5-Tetrazine

According to X-ray studies, 1,2,4,5-tetrazine is planar. Its structural parameters, bond lengths C-N 133.4 and N-N 132.1 pm, bond angles N-C-N 127.2 and C-N-N 115.6°, indicate a 

The H- and C-atoms of 1,2,4,5-tetrazine are more strongly deshielded than those of 1,3,5-triazine H-NMR 8= 11.05, i C-NMR 161.2 (acetone-d ). 

5-Tetrazines are coloured (red-violet). They have UVA IS maxima in the visible region at 520-570 mn (n - n transition), and in the UV region at 250-300 nm n - n transition). They have a characteristic simple fragmentation pattern in the mass spectrum  

Even more so than 1,2,4-triazines (see p 441), 1,2,4,5-tetrazines display heterodiene activity in their reactions towards electron-rich, multiply-bonded systems. Enol ethers, enamines, ketene acetals, imido esters, alkynylamines and nitriles undergo [4+2] cycloadditions with inverse electron demand across the ring positions C-3 and C-6 [176]. Olefinic dienophiles lead to diverse products depending on their substituents  

As a rule, the initial hetero-DiELS-ALDER adduct 2 cannot be isolated. It eliminates N2 in a retro-DiELS-Alder reaction and is converted into a 4,5-dihydropyridazine 3. This can be stabilized as a 1,4-dihydropyridazine 7 (especially if X = H) by a 1,5 hydrogen shift or (if X = OR and NR2) as the pyridazines 5 and 6 by dehydrogenation or HX elimination. As a diazadiene, it can also engage in a further Diels-Alder reaction with excess of alkene 3delding the stable 2,3-diazabicyclo[2.2.2]oct-2-ene 4. The initial Diels-Alder product tetraazabicyclo[2.2.2]octatriene 8, which arises from the reaction between alkynes and 1,2,4,5-tetrazines, undergoes a cycloreversion with N2 elimination affording the pyridazine 6. With nitriles, 1,2,4-triazines 9 are obtained. 

Even more than 1,2,4-triazines (cf p. 504), 1,2,4,5-tetrazines display heterodiene activity in their reactions toward electron-rich, multiply bonded systems. 

Ikariya, T. Ishikawa, Y Hirai, K. Yoshikawa, S. Chem. Lett. 1982, 1815. 

Numerous electron-rich alkynes have shown to undergo this transformation yielding a variety of substituted 4- or 4,5-substituted pyridazines in good yields. 

In a similar sense, cycloaddition of 1,2,4,5-tetrazine with alkynylboronate esters 4 yielded pyridamines 5 and 6 (eq 2). The resultant boronic ester in 5 was then capable of further Suzuki coupling reactions to generate l  

Preparative Method available from a few commercial vendors, though preparation is more common.  

Handling, Storage, and Precautions store at —20 °C to avoid deconqiosition. 

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Figure 9.46 shows an example of a fluorescence excitation spectmm of hydrogen bonded dimers of x-tetrazine (1,2,4,5-tetraazabenzene). The pressure of x-tetrazine seeded into helium carrier gas at 4 atm pressure was about 0.001 atm. Expansion was through a 100 pm diameter nozzle. A high-resolution (0.005 cm ) dye laser crossed the supersonic jet 5 mm downstream from the nozzle. 

Figure 9.46 Rotational structure of the Ojj bands in the fluorescence excitation spectra of s-tetrazine dimers at about 552 run. Bottom Ojj band of planar dimer. Middle Ojj band of T-shaped dimer with transition in monomer unit in stem of T. Top Ojj band of T-shaped dimer with transition in monomer unit in top of T. (Reproduced, with permission, from Haynam, C. A., Brumbaugh, D. V and Levy, D. H., J. Chem. Phys., 79, f58f, f983)...

C2F12C12F2 (1,2-dichloro-l, 2-difluoroethane) symmetry elements, 83 CF13C3CN (methyl cyanoacetylene) interstellar, 120 2142X4 (s-tetrazine) fl S3 — X Ag transition, 3971F F1COOCF13 (methyl formate) interstellar, 120... 

X4)2 (s-tetrazine dimer) electronic spectrum, 397tf... 

Among the molecules that have received greatest attention are 2,6-bis(picry1amino)-3,5-dinitropyridine (PYX) 3,6-dinitro-j -tetrazine ... 

Although all the rings in Figure 1 contain six tt-electrons, the accumulation of electronegative nitrogen atoms in the polyaza structures leads to hydrolytic as well as thermal instability. This is noticeable in pyrimidine, and marked in the triazines and tetrazine. Some stability can be conferred by appropriate substitution, as we shall outline later. 

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). 

In 1959 Carboni and Lindsay first reported the cycloaddition reaction between 1,2,4,5-tetrazines and alkynes or alkenes (59JA4342) and this reaction type has become a useful synthetic approach to pyridazines. In general, the reaction proceeds between 1,2,4,5-tetrazines with strongly electrophilic substituents at positions 3 and 6 (alkoxycarbonyl, carboxamido, trifluoromethyl, aryl, heteroaryl, etc.) and a variety of alkenes and alkynes, enol ethers, ketene acetals, enol esters, enamines (78HC(33)1073) or even with aldehydes and ketones (79JOC629). With alkenes 1,4-dihydropyridazines (172) are first formed, which in most cases are not isolated but are oxidized further to pyridazines (173). These are obtained directly from alkynes which are, however, less reactive in these cycloaddition reactions. In general, the overall reaction which is presented in Scheme 96 is strongly... 

The only recorded synthesis of this type from a pyridazine involves the [4 + 2] cycloaddition of the lactim ether (374) with l,2,4,5-tetrazine-3,6-dicarboxylic ester, which proceeds with loss of nitrogen and methanol from the intermediate adduct to give the pyrido[2,3-t/]pyridazine (375) (77AP936). 

Benzo[Z)]thiophene reacts with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate in a cyclo-addition-fragmentation reaction to yield (143), whereas benzo[A]furan and N- methylindole yield products (144) arising from ring opening and recyclization (76AP679). 

H-Azepine derivatives form a diene complex with tricarbonyliron, leaving uncomplexed the third of the double bonds. If the 3-position is substituted, two different such complexes are possible, and are in equilibrium, as seen in the NMR spectrum. An ester group in the 1-position of the complex can be removed by hydrolysis, to give an NH compound which, in contrast to the free 1/f-azepine, is stable. The 1-position can then be derivatized in the manner usual for amines (Scheme 22). The same tricarbonyliron complex can, by virtue of the uncomplexed 2,3-double bond, serve as the dienophile with 1,2,4,5-tetrazines. The uncomplexed N-ethoxycarbonylazepine also adds the tetrazine, but to the 5,6-double... 

The 27T-electrons of the carbon-nitrogen double bond of 1-azirines can participate in thermal symmetry-allowed [4 + 2] cycloadditions with a variety of substrates such as cyclo-pentadienones, isobenzofurans, triazines and tetrazines 71AHC(13)45). Cycloadditions also occur with heterocumulenes such as ketenes, ketenimines, isocyanates and carbon disulfide. It is also possible for the 27r-electrons of 1-azirines to participate in ene reactions 73HCA1351). 

A particularly interesting system where nitrogen is lost cheletropically after formation of the initial [4 + 2] cycloadduct involves the thermal reaction of azirines with tetrazines (82) (74CC45, 74TL2303, 74CC782, 75JHC183). A variety of heterocyclic products are produced depending on the structure of the azirine and tetrazine used and the reaction conditions. 

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