Professor Zhong Guofu and Professor Zhang Jian of Hangzhou Normal University: functionalization of alkenyl to carbon carbon bond via four eight external double bond ring metal transition state under the action of guiding group

Lead alkenes are large chemicals, which are widely found in drugs and natural products The direct hydrocarbon functionalization of olefins has the characteristics of high efficiency and high atom economy A series of achievements have been made in the functionalization of olefin hydrocarbon bonds under the guidance of functional groups This method is used to activate the o-alkenyl hydrocarbon bonds of the guiding groups It has experienced the transition state of five or six membered ring metals with double bonds in the ring, showing superior regional and stereoselectivity However, there are few reports about the activation and functionalization of hydrocarbon bonds in other positions of olefins under the action of guiding group, which is similar to the activation of hydrocarbon bonds in carbon position, because this process has to go through the transition state of ring metal with double bonds outside the ring which is difficult to form; at the same time, there are few reports about the formation of transition state of ring metal in small (quaternary) and middle (seven and eight) rings, which is very challenging Recently, Professor Zhang Jian and Zhong Guofu of Hangzhou Normal University published a research paper entitled "geminal group directed olefinal C-H functional via four - toeight member exo metallocycles" (DOI: 10.1038 / s41467-019-13098-1) in nature communications In this paper, the direct functionalization of alkenes with carbon bonds under the guidance of hydroxyl, amides and carbamates has been reported for the first time Prof Zhong Guofu's research team was founded in 2011 At present, the team consists of 3 professors, 3 associate professors and 1 experimenter There are 19 postgraduate students The main research directions include: (1) asymmetric catalysis and synthesis; (2) selective conversion of unsaturated hydrocarbons; (3) visible light induced green synthesis; (4) drug molecular green synthesis The research group undertakes a number of cooperation projects among the state, Zhejiang Province, Hangzhou city and enterprises The research group has been committed to the development of new clean organic synthesis methods for a long time, in order to realize the green manufacturing of fine chemicals, and has made a series of research achievements in asymmetric catalysis and synthesis, selective functionalization of unsaturated hydrocarbons, etc Prof Zhong Guofu, Professor of Hangzhou Normal University, doctoral supervisor, distinguished professor of Changjiang Scholars of the Ministry of education Director of Hangzhou innovative drug research center, director of pharmaceutical chemistry of key disciplines in Hangzhou, executive member of the founding Committee of Singapore society of catalysis sciences Mainly engaged in organic chemistry, asymmetric catalysis and pharmaceutical chemistry In 1983, he graduated from Nanjing University of science and technology and obtained a bachelor's degree in engineering In 1986, he obtained a master's degree in engineering from Shanghai East China University of science and technology and stayed in school In 1990, he went to the Institute of organic chemistry of the University of Lausanne, Switzerland, and studied metal organic chemistry from Professor Manfred Schlosser In 1995, he left Switzerland and joined the famous Scripps Institute in the United States At the beginning of 1998, he obtained a doctor's degree in organic chemistry of Scripps under the guidance of Professor Richard Lerner, director of Scripps and academician of the American Academy of Sciences In 1999, he was promoted to assistant professor and engaged in the research of catalytic antibody and organic catalysis In 2004, he was selected as a distinguished professor of Yangtze River scholars by the Ministry of education In early 2005, he returned from Scripps to join the Department of chemistry of Fudan University At the same time, he was employed as an outstanding Pi of Biomedical Research Institute of Fudan University In 2006, he was invited to join the Department of chemistry and biochemistry, Nanyang University of technology, Singapore, as one of the start-up teachers of the Department He was invited to work in Hangzhou Normal University at the end of 2011 So far, more than 100 SCI papers have been published in science, J am Chem SOC., angelw Chem Int ed., etc It has applied for more than 20 patents at home and abroad So far, the students cultivated have won more than 10 awards at home and abroad (including national outstanding young scholars, national ten thousand talents plan, National Youth thousand plan and national excellent self funded overseas students scholarship, etc.) Prof Zhang Jian, Professor of Hangzhou Normal University, master's supervisor The research direction is: transition metal catalyzed organic synthesis methodology, selective functionalization of hydrocarbon bonds, drug synthesis, etc He graduated from Department of chemistry and biochemistry, Nanyang University of technology, Singapore (2013); master's degree from school of chemistry, Nankai University (2006); bachelor's degree from school of chemistry and chemical engineering, Central South University (2003) Worked in Hangzhou Normal University since January 2015 He was selected as the "West Lake scholar" in 2015 and won the "second prize of Tianjin Natural Science" in 2008 In recent years, he has presided over 1 NSFC, 2 NSFC projects of Zhejiang Province, etc.; he has obtained a series of innovative achievements in the functionalization of alkenyl and aryl inert hydrocarbon bonds, alkyne (alkyne) hydrocarbon (oxidation) coupling and other fields under the catalysis of transition metals So far, he has published more than 20 SCI area I papers as the first author or (and) corresponding author in the international famous academic journals, such as NAT Commun., angelw Chem., int ed., J am Chem SOC., org Lett., chem Commun., etc., applied for 8 domestic and foreign patents, and has been authorized 3 Cutting edge scientific research achievements: the olefin cross coupling carbonyl controlled olefinization and alkylation reaction under the catalysis of cobalt is rich in sources, and it is a large amount of chemical raw materials The selective cutting and functionalization of olefin hydrocarbon bonds can be used to efficiently prepare olefin derivatives In recent years, the activation and functionalization of hydrocarbon bonds of olefins under the action of guiding groups have attracted people's attention A variety of guiding groups (mainly amides) have been used to activate hydrocarbon bonds of olefins at fixed points, followed by functionalization reactions, such as alkenylation, alkylation, boration, aromatization, etc Since 2015, the research group has been working on the functionalization of alkenyl hydrocarbon bonds, and has made some progress (chem Commun., 2017, 53, 533-536; chem Commun., 2017, 53, 9902-9905; chem Commun., 2017, 53, 12926-12929; org Lett 2017, 19, 2498-250; org Lett 2016, 18, 4582-4585; org Lett 2019, 21, 4868-4872; Chem Commun , 2019 , 55 , 9757-9760; Chem Commun , 2019 , 55 , 826-829; Org Lett 2019 , 21 , 8219-8224 ）。 Recently, Engle and carreira team have reported the N, n-coordination-oriented reactions of 8-aminoquinoline amide and 2-pyridylamide, including alkenylation (j.am.chem.soc 2018, 140, 5805-5813) and iodization (j.am.chem.soc., 2019, 141, 8758-8763) However, the installation and removal of N, n-double coordination guide group is tedious What's more, the hydrocarbon activation of alkenyl and carbon in the coordination mode only allows the transition state of six membered ring metal, so the substrate range is relatively narrow In this paper, the direct allylation of allylic and high allylic substituent substrates at the same carbon site is realized by using weak coordination guiding groups such as hydroxyl, carbamate or amide, and branched conjugated diene derivatives can be obtained The reaction undergoes a transition state of four to eight membered rings, showing a wide range of substrates and functional group compatibility It is worth noting that hydroxyl groups, amides and other functional groups exist widely in bioactive molecules and natural products, so this method avoids the cumbersome procedures of guide group installation and removal Figure 1 The selective functionalization of olefin hydrocarbon bond under the guidance (source: nature Communications) the author selected the reaction of alkenyl alcohol, carbamate, amide and acrylate as the template reaction, and optimized the reaction parameters to obtain the best conditions a, B, C (Table 1) It is found that only Z-type olefin substrates show good reactivity, while E-type bisubstituted olefins, terminal olefins and trisubstituted olefins have low reactivity, which may be caused by steric hindrance and / or electronic effect For allyl alcohol substrate, the reaction of high allyl alcohol substrate is the best; for allyl carbamate substrate, the derivative reaction of allyl alcohol is the best; for allylamide substrate, the reaction of high allylamide is the best It can be seen that different coordination groups will affect the formation of transition state of ring metal, thus affecting the reactivity of substrate It is worth noting that allyl alcohol can also be directly alkenylated at the same carbon site, and the reaction may experience the transition state of four membered ring metal; alkenylamide may experience the transition state of five membered, six membered, seven membered and eight membered ring metal, which greatly broadens the scope of the substrate Table 1 Reaction optimization a (source: nature Communications) after determining the optimal conditions, the author investigated the substrate application scope and functional group compatibility of the method High allyl alcohol can react smoothly with a variety of electron deficient alkenes, such as acrylate, alkenylketone, acrylamide and even p-chlorophenylethylene, with a yield range of 39-81% All kinds of substituted secondary alcohols can also be successfully coupled, showing good chemical selectivity However, tertiary alcohols are prone to cyclization In addition, allyl alcohol and high allyl alcohol also showed some reactivity (Fig 2) Figure 2 The development of alkenyl alcohol substrate (source: nature Communications) In addition, the author also expanded the substrate of carbamate of allyl alcohol (Figure 3) Although the reactivity of N, n-dimethylaminoformate is moderate, the conversion of substituent to N, N-Diisopropyl greatly increases the reactivity, and the yield reaches 70% By changing the substituent of cyclohexenol, if dimethyl is introduced in allylic position, the highest yield is 98% The reaction conditions showed good compatibility with benzyl and cinnamyl groups In addition, various alkenylamides were also investigated (Fig 4) There are 1, 2, 3 and 4 carbon atoms between the coordination amides and alkenyl carbon, and the yield is between 18-74% These experimental results fully prove that the substrate range of the functionalization method is wide and the functional group compatibility is good Figure 3 Expansion of alkenylcarbamate substrate (source: nature Communications) Figure 4 Expansion of alkenylamide substrate (source: nature Communications) Finally, the method is suitable for the direct olefinization of many natural products such as ricinoleic acid and drug molecules such as isotestosterone derivatives, showing excellent functional group compatibility and chemical selectivity, providing a shortcut for the efficient chemical modification and further activity screening of drug active molecules It is worth noting that if the mixture of Z and e-alkenylamides which are difficult to separate is reacted under the optimal conditions, z-alkenylamides can be well converted into corresponding alkenylation products, while e-alkenes can be separated and recovered smoothly (Fig 5) Figure 5 Synthetic applications (source: nature Communications), which was recently published in nature communications (nature communications 2019, 10, 5109 Meng, K., Li, T., Yu, C etal Geminal group-directed olefinic C-H functionalization via four- toeight-membered exo-metallocycles DOI:10.1038/s41467-019-13098-1 ）。 Meng Keke, Li Tingyan and Yu Chunbing, master students of the research group