ProPhos: A Ligand for Promoting Nickel-Catalyzed Suzuki-Miyaura Coupling Inspired by Mechanistic Insights into Transmetalation

• Published in: Journal of the American Chemical Society 2024-03, Vol.146 (9), p.6360-6368
• Main Authors: Yang, Jin, Neary, Michelle C., Diao, Tianning
• Format: Article
• Language: English
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.4c00370

Nickel-catalyzed Suzuki–Miyaura coupling (Ni-SMC) offers the potential to reduce the cost of pharmaceutical process synthesis. However, its application has been restricted by challenges such as slow reaction rates, high catalyst loading, and a limited scope of heterocycles. Despite recent investigations, the mechanism of transmetalation in Ni-SMC, often viewed as the turnover-limiting step, remains insufficiently understood. We elucidate the “Ni-oxo” transmetalation pathway, applying PPh2Me as the ligand, and identify the formation of a nickel-oxo intermediate as the turnover-limiting step. Building on this insight, we develop a scaffolding ligand, ProPhos, featuring a pendant hydroxyl group connected to the phosphine via a linker. The design preorganizes both the nucleophile and the nickel catalyst, thereby facilitating transmetalation. This catalyst exhibits fast kinetics and robust activity across a wide range of heteroarenes, with a catalyst loading of 0.5–3 mol %. For arene substrates, the catalyst loading can be further reduced to 0.1 mol %.