A simple and general approach for the synthesis of highly functionalized 6-oxo-1,6-dihydropyridines

A simple and general approach for the synthesis of highly functionalized 6-oxo-1,6-dihydropyridines

10.1016/j.tet.2013.04.082

  • Medicinal Chemistry Division, Glenmark Research Centre, Glenmark Pharmaceuticals Ltd., Navi Mumbai 400709, India

A simple and general approach for the synthesis of highly functionalized 6-oxo-1,6-dihydropyridines

http://www.sciencedirect.com/science/article/pii/S0040402013006285

ABSTRACT

A variety of 5-cyano-4-methylthio-6-oxo-1,6-dihydropyridine-3-carboxylates have been efficiently syn-thesized in a one-pot reaction from N-alkyl and N-aryl derivatives of 2-cyano-3,3-bis(methylthio)ac-rylamides and selected b-keto esters. The reaction proceeds via potassium hydrogen carbonate mediated conjugate addition of a b-keto ester to 2-cyano-3,3-bis(methylthio)acrylamide followed by loss of methyl mercaptan and subsequent intramolecular condensation of amide group with the acyl carbonyl group. The mechanism of the reaction has been established by isolation of the 2-acetyl-4-cyano-5-amino-3-(methylthio)-5-oxopent-3-enoate intermediate and its independent cyclization to the desired 6-oxo-1,6-dihydropyridine

Corresponding author. Tel.: þ91 22 6772 0000; fax: þ91 22 2778 1206; e-mail address: abraham_thomas@glenmarkpharma.com (A. Thomas).

 

4.2. Synthesis of carbamoyl ketene dithioacetals (1aem); general procedure23 The carbamoyl ketene dithioacetals were prepared by reported procedure by the reaction of 2-cyanoacetamides (100 mmol) with carbon disulfide (7.22 mL, 120 mmol) in the presence of excess potassium fluoride (116 g, 2000 mmol) in dry DMF (150 mL)followed by alkylation of the intermediate potassium dithiolate with methyl iodide (13.70 mL, 220 mmol) in a one-pot reaction. The spectral and analytical data of known carbamoyl ketene dithioacetals 1a, 22 1b, 29 1d, 30 1e, 31 1g, 15b 1h, 32 1i, 15b 1j15b were in agreement with those reported in the literature.

Conclusion

In summary, we have developed a versatile synthetic method for the preparation of a variety of poly-functional N-alkyl and Naryl 6-oxo-1,6-dihydropyridines using appropriate 2-cyano-3,3- bis(methylthio)acrylamides and a b-keto ester in a single-step using potassium hydrogen carbonate as the base in boiling acetone. The method developed has potential applications for assembling a variety of structurally diverse functionalized pyridones from readily available starting materials. The use of inexpensive starting materials, mild reaction conditions, relatively short reaction time, a straightforward purification process and good yields of products are the main attractions of the method. The present method for the synthesis of dihydropyridones with two points of structural diversity and bearing three functional groups for additional structural modification represents superiority over existing methods and holds enormous potential in synthetic and medicinal chemistry.

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