Mechanistic Investigation of Cu-Catalyzed Asymmetric Alkynylation of Cyclic N-Sulfonyl Ketimines with Terminal Alkynes

Abstract

Density functional theory calculations were employed to study the mechanism of the Cu-catalyzed alkynylation of the N-sulfonyl α-ketiminoester with phenylacetylene. Based on the characteristics of the terminal alkyne, two possible pathways were proposed and investigated. The favorable reaction pathway includes copper acetylide generation, outer-sphere nucleophilic addition, and protonation. Nucleophilic addition is considered to be the rate-and enantioselectivity-determining step. The oxidative state of Cu(I) remains unchanged in the whole process. The electrophilic attack of the C−C triple bond by the N-sulfonyl ketimine to form the vinyl cation intermediate is shown to be unfavorable. The independent gradient model analysis revealed that the origin of the enantioselectivity comes from the weak hydrogen bond between the ligand and the sulfonamide substrate. Moreover, the side-arm effect controls the enantioselectivity by restricting the distortion of the ligand. This work would be of benefit for the design of new ligands for copper catalysis.

Mechanistic Study of Asymmetric Alkynylation of Isatin-Derived Ketimine Mediated by a Copper/Guanidine Catalyst

“…The pathway associated with the electrophilic attack of the C�C bond by the N-sulfonyl ketimine to form the vinyl cation intermediate was unfavorable. 31 In the synthesis of propargylic α-tertiary amine for KAE609, Shibasaki and coworkers proposed that the electronic repulsion between the thioDpp group and the carbonyl group in isatin-derived ketimine made the thioDpp group occupy a spatial orientation different from that in the reaction between ketimine and an aryl alkyl group, leading to the opposite stereochemical outcomes in the Cu(I)-catalyzed asymmetric alkynylation. 18 Guanidines make up a versatile class of organic molecules that show a wide range of interesting applications in pharmaceutical chemistry and organic synthesis.…”

“…The generally accepted mechanism for copper-catalyzed alkynylation of imine involved the formation of a copper-acetylide intermediate, followed by the nucleophilic addition of activated imine and subsequent protonation. ,− In these processes, basic reagents (such as DABCO, i -Pr 2 NEt, NEt 3 , and an inorganic base) were employed to abstract the terminal proton of phenylacetylene, promoting the transformation of phenylacetylene into copper-acetylide active species. The metallic counterion proved to be important for the regulation of the reactivity of the metallic alkynylide (e.g., effecting deprotonation of terminal alkynes). In addition, they could also directly participate in the catalysis to form active species .…”

“…DFT calculations by Lan and Bai indicated that Cu­(I)-acetylide was generated by acetate-assisted deprotonation of phenylacetylene. The pathway associated with the electrophilic attack of the CC bond by the N -sulfonyl ketimine to form the vinyl cation intermediate was unfavorable . In the synthesis of propargylic α-tertiary amine for KAE609, Shibasaki and co-workers proposed that the electronic repulsion between the thioDpp group and the carbonyl group in isatin-derived ketimine made the thioDpp group occupy a spatial orientation different from that in the reaction between ketimine and an aryl alkyl group, leading to the opposite stereochemical outcomes in the Cu­(I)-catalyzed asymmetric alkynylation …”