5- Amino-3-methyl-l,2,4-thiadiazole

Amino-3-methyl-l,2,4-thiadiazole was reacted with EMME in boiling trichlorobenzene to give 1,2,4-thiadiazolo[4,5-a]pyrimidine-6-carboxylate (1132) (59JOC779). 

The condensation of 5-amino-3-methyl-l,2,4-thiadiazole (118) with aliphatic or aromatic nitriles yields 1 1 adducts, which are, according to their H NMR spectra, equilibrium mixtures of (119) and (120) (Scheme 28) <82AHC(32)285>. These adducts are produced by a bond switch at the n-hypervalent sulfur in (121). X-ray analysis of the adduct formed from the reaction of (118) with chloroacetonitrile showed the adduct to exist as (122) in the crystals <81AX(B)185>. Further examples of this type of bond switch at rc-hypervalent sulfur are observed in the reaction of 5-imino-1,2,4-thiadiazolines with various electrophilic reagents (Section 4.08.6.1). 

Amino-3-methyl-l,2,4-thiadiazole has a relatively high melting point and low solubility in water, compared with that of the 3-ethyl homolog and the parent compound the isosteric 4-aminopyrimidines show a parallel behavior (see Table VT).6 5-Amino-3-methoxy-l,2,4-thiadiazole melts at a higher temperature than does the ethoxy homolog.83... 

The reaction of 5-amino-l,2,4-thiadiazoles (16) with aldehydes produces a-amino alcohols (145), azomethines (146) or bis-amines (147) depending on the reactants and reaction conditions, as illustrated in Scheme 58. The nitration of 5-amino-3-methyl-l,2,4-thiadiazole (25) in a mixture of 98% sulfuric acid and 95% nitric acid at 0°C is reported to produce (148) in good yield (65AHC(5)119), but a similar reaction with 3-amino-l,2,4-thiadiazoles has not been described. Products of type (149) can be obtained, however, by the ring closure of Af-nitro-AT-thiocarbamylguanidines with alkaline hydrogen peroxide. 

Some typical rearrangements in this series have been reviewed in a different context, concerning 1,2,4-thiadiazole chemistry [82AHC(32)285]. 5-Amidinothiadiazoles 240, obtainable from the 5-amino-3-methyl-l, 2,4-... 

Pyrazblin-5-one, 3-alkyl-(l,2,4-thiadiazol-5-yl)-reactions, 6, 483 2-Pyrazolin-5-one, 3-amino-tautomerism, 5, 215 2-Pyrazolin-5-one, 4,4-diazido-rearrangement, 5, 720 2-Pyrazolin-5-one, 3-hydroxy-tautomerism, 5, 215 2-Pyrazolin-5-one, 3-methyl-1 -phenyl-reactions, 5, 252... 

Reaction of thio- and alkylthio derivatives of A -aminoazoles with aryl isothiocyanates leads to annelation of a 1,3,4-thiadiazole or a 1,2,4-triazole ring. Thus, 4-amino-3-methyl-l,2,4-triazoline-5-thione, on reaction with aryl isothiocyanates under mild conditions, gives products of addition (388), which on heating are transformed to 2-arylaminotriazolo[3,4-/>]thia-diazoles (389) (83S411 87JHC1173). 

Bond Switch at n-Hypervalent Sulphur.—Condensation of S amino-3-methyl-1,2,4-thiadiazole (190) with alkyl or aryl cyanides affords an equilibrium mixture of products (191) and (192). A similar bond switch is observed when the 5-imino-l,2,4-thiadiazoline (193) is treated with the imino-ester MeC(=NH)OEt, as... 

The Schiff base derivatives 73 of the 3-hetaryl-substituted 4-amino-3-thiol-l,2,4-triazoles, on treatment with acetic anhydride, undergo cyclization to give the corresponding 3-substituted-5-acetyl-5,6-dihydro-6-phenyl[l,2,4]triazolo[3,4-7][l,3,4]thiadiazoles 76 (Equation 16) <1990IJB135>. Similar treatment of 4-(A-bcnzoylamino)-4,5-dihydro-l-methyl-3-mcthylthio-1 //-[ 1,2,4 triazolc-5-thione 77 leads to the [l,2,4]triazolo[3,4-4][l,3,4]thiadiazolium trifluoromethanesulfonate 78 (Equation 17) <1986LA1540>. 

In the presence of triethylamine, the reaction of 2-amino-5-methyl[l,3,4]thiadiazole 134 with 2-benzyl-5-chloro-[l,2,4]thiadiazol-2-one 135 gives 3-(benzylcarbamoylimino)-6-methyl-3//-[l,3,4]thiadiazolo[2,3-c][l,2,4]thiadiazole 138. Presumably, the first-formed intermediate 136 rearranges through the thiapentalene intermediate 137 to the fused thiadiazole product 138 (Scheme 10) <1994T7019>. 

A wide variety of reagents have been used to convert amidines (282) into 1,2,4-thiadiazoles. Treatment of (282) with sodium hypochlorite followed by potassium thiocyanate at pH 3 produces 5-amino derivatives (284) in moderate to good yields (Scheme 98). In one example an unstable intermediate (283 R = OMe, R = H) was isolated but not fully characterized (65AHC(5)119). Products of type (285) are obtained when amidines are treated with iminochloromethylsulfenyl chlorides (269 Scheme 99) (71T4117). When R is aryl (285) is the exclusive product whereas a mixture of isomers is obtained when R is aroyl. 5-Amino-l,2,4-thiadiazoles related to (284) and (285) also are formed in good yields when (V-haloamidines are treated with isothiocyanates. Thus, 5-methylamino-3-trichloromethyl-1,2,4-thiadiazole (287) is obtained in 73% yield from the reaction of A-bromotri-chloroacetamidine (286) with methyl isothiocyanate (Scheme 100) (78USP4107377). 

Amino-l,2,5-thiadiazole is chlorinated or brominated at the 4-position at 20°C in acetic acid. 3-Methyl-l,2,5-thiadiazole can also be chlorinated in the 4-position (68AHC(9)107). Bromination of 2-amino-l,3,4-thiadiazole succeeds in the 5-position (65ACS2434). 

The thermal decomposition of some 3,5-disubstituted-l,2,4-thiadiazoles has been studied and some nonisothermal kinetic parameters have been reported <1986MI239>. Polarographic measurements of a series of methylated 5-amino-l,2,4-thiadiazoles show that thiadiazoles are not reducible in methanolic lithium chloride solution, while thiadiazolines are uniformily reduced at 0.5 = — 1.6 0.02 V. This technique has been used to assign structures to compounds which may exist theoretically as either thiadiazoles or thiadiazolines <1984CHEC(6)463>. The photoelectron spectrum for 1,2,4-thiadiazole has been published <1996CHEC-II(4)307>. 

Thiadiazoles are weak bases. They form salts with mineral acids and addition compounds with heavy-metal salts. Methylation of 5-amino-l,2,4-thiadiazoles 17 leads to the product of methylation at the 4-position 18 (Equation 2) <1996CHEC-II(4)307>. More recently, the reaction of the 3-methylthio derivative 19 with methyl iodide led to methylation at N-4 to afford product 20 (Equation 3) <2001CHE1005>. 

Contrasting with the reported formation of fused [l,3,4]thiadiazole rings in the course of the reaction of 3-substituted-4-amino-5-thio-47/-[l,2,4]triazoles 83 with various isothiocyanates (cf. Section 11.07.8.3, Table 3), the reactions with methyl isothiocyanate and with phenylisocyanate afford 3,7-disubstituted-6,7-dihydro-57/-[l,2,4]triazolo[4,3-f] [l,2,4]triazole-6-thiones 110 and -triazole-6-ones 111, respectively (Equation 29) <1986MI607, 1992IJB167>.The same reaction of 4-amino-l-methyl-3,5-bis(methylthio)[l,2,4]triazolium iodide 112 with aryl isothiocyanates yields the mesoionic compounds 113 (Equation 30) <1984TL5427, 1986T2121>. 

Methylation of 3-amino-5-phenyl-l,2,4-thiadiazole (111) with trimethyloxonium tetrafluoro-borate produces the N-2 quaternary salt (112) which on basification undergoes a Dimroth rearrangement to give the 3-methylamino derivative (113) (Scheme 27) <82AHC(32)285>. By analogy with 5-amino-l,2,4-thiadiazole (17) (R = H), the 3-amino-1,2,4-thiadiazole (111) is alkylated by benzhydryl and trityl chlorides to give (114) (Scheme 27). 

Only one representative of this class has been described. 3-Amino-5-phenyl-l,2,4-thiadiazole (269) and methyl iodide gave the iodide (270) which with silver oxide gave the meso-ionic l,2,4-thiadiazol-3-imine (268, R = Ph, R2 = Me, R = H). ... 

Methylation of 3-amino-5-phenyl-l,2,4-thiadiazole (206) proceeds remarkably slowly, yielding products of a zwitter-ion character the reaction has therefore been interpreted by the sequence 206- 207 -> 208.171... 

Although 3-amino-l,2,4-thiadiazoles (e.g. the 5-phenyl homolog) fail to yield nitrosamines under the usual conditions,126 5-nitrosamines are well known.81, 5,190,191 Thus, 3-alkoxy-,8 3-alkylthio-,85 3-dialkyl-amino-,87 and 3-alkylsulfonyl-5-amino-86 (243) as well as 3-aryl-5-arylamino-l,2,4-thiadiazoles,74 on treatment with the calculated quantity of sodium nitrite in dilute mineral acid, or concentrated formic acid, yield crystalline nitrosamines (244). Their unusual stability has permitted a close study of their formation and properties. 170 Their positive Liebermann reaction85,87,170 and the results of their methylation (outlined in the reaction scheme) show that nitro-sation occurs in the side-chain and not in the nucleus.170... 

The radioprotective action of 3,5-diamino-l,2,4-thiadiazole, its 3-toluene-p-sulfonyl derivative, and the corresponding 5-methyl-amino- and 5-anilino analogs has been determined.218 Administration of the parent compound results in 69% survival in mice after 900 r whole body X-radiation, a result that compares favorably with the effects of such established protectors as AET ([Pg.202]

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