Download PDF
Synlett 2009(11): 1765-1768  
DOI: 10.1055/s-0029-1217360
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of 3-Aminomethyl-3-fluoropiperidines

Eva Van Hendea, Guido Verniesta, Jan-Willem Thuringb, Gregor Macdonaldb, Frederik Derooseb, Norbert De Kimpe*a
a Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium
Fax: +32(0)92646243; e-Mail: norbert.dekimpe@ugent.be;
b Johnson & Johnson, Pharmaceutical Research & Development, a Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium
Further Information

Publication History

Received 4 March 2009
Publication Date:
12 June 2009 (online)

    Permissions and Reprints All articles of this category

Abstract

A synthetic route toward new 1-alkyl-3-aminomethyl-3-fluoropiperidines, which are of high interest as building blocks in medicinal chemistry, is described. The successful approach consists of the fluorination of ethyl 3-chloropropyl-2-cyanoacetate with N-fluorodibenzenesulfonimide (NFSI) and transformation of the ester moiety into different amides, yielding N-alkyl-5-chloro-2-cyano-2-fluoropentanamides. Ring closure was achieved under basic conditions, yielding 1-alkyl-3-fluoro-2-oxopiperidine-3-carbonitriles. After reduction of the obtained lactams with borane, the desired 3-aminomethyl-3-fluoropiperidines were obtained in good yields.

Key words

ring closure - NFSI - 3-fluoropiperidines - fluorine chemistry - heterocycles

    References and Notes

  • For examples, see:
  • 2a Papeo GME, Caronni D, Dalvit C, Giordano P, Mongelli N, Veronesi M, and Ciprandi F. inventors; Eur. Pat. Appl. EP  1923397.  ; A1 20080521
    Google Scholar
  • 2b Grabstein KH, Wang A, Nairn N, Winblade G, and Thomas J. inventors; U.S. Pat. Appl. Publ. US  2008096819.  ; A1 20080424
    Google Scholar
  • 2c Edmondson SD. Mastracchio A. Mathvink RJ. He J. Harper B. Park Y.-J. Beconi M. Di Salvo J. Eiermann GJ. He H. Leiting B. Leone JF. Levorse DA. Lyons K. Patel RA. Patel SB. Petrov A. Scapin G. Shang J. Roy RS. Smith A. Wu JK. Xu S. Zhu B. Thornberry NA. Weber AE. J. Med. Chem.  2006,  49:  3614 
    Google Scholar
  • 2d Celanire S, Quere L, Denonne F, and Provins L. inventors; PCT Int. Appl. WO  2007048595.  ; A1 20070503
    Google Scholar
  • 2e Keith JM. Gomez LA. Letavic MA. Ly KS. Jablonowski JA. Seierstad M. Barbier AJ. Wilson SJ. Boggs JD. Fraser IC. Mazur C. Lovenberg TW. Carruthers NI. Bioorg. Med. Chem. Lett.  2007,  17:  702 
    Google Scholar
  • 2f Parker JC, and Hulin B. inventors; US Pat. Appl. Publ. US  2005043292.  ; A1 24/02/2005; Chem. Abstr. 2005, 142, 261783
    Google Scholar
  • 3a Fluorine in Bioorganic Chemistry   Welch JT. Eswarakrishnan S. Wiley-Interscience; New York: 1991. 
    Google Scholar
  • 3b Bioorganic and Medicinal Chemistry of Fluorine   Bégué JP. Bonnet-Delpon D. John Wiley & Sons, Inc.; New Jersey: 2008. 
    Google Scholar
  • 4 Hagmann WK. J. Med. Chem.  2008,  51:  4359 
    CrossrefPubMedGoogle Scholar
  • 5 O" Hagan D. Chem. Soc. Rev.  2008,  37:  308 
    CrossrefGoogle Scholar
  • 6 Purser S. Moore PR. Swallow S. Gouverneur V. Chem. Soc. Rev.  2008,  37:  320 
    CrossrefPubMedGoogle Scholar
  • 7 Kirk KL. Org. Process Res. Dev.  2008,  12:  305 
    CrossrefGoogle Scholar
  • 8 Müller K. Faeh C. Diederich F. Science  2007,  317:  1881 
    CrossrefPubMedGoogle Scholar
  • 9 Differding E. Frick W. Lang RW. Martin P. Schmit C. Veenstra S. Greuter H. Bull. Soc. Chim. Belg.  1990,  99:  647 
    Google Scholar
  • 10 inventors; Barrow J. C., Lindsley C. W., Shipe W. D., Yang Z.: PCT Int. Appl.  WO/2007/002361.  ; Chem. Abstr. 2007, 146, 121830
  • 11 Verniest G. Surmont R. Van Hende E. Deweweire A. Deroose F. Thuring JW. De Kimpe N. J. Org. Chem.  2008,  73:  5458 
    CrossrefPubMedGoogle Scholar
  • 12 Van Niel MB. Collins I. Beer MS. Broughton HB. Cheng SKF. Goodacre SC. Heald A. Locker KL. MacLeod AM. Morrison D. J. Med. Chem.  1999,  42:  2087 
    CrossrefPubMedGoogle Scholar
  • 13 Sun A. Lankin DC. Hardcastle K. Snyder JP. Chem. Eur. J.  2005,  11:  1579 
    CrossrefGoogle Scholar
  • 14 Dechamps I. Gomez Pardo D. Cossy J. Eur. J. Org. Chem.  2007,  4224 
    CrossrefGoogle Scholar
  • 15a Ono N. Yoshimura T. Saito T. Tamura R. Tanikaga R. Kaji A. Bull. Chem. Soc. Jpn.  1979,  52:  1716 
    Google Scholar
  • 15b Muthusamy S. Gnanaprakasam B. Tetrahedron Lett.  2005,  46:  635 
    Google Scholar
  • 16 Zefirov NS. Kuznetsova TS. Kozhushkov SI. Surmina LS. Rashchupkina ZA. Zh. Org. Khim.  1983,  19:  541 
    Google Scholar
  • 17 Grossman RB. Varner MA. J. Org. Chem.  1997,  62:  5235 
    CrossrefGoogle Scholar
1

Postdoctoral Fellow of the Research Foundation - Flanders (FWO-Vlaanderen)