Copper-Catalyzed Benzylic C-H Cross-Coupling Enabled by Redox Buffers: Expanding Synthetic Access to Three-Dimensional Chemical Space.
Copper-Catalyzed Benzylic C-H Cross-Coupling Enabled by Redox Buffers: Expanding Synthetic Access to Three-Dimensional Chemical Space.
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DOI：
10.1021/acs.accounts.3c00580
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发表时间：
2023-12
影响因子：
18.3
通讯作者：
Si-Jie Chen;S. Krska;S. Stahl
中科院分区：
文献类型：
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作者：
Si-Jie Chen;S. Krska;S. Stahl
交叉偶联法是药物化学中应用最广泛的合成方法。现有的反应主要是通过酰胺偶联和芳基化反应等方法，这些方法与sp2杂化碳原子形成键，并有助于形成“扁平”分子。证据表明，三维结构往往具有改善的物理化学性质的药物应用，有助于不断增长的需求与sp3杂交反应伴侣的交叉偶联方法。连接到sp3碳原子的取代基本质上以三维显示。这些考虑已经导致努力建立与sp3交叉偶联配偶体的反应，所述sp3交叉偶联配偶体包括烷基卤化物、胺、醇和羧酸。由于C（sp3）-H键比这些更常规的偶联伙伴更丰富，我们一直在追求C（sp3）-H交叉偶联反应，实现位点选择性，合成效用，和范围竞争与常规的coupling reactions.In这个帐户，我们概述了铜催化的苄基C（sp3）-H键与各种亲核伙伴的氧化交叉偶联反应。这些反应通常使用N-氟苯磺酰亚胺（NFSI）作为氧化剂。通过使用“氧化还原缓冲剂”，反应性的范围大大提高，该“氧化还原缓冲剂”确保Cu催化剂以适当的氧化还原状态可用于促进反应。催化Cu/NFSI氧化偶联反应的早期先例，包括C-H氰化和芳基化，不需要氧化还原缓冲液，但与其他亲核试剂，如醇和唑类的反应，在类似条件下，效果要差得多。机理研究表明，一些亲核试剂，如氰化物和芳基硼酸，促进原位还原CuII到CuI，有助于成功的催化营业额。观察到与亲核试剂，如醇，不以相同的方式促进CuII还原反应性差。这一见解导致确定牺牲还原剂，称为“氧化还原缓冲液”，支持控制生成的CuI在反应过程中，并使成功的苄基C（SP3）-H交叉偶联与不同的亲核试剂。成功的反应包括那些特征在于（杂）苄基C-H底物与偶联配偶体（醇、唑）的直接偶联和顺序C（sp3）-H官能化/偶联反应的反应。后一种方法的特点是生成一种合成的关键物质，该关键物质可以与一系列广泛的亲核试剂进行后续反应。例如，卤化/取代级联提供苄基胺，（硫）醚，和杂二芳基甲烷衍生物，和异氰酸酯化/胺加成序列产生不同的苄基脲。总的来说，这些铜催化的（杂）苄基C（sp3）-H交叉偶联反应迅速获得不同的分子。它们的物理化学和拓扑性质的分析突出了“药物相似性”和增强的三维这些产品相对于现有的生物活性分子。这种考虑，加上高苄基C-H位点选择性和氧化还原缓冲策略所实现的广泛反应性，使得这些C（sp3）-H交叉偶联方法非常适合在高通量实验平台中实施，以探索药物发现和相关应用的新化学空间。
ConspectusCross-coupling methods are the most widely used synthetic methods in medicinal chemistry. Existing reactions are dominated by methods such as amide coupling and arylation reactions that form bonds to sp2-hybridized carbon atoms and contribute to the formation of "flat" molecules. Evidence that three-dimensional structures often have improved physicochemical properties for pharmaceutical applications has contributed to growing demand for cross-coupling methods with sp3-hybridized reaction partners. Substituents attached to sp3 carbon atoms are intrinsically displayed in three dimensions. These considerations have led to efforts to establish reactions with sp3 cross-coupling partners, including alkyl halides, amines, alcohols, and carboxylic acids. As C(sp3)-H bonds are much more abundant that these more conventional coupling partners, we have been pursuing C(sp3)-H cross-coupling reactions that achieve site-selectivity, synthetic utility, and scope competitive with conventional coupling reactions.In this Account, we outline Cu-catalyzed oxidative cross-coupling reactions of benzylic C(sp3)-H bonds with diverse nucleophilic partners. These reactions commonly use N-fluorobenzenesulfonimide (NFSI) as the oxidant. The scope of reactivity is greatly improved by using a "redox buffer" that ensures that the Cu catalyst is available in the proper redox state to promote the reaction. Early precedents of catalytic Cu/NFSI oxidative coupling reactions, including C-H cyanation and arylation, did not require a redox buffer, but reactions with other nucleophiles, such as alcohols and azoles, were much less effective under similar conditions. Mechanistic studies show that some nucleophiles, such as cyanide and arylboronic acids, promote in situ reduction of CuII to CuI, contributing to successful catalytic turnover. Poor reactivity was observed with nucleophiles, such as alcohols, that do not promote CuII reduction in the same manner. This insight led to the identification of sacrificial reductants, termed "redox buffers", that support controlled generation of CuI during the reactions and enable successful benzylic C(sp3)-H cross-coupling with diverse nucleophiles. Successful reactions include those that feature direct coupling of (hetero)benzylic C-H substrates with coupling partners (alcohols, azoles) and sequential C(sp3)-H functionalization/coupling reactions. The latter methods feature generation of a synthetic linchpin that can undergo subsequent reaction with a broad array of nucleophiles. For example, halogenation/substitution cascades afford benzylic amines, (thio)ethers, and heterodiarylmethane derivatives, and an isocyanation/amine-addition sequence generates diverse benzylic ureas.Collectively, these Cu-catalyzed (hetero)benzylic C(sp3)-H cross-coupling reactions rapidly access diverse molecules. Analysis of their physicochemical and topological properties highlights the "drug-likeness" and enhanced three-dimensionality of these products relative to existing bioactive molecules. This consideration, together with the high benzylic C-H site-selectivity and the broad scope of reactivity enabled by the redox buffering strategy, makes these C(sp3)-H cross-coupling methods ideally suited for implementation in high-throughput experimentation platforms to explore novel chemical space for drug discovery and related applications.