1.2.4- Triazoles 1.3.4- thiadiazoles

For both azole and benzazole rings the introduction of further heteroatoms into the ring affects the ease of quaternization. In series with the same number and orientation of heteroatoms, rate constants increase in the order X = 0requires stronger reagents and conditions methyl fluorosulfonate is sometimes used (78AHC(22)71). The 1-or 2-substituted 1,2,3-triazoles are difficult to alkylate, but methyl fluorosulfonate succeeds (7IACS2087). 

A rich coordination chemistry of aromatic diazine (N-N), especially pyridazine and phthalazine related ligands has emerged over the last three decades,1-72 and recently open-chain diazine (N-N) coordination chemistry has been well developed, especially by Thompson and others.62-113 Many types of aromatic heterocyclic compounds contain a 1,2-diazine (N-N) moiety, e.g., pyridazine and its 3,6-disubstituted derivatives (Scheme 1, Type 1), phthalazine, condensed phthalazines and their substituted derivatives (Scheme 1, Type 2), and other compounds such as pyrazole, triazole, thiadiazole, tetrazole, indazole, 1,2,4-triazine, 1,2,4,5-tetrazine, and thiadiazepines. Alternatively, the 1,2-diazine (N-N) moiety also exists as an open-chain entity in some related compounds, e.g., A-substituted-amide hydrazonimidates (Scheme 1, Type 3), A-substituted-amide hydrazonidates (Scheme 1, Type 4), A-substituted hydrazides (Scheme 1, Type 5), A-substituted amidrazones (Scheme 1, Type 6), and A-sub-stituted hydrazidates (Scheme 1, Type 7). 

The ring bond order deviation from uniformity partially agreed with the order of reactivity computed on the basis of FMO energy gaps. The least aromatic was 1,2,5-oxadiazole, while 1,2,3-thiadiazole should be most aromatic (Table 36). The order of reactivity was oxadiazole, triazole, thiadiazole in all 1,2,3-, 1,2,5- and 1,3,4-series of the three heteroatom heterocycles. Except for 1,3,4-oxadiazole, the two other 1,3,4- five-membered heterocycles were predicted to be more reactive than their 1,2,3- isomers (Table 36). The prediction that 1,2,5-oxadiazole was the most reactive heterocycle as a diene for Diels-Alder reaction was unacceptable due to the fact that two C-N bonds should be formed in the course of the reaction, which usually requires an exceptionally high activation barrier. 

For protection against nonferrous and copper ahoy corrosion, thiadiazole and triazole derivatives have been found especiahy useful (22). 

Fig. 1. HeterocycHc amines usedia azo dyes, (a) 2-Amino-6-nitrohenzothiazo1e [6285-57-0], (b) 3-amiao-5-nitro-2,l-benzisothiazole [14346-19-1], (c) 3-amiQo-4JT-l,2,4-triazole [65312-61 -0], (d) 5-amiQo-l,2,4-thiadiazole [7552-07-0, (e) 4,4 -diamiQo-2,2 -biphenylsulfone [6259-19-4], (f)...

Thiadiazoles are quaternized to give 3- or mixtures of 2- and 3-alkyl quaternary salts. In 5-amino-1,2,4-thiadiazole, quaternization takes place at the 4-position (90) (64AHC(3il). 1-Substituted 1,2,4-triazoles are quaternized in the 4-position (91), and 4-substituted 1.2,4-triazoles are quaternized in the 1- or the 2-position (92) 64AHC(3)l). 

Thiadiazole with MeaO BF gives the diquaternary salt (95) diquaternary salts are also known in the 1,2,4-triazole series. 1,3-Disubstituted 1,2,4-triazolium salts can be further alkylated to diquaternary derivatives. 

In azole chemistry the total effect of the several heteroatoms in one ring approximates the superposition of their separate effects. It is found that pyrazole, imidazole and isoxazole undergo nitration and sulfonation about as readily as nitrobenzene thiazole and isothiazole react less readily ica. equal to m-dinitrobenzene), and oxadiazoles, thiadiazoles, triazoles, etc. with great difficulty. In each case, halogenation is easier than the corresponding nitration or sulfonation. Strong electron-donor substituents help the reaction. 

Dipolar cyclization of (421) through X leads to oxadiazoles, thiadiazoles and triazoles (70CB1918, 65CB2966) (see also Chapter 4.13). 

Several thiadiazolo-triazoles 43 have been synthesized that show antifungal and cytotoxic properties. hiadiazoles 45 were prepared from hydrazones 44 by treating them neat with thionyl chloride at room temperatures. The thiadiazoles were formed regio-selectively on the methyl group of the hydrazone. 

Morpholino-3-[4-phenyl(thiosemicarbazido)carbonyl]quinoxaline (129) gave 2-morpholino-3-(4-phenyl-5-thioxo-5,6-drhydro-4//-l,2,4-triazol-3-yl)quin-oxaline (130) (2M NaOH, reflux, 3 h 35%), 2-(5-anilino-l,3,4-thiadiazol-2-yl)-3-morpholinoquinoxaline (131, X = S) (98% H2SO4, 0°C, 1 h, then 20°C, 12 h 89%), or 2-(5-anilino-l,3,4-oxadiazol-2-yl)-3-morpholinoquinoxaline (131, X = O) (NaOH, H2O, EtOH, I/Kii dropwise, 5°C 95°C, 4 h 81%) analogs of all three products were made similarly. ... 

With NJV -thiocarbonyldi-1,2,4-triazole the corresponding ethyl-5-(l,2,4-triazol-l-yl)-l,2,3-thiadiazole-4-carboxylate was obtained in 90% yield.[ 1291 However, analogous 1,3-dipolar reactions in the presence of (C2H5)3N are reported to yield the isomeric 2-(l-imidazolyl)-1,3,4-thiadiazoles 130],[ 1311... 

The 3f/-pyrazole-3,5(4//)-diones (7), prepared by lead tetraacetate,29,30 or tert-butyl hypochlorite31,32 oxidation of malonic acid cyclic hydrazides, are generally less stable than the triazoles 5, and are not isolable. The monocarbonyl derivatives (8-10) have been reported.33-36 The unstable 1,3,4-thiadiazole-2,5-dione (11) has been generated and reacted in situ.31,3 ... 

L abbe has studied the rearrangement reactions of 1,2,3-thiadiazoles to differently substituted 1,2,3-thiadiazoles <1983CC588>. He also studied many 5-azido-l,2,3-thiadiazoles 33 that rearranged to 1,2,3,4-thiatriazoles 34 (Equation 5) <1988BSB163>. He even found that l,2,3-thiadiazole-4-carboxaldehydes 35 upon treatment with amines underwent thermal rearrangement to 1,2,3-triazoles 36 (Equation 6) <1993J(P1)1719>. 

Electron-deficient 1,2,3-triazoles 222 can be converted into 1,2,5-thiadiazoles 223 with trithiazyl trichloride (Equation 51). The triazoles were proposed to react by initial ring opening to their diazoimine tautomers <2001J(P1)662>. 

Heating of a solution of 5-ethyl-3-phenyl-l,3,4-thiadiazol-2(377)-imine 85 in aq. NaOH to 80°C for 5h gave the 5-ethyl-2,3-dihydro-2-phenyl-l/7-l,2,4-triazole-3-thione 86 via Dimroth rearrangement (Scheme 7) <2002HCA1883>. Nucleophilic attack of the hydroxide on the electrophilic C-5 resulted in ring opening and, after rotation around the C(2)-N(3) bond and subsequent recyclization, triazole thione 86 formed. 

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>. 

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