Research group of Fu Junkai, associate professor of Northeast Normal University: the first realization of intermolecular heck coupling reaction between non activated alkenes and alkyl halides

Introduction heck coupling reaction is one of the important methods to construct carbon carbon bond However, there are few reports on the intermolecular heck coupling reaction between non activated olefins and alkyl halides, mainly due to the following problems: 1) alkyl halides (CSP3 Hybrid) it is difficult to oxidize and add with metal catalyst, and the carbon metal species formed after oxidation and addition are easy to eliminate their β - H; 2) the carbon carbon double bond formed by reaction has the problem of regional selectivity, which often leads to a variety of regional isomers that are not easy to separate (Fig 1) Recently, the research group of Fu Junkai, associate professor of Northeast Normal University, Professor Bi Xihe and Associate Professor Guan Wei have made a breakthrough in this field For the first time, copper catalyzed intermolecular heck coupling reaction between non activated olefins and alkyl halides has been realized, and alkylolefin coupling products have been obtained with high regionally and stereoselectively The results were published online in J am Chem SOC (DOI: 10.1021/jacs.8b10874), and were selected as the current cover Fig 1 Challenge of the coupling reaction of non activated olefin and alkyl halide heck (source: j.am Chem SOC.) current cover (source: j.am Chem SOC.) introduction to the research group of Fu Junkai, associate professor, since its establishment, the research group has been committed to the research of Organometallic Chemistry and novel organic synthesis methodology At present, some progress has been made in the fields of n-sulfonyltriazole chemistry, nitrogen radicals and Heck coupling reaction of non activated olefins Since its establishment two years ago, the research group has published many academic papers in internationally renowned academic journals, including J am Chem SOC., chem SOC Rev., org Lett., adv synth Catalyst Fu Junkai, associate professor, School of chemistry, Northeast Normal University Graduated from chemistry base class of Lanzhou University in 2010 From 2010 to 2015, he studied in the research group of Professor Yang Zhen, School of chemistry and molecular engineering, Peking University for his doctorate in organic chemistry In July 2015, he entered the David sarlah research group of the Department of chemistry, University of Illinois at Urbana Champaign to engage in postdoctoral research At the end of August 2016, he was employed as an associate professor and master tutor of organic chemistry in the school of chemistry of Northeast Normal University Frontier scientific research achievements: the first time to realize the intermolecular heck coupling reaction between non activated olefins and alkyl halides, the coupling between non activated olefins and alkyl halides is a very challenging subject in Heck reaction There are few reports on this kind of reaction, and there are only a few reports on intramolecular Heck reaction at present For example, for the first time, Fu group realized palladium catalyzed intramolecular alkylheck reaction (J am Chem SOC 2007, 129, 11340) Alexanian group realized palladium catalyzed radical alkylheck reaction by using palladium catalyzed single electron transfer (set) process (j.am Chem SOC 2011, 133, 20146; j.am Chem SOC 2017, 139, 11595) Oshima, pan, carreira, Cuerva, jarvo and other research groups have realized the intramolecular Heck reaction of alkyl halides by using the strategies of cobalt catalysis, nickel catalysis and nickel / titanium co catalysis, respectively In this paper, the elimination of β - H is inhibited by the generation of alkyl radical type in the single electron transfer process catalyzed by copper; at the same time, guide groups are introduced to enhance the activity of non activated olefins and control the regioselectivity of the reaction, and the coupling products of alkylolefins with high regioselectivity and stereoselectivity are successfully obtained (Fig 2) Fig 2 Copper catalyzed intermolecular heck coupling reaction between non activated olefins and alkyl halides (source: J am Chem SOC.) the author optimized the reaction conditions with terminal olefins containing 8-aminoquinoline and ethyl 2-bromoisobutyrate as model substrates Under the optimal conditions, the heck coupling products were obtained with 82% yield and 12:1 regioselectivity A series of alkene substrates with different functional groups were investigated (Fig 3) Firstly, alkene α substituted substrates, such as n-butyl and isopropyl substituted terminal alkenes, were investigated All of these substrates can obtain the target product in high yield Then, the author found that the alkene substrates with alkenyl, alkynyl or aryl groups at a position could react smoothly, which proved that the reaction had good functional group tolerance In addition, the alkenes substituted by two methyls at a position and the alkene substrates with double bonds in the six membered ring were also studied The single target product can be obtained in high yield It is worth mentioning that for the β - substituted olefin substrate, in addition to the expected coupling product 3P, there are also a small amount of isomeric product 3P " Figure 3 Study on the application scope of olefin substrate (source: J am Chem SOC.) later, the author explored the application scope of alkyl halide substrate (Figure 4) Most of the acyclic substituted alkyl halides can obtain the target products with high regioselectivity, while the regioselectivity of the four membered and six membered halides is slightly poor At the same time, the tolerance of the reaction to alkyl, aryl, alkenyl, alkynyl and other functional groups is very good For a-bromo with two electron absorbing groups, the reaction can also be carried out very well In addition to the third-order halides, the second-order and the first-order halides can also obtain the corresponding coupling products with high selectivity In addition, the gram scale preparation and derivatization of the alkylalkene coupling products were studied Derivatization involves the removal of 8-aminoquinoline guiding group, palladium hydrogenation, Sharpless dihydroxylation, reduction of ester group and amide group, which fully proves that the heck coupling reaction product has great application potential in natural products and drug molecular synthesis Figure 4 Study on the application scope of alkyl halides (source: J am Chem SOC.) finally, the author proposed the possible reaction mechanism (Figure 5a) First, univalent copper Cu (I) is coordinated with non activated olefin substrate 1a to form intermediate M1, and at the same time, alkyl halide and Cu (I) are transferred by single electron to form alkyl radical m3 and Cu (II) intermediate m2; then, after migration and insertion of olefins, alkyl radicals are added to double bonds, and the newly formed carbon radicals are combined with Cu (II) to form trivalent copper intermediate M4 At last, the main product of isomeric alkene 3A was obtained by the elimination of synergetic h B-Br, and the secondary product of isomeric alkene 3A was obtained by the elimination of synergetic h A-Br In order to fully understand the reason for high regioselectivity in the reaction process, Guan Wei, associate professor of Chemistry College of Northeast Normal University, and others, used density functional theory (DFT) to calculate Chemistry (Figure 5b), and explained the key role of dimethyl sulfoxide as a solvent in the cooperative selective elimination of h-br DFT calculation results show that the energy barrier (10.9 kcal / mol) eliminated by H B-Br is lower than that eliminated by H A-Br (13.9 kcal / mol) when the trimer DMSO is combined with the intermediate M4, so it is more conducive to the elimination of H B-Br, so that the coupling products mainly composed of non isomeric alkylalkenes can be obtained Fig 5 Reaction mechanism study and DFT calculation results (source: J am Chem SOC.), in conclusion, the author inhibited β - H elimination by the alkyl radicals produced in the single electron transfer process catalyzed by copper, enhanced the activity of non activated alkenes and controlled the regioselectivity of the reaction by using guide groups, and systematically realized the intermolecular interaction of non activated alkenes and alkyl halides for the first time Heck coupling reaction In this method, the mechanism of solvent assisted h-br elimination was proposed, and the coupling products of alkenes were obtained with high regioselectivity and stereoselectivity The substrate can be used in a wide range The first, second and third-order alkyl halides and various types of non activated olefins can be used in this reaction, which greatly expands the scope of Heck reaction The experimental part of the research work was jointly completed by Tang Chunlin, a master's degree candidate, and Zhang Ran, and the theoretical calculation part was jointly completed by Zhu Bo, a Ph Associate Professor Fu Junkai, Associate Professor Guan Wei and Professor Bi Xihe are co correspondents This work is supported by the National Natural Science Foundation of China, the excellent young talents fund of Jilin Provincial Science and Technology Department, the school startup fund of Northeast Normal University and the open project fund of Shenzhen Graduate School of Peking University 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, chembeangoapp, chembeango official microblog, CBG wechat subscription number and other platforms jointly launch the column of "people and scientific research", approach the domestic representative research group, pay attention to their research, listen to their stories, record their demeanor, and explore their scientific research spirit.