Direct C–H functionalisation of azoles via Minisci reactions

Abstract

Azoles have widespread applications in medicinal chemistry; for example, thiazoles, imidazoles, benzimidazoles, isoxazoles, tetrazoles and triazoles appear in the top 25 most frequently used N-heterocycles in FDA-approved drugs. Efficient routes for the late-stage C–H functionalisation of azole cores would therefore be highly desirable. The Minisci reaction, a nucleophilic radical addition reaction onto N-heterocyclic bases, is a direct C–H functionalisation reaction that has the potential to be a powerful method for C–H functionalisations of azole scaffolds. However, azoles have not been as widely studied as substrates for modern Minisci-type reactions as they are often more electron-rich and thus more challenging substrates compared to electron-poor 6-membered N-heterocycles such as quinolines, pyrazines and pyridines typically used in Minisci reactions. Nevertheless, with the prevalence of azole scaffolds in drug design, the Minisci reaction has the potential to be a transformative tool for late-stage C–H functionalisations to efficiently access decorated azole motifs. This review thus aims to give an overview of the C–H functionalisation of azoles via Minisci-type reactions, highlighting recent progress, existing limitations and potential areas for growth.