The mechanistic study of the palladium-catalyzed meta-selective C–H bond activation with a nitrile-containing template was done by Yu, Wu, Houk and their co-workers. The DFT calculations suggest that the regioselectivity is achieved in the C–H activation step, which is the rate-determining step. It proceeds via a concerted metalation-deprotonation (CMD) pathway, which means that palladation and deprotonation of the C–H bond happen at the same time. Surprisingly, calculations reveal that the Pd–Ag heterodimeric transition state leads to meta-selectivity while the Pd monomeric transition state leads to ortho-selectivity.
The role of mono-N-protected amino acid is proposed as a dianionic ligand which participates in the CMD step assisting the deprotonation of the C–H bond in the rate- and regio-determining step.