2,1,3-Thiadiazole

3-Thiadiazoles, in contrast to 1,2,3-oxadiazoles, can be isolated and are thermally relatively stable. NMR spectra indicate that the molecules are diatropic. 

3-Thiadiazole is aromatic. Calculation of the r-electron densities by the HMO method gives the following values  

This is again a r-excessive heterocycle with some Ti-deficiency on the C-atoms. Therefore, electrophilic reagents should attack on the heteroatoms. Electrophilic substitution on the C-atoms would be difficult and nucleophiles should prefer the 5-position. 

3-Thiadiazoles are weak bases. On quatemization, e.g. with dimethyl sulfate, mixtures of 2- and 3-methyl-1,2,3-thiadiazoles are formed. Electrophilic substitution of the C-atoms could not be achieved. With 1,2,3-benzothiazoles, substitution occurs on the benzene ring. For instance, with nitric acid the 4- and 7-nitro-l,2,3-benzothiadiazoles are obtained. Nucleophiles bring about ring-opening, e.g.  

Thermolysis and photolysis of 1,2,3-thiazoles and 1,2,3-benzothiazoles lead to elimination of nitrogen. Depending on the substituents in the 4- and 5-positions, the fragments attain stability to different degrees, forming mainly thioketenes and/or thiirenes [147]  

With 1,2,3-benzothiadizoles, SsAr reactions occur at the benzene ring for instance, with nitric acid 4- and 7-nitro-l,2,3-benzothiadiazoles are obtained. 

Strong bases bring about C-5 deprotonation and ring-opening with concomitant N2-elimination, for example  

3-Thiadiazoles can be prepared [476] by cyclocondensation of tosylhydrazones derived I I from a-methylene ketones with thionyl chloride or sulfur dichloride (Hurd-Mori — synthesis) [477]  

Condensation Reagent. As a reagent l//-tetrazole has been used as a condensation agent to mediate the coupling of ribonucleotides and phosphoramidites in the synthesis of oligonucleotides. l//-tetrazole has also been used to promote the coupling of phosphoramidite and protected inositols for the synthesis of myo-inositol phosphates (eq 11).  

Gary A. Sulikowski Michelle M. Sulikowski Texas A M University, College Station, TX, USA 

Handling compound known to possess potent biological activities in humans. Toxic by skin contact or inhalation. 

Thiadiazoles encompass five-membered aromatic compounds with two nitrogen atoms and a sulfur atom. The chemistry of these class of molecules has been extensively studied and reviewed. The 1,2,3-thiadiazoles are known to display a wide variety of biological activities, and can be accessed by the Hurd-Mori cyclization of hydrazones with thionyl chloride. Although 1,2,3-thiadiazole belongs to a well-studied class of heterocycles, most of the substituted 1,2,3-thiadiazoles are synthesized from then-acyclic counterparts instead of functionalization of the 1,2,3-thiadiazole. 

Functionalization of Thiadiazole. Mesoionic compounds prepared on the 1,2,3-thiadiazolium scaffold have been studied for their chemical and biological properties and are known to display monoamine oxidase inhibitory activity. The reaction of 1,2,3-thiadiazole with /7-toluenesulfonic acid affords quantitative conversion to thiazolium /7-toluenesulfonate. The thiazolium tosylate can be reacted with sulfur in the presence of sodium hydride in DMF to afford the 5-thiolated mesoionic compound in 48% yield (eqs 1 and 2).  

---

Values for tt-electron density on nitrogen atoms generally indicate the position of electrophilic attack, e.g. at the 3-position of 1,2,3-thiadiazoles. 

Photolysis of 1,2,3-thiadiazole (35) gives thiirene (36) which can be trapped by an alkyne (70AHC(ll)l). 4,5-Diphenyl-l,2,3-thiadiazole (37) is photolyzed at low temperatures to the thiobenzoylphenylcarbene triplet (38). Diphenylthioketene (39) is formed on warming (81AHC(28)231). 

Thiadiazoles are quaternized to give 3- or mixtures of 2- and 3-alkyl quaternary salts. In 5-amino-1,2,4-thiadiazole, quaternization takes place at the 4-position (90) (64AHC(3il). 1-Substituted 1,2,4-triazoles are quaternized in the 4-position (91), and 4-substituted 1.2,4-triazoles are quaternized in the 1- or the 2-position (92) 64AHC(3)l). 

Azole 7V-oxide groups are readily removed by reduction with Zn/HOAc, HI or PCI3, e.g. in the pyrazole series. 1,2,3-Thiadiazole 3-oxides isomerize on irradiation to the corresponding 2-oxides. 

Thermolysis of the 1,2,3-thiadiazoles (545) in the presence of carbon disulfide leads to the thiocarbonyl carbene (546) adduct, the ring-fused l,3-dithiole-2-thione (547) (76JOC730). 

Thiirenes have been isolated in argon matrices at 8 K by photolysis of 1,2,3-thiadiazoles or vinylene trithiocarbonates (Scheme 151) (80PAC1623, 8UA486). They are highly reactive and decompose to thioketenes and alkynes (Scheme 22). Electron withdrawing substituents stabilize thiirenes somewhat, but no known thiirene is stable at room temperature unlike the relatively stable thiirene 1-oxides and thiirene 1,1-dioxides. 

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

The Hurd-Mori 1,2,3-thiadiazole synthesis is the reaction of thionyl chloride with the N-acylated or tosylated hydrazone derivatives 1 to provide the 1,2,3-thiadiazole 4 in one simple step. ... 

In 1955, Hurd and Mori first described the preparation of 1,2,3-thiadiazole as an unexpected product from the reaction of the hydrazone 5 and thionyl chloride. The authors were attempting to prepare the six membered anhydride 7 in an analogous manner to the 5-membered anhydride 9, prepared from 8 using thionyl chloride. However, when the hydrazone 5 and thionyl chloride were mixed and heated at 60°C for 1 hour followed by cooling, the thiadiazole acid 6 precipitated out and was isolated by filtration. This serendipitous discovery led to a significant advance in the synthesis of thiadi azoles. 

The thiadiazole system contains the following members 1,2,3-thiadiazoles, 1,2,4-thiadiazoles, 1,2,5-thiadiazoles and 1,3,4-thiadiazoles. 

Thiadiazole 5-oxides and 5,5-dioxides are the least studied among the four possible isomers of thiadiazole system. The main summary is in the first and the second editions of Comprehensive Heterocyclic Chemistry (84CHEC-I(6)447, 96CHEC-II(4)289). Apparently the 5-oxide and the 5,5-dioxide derivatives have not yet been reviewed. There are very few papers in the literature treating these derivatives, and most of these are regarding polycyclic systems. 

The Hurd-Mori synthesis of 1,2,3-thiadiazoles from a-methylene ketones developed in 1955 is, even today, the method of choice for a number of 1,2,3-thia-diazole derivatives. Both the mechanism and the regiochemistry have been extensively studied, but since the isolation of the intermediate by Hurd and Mori (84CHEC-I(6)460), there has been no further work supporting the formation of this intermediate or its conversion into the aromatization product. In 1995 Kobori and coworkers published the isolation of several 1,2,3-thiadiazolin-1-oxides 186, finally demonstrating their participation in the formation of 1,2,3-thiadiazoles. Substituents R and R play an important role in the isolation of 1,2,3-thiadiazolin-1-oxide (95H(41)2413). 

A rearrangement involving a fluctuating 1,2,3-thiadiazole ring has been found by Haddock et al. (1970) after diazotization of 7-amino-6-substituted 1,2,3-benzothia-diazoles (Scheme 6-46). 

A range of 4-substituted l,3-dithiole-2-thiones (71) and 2,6-substituted 1,4-dithiafulvalenes (73) were synthesised from 4-substimted 1,2,3-thiadiazoles (72). Reaction of (72) with NaH in a mixture of CS2 and acetonitrile led to the formation of (71), whereas absence of CS2 gave fulvalenes (73). This route was found to be very efficient for the preparation of 4-formyl-1,3-dithiole-2-thione (71 R = CHO), which was previously difficult to prepare, and thus allowed the synthesis of the novel 2,6(7)-bisformyltetraAiafulvalene (74) <96T3171>. 

---