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

Chao Xu, Calum Muir, Andrew Leach, Alan Kennedy, Allan J. B. Watson

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19 Citations (Scopus)
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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.
Original languageEnglish
JournalAngewandte Chemie International Edition
VolumeIn press
Early online date1 Aug 2018
DOIs
Publication statusE-pub ahead of print - 1 Aug 2018

Keywords

  • Asymmetric catalysis
  • Brønsted acid
  • DFT
  • Heterocycles
  • Stereochemistry

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