Recent advances in photocatalytic Minisci reaction: an ecofriendly functionalization of biologically relevant heteroarenes

Abstract

“Minisci Reaction”, that is the nucleophilic substitution of protonated heteroaromatic bases by carbon centered radicals under oxidative conditions, probably represents the very first and mostly applied example proving that radical chemistry could be considered a valuable tool in organic synthesis. By showing how charged species could significantly affect the products’ distribution, Minisci and co-workers disclosed the potential of homolytic processes, revealing the key role of polar effects in driving the regioselectivity of the reaction. Over the last 50 years, Minisci Reaction has reached its full consecration, finding application in several organic synthetic routes for a wide range of molecules of pharmaceutical and biological interest. In the last two decades, the photocatalytic approach for the promotion of this chemo- and regio-selective substitution of heteroarenes has been proposed as a potential eco-friendly alternative to the classical thermal routes. In this context, the sunlight-induced nucleophilic radical addition to protonated heteroaromatic bases catalysed by TiO2-based semiconductors could be considered the genesis of the photocatalytic approach. This protocol, which was successfully applied for the generation of a wide range of radical sources, has been widely analysed in the first edition of this volume. Herein, after re-calling some key aspects of the TiO2-photocatalysis, and our progress in the molecular dynamic studies finalized to the future design of ideal TiO2 crystals, we mainly focus on the recent advances in sun- and visible-light mediated Minisci Reaction, outlining the progress behind the state-of-the-art to promote the regio- and even enantioselective functionalization of heteroaromatic bases under under milder and more benign conditions