Olefins 4+2 cycloadditions, 1,2,4,5-tetrazine

If DMAD is the electrophilic acetylene of choice, the commercially available 1-diethylaminopropyne is one of the finest nucleophilic acetylenes, Ynamines show a pronounced affinity for [2 + 2] cycloaddition to carbonyl groups as well as to olefins. Thus tetrazine-3,6-carboxamides (135) react with (136) to give (137) as one product. ... 

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). 

According to the mechanism proposed, the 1,4-cycloaddition (Diels-Alder reaction) of the diene part of the tetrazine to the dienophile (olefin) gives an unstable bicyclic intermediate, which spontaneously eliminates a molecule of nitrogen, forming a 4,5-dihydropyridazine, which in the absence of appropriate stabilization by gem disubstitution in positions 4 and 5, easily isomer-izes to the thermodynamically more stable 1,4-dihydropyridazine (38). The structure of the latter intermediates were unambiguously proved using NMR.91,92... 

A complex sequence of pericyclic reactions, intramolecular and intermolecular cycloadditions and cycloreversions, was studied in an attempt to readily achieve bicyclic five-membered heterocycles, the methyl 4,6-dihydrothieno- and methyl-4, 6-dihydrofuro[3,4-b]-furan-3-carboxylates 146 and 147. The results give further evidence of the potential of intramolecular Diels-Alder based multiple processes [129], 2-Substituted furans and thiophenes 148 and 149, heated in the presence of 3,6-di(pyridin-2 -yl)-,y-tetrazine, underwent intramolecular and intermolecular cycloadditions. The cycloadducts underwent double cycloreversion reactions with the loss of a nitrogen and dipyridyldiazine as illustrated in Scheme 2.55. The electron-deficient dipyridyltetrazine reacts with the isolated, electron-rich olefinic bond rather than with the bond conjugated with the methylcarboxylate. 

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 ... 

Since the early demonstrations of the participation of substituted 1,2,4,5-tetrazines and oxazoles in Diels-Alder reactions with olefinic and acetylenic dienophiles, the potential utilization of the [4 + 2] cycloaddition reactions of heteroaromatic systems possessing a suitable azadiene arrangement has been the focus of extensive investigations. In general, the heteroaromatic systems which possess an electron-deficient azadiene... 

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). 

---