Asymmetric copper-catalyzed hydrophosphinylation of ethynylazaarenes to access P-chiral 2-azaaryl-ethylphosphine oxides

Abstract

We report a cost-effective approach for the enantioselective hydrophosphinylation of ethynylazaarenes utilizing a chiral copper catalytic platform. This strategy efficiently converts racemic secondary phosphine oxides (SPOs) into P-chiral tertiary phosphine oxides (TPOs) bearing functionalized olefin substituents with azaarene moieties, achieving high yields and exceptional enantioselectivities. These adducts serve as crucial intermediates in the development of valuable chiral 1,5-hybrid P,N-ligands. The facile introduction of diverse additional carbon-centered chirality through the transformation of the olefin moiety effectively enhances the enantioselectivity of asymmetric metal catalysis compared to ligands exhibiting solely P-chirality. Mechanistic investigations reveal that the interaction between the chiral Cu(i) complex and azaarenes promotes the kinetic resolution of SPOs. The robustness of this method is further demonstrated by its ability to incorporate deuterium atoms into the olefins, highlighting its potential relevance in pharmaceutical applications.

Scheme 1. Outline of this work.

Scheme 2. Investigation on kinetic resolution.

Scheme 3. Synthetic utilities of the method and the obtained P-chiral secondary phosphine featuring central chirality.

Scheme 4. Mechanistic study.

Fig. 1. Free-energy profile for the Cu(i)-catalyzed hydrophosphorylation reaction between isopropyl(phenyl)phosphine oxide and 2-ethynylpyridine. The energies and bond distances are in kcal mol⁻¹ and Å.

Fig. 2. Non-covalent interaction (NCI) analysis of the two key transition states TS2-R and TS2-S (the blue, green, and red regions represent strong, weak, and repulsive interactions).