A radical chlorodifluoromethylation protocol for late-stage difluoromethylation and its application to an oncology candidate

Abstract

Radical fluoroalkylation is a powerful synthetic tool for the late-stage incorporation of fluorinated moieties into organic molecules, which is widely used in the development of pharmaceuticals and agrochemicals. Here, we report an efficient radical chlorodifluoromethylation protocol with sodium chlorodifluoromethanesulfinate, which is complementary to the existing late-stage difluoromethylation strategies. CF2Cl radical is a suitable surrogate for accessing the CF2H group while possessing completely different electronic properties compared to the CF2H radical. This method is chemoselective and regioselective for the chlorodifluoromethylation of (hetero)arenes and electron-rich alkenes and shows good functionality, tolerance, and generality on scope. The preparation of the sodium chlorodifluoromethanesulfinate is thoroughly investigated and can be scaled up to hundreds of kilograms. The method is successfully implemented on the synthesis of an oncology candidate compound 1.