Synthesizing C8-Chiral Substituted 5,6,7,8-Tetrahydroquinolines via Palladium-Catalyzed Enantioselective Arylation of Unactivated C(sp ³ )–H Bonds

Herein, we present a relatively green method for constructing C8-chiral substituted 5,6,7,8-tetrahydroquinoline (THQs) derivatives via palladium-catalyzed enantioselective arylation of unactivated C(sp³)-H bonds, using (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid as the chiral ligand, ArBpin as a coupling reagent, O₂ as the oxidant, and H₂O/t-AmylOH as the solvent under mild conditions. The reaction exhibits broad functional group tolerance and affords the desired products with good to excellent enantioselectivities (up to 99:1 er) and yields (up to 76%), even on a gram scale. The H/D exchange experiments indicate that this reaction may operate as a dynamic kinetic resolution process. Furthermore, the derivatization of butyrylcholinesterase (BuChE) inhibitors and the application of the resulting compounds in asymmetric Michael addition demonstrate the synthetic utility of this reaction.