Isoxazole 3- phenyl-4-nitro

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. 

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

Different results were obtained by Kochetkov and Khorautova. After nitrating 5-phenylisoxazole, they isolated two nitro derivatives, one of which contained a nitro group in the phenyl nucleus, the other one in the isoxazole ring. It is to be expected that the nitration of other phenylisoxazoles results in some second isomer that has not been isolated due to a negligible yield. It will also be noted that the nitration of arylisoxazoles proceeds faster and under milder conditions than necessary for the alkyl derivatives. 

A nitro group in the 4-position markedly increases the instability of the isoxazole ring in alkaline medium. This effect is clearly demonstrated by 3,5-dime thy 1-4-nitroisoxazole. Whereas 3,5-dimethyl-isoxazole is not affected by alkali, its 4-nitro-derivative (134) is cleaved by 2% sodium hydroxide. The structure of the product was proved by its conversion into a triazole (135) with phenyl diazonium chloride, according to the original authors. ... 

Assuming that the exothermicity is independent of phase and using the gas phase enthalpy of formation of water (—241.818 kJmol ) gives us the desired enthalpy of formation of the isoxazoline of —86kJmoR. If we assume that the liquid phase is appropriate, then with the enthalpies of formation of the liquid phenyl isoxazole and water we find —194 kJmol . Are these values plausible We will continue with our gas phase preference. Let us make the following assumptions. The introduction of a nitro group into isoxazoline is the same as in benzene, i.e. reaction 43 is thermoneutral. 

Quite independently of Cornforth s efforts, a similar approach was designed and executed by Stevens and coworkers (75JA5940, 76T1599). The isoxazoles were synthesized by one of the three routes outlined in Scheme 25, in which primary nitro compounds are transformed into nitrile oxides by dehydration with either phosphoryl chloride or phenyl isocyanate, or else the same oxides were formed by dehydrogenation with LTA (syn product) or NBS (syn and anti). Reaction of the unstable nitrile oxides in situ with an appropriately substituted alkyne then afforded the isoxazole (294). 

The introduction of electron-donating substituents into the isoxazole ring facilitates the nitration process. Thus, the nitration of 3,5-dialkylisoxazoles [168-171] or bis(3-methylisoxazolyl-5) [172] gave the corresponding 4-nitro derivatives Under the same conditions, however, 3-methyl-5-(2-methoxy-2-phenylethyl)isoxazole was only nitrated in the phenyl ring [173], Conversely, even at room temperature the nitration of 3-methyl-5-dichloromethyl- and 3-dichloromethyl-5-methylisox-azole gives the corresponding 4-nitro derivatives [174], The nitration of 3-bromo-5-methylisoxazole is similar [175]. 

A number of alkyl- and arylnitrile oxides have been reacted with methylenecyclopropane to give 4-oxa-5-azaspiro[2.4]hept-5-enes 1 (4,5-dihydrospiro[isoxazole-5-cyclopropane]). The nitrile oxides were usually generated in situ from the appropriate primary nitro compound with phenyl isocyanate and triethylamine. The addition is usually regioselective in such a way that the oxygen atom forms a bond with Cl of the three-membered ring. 

Benzisoxazoles and Other Annelated Isoxazoles. - The sodium-methoxide-induced cyclization of the nitro-ketone (348) furnishes 3-phenyl-2,l-benzisoxazole (349). 5-Chloro-2,l-benzisoxazole adds dimethyl acetylenedi-carboxylate to give the Diels-Alder product (350), while the parent com-... 

Alkylisoxazoles are converted to 4-nitro derivatives, whereas phenyl-isoxazoles (e.g. 48) are nitrated in the para position of the phenyl nuclei as proved by the degradative oxidation of nitro derivatives (49- 50). Ethyl 6-phenylisoxazole-3-carboxylate reacts similarly. 

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