碳-氢键活化及其在含氮杂环的合成应用

Classical cross-coupling reactions such as Stille, Suzuki, or Kumada require functionalization of both coupling partners. Metal-catalyzed C-H bond activation and arylation by aryl electrophiles have emerged recently as a powerful method to construct aryl-aryl bond. The methodology enables a carbon-hydrogen bond to work as a functional group in aryl-aryl cross-coupling reactions. In general, activation of C-H bond requires assistance of metal catalyst and directing group on the substrate to participate and form metallocycle. The directing group was preinstalled on the substrate before the activation of C-H bond took place. Afterwards, the directing group needs to be removed if it is not desired in the final product. Overall, the process added steps, resulted in additional cost and generated extra waste. In this proposal, we envision to design and adopt catalytic directing group for assistance of activation of C-H bond and subsequent coupling reaction. The directing group will be attached to the substrate temporarily through the formation of bond with substrate functional group. Upon activation of the desired C-H bond and completion of subsequent coupling reaction with electrophile, the directing group will be separated from substrate. In the meanwhile, the product will be released. We will take pyridine as a model substrate to test the new methodology concept. The nitrogen of pyridine undergoes acylation with acyl chloride to form N-acylpyridinium salt. Under the proper condition, α-C-H of N-acylpyridinium salt will be activated with the assistance of adjacent acyl group. Subsequent C-C bond formation with electrophile will generate the cross-coupling product. The final product will be released after the acyl group of the coupling product is replaced by unreacted pyridine nitrogen to enter the next catalytic cycle. We will complete research in this unexplored area and generate impact in the important field of C-H activation.

过渡金属催化的碳-氢键活化使原本惰性的碳-氢键与各类亲电子试剂联结生成碳-碳键，省略了对碳-氢键的预先官能化步骤。碳-氢键活化通常需要在固定的定向取代基的辅助下完成。如果定向取代基不是产物所需基团，反应结束后则要通过额外的步骤去除。此研究计划将设计采用催化式的定向取代基，通过与底物官能团生成键暂时依附在底物上，辅助对底物的碳-氢键活化。在底物完成与亲电子试剂的碳-碳键联结后，定向取代基随后离开底物并释放最终产物，接着进入下一个催化循环。我们将以吡啶作为研究模型起点，采用酰基氯与吡啶氮原子结合生成氮-酰基吡啶亚胺离子，其邻位碳-氢键在反应条件下被断裂活化并与亲电子试剂加成。加成产物的酰基随后被尚未反应的吡啶取代进入下一个碳-氢键活化循环，并释放最终产物。此研究计划将完成对这一领域的探索，填补碳-氢键活化研究在这方面的空白。

在国家自然科学基金(No.21272201)的支持下,我们的课题组在C-H键活化领域取得了如下成果包括（1）：发现以Pd(COD)Cl2/Ag3PO4为催化体系，实现了芳基碘代物对β-胺基丙烯酸酯的芳基加成，合成了一系列的β-芳基-β-胺基丙烯酸酯类化合物。我们的方法具有高产率及良好的区域及立体选择性，且底物普适性广（Gou, Q.; Den, B.; Zhang, H.; Qin, J. Org. Lett. 2013, 15, 4604）；（2）在导向基团的辅助下，我们发现使用二乙酸碘代芳基物ArI(OAc)2作为芳基源，在金属钯的催化下实现了脂肪链酰胺β位C(sp3)–H键的芳基化。这一方法学不需要使用昂贵的银盐，有很好的底物普适性，应用这一方法我们实现了药物分子phenibut的合成。这一研究成果已投稿（Gou, Q.; Zhang, Z.-F.; Liu, Z.-C.; Qin, J. Org. Lett. 2014, submitted）；（3）发现了一个高效的钯催化反应体系，实现了芳基碘代物作为芳基源对2-吡啶醛肟醚的芳基化，高效地合成了一系列的2-吡啶酮肟醚。这一方法学首次实现了立体选择性合成酮肟醚。应用这一方法学我们完成了中枢兴奋药利他灵（methyphenidate）的合成。这一研究结果即将被投稿（Gou, Q.; Deng, B.; Qin, J. Chem. Commun. to be submitted）；（4）发现了一个钯催化体系，在导向基团的辅助下，初步实现了对脂肪链酰胺C(sp3)–H键的活化及C-N键生成。我们现在积极地优化反应条件提高产率及探索反应的普适性。