Thiazolecarboxylic acids

Hydroxyalkylthiazoles are also obtained by cyclization or from alkoxyalkyl-thiazoles by hydrolysis (36, 44, 45, 52, 55-57) and by lithium aluminium hydride reduction of the esters of thiazolecarboxylic acids (58-60) or of the thiazoleacetic adds. The Cannizzaro reaction of 4-thiazolealdehyde gives 4-(hydroxymethyl)-thiazole (53). The main reactions of hydroxyalkyl thiazoles are the synthesis of halogenated derivatives by the action of hydrobroraic acid (55, 61-63), thionyl chloride (44, 45, 63-66), phosphoryl chloride (52, 62, 67), phosphorus penta-chloride (58), tribromide (38, 68), esterification (58, 68-71), and elimination that leads to the alkenylthiazoles (49, 72). 

As noted by Robinson and Strachan (1), after considerable activity in the period 1885 to 1895 thiazolecarboxylic acids received little attention until 1935. Isolation of 4-methyl-5-thiazolecarboxylic acid after degradation of vitamin Bj gave new interest to the chemistry of these compounds. 

On account of the high degree of stability of the thiazole ring a large variety of substituted derivatives yield thiazolecarboxylic acids upon oxidation. The oxidation of a methyl group or a substituted methyl group to a carboxyl group has been accomplished in a few instances. 

Thiazolecarboxylic acids can also be prepared by catalytic dehalogena-tion of 2-halo derivatives (22, 23, 24). 

Thiazolecarboxylic acid (24) has been synthesized in this way by the action of concentrated H2SO4 and HNO3 upon 4-(dichloromethyl)-thiazole. 

Thus 2-phenyl-4(hydroxymethyl) thiazole upon oxidation with aqueous chromic acid yields 2-phenyl-4-thiazolecarboxylic acid (25,26). 

A reaction carried out by Haruki et al. is the energic oxidation of 5-(l-hydroxyethyl)2-phenylthiazole (5) in dioxane by aqueous Kl-iodine to give 2-phenyl-5-thiazolecarboxylic acid (6) (Scheme 2) (28). 

Ozonolysis of 2-styryl-4-methylthiazole followed by oxidation of the intermediate carbonyl compound with peracetic acid yields 4-methyl-2-thiazolecarboxylic acid (30). 

The thiazolecarboxylic acids are stronger acids than their homologs in the pyridine series (45). 

As already noted by Sprague and Land (46), no accurate data are available for 2-thiazolecarboxylic acid, but it appears to be a considerably stronger acid than either 4- or 5-thiazolecarboxylic acid (7). It is difficult to study experimentally the acidity of these compounds because of their amphoteric character. 

To evaluate the dissociation constants it would be necessary to measure the equDibrium constant for the reaction in Scheme 4. The dissociation of thiazolecarboxylic acids has been studied principally by Erlenmeyer et al. (47, 48). It seems that no systematic and reliable determination of the acidity dissociation constants have been realized until now. 

Decarboxylation of 2-thiazolecarboxyIic acids occurs readily (49). 5-carboxylic acids can also be decarboxylated without difficulty (50). but 4-thiazolecarboxylic acids are relatively stable (7. 38). For example,... 

On the other hand, with 4,5-thiazoledicarboxylic acid the 5-carboxyl group is the more labile (3, 5, 51) contrary to results found by other workers (52). For example. Huntress et al. (5) have shown that pyrolysis of 2-phenyl-4,5-thiazoledicarboxylic acid (7) gives evolution of carbon dioxide and the formation of 2-phenyl-4-thiazolecarboxylic acid (8i (Scheme 5). 

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. 

The observed order of decreasing ease of decarboxylation for the three thiazolecarboxylic acids is 2>5>4. 

Iversen and Lund have realized the polarographic reduction of 2-thiazolecarboxylic acid and some of its derivatives in acid solution. They obtained 2-thiazolecarboxaldehyde (58),... 

The thiazolecarboxylic acids and especially 2-alkyl-5-thiazolecarboxylic acids have hypolimic vasodilatory and antiinflammatory activity (19, 59, 60). 

As previously mentioned the esters of thiazolecarboxylic acids are generally prepared by the Hantzsch s synthesis (17, 20),... 

Some esters of substituted alcohols have been synthesized by transesterification. Treatment of 4-methyl-5-thiazolecarboxylic acid (14) with 3-chloroethyldiethylamine in acetone in the presence of anhydrous potassium carbonate gives the desired ester (15) in good vield (60%) (Scheme 10) (163). 

Thiazolecarboxylic Acids. Thiazolecarboxaldehydes, and Thiazolyl Ketones B- Thiazolecarboxylic Acid Chlorides... 

Thiazolecarboxylic acid chlorides, generally prepared from the corresponding acid and thionyl chloride (Scheme 13), are relatively unstable (2,... 

The 2-thiazolecarboxylic acids are too readily decarboxylated to be converted to acid chlorides 16. 12, 79). 

Boon has observed that when 2,4-dimethyl-5-thiazolecarboxylic acid (22) is heated with an excess of thionyl chloride, the main product (76%) is 4-methyl-2,5-thiazoledicarboxylic acid dichloride (23) (Scheme 14 (7). 

Diamides and triamides have been obtained from the action of an aqueous saturated solution of ammonia on the corresponding ester (Scheme 18) (88). Amides can also be obtained by the Curtius (16) or Hofmann reactions (80). Thus the Curtius reaction with 2-substituted 4-thiazolecarboxylic acids gives the 4-acetamido compounds (16). 

Thiazolecarboxylic acid hydrazides are prepared by the same general methods used to prepare amides, that is, by treating acids, esters, amides, anhydrides, or acid halides with hydrazine or substitued hydrazines. For example, see Scheme 21 (92). The dihydrazides are obtained in the same way (88). With diethyl 2-chloro-4,5-thiazoledicarboxylate this reaction gives the mono hydr azide monoester of 2-hydrazine-4,5-... 

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). 

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