Theoretical Investigation on N-heterocyclic Carbene-Catalyzed Enantioselective [3 + 3] Annulation of Enal with 5-aminopyrazole for Construction of Pyrazolo[3,4-b]pyridone

The mechanism is investigated for [3 + 3] annulation of cinnamaldehyde with 5-aminopyrazole catalyzed by N-heterocyclic carbene (NHC) leading to pyrazolo [3,4-b]pyridone.The enal is attacked by NHC generating Breslow intermediate, the oxidation of which gives α,β-unsaturated acyazolium.After donating amino H, the 1,4-addition of 5-aminopyrazole is rate-limiting step.The enantioselectivity is determined by the attack to less hindered face of NHC-enal complex.Once NHC is departed, the intramolecular lactamization readily occurs followed by tautomerization.The product with favored s isomer is cooperatively controlled both by thermodynamics and kinetics with recovered NHC catalyst.Although the 1,4-addition reaction path is reasonable and more easily, the 1,2-addition followed by an intramolecular Claisen rearrangement reaction path is also possible.The positive solvation effect is suggested by decreased absolute and activation energies in THF solution compared with in gas.