Radical C-H 18F-Difluoromethylation of Heteroarenes with [18F]Difluoromethyl Heteroaryl-Sulfones by Visible Light Photoredox Catalysis

The F-18-labeling of CF2H groups has been recently studied in radiopharmaceutical chemistry owing to the favorable nuclear and physical characteristics of the radioisotope F-18 for positron emission tomography (PET). Following up on the reported efficiency of the [F-18]difluoromethyl benzothiazolyl-sulfone ([F-18]1) as a F-18-difluoromethylating reagent, we investigated the influence of structurally-related [F-18]difluoromethyl heteroaryl-sulfones in the reactivity toward the photoredox C-H F-18-difluoromethylation of heteroarenes under continuous-flow conditions. In the present work, six new [F-18]difluoromethyl heteroaryl-sulfones [F-18]5a-[F-18]5f were prepared and, based on the overall radiochemical yields (RCYs), three of these reagents ([F-18]5a, [F-18]5c, and [F-18]5f) were selected for the fully automated radiosynthesis on a FASTlab(TM) synthesizer (GE Healthcare) at high level of starting radioactivity. Subsequently, their efficiency as F-18-difluoromethylating reagents was evaluated using the antiherpetic drug acyclovir as a model substrate. Our results showed that the introduction of molecular modifications in the structure of [F-18]1 influenced the amount of fac-Ir-III(ppy)(3) and the residence time needed to ensure a complete C-H F-18-difluoromethylation process. The photocatalytic C-H F-18-difluoromethylation reaction with the reagents [F-18]5a, [F-18]5c, and [F-18]5f was extended to other heteroarenes. Radical-trapping experiments demonstrated the likely involvement of radical species in the C-H F-18-difluoromethylation process.