(ProPhos)Ni-Catalyzed Suzuki–Miyaura Coupling of (Hetero)aryl Pseudohalides under Homogeneous Conditions

Abstract

Suzuki–Miyaura coupling (SMC) of phenol-derived pseudohalides represents a compelling methodology for biaryl synthesis, given the ubiquity of phenolic motifs in active pharmaceutical ingredients (APIs) and the orthogonal reactivity of pseudohalides toward other common functional groups. Aryl sulfamates generally exhibit low reactivity with palladium catalysts due to slow oxidative addition. In contrast, nickel catalysts show significantly higher reactivity toward aryl sulfamates, but their application has been hampered by limited process compatibility in existing nickel-catalyzed protocols. Herein, we report a robust (ProPhos)Ni-SMC of aryl and heteroaryl pseudohalides, including sulfamates, triflates, and tosylates. Employing DIPEA as the base and an environmentally friendly i-PrOH/H2O solvent mixture enables a monophasic, homogeneous condition well-suited for scale-up. This method exhibits a broad scope across pharmaceutically relevant heterocycles and demonstrates notable tolerance for heteroatoms proximal to the reactive C–O bond. By leveraging palladium’s orthogonal reactivity toward sulfamates, a “mixed aryl (pseudo)halide” was telescoped in a Pd-SMC/Ni-SMC sequence to form multi-aryls while minimizing purification steps and waste generation.