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

Bingnan Du,Chun-Ming Chan,Zhenyang Lin,Xin Xu,Leong-Hung Cheung,Wing-Yiu Yu,Pui-Yiu Lee

doi:10.1038/s41467-020-20725-9

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.

Highlights

Gem-Difluoroalkene is a bioisostere of carbonyl group for improving bioavailability of drug candidates
Katz and co-workers reported the preparation of stable potassium trifluoroborate gem-difluoroenol ethers, which would deliver the gem-difluoroenol ethers by cross-coupling with aryl halides under palladium catalysis[41]
The BzO-DFs serve as versatile building blocks for synthesis of diverse gem-difluoroenol ethers and gem-difluoroalkenes by Ni-catalyzed arylation and alkylation using nucleophiles such as arylboronic acids, arylmagnesium bromides, alkylzinc bromides, potassium alkyltrifluoroborates

Summary

Introduction

Gem-Difluoroalkene is a bioisostere of carbonyl group for improving bioavailability of drug candidates. Transition metal-catalyzed defluorinative cross-coupling reactions are attracting considerable attention for the synthesis of structurally diverse gem-difluoroalkenes (Fig. 1b)[23,24,25,26]. The BzO-DFs serve as versatile building blocks for synthesis of diverse gem-difluoroenol ethers and gem-difluoroalkenes by Ni-catalyzed arylation and alkylation using nucleophiles such as arylboronic acids, arylmagnesium bromides, alkylzinc bromides, potassium alkyltrifluoroborates.

Results

Conclusion