Polystyrene-Supported Aminobenzenesulfonic Acids as Bifunctional Heterogeneous Catalysts for the Synthesis of Isoxazoline Skeletons

Abstract

The isoxazoline skeleton is a pivotal structural motif in pharmaceuticals and agrochemicals, necessitating the development of efficient synthetic methodologies. Conventional synthesis via 1,3-dipolar cycloaddition often requires multiple steps to prepare nitrile oxide precursors. While acid–base catalysis offers a more direct route from α,β-unsaturated aldehydes and ketoximes, catalyst recovery remains a significant challenge. In this study, we developed robust heterogeneous acid–base catalysts by immobilizing aminobenzenesulfonic acids—inexpensive dye precursors—onto polystyrene. These catalysts effectively promote the synthesis of isoxazolines from α,β-unsaturated aldehydes and acetoximes. Notably, the catalyst system is highly compatible with continuous flow reactions, maintaining yields above 70% for over 50 hours of operation. Mechanistic investigations, supported by DFT calculations, reveal two distinct, isomer-dependent pathways: (i) an iminium-mediated 1,4-addition for the 2-aminobenzenesulfonic acid-immobilized catalyst, and (ii) a concerted acid–base activation enabling direct 1,4-addition for the 3-amino isomer.