Three-Component Synthesis of 3,4,5-Trisubstituted Isoxazoles

Significance

A one-pot, three-component synthesis of 3,4,5-trisubstituted isoxazoles is described. Acylative Sonogashira coupling of acid chlorides 1 with acetylenes 2 gives the alkynones 3, which, without isolation undergo 1,3-dipolar cyclo­addition with nitrile oxides formed in situ from hydroximoyl chlorides 4 and base, to deliver the desired heterocycles 5 in poor to good yields. The use of microwave heating for the cycloaddition step gave much improved yields, reduced byproduct formation and greatly decreased reaction times (30 min vs 3 d under conventional heating). A wide range of functionality is tolerated, including electron-rich, neutral, and electron-poor aromatics, as well as heterocyclic and aliphatic groups. Product regioselectivity was proved by ¹³C NMR and, in some cases, by X-ray crystallography. The opposite cycloaddition regioisomers were not detected.