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Updated: Jun 20, 2026

Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives
Published on: January 19, 2016
Trifluoromethylation of pyridines through skeletal rearrangement
Haiwen Wang1, Nilanjan Bhaduri1, Michael F Greaney1
1Dept of Chemistry, University of Manchester Oxford Rd Manchester M13 9PL UK michael.greaney@manchester.ac.uk.
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.
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