3-Methyl-5-phenylisoxazole

A characteristic feature of picolines and many azoles is the well-known ability of methyl (and corresponding methylene) groups to undergo condensation of the aldol, crotonic, and Michael type. This is especially pronounced in the quaternary salts of these heterocycles where it occurs under comparatively mild conditions. Such condensations are not unknown for alkylisoxazoles. Lampe and Smolinska were the first to describe the condensation of the quaternary alkyl iodides of 3,5-dimethyl- (96) and 3-methyl-5-phenylisoxazole with... 

Methyl-5-phenylisoxazole is reported to react in mixed acid to produce only the 4-nitrophenyl product, whereas 5-methyl-3-phenylisoxazole gives the 3-nitrophenyl and 4-nitrophenyl products (42G537 57JA467). 

Later work has shown that 3-methyl-5-phenylisoxazole is nitrated as the conjugate acid in mixed acid to give the 4-nitrophenyl product exclusively, whereas in nitric acid acetic anhydride, poor yields of 4-nitro-5-(4-nitro-phenyl)isoxazole are obtained as the only product. 

In another study of the nitration of 5-phenyl- and 3-methyl-5-phenylisox-azole the action of nitric acid sulfuric acid on 5-phenylisoxazoIe produced a 1 1 1 mixture of the ortho, meta, and para 5-(nitrophenyl) products with minor amounts of 4-nitro-5-(3-nitrophenyl)- and 4-nitro-5-(4-nitrophenyl)-dinitro products. The action of nitric acid acetic anhydride produced 4-nitro-5-phenylisoxazole as the major product with some nitrophenyl compounds as minor products. 3-Methyl-5-phenylisoxazole also gave a mixture of the ortho, meta, and para 5-(nitrophenyl) products when mixed acids were used, but no dinitro products were observed. The use of nitric acid acetic anhydride resulted in nitration at the 4-position of the isoxa-zole ring as the largely predominant product, with some phenyl ring substitution (89H1965). 

On subjection of 3-methyl-5-phenylisothiazole or 3-methyl-5-phenylisoxazole to lithiation conditions, competitive side-chain and C-4 deprotonation is observed, except when lithium j-propyl(cyclohexyl)amide (LICA) is used - this allows exclusive side-chain Uthiation. ... 

The iso)tazole ring is rather resistant to sulfonation. However, on prolonged heating with chlorosulfonic acid, 5-methyl-, 3-methyl- and 3,5-diraethyl-isoxazoles are converted into a mixture of the sulfonic acid and the corresponding sulfonyl chloride. The sulfonic acid group enters the 4-position even when other positions are available for substitution. The sulfonation of the parent isoxazole occurs only under more drastic conditions (20% oleum) than that of alkyl isoxazoles isoxazole-4-sulfonic acid is obtained in 17% yield. In the case of 5-phenylisoxazole (64), only the phenyl nucleus is sulfonated to yield a mixture of m-and p-arenesulfonic acid chlorides (65) and (66) in a 2 1 ratio (63AHC(2)365). 

The idea of employing the reaction of a nitroarene or nitroheterocycle with a mtinchnone to synthesize a fused pyrrole ring system has been developed by two groups. Nesi et al. (109) found that mtinchnone 38 reacts with 3-methyl-4-nitroisoxazole (196) and 4-nitro-3-phenylisoxazole (197) to give the corresponding 5//-pyrrolo[3,4-tf]isoxazoles 198 and 199, respectively, in good yield. Presumably loss of carbon dioxide in a retro-Diels-Alder reaction follows loss of nitrous acid. 

Talley JJ, Brown DL, Carter JS, Graneto MJ, Koboldt CM, Masferrer JL, Perkins WE, Rogers RS, Shaflfer AF, Zhang YY, Zweifel BS, and Seibert K (2000) 4-[5-Methyl-3-phenylisoxazol-4-yl]- benzenesulfonamide, valdecoxib a potent and selective inhibitor of COX-2. /. Med. Chem. 43, 775-777. 

Synthesis The acylation of 4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide (valdecoxib), with propionic anhydride in a solution of TEA and DMAP in tetrahydrofurane gives A/-(4-(5-methyl-3-phenylisoxazol-4-yl)phenylsulfonyl)propionamide, which is treated with NaOH in ethanol to give parecoxib sodium salt (Talley (Parmacia Corp.), 1996 2000b Sorbera, 2001b). 

Talley, J. J., Bertenshaw, S. R., Brown, D. L., Carter, J. S., Graneto, M. J., Kellogg, M. S., Koboldt, C. M., Yuan. J., Zhang, Y. Y., Seibert, K. N-[[(5-methyl-3-phenylisoxazol-4-yl)-phenyl]sulfonyl]propanamide, sodium salt, parecoxib sodium A potent and selective inhibitor of COX-2 for parenteral administration, J. Med. Chem. 2000b, 43, 1661-1663. 

Methyl-3-phenylisoxazole is nitrated as a conjugate acid at the meta position but as the free base at the para position of the phenyl group (79AHC(25)147). Phenyl groups attached to oxazole rings are nitrated or sulfonated in the para position, with relative reactivities of the phenyl groups in the order... 

Ethyl 2-(2-quinolinyl)-5-oxo-2,5-dihydroisoxazole-4-carboxylates (346) with aqueous sodium azide in tetrahydrofuran gave mixtures of ethyl 3-hydroxy-l-oxo-l//-pyrimido[l,2-a]quinoline-2-carboxylates (347) and quinoline derivatives (348-350) (95AJC1861). When the base-catalyzed rearrangement of 346 was carried out in 2-2.5 M aqueous sodium hydroxide for 30 min, ethyl 3-hydroxy-l-oxo-l//-pyrimido[l,2-a]quinoline-2-carbox-ylates (347, R = R2 = H, R1 = H, Me and R = H, R1 = Me, Ph, R2 = OMe) were obtained in 65-99% yields (89AJC2161 92AJC1825). Treatment of 2-(2-quinolinyl)-4-phenylisoxazol-5(2//)-one (351) with butyllithium and then with methyl iodide afforded 3-hydroxy-2-phenyl-l//-pyrimido[l,2-a]quinolin-l-one (352) (94AJC1673). 

Propionic acid, 2-bromo-3-(3-indolyl)-methyl ester rearrangement, 4, 279 Propionic acid, 3-(3,4-dimethyoxyphenyl)-dihydrocoumarin synthesis from, 3, 848 Propionic acid, indolyl-synthesis, 4, 232 Propionic acid, 3-(l-indolyl)-sodium salt pyrolysis, 4, 202 Propionic acid, 3-(3-indolyl)-intramolecular acylation, 4, 220, 221 Propionic acid, 3-phenoxy-chroman-4-one synthesis from, 3, 855 Propionic acid, 3-(3-phenylisoxazol-5-yl)-bromination, 6, 25... 

E) 5-Methyl-3-Phenyl-4-Isoxazolylpenicillin A solution of 4.43 grams of 5-methyl-3-phenylisoxazole-4-carbonyl chloride in 120 ml acetone was added... 

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