Electrochemical C(sp3)–H Fluorination

Yusuke Takahira; Miao Chen; Yu Kawamata; Pavel Mykhailiuk; Hugh Nakamura; Byron K. Peters; Solomon H. Reisberg; Chao Li; Longrui Chen; Tamaki Hoshikawa; Tomoyuki Shibuguchi; Phil S. Baran

doi:10.1055/s-0037-1611737

Synlett, Table of Contents

Synlett 2019; 30(10): 1178-1182
DOI: 10.1055/s-0037-1611737

cluster

Electrochemical C(sp³)–H Fluorination

Yusuke Takahira

^aDepartment of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States Email: pbaran@scripps.edu

,

Miao Chen

^aDepartment of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States Email: pbaran@scripps.edu

,

Yu Kawamata

^aDepartment of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States Email: pbaran@scripps.edu

,

Pavel Mykhailiuk

^aDepartment of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States Email: pbaran@scripps.edu

^bEnamine Ltd., Chervonotkatska 78, 02094 Kyiv, , Ukraine and Taras Shevchenko National University of Kyiv, Chemistry Department, Volodymyrska 64, 01601 Kyiv, Ukraine

,

Hugh Nakamura

^aDepartment of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States Email: pbaran@scripps.edu

,

Byron K. Peters

^aDepartment of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States Email: pbaran@scripps.edu

,

Solomon H. Reisberg

^aDepartment of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States Email: pbaran@scripps.edu

,

Chao Li

^aDepartment of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States Email: pbaran@scripps.edu

,

Longrui Chen

^cAsymchem Life Science (Tianjin), Tianjin Economic-Technological Development Zone, Tianjin 300457, P. R of China

,

Tamaki Hoshikawa

^dDiscovery, Medicine Creation, Neurology Business Group, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki, 300-2635, Japan

,

Tomoyuki Shibuguchi

^dDiscovery, Medicine Creation, Neurology Business Group, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki, 300-2635, Japan

,

Phil S. Baran *

^aDepartment of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States Email: pbaran@scripps.edu

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Abstract

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Published as part of the Cluster Electrochemical Synthesis and Catalysis

Abstract

A simple and robust method for electrochemical alkyl C–H fluorination is presented. Using a simple nitrate additive, a widely available fluorine source (Selectfluor), and carbon-based electrodes, a wide variety of activated and unactivated C–H bonds are converted into their C–F congeners. The scalability of the reaction is also demonstrated with a 100 gram preparation of fluorovaline.

Key words

organic synthesis - electrochemistry - fluorination - C–H functionalization - radicals

Full Text

References

References and Notes

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7 General procedure for C(sp³)–H fluorination: To a 5 mL undivided ElectraSyn vial equipped with a stir bar was added substrate (0.30 mmol), Selectfluor (A) (3.0 equiv, 319 mg, 0.90 mmol), NaNO₃ (0.2 equiv, 5.1 mg, 0.06 mmol), and MeCN (3.0 mL). The vial cap equipped with a pair of RVC electrodes was screwed on, and the headspace of the vial was purged with Ar using a balloon, syringe and needle assembly prior to electrolysis. The reaction parameters of the ElectraSyn device were set up as follows: constant current, 3.0 mA; no reference electrode; total charge, 0.30 mmol substrate, ranging from 0.25 to 3.0 F/mol; alternate polarity, 2 min; stirring, 600 rpm. The mixture was electrolyzed under Ar atmosphere until complete or reasonable consumption of the starting material as judged by TLC. After electrolysis, the cap was removed, and the electrodes were taken out and rinsed with MeCN into the reaction mixture. The reaction mixture was poured into saturated aqueous NaHCO₃ and extracted with CH₂Cl₂. The combined organics were washed with brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crude material was purified by silica gel column chromatography or preparative thin-layer chromatography to furnish the desired product. See the Supporting Information for full details and graphical guide.
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Supplementary Material

Supporting Information