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, Wing Yiu Yu

Research output: Journal article publicationJournal articleAcademic researchpeer-review

3 Citations (Scopus)

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.

Original languageEnglish
Article number412
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - 18 Jan 2021

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this