An Improved Synthesis of 2-, 3-, and 4-(Trifluoromethyl)cyclohexylamines

Abstract

An improved synthesis of 2-, 3-, and 4-trifluoromethylcyclohexylamines on a multigram scale via PtO₂-mediated hydrogenation of the corresponding trifluoromethylanilines in trifluoroacetic acid at room temperature under atmospheric pressure is reported. The hydrogenation occurred with a remarkable stereo­selectivity favoring the formation of cis-isomers.

Key words

trifluoromethyl group - amines - cyclohexyl group - hydrogenation - trifluoroacetic acid

• References

• 1 There are 1148 N-substituted derivatives of cyclohexanamine in the ‘MDL Drug Data Report’ database.

For the use of amines 4, 5, and 6 within contemporary drug discovery programs, see:
• 2a Inoue T, Hatanaka K, Sasaki H, Takahashi F, Higashi Y, Hondo T, Sawada H, Okimoto A, Mukoyoshi K, Tanaka A, Shirakami S, Nakajima Y, Tojo T, Morita M. Patent WO2007/7919 A2, 2007
• 2b Weigand S, Bischoff H, Dittrich-Wengenroth E, Heckroth H, Lang D, Vaupel A, Woltering M. Bioorg. Med. Chem. Lett. 2005; 15: 4619
• 2c Aquila B, Lyne P, Pontz T. US Patent 2009/170849, 2009
• 2d Rehwinkel H, Hoelscher P, Jaroch S, Suelzle D, Hillmann M, Burton GA, Macdougall F. US Patent 2004/6075 A1, 2004
• 2e Priepke H, Doods H, Kuelzer R, Pfau R, Stenkamp D, Roenn R, Pelcman B. Patent WO2011/48004 A1, 2011
• 2f Stewart AJ. W, Bloxham J, Dupree TB, Hanrahan PE, Procter MJ, Smyth D, Schofield KL, Sambrook-Smith CP, Krulle TM, Fry PT, Bradley SE. Patent WO 2008/142454 A1, 2008
• 2g Flohr A, Jakob-Roetne R, Norcross RD, Riemer C. US Patent 2004/242576 A1, 2004
• 3 Since 2006 Enamine Ltd. has received 46 requests for providing amine 4, 59 for 5, and 119 for 6.
• 4a Rylander RN. Catalytic Hydrogenation over Platinum Metals . Academic Press; New York: 1967
• 4b Nishimura S. Handbook of Heterogeneous Catalytic Hydrogenation for Organic Synthesis. Wiley; New York: 2001
• 5a Vierhapper FM, Eliel EL. J. Org. Chem. 1975; 40: 2729
• 5b Hönel M, Vierhapper FM. J. Chem. Soc., Perkin Trans. 1 1980; 1933
• 5c Hönel M, Vierhapper FM. J. Chem. Soc., Perkin Trans. 1 1982; 2607
• 5d Hönel M, Vierhapper FM. Monatsh. Chem. 1984; 115: 1219
• 6 Prices quoted in the ABCR catalogue (2011) for 100 g of the compounds: aniline 1: € 16; 2: € 12; 3: € 205.
• 7a Ploeg HL. US Patent Application 3933815, 1976
• 7b Ziemann H, Alles H.-U. German Patent DE2630562 A1, 1978
• 8 Campbell JB, Gerald FS, Turner WW. US Patent Application 5135955, 1992
• 9 In all experiments described in refs. 7 and 8, a statistical mixture of cis- and trans-isomers of 4–6 was obtained.
• 10a Zalesskaya IM, Blakitnyi AN, Saenko EP, Fialkov YuA, Yagupolskii LM. J. Org. Chem. USSR (Engl. Transl.) 1980; 16: 1031
• 10b Alexeenko AN, Nazaretian VP. J. Fluorine Chem. 1994; 69: 241
• 10c Skupinska KA, Mcearchern EJ, Skerlj RT, Bridger GJ. J. Org. Chem. 2002; 67: 7890

Preparation of compounds 5 and 6 by other methods is mentioned in:
• 11a Della EW. Aust. J. Chem. 1970; 23: 2471
• 11b Baldry KW, Robinson MJ. T. Tetrahedron 1977; 33: 1663
• 11c Shukla D, Welter TR. Patent WO 2009/126203, 2009
• 12 The final atomic coordinates, and crystallographic data for compound 7 have been deposited at the Cambridge Crystallographic Data Centre, 12 Union Road, CB2 1EZ, UK [fax: [phone]; e-mail: [e-mail]]. They are available on request quoting the deposition number CCDC 857234.