3- Phenyl-5-substituted isoxazoles

A regioselective method affording directly 3-phenyl-5-substituted isoxazoles 57, without isolation of isoxazoline intermediates 56, is based on the reaction of hydroxylamine and -benzotriazolyl-,-unsaturated ketones 55 (Scheme 37) <2001JOC6787>. 

In a similar way, carboxylic esters have been obtained stoichiometrically by ortho palladation of aromatic amides (Scheme 25) [147] and of phenyl-substituted isoxazoles or oxazoles [148] followed by alkoxycarbonylation. 

In DMF diphenyloxazole is reduced in two one-electron reductions, the first resulting in a relatively stable radical anion, the second presumably in a dihydro derivative [276]. In MeCN, 3-phenyl-substituted isoxazoles are reduced to a monoimine that is hydrolized to the diketone [277]. 

The first 1,2-benzisoxazole, 3-phenyl-l,2-benzisoxazole, was obtained from the treatment of o-bromobenzophenone oxime with alkali in 1892 (1892CB1498,1892CB3291). 2,1-Benzisoxazole has been known since 1882, being obtained as a reduction product of o-nitrobenzaldehyde with tin and hydrochloric acid (1882CB2105). In general, benzisoxazoles behave much like substituted isoxazoles. Numerous structural ambiguities occur in the early literature of these two systems, and these have been discussed in the above reviews. 

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. 

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

Mass spectrometry (MS) has been commonly used for the structure determination of substituted isoxazoles and their derivatives either to validate their molecular weight or to determine their structure. Regioisomeric 4,5-dihydroisox-azoles 13 and 14 were distinguished on the basis of their MS fragmentation pattern only the 5-phenyl isomer exhibits a peak MH -106 in the mass spectrum corresponding to the loss of benzaldehyde <1998JOC6319>. 

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, 5-( p-bromophenyl)-3-phenyl-synthesis, 6, 63 Isoxazole, 3-chloro-reduction, 6, 58 4-substituted reactions, 6, 58... 

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). 

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,... 

The presence of a 2-substitutent in 3-phenylazirines (17, R —H in Scheme 21) modifies the mode of reaction with molybdenum carbonyl.47 In contrast to pyrazine formation for (17, R =H see Section V,C,2), the alkenyl azirine (18, Scheme 22) is transformed in excellent yield into 2-phenyl-5-carboxy-methylpyrrole. This product probably arises by intramolecular cyclization within an intermediate dienylnitrene intermediate, and related reactions have been devised to synthesize isoxazoles (see Section IV,E,2) and pyrazoles (see Section IV,D,1).47 The molybdenum carbonyl-promoted formation of 2,5-disubstituted pyrroles47 has analogy in uncatalyzed thermal, but not photochemical decomposition of 3-phenyl-2//-azirine 2-acrylate.49... 

Amino derivatives of 1,2,4-oxadiazoles, isoxazoles, and 1,2,5-oxadiazoles interact with phenyl isocyanate to produce various 3-substituted 5-amino-l,2,4-thiadiazoles, via intermediate thioureides which can be isolated. The tendency to rearrange follows the order 1,2,4-oxadiazoles, isoxazoles, and 1,2,5-oxadiazoles <1996CHEC-II(4)307>. 

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)." " ... 

Another type of semisynthetic penicillin that should undoubtedly be considered is penicillin derivatives of heteroylcarboxylic acids (as a rule an isoxazol) in the third position of which is present a substituted or nonsubstituted phenyl radical (oxacillin, cloxacilhn, dicloxaciUin), which plays the role of the radical in the acyl side group. These penicillins (oxacilhn, cloxacilhn, dicloxacilhn), which are resistant to penicillinase, are active with respect to peniciUin-G-resistant staphylococci. Their antimicrobial spectrum is restricted to Gram-positive microorganisms. 

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). 

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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