（来源：康龙化成）

转自：康龙化成

Unleashing the Power of Potassium 2‑Ethylhexanoate as a Mild and Soluble Base for Pd-Catalyzed C−N Cross-Coupling

William D. Lambert, Stephanie Felten, Nicholas Hadler, N. Ian Rinehart, Rafal Swiatowiec, Gregory E. Storer, Jeremy Henle, Mark A. Servos, Cassie Yang, Anna V. Bay, Pascal N. Eyimegwu, Shashank Shekhar,* and John Hartwig*

Process Research and Development, AbbVie Inc., North Chicago, Illinois 60064, United States; Department of Chemistry, University of California Berkeley, Berkeley, California 94720, United States.

—J. Am. Chem. Soc., 2025, DOI: https://doi.org/10.1021/jacs.5c07790

Recommended by Yuting Gao_MC3

KEY WORDS: C−N Coupling, Pd catalysis (反应类型),Csp2-N (成键类型), aryl halides,base-sensitive Amine(原料), aryl amine (产物),Phosphorinane Ligand L147,K-2-EH (其他)

ABSTRACT:Prof. John Hartwig et al reported the discovery of a combination of a phosphorinane ligand (L147) and a soluble carboxylate base, potassium 2-ethylhexanoate (K-2-EH), which leads to the coupling of a wide range of base-sensitive coupling partners. To explore the enhanced substrate scope of the reaction with this base and catalyst, they evaluated the scope using representative reactants selected from published partners, using chemical descriptors and clustering to ensure their chemical diversity. These results show that the combination of this phosphorinane ligand and K-2-EH can couple primary aliphatic amines, amides, sulfonamides, and heteroaromatic nucleophiles as well as acidic secondary nitrogen nucleophiles, such as arylamines, heteroarylamines, and amides, with a range of electrophiles. A side-by-side comparison to form selected coupling products in the presence of a range of previously reported bases and ligands showed that the products that decomposed under standard reaction conditions were stable with K-2-EH as a base.

Selected examples of bases used in Pd-catalyzed C−N coupling

Current work

Substrate scope

Evaluation of reaction generality by chemical space clustering and high-throughput experimentation

Prof. John Hartwig and his co-workersidentified K-2-EH as a mild, homogeneous, and inexpensive base for Pd-catalyzed C−N cross-coupling. K-2- EH (pKaH ∼ 12 in DMSO) is the mildest soluble base reported for this reaction. While Pd complexes of several phosphine ligands catalyze the reactions of acidic amines (pKaH < 8), the biarylphosphorinane ligand L147reported here led to the most active catalyst for the coupling of more basic amines (pKaH> 8). A chemically diverse set of reactants derived from the literature was used to evaluate the scope of couplings using L147 and K-2-EH, and we found that these conditions enable C−N couplings of a broad substrate scope with remarkable functional group tolerance.