基于内嵌定位策略的N-取代芳胺邻位C-H键选择性功能化的多组分反应直接构建喹唑啉酮衍生物的新方法

2,3-Dihydroquinazolin-4(1H)-ones and quinazoline-2,4(1H,3H)-diones posses valuable pharmacological and biological activities. To date, however, many defects are universally associated with their main synthetic methods such as complex raw materials, harsh reaction conditions, tedious operations, low atomic economy, high cost, and the lack of diversity of the products. While most of the directing-groups applied currently in the C-H bond selective activations are too difficult to be integrated into the products, which therefore can affect the properties of the products. Recently, during our studies on C-H bond activation and functionalization, we found that the ortho C-H bond of N-substituted anilines could be activated efficiently under mild conditions catalyzed by palladium, affording the corresponding anthranilamides smoothly via isatoic anhydride intermediate in the presence of CO and amines, which were exactly the raw materials of the approaches of isatoic anhydride and anthranilamide to the above two kinds of quinazolinones derivatives. So, in this study, with simple and cheap N-substituted anilines as raw materials and their amino groups as the embedded directing-groups, 2,3-dihydroquinazolin-4(1H)-ones and quinazoline-2,4(1H,3H)-diones are expected to be produced directly via the one-pot multi-component reactions of their ortho-selective C-H bond activation and functionalization. Thus, new facile, efficient, economical and green approaches to these two types of compounds will be expected to be put in place, respectively.

2,3-二氢喹唑啉-4(1H)-酮和喹唑啉-2,4(1H,3H)-二酮拥有宝贵的药理及生物活性，但目前其主要合成方法普遍存在原料复杂、条件苛刻、操作繁琐、原子经济性低、成本高、产物缺乏多样性等缺陷。而目前C-H键选择性活化反应中所用定位基大多难以融入产物中从而影响产物性能。我们近来在C-H键活化功能化研究中发现：钯催化N-取代苯胺的邻位C-H键在温和条件下可被有效活化，在CO和胺存在下经靛红酸酐中间体顺利生成邻氨基苯甲酰胺。而该中间体和产物恰恰是靛红酸酐法及邻氨基苯甲酰胺法合成上述两类喹唑啉酮衍生物的起始原料。故本项目中，拟以简单、廉价的N-取代芳胺为原料，以其胺基为内嵌反应型定位基，经其邻位C-H键活化功能化的一锅法多组分反应来直接合成2,3-二氢喹唑啉-4(1H)-酮和喹唑啉-2,4(1H,3H)-二酮类化合物，以期为这两类物质的合成各开辟出一条简易、高效、经济、绿色的崭新途径。

2,3-二氢喹唑啉-4(1H)-酮和喹唑啉-2,4(1H,3H)-二酮拥有宝贵的药理及生物活性，但目前其主要合成方法普遍存在原料复杂、条件苛刻、操作繁琐、原子经济性低、成本高、产物缺乏多样性等缺陷。本项目以简单、廉价的N-取代芳胺或(N-取代)邻氨基苯甲酸为原料，以其胺基为内嵌定位基，经一锅法的串联环加成反应来直接合成2,3-二氢喹唑啉-4(1H)-酮和喹唑啉-2,4(1H,3H)-二酮类化合物。首先通过对选取的模板反应进行条件优化探索，筛选出实施这些反应的较优条件；然后在优化条件下，研究探索了一系列代表性底物用于反应体系中的作用情况和规律，探明了这些反应的底物适用范围。通过上述研究方案，本项目一共完成了如下三方面的研究工作：1. 基于N-取代芳胺邻位C-H活化功能化反应合成2, 3-二氢喹唑啉-4(1H)-酮类衍生物；2. 基于N-取代芳胺邻位C-H活化功能化反应合成喹唑啉-2, 4(1H, 3H)-二酮类衍生物；3. 基于(N-取代)邻氨基苯甲酸与胺、醛的串联环加成反应合成N-取代的喹唑啉-2, 4(1H, 3H)-二酮类衍生物。从而分别为2,3-二氢喹唑啉-4(1H)-酮和喹唑啉-2,4(1H,3H)-二酮类化合物的合成构建出了简易、高效的新途径。项目资助发表SCI源期刊论文9篇（其中Top期刊论文5篇；化学1区论文3篇，影响因子大于10的化学1区论文1篇，影响因子大于5的化学1区论文2篇；化学2区论文3篇，影响因子大于5的化学2区论文2篇），待发表论文2篇。培养硕士研究生8名，其中4名已经毕业并获得硕士学位，4名在读。