Inverse Electron Demand Diels–Alder Reactions of 1,2,3-Triazines: Pronounced Substituent Effects on Reactivity and Cycloaddition Scope

Abstract

A systematic study of the inverse electron demand Diels–Alder reactions of 1,2,3-triazines is disclosed, including an examination of the impact of a C5 substituent. Such substituents were found to exhibit a remarkable impact on the cycloaddition reactivity of the 1,2,3-triazine without altering, and perhaps even enhancing, the intrinsic cycloaddition regioselectivity. The study revealed that not only may the reactivity be predictably modulated by a C5 substituent (R = CO2Me > Ph > H), but that the impact is of a magnitude to convert 1,2,3-triazine (1) 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. Significantly, the 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.

Bis‐Boron Compounds in Catalysis: Bidentate and Bifunctional Activation

“…The potential of this reaction was extensively studied by Boger and others . The group of Boger showed, for instance, that tetrazines and triazines are, in particular, excellent dienes reacting with a wide range of different dienophiles . The reason for this behavior is the electron‐poor structure and the release of nitrogen as the thermodynamic driving force.…”

1,2,4-Triazines Are Versatile Bioorthogonal Reagents

“…[24][25][26][27][28][29] Boger further showed that 1,2,3-triazines react with electron-rich dienophiles. 30 To compare the intrinsic DA reactivities of 1,2,3-and 1,2,4-triazines with that of 1,2,4,5-tetrazine, we evaluated the activation free energies for their reactions with ethylene by density functional theory (DFT) calculations ( Figure 1A, Table S1). [31][32][33] The computational analysis suggested that 1,2,4-triazine is much more reactive than 1,2,3-triazine (activation free energy: 29.3 versus 41.0 kcal/mol), but less reactive than 1,2,4,5-tetrazine (29.3 versus 21.9 kcal/mol).…”

Microwave-Assisted Synthesis of Bioactive Six-Membered Heterocycles and Their Fused Analogues

“…The pioneering work dealing with this so-called Carboni-Lindsey reaction has been reviewed by Boger [265]. Triazine and tetrazine derivatives are commonly used as commercial dyes [266], as insecticides [267] and more recently as pharmaceutical agents (Figure 17) [268,269].…”