Isoxazoles bromination

Examples of neighboring group participation in isoxazole bromination have been reported. When the isoxazolylpropanol (80) was treated with bromine in pyridine, it gave the spiro (furan-2,5-isoxazole) (81) (74BAU2566). The corresponding propenoic acid gave 82 [76JCS(P1)1694], whereas a similar process accounts for the reaction of... 

Isoxazoles can be halogenated in the 4-position (63AHC(2)365). Ring bromination of oxazoles with bromine or NBS occurs preferentially at the 5-position and, if this is occupied, at the 4-position (74AHCI 17)99). Aminooxazoles are readily halogenated. 

A good general method for iodination or bromination of isoxazoles is to use iodine or bromine in concentrated nitric acid. For example, the iodination of 3,5-dimethylisoxazole (53) with iodine in nitric acid gave 4-iodo-3,5-dimethylisoxazole (79 X = I) in 85% yield (60DOK598). 

Electrophilic mercuration of isoxazoles parallels that of pyridine and other azole derivatives. The reaction of 3,5-disubstituted isoxazoles with raercury(II) acetate results in a very high yield of 4-acetoxymercury derivatives which can be converted into 4-broraoisoxazoles. Thus, the reaction of 5-phenylisoxazole (64) with mercury(II) acetate gave mercuriacetate (88) (in 90% yield), which after treatment with potassium bromide and bromine gave 4-bromo-5-phenylisoxazole (89) in 65% yield. The unsubstituted isoxazole, however, is oxidized under the same reaction conditions, giving mercury(I) salts. 

The reaction of a dibromochalcone with hydroxylamine hydrochloride in pyridine gave three products with the expected 2-isoxazoline product as the predominate compound. A ring bromination product and an isoxazole were also isolated (70UC796). The reaction of hydroxylamine with /S-thiosulfates of propiophenone at reflux produced 3-phenyl-2-isoxazo-line (455). At room temperature a bis-Michael product (456) was produced. The reaction with N -phenylhydroxylamine yielded a mono-Michael type product (457) (74CPB1990). 

Isoxazole, 3-anilino-4-nitroso-5-phenyI-thermolysis, 6, 417 Isoxazole, 3-anilino-5-phenyl-bromination, 6, 24 Isoxazole, 3-(p-anisyl)-5-phenyl-synthesis, 6, 63... 

Isoxazole, 3,5-dimethyl-4-(p-nitrophenyl)-bromination, 6, 51 Isoxazole, 3,5-dimethyl-4-vinyl-oxidation, 6, 27, 54 Isoxazole, diphenyl-mass spectra, 6, 6-7 Isoxazole, 3,4-diphenyl-... 

Isoxazole, 3-methoxymethyl-5-methyl-oxidation, 6, 27 Isoxazole, methyl-bromination, S, 88 homolytic halogenation, 6, 51-52 potentiometry, 6, 10 Isoxazole, 3-methyl-basicity, 6, 20 halogenation, 6, 24 hydrogen exchange, 6, 21 sulfonation, 6, 24 synthesis, 6, 83 Isoxazole, 4-methyl-synthesis, 6, 83 Isoxazole, 5-methyl-basicity, 6, 20... 

Isoxazole, 4-methyI-3,5-diphenyI-bromination, 6, 51 Isoxazole, 3-methyI-4-nitro-5-styryI-photolysis, 6, 14 Isoxazole, 3-methyI-5-phenyl-copper complexes... 

Isoxazol-5-ones can exist in three different types of structures, cf. 45- 7 (R = H). Early investigators assigned structures to these compounds on the basis of unreliable chemical evidence thus the NH structure 47 was favored because the silver salt of 3-phenyl-isoxazol-5-one reacts with methyl iodide to give a product which was incorrectly (see reference 44) formulated as the iV-incthyl derivatives (cf. also reference 46). Bromine titration data led to assignment of an incorrect structure to 3,4-diphcnylisoxazol-5-one cf. article I (Volume 1), Section II,A. Comparison of the dipole moments of 3-phenyIisoxazol-5-one with those of the methyl derivatives 45 (R = Me) and 46... 

Halogenation of isoxazoles was also first performed with alkyl homologs.When treated with chlorine or bromine and exposed to sunlight or heated, the isoxazole nucleus undergoes halogenation in the 4-position (63 64). 

More recently Pino et al. have treated isoxazole with bromine without adding iron and obtained 4-bromoisoxazole in a 42% yield. The stepwise bromination of 5,5 - and 3,3 -diisoxazol3ds gives higher yields (70-80%). ... 

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... 

The isoxazole nucleus is also halogenated in the 4-position by N-bromosuccinimide provided there is no substituent in this position. This reaction does not proceed homolytically, as might have been expected, and appears to represent a simple electrophilic substitution by the bromine cation. Similar cases have been previously described for the bromination of certain aromatic compounds with A -bromo-succinimide. ... 

The 3-position of the isoxazole ring was substituted when 2-aryloxaz-olo[3,2-/]xanthines (185 X = O) were treated with bromine in acetic acid (90CHE1164). The analogous imidazoxanthines (185 X = NMe)also gave 3-bromo derivatives in 75-99% yields (82MI2). 

Chromone-3-carbonitrile oxide undergoes cycloaddition reactions with phenyl-and diphenylacetylenes to give isoxazoles 205 (R = H, Ph). The nitrile oxide is obtained from 3-formylchromone oxime by bromination and subsequent dehy-drobromination (175). 

This method gives a somewhat tower yield than method 1. Dissolve 14.1 g l-nitro-3-butanone in 30 ml glacial acetic acid and heat to 35° add slowly with stirring to a solution of 5.3 g bromine in 10 ml glacial acetic acid. Evaporate in vacuum, dissolve residue in ether and wash with water, NaHC03 and water. Dry and evaporate in vacuum the ether (can distill 84/2) to get 6 g 1 -nitro-4-Br-3-butanone (1). Add 4.4 g (I) to 25 ml 48% HBr and reflux three hours. Add 50 ml water and steam distill. Neutralize the distillate with K carbonate and extract with ether. Dry and evaporate the extract (can distill 128/20) to get 5.6 g 2-Br-5-Br-methyl-isoxazole... 

Kinetic studies on alkyl- and phenyl-isoxazoles in 85% acetic acid at 150°C have shown that isoxazoles are 100-1000 times more reactive than benzene. The relative 4-bromination rates for 5-phenyl- 3,4-diphenyl- ... 

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