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


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



fluorination; trifluoromethoxy group; xanthate; piperidine; protection group


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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  1. Haufe, G.; Leroux, F. R., Eds. Fluorine in Life Sciences: Pharmaceuticals, Medicinal Diagnostics, and Agrochemicals; Progress in Fluorine Science Series; Academic Press: San Diego, 2019; Vol. 4.
  2. Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, 2nd Ed.; Wiley-VCH: Weinheim, 2013.
  3. Gregory, L.; Armen, P.; Frederic, R. L. Trifluoromethyl Ethers and –Thioethers as Tools for Medicinal Chemistry and Drug Discovery. Curr. Top. Med. Chem. 2014, 14 (7), 941 – 951.
  4. Liu, J.-B.; Xu, X.-H.; Qing, F.-L. Silver-Mediated Oxidative Trifluoromethylation of Alcohols to Alkyl Trifluoromethyl Ethers. Org. Lett. 2015, 17 (20), 5048 – 5051.
  5. Koller, R.; Stanek, K.; Stolz, D.; Aardoom, R.; Niedermann, K.; Togni, A. Zinc-Mediated Formation of Trifluoromethyl Ethers from Alcohols and Hypervalent Iodine Trifluoromethylation Reagents. Angew. Chem. Int. Ed. 2009, 48 (24), 4332 – 4336.
  6. Umemoto, T.; Adachi, K.; Ishihara, S. CF3 Oxonium Salts, O-(Trifluoromethyl)dibenzofuranium Salts: In Situ Synthesis, Properties, and Application as a Real CF3+ Species Reagent. J. Org. Chem. 2007, 72 (18), 6905 – 6917.
  7. Shimizu, M.; Hiyama, T. Modern Synthetic Methods for Fluorine-Substituted Target Molecules. Angew. Chem. Int. Ed. 2005, 44 (2), 214 – 231.
  8. Kondratov, I. S.; Logvinenko, I. G.; Tolmachova, N. A.; Morev, R. N.; Kliachyna, M. A.; Clausen, F.; Daniliuc, C. G.; Haufe, G. Synthesis and physical chemical properties of 2-amino-4-(trifluoromethoxy)butanoic acid – a CF3O-containing analogue of natural lipophilic amino acids. Org. Biomol. Chem. 2017, 15 (3), 672 – 679.
  9. Logvinenko, I. G.; Markushyna, Y.; Kondratov, I. S.; Vashchenko, B. V.; Kliachyna, M.; Tokaryeva, Y.; Pivnytska, V.; Grygorenko, O. O.; Haufe, G. Synthesis, physico-chemical properties and microsomal stability of compounds bearing aliphatic trifluoromethoxy group. J. Fluorine Chem. 2020, 231, 109461.
  10. Логвиненко, І. Г.; Кондратов, І. С. Синтез, фізико-хімічні властивості та мікросомальна стабільність аліфатичних трифторометоксивмісних сполук. В Біоактивні сполуки, нові речовини і матеріали; Вовк, А. І., Ред.; За матеріалами ХХХV Наукової конференції з біоорганічної хімії та нафтохімії (23 квітня 2020 р., м. Київ); Інтерсервіс: Київ, 2020; с 125 – 129.
  11. Bryan, M. C.; Chan B.; Hanan E.; Heffron T.; Purkey H.; Elliott R. L.; Heald R.; Knight J.; Lainchbury M.; Seward E. M. Aminopyrimidine compounds as inhibitors of T760M containing EGFR mutants. International patent WO2014081718, May 30, 2014.
  12. Chen, H. S.; Chu, Y.; Do, S.; Estrada, A.; Hu, B.; Kolesnikov, A.; Lin, X.; Lyssikatos, J. P.; Shore, D.; Verma, V.; Wang, L.; Wu, G.; Yuen, P.-W. Substituted heterocyclic sulfonamide compounds useful as TRPA1 modulators. International Patent WO2015052264, April 16, 2015.
  13. Yang, B. V.; O’Rourke, D.; Li, J. Mild and Selective Debenzylation of Tertiary Amines Using α-Chloroethyl Chloroformate. Synlett 1993, 1993 (03), 195 – 196.
  14. Chang, D.; Feiten, H.-J.; Engesser, K.-H.; van Beilen, J. B.; Witholt, B.; Li, Z. Practical Syntheses of N-Substituted 3-Hydroxyazetidines and 4-Hydroxypiperidines by Hydroxylation with Sphingomonas sp. HXN-200. Org. Lett. 2002, 4 (11), 1859 – 1862.
  15. Barbe, G.; Charette, A. B. Highly Chemoselective Metal-Free Reduction of Tertiary Amides. J. Am. Chem. Soc. 2008, 130 (1), 18 – 19.



How to Cite

Logvinenko, I. G.; Dolovanyuk, V. G.; Kondratov, I. S. The Preparative Synthetic Approach to 4-(trifluoromethoxy)piperidine and 4-(trifluoromethoxymethyl)piperidine. J. Org. Pharm. Chem. 2021, 19, 3-9.



Original Researches