Advancing Base-Metal Catalysis: Developing Nickel Catalysis for the Direct Telescope of Miyaura Borylation and Suzuki–Miyaura Cross-Coupling Reactions

The development of an efficient and general telescoped nickel-catalyzed Suzuki–Miyaura coupling (SMC) process from a nickel-catalyzed borylation reaction to form Csp2–Csp2 bonds without isolation of the intermediate aryl boronate has been a long-standing interest for process chemists. Most scalable borylation/SMC sequences currently use palladium catalysts in subsequent catalytic steps, yet the ability to utilize nickel has the potential to greatly improve efficiency and decrease cost while also improving sustainability. This work introduces nickel-catalyzed SMC methodology that operates under homogeneous biphasic conditions to minimize inhibition from reaction byproducts of borylation and benefits from the addition of methanol as a cosolvent. These findings enabled the development of a one-pot, two-reaction method, which is demonstrated with a variety of complex heterocyclic coupling partners as both the nucleophilic aryl boronic acid and the electrophilic aryl halide, including an array of bioactive molecules that are representative of pharmaceutical synthetic targets. A comparison of this nickel-catalyzed telescoped process to the analogous palladium-catalyzed telescoped process is included to guide future use cases. A decagram scale telescoped process utilizing pharmaceutically relevant aryl halides demonstrates its scalability.