乙腈活化及其作为C2单元参与的环化反应研究

Two-carbon (C2) unit plays an important role in the formation of small- and mediumsized cyclic compounds. Ethylene, acetylene, trihaloethenes, which are used as common C2 building blocks, are still very limited because of their gas-phase reactants or human toxicity. Therefore, it is highly attractive and very challenging to develop new reagents that could be used under mild reaction conditions as a C2 building block in cycloaddition reactions. Acetonitrile has been widely used as common solvent in the laboratory and industry. A variety of cycloaddition reactions with the nitrile group of acetonitrile were developed to construct nitrogen-containing cyclic compounds, however, the cycloaddition with the two carbon atoms of acetonitrile, serving as a new C2 building block is still unknown and very challenging. The applicant have discovered a novel Tf2O-mediated acetonitrile activation for the construction of cyclobutenones by [2+2] cyclization. Acetonitrile is utilized for the first time as C2 cyclization building block. However, cyclizations with other unsaturated bonds are still need to be further explored. Based on the previous result, this project will focus on the novel activation model and the key intermediate, exploring more cyclizations, such as [2+2], [2+3], [2+4], [2+5] cyclization using acetonitrile as C2 unit with different cyclization precursor. A variety of cyclic compounds would be afforded during the project. Meanwhile, the novel strategies applied in this project will provide potential new late-stage modification for natural products and pharmaceuticals.

C2环化单元在构建环状化合物中扮演着重要角色。常见的C2环化前体如乙烯、乙炔、1,1,2-三卤乙烯因其气体特性和毒性使其在合成中的使用受到一定的局限性，因此，寻找并发展廉价、温和、高效的C2环化合成子是一个亟待解决的关键化学问题。乙腈作为一种常用的有机溶剂，其参与的环化反应主要集中在氰基的碳氮三键，而利用乙腈中的两个碳原子作为C2合成子参与的环化反应鲜有文献报道。申请人在前期使用三氟甲磺酸酐活化的策略，率先实现了乙腈作为C2环化单元与炔烃的[2+2]环化反应，然而与其他不饱和键的[2+2]环化反应仍有待进一步探索。本项目拟在此基础上，深入研究该类反应新颖的活化模式与活化中间体，探索乙腈作为C2环化单元参与的[2+2], [2+3], [2+4], [2+5]环化反应，从而构建更多的环状化合物。本项目的实施将为环状化合物提供集群式的合成方法，同时为药物分子和天然产物的后期修饰提供可能。

本项目计划对各类环化前体进行筛选，探索乙腈作为C2环化单元参与的[2+n]环化反应，从而为环状化合物的集群式合成提供方法。. 项目执行期间，我们系统的合成了多种环化前体，包括苯炔前体，苯乙烯类化合物，亚胺类前体，1,3-偶极子前体以及1,4-偶极子前体等，与三氟甲磺酸酐活化的乙腈反应，通过条件优化，底物变换等均未取得良好的效果。推测可能原因还是环化合成子之间的匹配问题以及预活化试剂与三氟甲磺酸酐的兼容性没有得到解决。后期我们将在该领域继续进行探索。. 在项目的资助下，我们研究了三氟甲磺酸酐活化的酰胺参与的环化反应，成功首次实现了苯乙酰胺类化合物与炔烃的[4+2]环化反应，为多取代β-萘胺类化合物的构建提供了简洁高效的合成方法。同时，在项目基金的支持下，我们也研究了惰性C-C单键断裂胺化反应，以羟胺衍生物为胺源，无金属条件下实现了烷基苯和苄醇类化合物的C-C键断裂氨基化反应，成功构建了苯胺和N-烷基苯胺类化合物。