1,3,4-Thiadiazoles, mesoionic

Functionalization of Thiadiazole. Mesoionic compounds prepared on the 1,2,3-thiadiazolium scaffold have been studied for their chemical and biological properties and are known to display monoamine oxidase inhibitory activity. The reaction of 1,2,3-thiadiazole with /7-toluenesulfonic acid affords quantitative conversion to thiazolium /7-toluenesulfonate. The thiazolium tosylate can be reacted with sulfur in the presence of sodium hydride in DMF to afford the 5-thiolated mesoionic compound in 48% yield (eqs 1 and 2). ... 

The mesoionic compound 78 adds to both PTAD and DEAZD as a 1,3-dipole to give 79 and 80, respectively, in high yield. The DEAZD adduct can be converted into 2,5-diphenyl-1,3,4-thiadiazole (Scheme 8).129... 

Benzothiadiazoles 3 have been extensively studied. Fully aromatic mesoionic compounds such as 4 continue to be synthesized. A number of examples of 4,5-dihydro-l,2,3-thiadiazole derivatives such as compound 5 <1993JOC82> and more recently the phenyl derivative 6 <2003RJ01501> have been reported. The corresponding 2,3-dihydro-l,2,3-thiadiazoles have also been reported and Hurd and Mori reported the N-Z phenylsulfonyl derivative 7. The electron spin... 

There are several examples of alkyl halides reacting with 1,2,3-thiadiazoles at nitrogen to yield either salts or mesoionic compounds <1996CHEC-II(4)289>. Similarly, with Meerwein s reagent, several substituted thiadiazoles yielded various 2- and 3-methylated 1,2,3-thiadiazoles (Scheme 4 Table 8) <1993JHC301>. The isomer ratios were determined by integrating the methyl singlets in the H NMR spectra and the compounds were further studied by 1SN NMR spectroscopy (Section 5.07.3.4). 

The most familiar examples of 1,2,3-thiadiazoles bearing substituents on nitrogen are mesoionic compounds (Section 5.07.1.3) but little has been reported about these compounds since CHEC-II(1996) was published. 

Mesoionic derivatives are generally synthesized from the parent 1,2,3-thiadiazoles. A new method based on the rearrangement of oxadiazoles under reductive conditions has been reported. For example, the oxadiazole 70 when... 

The numbering of the 1,3,4-thiadiazole ring is given below. The present chapter is intended to update the previous work on the aromatic 1,3,4-thiadiazole 1, the nonaromatic A2-thiadiazolines 2, A3-thiadiazolines 3, the thiadiazoli-dines 4, the tautomeric forms 5 and 6, and the mesoionic systems 7. Reference is made to earlier chapters of CHEC(1984) and CHEC-II(1996) where appropriate. 

The sulfide groups in mesoionic 1,3,4-thiadiazolium salts are activated toward nucleophilic substitution. The mercapto substituent of the thiadiazolium salt 117 can be displaced by cyclohexylamine to afford the 2//-thiadiazol-imine 118 (Equation 37) <2004BML4607>. 

The novel mesoionic 1,2,4-thiadiazole 78 was reported to be the unexpected byproduct in the reaction of the triazole 76 with ferric chloride (the bicyclic compound 77 also gave the same result). Besides spectroscopic and X-ray diffraction evidence, a preparative proof for the structure of 78 was also provided <00JHC261>. 

When thioxo (or thiol) derivatives (as part of a thiourea function incorporated into the heterocyclic system) are present, effective. Y-alkylation is observed. Thus, the 3-heteroaryl-substituted [l,2,4]triazolo[3,4-/)][l,3,4]thiadiazole-6(5//)-thiones 37 dissolved in sodium hydroxide solution react with alkyl halides to afford the corresponding 6-alkylthio derivatives 38 (Equation 4) <1992IJB167>. The mesoionic compounds 39, inner salts of anhydro-7-aryl-l-methyl-3-methylthio-6-sulfonyl-[l,2,4]triazolo[4,3-A [l,2,4]triazolium hydroxides, are methylated with methyl iodide to give the corresponding quaternary salts 40 (Equation 5) <1984TL5427, 1986T2121>. 

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>. 

In the case of thiazoline-2(3//)-thiones, the mesoionic thiazolo[2,3-h][l,3,4]thiadiazoles are obtained by two different routes (Scheme 65). On the one hand, thione 166 reacts with isothiocyanate via intermediate 167 and with a second equivalent isothiocyanate to afford the mesoionic 168 on the other hand, in the presence of isocyanate, the thione preferentially dimerizes 167 with the open-chain carbodiimide 169 to give the mesoionic 170. Addition of acid with removal of an amine group converts 170 into the symmetric heteroaromatic amine (171) (88CB1495 92T1285). The related transformation of an imidazoline into 1,3,4-thiadiazoles has also been described (90T4353). 

Molina et al. were able to prepare the mesoionic thiadiazole (292) from iminophosphorane 297 and carbon disulfide. As Scheme 106 shows, 298 reacts with a,w-dihalo compounds to form dimer 299 [91JCS(P1)1159]. The synthesis of the mesoionic thiazolo[2,3-6][l,3,4]thiadizole is described in (92T1285). 

Sulfur monochloride and N - (26) or N - (27) substituted amides of 2-aminoacids afforded different 1,2,5-thiadiazole derivatives l,2,5-thiadiazol-3(2H)-ones 28 (1979NLP7712033,1992CHP680220,1994JPP06306063) and mesoionic 1,2,5-thiadia-zolium-3-olates 29 (1981JCS(P1)1033 Scheme 15). 

Benzothiadiazoles have been extensively studied and their chemistry reviewed <84CHEC-I (6)447>. Fully aromatic mesoionic compounds such as (3) continue to be synthesized and studied but no review focusing on such systems has appeared. Very few examples of nonaromatic 1,2,3-thiadiazole derivatives such as (4) <93JOC82> and (5) exist and the area has not been reviewed. 

The x-ray structure of 1,2,3-benzothiadiazole complexed with AsFj (9) shows that the arsenic binds at N3 <86CJC849>. When Fe2(CO)9 reacted with (10) one of the products was (11), for which x-ray diffraction revealed the unusual feature of the nitrogen and sulfur joined by an iron atom (Equation (2)) <890M296l>. The mesoionic structure (13) is formed by methylation of 1,2,3-thiadiazole (12). It can best be described as a resonance hybrid of structures (13a) and (13b) and this was corroborated by the x-ray data (Scheme 1) <91jhC477>. 

Mesoionic compounds are often synthesized from the parent 1,2,3-thiadiazole. For example, (40) was synthesized from 5-phenyl-1,2,3-thiadiazole (Scheme 11) <83CPB1746>. 

Using a combination of techniques 1,3,4-thiadiazole was shown to have a dipole moment of 3.0 D directed from the sulfur atom toward the center of the N—N bond. Dipole moment measurements were useful for proving the mesoionic structure and the large negative charge of an exocyclic sulfur atom for certain 1,3,4-thiadiazole derivatives <84CheC-I(4)545>. 

Indian workers described the synthesis of l,3,4-thiadiazolo[3,2-a]-5-triazine-5(//)-thiones (61) by a hetero Diels-Alder reaction between 2-(arylideneamino)-5-ethylthio-l,3,4-thiadiazoles (60) and aromatic isothiocyanates (Equation (2)) <94MI 410-0I>. Thiadiazoles can be reduced with sodium amalgam to the aldehyde thiosemicarbazone while lithium aluminum hydride will reduce mesoionic thiadiazoles all the way to the hydrazine <84CHEC-I(4)545>. 

Thiadiazoles having one or two thio groups in the 2- and/or 5-positions react with metals to form bidentate ligands they are widely used as antioxidants. An interesting reaction of mesoionic (95) with acetylene dicarboxylate is the formation of thiophene (97) via the intermediate (96) (Scheme 15) <84CHEC-I(4)545>. 

Thiadiazoles and 1,3,4-oxadiazoles are closely related in their reactivity, and can also be prepared from common precursors. They also undergo ring transformations and the thiadiazoles can be obtained directly from the oxadiazoles. 2-Thio-5-(4-pyridyl)-l,3,4-oxadiazole (157) (Equation (23)) when heated under reflux in ethanolic HCl rearranges to the 2-hydroxythiadiazole derivative (158). The mesoionic oxadiazole (159) also rearranges to the thiadiazole (160) when heated in ethanol (Equation (24)) <84CHEC-I(4)545>. 

Thiadiazolines were also obtained by a 1,5-dipolar ring reconstruction of mesoionic ylides. The bromine adduct of 2,3-diphenyltetrazolium-5-thiolate (181) reacts with the sodium salt of diethyl malonate to yield as the only product 5,5-bis(ethoxycarbonyl)-4-phenyl-2-phenylazo-2,3-dihydro-1,3,4-thiadiazole (182) (Scheme 33). The same type of product was obtained from reactions with ethyl cyanoacetate and ethyl acetoacetate <88BCJ2979>. 

Proton NMR data are reported for substituted mesoionic l,2,3,4-thiatriazolium-5-olates and 5-thiolates. Although the spectra are of little diagnostic value they are consistent with the mesoionic structures <79JCS(P1)732>. Representative C shifts for C(5) of 5-substituted thiadiazoles are 5-Ph, 178.46 ppm 5-PhNH, 173.8 ppm 5-BzS, 179.8 ppm 5-PhCOS, 171.5 ppm and for the thiatriazolium salt (9) 186.42 ppm <84CHEC-I(6)579>. 

This approach is suitable for the formation of mesoionic 1,3,4-thiadiazoles. The thiohydrazide (427) with phosgene, thiophosgene or an isocyanide dichloride leads to ready ring closure and formation of the mesoionic 1,3,4-thiadiazoles (428 X = 0, S, NR, respectively) (b-79MI40300). 

Mesoionic 1,3,4-thiadiazoles of type 107 and 108 were originally reported not to give cycloadducts with DMAD but surprisingly added to diethyl azodicarboxylate.578-880 Later, Moriarty and Chin581 reported... 

Although thiadiazoles have been known for a long time, of the four possible isomers, 1,2,3-thiadiazoles account for the fewest literature citations. A substantial amount of this literature has dealt with thermal and photochemical reactions of 1,2,3-thiadiazoles, and most recently attention has been focused on mesoionic derivatives. Still, the many gaps that exist in our knowledge leave this field a fertile area for further research. 

X-Ray data have also been reported for a mesoionic compound, 5-acylamino-3-methyl -1,2,3-thiadiazole (2) (80TL2101), and for 5-phenyl-l,2,3-thiadiazole 3-JV-oxide (6) <78ZN(B)316). Molecular dimensions for (2) and (6) are in Tables 2 and 3 respectively. 

For a number of years it has been known that 1,2,3-thiadiazole reacts with methyl iodide (B-61MI42400), yet the site of alkylation was unknown. Owing to the increased interest in mesoionic compounds, the alkylation of 1,2,3-thiadiazoles has received renewed attention. 

The nitrogen-sulfur bond in reduced forms of 1,2,5-thiadiazole is much less stable than in the aromatic form. The reduced systems are readily hydrolytically desulfurized to the open-chain NCCN portion of the ring (80JPR273,690PP255, 69T4277). Mesoionic thiadiazoles are also sensitive to basic hydrolysis (81JCS(P1)1033). 

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