Recent Advances in the Regioselective Synthesis of Indoles via C–H Activation/Functionalization

Abstract

Indole is an important heterocyclic motif that occurs ubiquitously in bioactive natural products and pharmaceuticals. Immense efforts have been devoted to the synthesis of indoles starting from the Fisher indole synthesis to the recently developed C–H activation/functionalization-based methods. Herein, we have reviewed the progress made on the regioselective synthesis of functionalized indoles, including 2-substituted, 3-substituted and 2,3-disusbstituted indoles, since the year 2010.1 Introduction2 Metal-Catalyzed Synthesis of 2-Substituted Indoles3 Metal-Catalyzed Synthesis of 3-Substituted Indoles4 Metal-Free Synthesis of 3-Substituted Indoles5 Metal-Catalyzed 2,3-Disubstituted Indole Synthesis5.1 Metal-Catalyzed Intramolecular 2,3-Disubstituted Indole Synthesis5.2 Metal-Catalyzed Intermolecular 2,3-Disubstituted Indole Synthesis6 Metal-Free 2,3-Disubstituted Indole Synthesis6.1 N-Protected 2,3-Disubstituted Indole Synthesis6.2 N-Unprotected 2,3-Disubstituted Indole Synthesis7 Applications8 Summary and Outlook

Migraine drugs

“…It is not only the triptans that carry the indole motif, but there is a whole range of other active pharmaceutical ingredients for very different indications that incorporate this heterocycle as well (Fig. 30) [399][400][401].…”

One-pot, regioselective synthesis of functionalized indole derivatives: a three-component domino reaction of arylamine, arylglyoxal, and 4-hydroxycoumarin or 4-hydroxy-6-methyl-2-pyrone

“…23 Recently, new strategies have been developed for the synthesis of indole derivatives; these include: various metal-catalyzed, [24][25][26][27][28][29] multi-component method, 30 cyclization reaction, 31 Wittig reactions, 32 and various other methods. [33][34][35][36] Most of these protocols appear to suffer from some drawbacks such as tedious experimental procedures, difficult reaction conditions, multiple synthetic steps, low yields, and usage of expensive catalysts and reagents. Therefore, the development of more economic, convenient and efficient approaches to the regioselective synthesis of substituted indoles under mild conditions is still an attractive proposition.…”

Divergent electrosynthesis of 3-iodoindoles and indoles from 2-ethynylanilines under ambient and aqueous conditions

“…1 Particularly in synthetic chemistry, tremendous efforts have been made for the development of novel and efficient protocols for synthesizing indole derivatives, and cyclization of 2-ethynylanilines has been one of the many effective strategies. 2 Following such a design, 3-iodoindoles with potential for further cross-couplings have been accessed via oxidative iodocyclization with “I + equivalents” such as IPy 2 BF 4 , I 2 , and N -iodosuccinimide (NIS) systems (Scheme 1a); 3,4 while the formation of indoles via catalytic hydrocyclization has been achieved with various metals (Cu, Ag, Pt, Zn, etc .) and base catalysis (Scheme 1b).…”