Mechanistic Insights into Cobalt-Catalyzed Regioselective C4-Alkenylation of 3-Acetylindole: A Detailed Theoretical Study

Abstract

A detailed mechanistic study of Co­(III)-catalyzed C4-alkenylation of 3-acetylindole (1a) was done based on calculations at density functional theory (DFT) and correlated wave function levels. The whole catalytic cycle consists of four steps: C–H activation, olefin insertion, β-hydride elimination, and regeneration of the catalyst. The theoretical results support olefin insertion as the rate-determining step leading to the experimentally observed regioselectivity of the C4 site over the C2 site. By the analysis of three-dimensional (3D) geometries and the NCl plot, the preference for the C4 site over the C2 site could be attributed to the weaker repulsive interaction between the indole moiety and olefin in the transition states of the olefin insertion step for the former. The reliability of the theoretical mechanistic results is further confirmed through the DFT calculation of other related indole derivatives and olefin substrates.

Palladium-Catalyzed Regioselective C4-H Acyloxylation of Indoles with Carboxylic Acids via a Transient Directing Groups Strategy

“…Our study commenced with N -tosylindole-3-carboxaldehyde ( 1a ) and benzoic acid ( 2a ) as the model substrates (Table ). It is worth mentioning that (1) besides the aldehyde group, the acid group also has a directing property in transition-metal-catalyzed C–H bond functionalization (2) inherent active reactive sites in indole are the C2 and C3 positions, not C4 . Therefore, it is very challenging to achieve transition-metal-catalyzed regioselective C4-H direct acyloxylation of indoles with organic acid as the acyloxylation reagent and aldehyde group as the directing group.…”