Oxidative Heck Arylation for the Stereoselective Synthesis of Tetrasubstituted Olefins Using Nitroxides as Oxidants
Oxidative Heck Arylation for the Stereoselective Synthesis of Tetrasubstituted Olefins Using Nitroxides as Oxidants
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DOI：
10.1002/anie.201108211
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发表时间：
2012-01-01
影响因子：
16.6
通讯作者：
Studer, Armido
中科院分区：
文献类型：
--
作者：
He, Zhiheng;Kirchberg, Sylvia;Studer, Armido
Heck芳基化反应是形成C2C键的重要方法，在有机合成中有着广泛的应用。[1]各种卤化物或拟卤化物在Pd催化下容易与烯烃交叉偶联。相比之下，使用芳基硼酸与外部氧化剂和Pd催化剂组合的氧化Heck反应的研究较少。[2，3]氧化Heck型偶联受烯烃取代基的强烈影响，因此缺乏一般性。特别地，使用该方法合成高度取代的烯烃尚未建立。高取代烯烃的区域和立体选择性合成是非常具有挑战性的。[4]本文描述了温和的和高度立体选择性的连续氧化钯催化的C1 H4芳基化反应合成烷基三芳基乙烯。我们的方法是基于这样一个事实，即在烯烃的取代基强烈影响的区域和立体选择性的氧化赫克耦合。[2]目标是开发从丙烯酸甲酯（1）开始的迭代的三重Heck序列[Eq.①]。酯取代基很容易被还原成羟甲基，以调节中间体烯烃的反应性。此外，烯丙基OH基团可以进一步化学修饰以改变第四取代基。丙烯酸甲酯（1）是一种公认的用于与芳基硼酸进行Heck偶联的烯烃。各种氧化剂已被用于进行该反应。[2]经过一些实验，我们发现2，2，6，6-四甲基哌啶-N-氧自由基（克里思）[5，6]是该反应的合适氧化剂。当在室温下搅拌1与PhB（OH）2、KF、[Pd（acac）2]（5摩尔%）和克里思在丙酸中的溶液时，以96%产率获得具有优异的非对映选择性（仅E）的产物2a [Eq.②]。没有观察到双苯基化，这是当Pd（0Ac）2用作催化剂时的问题。[7]在这些温和的条件下，带有富电子和贫电子取代基的其他芳基硼酸以完全的非对映选择性反应（仅E，2b-d）。在室温下，在丙酸中使2与芳基硼酸、KF、4-HO-TEMPO和Pd（OAM）2反应，获得了引入第二个芳基的最佳产率（表1）。[8a]用[Pd（acac）2]在其它相同条件下仅获得中等产率。芳基硼酸的性质影响反应活性和选择性。用贫电子CF 3取代的同系物（> 98：2，参见3b）实现最高选择性，而用4-MeC 6 H4 B（OH）2（27：1，3a）和4-MeOC 6 H4 B（OH）2（10：1，3c）得到较低选择性。受这些结果的鼓舞，我们决定也测试基于非丙烯酸酯的二取代烯烃，并发现芪及其衍生物有效地反应。在这些反应中，我们使用特戊酸/THF（5：1）作为溶剂混合物。[8b]在反式二苯乙烯与间位和对位取代的芳基硼酸（3e-h）的反应中获得了优异的产率和良好的选择性。然而，邻甲苯基衍生物的产率显著下降，可能是由于空间原因（3 i）。我们通过X射线分析明确地指定了3e的相对构型（图1）。[9]反应的立体化学结果与氧化Heck型偶联的预期结果一致。[2]其他化合物通过类比指定。不对称的反式-苯基-α-聚乙烯与PhB（OH）_2的反应具有良好的空间选择性（9：1，3l），而PhCH= CHC_6F_5只产生一个区域异构体3 j，可能是电子的原因。正如所料，当芳基取代基的电子差不是那么大时，
The Heck arylation belongs to the most important methods for CÀC bond formation and has therefore found widespread application in organic synthesis.[1] Various halides or pseudo halides are readily cross-coupled with olefins under Pd catalysis. In contrast, the oxidative Heck reaction using aryl boronic acids in combination with an external oxidant and a Pd catalyst has been less intensively investigated.[2, 3] Oxidative Heck-type coupling is strongly influenced by the olefin substituents and therefore lacks generality. In particular the synthesis of highly substituted olefins using this approach is not established. The regio-and stereoselective synthesis of highly substituted olefins is very challenging.[4] Herein we describe the mild and highly stereoselective sequential oxidative Pd-catalyzed CÀH arylation of alkenes for the synthesis of alkyltriarylethenes. Our approach was based on the fact that substituents at the olefin strongly influence the regio-and stereoselectivity of the oxidative Heck coupling.[2] The goal was to develop an iterative threefold Heck sequence starting from methyl acrylate (1)[Eq.(1)]. The ester substituent is readily reduced to the hydroxymethyl group to adjust the reactivity of the intermediate olefins. Moreover, the allylic OH group can be further chemically modified to vary the fourth substituent. Methyl acrylate (1) is a well-established olefin for Heck coupling with aryl boronic acids. Various oxidants have been used to conduct that reaction.[2] After some experimentation we found that the 2, 2, 6, 6-tetramethylpiperidine-N-oxyl radical (TEMPO)[5, 6] is a suitable oxidant for this reaction. When a solution of 1 with PhB (OH) 2, KF,[Pd (acac) 2](5 mol%), and TEMPO in propionic acid was stirred at room temperature, product 2a was obtained with excellent diastereoselectivity (E only) in 96% yield [Eq.(2)]. Double phenylation, which is a problem when Pd (OAc) 2 is used as the catalyst, was not observed.[7] Under these mild conditions, other aryl boronic acids bearing electron-rich and also electron-poor substituents reacted with complete diastereoselectivity (E only, 2b–d).The best yields for the introduction of the second aryl group were achieved upon reacting 2 with an arylboronic acid, KF, 4-HO-TEMPO, and Pd (OAc) 2 in propionic acid at room temperature (Table 1).[8a] With [Pd (acac) 2] under otherwise identical conditions only moderate yields were obtained. The nature of the arylboronic acid influenced the reactivity and selectivity. The highest selectivity was achieved with the electron-poor CF3-substituted congener (> 98: 2, see 3b), whereas with 4-MeC6H4B (OH) 2(27: 1, 3a) and 4-MeOC6H4B (OH) 2 (10: 1, 3c) lower selectivities resulted. Encouraged by these results we decided to test also nonacrylate-based disubstituted olefins and found that stilbene and its derivatives reacted efficiently. In these reactions we used pivalic acid/THF (5: 1) as the solvent mixture.[8b] Excellent yields and good selectivities were obtained in the reaction of trans-stilbene with meta-and para-substituted aryl boronic acids (3e–h). However, the yield dropped significantly for the ortho-tolyl derivative, probably for steric reasons (3i). We unambiguously assigned the relative configuration of 3e by X-ray analysis (Figure 1).[9] The stereochemical outcome of the reaction agreed with that expected for an oxidative Heck-type coupling.[2] Other compounds were assigned by analogy. The unsymmetrical trans-phenyl-otolylethene reacted with with PhB (OH) 2 in good regioselectivity for steric reasons (9: 1, 3l), and PhCH= CHC6F5 delivered only one regioisomer 3j, probably for electronic reasons. As expected, when the electronic difference of the aryl substituents was not that …