Department of Chemistry & Pharmaceutical Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
J Org Chem. 2010 Mar 5;75(5):1723-32. doi: 10.1021/jo902613j.
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, alpha-aryl isocyanoacetates give moderate to high yields and result in a complete diastereoselectivity for the 3,4-cis isomer. Alpha-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 alpha-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 alpha-acidic esters.
一种广泛的异腈功能化的 3,4-二氢吡啶-2-酮可以通过膦酸盐、腈、醛和异氰基乙酸酯之间的四组分反应来制备。该反应涉及到 1-氮杂二烯中间体的初始形成，该中间体被异氰基乙酸酯原位捕获，通过环缩合得到所需的杂环支架。描述了这种四组分反应的全部范围和限制。腈和醛输入的变化被证明是广泛可能的，但膦酸盐输入的变化仍然有限。关于异氰基乙酸酯，α-芳基异氰基乙酸酯给出中等至高的产率，并导致 3,4-顺式异构体的完全非对映选择性。α-烷基异氰基乙酸酯以中等产率得到相应的二氢吡啶-2-酮，其中大多数是顺式异构体和反式异构体的混合物。环缩合过程中升高温度通常会提高产率，并导致非对映异构体比例向顺式异构体倾斜。除了异氰基乙酸酯之外，少数其他的α-酸性酯也导致了二氢吡啶-2-酮的形成，尽管产率要低得多。计算研究表明，观察到的产率差异不能简单地与不同的α-酸性酯的特定物理性质（包括酸度）相关联。
