Coupling Reactions of Alkynyl Indoles and CO2 by Bicyclic Guanidine: Origin of Catalytic Activity?

Density functional theory calculations were used to investigate the three possible modes of activation for the coupling of CO2 with alkynyl indoles in the presence of a guanidine base. The first of these mechanisms, involving electrophilic activation, was originally proposed by Skrydstrup et al. (Angew. Chem. Int. Ed. 2015, 54, 6682). The second mechanism involves the nucleophilic activation of CO2. Both of these electrophilic and nucleophilic activation processes involve the formation of a guanidine‐CO2 zwitterion adduct. We have proposed a third mechanism involving the bifunctional activation of the bicyclic guanidine catalyst, allowing for the simultaneous activation of the indole and CO2 by the catalyst. We demonstrated that a second molecule of catalyst is required to facilitate the final cyclization step. Based on the calculated turnover frequencies, our newly proposed bifunctional activation mechanism is the most plausible pathway for this reaction under these experimental conditions. Furthermore, we have shown that this bifunctional mode of activation is consistent with the experimental results. Thus, this guanidine‐catalyzed reaction favors a specific‐base catalyzed mechanism rather than the CO2 activation mechanism. We therefore believe that this bifunctional mechanism for the activation of bicyclic guanidine is typical of most CO2 coupling reactions. The computer never lies! DFT calculations revealed that the bicyclic guanidine‐catalyzed coupling reaction of alkynyl indoles with CO2 proceeds via a specific base‐catalyzed mechanism (via bifunctional activation) rather than an electrophilic or nucleophilic CO2 activation mechanism.