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

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 synthesis 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 for indole from early developments to recent advances in the field, with an 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.