Cyclohexadienes from the rearrangement of O-aroyl-N-acetyl-N-(2,6-dimethylphenyl)hydroxylamines. Reaction in aqueous solution to meta- and para-substituted 2,6-dimethylacetanilides

Abstract

O-Aroyl-N-acetyl-N-(2,6-dimethylphenyl)hydroxylamines (aroyl = benzoyl, 3-nitrobenzoyl, and pentafluorobenzoyl) rearrange in acetonitrile to 1,5-dimethyl-5-aroyloxy-6-N-acetyliminocyclohexa-1,3-dienes that can be isolated as pure compounds. These cyclohexadienes react in aqueous solutions, producing m-aroyloxy- and m-hydroxy-2,6-dimethylacetanilides in an H⁺-catalysed reaction and the corresponding para products in a non-catalysed reaction. Analysis of the effect of the aroyloxy group suggests that the latter reaction involves heterolysis to a reactive, non-selective, ion pair that collapses to the para product, or reacts at this position with water. The meta products arise from the N-protonated cyclohexadiene reacting with solvent in a conjugate addition to give the meta-substituted phenol, or in an intramolecular reaction with the carbonyl group to give the rearranged ester. This latter reaction is proposed to proceed via an intermediate 1,3-dioxolan-2-ylium ion. The nucleophiles azide, phenylsulfinate and the methyl thioglycolate anion react in a bimolecular fashion to give meta-substituted 2,6-dimethylacetanilides. With phenylsulfinate this requires H⁺, while methyl thioglycolate anion reacts with the neutral cyclohexadiene. Azide exhibits reaction by both processes. These reactions are proposed to involve conjugate additions, either to the N-protonated cyclohexadiene, or, with better nucleophiles, directly on the neutral compound. These cyclohexadienes model intermediates that may form during the metabolism of certain carcinogenic amines. These results establish the presence of three electrophilic species capable of reacting with cellular nucleophiles—the highly reactive and non-selective cation formed in the heterolysis, the less reactive and more selective N-protonated species, and the neutral cyclohexadiene itself. The last electrophile is relatively unreactive, but can be a target of very good nucleophiles such as thiol anions.