Download PDF
Synlett 2009(16): 2643-2646  
DOI: 10.1055/s-0029-1217749
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Construction of 5,6-Ring-Fused 2-Pyridones: An Effective Annulation Tactic Achieved in Water

Amos B. III Smith*a, Onur Atasoylua, Douglas C. Beshoreb
a Department of Chemistry, Monell Chemical Senses Center and Laboratory for Research on the Structure of Matter, University of Pennsylvania, Philadelphia, PA 19104, USA
Fax: +1(215)8985129; e-Mail: smithab@sas.upenn.edu;
b Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
Further Information

Publication History

Received 19 June 2009
Publication Date:
04 September 2009 (online)

    Permissions and Reprints All articles of this category

Abstract

An efficient protocol to annulate the 5,6-fused 2-pyridone ring system, exploiting a tandem condensation of propiol­amide and cyclic β-keto methyl esters in water, followed by acid- or base-promoted intramolecular ring closure and decarboxylation, has been developed.

Key words

heterocycles - condensation - fused-ring systems - tandem reactions - Michael additions

    References

  • 1a Wall ME. Wani MC. Cook CE. Palmer KH. McPhail AT. Sim GA. J. Am. Chem. Soc.  1966,  88:  3888 
    Google Scholar
  • 1b Wall ME. Med. Res. Rev.  1998,  18:  299 
    Google Scholar
  • 2a Kozikowski AP. Campiani G. Sun L.-Q. Wang S. Saxena A. Doctor BP. J. Am. Chem. Soc.  1996,  118:  11357 
    Google Scholar
  • 2b Campiani G. Kozikowski AP. Shaomeng W. Liu M. Nacci V. Saxena A. Doctor BP. Bioorg. Med. Chem. Lett.  1998,  8:  1413 
    Google Scholar
  • 3 Parreira RLT. Abrahao O. Galembeck SE. Tetrahedron  2001,  57:  3243 
    CrossrefGoogle Scholar
  • 4 For a discussion of the term ‘privileged structure(scaffold)’, see: Evans BE. Rittle KE. Bock MG. DiPardo RM. Freidinger RM. Whitter WL. Lundell GF. Veber DF. Anderson PS. Chang RSL. Lotti VJ. Cerino DJ. Chen TB. Kling PJ. Kunkel KA. Springer JP. Hirshfield J. J. Med. Chem.  1988,  31:  2235 
    CrossrefPubMedGoogle Scholar
  • 5 Torres M. Gil S. Parra M. Curr. Org. Chem.  2005,  9:  1757 
    CrossrefGoogle Scholar
  • 6 Decker H. Ber. Dtsch. Chem. Ges.  1892,  25:  443 
    CrossrefGoogle Scholar
  • 7 Baron H. Renfry FGP. Thorpe JF. J. Chem. Soc.  1904,  85:  1726 
    CrossrefGoogle Scholar
  • 8 Beshore DC. Smith AB. J. Am. Chem. Soc.  2007,  129:  4148 
    CrossrefGoogle Scholar
  • 9 Kozikowski AP. Reddy ER. Miller CP. J. Chem. Soc., Perkin Trans. 1  1990,  195 
    CrossrefGoogle Scholar
  • 10 Högenauer K. Baumann K. Enz A. Mulzer J. Bioorg. Med. Chem. Lett.  2001,  11:  262 
    Google Scholar
  • 11 Nagata W. Yoshioka M. Org. React.  1977,  25:  255 
    Google Scholar
  • 12 Feng S. He X. Yu G. Yu X. Bai D. Org. Prep. Proced. Int.  2004,  36:  129 
    CrossrefGoogle Scholar
  • 14a Krapcho AP. Synthesis  1982,  805 
    Google Scholar
  • 14b Krapcho AP. Synthesis  1982,  893 
    Google Scholar
  • 15 Popović-orević JB. Ivanović MD. Kiricojević VD. Tetrahedron Lett.  2005,  46:  2611 
    CrossrefGoogle Scholar
  • 17 Favorskii AE. J. Russ. Phys. Chem. Soc.   1894,  26:  590 
    Google Scholar
13

Representative procedure for Michael addition: To a solution of propiolamide (325 mg, 4.70 mmol) and Na2CO3 (270 mg, 2.75 mmol) in H2O (5 mL) at 0 ˚C, methyl 2-oxocyclopentanecarboxylate (5; 390 mg, 2.75 mmol) was added dropwise. The reaction mixture was warmed to r.t. over 2 h and then extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Purification by flash column chromatography (EtOAc-hexane, 1:1; R f = 0.2) afforded 6 as a white solid (511 mg, 88% yield).

16

Representative procedure for annulation: In a thick-walled tube, containing a stir bar methyl 1-(3-amino-3-oxoprop-1-enyl)-2-oxocyclopentanecarboxylate (6; 154 mg, 0.730 mmol) was dissolved in concd HCl (2 mL). The tube was sealed tightly and heated to 130 ˚C in an oil bath. After 6 h, the reaction mixture was allowed to cool to r.t., the lid was carefully opened and the reaction mixture poured onto ice
(5 g). The pH was adjusted to 7 by dropwise addition of saturated aqueous NaHCO3 and then the mixture was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to furnish a white solid. Purification through a short pad of silica gel (EtOAc, 100%) afforded 8 as a white amorphous solid (97.4 mg, 99% yield).