Rapid ¹⁸F‐ and ¹⁹F‐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 OÀ H, NÀ H and CÀ 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 Fdifluoromethylation. This new process is compatible with the wide range of functional groups typically encountered in medicinal chemistry campaigns, and the use of Ag 18 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 À 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.

Access to N-Difluoromethyl Amides, (Thio)Carbamates, Ureas, and Formamides

“…Indeed, the single reported synthesis to acyclic N -difluoromethyl amides relies on the unselective functionalization of low-functionality N -aromatic amides with difluorocarbene under highly basic conditions (in ≤30% yield in a mixture with O-difluoromethylation). 18 The current synthetic repertoire to N -CF 2 H compounds only provides efficient access to selected N -difluoromethylated heterocycles, 19 such as triazoles, 20 indoles, 21 2-pyridones 22a or (benz)imidazoles, 22b tosyl-protected N -CF 2 H amines, 23 tosyl-protected hydrazones, 24 or ammonium salts. 25 Any attempt to remove the tosyl group in Ts-protected N -CF 2 H amines to the corresponding free N -difluoromethyl amines [i.e., H- N (CF 2 H)R] has so far remained unsuccessful, however, owing to their instability.…”