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

Abstract

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 PPh 2 Me 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 %.

Data-Driven Phosphine Ligand Design of Ni-Catalyzed Enantioselective Suzuki–Miyaura Cross-Coupling Reaction for the Synthesis of Biaryl Atropisomers: standing on the shoulder of Pd catalysis giants

“…1B) 18g, 19 . Most recently, Diao et al have designed a novel ProPhos ligand for racemic Ni-catalyzed Suzuki-Miyaura cross-coupling reactions, emphasizing the acceleration of the pivotal transmetalation step 20 . Despite these recent advancements, the enantioselective synthesis of biaryl atropisomers using Ni-SMC remains an unexplored area for organic chemists, to the best of our knowledge.…”

Asymmetric 2,3-Addition of Sulfinylamines with Arylboronic Acids Enabled by Nickel Catalysis

“…Direct β-carbon elimination of INT2A through transition state TS3B requires overcoming an energy barrier of 28.1 kcal mol –1 , which is challenging to achieve at a reaction temperature of 45 °C. After alkalization with base, the boron center of INT2A-base becomes more electron-rich, making the connected aryl group more prone to nucleophilic attack on the metal nickel center, reducing the activation energy of β-carbon elimination . The energy barrier required for intermediate INT2A-base to undergo β-carbon elimination via transition state TS3A is 11.7 kcal mol –1 , resulting in the formation of aryl nickel intermediate INT3A .…”