Modern Alkyne Chemistry: Catalytic and Atom-Economic Transformations

Modern Alkyne ChemistryModern Alkyne Chemistry
Hashmi, A.S., Toste, F.D. (eds.)
Modern Gold Catalyzed
Rios Torres, R. (ed.)
Behr, A., Neubert, P.
Nugent, T.C. (ed.)
Applications
2010
Edited by
Modern Alkyne Chemistry
Stanford University
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1.1 History of Alkynes 1
1.2 Structure and Properties of Alkynes 2
1.3 Classical Reactions of Alkynes 2
1.4 Modern Reactions 4
2 Redox Isomerization of Propargyl Alcohols to Enones 11
Barry M. Trost
2.1 Introduction 11
Processes 27
3.1 Introduction and Reactivity Principles 27
3.1.1 The Reactivity of Carbophilic Lewis Acids in the Presence of Enyne
Substrates 27
Nucleophiles 28
VI Contents
Conia-Ene Reaction and Related Transformations 32
3.2.3 Formation of Bicyclic Derivatives 37
3.2.3.1 Formation of Bicyclopropanes 37
3.2.3.2 Formation of Bicyclobutenes 41
3.2.3.3 Formation of Larger Rings via Cycloisomerization-
Rearrangements 42
3.3.1 Domino Enyne Cycloisomerization–Nucleophile Addition
Reactions 44
3.3.1.2 Carbon Nucleophiles 54
Alois Fürstner
4.3 State-of-the-Art Catalysts 75
4.5 Selected Applications 85
4.5.7 Neurymenolide A 91
4.5.11 Lactimidomycin 96
4.5.12 Citreofuran 97
4.5.13 Polycavernoside 98
4.6 Conclusions 102
5 Alkyne–Azide Reactions 115
Sanne Schoffelen andMortenMeldal
5.1 Introduction 115
5.4 The Substrates for CuAAC 121
5.5 The Environment 124
5.7 The Catalyst 126
5.7.1 Recent Ligands and their Influence on Cu(1) Catalysis 126
5.7.2 Catalyst Structure–Activity Relationship 128
5.7.3 In Situ Generated CuAAC: Electro-, Photo-, and Self-Induced
“Click” 130
5.9 CuAAC in Biological Applications 132
5.10 Biocompatibility of the CuAAC Reaction 133
References 137
Fiona R. Truscott, Giovanni Maestri, Raphael Rodriguez, andMaxMalacria
6.3 (3 + 2) and (2 + 1) Cycloaddition 145
6.4 (4 + 2) Cycloaddition 146
6.5 (5 + 1) and (4 + 1) Cycloadditions 149
6.8 (2 + 2 + 1) Cycloaddition 153
6.9 (2 + 2 + 2) Cycloaddition 155
6.10 (3 + 2 + 1) Cycloaddition 158
6.11 (3 + 2 + 2) Cycloaddition 159
6.12 (4 + 2 + 1) and (4 + 2 + 2) Cycloaddition 160
6.13 (4 + 3 + 2) Cycloaddition 163
6.14 (5 + 2 + 1) and (5 + 1 + 2 + 1) Cycloadditions 163
6.15 (2 + 2 + 1 + 1) and (2 + 2 + 2 + 1) Cycloadditions 164
6.16 (2 + 2 + 2 + 2) Cycloaddition 165
6.17 Conclusions 166
7 Catalytic Conjugate Additions of Alkynes 173
Naoya Kumagai andMasakatsu Shibasaki
VIII Contents
7.2.1.1 Conjugate Addition of Metal Alkynylides to s-cis α,β-Enones 173
7.2.1.2 Conjugate Addition of Metal Alkynylides with a Catalytic
Promoter 176
Promoters 177
7.2.2.1 Use of a Stoichiometric Amount of Chiral Sources 178
7.2.2.2 Catalytic Enantioselective Conjugate Addition of Metal
Alkynylides 180
7.3.1.1 Introduction 182
7.3.1.3 Addition to β-Substituted α,β-Enones 184
7.3.2 Enantioselective Direct Catalytic Conjugate Addition of Terminal
Alkynes 188
References 196
Carbonyls 201
Nucleophiles 203
8.2.2 Oxidative Insertion and Ligand Exchange: Formal Metallation of
Terminal Alkynes 205
of Metal 207
Imines 207
8.4 Alkyne Additions with Catalytic Amounts of Metal 222
8.4.1 Asymmetric Alkyne Additions to Aldehydes and Ketones Catalyzed
by Zinc Salts 222
8.4.3 Chromium-Catalyzed Alkynylation of Aldehydes with
Haloacetylenes 225
Ketones 227
Trifluoropyruvate 229
Contents IX
Aldehydes 230
8.5 Concluding Remarks 232
9 Catalytic Nucleophilic Addition of Alkynes to Imines: The A3
(Aldehyde–Alkyne–Amine) Coupling 239
Nick Uhlig, Woo-Jin Yoo, Liang Zhao, and Chao-Jun Li
9.1 A3 Couplings Involving Primary Amines 239
9.2 A3 Couplings Involving Secondary Amines 242
9.3 Alkyne Additions with Reusable Catalysts 244
9.4 Asymmetric Alkyne Addition Reactions 246
9.4.1 Asymmetric A3-Type Couplings with Primary Amines 246
9.4.2 Asymmetric A3-Type Couplings with Secondary Amines 250
9.5 Alkyne Additions to Imines in Tandem Reactions 251
9.5.1 A3 Coupling with Tandem Cycloisomerizations Involving the Alkyne
Triple Bond 252
Triple Bond 257
9.5.3 Tandem Processes Involving Decarboxylations 259
9.5.4 Tandem Processes Involving Both the Amine and the Alkyne 260
9.6 Conclusion 262
10.2.1 Unsupported Palladium–Phosphorous Catalysts 270
10.2.1.1 Copper-Cocatalyzed Reactions 270
10.2.1.2 Copper-Free Reactions 273
10.3.1 Unsupported Palladium–Nitrogen Catalysts 276
10.3.2 Supported Palladium–Nitrogen Catalysts 277
10.4 N-Heterocyclic Carbene (NHC)-Palladium Catalysts 278
10.4.1 Unsupported NHC-Palladium Catalysts 278
10.4.2 Supported NHC-Palladium Catalysts 279
10.5 Palladacycles as Catalysts 280
10.5.1 Unsupported Palladacycles as Catalysts 280
10.5.2 Supported Palladacycles as Catalysts 281
10.6 Ligand-Free Palladium Salts as Catalysts 282
X Contents
10.7 Palladium Nanoparticles as Catalysts 283
10.7.1 Unimmobilized Palladium Nanoparticles as Catalysts 283
10.7.2 Immobilized Palladium Nanoparticles as Catalysts 284
10.8 Non-Palladium-Based Catalysts 287
10.9 Mechanistic Considerations 289
References 291
11 Catalytic Dimerization of Alkynes 301
Sergio E. Garca-Garrido
Osmium Complexes 302
11.2.2 Cross-Dimerization of Alkynes 310
11.3 Dimerization of Alkynes Catalyzed by Cobalt, Rhodium, and Iridium
Complexes 311
11.4 Dimerization of Alkynes Catalyzed by Nickel, Palladium, and
Platinum Complexes 317
11.5 Dimerization of Alkynes Catalyzed by Group 3, Lanthanide, and
Actinide Complexes 322
Hafnium Complexes 325
11.8 Summary and Conclusions 327
Acknowledgments 327
References 328
Synthesis and Applications of Conjugated 1,3-Diynes 335
Jean-Philip Lumb
12.3 Scope and Limitation of the Alkyne Dimerization Reaction 338
12.3.1 Choice of Copper Salt 338
Contents XI
12.3.3 Substituents on the Alkyne and Basic Additives 339
12.3.4 Additional Metals 340
Reactions 340
12.7 Alternative Methods for the Synthesis of Diynes 344
12.8 Mechanism of Alkyne Homo-Coupling Reactions 344
12.9 Mechanism of Alkyne Hetero-Coupling Reactions 347
12.10 Utility of 1,3-Diynes in the Synthesis of Natural Products 349
12.11 Synthetic Utility of Conjugated 1,3-Diynes 351
12.12 Utility of 1,3-Diynes in Materials Science 355
12.13 Conclusion 359
13.4.1 Galacto-Sugar γ-Lactones 371
13.4.2 Galacto-Sugar δ-Lactones 371
13.4.3 (-)–Apicularen A 371
13.4.4 Milbemycin β3 373
13.4.6 Tricolozin A 374
13.4.7 Elenic Acid 376
(ent)-Cladospolide D 379
13.4.14 Cephalosporolide H 387
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Alkyne is a basic functionality with “relatively low thermodynamic reactivities”
in the classical text of organic chemistry. These classical alkyne reactions often
require stoichiometric reagents, which result in low efficiency in chemical
syntheses, and “harsh” reaction conditions that cannot tolerate the presence
of the various “more reactive functional groups”. The pursuit of synthetic
efficiency combined with the recent emphasis of “future sustainability and Green
Chemistry,” and the pressing desire for new chemical tools in synthetic biology
inspire chemists to uncover new reactions that are catalytic in nature (rather than
consuming stoichiometric reagents), occur under ambient conditions (including
milder temperature and aqueous media), can tolerate various functional groups,
and render “dial-up” reactivity when needed. Alkynes provide the most ideal can-
didate for such features. While being relatively inert under “classical” conditions,
alkynes can be readily “activated” selectively, in the presence of other functional
groups and under mild conditions, via transition-metal catalysis through either
selective alkyne carbon-carbon triple bond reactions or terminal alkyne C-H
bond reactions. Such a unique reactivity allow alkynes to be embedded and
be “dialed-up” whenever needed. For the past few decades, modern alkyne
chemistry has thus been developed rapidly to feature these characteristics. These
developments further focus on atom-economic transformations where minimal
or no theoretical by-products are formed. Furthermore, many of these catalytic
transformations are orthogonal to biological conditions. These modern catalytic
alkyne reactions are much more resource-, time-, and manpower-efficient, and
provide an alternative to classical stoichiometric alkyne chemistry. This book
comprises a collection of contributions from leading experts and covers various
modern catalytic reactions of alkynes. We hope that this focused book will be
very helpful not only to students and researchers in chemistry but also to those in
material and biological studies and will provide themwith tools and opportunities
unavailable with classical alkyne chemistry.
Stanford Barry M. Trost
1.1
History of Alkynes
Alkyne is one of the fundamental functional groups that established the foun-
dation of organic chemistry [1]. The smallest member of this family, acetylene,
was first discovered in 1836 by Edmund Davy [2]. It was rediscovered and
named “acetylene” by Marcellin Berthelot in 1860 by passing vapors of organic
compounds through a red-hot tube or sparking electricity through a mixture
of cyanogen and hydrogen gas. Acetylene is a moderately common chemical
in the universe [3], often in the atmosphere of gas giants. In 1862, Friedrich
Wöhler discovered the generation of acetylene from the hydrolysis of calcium
carbide (Equation 1.1). Acetylene produced by this reaction was the main source
of organic chemicals in the coal-based chemical industry era. When petroleum
replaced coal as the chief source of carbon in the 1950s, partial combustion of
methane (Equation 1.2) or formation as a side product of hydrocarbon cracking
became the prevalent industrial manufacturing processes for acetylene. The
next member of the family, propyne, is also mainly prepared by the thermal
cracking of hydrocarbons. The first naturally occurring acetylic compound,
dehydromatricaria ester (1), was isolated in 1826 [4] from an Artemisia species.
Well over 1000 alkyne-containing natural products have been isolated since
then, among which many are polyyne-containing natural products isolated from
plants, fungi, bacteria, marine sponges, and corals [5].
CaC2 + H2O HH + Ca(OH)2 (1.1)
2CH4 + (3/2)O2 HH + 3H2O (1.2)
OH3CO
CH3
Dehydromatricaria ester (1)
Modern Alkyne Chemistry: Catalytic and Atom-Economic Transformations, First Edition. Edited by Barry M. Trost and Chao-Jun Li. © 2015 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2015 by Wiley-VCH Verlag GmbH & Co. KGaA.
2 1 Introduction
Thehighermembers of alkynes are generally derived from the smaller homologs
via alkyne homologation processes of the terminal alkynes (see Equation 1.8,
below), while some alkynes are generated through elimination reactions with
organic halides under basic conditions (Equation 1.3) [1]. A search in Sci Finder
shows that >70 000 terminal alkynes and >10 000 internal alkynes are now
commercially available from various sources.
R R′
Structure and Properties of Alkynes
Alkynes contain a tripe bond, composed of aσ-covalent bond formed from two sp-
hybridized carbons and two π-bonds resulted from the overlapping of two orthog-
onal unhybridized p-orbitals on each carbon (2) [1]. Consequently, alkynes are generally rod-like. Cyclic alkynes are less common with benzyne as an important
reactive intermediate in organic chemistry [6]. Acetylene is linear and intrinsically
unstable under pressure due to its high compressibility as well as its propensity
to undergo exothermic self addition reactions. Consequently, acetylene itself can
explode violently at high pressure and the safe limit for acetylene is 103 kPa.Thus,
acetylene is generally shipped in acetone or dimethyl formamide (DMF) solutions
or contained in a gas cylinder with porous filling [7]. Acetylene has been used as
a burning fuel and for illumination purposes in the late nineteenth century and
early twentieth century [8]. In modern times, alkynes have found a wide range
of applications ranging from organic electronic materials, metal-organic frame
works (MOF), pharmaceutical agents, and others [9]. The linearity of the alkyne
creates strain when an alkyne is part of a ring [10]. In spite of this fact, cyclopen-
tyne, cyclohexyne, and cycloheptyne can be generated at least fleetingly, their
existence being confirmed by in situ trapping, notably by 1,3-dipolar cycload-
ditions [11]. Cyclooctyne is still highly strained but has sufficient stability to be
isolated and used in click chemistry to study biological processes [12].
R R′
Classical Reactions of Alkynes
The higher degree of unsaturation of alkynes compared to alkenes increases their
reactivity toward addition to both alkenes and alkynes. In particular, virtually
all additions of HX and RX to alkynes are exothermic. Consequently, these
1.3 Classical Reactions of Alkynes 3
stoichiometric addition reactions have been the basis of most reactions in the
classical alkyne chemistry (Equation 1.4) [1]. These classical alkyne addition
reactions include the additions of hydrogen, halogens, water, hydrogen halides,
halohydrins, hydroborations, and others. With a stoichiometric amount of a
strong oxidizing reagent such as KMnO4, the addition may be followed by C–C
cleavage to give the corresponding acids (Equation 1.5). Less reactive reagents
can also be added through the use of a transition-metal catalyst. The unique
electronic character of alkynes wherein their HOMO–LUMO gap is rather small
makes them especially effective as coordinators to transition metals. Thus, they
function as chemoselective functional groups for catalytic transformations. For
example, catalytic addition of dihydrogen to alkynes can proceed to either alkenes
or alkanes depending on the choice of the catalysts (Equation 1.6) [13]. Further,
the hydroalumination [14], hydrosilylation [15], hydrostannylation [16], as well
as carboalumination [17] represent important modern advances of the alkyne
addition reactions.
(1.4)
cat. M R-CH2CH2-R (1.6)
A second class of reactions pertains to terminal alkynes. Due to the increased
s-character, the alkynyl C–Hbonds (pK a = 25) aremuchmore acidic than the cor-
responding alkenyl C–H bonds (pKa = 43) and alkyl C–H bonds (pK a > 50) [18].
Thus, base-promoted additions of terminal alkynes to carbonyl compounds can
occur under different basic conditions, a process discovered over a century ago
(Equation 1.7). Treatment of terminal alkynes with bases such as lithium amide,
butyllithium, or Grignard or zinc reagents generatesmetal acetylides stoichiomet-
rically, which can then react with different carbon-based electrophiles to produce
various higher alkyne homologs in the classical synthetic chemistry (Equation 1.8)
[1]. Such processes can be catalyzed to permit deprotonation with much weaker
bases as in the coupling with aryl halides under Pd/Cu catalysis (Sonogashira reac-
tion, see Equation 1.13).
R H + R′ R′′
tions, and homologation reactions have established the foundation of alkyne
chemistry, a rebirth of interest derives from recent concerns regarding societal
and ecological sustainability under the mantra of Green Chemistry [19], which
emphasizes chemical transformations that are more atom economic [20] and
chemoselective, thereby minimizing the use of protecting groups [21]. Further-
more, rapid developments in the field of chemical biology demand chemical
transformations that are orthogonal to biological conditions and functionalities
in bioorganisms and which can work efficiently under both in vitro and in vivo
biological conditions [22]. Alkynes, being both good π-donors and π-acceptors for transition metals as well as being energy rich, can be effectively activated
by a catalyst thereby lowering the energy barrier to proceed to the more stable
products while being unreactive toward various biological elements. At the same
time, they can be chemoselectively activated in the presence of most typical
functional groups (e.g., hydroxyl and carbonyl groups as well as alkenes) and in
protic solvents including water [23]. Such triggered reactivities are orthogonal
to the classical reactivities and can be tuned to target specific desired reaction
sites while maintaining tolerance toward other functionalities through the
discrete choice of catalyst, which will greatly simplify the syntheses of complex
compounds and allow direct modifications of biomolecules in their native states
and ambient environment. Modern developments, in view of atom economy,
can be represented by three major classes: (i) catalytic cyclization reactions, (ii)
catalytic homologations of terminal alkynes, and (iii) catalytic isomerization
reactions of alkyne.
Although alkyne oligomerization was known at a high temperature since the
late nineteenth century [2], various cyclization reactions of alkynes catalyzed by
transition metals are among the most important developments in modern alkyne
chemistry.Themost well-known examples include the transition-metal-catalyzed
[2 + 2 + 2] cycloaddition reactions (Equation 1.9) [24], the Pauson–Khand-type
reaction of alkyne–alkene–carbon monoxide (Equation 1.10) [25], the enyne
cyclization reactions (Equation 1.11) [26], and the 1,3-dipolar cycloaddition such
as that with azides (the archetypical Click reaction) (Equation 1.12) [27].
+ cat.
(1.9)
+ + CO
cat.
O
(1.10)
(1.12)
The second major class of modern alkyne reactions is the catalytic transfor-
mation of terminal alkyne C–H bonds. Although homologation of terminal
alkynes through the reactions of metal acetylides with organic halide is a classical
alkyne reaction, such a reaction cannot be applied to aryl and vinyl halides due
to their inert nature in nucleophilic substitution reactions. The development of
catalytic coupling of terminal alkynes with aryl and vinyl halides (the Sonogashira
reaction) has overcome this classical challenge and opened up a new reactivity
mode in alkyne homologation (Equation 1.13) [28]. Complimentary to the
classical Favorskii reaction (Equation 1.7), the modern development of catalytic
direct addition of terminal alkynes to aldehydes provides great opportunities in
generating optically active propargyl alcohols (Equation 1.14) [29]. The catalytic
direct additions of terminal alkynes to imines (and derivatives) (Equation 1.15)
[30] and conjugate addition to unsaturated carbonyl compounds (Equation 1.16)
[31] represent other major achievements in modern alkyne reactions. On the
other hand, the catalytic oxidative dimerization (Glaser–Hay coupling) [32] and
simple alkyne dimerization (Equation 1.17) [33] which date from the late 1800s
have become increasingly important in modern synthetic chemistry.
R X Ar+ R Ar cat.
−HX (1.13)
Two additional processes that have much unrealized potential in synthetic
chemistry are the alkyne disproportionation (metathesis) and the alkyne redox
isomerization reactions. Like the alkene metathesis, the catalytic alkyne–alkyne
metathesis reaction retains all functionalities by switching the groups attached
to the alkynes (Equation 1.18) [34]. Another unique atom-economic reaction
of alkynes that is currently under-utilized but will have a great potential for
future development is the “alkyne-zipper reaction” (Equation 1.19) [35]. Such
reactions shift readily accessible internal alkyne triple bond to terminal positions
for further homologations. A different type of “retaining functionality is found in
the redox isomerization of propargyl alcohols to generate conjugated ketones”
(Equation 1.20) [36].
(1.18)
R
O
(1.20)
1.5
Conclusion
With the recent emphasis on sustainability and the ever increasing needs in syn-
thetic efficiency, alkynes provide a truly unique functionality that is orthogonal to
other functional groups, biological conditions, and ambient environment, yet can
be selectively triggered to occur in a specific reaction mode with the absence of
protecting groups or anhydrous conditions. Such reactions will have great poten-
tial to simplify synthetic chemistry and will find wide applications in chemical
biology and organic materials. This book, comprising experts on related subjects,
provides an overview of developments of modern alkyne reactions. Due to the
limit of space, many other important developments in modern alkyne chemistry
References 7
such as various catalytic conversions of alkyne triple bonds [37] and alkyne poly-
merizations [38] have not been covered in this book.
References
Chemistry-A Biological Approach,
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Organic Chemistry, 5th edn, Pearson
Education, Upper Saddle River, NJ;
(d) Solomons, T.W.G. and Fryhle, C.B.
(2011) Organic Chemistry, 10th edn,
John Wiley & Sons, Inc., New York;
(e) Vollhardt, K.P.C. and Schore, N.E.
(2009) Organic Chemistry, 6th edn, W.H.
Freeman & Company; (f ) Fox, M.A. and
Whitesell, J.K. (2004) Organic Chemistry,
3rd edn, Jones & Bartlett Publishers.
2. For historical information of alkyne
chemistry, please see: (a) Nieuwland,
J.A. and Vogt, R.R. (1945) Chemistry of
Acetylenes, Reinhold Publishing, New
istry of Acetylenes, Marcel Dekker, New
York.
Universe, John Wiley & Sons, Inc., New
York.
Zdero, C. (1973) Naturally Occurring
Acetylenes, Academic Press, New York.
5. Shi Shun, A.L.K. and Tykwinski, R.R.
(2006) Angew. Chem. Int. Ed., 45, 1034. 6. Heaney, H. (1962) Chem. Rev., 62, 81. 7. Compressed Gases Association (1999)
Handbook of Compressed Gases,
Means of Public and Private Illumina-
tion, Cradley Heath.
R.R. (eds) (2005) Acetylene Chemistry,
Wiley-VCH Verlag GmbH, Weinheim.
131, 5233. 11. Wittig, G. (1962) Rev. Chim. Populaire
Roum., 7, 1393. 12. Sletten, E.M. and Bertozzi, C.R. (2011)
Acc. Chem. Res., 44, 666.
13. Smith, G.V. and Notheisz, F. (1989)
Heterogeneous Catalysis in Organic
Main Group Metals in Organic Synthesis,
John Wiley & Sons, Inc.
Advances, Springer.
John Wiley & Sons, Inc.
18. Smith, J.G. (2008) Organic Chemistry,
2nd edn, McGraw-Hill, Boston, MA.
19. Anastas, P.T. and Warner, J.C. (1998)
Green Chemistry: Theory and Practice,
Oxford University Press, Oxford.
20. Trost, B.M. (1995) Angew. Chem., Int.
Ed. Engl., 34, 259. 21. Li, C.-J. and Trost, B.M. (2008) Proc.
Natl. Acad. Sci. U.S.A., 105, 13197. 22. (a) Zorn, J.A. and Wells, J.A. (2010)
Nat. Chem. Biol., 6, 179; (b) Maeyer, G.
(2009) Angew. Chem. Int. Ed., 48, 2672. 23. Uhlig, N. and Li, C.-J. (2011) Chem. Sci.,
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J. Am. Chem. Soc., 102, 5253. 25. Blanco-Urgoiti, J., Añorbe, L.,
Pérez-Serrano, L., Domínguez, G., and
Pérez-Castells, J. (2004) Chem. Soc. Rev.,
33, 32. 26. Lu, X., Zhu, G., Wang, Z., Ma, S., Ji, J.,
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K.B. (2001) Angew. Chem. Int. Ed., 40, 2004.
28. Chinchilla, R. and Najera, C. (2011)
Chem. Soc. Rev., 40, 5084. 29. For reviews, see: (a) Trost, B.M. and
Weiss, A.H. (2009) Adv. Synth. Catal.,
351, 963; (b) Pu, L. (2003) Tetrahedron, 59, 9873; (c) Cozzi, P.G., Hilgraf, R.,
and Zimmermann, N. (2004) Eur. J.
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8 1 Introduction
Li, X.-S., and Chan, A.S.C. (2005) Coord.
Chem. Rev., 249, 1736. 30. For reviews, see: (a) Yoo, W.-J., Zhao,
L., and Li, C.-J. (2011) Aldrichim. Acta,
44, 43; (b) Wei, C., Li, Z., and Li, C.-J.
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Van der Eycken, E.V. (2012) Chem. Soc.
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in Chemistry of Acetylenes (ed. Viehe,
G.H.), Marcel Dekker, New York, p. 597.
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Catalytic Isomerization of Alkynes
11
2
Redox Isomerization of Propargyl Alcohols to Enones Barry M. Trost
2.1
Introduction
The synthesis of enones has classically relied upon aldol condensation (Figure 2.1)
[1]. Its strength lies in the ready availability of the substrates and its high atom
economy. It suffers from issues of chemo- and regioselectivity. Self-condensation
of the aldehyde and the ability to form two regioisomeric enone products has led
to numerous variations to minimize such issues. One solution employs olefina-
tion protocols which suffer from poor atom economy. A particularly interesting
strategy recognizes that propargyl alcohols are isomeric with enones as shown
in Scheme 2.1. The availability of propargyl alcohols by a simple addition of a
terminal acetylene to an aldehyde then can make enones readily available by an
atom economic sequence of simple addition followed by isomerization. In 1922,
Meyer and Schuster [2] described the rearrangement of the oxidation pattern of
propargyl alcohols wherein the hydroxyl group undergoes the equivalent of a 1,3-
shift to form the rearranged enone after tautomerization (Scheme 2.1, path a).The
Meyer–Schuster rearrangement has been well reviewed and will not be a subject
of this chapter.
An alternative which maintains the positional integrity of the hydroxyl group
involves the shift of two hydrogens (Scheme 2.1, path b) which may be referred to
as a redox isomerization. Mechanistically, such a rearrangement of hydrogens is
not straightforward. Classically, this transformation typically was performed by a
stoichiometric reduction of the triple bond followed by stoichiometric oxidation
of the alcohol (or vice versa). While early strides revealed base catalysis could be
effective for a certain very limited type of structure, the importance of making
synthesis more environmentally benign stimulated efforts to broaden the gener-
ality of the process, especially to include nonactivated types of propargyl alcohols.
In this chapter, an overview of redox isomerization is presented organized along
the line of catalysts.
12 2 Redox Isomerization of Propargyl Alcohols to Enones
R1 R2
O
2.2
Base Catalysis
In 1949, Ninaham and Raphael [3] reported the isomerization of a
γ-hydroxybutynoate to an E-γ-ketobutenoate in the presence of triethy-
lamine. In 1954, Vaitiekunas and Nord [4] extended this isomerization of a
γ-hydroxybutynoate (1) to an E-γ-ketobutenoate (3) under similar conditions
(Equation 2.1) in 85% yield when
Ar
OH
CO2C2H5
1
Ar
OH
O
OC2H5
O
CO2C2H5
O
Ar
4
3
2
(1)
(2.1)
Ar= 2-thienyl. The facility of the process derives from the stability of the
supposed enolate intermediate 2. Studies in 2007 revealed that the Z-enoate
4 (Ar=Ph or 2-furyl) can result from such a process, depending upon choice
of base. Using bicarbonate in dimethylsulfoxide (DMSO) gives the Z isomers,
presumably resulting from a kinetic protonation which occurs from the least
hindered face to deliver the Z-alkene 4 (Ar=Ph or 2-furyl) [5]. On the other hand,
1,4-diazabicyclo[2.2.2.]octane (DABCO) in DMSO gives the E-isomer 4 (Ar=Ph
or 2-furyl) [6]. It is possible that a tertiary amine base isomerizes the initial iso-
mer to the thermodynamically more stable E isomer. The electron-withdrawing
group can be an electron-deficient heterocycle as in 5 (Equation 2.2) [7]. The
2.2 Base Catalysis 13
electron-withdrawing group that enhances the activity of the propargylic proton
need not be directly attached to the alkyne. Thus, the alkyne 6 undergoes redox
isomerization with triethylamine (Equation 2.3) [8]. Since such substrates can be
produced by the Sonogashira coupling in the presence of
OH
N
N
O
OCH3
N
N
O
OCH3
O
triethylamine, the intermediate propargyl alcohol may undergo redox isomer-
ization during the coupling step although some role for the Pd in the redox
isomerization cannot be ruled out [8].
An alternative strategy places the anion stabilizing group at the propargylic cen-
ter.Thus, a substrate bearing a 2-pyridyl substituent at this position as in7 requires both acid and base catalysis to effect isomerization as shown in Equation 2.4 [9].
N
OH
TMS
7
N
O
TMS
Using an inductively strong electron-withdrawing group such as polyfluoro alkyl
as in 8 also allows base catalyzed isomerization. While a simple tertiary amine
suffices (Equation 2.5) [10], the isomerization also proceeds under
CH3O
CF3
OH
CH3O
O
CF3
(C2H5)3N
Mitsunobu conditions via a mechanism that is obscure at best (see below) [11].
Diyne carbinols 9wherein a second alkyne serves as an adequate anion stabilizing
group (Equation 2.6) also isomerizes with a somewhat stronger base such as 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) at an elevated temperature (Equation 2.6)
[12]. Surprisingly, 1,3-diarylpropargyl alcohol suffices. In one such case,
Ph
OH
Ph
O
9
DBU
12 (2.7)
the juxtaposition of a γ-hydroxyl group as in 10 led to trapping the interme-
diate enone 11 to form a benzodihydrofuran 12 under the reaction conditions
(Equation 2.7) [13]. The most useful variant is employing an o-aminophenyl
group as the alkyne-bound aryl group [14]. Again, since the Sonogashira coupling
proceeds under basic conditions, both redox isomerization and cyclization to a
quinolone 13may occur to provide a reasonably efficient atom economic reaction
wherein only 1 equiv of hydroxide base and 2 equiv of water
I
NH2
2.3 Ru Catalyzed 15
result along with an iodide salt (Equation 2.8) [15]. Most recently, even only one
aryl ring at the propargylic carbinol was sufficient to promote base-catalyzed
redox isomerization. The ability of the enone products to serve as Michael
acceptors allows an atom and step economic approach to β-substituted ketones
such as pyrazole adduct 14 (Equation 2.9) [16].
OH
Thefirst example of a transition-metal-catalyzed isomerization of primary propar-
gyl alcohols to enalswas reported byMa andLu [17] in 1989 using aRu complex 15 which required long reaction times at high temperatures. The reaction was envi-
sioned to proceed by hydrometallation–dehydrometallation to form an allenol
PhCH3, reflux 36 h
(2.10)
which tautomerized to the enone (Equation 2.10). An improvement was reported
in 1995 using η5-indenyl-bis-(triphenylphosphine) rutheniumchloride (16) as catalyst and indium trichloride as a cocatalyst [18a]. Subsequently,
Ph OH
Ph CHO
1% (16)
5% CSA
1% In(OSO2CF3)3
a significant further improvement used indium triflate as catalyst wherein
1–3mol% of Ru and In complexes sufficed and reactions occurred in 0.5–3 h
[18b]. Both primary (Equation 2.11) and secondary (Equation 2.12) alcohols
participate. The excellent chemoselectivity is illustrated by the examples of
propargyl alcohols 17–19 (Equations 2.12 [18b], 2.13 [18b], 2.14 [19]).
OH
7
17
71%
(2.14)
The dienal 20 served as a key intermediate in the synthesis of a leukotriene.
Particularly noteworthy is the chemoselective bis redox isomerization of 19 to
bis dienal 21 on the way to the polyacetylenic natural product adociacetylene.
The chemoselectivity demonstrated in these examples is inconsistent with a
hydrometallation–dehydrometallation mechanism. The ready availability of
butynediol as a building block is further enhanced by its chemoselective redox
isomerization. Indeed, the accessibility of the functional crotonaldehyde 22 via
TBDPSO TBDPSO CHOOH
5% Indenyl Ru(COD)CI
22
(2.15)
Ru-catalyzed isomerization (Equation 2.15) allowed it to provide easy access to
the sphingofungins. In this case, a more coordinatively unsaturated indenyl ruthe-
nium complex was employed as depicted in Equation 2.14. Such cycloocta-1,5-
diene (COD) ligands bound to Ru have been shown to be reacted off by a [2 + 2 + 2] cycloaddition with an alkyne to free two open coordination sites [18c].
Deuterium labeling studies revealed that a 1,2-hydride shift occurred generat-
ing a Ru carbenoid intermediate 23 (Scheme 2.2) [18b]. Further evidence for this
mechanism was the interception of the Ru carbenoid by intramolecular cyclo-
propanation of a tethered olefin (e.g., 24) as shown in Equation 2.16 [20]. This
reaction was a key step in
2.3 Ru Catalyzed 17
Scheme 2.2 Hydride shift mechanism for the Ru-catalyzed redox isomerization.
TsN OH
PPh3
PPh3
5%
(2.16)
a concise synthesis of echinopine A, 25 (Equation 2.17) [21]. A C–C bond rather
than H can migrate when a cyclopropyl ring is annealed to the propargyl carbon.
Depending upon the nature of the substituent on the alkyne terminus,
OH
CHO
25
(2.17)
either a 1,2 shift occurs to give the alkylidenecyclobutanone 26 (Equation 2.18) or a 1,3 shift occurs to form
81%
74%
HO
Ru
(2.19)
cyclopentenone 27 (Equation 2.19) [22].This selectivity may result from the pref-
erence to coordinate the alkyne with the hydroxyl group in the former but with
the cyclopropyl C–C bond in the latter.
The in situ formation of a Michael acceptor via redox isomerization sets
the stage for a cascade. Thus, juxtaposition of a suitable oxygen as in 28 (Equation 2.20) [23], nitrogen as in 29 (Equation 2.21) [24], or even carbon as in
30 (Equation 2.22) [25] nucleophiles provide easy access to the corresponding
heterocycles 31 and 32 or carbocycle 34. In the first two cases, cyclization to
the heterocycles occurred in tandem with the redox isomerization. On the other
hand, under
(2.22)
the acidic conditions of the redox isomerization, cyclization of the carbon pronu-
cleophile 33 did not occur. Thus, upon completion of the redox isomerization, a
chiral organocatalyst was added to effect the asymmetric cyclization of 33 to give
34 in high ee. Switching from the exo type of cyclization as in Equation 2.21 to an
endo geometry slowed the rate of cyclization too.Thus, in the case of the nitrogen
2.3 Ru Catalyzed 19
Michael donor, redox isomerization of the sulfonamide 35 (Equation 2.23) was
not accompanied by cyclization via Michael addition [24]. For completion of the
50%
cascade, simple addition of potassiumcarbonate inmethanol to the initial reaction
mixture allowed Michael addition to form the piperidinone 36. The vinyl ketones are also electrophilic enough in the presence of the redox cat-
alyst system, notably the presence of the In Lewis acid, that electrophilic aromatic
substitution can occur as shown in Equation 2.24 [26]. A similar
83%
reaction was effected using a cyclopentadienone Ru complex 37 although
higher temperatures were required (Equation 2.25) [27]. The chemoselectivity
of the Michael addition to the divinyl ketone intermediate is also noteworthy. A
38
Ru
Me
Me
Me
Me
dinuclear Ru complex 38 has also been reported to be effective under milder con-
ditions (10% NH4PF6, 1,2-dichloroethane (DCE), 60) although the yields were
considerably lower [28].
While a hydride shift mechanism appears to account for the above examples,
a hydrometallation–dehydrometallation mechanism is more likely in the case of
(Ph3P)3Ru(H2)CO (39) as the catalyst [29]. Using complex 39, a 1,4-dihydroxy-
2-alkyne 40 can be initially isomerized to a γ-hydroxyenone which can undergo
a second redox isomerization of the remaining allyl alcohol to a 1,4-diketone
(Equation 2.26). At the high temperature of the reaction in the presence of acid,
cyclodehydration occurs to generate the aromatic 2,5-disubstituted furan. If the
redox isomerization is performed under neutral conditions, the reaction stops at
the 1,4-diketone. Such
Br
O
Br
O
Br
[RuH]
OH
HO
Br
OH
HO
O
(2.26)
1,4-diketones are precursors to pyrroles by simple addition of a primary amine
(Equation 2.27) [29]. Alternatively, base treatment can provide cyclopentenone.
Then add
Rh Catalysis
In 1995, Sarah and Pellicciari [30], motivated by the synthesis of peptide
isosteres (Equation 2.41), examined the use of Wilkinson’s complex for the redox
isomerization of γ-hydroxy-α,β-acetylenic esters such as 39 (Equation 2.28) using
2.4 Rh Catalysis 21
a substrate derived from phenyl alanine. While the mechanism of this process
has not been established, a
3% (Ph3P)3RhCl
Ph
NHAc
O
[Rh]
40
OH
H
CO2C2H5
(2.28)
reasonable possibility is depicted in Equation 2.28. It invokes a coordinatively
unsaturated Rh complex bound to oxygen undergoing a β-hydrogen elimina-
tion forming a rhodium hydride. Hydrometallation of the alkyne followed by
protonation would complete the catalytic cycle.
Evidence for such a mechanism derives from the development of a more active
catalyst as shown in Equation 2.29 [31].This catalyst workswell for aryl- and vinyl-
substituted propargyl alcohols as illustrated with the
C3H7
OH
41
O
79%
(2.29)
cyclohexenyl substituent as in 41 in Equation 2.29.This catalyst also proved effec-
tive to convert 2-butyne-1,4-diols 42 to 1,4-diketones 43 (Equation 2.30) even
with saturated alkyl groups. Interestingly, the monomethyl ether delivered the
43
73%
C5H11
C5H11
44
C5H11
OR
OH
42
O
C5H11
(2.30)
(2.31)
preferably eliminated methanol to aromatize (Equation 2.31). An interesting
application of this process is its use to effect a kinetic resolution of propargylic
alcohols (Equation 2.32) [32]. While the desired product is the unchanged alcohol
enantioenriched, it does show a different dimension of the process.
76% ee @ 60% conv.
O
A major mechanism for Pd-catalyzed processes involves hydropalladation and
dehydropalladation such as in the migration of double bonds. In 1988, this mech-
anism was used to effect a redox isomerization as shown
Ph
CO2C2H5
OH
Ph
O
CO2C2H5
Ph
OH
(Ph3P)2Pd(OAc)2
Ph
[Pd]
PdH
(2.33)
in Equation 2.33 [33]. In this case, formate serves as the hydride source to gen-
erate the [Pd–H] species. Lu and coworkers [34] reported the use of a similar
mechanism for the redox isomerization of 2-butyne-1,4-diol-type compounds, 45, wherein the [Pd–H] species presumably derives by protonation of a Pd(0) by the
diol (Equation 2.34). This example
OH O 10% (C4H9)3P 72%
5% (dba)3Pd2·CHCl3
(2.34)
highlights the chemoselectivity of the process given the highly reactive nature of
a bis-enone as a product. It should be noted that these conditions failed with a
mono-propargyl alcohol. Using a stronger acid for such a bis-isomerization served
not only as a source for the Pd–Hby protonation of Pd(0) but also effected tandem
cyclodehydration to form furans (Equation 2.35) [35]. By using an external diol to
2.5 Palladium Catalysis 23
OH
O
nafion
O
O
(2.35)
the reaction now allowed it to proceed with a simpler propargyl alcohol
(Equation 2.36) [36]. Unfortunately, equilibration occurred under the reaction
conditions to give a mixture of α,β- and β,γ-unsaturated enones. The advantage
of a
(2.36)
bidentate phosphine, dppe, was noted in the synthesis of prostaglandin analogs
[37]. The redox isomerization provided access to the flavor and perfume ingredi-
ent damascene 46 (Equation 2.37) [38]. A particularly effective way to generate an
active form of the [Pd–H] species is by exposing a typical heterogeneous palla-
dium hydrogenation
(2.37)
catalyst to hydrogen gas. For example, employment of Pearlman’s catalyst pre-
treated with a small amount of hydrogen effected redox isomerization at room
temperature (Equation 2.38) [39] in work directed toward the synthesis of the
amphidinolides.
OH
OH
OPh
2.6
Miscellaneous
Lu and coworkers [40] established the effectiveness of an Ir complex to effect
redox isomerization via a hydrometallation–dehydrometallation mechanism.
This catalyst was equally effective for redox isomerization of a simple propargyl
alcohol (Equation 2.39) as well as a 2-butyne-1,4-diol system (Equation 2.40).
Unfortunately,
Ph
OH
(2.40)
isomerization of the conjugated double bond to the β,γ position accompanied the
redox isomerization.
While Pt complexes have not been described to perform a redox isomeriza-
tion of the type discussed herein, there is a silyl version (Equation 2.41) [41]. The
reaction appears to be initiated by a facile 1,2-silyl shift promoted
TBDMSO
C4H9-n
ity of the resultant vinylsilane to access geometrically defined trisubstituted olefins
makes this version of the redox isomerization a useful variation.
Themost unusual set of conditions for the redox isomerization of the propargyl
alcohol 47 is the use of
References 25
98% Ph
the conditions of the Mitsunobu reaction (Equation 2.42) [11]. Mechanistically
how this process proceeds is not defined nor even apparent.
2.7
Conclusions
While the field of redox isomerization is just emerging, its potential in improv-
ing both atom and step economy is already apparent. At this stage, Ru complexes
have progressed the most as appropriate catalysts. Indeed, reasonably mild con-
ditions give promise for good chemoselectivity. At the same time, prospecting for
other catalysts has barely begun. Equally exciting is the merging of redox isomer-
izations with other addition reactions leading to tandem or cascade events. The
combined prospects for future development are immense. At this time, redox iso-
merization is a great complement to theMeyer–Schuster rearrangement and thus
we can tune the regioselectivity of the resultant oxidation pattern from the same
precursor by just a simple change in catalyst.
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27
3
and Domino Processes
3.1
Enyne cycloisomerization reactions represent a class of thoroughly investigated
processes as they offer a unique entry to complexity in carbo- and heterocyclic
chemistry via atom economical transformations [1–12]. Over the years, a large
set of transition metals have shown promising activities for a variety of substrates
through reactions involving mechanisms based on metallacyclic intermediates,
hydro-, or carbometallation as a key step or metathesis. More than a decade ago,
a new trend of reactivity associated with the carbophilic character of late tran-
sition metals started to attract attention and paved the way for the development
of a new family of highly active and selective catalysts [13–35]. This contribu-
tion aims at highlighting the specific reactivity of carbophilic Lewis acids in the
presence of enynes substrates and at presenting a selection of the most striking
examples of transformations associated with this class of catalysts. The different
types of skeletal rearrangements and the subsequent formation of dienes or poly-
cyclic derivatives will be discussed. Transformations resulting from the trapping
of reactive intermediates with nucleophiles will be treated in a second part. A spe-
cific emphasis will be placed on the development of asymmetric versions of these
reactions [10–12, 36–41] and their application to the total synthesis of natural
products [23, 42].
3.1.1
The Reactivity of Carbophilic Lewis Acids in the Presence of Enyne Substrates
The carbophilic Lewis acid character of the late transition metals can be
delineated as the activation toward outer-sphere anti-nucleophilic attack of a
carbon–carbon unsaturation upon η2-coordination to the metal complex [43].
This principle was initially put in evidence by the group of Utimoto in the case
of the activation of alkynes by gold complexes in the presence of oxygen [44]
and nitrogen [45] nucleophiles. Alkenes have subsequently been found to be
excellent nucleophile reaction partners for this class of reaction. The reactivity of
28 3 Carbophilic Cycloisomerization Reactions of Enynes and Domino Processes
the active species resulting from the attack of the alkene on the alkyne activated
by coordination to the metal center can be summarized by the equation depicted
in Scheme 3.1. Upon attack of the nucleophile, slippage of the metal fragment
along the alkyne axis gives the γ-carbocationic vinylmetal intermediate 2. This
delocalized organometallic can best be viewed as a delocalized three center cation
3 whose mesomeric extremes can also be described by a cyclobutyl carbocationic
form 4 or a cyclopropyl carbocationic form 5, the latter often being assigned
a carbene or a carbenoid reactivity and is often represented by the cyclopropyl
carbene form 6. The debate between these different formula [46] arises from
the observation of different reaction products (depending on various factors
including the nature of the metal fragment, the nature and the position of the
substituents on the alkene and the alkyne, or the nature of the solvent), whose
structure and selectivity can be best understood by one of these ways to describe
the complex bonding properties associated with these highly unstable inter-
mediates.
Scheme 3.1
More recently, a lot of effort has been devoted to (i) the isolation and character-
ization of such reaction intermediates [47], especially in the case of gold catalysis
[48] and (ii) theoretical investigations of the related mechanisms operating with
these catalysts [49].
3.2.1
Synthesis of Dienes (1,3- and 1,4-Dienes)
The first occurrence of the report in the literature of an enyne cycloisomerization
reaction catalyzed by a carbophilic Lewis acid leading to a diene product dates
from 1996: The group of Murai [50, 51] reacted 1,6-enynes in the presence of
5mol%PtCl2 in toluene at 80 C to obtain the corresponding 1-vinylcyclopentenes
in good yields. Following this initial report, a variety of other metal salts and
3.2 Skeletal Rearrangement Reactions in the Absence of Nucleophiles 29
complexes, including Pt(II) [52, 53] and (IV) [54], Rh(II) [55], Hg(II) and Fe(III)
[56], Au(I) and Au(III) [57–59], In(III) [60] or Ga(III) [61], has been evaluated for
such transformations; the best activities being observed with gold complexes [62],
allowing the reaction to be run at room temperature or below at low catalyst load-
ings. In the case of cationic phosphine gold(I) complexes, complete conversion is
observed at room temperature using only 2mol% catalyst leading selectively to
the “double cleavage product” 9 in 91% yield (Scheme 3.2).
E
E
7
2 mol% [(PPh3)Au(CH3CN)]SbF6
skeletal rearrangement mechanisms that have been carefully studied by isotopic
labeling experiments [63] and DFT calculations [49, 64, 65]. Upon activation
of the alkyne by the metal fragment and nucleophilic attack of the alkene, the
cyclopropylcarbene 11 is generated via a 5-exo cyclization. 1,2-Alkyl shift allows
the formation of the cyclobutane zwitterion 12. This common intermediate can
subsequently evolve through two competitive pathways. Cyclobutane opening
and metal fragment elimination allows the formation of diene 14, known as the
single cleavage product. Alternatively, a second 1,2-alkyl shift from intermediate
12 leads to the cyclopropyl complex 15. Ring opening of this cyclopropyl zwitterion gives the carbene 16 that upon 1,2-hydride shift and elimination furnishes
the “double cleavage product” 17 (Scheme 3.3).
Such transformations have found applications in the total synthesis of an
array of natural products. The groups of Trost and Fürstner employed Pt cat-
alysts for the synthesis of the bicyclic core of prodiginine antibiotics such as
metacycloprodigiosin, streptorubin [66] 20, and roseophilin [67]. The group of
Sarpong exploited the GaCl3-catalyzed skeletal rearrangement of 1,7-enynes for
the synthesis of the core of (±)-salviasperanol [68, 69] 23 or (±)-icetexone [70]
(Scheme 3.4).
Elimination of the metal fragment can also occur via an alternative mechanism
to give the 1,4-dienes 25 and 26 associatedwith theAlder-ene reaction. Such reactivity has been observed for substrates possessing a trisubstituted alkene function
with Pt [71] or Bi [72] catalysts under relatively harsh conditions (Equation 4,
Z
1,2-Alkyl shift
MeO
HO
HO
O
Scheme 3.5). More recently, Malacria, Gandon, Fensterbank, and coworkers [73]
showed that for substrates possessing an alkyne substituted by a methylene frag-
ment, [1,5] hydride shift is a favored pathway compared to the [1,2] shift lead-
ing to the formation of cyclic allenes (see molecule 28, Equation 5, Scheme 3.5).
Formation of 1,4-dienes is also observed using allylsilanes and allylstannanes as
nucleophilic reactions partners in enyne cycloisomerization reactions. In the case
of the allylsilane substrates, protodesilylation occurs using PtCl2 as a catalyst and
acetone as a solvent [74], whereas in the case of the allylstannanes substrates, a
[1,5] trialkylstannyle migration can occur to deliver the corresponding vinylstan-
nanes in good yields in the presence of a silver catalyst (Equation 7, Scheme 3.5)
[75].This latter transformation can also be performed with 1,7-enynes via a 6-exo
E
E
E
E
E
E
24
O
O
Ph
O
O
Ph
modeof cyclization.An asymmetric version of this reaction has also been reported
using a bimetallic silver catalyst L2(AgOTf)2 incorporating a chiral bidentate lig-
and (with up to 78% ee).
In most cases, for 1,6-enynes, the 5-exo mode of cyclization is favored,
although for selected substrates, products resulting from the 6-endo cyclization
are observed [62].This is noteworthy, the case for gold-catalyzed transformations
involving substrates possessing a nitrogen tether at the position 4 [57–59].
Cycloisomerization reactions involving 1,7-enynes have also been cyclized in the
presence of gold complexes via the 6-exo mode of cyclization in excellent yields
[76, 77]. It is noteworthy that a single example of reaction of a 1,9-enyne has been
reported by the group of Porco [78]: cycloisomerization under forcing conditions
(55mol% catalyst) affording the corresponding macrocycle in moderate yield
featuring a 10-endo mode of cyclization.
The development of asymmetric versions of these transformations has so far
met limited success. Following the earlier investigations of the group of Chung
[79] on the gold-catalyzed 6-endo of nitrogen-tethered 1,6-enynes that resulted in
the formation of tetrahydropyridines with low enantioselectivities (up to 22% ee),
one should note the contributions of (i) the group of Tanaka [80] on the palladium-
catalyzed formation of atropisomeric 2-pyridone and (ii) the group of Sanz [81] on
the gold-catalyzed cycloisomerization of 2-alkynylstyrenes to the chiral vinylin-
denes with high enantioselectivities, respectively.
For alkenes substituted at the internal position, the 6-endo mode of cyclization
is favored. This selectivity has especially been used for the synthesis of aromatic
rings starting from 1,3,5-dienynes [82, 83]. 2-Alkynylstyrenes, such as 33, can eas- ily be transformed to the corresponding naphthalenes, for example, 34, in high
yields in the presence of PtCl2 at 90 C in toluene [84].The 6-endomode of cycliza-
tion leading to 1,3- and 1,4-cyclohexadienes has also been reported. Kozmin and
coworkers [85] showed that 5-alkenyl silylynol ethers (35) are cleanly converted to the cyclohexadienes (40) in excellent yields using 1mol% of AuCl at room temper-
ature in dichloromethane. The selectivity observed implies the initial formation
of the cyclopropylcarbene 36. Two 1,2-alkyl shift steps allow the formation of the
zwitterionic form 37 and 38, successively. Cyclopropane ring opening leads to the formation of carbene 39. Finally, elimination of the gold salt leads to the formation
of the diene 40 (Scheme 3.6).
Such strategies relying on 1,2-alkyl shifts have also found application for the
synthesis of aromatic rings.The group of Sanz [86] showed that 1,3,5-dienynes are
converted to benzene derivatives in good yields using a cationic gold(I) complex
possessing a 2-biphenyl-based monodentate phosphorus ligand L3 (Scheme 3.7).
3.2.2
and Related Transformations
The first report of a metal-catalyzed transformation involving the addition of an
enol equivalent to an alkyne dates from 1983 when the group of Conia reported
OTBS
C6H13
C6H13
OTBS
the intramolecular C-alkylation of a ε-acetylenic carbonyl derivative in a 5-exo
fashion to give methylene cyclopentenes in the presence of a catalyst formed from
the combination of HgCl2 and a Brønsted acid [87, 88].The proposed mechanism
implies the anti attack of the enol form of the carbonyl on the carbon-carbon
triple activated by η2-coordination to the mercury salt. In 2004, the group of
Toste [89] reported the superior reactivity of cationic gold(I) species in this trans-
formation. Using only 1mol% of [(PPh3)Au(OTf)], ε-acetylenic β-ketoester 46 is
transformed in dichloromethane at room temperature in 15min to the methylene
cyclopentane 47 in 94% yield. Deuterium label experiments support the former
mechanism implying anti nucleophilic attack as shown in the transition state 48 (Scheme 3.8, Equation 11). Soon after, the same group extended this methodology
to the 5-endo cycloisomerization of the δ-acetylenic carbonyl compounds [90].
Subsequent studies showed that the use of a sterically encumbered phosphine
monodentate ligand is crucial to observe the formation of methylene cyclohexane
products either via a 6-endo or a 6-exo mode of cyclization as demonstrated by
the group of Sawamura [91].
83% yield
94% yield
O
OMe
O
R = Me or Et 10 mol% HgCl2 10 mol% aq HCl
35°C, 8 h
Scheme 3.8
Following these pioneering contributions, a lot of effort has been devoted to
the search of efficient enantioselective catalytic systems for this class of transfor-
mations. In 2005, Corkey and Toste [92] introduced a catalytic system formed
from the dicationic diphosphine L4 palladium complex, ytterbium triflate, and
an excess of acetic acid allowing the cycloisomerization of substrate 49 to the
cyclopentane product 50 in 84% yield and 89% ee.This heterobimetallic approach
inducing a dual activation of both the carbonyl function, using an oxophilic
hard Lewis acid, and the alkyne function, using a carbophilic soft Lewis acid,
represents the paradigm of a series of asymmetric catalytic systems developed
recently. Among them, the La(Oi-Pr)3/Ag(OAc) system reported by Kumagai and
Shibasaki and colleagues [93] and the Zn(OAc)/Yb(OTf)3 reported by Shibata
[94] afford the best enantioselectivities for large sets of substrates (Scheme 3.9).
To further extend the scope of the carbophilic Lewis-acid-catalyzed Conia-ene
reaction so far restricted to enolizable 1,3-dicarbonyl compounds, research efforts
have been engaged to study the reactivity of enol surrogates such as silyl enol
ethers and enamines. In the presence of cationic gold(I) complexes as the active
R1 OR2
O O
5 mol%
Et2O, rt
CO2R2 R1
Me
CO2MePh
O
species, 1,5- and 1,6-enynes are converted to the corresponding cyclopentenes
in high yields following a 5-endo or 5-exo mode of cyclization, respectively
(Scheme 3.10) [95]. The presence of a protic oxygen co-nucleophile is essential
for the desilylation step of the transformation.
10 mol%
Scheme 3.10
In 2007, the group of Toste [96] showed that 1-silyloxy-1,6-enynes (e.g., 58) react cleanly to give the cyclopentane (e.g., 59) in high yields and excellent enan-
tioselectivities in the presence of a dicationic palladiumcomplex incorporating the
diphosphine ligand L6. The geometry of the silyl enol ether carbon–carbon dou-
ble bond and the steric hindrance of the silyl group have to be carefully controlled
to reach the best level of asymmetric induction [97] (Scheme 3.11).
BzN
OTIPS
BzN
Scheme 3.11
The synthetic potential of these methodologies has been demonstrated by their
application to the dia- or enantioselective total synthesis of (+)-lycopladine A
[95a], platencin [98], and (−)-laurebiphenyl [96] (Scheme 3.12).
O
Scheme 3.12
Enamines also efficiently play the role of nucleophilic partners in enyne cycloi-
somerization reactions. In 2008, in a key step of their asymmetric total synthesis
of (+)-Fawcettidine, Kozak and Dake [99] showed that the cyclic enamide 60 is
converted to the tricycle 61 with 87% yield in the presence of PtCl2 as the catalyst
in toluene at 90 C (Scheme 3.13).
NN
Me
O
S
N
The possibility of generating a catalytic amount of the enamine reaction part-
ner able to react with the alkyne activated by π-coordination to the carbophilic
Lewis acid via a dual metalloorganocatalytic approach has also been thoroughly
investigated. In 2008, the group of Kirsch [100] showed that aldehyde 62 reacts
at 70 C to form cyclopentane 64 in 71% yield in the presence of a catalytic
system consisting of a secondary amine and [(PPh3Au)3O](BF4) (Scheme 3.14,
Equation 18). The proposed mechanism implies the formation of intermediate
63. The scope of the transformation has been increased using successively (i) an
In/primary amine [101] and (ii) a copper/phosphine/primary amine system [102].
The use of the later system allows the synthesis of cyclopentane and pyrrolidine
products at room temperature in high yields. Using a chiral diphosphine, an
asymmetric version of this transformation has been reported by Montaignac
et al. [103]. Enantioselectivities up to 94% have been obtained using Cu(OTf)2,
4-methoxy-3,5-(t-Bu)2-MeOBIPHEP L7 in combination with cyclohexylamine
(Scheme 3.14, Equation 19).
71% yield
N H
Me MeO2C
Formation of Bicyclic Derivatives
3.2.3.1 Formation of Bicyclopropanes
In 1995, in one of the first contributions dealing with the reactivity of carbophilic
Lewis acids with enynes substrates, the group of Blum [104] reported the synthe-
sis of bicycloheptenes 68 by reacting allylpropargylethers 67 in the presence of
a catalytic amount of PtCl4. The reinvestigation of this transformation conducted
by the group of Fürstner [52] led to the identification of a catalytic system of wider
scope: PtCl2 in toluene at 80 C [52, 56, 105].The reactionwas noticeably extended
to nitrogen-tethered substrates. 1,5-Enynes are also cyclized to the correspond-
ing [3.1.0]-bicyclohexanes using either Pt [106] orAu catalysts [107] (Scheme 3.15,
Equation 21).
X = O R = Ph
X = NTs
Scheme 3.15
The mechanism implied in these transformations has been studied by compu-
tational methods in the case of 1,6-enynes by Soriano et al. [108]. At the initial
stage of the catalytic cycle, the alkyne function is activated by η2-coordination to
the platinum center and submitted to the anti nucleophilic attack of the alkene
(intermediate 71). Formation of the cyclopropylcarbene 72 is thus observed via a
6768
X
R2
6-endo cyclization. 1,2-Hydride shift furnishes the zwitterionic intermediate 73. The presence of the heteroatom at the position 4 of the substrate is essential to
observe the stabilization of the carbocation. Elimination of the metal fragment
completes the catalytic cycle and liberates the [4.1.0]-bicycloheptene product
(Scheme 3.16).
In 2013, the group of Ferreira reported the Pt-catalyzed enantiospecific bicy-
cloheptene synthesis of a variety of oxygen-tethered 1,6-enynes.The introduction
of a stereogenic center at the propargylic position allows the formation of
enantioenriched bycyclic products upon chirality transfer. Molecules containing
tetra- and pentasubstituted cyclopropanes rings with a wide variety of functional-
ities are formed in good yields and excellent enantioselectivities. Using substrates
possessing a chiral isopropyle group, the reaction proceeds enantiospecifically
in tetrahydrofurane at 70 C in the presence of PtCl2 as a catalyst (Scheme 3.17,
Equation 22).
O Me
74 75
Scheme 3.17
Intense efforts have been devoted to the development of an asymmetric version
of this transformation (Scheme 3.18). The first report in the literature dates
from 2005 when the group of Shibata introduced a catalytic system formed from
[{IrCl(cod)}2], AgOTf, and Tol-BINAP L2 under an atmosphere of CO. Enantios-
electivities excesses between 37% and 78% have been obtained for a restricted set
of nitrogen-tethered 1,6-enynes substrates. The group of Marinetti introduced
a family of monocationic Pt complexes possessing an achiral cyclometallated
N-heterocyclic carbene (NHC) bidentate ligand and a monodentate chiral
phosphine ligand. Excellent yields and very good enantioselectivities have been
obtained for N-tethered 1,6-enynes [109] and 3-hydroxylated 1,5-enynes [110].
Nishimura, Hayashi, and coworkers have proposed a similar approach for the
asymmetric Rh-catalyzed version of this transformation. Rhodium(I) complexes
coordinated with either the combination of a chiral diene and an achiral mon-
odentate phosphine ligand [111] or with a tridentate chiral phosphine-diene
ligand catalyze the cycloisomerization of a variety of oxygen- and nitrogen-
tethered 1,6-enynes. In 2013, the same group [112] reported the enantioselective
cycloisomerization of 1,6-enynamides in the presence of a chiral diene-rhodium
catalyst. In the case of gold(I) complexes, the first highly enantioselective system
based on the use of a [4-methoxy-3,5-(t-Bu)2-MeOBIPHEP(AuCl)2] complex
in combination with two equivalents of AgOTf allowed the formation of [4.1.0]
bicycloheptene derivatives in moderate yields and excellent enantioselectivities
No-TolSO2
Me
24 mol% AgOTf
Ph No-TolSO2
Scheme 3.18
[113]. A similar diphosphine digold catalyst was used in 2011 for the asymmetric
synthesis of the triple reuptake inhibitor GSK1360707F 80 with 59% ee [114].
The same year, the group of Fürstner [115] introduced a new family of sterically
hindered monodentate phosphoramidite ligands based on the TADDOL diol
unit in gold asymmetric catalysis. Under optimized conditions, enyne 78 reacts
to give bicycle 79 in 88% yield and 95% ee in the presence of the cationic Au(I)
complex incorporating the L8 ligand. Based on the concept of counterion strategy
introduced by Toste and coworkers [116], Barbazanges et al. [117] reported a
new methodology to access bicycloheptenes using a combination of an achiral
Ir(I) complex, that is, [IrCl(CO)(PPh3)2], and a chiral phosphate silver salt.
Enantiomeric excesses up to 93% have been obtained at 90 C in toluene.
Highly reactive metal carbene or carbenoid intermediates associated with
carbophilic Lewis acids can react through a variety of hydride or alkyl shift
rearrangement steps [118]. An investigation conducted by Horino, Toste, and
coworkers [119] showed that the spatial proximity between the carbenoid gold
bond and either C–C or C–H present in the enyne chain is the key factor
governing the selectivity of a transformation for a given substrate. For example,
substrate 81 containing a strained spirocyclobutane substituent on position 3 of
the enyne is converted to the tricycle 82 in 72% by a reaction involving a 1,2-alkyl
shift (see intermediate 83, Scheme 3.19, Equation 25); whereas substrate 85 containing a spirocycloheptane substituent is transformed to the tetracycle 87 in
Ph 10 mol%
2 mol% AgSbF6
Scheme 3.19
86% via a mechanism involving a C–H insertion in the carbenoid intermediate 86 (Scheme 3.19, Equation 26). A related reactivity has been reported by the group
of Fehr [120] in the cycloisomerization of enynols in the presence of cationic
copper salts. Reacting bicycle 88 with 1mol% of [(CH3CN)4Cu(BF4)] at 70 C in
toluene affords the polycycle 89 in 85% yield after 1,2-alkyl shift (Scheme 3.19,
Equation 27).
3.2.3.2 Formation of Bicyclobutenes
The formation of bicyclobutenes has been investigated for a variety of carbophilic
Lewis acid catalysts. The group of Fürstner [121] reported the low-yield isolation
of the tricycle 91 upon treatment of the 1,7-enyne 90 using catalytic PtCl2 (Scheme 3.20, Equation 28). A much higher reactivity can be observed with
cationic Au(I) species stabilized with a phosphine ligand L9 bearing a biphenyl
substituent: The reaction proceeds at room temperature in dichloromethane
to give, for example, the [3.2.0]bicycle 93 in 77% yield using a low catalyst
loading [122] (Scheme 3.20, Equation 29). Ynamides groups are excellent reaction
partners for this type of transformation [123]: Ene-ynamides such as 94 give
the nitrogen heterocycle 95 when treated in the presence of PtCl2 in toluene at
O
CO2Me
O
CO2Me
CH2Cl2, rt
P Cy
Toluene, 80 °C
Toluene, 80 °C
Scheme 3.20
80 C. 95 is rather unstable and can be transformed to the cyclobutane 96 upon
hydrolysis (Scheme 3.20, Equation 30).
3.2.3.3 Formation of Larger Rings via Cycloisomerization-Rearrangements
When the alkene moiety of the enyne is replaced by a 1,3-diene or a conjugated
polyene, different types of rearrangements occur to give a set of unsaturated
polycyclic structures. Among them, one can cite the cycloisomerization of
trienynes such as 97 that proceeds via a formal [6 + 2] cycloaddition to give the
tricycle 98 using either PtCl2 or AuCl3 as a catalyst as reported by Tenaglia and
Gaillard [124] (Scheme 3.21, Equation 31). The mechanism is proposed to occur
via an exocyclic cyclization followed by an electronic redistribution to furnish
98 in high yield. In the case of heteroatom-tethered substrates, the cycloisomer-
ization can also lead to [4.3.2]bicyclononanes 101 upon Cope rearrangement on
the [4.1.0]bicycloheptene intermediate 100 (Scheme 3.21, Equation 32) [125].
Alternatively, [4 + 2] cycloaddition reactions have also been disclosed using
cationic gold catalysts [122a, 126] (see Scheme 3.21, Equation 33).
Domino cycloisomerization-pinacol rearrangements methodologies have also
been reported using Pt and Au catalysts [127]. The stereoselectivity observed in
these processes found applications in the total synthesis of natural products. The
group of Toste [128] disclosed a total synthesis of ventricosene 108 taking advan-
tage of this methodology (Scheme 3.22, Equation 34). The 5-hydroxylated 1,6-
enyne 104 first cyclizes via the 6-exomode of cyclization to give the carbocationic
vinylaurate intermediate 105. A 1,2-alkyl shift followed by protodemetallation
furnishes the ketone 107 in 87% yield.
Silyloxyenynes possess a similar reactivity. Overman and coworkers [129]
recently reported the total synthesis of Sieboldine A 112 involving as a key
MeO2C
MeO2C
CH2Cl2, rt
Scheme 3.22
step the cycloisomerization of enyne 109 (Scheme 3.23, Equation 35). Upon
6-exo cyclization, the intermediate 110 is formed. Diastereoselective 1,2-alkyl
migration and protodemetallation produces the bicyclic ketone intermediate
111, which leads to the natural product in eight steps. The presence of an alcohol
additive is essential to trap the released silyl protecting group.
O
NOH
O
O
OTBDPS
O
Domino Enyne Cycloisomerization–Nucleophile Addition Reactions
The outcome of the cycloisomerization reactions of enynes A implies inter- or
intramolecular processes, when a carbon or heteroatom nucleophile is intro-
duced, as presented in Scheme 3.24 for 1,6-enynes. The cyclization of A firstly
involves the activation of the alkyne by the metal complex [M], leading to η2- complex B. The trapping of the carbenoid intermediates follows the formation of
either 6-endo-dig or 5-exo-dig intermediatesC andD, the chemoselectivity being
driven by the R1 and R2 substituents on the allylic chain, which influences the
stabilization of the metallic moieties. In the case of intermediate C, the addition of an external nucleophile leads to cyclic alkene E. The formation of H and I is related to the addition of nucleophiles on the carbon a or b of the cyclopropanyl
Z
R3
[M]
Z
R3
[M]
Z
Z
R1
R3
[M]
Z
R3
R2
Z
[M]
R2
3.3 Enyne Domino Processes 45
moiety D. The addition on the carbenoid moiety (carbon c) leads to the synthesis
of bicyclic derivative J, or alkenyl G (in the case of the transformation of D to F). In general, the addition of the nucleophile is dictated by the substitution pattern
of the double bond.
A variety of nucleophiles were used, including oxygen nucleophiles (water,
alcohols, sulfoxides, and carbonyl derivatives), unsaturated carbon compounds
(aromatic rings, alkenes allylsilanes, and 1,3-dicarbonyl derivatives), and nitrogen
compounds (amines). Selected examples will illustrate each type of rearrangement
in the following paragraphs.
3.3.1.1 Oxygen and Nitrogen Nucleophiles
Domino Processes in the Presence o Alcohols The domino processes in the presence
of alcohols have been the first studied process and was discovered by Genêt et al.
in 1997 [130] in the presence of a water-soluble palladium catalyst. Starting from
enyne 113, a diastereoselective process occurred in dioxane/water mixture and
led to alcohol 114 (Scheme 3.25, Equation 36). The synthesis of carbo- and hete-
rocycles implying the addition of water and alcohols has then been described in
the presence of platinum(II) and gold(I) catalysts [71, 131, 132]. Several catalytic
systems based on gold have been found to be efficient for such transformations,
the gold(I) complexes being directly used [133], or generated by acid catalysis
[57] or Au(III)/Au(I) [134] reduction process. The use of mercury [135] or ruthe-
nium [136] was also noticeable, but limited to oxygen-tethered enynes. Toste et al.
[137] disclosed an original variant for the synthesis of vinylsilanes. Intramolecular
cyclizations of 1,6-enynes having a hydroxyl substituent on the alkene chain have
also been described leading to bicyclic derivatives [56, 85].
Carboxylic acids have been found to be excellent partners for such transfor-
mations too, as exemplified in the case of enyne 115, which is stereospecifically
Z R1
Z
R1, R2, R3 = H, Me, Ph, 3,4-(OCH2O)C6H3
ROH = H2O, MeOH, allylOH
1,4-dioxane/H2O (6 : 1) 80 °C
5 mol% PtCl2 MeOH, reflux
10 mol% AuCl3 10 mol% PPh3
30 mol% AgSbF6 allyl-OH, rt
1 mol% Au(PPh3)Me 2 mol% TFA
MeOH, rt
Cy2
Ru
Cl
Cl
113 114
transformed to the cis bicyclic derivative 116, whereas the (E) isomer is giving
the trans adduct (Scheme 3.26, Equation 37) [138]. A formal [4 + 2] intramolecu-
lar cycloaddition of the N-alkynyl tert-butyloxycarbamate 117 in the presence of
cationic gold(I) catalyst has led to the bicyclic adduct 118 in 78% yield, the process
being totally diastereoselective (Scheme 3.26, Equation 38) [139].The intramolec-
ular enynes phenoxycyclization of 1,5-enynes was conducted in the presence of
platinum(II) and gold complexes (Scheme 3.26, Equation 39) [140].The enyne (E)- 119 was, for example, converted in the presence of 1mol% of the cationic gold(I)
Ph3PAuNTf2 platinum complex to the tricyclic derivative trans-120 in good 80%
yield, the trans relationship between the groups on both sides of the junction of
the ring formed being rationalized via a chair-type intermediate.
5 mol% Ph3PAuCl 5 mol% AgSbF6
CH2Cl2, rt
sions.The first example of domino hydroxycyclization involved a catalytic system
employing 5mol% of platinum(II) dichloride, 12.5mol% of silver salt AgSbF6, and
15mol% of an atropisomeric monophosphine ligand (Table 3.1, entry 1) [141].
The secondary alcohol 123 was obtained via a 5-exo-dig cyclization in 94% yield
and 85% enantiomeric excess. A similar system was proposed involving ligands
such as (S)-TolBINAP, but did not give better results (Table 3.1, entry 2) [142].
The use of bimetallic complexes of gold(I) or generation of Au(I) complex from
Au(III) catalyst, with an atropisomeric bidentate ligand such as a BINAP [142]
or MeOBIPHEP [143, 144] analog, has then been employed, the corresponding
ethers 125, 126, 127, and alcohol 128 being isolated in very good yields and
moderate to excellent enantiomeric excesses (Table 3.1, entries 3, 5, 6, 7). The
results highly depend on the structure and more precisely on the substitution
of the enyne. In the case of hindered enynes (Table 3.1, entries 6, 7), excellent
Table 3.1 Examples of asymmetric domino alkoxylation and carboxylation/cyclization
processes.
60 C MeO2C
6mol% AgSbF6 MeOH, rt
5 10mol% AuCl3/(R)-L2 [144]
30mol% AgSbF6 EtOH, rt
Table 3.1 (Continued)
DCE, rt
Table 3.1 (Continued)
N N
Ph Ph
CHAr2 Ar2HC
N L6
enantiomeric excesses were obtained for the resulting ether 127 or alcohol 128. The ligand as expected also influenced the enantioselection of the reaction. The
use of a chiral NHC ligand such as L5 (Table 3.1, entry 4) led to enantiomeric
excesses up to 72% [145, 146].
The addition of acetic acid as a nucleophile in the presence of an axially chiral
NHC ligand afforded the functionalized pyrrolidine 129 in excellent yield and 59% enantiomeric excess (Table 3.1, entry 8) [147]. Intramolecular asymmetric version
of the carboxy- and phenoxycyclization only appeared recently in the literature
(Table 3.1, entries 9, 10) [148].
Recently, this methodology was applied for the synthesis of functionalized
indene derivatives such as 133 (Scheme 3.27, Equation 40), the use of a bimetallic
gold complex giving rise to the ether 133 in 84% enantiomeric excess [81].
Ph
Ph
Ar = 3,5-Me2C6H3
MeO PAr2
MeO PAr2
(40)
Liu and coworker [149] reported the gold cationic Au(I)-catalyzed ben-
zoannulation of 3-alkoxy-1,5-enynes 134 bridged by a cyclopropyl group with
nucleophiles such as alcohols (Scheme 3.28).The best system for this transforma-
tion was the AuClPPh3/AgBF4 combination providing substituted benzenes 135. The reaction proceeds presumably through intermediates A, B, and C. Alcohols nucleophiles containing unsaturated alkenes and alkynes are tolerated in this
Au(I) catalytic transformation as shown in selected examples 135a–c.
R1
OMe
R3
R2
O R4
Apart from alcohols and carboxylic acids, other oxygenated nucleophiles have
been engaged in domino cyclization processes of enynes.
Domino Processes in the Presence of Sulfoxide or NitroneAdducts A peculiar reactiv-
ity of enynes was demonstrated by the presence of unsaturated oxygen derivatives
such as sulfoxides or oxygen. The first example of oxidative rearrangement was
described in the presence of palladium(II) dichloride in the case of enyne 136 (Scheme 3.29, Equation 41) [131c]. The alcohol 137a was formed according to
the previously described hydroxycyclization whereas the bicyclic aldehyde 137b was obtained in 10% yield. Toste’s group described few years later a very effi-
cient oxidative rearrangement by addition of diphenylsulfoxide in the presence of
N-heterocyclic gold(I) complex IPrAuCl and silver salt (Scheme 3.29, Equation 42)
[150]. Several 1,6-enynes 138 were cleanly converted to 139 via intermediate A, in 90–94% isolated yields.
5 mol% PdCl2
[Au]
H
Ph
O
SPh2
(41)
O
(42)
138
139
X
Ph2SO, CH2Cl2, rt
Scheme 3.29
In the case of enyne 140 (Scheme 3.29, Equation 43), an isomerization on the
cyclopropylcarbenoid specie as depicted in Scheme 3.1 most probably occurred,
leading finally to aldehyde 141 in 85% yield.
The first example of asymmetric version of this rearrangement appeared in 2011
in the presence of an axially chiral NHC ligand L8 (Scheme 3.30, Equation 44)
and was for the moment still limited to nitrogen-linked 1,6-enynes [147]. For
example, the ox

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Modern Alkyne Chemistry: Catalytic and Atom-Economic Transformations