| A systematic study of the inverse electron demand Diels--Alder reactions of 1,2,3- triazines is disclosed. In addition to the parent 1,2,3-triazine ring system, a variety of differentially substituted 1,2,3-triazines were examined (4-CO2Me-, 5-CO2Me, 5-Ph, 5- Br, 4,6-CO 2Et, 4,6-CO2Et-5-Me) in this reaction. These substituents were found to exhibit a remarkable impact on the reactivity of the 1,2,3-triazine and the regioselectivity of the cycloaddition reaction. While 5-substituents did not alter and perhaps even enhanced the intrinsic cycloaddition regioselectivity, substitution of the 4/6 position led to less regioselective reactions with ynamine and amidine dienophiles. The study revealed that not only may the reactivity of 1,2,3-triazines be predictably modulated by substitution (R = CO2Me > Ph > H), but that the impact is of a magnitude to convert 1,2,3-triazine and its modest cycloaddition scope into a heterocyclic azadiene system with a reaction scope that portends extensive synthetic utility, expanding the range of participating dienophiles. This methodology has been successfully applied towards the synthesis of lysergic acid and pyrimidoblamic acid. Significantly, these studies define a now powerful additional heterocyclic azadiene, complementary to the isomeric 1,2,4- triazines and 1,3,5-triazines, capable of dependable participation in inverse electron demand Diels--Alder reactions, extending the number of complementary heterocyclic ring systems accessible with implementation of the methodology. |
