Research group of Shi Shiliang, Shanghai organic Research Institute: asymmetric C-H alkylation of PFA catalyzed by N-heterocyclic carbene nickel

Introduction: due to the strongest electronegativity of fluorine atom, it can adjust the polarity, conformation, pKa value and metabolic stability of the molecule The introduction of polyfluoroaromatics into the structure of drug molecules can often adjust their physical and chemical properties and biological activities; in material science, by controlling multiple C-F in polyfluoroaromatics A highly polarized molecule can be obtained by the direction of the bond, which can be used as a dielectric material in liquid crystal (Fig 1) Therefore, the construction and functionalization of PFA have become more and more important in organic synthesis chemistry Among them, direct functionalization of the C-H bond is the most economical method At present, only some racemic reactions have been reported in this field Recently, the research group of Shi Shiliang, a researcher in the State Key Laboratory of organometallic chemistry, Shanghai Institute of organic chemistry, Chinese Academy of Sciences, has realized the catalytic asymmetric C-H bond functionalization of PFA for the first time Using the chiral Heterocyclic Carbene (NHC) ligands developed by our research group, they realized the asymmetric C-H alkylation of PFA catalyzed by cheap metal nickel and constructed the chiral pfthn compounds with high efficiency These compounds are bioisomers of tetrahydronaphthalene and many heterocycles, which are widely used in drug design The results were published in angew Chem Int ed (DOI: 10.1002 / anie 201907387) Figure 1 Some important natural products, drugs and materials (source: angelw Chem Int ed.) containing PFA and pftn The design, synthesis and application of novel chiral heterocyclic carbene ligands in important asymmetric catalytic reactions They successively developed anipe and sipe series of novel C 2-Symmetric large sterically hindered NHC ligands (angelw Chem Int ed 2018, 57, 1376; ACS catalyst 2019, 9, 1; J am Chem SOC 2019, 141, 5628; J am Chem SOC 2019, DOI: 10.1021 / JACS 9b08578) Due to the unique stereoscopic and electronic effects of heterocyclic carbene ligands, their metal complexes can activate inert substrates and catalyze some important reactions that are difficult to realize at present, so it is of great significance to develop new dominant chiral NHC ligands The research group is looking for postdoctoral and scientific research assistants in organic synthesis and polymer synthesis all the year round At the same time, master's degree, doctoral degree and lianpeisheng are welcome to join the research group Shi Shiliang, researcher, State Key Laboratory of organometallic chemistry, Shanghai Institute of organic chemistry, Chinese Academy of Sciences In 2011, he received his doctorate from Tokyo University, Japan, under the guidance of Professor masakatsu Shibasaki and Professor motomu Kanai From 2011 to 2012, he continued to stay in motomu Kanai professor's Laboratory for JSPS postdoctoral research From 2013 to 2016, he was engaged in postdoctoral research in Stephen Buchwald professor's Laboratory of Massachusetts Institute of technology He has worked in Shanghai Institute of organic chemistry, Chinese Academy of Sciences since June 2016 Researcher Shi Shiliang has published more than 20 research papers in nature, science, nature chemistry, J am Chem SOC., angew Chem Int ed and other internationally renowned academic journals In 2019, he won Thieme Chemistry Journals award At present, he has undertaken general projects and major research plan cultivation projects of NSFC, participated in major projects of NSFC and special projects of strategic leading science and Technology (class B) of Chinese Academy of Sciences Leading scientific achievements: asymmetric C-H alkylation of PFA catalyzed by N-heterocyclic carbene-nickel Fig 2 Synthesis and challenges of chiral PFT (source: angelw Chem Int ed.) Tetrahydronaphthalene (thn) is a bioisomer of many heterocyclic compounds and widely exists in the molecular structure of various drugs Its synthesis is of great significance for the design of new drugs However, there are no effective asymmetric catalytic synthesis methods for these compounds Classical methods for synthesis of tetrahydronaphthalene compounds, such as Friedel crafts alkylation and asymmetric hydrogenation of naphthalene, can not be used for synthesis of chiral polyfluorotetrahydronaphthalene compounds because of the difficulty in controlling the region and stereoselectivity Shi Shiliang's research group envisages whether the simple and easily available polyfluoroaromatics with olefins can be used as the substrate to realize the efficient synthesis of these compounds through the asymmetric C-H cyclization of polyfluoroaromatics catalyzed by nickel However, the side reactions of olefin isomerization promoted by nickel, the chemical and regioselective activation of C-H and C-F bonds, the low reactivity of c6fn Ni bonds and the control of enantioselectivity of products make this strategy challenging (Fig 2) However, they used anipe (L1, Fig 3), a new chiral NHC ligand developed by the research team, to obtain a chiral polyfluorotetrahydronaphthalene compound 2a with quantitative yield and excellent enantioselectivity (91% ee) Through further optimization, the optimal reaction conditions were determined It was found that sipe (L3), a saturated chiral NHC ligand, was suitable for alkene substrates (93-99% ee), while dm-anipe (L2), a highly hindered chiral NHC ligand, was suitable for non alkylated alkene substrates, including styrene, butadiene and enamine (86-99% ee) Fig 3 Some chiral heterocyclic carbene ligands (source: angelw Chem Int ed.) have a wide range of substrates Polyfluorobenzenes with different number of fluorine atoms and substitution methods, as well as phenol and amide substrates with various heterocycles and functional groups, even active hydrogen, are well compatible The reaction has excellent regioselectivity and stereoselectivity, and endo - Ring - closing products are completely obtained The average EE value of 36 examples is as high as 94.7% At the same time, the chemical selectivity of the reaction is single, and there is no C-F bond breaking reaction Interestingly, when there is no nitrogen or oxygen atom in the structure, the product can be obtained by simple filtration operation, which shows the high specificity of the reaction It is also important that the reaction can be successfully scaled up to gram scale, and can be used for the later modification of some highly functional drug derivatives (4 and 5), which may play an enlightening role in the design and development of new drugs (Figure 4) Figure 4 Substrate range of asymmetric C-H cyclization of PFA catalyzed by nickel (source: angel Chem Int ed.) based on the C-H bond functionalization method of PFA, they transformed PFA in various ways, and the enantioselectivity of the product can be fully maintained As shown in Fig 5, biphenyls 6 and 7 are obtained by palladium catalyzed aromatization and heterocyclic aromatization, and polyfluoro substituted styrene 8 is obtained by nickel catalyzed C-H bond olefinization In addition, the chiral tetrahydronaphthalene compound 9 was obtained by nickel catalyzed hydrofluorination, and the formal intramolecular asymmetric hydroformylation of olefins was realized Figure 5 Conversion of chiral polyfluorotetrahydronaphthalene compounds (source: angelw Chem Int ed.) finally, they studied the mechanism of the reaction Deuterium experiment shows that deuterium atom is completely transferred from PFB to the benzyl position of the product (Fig 6a); kinetic isotope experiments (KIE = 1.5) both inside and between molecules indicate that the fracture of C-H bond may not be a critical step (Fig 6b); isotope disruption experiment does not observe the formation of cross products (Fig 6c), indicating that the reaction may experience a direct hydrogen transfer process (Fig 6D ， patha ）。 Although the mechanism of C-H bond and Ni (0) oxidative addition and olefin insertion cannot be completely excluded (Fig 6D, pathb) for the time being, no matter what mechanism the reaction undergoes, the use of this kind of large steric hindrance and strong electron donor chiral heterocyclic carbene ligand (l1-3) is the key to achieve high reactivity and precise control of chemistry, region and enantioselectivity Fig 6 Study on reaction mechanism (source: angelw Chem Int ed.) this work reported the first case of asymmetric catalytic C-H functionalization of PFA, providing a new method for efficient synthesis of chiral pfthn This achievement was recently published in German Journal of Applied Chemistry (angel.chem.int.ed 2019, DOI: 10.1002/anie.201907387) The authors of this paper are Cai Yuan, ye Xiaodong, Liu Sheng and Shi Shiliang The above research work has been greatly supported by the National Natural Science Foundation of China, the strategic leading science and technology project of Chinese Academy of Sciences (class B), and the State Key Laboratory of organometallic chemistry 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.