Of 1,2,5-thiadiazoles

The microwave-assisted solid-supported synthesis of 1,3,4-thiadiazoles was described applying from acid and thiosemicarbazide on acidic aliunina... 

The chemistry of 1,3,4-thiadiazole and its derivatives has been previously covered in both CHEC(1984) <1984CHEC(6)545> and CHEC-II(1996) <1996CHEC-II(4)379>. A major review which covers the synthetic chemistry of the ring system up to 2002 has also appeared <2004HOU(13)349>. Since 1991 advances in the chemistry of 1,3,4-thiadiazole have been annually reviewed in Progress in Heterocyclic Chemistry <1991PHC149>. 

Table 1 Calculated vs. experimental bond lengths (pm) and angles (degrees) of 1,3,4-thiadiazole 1 <1995SAA995, 1996SAA33>...

The chemical reactivity of 1,3,4-thiadiazole 1 was predicted using DFT by calculating the net atomic charges and the Fukui functions /+,/ , and f° (Table 2). 

The ring nitrogens react with electrophiles to afford either 1,3,4-thiadiazolium salts or l,3,4-thiadiazol-2(37/)-ones depending on the tautomerisability of the substituents at the C-2 or C-5 positions. While N-alkylation is the most common electrophilic reaction of 1,3,4-thiadiazoles, reactions with acyl and cyanogen halides as well as Mannich salts have also been reported. 

Electrophilic substitution reactions on the carbon atoms of 1,3,4-thiadiazoles are rare due to the low electron density of ring carbons. G-Acylation can be accomplished via rearrangement of intermediate W-acylthiadiazolium salts while radical halogenation can give chlorinated or brominated 2-halo-5-substituted thiadiazoles. Examples can be found in CHEC(1984) <1984CHEC(6)545> and in Houben-Weyls Science of Synthesis <2004HOU(13)349>. 

Nucleophilic reactions at the carbon atoms of 1,3,4-thiadiazoles occur readily owing to the electron-deficient nature of this ring. Halo-substituted thiadiazoles are therefore highly activated and react with a wide range of nucleophiles. Carbon-based nucleophiles such as malonates have been used in the synthesis of 2-substituted thiadiazoles. When chlorothiadiazole 52 was treated with ethyl acetate in the presence of NaHMDS, the 2-phenyl-1,3,4-thiadiazol-5-ylacetic ester 53 was obtained (Equation 6) <20060L1447>. 

Table 4 Preparation of 1,3,4-thiadiazoles from acid-catalyzed cyclizations of monothiodiacylhydrazines...

The principal fragmentation of 1,3,4-thiadiazoles in the mass spectrometer is loss of a nitrile group as shown in Scheme 1. In the presence of a methylthio substituent, the major process is loss of SH and fragmentation at the heterocyclic sulfur atom (Scheme 2). In 1,3,4-thiadiazolines the major pathway is loss of PhS (Scheme 3) while 1,3,4-thiadiazolidinediones decompose by fragmentation of the ring . 

A new and convenient synthesis of 1,3,4-thiadiazoles was reported and involved the direct conversion of 1,3,4-oxadiazoles using thiourea as the thionating agent <98SC4611>. Courtois et al. have described an efficient monohydroxyarylation (or alkylation) and symmetrical bis-hydroxyarylation (or alkylation) of 2,5-dimethyl-1,3,4-thiadiazole using LDA and the appropriate carbonyl compound <99SC145>. 

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