Electrochemical Fluorination of Proline Derivatives

The introduction of a fluorine into aliphatic substituents of lead candidates can impart unique structural characteristics that allow fine tuning of drug interactions; therefore, mild, specific, or late‐stage fluorination procedures are of growing interest in medicinal chemistry, with the potential to be applied in F‐18 radiochemistry. In this work, we demonstrate the feasibility of “reagent‐less” electrochemical fluorination leading to mono‐ and gem‐difluorinated proline cores featured in important fibroblast‐activating protein inhibitors. Our study highlights the importance of using the appropriate activator substituents for allowing the process, the impact of different reaction parameters, and characterizes the various byproducts that are generated in the reaction. We have tested the reaction using a commercially available batch system and flow apparatus, achieving maximum yields of >90% (batch) for mono‐ and of 6% (batch) and 9% (flow) for the gem‐difluorinated proline model. These proof‐of‐concept results indicate that the flow approach is more efficient, but that different activating substituents will be needed to achieve higher yields.