Demonstrating the synergy of synthetic, mechanistic, and computational studies in a regioselective aniline synthesis

Tri- and tetrasubstituted anilines are formed in good to excellent yields by the addition of ketones to vinamidinium salts (up to 98%). The reaction proceeds via the formation of dienone intermediates, which react to form an enamine with the liberated amine. In the case of a nitro, or dimethylaminomethylene substituent, the enamines undergo a facile electrocyclic ring closure to form a cyclohexadiene, which goes on to form anilines with a high degree of selectivity (up to 50:1) with a minor competing pathway proceeding via the enol providing phenols. Competition experiments using isotopic substitution reveal that the rate determining step en route to dienone is enol/enolate addition to the vinamidinium salt, which is characterized by an inverse secondary isotope effect (k(H/D) 0.7-0.9). Computational studies have been used to provide a framework for understanding the reaction pathway. The original proposal for a [1,5]-H shift was ruled out on the basis of the calculations, which did not locate a thermally accessible transition state. The minimum energy conformation of the enamine is such that a facile electrocyclic ring closure is ensured, which is corroborated by the experimental studies. A framework for understanding the reaction pathway is presented.