Sulfonation of thiazole

Direct sulfonation of thiazole, as well as of 2-substituted thiazoles, leads mostly to substitution m the 5-position (330-332). 4-Thiazole sulfonic acid has been prepared through direct sulfonation of 2.5-dibromothiazole with subsequent Rane% Ni reduction (330). Sulfonation of 2.5-dimethyl- and 2-piperidyl-5-methylthiazoles affords the corresponding 4-sulfonic acids as barium salts (247). The 2-hydroxy group facilitates the sulfonation (201. 236). When the 4- and 5-positions are occupied direct sulfonation can occur in the 2-position. 5-hydroxyethyl-4-methyl-2-thiazole sulfonic acid has been prepared in this manner (7). 

Although sulfonation of thiazole only takes place under forcing conditions, it is possible to prepare 5-thiazole sulfonic acids using SO3 as sulfonating agent. The reaction must be carried out using three equivalents of sulfur trioxide. The use of one equivalent of sulfur trioxide leads exclusively to the formation of the thiazolium salt <87KGS1353>. 

As in the case of oxazoles, the pyridine-like N-atom makes electrophilic substitution reactions more difficult. Thus thiazole does not react with halogens. Donor substituents enhance the reactivity, e.g. 2-methylthiazole reacts with bromine to give 5-bromo-2-methylthiazole. Thiazole cannot be nitrated. 4-Methylthiazole reacts slowly to yield the 5-nitro compound, 5-methylthiazole even more slowly to give the 4-nitro compound, but 2,4-dimethylthiazole reacts fastest producing 2,4-dimethyl-5-nitrothiazole. Sulfonation of thiazole demands the action of oleum at 250°C in the presence of mercury(II) acetate, and occurs at the 5-position. Acetoxymercuration of thiazole with mercury(II) acetate in acetic acid/water proceeds stepwise by way of the 5-acetoxymercury compound and the 4,5-disubstituted product to 2,4,5-tris(acetoxymercury)thiazole. 

Sulfonation of thiazole requires the action of oleum at 250 °C in the presence of Hg(II)-acetate as activator and leads to the 5-sulfonic acid. 

No nitration of thiazole occurs with the classical nitration reagents, even in forcing conditions (341-343). In a study concerning the correlation between the ability of thiazole derivatives to be nitrated and the HNMR chemical shifts of their hydrogen atoms, Dou (239) suggested that only those thiazoles that present chemical shifts lower than 476 Hz can be nitrated. From the lowest field signal of thiazole appearing at 497 Hz one can infer that its nitration is quite unlikely. Thiazole sulfonation occurs... 

DiaminO 4,4-dimethyl-l,3,5-thiadiazine hydrobromide was isolated as by-product (418). Benzene sulfonates of cyanohydrin prepared from sodium cyanide and an halobenzoaldehyde, when treated with thiourea or its derivatives, afford 2,4-diamino-5-(p-halogenophenyl)-thiazole benzene sulfonates (447). Similarly, cyanoamido thiocarbamates obtained from cyanamide and isothiocyanates yield substituted 2,4-diaminothiazoles (598). 

Heteroaromatic sulfur compounds do form sulfoxides and sulfones, but these derivatives have their own special reactivity. Francesca Clerici (Milan, Italy) has now provided an up-to-date survey of the preparation and properties of the S-oxides of thiazoles and thiadiazoles, collecting literature scattered in many publications. 

The sulfur atom of thiazole has been reported to be resistant to oxidation to sulfoxide or sulfone <1996CHEC-II(3)373>. Desulfurization with Raney-nickel has been reviewed <1984CHEC(6)235>. 

Direct Anionic and sodium sulfonates of azo, stilbene, oxazine, and thiazole. 

The -oxidation of thiazoles to sulfoxides or sulfones has not been reported. Under base conditions both thiazoles and benzothiazoles are resistant to the action of PhI(OAc)2 <88IJC(B)929>. Raney Nickel promotes desulfuration of thiazoles, probably through an initial coordination of the sulfur at nickel, affording carbonyl compounds <84CHEC-I(4)240>. 

In fuming sulfuric acid (20% oleum) 2 aminothiazole (16. 27. 375. 389) and 2-amino-4-methylthiazole (374. 390) are sulfonated in the 5-position. When this position is substituted as in 2-amino-5-methyl-thiazole (27, 391) very small amounts of 4-sulfonation occur. 

Oxidation, already described in neutral and acidic media, may also be performed in basic medium. An alkaline solution of H2O2 reacts with 4-thiazoline 2-thione to yield thiazole-2-sulfonic acid (201-203), whereas alkaline oxidation performed with (NH )2S20g yields the disulfides (148). 

Action of HSO3CI on 2-substituted thiazoles affords the 5-chlorosulfonyl derivatives (337, 338). Addition of 6-phenylthiazolo[2,3-e]tetra2ole to oleum opens the tetrazole ring to form 2-azido-4-phenyI-thiazolyl-5-sulfonic acid, isolated as its salt (339). 5-Chloro-sulphonyl derivative is obtained similarly by action of HSO,Cl. 

Similarly, 5-thiazole alkanoic acids and their salts are obtained from thioamides and /3-halo -y-keto acids (695). Thus thioarylamides condensed with 3-aroyl-3-bromopropionic acid (88) in isopropanolic solution in the presence of Na COs give first 4-hydroxy-2-aryl-A-2-thiazoline-5-acetic acid intermediates (89), which were dehydrated in toluene with catalytic amounts of p-toluene sulfonic acid to 2,4-diaryl-5-thiazole acetic acid (90) (Scheme 39) (657), with R = H or Me Ar = Ph, o-, m- or p-tolyl, o-, m-, or P-CIC6H4, 0-, m-, or p-MeOC(iH4, P-CF3C6H4, a-thienyl, a-naphthyl (657). 

In azole chemistry the total effect of the several heteroatoms in one ring approximates the superposition of their separate effects. It is found that pyrazole, imidazole and isoxazole undergo nitration and sulfonation about as readily as nitrobenzene thiazole and isothiazole react less readily ica. equal to m-dinitrobenzene), and oxadiazoles, thiadiazoles, triazoles, etc. with great difficulty. In each case, halogenation is easier than the corresponding nitration or sulfonation. Strong electron-donor substituents help the reaction. 

The free base d(-f)6-phenyl-2,3,5,6-tetrahydroimida2o[2,1-bl thiazole Is dissolved in 112 ml of acetone and 178 ml of isopropanolic hydrogen chloride is added all at once. The hydrochloride crystallizes et once. After cooling to below 0°C, the salt is recovered by filtration and washed with acetone. The product weighs 75.2 g (0.312 mol), 91%, from the camphor-sulfonate, melting point 227 C to 227.5°C [alpM-H23.1°C (C = 15.H20). 

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