Isoxazoles with electrophiles

Electrophilic mercuration of isoxazoles parallels that of pyridine and other azole derivatives. The reaction of 3,5-disubstituted isoxazoles with raercury(II) acetate results in a very high yield of 4-acetoxymercury derivatives which can be converted into 4-broraoisoxazoles. Thus, the reaction of 5-phenylisoxazole (64) with mercury(II) acetate gave mercuriacetate (88) (in 90% yield), which after treatment with potassium bromide and bromine gave 4-bromo-5-phenylisoxazole (89) in 65% yield. The unsubstituted isoxazole, however, is oxidized under the same reaction conditions, giving mercury(I) salts. 

S612). However, more work is needed to determine its full utility. Table 16 lists the types of isoxazoles synthesized from the condensation of 1,4-dilithio oximes (358) and 2-nitro-acetophenone oximes with electrophiles. 

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... 

Hydroxy-isoxazoles and -pyrazoles can tautomerize in both of the ways discussed in Sections 3.4.3.7.3 and 3.4.3.7.5 (654 655 656). The hydroxy form is generally the least stable the alternative azolinone forms coexist in proportions depending on the substituents and the solvent, with non-polar media favoring the CH form (656) and polar media the NH form (655). The derived amibident anion can react with electrophiles at N, C or O depending on the reagent and conditions. 

However, alkyl groups at the C5 position of isoxazoles can be deprotonated and reacted with electrophiles. 

Ring deprotonation is also known with certain members of these series. Carbanion 8.15 is stable at low temperature (-70°C) and can be trapped with electrophiles, but on warming to room temperature it decomposes with ring fragmentation and extrusion of nitrogen. This fragmentation process is reminiscent of the base-catalysed cleavage of isoxazoles (Chapter 4). 

Both - and -alkylazolium ions, like the 2- and 4-alkylazoles themselves, can also react with electrophilic reagents without initial complete deprotonation. They undergo the same types of reactions as the alkylazoles but under milder conditions, and these reactions can often be catalyzed by piperidine. Thus, in quaternized pyrazoles, 5-methyl groups react with benzaldehyde to give styryl derivatives. The methyl groups in quaternized isoxazoles are also reactive, and here piperidine is sufficient as catalyst (Scheme 124). 

Isoxazoles are very weak bases. The Ka of isoxazole is -2.97. Protonation occurs at the N-atom. Reactions with electrophilic reagents... 

Oxadiazole (pfQ, sa —5) is less basic than isoxazole (pfCo = —2.97). 1,2,5-Oxadiazoles do not react with electrophiles, or react slowly. Thus, quaternization with dimethyl sulfate in sulfolane proceeds much more slowly than that of isoxazoles with iodomethane. 

The use of oximes as nucleophiles can be quite perplexing in view of the fact that nitrogen or oxygen may react. Alkylation of hydroxylamines can therefore be a very complex process which is largely dependent on the steric factors associated with the educts. Reproducible and predictable results are obtained in intramolecular reactions between oximes and electrophilic carbon atoms. Amides, halides, nitriles, and ketones have been used as electrophiles, and various heterocycles such as quinazoline N-oxide, benzodiayepines, and isoxazoles have been obtained in excellent yields under appropriate reaction conditions. 

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). 

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. 

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. 

Since an electron-withdrawing group such as ethoxycarbonyl at the a-carbon atom enhanced the electrophilicity of the )3-carbon atom, the reaction of a-ethoxycarbonyl-)3-ethoxyvinyl ketones (298) with hydroxylamine hydrochloride gave solely 5-substituted isoxazole-4-carboxylates (299) (55JOC1342, 59YZ836). 

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