Isothiocyanates 1.2.4- thiadiazoles, 5-amino

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>. 

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>. 

Scheme 44 also shows two further synthetic routes to [l,3,4]thiadiazolo[2,3-c][l,2,4]triazinones. Reaction of the 3-mercapto- or 3-methylsulfanyltriazinone 221 (R1 = H or R1 = Me) with a set of isothiocyanates was reported to give the 2-amino-substituted fused ring system 222 in medium to good yield (36-84%) <1997JHC1351>. Derivative 223 was described to undergo cyclization to a fused thiadiazole 224 by treatment with carbon disulfide in the presence of potassium hydroxide in ethanol <2001PHA376>. 

The amino group of 3-amino-1,2,4-oxadiazoles shows little nucleophilic character. For example, addition to phenyl isothiocyanate to give 3-(phenylthioureido) compounds requires heating of the components without solvent at 120-130 °C or the use of polar aprotic solvents (DMSO, DMF) and long reaction times (30 days at 23°C) <77JCS(P1)1616>. 3-(Thioureido)-1,2,4-oxadiazoles undergo fast ring transformations to thiadiazoles (see Section 4.04.5.1.1). 

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>. 

Alkyl-3-aminoisoxazoles, 5-alkyl-3-amino-l,2,4-oxadiazoles, and 5-alky 1-3-amino-1,2,5-oxa-diazoles, when heated with phenyl isothiocyanate produce the corresponding thioureas (308) (Equation (46)), (310) (Equation (47)) and (312) (Equation (48)) which subsequently rearrange by a common mechanism to yield 1,2,4-thiadiazoles (309), (311), and (313), respectively <84CHEC-I(6)463>. 

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. 

Amidoximes (278) yield 5-mercapto-l,2,4-thiadiazoles (279) when treated with carbon disulfide whereas the 5-amino derivatives (280) are obtained from isothiocyanates, as indicated in Scheme 96 <65AHC(5)li9). Products of type (280) are also produced in the reaction between /V-sulfenylamidines (281) and isothiocyanates (Scheme 97). 

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). 

Heating 5-alkyi-3-amino-l,2,4-oxadiazoIes, 5-alkyl-3-aminoisoxazoIes and 4-alkyl-3-amino-l,2,5-oxadiazoles with phenyl isothiocyanate produces the corresponding thioureas (344), (343) and (345) which rearrange by a common mechanism to the 1,2,4-thiadiazoles (372), (373) and (374), respectively (Schemes 134, 135, 136) (74CC358, 77JCS(P1)1616). 

The reaction of amidines with sodium hypochlorite and potassium thiocyanate (Scheme 145) is a mild method for producing a variety of 5-amino- and 3,5-diamino-1,2,4-thiadiazoles (16) in good yields (also see Scheme 98) (65AHC(5)119). Af-substituted derivatives are obtained when isothiocyanates (RCNS) are used in place of potassium thiocyanate (78USP4107377). 

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). 

Cyclization of aminothiones 198 with carbon disulfide, bromocyanogen, aryl isothiocyanates, and l-bromo-2-acetylacetylene leads to mercapto, amino, arylamino, and acetylmethyl derivatives of triazolo[3,4-/>]-1,3,4-thiadiazole (446, R = SH, NH2, NHAr, CHjCOMe), respectively [64CI(L)1919 66JOC3528 81JHC1353 86JHC1439 87JHC1173,... 

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... 

One of the most significant methods for the preparation of sulfides in the u-triazoles involves the rearrangement of S-amino-l,2,3-thiadiazoles (8.1-8) under basic conditions (Eq. 15). It was later suggested that the 8.1-8 structure is an intermediate in the reactions of isothiocyanates (8.1-9) with diazomethane (Eq. 16). This reaction, with various 8.1-8 compounds, has been extended with promising results, but the problem of product structure (compare 8.1-11 and 8.1-12 with 8.1-10 and Equation IS) remains to be examined (Eqs. 17, 18). 

Other fused 1,3,4-thiadiazoles have been prepared and include 4H-1,3,4-thiadiazolo[2,3-c]-l,2,4-triazin-4-ones (108) which were obtained by the reaction of 4-amino-4,5-dihydro-3-(methylthio)-l,2,4-triazin-5-ones (107) with benzoyl isothiocyanates and with methoxycarbonyl isothiocyanates. The corresponding five membered fused system (110) was prepared by reaction of the triazole (109) with benzoyl isothiocyanate <97JHC1351>. ... 

One of the most commonly used methods to obtain 2-amino-l, 3,4-thiadiazolines is the heterocyclization of thiosemicarbazides. An efficient one-pot synthesis of 2-amino-l,3,4-thiadiazoles 125 features the in situ formation of thiosemicarbazides 123 by the reaction of carboxylic acid hydrazides 121 with trimethylsilyl isothiocyanate (TMSNCS) 122, followed by cyclodehydration of thiosemicarbazides 123 under acidic conditions (13RSC6813). 

The reaction of the lithium salt of trimethylsilyldiazomethane 137 with isothiocyanates affords 2-amino-l,3,4-thiadiazoles . When the reaction product is quenched with alkyl... 

Amino-l,2,4-thiadiazoles from isothiocyanates and isoureas via thioiso-biurets s. 14, 374... 

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... 

Synthesis.—PechmanrCs Synthesis. The scope of Pechmann s synthesis, the 1,3-cycloaddition of aryl isothiocyanates to diazomethane, has been extended, using methyl, phenyl, and 1-alkenyl isothiocyanates. The resulting 5-(substituted amino)-l,2,3-thiadiazoles are rearranged, under the influence of an excess of diazomethane, to l-substituted-5-methylthio-l.ff-l,2,3-triazoles (1) (see Vol. 2, p. 717). 

The interaction, in boiling acetone, of 2-amino-5-ethyl-l,3,4-thiadiazole and benzoyl isothiocyanate produces, in addition to the expected thiourea formed by simple addition, small yields of 2-ethyl-5-thioxo-7-phenyl-5H-... 

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