ETHYL THIAZOLE-4-CARBOXYLATE

The submitters reported a yield of 5.8 g. (92%) of product as white needles, m.p. 53-54°. However, the checkers obtained colourless needles only after recrystallizing the product from hexane. The melting points of the discolored needles obtained initially by the checkers and the recrystallized material were the same. Melting points of 57° and 52-54° are recorded in the literature for ethyl thiazole-4-carboxylate. The spectral properties of the product are as follows infrared (chloroform) cm. 3130, 3030,... 

THIAZOLES FROM ETHYL ISOCYANOACETATE AND THIONO ESTERS ETHYL THIAZOLE-4-CARBOXYLATE... 

Ethyl thiazole-4-carboxylate has been prepared by hy-drogenolysis of ethyl 2-bromothiazole-4-carboxylate with Raney nickel in ethanol, by desulfurization of ethyl 2-mercaptothiazole-... 

The present procedure is illustrative of a mild and general method for preparing thiazoles substituted in the 4-position with electron-withdrawing substitutents such as carbethoxy, cyano, and p-toluenesulfonyl. Thus condensation of ethyl isocyanoacetate with various thiono esters affords the parent ethyl thiazole-4-carboxylate as well as a series of analogs bearing substituents in the... 

Ethyl thiazole-4-carboxylate 4-ThiazolecarboxyIic acid, ethyl ester (8,9) (14527-43-6)... 

A soln. of O-ethyl thioformate and ethyl isocyanoacetate in dry ethanol added drop wise with vigorous stirring to an ethanolic suspension of NaCN, and warmed 0.5 hr. at 50° ethyl thiazole-4-carboxylate. Y 92%. F. e. s. G. D. Hartman and L. M. Weinstock, Synthesis 1976, 681. 

Similarly, ethyl (or methyl) a-formyl chloroacetate (69), Rj = H, and its substituted derivatives, condensed with thioformamide or higher thioamides give 5-ethyl- or 5-rnethyl-thiazole carboxylates (70) in good... 

Esters of 2-thiazole carboxylic acids (75) (383) are also prepared from ethyl monothiooxamate (74) (Scheme 34), and several compounds of this type with hydrogen, alkyl, or aryl groups in the 4- or 5-position (201, 209, 210, 242, 294) or a nitro group in the 5-position (674) have been reported. 

The most widely used method for the preparation of carboxylic acids is ester hydrolysis. The esters are generally prepared by heterocyclization (cf. Chapter II), the most useful and versatile of which is the Hantzsch s synthesis, that is the condensation of an halogenated a- or /3 keto ester with a thioamide (1-20). For example ethyl 4-thiazole carboxylate (3) was prepared by Jones et al. from ethyl a-bromoacetoacetate (1) and thioformamide (2) (1). Hydrolysis of the ester with potassium hydroxide gave the corresponding acid (4) after acidification (Scheme 1). 

Hydrolysis of ethyl 4-methyl-2,5-thiazole dicarboxylate (9) or dicar-boxylic acid dichloride gives an excellent yield of 4-methyl-5 thiazole carboxylic acid (10) instead of the dicarboxylic acid (Scheme 6). This lability is a general Property of 2-thiazolecarboxylic acids. 

Prior to the 1947 report by Cook and Heilbron on their novel synthesis, 5-aminothiazoles were mostly unknown in the literature. Previous syntheses included the Curtius degradation of ethyl thiazole-5-carboxylates which did not have general applicability there was also difficultly in obtaining the necessary starting materials. During a study on penicillin, Cook and Heilbron found that the reaction between methyl dithiophenylacetate and ethyl aminocyanoacetate gave what was initially believed to be ethyl phenylthionacetamidocyanoacetate 4. However further studies proved the compound to be 5-amino-4-carbethoxy-2-benzyl-thiazole 5, which was basic. 

The acylation of 5-hydroxymethylimidazo[2,l-h]thiazoles 96 (with, e.g., R = H, R = Ph) has been reported (80FES896). In line with expectations, ethyl esters of imidazol[2,l-6]thiazole carboxylic acids on basic hydrolysis... 

To a precooled (ice bath) lithium aluminum hydride (76 mmol) in 250 mL of THF was added ethyl thiazole-5-carboxylate (11.82 g, 75.68 mmol) in 100 mL of THF dropwise over 1.5 hours to avoid excess foaming. The reaction was stirred for an additional hour, and treated cautiously with 2.9 mL of water, 2.9 mL of 15% NaOH, and 8.7 mL of water. The solid salts were filtered, and the filtrate set aside. The crude salts were refluxed in 100 mL of ethyl acetate for 30 min. The resulting mixture was filtered, and the two filtrates were combined, dried over Na2S04 and concentrated in vacuo. The product was purified by silica gel chromatography eluting sequentially with 0%-2%-4% methanol in chloroform, to provide the desired compound, Rf = 0.3 (4% methanol in chloroform), which solidified upon standing in 75% yield. 

The C-nucleoside analogs of this type of acyclonucleosides were prepared by essentially two methods sequential O-alkylation of 265 with methyl bromoacetate followed by amidation and sulfurization to give 413, which cyclized with ethyl bromopyruvate to the thiazole carboxylate, whose amidation and debenzylation gave thiazofurin analog 414 (87H947). 

The effect of the halogen of the aryl halide was also carefully studied using bromobenzene and chlorobenzene as the electrophile. When the arylation was performed on ethyl 4-oxazole carboxylate using di-tert-butyl(methyl)phosphine as the Ugand and cesium carbonate as the base, the product of C5 arylation B was obtained when bromobenzene was used as the electrophile. Conversely, the product of C2 arylation A was formed if chlorobenzene was employed (eq 16). Similar results were obtained for the arylation of tert-butyl 4-thiazole carboxylate when mbidium carbonate was used as the base (eq 16). Again, it should be noted that the regioselectivity is highly dependent on the choice of the base and the phosphine. 

Amino-4-mesitylthiazole (179) cannot be nitrated, in contrast with 2-amino-4-f-Bu-thiazole (194). Nitration is also reported to fail with ethyl-2- acetamidothiazol yl -4-carboxylate (58). 

Thiazole-5-carboxylic acid, 4-methyl-ethyl ester... 

Acidic and basic hydrolysis of ethyl 4-oxo-4//-pyrido[l, 2-u]pyrimidin-3-carboxylates gave 3-carboxylic acid derivatives (OlMIPl). Stirring rerr-butyl ( )-3-(2-hydroxy-8-[2-(4-isopropyl-l, 3-thiazol-2-yl)-l-ethenyl]-4-oxo-4//-pyrido[l,2-u]pyrimidin-3-yl)-2-propenoate in CF3CO2H at room temperature yielded ( )-3-substituted 2-propenoic acid. 

An intermediate a-bromo-a-formylacetate hemiacetal has been prepared by reaction of ethyl (3-ethoxyacrylate with A-bromosuccinimide (NBS). Cyclizat-ion of the in situ formed hemiacetal with thioureas affords 2-amino-1,3-thiazole-5-carboxylates (Scheme 58).141... 

Ochiai, who reported in 1936 the first synthesis of the imidazo[2,l-h]thia-zole system (36CB1650), transformed ethyl 2-mercapto-5-methyl-imidaz-oIe-4-carboxylate with monochloroacetone into 2-(acylalkylthio)-imidazole 36. Refluxing 36 in phosphorus oxychloride yields ethyl 3,5-dimethylim-idazo[2,l-h]thiazole-6-carboxylate. No cyclization could be achieved by heating 36 in acetic anhydride because N-acylation (to 37) inhibited further reaction to the bicyclic system. 

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