Cycloadditions of 1,2,4,5-tetrazines

A common method to synthesize pyridazines remains the inverse electron-demand Diels-Alder cycloaddition of 1,2,4,5-tetrazines with electron rich dienophiles. [4 + 2]-Cycloadditions of disubstituted 1,2,4,5-tetrazine 152 with butyl vinyl ether, acrylamide, phenylacetylene, and some enamines were performed to obtain fully substituted pyridazines 153 . This reaction was accelerated by electron withdrawing groups, and is slowed by electron donating groups, R1 and R2on the tetrazine. 

Various fused pyridazine derivatives can be prepared by the inverse-electron-demand DielsAlder cycloadditions of 1,2,4,5-tetrazines with a wide range of alkynes and alkenes . For example, 3,6-bis(trifluor-omethyl)-l,2,4,5-tetrazine 426 cycloadds to benzyne giving a quantitative yield of l,4-bis(trifluoromethyl)phthalazine 427 (Scheme 222) <1987AGE332>. 

An acetylenic side chain in 5-ethynyl-2 -deoxyuridine or its O-acetyl derivative is converted by this method into a new pyridazine ring (86JOC950). Intramolecular cycloaddition of 1,2,4,5-tetrazines with acetylenic side chain has been used to prepare various condensed heterocyclic rings (32) (85TL4355 86TL2747 87CZ16 88JOC1415). 

Intramolecular cycloaddition of 1,2,4,5-tetrazines to a nitrile group has also been reported. Heating 3-[(2-cyanophenyl)oxy(sulfanyl)]-l,2,4,5-tetrazines in chlorobenzene affords condensed 1,2,4-triazines 14.203... 

Cycloaddition of 1,2,4,5-tetrazines with C-N double or triple bonds yields dihydro-1,2,4-tri-azines 13 or 1,2,4-triazines 14 (see Section B.2.2.1.3.). Various systems with C—N double bonds have been used imines, including dihydropyrroles and dihydroisoquinolines 341 344 hydra-zones, including dihydropyrazoles,343 348 oxime ethers,343 imidates, including dihydrooxa-zoles 345 357 thioiniidates, including dihydrothiazoles 345,349,350 357 358 amidrazones 357,358 amidines 359 and isocyanates or isothiocyanates.351 Nitriles are the examples of systems with a C-N triple bond.352 -356... 

Intramolecular cycloaddition reactions of 1,2,4,5-tetrazines with a cyano group are also reported, giving rise to condensed 1,2,4-triazines <89CB2177>. The cycloadditions of 1,2,4,5-tetrazines are considered in detail in Chapter 6.24. 

The [4+2] cycloaddition of 1,2,4,5-tetrazines can be used for the synthesis of other heterocycles, e.g. isobenzofuran, isoindole and isobenzofulvene from 1,4-dihydronaphthalenes 10. 

Cycloadditions of 1,2,4,5-tetrazines 1 to tetradehydrodianthracene 168 have also been reported. Under mild conditions, 1 1 adducts 169 were obtained in high yields. Further treatment of 169 with another molecule of tetrazine 1, usually under more drastic conditions, gave 1 2 adducts 170 in excellent yields (Scheme 45) <1997LA1473>. 

Long reaction times, which are usually required in [4-1-2] cycloadditions of 1,2,4,5-tetrazines to various alkenes under classical heating, were shortened drastically by microwave-assisted reactions supported on graphite. In contrast to conventional conditions, microwave-assisted cycloadditions of 3,6-diphenyl-l,2,4,5-tetrazine 23 furnished fully conjugated pyridazines 212 (Scheme 54) <1996LA739>. 

Inverse electron demand cycloaddition of 1,2,4,5-tetrazine with alkenes and alkynes. Inverse electron demand Diels-Alder addition has also been employed for the synthesis of pyridazines and condensed pyridazines. The reaction of olefinic and acetylenic compounds with 3,6-disubstituted 1,2,4,5-tetrazines 142 to yield substituted pyridazines 144 by the intermediacy of 143 was first reported by Carboni and Lindsey (1959JA4342). Analogous reaction of 142 with a variety of aldehydes and ketones 145 in base at room temperature proceeded smoothly to yield the corresponding pyridazines 144. Compounds 146-148 are proposed nonisolable intermediates (1979JOC629 Scheme 26). 

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 ... 

In 1980, Sauer et al. synthesized 3,7-dicyanosemibullvalene 4-4 (Scheme 4.4). Cycloaddition of 1,2,4,5-tetrazines with 3,3 -bicyclopropenyl in a cycloaddition-cycloelimination sequence followed by hydrolysis, amination, and dehydration gave 3,7-dicyanosemibullvalene 4-4. The author also determined the activation barrier of Cope arrangement of 4-4 at -158 °C as 5.7 kcal/mol, slightly higher than the value 5.4 kcal/mol of unsubstituted SBV at the same temperature. This result indicates that electro-deficient cyano group at 3,7-position has little effect on the stabilization of delocalized structure [32]. 

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. 

In 1969 the reaction of 1,2,4,5-tetrazines (39) with imidates (198) was reported. The formation of the 1,2,4-triazine products (199) is explained by a [4 + 2] cycloaddition of the tetrazine with the C=N double bond of the imidate to give the bicyclic intermediate (200) which eliminates nitrogen and alcohol (69JHC497). Further studies on this reaction seem to... 

Reaction of 1,2,4,5-tetrazines (39) with AMhionitrosodimethylamine (217) and N-sulfinylanilines (218) led to the isolation of 4-dimethylamino-4// -1,2,4-triazoles (219) and 4-aryl-4//-1,2,4-triazoles (220), respectively. The formation of these products was explained by a [4 + 2] cycloaddition to give bicyclic intermediates, then elimination of nitrogen to yield the 1,2,4,5-thiatriazines, which form the products by extrusion of sulfur and sulfur oxide, respectively (Scheme 12) (79CZ230, 77AP269). 

The cycloaddition reaction of 1,2,4,5-tetrazines with olefins developed by Carboni and Lindsey90 represents a second major route to dihydropyri-dazines (Scheme 5). 

The most intensively studied reactions of 1,2,4,5-tetrazines are cycloaddition reactions with alkenes and alkynes, not only due to theoretical interest but also due to its importance in synthesis. The 1,2,4,5-tetrazines are diene components in this [4 + 2]-cycloaddition reaction while the alkynes and alkenes are the dienophiles. Kinetic studies have shown that these reactions should be classified as Diels Alder reactions with inverse electron demand. Therefore, 1,2,4,5-tetrazines with electron-withdrawing substituents (C02Me, CF3) and dienophiles with electron donating substituents are the most reactive compounds. However, dimethyl... 

Kinetic data for the [4 + 2]-cycloaddition reactions of a variety of 1,2,4.5-tetrazines with /V./V-diethylprop-l -ynaminc have been published.15... 

In addition to intermolecular cycloaddition reactions of 1,2,4,5-tetrazines with various dienophiles, intramolecular cycloaddition reactions with alkene367 and acetylene 360 367 dienophiles or nitrile groups355-356 have also been reported. By this method condensed pyrid-azines 15 or 1,2,4-triazines 16 (see Section B.2.2.1.3.) are obtained. In most cases the side chain is bound to the 1,2,4,5-tetrazine ring by a heteroatom (O, S or In ). In a few cases the side chain is bound by a carbon atom or contains an additional heteroatom. The general reaction scheme is shown. 

The interest of physical organic chemists in the physical and spectroscopic properties of 1,2,4,5-tetrazines, and of preparative organic chemists in the high reactivity of tetrazines as dienes in (4 + 2) cycloaddition reactions in particular, is still increasing. Therefore there are many methods known for the synthesis of 1,2,4,5-tetrazines (1) in very good yields, including the parent compound (see Section 6.21.8). 

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