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Synthesis of aryldifluoromethyl aryl ethers via nickel-catalyzed suzuki cross-coupling between aryloxydifluoromethyl bromides and boronic acids.

ABSTRACT: As a unique organofluorine fragment, gem-difluoromethylated motifs have received widespread attention. Here, a convenient and efficient synthesis of aryldifluoromethyl aryl ethers (ArCF₂OAr') was established via Nickel-catalyzed aryloxydifluoromethylation with arylboronic acids. This approach features easily accessible starting materials, good tolerance of functionalities, and mild reaction conditions. Diverse late-stage difluoromethylation of many pharmaceuticals and natural products were readily realized. Notably, a new difluoromethylated PD-1/PD-L1 immune checkpoint inhibitor was conveniently synthesized and showed both improved metabolic stability and enhanced antitumor efficacy. Preliminary mechanistic studies suggested the involvement of a Ni(I/III) catalytic cycle.

SUBMITTER: Lu H

PROVIDER: S-EPMC9814959 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Synthesis of aryldifluoromethyl aryl ethers via nickel-catalyzed suzuki cross-coupling between aryloxydifluoromethyl bromides and boronic acids.

Lu Heng H Xiao Ruo-Xuan RX Shi Chang-Yun CY Song Zi-Lan ZL Lin Hou-Wen HW Zhang Ao A

Communications chemistry 20220704 1

As a unique organofluorine fragment, gem-difluoromethylated motifs have received widespread attention. Here, a convenient and efficient synthesis of aryldifluoromethyl aryl ethers (ArCF<sub>2</sub>OAr') was established via Nickel-catalyzed aryloxydifluoromethylation with arylboronic acids. This approach features easily accessible starting materials, good tolerance of functionalities, and mild reaction conditions. Diverse late-stage difluoromethylation of many pharmaceuticals and natural products ...[more]

PMID: 36697792

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