Rapid 18 F- and 19 F-Difluoromethylation through Desulfurative Fluorination of Transient N-, O-, and C-Linked Dithioles

Abstract

The difluoromethyl group plays an important role in modern medicinal and agrochemistry. While several difluoromethylation reagents have been reported, these typically rely on difluoromethyl carbenes or anions, or target specific processes. Here, we describe a conceptually unique and general process for O-H, N-H and C-H difluoromethylation that involves the formation of a transient dithiole followed by facile desulfurative fluorination using silver(I) fluoride. We also introduce the 5,6-dimethoxy-1,3-benzodithiole (DMBDT) function, which undergoes sufficiently rapid desulfurative fluorination to additionally support ¹⁸ F-difluoromethylation. This new process is compatible with the wide range of functional groups typically encountered in medicinal chemistry campaigns, and the use of Ag¹⁸ F is demonstrated in the production of ¹⁸ F-labeled derivatives of testosterone, perphenazine, and melatonin, 58.0±2.2, 20.4±0.3 and 32.2±3.6 MBq μmol^-1 , respectively. We expect that the DMBDT group and this ¹⁸ F/¹⁹ F-difluoromethylation process will inspire and support new efforts in medicinal chemistry, agrochemistry and radiotracer production.

Keywords: desulfurative fluorination; difluoromethyl; heterocycles; medicinal chemistry; radiochemistry.