5-Amino-4-methylthiazole, reaction with

The halogen in the 5-position of 2-aminothiazoles is usually reactive and is used for further reaction (see Chapter V). The reaction may take place in the same medium as thiocyanation (437-440), rhodanation (441). or reaction with NaNO (435). Similarly, a mixture of 2-amino-4-methylthiazole and thiourea in H2O yields 5,5 -thiobis(2-amino-4-methyDthiazole (202) after addition of iodine (Scheme 128) (442). 

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,... 

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... 

Under appropriate conditions activated thiazoles are alkylated at the 5-position 2-amino 4-methylthiazole is alkylated in the 5-position by heating with /-butyl alcohol in sulfuric acid (24). Under similar conditions 4-methyl-2-phenylthiazole is alkylated by cyclohexanol. 2-Acetylamino-4-methylthiazole reacts with dimethylamine and formaldehyde to afford the corresponding Mannich base (25). 2-Hydroxy-4-methyIthiazole fails to react when submitted to Friedel-Crafts benzoylation conditions whereas it reacts normally in Gatter-mann and in Reimer-Tiemann formylation reactions yielding the 5-formyl derivative (26). 2,4-Dimethylthiazole undergoes perfluoroalkylation when heated at 200 °C for 8 h in a sealed tube with perfluoropropyl iodide and sodium acetate (27). 

The sodium salt of saccharin is first alkylated with methyl chloroacetate, and then rearranged with sodium methoxide to a benzothiazinone. Methylation at the nitrogen and then reaction with 2-amino-5-methylthiazole or with 2-ami-nopyridine gives meloxicam and piroxicam respectively. 

Reactions of 2-Amino-thiazoles.—K number of 2-amino-thiazoles have been diazotized and the resulting diazonium compounds used in synthesis. 2-Amino-4-(l- or 2-naphthyl)-thiazoles undergo the Mannich reaction with paraformaldehyde and acetophenone, whilst dehydro-iV-Mannich bases are formed on heating 2-amino-thiazoles with 1,3,5-triazine in the presence of secondary amines for example, 2-amino-4-methylthiazole gives compound (36). ... 

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 pre paration. 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 little 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 coohng in ice to a solid, m.p. 44-45°. The yield is 84 g. 

This reaction, thoroughly studied for 2-aminopyridine (14, 15), has received less attention in the case of the thiazole nucleus. 2-Amino-4-methylthiazole is formed when 4-methylthiazole is heated with sodium amide for 15 hr at 150°C (16). This reaction was used to identify 2-amino-4-butylthiazok (17). 

Maleic anhydride condenses with 2-aminothiazole-4-carboxylic acid giving the raaleimide 107 (269) another report claims, however, that the reaction of 2-amino-4-methylthiazole with this anhydride gives the N-substituted maleamic acid (108) (Scheme 73) (270). 

Amino-4-phenylthiazole when heated with Raney Ni is reported to yield acetophenone (469). In the course of a general study on reductive cleavage in heterocyclic systems Hoff et al. studied the reaction of 2-amino-4-methylthiazole with Na in liquid ammonia. Two equivalents of Na are necessary to obtain a mixture of 4-methyl-3-thiazoline (240) and... 

Synthesis The reaction of benzothiazolo-3(2H)-one-1,1-dioxide with methyl chloroacetate gives the methyl 2(3H) acetate derivative, which is isomerized with sodium methoxide in toluene/terf-butanol yielding methyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1 -dioxide. The subsequent methylation with methyl iodide in methanol yields the 2-methyl compound. Finally this compound is treated with 2-amino-5-methylthiazole in xylene (Trummlitz et al. (Thomae GmbH), 1979 Trummlitz et al., 1989 Kleemann et al., 1999). 

Rearrangement of 2-hydrazino-4-methylthiazole (291) to 2-amino-5-methyl-l,3,4-thiadiazine (296) in acidic medium has been reported (514. 531). We suggest that this reaction occurs by way of the retro-Hantzsch mechanism (Scheme 175). In this mechanism, a succession of reversible steps leads to the open-chain product (294), which can either revert to the starting product (291) or react further to give the thiadiazine (296). The whole reaction is expected to be reversible through this mechanism. The reaction would proceed from thiadiazine to 2-hydrazinothiazole if the 4-nitrogen atom and the 5-carbon atom of the thiadiazine were both substituted with bulkyl alkyl groups (343, 537). 

Examples in which heterocyclic haloarenes have been used include the photostimulated reactions of 2-chlorothiazole, 2-chloro-4-methylthiazole and 2-chloro-5-methylthiazole with pinacolone potassium enolate which lead to the formation of mono- and bis-2-thia-zolyl ketones672 and a study of the reactions of 3-halo-2-amino derivatives of benzo[ ]thio-phene with the potassium salts of acetophenone, pinacolone and cyclohexanone which indicated that, under S l conditions, mainly reduction products were formed673. 

Methyl-5-(2-furyl)-4-nitrothiazole and 2-methyl-4-nitrothiazole were isolated from the mixture of products from the reaction of 5-amino-2-methylthiazole-4-carboxylic acid with isoamyl nitrite in the presence of furan [421],... 

Seventy-six grams (i mole) of thiourea is suspended in 200 cc. of water (Note i) in a 500-cc. flask equipped with a reflux condenser, dropping funnel, and mechanical stirrer. The stirrer is started, and 92.5 g. (i mole) of chloroacetone (Note 2) is run in during thirty minutes. As the reaction proceeds the thiourea dissolves and the temperature rises. The yellow solution is refluxed for two hours and cooled, and, while the mixture is stirred continuously but not so rapidly as to produce a troublesome emulsion, 200 g. of solid sodimn hydroxide is added with cooling. The upper, oily layer is separated in a separatory funnel and the aqueous layer is extracted three times with ether, using a total of 300 cc. (Note 3). The dark red oil is combined with the ethereal extract, and the solution is dried over 30 g. of solid sodium hydroxide and filtered by gravity to remove small amoimts of tar. The ether is removed by distillation from a steam bath, and the oil is distilled at reduced pressure. After a very small fore-run, the 2-amino-4-methylthiazole is collected... 

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