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

• Published in: European journal of organic chemistry Vol. 2012; no. 30; pp. 6013 - 6020
• Main Authors: Nelson, Donna J., Kumar, Ravi, Shagufta
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.10.2012; WILEY‐VCH Verlag; Wiley-VCH
• Subjects: Catalysis; Catalysts: preparations and properties; Chemistry; Enolate chemistry; Exact sciences and technology; General and physical chemistry; Kinetics and mechanisms; Lewis acids; Noncondensed benzenic compounds; Organic chemistry; Preparations and properties; Reaction mechanisms; Reactivity and mechanisms; Regioselectivity; Sigmatropic rearrangement; Theory of reactions, general kinetics. Catalysis. Nomenclature, chemical documentation, computer chemistry; Lewis acid; Sigmatropic reaction; Hydroxylamine; Regioselectivity; Theoretical study; Lewis acids; Steric hindrance; Acid catalysis; Enolate chemistry; Sigmatropic rearrangement; Ketone; HSAB principle; Carbonyl Compounds; Reaction mechanism; Benzenic compound; Acetic acid; Reaction mechanisms; Enolate; Solvent; Catalyst; Nucleophile
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.201200893

The Lewis acid catalyzed reaction of nitrosobenzene with a ketone can produce an α‐aminooxy ketone or an α‐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 (C–N bond formation) is easily explained by attack of the enolate α‐carbon at the N atom, the former (C–O 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. A simple and reasonable mechanism for the Lewis acid catalyzed reaction of nitrosobenzene with a ketone or enamine to form an α‐aminooxy ketone (C–O, as opposed to C–N, bond formation) is proposed, and the reaction occurs by initial nucleophilic attack on Ph–N=O, which is governed by the principles of hard and soft acids and bases theory, followed by a [2,3]‐sigmatropic rearrangement.