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

In this work, we performed a mechanistic study of asymmetric alkynylation of isatin-derived -Boc ketimine that was first reported by Feng, Liu, and co-workers ( , , 678-681). Guanidine-amide promoted the formation of highly nucleophilic copper acetylene species by abstracting the terminal proton of phenylacetylene with an imine moiety. The guanidinium salt-Cu(I) complex was the most active species in the addition of the C═N bond, in which copper acetylene coordinated to the O atom of the amide moiety, and the isatin-derived ketimine substrate was activated by hydrogen bonding as well as -butoxycarbonyl···Cu(I) coordination. Due to weak interaction between Cu(I) and the Ph group in the amide of guanidine, as well as the repulsion between the -butyl group in ketimine and the cyclohexyl group in guanidine, the copper acetylene preferred to attack isatin-derived ketimine from the -face, leading to the -configuration product with excellent stereoselectivity. The affinity of the counterion for the Cu(I) center in the copper salt affected the deprotonation of phenylacetylene and the formation of guanidinium salt active species. In contrast to CuBr and CuCl, the combination of CuI with aniline-derived guanidine-amide exhibited high catalytic activity and a chiral induction effect, contributing to a high turnover frequency (9.70 × 10 s) in catalysis and ee%.