Isoxazoles acetylides

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 interaction of a-chlorooximes with sodium acetylides, leading to the isoxazoles 148 (Scheme 73) (27MI1 59G2466), may also be regarded as an example of intramolecular addition of oxime hydroxyl to the triple bond in the intermediate 147. However, in the formation of 3,5-di(ethoxycar-bonyl)pyridine 149 from formaldoxime and ethylpropiolate (Scheme 74), the hydroxyl group remains inert with respect to the triple bond (67T2641)... 

It should be noted that it is in many cases conceivable that isoxazoles and isoxazolines are formed from chloroximes without the intermediacy of a nitrile oxide. This route could occur if the substrate acted as a nucleophile to give an intermediate, such as the alkynyloxime (25) from an acetylide, which can cyclize to the isoxazole (26). In this case, by trapping with nonnucleo-philic alkenes, the reaction has been shown to involve a nitrile oxide.60,71 However, experiments on reactions of chloroximes with other nucleophiles suggest that a nitrile oxide is not invariably involved.72,73... 

The reaction of a lithium acetylide with the electrophilic 3-methylisoxazol-5-carbonyl chloride 30 afforded the substituted isoxazole 31 in 67% yield <04TL4935>. 

In contrast, Cu(I) catalysis makes possible the efficient synthesis of 3,5-disubsti-tuted isoxazoles 57 from aromatic or aliphatic aldehydes and alkynes. Stable nitrile oxides can be isolated and subsequently submitted to the reaction [21] in isolated form and submitted to the reaction in one-pot, three-step process [131]. Here, nitrile oxide intermediates 56 are generated in situ via the corresponding aldoxime and halogenation/deprotonation by Chloramine-T [132]. Capture of the intermediate nitrile oxide by copper(I) acetylides occurs presumably before dimerization. In this case, the Cu catalyst was obtained from copper metal and copper(II) sulfate, and the products were isolated by simple filtration or aqueous work-up. Trace amounts of toluenesulfonamide and unreacted acetylene are easily removed by recrystallization or by passing the product through a short plug of silica gel. 

---