Synthesis of 3,4,5-Trisubstituted Isoxazoles in Water via a [3+2]-Cycloaddition of Nitrile Oxides and 1,3-Diketones, β-Ketoesters, or β-Ketoamides: Base-mediated and Keto-enol-controlled Mechanism

Abstract

A selective [3+2]-cycloaddition reaction of nitrile oxides and 1,3-diketones, β-ketoesters, or β-ketoamides in water without the need of a metal catalyst is described. The selectivity of the reaction can be controlled by the polarity of solvents in the presence of an appropriate base. The optimized reaction condition circumvents other reactions, such as O-imidoylation or hetero [3+2]-cycloaddition. The reaction happens fast in water to provide an environment friendly access to 3,4,5-trisubstituted isoxazoles, specifically acyl-substituted, ester-substituted, or amide-substituted isoxazoles, which are important structures found in numerous bioactive natural products and pharmaceuticals.