Regiochemistry of the condensation of 2-aroyl-cyclohexanones and 2-cyanoacetamide: 13C-labeling studies and semiempirical MO calculations.

Hydroxy-aryl-5,6,7,8-tetrahydroisoquinoline-4-carbonitriles represent interesting chemical scaffolds, but synthetic access to these compounds is limited. The reaction of 2-aroyl-cyclohexanones with 2-cyanoacetamide and base in ethanol has been reported to lead to the formation of the tetrahydroisoquinoline isomer. We show that depending on the electronic nature of the para-substituent on the aryl ring, formation of the regioisomeric tetrahydroquinoline isomer can significantly compete. The electron-donating or -withdrawing properties of the para-substituent of the aryl ring determines the ratio of product isomers. A series of 2-aroyl-cyclohexanones, with para-substituents ranging from electron-donating to electron-withdrawing, were reacted with [2-13C]-cyanoacetamide. The product ratio and absolute regiochemistry were directly determined by quantitative 13C, HMBC, and NOESY NMR spectroscopy on the reaction mixtures. A clear relationship between the regioisomeric product ratio and the Hammett sigma values ...