A DFT Study on Organocatalytic Atroposelective Acylation of <i>N</i> ‐Aminoindoles: Mechanism and Origin of Axially Chirality

Possible mechanisms of isothiourea-catalyzed acylation of N-aminoindole with benzoyl chloride for constructing N─N axial chirality have been systematically investigated using density functional theory (DFT). Two pathways initiated by the nucleophilic addition of NEt₃ and isothiourea catalyst to benzoyl chloride have been explored, respectively. The calculation results revealed that the energetically favorable pathway proceeds in three steps, including formation of an amide iminium cation by nucleophilic addition of NEt₃ to benzoyl chloride, S_N2 reaction to form an acylisothiouronium intermediate using isothiourea catalyst coupled with elimination of NEt₃, and C-N bond formation accompanied by regeneration of isothiourea catalyst. Among these steps, the C-N bond formation between the acylisothiouronium intermediate and the amide anion has been identified as the stereoselectivity-determining step to construct the N─N axially chiral compound. Distortion-interaction analyses revealed that interaction energy dominates the stereoselectivity-determining step. Furthermore, the key factors that determine the stereoselectivity have been confirmed by noncovalent interaction (NCI) and atoms-in-molecules (AIM) analyses. The nucleophilicities of NEt₃ and the isothiourea catalyst have been further analyzed using Parr functions and Fukui function vectors.