Research group of Professor Zhong Guofu and Professor Zhang Jian of Hangzhou Normal University: cross coupling of olefins catalyzed by cobalt: olefinization and alkylation controlled by carbonyl

Introduction olefins represent a large group of important organic compounds, which are widely used in biology, agriculture, medicine, polymer science and many other fields, so it is particularly important to develop efficient and practical olefin functionalization methods It is a hotspot to control the activation and functionalization sites of hydrocarbon bonds by guiding groups How to realize the alkenylation / alkylation of hydrocarbon functionalization in a controllable way by using simple chemicals is an interesting research topic For example, sukbok Chang's team has reported the olefinization and alkylation of aryl hydrocarbon bonds controlled by guiding group under iridium Catalysis (j.am.chem.soc 2015, 137, 13448 − 13451) Recently, Professor Zhang Jian and Professor Zhong Guofu of Hangzhou Normal University reported the first direct cross coupling reaction between olefins catalyzed by cobalt Through the change of carbonyl group in coupling reagent (the change of ester or ketone carbonyl group), the direct alkenylation or alkylation of alkenyl hydrocarbon bond can be realized in a controllable way The reaction conditions are simple and mild, with high atomic economy The results were published in org Lett (DOI: 10.1021 / ACS Orglett 9b01766) 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 The research direction is: transition metal catalyzed organic synthesis methodology, selective hydrocarbon bond functionalization, 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 papers as the first author or (and) corresponding author in the famous international academic journals such as angelw Chem., int ed., J am Chem SOC., org Lett., chem Commun., adv synth Catalyst., and applied for 8 domestic and foreign patents As reviewer of international famous chemical journals such as chem Commun., org Bio Chem., adv synth Catalyst Leading scientific research achievements: cross coupling of olefins under the catalysis of cobalt: olefins are abundant in carbonyl controlled olefinization and alkylation reactions Olefins are large chemical raw materials Selective cutting and functionalization of olefin hydrocarbon bonds can be used to efficiently prepare olefin derivatives In recent years, the activation and functionalization of olefin hydrocarbon bonds under the action of guiding groups have attracted people's attention A variety of guiding groups (mainly amides) have been used to activate olefin hydrocarbon bonds at fixed points, followed by functionalization reactions, such as alkenylation, alkylation, boration, aromatization, etc Our research group has been committed to the research of alkenylation 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 ） 。
The oxidative cross coupling reaction between alkenes can be used to construct conjugated dienes with high value The coupling of olefins without guiding group under palladium catalysis often produces conjugated dienes with thermodynamically stable e, e-configuration; the cross coupling of olefins under guiding group can usually produce conjugated dienes with Z, e-configuration, and the selected catalyst can be the complexes of palladium, rhodium and ruthenium Recently, the research on the functionalization of Hydrocarbons Catalyzed by cobalt is relatively hot The functionalization of various aryl hydrocarbon bonds has been reported, but the activation of alkenyl hydrocarbon bonds is relatively small Professor Zhong Guofu and Professor Zhang Jian's research group have developed a direct cross coupling reaction between olefins catalyzed by cobalt The reaction has good stereoselectivity and can be used to prepare a variety of Z, e-configuration conjugated dienes (alkenylation) or Z-configuration trisubstituted olefin derivatives (alkylation) Interestingly, different carbonyls play an important role in chemical selectivity: alkenylketones form alkylation products, while acrylates form alkenylation products (Fig 1) Figure 1 Cross coupling reaction between olefins under the catalysis of cobalt: alkenylation and alkylation (source: org Lett.) Firstly, the research team selected acrylamide and acrylate as the substrate of template reaction Although the catalyst [Cp * CO (CO) I2] has no catalytic activity in combination with agoac, the substitution of agoac with agsbf6 greatly promoted the coupling reaction The conjugated diene product 3AA was obtained in 51% yield with excellent stereoselectivity (Z / E > 99 / 1) Other silver salts, such as agntf 2, agbf 4 and agotf, could not further optimize the reaction Interestingly, the addition of acetic acid further improved the reaction and increased the yield to 60% A variety of carboxylic acids, such as formic acid and tert valeric acid, have been tried in this paper Other oxidants, such as Ag 2CO 3 and Cu (OAC) 2, are also detrimental to the reaction The selection of various solvents shows that 1,2-dichloroethane is the best solvent (Table 1) Table 1 Condition optimization a (source: org Lett.) after determining the optimal condition, the author investigated the substrate application scope and functional group compatibility of the method The yield of acrylate was moderate to good Alkenylsulfone has poor reactivity and only 27% yield can be obtained Different substituents such as methyl group and isopropyl group on nitrogen atom had little effect on the reaction, and the third-order amide also showed moderate activity The yield of acrylamide with different substitution (such as phenyl and hexyl) was 43% and 64%, respectively However, the substrate containing Weinreb amide, NH Oh amide and nhts amide can not react (Fig 2) Fig 2 Substrate development (source: org Lett.) when alkenylketone was selected as coupling agent by the author, only alkylation products were generated in 65% yield Since oxidants are not necessary in the alkylation of hydrocarbons, the author also explored the reaction without agoac, and the yield increased to 75% (eq.1) (source: org Lett.) on this basis, the range of substrates for alkylation was extended The reaction also showed good functional group compatibility, and the presence of sensitive groups such as F, Cl, Br did not affect the reaction The highest yield was 85% (Fig 3) Figure 3 Substrate development (source: org Lett.) the author designed several isotope experiments to explore the reaction mechanism If deuterium acetic acid is added under the optimal conditions, no matter alkenylation or alkylation conditions, obvious hydrogen deuterium exchange can be observed in the reaction, indicating that the activation step of alkenyl hydrocarbon bond is reversible (Fig 4 (a) (b)) The deuterium substituted material reacts for 2 hours under the condition of alkenylation to obtain the monodeuterium product with 23% yield, and the material with 74% deuterium in cis alkenyl position is obtained with 74% recovery, which shows that the deuterium exchange and olefin insertion steps of alkenyl are competitive (Fig 4 (c)) In contrast, if the same deuterium substituted raw materials react under alkylation conditions, no deuterium hydrogen exchange is found in the recovered raw materials, indicating that the deuterium hydrogen exchange step is much slower than the olefin insertion step (Fig 4 (d)) It is suggested that keto carbonyl can lead to alkylation products, which may be due to the formation of enol salt intermediate in the reaction In order to verify this conjecture, the author designed the control experiment in Fig 4 (E) and found that 10% deuterium was introduced into the product 5LA (24% yield), which confirmed the existence of enol salt intermediate Finally, parallel and competitive KIE experiments have been carried out to confirm that the activation of alkenyl hydrocarbon bond is a critical step in the alkylation of hydrocarbons (Fig 4 (E)) The competitive reaction between molecules shows that the reaction activity of the electron rich substrate is higher than that of the electron deficient substrate (Fig 5) Fig 4 Isotopic experiment (source: org Lett.) Fig 5 Competitive reaction (source: org Lett.) finally, the author proposed the possible mechanism, as shown in Fig 6 First, silver salt reacts with [COCP * (CO) I2] to form the catalytic active intermediate [Cp * CO (III) (OAC)] + (I) With the aid of acetate radical, the activation of hydrocarbon in CMD takes place to form the transition state II of ring metal Through the migration and insertion of acrylate and β - hydrogen elimination, conjugated diene 3 was obtained, and CO (I) Cp * (IV) was released After further oxidation by silver salt, it regenerates the catalytic active intermediate [Cp * CO (III) (OAC)] + (I) (path a) If alkenylketone is involved in the reaction, the seven membered cobalt heterocyclic metal state combines with an acetic acid, and the ketone / enol isomerization transition takes place to obtain the macrocyclic intermediate VI The alkylation product is obtained by protonation of acetic acid, and the catalytic intermediate [Cp * CO (III) (OAC)] + (I) is regenerated The author thinks that the isomerization of ketone / enol is the key factor to control the alkylation reaction, while the isomerization of ester group is not stable, which promotes the occurrence of β - hydrogen elimination, so it is easy to occur alkenylation Figure 6 Possible