The preparative synthetic approach to 4-(trifluoromethoxy)piperidine and 4-(trifluoromethoxymethyl)piperidine

Abstract

Aim. To develop a convenient synthetic approach for the preparation of multigram amounts of 4-(trifluoromethoxy)-piperidine and 4-(trifluoromethoxymethyl)piperidine – promising building blocks for medicinal chemistry. Results and discussion. 4-(Trifluoromethoxy)piperidine (8.4 g) and 4-(trifluoromethoxymethyl)piperidine (12.9 g) were synthesized in 5 stages starting from 4-hydroxypiperidine (the overall yield 40 %) and 4-(hydroxymethyl)piperidine (the overall yield 13.5 %), respectively. Experimental part. The first stage of the synthetic strategy was acylation of 4-hydroxypiperidine with benzoyl chloride. N-benzoyl-4-hydroxypiperidine obtained was transformed to N-benzoyl-4-(trifluoromethoxy)piperidine in two stages using the Hiyama method (the synthesis of the corresponding S-methyl xanthate with the subsequent desulfurization/fluorination using N-bromosuccinimide and Olah’s reagent). Then the N-benzoyl group was reduced to benzyl one, which was removed using 1-chloroethyl chloroformate. The similar approach was applied to the synthesis of 4-(trifluoromethoxymethyl)piperidine starting from 4-(hydroxymethyl)piperidine. The structure and composition of the compounds synthesized were confrmed by 1Н, 13C and 19F NMR spectroscopy, mass-spectrometry and elemental analysis. Conclusions. The synthetic approach developed is a convenient method for the multigram preparation of 4-(trifluoromethoxy)piperidine and 4-(trifluoromethoxymethyl)piperidine and can be used for the synthesis of other secondary amines containing the CF3O-group.

Keywords

• fluorination
• trifluoromethoxy group
• xanthate
• piperidine
• protection group