2-Mercapto-4-

Williamson s lethod, more particularly lor hydroxy- and thloT (mercapto) compounds. The substance is treated either directly with sodium or (more usually) with a solution of sodium methoxide in methanol, to give the sodium derivative. The latter is then boiled with methvl iodide. 

The reaction of 2-mercapto-4-phenylthiazole with morpholine yields 2-morpholino-4-phenylthiazole (3) (Scheme 3) (31). 

The nucleophUic reactivity in neutral medium has been used extensively to prepare various thioethers of thiazole (122). In acidic medium, alkylation may be performed with alcohols (123, 124). An unexpected reaction encountered was the decarboxylation of 2-mercapto-4-methyl-5-thiazolecarboxyhc acid (60) when treated with butyl alcohol under acidic conditions (Scheme 27) (123). Reaction between A-4-thiazoline-2-thione... 

A-2-Thiazoline-5-thiones are generally not obtained by direct heterocyclization reactions (352). Instead, most of the reported preparations involve reactions in which the thiazole ring is already formed with the suitable mercapto precursors in the 5-position. 

Thus reduction of the 5-thiocyanato group of 151 by zinc (333, 360, 361) or aqueous sodium sulfide (348. 362), hydrolysis of the thiouronium group (7, 363, 364), and deacetylation of the 5-acetylthiothiazole with cold piperidine (365) have been performed to yield the 5-mercapto-thiazole (Scheme 78). It must be pointed out that depending on the experimental conditions, bis(5-thiazolyl(sulfide may be observed as a byproduct (363, 365). Thus 5-amino-4-methylthiazole (152) treated with... 

Mercapto- or 4-alkylidenethia2oIium hydroxide inner salts (1) (X = S or CRR ) have not been described. 

Dipolar reactivity of 5-mercapto-THISs has only been demonstrated for 16 (X = S), which, like its oxygen analog, produces with dimethylfumarate, 17. and with phenylisothiocyanate, 21 (25). Compound 16 (X = S) does not react with other typical dipolarenophiles (25). 

MercaptO THISs react with dimethoxycarbonylacetylene, producing tetramethoxycarbonylthiophene by an unknown mechanism (29). 

Mercapto-imida2oliuin inner salts have been reported to rearrange under the influence of hydrochloric acid, producing S-aminothiazolium chlorides (Scheme 25) (36). Their N-acylated derivatives are obtained by cyclization of N-thiobenzoyl alkylaminoacetonitriles, effected with acyl or sulfonyl halides (Scheme 26) (34, 35). 

The interesting reactions where a free mercapto group is linked to the nitrogen atom of the thiazole (63), after the cleavage of a fused ring, is another illustration of the additive properties of the carbocation (Scheme 40). 

In 1890, Gabriel and Lauer (92) established that a-bromoamines react with CS2 to give 2-mercaptothiazolines (61). In the same laboratory, Hirsch (93) reacted /x-mercapto -methylthiazoline (61) with various alkyl iodides and obtained the corresponding S-alkyl derivatives. 

Heating 5-amino-4-mercapto pyrimidines (61) with formic acid affords the corresponding thiazolo[5,4d]pyrimidines (62) (Scheme 28) (357, 382, 411, 431). 

The more reactive bromacetone gives not only 2-mercapto-4-methylthiazole but also its substitution products. The higher homologs, as far as C15. are obtained in reasonably good yield in absolute ethanol (150, 156. 234. 316, 530). The best result (85%) was obtained by working in aqueous solution with the 3-bromobutan-2-one (597). 

Ethyl-cf-chloroacetoacetate gives 5-carbethoxy-4-methyl-2-thiazole thiol (387), while 3-chloro-2,4-pentanedione affords the 2-mercapto-4-methyl-5-thiazolylmethylketone in good yield (74%) (387). 

Similarly, ethylbromopyruvate yields ethyl-2-mercapto-4-thiazole car-boxylate (488). 

Thioacids (191) react with ia -thiocyanatoacetophenone to produce 2-mercapto-4-phenylthiazole (192) (Scheme 99). With tbioacetic acid 192 is obtained directly while with thiobenzoic acid, an acyclic intermediate (193) has been isolated that is cyclized by heating with dilute acid (Scheme 100) (143). 

Other sulfur compounds such as thiourea, ammonium dithiocarbamate, or hydrogen sulfide also lead to 2-mercaptothiazoles. Thus thiourea has been used in the syntheses of 4,5-dimethyl (369) and 4-aryl-2-mercapto-thiazoles (Table 11-30) (519). The reactions were carried out by condensing the ia -thiocyanatoketones with thiourea in alcohol and water acidified with hydrochloric acid. By this procedure, 4-aryl-2-mercaptothiazoles were obtained in yields of 40 to 80% with bis-(4-aryl-2-thiazolyl) sulfides as by-products (519). These latter products (194) have also been observed as a result of the action of thiourea on 2-chloro-4-arylthiazole under the same experimental conditions. They can be separated from 2-mercaptothiazoles because of their different degrees of solubility in sodium hydroxide solution at 5%. In this medium bis-(4-phenyl-2-thiazolyl)sulfide is... 

The behavior of the 2-mercapto-4-arylthiazoles in this reaction would seem to be analogous to that of the 2-mercaptobenzothiazoles (137). It appears that monosulfide compound (195) cannot be obtained from 2-chloro- and 2-mercapto-4-phenylthiazoles (given the difficulty of preparing it in this way) but rather by the action of the 2-mercapto-4-phenyl-thiazole on the intermediary, 4-phenyl-2-isothiazolyl isothiouronium chloride (194), as in Scheme 101. 

Carbon disulfide readily reacts with a-aminonitriles giving 2-mercapto-5-aminothiazoles (213), (271, 293) which can be converted to 5-aminothiazoles unsubstituted in the 2-position (Scheme 110 and Table II-34a). If this reaction is carried out in the presence of benzyl chloride in phosphorus tribromide, a 2-S-substituted thiazole derivative (214) is obtained in quantitative yield (Scheme 111), with R = hydrogen or phenyl (68, 304). 

TABLE II-34a. 2-MERCAPTO-5-AMINOTH1AZOLE DERIVATJVES FROM a-AMINONITRUJES and carbon disulfide... 

When benzaldehyde or its substituted derivatives are added to carbon disulfide and a-aminonitrile, the corresponding 2-mercapto-5-(p-R-benzylideneamino)thiazoles (215), R = hydrogen atom or a propenyl or phenyl group and Ar = aryl, are obtained (Scheme 112) (393, 442, 694). Yields ranged from 40 to 60% (Table II-34b). 

Acetone reacts similarly to give the corresponding 2-mercapto-5-isopropylideneaminothiazoles (68, 293, 304). 

VI. THIAZOLES FROM IVITRILES AND a-MERCAPTO-KETONES OR ACIDS 2,4-DISUBSTITUTED AND 4-HYDROXYTHIAZOLE DERIVATIVES... 

The cyclization of a-mercaptoketones with ammonium thiocyanate leads to the corresponding 2-mercaptothiazoles (144). For example, 2-mercapto-3-pentanone in ethereal solution with sulfuric acid gives 4-ethyl-5-methyl-2-mercaptothiazole (10), Ri = SH, R2 = Et, R3 = Me, when allowed to stand for 3 hr without heating with ammonium thiocyanate. 

HYDROXYTHIAZOLE DERTVATIVES FROM NITRILES AND a-MERCAPTO ACIDS... 

This method has mainly been used to prepare thiazoles nonsubstituted in the 2-position and involves the replacement of a functional substituent (amino, halo, mercapto, hydroxy, or carboxy) by a hydrogen. In this way the often delicate cyclization of thioformamide can be avoided. 

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