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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
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Publikationsverlauf

Received 19 June 2009
Publikationsdatum:
04. September 2009 (online)

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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

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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).