

Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 152−158. (Re-view).

571

White Reagent

S SPh PhOO

Pd(OAc)2

·

White Reagent

The White Reagent 1 is a highly versatile, commercially-available catalyst for allylic C–H oxidation which allows for the construction of useful C–O, C–N, and C–C bonds directly from relatively inert allylic C–H bonds (Figure 1).1–11 The White Reagent enables novel and predictable disconnections for the synthesis of complex molecules which can streamline their synthesis.2,4,7,8 Widely available α-olefins undergo intra- and intermolecular C–H oxidation with remarkably high levels of chemo-, regio-, and stereoselectivity. Mechanistic studies provide evidence that the White Reagent promotes allylic C–H cleavage to generate π-allylpalladium intermediate 2 which can then be functionalized with an oxygen, nitrogen or carbon nucleophile (Figure 1).3 Figure 1

R

Pd(II)Ln

R

H

S SPh PhOO

Pd(OAc)2(10 mol%)

·

R

OC(O)R1

R NR'2 R

OC(O)R1

Ar

O

O

White Reagent

2

RNR'2

OH

RCO2Me

NO2

1

C−C

C−N

C−O

Common organic functionality such as Lewis basic phenol 3,3 acid-labile acetal 4,8 highly reactive aryl triflate 6,11 and depsipeptide 55 are well-tolerated under the mild reaction conditions (Figure 2). In all cases the products are isolated as one regioisomer and olefin isomer after column purification.

Current state-of-the-art methods for constructing C–N bonds rely on functional group interconversions or C–C bond forming reactions using preoxidized materials. Allylic amination using the White Reagent can streamline the synthesis of nitrogen-containing molecules by reducing the functional group manipulations necessary for working with oxygenated intermediates. Allylic C–H amination was used to synthesize (–)-8, an intermediate in the synthesis of L-acosamine derivative 9 (Figure 3A).7 The C–H amination route to (–)-8 proceeded in half the total number of steps, no functional group manipulations, and

572


comparable overall yield to the alternative C–O to C–N bond-forming route. Intermolecular C–H amination has also led to the construction of (+)-deoxynegamycin analogue 12 in five less steps and improved overall yield compared to the alternative route relying on C–O substitution (Figure 3B).8

Figure 2

R

CO2Me

NO2

H

MeO2C

TfOOMe

S SPh PhOO

Pd(OAc)2·

RR

linear allylic C-H amination

linear allylic C-H alkylation

branched allylic C-H oxidation

branched macrolactonization

linear product (L)

Nu

branched product (B)

or(10 mol%)

6, 64% yield, > 20:1 E:Z, > 20:1 L:B

HNNH

O

NO

OO

O

Ph

5, 61% yield, 3:1 dr

NTs

CO2MeO

O

OBn(+)-4, 63%, > 20:1 E:Z, > 20:1 L:B

conditions

pro-nucleophile (NuH)(1.5−2.0 equiv)

+

OH

O

O

p-BrPhO2C

3, 65% yield, > 20:1 B:L

BQ (2 equiv),dioxane, 43 oC

BQ (2 equiv)CH2Cl2, 45 oC

DMBQ (1.5 equiv),AcOH (0.5 equiv),

dioxane:DMSO (4:1)

Cr(salen)Cl (6 mol%),BQ (2 equiv), TBME,

45 oC

1Nu

Figure 3

TBSO

O

O

NHTsNTs

O

TBSO

O

PhBQ (1.05 equiv)THF, 50 oC, 72 h

S SPh PhOO

Pd(OAc)2·

(10 mol%) O

Me NHAc

OMe

OH78%, 9:1 dr crude(−)-N-acetyl-O-methyl

acosamine 9(+)-7 (−)-8

H(70% yield, 1 isomer)

OTMSE

O

NTsCBz

BocNH

(−)-10 (+)-11

NH

O

NH2

BocNHN

CO2H2 HBr(+)-deoxynegamycin

analogue 12BQ (2 equiv.), TBME

S SPh PhOO

Pd(OAc)2·

(10 mol%)

54%, 1 isomer

Cr(salen)Cl (6 mol%)

CbzNHTs (2 equiv)

BocNH

TMSEO2C

A.

B.

1

1

steps

steps

Similarly, allylic C–H oxidation can streamline the construction of oxygenated compounds by reducing functional group manipulations necessary for working with bisoxygenated intermediates. For example, a chiral allylic C–H oxidation/enzymatic resolution sequence furnished bisoxygenated compound 14 in 97% ee and in 42% overall yield in just 3 steps from a commercially available

573

monooxygenated precursor, 11-undecenoic acid (Figure 4).10 Alternative routes to similar molecules require protection/deprotection sequences and use a kinetic resolution giving a maximum of 50% yield. Figure 4

undecenoic acid

1. (MeO)NMeNMe

O

7

OAcMeO

42% overall yield> 20:1 B:L, 97% ee

AcOH (1.1 equiv)BQ (2 equiv)

4 Å MS, EtOAc, rt

1 (10 mol%)(R,R)-Cr(salen)F

(10 mol%)

2)

3) Novazyme 435

NMe

O H

7MeO

1314CDI, DCMHO

O H

7

In addition to allylic C–H oxidation, the White Reagent also catalyzes intermolecular Heck arylations.6 Notably, the arylation uses electronically unbiased α-olefins and aryl boronic acids and occurs under acidic, oxidative conditions. A one-pot allylic C–H oxidation/vinylic C–H arylation reaction furnishes E-arylated allylic esters with high regio- and stereoselectivities (Figure 5). This three-component coupling can be used to rapidly synthesize densely functionalized products from inexpensive hydrocarbon feedstocks. N-Boc glylcine allylic ester 9 was synthesized in one step using commercially available olefin, amino acid, and boronic acid reagents. Compounds similar to 15 have been transformed into medicinally relevant dipeptidyl peptidase IV inhibitors.6 Figure 5

Me7

Me7

O

O

Br

S SPh PhOO

Pd(OAc)2·

(10 mol%)

NHBoc

N-Boc-Gly (2 equiv)BQ (2 equiv) Me

7

O

ONHBoc

dioxane, 45 oC

(4-Br)PhB(OH)2(1.5 equiv), 45 oC

15, 75%> 20:1 E:Z

> 20:1 internal:terminal

H

1-undecene

Branched allylic C−H esterification Oxidative Heck

1

Besides the one-pot process described above, the White Reagent catalyzes a chelate-controlled oxidative Heck arylation between a wide range of α-olefins and organoborane compounds in good yields and with excellent regio- and stereoselectivities (Figure 6).9 Unlike other Heck arylation methods, no Pd–H isomerization is observed under the mild reaction conditions. Aryl boronic acids, styrenylpinacol boronic esters, and aryl potassium trifluoroborates (activated with boric acid) are all compatible with the general reaction conditions.

574

Figure 6

S SPh PhOO

Pd(OAc)2·

(10 mol%)AcOH (4 equiv)

quinone (2 equiv)dioxane, rt, 4 h

R

X

n = 0−2

M

ArBpin

M = B(OH)2 = BF3K

or R

X

Ar

R'

> 20:1 E:Z> 20:1 internal:terminal

1

Ph

NHBoc

NBoc

HO

18, 83% (+)-19, 81%

OPh

Bn

BocHN

(+)-17, 62%

HN

CO2MeO

F

F(+)-16, 60% Br

allylic amine

α,β-unsaturated carbonyls

free alcohols

amino acids

References 1. Chen, M. S.; White, M. C. J. Am. Chem. Soc. 2004, 126, 1346–1347. 2. Fraunhoffer, K. J.; Bachovchin, D. A.; White, M. C. Org. Lett. 2005, 7, 223–226. 3. Chen. M. S.; Prabagaran, N.; Labenz, N. A.; White, M. C. J. Am. Chem. Soc. 2005,

127, 6970–6971. 4. Covell, D. J.; Vermeulen, N. A.; White, M. C. Angew. Chem. Int. Ed. 2006, 45, 8217–

8220. 5. Fraunhoffer, K. J.; Prabagaran, N.; Sirois, L. E.; White, M. C. J. Am. Chem. Soc. 2006,

128, 9032–9033. 6. Delcamp, J. H.; White, M. C. J. Am. Chem. Soc. 2006, 128, 15076–15077. 7. Fraunhoffer, K. J.; White, M. C. J. Am. Chem. Soc. 2007, 129, 7274–7276. 8. Reed, S. A.; White, M. C. J. Am. Chem. Soc. 2008, 129, 3316–3318. 9. Delcamp, J. H.; Brucks, A. P.; White, M. C. J. Am. Chem. Soc. 2008, 129, 11270–

11271. 10. Covell, D. J.; White, M. C. Angew. Chem., Int. Ed. 2008, 47, 6448–6451. 11. Young, A. J.; White, M. C. J. Am. Chem. Soc. 2008, 129, 14090–14091.

575

Willgerodt–Kindler reaction Conversion of a ketone to thioamide, with functional group migration.

TsOH, S8, Δ thioamideAr

MeO

n

HNR2 Ar n NR2

S

In Carmack’s mechanism,2 the most unusual movement of a carbonyl group from methylene carbon to methylene carbon was proposed to go through an intricate pathway via a highly reactive intermediate with a sulfur-containing heterocyclic ring. The sulfenamide serves as the isomerization catalyst. e.g.:

OHN O

TsOH, S8, Δ

N

S

Othioamide

SSS

S SSS

S

NHO

SS S

SS

SSH

SNO

NHOsulfenamide

HS SSS

SSH

SNO

SNO

N

O

:

SN

O

NO

SN

O

N

O

SN

O

NO

H thiirene

:

:

:

H

HNO

SN

O

SN

O

N

O

N

O

SN

O:

SN

O

N

O

:H H

H

N

O

N

O

N

S

O

S8N OS

576


Example 1, The Willgerodt–Kindler reaction was a key operation in the initial synthesis of racemic Naproxen:3

O

OHN O

S8 O

N

S

O

O

OH

O

1. H+

2. CH3OH, H2SO4

3. NaH, CH3I4. NaOH Naproxen

Example 25

O HN ON

S

OS8, microwave4 min., 40%

Example 3, A domino annulation reaction under Willgerodt–Kindler conditions:10

N

Cl O HN O

S8, 130 oC, 6 h, 15%N

SS

NO

46%N

SS

N

O

26%

References 1. (a) Willgerodt, C. Ber. 1887, 20, 2467−2470. Conrad Willgerodt (1841−1930), born

in Harlingerode, Germany, was a son of a farmer. He worked to accumulate enough money to support his study toward his doctorate, which he received from Claus. He became a professor at Freiburg, where he taught for 37 years. (b) Kindler, K. Arch. Pharm. 1927, 265, 389−415.

2. Carmack, M.; Spielman, M. A. Org. React. 1946, 3, 83−107. (Review). 3. Harrison, I. T.; Lewis, B.; Nelson, P.; Rooks, W.; Roskowski, A.; Tomolonis, A.;

Fried, J. H. J. Med. Chem. 1970, 13, 203−205. 4. Carmack, M. J. Heterocycl. Chem. 1989, 26, 1319−1323. 5. Nooshabadi, M.; Aghapoor, K.; Darabi, H. R.; Mojtahedi, M. M. Tetrahedron Lett.

1999, 40, 7549−7552. 6. Alam, M. M.; Adapa, S. R. Synth. Commun. 2003, 33, 59−63. 7. Reza Darabi, H.; Aghapoor, K.; Tajbakhsh, M. Tetrahedron Lett. 2004, 45,

4167−4169. 8. Purrello, G. Heterocycles 2005, 65, 411−449. (Review). 9. Okamoto, K.; Yamamoto, T.; Kanbara, T. Synlett 2007, 2687−2690. 10. Kadzimirsz, D.; Kramer, D.; Sripanom, L.; Oppel, I. M.; Rodziewicz, P.; Doltsinis, N.

L.; Dyker, G. J. Org. Chem. 2008, 73, 4644−4649.

577

Wittig reaction Olefination of carbonyls using phosphorus ylides, typically the Z-olefin is ob-tained.

R1 R2

OPh3P

R3

R4 R2

R1 R3

R4

Ph3P O

R X

R1Ph3P: SN2

:B R

R1

Ph3PR

HR1X

PPh3

R2 O

R3 Ph3P O

R2R1

R3 R

O

PPh3

betaine

[2 + 2]

cycloaddition

RR1

R2

R3

“puckered” transition state, irreversible and concerted

R2

R3R1

R

Ph3P O

RR1 R2

R3 OPPh3

oxaphosphetane Example 13

CHO

NHTs

NaH, Et2O; then addCH2=CHPPh3

+Br−

DMF, reflux, 48 h, 50% NTs

Example 24

PPh3Cl

OHO O

1.8 N NaOEt, EtOH

−30 oC to rt

CO2H

2-cis-4-cis-vitamin A acid

CO2H

Accutane

578


Example 35

N

HN S

Ot-BuO2C

PPh3

OO

PhOTol., 70 oC

70%N

HN

O

O

PhOS

CO2t-Bu

Example 49

O

O

O

O

O

O

O

H H H

H HH H H

OTMS

PPh3

I

O

O

O

EtS

EtS

OH H H

OTBSH

OTPS 1. n-BuLi, HMPA

2. PPTS, 75%

O

O

OEtS

EtS

HH

H

TBSO

H

OTPS

O

O

O

O

O

O

O

H H H

H HH H H

OTMS

References

1. Wittig, G.; Schöllkopf, U. Ber. 1954, 87, 1318−1330. Georg Wittig (Germany, 1897−1987), born in Berlin, Germany, received his Ph.D. from K. von Auwers. He shared the Nobel Prize in Chemistry in 1981 with Herbert C. Brown (USA, 1912−2004) for their development of organic boron and phosphorous compounds.

2. Maercker, A. Org. React. 1965, 14, 270−490. (Review). 3. Schweizer, E. E.; Smucker, L. D. J. Org. Chem. 1966, 31, 3146–3149. 4. Garbers, C. F.; Schneider, D. F.; van der Merwe, J. P. J. Chem. Soc. (C) 1968, 1982–

1983. 5. Ernest, I.; Gosteli, J.; Greengrass, C. W.; Holick, W.; Jackman, D. E.; Pfaendler, H.

R.; Woodward, R. B. J. Am. Chem. Soc. 1978, 100, 8214–8222. 6. Murphy, P. J.; Brennan, J. Chem. Soc. Rev. 1988, 17, 1−30. (Review). 7. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1988, 89, 863−927. (Review). 8. Vedejs, E.; Peterson, M. J. Top. Stereochem. 1994, 21, 1–157. (Review). 9. Nicolaou, K. C. Angew. Chem., Int. Ed. 1996, 35, 589–607. 10. Rong, F. Wittig reaction in. In Name Reactions for Homologations-Part I; Li, J. J.,


579

Schlosser modification of the Wittig reaction

The normal Wittig reaction of nonstabilized ylides with aldehydes gives Z-olefins. The Schlosser modification of the Wittig reaction of nonstabilized ylides furnishes E-olefins instead.

R1 CHOBr PhLi PhLi t-BuOH

R1

R

t-BuOKR

Ph3P

RPh3P

Ph3PR

HH

Ph3PR

Ph

R1 O

HBr

phosphorus ylide

Ph

BrPh3P OLi

R R1H

t-BuOHBrPh3P OLi

R R1Li

LiBr complex of β-oxo ylide

These conditions allow for the erythreo betaine to interconvert to the threo betaine

Br

R1

RLiBr

R1H

H

PPh3

RLiO t-BuOH

t-BuOKPh3P O

LiBr complex of threo betaine

Example 16

NO

EtO2C

O

N

Ph HMe

O

PhMe

NO

EtO2C

O

NI 5 equiv Et3P, DMF, rt, 30 min.

then 0 oC, LDA, then

66%

580

Example 210

O PPh3Br

PhLi, Bu2O/THF66%

References

1. (a) Schlosser, M.; Christmann, K. F. Angew. Chem., Int. Ed. 1966, 5, 126. (b) Schlosser, M.; Christmann, K. F. Ann. 1967, 708, 1−35. (c) Schlosser, M.; Christ-mann, K. F.; Piskala, A.; Coffinet, D. Synthesis 1971, 29−31.

2. van Tamelen, E. E.; Leiden, T. M. J. Am. Chem. Soc. 1982, 104, 2061−2062. 3. Parziale, P. A.; Berson, J. A. J. Am. Chem. Soc. 1991, 113, 4595−606. 4. Sarkar, T. K.; Ghosh, S. K.; Rao, P. S.; Satapathi, T. K.; Mamdapur, V. R. Tetrahe-

dron 1992, 48, 6897−6908. 5. Deagostino, A.; Prandi, C.; Tonachini, G.; Venturello, P. Trends Org. Chem. 1995, 5,

103−113. (Review). 6. Celatka, C. A.; Liu, P.; Panek, J. S. Tetrahedron Lett. 1997, 38, 5449−5452. 7. Panek, J. S.; Liu, P. J. Am. Chem. Soc. 2000, 122 11090−11097. 8. Duffield, J. J.; Pettit, G. R. J. Nat. Prod. 2001, 64, 472−479. 9. Kraft, P.; Popaj, K. Eur. J. Org. Chem. 2004, 4995−5002. 10. Kraft, P.; Popaj, K. Eur. J. Org. Chem. 2008, 4806−4814.

581

[1,2]-Wittig rearrangement Treatment of ethers with bases, such as alkyl lithium, results in alcohols.

R OR1

R OH

R1

12

12

R2Li

The [1,2]-Wittig rearrangement is believed to proceed via a radical mechanism:

R OR1

H deprotonationR O

R1R2 homolytic

cleavage

Li

R O R1

Li

R OLi

R1

R OLi

R1

R OH

R1workup

Example 1, Aza [1,2]-Wittig rearrangement2

Ph N SnBu3CH3

n-BuLi Ph N LiCH3

PhHN

CH3

workup

83%

Example 23

OO

t-BuLi

58% O OH

Example 34

O

OTBDPS

O

OTBDPS

OH H

OH

TMS TMSn-BuLi, THF, ether

0 °C, 60%, > 98:2 dr

Example 46

O

O

NOMe2 eq. LDA, THF

−78 oC, 82% O

NOMe

OH

Example 58

582


TBSO O PhOTBS n-BuLi, THF

−20 to 0 oC, 32%TBSO

Ph

TBSO OH

Example 69

O PhO

NOMe

LDA, THF

−40 oC, 94%

PhO

NOMe

OH

References 1 Wittig, G.; Löhmann, L. Ann. 1942, 550, 260–268. 2 Peterson, D. J.; Ward, J. F. J. Organomet. Chem. 1974, 66, 209–217. 3 Tsubuki, M.; Okita, H.; Honda, T. J. Chem. Soc., Chem. Commun. 1995, 2135–2136. 4 Tomooka, K.; Yamamoto, H.; Nakai, T. J. Am. Chem. Soc. 1996, 118, 3317–3318. 5 Maleczka, R. E., Jr.; Geng, F. J. Am. Chem. Soc. 1998, 120, 8551–8552. 6 Miyata, O.; Asai, H.; Naito, T. Synlett 1999, 1915–1916. 7 Katritzky, A. R.; Fang, Y. Heterocycles 2000, 53, 1783–1788. 8 Tomooka, K.; Kikuchi, M.; Igawa, K.; Suzuki, M.; Keong, P.-H.; Nakai, T. Angew.

Chem., Int. Ed. 2000, 39, 4502–4505. 9 Miyata, O.; Asai, H.; Naito, T. Chem. Pharm. Bull. 2005, 53, 355–360. 10 Wolfe, J. P.; Guthrie, N. J. [1,2]-Wittig Rearrangement. In Name Reactions for Ho-


583

[2,3]-Wittig rearrangement Transformation of allyl ethers into homoallylic alcohols by treatment with base. Also known as the Still−Wittig rearrangement. Cf. Sommelet−Hauser rearrange-ment.

XY

1

231

2X

Y[2,3]-sigmatropic

rearrangement1

231

2

R2LiO R1

R

HO

R

R1

R2

R1 = alkynyl, alkenyl, Ph, COR, CN.

[2,3]-sigmatropic

rearrangementworkup

R

O R1

R

HO R1

Example 12

OO

KOt-Bu, HOt-Bu, THF

0 oC, 26 h, 22% HOO

Example 23

O CO2H

LDA, THF, −78 oC;

then TsCl, 87%TsO CO2H

> 95% E

Example 35

NO

O

O

H1.5 equiv LiHMDS

5 equiv HMPA, THF

−78 to −10 οC67%

H

H ON

O

HO

H

ON

O

HO

H

94 : 6

HHH

H

584


Example 46

O

Me

O

Me

HO

Me

MeO

OSEM

Me

n-BuLi

THF-pentane97%

OSEM

Me

References 1. Cast, J.; Stevens, T. S.; Holmes, J. J. Chem. Soc. 1960, 3521−3527. 2. Thomas, A. F.; Dubini, R. Helv. Chim. Acta 1974, 57, 2084−2087. 3. Nakai, T.; Mikami, K.; Taya, S.; Kimura, Y.; Mimura, T. Tetrahedron Lett. 1981, 22,

69−72. 4. Nakai, T.; Mikami, K. Org. React. 1994, 46, 105−209. (Review). 5. Kress, M. H.; Yang, C.; Yasuda, N.; Grabowski, E. J. J. Tetrahedron Lett. 1997, 38,

2633−2636. 6. Marshall, J. A.; Liao, J. J. Org. Chem. 1998, 63, 5962−5970. 7. Maleczka, R. E., Jr.; Geng, F. Org. Lett. 1999, 1, 1111−1113. 8. Tsubuki, M.; Kamata, T.; Nakatani, M.; Yamazaki, K.; Matsui, T.; Honda, T. Tetrahe-

dron: Asymmetry 2000, 11, 4725−4736. 9. Schaudt, M.; Blechert, S. J. Org. Chem. 2003, 68, 2913−2920. 10. Ahmad, N. M. [2,3]-Wittig Rearrangement. In Name Reactions for Homologations-

Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 241−256. (Review).

585

Wohl–Ziegler reaction The Wohl–Ziegler reaction is the reaction of an allylic or benzylic substrate with N-bromosuccinimide (NBS) under radical initiating conditions to provide the cor-responding allylic or benzylic bromide. Conditions used to promote the radical reaction are typically radical initiators, light and/or heat; carbon tetrachloride (CCl4) is typically utilized as the solvent.

R N

O

O

BrCCl4, reflux

initiatorR

Br

HN

O

O

Initiation:

N N CNNCΔ


2,2 -azobisisobutyronitrile (AIBN)

N Br

O

O

N

O

O

CN CNBr

Propagation:

N

O

O

HH abstraction

NH

O

O

N Br

O

O

N

O

O

Br

The succinimidyl radical is now available for the next cycle of the radical chain reaction.

Example 13

AcO

OAc OAc

NBS, CCl4

reflux, 30 min., 48%AcO

OAc O

AcO

OAc O

OBr

:

586


Example 27

CO2Me 1.2 eq. NBS, 0.1 eq. AIBN

solvent free, 60 to 65 oC89%

CO2Me

Br

Example 38

N

N NBS, CCl4

reflux, 71% N

N

Br

Br

Example 49

BocNO

NBS, AIBN (cat)

CCl4, reflux, 2 h,95%

BocNO

Br

References 1. Wohl, A. Ber. 1919, 52, 51−63. Alfred Wohl (1863−1939), born in Graudenz, Ger-

many, received his Ph.D. from A. W. Hofmann. In 1904, he was appointed Professor of Chemistry at the Technische Hochschule in Danzig.

2. Ziegler, K.; Spath, A.; Schaaf, E.; Schumann, W.; Winkelmann, E. Ann. 1942, 551, 80−119. Karl Ziegler (1898−1973), born in Helsa, Germany, received Ph.D. in 1920 from von Auwers at the University of Marburg. He became the director of the Max-Planck-Institut für Kohlenforschung at Mülheim/Ruhr in 1943 and stayed there until 1969. He shared the Nobel Prize in Chemistry in 1963 with Giulio Natta (1903−1979) for their work in polymer chemistry. The Ziegler−Natta catalyst is widely used in po-lymerization.

3. Djerassi, C.; Scholz, C. R. J. Org. Chem. 1949, 14, 660−663. 4. Allen, J. G.; Danishefsky, S. J. J. Am. Chem. Soc. 2001, 123, 351−352. 5. Detterbeck, R.; Hesse, M. Tetrahedron Lett. 2002, 43, 4609−4612. 6. Stevens, C. V.; Van Heecke, G.; Barbero, C.; Patora, K.; De Kimpe, N.; Verhe, R.

Synlett 2002, 1089−1092. 7. Togo, H.; Hirai, T. Synlett 2003, 702−704. 8. Marjo, C. E.; Bishop, R.; Craig, D. C.; Scudder, M. L. Mendeleev Commun. 2004,

278−279. 9. Yeung, Y.-Y.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 6310−6311. 10. Curran, T. T. Wohl–Ziegler reaction. In Name Reactions for Homologations-Part I;


587

Wolff rearrangement Conversion of an α-diazoketone into a ketene.

R2

N2O

R1 N2C

R1

R2O

H2O R1

R2 OH

O CO2 R2 R1Δ

α-diazoketone ketene intermediate

Step-wise mechanism:

R1

O N

R2

N

R1

O N

R2

NN2

R1 R2

OC

R2

R1

O

α-ketocarbene

Treatment of the ketene with water would give the corresponding homologated carboxylic acid.

Concerted mechanism:

R1

O N

R2

NN2 C

R2

R1

O

Example 12

H

O

N2

OΔ or hv

EtOH, dioxane (1:1)> 90%

OEt

O O

Example 23

N

O

MeO

N2 hv, MeOH

90% NMe

O

CO2Me

588


Example 34

O ON2

1. LiHMDS, TFEA

2. MsN3, Et3NO

OMe

hυ

CH3OH

Example 49

NBoc

OEtO2C

N2

Rh2Oct4

C5H11CONH2NBoc

CO2EtO

55%

HNO

C5H11

NBoc

OEtO2C

39%

HNO

C5H11

Wolff rearrangement N-H insertion

References 1. Wolff, L. Ann. 1912, 394, 23−108. Johann Ludwig Wolff (1857−1919) earned his

doctorate in 1882 under Fittig at Strasbourg, where he later became an instructor. In 1891, Wolff joined the faculty of Jena, where he collaborated with Knorr for 27 years.

2. Zeller, K.-P.; Meier, H.; Müller, E. Tetrahedron 1972, 28, 5831−5838. 3. Kappe, C.; Fäber, G.; Wentrup, C.; Kappe, T. Ber. 1993, 126, 2357−2360. 4. Taber, D. F.; Kong, S.; Malcolm, S. C. J. Org. Chem. 1998, 63, 7953−7956. 5. Yang, H.; Foster, K.; Stephenson, C. R. J.; Brown, W.; Roberts, E. Org. Lett. 2000, 2,

2177−2179. 6. Kirmse, W. “100 years of the Wolff Rearrangement” Eur. J. Org. Chem. 2002,

2193−2256. (Review). 7. Julian, R. R.; May, J. A.; Stoltz, B. M.; Beauchamp, J. L. J. Am. Chem. Soc. 2003,

125, 4478−4486. 8. Zeller, K.-P.; Blocher, A.; Haiss, P. Mini-Reviews Org. Chem. 2004, 1, 291−308. (Re-

view). 9. Davies, J. R.; Kane, P. D.; Moody, C. J.; Slawin, A. M. Z. J. Org. Chem. 2005, 70,

5840−5851. 10. Kumar, R. R.; Balasubramanian, M. Wolff Rearrangement. In Name Reactions for


589

Wolff–Kishner reduction Carbonyl reduction to methylene using basic hydrazine.

R R1

O NH2NH2

NaOH, refluxR R1

R R1

O

NH2NH2

R R1

NHONH2

R R1

NN

H

HHO

HO

H

:

:

H

R R1

R R1

HO

HH

NN R1

R

− N2HO

Example 1, Huang Minlon modification, with loss of ethylene here5

O

NH2NH2•H2ONH2NH2•2HCl

130 oC

KOH, 210 oC

36%

Example 27

O

MeO2C

80% NH2NH2•H2O

toluene, microwave20 min., 75%

N

MeO2C

H2N

KOH, microwave

30 min., 40% MeO2C

Example 38

OOH

OH

HO

85% NH2NH2•H2O, KOH

H2O, 30 min., 165 oC, 87%

590


OHOH

HO

H

O

1,5-hydride shift

OHOH

HO

H

HH

Example 4, Huang Minlon modification10

OMeHO

NOH

OMeHO

MeNH2NH2•H2O

diethylene glycolreflux, 4.75 h, 75%

References 1. (a) Kishner, N. J. Russ. Phys. Chem. Soc. 1911, 43, 582−595. (b) Wolff, L. Ann. 1912,

394, 86. (c) Huang, Minlon J. Am. Chem. Soc. 1946, 68, 2487−2488. (d) Huang, Minlon J. Am. Chem. Soc. 1949, 71, 3301−3303. (The Huang-Minlon modification).

2. Todd, D. Org. React. 1948, 4, 378−422. (Review). 3. Cram, D. J.; Sahyun, M. R. V.; Knox, G. R. J. Am. Chem. Soc. 1962, 84, 1734−1735. 4. Murray, R. K., Jr.; Babiak, K. A. J. Org. Chem. 1973, 38, 2556−2557. 5. Lemieux, R. P.; Beak, P. Tetrahedron Lett. 1989, 30, 1353−1356. 6. Taber, D. F.; Stachel, S. J. Tetrahedron Lett. 1992, 33, 903−906. 7. Gadhwal, S.; Baruah, M.; Sandhu, J. S. Synlett 1999, 1573−1592. 8. Szendi, Z.; Forgó, P.; Tasi, G.; Böcskei, Z.; Nyerges, L.; Sweet, F. Steroids 2002, 67,

31−38. 9. Bashore, C. G.; Samardjiev, I. J.; Bordner, J.; Coe, J. W. J. Am. Chem. Soc. 2003, 125,

3268−3272. 10. Pasha, M. A. Synth. Commun. 2006, 36, 2183−2187. 11. Song, Y.-H.; Seo, J. J. Heterocycl. Chem. 2007, 44, 1439−1443. 12. Shibahara, M.; Watanabe, M.; Aso, K.; Shinmyozu, T. Synthesis 2008, 3749−3754.

591

Woodward cis-dihydroxylation

Cf. Prévost trans-dihydroxylation.

1. I2, AgOAc

2. H2O, H+ OHHO

I I I

OAc

SN2 SN2I

OO:

cyclic iodonium ion intermediate neighboring group assistance

O O

H2O:

O O

OH

− H OHO

O

protonation

OHO

O

:OH2

H

OHO

HO OOHHO

hydrolysis

H Example 11

CH3

O

H3C

H H

CH3

O

H3C

H H

OR1

OR2R1 = Ac, R2 = HR1 = H, R2 = Ac

I2, AgOAcHOAc, H2O

23 → 95 °C3.5 h

CH3

O

H3C

H H

OH

OHKOH, MeOH

23 °C, 71% overall

Example 26

H3C

H

CH3

MeO2CHO

OH

HNBA, AgOAc, HOAc

23 °C, 75%

592


H3C

H

CH3

MeO2CHO

OH

H3C

H

CH3

MeO2CHO

OH

BrOAc

H H

OO

MeBr

References 1. Woodward, R. B.; Brutcher, F. V., Jr. J. Am. Chem. Soc. 1958, 80, 209−211. Robert

Burns Woodward (USA, 1917−1979) won the Nobel Prize in Chemistry in 1953 for his synthesis of natural products.

2. Kirschning, A.; Plumeier, C.; Rose, L. Chem. Commun. 1998, 33−34. 3. Monenschein, H.; Sourkouni-Argirusi, G.; Schubothe, K. M.; O’Hare, T.; Kirschning,

A. Org. Lett. 1999, 1, 2101−2104. 4. Kirschning, A.; Jesberger, M.; Monenschein, H. Tetrahedron Lett. 1999, 40,

8999−9002. 5. Muraki, T.; Yokoyama, M.; Togo, H. J. Org. Chem. 2000, 65, 4679−4684. 6. Germain, J.; Deslongchamps, P. J. Org. Chem. 2002, 67, 5269−5278. 7. Myint, Y. Y.; Pasha, M. A. J. Chem. Res. 2004, 333−335. 8. Emmanuvel, L.; Shaikh, T. M. A.; Sudalai, A. Org. Lett. 2005, 7, 5071−5074. 9. Mergott, D. J. Woodward cis-dihydroxylation. In Name Reactions for Functional


10. Burlingham, B. T.; Rettig, J. C. J. Chem. Ed. 2008, 85, 959−961.

593

Yamaguchi esterification Esterification using 2,4,6-trichlorobenzoyl chloride (the Yamaguchi reagent).

R OH

OCl

OCl

Cl

Cl

Et3N, CH2Cl2

R O

O O Cl

Cl Cl

R1HO

DMAP, Tol., reflux R O

OR1

R O

OCl

OCl

Cl

Cl

H

:NEt3R O

O Cl

Cl Cl

ClOR O

O O Cl

Cl ClN

N

:

DMAP (dimethylaminopyridine)

O

O Cl

Cl Cl

OR

N

N

O

O Cl

Cl Cl

R N

O

NO:R1H

Steric hindrance of the chloro substituents blocks attack of the other carbonyl of the mixed anhydride intermediate.

O N

N

ORR1

R O

OR1

Example 1, Intermolecular coupling5

ICO2H

OTES

OMen-Bu3Sn

ODMTOMe

OH

2,4,6-trichlorobenzoyl chlorideDMAP, Tol., Et3N

rt, 24 h, 89%

I

OTES

OMe

n-Bu3SnODMT

OMe

O

O

594


Example 2, Intramolecular coupling7

O O O

CO2H

O

HO

2,4,6-trichlorobenzoyl chlorideEt3N, THF

then DMAP, toluene, 62%

O O O

O

O

O

Example 3, Dimerization8

O

OH

O

BnO

OH

H H

Yamaguchi reagent

125 oC, 6 h, 66%

O

HH H

O

BnO

O

O

H

H H

OO

References 1. (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc.

Jpn. 1979, 52, 1989−1993. (b) Kawanami, Y.; Dainobu, Y.; Inanaga, J.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1981, 54, 943−944.

2. Richardson, T. I.; Rychnovsky, S. D. Tetrahedron 1999, 55, 8977−8996. 3. Paterson, I.; Chen, D. Y.-K.; Aceña, J. L.; Franklin, A. S. Org. Lett. 2000, 2,

1513−1516. 4. Hamelin, O.; Wang, Y.; Deprés, J.-P.; Greene, A. E. Angew. Chem., Int. Ed. 2000, 39,

4314−4316. 5. Quéron, E.; Lett, R. Tetrahedron Lett. 2004, 45, 4533−4537. 6. Mlynarski, J.; Ruiz-Caro, J.; Fürstner, A. Chem., Eur. J. 2004, 10, 2214−2222. 7. Lepage, O.; Kattnig, E.; Fürstner, A. J. Am. Chem. Soc. 2004, 126, 15970−15971. 8. Smith, A. B. III.; Simov, V. Org. Lett. 2006, 8, 3315−3318. 9. Ahmad, N. M. Yamaguchi esterification. In Name Reactions for Functional Group


10. Wender, P. A.; Verma, V. A. Org. Lett. 2008, 10, 3331−3334. 11. Carrick, J. D.; Jennings, M. P. Org. Lett. 2009, 11, 769−772.

595

Zincke reaction The Zincke reaction is an overall amine exchange process that converts N-(2,4-dinitrophenyl)pyridinium salts, known as Zincke salts, to N-aryl or N-alkyl pyridiniums upon treatment with the appropriate aniline or alkyl amine.

NO2N

NO2

Cl R NH2

RN Cl

NH2O2N

NO2Zincke salt

NO2N

NO2

ClH2N R:

NO2N

NO2

NH

RH

NO2N

NO2

NR

H ring-

opening

NHO2N

NO2

NR

HNH

O2N

NO2

NH

RNH2R :

1,6-addition/elimination

NHO2N

NO2

NH

RNH

R NH2O2N

NO2

:

HR

HN

HN

R RN

HN

Rcis-trans

inversion

RN N

HR

6π

electrocyclizationRN N

HR

RN N

H2

R:

RN Cl

H

596


Example 15

NO2N

NO2

Cl

ClNO2

NO2N

Et Acetone, Δ

overnight (79%)

NH2

PhOH

Et

Cl

n-BuOH, Δ

20 h, 86%N

Et

OHPh

Example 26

N N

ClNO2

NO2

OH OH

NH2

N N

ClH2O, Δ, 16 h

OH

OH

OEt

N

H

O

HO

N

EtO

CaCO3, H2O/THF (4:1)20 oC, 3 days25%, 2 steps

Example 39

NCO2t-Bu

NBoc

11

ClNO2

NO2

MeOH, reflux

89%

Cl

NCO2t-Bu

NBoc

11

NO2

O2N

NH2

N11

n-BuOH, heat, 61%

Cl

NCO2t-Bu

NBoc

11

11

N

597

Example 410

NO2N

NO2

Cl

ClNO2

NO2N

Zincke salt

Me2NHthen NaOH

58%

Me2NCHO Bu3Sn

CHOLiSnBu3

50−55%Zincke aldehyde

References 1. (a) Zincke, Th. Ann. 1903, 330, 361−374. (b) Zincke, Th.; Heuser, G.; Möller, W.

Ann. 1904, 333, 296−345. (c) Zincke, Th.; Würker, W. Ann. 1905, 338, 107−141. (d) Zincke, Th.; Würker, W. Ann. 1905, 341, 365−379. (e) Zincke, Th.; Weisspfenning, G. Ann. 1913, 396, 103−131.

2. Epszju, J.; Lunt, E.; Katritzky, A. R. Tetrahedron 1970, 26, 1665−1673. (Review). 3. Becher, J. Synthesis 1980, 589−612. (Review). 4. Kost, A. N.; Gromov, S. P.; Sagitullin, R. S. Tetrahedron 1981, 37, 3423−3454. (Re-

view). 5. Wong, Y.-S.; Marazano, C.; Gnecco, D.; Génisson, Y.; Chiaroni, A.; Das, B. C. J.

Org. Chem. 1997, 62, 729−735. 6. Urban, D.; Duval, E.; Langlois, Y. Tetrahedron Lett. 2000, 41, 9251−9256. 7. Cheng, W.-C.; Kurth, M. J. Org. Prep. Proced. Int. 2002, 34, 585−588. (Review). 8. Rojas, C. M. Zincke Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J.,

Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 355−375. (Review). 9. Shorey, B. J.; Lee, V.; Baldwin, J. E. Tetrahedron 2007, 63, 5587−5592. 10. Michels, T. D.; Rhee, J. U.; Vanderwal, C. D. Org. Lett. 2008, 10, 4787−4790.

598

Subject Index A abnormal Beckmann rearrangement, 34 abnormal Chichibabin reaction, 108 abnormal Claisen rearrangement, 121 acetic anhydride, 54, 167, 204, 424, 440, 442, 452 2-acetamido acetophenone, 92 acetone cyanohydrin, 534 acetonitrile as a reactant, 168 α-acetylamino-alkyl methyl ketone, 167 acetylation, 311 acetylenic alcohols, 100

, -acetylenic esters, 225 acid chloride, 11, 461, 476 acid scavenger, 202 acid-catalyzed acylation, 296 acid-catalyzed alkyl group migration, 566 acid-catalyzed condensation, 131, 133 acid-catalyzed cyclization, 409 acid-catalyzed electrocyclic formation of cyclopentenone, 383 acid-catalyzed reaction, 490 acid-catalyzed rearrangement, 436, 480 acidic alcohol, 339 acidic amide hydrolysis, 534 acidic methylene moiety, 337 acid-labile acetal, 572 acid-mediated cyclization, 444 acid-promoted rearrangement, 190 acrolein, 30, 509 acrylic ester, 30 acrylonitrile, 30 activated hydroxamate, 332 activated methylene compounds, 315 activating agent, 440 activating auxiliary, 458 activating effect of a base, 536 activating group, 288, 351, 440 activation of the hydroxamic acid, 332 activation step, 325 α-active methylene nitrile, 254 acyclic mechanism, 159 acyl anhydride, 234 acyl azides, 162 acyl derivative, 432 N-acyl derivative, 162 ortho-acyl diarylmethanes, 66 acyl group, 234

acyl halide, 234 acyl malonic ester, 263 acyl transfer, 14, 322, 424, 452 2-acylamidoketones, 472 acylation, 8, 51, 234, 235, 296, 322, 332, 440 O-acylation, 332 acylbenzenesulfonylhydrazines, 334 acylglycine, 205 acylium ion, 234, 240, 253, 319 acyl-o-aminobiphenyls, 371 α-acyloxycarboxamide, 415 α-acyloxyketone, 14 α-acyloxythioether, 452 adamantane-like structure, 432 1,4-addition of a nucleophile, 355 addition of Pd-H, 373 cis-addition, 496 1,6-addition/elimination, 596 ADDP, 366 adduct formation, 365 adenosine, 370 aglycon, 221 AIBN, 22, 23, 24, 25, 200, 546, 586, 587 air oxidation, 194 Al(Oi-Pr)3, 345 alcohol activation, 365 aldehyde cyanohydrin, 229 Alder ene reaction, 1, 2, 111 Alder’s endo rule, 184 aldol addition, 470 aldol condensation, 3, 42, 107, 212, 238, 274, 284, 375, 424, 470 Algar–Flynn–Oyamada reaction, 6 alkali metal amide, 517 alkali metal, 44, 517 alkaline medium, 460 alkene, 1, 30, 236, 399, 417, 419, 430, 448, 490 alkenyl anilines, 281 alkenylation, 277 alkoxide-catalyzed oxidation, 404 alkoxide-catalyzed rearrangements, 214 alkoxy methylenemalonic ester, 263 α-alkoxycarbonyl phosphonate, 341 alkyl alcohol, 231 alkyl amine, 596 alkyl cation, 236 alkyl fluorosilane, 233 alkyl group migration, 566

599

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_BM2, © Springer-Verlag Berlin Heidelberg 2009

alkyl halide, 171, 236, 247, 325, 357 O-allyl hydroxylamines, 350 alkyl lithium, 494, 582 alkyl migration, 319, 436 N-alkyl pyridinium, 596 O-alkylating agent, 343 alkylating agent, 236, 343 N-alkylation, 343 alkylation reaction, 203 alkyl-silane, 231 alkyne coordination, 198 alkyne insertion, 198 alkyne, 98, 100, 148, 198, 236, 257, 259, 419, 519 alkynyl copper reagent, 90, 98, 257, 519 alkynyl halide, 90 Allan–Robinson reaction, 8, 322 allenyl enyne, 382 all-trans-retinal, 88 allyl ether, 584 π-allyl Stille coupling, 529 allyl trimethylsilyl ketene acetal, 125 allylic acetate, 549 allylic alcohol, 100, 127, 363, 401, 406, 502, 570 allylic amination, 572 allylic amine, 426, 507 allylic bromide, 586 allylic carbamate, 507 allylic C–H amination, 572 allylic C–H cleavage, 572 allylic C–H oxidation, 572, 573, 574 allylic epoxide, 549 allylic ester enolate, 125 allylic ether, 549 allylic leaving group, 548 allylic substrate, 586 allylic sulfoxide, 363 allylic tertiary amine-N-oxides, 350 allylic transformation, 222 allylic transposition, 1 allylic trichloroacetamide, 406 allyloxycarbenium ions, 222 π-allylpalladium intermediate, 548, 572 allylsilane, 484 (R)-alpine-borane, 359, 360 aluminum chloride, 253 aluminum hydride, 100, 235 aluminum phenolate, 240 amalgamated zinc, 129

amide, 33, 102, 105, 123, 328, 379, 468, 490, 543562 amidine, 438 amination, 58, 80-82, 330, 572, 573 amine exchange, 596 amine-catalyzed rearrangements, 214 amino acid, 167, 534, 574, 575 α-amino acid, 167, 534 α-amino ketone, 238, 385 α-amino nitrile, 534 aminoacetal intermediate, 444 β-aminoalcohol, 177 gem-aminoalcohol, 330 o-aminobiphenyls, 371 β-aminocrotonate, 391 aminothiophene synthesis, 254 ammonia, 107, 270, 274, 276, 411 ammonium carbonate, 76 ammonium sulfite, 74 ammonium ylide intermediate, 517 amphotericin B, 89 aniline, 46, 81, 102, 131, 133, 194, 251, 263, 281, 373, 394, 509, 596 anilinomethylenemalonic ester, 263 anion-assisted Claisen rearrangement, 96 anionic oxy-Cope rearrangement, 138 p-anisyloxymethyl, 141 α-anomer, 222, 223 β-anomer, 320 anomeric center, 313 anthracenes, 66 AOM, 141 aprotic solvent, 16, 401 aralkyloxazole, 472 Arndt–Eistert homologation, 10 aromatic aldehyde, 229 aromatic solvent, 202 aromatization, 196, 234, 236, 517 Arthur C. Cope, 217 aryl aldehyde, 424 aryl boronic acid, 87, 102, 574 aryl diazonium salt, 262 aryl groups migrate intramolecularly, 393 aryl halide, 64, 80, 368, 531, 554 aryl hydrazine, 72 aryl migration, 36, 165 1,2-aryl migration, 215 aryl potassium trifluoroborate, 574 N-aryl pyridinium, 596

600

aryl–acetylene, 98 -arylamino-ketone, 46

arylation, 102, 277, 332, 574 O-arylation, 332 arylboronates, 368 β-arylethylamine, 434 2-aryl-3-hydroxy-4H-1benzopyran-4-ones, 6 arylhydrazone, 227 O-aryliminoethers, 105 3-arylindole, 46 aryllithium, 413 arylmethyl ether, 202 asymmetric [3+2]-cycloaddition, 144 asymmetric acyl Pictet–Spengler, 434 asymmetric aldol condensation, 212 asymmetric amino-hydroxylation, 496 asymmetric aza-Michael addition, 355 asymmetric Carroll rearrangement, 96 asymmetric Claisen rearrangement, 118 asymmetric construction of carbon–carbon bond, 351 asymmetric Diels–Alder reactions, 143 asymmetric dihydroxylation, 499 asymmetric epoxidation, 300, 502 asymmetric hydroboration, 71 asymmetric hydrogenation, 399 asymmetric intermolecular Heck reac-tion, 277 asymmetric Mannich reaction, 337, 338 asymmetric Mannich-type reaction, 337, 338 asymmetric Michael addition, 355 asymmetric Mukaiyama aldol reaction, 376 asymmetric Petasis reaction, 426 asymmetric reduction of ketones, 359 asymmetric reduction, 359, 399 asymmetric Robinson annulation, 271 asymmetric Simmons−Smith, 507 asymmetric Tsuji–Trost reaction, 550 α-attack, 6 β-attack, 6 aurone derivative, 7 aza [1,2]-Wittig rearrangement, 582 aza-Diels–Alder reaction, 187 aza-Grob fragmentation, 268 aza-Henry reaction, 284 azalactone, 167 aza-Myers−Saito reaction, 382 aza-Payne rearrangement, 421

aza-π-methane rearrangement, 192 azide, 52, 102, 162, 163, 458, 523 azido-alcohol, 52, 490 aziridine, 52, 146, 266 azirine intermediate, 385 N-aziridinyl imine, 16 azlactone, 204 2,2 -azobisisobutyronitrile, 22, 24, 200, 586 1,1'-(azodicarbonyl)dipiperidine, 366 B backside displacement, 454 Baeyer–Villiger oxidation, 12, 70, 165 Baker–Venkataraman rearrangement, 14 Balz−Schiemann reaction, 488 Bamford–Stevens reaction, 16, 494 Barbier coupling reaction, 18 Bartoli indole synthesis, 20 Barton ester, 22 Barton nitrite photolysis, 26 Barton radical decarboxylation, 22 Barton–McCombie deoxygenation, 24 base-catalyzed condensation, 169, 463 base-catalyzed self-condensation, 546 base-induced cleavage, 273 base-mediated rearrangement, 332 base-promoted radical coupling, 262 base-sensitive aldehyde, 341 basic condition, 203, 337, 430 basic hydrogen peroxide conditions, 165 basic oxidation, 70 BaSO4-poisoned palladium catalyst, 476 Batcho–Leimgruber indole synthesis, 28 Baylis–Hillman reaction, 30 9-BBN, 359 Beckmann rearrangement, 33 Belluš–Claisen rearrangement, 117 benzaldehyde, 95, 108, 515 1,4-benzenediyl diradical formation, 40 benzil, 36 benzilate, 36 benzilic acid rearrangement, 36 benzoin condensation, 38, 525 p-benzoquinone, 391 benzothiazole, 309 benzyl halide, 171, 515, 586 benzyl reagent, 202 benzylation, 202, 203 benzylic bromide, 586 benzylic quaternary ammonium salt, 517

601

benzylic substrate, 586 Bergman cyclization, 40, 382 betaine, 578, 580 biaryl, 554 cis-bicyclo[3.3.0]octane-3,7-dione, 568 Biginelli pyrimidone synthesis, 42 biindolyl, 369 bimolecular elimination, 30 Birch reduction, 44 2,4-bis(4-methoxyphenyl)-1,3-dithiadiphosphetane-2,4-disulfide, 328 bis(trifluoroethyl)phosphonate, 527 bis-acetylene, 90 bis-aryl halide, 531 1,4-bis(9-O-dihydroquinidine)-phthalazine, 496, 499 Bischler indole synthesis, 46 Bischler–Möhlau indole synthesis, 46 Bischler–Napieralski reaction, 48 B-isopinocampheyl-9-borabicyclo-[3.3.1]-nonane, 359 bisoxygenated intermediate, 573 Blaise reaction , 50 Blum–Ittah aziridine synthesis, 52 boat-like, 117 Bobbitt modification, 445 N-Boc glylcine allylic ester, 574 Boekelheide reaction, 54 Boger pyridine synthesis, 56, 188 9-borabicyclo[3.3.1]nonane, 359, see also 9-BBN borane, 70, 87, 89, 143, 359, 360, 536, 574 Borch reductive amination, 58 boric acid, 574 Z-(O)-boron-enolate, 212 boron trifluoride etherate, 222 boronate, 87, 368 boronic acid-Mannich, 426 boronic acid, 87, 88, 102,426, 574 boron-mediated Reformatsky reaction, 457 boron-protected haloboronic acid, 87, 88 Borsche–Drechsel cyclization, 60 Boulton–Katritzky rearrangement, 62 Bouveault aldehyde synthesis, 64 Bouveault–Blanc reduction, 65 Br/Cl variant of the Takai reaction, 541 Bradsher reaction, 66 bromine/alkoxide for Hofmann rear-rangement, 290

α-bromoacid, 282 bromodinitrobenzene, 347 N-bromosuccinimide, 586, see also NBS Brook rearrangement, 68 [1,2]-Brook rearrangement, 68, 69 [1,3]-Brook rearrangement, 68 [1,4]-Brook rearrangement, 68 [1,5]-Brook rearrangement, 69 Brown hydroboration, 70 BT, 309 Bu3P, 505 Bucherer carbazole synthesis, 72 Bucherer reaction, 74 Bucherer–Bergs reaction, 76 Büchner ring expansion, 78 Buchwald–Hartwig amination, 80, 102 t-BuLi, 69, 199, 390, 413, 414, 582 Burgess dehydrating reagent, 84, 339 Burke boronates, 87 butterfly transition state, 478 t-butyl peroxide, 502 C 13C-labelled α,β-unsaturated ketone, 196 Cadiot–Chodkiewicz coupling, 90, 98, 519 calystegine, 220 camphorsulfonic acid, 203, see also CSA Camps quinoline synthesis, 92 Cannizzaro reaction, 94 carbazole, 60, 70, 72 carbene generation, 460 carbene mechanism, 428 carbene, 10, 112, 156, 198, 428, 460, 588 carbocation rearrangement, 176, 177 β-carbocation stabilization by the silicon group, 231 β-carbocation stabilizationby the β-silicon effect, 484 carbocyclization, 220 carbodiimide, 332, 370 carbon Ferrier reaction, 222 carbon monoxide, 253, 419 carbon nucleophile, 222, 484, 548, 572, see also C- nucleophile carbon tetrachloride, 586, see also CCl4 carbon–boron bond, 306, 328, 387, 430, 434, 436 carbonyl oxide, 161

602

carbonyl, 335, 399, 456, 484, 490, 542 -carbonyl sulfide derivative, 251

1,2-carbon-to-nitrogen migration, 162 carboxylic acid, 10, 22, 94, 202, 214, 282, 304, 415, 551 carboxylic amide derivative, 273 Carroll rearrangement, 96 Castro–Stephens coupling, 90, 98, 519

in situ Castro–Stephens reaction, 99 catalytic asymmetric enamine aldol, 271 catalytic asymmetric inverse-electron-demand Diels–Alder reaction, 187 catalytic cycle, 81, 143, 277, 288, 325, 399, 401, 465, 496, 500, 502, 529, 536, 548, 564 catalytic Pauson−Khand reaction, 419 CBS reagent, 143 3CC, 415 4CC, 551 C–C bond rotation, 277 CCl4, 97, 298, 319, 447, 455, 473, 516, 586, 587 Celebrex, 318 CH2I2, 470, 507, 508 CH3OTf, 202 chair-like, 117 Chan alkyne reduction, 100 Chan–Lam C–X coupling reaction, 102 Chantix, 211 Chapman rearrangement, 105, 393 Chapman-like thermal rearrangement, 106 chelate-controlled oxidative Heck arylation, 574 chemoselective tandem acylation of the Blaise reaction intermediate, 51 chemoselectivity, 572 CHI3, 540 Chichibabin pyridine synthesis, 107 chiral allylic C–H oxidation, 573 chiral auxiliary, 212, 351 chiral ligand, 496 chiral oxazoline, 351 chlorination, 332

in situ chlorination, 455 chloro substituent, 594 chloroammonium salt, 292

-chlorobis-(cyclopentadienyl)-(dimethylaluminium)- -methylenetitanium, 542 chlorodinitrobenzene, 347

chloroiminium salt, 558 α-chloromethyl ketones, 276 2-chloro-1-methyl-pyridinium iodide, 379 3-chloropyridine, 112 N-chlorosuccinimide, 150, see also NCS cholesterol, 321 chromium (VI), 304 chromium trioxide, 304 chromium trioxide-pyridine complex, 304 chromium variant of the Nicholas reac-tion, 395 Chugaev reaction, 110 Chugaev syn-elimination, 110 Ciamician–Dennsted rearrangement, 112 cinchona alkaloid ligand, 499 cinnamic acid synthesis, 424 Claisen condensation, 113, 182 Claisen isoxazole synthesis, 115 Claisen rearrangement, 16, 96, 117 para-Claisen rearrangement, 119 ortho-Claisen rearrangement product, 119 classical Favorskii rearrangement, 217 cleavage of primary carbon–boron bond, 308 Clemmensen reduction, 129 C–O bond fragmentation, 240 CO insertion, 198 CO, 198, 319 cobalt-catalyzed Alder-ene reaction, 2 Collins oxidation, 304 Collins–Sarett oxidation, 305 Combes quinoline synthesis, 131, 133 combinatorial Doebner reaction, 195 Comins modification, 64 complexation, 87, 234, 240, 296, 484, 564 concerted oxygen transfer, 300 concerted process, 113, 117, 137, 184, 268, 499, 578, 588 condensation, 3, 28, 38, 42, 43, 60, 92, 107, 113, 131, 133, 169, 182, 196, 204, 212, 225, 229, 238, 254, 255, 270, 274, 284, 286, 315, 375, 423, 434, 444, 463, 470, 474, 525, 532, 534, 546, 551

Aldol, 3, 424 Benzoin, 38 Claisen, 113 Darzens, 169

603

Dieckmann, 182 Guareschi–Thorpe, 270 Knoevenagel, 254, 255, 315 Stobbe, 532

conjugate addition, 42, 196, 355, 391, 509, see also Michael addition Conrad–Limpach reaction, 131, 133 coordination and deprotonation, 102, 345 coordination, 102, 198, 345, 404, 548 Cope elimination reaction, 135, 136 Cope rearrangement, 119, 137 copper catalyst, 257 Corey’s PCC, 304 Corey’s oxazaborolidine, 143 Corey’s ylide, 146 Corey–Bakshi–Shibata (CBS) reagent, 143 Corey–Claisen, 117 Corey–Fuchs reaction, 148 Corey–Kim oxidation, 150 Corey–Nicolaou double activation, 152 Corey–Nicolaou macrolactonization, 152 Corey–Seebach dithiane reaction, 154 Corey–Winter olefin synthesis, 156 Corey–Winter reductive elimination, 156 Corey−Chaykovsky reaction, 146 coumarin, 423 (−)-CP-263114, 304 Cp2TiMe2, 428 Cr(CO)3-coordinated hydroquinone, 198 Cr(IV), 304 CrCl2, 540 Criegee glycol cleavage, 159 Criegee mechanism of ozonolysis, 161 Criegee zwitterion, 161 Crimmins procedure for Evans aldol, 212 Crixivan, 301 cross-coupling, 87, 88, 102, 259, 288, 289, 299, 325, 389, 519, 529, 531, 536 cross-McMurry coupling, 335, 336 Cr−Ni bimetallic catalyst, 401 CSA, 203, 271, 412, 453, 505 Cu(III) intermediate, 90, 98 Cu(OAc)2, 102, 103, 259, 260, 299, 565 cupric acetate, 102 Curtius rearrangement, 162 CuTC-catalyzed Ullmann coupling, 554

cyanamide, 562 cyanide, 38 cyanoacetic ester, 270 cyanogen bromide, 562 cyanohydrins, 76 cyclic intermediate, 159 cyclic iodonium ion intermediate, 447, 592 cyclic mechanism, 159 cyclic thiocarbonate, 156 cyclic transition state, 345, 404 cyclization of the Stobbe product, 532 cyclization, 6, 40, 46, 60, 66, 115, 131, 133, 173, 196, 220, 227, 255, 263, 281, 371, 382, 383, 385, 400, 413, 417, 423, 434, 444, 450, 463, 532, 596

Bergman, 40 Borsche–Drechsel, 60 Ferrier carbocyclization, 220 Myers−Saito, 382 Nazarov, 383 Parham, 423 Pshorr, 450

[2+2] cycloaddition, 78, 300, 465, 521, 542, 578 [2+2+1] cycloaddition, 419 [3+2]-cycloaddition, 143, 499 [4+2]-cycloaddition reactions, 184 cyclobutane cleavage, 173 cyclobutanone, 521 cyclodehydration, 472 cyclo-dibromodi- -methylene( -tetrahydrofuran)trizinc, 403 cyclohepta-2,4,6-trienecarboxylic acid ester, 78 cyclohexadiene, 44 cyclohexanone phenylhydrazone, 60 cyclohexanone, 60, 220, 383, 419, 470 cyclopentene, 560 cyclopropanation, 112, 507 cyclopropane, 146, 192, 560 cyclopropanone intermediate, 214 cycloreversion, 465 C−C bond cleavage, 268 C−C bond migration, 176, 177 D Dakin oxidation, 165 Dakin–West reaction, 167 Danishefsky diene, 184 Darzens condensation, 169

604

DBU, 15, 170, 206, 285, 290, 333, 341, 342, 377, 386, 406, 407, 471, 472, 526, DCC, 23, 245, 370 de Mayo reaction, 173 DEAD, 223, 243, 248, 365, 366 decalin, 432 decarboxylation, 96, 263, 315, 332, 474, 568 dehydrating reagent, 339, 432 dehydration, 46, 108, 408, 470, 480, 509 dehydrative ring closure, 371 Delépine amine synthesis, 171, 515 demetallation, 395 Demjanov rearrangement, 175 deoxygenation, 24 (+)-deoxynegamycin, 573 deprotonation of nitroalkanes, 284 depsipeptide, 572 Dess–Martin oxidation, 179, 180, 472 desulfonylation, 560 desymmetrization, 95 Dewar intermediate, 119 (DHQ)2-PHAL, 499 (DHQD)2-PHAL, 496 diamide, 551 diaryl compound, 262 diastereomer, 311, 451, 495 diastereoselective glycosidation, 313 diastereoselective Simmons−Smith cyclopro-panation, 507 1,8-diazabicyclo[5.4.0]undec-7-ene, 341, see also DBU diazoacetic esters, 78 2-diazo-1,3-diketone, 458 α-diazoketone, 588 2-diazo-3-oxoester, 458 diazomethane, 10 diazonium salt, 177, 262, 302, 486 diazotization, 176, 177 diboron reagents, 368 dibromoolefin, 148 1,3-dicarbonyl compounds, 317 1,4-dicarbonyl derivative, 525 1,3-dicyclohexylurea, 370 dichlorocarbene, 112, 460 Dieckmann condensation, 182 Diels–Alder adduct, 184 Diels–Alder reaction, 56, 66, 143, 184, 185, 186, 187 diene, 44, 184, 186, 188, 192

1,4-diene, 192

dienone, 119 Dienone–phenol rearrangement, 190 dienophile, 56, 184, 186, 187 diethyl diazodicarboxylate, 365, see also DEAD diethyl succinate, 532 diethyl tartrate, 502 diethyl thiodiglycolate, 286 dihydroisoquinolines, 48 cis-dihydroxylation, 499 1,4-dihydropyridine, 274 diketone, 14, 131, 173, 270, 286, 408,

409, 411, 458, 474 α-diketone, 286 β-diketones, 14, 131 1,4-diketone, 408, 409, 411 1,4-diketone condensation, 474 1,5-diketone, 173

dimerization, 255, 257, 299 dimethylaminomethylating agent, 206 dimethylaminomethylation, 206 dimethylaminopyridine, 594, see also DMAP N,N-dimethylformamide dimethyl acetal, 28 dimethylmethylideneammonium iodide, 206 dimethylsulfide, 150 dimethylsulfonium methylide, 146 dimethylsulfoxonium methylide, 146 dimethyltitanocene, 428 dinitrophenyl, 67 diol, 156, 159, 203, 250, 436, diosgenin, 130 1,3-dioxolane-2-thione, 156 dipeptidyl peptidase IV inhibitor, 574 diphenyl 2-pyridylphosphine, 244 diphenylphosphoryl azide, 163, see also DPPA DIPT, 503 1,3-dipolar cycloaddition, 161, 458, 459 2,2 -dipyridyl disulfide, 152 diradical, 40, 192, 382, 417, 560 N,N-disubstituted acetamide, 440 disubstituted azodicarboxylate, 365 3,4-disubstituted phenols, 190 4,4-disubstituted cyclohexadienone, 190 3,4-disubstituted thiophene-2,5-dicarbonyl, 42, 286, 317, 525 di-tert-butylazodicarbonate, 244 dithiane, 154

605

ditin reagent, 531 di-vinyl ketone, 383 di-π-methane rearrangement, 192 2,4-dinitro-benzenesulfonyl chloride, 243 DMAP, 78, 103, 157, 158, 161, 167, 245, 380, 453, 594, 595 DMFDMA, 28 DMS, 150 DNP, 67 Doebner quinoline synthesis, 194 Doebner–von Miller reaction, 196, 509 domino annulation reaction under Willgerodt–Kindler conditions, 577 Dötz reaction, 198 double Chapman rearrangement, 106 double imine, 227 double Robinson-type cyclopentene annulation, 471 double Tebbe, 542, 543 double Wagner–Meerwein rearrangement, 566 Dowd–Beckwith ring expansion, 200 Dowtherm A, 134 DPE-Phos, 82 DPPA, 163, 164 DTBAD, 244 Dudley reagent, 202 E E/Z geometry control, 125 E1cB, 271, 339 E2, 30, 31, 424, 430 E2 anti-elimination, 430 E2 elimination, 424 E-allylic alcohols, 100 EAN, 316 E-arylated allylic ester, 574 EDDA, 315 EDG, 184 Eglinton coupling, 259 Ei, 84 electrocyclic formation, 383 electrocyclic ring closure, 198 electrocyclic ring opening, 78 electrocyclization, 40, 131, 133, 417, 596 electron transfer, 18, 44, 215, 266, 311, 335, 456, 554 electron-deficient heteroaromatics, 361 electron-donating substituent, 44, 184

electronically unbiased α-olefin, 574 electron-rich alkyl group, 436 electron-rich carbocycle, 558, 558 electron-rich ligands, 80 electron-withdrawing substituent, 44, 184, 347 electrophile, 30, 89, 146, 266, 325, 484, 490, 558 electrophilic site, 413 electrophilic substitution, 234, 296 elemental sulfur, 254, 408 elimination, 30, 80, 84, 90, 98, 102, 110, 135, 136, 156, 229

α-elimination, 460 β-elimination, 281, 339, 519 syn-elimination, 505 syn-β-elimination, 277

Emil Fischer, 222 enamine formation, 271, 274 enamine, 56, 107, 131, 442, 546 enantioselective aromatic Claisen rear-rangement, 121 enantioselective borane reduction, 143 enantioselective cis-dihydroxylation, 499 enantioselective epoxidation, 502 enantioselective ester enolate-Claisen rear-rangement, 125 enantioselective Mukaiyama-aldol reaction, 4 enantiospecific Baker−Venkataraman rear-rangement, 14 ene reaction, 1, 110, 121, 140 enediyne, 40 ene-hydrazine, 227 enol, 96, 458 enol ether, 355, 377, 397 enol silane, 482 enolate, 3, 125, 182, 206, 212, 250, 274, 282, 355, 424, 458, 470, 532 enolates, enolsilylethers, 206 enolizable hydrogens for ketones, 217 enolizable α-haloketones, 214 enolization, 8, 42, 282, 322, 323, 337 enolsilane, 478 enone, 173, 323, 482 enophile, 1 enzymatic resolution, 573 episulfone intermediate, 454 epoxidation

Corey−Chaykovsky, 146

606

Jacobsen–Katsuki, 300 Payne, 421 Prilezhaev, 478 Sharpless, 502

epoxide migration, 421 epoxide, 146, 300, 421, 478, 502 549

cis-epoxide, 300 trans-epoxide, 300

2,3-epoxy alcohol, 421 α,β-epoxy esters, 169 α,β-epoxy ketone, 570 α,β-epoxy sulfonylhydrazones, 208 1,2-epoxy-3-ol, 421 α,β-epoxyketones, 208 Erlenmeyer−Plöchl azlactone synthesis, 204 erythreo betaine, 580 erythro (kinetic adduct), Horner–Wadsworth–Emmons reaction, 294 erythro isomer, 527 Eschenmoser hydrazone, 16 Eschenmoser’s salt, 206, 337 Eschenmoser–Claisen amide acetal rear-rangement, 123 Eschenmoser–Tanabe fragmentation, 208 Eschweiler–Clarke reductive alkylation of amines, 210, 330 6π-electrocyclization, 131, 133, 596 ester, 22, 26, 30, 50, 65, 78, 96, 103, 113, 115, 117, 125, 127, 133, 169, 214, 225, 240, 245, 263, 270, 286, 328, 343, 438, 525 esterification, 379, 574, 594 Et3O+BF4

−, 343 Et3SiH, 245 ether formation, 202, 339, 366, 584 ethyl oxalate, 463 ethylammonium nitrate, 316 ethylenediamine diacetate, 315 ethylformate, 458 Evans aldol reaction, 212 Evans syn, 212 evolution of CO2, 167 EWG, 184 exo complex, 419 extrusion of dinitrogen, 162 extrusion of nitrogen, 56, 490 F Favorskii rearrangement, 214

Feist–Bénary furan synthesis, 218 Ferrier carbocyclization, 220 Ferrier glycal allylic rearrangement, 222 Ferrier I reaction, 222 Ferrier II Reaction, 220 Ferrier reaction, 222 Ferrier rearrangement, 222 Fiesselmann thiophene synthesis, 225 Fischer carbene, 198 Fischer indole synthesis, 60, 72, 227 Fischer oxazole synthesis, 229 flavone, 8 flavonol, 6 Fleming–Tamao oxidation, 231 Fleming−Kumada oxidation, 233 fluoride, 288 fluoroarene, 488 fluoro-Meisenheimer complex, 347 fluorous Corey−Kim reaction, 150 fluorous Mukaiyama reagent, 380 formal [2+2+1] cycloaddition, 419 formaldehyde, 210, 330 formamide acetal, 28 formic acid, 210, 330 o-formylphenol, 460 formylation, 64, 253 four-component condensation, 551 four-electron system, 1 four-membered titanium oxide ring in-termediate, 428 fragmentation, 196, 208, 240, 268 Friedel–Crafts acylation reaction, 234 Friedel–Crafts alkylation reaction, 236 Friedel–Crafts reaction, 234 Friedländer quinoline synthesis, 238 Fries rearrangement, 240 ortho-Fries rearrangement, 241 Fries−Finck rearrangement, 240 Fukuyama amine synthesis, 243 Fukuyama reduction, 245 Fukuyama−Mitsunobu procedure, 243 functional group interconversion, 572 functional group migration, 576 furan ring as the masked carbonyl, 464 furan synthesis, 218, 409 fused pyridine ring, 263 G Gabriel amine synthesis, 249 Gabriel synthesis, 171, 246 Gabriel–Colman rearrangement, 250

607

Garner’s aldehyde, 266 Gassman indole synthesis, 251 Gattermann–Koch reaction, 253 Gewald aminothiophene synthesis, 254 Glaser coupling, 257, 299 glycerol, 509 glycidic ester, 169 glycol, 159, 222, 223, 225, 334, 591 glycosidation, 313, 320, 492 β-glycoside, 320 C-glycosidic product, 222 glycosyl acceptor, 313 Gomberg–Bachmann reaction, 262, 450 Gould–Jacobs reaction, 263 green Dakin–West reaction, 168 Grignard reaction, 18, 266 Grignard reagent, 16, 20, 266, 325, 490, 494 Grob fragmentation, 268 Grubbs’ catalyst, 78, 465, 467 Grubbs’ catalyst, intramolecular Buchner rea-ction, 78 Guareschi imide, 270 Guareschi–Thorpe condensation, 270 H [1,5]-H-atom shift, 121 Hajos–Wiechert reaction, 271 halfordinal, 230 Haller–Bauer reaction, 273 N-haloamines, protonated, 292 o-halo-aniline, 373 haloarene, 486 α-halocarbohydrate, 320 α-haloesters, 50, 169, 456 halogen effect, 472 α-halogenation, 282 halogen–lithium exchange, 413 α-haloketones, 171, 218 2-halomethyl cycloalkanones, 200 α-halosulfone, 454 Hantzsch 1,4-dihydropyridines, 274, 275 Hantzsch dihydropyridine synthesis, 274 Hantzsch pyrrole synthesis, 276 head-to-head alignment, 173 head-to-tail alignment, 173 Heck arylation, 574 Heck reaction, 277, 278, 280, 373, 574 Hegedus indole synthesis, 281 Hell–Volhard–Zelinsky reaction, 282 hemiaminal, 474, 515

(+)-hennoxazole, 472 Henry nitroaldol reaction, 284 heteroaryl Heck reaction, 280 heteroaryl recipient, 280 heteroaryllithium, 413 heteroarylsulfones, 309 hetero-Carroll rearrangemen, 96 hetero-Diels–Alder reaction , 56, 187 heterodiene addition, 187 heterodienophile addition, 187, 188 heteropoly acid catalyst, 168 hex-5-enopyranosides, 221 hexacarbonyldicobalt complex, 395, 419 hexacarbonyldicobalt-stabilized proper-gyl cation, 395 hexamethylenetetramine, 171, 172, 515 Hinsberg synthesis of thiophene deriva-tive, 286 Hiyama cross-coupling reaction, 288 Hoch–Campbell aziridine synthesis, 266 Hofmann degradation, 290 Hofmann rearrangement, 290 Hofmann–Löffler–Freytag reaction, 292 homoallylic alcohol, 584 homocoupling, 258, 299, 335, 554 homo-Favorskii rearrangement, 215 homologated carboxylic acid, 588 homolysis, 215 homolytic cleavage, 22, 24, 26, 200, 292, 298, 334, 582, 586 homo-McMurry coupling, 335 homo-Robinson, 470 Horner–Wadsworth–Emmons reaction, 294, 341 Horner−Emmons reaction, 527 Hosomi–Sakurai reaction, 484 Hosomi−Miyaura borylation, 368 Houben–Hoesch synthesis, 296 Huang Minlon modification, 590, 591 Hunsdiecker–Borodin reaction, 298 hydantoin, 76, 102, 497 hydrazine, 72, 102, 227, 249, 317, 334, 570, 590 hydrazoic acid, 490 hydrazone, 16, 60, 208, 227, 302, 570 hydride, 94, 100, 210, 330, 345, 359, 373, 404, 482, 515, 564, 591 β-hydride elimination, 373, 482 hydride shift, 564, 591 hydride source, 210 hydride transfer, 94, 345, 359, 404, 515

608

hydro-allyl addition, 1 o-hydroxyaryl ketones, 8 hydrogen atom abstraction, 24 1,5-hydrogen abstraction, 26 1,5-hydrogen atom transfer, 292 hydrogen donor, 40, 274 hydrogenation, 399, 476 hydrogenolysis, 251 hydrolysis of iminium salt, 271 hydrolysis, 54, 162, 165, 231, 247, 266, 271, 282, 286, 296, 315, 385, 393, 438, 447, 456, 460, 463, 478, 499, 534, 592 hydropalladation, 564 hydroxamic acid, 332 hydroxide-catalyzed rearrangements, 214 ω-hydroxyl-acid, 152 hydroxylamine, 115, 349 N-hydroxyl amines, 135 α-hydroxylation, 478 4-hydroxy-3-carboalkoxyquinoline, 263

-hydroxycarbonyl, 3 2 -hydroxychalcones, 6 5-hydroxylindole, 391 3-hydroxy-isoxazoles, 115 2-hydroxymethylpyridine, 54 β-hydroxy-β-phenylethylamine, 432 4-hydroxyquinoline, 263 β-hydroxysilane, 203, 430 3-hydroxy-2-thiophenecarboxylic acid deri-vatives, 225 hydrozinolysis, 62 hypohalite, 251, 290 I IBX, 179, 397 imide, 102, 270, 444, 474 imine, 58, 102, 107, 131, 490, 521, 546, 551 iminium formationhydrolysis, 315 iminium ion, 315, 330, 440, 442, 519, 534 imino ether, 438 iminochloride, 385 iminophosphorane, 523 indole, 20, 28, 46, 60, 72, 227, 251, 281, 373, 391, 463 indole synthesis, 227, 251, 281, 373, 391, 463 Bartoli, 20 Batcho–Leimgruber, 28

Bischler–Möhlau, 46 Fischer, 227 Gassman, 251 Hegedus, 281 Mori–Ban, 373 Nenitzescu, 391 Reissert, 463 indole-2-carboxylic acid, 463 Ing–Manske procedure, 249 Initiation, radical, 586 inositol, 220 insertion toward CH, 419 insertion, 198, 277, 280, 373, 419, 589 intercomponent interactions, 90 intermolecular addition, 361, 509 intermolecular aldol, 4 intermolecular Bradsher cycloaddition, 66, 67 intermolecular C–H amination, 573 intermolecular C–H oxidation, 572 intermolecular Friedel–Crafts acylation, 234 intermolecular Heck arylation, 280, 574 intermolecular Yamaguchi coupling, 594 internal acetylenes, 353 intramolecular acyl transfer, 424 intramolecular Alder-ene reaction, 1 intramolecular aldol condensation, 470 intramolecular Baylis–Hillman reaction, 31 intramolecular Boger pyridine synthesis, 56 intramolecular Bradsher cyclization, 66 intramolecular Büchner reaction, 78 intramolecular Cannizzaro reaction, 95 intramolecular C–H oxidation, 572 intramolecular condensation, 205 intramolecular cross-coupling, 531 intramolecular cyclization, 413 intramolecular Diels–Alder reaction, 184, 185 intramolecular ene reaction, 110 intramolecular Favorskii Rearrange-ment, 214 intramolecular Friedel–Crafts acylation, 234, 235 intramolecular Heck reaction, 278, 280, 285, 280, 373 intramolecular Horner–Wadsworth–Emmons, 295

609

intramolecular Houben−Hoesch reac-tion, 296 intramolecular mechanism, 304 intramolecular Michael addition, 356 intramolecular Minisci reaction, 362 intramolecular Mitsunobu reaction, 366 intramolecular Mukaiyama aldol reac-tion, 375 intramolecular Nicholas reaction using chromium, 396 intramolecular Nozaki–Hiyama–Kishi reaction, 401 intramolecular nucleophilic aromatic re-arrangement, 511 intramolecular pathway, 440 intramolecular Pauson−Khand reaction, 419 intramolecular Schmidt rearrangement, 491 intramolecular SN2, 169 intramolecular Stetter reaction, 525 intramolecular Suzuki–Miyaura cou-pling, 536 intramolecular Thorpe reaction, 546 intramolecular transamidation, 331 intramolecular Tsuji–Trost reaction, 549 intramolecular Yamaguchi coupling, 594 inverse electronic demand Diels–Alder reaction, 186 cis-trans inversion, 596 inversion of configuration, 548 iododinitrobenzene, 347 iodosobenzene diacetate for Hofmann rear-rangement, 290 O-iodoxybenzoic acid, 179, 397 ionic liquid, 316, 343 ionic liquid-promoted interrupted Feist–Benary reaction, 218

ionic mechanism, 266 ipso attack, 347 ipso substitution, 231, 347 Ireland–Claisen (silyl ketene acetal) rearrangement, 125 iron salt-mediated Polonovski reaction, 441 irreversible fragmentation, 196 C-isocyanide, 415, 551 isocyanate intermediate, 76, 162, 290, 332 isoflavone, 8

isomerization, 229, 353, 421, 470 isoquinoline 1,4-diol, 250 isoquinoline, 48, 250, 432, 434, 444, 461, 462 3-isoxazolol, 115 5-isoxazolol, 115 J Jacobsen–Katsuki epoxidation, 300 Japp–Klingemann hydrazone synthesis, 60, 302 Johnson–Claisen (orthoester) rearrange-ment, 127 Jones oxidation, 304, 305 Julia olefination, 309 Julia–Kocienski olefination, 309, 311 K Kahne glycosidation, 313 Kazmaier–Claisen, 117 ketene, 10, 123, 125, 127, 521, 588 ketene acetal, 123, 125, 127 ketene cycloaddition, 521 N,O-ketene acetals, 123 α-ketocarbene, 588 α-ketocarbene intermediate, 10 keto-enol tautomerization, 96 β-ketoester, 50, 96, 113, 115, 133, 218, 274, 276, 302, 423 2-ketophenols, 240 4-ketophenols, 240 α-keto-phosphonate, 341 ketoximes, 266 ketyl, 65 Kharasch cross-coupling reaction, 325 kinetic product, 16, 294, 494, 527 kinetic resolution, 574 Kishner reduction, 1 Knoevenagel condensation, 254, 255, 315 Knorr pyrazole synthesis, 317, 411 Knorr thiophene synthesis, 328 Koch–Haaf carbonylation, 319 Koenig–Knorr glycosidation, 320 Kostanecki acylation reaction, 322 Kostanecki reaction, 8, 322 Kostanecki−Robinson reaction, 322 Kröhnke pyridine synthesis, 333 Kumada coupling, 288, 325, 529, 536

610

L lactam, 240, 328, 521 β-lactam, 521 lactone, 204, 328, 403, 521

azalactone, 167, 204 β-lactone, 521 lactonization, 532 larger counterion, 309 Lawesson’s reagent, 328, 408 lead tetraacetate for Hofmann rear-rangement, 291 lead tetraacetate, 159 Lebel modification of the Curtius rear-rangement, 164 less-substituted olefin, 494 Leuckart–Wallach reaction, 210, 330, 331 Lewis acid catalyst, 222 Lewis acid, 1, 212, 222, 234, 236, 240, 375, 377, 395, 423, 484, 492 Lewis acid-catalyzed aldol condensa-tion, 375 Lewis acid-catalyzed Michael addition, 377 Lewis basic phenol, 572 LiBr complex, 580 ligand exchange, 80, 476, 548 Lipitor, 411 liquid ammonia, 44 long-lived radical, 26 Lossen rearrangement, 332 low-valent titanium, 335 L-phenylalanine, 271, 272 proline, 143, 271, 337, 338 LTA, 159 M macrolactonization, 152, 573 magnesium metal, 266 magnesium oxide, 202 maleimidyl acetate, 250 manganaoxetane intermediate, 300 Mannich base, 337 Mannich reaction, 206, 337, 426 Martin’s sulfurane dehydrating reagent, 339, 457 Masamune–Roush conditions, 341 masked carbonyl equivalent, 154 McFadyen–Stevens reduction, 334 McMurry coupling, 335 MCR, 42, 76

Me3O+BF4−, 343

Meerwein reagent, 343, 361 Meerwein’s salt, 343 Meerwein–Eschenmoser–Claisen rear-rangement, 123 Meerwein–Ponndorf–Verley reduction, 345, 404 Me-IBX, 397 Meisenheimer complex, 243, 347, 511 [1,2]-Meisenheimer rearrangement, 349 [2,3]-Meisenheimer rearrangement, 350 Meisenheimer−Jackson salt, 347 Meldrum’s acid, 116 4-membered ring transition state, 523 Mes, 465 mesityl, 465 mesyl azide, 458 metal-methylation, 343 methoxycarbonylsulfamoyl-triethylammonium hydroxide inner salt, 84 o-methyl-IBX, 397 methyl triflate, 202 methyl vinyl ketone, 470 methylenated ketones, 206 N-methylation, 344 N-methyliminodiacetic acid, 87 2-methylpyridine N-oxide, 54 Meyers oxazoline method, 351 Meyer–Schuster rearrangement, 353, 480 MgO, 202 Mg-Oppenauer oxidation, 404 Michael addition, 107, 271, 274, 323, 355, 377, 423, 470, 484, 525, see also conjugate addition Michaelis–Arbuzov phosphonate syn-thesis, 357 Michael−Stetter reaction, 525 microwave, 29, 33, 43, 47, 74, 210, 264, 298, 299, 334, 335, 356, 429, 470, 511, 577, 590 microwave Smiles rearrangement, 511 microwave-assisted Gould–Jacobs reac-tion, 264 microwave-assisted, solvent-free

Bischler-indole synthesis, 47 microwave-Hunsdiecker−Borodin, 298 microwave-indued Biginelli condensation, 43 MIDA, 87

611

Midland reduction, 359 migration order, 12, 436 migration, 12, 36, 68, 162, 165, 175, 177, 203, 215, 319, 393, 421, 436, 490, 566, 576 1,3-migration of an aryl group from oxygen to sulfur, 393 migratory insertion, 277 Minisci reaction, 361 Mislow–Evans rearrangement, 363 Mitsunobu reaction, 243, 332, 365, 366 mixed anhydride, 205, 594 mixed orthoester, 127 Miyaura borylation, 368 Mn(III)salen, 300 Mn(III)salen-catalyzed asymmetric ep-oxidation, 300 modified Ireland–Claisen rearrangement, 126 modified Skraup quinoline synthesis, 509 Moffatt oxidation, 370 monooxygenated precursor, 574 more-substituted olefin, 494 Morgan–Walls reaction , 371 Mori–Ban indole synthesis, 373 Morita–Baylis–Hillman reaction, 30 morpholine-polysulfide, 255 MPS, 255 Mukaiyama aldol reaction, 4, 375, 375, 376 Mukaiyama Michael addition, 377 Mukaiyama reagent, 379, 380 multicomponent reactions, 42, 62 MVK, 470 MWI, 43 Myers−Saito cyclization, 382 N-(2,4-dinitrophenyl)pyridinium salt, 596 N naphthol, 72 β-naphthol, 74 β-naphthylamines, 74 Naproxen, 577 Nazarov cyclization, 383 NBS variant of Hofmann rearrangement, 290 NBS, 290, 298, 516, 586, 587 NCS, 100, 150, 151, 292 Neber rearrangement, 385

Nef reaction, 387 Negishi cross-coupling reaction, 325, 389 neighboring group assistance, 447, 492, 592 Nenitzescu indole synthesis, 391 Newman−Kwart reaction, 393 Nicholas reaction, 395 Nicholas-Pauson–Khand sequence, 395 nickel-catalyzed cross-coupling, 325, 389 Nicolaou dehydrogenation, 397 nifedipine, 274 nitrene, 162 nitrile, 2, 34, 50, 98, 254, 296, 438, 468,, 490, 534, 546, 562 nitrile-Alder-ene reaction, 2 nitrilium ion intermediate, 468, 490 nitrite ester, 26 2-nitroalcohol, 284 nitroaldol condensation, 284 nitroalkanes, 284 nitroarenes, 20 nitrobenzene, 371 4-nitrobenzenesulfonyl, 499 nitrogen nucleophile, 572 nitrogen radical cation, 292 nitrogen source, 496 nitronate, 284, 347, 387 nitronic acid, 284, 387 o-nitrophenyl selenide, 505 o-nitrophenyl selenocyanate, 505 nitroso intermediate, 20, 26, 102 o-nitrotoluene derivatives, 28, 463 non-enolizable ketone, 217, 273 nonstabilized ylide, 580 Nos, 499 nosylate, 499 Noyori asymmetric hydrogenation, 399 Nozaki–Hiyama–Kishi reaction, 401 nucleophile, 89, 154, 162, 222, 355, 365, 395, 484, 548, 572, 573 C-nucleophile, 222, see also carbon nu-cleophile O-nucleophile, 222 S-nucleophile, 222 nucleophilic addition, 50, 351, 438, 456, 456 nucleophilic radical, 361 Nysted reagent, 403

612

O octacarbonyl dicobalt, 419 odorless Corey−Kim reaction, 150 olefin, 16, 66, 70, 84, 110, 135, 146, 148, 156, 157, 173, 277, 294, 309, 319, 335, 339, 373, 454, 494, 499, 500, 505, 507, 521, 564, 566, 572, 574, 578, 580

α-olefin, 572, 574 cis-olefin, 294 E-olefin, 300, 309, 311, 580 exo-olefin, 542 trans-olefin, 294 (Z)-olefin, 300, 527, 578, 580

olefin ether, 66 olefin formation, 294, 454, 505 olefin silfide, 66 olefination, 156, 309, 311, 335, 403, 428, 430, 578 olefination of ketones and aldehydes, 403 oleum, 446 one-carbon homologation, 10 , 148 one-pot PCC–Wittig reactions, 306 Oppenauer oxidation, 404, 345 optically pure diethyl tartrate, 502 organic azide, 523 organoborane, 70, 536, 574 organocatalyst, 4, 274 organohalide, 266, 288, 325, 519, 529, 536 organolithium, 325 organomagnesium compounds, 266, 325, see also Grignard reagent organosilicon, 288 organostannane, 529 organozinc, 389, 456 Ormosil-TEMPO, 545 osmium catalyst, 499 osmium-mediated, 496, 499 O-substituted glycal derivatives, 222 O-sulfonylation, 332 Overman rearrangement, 406 oxaphosphetane, 578 oxa-Pictet–Spengler, 434 oxatitanacyclobutane, 542 oxazete intermediate, 105 oxazole, 229, 472, 556 5-oxazolone, 205 oxazoline intermediate, 167 oxa-π-methane rearrangement, 193 oxetane, 417

manganaoxetane, 300 γ-oximino alcohol, 26 oxidation, 70, 107, 194, 572

Baeyer–Villiger, 12 Collins–Sarett, 305 Corey–Kim, 150 Dakin, 165 Dess−Martin, 179 Étard, 129 Fleming–Tamao, 231 Hooker, 196 Jacobsen–Katsuki, 300 Jones, 304 Moffatt, 370 Oppenauer, 404 PCC, 306 PDC, 307 Prilezhaev, 323 Riley, 336 Rubottom, 378 Saegusa, 482 Sarett, 538 Swern, 402 Tamao−Kumada, 233 TEMPO, 544 Wacker, 564

oxidative addition, 80, 90, 98, 245, 277, 280, 288, 325, 368, 373, 389, 401, 456, 476, 507, 519, 529, 531, 536, 548, 554 syn-oxidative elimination, 505 oxidative cyclization, 6, 281 oxidative demetallation, 395 oxidative homo-coupling, 257, 299 N-oxide, 54, 135, 300, 349, 350, 440, 442, 543 oxide-coated titanium surface, 335 oxime, 33, 266, 385 oxirane, 52 oxo-Diels–Alder reaction, 187 4-oxoform, 263 oxonium ion, 313, 320, 343 β-oxo ylide, 580 oxy-Cope rearrangement, 137, 138, 140 oxygen nucleophile, 572 oxygen transfer, 300 oxygenated compound, 572, 573 P P2O5, 432 P4O10, 432 P4–t-Bu, 311

613

Paal thiophene synthesis, 408 Paal–Knorr furan synthesis, 409 Paal–Knorr pyrrole synthesis, 317, 411 palladation, 281, 564 palladium, 80, 98, 277, 288, 325, 368, 389, 476, 482, 519, 529, 531, 536, 548, 564, 572 palladium-catalyzed alkenylation, 277 palladium-catalyzed arylation, 277 palladium-catalyzed oxidation, 564 palladium-promoted reaction

Buchwald–Hartwig amination, 80 Heck, 277 heteroaryl Heck, 280 Hiyama, 288 Kumada, 325 Miyaura borylation, 368 Mori–Ban indole, 373 Negishi, 389 Rosenmund reduction, 476 Saegusa, 482 Sonogashira, 519 Stille, 529 Stille–Kelly, 531 Suzuki–Miyaura, 536 Tsuji–Trost, 548 Wacker, 564

palladium-catalyzed substitution, 548 pancratistatin, 220 paniculide A, 220 paraffin, 134 Parham cyclization, 413, 415 Passerini reaction, 551 Paternò–Büchi reaction, 417 Pauson–Khand reaction, 395, 419, 420 Payne rearrangement, 421 Pb(OAc)4, 159 PCC oxidation, 304, 306 Pd(II) oxidant, 482 Pd(II) reduction to Pd(0), 519 Pd/C catalyst, 245 Pd/Cu-catalyzed cross-coupling, 519 PDC, 304, 307 Pd–H isomerization, 574 Pechmann coumarin synthesis, 423 pentacoordinate silicon intermediate, 68 peracid, 231 pericyclic reaction, 1 periodinane oxidation, 179, 180

Perkin reaction, 424

Petasis boronic acid-Mannich reaction, 426 Petasis reaction, 426 Petasis reagent, 428 Peterson elimination, 203 Peterson olefination, 430 Pfau−Platter azulene synthesis, 78 Pfitzner−Moffatt oxidation, 370 Ph3P, 52, 53, 99, 148, 149, 152, 223, 280, 288, 360, 365, 368, 373, 472, 519, 523, 536, 578 PhCuI, 554 phenanthridine cyclization, 371 β-phenethylamides, 48 phenol esters, 240 phenol, 102, 165, 190, 240, 296, 393, 423, 460, 492, 572 phenolic ether, 296 phenylhydrazine, 227 4-phenylpyridine N-oxide, 300 phenyltetrazolyl, 309 PhNO2, 509 phospha-Michael addition, 355 phosphate ester, 220 phosphazide, 523 phosphazo compound, 523 phosphite, 357 phosphonate synthesis, 357 phosphonate, 294, 341, 357, 527 phosphoric acid, 409 phosphorus oxychloride, 48, 49, 229, 235, 264, 371, 432, 558, 559, phosphorus pentoxide, 432 phosphorus ylide, 578, 580 [2+2]-photochemical cyclization, 173 photochemical decomposition, 292 photochemical rearrangement, 162 photo-Favorskii Rearrangement, 215 photo-Fries rearrangement, 241 photoinduced electrocyclization, 417 photolysis, 26, 192 photo-Reimer–Tiemann reaction without base, 460 photo-Schiemann reaction, 488 phthalimide, 247, 248, 249 Pictet–Gams isoquinoline synthesis, 432 Pictet–Spengler tetrahydroisoquinoline synthesis, 434 pinacol, 436, 574 pinacol rearrangement, 436 (1R)-(+)-α-pinene, 359

614

Pinner reaction, 438 piperidine, 292 pivalic acid, 411 PMB ethers, 202 PMB reagent, 202 PMB-protection, 203 Polonovski reaction, 440, 442 Polonovski–Potier rearrangement, 442 polyene skeleton, 89 polymer-support Hinsberg thiophene synthesis, 287 polymer-supported Mukaiyama reagent, 379 polyphosphoric acid, 34, 66, 332, see also PPA polysubstituted oxetane ring system, 417 Pomeranz–Fritsch reaction, 444, 446 potassium phthalimide, 247 PPA, 34, 66, 132, 134, 163, 164, 235, PPSE, 235 precatalyst, 465, 548 preoxidized material, 572 Prévost trans-dihydroxylation, 447, 592 Prilezhaev epoxidation, 478 primary alcohol, 304, 305, 339 primary amides, 290 primary amine, 171, 178, , 210, 243, 247, 290, 411, 474 primary cycle, 500 primary nitroalkane, 387 primary ozonide, 161 Prins reaction, 448 proline, 143, 271 (S)-(−)-proline, 271 propagation, 586 propargylated product, 395 protic acid, 33, 202, protic solvent, 16, 556 proton transfer, 38, 52, 131, 132, 133, 458 protonated heteroaromatic nucleus, 361 Pschorr cyclization, 450 PT, 309 puckered transition state, 521, 578 Pummerer rearrangement, 452 purine, 102 putative active catalyst, 502 PyPh2P, 244 PYR, 309 pyrazinone, 102 pyrazole, 317, 411

pyrazolone, 317 2-pyridinethione, 152 2-pyridone, 270 pyridinium chlorochromate, 304, see also PCC pyridinium dichromate, 304, see also PDC pyridium, 66 pyridone, 102 pyrimidine, 102 α-pyridinium methyl ketone salts, 323 pyrolysis, 156 pyrrole, 112, 276, 317, 411 pyrrolidine, 292 pyruvic acid, 194 Q quasi-axial bonds, 222 quasi-Favorskii rearrangement, 217 quinaldic acid, 461 quinoline, 92, 131, 133, 194, 196, 238, 263, 394, 461, 509, 510 quinolin-4-ones, 133 quinoline-4-carboxylic acid, 194 R racemization, 227, 273 radical, 22, 24, 26, 40, 44, 65, 129, 192, 200, 257, 262, 266, 292, 300, 335, 361, 382, 417, 450, 540, 544, 546, 560, 582, 586 radical anion, 44, 65, 129, 335 radical cation, 292 radical chain reaction, 586 radical coupling, 262 6-exo-trig radical cyclization, 450 5-exo-trig-ring closure, 182 radical decarboxylation, 22 radical initiating conditions, 586 radical intermediate, 300 radical mechanism, 257, 266, 540, 582 radical reactions

Barton radical decarboxylation, 22 Barton–McCombie, 240 Barton nitrite photolysis, 26 Dowd–Beckwith ring expansion, 200 Gomberg–Bachmann, 262 McFadyen–Stevens reduction, 334 McMurry coupling, 335 TEMPO-mediated oxidation, 544

radical Thorpe−Ziegler reaction, 546

615

radical-based carbon–carbon bond for-mation, 361 radical-mediated ring expansion, 200 Ramberg–Bäcklund reaction, 454 Raney nickel, 251 Ra-Ni, 29, 155 rate-limiting step, 218 Rawal diene, 188

RCM, 465 real catalyst, 465 rearomatization, 196 rearrangement

abnormal Claisen, 121 anionic oxy–Cope, 138 Baker–Venkataraman, 14 Beckmann, 33 Benzilic acid, 36 Boulton–Katritzky, 62 Brook, 68 Carrol, 96 Chapman, 105 Ciamician–Dennsted, 112 Claisen, 117 para-Claisen Cope, 119 Cope, 137 Curtius, 162 Demjanov, 175 Dienone–phenol, 190 Di-π-methane, 192 Eschenmoser–Claisen, 123 Favorskii, 214 Ferrier glycal allylic, 222 Fries, 240 Gabriel–Colman, 250 Hofmann, 290 Ireland–Claisen, 125 Johnson–Claisen, 127 Lossen, 332 [1,2]-Meisenheimer, 349 [2,3]-Meisenheimer, 350 Meyer–Schuster, 353 Mislow–Evans, 363 Neber, 385 Overman, 406 oxy-Cope, 140 Payne, 421 Pinacol, 436 Polonovski–Potier, 442 Pummerer, 452 Rupe, 480 quasi-Favorskii, 217

Schmidt, 490 siloxy-Cope, 141 Smiles, 511 Sommelet–Hauser, 513 Tiffeneau–Demjanov, 177 Truce−Smile, 513 Vinylcyclopropane−cyclopentene, 560 Wagner–Meerwein, 566 [1,2]-Wittig, 582 [2,3]-Wittig, 584 Wolff, 588

(S,S)-reboxetine, 503 Red-Al, 100 redox reaction, 94, 401 reducing agent, 210, 330, 274 reduction

Birch, 44 Bouveault–Blanc, 65 CBS, 143 Chan alkyne, 100 Clemmensen, 129 Fukuyama, 245 ketones, 345 McFadyen–Stevens, 334 Meerwein–Ponndorf–Verley, 345 Midland, 359 Rosenmund, 476 Staudinger, 532 Wolff–Kishner, 590

1,4-reduction, 44 reduction of Pd(OAc)2 to Pd(0) using Ph3P, 373 reductive amination, 58, 330 reductive cyclization, 463 reductive elimination, 58, 80, 90, 98, 102, 156, 245, 277, 288, 325, 330, 368, 389, 419, 476, 519, 529, 531, 536, 548, 564 reductive Heck reaction, 278 reductive methylation, 210 Reformatsky reaction, 456 regeneration of Pd(0), 373 regioisomer, 173, 572 regioselectivity, 52, 496, 572 Regitz diazo synthesis, 458 Reimer–Tiemann reaction, 460 Reissert aldehyde synthesis, 461 Reissert compound from isoquinoline, 462 Reissert compound, 461

616

Reissert indole synthesis, 463 retention of configuration, 231, 548 retro-[1,4]-Brook rearrangement, 69 retro-[2+2] cycloaddition, 542 retro-aldol reaction, 173 retro-benzilic acid rearrangement, 36 retro-Bucherer reaction, 74 retro-Claisen condensation, 60, 113 retro-Cope elimination, 136 retro-Diels−Alder reaction, 56, 185 retro-Henry reaction, 284 reverse Kahne-type glycosylation, 314 reversible conjugate addition, 196 rhodium carbenoid, 78 ring expansion, 200 ring opening, 532, 596 6-oxo-trig ring formation, 322 ring-closing metathesis, 465 trisubstituted phosphine, 365 Ritter intermediate, 490 Ritter reaction, 468 Robinson annulation, 271, 470 Robinson–Gabriel synthesis, 472 Robinson–Schöpf reaction, 474 room temperature Buchwald–Hartwig amination, 81 Rosenmund reduction, 476 Rosenmund–von Braun synthesis of aryl nitrile, 98 rotation, 277, 430 rotaxane, 90 Rubottom oxidation, 478 Rupe rearrangement, 353, 480 ruthenium(II) BINAP-complex, 399 S Saegusa enone synthesis, 482 Saegusa oxidation, 397, 482 safe surrogate for cyanide, 525 Sakurai allylation reaction, 484 Sandmeyer reaction, 486 Sanger’s reagent, 347 saponification, 263 Sarett oxidation, 304, 305 Saucy–Claisen, 117 Schiemann reaction, 488 Schiff base, 133 Schlittler–Müller modification, 446 Schlosser modification of the Wittig reaction, 580 Schmidt rearrangement, 490

Schmidt’s trichloroacetimidate glycosi-dation reaction, 492 Schmittel cyclization, 382 Schönberg rearrangement, 393 Schrock’s catalyst, 465 secondary alcohol, 179, 304, 339, 404 secondary amine, 210, 243 secondary cycle, 500 secondary nitroalkane, 387 secondary ozonide, 161 secondary α-acetylenic alcohol, 353 seleno-Mislow-Evans, 363 semi-benzylic mechanism, 217 SET, 18, 44, 65, 129, 155, 266, 311, 554, 335, 397, 554 Shapiro reaction, 16, 494 Sharpless asymmetric amino hydroxyla-tion, 496 Sharpless asymmetric dihydroxylation, 499 Sharpless asymmetric epoxidation , 502 Sharpless olefin synthesis, 505 1,3-shift, 353 Shioiri–Ninomiya–Yamada modification of Curtius rearrangement, 163 SIBX, 397 [1,2]-sigmatropic rearrangement, 349 [2,3]-sigmatropic rearranegment, 20, 251, 350, 363, 584 [3,3]-sigmatropic rearranegment, 60, 72, 96, 117, 119, 121, 123, 125, 127, 137, 138, 140, 141, 227, 406 sila-Stetter reaction, 525 sila-Wittig reaction, 430 silicon cleavage, 484 β-silicon effect, 484 siloxane, 102 α-silyloxy carbanions, 68 siloxy-Cope rearrangement, 141 silver carboxylate, 298 silver salt, 320 silver-catalyzed oxidative decarboxyla-tion, 361 silyation, 332 α-silyl carbanion, 430 silyl enol ether, 375, 377, 397 α-silyl oxyanions, 68 [1,2]-silyl migration, 68 β-silylalkoxide intermediate Simmons–Smith reaction , 507 Simmons−Smith reagent, 507

617

single electron transfer, 18, 44, 65, 129, 155, 266, 311, 554, 335, see also SET single-electron process, 335 singlet diradical, 417 six-membered α,β-unsaturated ketone, 470 Skraup quinoline synthesis, 196, 509 Skraup type, 263 SMEAH, 100 SmI2-mediated Reformatsky reaction, 457 Smile reaction, 393 Smiles rearrangement, 511, 513 SN1, 313 SN2 inversion, 365 SN2 reaction, 52, 129, 148, 179, 229, 247, 249, 240, 292, 357, 363, 365, 578, 592 SNAr, 243, 347, 379 sodium amalgam, 311 sodium bis(2-methoxyethoxy)aluminum hydride, 100 sodium bisulfite, 72 sodium cyanide, 534 sodium hypochlorite for Hofmann rear-rangement, 291 sodium tert-butoxide, 80 sodium, 65 solid-phase Cope elimination, 135 soluble cyanide source, 534 solvent-free Claisen condensation, 114 solvent-free Dakin oxidation, 165 Sommelet reaction, 171, 515 Sommelet–Hauser rearrangement, 251, 517, 584 Sonogashira reaction, 98, 519 (−)-sparteine, 213, 351 spirocyclic anion intermediate, 511 stabilized IBX, 397 stable nitroxyl radical, 544 stannane, 20, 102, 529, 531 statin side chain, 50 Staudinger ketene cycloaddition, 521 Staudinger reduction, 523 step-wise mechanism, 588 stereoselective conversion, 540 stereoselective oxidation, 231 stereoselective reduction, 100 stereoselectivity, 572 steric hindrance, 594 sterically-favored isomer, 419

Stetter reaction, 38, 525 Stille coupling, 529 Stille–Kelly reaction, 531 Still–Gennari phosphonate reaction, 527 Still−Wittig rearrangement, 584 Stobbe condensation and cyclization, 532 Stobbe condensation, 532 stoichiometric copper, 519 stoichiometric Pd(II), 281 Strecker amino acid synthesis, 534 strong acid, 319, 468, 598 styrenylpinacol boronic ester, 574 substituted hydrazine, 317 7-substituted indoles, 20 5-substituted oxazole, 556 2-substituted-quinolin-4-ol, 92 4-substituted-quinolin-2-ol, 92 substitution reactions, 351 succinimidyl radical, 586 sulfenamide, 576 sulfinate, 102 sulfonamides, 102 sulfone reduction, 309 sulfone, 30, 309, 311, 454 sulfonium ion, 251 sulfonyl azide, 458 sulfoxide activation, 313 sulfoxide, 313, 363, 452 sulfoximines, 102 sulfur ylide, 146, 538 sulfurane dehydrating reagent, 339, 340, 457 sulfur-containing heterocyclic ring, 576 sulfuric acid, 304 Suzuki, 298 Suzuki–Miyaura coupling, 102, 536 Swern oxidation, 150, 538 switchable molecular shuttles, 90 syn/anti, 377 syn-addition, 70 synchronized fashion, 515 T Takai reaction, 540 Tamao−Kumada oxidation, 233 d3-tamoxifen, 210 tautomerization, 74, 121, 133, 140, 167, 198, 227, 274, 353, 383, 408, 490, 509, 525, 570 TBABB, 377

618

TBAO, 239 TBTBTFP, 309 TDS, 141, 180 Tebbe olefination, 428, 542 Tebbe’s reagent, 428 TEMPO oxidation, 544 terminal acetylenic group, 353 terminal alkyne, 148, 299, 257, 519 tertiary alcohol, 84, 339, 490 tertiary amine, 30, 206, 349, 350, 562 tertiary amine N-oxide, 349 tertiary carbocation, 319 tertiary carboxylic acid formation, 319 tertiary N-oxide, 440, 442 tertiary phosphine, 523 tertiary α-acetylenic (terminal) alcohol, 480 tertiary α-acetylenic alcohols, 353 tetrahydrocarbazole, 60 tetrahydroisoquinoline, 434 tetramethyl pentahydropyridine oxide, 544 tetra-n-butylammonium bibenzoate, 377 1,1,3,3-tetramethylguanidine, 95 2,2,6,6-tetramethylpiperi-dinyloxy, 544 tetrazole, 309 Tf2O, 313, 314, 379 TFA, 14, 54, 287, 292, 354, 362, 375, 391, 415, 445, 507, 566 TFAA, 54, 262, 443 thermal aliphatic Claisen rearrangement, 16 thermal aryl rearrangement, 105 thermal Bamford–Stevens, 17 thermal decomposition, 292 thermal elimination, 110, 135 thermal rearrangement, 96, 162 thermal-catalyzed condensation, 133 thermal-mediated rearrangement, 332 thermodynamic adduct, 294 thermodynamic product, 16, 494 thermodynamic sink, 140 thermodynamically favored, 319 thermolysis, 62 thexyldimethylsilyl, 141, 180 thia-Fries rearrangement, 241 thia-Michael addition, 355 thiazolium catalyst, 525 thiazolium salt, 38 thiirane, 146 3-thioalkoxyindoles, 251

thioamide, 576 thiocarbonyl derivatives, 24, 328, 408 1,1 -thiocarbonyldiimidazole, 156 thioglycolic acid derivatives, 225 thiol, 102, 245 thiophene, 17, 225, 254, 286, 287, 328, 329, 408 thiophene from dione, 328 thiophene synthesis, 225, 408 thiophene-2,5-dicarbonyls, 286 thiophenol, 393 Thorpe−Ziegler reaction, 546 three-component aminomethylation, 337 three-component condensation, 415 three-component coupling, 194, 426, 574 threo (thermodynamic adduct), Horner–Wadsworth–Emmons reaction, 294 threo betaine, 580 Ti(0), 335 Ti=O, 542 TiCl3/LiAlH4, 335 Tiffeneau–Demjanov rearrangement, 177 titanium tetra-iso-propoxide, 502 TMG, 95 TMSO-P(OEt)2, 358 p-tolylsulfonylmethyl isocyanide, 556 tosyl amide, 458 tosyl ketoxime, 385 trans-β-dimethylamino-2-nitrostyrene, 28 transannular aldol reaction, 4 transition state, 1, 309, 345, 404, 478, 503, 521, 523, 578, transmetallation, 102, 288, 325, 368, 389, 401, 519, 529, 531, 536, 536 trapping molecule, 90 Traxler–Zimmerman trasition state, 193 triacetoxyperiodinane, 179 trialkyl orthoacetate, 127 trialkyloxonium salts, 343 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, 179 1,2,4-triazine, 56 triazole intermediate, 458 trichloroacetimidate intermediate, 406, 492 2,4,6-trichlorobenzoyl chloride, 594 trichloroisocyanuric/TEMPO oxidation, 545

619

triethyloxonium tetrafluoroborate, 343 triflate, 202, 288, 325, 389, 529, 536, 572 trifluoroacetic anhydride, 54, 442, see also TFAA trifluorotoluene, 202 1,3,3-trimethyl-6-azabicyclo[3.2.1]-octane, 239 trimethyloxonium tetrafluoroborate, 343 trimethylphosphite, 156 trimethylsilyl chloride, 125 trimethylsilyl polyphosphate, 235 tri-O-acetyl-D-glucal, 222 1, 1,2,3-trioxolane, 161 2,4-trioxolane, 161 triphenylphosphine, 365, see also Ph3P triplet diradical, 417 n, π* triplet, 417 tropinone, 474 Truce−Smile rearrangement, 513 Tsuji–Trost allylation, 548 Two sequential Stobbe condensations, 532 U Ugi reaction, 415, 551 UHP, 12, 165 Ullmann coupling, 554 umpolung, 154 11-undecenoic acid, 574 α,β-unsaturation of aldehydes, 397 α,β-unsaturation of ketones, 397 α,β-unsaturated aldehyde, 480 γ,δ-unsaturated amides, 123 α,β-unsaturated carbonyl compounds, 353 γ,δ-unsaturated carboxylic acids, 125 α,β-unsaturated ester, 525 γ,δ-unsaturated ester, 127 2,3-unsaturated glycosyl derivatives, 222 5,6-unsaturated hexopyranose deriva-tives, 220 α,β-unsaturated ketone, 323, 480, 525 γ-unsaturated ketones, 96 α,β-unsaturated system, 355, 377, 484 urea, 12, 42, 102, 162, 165, 332, 370 urea-hydrogen peroxide complex, 12, 165

V van Leusen oxazole synthesis, 556 van Leusen reagent, 556 varenicine, 211 vicinal diol, 159, 436 Vilsmeier–Haack reaction, 558, 558 Vinyl azide, 162 vinyl boronic acid, 426 vinyl Grignard, 20 vinyl halide, 401 E-vinyl iodide, 540 vinyl ketones, 30, 470 vinyl sulfones, 30 N,O-vinylation, 102 vinylcyclopropane, 192, 560 vinylcyclopropane−cyclopentene rearrangement, 560 vinylic alkoxy pentacarbonyl chromium carbene, 198 vinylic C–H arylation, 574 vinylogous Mukaiyama aldol reaction, 375 2-cis-vitamin A acid, 578 von Braun degradation, 562 von Braun reaction, 562 W Wacker oxidation, 281, 482, 564 Wagner–Meerwein rearrangement, 566 Wagner–Meerwein shift, 331 Weinstock variant of the Curtius rear-rangement, 163 Weiss–Cook reaction, 568 Wharton reaction, 570 White reagent, 572 Willgerodt–Kindler reaction, 576 Wittig reaction, 148, 294, 306, 430, 578, 580 Wittig reagent, 403 [1,2]-Wittig rearrangement, 582 [2,3]-Wittig rearrangement, 517, 584 Wohl–Ziegler reaction, 586 Wolff rearrangement, 40, 588 Wolff–Kishner reduction, 590 Woodward cis-dihydroxylation, 447, 592

X xanthate, 110 Xphos, 82, 83, 89, 369

620

Y Yamaguchi esterification, 594, 595 Yamaguchi reagent, 594, 595 ylidene-sulfur adduct, 254, 255 Z Zimmerman rearrangement, 192 zinc amalgam, 129 zinc-carbenoid, 129 zinc chloride, 371 zinc reagent, 389, 403, 456 Zincke anhydride, 598 Zincke reaction, 596 Zincke salt, 596, 598 Zn(Cu), 507 zwitterionic peroxide, 161

621

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