摘要：Chemical Process Development, BristolMyers Squibb, New Brunswick, New Jersey 08901, United States; [b] ChemicalProcess Development

转自：康龙化成

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

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

[a] Chemical Process Development, BristolMyers Squibb, New Brunswick, New Jersey 08901, United States; [b] ChemicalProcess Development, Bristol Myers Squibb, Summit, New Jersey 07901, UnitedStates

—Org.Process Res. Dev. 2024, doi: 10.1021/acs.oprd.4c00419

Recommended by Depei Meng_MC4

KEYWORDS: Miyaura borylation (反应类型), Pdcatalysis (反应类型),C(sp2)–B (成键类型), aryl halide (原料),boronic ester (产物), (XPhos)Pd(crotyl)Cl(催化剂), KOPiv (试剂)

ABSTRACT: Herein,we report that a combination of potassium pivalate (KOPiv, abase with improved solubility in organic solvents) and 2-PrOH cosolventobviates the challenges associated with performing Miyaura borylation with insoluble carboxylate bases on scale. This solubility-drivenprotocol improves both the physical properties of the reaction mixture and thekinetic behavior of the reaction and is compatible with a one-pot borylation-Suzukitelescope sequence to furnish structurally diverse biaryl products. Extensive studies into the identity and amount of the alcohol cosolvent wereconducted to maximize the solubility of KOPiv while minimizing undesired reduction and homocoupling impurities. The improved protocol for Miyaura borylation was applied toward the syntheticsequence of bromodomain andextra-terminal (BET) inhibitor BMS-986378 on a decagram scale, leading to a3-fold reduction of catalyst loading, replacement of an expensive, hygroscopicbase (CsOAc),and a simplified procedure for product isolation.

Frequencyof Bases Utilized in Large-scale(>100g) Miyaura Borylations

(a) Relative Reaction Rates ofPotassium Carboxylate Bases (b) Visual Comparison and KF Measurements ofDifferent Commercial Lots of Potassium 2-ethylhexanoate (KEHA)

Effectsof Alcohol Cosolvent on the Gelling of KOPiv and B2(pin)2

Demonstrationof High-throughput Reaction Screening Evaluating Pd Precatalyst, Solvent,and Cosolventfora Range of Borylation Substrates (8a−11a)from the BMS Portfolio

Optimized Miyaura Borylation Reaction Conditions from HTE Translated to a Preparative Scale Borylation/SuzukiTelescoped Reaction Sequence

Inconclusion JacobM. Ganley etal. havediscovered that Miyaura borylations thatutilize KOPiv as alipophilic, sterically encumbered carboxylate base in combination with alcoholco-solvent systemsprovide benefits to the reaction rates, mass-transfer, reaction physicalproperties, and robustness compared with traditional systems comprised ofinsoluble carboxylate bases in organic solvents. These reactions weresubsequently telescoped into Suzuki coupling to form biaryl compounds in good to excellent isolated yields. The authors anticipate thatthese findings will not only impact manufacturing applications of the Miyaura borylation but also translate to other reactions using insoluble carboxylatebases in organic solvents.

BMS公司的JacobM. Ganley等报道了一种使用特戊酸钾作为碱，醇作为共溶剂的Miyaura硼化反应。相比传统的不溶性羧酸盐作碱的条件，其反应速率、传质、反应物理性质和鲁棒性均有提升。其次，该方法也可同Suzuki偶联串联，以良好至优异的分离产率形成双芳基化合物。作者认为，这些发现不仅会进一步促进Miyaura硼化的应用，也为目前使用不溶性羧酸盐作为碱的其他反应提供了新的选择。

来源：新浪财经