Mechanism, Chemoselectivity, and Stereoselectivity of an NHC-Catalyzed Reaction of Aldehydes and Hydrazones: A DFT Study.

To elucidate the mechanism and origins of chemo- and enantioselectivities of the reaction between aliphatic aldehydes and hydrazones catalyzed by triazolium-derived NHC, density functional theory computations have been performed. According to our calculated results, the whole catalytic cycle for the formation of dihydropyridazinones proceeds via the initial nucleophilic addition of NHC to an aliphatic aldehyde, followed by the concerted intramolecular proton transfer and C-Cl bond cleavage. Subsequent deprotonation generates an enolate intermediate. The enolate intermediate then undergoes 1,4-addition to hydrazone to construct a new carbon-carbon bond. The following ring-closure would lead to a six-membered ring intermediate, which, upon the release of NHC, affords the final product dihydropyridazinone. The computation results reveal that intramolecular proton transfer is significantly promoted by the Brønsted acid DIPEA·H. The carbon-carbon bond formation step could determine not only the chemoselectivity but also the stereoselectivity and lead to the -isomer product. It was found that the stereoselectivity arises from a combination of weak interactions, including C-H···O, C-H···N, C-H···π, and LP···π. NHC could enhance the nucleophilicity of the aliphatic aldehyde and facilitate further reaction with hydrazone. This work could be beneficial for the development of new catalytic strategies in the future.