Trifluoromethylation of pyridines through skeletal rearrangement

Abstract

We report a skeletal rearrangement of pyridines that enables functionalisation of the 2 and 3-positions, via Zincke ketone intermediates. The ring-opened pyridines undergo selective reaction with cheap and readily available acylating agents, setting up an alternative ring closure pathway to afford rearranged structures incorporating groups such as CF₃, CF₂H, and CO₂Et at the pyridine C2 position. The process enables highly selective C2 over C4 trifluoromethylation of pyridines, a reaction that challenges conventional Minisci methods. Sequential functionalisation of the Zincke intermediate is further demonstrated, to access triply-substituted pyridine products from mono-substituted starting materials.