Azide-Induced Furan Ring Opening for the Synthesis of Functionalized Indoles

Abstract

We investigated the reactivity of various furans towards 2-azidobenzaldehydes, heterocyclic azidoaldehydes, and substituted 2-azidobenzyl alcohols to synthesize 2-(2-azidobenzyl)furan derivatives, revealing the azide group's remarkable compatibility with typical Friedel-Crafts reaction conditions. Additionally, we demonstrated that these derivatives could be efficiently synthesized via a diazotization/azidation sequence from 2-(2-aminobenzyl)furans containing electron-donating substituents, successfully avoiding undesirable side reactions. Furthermore, we developed a synthetic methodology for preparing 2-(2-acylvinyl)indoles, involving the thermal generation of nitrenes to initiate furan ring opening. Notably, our approach utilizes the azidoaryl group and the furan ring separated by a saturated carbon atom that distinguishes it from known indole syntheses in which these moieties are conjugated. The broad applicability and high efficiency of our method, using readily available starting materials, highlight its potential as a versatile synthetic tool.