Chiral Disulfonimide‐Catalyzed Atroposelective Iodination of (Hetero)arylamines: Generalizing the Brønsted Base Catalysis Strategy

Axially chiral (atropisomeric) scaffolds are increasingly deployed in drug discovery. Atroposelective halogenation provides an attractive strategy to install axial chirality while introducing a versatile synthetic handle for the introduction of functional groups. However, atroposelective halogenation of pro‐atropisomeric (hetero)arylamines is still underdeveloped, as most strategies rely on substrate‐embedded directing groups that limit generality. Herein, we show that Brønsted base catalysis with chiral disulfonimides (DSI) enables an atroposelective iodination for aminopyrimidines and anilines, with the discovery of a novel 2,6‐di‐ tert ‐butylpyridine (DTBP) effect. The enantiospecific substitution of the iodine substituent highlights the synthetic utility of this method. Control experiments and density functional theory (DFT) computations rationalize the effect of DTBP and support a mechanism in which reversible electrophilic aromatic substitution generates a Wheland intermediate that undergoes irreversible, enantio‐determining deprotonation by the chiral DSI conjugate base. Distortion/interaction model (DIM) and energy‐decomposition analyses (EDA) indicate that minimized distortion of the Wheland intermediate together with favorable noncovalent interactions stabilizes the preferred transition state.