Evolution of a fourth generation catalyst for the amination and thioetherification of aryl halides.
Evolution of a fourth generation catalyst for the amination and thioetherification of aryl halides.
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DOI：
10.1021/ar800098p
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发表时间：
2008-11-18
影响因子：
18.3
通讯作者：
Hartwig, John F.
中科院分区：
文献类型：
--
作者：
Hartwig, John F.
在芳香胺中形成碳-氮键的合成方法是基本的，足以被认为是有机入门课程的一部分。芳胺很重要，因为它们是以吨为单位生产的活性药物成分和除草剂的常见前体或亚结构，也是小规模生产的导电聚合物和有机发光二极管层。多年来，这类化合物是通过经典的方法制备的，如硝化、还原和还原性烷基化、高温下铜介导的化学反应、添加到苯中间体中，或在特别缺乏电子的芳香族或杂芳香族卤化物上直接亲核取代。在过去的十年中，这些生成芳香胺的方法已经被钯催化的胺与芳基卤化物的偶联反应所取代。随着催化剂的不断发展，钯催化工艺的范围和效率逐渐提高，现已可用于合成毫克级和千克级的产品。本帐户描述了我们最新的“第四代”催化剂的概念基础和用途，用于胺和相关试剂与芳基卤化物的偶联。本帐户的介绍性部分描述了从第一代到当前系统的催化剂发展的进展以及第四代催化剂组件选择的动机。这一进展开始于催化剂含有钯和空间阻碍单齿芳烃膦最初用于偶联锡酰胺与卤代烃在C-N偶联的第一个工作。第二代催化剂是基于钯和芳香族双膦的结合而开发的。这些系统之后是第三代系统催化剂钯和一个位阻烷基单膦或n -杂环卡宾的组合。在过去的五年里，我们研究了第四代催化剂，它含有配体，结合了第二代体系的螯合性能和第三代体系的空间位阻和强电子给体。这种组合创造了一种催化剂，可以将芳酰氯、溴化物和碘化物与伯胺、N-H亚胺和腙偶联，产率高，范围广，官能团耐受性高，对单芳基化的选择性近乎完美，并且用于C-N偶联的钯含量最低。该催化剂是基于钯和Josiphos家族的位阻型配体，该配体具有二茂铁-1-乙基骨架，受阻二叔丁基磷酸基和受阻二环己基磷酸基。这种最新一代的催化剂不仅改善了伯胺和相关亲核试剂的偶联，而且极大地改善了硫醇与卤代芳烃形成C-S键的偶联。该催化剂体系将脂肪族和芳香族硫醇与氯芳烃偶联，具有比以前观察到的更大的范围、官能团耐受性和周转率。Josiphos配体的结构特征对催化剂活性的影响已经通过检查由缺乏最活跃的催化剂的一个或多个结构元素的配体生成的催化剂的反应性来揭示。这些修饰的配体缺乏二茂铁-1-乙基主链的相对立体化学性质、二烷基膦基的强电子赋能性、烷基膦基的空间要求或二茂铁基单元的稳定性。这组研究表明，这些结构特征中的每一个都有助于含有受阻双齿Josiphos配体的催化剂具有高反应活性和选择性。最后，最近一系列关于电子性质对还原消去速率影响的研究区分了M-N σ键和氮电子对的性质对还原消去速率的影响。这些研究表明，与金属结合的氮原子或碳原子相连的取代基对还原消除速率的影响是相似的。由于氨基配体含有电子对，而烷基配体没有，因此我们得出结论，主要的电子效应是通过σ-键传递的。换句话说，我们已经得出结论，金属-氮σ键上的电子效应支配着氮电子对上的电子效应。
Synthetic methods to form the carbon-nitrogen bonds in aromatic amines are fundamental enough to be considered part of introductory organic courses. Arylamines are important because they are common precursors to or substructures within active pharmaceutical ingredients and herbicides produced on ton scales, as well as conducting polymers and layers of organic light-emitting diodes produced on small scale. For many years, this class of compound was prepared from classical methods, such as nitration, reduction and reductive alkylation, copper-mediated chemistry at high temperatures, addition to benzyne intermediates, or direct nucleophilic substitution on particularly electron-poor aromatic or heteroaromatic halides. During the past decade, these methods to form aromatic amines have been largely supplanted by palladium-catalyzed coupling reactions of amines with aryl halides. The scope and efficiency of the palladium-catalyzed processes has gradually improved with successive generations of catalysts to the point of being useful for the synthesis of both milligrams and kilograms of product. This Account describes the conceptual basis and utility of our latest, “fourth-generation” catalyst for the coupling of amines and related reagents with aryl halides. The introductory sections of this account describe the progression of catalyst development from the first-generation to current systems and the motivation for selection of the components of the fourth-generation catalyst. This progression began with catalysts containing palladium and sterically hindered monodentate aromatic phosphines used initially for coupling of tin amides with haloarenes in the first work on C-N coupling. A second generation of catalysts was then developed based on the combination of palladium and aromatic bisphosphines. These systems were then followed by third-generation systems catalysts on the combination of palladium and a sterically hindered alkylmonophosphine or N-heterocyclic carbene. During the past five years, we have studied a fourth-generation catalyst for these reactions containing ligands that combine the chelating properties of the second-generation systems with the steric hindrance and strong electron donation of the third-generation systems. This combination has created a catalyst that couples aryl chlorides, bromides and iodides with primary amines, N-H imines, and hydrazones in high yield, with broad scope, high functional group tolerance, nearly perfect selectivity for monoarylation, and the lowest levels of palladium that have been used for C-N coupling. This catalyst is based on palladium and a sterically hindered version of the Josiphos family of ligands that possesses a ferrocenyl-1-ethylbackbone, a hindered di-tert-butylphosphino group, and a hindered dicyclohexylphosphino group. This latest generation of catalyst not only improves the coupling of primary amines and related nucleophiles, but it has dramatically improved the coupling of thiols with haloarenes to form C-S bonds. This catalyst system couples both aliphatic and aromatic thiols with chloroarenes with much greater scope, functional group tolerance, and turnover numbers than had been observed previously. The effects of structural features of the Josiphos ligand on catalyst activity have been revealed by examining the reactivity of catalysts generated from ligands lacking one or more of the structural elements of the most active catalyst. These modified ligands lack the relative stereochemistry of the ferrocenyl-1-ethyl backbone, the strong electron donation of the dialkylphosphino groups, the steric demands of the alkylphosphine groups, or the stability of the ferrocenyl unit. This set of studies showed that each one of these structural features contributed to the high reactivity and selectivity of the catalyst containing the hindered, bidentate Josiphos ligand. Finally, a series of studies on the effect of electronic properties on the rates of reductive elimination have recently distinguished between the effect of the properties of the M-N σ-bond and the nitrogen electron pair on the rate of reductive elimination. These studies have shown that the effect of substituents attached to the metal-bound nitrogen or carbon atoms on the rate of reductive elimination are similar. Because the amido ligands contain an electron pair, while the alkyl ligands do not, we have concluded that the major electronic effect is transmitted through the σ-bond. In other words, we have concluded that the electronic effect on the metal-nitrogen σ bond dominates an electronic effect on the nitrogen electron pair.
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影响因子：
15
作者：
Driver, MS;Hartwig, JF
通讯作者：
Hartwig, JF
影响因子：
5.2
作者：
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通讯作者：
Hartwig, John F.
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通讯作者：
Hartwig, JF
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作者：
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影响因子：
1.6
作者：
KOSUGI, M;KAMEYAMA, M;MIGITA, T
通讯作者：
MIGITA, T