Catalytic Enantioselective Synthesis of α-Chiral Azaheteroaryl Ethylamines by Asymmetric Protonation
Dr. Chao Xu
EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews, Fife, KY16 9ST UK
Search for more papers by this authorCalum W. Muir
Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL UK
Search for more papers by this authorDr. Andrew G. Leach
School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF UK
Search for more papers by this authorDr. Alan R. Kennedy
Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL UK
Search for more papers by this authorCorresponding Author
Dr. Allan J. B. Watson
EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews, Fife, KY16 9ST UK
Search for more papers by this authorDr. Chao Xu
EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews, Fife, KY16 9ST UK
Search for more papers by this authorCalum W. Muir
Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL UK
Search for more papers by this authorDr. Andrew G. Leach
School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF UK
Search for more papers by this authorDr. Alan R. Kennedy
Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL UK
Search for more papers by this authorCorresponding Author
Dr. Allan J. B. Watson
EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews, Fife, KY16 9ST UK
Search for more papers by this authorGraphical Abstract
The direct enantioselective synthesis of chiral azaheteroaryl ethylamines from vinyl-substituted N-heterocycles and anilines is reported. A chiral phosphoric acid catalyst promotes dearomatizing aza-Michael addition to generate a prochiral exocyclic aryl enamine, which undergoes asymmetric protonation upon rearomatization, giving the products in high selectivity.
Abstract
The direct enantioselective synthesis of chiral azaheteroaryl ethylamines from vinyl-substituted N-heterocycles and anilines is reported. A chiral phosphoric acid (CPA) catalyst promotes dearomatizing aza-Michael addition to give a prochiral exocyclic aryl enamine, which undergoes asymmetric protonation upon rearomatization. The reaction accommodates a broad range of N-heterocycles, nucleophiles, and substituents 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.
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