3-Selective Pyridine Fluorination via Zincke Imine Intermediates

Fluorine substitution is a widely used approach to improve the properties of drugs bearing aromatic rings and has spawned numerous new methods for C-F bond formation. Reactions employing C-H bond precursors are particularly valuable, but pyridine-applicable variants are rare, especially at the C3-position. We developed an approach using ring-opened Zincke imines that undergo regioselective C-F bond formation with electrophilic fluorination reagents, resulting in C3-fluoropyridines after ring closure. This process can accommodate a wide range of pyridine substitution patterns, tolerates various appended functional groups, and is viable for the late-stage fluorination of pyridine-containing drugs.