Regioselective One-Pot Straightforward Synthesis of Isoxazoles

Significance

Reported is an efficient, regioselective one-pot synthesis of 3-substituted and 3,5-disubstituted isoxazoles by the reaction of readily available α,β-unsaturated aldehydes/ketones with N-hydroxyl-4-toluenesulfonamides. The reaction proceeds via regioselective conjugate addition of substrate 1 or 4 with N-hydroxylsulfonamide 2 ­followed by elimination of the tosyl moiety and cyclization. The resulting isoxazoline then undergoes dehydration under mild basic conditions into isoxazoles 3 or 5 (H.-G. Weinig et al. Tetrahedron Lett. 2002, 43, 4613). The 3-substituted isoxazoles are readily obtained for substrates 1 containing R^¹ = EWG or EDG. However, no isoxazoles result from substrates bearing R^¹ = Me or H. It may therefore be concluded that an unsaturated carbon at C-3 is required for the success of the reaction. Application of this sequence to enones 4 leads to 3,5-disubstituted isoxazoles 5 in moderate to excellent yield, albeit at higher temperature and longer reaction time.