A guide to contemporary advancements in the field of distal C-H functionalizations
An important and dynamic topic within the modern field of organic synthesis, selective functionalization of C-H bonds can be used in a variety of applications across the pharmaceutical and agrochemical industries. Remote C-H Bond Functionalizations presents an inclusive account of the most recent developments and potential applications of performing variegated functionalizations selectively at the distal positions of organic compounds.
Featuring contributions by an international team of experts, this authoritative volume provides deep insight into distal functionalizations, including detailed discussion of mechanisms, the engineering of templates, and the design of strategies. The text covers a diverse range of topics including C-H functionalization of palladium/norbornene catalysis, ruthenium-catalyzed remote functionalization, the non-directed distal C(sp2)-H, functionalization, transition metal catalyzed distal para-selective C-H functionalization, and much more. Reviewing contemporary advancements in the field while laying the foundation for future research, this important resource:
- Provides the most recent research and thorough coverage of the subject available in a single volume
- Offers practical information on C-H functionalizations in various industries
- Includes an up-to-date introduction to distal C-H functionalizations
Remote C-H Bond Functionalizations is a must-read for every synthetic chemist, including chemists working with organometallics, organic chemists and researchers, and industrial chemists.
Table of Contents
1 Introduction 1
Uttam Dutta, Srimanta Guin, and Debabrata Maiti
2 Transition Metal-Catalyzed Remote meta-C-H Functionalization of Arenes Assisted by meta-Directing Templates 7
Yuzhen Gao and Gang Li
2.1 Introduction 7
2.2 Template-Assisted meta-C-H Functionalization 9
2.2.1 Toluene Derivatives 9
2.2.2 Acid Derivatives 10
2.2.2.1 Hydrocinnamic Acid Derivatives 10
2.2.2.2 Phenylacetic Acid Derivatives 16
2.2.2.3 Benzoic Acid Derivatives 20
2.2.3 Amine and N-Heterocyclic Arene Derivatives 23
2.2.3.1 Aniline Derivatives 23
2.2.3.2 Benzylamine Derivatives 27
2.2.3.3 Phenylethylamine Derivatives 27
2.2.3.4 N-Heterocyclic Arene Derivatives 29
2.2.4 Sulfonic Acid Derivatives 33
2.2.5 Phenol Derivatives 40
2.2.6 Alcohol Derivatives 44
2.2.7 Silane Derivatives 50
2.2.8 Phosphonate Derivatives 51
2.3 Mechanistic Considerations 53
2.4 Conclusion 55
Abbreviations 56
References 57
3 C-H Functionalization of Arenes Under Palladium/Norbornene Catalysis 59
Juntao Ye and Mark Lautens
3.1 Introduction 59
3.2 Pd(0)-Catalyzed C-H Functionalization of Aryl (Pseudo)Halides 64
3.2.1 ortho-Alkylation 64
3.2.1.1 ortho-Alkylation with Simple Alkyl Halides 64
3.2.1.2 ortho-Alkylation with Bifunctional Alkylating Reagents 70
3.2.1.3 ortho-Alkylation with Three-Membered Heterocycles 75
3.2.2 ortho-Arylation 77
3.2.3 ortho-Acylation and Alkoxycarbonylation 89
3.2.4 ortho-Amination 94
3.2.5 ortho-Thiolation 101
3.3 Pd(II)-Catalyzed C-H Functionalization of Arenes 101
3.3.1 C2-Functionalization of Indoles and Pyrroles 101
3.3.2 meta-C-H Functionalization of Arenes Containing an ortho-Directing Group 102
3.3.3 ortho-C-H Functionalization of Arylboron Species 105
3.4 Conclusions and Outlook 108
Acknowledgments 109
References 110
4 Directing Group Assisted meta-C-H Functionalization of Arenes Aided by Norbornene as Transient Mediator 115
Hong-Gang Cheng and Qianghui Zhou
4.1 Introduction 115
4.2 meta-C-H Alkylation of Arenes 116
4.2.1 Amide as Directing Group 116
4.2.2 Sulfonamide as Directing Group 118
4.3 meta-C-H Arylation of Arenes 119
4.3.1 Amide as Directing Group 119
4.3.2 Sulfonamide as Directing Group 122
4.3.3 Tertiary Amine as Directing Group 122
4.3.4 Tethered Pyridine-Type Directing Group 123
4.3.5 Acetal-Based Quinoline as Directing Group 126
4.3.6 Free Carboxylic Acid as Directing Group 126
4.4 meta-C-H Chlorination of Arenes 127
4.5 meta-C-H Amination of Arenes 129
4.6 meta-C-H Alkynylation of Arenes 130
4.7 Enantioselective meta-C-H Functionalization 130
4.8 Conclusion 133
Abbreviations 134
References 134
5 Ruthenium-Catalyzed Remote C-H Functionalizations 137
Korkit Korvorapun, Ramesh C. Samanta, Torben Rogge, and Lutz Ackermann
5.1 Introduction 137
5.2 meta-C-H Functionalizations 138
5.2.1 C-H Alkylation 138
5.2.2 C-H Benzylation 146
5.2.3 C-H Carboxylation 150
5.2.4 C-H Acylation 151
5.2.5 C-H Sulfonylation 151
5.2.6 C-H Halogenation 152
5.2.7 C-H Nitration 155
5.3 para-C-H Functionalizations 158
5.4 meta-/ortho-C-H Difunctionalizations 161
5.5 Conclusions 161
Acknowledgments 163
References 163
6 Harnessing Non-covalent Interactions for Distal C(sp2)-H Functionalization of Arenes 169
Georgi R. Genov, Madalina T. Mihai, and Robert J. Phipps
6.1 Introduction 169
6.2 Non-covalent Interactions in Metal Catalyzed C - H Bond Functionalization 170
6.3 Overview of Iridium-Catalyzed Borylation 171
6.4 Non-covalent Interactions in Ir-Catalyzed Borylation 174
6.5 meta-Selective Borylation using Non-covalent Interactions 176
6.6 para-Selective Borylation using Non-covalent Interactions 181
6.7 Conclusions 186
References 186
7 The Non-directed Distal C(sp2)-H Functionalization of Arenes 191
Arup Mondal, Philipp Wedi, and Manuel van Gemmeren
7.1 Introduction 191
7.1.1 Mechanisms 192
7.2 C-Het Formation 193
7.2.1 Borylation 193
7.2.2 Silylation 195
7.2.3 Amination 196
7.2.4 Oxygenation 200
7.2.5 Other C - Het Bond Forming Reactions 202
7.3 C - C Bond Forming Reactions 205
7.3.1 C-H-Arylation 206
7.3.2 Alkenylation/Olefination 207
7.3.3 Cyanation 209
7.3.4 Other C - C Bond Forming Reactions 212
7.4 Outlook 212
References 213
8 Transition Metal Catalyzed Distal para-Selective C-H Functionalization 221
Uttam Dutta and Debabrata Maiti
8.1 Introduction 221
8.2 Template Assisted para-Selective C-H Functionalization 224
8.2.1 Palladium Catalyzed Methods 224
8.2.1.1 Alkenylation 224
8.2.1.2 Silylation 226
8.2.1.3 Ketonization 227
8.2.1.4 Acetoxylation 230
8.2.1.5 Cyanation 232
8.2.2 Rhodium Catalyzed Functionalization 233
8.2.2.1 Alkenylation 233
8.3 Steric Controlled and Lewis Acid-Transition Metal Cooperative Catalysis 233
8.3.1 Nickel Catalyzed Methods 234
8.3.1.1 Alkylation and Alkenylation 234
8.3.2 Iridium Catalyzed Methods 240
8.3.2.1 Borylation 240
8.4 Non-covalent Interaction Induced para-C-H Functionalization 242
8.4.1 Di-polar Induced Methods 242
8.4.2 Ion-Pair Induced Methods 243
8.5 Conclusion and the Prospect 244
Acknowledgments 246
References 246
9 Regioselective C-H Functionalization of Heteroaromatics at Unusual Positions 253
Koji Hirano and Masahiro Miura
9.1 Introduction 253
9.2 Indole 253
9.2.1 C-H Functionalization at C4 Position 254
9.2.2 C-H Functionalization at C7 Position 258
9.2.3 C-H Functionalization at C5 Position 261
9.2.4 C-H Functionalization at C6 Position 261
9.3 (Benzo)Thiophene 262
9.4 Pyrrole 264
9.5 Pyridine 266
9.6 Miscellaneous Heteroarenes 271
9.6.1 Thiazole 271
9.6.2 Quinoline 271
9.7 Conclusion 272
References 273
10 Directing Group Assisted Distal C(sp3)-H Functionalization of Aliphatic Substrates 279
Ya Li, Qi Zhang, and Bing-Feng Shi
10.1 Introduction 279
10.2 γ-C(sp3)-H Functionalization of Aliphatic Acids 280
10.3 δ-/ε-C(sp3) - H Bond Functionalization of Aliphatic Amines 288
10.4 γ-C(sp3) - H Bond Functionalization of Aliphatic Ketones or Aldehydes 301
10.5 γ-/δ-C(sp3) - H Bond Functionalization of Aliphatic Alcohols 305
10.6 Conclusions and Outlook 307
References 309
11 Radically Initiated Distal C(sp3)-H Functionalization 315
Weipeng Li and Chengjian Zhu
11.1 Introduction 315
11.2 Distal C(sp3)-H Functionalization Promoted by Carbon-Centered Radicals 317
11.3 Distal C(sp3)-H Functionalization Promoted by Nitrogen-Centered Radicals 325
11.3.1 Generation of Nitrogen Radical from N - X (X = F, Cl, Br, I) Bond 325
11.3.2 Generation of Nitrogen Radical from N - N Bond 328
11.3.3 Generation of Nitrogen Radical from N - O Bond 329
11.3.4 Nitrogen Radical Generated Directly from N - H Bond 331
11.4 Oxygen-Centered Radicals Initiate Distal C(sp3)-H Functionalization 333
11.4.1 Oxygen Radical Generated from O - X (X = N, O) bond 333
11.4.2 Oxygen Radical Generated Directly from O - H Bond 336
11.5 Summary and Outlook 338
References 339
12 Non-Directed Functionalization of Distal C(sp3) - H Bonds 343
Carlo Sambiagio and Bert U. W. Maes
12.1 Introduction 343
12.1.1 Bond Dissociation Energy (BDE) of C - H Bonds 344
12.1.2 Scope of the Chapter 346
12.2 Reactions Occurring Without Formation of Metal-Carbon Bonds 346
12.2.1 Oxidations with Dioxiranes 346
12.2.2 Decatungstate-Photocatalyzed Remote Functionalization 348
1.2.3 Electrochemical Remote Functionalizations 353
12.2.4 Carbene Insertion into C - H Bonds 356
12.3 Reactions Occurring via Formation of Metal-Carbon Bonds 360
12.3.1 Pt-Based Shilov Chemistry 361
12.3.2 Rh- and Ir-Catalyzed C-H Borylation of (Functionalized) Alkanes 363
12.4 Altering Innate Reactivity by Polarity Reversal Strategies 367
12.4.1 Remote Functionalization of Aliphatic Amines via Quaternary Ammonium Salts 368
12.4.2 Remote Functionalization of Alcohols and Amides via Hydrogen Bond Interactions 376
Acknowledgments 378
References 378
13 Remote Oxidation of Aliphatic C - H Bonds with Biologically Inspired Catalysts 383
Miquel Costas
13.1 Introduction 383
13.1.1 Bioinspired Catalysis as a Tool for Site Selective C - H Bond Oxidation 383
13.1.2 Typology of Bioinspired Catalysts 385
13.1.3 Site Selectivity in Aliphatic C-H Oxidation: Basic Considerations 387
13.2 Innate Substrate Based Aspects Governing Site Selectivity in C-H Oxidations 388
13.2.1 C - H Bond Strength 388
13.2.2 Electronic Effects 388
13.2.3 Steric Effects 391
13.2.4 Directing Groups 392
13.2.5 Stereoelectronic Effects 393
13.2.5.1 Hyperconjugation Effects 393
13.2.5.2 Strain Release and Torsional Effects 394
13.2.6 Chirality 395
13.3 Remote Oxidations by Reversal of Polarity 395
13.3.1 Remote Oxidation in Amine Containing Substrates by Protonation of the Amine Site 395
13.3.2 Remote Oxidation of Amide Containing Substrates by Methylation of the Amide Moiety 397
13.3.3 Remote Oxidation via Polarity Reversal Exerted by Fluorinated Alcohol Solvents 397
13.4 Remote Oxidations Guided by Supramolecular Recognition 401
13.4.1 Lipophilic Interactions 403
13.4.2 Lipophilic Recognition by Cyclodextrins 404
13.4.3 Ligand to Metal Coordination 406
13.4.4 Hydrogen Bonding 408
13.5 Selective Aliphatic C-H Oxidation at Dicopper Complexes 416
13.6 Conclusions 417
References 418
Index 423
