Synlett 2009(11): 1737-1740  
DOI: 10.1055/s-0029-1217373
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of 5-Acyl-3,4-dihydropyrimidine-2-thiones via Solvent-Free, Solution-Phase and Solid-Phase Biginelli Procedures

Horacio Comasa, David-Alexandre Buissona, Romain Najmana, Frank Kozielskib, Bernard Rousseaua, Roman Lopez*a
a CEA, LifeScience Division, iBiTec-S, Service de Chimie Bioorganique et de Marquage, Bat. 547, 91191 Gif sur Yvette, France
b Laboratoire des Moteurs Moleculaires, Institut de Biologie Structurale (CEA-CNRS-UJF), 41 Rue Jules Horowitz, 38027,Grenoble Cedex 01, France
Fax: +33(1)58103848; e-Mail: roman.lopez@ymail.com;
Further Information

Publication History

Received 20 January 2009
Publication Date:
12 June 2009 (online)

Abstract

Compounds belonging to the 5-acyl-3,4-dihydropyrimidine-2-thione family were obtained using a solvent-free Biginelli condensation with or without the use of a catalyst. An unprecedented solid-phase procedure involving a polymer-supported aldehyde allowed the preparation of a series of 5-aroyl derivatives starting with crude diketones obtained from their corresponding aryl esters.

    References and Notes

  • 3 Kappe CO. Eur. J. Med. Chem.  2000,  35:  1043 
  • 4a Blangy A. Lane HA. d’Herin P. Harper M. Kress M. Nigg EA. Cell  1995,  83:  1159 
  • 4b Mayer TU. Kapoor TM. Haggarty SJ. King RW. Schreiber SL. Mitchison TJ. Science  1999,  286:  971 
  • 5a Maliga Z. Kapoor TM. Mitchison TJ. Chem. Biol.  2002,  9:  989 
  • 5b DeBonis S. Simorre JP. Crevel I. Lebeau L. Skoufias DA. Blangy A. Ebel C. Gans P. Cross R. Hackney DD. Wade RH. Kozielski F. Biochemistry  2003,  42:  338 
  • 6a Jackson JR. Patrick DR. Dar MM. Huang PS. Nat. Rev. Cancer  2007,  7:  107 
  • 6b Duhl D. Renhowe P. Curr. Opin. Drug Discovery Dev.  2005,  431 
  • 6c Wood KW. Cornwell WD. Jackson JR. Curr. Opin. Pharmacol.  2001,  1:  370 
  • 7a Lopez R, Rousseau B, Kozielski F, Skoufias D, and DeBonis S. inventors; FR patent  2883284. 
  • 7b Lopez R, Rousseau B, Kozielski F, Skoufias D, and DeBonis S. inventors; WO patent  2006097617. 
  • 8a Biginelli P. Gazz. Chim. Ital.  1893,  23:  360 
  • 8b For a review, see: Kappe CO. Tetrahedron  1993,  49:  6937 ; and references cited therein
  • 8c Kappe CO. Acc. Chem. Res.  2000,  33:  879 
  • 8d For the mechanism, see: Kappe CO. J. Org. Chem.  1997,  62:  7201 
  • 8e Enantioselective version: Huang Y. Fengyue Y. Zhu C. J. Am. Chem. Soc.  2005,  127:  16386 
  • Two-step procedures:
  • 8f Atwal KS. O’Reilly BC. Heterocycles  1987,  26:  1185 
  • 8g Atwal KS. O’Reilly BC. Gougoutas JZ. Malley MF. Heterocycles  1987,  26:  1189 
  • Microwaves:
  • 8h Misra AK. Agnihotri G. Madhusudan SK. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  2004,  43:  2018 
  • 8i Dallinger D. Kappe CO. Nat. Protoc.  2007,  2:  317 
  • Ionic liquids:
  • 8j Peng J. Deng Y. Tetrahedron Lett.  2001,  42:  5917 
  • 8k Legeay JC. Vanden Eynde JJ. Bazureau JP. Tetrahedron  2005,  61:  12386 
  • 8l Legeay JC. Vanden Eynde JJ. Toupet L. Bazureau JP. ARKIVOC  2007,  (iii):  13 
  • Novel catalysts:
  • 8m Hu EH. Sidler DR. Dolling U.-H. J. Org. Chem.  1998,  63:  3454 
  • 8n Lu J. Bai Y. Wang Z. Yang B. Ma H. Tetrahedron Lett.  2000,  41:  9075 
  • 8o Ranu BC. Hajra A. Jana U. J. Org. Chem.  2000,  65:  6270 
  • 8p Ramalinga K. Vijayalakshmi P. Kaimal TNB. Synlett  2001,  863 
  • 8q Varala R. Alam MM. Adapa SR. Synlett  2003,  67 
  • 8r Gupta R. Gupta M. Paul S. Gupta R. Can. J. Chem.  2007,  85:  197 
  • Solvent free:
  • 8s Ma Y. Qian C. Wang L. Yang M. J. Org. Chem.  2000,  65:  3864 
  • 8t Brindaban CR. Alakananda H. Suvendu SD. Org. Process Res. Dev.  2002,  6:  817 
  • 8u Rodríguez-Domínguez JC. Bernardi D. Kirsch G. Tetrahedron Lett.  2007,  48:  5777 
  • 8v Shirini F. Marjani K. Nahzomi HT. ARKIVOC  2007,  (i):  51 
  • 9a Wang L. Qian C. Tian H. Ma Y. Synth. Commun.  2003,  33:  1459 
  • 9b Pathak P. Kaur R. Kaur B. ARKIVOC  2006,  (xvi):  160 
  • An elegant two-step procedure using a Liebeskind-Srog coupling to obtain 5-aroyl-3,4-dihydropyrimidines-2-ones was recently described, see:
  • 10a Prokopcova H. Pisani L. Kappe CO. Synlett  2007,  43 
  • 10b Pisani L. Prokopcova H. Kremsner JM. Kappe CO. J. Comb. Chem.  2007,  9:  415 
  • 11 Garcia-Saez I. DeBonis S. Lopez R. Trucco F. Rousseau B. Thuéry P. Kozielski F. J. Biol. Chem.  2007,  282:  9740 ; In this publication, compound 2 was named ‘Mon-97’
  • 12 Gartner M. Sunder-Plassmann N. Seiler J. Utz M. Vernos I. Surrey T. Giannis A. ChemBioChem  2005,  6:  1173 
  • 13a Swamer FW. Hauser CR. J. Am. Chem. Soc.  1950,  72:  1352 
  • 13b Chaney A. Astle MJ. J. Org. Chem.  1951,  16:  57 
  • 14 For solid-phase protocols with a supported ester or thiourea, see: Dallinger D. Stadler A. Kappe CO. Pure Appl. Chem.  2004,  76:  1017 
1

Present address: The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK

2

Present address: Hybrigenics, 3-5 Impasse Reille, 75014 Paris, France