Isoxazole, structure

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. 

A multiply bonded nitrogen atom deactivates carbon atoms a or y to it toward electrophilic attack thus initial substitution in 1,2- and 1,3-dihetero compounds should be as shown in structures (110) and (111). Pyrazoles (110 Z = NH), isoxazoles (110 Z = 0), isothiazoles (110 Z = S), imidazoles (111 Z = NH, tautomerism can make the 4- and 5-positions equivalent) and thiazoles (111 Z = S) do indeed undergo electrophilic substitution as expected. Little is known of the electrophilic substitution reactions of oxazoles (111 Z = O) and compounds containing three or more heteroatoms in one ring. Deactivation of the 4-position in 1,3-dihetero compounds (111) is less effective because of considerable double bond fixation (cf. Sections 4.01.3.2.1 and 4.02.3.1.7), and if the 5-position of imidazoles or thiazoles is blocked, substitution can occur in the 4-position (112). 

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. 

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). 

Novel steroids which contain an isoxazole fused ring within the structure have biological activity which is primarily contraceptive (74MI41604, 79MI41607, 79USP4160027) and a variety of other indications (75USP3869467, 75ZOB2090). 

Cyclopent-2-en-l-one, 2-hydroxy-3-methyl-synthesis, 3, 693 Cyclopentenone, 4-methoxy-formation, 1, 423 Cyclopenthiazide as diuretic, 1, 174 Cyclopent[2,3-d]isoxazol-4-one structure, 6, 975 Cyclophane conformation, 2, 115 photoelectron spectroscopy, 2, 140 [2,2]Cyclophane conformation, 2, 115 Cyclophanes nomenclature, 1, 27 Cyclophosphamide as pharmaceutical, 1, 157 reviews, 1, 496 Cyclopiloselloidin synthesis, 3, 743 Cyclopolymerization heterocycle-forming, 1, 292-293 6H-Cyclopropa[5a,6a]pyrazolo[l,5-a]pyrimidine pyrazoles from, 5, 285 Cydopropabenzopyran synthesis, 3, 700 Cyclopropachromenes synthesis, 3, 671 Cyclopropa[c]dnnolines synthesis, 7, 597 Cyclopropanation by carbenes... 

Isoxanthopterin-6-carboxylic acid chlorination, 3, 296 synthesis, 3, 304 Isoxanthopterins catabolism, 3, 322 chlorination, 3, 296 degradation, 3, 308 occurence, 3, 323 oxidation, 3, 287 8-riboside synthesis, 3, 319 silylation, 3, 297 structure, 3, 264, 273 synthesis, 3, 298 Isoxazole, 3-acetohydroximoyl-synthesis, 6, 409 Isoxazole, 5-acetyl-3-chloro-oxidation, 6, 53... 

Isoxazolo[5,4-d]isoxazole, 3a,6a-dihydro-structure, 6, 975 synthesis, 6, 1018 Isoxazoloisoxazoles synthesis, 3, 41 Isoxazoio[2,3-h]isoxazoies synthesis, 6, 1001 Isoxazolo[4,5-d]isoxazoles synthesis, 6, 989, 997... 

An amino group may take any of three possible positions in the five-membered isoxazole ring, giving rise to three tautomeric forms for 70 and 71 and four forms for 72 [76AHC(S1), pp. 416, 444, 445 84CHEC-I(5)1]. However, only amino structures 70a-72a have been detected using IR- or NMR-spectroscopic techniques (Scheme 33). 

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. 

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... 

Recently a definitive study of several isoxazol-5-ones using infrared and ultraviolet spectroscopy (Table I) has shown that the balance between the various tautomers is a delicate one and that all three of the structural types can predominate depending upon the nature of the substituents and the conditions of the experiment. However, the hydroxy form is only found when it is stabilized by chelation (i.e., a carbonyl substituent in the 4-position). The other compounds exist in the CH form in nonpolar media increasing polarity of the solvent stabilizes increasing amounts of the more polar NH forms. 

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... 

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. 

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... 

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). 

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. 

The mechanisms of the electrophilic substitutions in the isoxazole nucleus have not yet been studied. They should not differ fundamentally from those usually accepted for the substitution of aromatic systems but the structural specificity of the isoxazole ring might give rise to some peculiarities, as recently specially discussed.One important point is that isoxazole shows a clearcut tendency to form coordination compounds. Just as pyridine and other azoles, isoxazoles coordinate with halogens and the salts of heavy metals, for example of cadmium,mercury,zinc. Such coordination... 

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. ... 

The early stages of the reaction of the quaternary salt can be regarded as proceeding in a manner exactly analogous to that by which the isoxazoles themselves are degraded, the j8-oxoketene imine structure (148) being one mesomeric form of a compound which could alternatively be formulated as a nitrilium betaine. However, by contrast with the products from the isoxazoles (i.e., enolates of /3-keto-nitriles), this is electrically neutral and susceptible to further nucleophilic attack. 

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. -... 

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