2-Amino-l, 4-thiadiazoles

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). 

Reactions of 2-methylthio-4-oxo-3-phcnylpyrido[2,1 -/][l,2,4]triazinium iodide 73 with nucleophiles were carried out to obtain mesomeric betaines. Nucleophilic displacement of the methylthio group of 73 with 2-aminothiazole or 2-amino-l,3,4-thiadiazole afforded 74 (Equation 1) <1996T11349>. 

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>. 

The reaction of 2-amino-l,3,4-thiadiazole 470 and 3-amino-l,2,4-triazole 472 with benzaldehyde and fe/V-butylisoni-trile gives imidazo[2,l-A [l,3,4]thiadiazoles 471 and imidazo[l,2- ][l,2,4]triazoles 473, respectively, in a one-pot process (Equation 110) <1998AG(E)2234>. 

The alkylation of 2-amino-l,3,4-thiadiazoles was reported already by Freund and Meinicke (1896CB2514). See also Goerdeler and Roth (63CB534). 

The a-halo ketone has also been prepared in situ (NBS, benzoyl peroxide, light) [89IJC(B)500]. Similarly, imidazo[2,l-b][l,3,4]thiadiazoles are accessible from 2-amino-l,3,4-thiadiazoles and acetophenones in the presence of hydroxy(tosyloxy)iodobenzene (HTIB). This latter method has been proposed as more convenient and versatile than the reaction of 2-amino-1,3,4-thiadizoles with a-halo ketones [94IJC(B)686, 94JCR(S)38, 94MI5],... 

The parent compound 101 has been prepared by reaction of 2-amino-l,3,4-thiadiazole with bromoacetaldehyde (ethanol, reflux) as colorless needles with mp 107°C [80JCS(P2)421]. 

Condensed derivatives are also known. Treatment of 2-amino-l,3,4-thiadiazoles with 2,3-dichloro-l,4-naphthoquinone or 6-chloroquinoline-5,8-dione yields 102 and 103, respectively (82H333, 91JIC529). 

Finally the aminothiadiazoles have been used to prepare bright red dyes. In particular the dyes derived from 5-substituted 2-amino-l,3,4-thiadiazoles (52) (70GEP2028396) and the 3-substituted 5-amino-l,2,4-thiadiazoles (53) (70GEP2006131) by coupling with dialkyl-anilines are neutral to bluish-reds of outstanding brightness and colour strength. 

Amino-l,3(4-thiadiazole or 2-lmino-l,3,4-thiddiazoline, called by Freund "Imidothio-biazolin , HC-S-C-NH, or HC-S-C NH. 

Note Apparently the last two derivs of 2-amino-l,3,4 thiadiazole are identical... 

In a series of publications (75JOC2600, 70JOC1965, 73JOC3087), Potts and coworkers have reported that cyclic amidines (290) readily condense with trichloromethylsulfenyl chloride (329) to yield the sulfenamides (330 Scheme 119). Treatment of the latter compounds with aromatic amines in the presence of triethylamine results in cyclization, possibly via an intermediate such as (331), to produce bicyclic products of type (332). Heterocycles (290) which have been used successfully in this reaction include 2-amino-l,3,4-thiadiazoles, 3-aminopyridazines, 2-aminopyrimidines, 2-aminopyrazines, 2-aminopyridines, 3-aminoisoxazoles and 5-amino-1,2,4-thiadiazoles. The sulfenamide derivative (330) of 2-aminopyridine also was found to react with sodium sulfide and with diethyl malonate to produce (333) and (334) respectively. Attempts to hydrolyze (332) to (295) under acidic conditions failed. 

The 1,3,4-thiadiazole ring system, with three heteroatoms, does not exhibit tautomerism in its fully conjugated form. However, when certain substituents are present, tautomerism is possible. l,3,4-Thiadiazolin-2-ones (39 X = 0) and -2-thiones (39 X = S) exist in the oxo and thione forms, respectively, as shown by spectroscopic and LCAO-MO calculations. 2-Amino-l,3,4-thiadiazoles exist in the amino form in solution and in the solid state the Kt value is 10s as shown by basicity measurements. UV spectroscopy and LCAO-MO calculations show that the amino tautomer is also the main species when there is an alkoxy group in the 5-position (40 R1 = alkoxy, R2 = NH2), or if the exocyclic nitrogen atom is part of a hydrazone group (40 R2 = NHN=CR2). 

Various 2-substituted l,3,4-thiadiazoline-5-thiones can be prepared in good yield by the reaction of amidrazones with CS2 in ethanol at room temperature (Scheme 21a) (70CPB1696). 4-Aryl-2-benzoyl-5-imino-A2-l,3,4-thiadiazolines are prepared from activated thiocyanates and benzenediazonium chloride, presumably via a hydrazone (Scheme 21b) (75TL163). 2-Thio- and 2-amino-l,3,4-thiadiazoles carrying a carbamate in the 5-position are obtained in one step by the reaction of a dithioimidate with a hydrazide. The yields are quite high (Scheme 22a) (80ZC413). 

The early antimicrobial compounds such as lucosit (219 R = Me) and globucid (219 R = Et) can be prepared by treatment of the 2-amino-l,3,4-thiadiazole with (V-acetylsulfonyl chloride in pyridine followed by deacetylation. A more recent antimicrobial compound (224) can be efficiently synthesized by the route shown in Scheme 35. The thiadiazole (220) is obtained by the usual cyclization procedure and then oximated to (221). Dehydration and the Pinner amidine synthesis followed by treatment with aminoacetaldehyde dimethyl acetal yields (222). Sulfuric acid cyclization furnishes the thiadiazoloimidazole derivative (223) which is further methylated, acetylated, nitrated and hydrolyzed to the desired (224) <69JHC(6)835). 

Azole approach. 2-Amino-l,3,4-thiadiazoles react with appropriately substituted a,/3-unsaturated carbonyl compounds to form fused pyrimidines (729). The orientation of the substituents in the fusion products suggests that the reaction is initiated by Michael addition of the amino group. 1,3-Dicarbonyl compounds will condense in the same manner to yield the salt (729) from a /3-keto ester the 5-oxo derivative (730) is formed (73ABC1197). 

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