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.
Addition of methyl acetoacetate to 2-nitrovinamidinium hexafluorophosphate salts leads to the formation of anilines or phenols in good to excellent yields depending on the alkylamine substituents. Small substituents, e.g., pyrrolidine, lead to the formation of anilines while large substituents, e.g., N,N-diisopropyl, exclusively give phenols. Labeling studies implicate a [1,5]-H shift proceeding with excellent isotopic fidelity.
An Unexpected [1,5]-H Shift in the Synthesis of Nitroanilines.Page 439. The outcome of the reaction of methyl acetoacetate and nitrovinamidinium salts (1a-d) to give substituted anilines (2a-c) was rationalized as proceeding through a [1,5]-H shift. After publication of this work, we began to investigate the mechanistic pathway by computational methods in collaboration with Prof. Ken Houk (UCLA). All 1,5hydrogen shifts have barriers of greater than 45 kcal/mol according to B3LYP/6-31G* calculations for both neutral and anionic intermediates. Since we were unable to locate a thermally accessible transition state, these computational studies prompted us to revisit the structural assignment of the anilines. The regiochemistry was previously determined by an HMBC NMR experiment. Extensive NOE studies and preparation of the authentic alternative regioisomers have led us to revise the aniline 2a to 2-(dimethylamino)-5nitrobenzoic acid methyl ester. Additional support for the revision is based on X-ray crystallographic analysis of an analogue. The mechanisitic implication of this revision is a formal 1,5-dimethylamine shift.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.