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 (pKa ≈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 pKa 42.6 to pKa 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.