Quilico synthesis

Nitrile oxides 7 react as 1,3-dipoles with alkynes in a [3+2] cycloaddition to give isoxazoles (Quilico synthesis). The nitrile oxides are generated in situ. They are obtained, for instance, by dehy-drohalogenation of hydroxamic acid chlorides (cr-chloraldoximes) with triethylamine ... 

Three isoxazolidinones are possible, the 3-, 4- and 5-isoxazolidinones, with 3-isoxazolidinones being the group containing the most members. Only one synthesis of 4-isoxazolidinones has been reported, although a number of 4-arylmethylene compounds exist. A number of isoxazolidine-3,5-diones have been synthesized. A review by Quilico with nine references appeared in 1962 (62HC(17)l,p. 7> and since then the number of references has slightly more than tripled. 

The first synthesis of a 3,5-diarylisoxazole from aryl hydroxamic acid chlorides and sodium phenyl acetylides was that effected by Weygand and Bauer in 1927. Beginning in 1946, when Quilico and Speroni showed that acid chlorides of hydroxamic acids on treatment with alkalies readily yielded nitrile oxides,numerous isoxazole and especially A -isoxazoline derivatives have been prepared. 

The chemistry of nitrile oxides, in particular their application in organic synthesis, has been continuously developed over the past two decades and represents the main theme of this chapter. The parent compound, fulminic acid (formonitrile oxide), has been known for two centuries, and many derivatives of this dipole have been prepared since that time. Several simple and convenient methods for the preparation of nitrile oxides have evolved over the years. Dehydrochlorination of hydroximoyl chlorides was first introduced by Werner and Buss in 1894 (1). A convenient synthesis of isoxazoles was reported by Quilico et al. (2 ), and then the discovery of nitrile oxide cycloadditions to alkenes was subsequently noted by the same group (5). 

Synthesis of heterocycles. Quilico and co-workers used the reagent for the synthesis of 3-chloroisoxazoles from the Grignard derivatives of terminal acetylenes. 

In the 1930s and for several decades that followed, Quilico with his scholars developed a research line on the synthesis and properties of isoxazole and its derivatives, a heterocyclic system that had been rather neglected before [ 1 ]. In the course of these studies, nitrile oxides 1 and fuhninic acid (the simplest member of the series 1, R = H) were recognized as the key intermediates in the formation of the isoxazole ring from hydroximoyl chlorides 2 and base in the presence of alkenes... 

---