Scope and limitations of an efficient four-component reaction for dihydropyridin-2-ones

R. Scheffelaar, M. Paravidino, A. Znabet, R.F. Schmitz, F.J.J. de Kanter, M. Lutz, A.L. Spek, C.F. Guerra, F.M. Bickelhaupt, M.B. Groen, E. Ruijter, R.V.A. Orru

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(Chemical Equation Presentation) A broad range of isonitrile-functionalized 3,4-dihydropyridin-2-ones could be prepared using a fourcomponent 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, a-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. © 2010 American Chemical Society.
Original languageEnglish
Pages (from-to)1723-1732
Number of pages10
JournalJournal of Organic Chemistry
Publication statusPublished - 2010


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