Table of Contents
Preface xi
Discovery of Catalysis by Nucleophilic Carbenes xiii
About the Editor xvii
1 An Overview of NHCs 1
Matthew N. Hopkinson and Frank Glorius
1.1 General Structure of NHCs 2
1.1.1 Classes of NHCs and Related Stable Carbenes 2
1.1.2 Structural Features Common to All NHCs 4
1.1.3 Stabilization of the Carbene Center 5
1.2 NHCs as σ-Donating Ligands 7
1.2.1 The Nature of Bonding in NHC Adducts 10
1.2.2 Comparing NHC and Phosphine Ligands 10
1.3 Synthesis of NHCs 11
1.3.1 Generation of the Free Carbene 11
1.3.2 Synthetic Routes Toward Azolium Salt NHC Precursors 12
1.4 Quantifying the Electronic Properties of NHCs 16
1.4.1 pKa Measurements of Azolium Salts 16
1.4.2 Tolman Electronic Parameter (TEP) 17
1.4.3 NMR Measurements 21
1.4.4 Nucleophilicity and Lewis Basicity 24
1.4.5 Electrochemical Methods 24
1.4.6 Computational Methods 25
1.5 Quantifying the Steric Properties of NHCs 26
1.5.1 Percentage Buried Volume (%Vbur) 27
1.5.2 Steric Maps 29
1.6 Concluding Remarks 30
References 30
2 Benzoin Reaction 37
Steven M. Langdon, Karnjit Parmar, Myron M.D.Wilde, and Michel Gravel
2.1 Background and Mechanism 37
2.2 Standard Conditions and Substrate Scope 40
2.3 Enantioselective Homo-benzoin Reactions 41
2.4 Cross-benzoin Reactions 42
2.4.1 Intramolecular Cross-benzoin Reactions 42
2.4.2 Intermolecular Cross-benzoin Reactions 47
2.5 Aza-benzoin Reactions 51
2.5.1 Aza-benzoin Reactions of Aldimines 51
2.5.2 Aza-benzoin Reactions of Ketimines 53
References 54
3 N-Heterocyclic Carbene-catalyzed Stetter Reaction and Related Chemistry 59
Santigopal Mondal, Santhivardhana R. Yetra, and Akkattu T. Biju
3.1 Introduction 59
3.2 Proposed Mechanism of the Stetter Reaction 60
3.3 Intramolecular Stetter Reaction 61
3.4 Intermolecular Stetter Reaction 68
3.5 Cascade Processes Involving Stetter Reaction 79
3.6 NHC-catalyzed Hydroacylation Reactions 82
3.7 Conclusion 89
References 89
4 N-Heterocyclic Carbene (NHC)-Mediated Generation and Reactions of Homoenolates 95
Vijay Nair, Rajeev S. Menon, and Jagadeesh Krishnan
4.1 Homoenolates - An Introduction 95
4.2 N-Heterocyclic Carbenes (NHCs) 97
4.3 NHC-Derived Homoenolates - The Beginning 98
4.4 Mechanistic Pathways Available for NHC-Homoenolates 100
4.5 Reaction of NHC-Homoenolates with Ketones and Ketimines 102
4.6 Reaction of NHC-Homoenolates with Michael Acceptors 108
4.7 β-Protonation of Homoenolates and Subsequent Reactions 117
4.8 Homoenolates in Carbon-Nitrogen Bond Formation 122
4.9 Domino Reactions of Homoenolates 124
4.10 New Precursors for Homoenolates 126
4.11 Conclusion 129
References 129
5 Domino Processes in NHC Catalysis 133
Pankaj Chauhan, Suruchi Mahajan, Xiang-Yu Chen, and Dieter Enders
5.1 Introduction 133
5.2 Domino Reactions Involving Homoenolate-Enolate Intermediates 134
5.2.1 Domino Reactions Involving a Michael/Aldol Reaction Sequence 134
5.2.2 Domino Reactions Involving a Michael/Michael Reaction Sequence 138
5.2.3 Domino Reactions Involving a Michael/Mannich Reaction Sequence 140
5.2.4 Domino Reactions Involving a Homo-aldol/Michael Addition Sequence 142
5.3 Domino Reactions Involving Dienolate-Enolate Intermediates 142
5.4 Domino Reactions Involving Unsaturated Acyl Azolium-Enolate Intermediates 145
5.4.1 Domino Reactions Involving a Michael/Aldol Sequence 145
5.4.2 Domino Reactions Involving a Michael/Michael Addition Sequence 149
5.4.3 Domino Reactions Involving a Michael/Mannich Reaction Sequence 152
5.4.4 Domino Reactions Involving a Michael/SN2 Reaction Sequence 153
5.5 Conclusions and Outlook 153
References 154
6 N-Heterocyclic Carbene Catalysis via the 𝛂,𝛃-Unsaturated Acyl Azolium 157
Changhe Zhang and David Lupton
6.1 Introduction 157
6.2 Generation of the α,β-Unsaturated Acyl Azolium 157
6.3 Esterification of the α,β-Unsaturated Acyl Azolium 159
6.4 [3+n] Annulations of the α,β-Unsaturated Acyl Azolium 160
6.4.1 Annulation with Enolates 161
6.4.2 Annulation with Eenamines 165
6.4.3 Annulation with Other Nucleophiles 168
6.5 [2+n] Annulations of the α,β-Unsaturated Acyl Azolium 170
6.5.1 [2+4] Annulations Terminating in β-Lactonization 170
6.5.2 [2+4] Annulations Terminating in 𝛿-Lactonization 174
6.5.3 [2+3] Annulations Terminating in β-Lactonization 174
6.5.4 [2+1] Annulations 176
6.6 Cascades Involving Bond Formation at the γ-Carbon and Acyl Carbon 177
6.6.1 Annulations with Ketones and Imines 177
6.6.2 [4+2] Annulations with Electron-Poor Olefins 180
6.7 Other Reactions of the α,β-Unsaturated Acyl Azolium 181
6.8 Conclusions and Outlook 183
References 183
7 Recent Activation Modes in NHC Organocatalysis 187
Zhichao Jin, Xingkuan Chen, and Yonggui R. Chi
7.1 Introduction 187
7.2 Activation of Carboxylic Acid Derivatives 187
7.2.1 α-Carbon Activation of Saturated Carboxylic Esters 188
7.2.2 β-Carbon Activation of α,β-Unsaturated Carboxylic Compounds 191
7.2.3 Nucleophilic β-Carbon Activation of Saturated Carboxylic Esters 195
7.2.4 γ-Carbon Activation of α,β-Unsaturated Carboxylic Esters 198
7.3 Radical Reactions Catalyzed by NHC Organic Catalysts 199
7.3.1 Lessons from Nature 199
7.3.2 Pioneering SET Reactions in NHC Organocatalysis 200
7.3.3 NHC-Catalyzed Reductive β,β-couplings of Nitroalkenes 201
7.3.4 NHC-Catalyzed Benzylation of Electrophiles 202
7.3.5 NHC-Catalyzed β-hydroxylation of α,β-Unsaturated Aldehydes 204
7.3.6 Synthesis of Chiral 3,4-diaryl CyclopentanonesThrough SET Process 205
7.3.7 Polyhalides as Oxidants for NHC-Catalyzed Radical Reactions 206
7.3.8 New Mechanisms for Classical Reactions 208
7.4 Summary and Outlook into the Future NHC Organocatalysis 209
References 210
8 N-Heterocyclic Carbene-Catalyzed Reactions via Azolium Enolates and Dienolates 213
Zhao-Fei Zhang, Chun-Lin Zhang, and Song Ye
8.1 Introduction 213
8.2 Azolium Enolates from α-Functionalized Aldehydes 213
8.2.1 Synthesis of Carboxylic Compounds 213
8.2.2 Formal [2+4] Cycloaddition 217
8.2.3 Formal [2+2] Cycloaddition 222
8.2.4 Formal [2+3] Cycloaddition 222
8.3 Azolium Enolate from Ketenes 223
8.3.1 Formal [2+2] Cycloaddition 224
8.3.2 Asymmetric Formal [2+3] Cycloadditions 231
8.3.3 Asymmetric Formal [2+4] Cycloadditions 232
8.3.4 Asymmetric Protonation and Halogenation 236
8.4 Azolium Enolate from Enals 237
8.5 Azolium Enolate from Aldehydes with Oxidant 242
8.6 Azolium Enolates from Activated Esters 244
8.7 Azolium Enolates from Acids 247
8.8 Azolium Dienolate 249
8.9 Conclusions and Outlook 257
References 257
9 N-heterocyclic Carbenes as Brønsted Base Catalysts 261
Jiean Chen and Yong Huang
References 284
10 NHC-Catalyzed Kinetic Resolution, Desymmetrization, and DKR Strategies 287
Shenci Lu, Si B. Poh, Jun Y. Ong, and Yu Zhao
10.1 Introduction 287
10.2 NHC-Catalyzed Acylation 288
10.2.1 Acylation of Aliphatic Alcohols 290
10.2.1.1 Acylation of Aliphatic Alcohols 290
10.2.1.2 DKR Involving Acylation of Alcohols 292
10.2.2 Acylation of Phenols 294
10.2.3 Acylation of Amines and Sulfoximines 297
10.3 Benzoin and Stetter Reactions 299
10.3.1 Desymmetrization of Achiral Substrates 301
10.3.2 DKR of Racemic Substrates via Benzoin Condensation 302
10.4 Annulation Reactions 303
10.4.1 Annulation via Azolium Enolate Addition 303
10.4.2 Annulation via Azolium Homoenolate Addition 305
10.4.3 Annulation via γ-Addition 305
10.5 Conclusion 306
Acknowledgments 306
References 306
11 N-Heterocyclic Carbenes for Organopolymerization:Metal-Free Polymer Synthesis 309
Romain Lambert, Joan Vignolle, and Daniel Taton
11.1 Introduction 309
11.2 Main NHCs and Fundamental Mechanisms of NHC-Induced Polymerization 310
11.3 NHC-Mediated Chain-growth Polymerization 314
11.3.1 Ring-opening Polymerization 314
11.3.2 NHC-OROP (in the Presence of an Initiator) 314
11.3.3 Directly NHC-Mediated ROP (in the Absence of an Initiator): Synthesis of Cyclic vs. Linear Polymers 321
11.4 Reaction with Alkyl (meth) acrylates 328
11.4.1 Basic Nucleophilic Reactivity of Stable Carbenes in the Absence of Initiator 328
11.4.1.1 Ambiphilic Reactivity of Stable Carbenes 331
11.4.1.2 Noncatalytic Reactivity 332
11.4.1.3 Catalytic Reactivity 332
11.4.2 Reactivity of NHCs Toward α,β-Unsaturated Esters in the Presence of Initiators 334
11.4.3 Reactivity of NHCs in Conjunction with a Lewis Acid: Frustrated Lewis Pair-Type Reactivity 335
11.5 NHC-Mediated Step-growth Polymerization 336
11.6 Conclusion 340
References 341
12 N-Heterocyclic Carbene Catalysis in Natural Product and Complex Target Synthesis 345
M. Todd Hovey, Ashley A. Jaworski, and Karl A. Scheidt
12.1 Introduction 345
12.2 NHC-Catalyzed Benzoin Condensations 345
12.2.1 Synthesis of trans-Resorcylide 346
12.2.2 Synthesis of (+)-Sappanone B 346
12.2.3 Synthesis of Cassialoin 348
12.2.4 Synthesis of the Kinamycins and the Monomeric Unit of Lomaiviticin Aglycon 349
12.2.5 Synthesis of (−)-Seragakinone A 351
12.2.6 Synthesis of Originally Assigned Structure of Pleospdione 354
12.2.7 Formal Synthesis of Natural Inositols 355
12.2.8 Synthesis of (+)-7,20-Diisocyanoadociane 355
12.3 The Stetter Reaction 357
12.3.1 Annulation Reactions 358
12.3.1.1 Synthesis of Hirsutic Acid C 358
12.3.1.2 Formal Synthesis of Platensimycin 358
12.3.2 Fragment Coupling 360
12.3.2.1 Synthesis of cis-Jasmon and Dihydrojasmon 360
12.3.2.2 Synthesis of the Core of Atorvastatin 360
12.3.2.3 Synthesis of Roseophilin 361
12.3.2.4 Synthesis of trans-Sabinene Hydrate 362
12.3.2.5 Synthesis of (+)-Monomorine I and Related Natural Products 363
12.3.2.6 Synthesis of Haloperidol 363
12.3.2.7 Synthesis of (−)-Englerin A 364
12.3.2.8 Synthesis of Piperodione 366
12.4 NHC-homoenolate Equivalents 366
12.4.1 Synthesis of Salinosporamide A 367
12.4.2 Synthesis of Bakkenolides I, J, and S 367
12.4.3 Synthesis of Maremycin B 369
12.4.4 Synthesis of Clausenamide 369
12.4.5 Synthesis of (−)-Paroxetine and (−)-Femoxetine 370
12.4.6 Synthesis of (S)-Baclofen and (S)-Rolipram 371
12.4.7 Synthesis of 3-Dehydroxy Secu’amine A 374
12.5 NHC-Catalyzed Aroylation Reactions 374
12.5.1 Synthesis of Atroviridin 375
12.6 NHC-Catalyzed Redox and Oxidative Processes 376
12.6.1 Redox Esterifications 376
12.6.1.1 Synthesis of (+)-Davanone 376
12.6.1.2 Synthesis of Gelsemoxonine 377
12.6.1.3 Synthesis of (+)-Tanikolide 378
12.6.2 Oxidative Esterification 379
12.6.2.1 Synthesis of (+)-Dactylolide 379
12.6.2.2 Synthesis of Cyanolide A and Clavosolide A 380
12.6.2.3 Synthesis of Bryostatin 7 381
12.6.3 Carbon-Carbon Bond Formation 384
12.6.3.1 Synthesis of (−)-7-Deoxyloganin 384
12.6.4 Brønsted Base Catalysis 384
12.6.4.1 Synthesis of (1R)-Suberosanone 385
12.7 Summary 386
References 386
Index 405
