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Dr. Xiangbing Qi's laboratory first found the chemical selective migration and cross-coupling chemistry of alkyl zirconium

Publication Date:2020/06/08

On June 5th, Dr. Xiangbing Qi's laboratory published an article entitled “Chemoselective Cross-coupling of gem-Borazirconocene Alkanes with Aryl Halides.” (https://pubs.acs.org/doi/abs/10.1021/jacs.0c03821) in top chemistry journalJ. Am. Chem. Soc. The “chain walking” of zirconium reagent and further activation of remote chemical bond has been discovered for nearly half a century (1974), however, how to control the selective migration of zirconium metal, the direction of migration and how to activate the terminal single bond of alkane have been unsolved scientific problems. For the first time, the authors found the controllability of the remote migration of alkyl zirconium and realized that the boron-directed remote migration of zirconium reagent could efficiently generate the gem-gorazirconocene alkanes. Based on these results, the author further developed a simple visible light-promoted nickel-catalyzed cross-coupling method of alkylzirconiumboron reagents with aryl halides to achieve the efficient synthesis of secondary alkyl boron reagents. This research is the new direction of this group after their breaking through of the visible light promoted single nickel-catalyzed alkyl zirconium cross-coupling reaction. (https://doi.org/10.1016/j.chempr.2019.12.010Chem, 2020, 6, 675-688).

The alkyl zirconium reagent has the characteristics of remote migration via the "chain walking" process. While the zirconium reagent remote migration usually generates a thermodynamically stable terminal primary zirconium reagent, the primary zirconium migration reversely to afford the secondary zirconium reagent has never been found. For the first time, the research team achieved the migration selectivity of the zirconium reagent directed by the terminal borate group, and successfully achieved the secondary alkyl zirconium-boron reagent. The author also explored the mechanism of the borate ester-directed zirconium reagent migration through DFT calculation, and investigated the details of the high reactivity of alkyl-zirconium bond in the presence of boron.

Due to the high capacity of rapid constructing complex molecules, especially three-dimensional molecules, the chemically selective cross-coupling reaction of bimetallic alkyl reagents has a wide range of synthetic potentials. Among known bimetallic reagents, gem-borazirconocene alkanes are recognized as particularly valuable synthons that possess great synthetic application due to its different reactivity of carbon-zirconium bond, convenient operation, and good functional group tolerance. The polarity of carbon-zirconium bond and carbon-boron bond in alkyl zirconium boron reagents is quite different, which allows researchers to selectively functionalize the reagents through various reactions such as nucleophilic substitution or nucleophilic addition. Compared with the extensive research of this reagent in halogenation, deuteration, amination, Michael addition and nucleophilic addition reaction, the wide application of this reagent in cross-coupling reaction has not been reported. While cross-coupling reaction of primary alkylzirconocene reagents has been reported recently by our group, to date, no general cross-coupling reaction has been developed for secondary alkylzirconocene including gem-borazirconocene alkanes, likely owing to the lack of available π-systems to stabilize the binding capability of zirconium to achieve suitable transmetalation. Furthermore, the considerable steric hindrance caused by the zirconium complex decreases the nucleophilicity of the alkyl group with coupling partners.

Based on extensive experimental studies, Dr. Xiangbing Qi's laboratory discovered the photoactivity of alkyl zirconium boron reagent for the first time, and further developed a simple visible light-promoted nickel-catalyzed alkyl zirconium boron coupling method. The reaction possesses high regioselectivity and wide range of universality and good function group tolerance. A series of aryl halides containing ester, cyano, primary alcohol, amide groups and soon, can generate the corresponding benzyl secondary boron compound via their coupling reactions with alkyl zirconium boron reagent under mild light conditions. This coupling reaction can be scaled up on a gram scale and used in the late-stage modification of complex natural products. The authors also conducted an asymmetric version of this reaction, which could generate the enantiomeric pure alkyl boron reagents with high regioselectivity and high enantioselectivity.

In summary, Dr. Xiangbing Qi's laboratory realized the broad application of the alkyl zirconium boron reagent in the cross-coupling reaction, discovered and verified the terminal borate directed zirconium reagent "chain walking" remote migration process for the first time, providing a new idea for the remote migration process of zirconium "chain walking" in the field of zirconium chemistry and a new method for the rapid construction of alkyl boron reagents in the field of boron chemistry.

Chao Yang, a Ph.D. student at Qi’s laboratory (joint training students from Nanjing University of Science and Technology) is the first author of this article. Yadong Gao (joint training students at Qi’s laboratory from Nanjing University of Science and Technology) and Songlin Bai (2020 PTN student at Qi’s laboratory) have made great contributions to this work. This work was carried out at National Institute of Biological Sciences, Beijing.

Full text linkhttps://pubs.acs.org/doi/abs/10.1021/jacs.0c03821

Lab Linkhttp://qigroup.nibs.ac.cn/