Thiadiazoles, continued

Synthesis.—A variety of 1,3,4-thiadiazoles continue to be produced by well-established methods, generally in connection with biological or medical screening programmes. The methods of preparation include well-tried cyclizations, replacement reactions in the pre-formed heteronucleus, as well as the production of simple functional derivatives. With very few exceptions, the compounds concerned are derived from 2-amino-l,3,4-thiadiazole. 

Then, as described in U.S. Patent 2,55416, the 2-acetylamido-5-mercapto-1,3,4-thiadiazole is converted to the sulfonyl chloride by passing chlorine gas into a cooled (5°-10°C) solution in 33% acetic acid (66 parts to 4 parts of mercapto compound) used as a reaction medium. Chlorine treatment is continued for two hours. The crude product can be dried and purified by recrystallization from ethylene chloride. The pure compound is a white crystalline solid, MP l94°C,with decomposition, when heated rapidly. The crude damp sulfonyl chloride is converted to the sulfonamide by addition to a large excess of liquid ammonia. The product is purified by recrystallization from water. The pure compound is a white, crystalline solid, MP 259°C, with decomposition. The yield of sulfonamide was 85% of theory based on mercapto compound. 

Benzothiadiazoles 3 have been extensively studied. Fully aromatic mesoionic compounds such as 4 continue to be synthesized. A number of examples of 4,5-dihydro-l,2,3-thiadiazole derivatives such as compound 5 <1993JOC82> and more recently the phenyl derivative 6 <2003RJ01501> have been reported. The corresponding 2,3-dihydro-l,2,3-thiadiazoles have also been reported and Hurd and Mori reported the N-Z phenylsulfonyl derivative 7. The electron spin... 

Perhaps the earliest reported method for the synthesis of the 1,2,3-thiadiazole ring system was the one described by Pechmann and Nold in which diazomethane was reacted with phenyl isothiocyanate. Of the four possible isomers that could be obtained from the reaction, 5-anilino-l,2,3-thiadiazole 62 (R1 Ph, R2 = H) was the only product formed (Equation 16) <1896CB2588>. This method continues to be used as a route to 5-amino substituted 1,2,3-thiadiazoles. 4,5-Disubstituted 1,2,3-thiadiazoles have been produced in excellent yield by reaction of l,l -thiocar-bonyl diimidazole with ethyl diazoacetate <1988SUL155>. 

A direct aza-Wittig cyclization to triazolotriazine 176 (Scheme 67) takes place when triazinone 174 is treated with diphenylthiourea, the latter being substituted on the nitrogen. Elimination of triphenylphosphane sulfide from 175 makes 1,2,4-triazole accessible [86JCS(P1)2037]. When the nucleophilic attack continues on the sulfur, thiadiazoles are formed [86JCS(P1)2037]. 

Benzothiadiazoles have been extensively studied and their chemistry reviewed <84CHEC-I (6)447>. Fully aromatic mesoionic compounds such as (3) continue to be synthesized and studied but no review focusing on such systems has appeared. Very few examples of nonaromatic 1,2,3-thiadiazole derivatives such as (4) <93JOC82> and (5) exist and the area has not been reviewed. 

Pechmann and Nold utilized the reaction of diazomethane with phenyl isothiocyanate for one of the earliest syntheses of a 1,2,3-thiadiazole <84CHEC-I(6)447>. This method continues to be used <82MI 407-0l> for the synthesis of 5-amine substituted 1,2,3-thiadiazoles (34), and 4,5-disubstituted... 

Nucleophilic attack at the C-5 carbon atom of 1,2,4-thiadiazoles has been proposed as a reaction mechanism for many of the ring transformations described throughout this chapter. Thus, 2-methyl-3,5-diphenyl-1,2,4-thiadiazolium fluorosulfate (33) is cleaved by alkoxide giving the benzimidate (34) in the case of hydroxide ions, reaction continues to the benzoylamidine stage (35) (Scheme 10) <82AHC(32)285>. 

Novel indole derivatives continue to be found in marine organisms those reported recently include dendrodoine (3), a cytotoxic thiadiazole derivative, which occurs in the tunicate Dendrodoa grossularia, from Brittany,4 and the keto-lactam (4), one of two lactams isolated from the Caribbean sponge Hali-chondria melanodocia.5... 

The solution of N-ethyl-N-(l,3,4-thiadiazol-2-yl)amidophosphoryl chloride is added slowly at 10°C to a mixture of 9.5 parts of ethylenimine, 30.3 parts of triethylamine, and 44 parts of warm dry benzene. Agitation is continued for 2 h without cooling after which the triethylamine hydrochloride is filtered off. 

In continuation of efforts to identify Mi-selective muscarinic agonists capable of crossing the blood-brain barrier, the 3-carbo-methoxy group of arecoline was replaced by bioisosteric 1,2,5-oxadiazole (154) or by 1,2,5-thiadiazole rings with oxygen ether substituents at position 3 (155)or with thioether substituents at position 3 (156) (190). 

Two further papers in a series on the generation of nitrilimines (RC=NNR ) by irradiation of sydnones suggest that the reactive excited state is a (n, n ) triplet state,and demonstrate again the use of the reactive nitrilimines in the synthesis of heterocyclic compounds. In continuing studies on the formation of thiirens from 1,2,3-thiadiazoles (23), the parent thiiren has been characterized in a low-temperature matrix after photolysis of (23 R = R = H). Product analysis in experiments with C-substituted substrates suggests that thiiren is formed to a considerable extent thermally but to a lesser extent photochemically from (23 R = H, Ri = Ph). 

Hofmann s classical synthesis of 3,5-disubstituted 1,2,4-thiadiazoles by the oxidation of thioamides (1869)3 continues to be further exemplified. The oxidants employed include iodine,9-11 bromine,12 chlorine,13 and nitrous acid,14 as well as /V-chlorobenzamidine (which is recovered as benzamidine)15 and IV-sulfinyl-p-toluenesulfonamide (which evolves sulfur dioxide in the process).16 Irradiation with UV light in the presence of oxygen effects the same reaction, but has not been used on a preparative scale.17... 

Thiemann s classical synthesis of 1,2,4-thiadiazoles3 from amidoximes continues to be used occasionally for preparative purposes. 1,2,4-Thiadia-zoles of type 137, for example, arise from ethyl cyanoglyoxalate arylhydra-zones (136) by the successive action of hydroxylamine and isothiocyanate esters.109 The heteryl-substituted 1,2,4-thiadiazole 138 has been obtained similarly.110... 

The versatile and facile synthesis of 1,2,4-thiadiazoles by the oxidative cyclization of compounds incorporating an amidinothiono group3 continues to be widely used, partly because of the ready accessibility of many of the linear starting materials (221). The groupings flanking the amidinothiono core determine the nature of the 3- and 5-substituents of the resulting heterocycles the numerous examples are classified as far as possible, from this point of view. 

Continuous study of oxyacetamide chemistry shifted research from the paddy herbicide to an upland herbicide with increasing water solubility that is suitable for such upland use. To this end, benzanellated analogues such as the benzothia-zole moiety of mefenacet were changed to simple five-membered heterocycles that contain at least one nitrogen atom to increase water solubility, and sulfur or oxygen atom to decrease lipophilicity, for instance thiazoles, thiadiazoles, oxazoles and oxadiazoles (Fig. 8.2). Consequently, many patent applications of the new class of heteroxyacetamide herbicides were disclosed [17, 18]. 

Dimethyl potassium dithiophosphate, 2-methoxy-l,3,4-thiadiazol-5(4H)-one, and powdered paraformaldehyde added successively with cooling and vigorous stirring to aq. H2SO4, stirring continued 3 hrs. at 30° S-[5-methoxy-l,3,4-thia-diazol-2(3H)-on-3-yl)methyl] 0,0-dimethyl dithiophosphate. Y 83%. K. Riifenadit, Helv. 57, 518 (1968). 

A 1.6 M soln. of n-butyllithium in n-hexane added with acetone-Dry Ice cooling below -60° under Ng to a stirred suspension of 4-(2-thienyl)-l,2,3-thiadiazole (prepared from methyl 2-thienyl ketone) in anhydrous tetrahydrofuran, stirring continued 10 min. at - 60°, ethyl iodide added in one portion, and allowed to warm to 0° -> l-ethylthio-2-(2-thienyl)ethyne (Y 81%) refluxed 4hrs. with methanol and aq. 3 N H2SO4, the resulting ester mixture hydrolyzed with methanolic 3 N NaOH 2-thienylacetic acid (Y 88%). F. e., also reactions with dimethyl sulfate and acid halides instead of alkyl halides, s. R. Raap and R. G. Micetidi, Can. J. Chem. 46, 1057 (1968). 

A slurry of benzenediazonium 2-carboxylate (from anthranilic acid and pentyl nitrite) in THF added in portions during 30 min to startg. 1,2,5-thiadiazole in the same solvent under reflux, and heating continued for 30min - 5-(l,2-benzisothiazol-3-yl)pentanonitrile. Y 53% (based on recovered thiadiazole). F.e. inch 3-chloro- and 3-alkoxy-derivs., also Se-analogs, s. M.R. Bryce et al., J. Chem. Soc. Perkin Trans. I 1988, 2141-4. 

Ring Expansion to Thiazines. In continuation of their extensive work on the ring expansion of thiazoles to 1,4-thiazines (see p. 605), Takamizawa et have extended their studies to the comparable reaction of the 1,3,4-thiadiazole ring system. Thus, treatment of 4-substituted 1,3,4-thiadia-zolium iodides (173) with dialkylbenzoylphosphonates in dimethyl-formamide yields products identified by their spectral properties as 5,6-dihydro-4-substituted-5-oxo-2,6-diphenyl-477-l,3,4-thiadiazines (174). The course of this reaction is explained, in line with the one previously proposed for thiazolium salts, by the mechanism shown in Scheme 3. 

Pesin and his group have continued their investigation of benzo-2,1,3-thiadiazoles and have provided a summary of their recent work. In their opinion, the quinoid structure of benzo-2,1,3-thiadiazole and its selenium analogue is excluded by the sum of their physical and chemical properties, especially i.r. spectra. However, their preferred heteroaromatic structure... 

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