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Full Description
Streamlined, cost-effective, and environmentally benign concepts for the synthesis of chemical building blocks and pharmaceuticals
Directed C—H Bond Functionalization summarizes recent advances in the field of selective and efficient C—H bond functionalization using directing groups.
Written by a team of experts in the field, Directed C—H Bond Functionalization includes information on:
History of the C—H bond activation and its discovery
In-built functional group-directed C—H functionalization, proximal C—H bond functionalization, and template-assisted distal C—H bond functionalization
Transient-directing group-assisted C—H bond functionalization and bifunctional non-covalent template-assisted C—H functionalization
Redox catalytic methods and metal-free directed C—H functionalization reactions
Industrial and synthetic application of directed C—H bond functionalization in organic synthesis, medicinal, and process chemistry
With its all-encompassing approach, Directed C—H Bond Functionalization is a timely, essential reference for synthetic chemists in academia and industry working in the fields of organic synthesis, catalysis, sustainable chemistry, and drug design.
Contents
Preface xiii
1 History of Directed C—H Bond Activation and its Discovery 1
Susmita Mondal, Sumit Ghosh, Asim Kumar Ghosh, and Alakananda Hajra
1.1 Introduction 1
1.2 Importance of C—H Activation 2
1.3 Early Discoveries in Stoichiometric Metal-promoted Proximal C—H Bond Functionalization 3
1.4 Directing Group-assisted Catalytic Proximal C—H Bond Functionalization 3
1.4.1 In-built Functional-Group-directed Proximal C—H Bond Functionalization 3
1.4.2 Removable Directing Group-assisted Proximal C—H Bond Functionalization 11
1.4.2.1 Pre-installed and Post-removable Directing Groups-assisted C—H Bond Activation 11
1.4.2.2 Traceless Directing Group-assisted C—H Bond Functionalization 13
1.4.2.3 Transient Directing Group (TDG)-assisted C—H Bond Activation 15
1.5 Directed Distal C—H Bond Functionalization 17
1.5.1 meta-C—H Bond Functionalization 17
1.5.2 para-C—H Bond Functionalization 20
1.5.3 Remote C—H Functionalization 24
1.6 Conclusions 28
Acknowledgments 29
References 29
2 Pd-catalyzed In-built Functional Group-directed C—H Functionalization 37
Ananya Dutta and Masilamani Jeganmohan
2.1 Introduction 37
2.2 In-built Nitrogen Atom in a Heterocycle as the Efficient Directing Group 39
2.3 Aliphatic Amines as the In-built Functional Group 39
2.3.1 Pd-catalyzed Amine-directed Intramolecular C(sp3)—H Amination 40
2.3.2 Pd-catalyzed In-built Amine-directed C—H Arylation 40
2.3.3 Pd-catalyzed Amine-directed C—H Acetoxylation 44
2.3.4 Pd-catalyzed Amine-directed Alkenylation Reaction 45
2.3.5 Amine Group-directed Carbonylation Reactions 47
2.4 Carboxylic Acids as the In-built Functional Group in C—H Activation 48
2.4.1 Pd-catalyzed C(sp2)—H Bond Functionalization of Benzoic and Phenyl Acetic Acids 50
2.4.1.1 Pd-catalyzed Carboxylate Group-directed C(sp2)—H Bond Arylation of Benzoic Acids 50
2.4.1.2 Pd-catalyzed Carboxylate Group-directed Benzolactone and Isocoumarin Formation Using Benzoic Acids 50
2.4.1.3 Pd-catalyzed Carboxylate-assisted Halogenation, Amidation, Carboxylation, and Acylation Reaction of Benzoic Acids 53
2.4.1.4 Pd-catalyzed Carboxylate-assisted C(sp2)—H Bond Arylation of Phenyl Acetic Acids 55
2.4.1.5 Ligand-assisted Pd-catalyzed Olefination of Substituted Phenyl Acetic Acids 57
2.4.1.6 Pd-catalyzed ortho-C(sp2)—H Functionalizations of Phenyl Acetic Acids 57
2.4.2 Benzylic C(sp3)—H Activation of Carboxylate Directing Group 60
2.4.2.1 External ligand-assisted Benzylic C(sp3)—H Activation of Carboxylate Motifs 60
2.4.3 Pd-catalyzed C(sp3)—H Activation of Aliphatic Acids Assisted by In-built Carboxylate Group 61
2.4.3.1 Pd-catalyzed Carboxylate-assisted Arylation of Proximal Aliphatic C(sp3)—H Bonds 61
2.4.3.2 Pd-catalyzed External Ligand-assisted Lactonization of Proximal C(sp3)—H Bonds 63
2.4.3.3 Pd-catalyzed Carboxylate-assisted β-C(sp3)—H Acetoxylation 63
2.4.3.4 Pd-catalyzed β-C(sp3)—H Alkynylation and Deuteration of Free Carboxylic Acids 65
2.4.3.5 Pd-catalyzed Ligand-assisted Distal C(sp3)—H Bond Arylation 66
2.4.3.6 Pd-catalyzed Ligand-assisted Distal C(sp3)—H Bond Lactonization 66
2.4.3.7 Pd-catalyzed Enantioselective Carboxylate-directed C(sp3)—H Activation 68
2.5 Aldehyde as the In-built Functional Group in C—H Activation 69
2.5.1 Pd-catalyzed C(sp2)—H Functionalization of Free Aldehydes 71
2.6 Sulfonic Acid as the In-built Functional Group in C—H Activation 71
2.6.1 Pd-catalyzed C(sp2)—H Functionalization of Free Sulfonic Acids 71
2.7 Alcohols as the In-built Functional Group in C—H Activation 72
2.7.1 Phenethyl Alcohol as the In-built Functional Group 72
2.7.2 Phenol as the In-built Functional Group 73
2.7.3 Hydroxyl Moiety of Salicylaldehyde as the In-built Functional Group 74
2.7.4 Miscellaneous Examples of Free Alcohol as the In-built Functional Group 74
2.8 Conclusion 75
References 76
3 Traceless Directing Group in C—H Bond Functionalization 85
Shuvojit Haldar and Debasis Banerjee
3.1 Introduction 85
3.2 Classification of the Traceless Groups 87
3.3 Carbonyl Group as a Traceless Directing Group 87
3.3.1 Carboxylic Acid as a Traceless Directing Group for Various Organic Transformations 87
3.3.1.1 Carboxylic Acid as a Traceless Directing Group Toward Biaryl Synthesis 87
3.3.1.2 Carboxylic Acid as a Traceless Directing Group: Alkylation of Indole 90
3.3.1.3 Carboxylic Acid as a Traceless Directing Group in Alkylation/Alkenylation 93
3.3.2 Aldehyde and Ketone as a Traceless Directing Group 95
3.3.3 Ester as a Traceless Directing Group 96
3.3.4 Amide as a Traceless Directing Group 96
3.3.5 CO2 as a Traceless Directing Group in C—H Bond Activation 97
3.3.6 tert-Butoxycarbonyl (BOC) Group as a Traceless Directing Group 97
3.4 Nitrogen-containing Functional Groups as a Traceless Directing Group 98
3.4.1 Amine as a Traceless Directing Group 98
3.4.2 Hydrazone as a Traceless Directing Group 99
3.4.3 N-O Group as a Traceless Directing Group 100
3.4.4 Alkene-tethered Aldoxime as a Traceless Directing Group 101
3.5 Miscellaneous Groups as a Traceless Directing Group 102
3.5.1 ((Pinacolato)boron (Bpin)) Group as a Traceless Directing Group 102
3.5.2 Acetal as a Traceless Directing Group 102
3.5.3 Sulfur-based Group as a Traceless Directing Group 103
3.5.4 Silicon Group as a Traceless Directing Group 103
3.5.5 Halides as a Traceless Directing Group 104
3.6 Conclusions 106
Acknowledgments 106
References 106
4 Removable Directing Group in Proximal C—H Functionalization 111
Vikash Kumar, Malati Das, Sivakumar Sudharsan, and Parthasarathy Gandeepan
4.1 Introduction 111
4.2 Removable Directing Groups 112
4.2.1 C—H Functionalization of Amino Compounds 112
4.2.2 C—H Functionalization of Hydroxyl Compounds 116
4.2.3 C—H Functionalization of Aldehyde and Ketone Compounds 119
4.2.4 C—H Functionalization of Carboxylic Acids 123
4.2.5 C—H Functionalization of Sulfonic Acid 128
4.2.6 C—H Functionalization of Heterocycles 131
4.2.7 Silicon Tethers for C—H Functionalization 135
4.3 Summary and Conclusions 137
References 138
5 Removable Template-assisted Transition Metal-catalyzed Distal C—H Functionalization 165
Ke Yang, Dan Yuan, Faith Herington, and Haibo Ge
5.1 Introduction 165
5.2 Distal C(sp2)—H Bond Functionalization 166
5.2.1 Distal C(sp2)—H Functionalization of Arylalkyl and Aryl Acid Derivatives 166
5.2.2 Distal C(sp2)—H Functionalization of Arylalkyl and Aryl Amines 173
5.2.3 Distal C(sp2)—H Functionalization of Arylalkyl Alcohols and Phenols 178
5.2.4 Distal C(sp2)—H Functionalization of Arylalkyl Silanes 181
5.3 Distal C(sp3)—H Bond Functionalization 184
5.3.1 γ-C(sp3)—H Bond Functionalization of Carboxylic Acids 184
5.3.2 γ-C(sp3)—H Bond Functionalization of Aliphatic Ketones 190
5.3.3 δ-C(sp3)—H Bond Functionalization of Aliphatic Amines 192
5.4 Conclusions 195
Funding 196
References 196
6 Non-covalent Template-assisted C—H Bond Functionalization 203
Yoichiro Kuninobu
6.1 Introduction 203
6.2 Control of Site Selectivity 205
6.2.1 C(sp2)—H Transformations 205
6.2.1.1 Controlled by Hydrogen Bond 205
6.2.1.2 Controlled by Lewis Acid-Base Interaction 213
6.2.1.3 Controlled by Electrostatic Interaction 218
6.2.1.4 Controlled by Other Non-covalent Interactions 221
6.2.2 C(sp3)—H Transformations 226
6.2.2.1 Controlled by Hydrogen Bond 226
6.2.2.2 Controlled by Electrostatic Interaction 228
6.2.2.3 Controlled by Other Non-covalent Interactions 230
6.3 Acceleration of Reactions and Substrate and Functional Group Specificities 230
6.4 Summary and Conclusions 235
References 236
7 Pd/Norbornene (NBE) Cooperative Catalysis in C—H Bond Activation 241
Zhibo Yan and Zhe Dong
7.1 Introduction 241
7.2 The Early Organometallic Study and Reaction Discovery 242
7.2.1 The Stoichiometric Organometallic Study 242
7.2.2 The Initial Reaction Discovery by Catellani 246
7.3 Pd(0)/Pd(II)/Pd(IV) Catalytic Cycle: A Series of Chemoselectivity Puzzle 248
7.3.1 The S N -2-type Oxidative Addition vs Concerted Oxidative Addition: Electrophile Scope 250
7.3.2 Migratory Insertion vs β-carbon Elimination: Norbornene Modification 253
7.4 Palladium(II)-initiated Palladium/Norbornene Catalysis 254
7.4.1 N—H Bond-initiate Palladium/Norbornene Catalysis 255
7.4.2 C—H Bond-initiated Palladium/Norbornene Catalysis 258
7.4.2.1 Directed C—H Bond Activation 258
7.4.2.2 Non-directed C—H Bond Activation 268
7.5 Summary and Conclusions 271
References 271
8 Transient Directing Groups in C—H Bond Functionalization 277
Tsz-Kan Ma, Hannan M. Seyal, and James A. Bull
8.1 Introduction 277
8.1.1 The Concept of Transient Directing Groups for C—H Functionalization 277
8.1.2 Early Developments Using Stoichiometric Imine to Direct C—H Functionalization 279
8.2 Transient C(sp3)—H Functionalization 282
8.2.1 C(sp3)—H Functionalization of Aldehydes 282
8.2.2 C(sp3)—H Functionalization of Ketones 287
8.2.3 C(sp3)—H Functionalization of Amines 289
8.3 Transient C(sp2)—H Functionalization 294
8.3.1 C(sp2)—H Functionalization of Aldehydes 294
8.3.1.1 Palladium Catalysis 294
8.3.1.2 Rhodium and Ruthenium Catalysis 299
8.3.1.3 Iridium and Cobalt Catalysis 301
8.3.1.4 Copper Catalysis 301
8.3.2 C(sp2)—H Functionalization of Ketones 301
8.3.2.1 Rhodium Catalysis 301
8.3.2.2 Rhenium Catalysis 303
8.3.2.3 Iridium Catalysis 304
8.3.2.4 Palladium Catalysis 304
8.3.3 C(sp2)—H Functionalization of Amines 305
8.4 Conclusions and Outlook 306
References 307
9 Redox Reactions in Ru(II)-Catalyzed C—H Activations 315
Suman Dana, Suman Ghosh, Mainak Koner, Nityananda Ballav, and Mahiuddin Baidya
9.1 Introduction 315
9.2 Background and Early Findings 316
9.3 Aromatic C—H Bond Activation Through Ru(II/IV)-catalyzed Reactions 318
9.4 Standard Ru(II/0)-catalyzed Reactions 327
9.5 Aerobic Ru(II/0)-catalyzed Reactions 334
9.6 Ru(II)-catalyzed C—H Activations with the Directing Group as the Internal Oxidant 338
9.7 Ru(II)-catalyzed meta- and para-C—H Activations with Ru(II/III)-manifold 342
9.8 Ru(II)-catalyzed C—H Activations Under Photocatalysis 349
9.9 Ru(II)-catalyzed C—H Activations Under Electrocatalysis 351
9.10 Conclusion and Future Outlook 355
References 359
10 Emerging Metal-free Directed C—H Functionalization 373
Rahul Bangari and Supriya Rej
10.1 Introduction 373
10.2 Metal-free Directed Oxidative C—H Functionalization 374
10.3 Directed C—N Bond Formation 375
10.3.1 C(sp2)—N Bond Formation 375
10.3.2 C(sp3)—H Bond Formation 379
10.4 Directed C—O Bond Formation 380
10.4.1 C(sp2)—O Bond Formation 380
10.4.2 C(sp3)—O Bond Formation 382
10.5 Directed C—C Bond Formation 383
10.6 Directed C—H Borylation 384
10.6.1 C(sp2)—H Borylation 384
10.6.2 C(sp3)—H Borylation 390
10.7 Directed C—H Silylation 391
10.8 Summary and Outlook 393
Acknowledgments 394
References 394
11 Directed C(sp3)—H Functionalization in Asymmetric Synthesis 405
Floris Buttard, Balu Ramesh, Javid Rzayev, and Tatiana Besset
11.1 Introduction 405
11.2 Asymmetric Transition Metal-catalyzed C(sp3)—H Bond Activation with Chiral Catalysts 405
11.2.1 Palladium Catalysis 406
11.2.1.1 Classical Directing Group-directed Asymmetric C(sp3)—H Activation 406
11.2.1.2 Transition Metal-catalyzed C(sp3)—H Activation Directed via the Oxidative Addition of Palladium on Aryl Halides or Pseudo Halides 413
11.2.1.3 Native Group-directed Asymmetric C(sp3)—H Activation 416
11.2.2 Use of Other Transition Metal Catalysts 418
11.3 Chiral Transient Directing Groups for Asymmetric Transition Metalcatalyzed C(sp3)—H Activation 421
11.4 Supramolecular Assembly-directed Hydrogen Atom Abstractions for Asymmetric C(sp3)—H Bond Functionalization 423
11.5 Summary and Conclusions 424
References 425
12 Photoredox Catalysis in C—H Bond Functionalization 431
Sayak Ghosh, James Mortimer, and Patricia Z. Musacchio
12.1 Introduction 431
12.2 Direct Activation of Substrates via Oxidative SET 433
12.3 Oxygen-centered Radicals 434
12.3.1 Processes Utilizing Peroxide 434
12.3.1.1 Tert-butyl Hydroperoxide (TBHP) as an Oxygen Radical Source 436
12.3.1.2 Di-tert-butyl Peroxide (DTBP) as an Oxygen Radical Source 436
12.3.1.3 Dicumylperoxide (DCP) and Benzoyl Peroxide (BPO) as an Oxygen Radical Source 437
12.3.1.4 Tert-butyl Peroxybenzoate (TBPB) as an Oxygen Radical Source 437
12.3.1.5 Persulfate Salts as Oxygen Radical Source 438
12.3.2 Processes Using Pyridine N-Oxides and their Derivatives 438
12.3.3 Processes Using Carboxylate Radicals 439
12.3.4 Processes Utilizing Phosphate Radicals 439
12.3.5 Direct and Indirect Use of Alcohols as Precursors 441
12.4 Decatungstate Catalysis 445
12.4.1 Application to Giese-Type Hydroalkylation and Olefin Addition 446
12.4.2 Application to Minisci Alkylation 447
12.4.3 Heteroatom Incorporation via Electrophilic Radical Trapping 447
12.4.4 Application to Metallaphotoredox Cross-Coupling 449
12.4.5 Application to Radical-Polar Crossover 450
12.5 Halogen Radicals 450
12.6 Thiyl Radicals 456
12.7 Nitrogen-centered Radicals 458
12.7.1 Processes Utilizing Aminyl Radicals 458
12.7.2 Processes Utilizing Iminyl Radicals 461
12.7.3 Processes Utilizing Amidyl and Sulfonamidyl Radicals 461
12.7.4 Processes Utilizing Nitrogen Radical Cations 464
12.7.5 Processes Utilizing Azidyl Radical 464
12.8 Carbon-centered Radicals 466
12.9 Summary and Conclusions 467
References 467
13 Dual Transition Metal/Photoredox Catalysis for Directed C(sp2)—H Activations 477
Akshay M. Nair and Martin Fañanás-Mastral
13.1 Introduction 477
13.2 Photocatalysis for Transition Metal Catalyst Reoxidation 479
13.3 Photocatalysis for Coupling Partner Activation 494
13.4 Summary and Conclusions 502
References 504
14 Industrial and Flow Application of Directed C—H Bond Functionalization 509
Aritra Mukherjee, Rahul Bangari, and Supriya Rej
14.1 Introduction 509
14.2 Directed C(sp2)—H Functionalization 510
14.2.1 Homogeneous Catalysis 510
14.2.2 Heterogeneous Catalysis 516
14.3 Directed C(sp3)—H Functionalization 517
14.4 Summary and Conclusions 518
Acknowledgments 520
References 521
15 Applications of Directed C—H Functionalization in Medicinal and Process Chemistry 525
Krishnamay Pal, Rajesh Sahu, and Anant R. Kapdi
15.1 Introduction 525
15.2 C—H Functionalization in Medicinal Chemistry 526
15.2.1 Synthesis of Tie2 Tyrosine Kinase Inhibitor 526
15.2.2 Synthesis of Angiotensin II Receptor Blocker 528
15.2.3 Synthesis of BRD 3914 529
15.2.4 Synthesis of Zafirlukast (Accolate) 530
15.2.5 Synthesis of Palomid 529 531
15.2.6 Synthesis of Febuxostat 532
15.2.7 Synthesis of Tryprostatin A 533
15.2.8 Synthesis of Adiphenine 534
15.3 C—H Functionalization in Process Chemistry 535
15.3.1 Kilogram-Scale Synthesis of Beclabuvir 535
15.3.2 Commercial Synthesis of BMS- 911543 537
15.3.3 Commercial Synthesis of BMS- 919373 539
15.3.4 Multikilogram-Scale Preparation of AZD 4635 540
15.3.5 Developed Synthetic Procedure of LSZ 102 541
15.3.6 Developed Scalable Process of YLF466D 543
15.3.7 Multikilogram-Scale Synthetic Process of Nemiralisib 544
15.3.8 Kilogram-Scale Synthetic Process of AZD 4573 545
15.4 Conclusion 546
References 547
Index 553
