Carboxy-1,3,4-thiadiazoles

The pronounced electron-withdrawing nature of the 1,2,5-thiadiazole system is also evidenced by strong carbonyl electrophilic activation and by enhancement of carboxy acidity. The acid dissociation constants of thiadiazole acids, discussed in Section 4.09.4.1, fall in the range 1.5-2.5. The 1,2,3-thiadiazole carboxylic acids are easily decarboxylated at 160-200 °C. This reaction has been used for the synthesis of monosubstituted derivatives as well as the parent ring and deuterated derivatives <68AHC(9)107>. An efficient bromo-decarboxylation of 3-amino-1,2,5-thiadiazole-carboxylic acid has also been reported <70BRP1190359>. 

The 1,2,5-thiadiazole nucleus is stable to both dilute and concentrated mineral acids and to Lewis acids. Certain derivatives, however, are decomposed slowly by base. No decomposition of the parent 1,2,5-thiadiazole was detected after 16 hours at 25° in 1 N sodium hydroxide while at 80° approximately 30 % of the material decomposed in 1 hour. This contrasts with the oxygen analog, furazan, and the monosubstituted furazans which are rapidly decomposed by cold aqueous base to a-cyanooximes. Mono- and dimethyl thia-diazole are both stable in 1 A sodium hydroxide up to 80° but the monochloro and dichloro derivatives are both degraded more rapidly than the unsubstituted compound. Thiadiazoles bearing acidic functions (the hydroxy, carboxy, and sulfonamide derivatives) exhibit complete base stability. In general, 1,2,5-thiadiazoles can be employed in reactions carried out in basic media provided drastic conditions are not required. 

Method (6) has old traditions, but no recent applications seem to have been reported. In method (c), methylsulfonyl- and carboxy-methylsulfonyl-l,3,4-thiadiazoles ° have been used as starting materials. Even the carboxymethylthio group is sufficiently labile to undergo displacement by the hydroxide ion. ... 

Condensation of 2-amino-5-aryl-5//-thiazolo[4,3-6][I,2,4]oxadiazoles (93 X = 0) and -thia-diazoles (93 X = S) with formaldehyde and a-amino acids leads to 7-aryl-3-(carboxy-alkyl)thiazolo[3, 4 3,2][I,3,4]oxadiazoles (94 X = 0) and -thiadiazoles (94 X = S), respectively. Under the same reaction conditions 5-aryl-2-sulfonyl-l,5-dihydrothiazolo[3,4-Z)][l,2,4]triazoles (95) are converted into 7-aryl-3-(carboxyalkyl)thiazolo[3, 4 2,3][l,2,4]triazoles (96) (Equation (9)) <94MI 805-01 >. 

Nucleophilic Substitution.—The replacement of halogen in 2-bromo-5-carboxy-4-methylthiazoles (51 R = EtO or PhNH) by a wide variety of nucleophiles (including phenols, thiophenols, dithiocarbamic acids, and sulphinic acids) has provided the appropriate derivatives (52) in high yields, but some anomalies were observed. The products included examples incorporating 1,3,4-thiadiazole or benzothiazole nuclei in the 2-position of... 

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