The azaallylic anion as a synthon for Pd-catalyzed synthesis of heterocycles:: Domino two- and three-component synthesis of indoles
The azaallylic anion as a synthon for Pd-catalyzed synthesis of heterocycles:: Domino two- and three-component synthesis of indoles
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DOI：
10.1002/anie.200604407
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发表时间：
2007-01-01
影响因子：
16.6
通讯作者：
Aznar, Fernando
中科院分区：
文献类型：
--
作者：
Barluenga, Jose;Jimenez-Aquino, Agustin;Aznar, Fernando
钯催化的交叉偶联反应代表了现代合成有机化学中一些最强大和最通用的工具。[1]虽然大多数交叉偶联过程都是针对C±C键的形成，但在过去的十年中，为创建C±N键而开发的新方法变得非常流行，因为它们代表了非常有效地进入不同类型的重要氮化物。[2]另一方面，许多著名研究小组的努力为合成有机化学家提供了范围广泛和稳定性增强的高活性Pd催化体系。[3，4]因此，在相同的反应条件下，同一催化体系可以连续进行几种不同的交叉偶联反应。通过利用某些Pd催化剂的这种多功能性，并结合C？C和C？N成键反应，一些合成杂环的新方法已被开发出来。[5，6]例如，我们最近报道了一种Pd催化的级联过程，它包括烯胺化和随后的分子内Heck反应，这些共同代表了一种合成吲哚的新方法。[7]在寻找通过Pd催化的级联过程合成杂环的新方法时，我们将注意力转向氮烯丙基阴离子II(方案1)。这种物种很容易通过含有α-氢原子的亚胺的去质子化而产生。虽然氮杂烯丙基阴离子在经典杂环化学中被广泛用作三原子合成子，但据我们所知，它们作为亲核剂参与钯催化的分子间交叉偶联反应尚未见报道。本文介绍了我们对钯催化的亚胺α-芳基化反应的初步研究。此外，亚胺生成的氮烯丙基阴离子参与了钯催化的C±C和C±N键的有序形成反应，这使得合成吲哚的新方法得到了发展，并引入了亚胺作为一种新的合成子，用于通过钯催化的顺序交叉偶联反应合成杂环。在这个项目开始时，我们想知道在钯催化的芳基化条件下，亚胺I是否可能发生C-芳基化反应，类似于众所周知的酮、[9-12]酯或酰胺的烯醇酸盐的芳基化反应，在Buchwald-Hartwig胺化[2]类型的反应中，得到芳基化亚胺III，或进行N-芳基化反应，得到烯胺IV(图式1)。此外，氮烯丙基阴离子的双齿性质使我们相信它可能参与了两个连续的交叉偶联事件，因此可能是Pd催化的多米诺骨牌反应的理想底物，面向合成一般结构V的杂环。为了研究交叉偶联条件下氮烯丙基阴离子的反应活性，我们选择了苯乙酮亚胺1与间溴苯甲醚(2)的反应作为原型系统。我们用不同的碱基、支持配体对钯催化剂、溶剂和反应条件进行了广泛的实验。方案2给出了一些相关结果。
Pd-catalyzed cross-coupling reactions represent some of the most powerful and versatile tools in modern synthetic organic chemistry.[1] While most of the cross-coupling processes are oriented toward the formation of CÀC bonds, during the last decade, the new methodologies developed for the creation of CÀN bonds have became extraordinarily popular, as they represent a very efficient entry into different types of important nitrogenated compounds.[2] On the other hand, the efforts of many prominent research groups have provided the synthetic organic chemist with highly active Pd catalytic systems of wide scope and enhanced stability.[3, 4] Thus, under the same reaction conditions, several different cross-coupling processes can be carried out consecutively with the same catalytic system. By taking advantage of this versatility of some Pdcatalysts, and combining CÀC and CÀN bondforming reactions, some new methodologies for the synthesis of heterocycles have been developed.[5, 6] For instance, we have recently reported a Pd-catalyzed cascade process which involves an alkenyl amination and a subsequent intramolecular Heck reaction, which together represent a new method for the synthesis of indoles.[7] In the search for new strategies for the synthesis of heterocycles through Pd-catalyzed cascade processes, we turned our attention to the azaallylic anion II (Scheme 1). This species can be easily generated by deprotonation of an imine bearing α-hydrogen atoms. Although azaallylic anions have been extensively employed as three-atom synthons in classic heterocyclic chemistry,[8] to the best of our knowledge, no reaction has been reported of their participation as nucleophiles in Pd-catalyzed intermolecular cross-couplings. In the present paper we describe our preliminary studies on the Pd-catalyzed α-arylation of imines. Moreover, the participation of the azaallylic anions generated from imines in sequential Pd-catalyzed CÀC and CÀN bond-forming reactions has led to the development of a new and very efficient method for the synthesis of indoles, and has introduced the imine as a new synthon for the synthesis of heterocycles through sequential Pd-catalyzed cross-coupling reactions. At the outset of this project, we wondered whether under Pd-catalyzed arylation conditions the imines I might undergo C-arylation, in a reaction similar to the well-known arylation of enolates of ketones,[9–12] esters,[13] or amides,[14] to give arylated imine III, or undergo N-arylation, in a Buchwald–Hartwig amination [2] type of reaction, to provide the enamine IV (Scheme1). Moreover, the bidentate nature of the azaallylic anion led us to believe that it might participate in two consecutive cross-coupling events, and therefore might be an ideal substrate for Pd-catalyzed domino processes oriented toward the synthesis of heterocycles of the general structure V.To investigate the reactivity of azaallylic anions under cross-coupling conditions, we chose as a prototype system the reaction of the acetophenone imine 1 with m-bromoanisole (2). We carried out extensive experimentation with different bases, supporting ligands for the Pd catalyst, solvents, and reaction conditions. Some relevant results are represented in Scheme 2.