Tetrazines and derivs

A large number of pyridazines are synthetically available from [44-2] cycloaddition reactions. In one general method, azo or diazo compounds are used as dienophiles, and a second approach is based on the reaction between 1,2,4,5-tetrazines and various unsaturated compounds. The most useful azo dienophile is a dialkyl azodicarboxylate which reacts with appropriate dienes to give reduced pyridazines and cinnolines (Scheme 89). With highly substituted dienes the normal cycloaddition reaction is prevented, and, if the ethylenic group in styrenes is substituted with aryl groups, indoles are formed preferentially. The cycloadduct with 2,3-pentadienal acetal is a tetrahydropyridazine derivative which has been used for the preparation of 2,5-diamino-2,5-dideoxyribose (80LA1307). 

Several dihydrotetrazine materials have been promoted as oxygen scavengers, including 3,6-dimethyl,1-2-dihydro,1,2,4,5-tetrazine, and the diethyl- and diphenyl-derivatives. 3,6-Dimethyl,1-2-dihydro,1,2,4,5-tetrazine is a six-sided ring with a formula H3C-CN2C-CH3NHNH its MW equals 102. Its basic reaction with oxygen is shown here ... 

For the synthetic studies on the bicyclic 6-6 systems 1-3, with one ring junction nitrogen and five extra heteroatoms, refer to CHEC-II(1996) <1996CHEC-II(8)743>. In the studies of the newly available compounds, a one-pot procedure for the synthesis of [l,2,4]triazino-[4,3- ][l,2,4,5]tetrazine 4 derivatives is discussed below. Refluxing of hydrazonoyl halides 10 in chloroform (or ethanol) in the presence of triethylamine for 6h with either 4-amino-2,3-dihydro-6-substituted-3-thioxo-[l,2,4]triazin-5(4//)-ones 8 or 4-amino-3-methylthio-6-substituted-[l,2,4]-triazin-5(4//)-ones 9 yielded compounds 4 (Equation 1) <2000JPR342>. 

Van der Waals complexes of C2v symmetry between 1,2,4,5-tetrazine and a number of light gases (He, Ar, H2) have been observed and characterized by laser spectroscopic studies of free supersonic jet expansion of the tetrazine in the carrier gas (84CHEC-(3)53l). In these complexes, one equivalent of noble gas sits on top of the aromatic TT-system of the heterocycle. 1,2,4,5-Tetrazine, its 3-methyl, and 3,6-dimethyl derivative as well as aminotetrazine have all been used as heterocycles with noble gases, water, HC1, benzene, and acetylene, playing the role of the second partner. 

The other expl tetrazines consist of the parent compd, sym-Tetrazine and its derivatives Sym-Tetrazine (or 1,2,4,5-Tetrazine). C2H2N4 mw 82.08 N 68.27% OB to C02 -97.47% dark purple-red prisms with volatile red fumes... 

The formation of pyridazines from 1,2-diaza-1,3-butadienes and electron-rich dienophiles has been reported [308] on the other hand, tetrazine and triazole derivatives have been prepared from these heterodienes and azo esters [309]. Aza Diels-Alder reactions of 1,4-diaza-1,3-butadienes have been employed for the synthesis of unsymmetrical pyrazine derivatives by Heathcock et al. [310]. 

Dihydropyridazines are obtained from 1,4-dicarbonyl compounds and hydrazine (Section III,B) or from the reaction of sym-tetrazines and simple ethylenic compounds (Section III,H). There are also a few special reactions, such as that between a tetrahydrofuran and phenylhydrazine, or from a 1,4,5,6-tetrahydropyridazine derivative. The 1,4-dihydro structure has been found to be correct, rather than the 1,6-dihydro structure, postulated earlier for some of these reduced pyridazines (Section III,H). 1,4-Dihydropyridazines can be reduced or oxidized easily and acid treatment of l-tosyl-1,4-dihydropyridazine causes rearrangement to 1-tosylaminopyrrole. ... 

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). 

Tetrazine derivatives have been used widely in making pyridazines by inverse electron-demand Diels-Alder reactions with dienophiles (see Scheme 10), followed by loss of nitrogen from the usually unstable intermediate if the dienophile has a triple bond or potential triple bond properties, the final pyridazines will be aromatic. From the coordination chemistry point of view 3,6-dipyridin-2 -yl-l,2,4,5-tetrazine and dimethyl 1,2,4,5-tetrazinedicarboxylate and their analogs are probably the most useful starting compounds for making relevant ligands. 

The examples shown are illustrative of the many easy nucleophilic additions to the polyaza-azines both 3-phenyl-l,2,4,5-tetrazine and 1,3,5-triazine itself add ammonia and simple amines (contrast the requirement for hot sodamide (Chichibabin reaction) for pyridine (8.3.1.2)) and thus amino and alkyamino derivatives can be obtained via oxidative trapping with permanganate. 

ESR spectra of radical cations and anions of 1,2,4,5-tetrazines were recorded and showed that the anions have a re-SOMO concentrated on the four ring nitrogen atoms whilst all but the 3,6-(NMe2)2 derivative form cr-cations, again with the SOMO confined to the four nitrogen atoms.451,452 The observed energy difference between tetrazines and their corresponding radical anions are well correlated with the results of CNDO and self-consistent field re-electron calculations.256 258... 

In addition to the aromatic tetrazine system (1), dihydro-1,2,4,5-tetrazines, tetrahydro-1,2,4,5-tetrazines, and hexahydro-1,2,4,5-tetrazines are known. In almost all the cases which have been studied by x-ray diffraction the dihydro derivatives are best described as 1,4-dihydro isomers (2) structures such as 1,2- and 1,6-dihydro isomers, (3) and (4) respectively, are very rare. Tetrahydro and hexahydro tetrazines, such as (5) and (6), are also known. 

Mass spectra of 1,2,4,5-tetrazines are quite simple . The molecular ion loses Nj quickly with formation of ions of nitrile structure sometimes accompanied with (RCN - - H" ) and (RCN — H )ions. Diaryl tetrazines also show (M -t- 2) ions, probably by formation of 1,4-dihydro derivatives in the ion source. MS data of individual tetrazines are somewhat scattered in the experimental parts of publications dealing with 1,2,4,5-tetrazines and their reactions. 

Finally, the supersonic jet technique has been applied to study spectroscopic details of 3-methyl-tetrazine <83JPC2091, 84CPL141>, 3,6-dimethyltetrazine <84JCP(81)2270>, and 3-amino-.v-tetrazine and its 6-methyl derivative <91JCP(94)2475>. 

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