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.

中文翻译：

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由戊酸钾与醇助溶剂介导的 Pd 催化的 Miyaura 硼酸化反应


在有机溶剂中使用低溶解度的羧酸盐碱通常会在钯催化的芳基卤化物的 Miyaura 硼酸化反应的大规模应用中带来挑战，因为反应的动力学行为由规模依赖性传质效应引起。在此，我们报道了戊酸钾（KOPiv，一种在有机溶剂中溶解度更高的碱）和 2-PrOH 助溶剂的组合消除了与在规模上用不溶性羧酸盐碱进行 Miyaura 硼酸化相关的挑战。这种溶解度驱动的方案改善了反应混合物的物理性质和反应的动力学行为，并且与一锅硼酸化-Suzuki 望远镜序列兼容，以提供结构多样化的联芳基产物。对醇助溶剂的特性和用量进行了广泛的研究，以最大限度地提高 KOPiv 的溶解度，同时最大限度地减少不需要的还原和同偶联杂质。将改进的 Miyaura 硼酸化方案应用于十克级溴结构域和外末端 （BET） 抑制剂 BMS-986378 的合成序列，导致催化剂负载量减少 3 倍，替代昂贵的吸湿性碱 （CsOAc），并简化了产品分离程序。