Structure of isoxazoles

The isoxazoles 89 and 90 have been studied in detail by IR and H NMR spectroscopy. The structure of isoxazoles 89 was also confirmed by their oxidation with potassium permanganate in acetone to 3-alkyl(aryl)-5-isoxazolecarboxylic acids. 

This decade has brought a number of investigations of the physicochemical properties of isoxazole derivatives and the elucidation of some details concerning their structure. The data obtained are in a good agreement with the conceptions as to the structure of isoxazole as reviewed by Barnes. We shall therefore be concerned only with recent work. 

Spectroscopic methods have been successfully applied to the elucidation of some details of the fine structure of isoxazole derivatives. Thus IR spectra revealed steric hindrance in the case of some 3,4,5-trisubstituted isoxazoles for phenylisoxazoles this results in the nonplanarity of the benzene and isoxazole rings and decreasing mutual interaction. 

Figure 1 General structure of isoxazole series of antipicornavirus agents. 

The previous discussion has referred to photolysis and thermolysis only. Many of the transformations described have also been observed on mass spectrometry of isoxazoles, although it is not always clear whether they occur as a result of electron impact or by prior thermal reaction.211-212 It should be noted that such reactions can create problems in the use of mass spectrometry for elucidating the structures of isoxazoles. 

All unsymmetrical diketones can exist in two cis-enolic forms. A possible insight into the structures is given by the reaction with hydroxylamine. This involves the assumption, however, that the enolic form of the /3-diketone reacts at its carbonyl group to form the monooxime which is then cyclized to the isoxazole. The structures of isoxazoles thus obtained were corroborated by their independent synthesis and, for comparison, the synthesis of their isomers. The enolization of /3-diketones has also been discussed in Section V, C. 

X-ray analysis has aided in establishing the structure of isoxazoles <92JCS(P2)121, 92JHC1325, 93JCS(Pi)939) and transition metallic complexes <89JOM(372)287) unequivocally. 

Figure 5.11 Structure of isoxazole (bond lengths in pm, bond angles in degrees).

Details of bond lengths and bond angles for all the X-ray structures of heterocyclic compounds through 1970 are listed in Physical Methods in Heterocyclic Chemistry , volume 5. This compilation contains many examples for five-membered rings containing two heteroatoms, particularly pyrazoles, imidazoles, Isoxazoles, oxazoles, isothlazoles, thlazoles, 1,2-dlthloles and 1,3-dlthloles. Further examples of more recent measurements on these heterocyclic compounds can be found in the monograph chapters. 

Theoretical and structural studies have been briefly reviewed as late as 1979 (79AHC(25)147) (discussed were the aromaticity, basicity, thermodynamic properties, molecular dimensions and tautomeric properties ) and also in the early 1960s (63ahC(2)365, 62hC(17)1, p. 117). Significant new data have not been added but refinements in the data have been recorded. Tables on electron density, density, refractive indexes, molar refractivity, surface data and dissociation constants of isoxazole and its derivatives have been compiled (62HC(17)l,p. 177). Short reviews on all aspects of the physical properties as applied to isoxazoles have appeared in the series Physical Methods in Heterocyclic Chemistry (1963-1976, vols. 1-6). 

The fragmentation pattern of isoxazoles on electron impact has been well studied. It has been used as an important tool for the structural assignment of isoxazoles obtained from the reaction of chromones with hydroxylamine 79MI41600, 77JOC1356). For example, the structures of the isoxazoles (387) and (388) were assigned on the basis of their fragmentation patterns. Ions at mje 121 (100%) and mje 93 (19.8%) were expected, and indeed observed, for the isoxazole (388), and an ion at mje 132 (39.5%>) was similarly predicted and observed for the isoxazole (387). 

The structures of the isoxazoles (393) were all consistent with their mass spectral fragmentation patterns. The reaction of hydroxylamine with 3-phenylchromone (394) gave exclusively 5-(o-hydroxyphenyl)isoxazole (395) (78ACH(97)69). 

The well-known reaction of a-alkyl-/3-ketoaldehydes and hydroxyl-amine has been applied to the elucidation of the structure of formyl-ation products of ketones the conclusions are, however, open to question. Some workers attempted to overcome the ambiguity of the reaction of j8-ketoaldehydes and hydroxylamine, which results in a mixture of 3- and 5-monosubstituted isoxazoles and thus considerably lowers the preparative value of the method, by using various derivatives of yS-ketoaldehydes, especially those of their enolic forms (jS-substituted vinylketones) investigated by Kochetkov et al. The use of readily available /3-chlorovinylketones (12) in the reaction with hydroxylamine represents a rather useful preparative method to synthesize monoalkylisoxazoles but again gives rise to a mixture of 3- (13) and 5-alkylisoxazoles (14). This is due to the attack... 

The structural studies of isoxazol-5-ones have shown that these compounds can be found in one of the three tautomeric forms (45-47 59,90,96-98 establishcd that the 3-methyl-4-benzoyl... 

Recently, Kochetkov and Khomutova have reported on the mercuration of isoxazoles with mercuric acetate. The reaction occurs quite smoothly, more readily than for benzene derivatives and results in a 90-100% yield of 4-acetoxymercury derivatives (74) whose structure was proved by converting them to known 4-bromoisoxazoles (75). Under these reaction conditions isoxazole itself is oxidized by mercuric acetate, mercurous salts being thereby produced. 

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. ... 

As already mentioned, on passing from the aromatic system of isoxazoles to the nonaromatic ones of isoxazolines and isoxazolidines, the N—O bond becomes more labile. In these compounds the ring is extremely readily cleaved. Many such reactions are useful to determine the structure of reduced isoxazole derivatives and are also of preparative value. 

Under the conditions used for the reductive cleavage of the O—N bond in isoxazoles, a similar reaction readily occurs with isoxa-zolines, e.g. on treatment with organomagnesium compounds and on catalytic hydrogenation.- Hydrogenolysis of the O—N bond (180 181 182 183) was used to elucidate the structure of isoxa-zolones from -ketoesters. -... 

Dipolar cycloaddition of 2,4-(trimethylsilyl)- and 2,4-(trimethylgermyl)-substituted thiophene-1,1-dioxides as well as silylated 2,2 -bithiophene-1,1-dioxides was investigated. It was shown that only the C(4)=C(5) double bond of 2,4-disubstituted thiophene-1,1-dioxides interacts with acetonitrile oxide to give thienoisoxazoline dioxides. Bithiophene derivatives were inactive or their reaction with nitrile oxide was accompanied by desilylation. Cycloaddition of benzonitrile oxide with all mentioned sulfones did not occur. The molecular structure of 3a-methyl-5.6a-bis(trimethylgermyl)-3a,6a-dihydrothieno 2.3-c/ isoxazole 4,4-dioxide was established by X-ray diffraction (263). ... 

Oxidation of (alkenylthio)thiophenecarboxaldehyde oxime 350 (R = allyl) by NaOCl gives the nitrile oxide, which cyclizes to thieno[2,3-h]thiocino[4,5-c] isoxazole 351. However, isomeric 350 (R = isopropenyl), under the same conditions, is converted to the unusual product, thieno 2,3-/ thiocin 352. In both reactions, cyclodimerization products of nitrile oxides are also obtained. Structures of compounds 350 (R = isopropenyl) and 352 have been studied by X-ray diffraction analysis (411). 

Fig. 14 Projection showing the structure of [Fe(isoxazole)6](BF4)2 ([72] - reproduced with permission of the Royal Society of Chemistry)... 

Recently, this family of isoxazole compounds has been re-examined with particular emphasis on the tetrafluoroborate salt. These studies included the first extended magnetic and structural characterisation of [Fe(isoxa-zole)6](BF4)2 [72]. In addition, the double salt [Fe(isoxazole)6] [Fe(isoxa-zole)4(H20)2](BF4)4 was isolated [73]. 

A further report dealt with the synthesis, variable temperature magnetic susceptibility measurements, and crystal structure determination at various temperatures (115, 136, 140, 150 and 231 K space group P-1) of [Fe(isoxa-zole)6][Fe(isoxazole)4(H20)2](BF4)4 [73]. The molecular structure of this well-defined double salt consists of two mononuclear Fe(II) dications,... 

The X-ray structures of some perhydropyrrolo[l,2- ]isoxazoles have been established in order to determine the stereochemistry of the cycloadducts obtained by addition of nitrones to activated double bonds <1997T2979, 2005T8836, 2005JOC856>. 

The aromaticity of isoxazole has been reviewed in terms of theoretical and structural studies,138 139 and the conclusion is that it is slightly less aromatic than oxazole and furan. 

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