Angelw: NIH, Zhu Shaolin research group, Nanjing University, catalyzes the transfer and defluorination cross coupling of inactive olefins and trifluoromethyl substituted olefins to prepare amphibole

In recent years, with the wide application of fluoroorganic compounds in medicine, pesticide, functional materials and other fields, the establishment of new strategies for the synthesis of fluoroorganic small molecules has become a research hotspot of chemists As a kind of important organic fluorine-containing compounds, it can be regarded as the bioelectronic equivalent of aldehyde or ketone group in drug molecular design, which can significantly improve the stability and activity of drugs Meanwhile, it is also the polymerization monomer of fluorine-containing polymers, and can be converted into a variety of fluorine-containing compounds in organic synthesis Therefore, many chemists have paid attention to the development of mild and efficient synthesis methods of amphiphilic olefins Zhu Shaolin group, School of chemistry and chemical engineering, Nanjing University, reported a new method for the preparation of amphiphilic difluoroethylenes by the cross coupling of migration defluorination of inactive alkenes and trifluoromethyl substituted alkenes catalyzed by NIH The reaction is based on the easily obtained and abundant alkenes, and the selectivity of reaction site is controlled by the ligand and substrate This method has a wide range of substrates and good functional group compatibility It can realize the selectivity of a position of benzyl, O, N, B heteroatom and 2 position of a-olefin as well as the construction of challenging quaternary carbon centers, and realize the intramolecular reaction at the same time The results were published on ang EW Chem Int ed (DOI: 10.1002 / anie 201915840) Profile of Professor Zhu Shaolin Professor Zhu Shaolin graduated from Nanjing University in 2005 with a bachelor's degree, from Shanghai Institute of organic chemistry, Chinese Academy of Sciences in 2010 with a doctor's degree (Tutor: Ma Dawei researcher), and from 2010 to 2013, he was engaged in post doctoral research at Princeton University (tutor: David W C Professor Macmillan), who was engaged in postdoctoral research at MIT from 2013 to 2015 (Tutor: Professor Stephen L Buchwald), was selected into the 11th National Youth Millennium Program in February 2015, joined the school of chemistry and chemical engineering of Nanjing University in September of the same year to carry out independent research, was selected into the National Excellent Youth Program in 2018, and won the Thieme Chemistry Journals award in 2019 At present, the main research directions are organic synthesis and asymmetric catalysis Leading scientific research achievements: the preparation of amphiphilic difluoroethylene olefins by the migration defluorination cross coupling of inactive alkenes and trifluoromethyl substituted alkenes catalyzed by NIH is rich in sources and easy to prepare The development of the reaction of alkenes as starting materials has always been a hot research direction of chemists In the past two decades, chemists have developed a series of in-situ functionalization of olefins, while the migration functionalization of olefins developed in recent years has provided a new strategy for the activation of long-range C (SP 3) - H bonds In general, this kind of reactions introduce new functional groups through common coupling reagents, such as aryl halides, alkyl halides and so on However, the migration cross coupling of olefins developed with another olefin as coupling reagent has rarely been reported in literature The cross coupling reaction of olefins has always been an unsolved problem The main difficulty is that it is difficult to realize the cross selectivity because the two olefins have the same structure In order to obtain good selectivity, the corresponding metal hydrogen species should be able to selectively react with one of the olefins Zhu Shaolin group developed a NIH system to realize the cross coupling of migration and defluorination of inactive olefins and trifluoromethyl substituted olefins to prepare amphiphilic alkenes Fig 1 Optimization of reaction conditions (source: ang EW Chem Int ed.) the author first selected inactive 1,1-disubstituted end alkene (1a) and trifluoromethyl substituted electron deficient alkene (1b) as model substrate After a series of optimization, it is found that the ligands have a great influence on the reaction The C2 substituted bipyridine L1 (6,6 '- dimethyl-2,2' - bipyridine) is the best, the yield of the ligand L6 of Phenanthroline skeleton will be decreased, and the other ligands are less effective There is no reduction of LIF and almost no product formation At room temperature, the yield decreased sharply The reaction is not sensitive to air and water At last, it was found that the product of difluorocarbon can be obtained in high yield and regioselectivity by using NiCl2 · DME as nickel source, L1 as ligand, (ETO) 3sih as hydrogen source and LIF as base Figure 2 Substrate range (source: ang EW Chem Int ed.) after obtaining the best reaction conditions, the author expanded the substrate range The substrate has a wide range of application types, and the functional group compatibility is particularly good It is suitable for 1,1-disubstituted olefins, unactivated and activated end olefins, unactivated and activated inner olefins, a-olefins of B, O, n heteroatoms and cyclized olefins Fig 3 Substrate range (source: ang EW Chem Int ed.) when there are aryl or N, O heteroatom on the olefin chain, A-site harmonic difluoroalkylation products at benzyl or N, O heteroatom can be obtained with high selectivity Fig 4 Range of trifluoromethylolefins (source: ang EW Chem Int ed.) trifluoromethylolefins are suitable for electron rich, electron deficient aromatics and heterocycles, all of which can selectively obtain allylated products of benzyl harmonic difluoride Fig 5 Intramolecular reaction (source: ang EW Chem Int ed.) the methodology is also applicable to intramolecular reaction, and can be used to prepare the gemal difluoroethylene containing five or six membered rings Figure 6 Gram scale-up reaction (source: ang EW Chem Int ed.) the author further carried out gram scale-up reaction, which can also obtain benzyl harmonic difluoroallylation product with high selectivity and yield, further indicating that the reaction has certain practicability Figure 7 Deuterium experiment (source: ang EW Chem Int ed.) in order to know more about the reaction mechanism, the author conducted some deuterium experiments As a hydrogen source, DBPin has nearly one deuterium production, and there is no deuterium formation in the structure of trifluoroethylene In addition, when deuterium trifluoroethylene is used as raw material, deuterium in the product is not reduced and no transfer occurs It shows that the addition sequence of NIH is: first with electron rich alkene, then with electron deficient trifluoroethylene At last, a deuterium olefin and a non deuterium olefin are used as starting materials Only 5 a of the product contains deuterium, and 5 g of the product does not contain deuterium This indicates that NID does not dissociate from 1a and carry out intermolecular transfer, which is quite different from the previous work published by the author In the previous work, the dissociation and exchange of olefins will occur in the migration process of NID Figure 8 Reaction mechanism (source: ang EW Chem Int ed.) after a series of deuterium experiments and related literature research, the author proposed the above reaction mechanism Firstly, nickel and ligand are combined to produce in-situ NIMH species lnI IH (I) with SIH, and then NIMH and olefin 1A undergo insertion reaction to produce alkyl nickel II Trifluoroene 2A can be used as ligand to coordinate with intermediate (II) and stabilize intermediate (II) The intermediate (III) is split to produce nucleophilic free radicals, followed by Giese addition to the activated receptor trifluoroene 2a to generate intermediate (V), and finally B-F elimination to generate the target product It is worth noting that the site selectivity depends on the stability of free radicals Related work was published in angelw Chem Int ed (DOI: 10.1002 / anie 201915840) The corresponding author of the paper is Zhu Shaolin, Professor of the school of chemistry and chemical engineering of Nanjing University, and the first author is Chen Fenglin, a doctoral candidate The research work was greatly supported by NSFC At present, Zhu Shaolin has 1 associate researcher, 5 doctoral students and 4 master students The scale of the research group is small According to the website of the research group (http://hysz.nju.edu.cn/slzhu/), the research group plans to recruit one researcher, one postdoctoral and one research assistant each at present, providing a good platform, salary and reward to guarantee the project and further study opportunities 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.