Selective 1,2‐Hydroarylation(Alkenylation) of gem‐Difluoroalkenes to Access (−CF2H) Motifs

An emerging class of C−C coupling transformations that furnish drug‐like building blocks involves catalytic hydrocarbonation of alkenes. However, despite notable advances in the field, hydrocarbon addition to gem‐difluoroalkenes without additional electronic activation remains largely unsuccessful....

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Veröffentlicht in:Angewandte Chemie 2024-02, Vol.136 (7), p.n/a
Hauptverfasser: Lin, Leroy Qi Hao, Rentería‐Gómez, Ángel, Martin, Robert T., Zhang, Ying‐Qi, Ong, Kelvin Zhi Wei, Parris, Adam B., Gutierrez, Osvaldo, Koh, Ming Joo
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Sprache:eng
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Zusammenfassung:An emerging class of C−C coupling transformations that furnish drug‐like building blocks involves catalytic hydrocarbonation of alkenes. However, despite notable advances in the field, hydrocarbon addition to gem‐difluoroalkenes without additional electronic activation remains largely unsuccessful. This owes partly to poor reactivity and the propensity of difluoroalkenes to undergo defluorinative side reactions. Here, we report a nickel catalytic system that promotes efficient 1,2‐selective hydroarylation and hydroalkenylation, suppressing defluorination and providing straightforward access to a diverse assortment of prized organofluorides bearing difluoromethyl‐substituted carbon centers. In contrast to radical‐based pathways and reactions triggered by hydrometallation via a nickel‐hydride complex, our experimental and computational studies support a mechanism in which a catalytically active nickel‐bromide species promotes selective carbonickelation with difluoroalkenes followed by alkoxide exchange and hydride transfer, effectively overcoming the difluoroalkene's intrinsic electronic bias. A sterically bulky NHC‐nickel catalyst promoted site‐selective hydroarylation(alkenylation) of gem‐difluoroalkenes by coupling with organotriflates(bromides) and sodium 1‐phenylethoxide as hydride source to furnish products containing CF2H‐substituted carbon centers. Experimental and computational studies shed light on the non‐radical mechanism and the metal alkoxide's role in facilitating the reaction.
ISSN:0044-8249
1521-3757
DOI:10.1002/ange.202317935