Regiochemical Reversals in Nitrosobenzene Reactions with Carbonyl Compounds - α-Aminooxy Ketone versus α-Hydroxyamino Ketone Products

The Lewis acid catalyzed reaction of nitrosobenzene with a ketone can produce an a-aminooxy ketone or an a-hydroxyamino ketone; the reaction regiochemistry switches from the latter to the former upon the addition of a Lewis acid or sterically-hindered solvent. Whereas the latter (CN bond formation) is easily explained by attack of the enolate a-carbon at the N atom, the former (CO bond formation) has been an enigma, with few proposed explanations, and none that explains the simultaneous formation of both products and all the regiochemical reversals. Herein, the regiochemistry reversal is proposed to occur by (1) nucleophile formation governed by hard and soft acids and bases (HSAB) theory, (2) a nucleophilic attack by the enolate O atom at the N atom, followed by (3) a [2,3]-sigmatropic rearrangement. This mechanistic pathway and HSAB considerations account for the formation of both products and explain the three reported regiochemistry reversals, which are observed upon the introduction of (A) Lewis acid catalyst, (B) AcOH, or (C) solvent bulkiness.