Indole Ring Synthesis – From Natural Products to Drug Discovery

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.

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 Tauber Carbazole Synthesis 301 32 Queguiner 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, Dinitrostyrene Reductive Cyclization 325 40 Reissert Indole Synthesis 332 41 Leimgruber Batcho Indole Synthesis 338 42 Pschorr Hoppe Indole Synthesis 349 43 M kosza 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 Knolker 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 Soderberg 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