Cu‐Catalyzed Synthesis of Isoxazolidine/1,2‐Oxazinane‐3‐ylidene Sulfonamide from O‐Alkynyl Hydroxylamines: A Route to Sulfamethoxazole Analogues

A copper-catalyzed cascade reaction involving CuAAC (copper-catalyzed azide–alkyne cycloaddition), ketenimine formation, and hydroamination of alkynyl hydroxylamines enables the synthesis of isoxazolidines and novel 1,2-oxazinane-3-ylidene sulfonamides. A serendipitous imine-isomerization directly converts isoxazolidine-3-ylidene sulfonamides into 3-amino isoxazoline. This intermediate is then used in the total synthesis of sulfamethoxazole and its analogues.

Abstract

Cu-catalyzed cascade [3+2] azide-alkyne cycloaddition (CuAAC)/ketenimine/hydroamination reaction of alkynyl hydroxylamines that enables the rapid synthesis of isoxazolidine/1,2-oxazinane-3-ylidene sulfonamides. Notably, this study presents the first examples of 1,2-oxazinane-3-ylidene sulfonamide. The synthetic utility of this transformation is highlighted by the direct conversion of isoxazolidine-3-ylidine sulfonamides into 3-amino isoxazolines and isoxazole derivatives. This strategy was used as a key step in the total synthesis of antibiotic sulfamethoxazole and its analogues.

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