Isothiazoles quaternization

Although isothiazole (pK = 1.90) is less basic than thiazole, its rale of quaternization by dinitrophenyl acetate in water at 52°C is approximately 2.5 times higher (447). This deviation from the Bronsted relationship (A log k - 0.ApK, with positive) is interpreted as a consequence of the or effect of the adjacent sulfur lone pair in isothiazole that is responsible for its higher nucleophilicity (448, 449). 

Thus quaternized thiazoles (170) consume two equivalents of OH on titration because the pseudo bases (171) ring open to (172), which form anions (173). Quaternized oxazoles (174) are readily attacked by hydroxide to give open-chain products such as (175) (74AHC(17)99), and quaternized 1,3,4-oxadiazoles behave similarly. Quaternary isothiazoles (e.g. 176) are cleaved by hydroxide (72AHC(l4)l), as are 1,2,4-thiadiazolium salts (177 178). 

The isothiazole ring is very stable to moderate heating, but quaternized compounds are dequaternized by this means (see Section 4.02.3.12). Photolysis of isothiazole itself causes loss of hydrogen cyanide, forming thiirene, but substituted compounds are converted into mixtures of thiazoles and isothiazoles isomeric with the starting compound (Section 4.1.1.2). 

Isothiazoles and 2,1-benzisothiazoles are stable to most nucleophilic reagents, but quaternized compounds are dequaternized and/or suffer cleavage of the N—S bond. 

There are many references in the patent literature to azo dyes prepared from 4- and 5-aminoisothiazoles, 3-, 5- and 7-amino-1,2-benzisothiazoles, and their quaternized derivatives. These are particularly useful in the dyeing of synthetic fibres. Isothiazole compounds have also been suggested for other industrial purposes, such as corrosion inhibitors, fireproofing agents, additives in rubber vulcanization, photographic chemicals and fluorescent whiteners in detergents. 

Beckmann rearrangement, 6, 156 Isothiazole, 3-alkoxy-tautomerism, 6, 145 Isothiazole, alkyl-bromination, 5, 58 Isothiazole, 3-alkyl-5-amino-synthesis, 6, 166 Isothiazole, alkylthio-mass spectra, 6, 142 Isothiazole, amino-azo dyes from, 1, 330 tautomerism, 6, 157 Isothiazole, 3-amino-synthesis, 5, 135 tautomerism, 6, 146 Isothiazole, 4-amino-azo dyes from, 6, 175 diazotization, 6, 158 methylation, 5, 95 quaternization, 6, 158 reactions... 

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. 

Chloroethylamino)isothiazole (111) cyclizes to 3-aziridinylisothiazole (112) under the influence of potassium t-butoxide, but undergoes intramolecular quaternization if kept at 50 °C for two days, to give compound (113 Scheme 14) (79JOC1118). 

The 2-benzyl-sustituted salts 78 were prepared by quaternization of isothiazole 74 with benzyl bromide, iodide, fluorosulfonate and tosylate. 5-Phenylisothiazole 74 (R1 = R2 = H, R3 = Ph) reacted difficultly to salt 27c (10%) but 3,5-diphenyl-isothiazole are resisted quaternization by benzyl halides (27c,78a,b 72JCS(P1)2305 78b-d 65JCS(C)4577 78e 92JPR25, Scheme 23). 

The 4-chloromethyl isothiazole 86, which could be obtained from the isothiazolyl carbinol by treatment with thionyl chloride, was very reactive towards nucleophilic reagents. Thus 4-chloromethylisothiazole 86 underwent a self-quaternization to form the 4-chloromethyl-3-methyl-2-(3-methylisothiazol-4-ylmethyl)isothiazolium chloride 87 (68JCS(C)611, Scheme 27). 

The reactivity of isothiazolium salts toward nucleophiles is higher than that of isothiazoles. Therefore, on quaternization of isothiazoles to isothiazolium salts, the tendency of nucleophilic ring opening increases. 

Quaternization of isothiazole increases the tendency for nucleophilic ring cleavage. Accordingly, 2-phenylisothiazolium bromides 291 reacted with benzylamine or... 

Chemical Properties. - WQuatemization of Isothiazoles. 3-Chloroisothiazole is quaternized by FSOsMe the salt is then treated with MeNH2 and passed through an ion-exchanger (Cl ) to give (19 R = R = Me Z = Cl). Other... 

Isothiazoles are N-quaternized by iodoalkanes, dialkyl sulfates, and trialkyloxonium tetrafluoroborates. 

Alkylation. Rates of quaternization of isothiazole and its 2,1 and 1,2-benzologues have been examined as a part of a wider study on azoles. The isothiazoles react with methyl iodide in DMSO, and with dimethyl sulphate, affording novel A -methyl derivatives. Benzo-fusion exerts a rate-diminishing effect, but this influence is very small in 1,2-benzisothiazole. The stability of the heterocycles apparently increases in the order 2,1-benzisoxazole < iV -methylindazole < 2,1-benzisothiazole, which parallels the well-established order of stability and aromaticity of furan < pyrrole < thiophen. ... 

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