New developments in aromatic halogenation, borylation, and cyanation

英文原文与中文译文逐段对照 · English original with Chinese translation

Di Qiu, Fanyang Mo, Zhitong Zheng, Yan Zhang, and Jianbo Wang*

邱迪，莫凡洋，郑志通，张艳，王剑波*

Abstract: Several green procedures have been developed for synthesizing functionalized aromatics: i) AuCl ${}_{3}$ - catalyzed halogenation of aromatic compounds, including aryl boronates; ii) ${\mathrm{{Fe}}}_{2}{\mathrm{O}}_{3}$ -catalyzed direct aromatic C-H bond borylation; iii) Pd-catalyzed direct cyanation of indoles; iv) direct conversion of arylamines to pinacol boronates.

摘要:已开发出几种用于合成功能化芳烃的绿色方法:i)AuCl ${}_{3}$催化的芳香族化合物卤化，包括芳基硼酸酯；ii)${\mathrm{{Fe}}}_{2}{\mathrm{O}}_{3}$催化的直接芳香族C-H键硼化；iii)Pd催化的吲哚直接氰化；iv)芳胺直接转化为频哪醇硼酸酯。

Keywords: Au-catalyzed $\cdot$ Borylation $\cdot$ Cyanation $\cdot$ Fe-catalyzed $\cdot$ Green chemistry $\cdot$ Halogenation $\cdot$ Metal-free reactions

关键词:金催化$\cdot$ 硼化$\cdot$ 氰化$\cdot$ 铁催化$\cdot$ 绿色化学$\cdot$ 卤化$\cdot$ 无金属反应

Di Qiu was born in Tianjin, China. He received his B.Sc. degree from Peking University in 2009. He is now a graduate student in Prof. Jianbo Wang’s laboratory. His current research projects are focused on gold-catalyzed $\mathrm{C} - \mathrm{H}$ bond functionalization.

邱迪出生于中国天津。他于2009年从北京大学获得理学学士学位。他现在是王剑波教授实验室的研究生。他目前的研究项目集中在金催化的$\mathrm{C} - \mathrm{H}$键官能化。

Fanyang Mo was born in Liaoning Province, China in 1982. He received his B.Sc. and M.Sc. degrees from Beijing Institute of Technology (P. R. of China) in 2004 and 2006 under the supervision of Professor Zhiming Zhou. He then obtained his Ph.D. from Peking University, under the supervision of Prof. Jianbo Wang. He is currently a postdoctoral fellow at the Scripps Research Institute.

莫凡洋1982年出生于中国辽宁省。他于2004年和2006年在北京理工大学(中国)分别获得理学学士和硕士学位，导师为周志敏教授。然后他在王剑波教授的指导下从北京大学获得博士学位。他目前是斯克里普斯研究所的博士后研究员。

Zhitong Zheng was born in Beijing, China in 1990. He was enrolled in Peking University in 2008. He is currently working in Prof. Jianbo Wang’s laboratory and is expecting to obtain his B.Sc. degree in 2012.

郑志通1990年出生于中国北京。他于2008年进入北京大学。他目前在王剑波教授的实验室工作，预计2012年获得理学学士学位。

Yan Zhang was born in Shandong province, China in 1975. She received her B.Sc. and Ph. D. degrees from Lanzhou University. She continued her research as a postdoctoral fellow in Hong Kong University of Science and Technology (2002-2004), University of Innsbruck & Leibniz Institute of Surface Modification (IOM) e. V. (2004-2005), University of Missouri-St. Louis (2005-2006), and Auburn University (2006-2008). She joined Peking University in 2008 as an associate professor. Her research focuses on the application of transition metal complexes of $\mathbf{N}$ -heterocyclic carbenes and synthesis of small biological compounds. B.Sc. degree from Nanjing University of Science and Technology in 1983, and his Ph.D. from Hokkaido University (under the supervision of Prof. H. Suginome) in 1990. He was a postdoctoral associate at the University of Geneva from 1990 to 1993 (with Prof. C. W. Jefford), and University of Wisconsin-Madison from 1993 to 1995 (with Prof. H. E. Zimmerman and F. A. Fahien). He began his independent academic career at Peking University in 1995. His research interests include the catalytic metal carbene transformations.

张艳1975年出生于中国山东省。她于兰州大学获得理学学士和博士学位。她曾在香港科技大学(2002 - 2004年)、因斯布鲁克大学和莱布尼茨表面改性研究所(IOM)(2004 - 2005年)、密苏里大学圣路易斯分校(2005 - 2006年)和奥本大学(2006 - 2008年)担任博士后研究员。她于2008年加入北京大学担任副教授。她的研究重点是$\mathbf{N}$ - 杂环卡宾的过渡金属配合物的应用以及小生物化合物的合成。1983年于南京理工大学获得理学学士学位，1990年于北海道大学(在杉野博教授指导下)获得博士学位。1990年至1993年在日内瓦大学担任博士后助理(导师为C. W. Jefford教授)，1993年至1995年在威斯康星大学麦迪逊分校担任博士后助理(导师为H. E. Zimmerman教授和F. A. Fahien教授)。他于1995年在北京大学开始独立的学术生涯。他的研究兴趣包括催化金属卡宾转化。

Jianbo Wang was born in Zhejiang province, China in 1962. He received his

王剑波1962年出生于中国浙江省。他获得了他的

1. Introduction

1. 引言

The development of new methods to functionalize inert chemical bonds, such as aromatic carbon-hydrogen (C-H) and carbon-nitrogen (C-N) bonds, is highly important because these methods can serve as the bridge that links cheap and readily available materials to valuable and useful products. Mild, efficient and sustainable transformations of this type will undoubtedly find widespread applications across nearly every branch of chemical fields, including the synthesis of pharmaceuticals, natural products, agrochemicals, polymers, and feedstock commodity chemicals. As part of our ongoing research program on the development of practical transformations towards functionalized aromatic compounds, we have focused our efforts on maximally meeting the request of green chemistry. In this context, we have been interested in using metal catalysts (Au, Fe and Pd) to facilitate the conversion of aromatic C-H bonds into carbon-halogen (C-X, X = Cl, Br, I), carbon-boron (C-B) and carbon-carbon (C-C) bonds, respectively. ${}^{\left\lbrack 1 - 4\right\rbrack }$ We have also developed a metal-free borylation process that converts arylamines to arylboronates. ${}^{\left\lbrack 5\right\rbrack }$ This review briefly summarizes our recent studies.

开发新方法来官能团化惰性化学键，如芳族碳 - 氢(C - H)键和碳 - 氮(C - N)键，非常重要，因为这些方法可以作为连接廉价且易于获得的材料与有价值且有用产品的桥梁。这种温和、高效且可持续的转化无疑将在化学领域的几乎每个分支中得到广泛应用，包括药物、天然产物、农用化学品、聚合物和原料商品化学品的合成。作为我们正在进行的关于开发官能团化芳族化合物实用转化研究计划的一部分，我们致力于最大程度地满足绿色化学的要求。在此背景下，我们一直对使用金属催化剂(金、铁和钯)分别促进芳族C - H键转化为碳 - 卤(C - X，X = Cl、Br、I)键、碳 - 硼(C - B)键和碳 - 碳(C - C)键感兴趣。${}^{\left\lbrack 1 - 4\right\rbrack }$ 我们还开发了一种无金属硼化过程，可将芳胺转化为芳基硼酸酯。${}^{\left\lbrack 5\right\rbrack }$ 本综述简要总结了我们最近的研究。

*Correspondence: Prof. J. Wang

*通信作者:J. 王教授

Beijing National Laboratory of Molecular Sciences (BNLMS)

北京分子科学国家实验室(BNLMS)

and Key Laboratory of Bioorganic Chemistry and

以及生物有机化学与

Molecular Engineering of Ministry of Education

教育部分子工程重点实验室

College of Chemistry, Peking University

北京大学化学与分子工程学院

Beijing 100871, China

中国北京100871

$A =$ acid, $M =$ metal, and $X = {Br}, I,{CI}$ .

$A =$ 酸，$M =$ 金属，以及$X = {Br}, I,{CI}$ 。

2. Gold(iii)-catalyzed Halogenation of Arenes

2. 金(III)催化的芳烃卤化反应

Halogenation of aromatic compounds is one of the essential and frequently used reactions in both industrial and academic settings. The commonly used halogenating reagents in laboratories are $N$ -bromo-, $N$ -iodo-, and $N$ -chlorosuccinimide (NBS, NIS, and NCS, respectively) owing to their ease of handling, as well as the generation of relatively inert succinimide as the byproduct. Previous studies have focused primarily on enhancing the halogenating ability of NXS (X = Br, I, Cl) by using Lewis acid catalyst, which activates the carboxyl group (Scheme 1a). ${}^{\left\lbrack 6 - 8\right\rbrack }$ However, the catalysts used are in most cases not sufficiently efficient, and high catalyst loading (10% to one equivalent) is required in many cases. Lewis acid is used as solvent in particular cases. Consequently, there is still great need to develop a practical procedure for the efficient halogenation of aromatic compounds under milder reaction conditions.

芳香族化合物的卤化反应是工业和学术领域中重要且常用的反应之一。实验室中常用的卤化试剂是$N$-溴代-、$N$-碘代-和$N$-氯代琥珀酰亚胺(分别为NBS、NIS和NCS)，这是因为它们易于处理，并且会生成相对惰性的琥珀酰亚胺作为副产物。以往的研究主要集中在通过使用路易斯酸催化剂来增强NXS(X = Br、I、Cl)的卤化能力，该催化剂可活化羧基(方案1a)。${}^{\left\lbrack 6 - 8\right\rbrack }$然而，在大多数情况下所使用的催化剂效率不够高，并且在许多情况下需要高催化剂负载量(10%至一当量)。在特定情况下，路易斯酸用作溶剂。因此，仍然非常需要开发一种在更温和的反应条件下对芳香族化合物进行有效卤化的实用方法。

Since previous studies have already focused on the activation of the halogenating source, we therefore conceive that the activation of arene substrates may provide an alternative mode of activation with the potential of increased catalytic efficiency. A dual activation process as shown in Scheme 1b is thus proposed, which involves the activation of the $N$ -halosuccinimide by gold catalyst on one hand, and direct auration of the arene substrate on the other hand. We have observed that gold(III) catalyst demonstrates unique catalytic properties in halogenations, while the use of other acids in this system, such as ${\mathrm{{FeCl}}}_{3},{\mathrm{{FeBr}}}_{3},{\mathrm{{BF}}}_{3} \cdot {\mathrm{{OEt}}}_{3}$ (commonly used to activate $N$ -halosuccinimide), ${\mathrm{{NH}}}_{4}{\mathrm{{NO}}}_{3}$ and ${\mathrm{{ZrCl}}}_{4}$ , give substantially lower yields. ${}^{\left\lbrack 1\right\rbrack }$

由于先前的研究已经集中在卤化源的活化上，因此我们设想芳烃底物的活化可能提供一种具有提高催化效率潜力的替代活化模式。因此提出了如图1b所示的双重活化过程，一方面涉及金催化剂对$N$-卤代琥珀酰亚胺的活化，另一方面涉及芳烃底物的直接金化。我们已经观察到金(III)催化剂在卤化反应中表现出独特的催化性能，而在该体系中使用其他酸，如${\mathrm{{FeCl}}}_{3},{\mathrm{{FeBr}}}_{3},{\mathrm{{BF}}}_{3} \cdot {\mathrm{{OEt}}}_{3}$(通常用于活化$N$-卤代琥珀酰亚胺)、${\mathrm{{NH}}}_{4}{\mathrm{{NO}}}_{3}$和${\mathrm{{ZrCl}}}_{4}$，产率会显著降低。${}^{\left\lbrack 1\right\rbrack }$

${\mathrm{{AuCl}}}_{3}$ -catalyzed halogenation has wide substrate scope, including aromatic substrates bearing moderately electron-withdrawing substituents (Scheme 2). In the cases of electron-rich arenes, not only bromination, but also chlorination can be achieved. The regioselectivity of the reaction is dominated by the electronic properties of the substituents. Halogenation with electron-rich arenes provides high yields genation process. ${}^{\left\lbrack {20}\right\rbrack }$ For this purpose, we have further extended the ${\mathrm{{AuCl}}}_{3}$ -catalyzed halogenation reaction by employing aryl-boronates as substrates (Scheme 3).[2]

${\mathrm{{AuCl}}}_{3}$催化的卤化反应具有广泛的底物范围，包括带有中等吸电子取代基的芳香底物(方案2)。对于富电子芳烃，不仅可以实现溴化反应，还可以实现氯化反应。反应的区域选择性由取代基的电子性质决定。富电子芳烃的卤化反应在卤化过程中提供了高产率。${}^{\left\lbrack {20}\right\rbrack }$为此，我们通过使用芳基硼酸酯作为底物进一步扩展了${\mathrm{{AuCl}}}_{3}$催化的卤化反应(方案3)。[2]

Scheme 1. Halogenation through dual activation.

方案1. 通过双重活化进行卤化反应。

A variety of arylboronates substances have been subjected to ${\mathrm{{AuCl}}}_{3}$ -catalyzed halogenations. The results show that ${\mathrm{{AuCl}}}_{3}$ catalyzes a wide range of arylboronates, including those bearing heterocyclic rings. The substituent group can be halogen, methyl, methoxy, trifluoromethoxy, and under mild conditions with very low catalyst loading (down to 0.01 mol %). Arenes bearing moderately electron-withdrawing groups require higher catalyst loading and longer reaction times. Unfortunately, aromatic substrates bearing strongly electron-withdrawing groups, such as nitro group, are not reactive. The nearly quantitative yields and the clean reaction system with only succinimide as by-product make this reaction very attractive as a preparative method.

多种芳基硼酸酯物质已进行了${\mathrm{{AuCl}}}_{3}$催化的卤化反应。结果表明，${\mathrm{{AuCl}}}_{3}$催化多种芳基硼酸酯，包括那些带有杂环的芳基硼酸酯。取代基可以是卤素、甲基、甲氧基、三氟甲氧基，并且在温和条件下催化剂负载量非常低(低至0.01 mol%)。带有中等吸电子基团的芳烃需要更高的催化剂负载量和更长的反应时间。不幸的是，带有强吸电子基团(如硝基)的芳香底物没有反应活性。几乎定量的产率以及仅以琥珀酰亚胺作为副产物的清洁反应体系使得该反应作为一种制备方法非常有吸引力。

Scheme 2. ${\mathrm{{AuCl}}}_{3}$ -catalyzed halogenation.

方案2. ${\mathrm{{AuCl}}}_{3}$催化的卤化反应。

In recent years, considerable attention has been paid to functionalized arylboronic compounds due to their usefulness in organic synthesis and other fields. ${}^{\left\lbrack 9 - {14}\right\rbrack }$ Aryl-boronic acids and esters bearing halogen atom are extraordinary valuable because they afford the possibility to construct complex molecules by conducting multiple-step cross-coupling reactions. ${}^{\left\lbrack {15},{16}\right\rbrack }$ In general, the halogenation conditions are too harsh for aromatic boronates, because deborylation occurs very easily under the conventional halogenation conditions. ${}^{\left\lbrack {17} - {19}\right\rbrack }$ Therefore, it is necessary to develop methodology to achieve halogenation of aromatic boron compounds under mild conditions so that the boron group can remain intact during the halo-hydroxyl group. The reaction provides the corresponding halogenation products in good to excellent yields with the retention of the boron group. Interestingly, most of these halogenated boronates are unknown compounds, which may reflect the difficulties associated with the traditional method in preparing such functionalized aromatic boronates.

近年来，功能化芳基硼酸化合物因其在有机合成及其他领域的实用性而备受关注。${}^{\left\lbrack 9 - {14}\right\rbrack }$ 带有卤原子的芳基硼酸和硼酸酯具有极高的价值，因为它们能够通过多步交叉偶联反应构建复杂分子。${}^{\left\lbrack {15},{16}\right\rbrack }$ 一般来说，卤化条件对芳基硼酸酯过于苛刻，因为在传统卤化条件下很容易发生脱硼反应。${}^{\left\lbrack {17} - {19}\right\rbrack }$ 因此，有必要开发在温和条件下实现芳基硼化合物卤化的方法，以便在卤羟基化过程中硼基团能够保持完整。该反应能以良好至优异的产率提供相应的卤化产物，同时保留硼基团。有趣的是，这些卤化硼酸酯大多是未知化合物，这可能反映了传统方法在制备此类功能化芳基硼酸酯方面存在的困难。

While exploring the ${\mathrm{{AuCl}}}_{3}$ -catalyzed halogenation of arylboronates, we were puzzled by an intriguing question: how does the boronate group affect the halogenation activity and regioselectivity. We have investigated this issue by comparing the halogenation of benzene and pinacol phenylboronate under identical conditions. The experiments suggest that the pinacol boronate group is a weakly activating and ortho/para-directing group (Scheme 4). This may be due to a smaller value of electronegativity than that of carbon (2.04 versus 2.55), resulting in the inductive effect of boron being electron-donating. On the other hand, since boron has an empty $p$ -orbital, the resonance effect is electron-withdrawing, which is opposite to its inductive effect. However, the boron may be complexed with a Lewis base (such as carbonyl oxygen of succinimide) in the reaction system, which may counteract the electron-withdrawing effect.[21]

在探索${\mathrm{{AuCl}}}_{3}$催化的芳基硼酸酯卤化反应时，我们被一个有趣的问题所困扰:硼酸酯基团如何影响卤化活性和区域选择性。我们通过在相同条件下比较苯和频哪醇苯硼酸酯的卤化反应来研究这个问题。实验表明，频哪醇硼酸酯基团是一个弱活化的邻/对定向基团(方案4)。这可能是由于硼的电负性值(2.04)小于碳(2.55)，导致硼的诱导效应是供电子的。另一方面，由于硼有一个空的$p$轨道，共振效应是吸电子的，这与其诱导效应相反。然而，硼可能在反应体系中与路易斯碱(如琥珀酰亚胺的羰基氧)络合，这可能抵消吸电子效应。[21]

In addition, to demonstrate the utility of the halogenated boronates, we have carried out experiments of consecutive Suzuki-Miyaura coupling reactions to demonstrate the rapid construction of aromatic compounds with complex structure (Scheme 5).

此外，为了证明卤化硼酸酯的实用性，我们进行了连续的铃木 - 宫浦偶联反应实验，以展示具有复杂结构的芳香化合物的快速构建(方案5)。

As shown in Scheme 5, we have demonstrated that ${\mathrm{{AuCl}}}_{3}$ is an extraordinarily efficient catalyst for aromatic halogenation. In particular, arylboronates can be halogenated with the retention of the catalyst loading, mild high catalytic efficie and the compatibility transformations m potentially useful in t halides.

如图方案5所示，我们已经证明${\mathrm{{AuCl}}}_{3}$是一种非常有效的芳香卤化催化剂。特别是，芳基硼酸酯可以在保留催化剂负载量、温和的高催化效率以及对卤化物潜在有用的兼容性转化的情况下进行卤化。

Scheme 4. Comparison of the reactivity in ${\mathrm{{AuCl}}}_{3}$ -catalyzed bromination.

方案4. ${\mathrm{{AuCl}}}_{3}$催化溴化反应中的反应活性比较。

Scheme 5. Applications of halogenated boronates in consecutive coupling reactions.

方案5. 卤化硼酸酯在连续偶联反应中的应用。

Scheme 3. Au(iii)-catalyzed halogenation of arylboronates.

方案3. 金(III)催化的芳基硼酸酯卤化反应。

3. Iron-catalyzed Direct Borylation of Arenes

3. 铁催化芳烃的直接硼化反应

Borylation via C-H bond activation attracts great attention because of high efficiency as well as atom economy.[22] Direct borylation of arenes via C-H bond activation have been reported by several groups in recent years, ${}^{\left\lbrack {23}\right\rbrack }$ however, all of them utilize noble metal, such as iridium or rhodium. The application of inexpensive and nontoxic catalyst in such transformations is obviously more attractive and reflects the trend of green chemistry. In 2010, we published the primary results of an iron-catalyzed direct borylation of arenes (Scheme 6).[3]

通过C-H键活化进行硼化反应因其高效性和原子经济性而备受关注。[22]近年来，已有多个研究小组报道了通过C-H键活化实现芳烃的直接硼化反应，${}^{\left\lbrack {23}\right\rbrack }$ 然而，所有这些反应均使用了贵金属催化剂，如铱或铑。在这类反应中应用廉价且无毒的催化剂显然更具吸引力，也体现了绿色化学的发展趋势。2010年，我们发表了铁催化芳烃直接硼化反应的初步研究成果(方案6)。[3]

Among various iron catalysts, ${\mathrm{{Fe}}}_{2}{\mathrm{O}}_{3}$ shows the highest catalytic activity. Nano- ${\mathrm{{Fe}}}_{2}{\mathrm{O}}_{3}$ slightly increases the yields, presumably due to the fact that nanoscale heterogeneous catalysts have more surface area and consequently have enhanced catalytic activity. The substrate scope has been investigated under the optimized conditions (Scheme 6). The borylation of anisole gives a mixture of products of ortho, meta and para substitution, in which ortho-borylated product predominates. This selectivity is consistent with traditional electrophilic aromatic substitution reactions. In contrast, the regioselectivity of Rh- and Ir-catalyzed borylation of arenes is controlled by steric effect of the substit-uents. For methyl-substituted arenes, only aromatic C-H bonds are functionalized under these conditions. the retention of the boron group. Low catalyst loading, mild reaction conditions, high catalytic efficiency, easy separation, and the compatibility of direct subsequent transformations make this method potentially useful in the preparation of aryl halides.

在各种铁催化剂中，${\mathrm{{Fe}}}_{2}{\mathrm{O}}_{3}$ 表现出最高的催化活性。纳米级的 ${\mathrm{{Fe}}}_{2}{\mathrm{O}}_{3}$ 能略微提高产率，这可能是由于纳米级非均相催化剂具有更大的表面积，从而增强了催化活性。我们在优化条件下研究了底物范围(方案6)。苯甲醚的硼化反应生成了邻位、间位和对位取代产物的混合物，其中邻位硼化产物占主导。这种选择性与传统的亲电芳香取代反应一致。相比之下，铑和铱催化的芳烃硼化反应的区域选择性受取代基的空间效应控制。对于甲基取代的芳烃，在这些条件下只有芳香C-H键发生官能团化反应。硼基团得以保留。低催化剂用量、温和反应条件、高催化效率、易于分离以及与后续直接转化反应的兼容性使得该方法在芳基卤化物的制备中具有潜在应用价值。

Although the efficiency of this nano- ${\mathrm{{Fe}}}_{2}{\mathrm{O}}_{3}$ -catalyzed system still needs to be improved, it opens up new possibilities to develop direct aromatic borylation with inexpensive iron catalysts.

尽管这种纳米级 ${\mathrm{{Fe}}}_{2}{\mathrm{O}}_{3}$ 催化体系的效率仍有待提高，但它为开发使用廉价铁催化剂的直接芳烃硼化反应开辟了新的可能性。

Scheme 7. Palladium-catalyzed direct cyanation of indoles.

方案7. 钯催化吲哚的直接氰化反应。

Scheme 6. Iron-catalyzed direct borylation of arenes.

方案6. 铁催化芳烃的直接硼化反应。

4. Palladium-catalyzed Direct Cyanation of Indoles

4. 钯催化吲哚的直接氰化反应

Aryl nitriles have found wide application, especially in the fields of pharmacy and agriculture. They are also important intermediates in organic synthesis. Traditional approaches for the preparation of aromatic cyanides rely on functional group transformation, such as the Sandmeyer reaction[24] and the Rosenmund-von Braun reaction.[25] Recently, transition-metal-catalyzed cyan-ation of aryl halides has emerged as a use -ful method for preparing aromatic cyanides. ${}^{\left\lbrack {26} - {29}\right\rbrack }$ Compared with the traditional transformations, the direct cyanation of C-H bond is much more attractive in terms of step, atom and redox economy. While some achievements have been made in this arena by employing a directing group,[30-32] more general aromatic cyanation through direct C-H bond activation remains a challenging task. In 2010, we reported the first Pd-catalyzed direct cyanation of indoles (Scheme 7). ${}^{\left\lbrack 4\right\rbrack }$

芳基腈已得到广泛应用，尤其是在制药和农业领域。它们也是有机合成中的重要中间体。传统的制备芳香族氰化物的方法依赖于官能团转化，如桑德迈尔反应[24]和罗森蒙德 - 冯·布劳恩反应[25]。最近，过渡金属催化的芳基卤化物氰化反应已成为制备芳香族氰化物的一种有用方法。${}^{\left\lbrack {26} - {29}\right\rbrack }$与传统转化方法相比，C - H键的直接氰化反应在步骤、原子和氧化还原经济性方面更具吸引力。虽然通过使用导向基团在这个领域已经取得了一些成果[30 - 32]，但通过直接C - H键活化实现更普遍的芳香族氰化反应仍然是一项具有挑战性的任务。2010年，我们报道了首例钯催化的吲哚直接氰化反应(方案7)。${}^{\left\lbrack 4\right\rbrack }$

In this reaction, ${\mathrm{K}}_{4}\left\lbrack {\mathrm{{Fe}}{\left( \mathrm{{CN}}\right) }_{6}}\right\rbrack$ is used as the cyano source and offers the advantage of nontoxicity. Equivalent copper and oxygen are used as the terminal oxidants. The only by-product in this Pd-catalyzed cyanation is derived from homocoupling of indole at the C(2) and C(3) positions. We found that addition of potassium acetate (KOAc) in the system could dramatically suppress the homocoupling. Besides, the substituents on pyrrole ring of the indoles significantly affect the reaction. Electron-withdrawing groups either on $\mathrm{C}\left( 2\right)$ or on nitrogen completely deactivate the indole substrate toward cyanation, while electro-donating groups seem to promote the cyanation reaction. On the contrary, the electronic nature of substituents on the benzene ring of the indoles has relatively less effect on the cyanation.

在该反应中，${\mathrm{K}}_{4}\left\lbrack {\mathrm{{Fe}}{\left( \mathrm{{CN}}\right) }_{6}}\right\rbrack$用作氰基源，具有无毒的优点。等量的铜和氧气用作终端氧化剂。此钯催化氰化反应中唯一的副产物来自吲哚在C(2)和C(3)位的自身偶联。我们发现体系中加入醋酸钾(KOAc)可显著抑制自身偶联。此外，吲哚吡咯环上的取代基对反应有显著影响。$\mathrm{C}\left( 2\right)$或氮上的吸电子基团会使吲哚底物完全失去氰化反应活性，而供电子基团似乎能促进氰化反应。相反，吲哚苯环上取代基的电子性质对氰化反应的影响相对较小。

5. Direct Conversion of A to Arylboronates

5. A直接转化为芳基硼酸酯

Arylboronic compounds wide application in organi particularly for the Suzuki-Mi coupling reaction. ${}^{\left\lbrack 9,{10}\right\rbrack }$ This ha increasing demand for various and esters from both academia The traditional method fo arylboronic acid is by the reaction of Grignard reagent reagents with $\mathrm{B}{\left( \mathrm{{OMe}}\right) }_{3}.{}^{\left\lbrack {33},{34}\right\rbrack }A$ method is widely practiced, t] is also apparent: anhydrous and poor functional group to development of alternative methods has continued over 1 1995, Miyaura and co-work the palladium-catalyzed bory aryl halides. ${}^{\left\lbrack {35}\right\rbrack }$ More recently, have been directed toward tl metal-catalyzed direct bo aromatic C-H bonds. ${}^{\left\lbrack {22}\right\rbrack }$

芳基硼酸化合物在有机合成中有着广泛的应用，特别是在铃木 - 宫浦(Suzuki-Miyaura)偶联反应中。${}^{\left\lbrack 9,{10}\right\rbrack }$ 这引发了学术界和工业界对各种芳基硼酸及其酯类日益增长的需求。传统的制备芳基硼酸的方法是通过格氏试剂与硼酸酯试剂反应，$\mathrm{B}{\left( \mathrm{{OMe}}\right) }_{3}.{}^{\left\lbrack {33},{34}\right\rbrack }A$ 这种方法被广泛应用，但也存在明显的缺点:无水条件要求苛刻且官能团耐受性差。因此，替代方法的开发一直在持续。1995年，宫浦及其同事报道了钯催化芳基卤化物的硼化反应。${}^{\left\lbrack {35}\right\rbrack }$ 最近，研究方向已经转向过渡金属催化的直接硼化芳香族C-H键。${}^{\left\lbrack {22}\right\rbrack }$

All of these approaches req the transformations, either as as stoichiometric reagents. Th contaminate the final boron cause environmental probler scale production. In 2010, we metal-free direct conversion of to arylboronic pinacol este temperature (Scheme 8).[5] transformation follows a type reaction sequence: the is first converted into the co diazonium ion by reaction wi nitrite, and then the diazoniu e diboron reagent ${\mathrm{B}}_{2}{\mathrm{{pin}}}_{2}$ to deliver Il product.

所有这些方法都需要使用金属催化剂，无论是作为催化剂还是化学计量试剂。这些金属会污染最终的硼产物，并在大规模生产中造成环境问题。2010年，我们报道了一种无金属的直接转化芳香胺为芳基硼酸频哪醇酯的方法，该反应在室温下进行(方案8)。[5] 该转化遵循一种典型的反应序列:芳香胺首先通过与亚硝酸反应转化为相应的重氮离子，然后重氮离子与双联硼试剂${\mathrm{B}}_{2}{\mathrm{{pin}}}_{2}$ 反应生成目标产物。

rect cyanation of indoles.

吲哚的直接氰化反应。

ariety of arylamines are subjected optimized reaction conditions. All ylation reactions complete at room ature within two hours, and afford responding products with good to nt yields. Reaction with substrates either an electron-donating group lectron-withdrawing group affords esponding boronates in good yields. er, for some ortho-substituted ines the reaction only results in roduct. These results demonstrate reaction is significantly subject to nd electronic effects.

多种芳胺在优化的反应条件下进行反应。所有的硼化反应在室温下两小时内完成，并以良好到优异的产率得到相应的产物。与带有供电子基团或吸电子基团的底物反应都能以良好的产率得到相应的硼酸酯。然而，对于一些邻位取代的芳胺，反应只得到低产率的产物。这些结果表明该反应显著受到空间和电子效应的影响。

advantages of this novel rmation could be summarized as : First, compared with aryl halides, ines are generally cheap and largely le. Secondly, the metal-free process unnecessary metal contamination in ts. Thirdly, the reaction condition is t of ambient air and moisture. All of low this method to be an alternative ant method for arylboronates is.

这种新转化方法的优点可以总结如下:第一，与芳基卤化物相比，芳胺通常便宜且易于大量获得。第二，无金属过程避免了产物中的金属污染。第三，反应条件是在空气和水分的环境中。所有这些使得该方法成为一种替代的、有吸引力的制备芳基硼酸酯的方法。

Iclusion

包含

ummary, we have developed several

总结，我们已经开发了几种

efficient and environmentally transformations that convert cheap sily available starting materials inctionalizing aromatics. These rmations have the potential to be oth in academic laboratories and in industry. Further exploration of green procedures is currently undergoing in our laboratory.

高效且环保的转化方法，可将廉价且易于获得的起始原料转化为功能化芳烃。这些转化方法有潜力在学术实验室和工业中都得到应用。我们实验室目前正在对绿色程序进行进一步探索。

Scheme 8. Direct borylation of arylamines.

方案8. 芳胺的直接硼化反应。

Acknowledgements

致谢

The research presented in this article has been supported by 973 Program (No. 2009CB825300) and the NSFC (Grant No. 20902005, 20832002, 21072009, 20821062).

本文所呈现的研究得到了973计划(项目编号:2009CB825300)以及国家自然科学基金(批准号:2009CB825300、20832002、21072009、20821062)的支持。

Received: September 25, 2011

收到日期:2011年9月25日

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