2.5- Diaryl-1,3,4-thiadiazoles

Aldehydes react with hydrazine hydrate and sulfur in a high yielding one-pot synthesis of 2,5-dialkyl- and 2,5-diaryl-1,3,4-thiadiazoles via a diazene intermediate (see Section 5.10.9.2.1) <1980LA1216, 1983JHC1399>. Although this synthetic procedure is rare, examples can be found in CHEC-II(1996) <1996CHEC-II(4)379>. 

Table 9 Preparation of 2,5-diaryl-1,3,4-thiadiazoles from 2,5-diaryl-1,3,4-oxadiazoles using thiourea...

Fluorinated 4,5-diaryl thiadiazoles 241 and 242 were evaluated as cyclooxygenase-2 (COX-2) inhibitors (Fig. 8). They showed good cell viabihty but poor inhibitor activity [120],... 

Ostad SN, Amini M, Haghipour Z, Karimi L, Navidpour L, Gheihremani MH, Shafiee A (2005) Inhibitory activities of new series of 4,5-diaryl thiadiazoles derivatives on lipopolysaccharide-induced COX-2 expression. Int J Pharm 1 79-84... 

Diaryl-l,2,3-thiadiazoles and 1,2,3-benzothiadiazoles have been alkylated at N-3 with trimethylsilylmethyl trifluoromethanesulfonate and treatment of these salts with cesium fluoride generate new l,2,3-thiadiazol-3-ium-3-methanide 1,3-dipoles (see Section 5.07.8.1) <1999J(P1)1415>. 

Alkylation of 3,5-diaryl-l,2,4-thiadiazoles 22 with trimethylsilylmethyl triflate, in contrast to methyl iodide, occurs at N-2 to afford the salt 23 (Equation 5) and the quaternization at N-2 was confirmed by analysis of the 1SN NMR spectrum <1999J(P1)1709>. 

The oxidative cyclization of thioacylamidines 83 is one of the best methods for the synthesis of unsymmetrical 3,5-diaryl- or dialkyl-1,2,4-thiadiazoles 84 (Equation 23) <2004HOU277>. Typical oxidants used in the cyclization step include bromine, iodine, or nitric acid, and, more recently, hydrogen peroxide in the presence of perchloric acid has been used. N-Substituted thioacylamidines give rise to 1,2,4-thiadiazolium salts <1997JOC3480>. 

The coupling of thioamides with a variety of oxidizing agents is a widely utilized method for the synthesis of 3,5-diaryl-l,2,4-thiadiazoles (see Section 5.08.9.2). This method is not suitable for alkyl derivatives. 3,5-Dialkyl derivatives can be more effectively prepared from a suitably substituted thioacylamidine (see Equation 22), and this method allows a range of unsymmetrical derivatives to be prepared. 

Diaryl-5-anilino-l,2,4-thiadiazoles are found to be potent and selective melanocortin-4-receptor (MC4) agonists for potential use for nerve regeneration and drug addiction <2003BMG185>. Compounds like 56 are being developed as cysteine protease inhibitors (see also Section 5.07.10) <2005JOC6230>. 

The reaction of the trichloromethylarenes 146 with thiosemicarbazide 138 in a boiling methanol-pyridine mixture afforded the 2-amino-5-aryl-l,3,4-thiadiazoles, while under similar conditions trichloromethylarenes 146 were converted to the diaryl-1,3,4-thiadiazoles with thiobenzhydrazide 147 (Equation 52, Table 7) <1996RCB1185>. 

Methylpyridines and methylquinolines react with aroylhydrazines in the presence of sulfur to afford 5-aryl-l,3,4-thiadiazoles in low yields <1984JHC181>. The method, which requires high temperatures and long reaction times, gives a mixture of the desired product, 1,3,4-oxadiazoles and symmetrical diaryl-1,3,4-thiadiazoles. 

Diaryl-l,3,4-oxadiazoles 163 react with thiourea to give 2,5-diaryl-l,3,4-thiadiazoles 165 (Table 9) <1998SC4611>. The proposed mechanism proceeds via ring contraction of an intermediate oxathiadiazepine 164 to give the thiadiazole 165 (Scheme 15). 

The reaction of a fourfold excess of aryldiazomethanes 130 with dichlorosulfine leads to 3,5-diaryl[l,2,4]triazolo[5,l+]-[l,3,4]thiadiazole-4-oxides 131. The formation of the fused heterocycles 131 is rationalized on the basis of two consecutive cycloaddition steps, each followed by elimination of hydrogen chloride promoted by the excess of aryldiazomethane (Scheme 9) <1984JCM175>. 

The thermolysis of l-([l,3,4]thiadiazol-2-yl)tetrazoles 133 gives rise to the loss of dinitrogen from the tetrazole ring and the formation of 2,6-diaryl[l,2,4]triazolo[5,l+][l,3,4]thiadiazoles 71 (Equation 39) <1985IJB908, 1990FA953>. (For another synthesis of compounds 71, see Section 11.07.8.1.5.)... 

Hydrazones are useful materials for the synthesis of thiadiazoles. Benzal-dehyde hydrazone and its derivatives substituted in the aromatic ring with sulfur monochloride in the presence of DBU gave 2,5-diaryl-l,3,4-thiadiazoles 63 in... 

Reaction of 2-amino-5-aryl-thiadiazole (88 R = Ar) with aryl nitriles in the presence of aluminum chloride produced the aryl amidine (89) which was oxidized with lead tetraacetate to yield the 2,6-diaryl-[ 1,2,4]-triazolo[5,1 -( ]-1,3,4-thiadiazoles (90) <91 UC(B)435>. 

Butler and co-workers studied the quatemisation of 3,5-diaryl-l,2,4-thiadiazoles 77 with trimethylsilylmethyl triflate at 40 °C and observed reaction at N-2 to give salt 78. Desilyation of 78 with caesium fluoride resulted in ring expansion to 2ff-l,3,5-thiadiazines 79 which on heating in ethanolic sodium ethoxide gave 2,4-... 

The reaction has been extended to the preparation of other 3,5-diaryl (and alkyl)-l,2,4-thiadiazoles21-28 and to diheteryl analogs, including 3,5-difuryl-24 and 3,5-di-(3-[or 4]-pyridyl)-l,2,4-thiadiazoles.19,24 Xanthamide (14) similarly yields 3,5-diethoxy-l,2,4-thiadiazole (15).25,28... 

The coupling of thioamides (253) by use of IV-sulfinylsulfonamides (Scheme 142) appears to be a practical method for the synthesis of a variety of 3,5-diaryl- and 3,5-dialkyl-l,2,4-thiadiazoles (301) in moderate yields. However, the procedure has not been widely utilized (see Scheme 91) (62AG135). Thioamides also have been coupled by the use of numerous oxidizing agents (65AHC(5)119) but the reported yields of 1,2,4-thiadiazoles have been quite variable (see Scheme 89). 

Thioacylation of thiohydrazides, preferably with carboxymethyl dithioates, has been demonstrated as a general method for the preparation of 2,5-dialkyl- or 2,5-diaryl-l,3,4-thiadiazoles. The intermediate 1,2-bisthioacylhydrazines in most cases are too unstable to be isolated. 

Alkyl-5-aryl- and 2,5-diaryl-l,3,4-thiadiazoles were prepared by cyclization of II with ethyl imidate hydrochlorides. Holmberg prepared 2-methyl-5-phenyl-l,3,4-thiadiazole by acetylating 11 with carboxymethylthiolacetate, followed by spontaneous cyclization, and by oxidation of acetaldehyde thiobenzhydrazone with ferric chloride. A considerable number of 2-alkyl-5-aryl-l,3,4-thiadiazoles have been prepared by the method of Stolle. ... 

These tellurium-containing polymers were checked for their catalytic activity in the ep-oxidation of olefins and as oxidizing agents. The polymeric 4-methoxyphenyl tellurium oxide did not react with amines, amides, alcohols, or phenols, but oxidized hydroquin-ones to quinones, thiols to disulfides, thioketones to ketones, thioesters to esters, and thiobenzamides in organic solvents to cyanobenzenes and in acetic acid to 2,5-diaryl-4,l, 3-thiadiazoles. ... 

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