N-Heterocyclic Carbenes in Organocatalysis

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 pK_a 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 (%V_bur) 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

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).