Pd-Catalyzed Miyaura Borylations Mediated by Potassium Pivalate with Alcohol Cosolvents

The use of carboxylate bases with low solubility in organic solvents often poses a challenge in the large-scale application of palladium-catalyzed Miyaura borylation of aryl halides due to variability in the kinetic behavior of the reaction stemming from scale-dependent mass-transfer effects. Herein, we report that a combination of potassium pivalate (KOPiv, a base with improved solubility in organic solvents) and 2-PrOH cosolvent obviates the challenges associated with performing Miyaura borylation with insoluble carboxylate bases on scale. This solubility-driven protocol improves both the physical properties of the reaction mixture and the kinetic behavior of the reaction and is compatible with a one-pot borylation-Suzuki telescope sequence to furnish structurally diverse biaryl products. Extensive studies into the identity and amount of the alcohol cosolvent were conducted to maximize the solubility of KOPiv while minimizing undesired reduction and homocoupling impurities. The improved protocol for Miyaura borylation was applied toward the synthetic sequence of bromodomain and extra-terminal (BET) inhibitor BMS-986378 on a decagram scale, leading to a 3-fold reduction of catalyst loading, replacement of an expensive, hygroscopic base (CsOAc), and a simplified procedure for product isolation.