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
(kH/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.