【作者】 张伟；

【导师】 曾伟；

【作者基本信息】 华南理工大学 ， 有机化学， 2015， 硕士

【摘要】 吲哚烯基化合物及其衍生物在许多手性药物分子和生物活性物质的骨架中大量存在,并被广泛地应用在药物化学和生物化学的领域。而过渡金属催化、功能基导向的C-C键偶联为这类化合物的合成提供了有效的合成方法,但导向基团的脱除通常需要烦琐的步骤和苛刻的反应条件。为此,发展过渡金属催化、配体导向,同时导向基在反应过程中可经过“一锅法”途径脱除的新型有机反应是近年来C-H功能化反应中噬待解决的科学问题。目前,已有的吲哚烯基化反应合成方法则以反式的烯基化产物为主,过渡金属催化吲哚C2-syn烯基化反应则未见报道。考虑到酰胺类化合物易被亲核进攻而导致C-N键的断裂,本论文以酰胺为导向功能基,Ru(II)盐为催化剂,深入系统地研究了N-amido indoles与炔烃的偶联反应性能。反应条件优化表明以1,2-二氯乙烷(DCE)作为溶剂,在[RuCl2(p-cymene)]2(10 mol%)/Cu(OAc)2(0.5 eq)/AcOH(1 eq)催化体系下,N-苄基-1H-吲哚-1-甲酰胺与炔烃可高立体选择性地构建吲哚C2-syn烯基化产物,产率中等到良好。产物结构皆通过1HNMR、13C NMR、HR-MS及单晶数据以及二维NOE 1H NMR予以确认。该反应的底物适用性较广,该反应体系对不同取代功能基团具有良好的忍受性,包括较为敏感的OH和卤素等取代基团。其中,吲哚衍生物苯环上取代基电子效应对反应产率影响较小:富电子或者贫电子吲哚底物皆能导致良好至优秀产率的吲哚C2-syn烯基化产物;但炔烃底物分子中取代基的电子效应则比较明显,即含有给电子基团或者弱吸电子基团内炔导致优良产率的烯基化目标产物;而含有硝基等强吸电子基团的内炔则只能形成中等产率的目标产物。最后,通过相关的机理研究,提出了可能的反应历程,并进一步证实了Cu(II)盐在Ru(II)-催化吲哚C2-syn烯基化过程中起着重要的立体选择性控制作用。更多还原

【Abstract】 C2-alkenylated indoles and their derivatives are commonly encountered in many drugs and bioactive natural products. Transition-metal-catalyzed functional group directed C-C bond coupling reaction provides a convienent route for rapid assemble of these compounds. But removal of directing group usually suffers from tedious reaction steps and harsh reaction conditions. Therefore, developing transition metal-catalyzed chelation-assisted/de-directing group cascade reaction is a subject of great importance in C-H functionalization.However, existing coupling strategies between indoles with alkynes were only limited to constructing C2-trans alkenylated indole derivatives. Up to now, transition metal-catalyzed stereoselective C2-syn alkenylation of indoles was rarely reported. Meanwhile, the carbonyl carbon atom of amides derivatives is easily attacked by nucleophilic reagents and leads to cleavage of C-N bonds. Herein, we systematically investigated Ru(II)-catalyzed C2-hydroindolation of N-amido indoles with alkynes, in which amides were employed directing groups. Detailed optimization of this transformation showed that [RuCl2(p-cymene)]2(10 mol %)/Cu(OAc)2(0.5 eq)/AcOH(1.0 eq) reaction system could efficiently realize C2-syn-alkenylation of N-benzyl-1H-indole-1-carboxamide with alkynes in moderate to good yield. All of the C2-syn-alkenylation products were confirmed by 1H NMR、NOE 1H NMR、13C NMR、HR-MS and X-ray crystallographic analysis. Expanding the substrate scope demonstrated broad functional group compatibility. Electron-donating group or electron-withdrawing group at phenyl rings of indoles did not significantly affect the reaction yield. On the contrary, the substituted group from alkynes showed significant electronic effects. The substrate alkynes with electron-donating group and weak electron-withdrawing group could furnish the corresponding products with excellent yield, however the substrate alkynes with strong electro-withdrawing group underwent worse conversion and provided moderate yield. Finally, a possible reaction mechanism about this transformation was proposed based on several controlled experiments which confirmed that copper(II) salts play a key role in controlling the stereoselectity in Ru(II)-catazlyzed C2-syn-alkenyltion of N-amido indoles.更多还原