The amination of aryl halides has become one of the most commonly practiced C-N bond-forming reactions in pharmaceutical and laboratory syntheses. The widespread use of strong or poorly soluble inorganic bases for amine activation nevertheless complicates the compatibility of this important reaction class with sensitive substrates as well as applications in flow and automated synthesis, to name a few. We report a palladium-catalyzed C-N coupling using Et3N as a weak, soluble base, which allows a broad substrate scope that includes bromo- and chloro(hetero)arenes, primary anilines, secondary amines, and amide type nucleophiles together with tolerance for a range of base-sensitive functional groups. Mechanistic data have established a unique pathway for these reactions in which water serves multiple beneficial roles. In particular, ionization of a neutral catalytic intermediate via halide displacement by H2O generates, after proton loss, a coordinatively unsaturated Pd-OH species that can bind amine substrate triggering intramolecular N-H heterolysis. This water-assisted pathway operates efficiently with even weak terminal bases, such as Et3N. The use of a simple, commercially available ligand, PAd3, is key to this water-assisted mechanism by promoting coordinative unsaturation in catalytic intermediates responsible for the heterolytic activation of strong element-hydrogen bonds, which enables broad compatibility of carbon-heteroatom cross-coupling reactions with sensitive substrates and functionality.

中文翻译：

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水辅助机制使用可溶性弱碱进行芳基胺化

芳基卤化物的胺化已成为药物和实验室合成中最常用的 CN 键形成反应之一。然而，广泛使用强或难溶性无机碱进行胺活化使这一重要反应类别与敏感底物的相容性以及在流动和自动合成中的应用变得复杂，仅举几例。我们报告了使用 Et3N 作为弱可溶性碱的钯催化 CN 偶联，其允许广泛的底物范围，包括溴-和氯（杂）芳烃、伯苯胺、仲胺和酰胺型亲核试剂以及对一系列的耐受性碱敏感的官能团。机械数据为这些反应建立了独特的途径，其中水发挥多种有益作用。特别是，中性催化中间体通过 H2O 的卤化物置换电离，在质子丢失后产生配位不饱和 Pd-OH 物质，该物质可以结合胺底物触发分子内 NH 杂解。这种水辅助途径即使在弱终端碱（如 Et3N）下也能有效运行。使用简单的市售配体 PAd3 是这种水辅助机制的关键，通过促进催化中间体的配位不饱和度，负责强元素 - 氢键的异裂活化，从而实现碳 - 杂原子交叉偶联的广泛相容性与敏感底物和功能的反应。一种配位不饱和 Pd-OH 物质，可以结合胺底物触发分子内 NH 杂解。这种水辅助途径即使在弱终端碱（如 Et3N）下也能有效运行。使用简单的市售配体 PAd3 是这种水辅助机制的关键，通过促进催化中间体的配位不饱和度，负责强元素 - 氢键的异裂活化，从而实现碳 - 杂原子交叉偶联的广泛相容性与敏感底物和功能的反应。一种配位不饱和 Pd-OH 物质，可以结合胺底物触发分子内 NH 杂解。这种水辅助途径即使在弱终端碱（如 Et3N）下也能有效运行。使用简单的市售配体 PAd3 是这种水辅助机制的关键，通过促进催化中间体的配位不饱和度，负责强元素 - 氢键的异裂活化，从而实现碳 - 杂原子交叉偶联的广泛相容性与敏感底物和功能的反应。