基于钯卡宾的迁移插入反应合成中环内酯和中环内酰胺

Medium-sized ring lactones and lactams are important structural motifs that occur in a wide range of biologically active natural products. However, efficient approaches to these compounds based on intermolecular reaction of simple building blocks are lacking. In this project, we will explore palladium-catalyzed reaction of ortho-halo-substituted benzaldehydes with diazo compounds, aiming to provide reliable methods for the synthesis of medium-sized lactones and lactams. Diazo compounds have been considered as useful building blocks to participate in　transition-metal catalyzed cross-coupling reactions. In general, migratory　insertion of metal carbene is the key step for this kind of transformation. Recently, we have reported a palladium-catalyzed formal [3+3] annulation of ortho-bromo benzaldehydes with aryl diazoesters, and subsequently, we realized that the way to construct thermal dynamically stable palladacycles may find synthetic potential for other reactions. Inspired by this work, diazo compounds containing suitable nucleophililic moiety will serve as modular C1-unit to build up the key five-membered palladacycles. Upon reductive elimination, transient cyclobutenones will be obtained. Following a reaction sequence of nucleophilic addition/ring expansion, a variety of medium-sized ring compounds will be produced. To our knowledge, such kind of reaction has never been reported in the literature. In a word, the significance of this project is to provide reliable methods for the synthesis of medium ring lactones and lactams.

中环内酯、中环内酰胺作为核心结构单元存在于很多具有生物活性的天然产物当中。但是，基于简单原料参与的分子间反应合成这两类化合物的通用方法还比较欠缺。在本项目，我们将研究钯催化的卤代醛与重氮化合物的反应，发展合成中环内酯和中环内酰胺的新方法。重氮化合物作为一种重要的有机合成子已被广泛用于过渡金属催化的交叉偶联反应。金属卡宾的迁移插入也被认为是成功实现这一反应的关键步骤。近期，我们报道了钯催化的邻溴苯甲醛与芳基重氮酸酯的形式上的[3+3]环加成反应，发展了一种构筑环钯金属中间体的新策略。受此启发，我们计划通过设计反应物，将重氮化合物变成不可或缺的C1单元参与到五元环钯中间体的形成反应。通过还原消除得到的环丁酮与分子内的亲核基团发生加成/扩环反应，就可以生成各种中环化合物。与之类似的研究尚未见文献报道。我们希望通过本项目研究工作的开展，为中环内酯和中环内酰胺的快速合成提供行之有效的方法。

本项旨在基于钯卡宾的迁移插入反应，发展合成中环内酯和中环内酰胺的新方法。研究内容可分以下几个部分：.第一、基于钯卡宾参与的串联反应合成2-磺酰基萘类化合物；.第二、钯卡宾迁移插入反应促进的中环内酯的模块化合成；.第三、钯催化的三组分反应合成苄基苯甲酸甲酯和二芳基甲醚；.第四、钯卡宾迁移插入反应促进的中环内酰胺的模块化合成；.第五、钯卡宾迁移插入反应促进的吡啶并异喹啉酮的模块化合成。.通过以上研究工作的开展，在完成既定目标的同时，我们提出了一种新碳氢活化反应策略，即卡宾桥联碳氢键活化（Carbene Bridging C-H Activation)。根据英文字母缩写，我们将此类反应称为CBA反应。该反应策略为后续研究工作的开展奠定了基础。