Isoxazole 5-methyl-3-phenyl

It is only recently that the chloromethylation reaction, well known in the benzene series, has been extended to isoxazoles. It has been thereby found that this reaction results in 4-chloromethyl derivatives (69), their yield decreasing as follows 5-phenyl > 3,5-dimethyl > 5-methyl > 3-methyl isoxazoles > isoxazole. To prove the position of the chloromethyl group these compounds were oxidized to the known isoxazole-4-carboxylic acids (70). It is especially noteworthy that pyridine and its homologs do not undergo chloromethylation. 

Despite the weak basicity of isoxazoles, complexes of the parent methyl and phenyl derivatives with numerous metal ions such as copper, zinc, cobalt, etc. have been described (79AHC(25) 147). Many transition metal cations form complexes with Imidazoles the coordination number is four to six (70AHC(12)103). The chemistry of pyrazole complexes has been especially well studied and coordination compounds are known with thlazoles and 1,2,4-triazoles. Tetrazole anions also form good ligands for heavy metals (77AHC(21)323). 

Methyl groups on C-linked phenyl attached to oxazoles, isoxazoles and oxadiazoles react with benzylidineaniline to give stilbene derivatives (Scheme 51) <78AHC(23)l7l). 

Although isoxazoles are comparatively weak electron donors, complexes with numerous metal ions, notable metal(II) ions, have been reported. The ligands include isoxazole and its methyl, phenyl, amino and hydroxy derivatives. They are listed with references in Table 5. 

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). 

Nitrones or aci-nitro esters react with alkenes to give in some cases A/-substituted isoxazolidines and in others 2-isoxazolines. When the intermediate isoxazolidines were observed, a number of procedures transformed them into the 2-isoxazolines. Acrylonitrile and phenyl rzcf-nitrone esters produced an A/-methoxyisoxazolidine. Treatment with acid generated a 2-isoxazole while treatment with base generated an oxazine (Scheme 118) (68ZOR236). When an ethoxycarbonyl nitrone ester was reacted with alkenes, no intermediate isoxazolidine was observed, only A -isoxazolines. Other aci-mtro methyl esters used are shown in Scheme 118 and these generate IV-methoxyisoxazolidines or A -isoxazolines which can be further transformed (72MI41605). 

Isoxazole-4-carbaldehyde, 6, 84 Isoxazole-4-carbaldehyde, 5-methyl-3-phenyl-oxidation, 6, 27, 53 Isoxazole-5-carbaldehyde synthesis, 6, 84 Isoxazole-3-carboxylic acid esters... 

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... 

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). ... 

Decarboxylation of isoxazole-3-carboxylic acids is related to the nucleophilic cleavage of the isoxazole ring as far as the nature of the reaction products is concerned. It occurs at temperatures above 200°C and is accompanied by the cleavage of the nitrogen-oxygen bond of the heterocyclic ring to yield a j8-ketonitrile. It was first reported by Claisen with 5-methyl- and 5-phenyl-isoxazole-3-carboxylic acids (153- 154).Under the reaction conditions, j8-ketonitriles condense... 

The product has the following spectral properties infrared (KBr) cm.-1 3103 and 3006 (aromatic C—H), 2955, 2925, and 2830 (aliphatic C—H stretching), 1257 and 1032 (aromatic methyl ether), 841 and 812 (C—H out-of-plane bending of isoxazole C4—H and 4-substituted phenyl) proton magnetic resonance (trifluoroaeetic acid) 5, multiplicity, number of protons, assignment 3.98 (singlet,... 

Benzopyran-3-one, l,4-dihydro-6,7-dimethoxy-], 55, 45 Isocyamde, benzyl-, 55, 98 Isocyanide, butyl-, 55, 98 ISOCYANIDE, tert-butyl- [Isocyamde, 1,1-dimethylethyl-], 55, 96 Isocyamde, cyclohexyl-, 55, 98 Isocyamde, dodecanyl-, 55, 98 Isocyamde, ethyl, 55,98 Isocyamde, methyl, 55, 98 Isocyamde, phenyl-, 55, 98 (-)-2,3 4,6-Di-0-isopropylidene-2-keto-L-gulomc acid, hydrate [L-jcy/o-2-Hex-ulosomc acid, bis-<9-( 1 -mcthylcthyl-ldene)-], 55,80, 81 ISOXAZOl F, 3-(4-chlorophenv1)-5-(4-methoxyphenyl)-, 55, 39 Isoxazole,5 -(4-chloropheny l)-3-(4-me th-oxyphenyl)-, 55,42... 

This regioselectivity is practically not influenced by the nature of subsituent R. 3,5-Disubstituted isoxazolines are the sole or main products in [3 + 2] cycloaddition reactions of nitrile oxides with various monosubstituted ethylenes such as allylbenzene (99), methyl acrylate (105), acrylonitrile (105, 168), vinyl acetate (168) and diethyl vinylphosphonate (169). This is also the case for phenyl vinyl selenide (170), though subsequent oxidation—elimination leads to 3-substituted isoxazoles in a one-pot, two-step transformation. 1,1-Disubstituted ethylenes such as 2-methylene-1 -phenyl-1,3-butanedione, 2-methylene-1,3-diphenyl- 1,3-propa-nedione, 2-methylene-3-oxo-3-phenylpropanoates (171), 2-methylene-1,3-dichlo-ropropane, 2-methylenepropane-l,3-diol (172) and l,l-bis(diethoxyphosphoryl) ethylene (173) give the corresponding 3-R-5,5-disubstituted 4,5-dihydrooxazoles. 

Chloro(hydroxyimino)methyl]-3-phenyl-l,2,3-oxadiazolium-5-olate-(3-phenylsydnone-4-carbohydroximoyl chloride) reacts in situ (through nitrile oxide) with N-arylmaleimides or 2-methyl-N-phenylmaleimide to give 5-aryl-3-(3-phenylsydnon-4-yl)-3a,6a-dihydropyrrolo[3,4-r/]isoxazole-4,6-diones or dame thyl-5-pheny l-3-(3-phenylsydnon-4-yl)-3a,6a-dihydropyrrolo[3,4-d]isoxazole-4,6-diones, respectively (265). 

A study of the regioselectivity of the 1,3-dipolar cycloaddition of aliphatic nitrile oxides with cinnamic acid esters has been published. AMI MO studies on the gas-phase 1,3-dipolar cycloaddition of 1,2,4-triazepine and formonitrile oxide show that the mechanism leading to the most stable adduct is concerted. An ab initio study of the regiochemistry of 1,3-dipolar cycloadditions of diazomethane and formonitrile oxide with ethene, propene, and methyl vinyl ether has been presented. The 1,3-dipolar cycloaddition of mesitonitrile oxide with 4,7-phenanthroline yields both mono-and bis-adducts. Alkynyl(phenyl)iodonium triflates undergo 2 - - 3-cycloaddition with ethyl diazoacetate, Ai-f-butyl-a-phenyl nitrone and f-butyl nitrile oxide to produce substituted pyrroles, dihydroisoxazoles, and isoxazoles respectively." 2/3-Vinyl-franwoctahydro-l,3-benzoxazine (43) undergoes 1,3-dipolar cycloaddition with nitrile oxides with high diastereoselectivity (90% de) (Scheme IS)." " ... 

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