Isoxazole ring cleavage

In this sequence, a nitrile oxide addition to an enol ether then elimination formed the isoxazole. Ring cleavage of the isoxazole accompanying decarboxylation, showed how the heterocycle can serve as a synthon for an a-cyano aldehyde. 

Reactions of isoxazoles are less prolific due to facile isoxazole ring cleavage. Isoxazoles can be treated with V-bromosuccinimide to brominate the C4-position of the isoxazole. In contrast to oxazoles, when an isoxazole engages in a [4 + 2] cycloaddition, the isoxazole acts as a dienophile, not a diene. ... 

Irradiation of 3,5-disubstituted isoxazoles in alcoholic solvents gave reaction products such as acetals incorporating the reaction solvent. The use of triethylamine in acetonitrile media produced ketene-aminals by reductive ring cleavage. The reductive ring cleavage product was also obtained by irradiation of the isoxazole in alcohol in the presence of copper(II) salts (Scheme 3) (76JCS(P1)783). 

Nucleophilic replacement of hydrogen on an isoxazole is unknown and replacement of substituents is discussed in Section 4.16.3.3. In this series it is difficult to identify reactions involving addition to the ring as, in many instances, they are rapidly followed by elimination or ring cleavage sequences. 

The importance of this group of reactions to the chemistry of isoxazoles is shown by the considerable amount of effort expended on this topic (63AHC(2)365,79AHC(25)147). The lability of the isoxazole nucleus towards nucleophiles and bases distinguishes this heterocycle from other azoles. The conditions which lead to ring cleavage are quite varied and depend on the position and the nature of the substituents. 

Unsubstituted 3-alkyl- or 3-aryl-isoxazoles undergo ring cleavage reactions under more vigorous conditions. In these substrates the deprotonation of the H-5 proton is concurrent with fission of the N—O and C(3)—-C(4) bonds, giving a nitrile and an ethynolate anion. The latter is usually hydrolyzed on work-up to a carboxylic acid, but can be trapped at low temperature. As shown by Scheme 33, such reactions could provide useful syntheses of ketenes and /3-lactones (79LA219). 

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). 

Furoxans, bis[(acetoxyalkyl)carbonyl]-synthesis, 6, 421 Furoxans, bisarylsulfonyl-synthesis, 6, 423 Furoxans, bis(dialkylamino)-synthesis, 6, 414 Furoxans, butylhexynyl-synthesis, 6, 423 Furoxans, decamethylenering cleavage, 6, 405 Furoxans, diacyl-thermolysis, 6, 81 synthesis, 6, 442 Furoxans, diadamant-1-yl-ring cleavage, 6, 404 Furoxans, dialkoxycarbonyl-synthesis, 6, 423 Furoxans, dialkyl-synthesis, 6, 423 Furoxans, diaryl-ozonolysis, 6, 405 Furoxans, diaroyl-isoxazoles from, 6, 82 Furoxans, dibenzoyl-synthesis, 6, 423 Furoxans, diethoxycarbonyl-synthesis, 6, 423... 

Isoxazole, 5-(p-anisyl)-3-phenyI-synthesis, 6, 63 Isoxazole, 4-aroyl-3,5-diaryI-synthesis, 6, 71 Isoxazole, aryl-UV spectra, 6, 4 Isoxazole, 3-aryl-5-unsubstituted ring cleavage, 6, 30 Isoxazole, 5-aryl-3-chloro-reactions, 5, 104 Isoxazole, 3-aryI-4-formyl-synthesis, 6, 84 Isoxazole, 3-aryl-5-methoxy-thermal isomerization, 6, 15 Isoxazole, 3-aryl-5-methyl-synthesis, 6, 63, 84 Isoxazole, 4-azorearrangement, 5, 719... 

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 characteristic peculiarity of isoxazole derivatives is the relatively facile ring cleavage under suitable conditions, and this is a severe limitation on reactions of substitution in the isoxazole series. The best, though as yet inadequately, studied reactions, are the... 

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... 

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. 

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). ... 

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... 

Decarboxylation of isoxazole-3-carboxylic acids is related to the nucleophilic cleavage of the isoxazole ring as far as the nature of the reaction products is concerned. It occurs at temperatures above 200°C and is accompanied by the cleavage of the nitrogen-oxygen bond of the heterocyclic ring to yield a j8-ketonitrile. It was first reported by Claisen with 5-methyl- and 5-phenyl-isoxazole-3-carboxylic acids (153- 154).Under the reaction conditions, j8-ketonitriles condense... 

Claisen first observed cleavage of the isoxazole ring by the action of reducing agents. He isolated acetylacetone imine (162) by re-... 

The cleavage of the isoxazole ring by organomagnesium compounds may proceed by either one or both of two alternative mechanisms. Magnesium subhalides produced during the associated reaction may act as reducing agents as proved in specific cases.Another possibility is that the reduction involves a six-membered cyclic complex (171). 

The isoxazoline ring is also readily cleaved by such reducing agents as do not affect the isoxazole ring. Thus, for example, the treatment of isoxazolines (186) with LiAlHj proceeds with a smooth cleavage of the heterocyclic ring to form substituted 3-amino-propan->l-ols... 

The ring cleavage of 3-aryl-2-substituted-2//-azirines by molybdenum hexacarbonyl has been described earlier in regard to the synthesis of pyrroles, pyrazoles and isoxazoles. In contrast to this behavior, analogous reactions of 2-unsubstituted derivatives lead to the formation of mixtures of 2,5-diarylpyrazines (139) and isomeric 3,6- and 1,6-dihydropyrazine derivatives (140,141) (Scheme 163).47,53 It is possible that the pyrazine products are formed by an intermolecular nitrene mechanism akin to the intramolecular processes described earlier (see Scheme 22 in Section IV,A,1). 

The same type of ring cleavage occurs in the benz[d]isoxazole series. Thus, benz[d]isoxazole is cleaved by aqueous alkali to give the anion of 2-hydroxybenzonitrile (27) (73JOC2294). As for the monocyclic systems, the reaction can be represented as a concerted E2 elimination since there is a substantial kinetic isotope effect. Salts of benz[d]isoxazole-3-carboxylic adds are also cleaved, with loss of carbon dioxide, in a concerted manner (72JOC2498 75JA7305). 

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