Catalytic Enantioselective Synthesis of α‐Chiral Azaheteroaryl Ethylamines by Asymmetric Protonation

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 protona...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2018-08, Vol.57 (35), p.11374-11377
Main Authors: Xu, Chao, Muir, Calum W., Leach, Andrew G., Kennedy, Alan R., Watson, Allan J. B.
Format: Article
Language:English
Subjects:
Aromatic compounds
asymmetric catalysis
Asymmetry
Brønsted acids
Catalysis
Catalysts
Chemical synthesis
Enantiomers
heterocycles
Nucleophiles
organocatalysis
Phosphoric acid
Protonation
stereochemistry
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Summary: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. 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.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201806956