1.4- Dihydropyridazine from Diels-Alder reactions

The first product of the reaction of 1,2,4,5-tetrazines (39) with alkenes (142) is the bicyclic compound (143), which has never been isolated since it loses nitrogen immediately by a retro-Diels-Alder reaction to give 4,5-dihydropyridazine (144). These compounds have been isolated in a few cases but usually a product is obtained which is formed from (144) in one of four different ways ... 

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. 

Since cycloadditions of tetrazines follow the inverse electron demand in Diels-Alder reactions, cycloadditions to electron-rich enamines usually proceed easily and under mild conditions. In general, elimination of amine takes place from the initially formed dihydropyridazine to give the fully conjugated pyridazines as products. 

A Diels-Alder type [4+2] cycloadditions of 4,5-dihydropyridazine, prepared in situ from its trimer, with 2-methyl- and 2,3-dimethyl-1,3-butadienes (65, R = H, Me R = Me) afforded a complex reaction mixture, from which 6-methyl- and 6,7-dimethyl-3,4,4n,5-tetrahydro-8//-pyrido[l,2-ftjpyridazines (66, R = H, Me R =Me) could be isolated (97CEJ1588). With 1,3-butadiene (65, R = R =H) only a mixture of endo and exo isomers 67 and 68 (R = R =H) was obtained. 

Warrener reported that when 3,6-disubstituted-s-tetrazine 147 was employed as a heterodiene in Diels-Alder cycloadditions with alkenes such as 146, tandem [4 + 2]/[4 + 2] reaction takes place under high pressure (8-14 kbar, 16h) (Scheme 36) [55]. Due to its high reactivity, initial [4 + 2] cycloaddition of tetrazine 147 and nor-bornene 146 is carried out at atmospheric pressure. Spontaneous elimination of nitrogen from primary formed Diels-Alder adduct liberates the second diene, 1,2-dihydropyridazine. By addition of another equivalent of alkene 148 and application of high pressure, the second [4 + 2] cycloaddition generates the central diazabicy-clo[2.2.2]octene skeleton in high yield. A number of functionalized polynorbornane systems were prepared by this synthetic protocol [56]. 

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