3- Amino-1,2,5-thiadiazol, formation

The reaction of Tentagel-bound carboxylic esters with amidooximes has been used to prepare oxadiazoles (Entry 11, Table 15.20). Thiadiazoles have been prepared from support-bound iV-sulfonylhydrazones by treatment with thionyl chloride. Thiadiazole formation and cleavage from the support occurred simultaneously (Entry 12, Table 15.20). Perhydro-l-thia-2,5-diazole-2,2-dioxides (sulfahydantoins) have been prepared by aminosulfonylation of amino acids esterified with Wang resin, followed by ring-closure with simultaneous cleavage from the support [257]. 

In Section 3.4 we discussed the problem of reversibility of diazotization of aromatic and heteroaromatic amines. Simple stoichiometric considerations indicate that the reverse reaction (ArNJ -> ArNH2) may take place under strongly acidic conditions. Experimentally the reverse reaction was found only with heteroaromatic diazonium salts (Kavalek et al., 1989). Reaction conditions of hydroxy-de-diazonia-tion are comparable to those used for the reverse reactions of diazotization (e.g., 10 m H2S04, but at 0°C for the formation of 2-amino-5-phenyl-l,3,4-thiadiazol from the corresponding diazonium salt, Kavalek et al., 1979). So far as we know, however, amines have never been detected in aromatic hydroxy-de-diazoniations, not even in small amounts. 

The synthesis of the benzoimidazo[l,2- ][l,2,3]thiadiazole 61 can be explained using the same mechanistic model to that used for the Hurd-Mori reaction. The amino benzimidazole 58 when treated with thionyl chloride at reflux affords the benzoimidazo[l,2-r ][l,2,3]thiadiazole 61. If, however, the reactant 58 is treated with thionyl chloride at room temperature, the chloromethyl derivative 59 is formed. This derivative was then transformed into product 61 on reflux with thionyl chloride. The proposed mechanism for the formation of product 61 is for the initial formation of the sulfoxide 60, which then undergoes a Pummerer-like rearrangement, followed by loss of SO2 and HC1 to give the c-fused 1,2,3-thiadiazole 61 (Scheme 7) <2003TL6635>. 

The synthesis of 1,2,5-thiadiazoles from amino acetonitrile salts 172 was reviewed in CHEC-II(1996). Owing to the ready formation of 2-amino acetonitrile salts from aldehydes via a one-pot Strecker synthesis, this synthetic pathway... 

JME538, 1997CH739>. The main thiadiazole product 185, however, suffered chlorination in the a-position. The isolation of 2-amino acrylonitrile 184 from the reaction mixture supported decomposition of the 2-oximino acetonitrile 183 furthermore, treatment of the pure acrylonitrile under typical reaction conditions gave exclusively ot-chloro-3-chloro-l,2,5-thiadiazole 185 (Scheme 27 Table 11). Mechanisms explaining the formation of both thiadiazoles were proposed <1998H(48)2111>. 

A useful strategy for the formation of fused thiadiazoles is the annulation of suitably functionalized 1,2,5-thiadiazoles. Common routes involve the use of 3,4-difluoro-l,2,5-thiadiazole, 3,4-diamino-1,2,5-thiadiazole, l,2,5-thiadiazole-3,4-dicarbonyls, l,2,5-thiadiazole-3,4-dicarbonitrile, amino-1,2,5-thiadiazole-3-carboxamides and carboxamidines. These afford heteroarene-fused 1,2,5-thiadiazoles (which are covered in Volume 9). Below follows a brief description of fused thiadiazoles that fall within the scope of this chapter. 

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>. 

The last example for the synthesis of this ring system discussed in this section is somewhat different from the previous ones as it presents formation of a positively charged thiadiazolo[3,2-tf][l,3,5]triazinium salt as published by Okide 1994JHC535 the 2 amino 5 alkyl[l,3,4]thiadiazole 167 was reacted with l chloro l,3 bis(dimethylamino) 3-phenyl-2-azaprop-2-enylium perchlorate (a reagent which was synthesized by the same author earlier <1992JHC1551>) to give the quaternary salt 168 in moderate yield (45%) (Scheme 32). 

As mentioned in Section 4.10.6.5, substituents on C(2) and C(5) are strongly activated and control the reactivity of the thiadiazole molecule as a whole. The amino group is by far the most popular substituent for further modifications, due to its nucleophilicity and ease of ring formation with the annular N(3). To a somewhat lesser extent, the thiol group has also been utilized in further derivatizing, with the carbon and halogen substituents being the least amenable to further reactions. 

Martin et al. reacted alkyl and aryl cyanates with 5-aminothiatriazoles (13) at 0°C in aprotic solvents <85J0C1295>. The reaction led to evolution of nitrogen and the formation of 3-substituted-5-amino-l,2,4-thiadiazoles (117) in 40-65% yield. If the reaction was carried out at 30°C or if two equivalents of cyanate was employed a subsequent reaction to the corresponding amidino compound (118) took place (Scheme 22). 

Trichloroacetonitrile reacts with 5-aminothiatriazole in a similar way to give the 3-substituted-5-amino-l,2,4-thiadiazole <85JOC1295>. Martin et al. discussed three different pathways for the formation of the 1,2,4-thiadiazole (117) (Scheme 23). 

The novel heterocyclic system 92 has been prepared by reaction of 2-amino-1,3,4-thiadiazoles 91 with either l-(haloalkyl)pyridinium halides 89 or N,N -methylenebis(pyridinium) dihalides 90. A mechanism for the formation of 92 was proposed and involved a series of specific proton migrations, bond-breaking and bond-forming processes <98EJOC2923>. 

PCls-induced dehydrative cyclization of the amino and amide functionalities of the thiadiazole moiety of the pyrazolopyrimidine 172 led to the formation of the imidazo[4,5-f][l,2,5]thiadiazole suhstmcture (Equation 13) <2001W0040231>. 

Treatment of the symmetrical triaminopyrimidine (50-1) with sulfuryl chloride ties up the two adjacent amines in a thiadiazole ring, protecting those groups from attacks in subsequent reactions. Reaction of the product (50-2) with ortho difluorinated benzylamine (50-3) results in the replacement of the pyrimidine amino group by that in the reagent most hkely by an addition-elimination sequence to afford (50-4). That amino group is then converted to the formamide (50-5) with formic acid. Exposure of the product to Raney nickel leads to a loss of sulfur and the formation of the transient intermediate (50-6). This cyclizes to a purine... 

The scope of the synthesis is greatly widened by the preliminary preparation of the N-halogenoamidines (56), preferably in situ subsequent displacement of halogen by thiocyanate results in the formation of the desired 5-amino-1,2,4-thiadiazoles (58) in good yields (50-80%).6,79, 80 The use of formamidine affords the parent, 5-amino-1,2,4-thiadiazole (58 R = H) while use of AT-methylformamidine (59) leads to 5-imino-4-methyl-Zl4-1,2,4-thiadiazolines (60).81... 

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-5-methylamino-l,2,4-thiadiazole similarly gives a 3-toluene-p-sulfonamido111,122 (237) and a monobenzamido derivative (for structure, see ref. 122) an excess of the appropriate reagent yields non-acidic di- and tri-substitution products, the latter probably of structure 239. With acetic anhydride, however, acylation terminates with the formation of the 3-monoacyl derivative.111,122 Similar observations areon record concerning 3-amino-5-anilino-1,2,4-thiadiazole86 the only anomalous observation is the ability of this compound to form di- and tri-acetyl derivatives.58... 

Although 3-amino-l,2,4-thiadiazoles (e.g. the 5-phenyl homolog) fail to yield nitrosamines under the usual conditions,126 5-nitrosamines are well known.81, 5,190,191 Thus, 3-alkoxy-,8 3-alkylthio-,85 3-dialkyl-amino-,87 and 3-alkylsulfonyl-5-amino-86 (243) as well as 3-aryl-5-arylamino-l,2,4-thiadiazoles,74 on treatment with the calculated quantity of sodium nitrite in dilute mineral acid, or concentrated formic acid, yield crystalline nitrosamines (244). Their unusual stability has permitted a close study of their formation and properties. 170 Their positive Liebermann reaction85,87,170 and the results of their methylation (outlined in the reaction scheme) show that nitro-sation occurs in the side-chain and not in the nucleus.170... 

Substituted amino groups in the 5-position interfere with the course of the reaction, possibly because of nitrosamine formation thus, 3-amino-5-methylamino- and 3-amino-5-anilino-l,2,4-thiadiazole afford the corresponding 3-chloro derivatives (311 R = MeNH PhNH X = Cl) in only minute yields (5 and 8%, respectively).178... 

In accordance with the general stability of alkylthio groups in heteroaromatic systems, 3-alkylthio groups in 1,2,4-thiadiazoles are not easily replaced.Thus, 3-alkylthio-1,2,4-thiadiazoles resist theaction of aniline at 100°, ammonia at 120°, or molten urea or ammonium acetate.99 On the other hand, hydrazine attacks 3-methylthio-l,2,4-thiadiazole under restrained conditions, with formation of 3-amino-... 

The thermal reaction of 6-amino-4-oxopyrano[3,4-d][l,2,3]thiadiazoles (32) leads to 6-hydroxy-4-oxo-[l,2,3]thiadiazolo[4,5-c]pyridines (33) and 2-cyano-2-(l,2,3-thiadia-zol-5-yl)acetamide (34).58 Formation of (33), a Dimroth-type rearrangement, proceeds by thermal opening of the pyrane ring, followed by the simultaneous rotational isomerization of the ketene intermediate and its recyclization on to the amido group to form the pyridin-2-one cycle. 

Electron-poor nitriles react with compound 87 and its derivatives to form the 5-amino-l,2,4-thiadiazole derivatives 104 <1985JOC1295>. Therefore, the formation of product 94 (see Scheme 21) may be explained alternatively by the addition of amidonitrile 93 to compound 90. The mechanism of the formation of product 104 was discussed in detail in CHEC-II(1996) <1996CHEC-II(4)691> but most probably the steps involved are (1) reaction of the electrophilic nitrile with the exocyclic nitrogen of compound 87 or its derivatives (2) loss of nitrogen similarly to the previous reactions and formation of an imine 103 (3) masked 1,3-dipolar cycloaddition/elimination reaction of the nitrile to the imine 103. Since the same nitrile is expelled in the elimination step, only 1 equiv of reagent is needed (Scheme 24). 

Acylation of 3-amino-5-methylamino-l,2,4-thiadiazole (28) with benzoyl chloride (or arenesulfonyl chlorides) introduces one acyl group when one equivalent is employed, and three when a large excess is used to produce (29) and (30), respectively (Scheme 16). With acetic anhydride, however, acylation terminates with the formation of the 3-monoacyl derivative (65AHC(5)ll9). For the mechanism of acylation, see Scheme 3. In the case of 3,5-diarylamino-l,2,4-thiadiazoles, no triacyl derivative is obtained even when excess of acylating agent is employed. Acetyl and benzoyl chlorides give monoacyl derivatives and p-toluenesulfonyl chloride forms 3,5-di(p-toIuenesulfonyl) derivatives (65AHC(5)119). 

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