Liang Yun, Professor of Hunan Normal University: palladium catalyzed synthesis of indole [2,1-a] isoquinoline

Lead indole [2,1-a] isoquinoline is a kind of polycyclic fused nitrogen heterocyclic compound, and it is also the structural unit of many bioactive molecules Because of its complex structure, there are few reports on its synthesis Recently, Dr Yang Yuan of Liang Yun's research group of Hunan Normal University, based on the palladium catalytic cascaded cyclization reaction strategy, synthesized several kinds of fused indole [2,1-a] isoquinoline derivatives by using olefin substituted 2 - (2-haloaryl) - 1h-indole and o-bromobenzoic acid The results were published online in organic letters (DOI: 10.1021/acs.orglett.9b0541) The research group has been engaged in the research on the synthesis methods of selective cutting and formation of hydrocarbon bond, carbon carbon bond and carbon heteroatom bond since its establishment At present, a series of progress has been made in the series reaction of C-H bond activation catalyzed by transition metals and the synthesis of heterocyclic sulfur compounds from inorganic sulfur sources Professor Liang Yun has published more than 60 papers in international famous academic journals such as J am Chem SOC., angel Chem Int ed., org Lett., chem Commun., etc the current members of the research group include two teachers, four doctors and 14 masters Brief introduction to Professor Liang Yun, Professor of School of chemistry and chemical engineering, Hunan Normal University, doctoral supervisor, director of Department of chemistry, director of Hunan Key Laboratory of organic functional molecular assembly and application He graduated from Hunan Normal University with a bachelor's degree in 1994 In 2007, he received his doctorate from Hunan Normal University and was employed as an associate professor In 2009-2011, he conducted postdoctoral research in Peking University, and his co tutor was academician Xi Zhenfeng Professor of Hunan Normal University in 2013 He has presided over and completed 3 National Natural Science Funds, 1 key project of Hunan Natural Science Fund, and 1 science and technology project of the Ministry of education Leading research achievements: palladium catalyzed synthesis of indole [2,1-a] isoquinoline by cascaded cyclization; indole [2,1-a] isoquinoline, as a kind of important polycyclic fused nitrogen heterocyclic compounds, widely exists in drugs, bioactive molecules and functional materials For example, it can be used as a microtubule protein polymerization inhibitor, melatonin antagonist, estrogen receptor nucleophilic cell inhibitor and hole transport material (Figure 1) Fig 1 In the past few decades, there have been few reports on the construction of indole [2,1-a] isoquinoline derivatives In recent years, a series of indole [2,1-a] isoquinoline derivatives (Figure 2-1) have been synthesized by Nevada, Li and Xu groups based on the free radical cascade cyclization strategy However, due to the complexity of indole [2,1-a] isoquinoline skeleton, it is still urgent to develop novel and efficient methods to synthesize indole [2,1-a] isoquinoline derivatives The cascade reaction of C-H bond activation catalyzed by transition metals is a very attractive strategy The research group of the author has made a series of progress in related fields in the early stage (org Lett 2018, 20, 2997; org Lett 2018, 20, 5402; org Lett 2019, 21, 2718) In this paper, we report a novel palladium catalyzed cyclization of 2 - (2-haloaryl) - 1h-indole substituted by alkenes Using o-bromobenzoic acid as coupling agent, we have effectively synthesized the fused six ring skeleton containing indole [2,1-a] isoquinoline (Fig 2-2) Fig 2 Based on two different strategies for the synthesis of indole [2,1-a] isoquinoline derivatives (source: Organic letters), the author selected the corresponding aryl iodine 1a and o-bromobenzoic acid 2A as the substrate, and selected the reaction conditions such as catalyst, ligand, alkali, solvent, temperature, etc under the optimal conditions, the yield of the target product was 88% Next, the scope of application of the substrate for this reaction was explored Firstly, the electronic effects on indole ring and o-bromobenzoic acid and the presence of naphthalene ring, thiophene, pyridine and other aromatic heterocycles in the substrate were examined These substrates have good applicability It was found that TBAB could promote the conversion Based on literature reports and a series of control experiments, the authors speculate that TBAB may play a role in activating and stabilizing palladium complexes (Fig 3) Figure 3 Study on the application scope of substrate (source: Organic letters) It is worth mentioning that when 8-bromo-1-naphthoic acid is used as coupling agent, the reaction can form the target product by constructing a seven membered ring At the same time, the reaction also shows good functional group compatibility, and the target product can be obtained at a medium yield (Figure 4) Figure 4 Substrate applicability study (source: Organic letters) in order to explore the mechanism of the reaction, the author designed and implemented isotope experiments The results show that there are two positions of hydrogen in product 3A - D which are deuterized The author speculates that the reaction mechanism may be related to the formation of palladium ring intermediate C Based on the experimental results and literature reports, the author proposed a possible reaction mechanism (Figure 5): first, Pd (0) oxidizes and adds C-I bond to form aryl PD (II) intermediate a, which undergoes intramolecular Heck reaction and C-H bond activation to form palladium ring intermediate C; then the C-Br bond of o-bromobenzoic acid oxidizes and adds C bond to form PD (IV) intermediate D, D Through continuous reduction elimination and decarboxylation, seven membered palladium intermediate e was formed Finally, e was reduced and eliminated to obtain the target product and Pd (0) Fig 5 Study on reaction mechanism (source: Organic letters) To sum up, the author developed an efficient palladium catalyzed cascade cyclization reaction for the construction of indole [2,1-a] isoquinoline derivatives Three C-C bonds were formed by continuous intramolecular Heck reaction, C-H bond activation and decarboxylation coupling, which provided a new strategy for the synthesis of indole [2,1-a] isoquinoline derivatives This achievement was recently published in organizational letters (DOI: 10.1021 / ACS Orglett 9b02541) The authors of this paper are: Xiumei Yang, Haiyan Lu, Xiaoming Zhu, Liwei Zhou, Guobo Deng, Yuan Yang, and Yun Liang The above research work was supported by NSFC, science and technology program of Hunan Province and Science Foundation of Hunan Education Department Nowadays, people and scientific research have been paid more and more attention in the economic life China has ushered in the "node of science and technology explosion" Behind the progress of science and technology is the work of countless scientists In the field of chemistry, in the context of the pursuit of innovation driven, international cooperation has been strengthened, the influence of Returned Scholars in the field of R & D has become increasingly prominent, and many excellent research groups have emerged in China For this reason, CBG information adopts the 1 + X reporting mechanism CBG information website, chembeangoapp, chembeango official micro blog, CBG information wechat subscription number and other platforms jointly launch the column of "people and scientific research", approach the representative research groups in China, pay attention to their research, listen to their stories, record their demeanor, and explore their scientific research spirit.