2-Amino-5-aryl-1,3,4-thiadiazoles

Reaction of 2-amino-5-aryl-thiadiazole (88 R = Ar) with aryl nitriles in the presence of aluminum chloride produced the aryl amidine (89) which was oxidized with lead tetraacetate to yield the 2,6-diaryl-[ 1,2,4]-triazolo[5,1 -( ]-1,3,4-thiadiazoles (90) <91 UC(B)435>. 

Aroylformamido-4-aryl-l,2,5-thiadiazoles 120 on treatment with MCPBA in chloroform at reflux afford 3-amino-4-aryl-l,2,5-thiadiazoles 121 (Scheme 18), but in the presence of ethanol the 3-ethoxycarbamoyl-4-aryl-l,2,5-thiadiazole 122 was also isolated <1999JHC515>. A-Aroylation could readily be achieved to give thiadiazoles 123 using the acid chloride in chloroform at room temperature. 

Alkyl and aryl thiohydrazide derivatives react with orthoesters and trihalomethyls to afford 1,3,4-thiadiazoles. The reactions proceed via a thiosemicarbazone intermediate which cyclizes to eliminate either alcohol or hydrogen chloride. Treatment of the iV-thiohydrazide pyrazole 143 with triethyl orthoformate in acetic acid at reflux gave the 5-acetamido-l,3,4-thiadiazol-2-ylpyrazole 144 (Equation 51), and in the absence of acetic acid the 5-amino-l,3,4-thiadiazol-2-ylpyrazole 145 in 76% yield <2000JCM544>. 

The reaction of the trichloromethylarenes 146 with thiosemicarbazide 138 in a boiling methanol-pyridine mixture afforded the 2-amino-5-aryl-l,3,4-thiadiazoles, while under similar conditions trichloromethylarenes 146 were converted to the diaryl-1,3,4-thiadiazoles with thiobenzhydrazide 147 (Equation 52, Table 7) <1996RCB1185>. 

On treatment with phosphorus pentasulfide, 4-amino-5-thio-477-[l,2,4]triazoles 86 are converted into 6-aryl-3-(2-aminophenyl)[l,2,4]triazolo[3,4-4][l,3,4]thiadiazoles 3. This transformation is presumed to involve three steps first, the transformation of the amide into the thioamide second, transfer of the thioaroyl group from the phenylamino side chain to the iV-amino group of the triazole ring and, finally, cyclodehydrosulfurization leading to 3 (Equation 21) <1989LA1055>. 

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>. 

In a variation of this approach the reaction of amidrazone ylides (230) with both alkyl and aryl isothiocyanates yields thiocarbonyl substituted amidrazone ylides (231) which can be thermally cyclized to 5-amino-1,2,4-thiadiazoles (232) with the elimination of trimethylamine (Scheme 50) <81JHC201>. 

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>. 

Due to the lack of suitable aliphatic starting materials, the synthesis of aromatic forms of monocyclic 1,2,5-thiadiazoles was not accomplished for more than 70 years after the first report of the benzo analogues. General synthetic methodology for monocyclic 1,2,5-thiadiazoles was devized which readily leads to a variety of substituted derivatives, alkyl, aryl, halo, hydroxy, alkoxy, cyano, and amino as well as the parent system. A general model for substrates applicable in these syntheses... 

Research on the fluorination of aromatic amines has provided access to 4-fluoro-2,l,3-benzo-thiadiazole (77). Treatment of 4-amino-2,l,3-benzothiadiazole (1) with nitrosonium tetra-fluoroborate (NOBF4), followed by heating of the resulting diazonium salt, gave the aryl fluoride (77) in 23% yield <92SC73>. 

Proton, C, and N NMR spectroscopy has been employed to demonstrate the existence of ring-chain tautomerism between protonated forms of thiosemicarbazones and protonated 2-aryl-5-amino-2,3-dihydro-1,3,4-thiadiazoles <92KGS1689>. The use of NMR in various solvents, indicates that the isoxazoline (28) contains between 24% and 34% of the thiadiazoline (29) <85KGS1001>. Tautomerism was also discussed in Sections 4.10.2 <90BCJ2991> and 4.10.3.3 <83HCA1755>. 

Amino-5-aryl-l,3,4-thiadiazole was treated with thionyl chloride in dry benzene to yield the N-sulfinylamine (93) an unstable compound, characterized by NMR and further derivatization. The sulfinylamine moiety caused an upheld shift on C(2) (4 6 ppm) comparable to a carbonyl or sulfonyl group, indicating the double-bond character of the N—S bond. Reaction of (93) with 2,3-dimethylbuta-1,3-diene yielded (94) via thermal cycloaddition <89JCS(P2)i855>. 

There are many heterocyclic molecules in which 1,3,4-thiadiazoles are fused to other ring systems. For example, Molina et al. developed a procedure for building a thiadiazole ring on to a properly substituted imidazole moiety (Scheme 29). Reaction of l-amino-2-methylthio-4-phenylimidazole (161) with triphenylphosphine dibromide in dry benzene furnished the 2-methylthio-4-phenyl-l-triphenylphosphoranylidenamino imidazole (162) in a 95% yield. With aroyl chlorides at elevated temperature, this gave the 2-aryl-6-phenylimidazo[2,l-Z ][l,3,4]thiadiazoles (164) in yields between 50% and 70% via the imidoyl chloride intermediate (163) which could be isolated and shown to cyclize to the thiadiazole. The method developed for the imidazole ring was also applicable to the thiadiazolotriazine ring system <88H(27)1935). 

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). 

Amidoximes (46) were first used as a source of 1,2,4-thiadiazoles in 1889 their condensation with carbon disulfide or with an excess of aryl isothiocyanate yields 3-aryl-5-mercapto- (47)6 -73 or 3-aryl-5-aryl-amino- 1,2,4-thiadiazoles (50),71,74,75 respectively. The latter reaction has been reexamined and discussed by Gheorgiu and Barbos76 who suggest that an initial addition of two moles of phenyl isothiocyanate to one of benzamidoxime is followed by cyclization of the intermediate (49), with elimination of phenylthiocarbamic acid (51). Decomposition of the latter gives rise to the by-products observed (cf. following scheme). 

Di(alkyl or aryl)amino-l,2,4-thiadiazoles (90 R,R = alkyl or aryl) are similarly obtainable in 60-85% yields from the appropriate disubstituted amidinothioureas (89 R,R = alkyl or aryl).56,57 The preparation of the latter from monosubstituted guanidines (87) and isothiocyanate esters (88) might conceivably yield the isomeric ami-... 

Alkyl(or aryl)amino-3-substituted-l,2,4-thiadiazoles (115) are synthesized129 without difficulty from A-substituted-iV -acetimidoyl-(or benzimidoyl)thioureas (114), obtained by condensing amidines and isothiocyanates. 

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... 

Phenyl-3-ureido-1,2,4-thiadiazoles (222) are obtainable by successive treatment of the 3-amino heterocycle (220) with ethyl chloro-formate at 120° and the appropriate amine.188 Direct action of aryl-sulfonylurethanes (on 220) affords 3-arylsulfonylureido-5-phenyl-l,2,4 4-thiadiazole8 (223) in one stage.188... 

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... 

Treatment of 5-alkyl(or aryl)amino-3-alkylthio-l,2,4-thiadiazoles with hydrogen sulfide in pyridine-triethylamine, or with sodium in liquid ammonia, yields 1-substituted dithiobiurets.182 Since, in the... 

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

In connection with a study of the electron impact-induced fragmentations of 1,2,3-thiadiazoles, the mass spectrum of 5-phenylthiatriazole has been scrutinized.13 Jensen et al.1 have undertaken a detailed investigation including 5-aryl-, 5-amino-, and 5-alkylthiothiatriazoles. The electron impact-induced decompositions resemble the pyrolytic loss of N2S (Section III, A). In all cases the M—N2S ion together with its fragmentation is responsible for the major part of the total ion current. A detailed discussion of the spectra is outside the scope of this review. 

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