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.
- asymmetric catalysis
- Brønsted acids
Xu, C., Muir, C. W., Leach, A. G., Kennedy, A. R., & Watson, A. J. B. (2018). Catalytic enantioselective synthesis of α-chiral azaheteroaryl ethylamines by asymmetric protonation. Angewandte Chemie International Edition. https://doi.org/10.1002/anie.201806956