Isoxazoles quaternization

Quaternization. 2-Isoxazolines are also weak bases, but slightly higher than that of corresponding isoxazoles. Quaternization of 2-isoxazoline was easily accomplished by treatment with excess trimethyl (or triethyl)-oxonium tetrafluroborate in dichloromethane at room temperature <83LA906>. Several other conditions to accomplish quaternization of 2-isoxazolines are discussed <9lHC(49)l>. In some cases, quaternization is achieved not directly from 2-isoxazolines. For example the cyclopropane (140) with nitrosonium tetrafluroborate afforded a mixture of isoxazolium salts (141) and (142) (Equation (26)) <89CL457>. 

Isoxazolium salts can be prepared by reaction with alkyl iodides or sulfates, although the low basicity of isoxazoles and their sensitivity to nucleophilic attack may necessitate special care. Isoxazolium salts containing bulky Af-substituents can be prepared by the reaction of isoxazoles with alcohols in the presence of perchloric acid. For example, the reaction of 3,5-dimethylisoxazole (53) with some alcohols in the presence of 70% perchloric acid gave isoxazolium salts, (54a) in 29%, (54b) in 57% and (54c) in 82% yield 79AHC(25)147, 68JOC2397). Attempts to quaternize 3,5-dimethyl-4-nitroisoxazole failed 71JCS(B)2365). 

The reactivity of isoxazole toward quaternization is compared with those of pyridine-2-carbonitrile, pyridine and five other azoles in Table 6 (73AJC1949). Isoxazole is least reactive among the six azoles and times less reactive than pyridine. There is also a good correlation between the rate of quaternization and basicity of the azole. 

Fio. 1. Bronsted plot for azoles reacting with methylating agents in quaternization reactions. Pyridine is the reference substrate. 1, 1-methylimidazole 2, 1-methylbenzimidazole 3, thiazole 4, 1-methylpyrazole 5, 2-methylindazole 6, benzo-thiazole 7, oxazole 8, 1-methylindazole 9, benzoxazole 10, 2,1-benzisothiazole 11, isothiazole 12, 2,1-benzisoxazole 13, isoxazole and 14, 1,2-benzisoxazole. 

Sections VI,A, B, D, and E give information about indazoles, oxazole, benzoxazole, isoxazole, benzisoxazoles, isothiazole, benziso-thiazoles, and benzothiazole. In addition, Sections II and VI,F,1 refer to quaternization reactions of isoxazole and benzisothiazoles, respectively. 

Azoles having heteroatoms in the 1,3-orientation are more reactive than those in which the arrangement is 1,2. However, the magnitude of the factor varies, thus oxazole is 68 times more reactive than isoxazole, whereas benzox-azole quaternizes 26 times faster than does 1,2-benzisoxazole. 

Dihydropyrazoles and -isoxazoles 502 (Z = NH, O) are cyclic hydrazones and oximes, respectively. 4,5-Dihy-dropyrazoles are quaternized at the 1-position (502 503). 2,3-Dihydro-l,3,4-oxadiazoles (e.g., 504) are very easily ring opened hydrolytically. 

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). 

The hypothesis that oximes with a positive charge on nitrogen are reductively cleaved at N-O is supported by the observation that after quaternization, isoxazoles or 4,5-dihydroisoxazoles can be cleaved in neutral solution without reduction of the C=N bond [253]. As isoxazolines can be made conveniently from alkenes and oximes (through nitrile oxides), this is a convenient way of preparing )6-hydroxyketones the use of CPE makes it possible to tolerate substituents that are attacked by other reducing agents. 

Quaternization of the isoxazole nitrogen atom makes the ring particularly susceptible toward nucleophilic attack there is a certain analogy here with pyridine. The cleavage of the ring proceeds extremely readily in quaternary salts of isoxazole, even occurring by the action of such weak nucleophilic agents as the anions of carboxylic acids. 

Another example is provided by the quaternization of a saturated pyrrolo[l,2-6]isoxazole with methanesulfonyl chloride and further treatment with Zn powder in aqueous acetic acid <82T2627>. When compound (152) was treated with Zn in aqueous acetic acid at 50-60 °C, the isoxazolidine underwent reductive N—O bond cleavage with in situ cyclization to afford pyrrolizidine (153) in 86% yield. When (152) is treated directly with Zn in 90% aqueous acetic acid at higher temperature (130-140°C) and prolonged reaction time, pyrrolizidine (154) is obtained (Scheme 28) <85CPB351>. 

Isoxazoles are very weak bases (parent compound PIQ, = —2.97). Protonation occurs at the N-atom, Hkewise quaternization by R-X or (R0)2S02-... 

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. 

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