Synlett 2019; 30(10): 1178-1182
DOI: 10.1055/s-0037-1611737
cluster
© Georg Thieme Verlag Stuttgart · New York

Electrochemical C(sp3)–H Fluorination

Yusuke Takahira
a  Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States   Email: pbaran@scripps.edu
,
Miao Chen
a  Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States   Email: pbaran@scripps.edu
,
Yu Kawamata
a  Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States   Email: pbaran@scripps.edu
,
Pavel Mykhailiuk
a  Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States   Email: pbaran@scripps.edu
b  Enamine Ltd., Chervonotkatska 78, 02094 Kyiv, , Ukraine and Taras Shevchenko National University of Kyiv, Chemistry Department, Volodymyrska 64, 01601 Kyiv, Ukraine
,
Hugh Nakamura
a  Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States   Email: pbaran@scripps.edu
,
Byron K. Peters
a  Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States   Email: pbaran@scripps.edu
,
Solomon H. Reisberg
a  Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States   Email: pbaran@scripps.edu
,
Chao Li
a  Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States   Email: pbaran@scripps.edu
,
Longrui Chen
c  Asymchem Life Science (Tianjin), Tianjin Economic-Technological Development Zone, Tianjin 300457, P. R of China
,
Tamaki Hoshikawa
d  Discovery, Medicine Creation, Neurology Business Group, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki, 300-2635, Japan
,
Tomoyuki Shibuguchi
d  Discovery, Medicine Creation, Neurology Business Group, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki, 300-2635, Japan
,
a  Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States   Email: pbaran@scripps.edu
› Author Affiliations

Financial support for this work was provided by the NSF (#1740656), Pfizer, AGC Inc. (to Y.T.), Nankai University (to M.C.), the George E. Hewitt Foundation (to Y.K.), a Fulbright Scholar Fellowship (to P.M.), JSPS (to H.N.), the Swedish Research Council (VR 2017-00362 to B.K.P.), NSF GRFP (#2017237151) and a Donald and Delia Baxter Fellowship (to S.H.R.).
Further Information

Publication History

Received: 23 January 2019

Accepted after revision: 27 January 2019

Publication Date:
01 March 2019 (online)


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.

Supporting Information

 
  • 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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