2,2-difluorovinyl benzoates for diverse synthesis of gem-difluoroenol ethers by Ni-catalyzed cross-coupling reactions

Bingnan Du, Chun-Ming Chan, Pui-Yiu Lee, Leong-Hung Cheung, Xin Xu, Zhenyang Lin () and Wing-Yiu Yu ()
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Bingnan Du: The Hong Kong Polytechnic University
Chun-Ming Chan: The Hong Kong Polytechnic University
Pui-Yiu Lee: The Hong Kong Polytechnic University
Leong-Hung Cheung: The Hong Kong Polytechnic University
Xin Xu: The Hong Kong University of Science and Technology
Zhenyang Lin: The Hong Kong University of Science and Technology
Wing-Yiu Yu: The Hong Kong Polytechnic University

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: Abstract gem-Difluoroalkene is a bioisostere of carbonyl group for improving bioavailability of drug candidates. Herein we develop structurally diverse 2,2-difluorovinyl benzoates (BzO-DFs) as versatile building blocks for modular synthesis of gem-difluoroenol ethers (44 examples) and gem-difluoroalkenes (2 examples) by Ni-catalyzed cross coupling reactions. Diverse BzO-DFs derivatives bearing sensitive functional groups (e.g., C = C, TMS, strained carbocycles) are readily prepared from their bromodifluoroacetates and bromodifluoroketones precursors using metallic zinc as reductant. With Ni(COD)2 and dppf [1,1’-bis(diphenylphosphino)ferrocene] as catalyst, reactions of BzO-DFs with arylboronic acids and arylmagnesium/alkylzinc reagents afforded the desired gem-difluoroenol ethers and gem-difluoroalkenes in good yields. The Ni-catalyzed coupling reactions features highly regioselective C(vinyl)–O(benzoate) bond activation of the BzO-DFs. Results from control experiments and DFT calculations are consistent with a mechanism involving initial oxidative addition of the BzO-DFs by the Ni(0) complex. By virtue of diversity of the BzO-DFs and excellent functional group tolerance, this method is amenable to late-stage functionalization of multifunctionalized bioactive molecules.

Date: 2021
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DOI: 10.1038/s41467-020-20725-9

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