铑催化苯甲酰亚胺导向C—H活化合成茚[1,2-c]异喹啉-11-酮  

Synthesis of Indene[1,2-c]isoquinoline-11-one by Rhodium-catalyzed Benzimide-directed C—H Activation

作　　者：黄佳鑫 刘敏 徐辉 戴辉雄 Huang Jiaxin;Liu Min;Xu Hui;Dai Hui-Xiong(State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China;State Key Laboratory of Organometallic Chemistry,Shanghai Institute of Organic Chemistry,Chinese Academy of Sciences,Shanghai 200032,China;University of Chinese Academy of Sciences,Beijing 100049,China)

机构地区：[1]中国科学院上海药物研究所原创新药研究全国重点实验室,上海201203 [2]中国科学院上海有机化学研究所金属有机化学国家重点实验室,上海200032 [3]中国科学院大学,北京100049

出　　处：《化学学报》2024年第6期565-569,共5页Acta Chimica Sinica

基　　金：国家自然科学基金(Nos.22171276,21920102003);上海市科委(Nos.17JC1405000,21ZR1475400,23ZR1474400,18431907100);上海市优秀学术带头人计划(No.19XD1424600)资助。

摘　　要：茚并[1,2-c]异喹啉是一类非常重要的有机杂环骨架,在药物化学、有机光电材料方面有着广泛的应用.本工作以苯甲酰亚胺乙酯及α-重氮-1,3-二酮为底物,通过金属铑催化,构建了茚[1,2-c]异喹啉酮骨架.进一步通过还原反应,高效合成具有生物活性的茚并[1,2-c]异喹啉产物.该反应具有良好的底物普适性和官能团兼容性.机理试验表明该反应可能经历了五元环铑中间体,且碳氢键活化为反应的决速步.Indene[1,2-c]isoquinoline is a novel non-camptothecin-like Topo1 inhibitor,and possesses good antitumour effect on lung cancer,lymphoma,etc.Thus,the development of new methodologies to construct indene[1,2-c]isoquinoline and its derivatives has been a hot topic in organic chemistry.In recent years,benzimidate has been widely used as a building block in the construction of nitrogen-containing heterocycles via transition metal-catalyzed C(sp2)—H bond activation and subsequent cyclization reaction with different reagents,such as alkyne,alkene,carbenes.Meanwhile,α-diazo carbonyl compounds have been widely used as C2 synthons in organic synthesis.In particular,with cyclicα-diazo-1,3-diketones,fused polycyclic compounds could also be prepared via Rh(III)-catalyzed[4+2]oxidative annulations.Herein,we report the construction of indene[1,2-c]isoquinoline-11-one using benzimidate andα-diazo carbonyl compounds as the starting material.The reaction proceeds via a rhodium-catalyzed C—H activation/carbenoid insertion/dehydration process.The protocol showed high atom economy,excellent functional group tolerance,and heterocycle compatibility,giving the indene[1,2-c]isoquinoline-11-one in moderate-to-good yields.Wolff-Kishner reduction of the product with N2H4•H2O affords the indene[1,2-c]isoquinoline.To demonstrate the synthetic utility of this protocol,gram-scale synthesis and late-stage modification of drug molecule were showcased.The KIE value of 3.4∶1 indicated that the C—H cleavage step is probably involved in the rate-determined step.A typical general procedure for the synthesis of indene[1,2-c]isoquinoline-11-one 3a is described as the following:To a solu-tion of ethyl benzimidate(0.1 mmol),[Cp*RhCl2]2(1.5 mg,2.5 mol%),and AgOAc(3.2 mg,20 mol%)in hexafluoroisopro-panol(2 mL)was added diazooxindole(0.11 mmol)under N2.The mixture was stirred at 100℃for 12 h.Then the reaction mixture was cooled to room temperature.The mixture was filtered through Celite,and the filtrate was evaporated to give the crude product

关 键 词：茚并[1 2-c]异喹啉 C—H键活化 铑催化 

分 类 号：O626.323[理学—有机化学]