Direct Asymmetric α-C-H Addition of N-unprotected Propargylic Amines to Trifluoromethyl Ketones by Carbonyl Catalysis

Abstract

Direct asymmetric functionalization of the inert α C-H bonds of N-unprotected propargylic amines is a big challenge in organic chemistry, due to the low acidity (pK_a ≈42.6) of the α C-H bonds and interruption of the nucleophilic NH₂ group. By using a chiral pyridoxal as carbonyl catalyst, we have successfully realized direct asymmetric α-C-H addition of N-unprotected propargylic amines to trifluoromethyl ketones, producing a broad range of chiral alkynyl β-aminoalcohols in 54-84 % yields with excellent stereoselectivities (up to 20 : 1 dr and 99 % ee). The α C-H bonds of propargylic amines are greatly activated by the pyridoxal catalyst via the formation of an imine intermediate, resulting in the increase of acidity by up to 10²² times (from pK_a 42.6 to pK_a 20.1), which become acidic enough to be deprotonated under mild conditions for the asymmetric addition. This work presented an impressive example for asymmetric functionalization of inert C-H bonds enabled by an organocatalyst.

Keywords: Biomimetic Catalysis; Carbonyl Catalysis; Chiral Pyridoxal; C−H Functionalization; Organocatalysis.