In a study published in Science Advances, a team led by Prof. HE Zhitao from Shanghai Institute of Organic Chemistry of the Chinese Academy of Sciences developed a palladium/amine synergistic catalysis strategy for the asymmetric remote substitution of alkynes, and revealed a complex redox change at palladium metal center and the formation of conjugated diene intermediate.

Propargylic substitution has been extensively studied as an efficient way to prepare chiral alkyne or allene skeletons. In 2023, Prof. HE and collaborators uncovered that internal alkyne can undergo the formation of conjugated diene prior to hydrofunctionalization. They then made a rational substrate design by introducing a leaving group at the γ position of alkyne substrates. 

Reseachers hypothesized that if the conjugated diene was generated quickly from alkyne prior to hydrofunctionalization, the remote leaving group at the γ position might be cleaved through the oxidation addition of low-valent metal by the newly formed diene intermediate.

In this study, researchers realized the design by using 2-phenylpropanal as the nucleophile, diglyme as the solvent, and PhCO₂H as the additive, which proved the hypothesis feasible. They found that a set of newly modified diamine organocatalysts were critical to guarantee the excellent regio-, geometry- and enantioselectivity of the transformation. A series of aryl and ester-derived alkynes were compatible with the reaction.

Researchers then conducted mechanistic experiments. They found that a crucial conjugated diene intermediate was generated from alkyne by β-H elimination, and the PdH catalyst underwent reductive elimination to give Pd(0) species, which could catalyze an asymmetric allylation substitution to obtain the product from the diene intermediate. 

Deuterium labelled experiments suggested that the hydrofunctionalization of diene, allene or alkyne was strictly inhibited during the transformation. Kinetic experiments and kinetic isotope effect illustrated that the rate-determining step might be the alkyne isomerization.

This study establishes a novel asymmetric remote substitution of alkynes via Pd/chiral amine synergetic catalysis with excellent yield and selectivity.