Isoxazoles isomerization

Pyrazoles, isoxazoles and isothiazoles with a hydroxyl group in the 3-position (491 Z = NR, O, S) could isomerize to 3-azolinones (492). However, these compounds behave as true hydroxy derivatives and show phenolic properties. They give an intense violet color with iron(III) chloride and form a salt (493) with sodium hydroxide which can be O-alkylated by alkyl halides (to give 494 R = alkyl) and acylated by acid chlorides (to give 494 R = acyl). 

Scheme 4 also represents the classical route to isoxazoles, first studied in 1888 by Claisen and his coworkers (1888CB1149). Reaction of a 1,3-diketone with hydroxylamine gives, via the isolable monoxime (108) and the 4-hydroxyisoxazole (109), the isoxazole (110). Unsym-metrical 1,3-diketones result in both possible isomers (110) and (111), but the ratio of the isomeric products can be controlled by the right combination of the 1,3-dicarbonyl component and the reaction conditions used. These important considerations are described in Chapter 4.16, along with the variations possible in the 1,3-dicarbonyl component designed to yield diverse substituents in the resultant isoxazole. 

Isoxazoles largely undergo photochemical isomerization to azirines, which sometimes undergo a further thermal or photochemical reaction. 3,4,5-Triarylisoxazole (529) formed the 2,3-diphenyl-3-benzoylazirine (530) which underwent further reaction to the oxazole (531) 72JA1199). A small amount of the corresponding benzoyl ketenimine was also obtained. 

Benzisoxazoles undergo electrophilic substitution in the benzo ring, but with nucleophiles the reaction occurs in the isoxazole moiety, often leading to salicylonitriles with 3-unsubstituted systems. The isomeric 2,1-benzisoxazoles are characterized by the ease with which they may be converted into other heterocyclic systems. 

Nitro groups in the homocyclic ring of 1,2-benzisoxazoles have been reduced to the corresponding amino groups without opening of the isoxazole nucleus. SnCU/HCl and Adam s catalyst/H2 have both proved effective in this respect. Similar behavior was observed for nitro groups in the isomeric 2,1-benzisoxazoles (67AHC(8)277,pp.295,33l). 

It was soon found that the reaction of unsymmetrtcal 1,3-diketones (290) or their derivatives with hydroxylamine results in both possible isomeric isoxazoles (291) and (292), a complication which not only reduces the yield of desired product but also often leads to separation problems, particularly when R and R are similar. However, the reaction does give one isomer, or predominantly one isomer, if the right combination of the CCC... 

To synthesize isomeric 3-substituted isoxazoles (301) the reaction of ethylene acetals of )3-ketoaldehydes (300) (readily available from -chlorovinyl ketones (57IZV949)) with hydroxylamine was employed. Owing to the comparative stability of the dioxolane group, this reaction gave exclusively 3-substituted isoxazoles (301) (60ZOB954). The use of noncy-clic, alkyl S-ketoacetals in this reaction resulted in a mixture of 3- and 5-substituted isoxazoles (55AG395). 

The reaction of methyl acetylpyruvate (312) with hydroxylamine hydrochloride gave the 3-carboxylate (313) in 76% yield together with traces of the isomeric 5-carboxylate (314) (78MIP41600). However, the sodium salt (315) of acetylpyruvic acid resulted in 3-methyl-isoxazole-5-carboxylic acid (316) as the major product. 

The nucleophilic attack of hydroxylamine at the 5-position of 4-trifluoroacetyloxazoles (414) led to a mixture of stereoisomeric isoxazolines (415). Dehydration of these isomeric isoxazolines (415) in the presence of trifluoroacetic anhydride gave isoxazoles (416) in good yields (76JHC825). 

Among the three isomeric parent isoxazolethiols (C3H3NOS) only isoxazole-3-thiol has been reported recently (80CPB552). 

The conversion of small rings to smaller ones, without loss, is not common. 3-Chloroazetidine isomerizes reversibly to 2-chloromethylaziridine (Section 5.09.2.2.5). Flash vacuum pyrolysis can convert isoxazoles to azirines (Section 5.04.4.3). More common is the isomerization of medium-sized, i.e. five- or six-membered rings, e.g. certain succinimides (Scheme 23) (81JOC27) to azetidinediones, or bicyclic 1,2-dioxetanes to bis-oxiranes (Section 5.05.4.3.2). 

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... 

A. Isomerization of Isoxazoles Bearing Electron-Donating Groups. 60... 

In the photochemical isomerization of isoxazoles, we have evidence for the presence of the azirine as the intermediate of this reaction. The azirine is stable and it is the actual first photoproduct of the reaction, as in the reaction of r-butylfuran derivatives. The fact that it is able to interconvert both photochemically and thermally into the oxazole could be an accident. In the case of 3,5-diphenylisoxazole, the cleavage of the O—N bond should be nearly concerted with N—C4 bond formation (8IBCJ1293) nevertheless, the formation of the biradical intermediate cannot be excluded. The results of calculations are in agreement with the formation of the azirine [9911(50)1115]. The excited singlet state can convert into a Dewar isomer or into the triplet state. The conversion into the triplet state is favored, allowing the formation of the biradical intermediate. The same results [99H(50)1115] were obtained using as substrate 3-phenyl-5-methylisoxazole (68ACR353) and... 

Some data were obtained from the photochemical isomerization of amino-isoxazoles. 5-Aminoisoxazoles gave the corresponding azirine (Scheme 21) [70JCS(C)1825] when a4-carboethoxy-substituted derivative was used, no azirine was isolated and the oxazole was the only product obtained (Scheme 21) (72CB748). The azirine intermediate was not observed upon irradiating 3-amino derivatives [91H(32)1765]. 

Toward a unitary description of the photochemical isomerization of furan, thiophene, pyrrole, isoxazole, imidazole, andpyrazole derivatives 99H(50)1115. 

Further work by Adembri et al. describes the irradiation of 5-hydrazino-isoxazoles 291a-b under nitrogen, which gives a mixture of products analogous to that obtained by thermal isomerization 5-methylaminopyrazol-3-ones 292a-b, 4-aminopyrazol-3-ones 293a-b, and l,2,4-triazin-6-ones 294 -b (78TL4439). 

With hydroxylamine, diphenylbuta-l,3-diyne gives the isoxazole 30, isomeric to the isoxazole 32 obtained from dicarbonyl compound 31 and hydroxylamine (69JOC999). 

Alkoxybutenones in the same reaction give the two isomeric isoxazoles 266 and 271 i.e., along with the intermediates 267 and 268, the formation of intermediates 269 and 270 takes place (70ZOR2371). 

Though not extensively proven, the reaction path leading to only one of the possible isomers is peculiar to this synthesis of 4-chloroisoxazoles. The not infrequent formation of a mixture of two isomeric 3,5-disubstituted isoxazoles, which are difficult to separate, is recognized as one of the chief disadvantages of the use of -diketones to synthesize isoxazoles. 

Several reactions giving rise to hydroxy- and amino-isoxazoles have also been investigated. Thus the reaction of alkoxymethylene-cyanoacetates and hydroxylamine leading to 5-amino- or 5-hydroxy-isoxazoles proved to be rather useful.It is of particular interest that, by changing the reaction conditions, Bauer and Nambury succeeded in obtaining isomeric aminoisoxazolones (24 25 26). It is also possible to prepare isoxazol-3-ones from some /S-ketoesters. ... 

Isomeric 3,5-disubstituted isoxazoles can be prepared from vinylogous azolides and hydroxylamine hydrochloride. 1391 In this reaction the ratio of the two isomers A and B formed can be controlled by the nature of the base ... 

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). 

Allenes add nitrile oxides either to one or two double bonds. For mono- and 1,1-disubstituted allenes, relative activity of the two bonds depends on the nature of substituents. The reaction (Scheme 1.18) of N-propadienylanilines 54 with 3,5-dichloro-2,4,6-trimethylbenzonitrile oxide proceeds site- and regioselectively to give 5-substituted 4-methylene-4,5-dihydroisoxazoles 55, which add a second molecule of nitrile oxide to afford 4,5/-spirobi-(4,5-dihydroisoxazoles) 56. Dihy-droisoxazoles 55 isomerize to 4-(2-aminobenzyl)isoxazoles 57 via a Claisen-type rearrangement (224). 

Oxidation of (alkenylthio)thiophenecarboxaldehyde oxime 350 (R = allyl) by NaOCl gives the nitrile oxide, which cyclizes to thieno[2,3-h]thiocino[4,5-c] isoxazole 351. However, isomeric 350 (R = isopropenyl), under the same conditions, is converted to the unusual product, thieno 2,3-/ thiocin 352. In both reactions, cyclodimerization products of nitrile oxides are also obtained. Structures of compounds 350 (R = isopropenyl) and 352 have been studied by X-ray diffraction analysis (411). 

Nitrile oxides also undergo [3 + 2]-cydoaddition with allenes. As shown below, a variety of products were formed depending on the substituents of both nitrile oxide and allene [72b, 79]. The cycloadduct 80 was slowly converted to the isomeric isoxazole 81 in the presence of ZnCl2 via a sigmatropic rearrangement [79a]. 

Dioximes are known to generate isoxazoles and related compounds when oxidized with IBTA. However, these reactions are of limited use because of formation of side products. For example, oxidation of dioximes of /B-diketones 159 gives rise to a mixture of 3,5-disubstituted oxazoles 160 and pyrazole-di-N-oxides 161 (82MI1). In another case, oxidation of dioximes 162 affords a mixture of the isomeric dihydroisoxazolo-isoxazoles 163 and pyridazine dioxides 164 (76S837 79JOC3524 82MI1). 

Hydrogenated isoxazole derivatives were obtained by single electron transfer (SET) cyclization of /9,y-unsaturated oximes , by thermal [4- -2] cycloaddition of aldox-imes or ketoximes to conventional dienophiles or isomerization/cyclization of an ortho halogeno or nitro-substituted amidoximes. Preparation of 1,4-disubstituted 3-hydroximino-2-nitro-l-butenes and their oxidative cyclization to 4-nitroisoxazoles are reported " . Synthesis of fluorine-containing substituted isoxazolidines as well as isoxazoles by ultrasonic methods has been also described. 

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