Synthesis of Trisubstituted Isoxazoles via Gold-Catalyzed Domino Reaction

Significance

Reported is an efficient synthesis of trisubstituted isoxazoles 4 and 6 from alkynyl oxime ethers 1 and 5. Based on previous work (C. Praven, A. Kalyanasundaram, P. T. Perumal Synlett 2010, 777), a π-acidic gold-catalyzed ­intramolecular cyclization of alkynyl oxime ether ­(intermediate 2) followed by an allyl oxonium Claisen-type rearrangement led to the formation of the trisubstituted isoxazoles 4 and 6. After optimization, the cyclization-rearrangement reaction required the use of AuCl₃ as catalyst. Firstly, the scope of this reaction was investigated with different R^¹ substituents (alkyl, electron-rich and -poor aryl groups) and various substituents on the terminal triple bond (R^²) providing isoxazoles 4 and 6 in moderate to good yields. Then, the substituent effect on the allyl moiety (R^³, compound 5) was investigated. The additional substituent caused an increase in catalyst loading and prolonged reaction time due to steric repulsion. A plausible mechanism has been proposed without evidence.