Molecular editing such as insertion, deletion and single atom exchange in highly functionalized compounds is an aspira-tional goal for all chemists. Here, we disclose a photoredox protocol for the replacement of a single fluorine atom with hydrogen in a range of electron-deficient trifluoromethylarenes including complex drug molecules. A robustness screening experiment shows that this reductive defluorination tolerates a range of functional groups and heterocycles commonly found in bioactive molecules. Preliminary mechanistic studies allude to a catalytic cycle whereby the excited state of the organophotocatalyst is reductively quenched by the hydrogen atom do-nor, and returned in its original oxidation state by the trifluoromethylarene.

Despite a growing interest in CHF₂ in medicinal chemistry, there is a lack of efficient methods for the insertion of CHF¹⁸F into druglike compounds. Herein described is a photoredox flow reaction for ¹⁸F‐difluoromethylation of N‐heteroaromatics that are widely used in medicinal chemistry. Following the two‐step synthesis for a new ¹⁸F‐difluoromethylation reagent, the photoredox reaction is completed within two minutes and proceeds by C−H activation, circumventing the need for pre‐functionalization of the substrate. The method is operationally simple and affords straightforward access to radiolabeled N‐heteroaromatics with high molar activity suitable for biological in vivo studies and clinical application.

The ¹⁸F-labeling of CF₂H groups has been recently studied in radiopharmaceutical chemistry owing to the favorable nuclear and physical characteristics of the radioisotope ¹⁸F for positron emission tomography (PET). Following up on the reported efficiency of the [¹⁸F]difluoromethyl benzothiazolyl-sulfone ([¹⁸F]1) as a ¹⁸F-difluoromethylating reagent, we investigated the influence of structurally-related [¹⁸F]difluoromethyl heteroaryl-sulfones in the reactivity toward the photoredox C–H ¹⁸F-difluoromethylation of heteroarenes under continuous-flow conditions. In the present work, six new [¹⁸F]difluoromethyl heteroaryl-sulfones [¹⁸F]5a–[¹⁸F]5f were prepared and, based on the overall radiochemical yields (RCYs), three of these reagents ([¹⁸F]5a, [¹⁸F]5c, and [¹⁸F]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 ¹⁸F-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 [¹⁸F]1 influenced the amount of fac-Ir^III(ppy)₃ and the residence time needed to ensure a complete C–H ¹⁸F-difluoromethylation process. The photocatalytic C–H ¹⁸F-difluoromethylation reaction with the reagents [¹⁸F]5a, [¹⁸F]5c, and [¹⁸F]5f was extended to other heteroarenes. Radical-trapping experiments demonstrated the likely involvement of radical species in the C–H ¹⁸F-difluoromethylation process.

Despite a growing interest in CHF₂ in medicinal chemistry, there is a lack of efficient methods for the insertion of CHF¹⁸F into druglike compounds. Herein described is a photoredox flow reaction for ¹⁸F‐difluoromethylation of N‐heteroaromatics that are widely used in medicinal chemistry. Following the two‐step synthesis for a new ¹⁸F‐difluoromethylation reagent, the photoredox reaction is completed within two minutes and proceeds by C−H activation, circumventing the need for pre‐functionalization of the substrate. The method is operationally simple and affords straightforward access to radiolabeled N‐heteroaromatics with high molar activity suitable for biological in vivo studies and clinical application.