Isoxazoles, formation

This procedure is illustrative of a general method for preparing a wide range of pure 3,5-disubstituted-4-isoxazole-carboxylic esters and (by hydrolysis) their acids,2 free from positional isomers. A wide range of both primary nitro compounds and of enamino esters can be used,2,3 and the esters thus obtained may then be used as reagents in the isoxazole annela-tion reaction.3,4 The only other general synthesis of these compounds involves chloromethylation and oxidation of a suitable 4-unsubstituted isoxazole.5 This procedure suffers from two difficulties low yields and the unavailability of starting isoxazole. Most methods of isoxazole formation yield a... 

Suggest a mechanism for isoxazole formation which accounts for these observations. 

A synthesis of 2-cyanocyclohexanone 4.45 from cyclohexanone is shown below. Formylation of cyclohexanone produces a mixture of keto/enol tautomers 4.42 and 4.43, the equilibrium lying to the side of the enol 4.42. Treatment with hydroxylamine affords isoxazole 4.44, and base-induced fragmentation of the isoxazole ring affords 4.45. Explain the regioselectivity of the isoxazole formation, and the mechanism of the fragmentation process. 

Fig. 15.44. Isoxazole formation by way of a 1,3-dipolar addition of an isolable nitrile oxide.

Compounds of this type are regarded as 4,5-disubstituted isoxazoles, and as such they react. Their formation from 2-acylcyclohexanones and hydroxylamine is a special case of the general method of isoxazole formation from /9-diketones. 2-Formyl (hydroxymethylene) cyclohexanones, obtained from the respective cyclohexanones and ethyl formate, give 3-unsubstituted derivatives [Eq. (7)].84-91 This reaction has been applied to a stereospecific synthesis of estrone.87,89... 

In Section III.E we noted that alkynes may be attacked by hydroxylamines at oxygen or nitrogen and illustrated nitrone formation in equation (111). The possibility of rearrangement of the nitrogen and oxygen products was also indicated. Hiere we give an example of the former (equation 176) . By comparison, isoxazole formation from keto alkynes is routine (equation 177) . 

Isoxazoles. - Formation. The combined action of copper(II) nitrate and acetic anhydride on 1,2-diphenylcyclopropane leads to a mixture of 3,5 diphenylisoxazole and its 4-nitro-derivative. Dimethyl azidomaleate affords the azirine (324) on heating, whereas the azidofumaric ester yields the isoxazole (325). 5-Amino-4-ethylthio-3-methylisoxazole (326) is produced from the acrylonitrile derivative MeCBr=C(SEt)CN and hydroxyl-amine." ... 

Cyclocondensation of a,y0-unsaturated ketones with hydroxylamine. This reaction is analogous to isoxazole formation via the corresponding ketoxime ... 

The formation of cyclic isoxazolinones on reaction of organic acids with hydroxylamine hydrochloride [13] is utilized for the derivatization of succinylacetone (2,4-dioxoheptanoic acid). After stabilization of the keto groups by isoxazole formation in this way, the remaining carboxylic acid group is esterified with pentafluoro-benzyl bromide for GC—MS assay in El [193] or NlCl [194] mode. The latter mode is required to measure the low levels present in amniotic fluid. 

Scheme 6.26. Regioselectivity in isoxazole formation on a solid support compared to solution phase.

As predicted by retrosynthesis, isoxazole formation proceeds via (isolable) intermediates 10 and 11. In the case of unsymmetrically substituted P-dicarbonyl systems, regioselectivity can be controlled by utilizing different carbonyl electrophilicities and observing defined reaction conditions. 

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