Copper(II)-Catalyzed meta-Selective Direct Arylation of α-Aryl Carbonyl Compounds
Copper(II)-Catalyzed meta-Selective Direct Arylation of α-Aryl Carbonyl Compounds
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DOI：
10.1002/anie.201004704
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发表时间：
2011-01-01
影响因子：
16.6
通讯作者：
Gaunt, Matthew J.
中科院分区：
文献类型：
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作者：
Duong, Hung A.;Gilligan, Ruth E.;Gaunt, Matthew J.
取代芳烃控制着许多天然产物、药物和材料的性质。[1]因此，开发直接和选择性的芳香族官能化的新方法对合成化学家来说是一个长期的挑战。[2]一类特别重要的取代芳香族化合物是α-芳基羰基结构。这些分子代表了复杂分子合成的广泛有用的起始材料，基本结构框架存在于广泛的医学相关分子中。[3]尽管这些结构很重要，但令人惊讶的是，在没有其他基团的情况下，能够选择性地使芳烃核功能化的直接方法很少：芳香取代反应需要直接官能团来控制反应性和选择性；交叉偶联过程需要预先安装官能团；虽然芳烃和羰基之间的C±H键的酸性促进了丰富的烯醇化学，但它排除了定向邻锂反应的使用。[4]最近通过开发邻位选择性PdII催化的C±H键功能化反应，提出了一些潜在的解决方案。然而，由于限制性的几何限制，在这些转化中采用的环金属化策略不能用于促进这些分子的偏位或对位官能化。8]通过一种提供直接获得具有潜在有益治疗价值的异构体分子的方法学，将大大扩大通用α-芳基乙酸基序的合成用途(方案1A)。在这里，我们报道了一种铜催化的α-芳基羰基支架与二芳基碘盐的间位选择性芳基化反应，该反应是由一个遥远且多功能的Weinreb酰胺基团引导的(方案1B)。该方法为合成具有不同取代、苄基手性和四元中心的芳烃提供了一条新的途径。通过与迭代C±H键功能化方法的兼容性，进一步增强了它的潜力，这些方法将在合成高度官能化的芳烃方面具有广泛的用途。作为我们对间位选择性功能化过程研究的一部分，[8d]我们假设，在我们的CuII催化的间位芳基化反应中，羰基的位置起着关键作用。为了验证这一假说，我们推测α-芳基羰基也将提供类似的反应平台，因为羰基基序相对于芳烃核显示在类似的位置。值得注意的是，电子中性的α-芳基羰基基序的芳烃亲核性与富含电子的比香兰基有很大的不同。为了测试α-芳基羰基化合物是否可以在间位上官能化，我们制备了二乙胺1a，并在708℃的二氯乙烷中用二苯基碘三氟化铵和20mol%Cu(OTf)2处理它，条件与用于哌香胺芳基化的条件相同。[8D]反应24小时后，我们高兴地分离出了72%的偏位芳基化产物2a，重要的是，这是反应中观察到的唯一芳基化产物(表1，条目1)。这一结果不仅证实了羰基确实对该反应的选择性负责，而且还表明缺乏任何强电子或空间定向取代基的芳香族基团仍然与这种偏选过程相容。据我们所知，只有红外催化的1，3-二取代芳烃[8b，c]的硼化反应才能实现这种类型的转化。
Substituted arenes dominate the properties of many natural products, medicines, and materials.[1] Therefore, the development of new methods for direct and selective aromatic functionalization is a persistent challenge for synthetic chemists.[2] A particularly important class of substituted aromatic compounds is the α-aryl carbonyl structure. These molecules represent broadly useful starting materials for complex molecule synthesis, and the basic structural framework is present in a wide range of medicinally relevant molecules.[3] Despite the importance of these structures, surprisingly few direct methods are available to selectively functionalize the arene nucleus in the absence of other groups: aromatic substitution reactions require directing functionality to control reactivity and selectivity; cross coupling processes need pre-installed functional groups; and while the acidity of the CÀH bonds between the arene and carbonyl groups facilitates a wealth of enolate chemistry, it precludes the use of directed ortho-lithiation reactions.[4] A potential solution to some of these limitations has recently been presented through the development of orthoselective PdII-catalyzed CÀH bond functionalization reactions.[5, 6] The cyclometalation strategy employed in these transformations, however, cannot be used to facilitate metaor para-functionalization of these molecules due to restrictive geometric constraints.[7, 8] The synthetic utility of the generic α-aryl acetic acid motif would be significantly expanded by a methodology that provides direct access to isomeric molecules of potentially beneficial therapeutic value (Scheme 1A). Herein, we report a copper-catalyzed meta-selective arylation of the α-aryl carbonyl scaffold with diaryliodonium salts that is directed by a remote and versatile Weinreb amide group (Scheme 1B). This method provides a novel synthetic route to arenes displaying diverse substitution, benzylic chirality and quaternary centers. Its potential is further enhanced through its compatibility with iterative CÀH bond functionalization methods that will have broad utility in the synthesis of highly functionalized arenes. As part of our studies towards meta-selective functionalization processes,[8d] we postulated that the location of a carbonyl group plays a key role in determining the selectivity of our CuII-catalyzed meta-arylation of pivanilides. To test this hypothesis, we speculated that the α-aryl carbonyl would also provide a similar reactivity platform because the carbonyl motif is displayed in a similar position relative to the arene nucleus. Notably, the arene nucleophilicity of the electronically neutral α-aryl carbonyl motif is drastically different to the electron-rich pivanilide.To test whether α-aryl carbonyl compounds could be functionalized at the meta-position, we prepared diethylamide 1a and treated it with diphenyliodonium triflate and 20 mol% Cu (OTf) 2 in dichloroethane at 708C, conditions that are identical to those used for the arylation of pivanilides.[8d] After reaction for 24 h we were delighted to isolate a 72% yield of the meta-arylation product 2a, importantly this was the only arylation product observed in the reaction (Table 1, entry 1). Not only does this result confirm that the carbonyl group is indeed responsible for the selectivity of this reaction, it also demonstrates that aromatic groups that lack any strong electronically or sterically directing substituents are still compatible with this meta-selective process. To the best of our knowledge, only Ir-catalyzed borylation of 1, 3-disubstituted arenes [8b, c] is capable of achieving this type of transformation.