Professor Xiao Jian's research group of Qingdao Agricultural University: Series [1,5] - hydrogen transfer / cyclization reaction initiated by carbon positive ion to construct dibenzo-azazol framework efficiently

Lead 7-azacyclodibenzo [b, e] azatrel is the core skeleton of many natural products and commercial drugs For example, the popular antidepressants, mianserin and mirtazapine, both contain this core skeleton However, there are few methods to synthesize the core skeleton of the seven membered nitrogen heterocycle Therefore, it is of great significance to develop a green and efficient new method for the construction of dibenzo [b, e] azazoles Recently, Professor Xiao Jian's research group of Qingdao Agricultural University has made a breakthrough in this field, and developed a kind of green and efficient new method for the construction of dibenzo [b, e] azazoles Dibenzo [b, e] azazoles can be synthesized in one step by series [1,5] - hydrogen transfer / cyclization reaction initiated by carbon positive ion, and another important core structure of natural product, octahydropyrrole quinoline skeleton, can be synthesized by substrate substituent A brief introduction to Xiao Jian's research group on the synthesis of dibenzo [b, e] azazhuo skeleton and octahydropyrroloquinoline skeleton (origin: org Lett.) initiated by carbon positive ion in series [1,5] - hydrogen transfer / cyclization reaction was established in April 2013 At present, there are 3 professors, 2 associate professors and 12 master students in the research group Members of the research group have published more than 60 papers in the journals of angelw Chem Int ed., org Lett., green chem Facing the major national strategic needs and international frontier important scientific issues, the research group solved the important scientific issues in the process of new generation material creation and transformation through the fracture and recombination of chemical bonds and interdisciplinary intersection and integration, and efficiently created new functional molecules At the same time, it took synthesis as the core, and engaged in the research of related interdisciplinary subjects for energy, medicine and materials Brief introduction to Professor Xiao Jian, high-level talent introduction of Qingdao Agricultural University, and head of functional organic molecular team of Qingdao Agricultural University In 2009, he graduated from the Department of chemistry and biochemistry, Nanyang University of technology, Singapore, under the guidance of Professor Teck Peng LOH, an organic chemist From 2009 to 2010, he was engaged in postdoctoral research in Nanyang University of technology From 2010 to 2012, he worked as an associate researcher in Dalian Institute of Chemical Physics, Chinese Academy of Sciences From 2013 to 2014, he did postdoctoral research at the Scripps Research Institute in California, USA, under the guidance of biochemist carlosf Barbas III Since September 2012, he has been a professor in the school of chemistry and medicine of Qingdao Agricultural University So far, 46 SCI papers have been published in the world-renowned journals such as angelw.chem.int.ed., green chem., org Lett., etc as the first or corresponding author, including more than 200 citations for a single paper, and 3 papers have been selected into the highly cited papers of ESI He presided over 8 projects such as the National Natural Science Foundation of China, the natural science Distinguished Youth Fund of Shandong Province, the key research and development plan of Shandong Province, authorized 2 international PCT patents, was invited to write 3 English reviews, and edited one English academic work It has successively won the Shandong Youth Science and Technology Award (2017), the first prize of science and technology of Shandong colleges and universities (2017), the teaching gold of Changhe International Award (2017), the Shandong natural science Outstanding Youth Fund (2016), the Shandong Natural Science Academic Innovation Award (2016), and other honors Leading scientific research achievements: Series [1,5] - hydrogen transfer / cyclization reaction initiated by carbon positive ion can efficiently construct the direct C (SP 3) - H bond functionalization of the α - position of dibenzo-azazol skeleton tertiary amine, which can simply and efficiently synthesize various nitrogen-containing heterocyclic compounds, and has wide application in the synthesis of drugs and natural products Although the traditional strong base model and the recent cross dehydrogenation coupling method have been applied to some extent, the toxic transition metals, additional oxidants and harsh reaction conditions limit the application of these methods in industry As an effective method for the direct functionalization of the C (SP 3) - H bond of nitrogen atom, the tandem hydrogen transfer / cyclization strategy has unique advantages compared with the traditional transition metal catalytic strategy for the activation of hydrocarbon Bond: (1) the reaction does not need additional oxidants or reducers, It is a kind of neutral redox reaction; (2) the reaction has a high atom economy; (3) the synthesis of various nitrogen-containing heterocyclic compounds by series cyclization Despite its unique advantages, the application of this kind of reaction is still very limited, and there are many challenges: (1) the type of hydrogen receptor is very limited: mainly concentrated in α, β - unsaturated compounds, unsaturated C = x (x = C, N, O) The further application of the strategy is limited by bond, etc.; (2) the type of substrate is very limited: most of the reactions are based on o-aniline skeleton, and there are very few examples of other skeletons; (3) the synthesis skeleton is very limited, in most cases, the method can only construct six membered rings, and there are few reports on the construction method of seven membered nitrogen heterocycle skeleton Therefore, it is of great significance to find a new driving force to initiate the series hydrogen transfer / cyclization reaction to construct the heterocyclic framework Xiao Jian, Professor, School of chemistry and pharmacy, Qingdao Agricultural University, has been committed to the research of organic catalytic C (SP3) - H bond functionalization reaction system Through the olefin imine tautomerization strategy and the tandem hydrogen transfer / cyclization strategy, the C (SP3) - H bond can be activated to efficiently construct a complex heterocyclic system In view of the above important scientific issues of serial hydrogen transfer / cyclization, the research group based on the previous research on carbon positive ion chemistry (org Lett 2017, 19, 5724; org Lett 2012, 14, 1716; green chem 2016, 18, 1032; adv synth Catalyst 2015, 357, 4023; org BIOMOL Chem 2016, 14, 11510), it is assumed that the dibenzo [b, e] azadiazepine skeleton can be efficiently constructed in one step by using alcohol as the substrate and in-situ forming carbon positive ions under the catalysis of protonic acid to initiate a series [1,5] - hydrogen transfer / cyclization reaction However, the challenge to achieve this reaction is also obvious: (1) the in-situ carbon positive ions must be stable enough to induce α - H migration of tertiary amines; (2) the nucleophiles selectively attack the imines formed after hydrogen migration rather than the first carbon positive ions formed; (3) the intramolecular nucleophilic attack is faster than the intermolecular attack (Figure 1) Fig 1 Comparison of hydrogen transfer / cyclization reaction strategies (source: org Lett.) the author optimized the reaction conditions with 3,5-dimethoxyphenyl - (2-tetrahydropyrrole) - phenylmethanol as template substrate (Fig 2) The screening process of reaction conditions also proved the challenge of the reaction The common proton acid catalysts are either non reaction (such as trifluoromethylsulfonic acid and trifluoroacetic acid), or low yield (methanesulfonic acid and trifluoromethylsulfonic acid) The final conditions showed that camphor sulfonic acid (CSA) was the best protonic acid catalyst In anhydrous DCE, 30% CSA was used as catalyst, and the target product (entry 17) was obtained in 93% yield at 100 ℃ Fig 2 Optimization of reaction conditions (source: org Lett.) later, the author explored the universality of the substrate, and the substituents on 2-tetrahydropyrrole-phenyl, whether the electron donor or the electron acceptor, could get a better yield (2a-2g) However, when 4-methyl is replaced by 4-methoxy, the reaction does not take place This energy is due to the strong electronic properties of methoxy, which leads to the over stability of carbon positive ions and the inability of hydrogen transfer It is gratifying that the corresponding product (2H) can also be obtained in 37% yield when the benzene ring is replaced with quinoline framework The author also inspected the universality of hydrogen donor in the substrate (2i-2p) Five, six and non cyclic amines can get good yields (Fig 3) Fig 3 substrate development (source: org Lett.) after the above work, the author considers whether the reaction can occur after changing the electron supplying ability of benzyl alcohol (Fig 4) When one methoxy is substituted or one of two methoxy is replaced by one methyl, the expected target product can not be obtained, but the dimer octahydropyroquinoline skeleton product (3A-3D) is obtained in excellent yield The tetracyclooctahydropyrroloquinoline skeleton is also the core skeleton of many natural products and bioactive molecules, such as the natural products ingargranine and seneciobipyrrolidine The author further tried asymmetric control and only got 18% ee Fig 4: substrate controlled series hydrogen transfer / dimerization reaction (source: org Lett.) the author also derived the product, obtained the corresponding product in a good yield (Fig 5), and verified the mechanism through deuterium experiment (Fig 6) Fig 5 product derivation (source: org Lett.) Fig 6 deuterium experiment (source: org Lett.) finally, the author gives the possible reaction mechanism, as shown in Fig 7 Under the catalysis of acid, substrate 1 is dehydrated to form carbonium ion intermediate I, and then [1,5] - negative hydrogen transfer is initiated to obtain imine ion intermediate II When the aromatic ring is electron rich enough, Pictet Spengler type ring closing reaction will take place to obtain the desired cyclized product 2 (path a) When there is only one methoxy substituent in the aromatic ring, imine II is rapidly isomerized to the intermediate III of enamine to capture another II to produce intermediate IV, and finally the intramolecular Pictet Spengler type reaction takes place to generate dimer 3 (path B) Route B underwent [1,5] - hydrogen transfer / isomerization / addition / Pictet Spengler multi-step series reaction to obtain octahydropyrrole quinoline skeleton products It should be noted that in this reaction, the path a or B depends on the electron cloud density of benzene ring In addition, the formation of product 3C provides evidence that carbon positive ion is the driving force of [1,5] - hydrogen transfer reaction, rather than O-alkylated o-methylene quinone Fig 7 reaction mechanism (source: org Lett.) Summary: Xiao Jian's research group developed a method to efficiently construct dibenzo [b, e] azatrel skeleton by series hydrogen transfer / cyclization reaction initiated by in-situ formation of carbon positive ions from alcohols This method is the first to realize the hydrogen transfer / cyclization reaction initiated by carbon positive ion as hydrogen acceptor It not only overcomes the limitation of traditional [1,5] - hydrogen transfer / cyclization reaction acceptor, but also provides a one-step and efficient method to construct aza-7-membered ring through (SP 3) - H bond functionalization strategy By changing the substituents of the reaction, the dual functionalization of the N-atom α, β C (SP 3) - H bond was realized to construct the core framework of the natural product, octahydropyrroloquinoline, efficiently and rapidly This achievement was recently published in organic letter (2018, 20, 138 – 141) Dr Li Shuai and master's student Zhou Lan are the co first authors The research work was supported by the National Natural Science Foundation of China (21702117, 21776148), the natural science outstanding youth fund of Shandong Province (jq201604), the key R & D project of Shandong Province (2017gsf218073), the general program of the natural science foundation of Shandong Province (zr2016bm07), the Doctoral Fund (zr2017bb005) and the high level talent introduction project of Qingdao Agricultural University (6631112323) Paper link: https://pubs.acs.org/doi/abs/10.1021/acs.orglett.7b03492 page of Xiaojian research group: http://www.science.cn/people/xiaogroup/index.html http://hxyyxy.qau.edu.cn/content/kytd/11d1adf75394eadbfeb7a72c497cc ා opennewwindow about people and research, CBG information decided to change the "CBG people" channel to "people and research" channel After the name change, we will continue to pay attention to and follow up the scientific research activities and achievements of researchers, and report them in a richer form With the increasing attention paid to the elements of science and technology in economic life, China ushered in the "outbreak of science and technology"