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

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2024-12-17 DOI:10.1021/acs.oprd.4c00419

Jacob M. Ganley, Senjie Ma, Cheng Peng, Eric M. Simmons

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Abstract

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.

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来源期刊

Organic Process Research & Development 化学-应用化学

CiteScore

6.90

自引率

14.70%

发文量

251

审稿时长

2 months

期刊介绍： The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools，process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.