A novel route to 5-substituted 3-isoxazolols. Cyclization of N, O-DiBoc beta-keto hydroxamic acids synthesized via acyl Meldrum's acids

3-Isoxazolols are most often synthesized from a beta-keto ester and hydroxylamine. This cyclization typically gives rise to a major byproduct, the corresponding 5-isoxazolone. We have found that N, O-diBoc-protected beta-keto hydroxamic acids can be synthesized and cyclized to 5-substituted 3-isoxazolols without formation of any byproduct. We present a novel and versatile three-step procedure in which carboxylic acid derivatives are converted into acyl Meldrum's acids which, upon aminolysis with N, O-bis(tert-butoxycarbonyl)hydroxylamine, lead to the N, O-diBoc-protected beta-keto hydroxamic acids. These hydroxamic acid analogues were then, upon treatment with hydrochloric acid, cyclized to the corresponding 5-substituted 3-isoxazolols.