Isoxazoles from nitrile oxides

Azine approach. Acid-catalyzed cyclization of 2-/3 -oxoalkylpyridine 1-oxides (37) constitutes a general method for the preparation of the isoxazolo[2,3-a]pyridinium ring system (77JOC1364). By analogy to the synthesis of isoxazoles from nitrile oxides, the oxo chain should be replaceable by an alkynyl or ethenyl chain, the latter containing a substituent which can readily be eliminated from the cyclic product. 

Isoxazoles from nitrile oxides and acetylene derivatives—Diene syntheses s, 18, 758 isoxazoles from stable sterically hindered nitrile oxides s. G. Grund-mann and J. M. Dean, J. Org. Ghem. 30, 2809 (1965) reactions with cyanogen di-N-oxide s. G. Grundmann et al., A. 687, 191 (1965)... 

Isoxazoles from nitrile oxides and acetylene derivatives. Dicyanoacetylene added to an ethereal soln. of benzonitrile oxide, and refluxed 40 min. 

Hi) Preparation of isoxazoles from nitrile N-oxides The reaction between a nitrile //-oxide and an alkyne is so facile that it is usually sufficient to leave an ether solution of the reactants at room temperature to obtain the desired isoxazole in good yield. The reaction is in general sensitive to the size of the substituent on the alkyne but not on the nitrile -oxide. In the case of poorly reactive alkynes, the difficulty may be overcome by generating the nitrile -oxide in situ and keeping its concentration low. 

Table 13 Isoxazoles from Nitrile iV-Oxides and Alkynes...

Table 14 Isoxazoles from Nitrile N-Oxides and C=C Dipolarophiles...

The general synthetic scheme starting from nitrile oxides, which condense with acetylenes to yield isoxazoles and with olefins to yield A -isoxazoIines may be represented by Eqs. (1) and (2). The forma-... 

Here, isoxazole-3-carboxylic acid (IV)-the main product of the reaction-is formed from nitrile oxide (III) on adding acetylene to it. 

Table 15 Isoxazoles from Nitrile JV-Oxides and Doubly Activated Methylene Compounds...

A very significant contribution to the development of isoxazole chemistry came in the period 1930-1946 from Quilico s studies on synthetic approaches to the ring system from nitrile oxides and unsaturated compounds <19300172, 1950NAT226>. However, the study of isoxazolidines began very much more recently being related to the availability of this nucleus and then to the discoveries of cycloadditions of nitrones to olefins <1960TL9> and intramolecular cyclizations of unsaturated nitrones <1959JA6334>. 

Perfluoroalkylsubstituted isoxazoles were prepared in satisfactory yields from nitrile oxides and ethyl 3-perfluoroalkyl-3-pyrrolidino acrylates <01T5781>. 

Phototransformation of pyridazine 1,2-dioxides sharply contrasts with that of pyridazine 1-oxides. Pyridazine 1,2-dioxide derivatives give 3a,6a-dihydroisoxazolo[5,4- f]isoxazoles (53) through postulated bisiminoxyl radicals. 3,6-Diphenylpyridazine 1,2-dioxide gives, besides the corresponding bicyclic derivative (53), 3-phenylisoxazole (54) and 4,5-diphenyl-furoxan (55). The last two products can be explained by generation of the nitrile oxide from the intermediate (53) with subsequent dimerization to the furoxan (55 Scheme 18) (79T1267). 

A -Isoxazolines are readily available from the 1,3-dipolar cycloaddition of nitrile -oxides with alkenes and from the condensation reaction of ehones with hydroxylamine. Therefore, methods of conversion of -isoxazolines into isoxazoles are of particular interest and of synthetic importance. 

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. 

Although the unsaturated nitrile oxides 124 can be prepared via the aldoxime route (see Scheme 8), the older procedure suffers from the disadvantage that a tenfold excess of allyl alcohol and two additional steps are required when compared to Scheme 15. Therefore, unsaturated nitro ether 123 that can be prepared by condensation of an aldehyde 120 and a nitro alkane followed by Michael addition of alcohol 122, was a useful precursor to nitrile oxide 124 [381. The nitrile oxide 124 spontaneously cyclized to ether 125. This procedure is particularly suitable for the synthesis of tetrahydrofurans (125a-h) and tetrahydropyrans (125i-k) possessing Ar substituents in 72-95% yield (Table 12). The seven-membered ether 1251 was obtained only in 30% yield on high dilution. The acetylenic nitro ether 126 underwent INOC reaction to provide the isoxazole 127. 

As discussed in Section 6.2, nitro compounds are good precursors of nitrile oxides, which are important dipoles in cycloadditions. The 1,3-dipolar cycloaddition of nitrile oxides with alkenes or alkynes provides a straightforward access to 2-isoxazolines or isoxazoles, respectively. A number of ring-cleaving procedures are applicable, such that various types of compounds may be obtained from the primary adducts (Scheme 8.18). There are many reports on synthetic applications of this reaction. The methods for generation of nitrile oxides and their reactions are discussed in Section 6.2. Recent synthetic applications and asymmetric synthesis using 1,3-dipolar cycloaddition of nitrile oxides are summarized in this section. 

Isoxazole (as well as isoxazoline, and isoxazolidine) analogues of C-nucleosides related to pseudouridines 25 and 27 have been regioselectively synthesized by 1,3-dipolar cycloaddition (1,3-DC) of nitrile oxides (and nitrones) derived from uracyl-5-carbaldehyde 24 and 2,4-dimethoxypyrimidine-5-carbaldehyde 26 respectively <06T1494>. 

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