1.2.5- Thiadiazoles formation

A parallel synthesis of 1,2,3-thiadiazoles employing a catch-and-release strategy has been reported using the Hurd-Mori reaction. A polymer-bound tosyl hydrazide resin reacted with a-methylene ketones to afford a range of sulfonyl hydrazones. Treatment of these sulfonyl hydrazones with thionyl chloride causes 1,2,3-thiadiazole formation and cleavage of the resin in one step <1999JOC1049>. 

A mechanism for 1,2,5-thiadiazole formation was proposed in the 1960s (1967JOC2823) and seems to be reliable this includes the formation of the M-chlorodithio intermediate followed by chlorination of the nitrile function, ring closure, addition of the second molecule of sulfur monochloride and formation of the heteroaromatic 1,2,5-thiadiazole cycle (Scheme 18). 

This method is also useful for the functionalization of substituents at C(5) during 1,2,3-thiadiazole formation (Equation (13)). The ratio of thiadiazoles and their sulfine derivatives is a function of both the acyl and alkylidine groups of the hydrazone starting materials <84JOC4773>. 

Thiadiazole, formation, 312, 313, 445 Thiazole formation bromoester, 298-304 bromoketone, 565 Thiazolidinone formation beta lactam, disulfide cleavage, 552 nitrile addition, 301 Thiehopyridine formation, 586 Thienothiazinol formation, 593 Thioacetal formation, 130, 185, 248 glyoxylate, 355 ethyl mercaptopropionate, 447 Thioacid formation, thioformamidoyl chloride, 184... 

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]. 

An interesting formation of the thiadiazole (12, R = pyrid-4-yl) occurs when 4-methylpyridine containing dissolved sulfur is heated with ammonia under pressure. The same reaction converts 2-methylpyridine to the 2-thioamide or 2-nitrile, depending on the conditions. Thiadiazole formation may thus occur by the usual condensation of these two components to the thioacylamidine (13, R = pyrid-4-yl), which is cyclized by the oxidizing action of the sulfur.26... 

Thiadiazoles 5 with identical substituents in the 3- and in the 5-positions can be obtained [478] from thioamides by oxidation with hydrogen peroxide or by the action of SOCI2, SO2CI2, or PCI5. The mechanism of thiadiazole formation is not completely elucidated. 

The mechanism of thiadiazole formation has not been elucidated. It should be mentioned that (2-aminoaryl)-5-aryl-l,3,4-thiadiazoles have been efficiently prepared from aryhsothiocyanates, hydrazine hydrate, and arylaldehydes in ionic liquid [Mmim]BF4 as dual solvent and catalyst [479]. 

Deacylations are known. C-Acyl groups in 1,3,4-thiadiazoles are cleaved by sodium ethoxide in ethanol (68AHC(9)165). Imidazole-2-carbaldehyde behaves similarly, yielding imidazole and ethyl formate this reaction involves an ylide intermediate. 3-Acylisoxazoles (405) are attacked by nucleophiles in a reaction which involves ring opening (79AHC(25)147). 

High-speed synthesis of thiadiazoles has been recently completed on a solid support system using a catch and release technology to provide novel thiadiazoles. The solid-supported sulfonylhydrazine reacts with ketones to provide the solid phase hydrazones (catch) and formation of the thiadiazole with subsequent release of the... 

Heating the 5-isocyano-l,3,4-thiadiazolo[3,2- ]pyrimidin-5-one 115 with 10% hydrochloric acid gave a mixture of the 5-imino-l,3,4-thiadiazolo[3,2- ]pyrimidin-7-one 116 (10%) and the l,2,4-triazolo[l,5-c]pyrimidine-5,7-dione 117 (35%) (91JHC489). Formation of 117 probably occurred through thiadiazole ring rupture of 116 and recyclizatioii with its imino function together with desulfurization (Scheme 43). 

The Hurd-Mori synthesis of 1,2,3-thiadiazoles from a-methylene ketones developed in 1955 is, even today, the method of choice for a number of 1,2,3-thia-diazole derivatives. Both the mechanism and the regiochemistry have been extensively studied, but since the isolation of the intermediate by Hurd and Mori (84CHEC-I(6)460), there has been no further work supporting the formation of this intermediate or its conversion into the aromatization product. In 1995 Kobori and coworkers published the isolation of several 1,2,3-thiadiazolin-1-oxides 186, finally demonstrating their participation in the formation of 1,2,3-thiadiazoles. Substituents R and R play an important role in the isolation of 1,2,3-thiadiazolin-1-oxide (95H(41)2413). 

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. 

A range of 4-substituted l,3-dithiole-2-thiones (71) and 2,6-substituted 1,4-dithiafulvalenes (73) were synthesised from 4-substimted 1,2,3-thiadiazoles (72). Reaction of (72) with NaH in a mixture of CS2 and acetonitrile led to the formation of (71), whereas absence of CS2 gave fulvalenes (73). This route was found to be very efficient for the preparation of 4-formyl-1,3-dithiole-2-thione (71 R = CHO), which was previously difficult to prepare, and thus allowed the synthesis of the novel 2,6(7)-bisformyltetraAiafulvalene (74) <96T3171>. 

The first A/ -oxides of the 1,2,4-thiadiazole ring system have been reported and were prepared by condensation of benzamidoximes (86) with 4,5-dichloro-l,2,3-dithiazohum chloride (87). A -labelling showed the compounds to be 4-oxides (88) and a mechanism was proposed for their formation. Alkyl amidoximes and arylamidoximes with electron-withdrawing substituents did not give A/ -oxides, but only the dithiazolone (89) and the dithiazolthione (90) <96CC1273>. 

Reaction of equimolar amounts of the thiocarbamate (91) with (chlorocarbonyl)sulphenyl chloride gave l,2,4-dithiazoline-5-one (92) and the 1,2,4-thiadiazole (93) the relative amounts of (92) and (93) being very dependent on the solvent used in the reaction. The mechanism of formation of both (92) and (93) was discussed <96JOC6639>. 

As 1,2,5-thiadiazole analogues, potent HlV-1 reverse transcriptase inhibitors, some simple 1,2,5-oxadiazoles, compounds 4-6 (Fig. 9), have been synthesized using the traditional Wieland procedure as key for the heterocycle formation [121]. Such as thiadiazole parent compounds, derivative with chlorine atoms on the phenyl ring, i.e., 5, showed the best anti-viral activity. Selectivity index (ratio of cytotoxic concentration to effective concentration) ranked in the order of 5 > 6 > 4. The activity of Fz derivative 6 proved the N-oxide lack of relevance in the studied bioactivity. These products have been claimed in an invention patent [122]. On the other hand, compound 7 (Fig. 9) was evaluated for its nitric oxide (NO)-releasing property (see below) as modulator of the catalytic activity of HlV-1 reverse transcriptase. It was found that NO inhibited dose-dependently the enzyme activity, which is hkely due to oxidation of Cys residues [123]. 

Formation of the outer pyrimidine ring, by a different route, is also the final step in the synthesis of the benzothi-azolopyrimidopyrimidine 264 (Equation 82) <1997JIC818>, and similarly the outer six-membered ring is formed in the final step which leads to the thiadiazole-fused compounds 265 and 266 (Scheme 64) <1995RCB1957,1999RCB364>. 

A nitrogen to carbon linkage is exemplified by the formation of dichloro-1,2,4-thiadiazole (27) from phosphorus tricyanide and sulfur dichloride.32... 

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