Transition-Metal-Catalyzed C-H Functionalization of Heterocycles, 2 Volumes

A comprehensive guide to recent advances in this field

Constituting the majority of all known compounds, heterocycles are structures that incorporate one or more heteroatoms within their core, thus exhibiting properties that are quite different from their all-carbon analogs. They are fundamental to all fields of chemistry and, therefore, their synthesis and modification has attracted a great deal of attention in the recent years. In this vein, transition-metal-catalyzed C-H bond functionalization forms a crucial tool for generating and analyzing heterocyclic compounds.

Transition-Metal-Catalyzed C-H Functionalization of Heterocycles, Two-Volume Set, showcases diverse C-H functionalization methodologies and their incorporation into the latest research. The chapters serve as an essential tool depicting detailed site-selective functionalization of heterocyclic cores, along with a comprehensive discussion on their mechanistic approaches.

Readers of Transition-Metal-Catalyzed C-H Functionalization of Heterocycles, Two-Volume-Set will also find:

• A detailed introduction to C-H activation along with the mechanistic aspects of transition-metal-catalyzed C-H bond activation reactions
• Easy-to-use structures with each chapter dedicated to a type of heterocycle and its specific functionalization methodologies
• A leading team of international authors in C-H bond functionalization

Transition-Metal-Catalyzed C-H Functionalization of Heterocycles, Two-Volume-Set is a valuable guide for students and researchers in organic synthesis and process development, in both academic and industrial contexts.

Tharmalingam Punniyamurthy, PhD is Professor and Head of the Department of Chemistry at the Indian Institute of Technology Guwahati, India.

Anil Kumar, PhD is Professor in the Department of Chemistry at the Birla Institute of Technology and Science, Pilani, India.

Contents

List of Contributors xiii

8 Functionalization of Pyridines, Quinolines, and Isoquinolines 357

Jun Zhou and Bing-Feng Shi

8.1 Introduction 357

8.2 C2-Selective Functionalization 358

8.2.1 Alkylation 358

8.2.2 Arylation 361

8.2.2.1 Pyridine Derivatives as Substrates 361

8.2.2.2 Pyridine N-oxides as Substrates 363

8.2.2.3 N-iminopyridinium Ylides as Substrates 365

8.2.3 Alkenylation 365

8.2.4 Acylation, Amination, and Aminomethylation 367

8.3 C3-Selective Functionalization 370

8.3.1 Alkylation 370

8.3.2 Arylation 371

8.3.3 Alkenylation 374

8.3.4 Borylation 377

8.4 C4-Selective Functionalization 378

8.4.1 Alkylation 378

8.4.2 Arylation 380

8.4.3 Alkenylation 381

8.4.4 Borylation 382

8.5 C8-Selective Functionalization 382

8.6 Summary and Conclusions 387

9 Transition Metal-Catalyzed C-H Bond Functionalization of Diazines and Their Benzo Derivatives 393

Christian Bruneau and Rafael Gramage-Doria

9.1 Introduction 393

9.2 Carbon-carbon Bond Formation 394

9.2.1 C-H Bond (Hetero)arylations 394

9.2.2 C–H Bond Olefinations 406

9.2.3 C–H Bond Alkylations 415

9.2.4 C–H Bond Alkynylations 418

9.2.5 C–H Bond Carboxylations 419

9.3 Carbon-nitrogen Bond Formation 420

9.4 Carbon-oxygen Bond Formation 424

9.5 Carbon-sulfur Bond Formation 424

9.6 Carbon-boron Bond Formation 425

9.7 Carbon-silicon Bond Formation 425

9.8 Carbon-halogen Bond Formation 427

9.9 Conclusions 428

Acknowledgments 429

10 Functionalization of Chromenes and Their Derivatives 435

Laura Cunningham, Sundaravel Vivek Kumar, and Patrick J. Guiry

10.1 Introduction 435

10.2 2 H-Chromenes 435

10.3 2 H-Chromene-ones (Coumarins) 437

10.3.1 C3-Selective Functionalization 437

10.3.1.1 Alkenylation 437

10.3.1.2 Arylation 438

10.3.1.3 Other 441

10.3.1.4 Annulation/Cyclization 442

10.3.2 C4–H Selective Functionalization 449

10.3.3 C5-Selective Functionalization 456

10.4 4 H-Chromene 459

10.5 4 H-Chromenones (Chromones) 462

10.5.1 C2-Selective C–H Activation 462

10.5.2 C3-Selective C–H Activation 463

10.5.3 C5-Selective C–H Activation 468

10.5.3.1 Alkenylation 468

10.5.3.2 Alkylation 471

10.5.3.3 (Hetero)arylation 473

10.5.3.4 Amination/Amidation 474

10.5.3.5 Others 477

10.5.4 C6-Selective C–H Activation 478

10.5.5 Conclusions 478

11 Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles 485

Rajeev Sakhuja and Anil Kumar

11.1 Introduction 485

11.2 C–C Bond Formation 486

11.2.1 Alkylation 486

11.2.1.1 Fluoro Alkylation 486

11.2.1.2 Alkoxycarbonyl Alkylation 488

11.2.1.3 Aryl/heteroaryl Alkylation 489

11.2.1.4 Amino Alkylation 493

11.2.1.5 Sulfonyl/Carbonyl/Cyano Alkylation 496

11.2.2 Alkenylation/Alkynylation/Allenylation 498

11.2.3 Cyanation/Carbonylation 503

11.2.4 Arylation/Heteroarylation 509

11.3 C–S/Se Bond Formation 525

11.4 C–N Bond Formation 532

11.5 C–P Bond Formation 533

11.6 C–Si Bond Formation 535

11.7 Conclusions 535

Acknowledgments 536

12 Dehydrogenative Annulation of Heterocycles: Synthesis of Fused Heterocycles 543

Neha Jha and Manmohan Kapur

12.1 Dehydrogenative Coupling: An Overview 543

12.2 Importance of Heterocycles and Their Fused Congeners 545

12.3 Metal-Catalyzed Dehydrogenative-coupling Reactions: Formation of C–Z Bonds 546

12.3.1 C–C Bond Formation 546

12.3.1.1 Synthesis of Large-sized Molecules: COTs 549

12.3.2 Formation of C–N Bonds 550

12.3.3 Formation of C–B Bonds 557

12.4 Conclusions 562

13 C–H Functionalization of Saturated Heterocycles Beyond the C2 Position 567

Amalia-Sofia Piticari, Natalia Larionova, and James A. Bull

13.1 Introduction 567

13.2 Heterocycle Functionalization with a C2 Directing Group 567

13.2.1 Carboxylic Acid-Linked C2 Directing Groups 567

13.2.2 Applications of N-Heterocycle Functionalization with C2 Directing Groups 580

13.3 Heterocycle Functionalization with C3 Directing Groups 586

13.3.1 Carboxylic Acid-Linked C3 Directing Groups 586

13.3.2 Amine-Linked C3 Directing Groups 590

13.3.3 Alcohol-Linked C3 Directing Groups 592

13.4 Heterocycle Functionalization with a C4 Directing Group 594

13.5 Transannular Heterocycle Functionalization with N-linked Directing Groups 598

13.6 Conclusions 603

14 Asymmetric Functionalization of C–H Bonds in Heterocycles 609

Olena Kuleshova and Laurean Ilies

14.1 Introduction 609

14.2 Enantioselective C–H Activation 609

14.2.1 Activation of C(sp²)–H Bonds 609

14.2.2 Activation of C(sp³)–H Bonds 611

14.3 C–H Activation Followed by Enantioselective Functionalization 615

14.3.1 Intramolecular Coupling 615

14.3.1.1 Indoles and Pyrroles as Coupling Partners 615

14.3.1.2 Imidazoles and Benzoimidazoles as Coupling Partners 618

14.3.1.3 Pyridines and Pyridones as Coupling Partners 618

14.3.2 Intermolecular Coupling 619

14.3.2.1 Directing-Group-Free C–H Functionalization 619

14.3.2.2 Functionalization Assisted by a Directing Group at the C3 Site 621

14.3.2.3 Functionalization Assisted by a Directing Group at the N-1 Site 623

14.3.3 Atropo-enantioselective Synthesis of Heterobiaryls 624

14.4 Conclusions and Perspectives 627

15 Transition Metal-Catalyzed C–H Functionalization of Nucleoside Bases 631

Yong Liang and Stanislaw F. Wnuk

15.1 Introduction 631

15.2 Direct Functionalization of the C5-H Bond in Uracil Nucleosides 632

15.2.1 Cross-Dehydrogenative Alkenylation at the C5 Position 632

15.2.2 Direct C–H Arylation at the C5 Position 634

15.2.3 Direct C–H Alkylation at the C5 Position 635

15.2.4 Miscellaneous Direct C–H Functionalizations 636

15.3 Direct Functionalization of C6-H Bond in Uracil 637

15.3.1 Stepwise C6-H Functionalization of Pyrimidine Nucleoside via Lithiation and Alkylation 637

15.3.2 Direct C6-H Functionalization of the Uracil Base 637

15.3.2.1 Functionalization with Aryl Halides 637

15.3.2.2 Cross-Dehydrogenative Functionalization with Arenes 638

15.3.2.3 Functionalization with Aryl Boronic Acid 639

15.3.2.4 Intramolecular C6-H Functionalization of Uracil Derivatives 639

15.4 Inverted C–H Functionalization of Uracil Nucleosides 640

15.4.1 Inverted C5-H Functionalization of Uracil Nucleosides 640

15.4.2 Inverted C6-H Functionalization of Uracil 641

15.5 Direct C2-H Functionalization of Adenosine 641

15.6 Direct C6-H Functionalization of Purine Nucleoside 642

15.6.1 Direct C6-H Alkylation 642

15.6.1.1 With Cycloalkanes 642

15.6.1.2 With Boronic Acid 643

15.6.1.3 With Alkyltrifluoroborate 643

15.6.1.4 With Alkyl Carboxylic Acid 643

15.6.1.5 With tert-Alkyl Oxalate Salts 644

15.6.2 Direct C6-H Arylation 644

15.6.3 Other Direct C6-H Functionalization 645

15.7 Direct Activation of C8-H Bond in Purine and Purine Nucleosides 645

15.7.1 Cross-Coupling of Adenine Nucleosides with Aryl Halides 645

15.7.2 Cross-Coupling of Inosine and Guanine Nucleosides with Aryl Halides 647

15.7.3 Cross-Coupling of Adenine Nucleosides with Alkanes 648

15.7.4 Miscellaneous Functionalization of Adenosine-related Substrates 649

15.8 Conclusions 650

16 C–H Activation for the Synthesis of C1-(hetero)aryl Glycosides 657

Morgane de Robichon, Juba Ghouilem, Angélique Ferry, and Samir Messaoudi

16.1 General Introduction 657

16.2 Classical Methods to Prepare C-aryl Glycosides 657

16.3 Directed C-H Activation Approach 658

16.3.a Directed Csp²-Csp² Bond Formation 659

16.3.a.1 Directing Group Attached to the Aryl Partner 659

16.3.a.2 Directing Group Attached to the Sugar Nucleus 661

16.3.b Directed Csp²-Csp³ Bond Formation 662

16.3.b.1 The Directing Group (DG) Attached to the Coupling Partner 662

16.3.b.2 The Directing Group Attached to the Sugar Nucleus 675

16.4 Conclusions and Perspectives 679

17 Late-stage C–H Functionalization: Synthesis of Natural Products and Pharmaceuticals 683

Harshita Shet and Anant R. Kapdi

17.1 Introduction 683

17.2 Synthesis of (±)-Ibogamine 684

17.3 Synthesis of YD-3 and YC-1 (C–H Arylation of Indazoles) 685

17.4 Synthesis of Complanadine A 685

17.5 Synthesis of Diptoindonesin G (C–H Arylation of Benzofuran) 686

17.6 Synthesis of Dragmacidin D (C–H Arylation of Indoles at the C3 Position) 687

17.7 Synthesis of Celecoxib (C–H Arylation of Pyrazoles) 688

17.8 Synthesis of Aspidospermidine 689

17.9 Synthesis of Pipercyclobutanamide A 690

17.10 Synthesis of Nigellidine Hydrobromide 691

17.11 Synthesis of (+)-Linoxepin 691

17.12 Synthesis of (±)-Rhazinal 692

17.13 Synthesis of Podophyllotoxin (C–H Arylation) 693

17.14 Synthesis of (±)-Rhazinilam 694

17.15 Synthesis of Aeruginosins (sp3 C–H Alkenylation and Arylation) 694

17.16 Synthesis of Gamendazole 696

17.17 Synthesis of Beclabuvir (BMS-791325) 697

17.18 Conclusions 698

18 Late-stage Functionalization of Pharmaceuticals, Agrochemicals, and Natural Products 703

François Richard, Elias Selmi-Higashi, and Stellios Arseniyadis

18.1 C–H Methylation and Alkylation 704

18.2 C–H Arylation and Olefination 705

18.3 Formation of Other C−C Bonds 711

18.4 C–H Hydroxylation 714

18.5 C–H Amination 715

18.6 C–H Trifluoromethylation 716

18.7 C–H Difluoromethylation 716

18.8 C–H Fluorination 718

18.9 C–H Silylation 718

18.10 C–H Phosphorylation 719

18.11 C–H Deuteration and Tritiation 720

18.12 Conclusions 723

Index 727

Brief Contents

Volume 1:

List of Contributors xiii

Preface xvii

1 Historical Perspective and Mechanistic Aspects of C–H Bond Functionalization 1

Tariq M. Bhatti, Eileen Yasmin, Akshai Kumar, and Alan S. Goldman

2 Recent Advances in C–H Functionalization of Five–Membered Heterocycles with Single Heteroatoms 61

B. Prabagar and Zhuangzhi Shi

3 Functionalization of Five-membered Heterocycles with Two Heteroatoms 109

Jung Min Joo

4 Transition Metal-Catalyzed C–H Functionalization of Indole Benzenoid Ring 155

Vikash Kumar, Rajaram Maayuri, Lusina Mantry, and Parthasarathy Gandeepan

5 Transition Metal-Catalyzed C2 and C3 Functionalization of Indoles 193

Pinki Sihag, Meledath Sudhakaran Keerthana, and Masilamani Jeganmohan

6 C(sp2)–H Functionalization of Indolines at the C7-Position 251

Neeraj Kumar Mishra and In Su Kim

7 Transition Metal-Catalyzed C–H Functionalization of Benzofused Azoles with Two or More Heteroatoms 319

Tanumay Sarkar, Subhradeep Kar, Prabhat Kumar Maharana, Tariq. A. Shah, and Tharmalingam Punniyamurthy

Volume 2:

List of Contributors xiii

8 Functionalization of Pyridines, Quinolines, and Isoquinolines 357

Jun Zhou and Bing-Feng Shi

9 Transition Metal-Catalyzed C-H Bond Functionalization of Diazines and Their Benzo Derivatives 393

Christian Bruneau and Rafael Gramage-Doria

10 Functionalization of Chromenes and Their Derivatives 435

Laura Cunningham, Sundaravel Vivek Kumar, and Patrick J. Guiry

11 Transition Metal-Catalyzed C–H Functionalization of Imidazo-fused Heterocycles 485

Rajeev Sakhuja and Anil Kumar

12 Dehydrogenative Annulation of Heterocycles: Synthesis of Fused Heterocycles 543

Neha Jha and Manmohan Kapur

13 C–H Functionalization of Saturated Heterocycles Beyond the C2 Position 567

Amalia-Sofia Piticari, Natalia Larionova, and James A. Bull

14 Asymmetric Functionalization of C–H Bonds in Heterocycles 609

Olena Kuleshova and Laurean Ilies

15 Transition Metal-Catalyzed C–H Functionalization of Nucleoside Bases 631

Yong Liang and Stanislaw F. Wnuk

16 C–H Activation for the Synthesis of C1-(hetero)aryl Glycosides 657

Morgane de Robichon, Juba Ghouilem, Angélique Ferry, and Samir Messaoudi

17 Late-stage C–H Functionalization: Synthesis of Natural Products and Pharmaceuticals 683

Harshita Shet and Anant R. Kapdi

18 Late-stage Functionalization of Pharmaceuticals, Agrochemicals, and Natural Products 703

François Richard, Elias Selmi-Higashi, and Stellios Arseniyadis

Index 727

The New copy of this book will include any supplemental materials advertised. Please check the title of the book to determine if it should include any access cards, study guides, lab manuals, CDs, etc.

The Used, Rental and eBook copies of this book are not guaranteed to include any supplemental materials. Typically, only the book itself is included. This is true even if the title states it includes any access cards, study guides, lab manuals, CDs, etc.