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.
Table of Contents
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
