Highly Enantioselective Arylation and Alkenylation of Pallada‐Endocyclic Enamines Under Mild Conditions: Reaction Development and Computational Mechanistic Studies

A highly enantioselective palladium‐catalyzed cross‐coupling reaction between 2‐(hetero)aryl‐1‐piperideines and C(sp 2 ) electrophiles is developed. The reaction is performed with a modified BI‐DIME‐type ligand under mild conditions, and following reduction ultimately provides unprotected cis ‐2,3‐di(hetero)arylpiperidines and 2‐(hetero)aryl‐3‐alkenylpiperidines in generally above 95% ees. Based on combined experimental and computational studies, it is proposed that the dominant pathway of this reaction likely does not involve an endocyclic 1‐azaallyl anion intermediate. Instead, the imine substrate coordinates to the Pd(II) first, followed by deprotonation to directly form a pallada‐endocyclic enamine. Due to the rigid ring conformation and the steric effect of the imine, it can only bind to the Pd(II) while the BI‐DIME changes from bidentate to monodentate via a ligand rotation. The imine binding and the ligand rotation are concerted in a way that leads to the favored enantiomer of the product. Formation of the other enantiomer requires the two processes to occur in a stepwise manner, which has a high energy barrier for the ligand rotation due to a steric interaction brought by the substituent between the phosphorus and the oxygen atoms of the ligand.