1, 2, 4-Thiadiazole-carboxylates

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)... 

Heating of ori/w-arenediazonium carboxylates or 1,2,3-areno-thiadiazole-1,1 -dioxides,... 

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... 

The highly complex reaction of tctrasulfur tetranitride with dimethyl acctylenedicarboxylale gives a mixture of dimethyl l,2,5-thiadiazole-3,4-dicarboxylate (67%), dimethyl 1,2,4-thiadiazolc-3,5-dicarboxylate (3 %), dimethyl l,3/.4,5.2,4-trithiadiazepine-6,7-dicarboxylate (le, 5%) and methyl l,37 4,5,2,4,6-trithiatriazepine-7-carboxylate (14%, see Section 4.5.).385... 

Ethyl diazoacetate and ImCSIm can be cyclized by a dipolar addition to give the corresponding ethyl 5-imidazolyl-l,2,3-thiadiazole-4-carboxylate ... 

With NJV -thiocarbonyldi-1,2,4-triazole the corresponding ethyl-5-(l,2,4-triazol-l-yl)-l,2,3-thiadiazole-4-carboxylate was obtained in 90% yield.[ 1291 However, analogous 1,3-dipolar reactions in the presence of (C2H5)3N are reported to yield the isomeric 2-(l-imidazolyl)-1,3,4-thiadiazoles 130],[ 1311... 

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. 

Phenyl-l,2,5-thiadiazole-3-carboxamide can be converted to the methyl 4-phenyl-l,2,4-thiadiazole-3-carboxylate with BF3-OEt2 in MeOH at reflux <2001H(55)75>. Alkyl substituents bearing a-chlorines can be dehalogenated with Pd/C-H2 in EtOH <1998JME4378>, or with Raney-Ni and H2 at atmospheric pressure in EtOH <1995USP5418240>. 

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). 

The reactions of 2-amino-1,3,4-thiadiazoles and diethyl 1-ethoxyethyli-denemalonate in diglyme at 140°C for 20 hr gave 7-methyl-1,3,4-thiadia-zolo[3,2-a]pyrimidine-6-carboxylates (672) in 14-25% yields after column chromatography (86FES737). Reactions in ethanol or dimethylacetamide were unsuccessful. 

Amino-5-mercapto-l,3,4-thiadiazole was reacted with EMME in boiling DMF for 16 hr to afford thiadiazolo[3,2,-n]pyrimidine-6-carboxylate (1131, X = S, R = SH) in 80% yield [85EUP150507]. 

Amino-3-methyl-l,2,4-thiadiazole was reacted with EMME in boiling trichlorobenzene to give 1,2,4-thiadiazolo[4,5-a]pyrimidine-6-carboxylate (1132) (59JOC779). 

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). 

---