A Quinidine-Based Squaramide-Catalyzed Asymmetric Cascade Double Hetero-Michael Addition-Cyclization of N-Benzylhydroxylamine: Synthesis of Chiral 1,2-Benzoxazines

Abstract

The double hetero-Michael addition (DHMA), leveraging the reactivity of two distinct nucleophilic centers (oxygen and nitrogen), has emerged as a transformative strategy in organic synthesis for constructing carbon-hetero nuclear bonds in a single step. In this work, we report an innovative intermolecular DHMA cascade cyclization reaction catalyzed by a quinidine-based squaramide catalyst. The use of the squaramide catalyst is particularly noteworthy, as it enhances the electrophilicity of the α,β-unsaturated bis-enone, thereby promoting excellent enantioselective formation of the 1,2-benzoxazine. The process demonstrates excellent enantiomeric excess (up to 99 % ee), moderate diastereoselectivity (up to 6 : 1 dr), and high yields. The four different 1,2-benzoxazine stereoisomers have been synthesized with excellent enantiomeric excess. Furthermore, the scaleup reaction of the methodology has been extended with excellent outcomes.