Highly chemoselective ligands for Suzuki-Miyaura cross-coupling reaction based on virtual ligand-assisted screening

Ligand screening is a crucial step in the development of transition metal catalysis, as it involves identifying the optimal ligand for a particular reaction from a large pool of candidate molecules. Conventionally, this process is performed through an experimental trial-and-error, which can be time-consuming and resource-intensive in many cases. One of the ideal strategies for streamlining this process is a transition state theory (TST)-based approach, which aims to design optimal catalysts that results in the best energy profile for the desired reaction. However, the implementation of TST-based ligand screening remains challenging mainly due to the large number of potential ligands that need to be individually evaluated through quantum chemical calculations. In this study, we experimentally demonstrated a practical TST-based ligand screening in accordance with our virtual ligand-assisted (VLA) screening strategy. As a case study, the electronic anc steric features of phosphine ligands that maximize chemoselectivity in the Suzuki-Miyaura cross-coupling (SMC) reaction of p-chlorophenyl triflate were determined through quantum chemical calculations using virtual ligands, and several phosphine ligands were suggested to exhibit high chemoselectivity. Based on this suggestion, we successfully found that tri(1-adamantyl)phosphine and tri(neopentyl)phosphine show high to excellent selectivity for the C-Cl bond activation. This case study suggests that the VLA screening strategy could be a useful tool for ligand screening.