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Dr. Xiangbing Qi's laboratory found the novel cross-coupling method with alkylzirconocenes

Publication Date:2020/01/08

On January 6th, 2020, Dr. Xiangbing Qi's laboratory published an article entitled “Visible-light-induced Nickel-catalyzed Cross-coupling with Alkylzirconocenes from Unactivated Alkenes.” in journal Chem, a flagship chemistry journal of Cell Press. This work reported a visible-light-induced single nickel catalyzed C(sp3)–C(sp3), C(sp3)–C(sp2), and C(sp3)–C(sp) cross-coupling reactions using alkylzirconocenes. This research represents the breakthrough application of alkylzirconocenes in cross-coupling reactions.

Transition-metal-catalyzed cross-coupling reactions have become one of the most versatile synthetic methods for constructing carbon–carbon and carbon-heteroatom bonds. Cross-coupling reactions between naturally abundant sp3-hybridized carbon centers facilitate access to diverse molecules with complex three-dimensional structures. The Nobel Prize in Chemistry 2010 was awarded jointly to Richard F. Heck, Ei-ichi Negishi and Akira Suzuki for palladium-catalyzed cross couplings in organic synthesis. Organometallic compounds are among one of the most powerful reagents that are broadly used in cross-coupling reactions, however, there are still limitations for distinguished examples such as Negishi reaction (organic zinc, harsh preparation conditions), Kumada reaction (organic magnesium, low functional group compatibility), Stille reaction (organic tin, poisonous), Hiyama reaction (organic silicon, narrow reaction scope), and Suzuki reaction (organic boron, lack of chain-walking property), etc. Organic zirconium reagents, especially alkylzirconocene, developed from 1970s, easily generated in situ from terminal or internal unactivated alkenes through hydrozirconation and chain walking, have been far less explored in cross-coupling reactions, likely due to the lack of π-systems to stabilize the binding capability of zirconium to achieve suitable transmetalation.

The work from Dr. Xiangbing Qi's laboratory discovered a visible-light-induced single nickel-catalyzed cross-coupling method with alkylzirconocenes, which is mild and applicable for a large range of substrates including primary, secondary, tertiary alkyl, aryl, alkenyl, alkynyl halides and a variety of alkenes. High functional group tolerance under mild conditions enable this method to be of practical significance. Employing a one-pot chain walking and cross-coupling relay strategy, a range of internal alkenes and isomeric mixture of alkenes could be efficiently functionalized to give terminal coupled products. Synthetic applications including natural products and pharmacophore derivatization further demonstrated its advances of utilities and generalities. Furthermore, the potential application of this visible-light induced cross-coupling in modern synthesis was demonstrated by carrying out at a gram scale process using flow chemistry.

On the basis of the mechanistic investigations including radical clock experiments, radical capture experiments, Hammett equation experiments, competition experiments, UV-visible absorption spectra, and DFT (density functional theory) calculations of each single step, the work tentatively propose a novel nickel-catalyzed radical cross-coupling pathway. The homolysis of alkylzirconocenes generates the alkyl radical and the ZrIII species under blue light excitation, and the Ni0 complex is generated from the NiII species via reduction by ZrIII, which undergoes alkyl radical capture to provide the NiI-alkyl complex. A subsequent radical oxidative addition of the alkyl halide or a concerted oxidative addition of the aryl or alkynyl halide species forms a NiIII complex. Finally, reductive elimination affords the desired cross-coupled products and simultaneously regenerates the NiI halide catalyst. The reductive ZrIII species could reduce NiI halide to Ni0, which could participate in the next catalytic cycle.

In summary, Dr. Xiangbing Qi's laboratory disclosed the first visible-light-induced single nickel-catalyzed cross-coupling method with alkylzirconocenes, mechanistic experiments suggest a nickel-catalyzed radical type reaction pathway. Given its mild conditions, scalability, and extremely general scope across a large range of organic halides, and considered alongside its excellent functional group compatibility, this strategy will serve as an innovative cross-coupling paradigm and will inspire researchers to revisit the synthetic potential of organozirconium chemistry.

Yadong Gao, 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. Chao Yang (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. Other authors of the paper include Qingcui Wu (manager at Qi’s laboratory), Xiaolei Liu ((joint training students from Jinan University), Dr. Jing Wang (School of Pharmaceutical Sciences, Peking University), etc. The work was supported by Chinese Ministry of Science and Technology 973 grant, National Natural Science Foundation of China, Beijing Municipal Science & Technology Commission, Tsinghua University and the Priority Academic Program Development of Jiangsu Higher Education Institutions-China (PAPD). This work was carried out at National Institute of Biological Sciences, Beijing.

Link: https://www.cell.com/chem/fulltext/S2451-9294(19)30557-1