Synthesis of 1,2,5-Thiadiazoles

Synthesis of Thiadiazoles.— The use of S4N4 in the preparation of nitrogen-sulphur heterocycles (see Vol. 5, pp. 104, 345) has been extended in that it has now been shown that its reaction with, for example, methyl propiolate in toluene, under reflux, yields mainly the 1,2,5-thiadiazole (132), with lesser amounts of the 1,2,4- and 

3- isomers (133) and (134), respectively. With diphenylacetylene, the yield of 3,4-diphenyl-l,2,5-thiadiazole is a remarkable 87%. Thionyl chloride is another useful sulphur reagent, and its reaction with substituted hydrazones (135 R , R — alkyl, aryl, or H R = COMe, CO Et, SOjTol, or CONHj) gives good yields of 

The First S -N Bond in a Natural Product —Dendrodoine, of which 98 mg was isolated from 2.2 tonnes of a marine tunicate, Dendrodoa grossularia (Styelidae), has been shown by JT-ray and spectral data to be an indole derivative of 1,2,4-thiadiazole (139). A noteworthy feature is that, as far as this Reporter is aware, this is the first natural product with a sulphur(ii)-nitrogen bond. All the other fourteen possible combinations of the five common biological elements (C, H, N, O, and bivalent S) are elaborated by living cells only S—N has, so far, been missing. 

The great majority of new 1,3,4-thiadiazoles have been produced by well-tried routes. These include known cyclizations of compounds related 

A series of 2,4-diary 1-1,3,4-thiadiazolium salts (108) have been synthesized by the condensation of thiobenzoylphenylhydrazine hydrochloride and triethyl orthoformate in ether at 0 C, for a study of the influence of the 2-and 4-substituents on the acidity of the hetero-proton by deuterium exchange. At 90 °C, the free hydrazine base (107) reacts differently, and produces the spiro-compound (109) as the main product  

Minami, M. Tomita, and K. Kawaguchi, Chem. and Pharm. Bull. (Japan), 1972,20,1716. 

3- 5-Substituted-1,3,4-thiadiazol-2-yl)-4-quinazolones 2-Amino-5-(l-iftethyl-2-nitro-5-imidazolyl)-1,3,4-thiadiazole 2-Anilino-5-(amino-oxy)methyl-l,3,4-thiadiazole Substituted 2-acylamino-1,3 4-thiadiazoles l,3,4-Thiadiazol-2-yl- -mercaptocinnamamides N-(2-Anilino-l,3,4-thiadiazol-S-ylmethoxy)phthalimide N -(l,3,4-Thiadiazol-2-yl)-N -benzylidenesulphanUainides 2-p -AminobenzenesuIphonamido-S-ethyl 1,3,4- 

2-alkylamino-l,3 4-thiadiazoles by the condensation of 4-alkylthiosemicarbazides and orthoformate esters by the addition of a little mineral acid this suppresses the parallel formation of the isomeric 4-alkyl-l,2,4-triazoline-3-thiones that are otherwise invariably formed.  

No naturally occurring 1,2,4-thiadiazole having been reported so far, all compounds are of synthetic origin. The parent of the series, 1,2,4-thiadiazole, was first synthesized in 1955s by the sequence of reactions 8- 9— -10- -2,B 6 but remains relatively inaccessible. Because of its sensitivity it is not a practicable starting material for the preparation of derivatives these are therefore always built up directly by suitable cyclization reactions and subsequent modification of the substituentB as required. This section is confined to direct syntheses the numerous interconversions that furnish additional derivatives from the preformed 1,2,4-thiadiazole nucleus are considered with the chemical properties of the individual classes of compounds. 

4-thiadiazole ring (2) may obviously be built up from simpler fragments in many ways, but of these only three general routes are important these approaches, classified according to the nature of the components which join to form the ring, are illustrated by A-C. A 

This group of syntheses comprises the oxidation of compounds containing the thiocarbamoyl group, including thioamides and thioureas  

The inclusion of reactions under this heading is convenient merely for the purpose of formal classification it is not intended to suggest the mechanism by which the thiadiazoles arise. Present trends indicate that these routes proceed by way of intermediates that will eventually justify their classification as syntheses of type C. 

Other oxidizing agents that have been successfully employed are sulfur monochloride,10,11 thionyl chloride,12 sulfuryl chloride,12 phosphorus pentachloride,13 ammonium persulfate,1 i hydrogen peroxide,15 

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Reactions of 1,2,4-thiadiazoles with radicals and carbenes are virtually unknown. Catalytic hydrogenations and dissolving metal reductions usually cleave the N-S bond in a reversal of the oxidative cyclization procedures used in synthesis of 1,2,4-thiadiazoles (see Section 5.08.9.4). 

Type C syntheses are typified by the oxidative cyclization of amidinothiono groups, and this has become the basis of a versatile synthesis of 1,2,4-thiadiazoles. This type of reaction is known for its speed and absence of side reactions. The synthesis of unsymmetrical 3,5-disubstituted-l,2,4-thiadiazoles of unambiguous structure in high yields is possible by this method. 

The only synthesis of 1,2,4-thiadiazole 1 was reported by Goerdler and co-workers in 1955, and details of this synthesis can be found in CHEC-II(1996) <1996CHEC-II(4)307>. The sensitivity of 1,2,4-thiadiazole 1 to ringopening reactions means it is not a suitable starting material for the preparation of other derivatives. 

Figure 3 Potential ring closure routes in the synthesis of 1,2,4-thiadiazoles.

Vivona, N., Buscemi, S., Asta, S. and Caronna, T. (1997) Photoinduced molecular rearrangements. The photochemistry of 1,2,4-oxadiazoles in the presence of sulphur nucleophiles. Synthesis of 1,2,4-thiadiazoles. Tetrahedron, 53 (37), 12629-12636. 

The synthesis of heterocyclic compounds with aryl->o3-iodanes extends to oxidative-condensation reactions. This approach has recently been employed for the synthesis of 1,2,4-thiadiazoles 82 by the treatment of thioamides with DAIB or its polystyrene variant (Scheme 24) (02SC2155). The production of 82 in these reactions is accompanied by the formation of elemental sulfur. 

The ingenious general synthesis of 1,2,4-thiadiazoles from amidino compounds and tri-, di-, and monochloromethanesulfenyl chlorides has been employed repeatedly since its original development by Goerdeler and his co-workers.3,119 By far the greatest number of these applications has involved the use of the fully chlorinated methyl mercaptan, resulting in 5-chloro-1,2,4-thiadiazoles. 

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. 

An interesting and effective synthesis of 1,2,4-thiadiazoles is the direct condensation at high temperatures of aromatic nitriles and sulfur under the influence of suitable catalysts. Benzonitrile, for example, reacts with sulfur in the presence of tri-n-octylamine in closed vessels at 250°C to afford 3,5-diphenyl-1,2,4-thiadiazole in 75% yield. The effectiveness of the catalysts increases with their chain length, tri-n-octylamine being five times as active as triethylamine.250... 

In addition to the aforementioned synthesis of 1,2,4-thiadiazoles, Sonnenschein and co-workers have demonstrated a Boulton-Katritzky rearrangement that is initiated through nucleophilic attack. Nucleophilic addition of methanol (or dimethylamine) to 5-(cyanoimino)thiadiazoline 29 forms the intermediate 30 that can then undergo rearrangement to 31. Elimination of a nitrile then affords the desired 3-methoxythiadiazole 32 in excellent yield. These produets have been employed as redox switchable... 

The dipotassium sail of 3,5-dimercapto-l,2,4-thiadiazole ( perthiocyanic acid ) (36) is most conveniently prepared by refluxing a solution of (31) in methanol with sulphur. The salt is readily chlorinated to the stable bis(sulphenylchloride) (37). The observations supplement and further clarify previous work on the synthesis of 1,2,4-thiadiazoles from thiocyanic acid (see Volume 1, p. 448 and ref. 15). 

Type C Syntheses [N—C—N—C—S]. From amidino-thiono-compounds. The general synthesis of 1,2,4-thiadiazoles by the oxidative cyclization of compounds incorporating the amidino-thiono-grouping [—C(=NH)NHCS—] has been extended by the synthesis of l-acyl(and -sulphonyl)-3-thioacyl-guanidines (41) from acyl- or sulphonyl-guanidines (40) with thioacid O-esters in the presence of sodium hydride, followed by their oxidation with hydrogen peroxide in pyridine. 

Oxidation of thioureas. The well-established synthesis of 1,2,4-thiadiazole derivatives by the oxidation of arylthioureas has been further studied by an examination of the oxidation products of mixtures of equimolar quantities of two thioureas. Oxidation of a mixture of syw-diarylthiourea and thiourea by hydrogen peroxide in acidified ethanol yields 3-amino-4-aryl-5-arylimino-A -1,2,4-thiadiazolines (42 R = H). These compounds are considered to be formed by the cyclization of amidino-thioureas (43), which can be isolated from the oxidation of mixtures of l-alkyl-3-arylthioureas and thiourea. The overall mechanism resembles that postulated for the formation of Hector s Bases. The oxidation of binary mixtures of sym-diaryl- and iV-alkyl-thioureas similarly furnishes the trisubstituted thiadiazolines (42 R = alkyl). ... 

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