Rare-Earth Metal-Catalyzed Asymmetric Addition/ Hydroamidination of Nitriles and Allylamines for the Concise Synthesis of Chiral Imidazolines

Chiral 2-substituted imidazolines are not only privileged scaffolds in many bioactive compounds, but they are also widely used as ligands and catalysts in asymmetric synthesis. However, the synthesis of enantioenriched 2-substituted imidazolines is heavily relied on in step-wise synthetic approaches to chiral diamines under relatively harsh conditions. Herein, we present a highly enantioselective addition/hydroamidination of nitriles to allylamines enabled by chiral bis(oxazolinato) rare-earth metal catalysts. This protocol provides a straightforward and atom-economical route to structurally diverse enantioenriched 2-susbtituted imidazolines (in 67 examples up to 99% yield, 99% ee) under mild conditions. The utility of the current method is demonstrated by the late -stage modification of complex and bioactive compounds as well as further transformations of products to other important compounds. The preliminary bioactivity study reveals that two of the new chiral imidazolines display a high inhibitory effect on lung cancer cells and hepatocellular carcinoma cells. Moreover, the possible reaction mechanism and origin of enantioselectivity were elucidated based on experimental studies and theoretical calculations.