1.2.5- Thiadiazoles using

Thiadiazoles. An acyclic NCCN system in which the NC links may be sp, sp2, or sp3 hybridized reacts with sulfur monochloride or sulfur dichloride to form the appropriate 1,2,5-thiadiazole <1968AHC(9)107, CHEC-111(5.09.9.1.5)545>. Aliphatic 1,2-diamines can be converted into 1,2,5-thiadiazoles using various sulfur sources such as tetrasulfur tetranitride, disulfur dichloride, sulfur dichloride, thionyl chloride, and V(V-ditosylsulfur diimide. Thus, l,2,5-thiadiazole-3,4-dicarbonitrile 555 is prepared from diaminomaleonitrile 554 using neat excess thionyl chloride (Scheme 250) <1995SR299>. 

Examples of the synthesis of 1,2,3-thiadiazoles using the Hurd-Mori reaction are prevalent in the most recent literature <2004RJ099, 2003JHC427, 2003JOC1947, 2003JHC925, 2003FA63, 2003JHC149>. 

A comparison between the positive and negative ion mass spectra of 3-amino-5-methylthio-l,2,4-thiadiazole and a study of the positive ion mass spectrum of 3-amino-5-methylthio-l,2,4-thiadiazole using 1SN isotopes appeared in Cl I EC-11(1996) <1996CHEC-II(4)307>. Since the publication of CHEC-II(1996), no new studies focusing on the mass spectra of 1,2,4-thiadiazoles have appeared. 

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>. 

The unusual N—S—N bond system in 1,2,5-thiadiazoles poses interesting theoretical questions. Some insight into the structure and properties of 1,2,5-thiadiazoles was gained through studies of electron and X-ray diffraction, the microwave spectrum, and the Baman and infrared spectra of 4 and its derivatives. The iso-iT-electronic relationship between the 1,2,5-thiadiazoles and the pyrazines was examined in detail and a comparative study of the four isomeric thiadiazoles using the MO method in the LCAO approximation for small heterocyclic molecules was reported. 

Irradiation (2 = 235.0-280.0 nm) of either [4-l3C]-l,2,3-thiadiazole or [5-l3C]-l,2,3-thiadiazole gives [l3C]-thiirene with bands shifted to 3198 cm-1, 3163 cm-1, 3158 cm-1, 1634 cm-1, 910 cm-1 and 558 cm-1. [l3C]-Thiirene is transformed with light of wavelength = 33-37 nm to ethynyl mercaptane and thioketene, with the C-13 label scrambled in both products (Equation (4)). Irradiation of either 4-methyl-5-carboethoxy- or 5-methyl-4-carboethoxy-l,2,3-thiadiazole using a 265 nm interference filter resulted in the appearance of a spectrum with significant absorptions at... 

Figure 10.2. Synthesis of 1,3,4-oxadiazoles and 1,3,4-thiadiazoles using an acyidithiocarbazate.

Fig. 5 Fluorinated thiadiazoles used as pharmaceutical analogues of resveratrol...

Due to the peculiar features introduced by fluorinated moieties, the synthesis, the reactivity, and the appUcation of fluorinated oxadiazoles and thiadiazoles still are challenging research topics. Therefore, the updated synthetic guidelines reported in this chapter will represent a useful tool for both the experienced synthetic chemists and those willing to embrace the study of fluorinated azoles. For this reason, it is the authors opinion that synthetic information organized by kind of heterocycle is better approached by the reader for faster consultation. On the other hand, reactivity has been presented by focusing on the type and position of the fluorinated moiety, in the attempt to provide general concepts transferable also to other heterocycUc systems. Finally, examples of fluorinated oxadiazoles and thiadiazoles used in materials chemistry or as bioactive compounds have been briefly illustrated to suggest the potential application of newly synthesized compounds. 

Gierczyk B, Zalas M (2005) Synthesis of substituted 1,3,4-thiadiazoles using Lawesson s reagent. Org Prep Proced Int 37 213-222... 

Thiosemicarbazides are useful in forming 1,3,4-thiadiazoles, a class of compounds having herbicidal activity. 

Table 15 gives a sampling of other pharmaceuticals derived from hydraziae. Cefazolin, a thiadiazole tetrazole derivative, is one of the most widely used antibacterial dmgs in U.S. hospitals (see Antibiotics, P-LACTAMs). Procarbazine, an antineoplastic, is a monomethyUiydrazine derivative (220). Fluconazole has shown some promise in the treatment of AIDS-related fungal infections. Carbidopa is employed in the treatment of Parkinson s disease. FurazoHdone is a veterinarian antibacterial. 

For protection against nonferrous and copper ahoy corrosion, thiadiazole and triazole derivatives have been found especiahy useful (22). 

Filter paper impregnated with dicarbonyl(benz-2,l,3-thiadiazole)rhodium chloride gives characteristic colorations with the aminophenol isomers after fixation and can be used as an indicator paper (99). 

Other Accelerators. Amine isophthalate and thiazolidine thione, which are used as alternatives to thioureas for cross-linking polychloroprene (Neoprene) and other chlorine-containing polymers, are also used as accelerators. A few free amines are used as accelerators of sulfur vulcanization these have high molecular weight to minimize volatility and workplace exposure. Several amines and amine salts are used to speed up the dimercapto thiadiazole cure of chlorinated polyethylene and polyacrylates. Phosphonium salts are used as accelerators for the bisphenol cure of fluorocarbon mbbers. 

Dimercapto-l,3,4-thiadiazole derivatives, accelerated by amines, are used to cross-link chlorinated polyethylene. Polyisobutylene containing brominated i ra-methylstyrene cure functionahty can be cross-linked in polymer blends with dimercapto-1,3,4-thiadiazole derivatives accelerated with thiuram disulfides. Trithiocyanuric acid is suggested for use in polyacrylates containing a chlorine cure site and in epichlorohydrin mbbers. 

Curing Systems. The most commonly used vulcanizing agent for the polyethers not containing AGE, that is, ECH and ECH—EO, is 2-mercaptoimidazoline, also called ethylenethiourea [96-45-7]. Other commercially appHed curing agents include derivatives of 2,5-dimercapto-l,3,4-thiadiazole, trithiocyanuric acid and derivatives, bisphenols, diamines, and other substituted thioureas. 

For both azole and benzazole rings the introduction of further heteroatoms into the ring affects the ease of quaternization. In series with the same number and orientation of heteroatoms, rate constants increase in the order X = 0requires stronger reagents and conditions methyl fluorosulfonate is sometimes used (78AHC(22)71). The 1-or 2-substituted 1,2,3-triazoles are difficult to alkylate, but methyl fluorosulfonate succeeds (7IACS2087). 

The conversion of octachloronaphthalene to octafluoronaphthalene with potassium fluoride and either 18-crown-6, dibenzo-18-crown-6, cis,j>m,cis-dicyclohexano-18-crown-6, cis,anti,cis-dicyclohexano-l 8-crown-6, or irons,syn,trails-dicyclohexano-18-crown-6 demonstrates that 18-crown-6 or dibenzo-18-crown-5 increases the yield and selecuvity and decreases the reaction time [55] Treatment of 3,4-dichloro-],2,5-thiadiazole with potassium fluonde in sulfolane with and without 18-crown-6 present shows that less severe conditions can be used with either 18-crown-6 or dibenzo-18-crown-6 to form 3,4-difluoro-l,2,5-thiadiazole (equation 34)... 

Cyclotrithiazyl chloride is also a useful reagent in organic chemistry in the fusion of 1,2,5-thiadiazoles to quinones as well as the synthesis of (a) isothiazoles from 2,5-disubstituted furans and (b) bis-1,2,5-thiadiazoles from A-alkylpyrroles (Scheme 8.4). Alkenes and alkynes react readily with (NSC1)3 to give 1,2,5-thiadiazoles, while 1,4-diphenyl-1,3-butadiene gives a variety of heterocyclic products including a bis(l, 2,5-thiadiazole). ... 

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. 

Preparation of thiadiazoles via the Hurd-Mori cyclization has led to the synthesis of a variety of biologically active and functionally useful compounds. Discussion of reactions prior to 1998 on the preparation of thiadiazoles have been compiled in a review by Stanetty et al Recent syntheses of thiadiazoles as intermediates for useful transformations to other heterocycles have appeared. For example, the thiadiazole intermediate 36 was prepared from the hydrazone 35 and converted to benzofuran upon treatment with base. Similarly, the thiadiazole acid chloride 38 was converted to the hydrazine 39 which, upon base treatment, provided the pyrazolone, which can be sequentially alkylated in situ to provide the product 40. ... 

High-speed synthesis of thiadiazoles has been recently completed on a solid support system using a catch and release technology to provide novel thiadiazoles. The solid-supported sulfonylhydrazine reacts with ketones to provide the solid phase hydrazones (catch) and formation of the thiadiazole with subsequent release of the... 

Polarographic techniques have been used by Sturm and Hans to demonstrate that certain amino-thiadiazoles and -benzthiazoles exist in the amino form (cf. also references 62, 63). This method, which involves comparison of the polarographic rdeuction potentials of the potentially tautomeric substance with those of alkylated reference compounds, has not been applied often, but may well prove to be a means to obtain qualitative information quickly. There is a possibility that the method can be modified to yield quantitative data. ... 

Interest in 1,3,4-thiadiazole salts has been stimulated by their use as intermediates for the preparation of cyanine dyes. 2,5-Dimethyl-... 

Ethyl iodide and 5-amino-2-methyl-l,3,4-thiadiazole react at 110° to give the N-3 salt (78 R = Me, R = NH2, R" = Et), as shown by the presence of the very reactive methyl group this salt is also used to prepare cyanine dyes. The slow quatemization at the ring-nitrogen atom furthest from the amino group is consistent with the reactions observed in other ring systems. As would be e pected, 5-alkylthio-2-methyl-l,3,4-thiadiazoles form salts at the N-3 (78 R = Me, R - S-alkyl).i ... 

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