1,2,3-thiadiazole, 4-carboxylic acid

Hansen PR, Flyge H, Hohn A, Lauritzen E, Larsen BD (1996) Photochemical conjugation of peptides to carrier proteins using 1,2,3-thiadiazole-4-carboxylic acid. Int J Pept Protein Res 47 419—126. 

Thiadiazole-4-carboxylic acids biological activity, 6, 462 photochemistry, 6, 462... 

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 modified cephalosporin ceftobiprole (31-8), yet another compound that contains a double bond at the ring carbon, though in this case with a rather complex extended side chain, has shown activity in the clinic against some strains of multidrug resistant bacteria. The synthesis starts with the weU-precedented acylation of the cephalosporin (31-2), available in several steps from the commercially available 7-acetoxy cephalosporanic acid, with the activated thiadiazole carboxylic acid (31-1). The hydroxyl group in the product (31-3) is then oxidized with manganese dioxide to afford the corresponding aldehyde (31-4). This product is then condensed with the fcw-pyrrolidyl phosphonium salt (31-5), itself protected with the... 

The pronounced electron-withdrawing nature of the 1,2,5-thia-diazole ring is evidenced by the fact that its carboxylic acid derivatives are highly acidic. The titration curve of the dicarboxylic acid exhibits two breaks with and Kai, equal to 1.59 and 4.14, respectively. The monocarboxylic acid is also strongly acidic and has a piTa of 2.47, comparable to that of ornitrobenzoic acid 2.18) and pyrazine-2-carboxylic acid (pifa 2.80). In general the piTa values for the thiadiazole carboxylic acids are in fair agreement with the pica s of the corresponding p3U azine acids (see Table II). 

Werber and Maggio have shown that electron-donating substituents in position 2 can increase the stability of 1,3,4-thiadiazole carboxylic acids. They oxidized ethyl and butyl glyoxylate thiosemi-carbazones (27) with ferric chloride and obtained ethyl (butyl)... 

Chemical Name (6R-trans)-3-([(5-methyl-1,3,4-thiadiazol-2-yl)thio] methyl)-8-oxo-7-([(1-H-tetrazol-1 -yl)acetyl] amino)-5-thia-1-azabicyclo[4.2.0] oct-2-ene-2-carboxylic acid sodium salt... 

Condensations of 5-methyl-substituted 1,2,4-thiadiazoles with aromatic aldehydes lead to 5-styrylthiadiazoles. With carboxylic acid esters, ethoxalyl derivatives are formed, and isoamyl nitrite produces the corresponding oximes <1982AHC285>. These reactions are restricted exclusively to the 5-methyl-substituted 1,2,4-thiadiazoles reflecting the greater reactivity of substituents in the 5-position compared to the 3-position in 1,2,4-thiadiazoles. 

Macrocyclic 14-membered lactams, lactones, and thiolactones 211 have also been prepared from 3-amino-l,2,5-thiadiazole-4-carboxylic acids 210 (Equation 47) <1996CHE975>. 

Monothiodiacylhydrazines 127, derived from the acylation of thiosemicarbazides or as intermediates in the reactions of (1) thiohydrazides with carboxylic acids and their derivatives (see Section 5.10.9.2.2(i)) or (2) hydrazides with thiocarbonyl compounds (see Section 5.10.9.2.3(i)), cyclize in the presence of an acid catalyst to give 1,3,4-thiadiazoles 128 (Equation 39, Table 4). 

Table 6 Preparation of 1,3,4-thiadiazoles from thiohydrazide 138 and carboxylic acids...

Attempted hydrolysis of the ester group in the thienothiadiazine 66 using H2SO4 and AcOH at 100 °C gave a moderate yield of the ring-contracted thieno[2,3-carboxylic acid. Compound 67 was... 

More recently, some AMPA agonists showing unusual stereostructure-activity have been compared using the commercial docking package Glide (21). These include the enantiomers of 2-amino-3-(3-hydroxy-l,2,5-thiadiazol-4-yl)propionic acid (TDPA) and 2-amino-3-hydroxy-5-phenyl-4-isoxazolyl propionic acid (APPA) (28), as well as 3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-5-carboxylic acid (5-HPCA). 

SN/N Imidazo[2,l- ][l,3,4]thiadiazole 135 <2004S1067> (Figure 20), 136 and 137 (Table 44) <2004BMC5651> 6-aryl-2-aryloxymethylimidazo[2,l- ][l,3,4]thiadiazoles 120 (Table 45) <2005SC2881> NN/N 4-methyl-3-phenyl-2-phenylcarbamoyloxy-37/,47/-imidazo[l,2- ][l,2,4]triazole-3a-carboxylic acid ethyl ester 125 and 4,3a-dimethyl-3-phenyl-2-phenylcarbamoyloxy-37/,4/7-imidazo[l,2- ][l,2,4]triazole-6-carboxylic acid methyl ester 126 (Table 46) <2001JOC8528>. 

The most widely used method for the preparation of [l,2,4]triazolo[3,4-A][l,3,4]thiadiazoles 85 employs 4-amino-5-thio-4/7-[l,2,4]triazoles 83 or 4-amino[l,2,4]-triazole-5(47T)-thiones 84 as starting materials. The reaction of the triazoles 83 or 84 with carbonic acid derivatives furnishes [l,2,4]triazolo[3,4-4][l,3,4]thiadiazoles with a heteroatom substituent (N, O, S) at position 6 the O- and S-functions are formulated as 6-hydroxy and 6-thio derivatives 85a or as thiadiazol-(5/7)6-ones and -thiadiazole-(577)6-thiones 85b, respectively reaction with carboxylic acid derivatives provides the 6-substituted-[l,2,4]triazolo[3,4-4][l,3,4]-thiadiazoles 85c (Equation 20 Table 3). 

When treated with either sulfur monochloride or thionyl chloride, AAs and 2,3-diaminopropionic acid afforded neither l,2,5-thiadiazole-3-carboxylic acid or 3-alkyl-4-hydroxy-l,2,5-thiadiazoles in fair to low yields (66JOC1964 67JOC2823). 

Condensation of the 5-methyl group in (80) (R = Me, Et, Ph, SMe) with aromatic aldehydes leads to 5-styrylthiadiazoles (79). The action of carboxylic acid esters gives ethoxalyl derivatives (81) and that of isoamyl nitrite produces the oxime (82) (Scheme 20) <82AHC(32)285>. These reactions are restricted exclusively to the 5-methyl group in (80) (R = Me), reflecting the greater reactivity of substituents in the 5-position compared to the 3-position in 1,2,4-thiadiazoles. This point is further illustrated when (80) (R = Me) is selectively converted into the carboxylic acid (83) on treatment with n-butyllithium and carbon dioxide (Scheme 20) <84CHEC-I(6)463). 

Acetylation of 3-alkyl-5-hydroxy-l,2,4-thiadiazoles with ethyl chloroformate or carboxylic acid chlorides leads to N-4 derivatives of type (136) <75GEP(O)2405324>. 

Different functional groups can be introduced at the 5-position of thieno[2,3- / -l,2,3-thiadiazole-6-carbo-xylates 43a and 43b by lithiation and subsequent reaction with the desired electrophile <1999JPR341>. For example, reaction of carboxylic acid 43a with lithium diisopropylamide (LDA) followed by CI3CCCI3 produced the 5-chloro product 44a while amide 43b treated with -BuLi then dimethylformamide (DMF) gave aldehyde 44b (Equations 4 and 5). 

K. Other 1,2,4-Thiadiazole Derivatives 1. Carboxylic Acids and Esters... 

The polarographic reductions of cephaloridine, cephalothin, and cephalosporin C each yield one wave that is both pH and concentration dependent [126]. The reduction of these compounds and a related derivative, 3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-7-[2-(3-sydnone)acetamido]-3-cephem-4-carboxylic acid-sodium salt [I], have been described [127]. The reduction of I yields two waves. The first is believed to be the two-electron reductive elimination of the... 

Thioketenes can be prepared in several ways, from carboxylic acid chlorides by thionation with phosphorus pentasulfide [1314-80-3], P2S5, from ketene dithioacetals by p-elimination, from 1,2,3-thiadiazoles with flash pyrolysis, and from alkynyl sulfides (thioacetylenes). The dimerization of thioketenes to 2,4-bis(alkylidene)-l,3-dithietane compounds occurs quickly. They can be cleaved back pyrolytically (63). For a review see Reference 18. 

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