Predictable site-selective radical fluorination of tertiary ethers

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  • ReceivedOct 5, 2019
  • AcceptedOct 10, 2019
  • PublishedNov 13, 2019


Funded by

the National Natural Science Foundation of China(21702098,21732003,21672099)

and “1000-Youth Talents Plan”. Mr. Xu was supported by the Scientific Research Foundation of Graduate School of Nanjing University(2018CL05)


This work was supported by the National Natural Science Foundation of China (21971108, 21702098), the Natural Science Foundation of Jiangsu Province (BK20190006), Fundamental Research Funds for the Central Universities (020514380176), “Jiangsu Six Peak Talent Project”, “1000-Youth Talents Plan’’, and start-up funds from Nanjing University. Mr. Xu was supported by the Scientific Research Foundation of Graduate School of Nanjing University (2018CL05).

Interest statement

The authors declare that they have no conflict of interest.


The supporting information is available online at http://chem.scichina.com and http://link.springer.com/journal/11426. The supporting materials are published as submitted, without typesetting or editing. The responsibility for scientific accuracy and content remains entirely with the authors.


[1] Remete AM, Nonn M, Fustero S, Fülöp F, Kiss L. Tetrahedron, 2018, 74: 6367-6418 CrossRef Google Scholar

[2] Müller K, Faeh C, Diederich F, Purser S, Moore PR, Swallow S, Gouverneur V. Science, 2007, 317: 1881-1886 CrossRef PubMed ADS Google Scholar

[3] Campbell MG, Ritter T, Yan H, Zhu C, Szpera R, Moseley DFJ, Smith LB, Sterling AJ, Gouverneur V. Chem Rev, 2015, 115: 612-633 CrossRef PubMed Google Scholar

[4] Champagne PA, Desroches J, Hamel JD, Vandamme M, Paquin JF, Liang T, Neumann CN, Ritter T. Chem Rev, 2015, 115: 9073-9174 CrossRef PubMed Google Scholar

[5] Patrick TB, Johri KK, White DH, Yin F, Wang Z, Li Z, Li C, Ventre S, Petronijevic FR, MacMillan DWC, Wang Z, Guo CY, Yang C, Chen JP. J Org Chem, 1983, 48: 4158-4159 CrossRef Google Scholar

[6] Li Z, Wang Z, Zhu L, Tan X, Li C. J Am Chem Soc, 2014, 136: 16439-16443 CrossRef PubMed Google Scholar

[7] Nishikata T, Ishida S, Fujimoto R, Chen H, Liu Z, Lv Y, Tan X, Shen H, Yu HZ, Li C. Angew Chem Int Ed, 2016, 55: 10008-10012 CrossRef PubMed Google Scholar

[8] Bloom S, Knippel JL, Lectka T, Halperin SD, Fan H, Chang S, Martin RE, Britton R, Liu W, Huang X, Cheng MJ, Nielsen RJ, Goddard WA, Groves JT, West JG, Bedell TA, Sorensen EJ, Xia JB, Zhu C, Chen C, Bloom S, McCann M, Lectka T. Chem Sci, 2014, 5: 1175-1178 CrossRef Google Scholar

[9] Brioche J, González-Esguevillas M, Miró J, Jeffrey JL, MacMillan DWC, Su JY, Grünenfelder DC, Takeuchi K, Reisman SE. Tetrahedron Lett, 2018, 59: 4387-4391 CrossRef Google Scholar

[10] Xu W, Ma J, Yuan XA, Dai J, Xie J, Zhu C. Angew Chem Int Ed, 2018, 57: 10357-10361 CrossRef PubMed Google Scholar

[11] Shaw MH, Twilton J, MacMillan DWC, Marzo L, Pagire SK, Reiser O, König B, Xie J, Jin H, Hashmi ASK, Chen Y, Lu LQ, Yu DG, Zhu CJ, Xiao WJ. J Org Chem, 2016, 81: 6898-6926 CrossRef PubMed Google Scholar

[12] Capaldo L, Ravelli D. Eur J Org Chem, 2017, 2017(15): 2056-2071 CrossRef PubMed Google Scholar

[13] Zhou N, Yuan XA, Zhao Y, Xie J, Zhu C, Zhang M, Yuan XA, Zhu C, Xie J. Angew Chem Int Ed, 2018, 57: 3990-3994 CrossRef PubMed Google Scholar

[14] Borodkin GI, Shubin VG. Russ Chem Rev, 2019, 88: 160-203 CrossRef ADS Google Scholar

[15] Talukdar R. Synlett, 2019, 30: 1713-1718 CrossRef Google Scholar

[16] Middleton WJ, Umemoto T, Singh RP, Xu Y, Saito N. J Org Chem, 1975, 40: 574-578 CrossRef Google Scholar

[17] Hayashi H, Sonoda H, Fukumura K, Nagata T, Sladojevich F, Arlow SI, Tang P, Ritter T, Li L, Ni C, Wang F, Hu J. Chem Commun, 2002, : 1618-1619 CrossRef PubMed Google Scholar

[18] Nielsen MK, Ugaz CR, Li W, Doyle AG. J Am Chem Soc, 2015, 137: 9571-9574 CrossRef PubMed Google Scholar

[19] Guo J, Kuang C, Rong J, Li L, Ni C, Hu J. Chem Eur J, 2019, 25: 7259-7264 CrossRef PubMed Google Scholar

[20] Jeffrey JL, Terrett JA, MacMillan DWC, Zhang X, MacMillan DWC, Tanaka H, Sakai K, Kawamura A, Oisaki K, Kanai M. Science, 2015, 349: 1532-1536 CrossRef PubMed ADS Google Scholar

[21] Hua AM, Bidwell SL, Baker SI, Hratchian HP, Baxter RD, Egami H, Masuda S, Kawato Y, Hamashima Y, Danahy KE, Cooper JC, Van Humbeck JF. ACS Catal, 2019, 9: 3322-3326 CrossRef Google Scholar

  • Scheme 1

    The prevalence of tertiary alkyl fluorides in bioactive compounds (a) and general radical fluorination strategies (b) (color online).

  • Scheme 2

    Mechanistic hypothesis (radical chain pathway was added: path B) (color online).

  • Scheme 3

    Scope of the ethers in 0.2 mmol scale (yields of isolated products are given) (color online).

  • Scheme 4

    Late-stage modification of complex molecules. See Supporting Information online for details of conditions (color online).

  • Scheme 5

    Consecutive procedures for C–O bond radical fluorination of complex tertiary alcohols (color online).

  • Scheme 6

    The mechanistic investigation. (a) Radical inhibition experiments; (b) radical-clock experiments; (c) luminescence quenching experiments (color online).

  • Table 1   Optimization of the reaction conditions


    Variation of standard conditions

    Yield b) (%)



    81 (75)


    2b instead of 2a



    2c instead of 2a



    2d instead of 2a



    DBU c) instead of DBN



    Quinuclidine instead of DBN



    N-phenylmethanesulfonamide instead of DBN



    1 equiv. DBN



    0.1 equiv. DBN



    No DBN



    No photocatalyst





    Standard conditions: 1a (0.2 mmol), 2a (2 mol%), DBN (50 mol%), Selectfluor (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), 3 equiv.), MeCN (3 mL), blue LEDs, room temperature, 12 h. b) Measured by GC using acetophenone as internal standard. The isolated yield was given in the parentheses. c) DBU=1,8-diazabicyclo [5.4.0] undec-7-ene.


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