Download PDF
Synthesis 2010(13): 2147-2160  
DOI: 10.1055/s-0029-1218808
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of 5-Substituted 7,8-Benzomorphans by Intramolecular Cyclization of N-Protected 4,4-Disubstituted 1,4-Dihydropyridines

Cornelia E. Schmaunz, Jörg Pabel, Klaus T. Wanner*
Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-Universität München, Butenandtstrasse 7, Haus C, 81377 München, Germany
Fax: +49(89)218077247; e-Mail: klaus.wanner@cup.uni-muenchen.de;
Further Information

Publication History

Received 15 April 2010
Publication Date:
28 May 2010 (online)

    Permissions and Reprints All articles of this category

Abstract

An efficient and high yielding method for the synthesis of 7,8-benzomorphans with varying substituents at C5 has been developed. It is based on an acid-catalyzed intramolecular cyclization reaction of N-protected 4,4-disubstituted 1,4-dihydropyridines, which are easily accessible by the addition of diorganomagnesium compounds to N-silylpyridinium ions. The cyclization reaction proceeds via N-acyliminium ions generated from the 1,4-dihydropyridine moiety that undergo electrophilic aromatic substitution reaction at the benzyl substituent present at C4 of the 1,4-dihydropyridine ring system.

Key words

alkaloids - benzomorphans - electrophilic aromatic substitution - N-acyliminium ion - intramolecular cyclization

    References

  • 1 Bosch J. Bonjoch J. Heterocycles  1980,  14:  505 
    CrossrefGoogle Scholar
  • 2 Frackenpohl J. Chem. Unserer Zeit  2000,  34:  99 
    CrossrefGoogle Scholar
  • 3 Palmer DC. Strauss MJ. Chem. Rev.  1977,  77:  1 
    CrossrefGoogle Scholar
  • 4a Carroll FI. Melvin MS. Nuckols MC. Mascarella SW. Navarro HA. Thomas JB. J. Med. Chem.  2006,  49:  1781 
    Google Scholar
  • 4b Kim IJ. Dersch CM. Rothmann RB. Jacobson AE. Rice KC. Bioorg. Med. Chem.  2004,  12:  4543 
    Google Scholar
  • 4c Thomas JB. Zhang L. Navarri HA. Carroll FI. J. Med. Chem.  2006,  49:  5597 
    Google Scholar
  • 5a Latshaw WE. MacDonnell DR. J. Pharm. Sci.  1961,  50:  792 
    Google Scholar
  • 5b Englberger W, Sattlegger M, and Przewosny M. inventors; WO  9,965,485. 
  • 6 Yokoyama N. Almaula PI. Block FB. Granat FR. Gottfried N. Hill RT. McMahon EH. Munch WF. Rachlin H. Saelens JK. Siegel MG. Tomaselli HC. Clarke FH. J. Med. Chem.  1979,  22:  537 
    CrossrefGoogle Scholar
  • 7a Bosch J. Canals J. Granados R. J. Heterocycl. Chem.  1975,  12:  1117 
    Google Scholar
  • 7b Khartulyari AS. Maier ME. Eur. J. Org. Chem.  2007,  317 
    Google Scholar
  • 7c Magnus P. Fairhurst RA. J. Chem. Soc., Chem. Commun.  1994,  1541 
    Google Scholar
  • 8 Bosch J. Bonjoch J. Diez A. Linares A. Moral M. Rubiralta M. Tetrahedron  1985,  41:  1753 
    CrossrefGoogle Scholar
  • 9 Klegraf E. Knauer S. Kunz H. Angew. Chem. Int. Ed.  2006,  45:  2623 
    CrossrefPubMedGoogle Scholar
  • 10 Kometani T. Shiotani S. J. Med. Chem.  1978,  21:  1105 
    CrossrefGoogle Scholar
  • 11a Bräckow J. Wanner KT. Tetrahedron  2006,  62:  2395 
    Google Scholar
  • 11b Bräckow J. Ph.D. Thesis   LMU München; Germany: 2006. 
    Google Scholar
  • 12 Reichardt C. Solvents and Solvent Effects in Organic Chemistry   Vol. 3:  VCH; Weinheim: 2003. 
    Google Scholar
  • 13 Perrin DD. Armarego WLF. In Purification of Laboratory Chemicals   Vol. 3:  Pergamon; New York: 1988. 
    Google Scholar
  • 14 Shiao M.-J. Chia W.-L. Synth. Commun.  1991,  21:  401 
    CrossrefGoogle Scholar
  • 15 Wakefield BJ. Organomagnesium Methods in Organic Synthesis   Academic; New York: 1995.  p.65-67  
    Google Scholar
  • 16a Akiba K.-Y. Iseki Y. Wada M. Tetrahedron Lett.  1982,  23:  3935 
    Google Scholar
  • 16b Kalashnikov VV. Tomilova LG. Mendeleev Commun.  2007,  17:  343 
    Google Scholar
  • 17a Sperger CA. Wanner KT. Tetrahedron  2009,  65:  5824 
    Google Scholar
  • 17b Wallace DJ. Gibb AD. Cottrell IF. Kennedy DJ. Brands KMJ. Dolling UH. Synthesis  2001,  1784 
    Google Scholar
18

Due to the small percentage of the minor rotamer, only the signals of the major rotamer are listed.