1.2.4- Thiadiazoles, 5-amino— from amidines

In 1954, Goerdeler6 introduced a general synthesis of 1,2,4-thia-diazoles from amidines. This versatile method has since been widely extended and has made a great variety of 1,2,4-thiadiazole derivatives readily accessible. Basically, an amidine is converted into its i T-thio-cyanato derivative, which cyclizes spontaneously to the 5-amino-1,2,4-thiadiazole. 

Amino-l,2,4-thiadiazoles 3 are accessible from amidines and potassium thiocyanate by oxidation with sodium hypochlorite ... 

Potassium thiocyanate 5-Amino-l,2,4-thiadiazoles from amidines... 

The condensation reaction of cyclic amidines with trichloromethylsulfenyl chloride yields sul-fenamides, which afford 5-arylimino-l,2,4-thiadiazolines on treatment with aromatic amines <84CHEC-I(6)463>. An example of this type of reaction starting from 2-amino-4-arylthiazoles (271) affords 3/f-thiazolo[2,3-c]-l,2,4-thiadiazoles (272), via the sulfenamide (270) (Scheme 60) <88IJC(B)501>. 

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. 

Amino-l,2,4-thiadiazoles are usually prepared by treating amidine hydrochlorides with halogen and thiocyanates to yield the 3-alkyl derivatives or treating alkylisothiouronium salts similarly to yield the 3-alkylthio derivatives (56CB2742). Diazonium salts derived from 5-amino-l,2,4-thiadiazole derivatives, which are prepared in acetic acid, are extremely reactive and are capable of coupling with m -xylene (60CB397). 

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). 

From a.-Amino Acid Amides and Amidines a-Amino acid amides, which fall into the amine-imine class according to the general model (beginning of Section II,B), are converted to 3-alkyl-4-hydroxy-l,2,5-thiadiazoles by reaction with sulfur mono-chloride, thionyl chloride, or thionyl aniline. A large number of -amino acid amides were employed in the synthesis (see Table I)... 

Goerdeler s general synthesis3 of 5-amino-1,2,4-thiadiazoles by the cyclization of N-thiocyanatoamidino compounds formed in situ has been further exploited.114-116 l-Amino-3-iminoisoindoleninium thiocyanates (144), which are accessible from o-dinitriles, can function as the amidine, and yield, by the usual simultaneous action of bromine and sodium methoxide,117 or of sodium hypobromite,118 3-substituted 5-amino-l,2,4-thiadiazoles (145). 

Type B Syntheses [NCN + CS].—l-Amino-3-imino-isoindoleninium thiocyanates (60), which are accessible from o-dinitriles (59), are convertible into 3-substituted 5-amino-1,2,4-thiadiazoles (61) by the simultaneous action of bromine and sodium methoxide. The reactants (60) thus play the role of the linear amidines in Goerdeler s synthesis, of which the present modification is a useful extension/ ... 

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