Experimental and Theoretical Investigation of the Reaction of Amines with Methyl Propiolate

Abstract Michael addition of secondary amines, R 1 R 2 NH to methyl propiolate occurs with complete stereoselectivity to give trans ‐methyl β‐aminoacrylate in 71–91% yields. The reaction with benzylamine, however, leads to the formation of a mixture of the corresponding trans ‐ and cis ‐isomers in 26:74% respectively as indicated by 1 H NMR. A theoretical investigation of the model reactions at the DFT level reveals that the reaction occurs in two steps, the first step leading to the formation of a zwitterionic intermediate being rate determining. Furthermore, formation of an initial reactant‐complex of methyl propiolate with a molecule of amine followed by the nucleophilic attack of the amine is a lower energy path than the one followed by direct reaction between the two reactants. The low activation enthalpies, ▵H # (ca. 12–20 kcal mol −1 ) in the gas phase are further lowered (ca. 7–15 kcal mol −1 ) in methylene chloride. The initially formed zwitterionic intermediate undergoes 1,3‐prototropic shift through a bridge established by a molecule of amine between the donor ( + NH) and the acceptor ( − C2) sites. In the reaction with benzylamine, theoretical calculations indicate the cis‐ isomer to be thermodynamically more stable than the trans ‐isomer by 0.5 kcal mol −1 which corresponds to 70% of the former. Furthermore, existence of the “enamine‐imine‐enamine” phenomenon is established theoretically, which facilitates trans‐cis isomerization.