Table of Contents
Preface xiii
1 The Development of New Reagents and Reactions for Synthetic Organofluorine Chemistry by Understanding the Unique Fluorine Effects 1
Qiqiang Xie and Jinbo Hu
1.1 Introduction 1
1.2 The Unique Fluorine Effects in Organic Reactions 3
1.2.1 Fluorine-Enabled Stability of “CuCF3” inWater, and the Unusual Water-Promoted Trifluoromethylation 3
1.2.2 Fluorine Enables β-Fluoride Elimination of Organocopper Species 4
1.2.3 The “Negative Fluorine Effect” Facilitates the α-Elimination of Fluorocarbanions to Generate Difluorocarbene Species 5
1.2.4 Tackling the β-Fluoride Elimination of Trifluoromethoxide Anion via a Fluoride Ion-Mediated Process 9
1.3 The Relationships Among Fluoroalkylation, Fluoroolefination, and Fluorination 9
1.3.1 From Fluoroalkylation to Fluoroolefination 9
1.3.2 From Fluoroolefination to Fluoroalkylation 13
1.3.3 From Fluoroalkylation to Fluorination 18
1.4 Conclusions 20
References 20
2 Perfluoroalkylation Using Perfluorocarboxylic Acids and Anhydrides 23
Shintaro Kawamura and Mikiko Sodeoka
2.1 Introduction 23
2.2 Perfluoroalkylation with Perfluorocarboxylic Acids 23
2.2.1 Electrochemical Reactions 24
2.2.1.1 Reactions of Alkenes and Alkynes 24
2.2.1.2 Reaction of Aromatic Compounds 30
2.2.2 Reactions Using XeF2 30
2.2.3 Reactions Using Copper and Silver Salts 31
2.2.3.1 Using Copper Salts 31
2.2.3.2 Using Silver Salts 35
2.2.4 Photochemical Reactions 36
2.2.5 Other Methods 38
2.2.5.1 Hydro-Trifluoromethylation of Fullerene 38
2.2.5.2 Metal-Free Aryldifluoromethylation Using S2O8 2- 39
2.3 Perfluoroalkylation with Perfluorocarboxylic Anhydride 39
2.3.1 Reactions Using Perfluorocarboxylic Anhydride/Urea⋅H2O2 40
2.3.2 Photocatalytic Reactions Using Perfluorocarboxylic Anhydride/Pyridine N-oxide 42
2.4 Summary and Prospects 43
References 43
3 Chemistry of OCF3, SCF3, and SeCF3 Functional Groups 49
Fabien Toulgoat, François Liger and Thierry Billard
3.1 Introduction 49
3.2 CF3O Chemistry 49
3.2.1 De Novo Construction 49
3.2.1.1 Trifluorination of Alcohol Derivatives 49
3.2.1.2 Fluorination of Difluorinated Compounds 50
3.2.2 Indirect Methods 51
3.2.2.1 O-(Trifluoromethyl)dibenzofuranium Salts 51
3.2.2.2 Hypervalent Iodine Trifluoromethylation Reagents 51
3.2.2.3 CF3SiMe3 51
3.2.3 Direct Trifluoromethoxylation 52
3.2.3.1 Difluorophosgene and Derivatives 53
3.2.3.2 Trifluoromethyl Hypofluorite and Derivatives 53
3.2.3.3 Trifluoromethyl Triflate (TFMT) 53
3.2.3.4 Trifluoromethoxide Salts Derived from TFMT or Difluorophosgene 55
3.2.3.5 Trifluoromethyl Arylsulfonates (TFMSs) 57
3.2.3.6 Trifluoromethylbenzoate (TFBz) 60
3.2.3.7 2,4-Dinitro(trifluoromethoxy)benzene (DNTFB) 60
3.2.3.8 (Triphenylphosphonio)difluoroacetate (PDFA) 61
3.2.3.9 N-Trifluoromethoxylated Reagents 62
3.3 CF3S Chemistry 63
3.3.1 Indirect Methods 63
3.3.2 Direct Trifluoromethylthiolation 64
3.3.2.1 CF3SAg, CF3SCu, CF3SNR4 65
3.3.2.2 Trifluoromethanesulfenamides 65
3.3.2.3 N-Trifluoromethylthiophthalimide 66
3.3.2.4 N-Trifluoromethylthiosaccharin 67
3.3.2.5 N-Trifluoromethylthiobis(phenylsulfonyl)amide 68
3.4 CF3Se Chemistry 69
3.4.1 Introduction 69
3.4.2 Indirect Synthesis of CF3Se Moiety 70
3.4.2.1 Ruppert-Prakash Reagent (CF3SiMe3) 71
3.4.2.2 Fluoroform (HCF3) 72
3.4.2.3 Other Reagents Involved in CF3 - Anion Generation 73
3.4.2.4 Sodium Trifluoromethylsulfinate (CF3SO2Na) 73
3.4.3 Direct Introduction of the CF3Se Moiety 74
3.4.3.1 Trifluoromethyl Selenocopper DMF Complex 74
3.4.3.2 Trifluoromethyl Selenocopper Bipyridine Complex: [bpyCuSeCF3]2 75
3.4.3.3 Tetramethylammonium Trifluoromethylselenolate [(NMe4)(SeCF3)] 76
3.4.3.4 In Situ Generation of CF3Se- Anion from Elemental Selenium 79
3.4.3.5 Trifluoromethylselenyl Chloride (CF3SeCl) 80
3.4.3.6 Benzyltrifluoromethylselenide (CF3SeBn) 81
3.4.3.7 Trifluoromethylselenotoluenesulfonate (CF3SeTs) 83
3.4.3.8 Benzylthiazolium Salt BT-SeCF3 85
3.5 Summary and Conclusions 85
References 86
4 Introduction of Trifluoromethylthio Group into Organic Molecules 99
Hangming Ge, He Liu and Qilong Shen
4.1 Introduction 99
4.2 Nucleophilic Trifluoromethylthiolation 99
4.2.1 Preparation of Nucleophilic Trifluoromethylthiolating Reagent 99
4.2.1.1 Preparation of Hg(SCF3)2, AgSCF3, and CuSCF3 99
4.2.1.2 Preparation of MSCF3 (M = K, Cs, Me4N, and S(NMe2)3) 100
4.2.1.3 Preparation of Stable Trifluoromethylthiolated Copper(I) Complexes 100
4.2.2 Formation of C(sp2)-SCF3 by Nucleophilic Trifluoromethylthiolating Reagents 101
4.2.2.1 Reaction of CuSCF3 with Aryl Halides 101
4.2.2.2 Sandmeyer-Type Trifluoromethylthiolation 102
4.2.2.3 Transition Metal-Catalyzed Trifluoromethylthiolation 103
4.2.2.4 Oxidative Trifluoromethylthiolation 107
4.2.2.5 Transition Metal-Catalyzed Trifluoromethylthiolation of Arenes via C-H Activation 108
4.2.2.6 Miscellaneous Methods for the Formation or Aryl Trifluoromethylthioethers via Nucleophilic Trifluoromethylthiolating Reagents 110
4.2.3 Formation of C(sp3)-SCF3 by Nucleophilic Trifluoromethylthiolating Reagents 112
4.2.3.1 Reaction of CuSCF3 with Activated Alkylated Halides 112
4.2.3.2 Reaction of MSCF3 with Unactivated Alkyl Halides 114
4.2.3.3 Nucleophilic Dehydroxytrifluoromethylthiolation of Alcohols 114
4.2.3.4 Nucleophilic Trifluoromethylthiolation of Alcohol Derivatives 116
4.2.3.5 Nucleophilic Trifluoromethylthiolation of α-Diazoesters 116
4.2.3.6 Formation or Alkyl Trifluoromethylthioethers via In Situ Generated Nucleophilic Trifluoromethylthiolating Reagent 118
4.2.3.7 Formation of Alkyl Trifluoromethylthioethers via C - H Bond Trifluoromethylthiolation 120
4.3 Electrophilic Trifluoromethylthiolating Reagents 120
4.3.1 CF3SCl 120
4.3.2 CF3SSCF3 121
4.3.3 Haas Reagent 121
4.3.4 Munavalli Reagent 123
4.3.5 Billard Reagent 128
4.3.6 Shen Reagent 131
4.3.7 Shen Reagent-II 136
4.3.8 Optically Active Pure Trifluoromethylthiolation Reagents 140
4.3.9 Lu-Shen Reagent 141
4.3.10 α-Cumyl Bromodifluoromethanesulfenate 144
4.3.11 Shibata Reagent 145
4.3.12 In Situ-Generated Electrophilic Trifluoromethylthiolating Reagents 146
4.3.12.1 AgSCF3 +TCCA 146
4.3.12.2 AgSCF3 +NCS 148
4.3.12.3 Langlois Reagent (CF3SO2Na) with Phosphorus Reductants 148
4.3.12.4 Use of CF3SO2Cl with Phosphorus Reductants 149
4.3.12.5 Reagent Based on CF3SOCl and Phosphorus Reductants 151
4.4 Radical Trifluoromethylthiolation 151
4.4.1 Trifluoromethylthiolation by AgSCF3/S2O8 2- 152
4.4.2 Electrophilic Reagents Involved in Radical Trifluoromethylthiolation 158
4.4.3 Visible Light-Promoted Trifluoromethylthiolation by Using Electrophilic Reagents 159
4.5 Summary and Prospect 165
References 165
5 Bifunctionalization-Based Catalytic Fluorination and Trifluoromethylation 173
Pinhong Chen and Guosheng Liu
5.1 Introduction 173
5.2 Palladium-Catalyzed Fluorination, Trifluoromethylation, and Trifluoromethoxylation of Alkenes 173
5.2.1 Palladium-Catalyzed Fluorination of Alkenes 174
5.2.2 Palladium-Catalyzed Trifluoromethylation of Alkenes 179
5.2.3 Palladium-Catalyzed Trifluoromethoxylation of Alkenes 180
5.3 Copper-Catalyzed Trifluoromethylative Functionalization of Alkenes 183
5.3.1 Copper-Catalyzed Trifluoromethylamination of Alkenes 184
5.3.2 Copper-Catalyzed Trifluoromethyloxygenation of Alkenes 185
5.3.3 Copper-Catalyzed Trifluoromethylcarbonation of Alkenes 187
5.3.4 Enantioselective Copper-Catalyzed Trifluoromethylation of Alkenes 190
5.4 Summary and Conclusions 197
References 197
6 Fluorination, Trifluoromethylation, and Trifluoromethylthiolation of Alkenes, Cyclopropanes, and Diazo Compounds 201
Kálmán J. Szabó
6.1 Introduction 201
6.2 Fluorination of Alkenes, Cyclopropanes, and Diazocarbonyl Compounds 202
6.2.1 Application of Fluoro-Benziodoxole for Fluorination of Alkenes 202
6.2.1.1 Geminal Difluorination of Styrene Derivatives 203
6.2.1.2 Iodofluorination of Alkenes 205
6.2.1.3 Fluorocyclization with C - N, C - O, and C - C Bond Formation 205
6.2.2 Fluorinative Cyclopropane Opening 207
6.2.3 Fluorine-18 Labeling with Fluorobenziodoxole 207
6.3 Fluorination-Based Bifunctionalization of Diazocarbonyl Compounds 209
6.3.1 Rhodium-Catalyzed Geminal Oxyfluorination Reactions 209
6.3.2 [18F]Fluorobenziodoxole for Synthesis of α-Fluoro Ethers 210
6.4 Trifluoromethylation of Alkenes, Alkynes, and Diazocarbonyl Compounds with the Togni Reagent 212
6.4.1 Bifunctionalization of C - C Multiple Bonds 213
6.4.1.1 Oxytrifluoromethylation of Alkenes and Alkynes 213
6.4.1.2 Cyanotrifluoromethylation of Styrenes 214
6.4.1.3 C-H Trifluoromethylation of Benzoquinone Derivatives 215
6.4.2 Geminal Oxytrifluoromethylation of Diazocarbonyl Compounds 217
6.5 Bifunctionalization-Based Trifluoromethylthiolation of Diazocarbonyl Compounds 218
6.5.1 Multicomponent Approach for Geminal Oxy-Trifluormethylthiolation 218
6.5.2 Simultaneous Formation of C - C and C - SCF3 Bonds via Hooz-Type Reaction 219
6.6 Summary 220
References 221
7 Photoredox Catalysis in Fluorination and Trifluoromethylation Reactions 225
Takashi Koike and Munetaka Akita
7.1 Introduction 225
7.2 Fluorination 226
7.2.1 Fluorination Through Direct HAT Process by Excited Photocatalyst 226
7.2.2 Fluorination Through Photoredox Processes 228
7.3 Trifluoromethylation 234
7.3.1 Trifluoromethylation of Aromatic Compounds 234
7.3.2 Trifluoromethylative Substitution of Alkyl Bromides 238
7.4 Summary and Outlook 239
References 239
8 Asymmetric Fluorination Reactions 241
Edward Miller and F. Dean Toste
8.1 Introduction 241
8.2 Electrophilic Fluorination 242
8.2.1 Stoichiometric Asymmetric Fluorination 242
8.2.1.1 Chiral Auxiliary 242
8.2.1.2 Chiral Reagents 243
8.2.2 Catalytic Electrophilic Fluorination 244
8.2.2.1 Organocatalytic Fluorination 244
8.2.2.2 Transition Metal-Catalyzed Fluorinations 259
8.3 Nucleophilic Fluorination 269
8.3.1 Metal-Catalyzed Nucleophilic Fluorination 270
8.3.1.1 Ring Opening of Strained Ring Systems 270
8.3.1.2 Allylic Functionalization 272
8.3.2 Organocatalytic Nucleophilic Fluorination 273
8.4 Summary and Conclusions 274
References 276
9 The Self-Disproportionation of Enantiomers (SDE): Fluorine as an SDE-Phoric Substituent 281
Jianlin Han, Santos Fustero, Hiroki Moriwaki, Alicja Wzorek, Vadim A. Soloshonok and Karel D. Klika
9.1 Introduction 281
9.2 General Concepts and the Role of Fluorine in the Manifestation of the SDE 283
9.3 The SDE Phenomenon 285
9.3.1 SDE via Distillation 285
9.3.2 SDE via Sublimation 286
9.3.3 SDE via Chromatography 288
9.3.3.1 SDEvC for Compounds Containing a -CF3 Moiety 289
9.3.3.2 SDEvC for Compounds Containing a Cq-F1/2 Moiety 290
9.3.3.3 SDEvC for Compounds Containing a -COCF3 Moiety 291
9.4 The SIDA Phenomenon 294
9.5 Conclusions and Recommendations 296
References 299
10 DFT Modeling of Catalytic Fluorination Reactions: Mechanisms, Reactivities, and Selectivities 307
Yueqian Sang, Biying Zhou, Meng-Meng Zheng, Xiao-Song Xue and Jin-Pei Cheng
10.1 Introduction 307
10.2 DFT Modeling of Transition Metal-Catalyzed Fluorination Reactions 308
10.2.1 Ti-Catalyzed Fluorination Reaction 308
10.2.2 Mn-Catalyzed Fluorination Reactions 309
10.2.3 Fe-Catalyzed Fluorination Reactions 310
10.2.4 Rh-Catalyzed Fluorination Reactions 312
10.2.5 Ir-Catalyzed Fluorination Reactions 316
10.2.6 Pd-Catalyzed Fluorination Reactions 317
10.2.6.1 Pd-Catalyzed Nucleophilic Fluorination 317
10.2.6.2 Pd-Catalyzed Electrophilic Fluorination 322
10.2.7 Cu-Catalyzed Fluorination Reactions 328
10.2.7.1 Cu-Catalyzed Nucleophilic Fluorination 328
10.2.7.2 Cu-Mediated Radical Fluorination 331
10.2.8 Ag-Catalyzed Fluorination Reactions 333
10.2.9 Zn-Catalyzed Fluorination Reactions 339
10.3 DFT Modeling of Organocatalytic Fluorination Reactions 340
10.3.1 Fluorination Reactions Catalyzed by Chiral Amines 340
10.3.1.1 Chiral Secondary Amines-Catalyzed Fluorination Reactions 340
10.3.1.2 Chiral Primary Amines-Catalyzed Fluorination Reactions 342
10.3.2 Tridentate Bis-Urea Catalyzed Fluorination Reactions 345
10.3.3 Hypervalent Iodine-Catalyzed Fluorination Reactions 347
10.3.4 N-Heterocyclic Carbene-Catalyzed Fluorination Reactions 351
10.4 DFT Modeling of Enzymatic Fluorination Reaction 354
10.5 Conclusions 357
Acknowledgments 357
References 358
11 Current Trends in the Design of Fluorine-Containing Agrochemicals 363
Peter Jeschke
11.1 Introduction 363
11.2 Role of Fluorine in the Design of Modern Agrochemicals 363
11.3 Fluorinated Modern Agrochemicals 365
11.3.1 Herbicides Containing Fluorine 366
11.3.1.1 Acetohydroxyacid Synthase/Acetolactate Synthase Inhibitors 366
11.3.1.2 Protoporphyrinogen Oxidase Inhibitors 366
11.3.1.3 Cellulose Biosynthesis Inhibitors 367
11.3.1.4 Very Long-Chain Fatty Acid Synthesis Inhibitors 368
11.3.1.5 Auxin Herbicides 368
11.3.1.6 Hydroxyphenylpyruvate Dioxygenase Inhibitors 369
11.3.1.7 Selected Fluorine-Containing Herbicide Development Candidates 370
11.3.2 Fungicides Containing Fluorine 371
11.3.2.1 Fungicidal Succinate Dehydrogenase Inhibitors 371
11.3.2.2 Complex III Inhibitors 373
11.3.2.3 Sterolbiosynthesis (Sterol-C14-Demethylase) Inhibitors 374
11.3.2.4 Polyketide Synthase Inhibitors 374
11.3.2.5 Oxysterol-Binding Protein Inhibitors 376
11.3.2.6 Selected Fluorine-Containing Fungicide Development Candidates 377
11.3.3 Insecticides Containing Fluorine 378
11.3.3.1 Nicotinic Acetylcholine Receptor Competitive Modulators 378
11.3.3.2 Ryanodine Receptor (RyR) Modulators 382
11.3.3.3 GABA-Gated CI-Channel Allosteric Modulators 383
11.3.3.4 Selected Fluorine-Containing Insecticide Development Candidates 385
11.3.4 Acaricides Containing Fluorine 386
11.3.4.1 Mitochondrial Complex II Electron Transport Inhibitors 386
11.3.4.2 Selected Fluorine-Containing Acaricide Development Candidates 387
11.3.5 Nematicides Containing Fluorine 387
11.3.5.1 Nematicides with Unknown Biochemical MoA 387
11.3.5.2 Nematicidal Succinate Dehydrogenase Inhibitors 388
11.3.5.3 Selected Fluorine-Containing Nematicide Development Candidates 388
11.4 Summary and Prospects 389
References 390
12 Precision Radiochemistry for Fluorine-18 Labeling of PET Tracers 397
Jian Rong, Ahmed Haider and Steven Liang
12.1 Introduction 397
12.2 Electrophilic 18F-Fluorination with [18F]F2 and [18F]F2-Derived Reagents 398
12.3 Nucleophilic Aliphatic 18F-Fluorination 399
12.3.1 Transition Metal-Free Nucleophilic Aliphatic Substitution with [18F]Fluoride 399
12.3.2 Transition Metal-Mediated Aliphatic 18F-Fluorination 403
12.4 Nucleophilic Aromatic 18F-Fluorination with [18F]Fluoride 405
12.4.1 Transition Metal-Free Nucleophilic Aromatic 18F-Fluorination with [18F]Fluoride 405
12.4.2 Transition Metal-Mediated Aromatic 18F-Fluorination 413
12.5 18F-Labeling of Multifluoromethyl Motifs with [18F]Fluoride 418
12.6 Summary and Conclusions 421
References 421
Index 427
