Asymmetric α-C(sp3)−H allylic alkylation of primary alkylamines by synergistic Ir/ketone catalysis

• Published in: Nature communications Vol. 15; no. 1; pp. 939 - 8
• Main Authors: Li, Jianyu, Gong, Sheng, Gao, Shaolun, Chen, Jianfeng, Chen, Wen-Wen, Zhao, Baoguo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31.01.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 639/638/77/883; 639/638/77/889; Acidity; Alkylamines; Alkylation; Amination; Amines; Asymmetry; Bonding; Carbonates; Catalysis; Catalysts; Humanities and Social Sciences; Iridium; Ketones; Ligands; multidisciplinary; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-45131-3

Primary alkyl amines are highly reactive in N-nucleophilic reactions with electrophiles. However, their α-C−H bonds are unreactive towards electrophiles due to their extremely low acidity (p K a  ~57). Nonetheless, 1,8-diazafluoren-9-one (DFO) can activate primary alkyl amines by increasing the acidity of the α-amino C−H bonds by up to 10 44 times. This makes the α-amino C−H bonds acidic enough to be deprotonated under mild conditions. By combining DFO with an iridium catalyst, direct asymmetric α-C−H alkylation of NH 2 -unprotected primary alkyl amines with allylic carbonates has been achieved. This reaction produces a wide range of chiral homoallylic amines with high enantiopurities. The approach has successfully switched the reactivity between primary alkyl amines and allylic carbonates from intrinsic allylic amination to the α-C−H alkylation, enabling the construction of pharmaceutically significant chiral homoallylic amines from readily available primary alkyl amines in a single step. Primary alkyl amines are highly reactive in N-nucleophilic reactions with electrophiles but their α-C–H bonds are unreactive towards electrophiles due to their extremely low acidity. Combining 8-diazafluoren-9-one with an iridium catalyst, the authors demonstrate direct asymmetric α-C-H alkylation of unprotected primary alkyl amines with allylic carbonates.