Reaction of Aldehydes/Ketones with Electron-Deficient 1,3,5-Triazines Leading to Functionalized Pyrimidines as Diels–Alder/Retro-Diels–Alder Reaction Products: Reaction Development and Mechanistic Studies

Catalytic
inverse electron demand Diels–Alder (IEDDA) reactions
of heterocyclic aza-dienes are rarely reported since highly reactive
and electron-rich dienophiles are often found not compatible with
strong acids such as Lewis acids. Herein, we disclose that TFA-catalyzed
reactions of electron-deficient 1,3,5-triazines and electron-deficient
aldehydes/ketones can take place. These reactions led to highly functionalized
pyrimidines as products in fair to good yields. The reaction mechanism
was carefully studied by the combination of experimental and computational
studies. The reactions involve a cascade of stepwise inverse electron
demand hetero-Diels–Alder (ihDA) reactions,
followed by retro-Diels–Alder (rDA) reactions
and elimination of water. An acid was required for both ihDA and rDA reactions. This mechanism was further
verified by comparing the relative reactivity of aldehydes/ketones
and their corresponding vinyl ethers in the current reaction system.