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Etherification of Fluoroarenes with Alkoxyboronic Acid Pinacol Esters via C-F Bond Cleavage

Jun Zhou, Bingyao Jiang, Zhengyu Zhao and Norio Shibata*

*Department of Nanopharmaceutical Sciences, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan, Email: nozshibanitech.ac.jp

J. Zhou, B. Jiang, Z. Zhao, N. Shibata, Org. Lett., 2022, 24, 5084-5089.

DOI: 10.1021/acs.orglett.2c01864


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Abstract

KHMDS mediates a defluoroetherification of aryl and heteroaryl fluorides with alkoxyboronic acid pinacol esters under transition-metal-free conditions to efficiently and safely provide a wide variety of aryl ethers in high yields. This method can be applied to the late-stage etherification of structurally complex bioactive compounds.

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proposed mechanism



General procedure for the preparation of ROBpin

In an argon gas-filled glovebox, alcohol (1.0 mmol) and CDCl3 (0.5 mL) were added to a sample vial equipped with a magnetic stir bar. Subsequently, pinacol borane (152 L, 1.05 mmol) was added to the reaction mixture, and the reaction was left stirring at room temperature until the reaction was complete (1-5 h). After 1H NMR analysis, concentration under vacuum affords the desired product RO-Bpin. The RO-Bpin was used directly without further purification.

General procedure for the etherification of fluoroarenes with ROBpin via C-F bond cleavage

To a flame-dried screw-capped test tube were added a fluoroarenes (0.2 mmol, 1.0 equiv), ROBpin (commercially available or freshly prepared, 0.3 mmol, 1.5 equiv), KHMDS (120 mg, 3.0 equiv), and DME (2.0 mL) in a glovebox filled with nitrogen gas. The tube was then sealed and removed from the glovebox. The solution was stirred for 12 h at 110 C using a liquid phase organic synthesizer SIBATA CP-1000. The reaction tube was cooled to room temperature, followed by the addition of n-hexane (5 mL). The reaction mixture was then filtered through a short silica pad, washed with ethyl acetate, and concentrated under vacuum, followed by 3-fluoropyridine (8.6 μL, 0.1 mmol) as an internal standard. After NMR analysis was conducted, the mixture was concentrated again to afford residue, which was purified by column chromatography on silica gel to give the corresponding aryl ethers.


Key Words

etherification


ID: J54-Y2022