1,2,5-Thiadiazoles, aryl

An original method has recently been developed starting either from 1.3-dithiolane (10) or from 1.3.4-thiadiazole-2-thione derivatives (11) (Scheme 4) (3). This method does not work when Ri is an aryl group. 

A new method for the synthesis of 1,2,5-thiadiazoline 5,5-dioxides 231 was achieved by reacting activated aryl nucleophiles to the C=N double bond of the corresponding thiadiazoles 230 in the presence of AlClj as a catalyst at room temperature (00MI4). The yields of 4-aryl-derivatives ranged from 38 to 92%. 

Equimolar amounts of aromatic aldehydes, thioglycolic acid and thionohydrazides in sulphuric acid at room temperature afforded 2-methylthio-5-aryl-5ff-thiazolo[4,3-h]-l,3,4-thiadiazoles in a one pot procedure <96HC243>. 

Thiadiazoles (57) are produced by the reaction of fV-substituted hydrazones (58 R1, R2 = alkyl, aryl, H R3 = acetyl, ester, tosylate, etc.) with thionyl chloride.67... 

Treated with thionyl chloride, hydrazones 490 (R1 = H, R2 = aryl) undergo cyclocondensation to thiadiazoles 506 whereas from aliphatic derivatives 490 (R1 = H, R2 = alkyl), mixtures of thiadiazoles 507 and 508 are formed... 

This method has been extended to include arylhydrazono thioacetamides, such as 75, which undergo oxidative cyclization using bromine to afford 2-aryl-1,2,3-thiadiazol-5(277)imines 76 (Equation 23) <2004RJ0818>. 

Aryl halodiazarines 119 when reduced with potassium ethyl xanthate are reported to give 3-aryl-5-ethoxy-1,2,4-thiadiazoles 120 (13%) along with the expected product benzonitrile (87%) (Equation 31). A mechanism involving fragmentation of the diazirine 119 is proposed <1999TL29>. 

Aryl-l,2,5-thiadiazole-4-carboxamides were readily converted into carbonitriles on treatment with either thionyl chloride in benzene at reflux or more surprisingly with P4S10 in pyridine at reflux <2001H(55)75>. 

Aroylformamido-4-aryl-l,2,5-thiadiazoles 120 on treatment with MCPBA in chloroform at reflux afford 3-amino-4-aryl-l,2,5-thiadiazoles 121 (Scheme 18), but in the presence of ethanol the 3-ethoxycarbamoyl-4-aryl-l,2,5-thiadiazole 122 was also isolated <1999JHC515>. A-Aroylation could readily be achieved to give thiadiazoles 123 using the acid chloride in chloroform at room temperature. 

Aroylformamido-4-aryl-l,2,5-thiadiazoles 156 can also be prepared from aryl dibromomethyl ketones 155 on treatment with tetrasulfur tetranitride at 115 °C (Equation 31) <1995J(P1)253>. These reactions are, however, complex, and the 1,2,4-thiadiazole 157 is often produced as a minor product. 

No mechanistic discussion was offered and the proposed conversion of 1,2,5-thiadiazole 156 into 1,2,4-thiadiazole 157 with MCPBA <1995J(P1)253> was incorrect, the error caused by incompletely purified 1,2,5-thiadiazole <1999JHC515>. In contrast, monohalogenated methyl aryl ketones gave 1,2,4-thiadiazoles 157 with tetrasulfur tetranitride in chlorobenzene at 110-115 °C <1992JHC1433>. 

Unlike the reaction of alkyl aryl ketoximes with tetrasulfur tetranitride <1996CHEC-II(4)355>, the treatment of alkyl methyl ketoximes 189 with tetrasulfur tetranitride antimony pentachloride complex in either benzene or toluene at 50-80°C gave low yields (3-37%) of 3-alkyl-4-methyl-l,2,5-thiadiazoles 190 (Equation 39) <1999H(50)147>. Compounds 190 were volatile and the low yields are in part attributed to their loss as the solvent was removed in vacuo. Suprisingly, only single regioisomers were obtained. 3-Heptanone oxime 191 did, however, give a mixture of two isomers 192 and 193 (Equation 40). 

In a development on the reaction of monohaloalkyl aryl ketoximes with tetrasulfur tetranitride, the introduction of two halogens such as chlorine, bromine, or fluorine at the a-position of alkyl aryl ketoximes significantly improved the yields of thiadiazoles <1998J(P1)109>. The preferential displacement of chlorine over bromine or fluorine allowed the preparation of monobromo- and monofluoro-3-aryl-thiadiazoles 195 from a,a-chlorobromoalkyl- and a,a-chlorofluoro-alkyl aryl ketoximes 194 (Equation 41). 

Less common synthetic methods for 1,3,4-thiadiazoles include the oxidative thermal base-catalyzed cyclization of thiosemicarbazido arylates (Equation 40) <2005HAC12> and a tetracyanoethylene (TCNE)-assisted cyclization (Equation 41) <2004ZNB910>. 

Alkyl and aryl thiohydrazide derivatives react with orthoesters and trihalomethyls to afford 1,3,4-thiadiazoles. The reactions proceed via a thiosemicarbazone intermediate which cyclizes to eliminate either alcohol or hydrogen chloride. Treatment of the iV-thiohydrazide pyrazole 143 with triethyl orthoformate in acetic acid at reflux gave the 5-acetamido-l,3,4-thiadiazol-2-ylpyrazole 144 (Equation 51), and in the absence of acetic acid the 5-amino-l,3,4-thiadiazol-2-ylpyrazole 145 in 76% yield <2000JCM544>. 

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>. 

Alkyl and aryl nitriles 151 react with thiosemicarbazide 138 under acidic conditions to give 1,3,4-thiadiazoles (Scheme 14 and Table 8) <1995BML1995, 1996IJB273, 1997IJB394>. The acidic conditions promote the elimination of ammonia from the intermediate iminothioacylhydrazine 152. 

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. 

Substituted tetrazoles reacted with 4,5-dichloro-l, 2,3-thiazolium chloride (Appel salt) to give 1,3,4-thiadiazole oligomers <00TL9407>. 2-Benzyloxymethyl-5-(tributylstannyl)tetrazole (203) was found to be a versatile reagent for the conversion of aryl-and heteroarylhalides to 5-aryl- and 5-heteroaryl-lf/-tetrazoles 204 <00TL2805>. 

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>. 

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