Isoxazole-4-sulfonic acid

The iso)tazole ring is rather resistant to sulfonation. However, on prolonged heating with chlorosulfonic acid, 5-methyl-, 3-methyl- and 3,5-diraethyl-isoxazoles are converted into a mixture of the sulfonic acid and the corresponding sulfonyl chloride. The sulfonic acid group enters the 4-position even when other positions are available for substitution. The sulfonation of the parent isoxazole occurs only under more drastic conditions (20% oleum) than that of alkyl isoxazoles isoxazole-4-sulfonic acid is obtained in 17% yield. In the case of 5-phenylisoxazole (64), only the phenyl nucleus is sulfonated to yield a mixture of m-and p-arenesulfonic acid chlorides (65) and (66) in a 2 1 ratio (63AHC(2)365). 

It was not until 1940 that the sulfonation of alkylisoxazoles by heating them with chlorosulfonic acid was reported. This gave a mixture of isoxazole-4-sulfonic acids (58) and their acid chlorides (59). The position of the sulfonic group in derivatives of monomethyl isoxazoles has been proved by nucleophilic cleavage of the isoxazole ring (60 61). Recently it proved possible to sulfonate isoxazole... 

In these compounds the following substituents can be present alkyl,alkenyl,aryl, halogen,sulfonic acid, amino, hydroxyalkyl, acyl, and carboxyl. The cleavages of 5,5 - (109) and 3,5 -diisoxazolyl (111) proceed similarly both isoxazole rings are cleaved in the former (109—> 110). ... 

In the second example, Hamelin et al. [47] reported the first microwave-assisted solvent-free catalyzed conditions for generation of nitrile oxide intermediates 17. In this work, a mixture of methyl nitroacetate 16 (as 1,3-dipole precursor), dimethyl acetylene dicarboxylate (DMAD) 18 (as dipolarophile), and p-toluene sulfonic acid (PTSA) as catalyst (10% w/w) was irradiated neat for 30 min. The reaction was performed in an open vessel from which water was continuously removed [48]. In this manner, the desired isoxazole adduct 19 was obtained in excellent yield (91%). 

The first report of the use of cellulose beads as support for microwave-assisted SPOS was published in 2003 and described the generation of a library of pyrazoles and isoxazoles [49]. The synthesis was performed using commercially available amino cellulose (Perloza VT-100) containing aminoaryl ethyl sulfone groups in flexible chains (Scheme 16.27). Initially, the solid support was treated with excess formyl imidazole and the corresponding yS-keto compounds to generate cellulose-bound enaminones in a one-pot Bredereck-type condensation. The reaction was catalyzed by (+)-camphor-10-sulfonic acid (CSA) and performed under microwave-irradiation conditions in an open vessel to enable the methanol formed to be removed from the reaction equilibrium [49]. 

An aq. soln. of NaHCOg added to a stirred soln. of / -ionone oxime (prepared from / -ionone, hydroxylamine hydrodiloride, and K-carbonate in water-ethanol) in tetrahydrofuran, protected from light, KI and iodine in water added, and refluxed 4 hrs. -> isoxazole deriv. (Y 91%) mixed with liq. NHg, tetrahydrofuran, and rerf-butanol, treated with Na until the soln. remains dark blue, stirred 15 min., and the crude / -aminoketone refluxed 24 hrs. with a trace of p-toluene-sulfonic acid in toluene / -damascone (Y 84%). F. e. s. G. Budii and J. C. Vederas, Am. Soc. 94, 9128 (1972) s. a. K. H. Sdiulte-Elte, B. L. Muller, and G. Ohloff, Helv. 56, 310 (1973). 

Isoxazole reacts with 20% oleum at 90 °C to give a low yield of the 4-sulfonic acid (17%). The isoxazole ring is found to be rather resistant to sulfonation with the 4-position the most favoured site of attack. The action of boiling excess chlorosulfonic acid on 3- and 5-methylisoxazole gave a mixture of the 4-sulfonic acid and the 4-sulfonyl chloride, whereas 3,5-dimethylisoxazole on similar treatment afforded only the 4-sulfonic acid derivative. " " However, 3,5-dimethylisoxazole, by dropwise treatment with chlorosulfonic acid at 80 °C, heating at 110 °C (2 hours), followed by further heating with thionyl chloride at 60-110 °C for 2 hoins, afforded an excellent yield of the 4-sulfonyl chloride (81.7%)." ... 

Sulfonation of isoxazoles has been less extensively studied than nitration. This is possibly due to the difficulty encountered in isolating isoxazolesulfonic acids and to the ambiguous reaction course. 

A quantitative study has been carried out by Ridd and co-workers126 on the nitration of imidazole and pyrazole in 98% sulfuric acid the partial rate factors for the 4-positions of imidazolium and pyrazolium cations are 3.0 xlO-9 and 2.1 x 10-10, respectively. Thiazole and isoxazole cations are also far less reactive than benzene. As a consequence, phenyl derivatives give products substituted in the benzene ring, on sulfonation or nitration.208-210... 

Electrophilic sulfonation of isoxazole is of no preparative value the substitution of only the phenyl-substituent of 5-phenylisoxazole with chlorosulfonic acid makes the same point. Both isothiazole and pyrazole can be satisfactorily sulfonated at C-4. 

---