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 <i>para-</i>substituent on the aryl ring, formation of the regioisomeric tetrahydroquinoline isomer can significantly compete. The electron-donating or -withdrawing properties of the <i>para-</i>substituent of the aryl ring determines the ratio of product isomers. A series of 2-aroyl-cyclohexanones, with <i>para</i>-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 of the substituents is demonstrated. This is explained by the separate in situ yields, which reveal that the pathway leading to the tetrahydroquinoline regioisomer is significantly more sensitive toward the electronic nature of the <i>para</i>-substituent than the pathway leading to the tetrahydroisoquinoline. Semiempirical AM1 molecular orbital calculations on the starting electrophile 2-aroyl-cyclohexanone support a correlation between the energy of the LUMOs and the regioisomeric product ratio. Our results facilitate synthetic access to a range of these interesting synthetic intermediates