Halogen-mediated C2/C3 functionalization of indoles: A concise overview

Abstract

Indole and its derivatives represent a pivotal class of heterocycles in organic and medicinal chemistry, owing to their presence in numerous natural products and a wide range of pharmacologically active compounds. The functionalization of indoles under transition metal-free conditions has emerged as a significant area of research, driven by the demand for more sustainable synthetic methods and the structural versatility of the indole scaffold. Among the various strategies explored, halogen-mediated functionalization offers a versatile and efficient approach for introducing diverse functional groups at specific positions on the indole ring. This review comprehensively highlights halogen-mediated functionalization strategies of indole, with emphasis on the use of molecular iodine, bromine, and N-halosuccinimides (NXS) as halogenating agents or reaction mediators. A diverse array of bond-forming reactions, including C–C, C–N, C–O, and C–S couplings, as well as multiple bond formations, are systematically discussed in the context of electrophilic halogenation and subsequent functionalization. Furthermore, the role of iodine–DMSO-mediated oxidative protocols in the modification of indole-based frameworks is also examined. This review aims to provide a detailed overview of halogen-based methodologies for the functionalization of indole and its derivatives, serving as a valuable resource for researchers exploring halogen-driven methodologies in the functionalization of indole and its derivatives.