Foreword xiii
Preface xv
Part I Late-Stage Functionalization Strategies 1
1 Late-Stage Functionalization by Transition Metal-Catalyzed Câ"H Functionalization 3
Erwan Brunard and Joanna Wencel-Delord
1.1 Introduction 3
1.2 Late-Stage Functionalization of Aromatic Compounds 4
1.2.1 LSF via Direct Alkylation 4
1.2.2 LSF via Alkenylation 6
1.2.3 LSF via Arylation 9
1.2.4 LSF via Câ"O Bond Formation 11
1.2.5 LSF via Câ"N Bond Formation 13
1.2.6 LSF via Câ"B Bond Formation 15
1.2.7 LSF via Câ"X Bond Formation 19
1.2.8 LSF via Câ"D Bond Formation 21
1.3 Late-Stage Functionalization of Aliphatic Compounds 23
1.3.1 LSF of Aliphatic Substrates via Direct Câ"C Bond Formation 24
1.3.2 LSF via Câ"O Bond Formation 25
1.3.3 LSF via Câ"N Bond Formation 27
1.3.4 LSF via Câ"D Bond Formation 28
1.4 Conclusions and Perspectives 29
References 30
2 Light-Triggered Methods for Late-Stage Functionalization 39
Camilla Russo, Gian Cesare Tron, and Mariateresa Giustiniano
2.1 Introduction 39
2.1.1 Definition of Late-Stage Functionalization 39
2.1.2 Photo(Redox) Catalysis in LSF 41
2.2 C(sp3)â"H Functionalization 41
2.2.1 LSF of Hydrocarbon Câ"H Bonds 43
2.2.2 LSF of Aliphatic Câ"H Bonds with Heteroatoms at the α-Position 45
2.2.2.1 LSF via α-Amino Alkyl Radicals 45
2.2.2.2 LSF Via α-Oxyalkyl Radicals 46
2.3 C(sp2)â"H Functionalization 48
2.3.1 LSF of Alkene Functional Groups 48
2.3.2 Arenes and Heteroarenes LSF 52
2.4 Functional Group-Enabled LSF 55
2.4.1 Carboxylic Acids in LSF 55
2.4.2 Amines in LSF 56
2.4.3 Halides in LSF 58
2.5 Conclusion 59
References 59
3 Electrochemical Late-Stage Functionalization 67
Yanjun Li, Zhipeng Lin, Hao Long, Yang Xu, and Lutz Ackermann
3.1 Introduction 67
3.2 Electrochemical Late-Stage Functionalization of Câ"H Bonds 68
3.2.1 Electrochemical Late-Stage Functionalization of C(sp2)â"H Bonds 68
3.2.2 Electrochemical Late-Stage Functionalization of C(sp3)â"H Bonds 76
3.2.3 Electrochemical Late-stage of C(sp)â"H bonds 85
3.3 Electrochemical Late-Stage Functionalization Through Electrochemical Substitution of Functional Groups 87
3.3.1 Electrochemical Late-Stage Functionalization of Alkenes and Alkynes 88
3.3.2 Electrochemical Late-Stage Functionalization of Organic Halides 89
3.3.3 Electrochemical Late-Stage Functionalization of Organic Carboxylic Acids 92
3.3.4 Electrochemical Late-Stage Functionalization of Alcohols 92
3.4 Photoelectrochemical Late-Stage Functionalization of Drug Molecules 93
3.4.1 Photoelectrochemical Late-Stage Functionalization for Câ"C Bond Formation 93
3.4.2 Photoelectrochemical Late-Stage Functionalization for Câ"X Bond Formation 96
3.4.3 Late-Stage Functionalization of Asymmetric Photoelectrocatalysis 99
3.5 Conclusions 101
References 102
4 Flow Chemistry Applied for Late-Stage Functionalization and Other Functional Group-Tolerant Manipulation 117
Philipp Natho, Marco Colella, and Renzo Luisi
4.1 Introduction 117
4.2 Photochemical Flow 119
4.3 Electrochemical Flow 124
4.4 Flash Chemistry 130
4.5 Homogeneous and Heterogeneous Metal Catalysis in Flow 137
4.6 Summary and Conclusions 141
References 142
5 Radioisotope Insertion Through Late-Stage Functionalization 147
Emmanuelle Dubost, Maxime Jay, and Thomas Cailly
5.1 Introduction 147
5.2 Tritium 150
5.2.1 Transition Metal-Catalyzed HIE 150
5.2.1.1 Iridium-Based Catalysts 151
5.2.1.2 Iron-Based Catalysts 152
5.2.1.3 Ni-Catalyzed Tritiation 153
5.2.1.4 Palladium-Based Catalysts 153
5.2.1.5 Ruthenium Catalysis 155
5.2.1.6 Rhodium Catalysis 156
5.2.2 Photocatalysis 156
5.2.3 Alkali-Based HIE 157
5.3 Carbon Isotopes 157
5.3.1 Isotopic Exchange 160
5.3.1.1 Decarboxylation/Recarboxylation Strategies 160
5.3.1.2 Nitrile Group Exchange 164
5.3.2 Câ"F Activation 165
5.4 Fluorine- 18 166
5.4.1 Functional Group Transformation 167
5.4.2 Câ"H Activation 169
5.4.3 Câ"F Activation 174
5.5 Iodine Radioisotopes 174
5.5.1 Functional Group Transformation 176
5.5.2 Câ"H Activation Reactions 176
5.6 Summary and Conclusions 177
References 177
Part II Diversity-Oriented Synthesis 183
6 Late-Stage Functionalization Strategies Using Câ"O Bond Activation 185
R©mi Blieck
6.1 Introduction 185
6.2 Late-Stage Activation of Free Alcohols 185
6.2.1 N- and C-Alkylation by Hydrogen Borrowing Mechanism 186
6.2.2 Radical Activation of Alcohols 187
6.2.3 Deoxyhalogenation of Alcohols 187
6.2.4 Transition Metal-Catalyzed Arylation and Alkylation of Free Alcohols 189
6.2.4.1 Arylation 189
6.2.4.2 Alkylation 189
6.2.5 Alcohols Oxidation 190
6.2.6 Deoxyborylation of Alcohols 190
6.2.7 Deoxyazidation of Alcohols 191
6.3 Activation of Carboxylic Acids 192
6.3.1 Decarboxylative Couplings 192
6.3.1.1 Decarboxylative Arylation 192
6.3.1.2 Decarboxylative Alkylation, Alkenylation, and Alkynylation 193
6.3.1.3 Decarboxylative Cyanation 195
6.3.1.4 Decarboxylative Câ"Heteroatom Bond Formation 195
6.3.2 Non-decarboxylative Couplings 197
6.3.2.1 Conversion to Ketones 197
6.3.2.2 Amidation 197
6.3.2.3 Esterification 199
6.3.2.4 Fluorination 200
6.3.3 Reductions 200
6.4 Activation of Ketones and Aldehydes 201
6.4.1 Alkylation and Arylation 202
6.4.2 Deoxygenative Couplings 203
6.4.3 Rearrangement and Chain-Walking 203
6.5 Activation of Esters 204
6.5.1 Metal-Catalyzed Câ"C Bond Formation 204
6.5.2 Amidation 205
6.5.3 Decarbonylation 206
6.6 Activation of Ethers 206
6.6.1 Metal-Catalyzed Cross-Coupling 207
6.6.2 Metal-Free Cross-Coupling 207
6.6.3 Dealkylation 209
6.6.4 Opening of Cyclic Ethers 209
6.7 Summary and Conclusions 210
References 211
7 Câ"N Bond Activation Under Redox-Neutral Conditions 225
Xu Chen, Qun Zhao, and Michal Szostak
7.1 Introduction 225
7.2 Câ"N Activation of Ammonium Salts 226
7.2.1 Ni-Catalyzed Câ"N Activation of Ammonium Salts 226
7.2.2 Pd-Catalyzed Câ"N Activation of Ammonium Salts 229
7.2.3 Fe-Catalyzed Câ"N Activation of Ammonium Salts 231
7.3 Câ"N Activation of Arylamines 232
7.3.1 Ru-Catalyzed Câ"N Activation of Arylamines 232
7.3.2 Ni-Catalyzed Câ"N Activation of Arylamines 234
7.3.3 Cr-Catalyzed Câ"N Activation of Arylamines 237
7.3.4 Miscellaneous Examples 238
7.4 Câ"N Bond Activation in Nitroarenes 239
7.4.1 Pd-Catalyzed Câ"N Activation of Nitroarenes 240
7.5 Summary 244
Acknowledgments 244
References 244
8 Late-Stage Functionalization by Câ"S Bond Activation 249
Jun-Jie Chen and Huan-Ming Huang
8.1 Introduction 249
8.2 Transition Metal-Catalyzed Late-Stage Functionalization by Câ"SBond Activation 250
8.3 Late-Stage Functionalization by Câ"S Bond Activation under Electrochemical Condition 254
8.4 Late-Stage Functionalization by Câ"S Bond Activation through Photoredox Chemistry 255
8.5 Late-Stage Functionalization by Câ"S Bond Activation Enabled by Metallaphotoredox Chemistry 262
8.6 Late-Stage Functionalization by Câ"S Bond Activation Enabled by Traditional Radical Approaches 267
8.7 Summary and Conclusions 269
References 270
Part III Molecular/Stereochemical Editing 273
9 Molecular Editing-Based Strategies 275
Javid Rzayev, Illia Ruzhylo, Philippe Jubault, and Tatiana Besset
9.1 Introduction 275
9.2 Atom Insertion 275
9.2.1 Carbon Atom Insertion 275
9.2.2 Nitrogen Atom Insertion 278
9.2.3 Oxygen Atom Insertion 283
9.2.4 Other Heteroatom Insertion 284
9.3 Atom Deletion 286
9.3.1 Nitrogen Atom Deletion 286
9.3.2 Oxygen Atom Deletion 286
9.3.3 Carbon Atom Deletion 287
9.4 Atom Swapping 288
9.4.1 Nitrogen-to-Carbon Swapping 288
9.4.2 Carbon-to-Nitrogen Swapping 290
9.4.3 Carbon-to-Oxygen Swapping 292
9.4.4 Heteroatom-to-Heteroatom Swap 292
9.4.5 A Swap of Two Atoms by Two Atoms 294
9.5 Functional Group Transposition 294
9.6 Stereochemical Editing 298
9.7 Conclusion 298
Acknowledgments 299
References 300
Index 307
