Effective Synthesis of 3,4‐Diaryl‐isoxazole‐5‐carboxamides and their Antiproliferative Properties

A simple scalable procedure for the synthesis of 3,4‐diaryl‐isoxazole‐5‐carboxamides 6 under mild conditions from readily available material was developed. The targeted compounds 6 , structural analogues of heat shock protein inhibitors, were obtained by the rearrangement of intermediate 3,4‐diaryl‐5‐carboxamido‐isoxazoline N‐oxides 5 . In contrast to carboxamido‐isoxazoline oxides 5 , base‐catalyzed recyclization of 3,4‐diaryl‐5‐(ethoxycarbonyl)isoxazoline N‐oxides 9c unexpectedly yielded 5‐hydroxy‐1,2‐oxazin‐6‐ones 17c instead of ethyl 3,4‐diaryl‐isoxazole‐5‐carboxylates 10 . Crystal and molecular structure of 4‐(2,5‐dimethoxy‐3,4‐methylenedioxyphenyl)‐5‐hydroxy‐3‐phenyl‐6 H ‐1,2‐oxazin‐6‐one 17c was established by single‐crystal X‐ray diffraction study. In a phenotypic sea urchin embryo assay, carboxamide 6f showed moderate antimitotic antitubulin activity compared to 5‐unsubstituted 3,4‐diarylisoxazoles 15 , which featured strong microtubule destabilizing effect.