5- -4-methylthiazoles, preparation

Methyl iodide, reactions with dialkyl-amino-thiazoles, 32. See also Alkylation 4-Methylthiazole, preparation of, from Na/NH3 reduction of 4-methyl-A-4-thiazoline-2-thione, 397 2-Methylthio-3-methylthiazolium salts, as catalyst for methylthiothiazole rearrangement, 406 Methylvinylketone, reaction of, with... 

Vollmann found that the reaction between l-imino-3-amino isoin dolenine (124) and 2-amino-4-methylthiazole is catalyzed by ammonium chloride and involves the exocyclic nitrogen (285). This reaction (Scheme 82) was later used to prepare dyes (286). 

Attempts to prepare the diprOpylamino-5-sulfonic acid by sulfonation in oleum failed (385). With 2-piperidino-4-methylthiazole Ochiai reports cleavage of the 2-piperidino ring (391). 

The rearrangement discovered by Kolosova et al. probably involves such reactivit (159). This reaction provides a good preparative method for various 5-amino-methylthiazoles (Scheme 43). No mechanism is proposed in the report, and it is not easy to understand how the C-5 enamine-like position competes with the very nucleophilic thiocarbonyl group of the formed A-4-thiazoline-2-thione. An alternative mechanism could start with ethanol addition at C-2. leading to the A-4-thiazoline (90) (Scheme 44). In this intermediate, C-5 nucleophilic reactivity would be favored bv the true enaminic structure. After alkylation on C-5,... 

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). 

In I887, Hantzsch and Weber (1) proposed the structure of p-amino-Q-methylthiazole (66) for the Rhodanpropimin prepared by Tcherniac and Norton (18), and, until then, believed to be thiocyanoacetoneimine (65). 

Schatzmann, in 1891, tried to prepare 2-thiazolines by hydrogenation of thiazoles and by the action of sodium and ethanol on 2,4-dimethyl-thiazole, 2-methylthiazole, and 2-methyl-4-phenylthiazole (476). None of these substrates was reduced to thiazoline the second gave no reaction and the first underwent ring cleavage, leading to a mixture of n-propylmercaptan and ethylamine (Scheme 90). Three years later the same... 

For example, with thioacetamide prepared in situ in dioxane solution at 45 C, Cottet and Metzger (578) prepared the 4-methylthiazole (3), R] = Me, in 39% yield, while Erlenmeyer et al. (285) obtained a similar result in benzene and acetic anhydride. 

Hydroxy-4-methylthiazole has been prepared in 68% yield through the reaction of barium thiocyanate with chloroacetone (70). 

Alkylthiazoles can be oxidized to nitriles in the presence of ammonia and a catalyst. For example, 4-cyanothiazole was prepared from 4-methylthiazole by a one-step vapor-phase process (94) involving reaction with a mixture of air, oxygen, and ammonia at 380 to 460°C. The catalyst was M0O3 and V Oj or M0O3, VjOj, and CoO on an alumina support. 

As mentioned previously, aldehydes can be prepared by Stephen s method of reduction of nitriles by stannous chloride (37, 91). Polaro-graphic reduction of thiazolecarboxylic acids and their derivatives gives lower yields of aldehydes (58). Ozonolysis of styrylthiazoles, for example, 2-styryl-4-methylthiazole, followed by catalytic reduction gives aldehyde with 47% yield of crude product (30). 

Amino-5-methylthiazole. Suspend 76 g. of thiourea in 200 ml. of water in a 500 ml. three-necked flask equipped as in the preceding preparation. Stir and add 92-5 g. (80 ml.) of monochloroacetone (1) over a period of 30 minutes. The thiourea dissolves as the reaction proceeds and the temperature rises. Reflux the yellow solution for 2 hours. To the cold solution immersed in an ice bath add, with stirring, 200 g. of solid sodium hydroxide. Transfer to a separatory funnel, add a httle ice water, separate the upper oil layer and extract the aqueous layer with three 100 ml. portions of ether. Dry the combined oil and ether extracts with anhydrous magnesium sulphate, remove the ether by distillation from a steam bath, and distil the residual oil under diminished pressure. Collect the 2-amino-5-methylthiazole at 130-133°/18 mm. it solidifies on cooling in ice to a solid, m.p. 44-45°. The yield is 84 g. 

Hydroxy-4-methylthiazole-2(3//)thione carbamates, e.g. the cyclohexyl derivative 336, are precursors for monoalkylaminium cation radicals, which cannot be prepared from 2-thioxopyridinyloxycarbamates. The carbamate is obtained from 3-hydroxy-4-methylthiazole-2(3//)-thione and cyclohexyl isocyanate. When irradiated in the presence of malonic acid and /-butyl hydrogen sulphide it yields the cyclohexylaminium cation... 

Commercially available 5-hydroxyethyl-4-methylthiazole has been used in the preparation of the azomethine ylides (588) and (589) (81TL2727). These reacted in good yield with several unsaturated alkenes to provide the adducts (590) which cyclized on silica gel chromatography to (591). The product with X = OEt and Z = C02Et was further transformed into the pyrrole (592) by reaction with methanesulfonic acid in methanol followed by quenching with triethylamine (Scheme 129). 

This nucleophilic reactivity of 2-aminothiazoles has been used to prepare biheterocyclic compounds. Thus 2-aminothiazole reacts with chlorovinyl methyl ketone yielding 5-methyl-thiazolo[3,2-a]pyrimidinium chloride (Scheme 109). In the presence of formaldehyde, aminothiazoles react with ends affording condensation products, through the intermediacy of Mannich bases (Scheme 110). In acidic medium and at higher temperatures, condensation of 4-aryl-2-aminothiazole with benzaldehyde takes place at the C-5 position (Scheme 111). The same orientation is observed when 2-amino-4-methylthiazole is alkylated by secondary or tertiary alcohols in 85% sulfuric acid (Scheme 112). 

Methylthiazol - 2-yl)-10-(2 - methyl - 3 - dimethy laminopropyl )-phenothiazine (176) was prepared from 2-thiocarboxamido-10-(2-methyl-3-dimethyIaminopropyl)phenothiazine (175) and chloro-acetone. ... 

Thiazole-N oxides are prepared by the action at low temperature (—10°C) of hydrogen peroxide in acetic acid (474). 4-Methylthiazole and 2,4-dimethylthiazole afforded the corresponding N-oxides with yields of 27 and 58%, respectively (Scheme 88). Thiazole-N-oxides without a methyl group in the 2-position are so unstable that they have a tendency to form 2-hydroxythiazoles and are decomposed by oxidation, whereas a 2-methyl group would prevent such rearrangement (474). 

Thiazole A -oxides can easily be alkylated on the oxygen. For example, Ar-(alkoxy)-5-(p-methoxyphenyl)-4-methylthiazole-2(377)-thiones were prepared from Ar-(hydroxy)-5-( -methoxyphenyl)-4-methylthiazole-2(3//)-thione tetraethylammonium salt and an appropriate alkyl chloride or tosylate in moderate to good yields <20060BC2313>. A -Methoxythiazole-2(377)-thiones were synthesized from the A -hydroxythiazole-2(3//)-thiones by treatment first with a tetraalkylammonium hydroxide in methanol and then methyl ra-toluenesulfonate in DMF <2005EJ0869>. 

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