An efficient approach towards introducing (cyclo)alkyl substituents at C-2, C-3 or C-4 positions of the piperidine ring was described. The method based on the straightforward two-step reaction sequence based on the formal sp3–sp3 retrosynthetic disconnection. The procedure commenced with selective directed ortho metalation of 2- and 3-bromopyridine 1 or 2, followed by reaction with aldehydes or ketones. The optimized methods were developed for all three isomers of hydroxyalkyl-substituted pyridines 3. Catalytic hydrogenation of these adducts could be performed selectively with or without retention of the hydroxyl group in their molecules, so that either (cyclo)alkylpiperidines 5 or the corresponding saturated amino alcohols 6 were obtained. After minor modifications, the developed method was also implemented in a flow reactor and a 5 L autoclave, which allowed for the preparation of up to 0.5 kg of the representative (cyclo)alkylpiperidines. Also the DAST -mediated nucleophilic fluorination of 2-bromopyridin-3-yl alcohols 3b and ketones 5 affords to 2-bromo-3-(1-fluoroalkyl)pyridines 6 and 2-bromo-3-(1,1-difluoroalkyl)pyridines 7, respectively, which can be catalytically hydrogenated. 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 preparative applicability of the strategy using Rh/C was illustrated for 3-(1,1-difluoroalkyl)piperidines 9, as well as for the 3-(1-fluoroalkyl)piperidine 8 derivative bearing a hindered isopropyl substituent in a close proximity to the C–F bond.

Straightforward synthesis of all isomeric cyclo- and fluoro-alkylpiperidines

2019 Fall National Meeting

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