Indole Ring Synthesis

Of the myriad of heterocycles known to man, the indole ring stands foremost for its remarkably versatile chemistry, its enormous range of biological activities, and its ubiquity in the terrestrial and marine environments.

The indole ring continues to be discovered in natural products and to be employed in man-made pharmaceuticals and other materials. Given the enormous resurgence in indole ring synthesis over the past decade — highlighted by the power of transition metal catalysis — this authoritative guide addresses the need for a comprehensive presentation of the myriad of methods for constructing the indole ring, from the ancient to the modern, and from the obscure to the well-known.

Following presentation of the classic indole ring syntheses and many newer methods, coverage continues with indole ring syntheses via pyrroles, indolines, oxindoles, isatins, radical and photochemical reactions, aryne cycloadditions. This extensive volume concludes with the modern transition metal–catalyzed indole ring syntheses that utilize copper, palladium, rhodium, gold, ruthenium, platinum, and other metals to fashion the indole ring

Indole Ring Synthesis is a comprehensive, authoritative and up-to-date guide to the synthesis of this important heterocycle for organic chemists, pharmaceutical researchers and those interested in the chemistry of natural products.

1 Introduction 1

1.1 Preview 1

1.2 Indole‐Containing Natural Products 1

1.3 Biological Activity of Indoles 4

1.4 Indole‐Containing Pharmaceuticals 15

1.5 Indole‐Containing Materials 21

1.6 Indole‐Containing Ligands 28

1.7 Reviews of Indole‐Ring Synthesis 32

1.7.1 General Reviews on Indole Ring Synthesis 32

1.7.2 Specialized Reviews 32

1.7.3 Name Reactions 33

1.7.4 Miscellaneous Reviews 33

1.7.5 Synthesis of Carbazoles, Carbolines, and Indolocarbazoles 34

1.7.6 Reviews of Indole Analogues 34

References 34

PART I Sigmatropic Rearrangements 39

2 Fischer Indole Synthesis 41

2.1 Preview 41

2.2 Methods 41

2.2.1 Traditional Methods 41

2.2.2 Metal‐Catalyzed Methods 44

2.2.3 Solid‐Phase Fischer Indolization Method 56

2.2.4 Other General Methods 57

2.2.5 Hydrazones 63

2.2.6 Other Variations of Fischer Indole Synthesis 66

2.3 Applications of Fischer Indolizations 68

2.3.1 Drug Targets 68

2.3.2 Natural Products 82

2.3.3 Materials 97

2.3.4 General 98

References 108

3 Gassman Indole Synthesis 116

4 Bartoli Indole Synthesis 121

5 Thyagarajan Indole Synthesis 131

6 Julia Indole Synthesis 137

7 Miscellaneous Sigmatropic Rearrangements 139

PART II Nucleophilic Cyclization 145

8 Madelung Indole Synthesis 147

9 Wittig–Madelung Indole Synthesis 156

10 Jones–Schmid Indole Synthesis 165

11 Couture Indole Synthesis 174

12 Wender Indole Synthesis 176

13 Smith Indole Synthesis 181

14 Kihara Indole Synthesis 186

15 Nenitzescu 5‐Hydroxyindole Synthesis 188

16 Engler‐Kita Indole Synthesis 206

17 Bailey–Liebeskind–O’Shea Indoline–Indole Synthesis 213

18 Wright Indoline Synthesis 219

19 Saegusa Indole Synthesis 221

20 Ichikawa Indole Synthesis 228

21 Miscellaneous Nucleophilic Cyclizations that Form the Indole Ring 230

22 Sugasawa Indole Synthesis 244

PART III Electrophilic Cyclization 247

23 Bischler Indole Synthesis 249

24 The Nordlander Indole Synthesis 260

25 Nitrene Cyclization 264

26 Cadogan–Sundberg Indole Synthesis 266

27 Sundberg Indole Synthesis 278

28 Hemetsberger Indole Synthesis 287

29 Taber Indole Synthesis 296

30 Knochel Indole Synthesis 299

31 Täuber Carbazole Synthesis 301

32 Quéguiner Azacarbazole Synthesis 304

33 Iwao Indole Synthesis 307

34 Hewson Indole Synthesis 309

35 Magnus Indole Synthesis 310

36 Feldman Indole Synthesis 311

37 Butin Indole Synthesis 313

38 Miscellaneous Electrophilic Cyclizations 317

PART IV Reductive Cyclization 323

39 Nenitzescu o,β‐Dinitrostyrene Reductive Cyclization 325

40 Reissert Indole Synthesis 332

41 Leimgruber–Batcho Indole Synthesis 338

42 Pschorr–Hoppe Indole Synthesis 349

43 Mąkosza Indole Synthesis 354

44 Rawal Indole Synthesis 361

45 The Baeyer–Jackson Indole Synthesis and Miscellaneous Reductive Cyclization Indole Syntheses 363

PART V Oxidative Cyclization 381

46 Watanabe Indole Synthesis 383

47 Knölker Carbazole Synthesis 391

48 Miscellaneous Oxidative Cyclizations 396

PART VI Radical Cyclization 403

49 Fukuyama Indole Synthesis 405

50 Other Tin‐Mediated Indole Syntheses 409

51 The Murphy Indole Synthesis 412

52 Miscellaneous Radical‐Promoted Indole Syntheses 414

53 The Graebe–Ullmann Carbazole‐Carboline Synthesis 424

PART VII Cycloaddition and Electrocyclization 435

54 Diels–Alder Cycloaddition 437

55 Plieninger Indole Synthesis 464

56 Photochemical Synthesis of Indoles and Carbazoles 468

57 Dipolar Cycloaddition, Anionic, and Electrocyclization Reactions 483

PART VIII Indoles from Pyrroles 493

58 Electrophilic Cyclization of Pyrrole 495

59 Palladium‐Catalyzed Cyclization of Pyrroles 503

60 Cycloaddition Syntheses from Vinyl Pyrroles 506

61 Electrocyclization of Pyrroles 512

62 Indoles from Pyrrolo‐2,3‐Quinodimethanes 517

63 Indoles via Dehydrogenation of Pyrroles 520

64 Miscellaneous Indole Syntheses from Pyrroles 525

65 Indoles via Arynes 528

PART IX Indoles from Indolines 537

66 Indoline Dehydrogenation 539

67 Indolines to Indoles by Functionalized Elimination 553

68 Indolines from Oxindoles, Isatins, and Indoxyls 558

PART X Metal‐Catalyzed Indole Synthesis 573

69 Copper‐Catalyzed Indole Synthesis 575

70 Palladium‐Catalyzed Indole Ring Synthesis: Hegedus 588

71 Palladium‐Catalyzed Indole Ring Synthesis: Mori–Ban–Heck 592

72 Palladium‐Catalyzed Indole Ring Synthesis: Aryl‐Heck 597

73 Palladium‐Catalyzed Indole Ring Synthesis: Oxidative Cyclization 600

74 Palladium‐Catalyzed Indole Ring Synthesis: Watanabe–Cenini–Söderberg 604

75 Palladium‐Catalyzed Indole Ring Synthesis: Yamanaka–Sakamoto–Sonogashira 607

76 Palladium‐Catalyzed Indole Ring Synthesis: Larock 611

77 Palladium‐Catalyzed Indole Ring Synthesis: Cacchi 615

78 Palladium‐Catalyzed Indole Ring Synthesis: Buchwald–Hartwig 619

79 Palladium‐Catalyzed Indole Ring Synthesis: Miscellaneous 623

80 Rhodium‐Catalyzed Indole Ring Synthesis 632

81 Gold‐Catalyzed Indole Ring Synthesis 640

82 Ruthenium‐Catalyzed Indole Ring Synthesis 645

83 Platinum‐Catalyzed Indole Ring Synthesis 648

84 Silver‐ and Zinc‐Catalyzed Indole Ring Synthesis 651

85 Iron‐, Iridium‐, and Indium‐Catalyzed Indole Ring Syntheses 655

86 Nickel‐, Cobalt‐, and Molybdenum‐Catalyzed Indole Ring Syntheses 660

87 Mercury‐ and Chromium‐Catalyzed Indole Ring Syntheses 663

88 Miscellaneous Metal‐Catalyzed Indole Ring Syntheses 666

PART XI Miscellaneous 669

89 Miscellaneous Indole Ring Syntheses 671

Index 676

Professor Gordon Gribble, Department of Chemistry, Dartmouth College, USA
Professor Gribble has been the co-editor of the annual book series Progress in Heterocyclic Chemistry for the past 10 years. His research programs involve several areas of organic chemistry, most of which involve synthesis: biologically active natural products, novel indole chemistry, anticancer triterpenoid synthesis, new synthetic methodology, and novel radical and cycloaddition chemistry of heterocycles.