转自：康龙化成

Aryl Acid-Alcohol Cross-Coupling C(sp3)–C(sp2) Bond Formation from Nontraditional Precursors

Eva Lin, Johnny Z. Wang, Edna Mao, Stephanie Tsang, Kurtis M. Carsch, Cesar N. Prieto Kullmer, Ryan E. McNamee, Jeffrey R. Long,* Chi “Chip” Le,* and David W.C. MacMillan*

1 Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, United States. 

2 Department of Discovery Chemistry, Merck & Co., Inc., Boston, Massachusetts 02115, United States.

3 Institute for Decarbonization Materials, Department of Chemistry, Department of Chemical and Biomolecular Engineering, and Department of Materials Science and Engineering, University of California, Berkeley, Berkeley, California 94720, United States; Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States;

—J. Am. Chem. Soc., 2025, doi: 10.1021/jacs.4c15827

Recommended by Depei Meng_MC4

KEY WORDS:photo chemistry, deoxygenation, decarbonylation, acid-alcohol cross-coupling, Ni catalysis (反应类型), C(sp3)–C(sp2) (成键类型), aryl acids, alcohols (原料), aryl alkyl (产物), NHC (其他)

ABSTRACT: Alcohols and aryl carboxylic acids are among the most commercially abundant, synthetically versatile, and operationally convenient building blocks in organic chemistry. Despite their widespread availability, the direct formation of C(sp3)–C(sp2) bonds from these functional groups remains a challenge. Recently, our group developed robust protocols to harness alcohols as alkyl radical precursors, but the activation of aryl acids remains relatively unexplored. Herein, we describe the merger of N-heterocyclic carbene (NHC)-mediated deoxygenation and nickel-mediated decarbonylation of aryl acids toward C(sp3)–C(sp2) bond formation. The utility of this method is demonstrated through the synthesis of a diverse range of aryl–alkyl cross-coupled products and the late-stage functionalization of complex molecules, including drugs, natural products, and biomolecules.

Cross-coupling of aryl acids and alkyl alcohols (a-c) and Optimized conditions and control reactions (Table 1.)Alkyl Alcohol and Alkyl Acid Scope (selected)Aryl Acid Scope (selected)

Proposed reaction mechanism

In conclusion, Eva Lin et al.present a formal cross-coupling of aryl carboxylic acids and alkyl alcohols to form C(sp3)–C(sp2) bonds, offering not only a complementary strategy to conventional cross-coupling methods but also an orthogonal alternative to traditional esterification protocols. By combining NHC-mediated deoxygenation with nickel-mediated decarbonylative bond formation, the authors have developed a nickel/photoredoxcatalyzed approachapplicable to a broad range of aliphatic alcohols and aryl carboxylic acids. A key factor in the success of this transformation was the incorporation of molecular sieves and other scavengers to efficiently remove CO, thereby minimizing undesired ketone formation and enhancing reaction robustness. Overall, this aryl acid−alcohol coupling provides a versatile platform for expanding accessible chemical space.

总地来说，Eva Lin等开发了一种芳基羧酸与烷基醇形式上交叉偶联形成C(sp3)–C(sp2)键的反应，其可作为传统交叉偶联的补充，或作为经典酯化反应的正交替代方案。这一适用于多种脂肪醇和芳基羧酸的镍/光氧化还原协同催化体系是通过将NHC介导脱氧与镍催化脱羰相结合得到实现的。其成功的关键在于引入分子筛等清除剂有效捕获一氧化碳，从而抑制酮类副产物的生成并提升反应稳定性。总体而言，这种芳基羧酸和醇的偶联反应为拓展新的化学提供了多功能平台。

（转自：康龙化成）