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.