Isoxazoles electrophilic substitution

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). 

Polarization and dipole moment studies for alkyl-, aryl-, carbonyl- hydroxy- (keto-) and amino-isoxazoles have been compiled and likewise support the low electron nature of the ring 63AHC(2)365, 62HC(l7)l,p. 177). More recent studies predict the order of electrophilic substitution to be 5>4> 3 on frontier electron density values of 0.7831, 0.3721 and 0.0659, respectively 7lPMH(4)237,pp.245,247). This contrasts with earlier reports of 4>5>3 on density values of —0.09, -t-0.14 and -t-0.18 in that order 63AHC(2 365). 

Benzisoxazoles undergo electrophilic substitution in the benzo ring, but with nucleophiles the reaction occurs in the isoxazole moiety, often leading to salicylonitriles with 3-unsubstituted systems. The isomeric 2,1-benzisoxazoles are characterized by the ease with which they may be converted into other heterocyclic systems. 

It should be expected that the orientation and rate of electrophilic substitution in the isoxazole nucleus would be affected by both hetero atoms. Because of the electron-accepting effect of the nitrogen atom, electrophilic substitution of the isoxazole nucleus should proceed less readily than in the case of benzene and should occur essentially at the position jS to the nitrogen atom, just as in pyridine and other azoles. Simultaneously the electron-donating oxygen atom should facilitate such reactions in isoxazole as compared with the substitution in pyridine. These predictions are confirmed by the available experimental evidence. 

Isoxazoles are known at present to undergo the following electrophilic substitution reactions nitration, sulfonation, halogenation, chloroalkylation, hydroxymethylation, and mercuration. Repeated attempts to effect the Friedel-Crafts reaction in the isoxazole series in the authors laboratory failed. The isoxazole nucleus seems not active enough to react with weak electrophilic reagents. 

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. 

As with other electrophilic substitution reactions, there is practically no work available on the halogenation of isoxazoles with functional substituents. The only instance that indicates that the general pattern holds true here is the extremely rapid bromination of 3-anilino-5-phenylisoxazole (65), in which the isoxazole ring is the first to react with 1 mole of bromine, yielding... 

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. ... 

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. 

In the reactions of electrophilic substitution, isoxazole is far less active than the five-membered heterocycles with one hetero atom and pyrazole. It is closer to pyridine, but more reactive. 

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 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... 

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). ... 

This useful methodology (complementary to the C4 selectivity of normal electrophilic substitution) is not applicable to isoxazole chemistry because the intermediate anions (such as 4.35) are rather unstable and decompose via oxygen-nitrogen cleavage. 

Electrophilic substitution in isoxazoles occurs most readily in the 4-position. The latter is part of the ring junction in the fused systems and is only free in the N-bridgehead series. 

It was well established by previous work that electrophilic substitution in the isoxazole ring proceeds readily and occurs in the 4-position.1 Quantita-... 

Five-membered rings with two or more heteroatoms are usually good at electrophilic substitution as one of the heteroatoms must be either O or S or a pyrrole-like nitrogen atom any of which supply lone pair electrons. Pyrazole 12, imidazole 13, oxazole 17, thiazole 18, isoxazole 19 and isothiazole 20 are examples. Multiple substitution can be a problem but is less so than for pyrrole because there are fewer carbon atoms available and the pyridine-like nitrogen atoms deactivate the ring. 

Meanwhile, electrophilic substitution in AI is noticeably more feasible than that in isoxazoles without amino groups. However, examples of electrophilic substitution were reported only for 3-AI and 5-AI. There is no data for 4-AI on electrophilic substitution in positions 3 or/and 5, despite the strong electron-donating effect of the... 

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