Research group of Professor Wang Chuan, University of science and technology of China: nickel catalyzed asymmetric intramolecular reduction of non activated olefins Heck reaction

The reduction Heck reaction of Professor Wang Chuan's group is an important method to construct saturated C-C bond in organic chemistry, and it has an important application in the field of natural product synthesis As early as 1980s, cacchi and Umani Ronchi developed palladium and nickel catalyzed reduction Heck reactions respectively In recent years, palladium, copper and other transition metal catalysts have been used to realize the reduction of various olefins, and palladium catalysts have made many important progress in asymmetric reduction of heck Compared with palladium, nickel has the advantages of high abundance and low cost In recent years, nickel has been reported as an effective catalyst However, the enantioselective reduction of Heck reaction catalyzed by nickel is very rare Only Professor Zhou Jianrong of Nanyang University of technology in Singapore reported an asymmetric reduction of Heck reaction of aryl chloride to electron rich indole ring in 2017 Professor Wang Chuan's research group of University of science and technology of China has been devoted to the methodology research of reductive nickel catalyzed electrophilic functionalization of olefins In 2019, the research group realized the asymmetric aryl alkylation of non activated olefins catalyzed by reductive nickel (angel Chem Int ed., 2019, 58, 6722) On the basis of this research, the research group recently developed the intramolecular reduction Heck reaction of 1,1-disubstituted olefins under the catalysis of reduced nickel, synthesized a series of cyclic compounds containing quaternary carbon chiral centers, and obtained excellent asymmetric induction effect in this reaction (Figure 1) This article was recently published in the organic letters (DOI: 10.1021 / ACS Orglett 9b02577) Yang Feiyan, a graduate student of the University of science and technology of China, and Jin Youxiang, a doctoral student, are the co first authors of this paper, and the corresponding author is Professor Wang Chuan Fig 1 asymmetric intramolecular reduction of nonactivated olefins in Heck reaction catalyzed by nickel (source: org Lett.) Firstly, the author used aryl bromine 1A with 1,1-disubstituted olefins as the substrate and water as the hydrogen source for the reaction It was found that the target product can be obtained only when the chiral oxazoline ligand is used Then, when the author used different nickel catalysts, it was found that the effect of Ni (BF 4) 2 · 6h 2O was the best Then the author screened the common solvents and found that when isopropanol was used as the solvent, 98% separation yield and 94% ee value could be obtained Surprisingly, when no water was added, the same results were obtained When manganese powder was used instead of zinc powder as reducing agent, the yield and EE value decreased When the amount of catalyst is reduced, the yield will be reduced, but the EE is worth to keep (Fig 2) Figure 2 Screening of reaction conditions (source: org Lett.) then, the author expanded the substrate (Figure 3) Higher yields and EE values (2A - 2L) can be obtained with different functional groups on 1,1-disubstituted alkenes It is worth noting that when the alkyl chain is changed to an aromatic ring, the reaction can still be carried out with a medium yield and a high EE value (2m - 2S) When aryl bromine or aryl iodide with different substituents are added to the benzene ring, the yield and excellent EE value of the target product (2t - 2W) can also be obtained When oxygen atoms and NTS substituted alkenes are used, chiral benzotetrahydrofurans and indolines (2x - 2Ac) can be obtained When the alkene with CD 2H is used, the yield of the reaction can reach 72% and the EE value of 94% to the target product 2ad In addition, a 5 mmol gram scale reaction was carried out for the template reaction, and similar results were found Fig 3 substrate extension (source: org Lett.) the author then used the product 2a of this paper to carry out the derivatization experiment (Fig 4), and found that it can produce tetrahydroninone compounds 3 through oxidation reaction, and then 3 can produce Baeyer Villiger oxidation reaction mediated by m-CPBA and Beckmann oxidation reaction mediated by PCL 5 By rearrangement, dihydrocoumarins 4 and dihydroquinolinones 5 were obtained They are the basic framework of a large number of drug molecules and bioactive molecules, and have potential application value Fig 4 derivation of Heck reaction products (source: org Lett.) finally, the author puts forward the hypothesis of reaction path The author thinks that the source of hydrogen may be proton or hydrogen radical, so we have done equivalent reaction experiment and isotope labeling experiment The experiment shows that both water and alcohol solvent may be the source of hydrogen According to the experimental results, the possible mechanism of the reaction is proposed (Fig 5): Ni (0) (I) oxidizes and adds aryl bromide (1) to form Ni (II) complex (II), which is intercalated by intramolecular double bond migration to form cyclic Ni (II) intermediate (III); then, the reduction Heck reaction product 2 and Ni (II) are obtained by protonation of Ni (II) intermediate with alcohol solvent Species (IV); finally, Ni (II) species are reduced to Ni (0) by zinc powder for the next catalytic cycle Figure 5 possible reaction mechanism (source: org Lett.) Summary: Professor Wang Chuan's research team developed a nickel catalyzed asymmetric intramolecular reduction Heck reaction of non activated olefins This reaction not only has a wide range of substrate applications and high enantioselectivity, but also provides a new idea and method for the asymmetric synthesis of benzo ring compounds containing quaternary carbon centers.