5- Amino-l,2,3-thiadiazole

A variation of Wolffs synthesis involves the reaction of diazonitrile with H2S as the thionating agent to give 5-amino-l,2,3-thiadiazole in 73% yield (Equation 21) <1997H(44)197>. 

Examples of the Dimroth rearrangement (Section IV, F) include several s3mtheses of monocyclic triazoles from other heterocyclic systems (cf. Scheme 25). Triazole-5-thiols can be prepared by treatment of 5-amino-l,2,3-thiadiazoles with bases.A similar base-induced rearrangement of sydnoneimines provides a synthesis of 4-hydroxy-triazoles. ... 

Dimroth rearrangement also occurs between the 5-mercapto-l,2,3-triazoles (109) and the 5-amino-l,2,3-thiadiazoles (110). If the thiadiazoles (110) are heated in basic solvents they are converted into the triazoles, whereas the reverse reaction is observed in acidic media (67LA(710)118, 69CB417, 72ACS1243). Thermal equilibria of thiadiazoles and triazoles, with both isomers present, have been reported (62Acs(B)1800, 66CB1618). 

Amino-l,2,3-thiadiazole-4-carboxamides 25 react with orthoesters to yield 1,2,3-thiadiazolo[5,4-cQpyrimidines 26 <96KGS1124 97CA( 126)59926>. 

Sodium hydroxide 5-Mercapto-l,2,3-triazoles from 5-amino-l,2,3-thiadiazoles... 

Thiadiazoles.—, 2,3-Thiadiazoles. Syntheses of 5-amino-l,2,3-thiadiazoles (664 = Ar or ArSOa R = H or PhCO) from isothiocyanates R NCS and... 

Within the huge field of heterocyclic rearrangements [53], the Dimroth rearrangement gives 5-mercapto-l,2,3-triazoles from 5-amino-l,2,3-thiadiazoles and allows interconversion of 5-amino-l,2,3-triazoles into a mixture of isomers under basic condition [54]. Thus, this reaction, discovered in 1909, involves a linear intermediate that can cyclize into two isomeric compounds (Scheme 15) [55]. This ring-chain tautomerization is reversible, but the equilibrium can be pushed toward an end if one of the two isomers is stabilized. 

Synthesis of 5-Mercapto-l,2,3-Triazole Derivatives from 5-Amino-l,2,3-Thiadiazoles... 

The thermally induced rearrangements in the furoxan series have also been found. In particular, the transformation of 3-R-substituted 4-(3-ethoxycarbonylthioureido)-l,2,5-oxadiazole 2-oxides into derivatives of 5-amino-3-(a-nitroalkyl)-l,2,4-thiadiazole and into (5-amino-l,2,4-thiadiazol-3-yl)nitroformaldehyde arylhydrazones has been reported (Equation 8) <2003MC188>. 

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>. 

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>. 

Amino and 5-amino-l,2,4-thiadiazoles both exist predominantly in the amino forms. The IR spectrum of 5-mercapto-l,2,4-thiadiazole does not show a clear SH absorption as would be expected for structure 6 and therefore the thione tautomers 7 and 8 have been suggested (Scheme 2). Similarly, IR evidence suggests that perthiocyanic acid exists as the dithione 9 as opposed to stmcture 10 <1984CHEC(6)463>. 

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>. 

Amino- and 5-amino-l,2,4-thiadiazoles can be diazotized and they can be coupled under standard conditions <1996CHEC-II(4)307>. 

The 3-thiomethyl-5-amino-l,2,4-thiadiazole 49 reacts with epichlorohydrin to afford the pyrimidino-l,2,4-thiadia-zole 50 (Equation 14) <2001CHE1005>. 

A variation using thioacylguanidines affords 5-substituted-3-amino-l,2,4-thiadiazoles. If an amidinothiourea is oxidized, 5-amino-l,2,4-thiadiazoles are obtained. A recent example of this type of synthesis has been reported the amidinothiourea 87 was oxidized to the 1,2,4-thiadiazolium salt 88 on treatment with bromine (Equation 25) <2003SC2053>. 

Amino derivatives of 1,2,4-oxadiazoles, isoxazoles, and 1,2,5-oxadiazoles interact with phenyl isocyanate to produce various 3-substituted 5-amino-l,2,4-thiadiazoles, via intermediate thioureides which can be isolated. The tendency to rearrange follows the order 1,2,4-oxadiazoles, isoxazoles, and 1,2,5-oxadiazoles <1996CHEC-II(4)307>. 

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). 

Aminothiatriazole (328) reacts with a number of aryl cyanates at 0°C to afford 3-substituted 5-amino-l,2,4-thiadiazoles (17) in moderate yields. 5-Aminothiatriazole (328) also reacts with trichloroacetonitrile to give (17) (R = CCI3) in 92% yield. When these reactions are carried out at 30 °C, the thiadiazoles (17) react with a second mole of aryl cyanate to give the amidino compounds (329) (Scheme 72) <85JOCl295>. 

Martin et al. reacted alkyl and aryl cyanates with 5-aminothiatriazoles (13) at 0°C in aprotic solvents <85J0C1295>. The reaction led to evolution of nitrogen and the formation of 3-substituted-5-amino-l,2,4-thiadiazoles (117) in 40-65% yield. If the reaction was carried out at 30°C or if two equivalents of cyanate was employed a subsequent reaction to the corresponding amidino compound (118) took place (Scheme 22). 

Trichloroacetonitrile reacts with 5-aminothiatriazole in a similar way to give the 3-substituted-5-amino-l,2,4-thiadiazole <85JOC1295>. Martin et al. discussed three different pathways for the formation of the 1,2,4-thiadiazole (117) (Scheme 23). 

Amino-l,2,4-thiadiazoles 191 are obtained when ether is used (249), while 5-alkylthio-1,2,3-triazoles 192 result when the reaction is carried out in THF (250). Reaction of 3 with carbon disulfide leads to 5-alkylthio-l,2,3-thiadiazoles 193 (251). While 3 can act as a synthetic equivalent of the RC—N—N synthon (R = H, SiMea) in all these reactions, it should be emphasized that it does not react by a concerted 1,3-dipolar cycloaddition but rather by a stepwise polar mechanism. The highly nucleophilic character of 3 can account for why diazomethane and... 

Isothioureas similarly give, in neutral media, the corresponding 3-alkylthio-5-amino-l,2,4-thiadiazoles (65) in yields exceeding 70%.84"86 However, the attempted preparation of the parent 5-amino-3-mercap-to-l,2,4-thiadiazole from thiourea or dithioformamidine by this route yielded only intractable mixtures.85... 

A number of phenolic ethers of this series show the expected properties. 5-Amino-3-ethoxy-l,2,4-thiadiazole is considerably more soluble in water than its 3-methoxy homolog (3.24 and 0.76 g/100 ml, respectively).88 Their ultraviolet spectra resemble those of the 3-alkyl (or aryl)-5-amino-l,2,4-thiadiazoles.88 3-Alkoxy(or aryloxy)-l,2,4-thiadiazoles are more sensitive towards acids than are the 3-alkyl(or aryl) analogs.88... 

Alkoxy derivatives are attacked more rapidly by 2N hydrochloric acid, with liberation of sulfur, than are the 3-alkyl derivatives.88 3-Alkylthio groups also increase the sensitivity of 5-amino-l,2,4-thiadiazoles to hydrolysis the 3-phenylthio homolog, for example, tends to decompose on crystallization from boiling water.85... 

Alkylthio-5-amino-l,2,4-thiadiazoles are generally insoluble in acids and alkalis, and resist desulfurization by alkaline sodium plum-bite.132 The higher members are Bomewhat sensitive to hydrolysis85,90 the 3-phenylthio homolog is slowly destroyed by concentrated alkali, but its stability is much increased by acylation.85... 

Alkyl(or aryl)-5-amino-l,2,4-thiadiazoles and homologs 5-Alkyl(or aryl)amino-3-pyrazol-l -yl-l,2,4-thiadiazoles... 

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