作者:       邢兴龙  
论文题目:   微波辅助多组分及成环反应在杂环化合物合成中的应用
学位：      博士
年份：      2006
摘要：      多样性导向合成有机小分子化合物是近年来迅速发展的一个新兴研究领域，通过合成众多结构复杂的小分子化合物用于进行生物学方面的系统探索。利用取代基，立体化学和分子骨架三个不同层次的多样性要素，多样性导向合成提供了获得具复杂性和多样性的小分子化合物的有效方法。另一方面，多组分反应与组合化学技术相结合可以高效地制备所需要的多样性化合物，用于发现新的前导化合物或者用来进行优化前导化合物。因此，多组分反应是多样性导向合成中强有力的合成手段之一。本论文主要集中在微波辅助多组分反应的研究并用于快速高效地合成论及的几种杂环化合物的分子骨架。

            第一章简要介绍了与多样性导向合成、微波辅助有机合成以及多组分反应有关的一些基本情况。第二章列出了我们在微波辅助aza-Diels-Alder 反应方面的研究结果。从2-氨基酚出发，在TFA催化下，应用可控温微波仪在60 °C加热15分钟就可以快速地合成并吡喃和并呋喃基四氢喹啉。产物的非对映异构体比例为35:75-16:84，其中反式异构体占主要。然而，可能是因为2-氨基酚在aza-Diels-Alder 反应中本身的反应性比较低，所以只得到了中等程度的反应产率(39-59%)。

            三、四两章是本论文研究的重点。第三章列出的实验结果表明，我们建立了微波辅助一锅法进行Ugi 四组分和分子内氧-烷基化反应的方法。该方法可用于合成具有6/6并双环体系的3,4-二氢-3-羰基-2H-1,4-苯并噁嗪类化合物。通过室温和微波加热两种反应条件的比较发现，微波辅助的方法可以使反应时间从31-49小时大大缩短至35分钟，而反应产率基本保持不变。第四章是第三章工作的进一步扩展，通过微波辅助一锅法Ugi 四组分和分子内氧-芳基化反应来合成具有6/7/6 并三环体系的二苯并[b,f][1,4]噁卓-11-酮类化合物。该方法总共仅需30分钟就可以81-97%的高收率得到产物。此外，通过后续的进一步修饰，利用Pd-催化分子内成酰胺反应，我们成功地构筑了含二苯并[b,f][1,4]噁卓-11-酮和2-氧化吲哚两种不同杂环经C-N单键连接的轭合物(conjugates)。

            总的来说，将2-氨基酚作为共用的胺组分，我们验证了两种微波辅助一锅法进行Ugi 四组分和分子内氧-烷基化和氧-芳基化反应的合成策略。通过选择不同的醛和酸组分，可以得到6/6并双环和6/7/6并三环两种杂环骨架。其合成时间都非常短(<35 分钟)，且产率很好。通过钯催化分子内二级酰胺的氮-芳基化反应，又可以得到一个新的杂环，首次成功地用于合成以C-N 单键连接两种不同杂环的轭合物。本论文研究提供了所述杂环体系的高效合成方法，为今后进一步研究微波辅助多组分反应和后续的结构修饰打下了基础。

关键词：   aza-Diels-Alder 反应、多样性导向合成、微波辅助多组分反应、Ugi 四组分反应、杂环化合物、分子内氧-芳基化反应

Author:             Xinglong XING
Title:                 Microwave-Assisted MCR-Annulation Approaches toward Heterocycles Synthesis
Degree:            PhD
Year:                2006
Abstract:          Diversity-oriented synthesis of small organic molecules is a rapidly developing interdisciplinary field in recent years, which aims to synthesize libraries of compounds with structural complexity and diversity for use in a systematic exploration in biology. Diversity-oriented synthesis offers a powerful means to access structurally complex and diverse small molecules by considering three distinct diversity elements: building blocks, stereochemistry, and skeletons. Multicomponent reactions along with combinatorial chemistry techniques can efficiently provide products with structural diversity needed for discovery of new lead compounds and for lead optimization. Therefore, multicomponent reactions are the most enabling synthetic tools in diversity-oriented synthesis. This thesis research focuses on microwave-assisted multicomponent reactions and their application in efficient synthesis of selected heterocyclic skeletons.

                        After a brief review in Chapter 1 on the basic aspects of diversity-oriented synthesis of small molecules, microwave-assisted organic synthesis, and multicomponent reactions, our study on microwave-assisted aza-Diels-Alder reaction is presented in Chapter 2. Starting from 2-aminophenols, a rapid acid-catalyzed synthesis of highly functionalized furano- and pyrano-quinolines has been established under controlled microwave heating at 60 °C for 15 min. The diastereoselectivity is 35:75-16:84 in favor of the trans products. However, the yields are moderate (39-59%) probably due to the intrinsic lower reactivity of 2-aminophenols in the aza-Diels-Alder reaction.

                        Chapter 3 describes the results on establishment of one-pot microwave-assisted Ugi-4CR and intramolecular O-alkylation process for synthesis of 3,4-dihydro-3-oxo-2H-1,4-benzoxazines, which feature a 6/6-fused bicyclic ring system. Comparison between the microwave-assisted and the room temperature syntheses has been made, revealing that the microwave-assisted protocol can significantly shorten the reaction times from 31-49 h to 35 min while maintaining similar or slightly lower yields (56-90%) for the desired products.

                        Chapter 4 is a continuation of the above mentioned work and it deals with one-pot microwave-assisted Ugi-4CR and intramolecular O-arylation process for synthesis of dibenz[b,f][1,4]oxazepin-11(10H)-ones possessing a 6/7/6-fused tricyclic ring system. The synthesis takes a total of 30 min for each compound and the yields are in the range of 81-97%. Furthermore, a Pd-catalyzed intramolecular amidation has been successfully performed to furnish the conjugates of dibenz[b,f][1,4]oxazepin-11(10H)-ones with a 2-oxindole subunit linked through a C-N single bond.

                        Overall, by using 2-aminophenols as the common amine component, two one-pot Ugi-4CR and intramolecular O-alkylation / O-arylation processes have been successfully established with controlled microwave heating. According to the structures of the selected aldehyde and acid components, the 6/6-fused bicyclic and 6/7/6-fused tricyclic ring systems can be obtained. The reaction times for both synthetic processes are remarkably short (<35 min) and the product yields are good to excellent. Moreover, additional ring formation has been demonstrated by using the Pd-catalyzed intramolecular N-arylation of secondary amides, leading to the first synthesis of a novel class of heterocyclic conjugates tethered through a C-N single bond. The thesis research provides efficient synthetic methods for the described heterocyclic scaffolds and encourages further studies on microwave-assisted multicomponent reactions and post structural modifications.

Keywords:       aza-Diels-Alder cycloaddition, diversity-oriented synthesis, heterocycles, intramolecular O-arylation, microwave-assisted MCRs, Ugi-4CR