Metal-Free Photocatalyzed Difunctionalization of Pyridines via Oxazinopyridine Intermediates

Abstract

C–H functionalization of pyridines holds significant importance in the fields of medicine, chemistry, and materials science. Due to the intrinsic electronic properties of pyridines, their C–H functionalization reactions face considerable limitations, particularly in the case of difunctionalization, for which reports remain scarce. In this study, we developed a method for the difunctionalization of pyridines and their derivatives using nitrosamines as bifunctional reagents, based on the persistent radical effect and a redox-neutral dearomatization–rearomatization strategy. This approach features mild reaction conditions, no requirement for metal catalysts, and moderate to excellent yields, and is applicable to the late-stage modification of pharmaceuticals, prodrugs, and ligands. Moreover, with the aid of microflow technology, the method was successfully scaled up under continuous-flow conditions. The products can be further converted into other valuable compounds through simple transformations such as oxidation and reduction, for example, 4-amino-3-pyridinesulfonamide, a key intermediate of Torasemide, demonstrating the considerable application potential of this methodology.