Download PDF
Synthesis 2008(22): 3639-3648  
DOI: 10.1055/s-0028-1083202
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Ethyl Pyrimidine-4-carboxylates from Unsymmetrical Enamino Diketones and Their Application in the First Synthesis of Pyrimido[4,5-d]pyridazin-8(7H)-ones

Fernanda A. Rosa, Pablo Machado, Gabriela F. Fiss, Pâmela S. Vargas, Tanize S. Fernandes, Helio G. Bonacorso, Nilo Zanatta, Marcos A. P. Martins*
Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, Brazil
Fax: +55(55)3220 8031; e-Mail: mmartins@base.ufsm.br;
Further Information

Publication History

Received 25 June 2008
Publication Date:
23 October 2008 (online)

    Permissions and Reprints All articles of this category

Abstract

The reaction of unsymmetrical enamino diketones [RC(O)C(=CNMe2)C(O)CO2Et, where R = Ph, 4-MeC6H4, 4-MeOC6H4, 4-BrC6H4, 4-ClC6H4, 4-FC6H4, 4-O2NC6H4, 2-thienyl, benzofuran-2-yl, and CF3] with N-C-N dinucleophiles, such as benzamidine hydrochloride or 1H-pyrazole-1-carboxamidine monohydrochloride, afforded a series of ethyl 2,5-disubstituted pyrimidine-4-carboxylates in a chemoselective and highly chemo­selective manner (51-86%). Reaction of these two series of pyrimidines (R = Ph, 4-MeOC6H4, 4-FC6H4, and 2-thienyl) with hydrazine monohydrate under mild conditions led to 2,5-substituted pyrimido[4,5-d]pyridazin-8(7H)-ones in high yields (81-92%).

Key words

cyclizations - enones - ring closure - heterocycles - pyrimidines - regioselectivity

    References

  • 1a Nargund LVG. Badiger VV. Yarnal SU. Eur. J. Med. Chem.  1994,  29:  245 
    Google Scholar
  • 1b Ouf NH. Amr A. El-G E. Fayed AA. Monatsh. Chem.  2008,  139:  281 
    Google Scholar
  • 1c Tafi A. Bernardine C. Botta M. Corelli F. Andreini M. Martineli A. Ortore G. Baraldi PG. Fruttarolo F. Borea PA. Tuccinardi T. J. Med. Chem.  2006,  49:  4085 
    Google Scholar
  • 1d Orjales A. Mosquera R. López B. Olivera R. Labeaga L. Núñez MT. Bioorg. Med. Chem.  2008,  16:  2183 
    Google Scholar
  • 1e Danel K. Pedersen EB. Nielsen C. J. Med Chem.  1998,  41:  191 ; and references therein
    Google Scholar
  • 2a Brown DJ. In Comprehensive Heterocyclic Chemistry   Vol. 3:  Katritzky AR. Rees CW. Pergamon; Oxford: 1984. 
    Google Scholar
  • 2b Undheim K. Benneche T. In Comprehensive Heterocyclic Chemistry II   Vol. 6:  Katritzky AR. Rees CW. Scriven EF. Pergamon; Oxford: 1996. 
    Google Scholar
  • 2c Martins MAP. Frizzo CP. Moreira DN. Zanatta N. Bonacorso HG. Chem. Rev.  2008,  108:  2015 
    Google Scholar
  • 2d Martins MAP. Cunico W. Pereira CMP. Sinhorin AP. Flores AFC. Bonacorso HG. Zanatta N. Curr. Org. Synth.  2004,  1:  391 
    Google Scholar
  • 3a Jones RG. Whitehead CW. J. Org. Chem.  1955,  20:  1342 
    Google Scholar
  • 3b Krapcho AP. Maresch MJ. Helgason AL. Rosner KE. Hacker MP. J. Heterocycl. Chem.  1993,  30:  1597 
    Google Scholar
  • 4 Bradshaw JS. Huszthy P. Izatt RM. J. Heterocycl. Chem.  1994,  31:  1047 
    Google Scholar
  • 5 Riley TA. Hennen WJ. Dalley NK. Wilson BE. Robins RK. Larson SB. J. Heterocycl. Chem.  1987,  24:  955 
    CrossrefGoogle Scholar
  • 6 Jones RG. J. Am. Chem. Soc.  1956,  78:  159 
    CrossrefGoogle Scholar
  • 7a Kuderna JG. Skiles RD. Pilgram K. J. Org. Chem.  1971,  36:  3506 
    Google Scholar
  • 7b Mátyus P. Szilágyi G. Kasztreiner E. Rabloczky G. J. Heterocycl. Chem.  1988,  25:  1535 
    Google Scholar
  • 8 Treu M. Jordis U. Lee VJ. Molecules  2001,  6:  959 
    Google Scholar
  • 9 Rosa FA. Machado P. Rossatto M. Vargas PS. Bonacorso HG. Zanatta N. Martins MAP. Synlett  2007,  3165 
    Article in Thieme ConnectGoogle Scholar
  • 10 Rosa FA. Machado P. Vargas PS. Bonacorso HG. Zanatta N. Martins MAP. Synlett  2008,  1673 
    Article in Thieme ConnectGoogle Scholar
  • 12 Farrugia LJ. J. Appl. Crystallogr.  1997,  30:  565 
    Google Scholar
  • 13 Dewar MJS. Zoebisch EG. Healey EF. Stewart JJP. J. Am. Chem. Soc.  1985,  107:  3902 
    CrossrefGoogle Scholar
  • 15 Echevarría A. Elguero J. Llamas-Saiz AL. Foces-Foces C. Schultz G. Hargittai I. Struct. Chem.  1994,  5:  255 
    CrossrefGoogle Scholar
  • 16 Perrin DD. Armarego WLF. In Purification of Laboratory Chemicals   Pergamon; Oxford: 1998. 
    Google Scholar
  • 18 Farrugia LJ. J. Appl. Crystallogr.  1999,  32:  837 
    CrossrefGoogle Scholar
11

Crystallographic data for compounds 4a, 6h, and 7a reported in this paper, have been deposited with the Cambridge Crystallographic Data Centre (CCDC Number 686848, 686847, and 687296, respectively). Copies of the data can be obtained, free of charge, on application to CCDC 12 Union Road, Cambridge CB2 1EZ, UK [Fax: +44(1223)336033 or e-mail: deposit@ccdc.cam.ac.uk].

14

HYPERCHEMTM Professional 7.52(2002), Hypercube, Inc.: 1115 NW 4th Street, Gainesville, FL 32601, USA.

17

SHELXTL 6.14, Bruker AXS Inc.: Madison WI, 2003.