Isoxazole ring

The stability of various heterocycles can be also compared using oxidation procedures. Thus, the oxidation of the heterocycles in Scheme 29 with potassium permanganate showed that under these reaction conditions the isoxazole ring is more stable than the furan ring but less stable than the pyrazole and furazan rings. 

If the substituent at the 3-position is a group that can be eliminated as an anion (such as Cr, CN and NJ), the reaction proceeds without the cleavage of the C(3)—C(4) bond in the isoxazole ring and involves the ejection of the 3-substituent as an anion. For example, 3-cyanoisoxazole (114) reacted with sodium ethoxide at room temperature to give ethyl cyanoacetate (115) via an intermediate cyanoketene (32G436). 

Isoxazoles are readily cleaved under reducing conditions, and many examples have been reported (79AHC(25)147,63AHC(2)365). In the last three decades the potential of these reactions in synthesis has finally been realized, and the isoxazole ring has become a major tool as a masked enaminone (137) or 1,3-diketone, particularly for the synthesis of heterocycles. 

Applications of the isoxazole ring as a masked enaminone for the synthesis of various heterocycles are shown in Scheme 38. 

Most reactions leading to isoxazoles must involve at some stage cyclization of an intermediate which contains all five atoms of the isoxazole ring. In some cases the acyclic intermediates are short-lived and unisolable, in others they are stable and able to be isolated. In this section we discuss reactions which involve an isolable acyclic precursor. These reactions mostly utilize (CCCNO) synthons although a few examples of (OCCCN), (CCCON) and (CONCC) synthons are encountered. We are unaware of examples involving (CNOCC) synthons. 

The synthesis of isoxazolecarboxylic acids has been well investigated. They can be prepared either from compounds which already contain an isoxazole nucleus or by isoxazole ring-closure methods using appropriate starting materials containing carboxy or alkoxycar-bonyl groups. 

An amino group may take any of three possible positions in the five-membered isoxazole ring, giving rise to three tautomeric forms for 70 and 71 and four forms for 72 [76AHC(S1), pp. 416, 444, 445 84CHEC-I(5)1]. However, only amino structures 70a-72a have been detected using IR- or NMR-spectroscopic techniques (Scheme 33). 

The methyl group position was fixed both by cleavage of the isoxazole ring with sodium ethylate and by isolation of the cyanacetone sodium salt 125. The reaction of this salt with phenylhydrazine resulted in the phenylhydrazone of cyanacetone (126) (69ZOR1179). 

V. Reactions Proceeding with Cleavage of the Isoxazole Ring. , 397... 

A. The Opening of the Isoxazole Ring by the Action of Nucleophilic Agents.398... 

For the preparation of compounds with an aromatic isoxazole system, two synthetic paths are of high importance first the condensation to form the 1—5 and the 2—3 bonds of the isoxazole ring (I—>2) and second that to form the 1—5 and 3—4 bonds of this... 

The isoxazole ring is synthesized through the long known and extensively elaborated method of condensing j8-diketones or their derivatives with hydroxylamine. 

Spectroscopic methods have been successfully applied to the elucidation of some details of the fine structure of isoxazole derivatives. Thus IR spectra revealed steric hindrance in the case of some 3,4,5-trisubstituted isoxazoles for phenylisoxazoles this results in the nonplanarity of the benzene and isoxazole rings and decreasing mutual interaction. 

The nucleophilic substitution reactions are still more limited in scope owing to the instability of the isoxazole ring toward nucleophilic reagents. Homolytic reactions appear to be unknown though some of the reactions being studied are possibly of this type. Besides those reactions which are characteristic of the reactivity of the isoxazole nucleus itself, we shall consider in this section some substitution reactions in the side chain organomagnesium synthesis in the isoxazole series, condensation reactions of the methyl groups of methyl-isoxazoles, and finally some miscellaneous reactions. 

Different results were obtained by Kochetkov and Khorautova. After nitrating 5-phenylisoxazole, they isolated two nitro derivatives, one of which contained a nitro group in the phenyl nucleus, the other one in the isoxazole ring. It is to be expected that the nitration of other phenylisoxazoles results in some second isomer that has not been isolated due to a negligible yield. It will also be noted that the nitration of arylisoxazoles proceeds faster and under milder conditions than necessary for the alkyl derivatives. 

It was not until 1940 that the sulfonation of alkylisoxazoles by heating them with chlorosulfonic acid was reported. This gave a mixture of isoxazole-4-sulfonic acids (58) and their acid chlorides (59). The position of the sulfonic group in derivatives of monomethyl isoxazoles has been proved by nucleophilic cleavage of the isoxazole ring (60 61). Recently it proved possible to sulfonate isoxazole... 

As with other electrophilic substitution reactions, there is practically no work available on the halogenation of isoxazoles with functional substituents. The only instance that indicates that the general pattern holds true here is the extremely rapid bromination of 3-anilino-5-phenylisoxazole (65), in which the isoxazole ring is the first to react with 1 mole of bromine, yielding... 

This activation is more pronounced on the introduction of stronger electron-donor substituents, but this point is not yet sufficiently studied. The isoxazole ring is unsymmetrical, and the activating effect of the substituent depends on its position. The available evidence shows that a substituent at C-5 activates the nucleus (or rather the 4-position) more strongly than does a substituent at C-3. 

The mechanisms of the electrophilic substitutions in the isoxazole nucleus have not yet been studied. They should not differ fundamentally from those usually accepted for the substitution of aromatic systems but the structural specificity of the isoxazole ring might give rise to some peculiarities, as recently specially discussed.One important point is that isoxazole shows a clearcut tendency to form coordination compounds. Just as pyridine and other azoles, isoxazoles coordinate with halogens and the salts of heavy metals, for example of cadmium,mercury,zinc. Such coordination... 

No direct nucleophilic substitution of the hydrogen atoms in the isoxazole nucleus a or y to the nitrogen is as yet known. Thus, the Chichibabin reaction fails in the isoxazole series because of the cleavage of the heterocyclic nucleus under these conditions. It is the lability of the isoxazole ring toward nucleophilic reagents that makes the chemical behavior of isoxazole fundamentally different from that of pyridine. 

Mention must also be made of an interesting reaction (103 —> 104) that makes use of the isoxazole nucleus of anthranil as a diene in the reaction with A-phenylmaleimide. This instance is of considerable interest, for it has proved impossible to introduce into the diene synthesis other derivatives with a noncondensed isoxazole ring. ... 

This group of reactions has already been reviewed by Quilico and Barnes. However, the important data recently published make it advisable to reassess the subject. In 1891 Claisen first gave an example of the cleavage of the isoxazole ring he treated 5-phenylisoxazole with dilute sodium hydroxide or sodium ethylate at room temperature,the reaction involving the cleavage of the 0—N bond to yield a y8-ketonitrile (106). 

In these compounds the following substituents can be present alkyl,alkenyl,aryl, halogen,sulfonic acid, amino, hydroxyalkyl, acyl, and carboxyl. The cleavages of 5,5 - (109) and 3,5 -diisoxazolyl (111) proceed similarly both isoxazole rings are cleaved in the former (109—> 110). ... 

To cleave the isoxazole ring, good results were also obtained by using other alcoholates as well as the recently suggested sodium amide, The latter is, however, hardly to be recommended as a general reagent. 

The opening of the isoxazole ring with a substituent at C-3 proceeds differently and the reaction can take various courses depending on the nature of the substituent. Besides sodium ethylate this reaction has been effected with sodium and potassium hydroxides in alcoholic or aqueous media (see, for instance, references 125 and 142). 

A nitro group in the 4-position markedly increases the instability of the isoxazole ring in alkaline medium. This effect is clearly demonstrated by 3,5-dime thy 1-4-nitroisoxazole. Whereas 3,5-dimethyl-isoxazole is not affected by alkali, its 4-nitro-derivative (134) is cleaved by 2% sodium hydroxide. The structure of the product was proved by its conversion into a triazole (135) with phenyl diazonium chloride, according to the original authors. ... 

The mechanism of the nucleophilic cleavage of the isoxazole nucleus can now be considered as well understood. The first stage of almost all variants of this reaction consists in the removal of the proton by the nucleophile from the unsubstituted carbon atom with the lowest electron density of the isoxazole ring, usually C-3 or C-5. Neutralization of the negative charge of the resulting isoxazolyl anion causes the... 

The preceding mechanism of the nucleophilic opening of the isoxazole ring is in accordance with the kinetic evidence of Pino... 

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