5-methylisoxazol

AMINESBYREDUCTION] (Vol2) a-Amino-3-hydroxy-5-methylisoxazole-4-propionate... 

Modification of functional groups incorporated in a heterocycle is possible via ylide reactions. The 5-methylisoxazole (578) on reaction with n-butyllithium and methanesulfenyl... 

The enthalpy of combustion of isoxazole was only determined several years ago (78MI41615). For isoxazole, AH°c (298.15 K) =-(1649.85 0.50) kJ mol , from which the entropy of formation in the gas phase was derived as AH tig) = 78.50 0.54 kJ moF. The enthalpies of combustion of 3-amino-5-methylisoxazole and 5-amino-3,4-dimethyl-isoxazole have also been determined (73MI41606). 

Properly substituted isoxazolecarboxylic acids can be converted into esters, acid halides, amides and hydrazides, and reduced by lithium aluminum hydride to alcohols. For example, 3-methoxyisoxazole-5-carboxylic acid (212) reacted with thionyl chloride in DMF to give the acid chloride (213) (74ACS(B)636). Ethyl 3-ethyl-5-methylisoxazole-4-carboxylate (214) was reduced with LAH to give 3-ethyl-4-hydroxymethyl-5-methylisoxazole (215) (7308(53)70). 

Alkyl(or 3-aryl)-5-methylisoxazoles (306) were prepared by the regiospecific reaction of phosphonium salts (304) with hydroxylamine, followed by the treatment of the resulting isoxazole-containing phosphonium salts (305) with aqueous sodium hydroxide (80CB2852). 

Methylisoxazole (297 R = Me) and its homologs can be synthesized by reaction of hydroxylamine hydrochloride with 1-alkyl-3-dimethylamino-2-propen-l-one (296) (54IZV47), the anilino derivatives of acetoacetaldehyde (47G556), 3-dimethyl-aminomethylene-l-propyne (equation 7) (69ZOR1179) and the /3-ketoaldehyde (293) (66JOC3193). 

The reaction of appropriate 1,3-diketones (302) with hydroxylamine hydrochloride in pyridine (79MI41601) has been reported to result in a regiospecific synthesis of 3-alkyl-5-arylisoxazoles, as has the reaction of an a -bromoenone (307) with hydroxylamine hydrochloride in ethanol in the presence of potassium carbonate (81H(16)145). Regiospecific syntheses of 5-alkyl-3-phenylisoxazoles also result from the reaction of an a-bromoenone (307) with hydroxylamine in the presence of sodium ethoxide (81H(16)145). 3-Aryl-5-methylisoxazoles were prepared from phosphonium salts (304) and hydroxylamine (80CB2852). 

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... 

The irradiation of 3-phenyl-4-acetyl-5-methylisoxazole (49) gave the isomeric oxazole (50) (Scheme 22) (75JA6484 76HCA2074). The reaction can involve the formation of the biradical intermediate starting from the triplet state, in agreement... 

With hydroxylamine, aminobutenones yield exclusively 5-methylisoxazole (266), evidently via the intermediates 264 and 265 (69ZOR223). 

The chlorination of 3-isopropenyl-5-methylisoxazole and of dimethyl-(5-methylisoxazol-3-yl)carbinoP and, recently, the bromina-tion of 5- and 3-phenylisoxazoles and unsubstituted isoxazole have also been studied. Reaction is effected by heating in the presence of powdered iron and gives 4-bromoisoxazoles (63 64, Hal Br R,R = H, Ph). 

Under more vigorous conditions such as prolonged heating, the degradation of these isoxazoles is also effected by weaker nucleophilic reagents. Thus, 5-methylisoxazole (113) on treatment with ammonia is partly converted into cyanoacetoneimine (112) and when refluxed with phenylhydrazine yields l-phenyl-3-methyl-5-aminopyrazole (115), in the latter case undoubtedly via the intermediate formation of cyanoacetone (114). ... 

It has already been mentioned that 5-methylisoxazole is converted into a pyrazole derivative by phenylhydrazine. All 4-nitroisoxazoles undergo this same reaction (136— 137)/° 5,5 -Dimethyl-4,4 -dinitro-3,3 -diisoxazolyI reacts similarly... 

Acetylisoxazoles are converted to carboxylic acids by boiling with dilute nitric acid. This method allowed the development of a one-stage preparative method for 5-methylisoxazole-3-carboxylic acid (191) starting with acetonylacetone (190). ... 

Dichlorophenyl)-5-methylisoxazole-4carbonyl chloride Sodium bicarbonate... 

A suspension of 6-aminopenicillanic acid (36.4 grams) in water was adjusted to pH 7.2 by the addition of N aqueous sodium hydroxide and the resulting solution was treated with a solution of 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride (46.1 grams) in isobutyl methyl ketone. The mixture was stirred vigorously for hours and then filtered through Dicalite. The layers were separated and the isobutyl methyl ketone layer was shaken with saturated brine. Then, precipitation of the sodium salt only took place after dilution of the mixture with ether. In this way there was obtained 60.7 grams of the penicillin sodium salt having a purity of 88% as determined by alkalimetric assay. 

A mixture of 40.5 g (0.15 mol) of 3-carbethoxy-4-hydroxy-2-methyl-2H-1.2-benzothiazine 1,1 -dioxide, 20.6 g (0.21 mol) of 3-amino-5-methylisoxazole, and 2,500 ml of xylene was refluxed for 24 hours in a Soxhiet apparatus, the thimble of which contained 60 g of Linde type 4A molecular sieve. The mixture was cooled to 25°C and the resulting crystalline precipitate was collected and washed with ether to give 44 g of crude product. Recrystallization from 1,6(X) ml of 1,4-dioxan gave 34.7 g of material, MP 265°C to 271°C dec. 

Preparation of 3-Amino-5-Methylisox3Zo/e 1.7 grams of ethyl 5-methylisoxa2ole-3-car-bamate was heated on a boiling water-bath with 5 cc of a 10% aqueous sodium hydroxide solution for 8 hours, then the reaction mixture was extracted several times with ether or benzene and the extract was cooled followed by the removal of the solvent and drying. The residue was solidified after a while and gave prismatic crystals, melting point 61° to 62°C, of 3-amino-5-methylisoxazole by recrystallization from benzene. 

Preparation of S-Acetylsulfanilamido-S-Methy/isoxazole 0.9 gram of 3-amino-5-methyl-isoxazole in 5 cc of pyridine was allowed to react with 2.0 grams of acetylsulfanil chloride accompanied by the generation of heat. After about one hour, water was added to the reaction mixture and the crystal precipitated out was recrystallized from alcohol to give 2.5 grams of 3-acetylsulfanilamido-5-methylisoxazole, melting point (decomposition) 220° to 221°C. 

Preparation of J-Sulfanilamido-S-Methylisoxazole 2 grams of 3-acetylsulfanilamido-5-methylisoxazole was heated with 10 cc of an aqueous sodium hydroxide solution on a water-bath for one hour and after cooling the reactant was acidified by addition of acetic acid. The precipitate thus formed was recrystallized from dilute alcohol to give 15 grams of colorless prisms of 3-sulfanilamido-5-methylisoxazole, melting point 167°C. 

Dichloropheny )-5-methylisoxazole-4-carbonyl chloride icioxacillln sodium... 

Both of the 4,5-tran.v-diaslereomers of 4,5-dihydro-4-(4-methoxyphenyl)-5-methyl-3-[(7 )-(4-methylphenylsulfinyl)methyl]isoxazole (24) show excellent stereoselection in reactions with aldehydes. Despite the bulky substituents at the 4,5-dihydroisoxazole nucleus, the stereochemical outcome of the reaction is controlled by the sulfoxide stereogenicity. The pairs of 4,5-dihydro-3-(2-hydroxyalkyl)-4-(4-methoxyphenyl)-5-methylisoxazoles, obtained by desulfurization of the corresponding aldol adducts, have the same configuration at the hydroxy-substituted carbon (C-2 ) and opposite configuration in the 4- and 5-positions of the dihydroisoxazole ring24. 

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