Diamino- 1,2,4-thiadiazoles

Diamino-1,2,4-thiadiazoles 66, also known as Hector s bases, are the oxidation products from iV-arylthioureas 65 a large number of examples of this type of reaction are known. Typical oxidants that give good yields are acidic hydrogen peroxide, nitrous acid, and iron(m) chloride (Equation 20) <1996CHEC-II(4)307>. 

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. 

The treatment of thiurets (diimino-l,2,4-dithiazolidines, (297)) with aromatic amines results in ring opening to form thiocarbamylguanidines (298) and sulfur cyclization to 3,5-diamino-1,2,4-thiadiazole derivatives (299) can occur spontaneously or upon oxidation (Scheme 67) <84CHEC-1(6)463 >. 

The oxidation of A-arylthioureas produces Hectors bases which readily isomerize to give 3,5-diamino-1,2,4-thiadiazoles (Equation (28)). Imidoylthioureas (228) when treated with A-chloro-succinimide afford 5-imino-l,2,4-thiadiazolines (229) (Scheme 49) <85S83>. 

Diamino-1,2,4-thiadiazoles of type (361) have been patented for use in the treatment of hypertension <82EUP44266), while 5-amino-1,2,4-thiadiazoles such as (362) are claimed to be useful for treating autoimmune diseases and in the prevention of graft rejection. Compounds of type (362) also have antirheumatic properties and are, in particular, useful in the treatment of rheumatoid arthritis and immune diseases such as systemic lupus <91EUP455356). 

The preparations of 1,2,4-thiadiazoles and 1,2,4-thiadiazolidines from thioureas are well known and have been summarized in three reviews those of Bambas,188 Sherman,189 and Kurzer.170 Contained in these reviews are discussions of the controversies that surrounded some of the products, notably Hector s bases, which resulted from oxidation of substituted thioureas.171,172 Subjects covered in the above reviews, but too extensive to outline in detail here, are the oxidation of amidinothioureas to 3,5-diamino-1,2,4-thiadiazoles (71),173,174 the oxidation of phenylthiourea175 and of substituted amidinothioureas176 to 3,5-diimino-l,2,4-thiadiazolidines (72, Hector s bases), the reaction of thiopseudoureas with trichloromethanesulfenyl chloride to form 3-alkylthio-5-chloro-l,2,4-thiadiazoles (73),177 the reaction of thiopseudoureas with sodium thiocyanate and bromine178 and the oxidation... 

The reaction of amidines with sodium hypochlorite and potassium thiocyanate (Scheme 145) is a mild method for producing a variety of 5-amino- and 3,5-diamino-1,2,4-thiadiazoles (16) in good yields (also see Scheme 98) (65AHC(5)119). Af-substituted derivatives are obtained when isothiocyanates (RCNS) are used in place of potassium thiocyanate (78USP4107377). 

Thiadiazole has an absorption maximum at 229 nm (log e 3.7). The introduction of amino groups into the heteroaromatic nucleus results in a bathochromic shift. Thus, the maximum due to 1,2,4-thiadiazole is moved to 247 nm in 5-amino and to 256 nm in 3,5-diamino-1,2,4-thiadiazole. The UV spectra of a variety of substituted 1,2,4-thiadiazoles have been determined, but the information so far available does not provide any broad correlation between structure and absorption characteristics (65AHC(5)ii9>. 

By contrast, however, 3,5-diamino-l,2,4-thiadiazoles are selectively converted into amides and sulfonamides in good yields. Thus, acetylation of 3,5-diamino-1,2,4-thiadiazole (53) with excess acetic anhydride yields the symmetrical derivative (133) whereas under similar conditions 3-amino-5-methylamino-l,2,4-thiadiazole and 3,5-diarylamino-l,2,4-thiadiazoles (65AHC(5)119) produce the monoacylated derivatives (134) and (135), respectively. Sulfonylation also results in the preferential formation of the 3-sulfonamides but reaction with excess reagent eventually produces the 3,5-disubstituted derivatives (136) and (137) in good yields (65AHC(5)119). 

Oxidation of Af-arylthioureas (261) with acidic hydrogen peroxide produces Hector s bases (73) which readily isomerize under basic conditions to afford 3,5-diamino-1,2,4-thiadiazoles (84 Scheme 146) (65AHC(5)ll9> (also see Scheme 92). A variety of 3-amino-and 3,5-diamino-l,2,4-thiadiazoles (325) also have been obtained by the treatment of iminocarbonates (322) with chloramine at low temperature, as illustrated in Scheme 147 (also see Scheme 115) (76EGP119791). 

The condensation of alkali salts of N-substituted N -cyanoisothioureas (321) and chloramine (prepared in situ from aqueous ammonia and chlorine) produces the substituted 3,5-diamino-1,2,4-thiadiazole (322). The reaction is an extension of the comparable ring closures involving potassium S-alkylcyanodithioimidocarbonates (see Section II.C.2.C).223,224... 

Acylation of 3,5-diamino-1,2,4-thiadiazole by ethyl chloroformate yields the 3,5-bis(ethoxycarbonylamino) derivative.67 Phosphorochloridic esters [(RO)2POCl] attack the 3-position preferentially, producing the phosphor-amidic esters (509).390 The action of diphenylphosphinothioic chloride (Ph2PSCl) (see Section IV,C) on Hector s base in pyridine yields a monoacyl derivative, substitution occurring probably at the exocyclic imino group.391 Methylation of 3,5-bisanilino-l,2,4-thiadiazole with sodium hydride-methyl iodide in dimethylformamide produces the mono and dimethyl derivatives, of structures 510 and 511, as shown by 15N and 13C NMR spectroscopy.31... 

Like Terrazole, 3,5-diamino-1,2,4-thiadiazole acts as an effective inhibitor of the oxidation of ammonium salts to nitrates in soil.506... 

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>. 

Among more exotic surrogates, the 3,4-diamino thiadiazole dioxide moiety was proposed as a weakly acidic urea equivalent (Figure 15.38). The similar thiatriazole dioxide is found in the H2 antagonist tuvatidine (HUK 978). Other bioisosteres are exo-endo amidinic heterocyles bearing an electron-attracting function in the a position (Figure 15.38). 

Treatment of 5,7-diamino-l,3,4-thiadiazolo[3,2-n]pyrimidinium ehloride (25) with Vilsmeier reagent gave the 7-formamido-l,2,4-triazolo[l,5-c]pyrimidin-5-one (27) (90JHC851) (Seheme 42). Compound 27 has presumably been formed via rupture of the 1,3,4-thiadiazole ring of 25 and... 

The transamination reaction on 3,4-diamino-1,2,5-thiadiazole 5,5-dioxide 200 with pyridylamines afforded the 3-monoheteroarylamino thiadiazole... 

Die Elektrolyse von Benzo-l,2,5-thiadiazol bzw. -selenadiazol in waBriger Losung an Quecksilber fiihrt ebenfalls zu 1,2-Diamino-benzol4 ... 

The oxidation of acetylthiourea and phenylthiourea to afford the corresponding 1,2,4-thiadiazoles has been reported using [bis(acyloxy)iodo]arenes as the oxidants. The proposed mechanism involves the formation of a polyvalent iodine compound 74. After the elimination of iodobenzene, the 1,6-dip he nyl-dithioformamidine 75 is formed, which is set up to undergo a further oxidation to give the bis 3,5-diamino-l,2,4-thiadiazole 76 (Scheme 7) <2003T7521>. 

A good method for the preparation of substituted 3,5-diamino-l,2,4-thiadiazoles is the rearrangement of dithiazolium cations with sodium azide <2004HOU277>. If the amino groups at the 3- and 5-positions are different, then a mixture of isomeric 3,5-diamino-l,2,4-thiadiazoles is obtained. 

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). 

A variety of 3-amino- and 3,5-diamino-l,2,4-thiadiazoles have been obtained by the treatment of iminocarbonates with chloroamine at low temperatures (see Equation (27), Section 5.08.9.6). 

A useful strategy for the formation of fused thiadiazoles is the annulation of suitably functionalized 1,2,5-thiadiazoles. Common routes involve the use of 3,4-difluoro-l,2,5-thiadiazole, 3,4-diamino-1,2,5-thiadiazole, l,2,5-thiadiazole-3,4-dicarbonyls, l,2,5-thiadiazole-3,4-dicarbonitrile, amino-1,2,5-thiadiazole-3-carboxamides and carboxamidines. These afford heteroarene-fused 1,2,5-thiadiazoles (which are covered in Volume 9). Below follows a brief description of fused thiadiazoles that fall within the scope of this chapter. 

Large macrocyclic phthalocyanines can be obtained from the condensation reactions of 2,5-diamino-l,3,4-thiadiazole <2006SC1801,2006MI837,20010L2153>. Diaminothiadiazole reacts with 5- z/-butyl-l,3-diiminoisoindoline in 2-ethoxy-ethanol at 135 °C for 24 h to give macrocycles 107 and 108 in 54% and 15% yields, respectively <20010L2153>. 

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)). 

A detailed study of the conversion of 3,4-dichloro-l,2,5-thiadiazole into 3,4-diamino-l,2,5-thia-diazole has been carried out <76JHC13>. Reaction with lithium or sodium amide produces only 4% of the diamine together with cyano-containing by-products, a consequence of direct attack on sulfur. Use of a less powerful nucleophile, ammonia or potassium phthalimide, resulted in an increased attack on carbon and produced the diamine in 24% and 66% yields, respectively. Secondary amines, e.g. morpholine <76JOC3l2l> and dimethylamine <72JMC315>, produce the normal displacement products. The reaction of dichlorothiadiazole with potassium fluoride in sulfolane gives a mixture of 3-chloro-4-fluoro and 3,4-difluoro-l,2,5-thiadiazole <82CB2135>. 

Azirines are dimerized under various conditions to dihydropyrazines or their dehydrogenated products, namely pyrazines (Section 8.03.9.5). Quinoxalines are oxidized with potassium permanganate to afford 2,3-pyrazinedicarboxylic acids, and pteridines are hydrolyzed to give 3-amino-2-pyrazinecarboxylic acid derivatives. Condensation of 3,4-diamino-l,2,5-thiadiazole 176 with a-diketones produces l,2,5-thiadiazolo[3,4- Jpyrazines 177, which are reduced to provide 2,3-diaminopyrazines 178 (Scheme 51) <1997JCM250>. 

The oxidation of AT-acetylthiourea in pyridine by hydrogen peroxide to the diacetyl derivative of 3,5-diamino-l,2,4-thiadiazole (12, R = AcNH) (in 35% yield)27 may also be included under this general heading. 

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 ... 

Amongst oxidizing reagents, arylsulfonyl chlorides in pyridine simultaneously cyclize and acylate amidinothiourea (and its 2V-phenyl and AT -diphenylhomologs), producing moderate yields of sulfonyl derivatives of 3,5-diamino-l,2,4-thiadiazoles in one step.116... 

---