Isoxazole, aromaticity

The carbon atoms of azole rings can be attacked by nucleophilic (Section 4.02.1.6 electrophilic (Section 4.02.1.4) and free radical reagents (Section 4.02.1.8.2). Some system for example the thiazole, imidazole and pyrazole nuclei, show a high degree of aromati character and usually revert to type if the aromatic sextet is involved in a reaction. Othei such as the isoxazole and oxazole nuclei are less aromatic, and hence more prone to additio reactions. 

Acid-catalyzed hydrogen exchange is used as a measure of the comparative reactivity of different aromatic rings (see Table 5). These reactions take place on the neutral molecules or, at high acidities, on the cations. At the preferred positions the neutral isoxazole, isothiazole and pyrazole rings are all considerably more reactive than benzene. Although the 4-position of isothiazole is somewhat less reactive than the 4-position in thiophene, a similar situation does not exist with isoxazole-furan ring systems. 

The distinction between these two classes of reactions is semantic for the five-membered rings Diels-Alder reaction at the F/B positions in (269) (four atom fragment) is equivalent to 1,3-dipolar cycloaddition in (270) across the three-atom fragment, both providing the 47t-electron component of the cycloaddition. Oxazoles and isoxazoles and their polyaza analogues show reduced aromatic character and will undergo many cycloadditions, whereas fully nitrogenous azoles such as pyrazoles and imidazoles do not, except in certain isolated cases. 

The 4- and 5-hydroxy-imidazoles, -oxazoles and -thiazoles (499, 501) and 4-hydroxy-pyrazoles, -isoxazoles and -isothiazoles (503) cannot tautomerize to an aromatic carbonyl form. However, tautomerism similar to that which occurs in hydroxy-furans, -thiophenes and -pyrroles is possible (499 500 503 504 501 502), as well as a zwitterionic... 

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). 

A Hiickel model used for calculating aromaticity indicated that the isoxazole nucleus is considerably less aromatic than other five-membered heterocycles, including oxazole and furan. SCF calculations predicted that isoxazole is similar to oxazole. Experimental findings are somewhat difficult to correlate with calculations (79AHC(25)147). PRDDO calculations were compared with ab initio values and good agreement for the MO values was reported... 

Microwave irradiation has been used to probe aromatic character in isoxazoles (74JA7394)... 

Aromatic character in isoxazoles has been studied from a number of viewpoints, and these studies indicate that although isoxazole may be formally considered an aromatic system, the disposition of the ring heteroatoms modifies this character to an appreciable extent. From a qualitative viewpoint, thermal stability and electrophilic attack at the 4-position may be considered consistent with an aromatic character. Furthermore, NMR chemical shifts of the ring protons are consistent with those of an aromatic compound. References related to these studies may be found in Section 4.16.2.3.4. 

Table 7 also indicates that the rate enhancements for a 3- and 5-methyl group vary significantly among 1,2-azoles. The difference between the increments in log units for a 3-and 5-methyl group, which should vary directly with bond fixation in the ground state, is larger for isoxazole (1.4) than for pyrazole (0.7) and for isothiazole (0.2). This indicates that the aromaticity increases in the same order and contributes the first quantitative evidence that the 1,2-azoles follow the same aromaticity order as furan < pyrrole < thiophene. 

For the preparation of compounds with an aromatic isoxazole system, two synthetic paths are of high importance first the condensation to form the 1—5 and the 2—3 bonds of the isoxazole ring (I—>2) and second that to form the 1—5 and 3—4 bonds of this... 

The spectra of isoxazoles have recently been examined in detail. Pino et al. investigated the UV spectra of isoxazole and the methyl-isoxazoles. These spectra revealed characteristic shifts in the maxima depending on the number and position of methyl groups. Such regularities are characteristic only for aromatic systems. The shift is most marked for a C-4 methyl group, and is absent for a C-3 methyl group. 

To understand the general character of the isoxazole nucleus and to establish its place among the other heterocyclic aromatic systems, it is of the greatest interest to investigate the reactions of isoxazole derivatives in which the heterocyclic nucleus remains intact, especially substitution reactions. 

The isoxazole nucleus is also halogenated in the 4-position by N-bromosuccinimide provided there is no substituent in this position. This reaction does not proceed homolytically, as might have been expected, and appears to represent a simple electrophilic substitution by the bromine cation. Similar cases have been previously described for the bromination of certain aromatic compounds with A -bromo-succinimide. ... 

Further, isoxazole derivatives were subjected to two related reactions. 3,5-Dimethylisoxazole was found to react in the presence of dry hydrogen chloride with aromatic aldehydes (chlorobenzylation, 72- 71),and with formaldehyde in the presence of sulfuric acid it undergoes hydroxymethylation (72- 73). ... 

Whereas most reactions in the isoxazole series are undoubtedly those of electrophilic substitution, mercuration of isoxazoles, as well as some cases of mercuration of aromatic compounds, could be considered as homolytic reactions. However, the ready mercuration of... 

If one bears in mind the peculiarities noted at the beginning of this section, the electrophilic substitution reactions which are known at present in the isoxazole series proceed in accordance with general pattern of electrophilic substitution in aromatic systems. 

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... 

Hydrogenolysis of the ring of di- and tetra-hydroisoxazole derivatives proceeds, of course, more readily than in the case of the aromatic system of isoxazole. These two reactions are discussed separately below. 

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. 

The action of oxidizing agents on isoxazoles fully confirms the aromaticity of this heterocyclic system and is widely used to prepare... 

Heating isoxazole derivatives with aqueous-alkaline permanganate leads to a complete degradation of the heterocycle. With arylisoxa-zoles this results in readily identifiable aromatic acids, from which can be deduced the orientation of electrophilic substitution reac-tions. ° Also, the stability of various heterocycles can be compared. Thus, under these reaction conditions, the pyrazole ring is more stable than that of isoxazole (cf. 197198). ... 

Bextra, a COX-2 inhibitor used in the treatment of arthritis, contains an isoxazole ring. Why is the ring aromatic ... 

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,... 

Isoxazoles are privileged aromatic heterocycles due to their wide spectrum of biological activities and their use as versatile building blocks in organic synthesis. Recent progress in the field of transition-metal-catalyzed cross-coupling reactions on isoxazole systems has been summarized and discussed <06EJO3283>. 

Analogous studies on 1-monoxides and 1,1-dioxides support the nonaromaticity of these derivatives. The. /(C—C) spin-spin coupling between 13C nuclei has been determined for 1,2,5-thiadiazole (48.1 Hz) and correlated to bond length and tentatively to aromaticity <1994MRC62>. Based on this, a low aromaticity was assigned to 1,2,5-thiadiazole similar to furan and isoxazole while a high aromaticity assignment was made for 1,2,3-thiadiazole, contrary to that reported by Bird. 

Condensation of aromatic or aliphatic esters with resin-supported acetyl carboxylic acids 28 followed by cyclisation with hydroxylamine, activation of the linker, and cleavage using amines, provided highly substituted isoxazoles 30 and 31. This general method gave products in excellent yields and purities in which the regioisomers ratio can be easily controlled . 

Cycloaddition of 5,6-dihydropyran-2-one with aromatic nitrile oxides leads to 3-aryl-3a,6,7,7a-tetrahydropyrano[3,4-d]isoxazol-4(47/)-ones 98. The latter react with nickel peroxide to give the corresponding dihydropyranoisoxazolones 99. Similar to 2-bromocyclohex-2-enone, 3-bromo-5,6-dihydropyran-2-one undergoes nitrile oxide cycloaddition, followed by dehydrobromination, to form regioi-someric 3-aryl-5,7-dihydropyrano 4,3-c/ isoxazol-7(4//)-ones 100 (Scheme 1.24) (242). 

There are two distinct classes of compounds that fit the criteria mentioned above alkene-functionalized chalcone derivatives (Fig. IB) and enone-functionalized chalcone derivatives (Fig. 1C). Within each class, both aromatic and non-aromatic compounds exist. Those compounds functionalized at the alkene include i) 3-membered heterocycles, e.g., epoxide and aziri-dine compounds, ii) 5-membered aromatic derivatives including fused and non-fused compounds, and iii) 6-membered aromatic pyrazine compounds. The enone-functionalized compounds include i) 5-membered aromatics such as pyrazole and isoxazole compounds, ii) 5-membered non-aromatic compounds for example pyrazolines and isoxazolines, and iii) 6-membered non-aromatics where a discussion of heterocyclic and non-heterocyclic compounds will be given for completeness. 

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