Isoxazoles nitration

Pyrazole and isothiazole " undergo straightforward nitration, at C-4, but the less reactive isoxazole nitrates in negligible yield 3-methylisoxazole, however, has sufficient extra reactivity that it can be satisfactorily nitrated, at C-4. With acetyl nitrate or dinitrogen tetraoxide/ozone, 1-nitropyrazole is formed but this can be rearranged to 4-nitropyrazole in acid at low temperature. ... 

In azole chemistry the total effect of the several heteroatoms in one ring approximates the superposition of their separate effects. It is found that pyrazole, imidazole and isoxazole undergo nitration and sulfonation about as readily as nitrobenzene thiazole and isothiazole react less readily ica. equal to m-dinitrobenzene), and oxadiazoles, thiadiazoles, triazoles, etc. with great difficulty. In each case, halogenation is easier than the corresponding nitration or sulfonation. Strong electron-donor substituents help the reaction. 

Isoxazoles are presently known to undergo hydrogen exchange, nitration, sulfonation, halogenation, chloroalkylation, hydroxymethylation, Vilsmeier-Haack formylation, and mercuration. The Friedel-Crafts reaction on the isoxazole nucleus has not yet been reported. 

Nitration of alkylisoxazoles and phenylisoxazoles has received considerable attention (71JCS(B)2365, 75JCS(P2)1627). Alkylisoxazoles underwent nitration as the free base at the 4-position of the isoxazole nucleus the non-reactivity under similar conditions of the... 

The parent isoxazole was nitrated under strictly controlled conditions (35-40 °C) in only 3.5% yield whereas 3,5-dimethylisoxazole was nitrated in mixed acid at 100 °C to give... 

Vilsmeier-Haack formylation, 6, 26 Isoxazole, 3-anilino-nitration, 6, 22... 

The first electrophilic substitution reaction studied in the isoxazole series was the nitration of 3,5-dimethylisoxazole reported by Morgan and Burgess in 1921.The reaction occurs smoothly on heating with mixed nitric and sulfuric acids at 100°C and leads to the 4-nitro derivative in 86% yield. 

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. 

It is most difficult to nitrate isoxazole itself. 4-Nitroisoxazole (51) is formed only under strictly controlled conditions (35-40°C), and in but 3.5% yield. Its structure was proved by reaction with aniline (see Section V,A) to give nitrocyanoacetaldehyde anil (52). 

Sulfonation of isoxazoles has been less extensively studied than nitration. This is possibly due to the difficulty encountered in isolating isoxazolesulfonic acids and to the ambiguous reaction course. 

The presently known electrophilic substitution reactions all occur at the 4-position of the isoxazole nucleus, corresponding to the j3-position in pyridine. Thus the influence of the nitrogen atom is predominant. The introduction of alkyl and, particularly, aryl substituents into the isoxazole nucleus markedly increases its reactivity (on the other hand, during nitration and sulfonation the isoxazole nucleus also activates the phenyl nucleus). 

Ammonium cerium(IV) nitrate on reaction with acetone or acetophenone generates acetyl- or benzoylformonitrile oxides, respectively (99). These nitrile oxides dimerize to furoxans and give, in the presence of alkenes and alkynes, 3-acetyl- or 3-benzoyl-4,5-dihydroisoxazoles and 3-acetyl- or 3-benzoylisoxazoles, respectively the yield of the isoxazole derivatives was improved on using ammonium cerium(III) nitrate tetrahydrate-formic acid (99). 

ALKYL NITRATES Icwis acids CYANIDES hypochlorites DEVARDA S ALLOY DIAZONIUM TETRAHALOBORATES ISOXAZOLES NITROBENZALDEHYDES NITROBENZYL COMPOUNDS... 

Extensive studies on hydrogen exchange in aqueous sulfuric acid on 1 -methylpyrazole,252 isoxazole,328 and isothiazole328 and their methylated derivatives252,328 have been reported, but calculated partial rate factors derived from treatment of the form of Eq. (12) do not tally with those observed. This emphasizes the contribution from interactions between donor and acceptor groups or solvent effects which also lead to breakdown in the interpretation of nitration results.83... 

Isosorbide mononitrate, see 1,4,3,6-Dianhydroglucitol 2-nitrate, 2390 3-Isothiocyanatopropene, see Allyl isothiocyanate, 1467 f Isovaleraldehyde, 1952 f Isoxazole, 1107... 

Sec. II.B] NITRATION OF PHENYL-SUBSTITUTED HETEROCYCLES 239 5. Oxazoles and Isoxazoles... 

When 4-phenylisoxazole is nitrated in sulfuric acid at - 10°C using nitric acid (d 1.5), a 98% yield of 4-(4-nitrophenyl) isoxazole is obtained. A mixture of 4-phenylisoxazole in sulfuric acid and 99% nitric acid at 70°C (30 min) gives the dinitro product 4-(2,4-dinitrophenyl)isoxazole (67G1604). 

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. 

A quantitative study has been carried out by Ridd and co-workers126 on the nitration of imidazole and pyrazole in 98% sulfuric acid the partial rate factors for the 4-positions of imidazolium and pyrazolium cations are 3.0 xlO-9 and 2.1 x 10-10, respectively. Thiazole and isoxazole cations are also far less reactive than benzene. As a consequence, phenyl derivatives give products substituted in the benzene ring, on sulfonation or nitration.208-210... 

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