Download PDF
Synlett 2011(14): 1997-2000  
DOI: 10.1055/s-0030-1261174
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Domino Microwave-Assisted Protocol for the Synthesis of 2,6-Disubstituted Pyrimidinones

Marco Radia,, Gianni Casalucea,, Maurizio Botta*a,b
a Dipartimento Farmaco Chimico Tecnologico, University of Siena, Via Alcide de Gasperi 2, 53100 Siena, Italy
b Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, BioLife Science Building, Suite 333, 1900 N 12th Street, Philadelphia, PA 19122, USA
Fax: +39(0577)234333; e-Mail: botta.maurizio@gmail.com;
Further Information

Publication History

Received 10 June 2011
Publication Date:
10 August 2011 (online)

    Permissions and Reprints All articles of this category

Abstract

A practical microwave-assisted protocol for the synthesis of 2,6-disubstituted pyrimidinones has been developed. This approach is based on a domino Michael addition-cyclocondensation reaction between substituted thioureas/guanidines and acetylenecarboxylates. The application of such protocol for the synthesis of not easily accessible N-DABO derivatives as potential antiviral agents is also reported.

Key words

microwave - pyrimidinones - acetylenecarboxylates - ­S-DABO - N-DABO

    References and Notes

  • 2a Radi M. Schenone S. Botta M. Org. Biomol. Chem.  2009,  7:  2841 
    Google Scholar
  • 2b Hill MD. Movassaghi M. Chem. Eur. J.  2008,  14:  6836 
    Google Scholar
  • 3 Boone LR. Curr. Opin. Invest. Drugs  2006,  7:  128 
    Google Scholar
  • 4 Barbaro G. Scozzafava A. Mastrolorenzo A. Supuran CT. Curr. Pharm. Des.  2005,  11:  1805 
    CrossrefGoogle Scholar
  • 5 Botta M. Artico M. Massa S. Gambacorta A. Marongiu ME. Pani A. La Colla P. Eur. J. Med. Chem.  1992,  27:  251 
    CrossrefGoogle Scholar
  • 6a Radi M. Maga G. Alongi M. Angeli L. Samuele A. Zanoli S. Bellucci L. Tafi A. Casaluce G. Giorgi G. Armand-Ugon M. Gonzalez E. Esté JA. Baltzinger M. Bec G. Dumas P. Ennifar E. Botta M. J. Med. Chem.  2009,  52:  840 
    Google Scholar
  • 6b Mugnaini C. Alongi M. Togninelli A. Gevariya H. Brizzi A. Manetti F. Bernardini C. Angeli L. Tafi A. Bellucci L. Corelli F. Massa S. Maga G. Samuele A. Facchini M. Clotet-Codina I. Armand-Ugón M. Esté JA. Botta M. J. Med. Chem.  2007,  50:  6580 
    Google Scholar
  • 7 Botta M, Corelli F, Petricci E, Radi M, Maga G, Esté JA, and Mai A. inventors; Int. Patent  WO2007043094. 
  • 8 Rotili D. Artico M. Sbardella G. Clotet-Codina I. Esté JA. Crespan E. Zanoli S. Hübscher U. Spadai S. Maga G. ChemMedChem  2007,  2:  445 
    CrossrefGoogle Scholar
  • 9 Mai A. Artico M. Ragno R. Sbardella G. Massa S. Musiu C. Mura M. Marturana F. Cadeddu A. Maga G. La Colla P. Bioorg. Med. Chem.  2005,  13:  2065 
    CrossrefGoogle Scholar
  • 10 Botta M. De Angelis F. Finizia G. Gambacorta A. Nicoletti R. Synth. Commun.  1985,  15:  27 
    CrossrefGoogle Scholar
  • 11 Mai A. Artico M. Rotili D. Tarantino D. Clotet-Codina I. Armand-Ugn M. Ragno R. Simeoni S. Sbardella G. Nawrozkij MB. Samuele A. Maga G. Est JA. J. Med. Chem.  2007,  50:  5412 
    CrossrefGoogle Scholar
  • 12a Radi M. Botta L. Casaluce G. Bernardini M. Botta M. J. Comb. Chem.  2010,  12:  200 
    Google Scholar
  • 12b Radi M. Bernardo V. Bechi B. Castagnolo D. Pagano M. Botta M. Tetrahedron Lett.  2009,  50:  6572 
    Google Scholar
  • 12c Radi M. Saletti S. Botta M. Tetrahedron Lett.  2008,  49:  4464 
    Google Scholar
  • 12d Castagnolo D. Dessì F. Radi M. Botta M. Tetrahedron: Asymm.  2007,  18:  1345 
    Google Scholar
  • 13 Karpov AS. Müller TJJ. Synthesis  2003,  2815 
    Article in Thieme ConnectGoogle Scholar
  • 14 Karpov AS. Müller TJJ. Org. Lett.  2003,  5:  3451 
    CrossrefGoogle Scholar
  • 15 Gupta KA. Saxena AK. Jain P. Synthesis  1981,  905 
    Article in Thieme ConnectGoogle Scholar
  • 16 Piers E. Chong JM. Morton HE. Tetrahedron  1989,  45:  363 
    CrossrefGoogle Scholar
  • 17 Bartoccini G. Master’s Thesis   University of Siena; Italy: 2010. 
    Google Scholar
  • 19 Corey EJ. Fuchs PL. Tetrahedron Lett.  1972,  36:  3769 
    Google Scholar
  • 20 Ohira S. Synth. Commun.  1989,  19:  561 
    CrossrefGoogle Scholar
  • 21 Müller S. Liepold B. Roth GJ. Bestmann HJ. Synlett  1996,  521 
    Article in Thieme ConnectGoogle Scholar
  • 22 Vasilevsky SF. Trofimov BA. Mal’kina AG. Brandsma L. Synth. Commun.  1994,  24:  85 
    CrossrefGoogle Scholar
  • 24 Skulnick HI. Ludens JH. Wendling MG. Glenn EM. Rohloff NA. Smith RJ. Wierenga W. J. Med. Chem.  1986,  29:  1499 
    CrossrefGoogle Scholar
1

These authors contributed equally to this work.

18

Typical Experimental Procedure: In a microwave sealed tube, S-methylisothiourea sulfate (1; 79 mg, 0.283 mmol), ethyl 4-(tetrahydro-2H-pyran-2-yloxy)but-2-ynoate (2; 50 mg, 0.236 mmol) and Na2CO3 (60 mg, 0.566 mmol) in DMF or t-BuOH (3 mL) were irradiated for 20 min in a self-tunable CEM microwave synthesizer at 120 ˚C and finally allowed to cool to r.t. When DMF was used as solvent, H2O was added and the aqueous layer was extracted with EtOAc (2 ×). The organic layers were collected, washed with brine, dried over Na2SO4 and concentrate under reduced pressure. When t-BuOH was used as solvent, the reaction mixture was directly evaporated to dryness to give a solid crude material. The residue was purified by flash chromatography (petroleum ether-EtOAc) to obtain 2-(methylthio)-6-[(tetrahydro-2H-pyran-2-yloxy)methyl]pyrimidin-4(3H)-one (3; 52-54%) as a white solid. ¹H NMR (400 MHz, CDCl3): δ = 12.68 (br s, 1 H), 6.34 (s, 1 H), 4.68 (s, 1 H), 4.52 (d, J = 16.0 Hz, 1 H), 4.32 (d, J = 16.0 Hz, 1 H), 3.77 (m, 1 H), 3.47 (m, 1 H), 2.48 (s, 3 H), 1.40-1.90 (m, 8 H). ¹³C NMR (100 MHz, CDCl3): δ = 166.33, 165.29, 161.36, 105.81, 98.12, 67.81, 61.91, 30.33, 25.36, 18.93, 13.19. MS (ESI): m/z = 257.3 [M + H]+.

23

Data not shown.