Catalytic Enantioselective Synthesis of α‐Chiral Azaheteroaryl Ethylamines by Asymmetric Protonation |
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| Authors: | Dr Chao Xu Calum W Muir Dr Andrew G Leach Dr Alan R Kennedy Dr Allan J B Watson |
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| Institution: | 1. EaStCHEM, School of Chemistry, University of St Andrews, St Andrews, Fife, UK;2. Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow, UK;3. School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK |
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| 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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| Keywords: | asymmetric catalysis Brø nsted acids heterocycles organocatalysis stereochemistry |
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