Dienes 1,2,4,5-tetrazines

L-Pro has been used as an organocatalyst in an inverse-electron-demand Diels-Alder reaction of ketones with 1,2,4,5-tetrazines to furnish pyrazines with medicinal interest.The transformation proceeds by the reaction of the diene 1,2,4,5-tetrazine with the enamine formed in situ from the ketone and L-Pro. A retro-Diels-Alder step eliminates nitrogen and forms the pyr-azine product after catalyst elimination. The transformation is, however, not regioselective with unsymmetrical ketones. 

Contrary to the normal Diels-Alder processes, the FMO (Frontier Molecular Orbitals) involved in inverse electron demand Diels-Alder reactions are the LUMO of the diene (1,2,4,5-tetrazine) and the HOMO of the dienophile (electron-rich al-kene). The reactivity of tetrazines 1 toward ethyl vinyl ether would depend on the LUMO diene-HOMO dienophile gap. Thus, the combination LUMO-HOMO having a smaller energy gap will lead to the faster reaction. In this case the LUMO for la has a lower energy than that of lb and this will be reflected in their relative reactivities. Energy gaps between tetrazines 1 and ethyl vinyl ether are 6.61 eV for la and 6.64 eV for lb. In consequence, tetrazine la will be more reactive toward ethyl vinyl ether than lb. 

Compound 10 has a diene (1,2,4,5-tetrazine) tethered to a dienophile (C-C triple bond), so it is reasonable to formulate an intramolecular [4+2] cycloaddition in the first place, leading to adduct 11. The next step would be a retro-Diels-Alder process with N2 extrusion, to obtain the bicyclic diazine 12 (Scheme 30.7). 

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). 

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... 

Certain trifluoromethyl-substituted 1,2,4,5 tetrazines [260, 26i] and 1,2,4 triazines [i06] can be used as cyclic hetero-1,3-dienes and provide efficient preparative routes to partially fluorinated heterocycles (equations 55 and 56)... 

Another type of special diene, the polyaza benzene heterocyclics, such as triazines and tetrazines, is discussed in Section 6.6.2. 

The hetero-Diels-Alder reaction can also employ dienes containing heteroatoms. Cycloaddition of substituted styrenes with di-(2-pyridyl)-1,2,4,5-tetrazine was investigated by Engberts (Eq. 12.56).127 Again, the rate of the reaction increased dramatically in water-rich media. Through kinetic studies, they showed that the solvent effects on the... 

Tetrazine (171) and its derivatives are electron-deficient cycloaddends, which undergo [4 + 2] cycloadditions with inverse electron demand. When bicyclopropylidene (3) was added to a dichloromethane solution of 171, its red color disappeared within 1.5 h at room temperature. The white crystalline product isolated in 86% yield turned out to be a mixture of at least two stereoisomeric compounds 174, trimers of the 8,9-diazadispiro[2.0.2.4]deca-7,9-diene (173) evidently formed via the normal [4 + 2]-cycloadduct 172 after nitrogen extrusion (Scheme 25) [13b]. 

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 inverse electron demand Diels-Alder [4- -2]-cycloaddition of imidazoles to electron-poor dienes to yield imidazo[4,5-i pyridazines, reported in CHEC-II(1996), has been further developed. It was reported that the reaction of267 with tetrazines 268 was fruitless. However, 267 reacted with excess of 268 to yield aromatic 271 along with 1,4-dihydrotetrazine 270. Most likely, 271 arose from dehydrogenation of first-formed 269 by an extra equivalent of 268 <2001T5497> (Scheme 18). 

Such cycloadditions are dependent on the interactions of the azepine HOMO and the diene LUMO. Theoretical consideration of these orbitals reveals that bonding overlap is favourable for C-6—C-7 and C-4—C-5 additions and that, on the basis of secondary orbital interactions, the endo product is favored. Experimentally, however, it is found that additions are periselective and C-4—C-5 addition predominates in the cycloaddition of 1//-azepines with cyclopentadienones, isobenzofurans, tetra- and hexa-chlorocyclopentadienes, 1,2,4,5-tetrazines, a-pyrones and 3,4-diazacyclopentadienones (8lH(15)1569). 

The reaction of ring-strained cycloalkcnes with tetrazines often proceeds under mild conditions for example, reaction of trieyclo[4.2.2.0i-5]deca-3,7-dienes with the dipyridyltetrazine 18 at room temperature gave 3,4-diazabicyclo[4.2.0]octa-2,4-diene derivatives 19 after nitrogen extrusion.24... 

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. 

Pyridazines and their partially saturated analogs have been prepared on insoluble supports by Diels-Alder reaction of electron-rich alkenes or alkynes with 1,2,4,5-tetrazines (Entries 1-3, Table 15.27). The mechanism of this reaction is outlined in Figure 15.15. An additional approach, also based on the Diels-Alder reaction, is the cycloaddition of azo compounds to 1,3-dienes (Entries 4 and 5, Table 15.27). The resulting tetrahydropyridazines (Entry 4) have been used as constrained 3-strand mimetics for the discovery of new protease inhibitors [323], An example of the N-alkylation of hexahydropyridazines on solid phase is given in Section 10.3. 

Arene oxide-oxepin systems have also been reported to undergo [2 + 4] or [4 + 6] pericyclic cycloaddition reactions with heterocyclic dienes like the tetrazine 279 and the triazine 280. 65 Thus 86 96 reacts with 279 and 280 to yield the dihydrooxepino [4,5-d] pyridazine 281 and the oxepino [4,5-c] pyridine 282, respectively, via a [2 + 4] cycloaddition as well as the phthalazine 283 and isoquinoline 284, respectively, probably via a [6 + 4] cycloaddition reaction. However, 157 gives only 285 and 286 arising from a [2 + 4] cycloaddition reaction. 

Tetradehydrodianthracene undergoes 4 + 2-cycloaddition with electron-deficient dienes such as 1,2,4,5-tetrazines.263 The Diels-Alder reactions of [3.3 ortho-anthracenophanes witli A-(p-nitro, chloro, or methoxy-substituted phenyl)malehnides yield approximately equal quantities of inside and outside adducts.264 The photooxidation of bulky water-soluble 1,4-disubstituted naphthalenes with singlet oxygen yields both the expected 1,4- and the unexpected 5,8-endoperoxides.265... 

In a different pattern, by using silylated acetylenes, substituted pyridazines are obtainable217 from the tetrazine derivative 401 in a diene-type reaction, first introduced by Carboni and Lindsey218. Via this reaction 4-TMS- (402) and 4,5-bis(TMS)-3,6-bis(methoxycarbonyl)pyridazine (403) can be achieved in very high yield, being inert against acid catalyzed desilylation (Scheme 59). 

Cyclic, electron-deficient diaza-1,3-butadienes, e. g. pyrimidines, pyridazines, triazines and tetrazines have proved to be an extremely versatile synthetical tool. Extensive studies aimed at the use of these dienes in the synthesis of natural products stem from Boger s group [11]. 

Thiophenes can act as dienophiles in Diels-Alder reactions with electron-poor dienes such as hexachlorocyclopen-tadiene, tetrazines, or o-quinone monoimines. The masked o-benzoquinone 64 can undergo inverse electron demand cycloadditions with thiophene itself or simple derivatives such as 2-methyl-, 2-methoxy-, and 2,4-dimethylthiophene (Scheme 5) <2001TL7851>. Depending on the substitution pattern on the thiophene skeleton, different cycloadducts can be observed. The basic thiophene skeleton gives rise to a bis-adduct 65. By blocking the second double bond with a methyl or methoxy group, a 1 1 adduct 66 or 67, respectively, is obtainable in moderate yield. 

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... 

Boger et al. developed a common strategy useful for the synthesis of related natural products and analogues <99JA54>. Their approach employs an aza Diels-Alder reaction <86CRV781, 89PHC30> using as diene the dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate 25 to... 

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