2-Amino-5-ethyl-1,3,4-thiadiazole

Amino-5-ethyl-1.3,4-thiadiazole p-Acetylaminobenzene sulfonyl chloride... 

Ethyl iodide and 5-amino-2-methyl-l,3,4-thiadiazole react at 110° to give the N-3 salt (78 R = Me, R = NH2, R" = Et), as shown by the presence of the very reactive methyl group this salt is also used to prepare cyanine dyes. The slow quatemization at the ring-nitrogen atom furthest from the amino group is consistent with the reactions observed in other ring systems. As would be e pected, 5-alkylthio-2-methyl-l,3,4-thiadiazoles form salts at the N-3 (78 R = Me, R - S-alkyl).i ... 

Chemical Name 4-Amino-N-(5-ethyl-1,3,4-thiadiazol-2-vl)benzenesulfonamide Common Name —... 

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 stepwise condensation of 2-amino-5-ethyl-l,3,4-thiadiazole 83 with a mixture of salicylic aldehyde and acetylacetone in ethanol in a reagent mixture of 1 1 1 gave compound 84 in 36% yield <99RJOC624>. 

Substituted (ethyl, -propyl, benzyl), cyclohexyl, 2-furyl, and 2-thienyl) 2-amino-l,3,4-thiadiazoles 451 react with a-bromoarylketones to give imidazo[2,l- ][l,3,4]thiadiazoles 161 in good yields (Equation 103) (Table 59) <2006BMC3069, 2006TL2811>. 

Amino-5-ethyl[l,3,4]thiadiazole 105 upon reaction with 1-chloro-l-phenyliminomethanesulfenyl chloride yields 6-ethyl-3-phenylimino-37/-[l,3,4]thiadiazolo[2,3-7][l,2,4]thiadiazole 106 (Equation 27) <1986S1027>. For another synthesis of a compound related to compound 106, see Section 11.07.9.2 <1994T7019>. 

Compounds containing an a-aminoimidate fragment (HN=C-C-NH2) as in ethyl 2-amino-2-oxoethanimidoate 30 and 2-aminoethanimidamide 31 reacted with sulfur monochloride to give, respectively, 4-ethoxy-l,2,5-thiadiazol-3-ol (32) and 3-amino-l,2,5-thiadiazol (33) (1967JCX72823 Scheme 16). Yields were moderate. 

Tsuji obtained two isomeric l,3,4-thiadiazolo[3,2-a]pyrimidino compounds by changing the pH (Scheme 13) <91JHC489>. Thus treatment of 2-amino-5-substituted-thiadiazoles (82) with ethyl cyanoacetate (83) in the presence of sodium methoxide gave the 2-substituted 5-imino-6//-[ 1,3,4]-thiadiazolo[3,2-a]pyrimidine-7-one (84). When the same reaction was carried out in the presence of P2O5 and CH3SO3H instead of sodium methoxide, 7-amino[l,3,4]thiadiazolo[3,2-a]pyrimidine-5-one... 

The corresponding ethylation proceeds in lower yields, and may be suppressed entirely by the presence of substituents elsewhere in the nucleus (e.g. 192 R = Ph).171 The attempted introduction of higher alkyl, allyl, and benzyl residues also failed.171 The derivative (204) obtained with phenacyl bromide is readily ring-closed to the diheterocycle 205.171 Diphenyl- and triphenyl-methyl halides, on the other hand, alkylate 5-amino-1,2,4-thiadiazoles in the exocyclic amino group,171 as shown by the lower basicity of the resulting products (e.g. 202). 

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... 

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... 

Reaction of 9-fluoro-8-isothiocyanato- and 8-iso(thio)cyanato-3,5, 6,7-tetrahydro-2//-pyrido[l,2,3-de]-l,4-benzoxazines with 2-amino-4,4-dimethylpyrroline, then with Br2, and with ethyl pipecolinate yielded 8-(6, 6-dimethyl-3,5,7,7-tetrahydropyrrolo[2,l-c][l,2,4]thiadiazol-3-ylidenamino)-9-fluoro and 8-(l,3-dioxo and l-oxo-3-thioxoperhydroimidazo[l,5-a]-pyridin-2-yl) derivatives, respectively (89EUP406993). Treatment of 9-fluoro-8-(2-hydroxymethylpiperidinothiocarbonylamino)-3,5,6,7-tetrahydro-2//-pyrido[l,2,3-de]-l,4-benzoxazine with HC1 gas in EtOH gave the 8-(perhy-dropyrrolo[l,2-c]thiazol-3-ylidenamino) derivative. 

Methylation of 5-amino-l,2,4-thiadiazoles (16 R = H, Ph), leads to N-4 derivatives (19) which on warming in ethanol undergo a Dimroth rearrangement to 5-methylamino-l,2,4-thiadiazoles (20) when R = H. Available evidence suggests that the isomerization proceeds by the sequence shown in Scheme 12. Ethylation of (16) proceeds in low yield and no reaction is observed when R = Ph. Introduction of higher alkyl, allyl and benzyl groups is also unsuccessful. 

The reaction of unsubstituted 2-amino-1,3,4-thiadiazole (131) with 1,3-dicarbonyl compounds is dependent on the nature of the dicarbonyl compound (Scheme 13). Thus, reaction of (131) with pentane-2,4-dione gives the 4,6-dimethyl-2-thiocyanatopyrimidine (132). The formation of (132) may proceed via the cation (132a). With ethyl acetoacetate, however, a mixture of (133) and (134) is formed, (133) also being converted into (134) on heating. 

Ethyl imidate hydrochlorides can also be used to cyclize thiosemi-carbazides. In acid medium the reaction leads to 2-amino-l,3,4-thiadiazoles, and in basic to l,2,4-triazoline-3(2)-thiones. Possibly the ethoxymethylene derivatives corresponding to 33 are intermediates in this case also. 

Tandem mass spectrometric experiments have been used to characterize both ionic and neutral parent dithiirane 3a in the gas phase <1999PCA5123>. Collision activation experiments have established the connectivity of dithioformic acid, dimercaptocarbene, and dithiirane 3a for the ion at miz 78 generated by electron ionization of ethyl carbamoylmethane-dithioate, 5-amino-l,3,4-thiadiazole-2-thiol, rhodanine, and 1,2-dithiacyclopentane, respectively. Theoretical calculation of the CH2S2 isomers and their radical cations at B3LYP/6-31G level have supported experimentally obtained data. 

A literature report57 indicated that 3-amino-5-phenyl-l,2,4-oxadiazole 76 (R = Ph) reacted with ethoxycarbonylisothiocyanate in refluxing ethyl acetate to give the stable thiourea 79. A reexamination30 of this reaction showed that the product was the rearranged 1,2,4-thiadiazole 80 probably obtained through the intermediate formation of 79. 

In a variation of this synthesis, the amidine is N-halogenated prior to its condensation with an isothiocyanate ester the resulting IV-haloimidoyl-thioureas (238) are readily cyclized to 239 by alkalis. By employing bromine in conjunction with methylene chloride-aqueous alkali as the reaction medium, the reaction may be performed in one operation. 3-Trichloromethyl-5-(substituted)amino-l,2,4-thiadiazoles have been produced by this method.187 The use of potassium ethyl xanthate similarly yields the 5-ethoxy analogs (240 e.g., R = CC13, R1 = Et) directly, with elimination of the elements of hydrogen sulfide.188... 

Chemical Properties. - Cyclocondensation of 4-amino-1,2,3-thiadi-azoles with R1COCHR2COR3 gave 1,2,3-thiadiazolof3,4-aJpyrimidinium salts [317 R,R1, R2,R3 = mix of H,Me,Ph (for R2-R1< only)] in 17-7 yield333. 5-Amino-1,2,3-thiadiazole is converted to the Na or Ba salt of (318) with aqueous NaOH 1 or Ba(0H)2 8H2033, respectively. 5-Azido-4-carbethoxy-1,2,3-thiadiazole could not be prepared from NaN3 and the 5-chloro analogue the diazo compound (319) was isolated in 73 yield. Confirmation for (319) was derived from its spectral data and its thermolysis to ethyl a-... 

---