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

Xu, Chao and Muir, Calum W. and Leach, Andrew G. and Kennedy, Alan R. and Watson, Allan J. B. (2018) Catalytic enantioselective synthesis of α-chiral azaheteroaryl ethylamines by asymmetric protonation. Angewandte Chemie International Edition. ISSN 1521-3773 (https://doi.org/10.1002/anie.201806956)

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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.

ORCID iDs

Xu, Chao, Muir, Calum W. ORCID logoORCID: https://orcid.org/0000-0003-1032-8248, Leach, Andrew G., Kennedy, Alan R. ORCID logoORCID: https://orcid.org/0000-0003-3652-6015 and Watson, Allan J. B.;
CORE (COnnecting REpositories)