Diamino- 1,2,4-thiadiazoles synthesis

The standard synthetic method for the synthesis of this system is the condensation of diamino-thiadiazoles with 1,2-diketones. A variation on this method, as shown in Equation (27), is the use of the thiadiazolothiadiazole (182) <84BRP2122492>. 

The oxidative cyclization of amidinothioureas, which is probably the most frequently used variation of this synthesis, provides 3,5-diamino-1,2,4-thiadiazoles with varying degrees of substitution. 

Other methods for the synthesis of 3,5-diamino-l,2,4-thiadiazoles discussed in Section 5.08.9.4 are only suitable for the synthesis of mono- or unsubstituted 3,5-diamino-l,2,4-thiadiazoles. 

The oxidation of amidinothioureas by a range of oxidizing agents to give 3,5-diimino derivatives is still one of the most versatile methods for the synthesis of N-linked derivatives (see Section 5.08.9.4). An alternative method which gives symmetrical derivatives is the oxidation of A-arylthioureas to produce Hector s bases which readily isomerize to give 3,5-diamino-l,2,4-thiadiazoles (see Section 5.08.9.2). 

An unexpected production of 2,4,6-triphenyl-l, 3,5-triazine in the electroreduction of 3,4-diphenyI-l,2,5-thiadiazole 1-oxide has been reported . Synthesis of 1,3-diyne derivatives of 2,4-diamino-l,3,5-triazine, 9a and 9b, has been accomplished by reaction of biguanidine with mono- and di-esters 8a and 8b, respectively <00T1233>. 

Aminotriazoles which are appropriately substituted at the C(5)-position are important intermediates for the synthesis of 8-azapurines. These reactions have been reviewed <86AHC(39)ll7>. The pharmaceutically useful acyclonucleosides bearing 1,2,3-triazolines and 8-azapurines have been synthesized <888879). 4,5-Diaminotriazoles react with 1,2-dicarbonyl reagents to give 1,2,3-triazolo[4,5- )]pyrazines. 4,5-Diamino-2-phenyltriazole and sulfur monochloride afford the triazolo[4,5-c][l,2,5]thiadiazole (855) <86AHC(40)129>. The synthesis of triazolopyridines from triazoles has been described in a review <83AHC(34)79>. For further applications of substituted triazoles in preparations of complex heterocycles, see Section 4.01.4. 

Reactions of 1,2,4-thiadiazoles with radicals and electron-deficient species are virtually unknown. Catalytic and dissolving metal reductions usually cleave the nucleus at its N—S bond by a reaction that may be regarded as the reverse of its synthesis by the oxidative cyclization of amidinothiono structures (Section 4.08.9.4). For example, reduction of the diamino compound (37) gives the amidinothiourea (38) from which it may be prepared by oxidation (Equation (8)). 

Further extension of this synthesis to guanidines leads to 3,5-diamino-l,2,4-thiadiazoles. Examples are so far confined to the conversion, by the usual procedure, of 2V,2V-disubstituted guanidines into 5-amino-3-dialkyl(or diphenyl)amino-l,2,4-thiadiazoles (66).84,87 In general, this variant of the reaction proceeds less uniformly than with amidines or iso(thio)ureas, and is performed without isolation of the intermediate AT-halogenoguanidines. In some cases (e.g. dimethyl and cyclopentamethylene homologs) the yields are low, and guanidine is formed as a by-product. The 3-dimethylamino homolog (66 R = R ... 

Freund and Wolf10 reported that 2,4-diphenyl-l,2,4-thiadiazolidine-3,5-dithione was formed by heating l,3-diphenyl-2-thiourea with thiophosgene in benzene whereas, a 1,3-thiazetidine was produced at lower temperatures in ether (see Section II). Ohande181 has reported that 3,5-diamino-l,2,4-thiadiazoles are formed by the reaction of thiopseudoureas with carbon disulfide in the presence of bromine. Use has also been made of thioureas in the synthesis of 1,3,4-thiadiazolines (79) via reaction with the halohydrazones 78.185,186 The analogous reaction with solenoureas was recently reported by Bulka and Ehlers187 to yield 1,3,4-selenadiazolines. 

Diamino-l,2,4-thiadiazole possesses radioprotective activity3, a correlation has been established466 between this property and a depressive effect on thymidine uptake on myelocytes, and on the rate of DNA synthesis in bone marrow and intestinal epithilium. The radioprotective activity of 5-amino-3-methylthio-l,2,4-thiadiazole has also been reported.467... 

Synthesis of the benzo[l,2-c 3,4-c ]bis[l,2,5]thiadiazole (509) required cyclization of diamine (508). Nitration of (505) led to 4-nitro-2,1,3-benzothiadiazole (506) in 95% yield. Amination of (506) with hydroxylamine in basic medium led to compound (507), immediately reduced to the diamino derivative (508). Ring closure of (508) with thionyl chloride and pyridine led to the benzo[l,2-c 3,4-c ]bis[l,2,5]thiadiazole (509) in 89% yield. Compound (509) has been successfully used in the synthesis of several fused tetracyclic compounds (Scheme 40) <75JHC829>. 

Synthesis of Heterocyclic Compounds. Thionyl chloride and pyridine at elevated temperatures convert diarylalkenes, styrenes, and cinnamic acids to benzo[i>]thiophenes and adipic acid to 2,5-bis(chlorocarbonyl)thiophene. Additional heterocycles which have been prepared include thiazolo[3,2-a]indol-3(2//)-ones, oxazolo[5,4- /]pyrimidines, and 1,2,3-thiadiazoles. Treatment of 1,2-diamino aromatic compounds with thionyl chloride gives good yields of fused 1,2,5-thiadiazoles. ... 

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