Aryl Amination Using Soluble Weak Base Enabled by a Water-Assisted Mechanism.
Aryl Amination Using Soluble Weak Base Enabled by a Water-Assisted Mechanism.
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DOI：
10.1021/jacs.0c09275
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发表时间：
2020-11-25
影响因子：
15
通讯作者：
Carrow BP
中科院分区：
文献类型：
--
作者：
Lau SH;Yu P;Chen L;Madsen-Duggan CB;Williams MJ;Carrow BP
芳基卤的胺化反应已成为药物和实验室合成中最常用的C-N键形成反应之一。然而，广泛使用强或难溶的无机碱用于胺活化使得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化合成中的应用复杂化，仅举几例。我们报告了一种钯催化的C-N偶联使用Et 3 N作为一种弱的，可溶性的碱，它允许一个广泛的底物范围，包括溴和氯（杂）芳烃，伯苯胺，仲胺，酰胺型亲核试剂连同宽容的范围内的碱敏感的官能团。机理数据已经为这些反应建立了一个独特的途径，其中水起着多种有益的作用。特别地，通过H2O的卤化物置换的中性催化中间体的电离在质子损失后产生配位不饱和的Pd-OH物质，其可以结合胺底物，触发分子内N-H异裂解。这种水辅助的途径即使在弱末端碱基如Et 3 N的情况下也有效地运作。使用简单的市售配体PAd 3是这种水辅助机制的关键，其通过促进催化中间体中的配位不饱和度来负责强元素-氢键的异相活化，这使得碳-杂原子交叉偶联反应与敏感底物和功能具有广泛的相容性。
Amination of aryl halides has become one of the most commonly practiced C–N bond-forming reactions in pharmaceutical and laboratory synthesis. 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.
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影响因子：
15
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