Synthesis 2012; 44(17): 2739-2742
DOI: 10.1055/s-0032-1316985
paper
© Georg Thieme Verlag Stuttgart · New York

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

Anatoliy N. Alekseenko
a  Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 02660 Kiev-94, Murmanska St. 5, Ukraine
,
Klukovsky Denis
a  Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 02660 Kiev-94, Murmanska St. 5, Ukraine
,
Oleg Lukin*
b  ChemBioCenter, Kiev National Taras Shevchenko University, Volodymyrska St. 62, Kiev 01033, Ukraine, Fax: +380(44)2351273   Email: oleg.lukin@gmail.com
,
Pavel K. Mykhailiuk*
c  Enamine Ltd., Aleksandr Matrosov St. 23, Kiev 01103, Ukraine
d  Department of Chemistry, Kiev National Taras Shevchenko University, Volodymyrska St. 64, Kiev 01033, Ukraine, Email: pavel.mykhailiuk@gmail.com
,
Oleg V. Shishkin
e  STC, Institute for Single Crystals, National Academy of Science of Ukraine, Lenin Ave. 60, Kharkov 61001, Ukraine
,
Yurii M. Pustovit
a  Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 02660 Kiev-94, Murmanska St. 5, Ukraine
› Author Affiliations
Further Information

Publication History

Received: 12 June 2012

Accepted after revision: 08 July 2012

Publication Date:
08 August 2012 (eFirst)

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.

 
  • 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.
    • 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 46 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: +44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk]. They are available on request quoting the deposition number CCDC 857234.