3-Selective Pyridine Fluorination via Zincke Imine Intermediates

Abstract

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.