Chlorination‐Mediated Oxidative 3+2 Cycloaddition of Aldoximes With Enaminones via Elimination: A Synthesis of 3,4‐Disubstituted Isoxazoles

ABSTRACT

A chlorination‐mediated strategy that enhances the oxidative coupling of aldoximes with enaminones to form isoxazoles via cycloaddition is described. Aldoximes are converted in situ to nitrile oxides with NCBSI as an oxidizing agent. The nitrile oxides subsequently undergo a 3 + 2 cycloaddition with enaminones. Based on the optimization parameters, acetonitrile was identified as the optimal solvent for the synthesis of 3,4‐disubstituted isoxazoles in good to excellent yields under mild conditions. Electron‐donating, electron‐withdrawing, and sterically hindered substituents on benzaldoximes gave good yields of the desired isoxazoles. Aldoximes are first chlorinated to generate nitrile oxides, which undergo 3 + 2 cycloaddition with enaminones and further undergo β‐elimination of dimethylamine, according to a plausible mechanism. This methodology provides an efficient and sustainable approach for synthesizing isoxazole scaffolds, which are widely used in medicinal chemistry and materials research.