3-Chloro isoxazoles, reaction with

In theory, three isoxazolines are capable of existence 2-isoxazoline (2), 3-isoxazoline and 4-isoxazoline. The position of the double bond may also be designated by the use of the prefix A with an appropriate numerical superscript. Of these only the 2-isoxazolines have been investigated in any detail. The preparation of the first isoxazoline, 3,5-diphenyl-2-isoxazoline, from the reaction of )3-chloro-)3-phenylpropiophenone with hydroxylamine was reported in 1895 (1895CB957). Two major syntheses of 2-isoxazolines are the cycloaddition of nitrile A-oxides to alkenes and the reaction of a,/3-unsaturated ketones with hydroxylamine. Since 2-isoxazolines are readily oxidized to isoxazoles and possess some of the unique properties of isoxazoles, they also serve as key intermediates for the synthesis of other heterocycles and natural products. 

Isoxazole, 3-acetyl-4-chloro-5-methyl-oxidation, 6, 27, 53 Isoxazole, 3-acetyl-4,5-dimethyl-oxidation, 6, 27, 53 Isoxazole, 5-acetyl-3-methoxy-reactions, 6, 53 Isoxazole, 3-acyl-furazans from, 6, 417 nucleophilic attack, S, 93 reactions with bases, 6, 30... 

Structure 159 has been erroneously assigned to the product of the reaction between 3-benzoyl-3-methyl-47/-isoxazol-5-one 157 and SOCI2 (53GA192). In reality, the compound has the structure of isoxazolone 158 (74HCA1934). The reactions of chloro compound 158 with ammonia, phenylenediamine, and phenylhydrazine produce enamine 160, isoxazolo[5,4-e]1.4-diazepine 161, and isoxazolo[5,4-c]pyrazole 162, respectively (59ZOB3446). The formation of 161 and 162 represents examples of substitution at the keto group in position 5 (Scheme 71). 

In contrast to the 3-substituted products above, 4-chloro-, 4-bromo- and 4-iodo-isoxazoles are readily prepared by direct halogenation of the corresponding isoxazoles, from 4-isoxazolediazonium salts by the Sandmeyer reaction, or by reaction of hydroxylamine with a-halo- 8-dicarbonyl compounds (62HC(l7)l, p. 66, 63AHC(2)365). 3,5-Bis(dimethyl-amino)-4-fluoroisoxazole has been synthesized by reaction of (Me2NCO)2CHF with hydroxylamine (78BSB391). 

Chloro- and 5-bromo-isoxazoles have been prepared by reaction of 5-isoxazolones with the appropriate phosphoryl halide (77JMC934). 3-Phenyl-5-trifluoromethylisoxazole has been synthesized by reaction of benzonitrile iV-oxide with 3,3,3-trifluoropropyne (77JMC934). 

Sprio et al. reported the preparation of 6-acetylimidazo[2,l-Z)]thiazoles derivatives 57 (74JHC91). TTie synthesis involves substituted 4-(2-thiazo-lyl)aminoisoxazoles 56, which were obtained in good yield by the reaction of N-(3,5-dimethylisoxazol-4-yl) thiourea 55 with a-chloro ketones. Subsequent isoxazole ring opening led to intermediates which readily underwent cyclization by refluxing in acetic acid or ethanol/hydrochloric acid. 

Thermal decomposition of 3-azido-2-formylfuran, -thiophene, and -selenoles has also been used to prepare furo[3,2-c]isoxazole (97), thieno[3,2-c]isoxazole (4), and selenolo[3,2-c]isoxazoles (98) (Equation (27)) <76CS165>. In contrast, some azido ketones eliminate nitrogen at ambient temperature and cyclize as exemplified in the reactions of 2-chloro-3-acetylindole (99) (Equation (28)) and 3-chloro-2-benzoylbenzothiophene dioxide (101) (Equation (29)) with sodium azide (78CB1521, 92JOC2127). 

The cycloaddition of 1-halogeno-l-nitroethene with nitrile /V-oxides leads to the nitro derivatives of isoxazole [520-524], Thus, for example, the reaction of equimolar amounts of 1-chloro- or 1-bromonitroethene with benzonitrile /V-oxidc gave 5-nitro-3-phenylisoxazole [520], The same compound is formed in the reaction of nitrile /V-oxides with ra .s-2-chloro-1 -nitrocthcnc [485], The formation of nitroisoxazoles in these reactions can be explained by the fact that the initial products from the cycloaddition of halogenonitro-A2-isoxazolines more readily eliminate a molecule of hydrogen halide and not HNOr... 

Indoles have been prepared from reactions of o-aminophenylketones with reactive , or stable " arsonium ylides. Oxo-stabilized ylides reacted with 2-chloro-oximes to give trans-5-acyl-A -isoxazolines, and isoxazoles have been obtained from reactive arsonium ylides and a-isonitrosoketones, and from triphenylarsonium methylide and nitrile oxides The latter ylide reacts similarly with nitrile imines to give pyrazoles. With triphenylarsonium benzylides and benzoylylides,benzene diazonium salts give 1,3,4,6-substituted 1,4-dihydro-1,2,4,5-tetrazines in a reaction in which initial coupling of the reagents is followed by a dimerisation. ... 

Numerous examples of nucleophilic substitution in isoxazoles have been reported these reactions have been used for the preparation of AI (Section IV.B.2). A strong electron-donating effect of the amino group hampers the nucleophilic substitution, which is rarely observed in AI. Treatment of 5-chloro-4-AI 1 with the lithium salt of 2-aminoethanethiol gave 4-AI 2 (89MI1) (Scheme 1). 

Reactions of Isoxazoles. The kinetics of the isoxazole azirine rearrangement (336) -> (337) and those of the isoxazole oxazole transformation (338) (339) have been determinedPalladium(II) chloride-triphenyl-phosphine catalyses the cross-coupling of 4-iodo-3,5-dimethylisoxazole with styrene to yield the trans- compound (340). 3,5-Dimethylisoxazole can be lithiated in two stages, first at the 5-methyl group and then at the 3-methyl group. Isoxazoles add hypochlorous acid to form 4-chloro-2,3-dihydro-... 

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