Catalytic asymmetric α C(sp3)-H addition of benzylamines to aldehydes

Carbonyl catalysis is mainly limited to strongly activated primary amines. Now, a chiral bifunctional pyridoxal organocatalyst is developed that enables the activation of the inert alpha C(sp(3))-H bond of NH2-unprotected benzylamines affording chiral beta-aminoalcohols with high diastereo- and enantioselectivities. Functionalization of inert C-H bonds has received tremendous attention due to the inherent atom economy and efficiency of the transformations of the starting materials. As compared to transition-metal-catalysed C-H activation, organocatalysis is much less commonly applied for direct functionalization of inert C-H bonds. The alpha C(sp(3))-H bonds of NH2-unprotected benzylamines usually are inert in most reactions due to the extremely low Bronsted acidity. Here we utilize a chiral pyridoxal bearing a quaramide side chain as a bifunctional carbonyl catalyst to activate the alpha C(sp(3))-H bond of NH2-unprotected benzylamines, making it acidic enough to be deprotonated under mild conditions. Based on the carbonyl catalysis strategy, we develop a direct asymmetric alpha C-H addition of benzylamines to aldehydes, providing one of the most straightforward methods for the synthesis of chiral beta-aminoalcohols with excellent diastereo- and enantioselectivities.

Automated summary

In this study, a chiral bifunctional catalyst was developed to activate inert C-H bonds and synthesize chiral beta-aminoalcohols. Organic catalysis is less commonly used compared to transition-metal catalysis for this type of functionalization. This research provides a straightforward and efficient method with excellent diastereo- and enantioselectivities.