State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, 222 South Tianshui Road, Lanzhou, 730000, China.
J Am Chem Soc. 2021 Jan 13;143(1):513-523. doi: 10.1021/jacs.0c12462. Epub 2020 Dec 28.
Catalytic transformation of alcohols via metal-catalyzed cross-coupling reactions is very important, but it typically relies on a multistep procedure. We here report a dynamic kinetic cross-coupling approach for the direct functionalization of alcohols. The feasibility of this strategy is demonstrated by a nickel-catalyzed cross-electrophile arylation reaction of benzyl alcohols with (hetero)aryl electrophiles. The reaction proceeds with a broad substrate scope of both coupling partners. The electron-rich, electron-poor, and ortho-/meta-/para-substituted (hetero)aryl electrophiles (e.g., Ar-OTf, Ar-I, Ar-Br, and inert Ar-Cl) all coupled well. Most of the functionalities, including aldehyde, ketone, amide, ester, nitrile, sulfone, furan, thiophene, benzothiophene, pyridine, quinolone, Ar-SiMe, Ar-Bpin, and Ar-SnBu, were tolerated. The dynamic nature of this method enables the direct arylation of benzylic alcohol in the presence of various nucleophilic groups, including nonactivated primary/secondary/tertiary alcohols, phenols, and free indoles. It thus offers a robust alternative to existing methods for the precise construction of diarylmethanes. The synthetic utility of the method was demonstrated by a concise synthesis of biologically active molecules and by its application to peptide modification and conjugation. Preliminary mechanistic studies revealed that the reaction of in situ formed benzyl oxalates with nickel, possibly via a radical process, is an initial step in the reaction with aryl electrophiles.
通过金属催化交叉偶联反应实现醇的催化转化非常重要，但通常需要多步反应。我们在此报告了一种通过动态动力学交叉偶联方法直接对醇进行功能化的方法。该策略的可行性通过镍催化的苄醇与（杂）芳基亲电试剂的交叉电芳基化反应得到证明。该反应具有广泛的偶联伙伴底物范围。富电子、缺电子以及邻位/间位/对位取代的（杂）芳基亲电试剂（例如，Ar-OTf、Ar-I、Ar-Br 和惰性 Ar-Cl）都能很好地偶联。大多数官能团，包括醛、酮、酰胺、酯、腈、砜、呋喃、噻吩、苯并噻吩、吡啶、喹诺酮、Ar-SiMe、Ar-Bpin 和 Ar-SnBu，都能耐受。该方法的动态性质使得在存在各种亲核基团的情况下能够直接对苄基醇进行芳基化，包括非活化的伯/仲/叔醇、酚和游离吲哚。因此，它为精确构建二芳基甲烷提供了一种替代现有方法的可靠方法。该方法的合成实用性通过生物活性分子的简明合成以及在肽修饰和缀合中的应用得到了证明。初步的机理研究表明，原位形成的苄基草酸酯与镍的反应，可能通过自由基过程，是与芳基亲电试剂反应的初始步骤。
