1.2.4- Thiadiazoles, 5-amino— from

In this method, the 1,2-N-S bond and the 2,3-N-C bond are formed. This is a useful method for the preparation of 3-hydroxy- or 3-amino-5-substituted-l,2,4-thiadiazoles starting from either an ethoxycarbonyl or a cyano thioimino-carbonate. Thus the condensation reaction of the ethoxycarbonyl thioiminocarbonate 100 with chloramine at low temperatures affords 3-hydroxy-5-substituted-l,2,4-thiadiazoles 100 (Equation 28) <2004HOU277>. 

Table 11 Preparation of 3,6-disubstituted [l,2,4]triazolo[3,4-6][l,3,4]thiadiazoles (3) from the reaction of 4-amino-5-sulfonyl-4//-[l,2,4]triazole (104) with carboxylic acids and phosphorus trichloride.

Thiadiazole, 2-amino-5-mercapto-azo dyes from, 1, 330 radioprotective agent, 6, 576 tautomerism, 6, 557... 

Ethyl iodide and 5-amino-2-methyl-l,3,4-thiadiazole react at 110° to give the N-3 salt (78 R = Me, R = NH2, R" = Et), as shown by the presence of the very reactive methyl group this salt is also used to prepare cyanine dyes. The slow quatemization at the ring-nitrogen atom furthest from the amino group is consistent with the reactions observed in other ring systems. As would be e pected, 5-alkylthio-2-methyl-l,3,4-thiadiazoles form salts at the N-3 (78 R = Me, R - S-alkyl).i ... 

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 literature synthesis of the racemic 2-azidonitrile (80) by diazotisation of the 5-amino-1,2,3-thiadiazole (78) could not be repeated the 2-chloronitrile (79) was the only product obtained from the reaction <96TA607>. 

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>. 

Type B syntheses are characterized by the reaction of an amidoxime 77 with carbon disulfide to afford 5-mercapto-1,2,4-thiadiazoles 78. The corresponding 5-amino derivatives 80 are obtained from the reaction of iV-sulfenylami-dines 79 with arylisothiocyanates (Scheme 8) <1996CHEC-II(4)307>. 

Unsymmetrical 3,4-dihalo-l,2,5-thiadiazoles 118 and 119 were prepared from 3-amino-4-chloro-l,2,5-thiadiazole 117 via a Sandmeyer-like reaction involving successively tert-butyl nitrite and either copper bromide or copper iodide in anhydrous acetonitrile (Scheme 17) <2003H(60)29>. The bromo and iodo thiadiazoles 118 and 119 undergo selective Stille and Suzuki C-C coupling chemistry (see Section 5.09.7.6). 

The /-butyl group was removed from the A-2-substituted thiadiazol-3-one 143 in the presence of aqueous hydrogen bromide and TFA to afford (A ,.S )-2-amino-3-(3-hydroxy-1,2,5-thiadiazol-4-yl (propionic acid 42... 

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>. 

The introduction of sulfur between two ortho amino groups is the oldest and still the most commonly used route to benzo- and heteroarene-fused 1,2,5-thiadiazoles. The reaction has been extensively reviewed in both CHECK 1984) and CHEG-II(1996). The in situ preparation of Ar-sulfinylanilinc via /3-elimination of chloroform from trichlorometh-anesulfinamides 200 was recently supported by trapping with 1,2-benzenediamine to give the benzothiadiazole 2 in 85% yield (Equation 43) <1997TL487>. 

Macrocyclic 14-membered lactams, lactones, and thiolactones 211 have also been prepared from 3-amino-l,2,5-thiadiazole-4-carboxylic acids 210 (Equation 47) <1996CHE975>. 

On treatment with phosphorus pentasulfide, 4-amino-5-thio-477-[l,2,4]triazoles 86 are converted into 6-aryl-3-(2-aminophenyl)[l,2,4]triazolo[3,4-4][l,3,4]thiadiazoles 3. This transformation is presumed to involve three steps first, the transformation of the amide into the thioamide second, transfer of the thioaroyl group from the phenylamino side chain to the iV-amino group of the triazole ring and, finally, cyclodehydrosulfurization leading to 3 (Equation 21) <1989LA1055>. 

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). 

Instead of the corresponding cyclized product, only the N-(, 2,4-thiadi-azol-3-yl)aminomethylenemalonate (1133) was obtained in 12% yield from the reaction of 3-amino-5-ethoxycarbonylamino-l,2,4-thiadiazole and EMME in polyphosphoric acid at 110°C for 3 hr (77JHC621). 

Examples of the Dimroth rearrangement (Section IV, F) include several s3mtheses of monocyclic triazoles from other heterocyclic systems (cf. Scheme 25). Triazole-5-thiols can be prepared by treatment of 5-amino-l,2,3-thiadiazoles with bases.A similar base-induced rearrangement of sydnoneimines provides a synthesis of 4-hydroxy-triazoles. ... 

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],... 

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