On the Brønsted acid-catalyzed aza-Michael reaction of isoxazol-5-ones to enones: reaction optimization, scope, mechanistic investigations and scale-up

• Published in: Reaction chemistry & engineering 2023-05, Vol.8 (5), p.124-1215
• Main Authors: de Siqueira, Marcelo M, de Castro, Pedro P, dos Santos, Juliana A, Flores, Leonã S, de Paiva, Walysson F, Fernandes, Sergio A, Amarante, Giovanni W
• Format: Article
• Language: English
• Subjects: Catalysts; Hydrochloric acid; Investigations; Michael reaction; Nitrogen; Optimization; Reaction kinetics; Reaction mechanisms; Regioselectivity; Sulfonic acid
• ISSN: 2058-9883; 2058-9883
• DOI: 10.1039/d3re00050h

A robust and metal-free methodology for the aza-Michael reaction between isoxazol-5-ones and enones is presented, allowing the preparation of a broad reaction scope in moderate to excellent yields under mild reaction conditions. Notably, the isoxazol-5-ones (Michael donor) reacted selectively at the nitrogen (no attack at the C4 position was observed). In this study, two accessible Brønsted acids (hydrochloric acid and p -sulfonic acid calix[4]arene) were investigated as catalysts for this transformation. The use of catalytic hydrochloric acid led to the desired derivatives in slightly better yields when dibenzylideneacetones were employed as Michael acceptors. In contrast, better yields were attained for the p -sulfonic acid calix[4]arene when chalcones were used as Michael acceptors, also allowing catalyst recovery and reuse for consecutive cycles without significant loss of performance. The reaction mechanism was investigated through theoretical calculations and control experiments, which revealed that the reaction kinetics favor the isoxazol-5-one attack at the nitrogen (instead of the carbon at the 4-position), explaining the regioselectivity of this transformation. A scale-up experiment was also carried out with no loss in the entire reactivity. Regioselective aza-Michael-type of isoxazol-5-ones to activate double bonds.