An approach to the synthesis of 3-substituted piperidines bearing partially fluorinated alkyl groups

An approach to the synthesis of 3-substituted piperidines bearing partially fluorinated alkyl groups was proposed. The method was based on the DAST-mediated nucleophilic fluorination of easily available 2-bromopyridin-3-yl alcohols and ketones affording 2-bromo-3-(1-fluoroalkyl)pyridines and 2-bromo-3-(1,1-difluoroalkyl)pyridines, respectively, followed by catalytic hydrogenation. The hydrogenation step was studied with common heterogeneous Pd-, Pt-, and Rh-based catalyst. It was found that in the case of fluoroalkyl derivatives, the pyridine core reduction was accompanied by hydrodefluorination, which became a limitation of the strategy. Nevertheless, the method worked well with 1,1-difluoroalkyl derivatives.