A Unified Approach to Mono- and 2,3-Disubstituted N–H Indoles

Abstract

A unified approach to mono- and disubstituted N–H indoles is described by means of oxidative cyclization of 2-alkenyl anilines, which are prepared by cross-coupling of the corresponding o-bromoanilines. This procedure is operationally expedient and tolerant of common functional groups to allow regiospecific installation of the alkyl and aryl substituents.

Synthesis of Indoles from o-Haloanilines

“…During an initial phase of this work the Suzuki coupling of 1 or the Stille reaction of vinyl stannanes (when readily available) was employed for the preparation of the requisite 2-alkenylanilines . Our attention was shifted to a more expedient option of the Barluenga–Valdés cross-coupling reaction involving typically crystalline tosylhydrazones to bypass the otherwise necessary pre-functionalization (e.g., the intermediacy of enol triflates and/or boronates) of carbonyl compounds. , Barluenga’s seminal application of tosylhydrazones as diazo precursors provides new routes to an array of alkenes.…”

“…The palladium-catalyzed coupling reactions of o -haloaniline derivatives offer valuable alternatives to the Fischer indole synthesis. , As part of the projected total syntheses of structurally complex indole alkaloids, a flexible method for installing an indole scaffold to an advanced intermediate at a late stage of synthesis was required; and a new approach of employing ketones or aldehydes that are regioisomeric to the substrates for the Fischer indole synthesis and variants was highly desirable. , An operationally expedient method for preparing N –H indoles without the use of an N -protecting group, while accessing all substitution patterns was also ideal. Toward this end, an effective strategy was recently found in oxidative cyclization of 2-alkenylanilines, which were easily accessible from o -haloanilines. We report herein a convenient synthesis of indoles by the sequential implementation of Pd-catalyzed cross-coupling reactions of o -haloanilines and oxidative cyclization of the resulting 2-alkenylanilines (Scheme ).…”