Amidines 1,2,4-thiadiazoles, 5-amino

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)... 

Hydrolysis of amino-alkylamino-l,2,5-thiadiazole 1-oxides 55 with concentrated aqueous HC1 gave the amidines 56 (Equation 4) <2001JME1231>. The hydrolysis reactions of 2-alkyl-4-amino-2,3-dihydro-l, 2,5-thiadiazol-3-one 1,1-dioxides 57 in the range 24-73 °C in buffered aqueous solutions gave the corresponding 2-amino-2-[(iV-alkyl-substituted-sulfamoyl)imino]acetic acid salts 58 (Equation 5) <1998JP0489>. 

A -Chloro derivatives of amidines, isoureas and guanidines react with potassium 5-methyl-cyanodithioiminocarbonate (266) to yield 2,5-substituted 3-amino-1,2,4-thiadiazoles (Equation (37))... 

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>. 

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>. 

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. 

Further extension of this synthesis to guanidines leads to 3,5-diamino-l,2,4-thiadiazoles. Examples are so far confined to the conversion, by the usual procedure, of 2V,2V-disubstituted guanidines into 5-amino-3-dialkyl(or diphenyl)amino-l,2,4-thiadiazoles (66).84,87 In general, this variant of the reaction proceeds less uniformly than with amidines or iso(thio)ureas, and is performed without isolation of the intermediate AT-halogenoguanidines. In some cases (e.g. dimethyl and cyclopentamethylene homologs) the yields are low, and guanidine is formed as a by-product. The 3-dimethylamino homolog (66 R = R ... 

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). 

V-Chloro derivatives of amidines, isoureas and guanidines react with potassium 5-methyl cyanodithioiminocarbonate (320 R = Me) to yield thiadiazole systems of type (324 Scheme 114) (75BCJ310 73CL917). A related transformation occurs when the cyanothioiminocarbon-ates (322) and chloramine are allowed to condense at low temperature (76EGP119791). In this manner a variety of 5-substituted 3-amino-l,2,4-thiadiazoles (325) are obtained in good yields (Scheme 115). The use of ethoxycarbonylthioiminocarbonates (326) in this... 

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 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). 

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). 

Amino derivatives of isoxazole, 1,3,4-oxadiazole, thiazole, 1,2,4-thiadiazole and 1,3,4-thiadiazole containing the amino group as part of a partial amidine structure react with trichloromethanesulfenyl chloride to give isolable trichloromethanesulfenamides which react with substituted anilines to yield fused thiadiazoles of general structure shown in equation (9). The method has been used to prepare 3H-isoxazolo[3,2-c]-, 3H-thiadiazolo[2,3-c]-, 3H- l,3,4-thiadiazolo[2,3-c]- and 3//-[l,2,4]thiadiazolo[4,3-d]-[l,2,4]thiadiazoles, as well as 3//-[l,2,4]thiadiazolo[3,4-6][ 1,3,4]oxadiazoles (75JOC2600). 

Hydrolysis of amino-alkylamino-l,2,5-thiadiazole 1-oxides 240 with concentrated aqueous HCI gives the amidines 241 <2001JME1231>. 

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). 

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... 

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... 

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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