N-Heterocyclic Carbenes in Organocatalysis

A. T. Biju received his M. Sc. from Sacred Heart College Thevara (affiliated to MG University, Kerala, India) and Ph.D. under the guidance of Dr. Vijay Nair at the CSIR-NIIST (Formerly RRL), Trivandrum, India. Subsequently, he has been a post-doctoral fellow with Prof. Tien-YauLuh at the National Taiwan University, Taipei and an Alexander von Humboldt fellow with Prof. Frank Glorius at the Westfälische Wilhelms-Universität Münster, Germany. In June 2011, he began his independent research career at the CSIR-National Chemical Laboratory, Pune. From June 2017 onwards, he has been an Associate Professor at the Department of Organic Chemistry, Indian Institute of Science, Bangalore. His research focuses on the development of transition-metal-free carbon-carbon and carbon-heteroatom bond-forming reactions using aryne chemistry and N-heterocyclic carbene (NHC) organocatalysis, and their application in organic synthesis. He is the recipient of AVRA Young Scientist Award (2016), CRSI Young Scientist Award (2015), NCL-Research Foundation Scientist of the Year Award (2014), ISCB Young Scientist Award (2014), Thieme Chemistry Journals Award (2014), OPPI Young Scientist Award (2012), Alexander von Humboldt Fellowship (2009), and is a member of the National Academy of Sciences, India (NASI), Allahabad (2012).

• Preface xiDiscovery of Catalysis by Nucleophilic Carbenes xiiiAbout the Editor xvii1 An Overview of NHCs 1Matthew N. Hopkinson and Frank Glorius1.1 General Structure of NHCs 21.1.1 Classes of NHCs and Related Stable Carbenes 21.1.2 Structural Features Common to All NHCs 41.1.3 Stabilization of the Carbene Center 51.2 NHCs as σ-Donating Ligands 71.2.1 The Nature of Bonding in NHC Adducts 101.2.2 Comparing NHC and Phosphine Ligands 101.3 Synthesis of NHCs 111.3.1 Generation of the Free Carbene 111.3.2 Synthetic Routes Toward Azolium Salt NHC Precursors 121.4 Quantifying the Electronic Properties of NHCs 161.4.1 pKa Measurements of Azolium Salts 161.4.2 Tolman Electronic Parameter (TEP) 171.4.3 NMR Measurements 211.4.4 Nucleophilicity and Lewis Basicity 241.4.5 Electrochemical Methods 241.4.6 Computational Methods 251.5 Quantifying the Steric Properties of NHCs 261.5.1 Percentage Buried Volume (%Vbur) 271.5.2 Steric Maps 291.6 Concluding Remarks 30References 302 Benzoin Reaction 37Steven M. Langdon, Karnjit Parmar, Myron M.D.Wilde, and Michel Gravel2.1 Background and Mechanism 372.2 Standard Conditions and Substrate Scope 402.3 Enantioselective Homo-benzoin Reactions 412.4 Cross-benzoin Reactions 422.4.1 Intramolecular Cross-benzoin Reactions 422.4.2 Intermolecular Cross-benzoin Reactions 472.5 Aza-benzoin Reactions 512.5.1 Aza-benzoin Reactions of Aldimines 512.5.2 Aza-benzoin Reactions of Ketimines 53References 543 N-Heterocyclic Carbene-catalyzed Stetter Reaction and Related Chemistry 59Santigopal Mondal, Santhivardhana R. Yetra, and Akkattu T. Biju3.1 Introduction 593.2 Proposed Mechanism of the Stetter Reaction 603.3 Intramolecular Stetter Reaction 613.4 Intermolecular Stetter Reaction 683.5 Cascade Processes Involving Stetter Reaction 793.6 NHC-catalyzed Hydroacylation Reactions 823.7 Conclusion 89References 894 N-Heterocyclic Carbene (NHC)-Mediated Generation and Reactions of Homoenolates 95Vijay Nair, Rajeev S. Menon, and Jagadeesh Krishnan4.1 Homoenolates – An Introduction 954.2 N-Heterocyclic Carbenes (NHCs) 974.3 NHC-Derived Homoenolates – The Beginning 984.4 Mechanistic Pathways Available for NHC-Homoenolates 1004.5 Reaction of NHC-Homoenolates with Ketones and Ketimines 1024.6 Reaction of NHC-Homoenolates with Michael Acceptors 1084.7 β-Protonation of Homoenolates and Subsequent Reactions 1174.8 Homoenolates in Carbon–Nitrogen Bond Formation 1224.9 Domino Reactions of Homoenolates 1244.10 New Precursors for Homoenolates 1264.11 Conclusion 129References 1295 Domino Processes in NHC Catalysis 133Pankaj Chauhan, Suruchi Mahajan, Xiang-Yu Chen, and Dieter Enders5.1 Introduction 1335.2 Domino Reactions Involving Homoenolate–Enolate Intermediates 1345.2.1 Domino Reactions Involving a Michael/Aldol Reaction Sequence 1345.2.2 Domino Reactions Involving a Michael/Michael Reaction Sequence 1385.2.3 Domino Reactions Involving a Michael/Mannich Reaction Sequence 1405.2.4 Domino Reactions Involving a Homo-aldol/Michael Addition Sequence 1425.3 Domino Reactions Involving Dienolate–Enolate Intermediates 1425.4 Domino Reactions Involving Unsaturated Acyl Azolium–Enolate Intermediates 1455.4.1 Domino Reactions Involving a Michael/Aldol Sequence 1455.4.2 Domino Reactions Involving a Michael/Michael Addition Sequence 1495.4.3 Domino Reactions Involving a Michael/Mannich Reaction Sequence 1525.4.4 Domino Reactions Involving a Michael/SN2 Reaction Sequence 1535.5 Conclusions and Outlook 153References 1546 N-Heterocyclic Carbene Catalysis via the 𝛂,𝛃-Unsaturated Acyl Azolium 157Changhe Zhang and David Lupton6.1 Introduction 1576.2 Generation of the α,β-Unsaturated Acyl Azolium 1576.3 Esterification of the α,β-Unsaturated Acyl Azolium 1596.4 [3+n] Annulations of the α,β-Unsaturated Acyl Azolium 1606.4.1 Annulation with Enolates 1616.4.2 Annulation with Eenamines 1656.4.3 Annulation with Other Nucleophiles 1686.5 [2+n] Annulations of the α,β-Unsaturated Acyl Azolium 1706.5.1 [2+4] Annulations Terminating in β-Lactonization 1706.5.2 [2+4] Annulations Terminating in 𝛿-Lactonization 1746.5.3 [2+3] Annulations Terminating in β-Lactonization 1746.5.4 [2+1] Annulations 1766.6 Cascades Involving Bond Formation at the γ-Carbon and Acyl Carbon 1776.6.1 Annulations with Ketones and Imines 1776.6.2 [4+2] Annulations with Electron-Poor Olefins 1806.7 Other Reactions of the α,β-Unsaturated Acyl Azolium 1816.8 Conclusions and Outlook 183References 1837 Recent Activation Modes in NHC Organocatalysis 187Zhichao Jin, Xingkuan Chen, and Yonggui R. Chi7.1 Introduction 1877.2 Activation of Carboxylic Acid Derivatives 1877.2.1 α-Carbon Activation of Saturated Carboxylic Esters 1887.2.2 β-Carbon Activation of α,β-Unsaturated Carboxylic Compounds 1917.2.3 Nucleophilic β-Carbon Activation of Saturated Carboxylic Esters 1957.2.4 γ-Carbon Activation of α,β-Unsaturated Carboxylic Esters 1987.3 Radical Reactions Catalyzed by NHC Organic Catalysts 1997.3.1 Lessons from Nature 1997.3.2 Pioneering SET Reactions in NHC Organocatalysis 2007.3.3 NHC-Catalyzed Reductive β,β-couplings of Nitroalkenes 2017.3.4 NHC-Catalyzed Benzylation of Electrophiles 2027.3.5 NHC-Catalyzed β-hydroxylation of α,β-Unsaturated Aldehydes 2047.3.6 Synthesis of Chiral 3,4-diaryl CyclopentanonesThrough SET Process 2057.3.7 Polyhalides as Oxidants for NHC-Catalyzed Radical Reactions 2067.3.8 New Mechanisms for Classical Reactions 2087.4 Summary and Outlook into the Future NHC Organocatalysis 209References 2108 N-Heterocyclic Carbene-Catalyzed Reactions via Azolium Enolates and Dienolates 213Zhao-Fei Zhang, Chun-Lin Zhang, and Song Ye8.1 Introduction 2138.2 Azolium Enolates from α-Functionalized Aldehydes 2138.2.1 Synthesis of Carboxylic Compounds 2138.2.2 Formal [2+4] Cycloaddition 2178.2.3 Formal [2+2] Cycloaddition 2228.2.4 Formal [2+3] Cycloaddition 2228.3 Azolium Enolate from Ketenes 2238.3.1 Formal [2+2] Cycloaddition 2248.3.2 Asymmetric Formal [2+3] Cycloadditions 2318.3.3 Asymmetric Formal [2+4] Cycloadditions 2328.3.4 Asymmetric Protonation and Halogenation 2368.4 Azolium Enolate from Enals 2378.5 Azolium Enolate from Aldehydes with Oxidant 2428.6 Azolium Enolates from Activated Esters 2448.7 Azolium Enolates from Acids 2478.8 Azolium Dienolate 2498.9 Conclusions and Outlook 257References 2579 N-heterocyclic Carbenes as Brønsted Base Catalysts 261Jiean Chen and Yong HuangReferences 28410 NHC-Catalyzed Kinetic Resolution, Desymmetrization, and DKR Strategies 287Shenci Lu, Si B. Poh, Jun Y. Ong, and Yu Zhao10.1 Introduction 28710.2 NHC-Catalyzed Acylation 28810.2.1 Acylation of Aliphatic Alcohols 29010.2.1.1 Acylation of Aliphatic Alcohols 29010.2.1.2 DKR Involving Acylation of Alcohols 29210.2.2 Acylation of Phenols 29410.2.3 Acylation of Amines and Sulfoximines 29710.3 Benzoin and Stetter Reactions 29910.3.1 Desymmetrization of Achiral Substrates 30110.3.2 DKR of Racemic Substrates via Benzoin Condensation 30210.4 Annulation Reactions 30310.4.1 Annulation via Azolium Enolate Addition 30310.4.2 Annulation via Azolium Homoenolate Addition 30510.4.3 Annulation via γ-Addition 30510.5 Conclusion 306Acknowledgments 306References 30611 N-Heterocyclic Carbenes for Organopolymerization:Metal-Free Polymer Synthesis 309Romain Lambert, Joan Vignolle, and Daniel Taton11.1 Introduction 30911.2 Main NHCs and Fundamental Mechanisms of NHC-Induced Polymerization 31011.3 NHC-Mediated Chain-growth Polymerization 31411.3.1 Ring-opening Polymerization 31411.3.2 NHC-OROP (in the Presence of an Initiator) 31411.3.3 Directly NHC-Mediated ROP (in the Absence of an Initiator): Synthesis of Cyclic vs. Linear Polymers 32111.4 Reaction with Alkyl (meth) acrylates 32811.4.1 Basic Nucleophilic Reactivity of Stable Carbenes in the Absence of Initiator 32811.4.1.1 Ambiphilic Reactivity of Stable Carbenes 33111.4.1.2 Noncatalytic Reactivity 33211.4.1.3 Catalytic Reactivity 33211.4.2 Reactivity of NHCs Toward α,β-Unsaturated Esters in the Presence of Initiators 33411.4.3 Reactivity of NHCs in Conjunction with a Lewis Acid: Frustrated Lewis Pair-Type Reactivity 33511.5 NHC-Mediated Step-growth Polymerization 33611.6 Conclusion 340References 34112 N-Heterocyclic Carbene Catalysis in Natural Product and Complex Target Synthesis 345M. Todd Hovey, Ashley A. Jaworski, and Karl A. Scheidt12.1 Introduction 34512.2 NHC-Catalyzed Benzoin Condensations 34512.2.1 Synthesis of trans-Resorcylide 34612.2.2 Synthesis of (+)-Sappanone B 34612.2.3 Synthesis of Cassialoin 34812.2.4 Synthesis of the Kinamycins and the Monomeric Unit of Lomaiviticin Aglycon 34912.2.5 Synthesis of (−)-Seragakinone A 35112.2.6 Synthesis of Originally Assigned Structure of Pleospdione 35412.2.7 Formal Synthesis of Natural Inositols 35512.2.8 Synthesis of (+)-7,20-Diisocyanoadociane 35512.3 The Stetter Reaction 35712.3.1 Annulation Reactions 35812.3.1.1 Synthesis of Hirsutic Acid C 35812.3.1.2 Formal Synthesis of Platensimycin 35812.3.2 Fragment Coupling 36012.3.2.1 Synthesis of cis-Jasmon and Dihydrojasmon 36012.3.2.2 Synthesis of the Core of Atorvastatin 36012.3.2.3 Synthesis of Roseophilin 36112.3.2.4 Synthesis of trans-Sabinene Hydrate 36212.3.2.5 Synthesis of (+)-Monomorine I and Related Natural Products 36312.3.2.6 Synthesis of Haloperidol 36312.3.2.7 Synthesis of (−)-Englerin A 36412.3.2.8 Synthesis of Piperodione 36612.4 NHC-homoenolate Equivalents 36612.4.1 Synthesis of Salinosporamide A 36712.4.2 Synthesis of Bakkenolides I, J, and S 36712.4.3 Synthesis of Maremycin B 36912.4.4 Synthesis of Clausenamide 36912.4.5 Synthesis of (−)-Paroxetine and (−)-Femoxetine 37012.4.6 Synthesis of (S)-Baclofen and (S)-Rolipram 37112.4.7 Synthesis of 3-Dehydroxy Secu’amine A 37412.5 NHC-Catalyzed Aroylation Reactions 37412.5.1 Synthesis of Atroviridin 37512.6 NHC-Catalyzed Redox and Oxidative Processes 37612.6.1 Redox Esterifications 37612.6.1.1 Synthesis of (+)-Davanone 37612.6.1.2 Synthesis of Gelsemoxonine 37712.6.1.3 Synthesis of (+)-Tanikolide 37812.6.2 Oxidative Esterification 37912.6.2.1 Synthesis of (+)-Dactylolide 37912.6.2.2 Synthesis of Cyanolide A and Clavosolide A 38012.6.2.3 Synthesis of Bryostatin 7 38112.6.3 Carbon–Carbon Bond Formation 38412.6.3.1 Synthesis of (−)-7-Deoxyloganin 38412.6.4 Brønsted Base Catalysis 38412.6.4.1 Synthesis of (1R)-Suberosanone 38512.7 Summary 386References 386Index 405