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Modern Alkyne Chemistry

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Edited byBarry M. Trost and Chao-Jun Li

Modern Alkyne Chemistry

Catalytic and Atom-Economic Transformations

The Editors

Prof. Dr. Barry M. TrostStanford UniversityDepartment of Chemistry330 Roth WayStanfordCA 94305-5080USA

Prof. Dr. Chao-Jun LiMcGill UniversityDepartment of Chemistry801 Sherbrook Street WestMontrealQuebec H3A 0B8Canada

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V

Contents

List of Contributors XIIIPreface XVII

1 Introduction 1Chao-Jun Li and Barry M. Trost

1.1 History of Alkynes 11.2 Structure and Properties of Alkynes 21.3 Classical Reactions of Alkynes 21.4 Modern Reactions 41.5 Conclusion 6

References 7

Part I Catalytic Isomerization of Alkynes 9

2 Redox Isomerization of Propargyl Alcohols to Enones 11Barry M. Trost

2.1 Introduction 112.2 Base Catalysis 122.3 Ru Catalyzed 152.4 Rh Catalysis 202.5 Palladium Catalysis 222.6 Miscellaneous 242.7 Conclusions 25

References 25

3 Carbophilic Cycloisomerization Reactions of Enynes and DominoProcesses 27Jean-Pierre Genet, Patrick Y. Toullec, and VéroniqueMichelet

3.1 Introduction and Reactivity Principles 273.1.1 The Reactivity of Carbophilic Lewis Acids in the Presence of Enyne

Substrates 273.2 Skeletal Rearrangement Reactions in the Absence of

Nucleophiles 283.2.1 Synthesis of Dienes (1,3- and 1,4-Dienes) 28

VI Contents

3.2.2 Cycloisomerization Reactions Involving Activated Alkene Partners:Conia-Ene Reaction and Related Transformations 32

3.2.3 Formation of Bicyclic Derivatives 373.2.3.1 Formation of Bicyclopropanes 373.2.3.2 Formation of Bicyclobutenes 413.2.3.3 Formation of Larger Rings via Cycloisomerization-

Rearrangements 423.3 Enyne Domino Processes 443.3.1 Domino Enyne Cycloisomerization–Nucleophile Addition

Reactions 443.3.1.1 Oxygen and Nitrogen Nucleophiles 453.3.1.2 Carbon Nucleophiles 543.4 Conclusion 61

References 62

4 Alkyne Metathesis in Organic Synthesis 69Alois Fürstner

4.1 Introduction 694.2 Mechanistic Background and Classical Catalyst Systems 704.3 State-of-the-Art Catalysts 754.4 Basic Reaction Formats and Substrate Scope 804.5 Selected Applications 854.5.1 Dehydrohomoancepsenolide 854.5.2 Olfactory Macrolides 864.5.3 Haliclonacyclamine C 874.5.4 Hybridalactone 884.5.5 Cruentaren A 884.5.6 The Tubulin-Inhibitor WF-1360F 894.5.7 Neurymenolide A 914.5.8 Leiodermatolide 914.5.9 Tulearin C 944.5.10 The Antibiotic A26771B 954.5.11 Lactimidomycin 964.5.12 Citreofuran 974.5.13 Polycavernoside 984.5.14 Amphidinolide F 994.5.15 Spirastrellolide F Methyl Ester 1014.6 Conclusions 102

References 108

Part II Catalytic Cycloaddition Reactions 113

5 Alkyne–Azide Reactions 115Sanne Schoffelen andMortenMeldal

5.1 Introduction 115

Contents VII

5.2 Reviews on Cu-Catalyzed Azide–Alkyne Cycloaddition 1175.3 Mechanistic Considerations on the Cu(1) Catalysis 1185.4 The Substrates for CuAAC 1215.5 The Environment 1245.6 Modified 1,2,3-Triazoles and CuAAC Side Reactions 1255.6.1 Oxidative Couplings of Cu(1)–Triazole Complexes 1255.6.2 Reactions in the 5-Position of Triazoles 1255.6.3 Side Reactions due to Substrate Instability 1265.7 The Catalyst 1265.7.1 Recent Ligands and their Influence on Cu(1) Catalysis 1265.7.2 Catalyst Structure–Activity Relationship 1285.7.3 In Situ Generated CuAAC: Electro-, Photo-, and Self-Induced

“Click” 1305.8 Optimizing Conditions for CuAAC Reactions 1315.9 CuAAC in Biological Applications 1325.10 Biocompatibility of the CuAAC Reaction 133

References 137

6 Catalytic Cycloaddition Reactions 143Fiona R. Truscott, Giovanni Maestri, Raphael Rodriguez, andMaxMalacria

6.1 Introduction 1436.2 (2 + 2) Cycloaddition 1436.3 (3 + 2) and (2 + 1) Cycloaddition 1456.4 (4 + 2) Cycloaddition 1466.5 (5 + 1) and (4 + 1) Cycloadditions 1496.6 (5 + 2) Cycloaddition 1506.7 (6 + 2) Cycloaddition 1526.8 (2 + 2 + 1) Cycloaddition 1536.9 (2 + 2 + 2) Cycloaddition 1556.10 (3 + 2 + 1) Cycloaddition 1586.11 (3 + 2 + 2) Cycloaddition 1596.12 (4 + 2 + 1) and (4 + 2 + 2) Cycloaddition 1606.13 (4 + 3 + 2) Cycloaddition 1636.14 (5 + 2 + 1) and (5 + 1 + 2 + 1) Cycloadditions 1636.15 (2 + 2 + 1 + 1) and (2 + 2 + 2 + 1) Cycloadditions 1646.16 (2 + 2 + 2 + 2) Cycloaddition 1656.17 Conclusions 166

References 166

Part III Catalytic Nucleophilic Additions and Substitutions 171

7 Catalytic Conjugate Additions of Alkynes 173Naoya Kumagai andMasakatsu Shibasaki

7.1 Introduction 1737.2 Metal Alkynylides as Nucleophiles 173

VIII Contents

7.2.1 Conjugate Addition of Metal Alkynylides 1737.2.1.1 Conjugate Addition of Metal Alkynylides to s-cis α,β-Enones 1737.2.1.2 Conjugate Addition of Metal Alkynylides with a Catalytic

Promoter 1767.2.1.3 Conjugate Addition of Metal Alkynylides with Stoichiometric

Promoters 1777.2.2 Enantioselective Conjugate Addition of Metal Alkynylides 1787.2.2.1 Use of a Stoichiometric Amount of Chiral Sources 1787.2.2.2 Catalytic Enantioselective Conjugate Addition of Metal

Alkynylides 1807.3 Direct Use of Terminal Alkynes as Pronucleophiles 1827.3.1 Direct Catalytic Conjugate Addition of Terminal Alkynes 1827.3.1.1 Introduction 1827.3.1.2 Addition to Vinyl Ketones and Acrylates 1827.3.1.3 Addition to β-Substituted α,β-Enones 1847.3.2 Enantioselective Direct Catalytic Conjugate Addition of Terminal

Alkynes 1887.4 Summary and Conclusions 196

References 196

8 Catalytic Enantioselective Addition of Terminal Alkynes toCarbonyls 201Barry M. Trost andMark J. Bartlett

8.1 Introduction 2018.2 Metallation of Terminal Alkynes: Formation of Alkynyl

Nucleophiles 2038.2.1 Deprotonation of Terminal Alkynes 2038.2.2 Oxidative Insertion and Ligand Exchange: Formal Metallation of

Terminal Alkynes 2058.3 Ligand-Catalyzed Alkyne Additions with Stoichiometric Quantities

of Metal 2078.3.1 Addition of Alkynylzinc Nucleophiles to Aldehydes, Ketones, and

Imines 2078.3.2 Titanium-Catalyzed Alkynylation of Aldehydes and Ketones 2178.3.3 Asymmetric Boron-Catalyzed Alkyne Additions to Aldehydes 2228.4 Alkyne Additions with Catalytic Amounts of Metal 2228.4.1 Asymmetric Alkyne Additions to Aldehydes and Ketones Catalyzed

by Zinc Salts 2228.4.2 Indium-Catalyzed Alkyne Additions to Aldehydes 2248.4.3 Chromium-Catalyzed Alkynylation of Aldehydes with

Haloacetylenes 2258.4.4 Copper-Catalyzed Alkynylation of Aldehydes and Trifluoromethyl

Ketones 2278.4.5 Palladium-Catalyzed Additions to α,β-Unsaturated Carbonyls and

Trifluoropyruvate 229

Contents IX

8.4.6 Enantioselective Ruthenium-Catalyzed Alkynylation ofAldehydes 230

8.4.7 Rhodium-Catalyzed Alkynylation of α-Ketoesters 2318.5 Concluding Remarks 232

References 233

9 Catalytic Nucleophilic Addition of Alkynes to Imines: The A3

(Aldehyde–Alkyne–Amine) Coupling 239Nick Uhlig, Woo-Jin Yoo, Liang Zhao, and Chao-Jun Li

9.1 A3 Couplings Involving Primary Amines 2399.2 A3 Couplings Involving Secondary Amines 2429.3 Alkyne Additions with Reusable Catalysts 2449.4 Asymmetric Alkyne Addition Reactions 2469.4.1 Asymmetric A3-Type Couplings with Primary Amines 2469.4.2 Asymmetric A3-Type Couplings with Secondary Amines 2509.5 Alkyne Additions to Imines in Tandem Reactions 2519.5.1 A3 Coupling with Tandem Cycloisomerizations Involving the Alkyne

Triple Bond 2529.5.2 Tandem Processes Involving Other Transformations of the Alkyne

Triple Bond 2579.5.3 Tandem Processes Involving Decarboxylations 2599.5.4 Tandem Processes Involving Both the Amine and the Alkyne 2609.6 Conclusion 262

References 263

10 The Sonogashira Reaction 269Rafael Chinchilla and Carmen Nájera

10.1 Introduction 26910.2 Palladium–Phosphorous Catalysts 27010.2.1 Unsupported Palladium–Phosphorous Catalysts 27010.2.1.1 Copper-Cocatalyzed Reactions 27010.2.1.2 Copper-Free Reactions 27310.2.2 Supported Palladium–Phosphorous Catalysts 27410.2.2.1 Copper-Cocatalyzed Reactions 27410.2.2.2 Copper-Free Reactions 27510.3 Palladium–Nitrogen Catalysts 27610.3.1 Unsupported Palladium–Nitrogen Catalysts 27610.3.2 Supported Palladium–Nitrogen Catalysts 27710.4 N-Heterocyclic Carbene (NHC)-Palladium Catalysts 27810.4.1 Unsupported NHC-Palladium Catalysts 27810.4.2 Supported NHC-Palladium Catalysts 27910.5 Palladacycles as Catalysts 28010.5.1 Unsupported Palladacycles as Catalysts 28010.5.2 Supported Palladacycles as Catalysts 28110.6 Ligand-Free Palladium Salts as Catalysts 282

X Contents

10.6.1 Unsupported Ligand-Free Palladium Salts as Catalysts 28210.6.2 Supported Ligand-Free Palladium Salts as Catalysts 28310.7 Palladium Nanoparticles as Catalysts 28310.7.1 Unimmobilized Palladium Nanoparticles as Catalysts 28310.7.2 Immobilized Palladium Nanoparticles as Catalysts 28410.7.2.1 Copper-Cocatalyzed Reactions 28510.7.2.2 Copper-Free Reactions 28510.8 Non-Palladium-Based Catalysts 28710.9 Mechanistic Considerations 28910.10 Summary and Conclusions 291

References 291

Part IV Other Reactions 299

11 Catalytic Dimerization of Alkynes 301Sergio E. Garćıa-Garrido

11.1 Introduction 30111.2 Dimerization of Alkynes Catalyzed by Iron, Ruthenium, and

Osmium Complexes 30211.2.1 Homo-Coupling of Terminal Alkynes 30211.2.2 Cross-Dimerization of Alkynes 31011.3 Dimerization of Alkynes Catalyzed by Cobalt, Rhodium, and Iridium

Complexes 31111.3.1 Homo-Coupling of Terminal Alkynes 31111.3.2 Cross-Dimerization of Alkynes 31511.4 Dimerization of Alkynes Catalyzed by Nickel, Palladium, and

Platinum Complexes 31711.4.1 Homo-Coupling of Terminal Alkynes 31711.4.2 Cross-Dimerization of Alkynes 32011.5 Dimerization of Alkynes Catalyzed by Group 3, Lanthanide, and

Actinide Complexes 32211.6 Dimerization of Alkynes Catalyzed by Titanium, Zirconium, and

Hafnium Complexes 32511.7 Dimerization of Alkynes Catalyzed by Other Compounds 32611.8 Summary and Conclusions 327

Acknowledgments 327References 328

12 The Oxidative Dimerization of Acetylenes and Related Reactions:Synthesis and Applications of Conjugated 1,3-Diynes 335Jean-Philip Lumb

12.1 Introduction 33512.2 Syntheses of Conjugated 1,3-Diynes 33612.3 Scope and Limitation of the Alkyne Dimerization Reaction 33812.3.1 Choice of Copper Salt 338

Contents XI

12.3.2 Choice of Solvent 33912.3.3 Substituents on the Alkyne and Basic Additives 33912.3.4 Additional Metals 34012.4 Scope and Limitation of Copper-Catalyzed Hetero-Coupling

Reactions 34012.5 The Cadiot–Chodkiewicz Reaction 34112.6 Palladium-Catalyzed Acetylenic Coupling Reactions 34312.7 Alternative Methods for the Synthesis of Diynes 34412.8 Mechanism of Alkyne Homo-Coupling Reactions 34412.9 Mechanism of Alkyne Hetero-Coupling Reactions 34712.10 Utility of 1,3-Diynes in the Synthesis of Natural Products 34912.11 Synthetic Utility of Conjugated 1,3-Diynes 35112.12 Utility of 1,3-Diynes in Materials Science 35512.13 Conclusion 359

References 359

13 The Alkyne Zipper Reaction in Asymmetric Synthesis 365Kenneth Avocetien, Yu Li, and George A. O’Doherty

13.1 Introduction 36513.2 Mechanism of KNH2/NH3 Isomerization 36613.3 Mechanism of KAPA Isomerization 36813.4 Applications in Natural Products 37013.4.1 Galacto-Sugar γ-Lactones 37113.4.2 Galacto-Sugar δ-Lactones 37113.4.3 (-)–Apicularen A 37113.4.4 Milbemycin β3 37313.4.5 Cryptocaryols A and B 37313.4.6 Tricolozin A 37413.4.7 Elenic Acid 37613.4.8 Daumone 37713.4.9 (+)–Broussonetine G 37913.4.10 Cladospolides A, B, C, iso-Cladospolide B and

(ent)-Cladospolide D 37913.4.11 Shingolipid Analogs 38413.4.12 Irciniasulfonic Acids 38613.4.13 Clathculins A and B 38613.4.14 Cephalosporolide H 38713.4.15 (+)–Aspicilin 38913.4.16 Merremoside D 38913.4.17 Aspergillide B 39213.5 Conclusion 393

References 393

Index 395

XIII

List of Contributors

Kenneth AvocetienNortheastern UniversityDepartment of Chemistry andChemical Biology102 Hurtig Hall360 Huntington AveBostonMA 02115USA

Mark J. BartlettUniversity of California BerkeleyDepartment of ChemistryBerkeleyCA 94720-1460USA

Rafael ChinchillaUniversity of AlicanteDepartment of OrganicChemistryFaculty of Sciences and Instituteof Organic Synthesisctra. San Vicente s/n03690 AlicanteSpain

Alois FürstnerMax-Planck-Institut fürKohlenforschungKaiser-Wilhelm-Platz 145470 Mülheim an der RuhrGermany

Sergio E. Garćıa-GarridoUniversidad de OviedoLaboratorio de CompuestosOrganometálicos y CatálisisRed ORFEO-CINQA - Centro deInnovación en Quı́micaAvanzadaIUQOEM, Facultad de Quı́micaC/Julián Claveŕıa 833006 OviedoSpain

Jean-Pierre GenetPSL Research UniversityChimie ParisTech - CNRSInstitut de Recherche de ChimieParis11 rue P. et M. Curie75005 Paris Cedex 05France

XIV List of Contributors

Naoya KumagaiInstitute of Microbial Chemistry(Bikaken)Laboratory of Synthetic OrganicChemistry3-14-23 KamiosakiShinagawa-kuTokyo 141-0021Japan

Chao-Jun LiMcGill UniversityDepartment of Chemistry801 Sherbrook Street WestMontrealQuebec H3A 0B8Canada

Yu LiNortheastern UniversityDepartment of Chemistry andChemical Biology102 Hurtig Hall360 Huntington AveBostonMA 02115USA

Jean-Philip LumbMcGill UniversityDepartment of Chemistry801 Sherbrooke Street West,Room 322MontrealQuebec H3A 0B8Canada

Giovanni MaestriInstitut de Chimie desSubstances NaturellesCNRS-UPR 23011, avenue de la Terrasse-Bât.2791198 Gif/Yvette CedexFrance

MaxMalacriaInstitut de Chimie desSubstances NaturellesCNRS-UPR 23011, avenue de la Terrasse-Bât.2791198 Gif/Yvette CedexFrance

MortenMeldalUniversity of CopenhagenDepartment of ChemistryCenter for EvolutionaryChemical Biology (CECB)Universitetsparken 52100 CopenhagenDenmark

VéroniqueMicheletPSL Research UniversityChimie ParisTech - CNRSInstitut de Recherche de ChimieParis11 rue P. et M. Curie75005 Paris Cedex 05France

Carmen NájeraUniversity of AlicanteDepartment of OrganicChemistryFaculty of Sciences and Instituteof Organic Synthesisctra. San Vicente s/n03690 AlicanteSpain

George A. O’DohertyNortheastern UniversityDepartment of Chemistry andChemical Biology102 Hurtig Hall360 Huntington AveBostonMA 02115USA

List of Contributors XV

Raphael RodriguezInstitut de Chimie desSubstances NaturellesCNRS-UPR 23011, avenue de la Terrasse-Bât.2791198 Gif/Yvette CedexFrance

Sanne SchoffelenUniversity of CopenhagenDepartment of ChemistryCenter for EvolutionaryChemical Biology (CECB)Universitetsparken 52100 CopenhagenDenmark

Masakatsu ShibasakiInstitute of Microbial Chemistry(Bikaken)Laboratory of Synthetic OrganicChemistry3-14-23 KamiosakiShinagawa-kuTokyo 141-0021Japan

Patrick Y. ToullecPSL Research UniversityChimie ParisTech - CNRSInstitut de Recherche de ChimieParis11 rue P. et M. Curie75005 Paris Cedex 05France

BarryM. TrostStanford UniversityDepartment of Chemistry330 Roth WayStanfordCA 94305-5080USA

Fiona R. TruscottInstitut de Chimie desSubstances NaturellesCNRS-UPR 23011, avenue de la Terrasse-Bât.2791198 Gif/Yvette CedexFrance

Nick UhligMcGill UniversityDepartment of Chemistry801 Sherbrook Street WestRoom 322MontrealQuebec H3A 2K6Canada

Woo-Jin YooMcGill UniversityDepartment of Chemistry801 Sherbrook Street WestRoom 322MontrealQuebec H3A 2K6Canada

Liang ZhaoMcGill UniversityDepartment of Chemistry801 Sherbrook Street WestRoom 322MontrealQuebec H3A 2K6Canada

XVII

Preface

Alkyne is a basic functionality with “relatively low thermodynamic reactivities”in the classical text of organic chemistry. These classical alkyne reactions oftenrequire stoichiometric reagents, which result in low efficiency in chemicalsyntheses, and “harsh” reaction conditions that cannot tolerate the presenceof the various “more reactive functional groups”. The pursuit of syntheticefficiency combined with the recent emphasis of “future sustainability and GreenChemistry,” and the pressing desire for new chemical tools in synthetic biologyinspire chemists to uncover new reactions that are catalytic in nature (rather thanconsuming stoichiometric reagents), occur under ambient conditions (includingmilder 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 functionalgroups and under mild conditions, via transition-metal catalysis through eitherselective alkyne carbon-carbon triple bond reactions or terminal alkyne C-Hbond reactions. Such a unique reactivity allow alkynes to be embedded andbe “dialed-up” whenever needed. For the past few decades, modern alkynechemistry has thus been developed rapidly to feature these characteristics. Thesedevelopments further focus on atom-economic transformations where minimalor no theoretical by-products are formed. Furthermore, many of these catalytictransformations are orthogonal to biological conditions. These modern catalyticalkyne reactions are much more resource-, time-, and manpower-efficient, andprovide an alternative to classical stoichiometric alkyne chemistry. This bookcomprises a collection of contributions from leading experts and covers variousmodern catalytic reactions of alkynes. We hope that this focused book will bevery helpful not only to students and researchers in chemistry but also to those inmaterial and biological studies and will provide themwith tools and opportunitiesunavailable with classical alkyne chemistry.

Stanford Barry M. TrostMontreal Chao-Jun LiAugust 2014

1

1IntroductionChao-Jun Li and Barry M. Trost

1.1History 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 andnamed “acetylene” by Marcellin Berthelot in 1860 by passing vapors of organiccompounds through a red-hot tube or sparking electricity through a mixtureof cyanogen and hydrogen gas. Acetylene is a moderately common chemicalin the universe [3], often in the atmosphere of gas giants. In 1862, FriedrichWöhler discovered the generation of acetylene from the hydrolysis of calciumcarbide (Equation 1.1). Acetylene produced by this reaction was the main sourceof organic chemicals in the coal-based chemical industry era. When petroleumreplaced coal as the chief source of carbon in the 1950s, partial combustion ofmethane (Equation 1.2) or formation as a side product of hydrocarbon crackingbecame the prevalent industrial manufacturing processes for acetylene. Thenext member of the family, propyne, is also mainly prepared by the thermalcracking 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 sincethen, among which many are polyyne-containing natural products isolated fromplants, 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 homologsvia alkyne homologation processes of the terminal alkynes (see Equation 1.8,below), while some alkynes are generated through elimination reactions withorganic halides under basic conditions (Equation 1.3) [1]. A search in Sci Findershows that >70 000 terminal alkynes and >10 000 internal alkynes are nowcommercially available from various sources.

RR′

X

XR

R′X X B

−

R′Ror (1.3)

1.2Structure 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 aregenerally rod-like. Cyclic alkynes are less common with benzyne as an importantreactive intermediate in organic chemistry [6]. Acetylene is linear and intrinsicallyunstable under pressure due to its high compressibility as well as its propensityto undergo exothermic self addition reactions. Consequently, acetylene itself canexplode violently at high pressure and the safe limit for acetylene is 103 kPa.Thus,acetylene is generally shipped in acetone or dimethyl formamide (DMF) solutionsor contained in a gas cylinder with porous filling [7]. Acetylene has been used asa burning fuel and for illumination purposes in the late nineteenth century andearly twentieth century [8]. In modern times, alkynes have found a wide rangeof applications ranging from organic electronic materials, metal-organic frameworks (MOF), pharmaceutical agents, and others [9]. The linearity of the alkynecreates 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, theirexistence being confirmed by in situ trapping, notably by 1,3-dipolar cycload-ditions [11]. Cyclooctyne is still highly strained but has sufficient stability to beisolated and used in click chemistry to study biological processes [12].

R R′

2

1.3Classical Reactions of Alkynes

The higher degree of unsaturation of alkynes compared to alkenes increases theirreactivity toward addition to both alkenes and alkynes. In particular, virtuallyall 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 theclassical alkyne chemistry (Equation 1.4) [1]. These classical alkyne additionreactions include the additions of hydrogen, halogens, water, hydrogen halides,halohydrins, hydroborations, and others. With a stoichiometric amount of astrong oxidizing reagent such as KMnO4, the addition may be followed by C–Ccleavage to give the corresponding acids (Equation 1.5). Less reactive reagentscan also be added through the use of a transition-metal catalyst. The uniqueelectronic character of alkynes wherein their HOMO–LUMO gap is rather smallmakes them especially effective as coordinators to transition metals. Thus, theyfunction as chemoselective functional groups for catalytic transformations. Forexample, catalytic addition of dihydrogen to alkynes can proceed to either alkenesor alkanes depending on the choice of the catalysts (Equation 1.6) [13]. Further,the hydroalumination [14], hydrosilylation [15], hydrostannylation [16], as wellas carboalumination [17] represent important modern advances of the alkyneaddition reactions.

RRX Y

YR

RX

RR

YX+

X Y: halogens, HX, HOH, HOCl, HBR2, etc.

(1.4)

RRKMnO4 RCO2H + HO2CR′ (1.5)

RRH2

cat. M RR

HH H2

cat. MR-CH2CH2-R (1.6)

A second class of reactions pertains to terminal alkynes. Due to the increaseds-character, the alkynyl C–Hbonds (pK a = 25) aremuchmore acidic than the cor-responding alkenyl C–H bonds (pK a = 43) and alkyl C–H bonds (pK a > 50) [18].Thus, base-promoted additions of terminal alkynes to carbonyl compounds canoccur 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 producevarious higher alkyne homologs in the classical synthetic chemistry (Equation 1.8)[1]. Such processes can be catalyzed to permit deprotonation with much weakerbases as in the coupling with aryl halides under Pd/Cu catalysis (Sonogashira reac-tion, see Equation 1.13).

R H +R′ R′′

O BaseR

R′R′′

OH(1.7)

R + B− RHE+

R E (1.8)

4 1 Introduction

1.4Modern Reactions

Although the classical stoichiometric addition reactions, alkyne cleavage reac-tions, and homologation reactions have established the foundation of alkynechemistry, a rebirth of interest derives from recent concerns regarding societaland ecological sustainability under the mantra of Green Chemistry [19], whichemphasizes chemical transformations that are more atom economic [20] andchemoselective, thereby minimizing the use of protecting groups [21]. Further-more, rapid developments in the field of chemical biology demand chemicaltransformations that are orthogonal to biological conditions and functionalitiesin bioorganisms and which can work efficiently under both in vitro and in vivobiological conditions [22]. Alkynes, being both good π-donors and π-acceptorsfor transition metals as well as being energy rich, can be effectively activatedby a catalyst thereby lowering the energy barrier to proceed to the more stableproducts while being unreactive toward various biological elements. At the sametime, they can be chemoselectively activated in the presence of most typicalfunctional groups (e.g., hydroxyl and carbonyl groups as well as alkenes) and inprotic solvents including water [23]. Such triggered reactivities are orthogonalto the classical reactivities and can be tuned to target specific desired reactionsites while maintaining tolerance toward other functionalities through thediscrete choice of catalyst, which will greatly simplify the syntheses of complexcompounds and allow direct modifications of biomolecules in their native statesand 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 isomerizationreactions of alkyne.Although alkyne oligomerization was known at a high temperature since the

late nineteenth century [2], various cyclization reactions of alkynes catalyzed bytransition metals are among the most important developments in modern alkynechemistry.Themost well-known examples include the transition-metal-catalyzed[2 + 2 + 2] cycloaddition reactions (Equation 1.9) [24], the Pauson–Khand-typereaction of alkyne–alkene–carbon monoxide (Equation 1.10) [25], the enynecyclization reactions (Equation 1.11) [26], and the 1,3-dipolar cycloaddition suchas that with azides (the archetypical Click reaction) (Equation 1.12) [27].

+cat. (1.9)

+ + COcat.

O

(1.10)

1.4 Modern Reactions 5

cat.

cat.(1.11)

R + N3 R′ NNN

R R′cat.

(1.12)

The second major class of modern alkyne reactions is the catalytic transfor-mation of terminal alkyne C–H bonds. Although homologation of terminalalkynes through the reactions of metal acetylides with organic halide is a classicalalkyne reaction, such a reaction cannot be applied to aryl and vinyl halides dueto their inert nature in nucleophilic substitution reactions. The development ofcatalytic coupling of terminal alkynes with aryl and vinyl halides (the Sonogashirareaction) has overcome this classical challenge and opened up a new reactivitymode in alkyne homologation (Equation 1.13) [28]. Complimentary to theclassical Favorskii reaction (Equation 1.7), the modern development of catalyticdirect addition of terminal alkynes to aldehydes provides great opportunities ingenerating optically active propargyl alcohols (Equation 1.14) [29]. The catalyticdirect 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 theother hand, the catalytic oxidative dimerization (Glaser–Hay coupling) [32] andsimple alkyne dimerization (Equation 1.17) [33] which date from the late 1800shave become increasingly important in modern synthetic chemistry.

R X Ar+ R Arcat.

−HX(1.13)

R +R′ R′′

O

R′ R′′

OH

R

cat.(1.14)

R +R′ R′′

NR′′′

R′ R′′

NHR′′′

R

cat.(1.15)

R +

R

O

R′R′

Ocat. (1.16)

6 1 Introduction

R R+cat.

[O]RR

R

R+

R

R

(1.17)

Two additional processes that have much unrealized potential in syntheticchemistry are the alkyne disproportionation (metathesis) and the alkyne redoxisomerization reactions. Like the alkene metathesis, the catalytic alkyne–alkynemetathesis reaction retains all functionalities by switching the groups attachedto the alkynes (Equation 1.18) [34]. Another unique atom-economic reactionof alkynes that is currently under-utilized but will have a great potential forfuture development is the “alkyne-zipper reaction” (Equation 1.19) [35]. Suchreactions shift readily accessible internal alkyne triple bond to terminal positionsfor further homologations. A different type of “retaining functionality is found inthe redox isomerization of propargyl alcohols to generate conjugated ketones”(Equation 1.20) [36].

R R R′ R′+ R R′ R R′+cat.

(1.18)

Rn

cat.nR (1.19)

R′R

OHcat.

R R′

O

(1.20)

1.5Conclusion

With the recent emphasis on sustainability and the ever increasing needs in syn-thetic efficiency, alkynes provide a truly unique functionality that is orthogonal toother functional groups, biological conditions, and ambient environment, yet canbe selectively triggered to occur in a specific reaction mode with the absence ofprotecting groups or anhydrous conditions. Such reactions will have great poten-tial to simplify synthetic chemistry and will find wide applications in chemicalbiology and organic materials. This book, comprising experts on related subjects,provides an overview of developments of modern alkyne reactions. Due to thelimit 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

1. (a) McMurry, J. (2007) OrganicChemistry-A Biological Approach,Thomson Brooks/Cole, Belmont, CA;(b) Bruce, P.Y. (2004) Organic Chem-istry, 4th edn, Pearson Education, UpperSaddle River, NJ; (c) Wade, L.G. (2006)Organic Chemistry, 5th edn, PearsonEducation, 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. andWhitesell, J.K. (2004) Organic Chemistry,3rd edn, Jones & Bartlett Publishers.

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Handbook of Compressed Gases,Springer, London.

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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.

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25. Blanco-Urgoiti, J., Añorbe, L.,Pérez-Serrano, L., Domínguez, G., andPérez-Castells, J. (2004) Chem. Soc. Rev.,33, 32.

26. Lu, X., Zhu, G., Wang, Z., Ma, S., Ji, J.,and Zhang, Z. (1997) Pure Appl. Chem.,69, 553.

27. Kolb, H.C., Finn, M.G., and Sharpless,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. andWeiss, 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.Org. Chem., 4095; (d) Lu, G., Li, Y.-M.,

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.(2004) Synlett, 1472; (c) Zani, L. andBolm, C. (2006) Chem. Commun., 4263;(d) Peshkov, V.A., Pereshivko, O.P., andVan der Eycken, E.V. (2012) Chem. Soc.Rev., 41, 3790.

31. Yazaki, R., Kumagai, N., and Shibasaki,M. (2010) J. Am. Chem. Soc., 132, 10275.

32. Cadiot, P. and Chodkiewicz, W. (1969)in Chemistry of Acetylenes (ed. Viehe,G.H.), Marcel Dekker, New York, p. 597.

33. Trost, B.M., Sorum, M.T., Chan, C.,Harms, A.E., and Rühter, G.(1997) J. Am. Chem. Soc., 119,698.

34. Fürstner, A. and Davies, P.W. (2005)Chem. Commun., 2307.

35. Brown, C.A. and Yamashita, A. (1975)J. Am. Chem. Soc., 97, 891.

36. Trost, B.M. and Livingston, R.C.(1995) J. Am. Chem. Soc., 117,9586.

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38. Buchmeiser, M.R. (2005) Adv. Polym.Sci., 176, 89.

9

Part ICatalytic Isomerization of Alkynes

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.

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