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

• Published in: Angewandte Chemie International Edition Vol. 61; no. 48; pp. e202206111 - n/a
• Main Authors: Ji, Pengwei, Liu, Xiaopei, Xu, Jiwei, Zhang, Xu, Guo, Jianhua, Chen, Wen‐Wen, Zhao, Baoguo
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 25.11.2022; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Acidity; Amines; Asymmetry; Biomimetic Catalysis; Carbonyl Catalysis; Carbonyl compounds; Carbonyls; Catalysis; Catalysts; Chemistry; Chemistry, Multidisciplinary; Chiral Pyridoxal; C−H Functionalization; Ketones; Organic chemistry; Organocatalysis; Physical Sciences; Science & Technology; Carbonyl Catalysis; ALCOHOLS; BIOMIMETIC TRANSAMINATION; Chiral Pyridoxal; ACTIVATION; COPPER REAGENTS; ALKYLATION; C-H Functionalization; DYNEMICIN; ALDEHYDES; Biomimetic Catalysis; Organocatalysis
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202206111

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. Despite the very low acidity of the inert α C−H bonds (pKa≈42.6), direct asymmetric α‐C(sp3)−H addition of N‐unprotected propargylic amines to trifluoromethyl ketones has been achieved by using a chiral pyridoxal as the carbonyl catalyst, producing a broad variety of chiral alkynyl β‐aminoalcohols in high yields with excellent stereoselectivities (up to 84 % yield, >20 : 1 dr, 99 % ee).