Direct asymmetric α-C–H functionalization of N-unprotected allylamine catalyzed by chiral pyridoxal

Abstract

Allylamine is a versatile scaffold in organic synthesis. Common methods for its asymmetric α-C–H functionalization require protection of the NH₂ group to prevent N-nucleophilic interference. Direct asymmetric α-C–H functionalization of N-unprotected allylamine (with low α-C–H acidity) remains challenging and underdeveloped to date. In this paper, we report a chiral pyridoxal catalyzed direct asymmetric addition reaction of N-unprotected allylamines to trifluoromethyl ketones, yielding synthetically and pharmaceutically valuable α-trifluoromethyl-β-amino alcohols with up to 87% yield and 99% enantiomeric excess (ee). Despite unsatisfactory diastereoselectivity for products, the isomers can be conveniently separated and further utilized. pK_a calculations indicate that the α-C–H acidity of activated allylamine increases by 10¹⁸-fold in the presence of chiral pyridoxal, verifying the powerful catalytic capability of chiral pyridoxal for asymmetric α-C–H functionalization of primary amines.