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.

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