Catalytic enantioselective synthesis of α-chiral azaheteroaryl ethylamines by asymmetric protonation

The direct enantioselective synthesis of chiral azaheteroarylethylamines from vinyl aza-heterocycles and anilines is reported. A chiral phosphoric acid (CPA) catalyst promotes dearomatizing aza-Michael addition giving a prochiral exocyclic aryl enamine, which undergoes asymmetric protonation upon rearomatization. The reaction accommodates a broad range of azaheterocycle, nucleophile, and substituent on the prochiral centre, generating the products in high enantioselectivity. DFT studies support a facile nucleophilic addition based on catalyst-induced LUMO lowering, with site-selective, rate-limiting, intramolecular asymmetric proton transfer from the ion-paired prochiral intermediate