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Scope and Limitations of an Efficient Four-Component Reaction for Dihydropyridin-2-ones

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journal contribution
posted on 05.03.2010, 00:00 by Rachel Scheffelaar, Monica Paravidino, Anass Znabet, Rob F. Schmitz, Frans J. J. de Kanter, Martin Lutz, Anthony L. Spek, Célia Fonseca Guerra, F. Matthias Bickelhaupt, Marinus B. Groen, Eelco Ruijter, Romano V. A. Orru
A broad range of isonitrile-functionalized 3,4-dihydropyridin-2-ones could be prepared using a four-component reaction between phosphonates, nitriles, aldehydes, and isocyanoacetates. The reaction involves initial formation of a 1-azadiene intermediate which is trapped in situ by an isocyanoacetate to give the desired heterocyclic scaffold through cyclocondensation. The full scope and limitations of this four-component reaction are described. Variation of the nitrile and aldehyde inputs proved to be extensively possible, but variation of the phosphonate input remains limited. Regarding the isocyanoacetate, α-aryl isocyanoacetates give moderate to high yields and result in a complete diastereoselectivity for the 3,4-cis isomer. α-Alkyl isocyanoacetates gave the corresponding dihydropyridin-2-ones in moderate yields, most of them as mixtures of diastereomers. Elevated temperatures during cyclocondensation generally increased the yield and resulted in a change of the diastereomeric ratio in favor of the cis-diastereomer. In addition to isocyanoacetates, a limited number of other α-acidic esters resulted in the formation of dihydropyridin-2-ones, albeit in much lower yield. Computational studies show that the observed difference in yield cannot be simply correlated to specific physical properties (including acidity) of the different α-acidic esters.