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

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

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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.
LanguageEnglish
JournalAngewandte Chemie International Edition
Early online date1 Aug 2018
DOIs
Publication statusE-pub ahead of print - 1 Aug 2018

Fingerprint

Ethylamines
Aniline Compounds
Protonation
Protons
Ions
Nucleophiles
Catalysts
Proton transfer
Enantioselectivity
Catalyst supports
Discrete Fourier transforms
phosphoric acid

Keywords

  • asymmetric catalysis
  • Brønsted acids
  • heterocycles
  • organocatalysis
  • stereochemistry

Cite this

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title = "Catalytic enantioselective synthesis of α-chiral azaheteroaryl ethylamines by asymmetric protonation",
abstract = "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.",
keywords = "asymmetric catalysis, Br{\o}nsted acids, heterocycles, organocatalysis, stereochemistry",
author = "Chao Xu and Muir, {Calum W.} and Leach, {Andrew G.} and Kennedy, {Alan R.} and Watson, {Allan J. B.}",
year = "2018",
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doi = "10.1002/anie.201806956",
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Catalytic enantioselective synthesis of α-chiral azaheteroaryl ethylamines by asymmetric protonation. / Xu, Chao; Muir, Calum W.; Leach, Andrew G.; Kennedy, Alan R.; Watson, Allan J. B.

In: Angewandte Chemie International Edition, 01.08.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Catalytic enantioselective synthesis of α-chiral azaheteroaryl ethylamines by asymmetric protonation

AU - Xu, Chao

AU - Muir, Calum W.

AU - Leach, Andrew G.

AU - Kennedy, Alan R.

AU - Watson, Allan J. B.

PY - 2018/8/1

Y1 - 2018/8/1

N2 - 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.

AB - 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.

KW - asymmetric catalysis

KW - Brønsted acids

KW - heterocycles

KW - organocatalysis

KW - stereochemistry

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U2 - 10.1002/anie.201806956

DO - 10.1002/anie.201806956

M3 - Article

JO - Angewandte Chemie International Edition

T2 - Angewandte Chemie International Edition

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