Nucleophilic aromatic substitutions enable diversity-oriented synthesis of heterocyclic atropisomers via non-atropisomeric intermediates.

Atropisomers are sterically hindered molecules whose formation typically proceeds via atropisomeric intermediates and encumbered transition states. It is therefore largely accepted that the activation energy is higher for synthesis of atropisomers than for synthesis of similar, less sterically congested non-atropisomeric compounds. Here we show that atropisomer formation by nucleophilic aromatic substitution (SAr) reactions can progress via non-atropisomeric intermediates and transition states. We put forth fast, mild, practical, regio- and chemoselective SAr reactions that generate a diverse array of difficult-to-access heterobiaryl C─N atropisomers starting with readily available N─H heterocycles and aryl fluorides, as well as two catalytic methods employing N─SiR and N─H heterocycles for synthesis of title atropisomers in seconds. Products of SAr are readily diversifiable, streamlining access to countless drug-like C─N atropisomers, including macrocycles, peptides, and analogs of achiral heterobiaryl pharmaceuticals. Supported by experimental and computational data, we discuss how steric repulsion is minimized in stereogenic axis-forming SAr processes.