Tetrazines, reactivity

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... 

Two oxadisilole-fused benzo[c]furans illustrated below were prepared making use of Warrener s tetrazine protocol <06JOC3512>. Their reactivities, photophysical, redox and thermal properties were all assessed. As shown below, an isocorannulenofuran was also synthesized, again by employing Warrener s route, from readily accessible bromocorannulene <060L5909>. 

Among the dienes known as weakly reactive are anthracene (1), metacrolein di-methylhydrazone (2) and 3,6-diphenyl-l,2,4,5-tetrazine (3). DA cycloadditions with these dienes require long reaction times under classical heating conditions (Tab. 7.1). 

The occurrence of degenerate ring transformation reactions in the hy-drazinodehalogenation of halogeno-l,2,4,5-tetrazines (see Section II,D,3.) raised the question as to whether corresponding reactions would also occur with the less reactive halogenopyridazines. Extensive investigations on hy-... 

Electron-deficient heteroaromatic systems such as 1,2,4-triazines and 1,2,4,5-tetrazines easily undergo inverse electron demand Diels-Alder (lEDDA) reactions. 1,2-Diazines are less reactive, but pyridazines and phthalazines with strong electron-withdrawing substituents are sufficiently reactive to react as electron-deficient diazadienes with electron-rich dienophiles. Several examples have been discussed in CHEC-II(1996) <1996CHEC-II(6)1>. This lEDDA reaction followed by a retro-Diels-Alder loss of N2 remains a very powerful tool for the synthesis of (poly)cyclic compounds. 

The reactivity of tetrazines with electron-attracting substituents (e.g. R3 = R6 = C02Me) is particularly high, so it was proposed to use them as titrating agents to determine the purity of liquid alkenes (62CB2248). 

In the diazines, triazines and tetrazines, the effects of the additional nitrogen atom(s) are roughly additive. In Table 4 the positions of substituents in the common azine ring systems are listed in order of increasing reactivity. The limit is reached in 2-, 4- or 6-substituted 1,3,5-triazines for which the reactivity approximates to that in the corresponding carbonyl compound (559). 

Pyrimidines are expected to be much less reactive in cycloadditions of this type than triazines and tetrazines. Normally, the presence of electron-withdrawing substituents on the pyrimidine ring is essential. The best results are obtained with a nitro group in position 5. Reaction of 5-nitropyrimidine with various enamines affords fused nitropyridines (82TL3965 89T2693) (Scheme 59). The mechanism (89T2693) is in agreement with the usual expectations. 

Tetrazines (624) are reactive dienes in Diels-Alder reactions with inverse electron demand. They react with both C—C and C—N multiple bonds. Cycloaddition of (624) with imidates thus affords 1,2,4-triazines (625) which are formed via the bicyclic intermediates (626) and the dihydro-1,2,4-triazines (627) (69JHC497). Further studies have been made on the limitations of this reaction. 

There are many methods known for the synthesis of 1,2,4,5-tetrazines (39) but most afford the desired compounds only in low yield. There has been great interest in these compounds by physical organic chemists on account of their physical and spectroscopic properties, while preparative organic chemists have been interested in their high reactivity as dienes in cycloaddition reactions. 

The number of 1,2,4,5-tetrazines used in these cycloaddition reactions is limited. The most frequently used are the 3,6-dicarboxylates, the 3,6-diphenyl, 3,6-dimethyl, 3,6-di(2-pyridyl) and bis(perfluoroalkyl) compounds a few others have also been used. The most reactive substances seem to be the 1,2,4,5-tetrazinedicarboxylates, possessing the extra electron-withdrawing effect of the two carboxylate groups. 

Preparation and Diels-Alder Reaction of a Reactive, Electron-Deficient Heterocyclic Azadiene Dimethyl 1,2,4,5-Tetrazine-3,S-Dicarboxylate. 1,2-Diazine and Pyrrole Introduction. 

Much larger effects of this type are observed in cycloadditions of enol ethers to tetrazines (Fig. 26), a reaction shown by Sauer and co-workers to be an example of a Diels-Alder reaction with inverse electron demand 75. The rates of 3,6-di-(2 -pyridyl)-s-tetrazine to various enol ethers and styrenes are summarized in Fig. 27. These were obtained by measuring the disappearance of the 540 nm band in the absorption spectra of the tetrazine76. These results are of particular interest, since there is little or no correspondence between the electron-donor ability of the enol ether, as measured by the ir ionization potentials (Table 5), and the rate of reaction of the enol ether. For example, although the conversion of methyl vinyl ether to 1,1-dimethoxyethylene results in a 4.3 times increase in rate, in line with the 0.2 — 0.3 eV decrease in IP, the 1,2-dimethoxyethylenes are 13 to 25 times less reactive than methyl vinyl ether, even though the IPs of these molecules are much lower... 

Tetrazines with electron-withdrawing substituents in the 3 and 6 positions constitute extremely electron-poor dienes [19]. In order to test their reactivity towards the disilene 3 we have selected the compound 18 because its CF3 groups should not be so susceptible to the otherwise readily occurring halogen abstraction by 1 and its photolysis products. However, irrarliation of 18 in the presence of an excess of 1 did not lead to the expected product 17 instead the compound 19 was isolated and its structure confirmed by X-ray crystallography. The structure of 19 clearly reveals that not only has one... 

Significantly, the oxygenation pattern found in the two aryl groups, as in 24, would be expected to increase the nucleophilic character of the acetylene and improve what is a typically poor reactivity of alkynes toward 1,2,4,5-tetrazine derivatives <65CB1435> for an inverse electron demand Diels-Alder cycloaddition. 

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