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

Authors

  • Ivan G. Logvinenko V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine, Enamine Ltd
  • Violetta G. Dolovanyuk V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
  • Ivan S. Kondratov V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine, Enamine Ltd

DOI:

https://doi.org/10.24959/ophcj.21.222669

Keywords:

fluorination; trifluoromethoxy group; xanthate; piperidine; protection group

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.
Key words: fluorination; trifluoromethoxy group; xanthate; piperidine; protection group

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Published

2021-03-15

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Section

Articles