Pd-Catalyzed Miyaura\nBorylations Mediated by Potassium\nPivalate with Alcohol Cosolvents

The\nuse of carboxylate bases with low solubility in organic solvents\noften poses a challenge in the large-scale application of palladium-catalyzed\nMiyaura borylation of aryl halides due to variability in the kinetic\nbehavior of the reaction stemming from scale-dependent mass-transfer\neffects. Herein, we report that a combination of potassium pivalate\n(KOPiv, a base with improved solubility in organic solvents) and 2-PrOH\ncosolvent obviates the challenges associated with performing Miyaura\nborylation with insoluble carboxylate bases on scale. This solubility-driven\nprotocol improves both the physical properties of the reaction mixture\nand the kinetic behavior of the reaction and is compatible with a\none-pot borylation-Suzuki telescope sequence to furnish structurally\ndiverse biaryl products. Extensive studies into the identity and amount\nof the alcohol cosolvent were conducted to maximize the solubility\nof KOPiv while minimizing undesired reduction and homocoupling impurities.\nThe improved protocol for Miyaura borylation was applied toward the\nsynthetic sequence of bromodomain and extra-terminal (BET) inhibitor\nBMS-986378 on a decagram scale, leading to a 3-fold reduction of catalyst\nloading, replacement of an expensive, hygroscopic base (CsOAc), and\na simplified procedure for product isolation.