Regio- and Chemoselective C-H Chlorination/Bromination of Electron-Deficient Arenes by Weak Coordination and Study of Relative Directing-Group Abilities
Regio- and Chemoselective C-H Chlorination/Bromination of Electron-Deficient Arenes by Weak Coordination and Study of Relative Directing-Group Abilities
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DOI：
10.1002/anie.201300176
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发表时间：
2013-01-01
影响因子：
16.6
通讯作者：
Rao, Yu
中科院分区：
文献类型：
--
作者：
Sun, Xiuyun;Shan, Gang;Rao, Yu
芳香氯化物是一类用于药物和天然产物合成的重要化合物。[1]如今，大约 85% 的药品含有氯或使用氯制造。迄今为止，制备芳族氯化物最流行的策略仍然是经典的定向邻位锂化、亲电芳族取代和桑德迈尔反应。然而，这些方法通常受到一种或多种限制，包括区域选择性差、收率低、反应条件苛刻、反应时间长和反应程序繁琐。因此，由于其重要性，开发一种通用的、温和的、实用的芳香氯化物方法仍然是非常有必要的。在过去的十年中，用于合成芳香族化合物的过渡金属催化的 CĀH 活化方法 [2, 3] 已成为 CArĀC 和 CArĀ杂原子 [4] 键形成的有力工具。在这些重大进展中，Yu 和同事已经在各种 CĀH 官能化反应中充分确立了通过弱配位 [5] 与环上常见官能团进行直接 CĀH 裂解。例如，这种方法已成功用于用苯甲酸、苯乙酸和磺酰胺制备芳香族碘化物[5d，e]（方案1）。然而，应用这种策略来创建 CArĀCl 键仍然令人惊讶地不发达。尽管钯催化剂取得了令人印象深刻的进展 [6]，但定向 CĀH 氯化在这些方案的范围、效率和实用性方面仍然存在重大挑战。目前，CĀH氯化的反应范围通常仅限于具有杂芳基或给电子导向基团（DG）的底物，例如苯胺。相比之下，缺电子芳烃如苯甲酸酯、磺酰胺、苯甲酰胺和芳香酮尚未被报道为直接 CĀH 氯化的底物。通过弱配位方法将这些底物区域和化学选择性转化为相应的氯化产物可以说是一种高效、原子经济且理想的方法。在此，我们报告了钯 (II) 催化的各种具有挑战性的底物（包括苯甲酸盐、苯甲酰胺、磺酰胺、芳香酮和 2-苯基乙酸酯）的区域选择性和化学选择性氯化的第一个例子，及其在有机合成中的广泛用途。这些底物的邻位溴化产物也可以通过在相同的反应条件下用NBS简单替代NCS作为溴源来容易地制备。此外，对相关 DG 能力进行了初步研究，以帮助为使用这种化学设计合成策略提供一些指导。我们提出，在适当的酸性条件下，钯（II）催化剂可以通过与苯甲酸酯、苯甲酰胺、磺酰胺、苯甲酸或芳香酮的羰基氧原子的弱配位[5]，通过邻位金属化过程促进CĀH键断裂。因此，使用合适的氯源和共氧化剂，可以通过 PdIV [7] 的还原消除形成 CĀCl 键，得到相应的氯化芳烃。为了检验我们的假设，选择苯甲酸酯作为初始底物，原因如下：1) 苯甲酸酯相当缺乏电子，2) 酯官能团作为 CĀH 活化中可行的 DG 的用途很少报道，[4, 8] 3) 苯甲酸酯不仅容易获得，而且很容易转化为醇、酰胺和其他羰基化合物。
Aromatic chlorides are an important class of compounds utilized in drug and natural product syntheses.[1] Today, about 85% of all pharmaceuticals contain or are manufactured using chlorine. By far the most prevalent strategies for preparing aromatic chlorides are still the classic directed ortho lithiation, eletrophilic aromatic substitution, and Sandmeyer reaction. However, these methods usually suffer from one or more limitations including poor regioselectivity, low yield, harsh reaction conditions, long reaction time, and tedious reaction procedures. Therefore, the development of a general, mild, and practical approach to aromatic chlorides is still highly desired because of their significance. Over the past decade, transition-metal-catalyzed CĀH activation methods for the synthesis of aromatic compounds [2, 3] has emerged as a powerful tool for CArĀC and CArĀheteroatom [4] bond formation. Among these significant advances direct CĀH cleavage, through weak coordination [5] to commonly occurring functional groups on the ring has been well established by Yu and co-workers for various CĀH functionalization reactions. For instance, this approach has been successfully employed to make aromatic iodides with benzoic acids, phenyl acetic acids, and sulfonamides [5d, e](Scheme 1). However, application of this strategy to create a CArĀCl bond is still surprisingly underdeveloped. Although impressive progress [6] had been made with palladium catalysts, important challenges remain for directed CĀH chlorination in terms of scope, efficiency, and practicality of these protocols. Currently the reaction scope of CĀH chlorination is generally limited to substrates having heteroaromatics or electron-donating directing groups (DGs), such as anilide. In contrast, electron-poor arenes such as benzoic esters, sulfonamides, benzamides, and aromatic ketones have not yet been reported as substrates for directed CĀH chlorination. Regioand chemoslective transformation of these substrates into the corresponding chlorinated products through a weak-coordination approach is arguably a highly efficient, atom-economic, and desirable method. Herein, we report the first example of a palladium (II)-catalyzed regio-and chemoselective chlorination of a variety of challenging substrates including benzoates, benzamides, sulfonamides, aromatic ketones, and 2-phenylacetates, and its broad utility in organic synthesis. The ortho-bromination products of those substrates can also be readily prepared by the simple replacement of NCS with NBS as the bromine source under the same reaction conditions. Furthermore, a preliminary study of relative DG abilities was conducted to help provide some guidance for designing synthesis strategies using this chemistry. We proposed that under proper acidic conditions, palladium (II) catalysts can promote CĀH bond cleavage by an orthometalation process through weak coordination [5] with the carbonyl oxygen atom of a benzoate, benzamide, sulfonamide, benzoic acid, or aromatic ketone. Consequently, with suitable chlorine sources and co-oxidants, a CĀCl bond formation is possible through the reductive elimination from PdIV [7] to afford the corresponding chlorinated arenes. To test our hypothesis, benzoates were selected as the initial substrates for the following reasons: 1) benzoates are rather electron poor, 2) the utility of an ester functionality as a feasible DG in CĀH activation has been rarely reported,[4, 8] 3) benzoic esters are not only readily available but also easily converted into alcohols, amides, and other carbonyl com-