Selective Defluorination of Trifluoromethyl Substituents by Conformationally Induced Remote Substitution

The selective reduction of an aromatic trifluoromethyl substituent to a difluoromethyl substituent may be achieved by base-promoted elimination to form a difluoro-p-quinomethide which is trapped by an intramolecular nucleophile. High yields are obtained when the nucleophilic trap entails the conformationally favoured cyclisation of an aminoisobutyric acid (Aib) derivative. The resulting cyclised difluoromethyl-substituted arylimidazolidinone products are readily converted to versatile difluoromethyl-substituted aldehydes by reduction and hydrolysis. Defluorination is successful on a range of benzenoid (both para and ortho CF₃-substituted) and heterocyclic substrates. Double defluorination may likewise be achieved sequentially, or in a single step, from an Aib dipeptide derivative.