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Synlett 2018; 29(11): 1525-1529
DOI: 10.1055/s-0037-1610130
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© Georg Thieme Verlag Stuttgart · New York

Copper-Catalyzed Direct C-5 Fluorination of 8-Aminoquinolines by Remote C–H Activation

Si-Si Luo
a   School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, 430074, P. R. of China   Email: sunh15@163.com   Email: jkliu@mail.kib.ac.cn
,
Lan-Jun Su
a   School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, 430074, P. R. of China   Email: sunh15@163.com   Email: jkliu@mail.kib.ac.cn
,
Yue Jiang
a   School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, 430074, P. R. of China   Email: sunh15@163.com   Email: jkliu@mail.kib.ac.cn
,
Xiao-Bao Li
b   Department of Civil and Environmental Engineering, Northwestern University, Evanston, IL, 60060, USA
,
Zheng-Hui Li
a   School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, 430074, P. R. of China   Email: sunh15@163.com   Email: jkliu@mail.kib.ac.cn
,
Huan Sun*
a   School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, 430074, P. R. of China   Email: sunh15@163.com   Email: jkliu@mail.kib.ac.cn
,
Ji-Kai Liu*
a   School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, 430074, P. R. of China   Email: sunh15@163.com   Email: jkliu@mail.kib.ac.cn
› Author AffiliationsThe authors gratefully acknowledge funding from National Natural Science Foundation of China (81561148013, 31560010, 21502239), Key Projects of Technological Innovation of Hubei Province (No. 2016ACA138), Hubei Provincial Natural Science Foundation of China (2018CFB222), "the Fundamental Research Funds for the Central ­Universities", South-Central University for Nationalities (CZQ17008).
Further Information

Publication History

Received: 02 February 2018

Accepted after revision: 06 April 2018

Publication Date:
16 May 2018 (online)

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Abstract

A convenient method was developed for direct regioselective fluorination of 8-aminoquinolines at the C-5 position by copper-catalyzed remote C–H activation using Selectfluor as the electrophile fluorinating reagent. With this method, diverse fluorinated quinoline derivatives were facilely obtained under mild conditions with moderate yields.

Key words

fluorination - copper-catalyzed - 8-aminoquinolines - Selectfluor - remote C–H activation

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0037-1610130.
  • Supporting Information

Primary Data

    for this article are available online at https://doi.org/10.1055/s-0037-1610130. Please note that the DOI for the Primary Data associated with this article was updated on April 20, 2021 and is now 10.4125/pd0088th.
  • Primary Data
 

  • References and Notes

  • 2 Hamer FM. J. Chem. Soc., Trans. 1921; 119: 1432
    CrossrefPubMedSearch in Google Scholar
  • 5 Zaitsev VG. Shabashov D. Daugulis O. J. Am. Chem. Soc. 2005; 127: 13154
    CrossrefPubMedSearch in Google Scholar
  • 6 Sun H. Zhang Y. Chen P. Wu Y.-D. Zhang X. Huang Y. Adv. Synth. Catal. 2016; 358: 1946
    CrossrefPubMedSearch in Google Scholar
  • 9 Suess AM. Ertem MZ. Cramer CJ. Stahl SS. J. Am. Chem. Soc. 2013; 135: 9797
    CrossrefPubMedSearch in Google Scholar
  • 11 Whiteoak CJ. Planas O. Company A. Ribas X. Adv. Synth. Catal. 2016; 358: 1679
    CrossrefPubMedSearch in Google Scholar
  • 12 Liang HW. Jiang K. Ding W. Yuan Y. Shuai L. Chen YC. Wei Y. Chem. Commun. 2015; 51: 16928
    PubMedSearch in Google Scholar
  • 13 Dou YD. Xie ZD. Shen C. Zhang PF. Zhu Q. ChemCatChem 2016; 8: 3570
    Search in Google Scholar
  • 14 Du C. Li P.-X. Zhu X. Suo J.-F. Niu J.-L. Song M.-P. Angew. Chem. Int. Ed. 2016; 55: 13571
    PubMedSearch in Google Scholar
  • 15 Sun MM. Sun SY. Qiao HJ. Yang F. Zhu Y. Kang JX. Wu YS. Wu YJ. Org. Chem. Front. 2016; 3: 1646
    Search in Google Scholar
  • 21 Ding J. Zhang Y. Li J. Org. Chem. Front. 2017; 4: 1528
    Search in Google Scholar
  • 22 Fluorinated Product 2a–t, General Procedure 8-Aminoquinoline derivatives 1 (0.1 mmol, 1.0 equiv), Cu(OAc)2 (0.02 mmol, 0.2 equiv), Selectfluor (0.15 mmol, 1.5 equiv), KH2PO4 (0.2 mmol, 2.0 equiv), and Na2SO4 (50 mg) were weighed into an oven-dried Schlenk tube, and MeOH (1 mL) was added. The reaction vessel was capped and vacuum-flushed with N2 three times. The reaction was stirred under N2 atmosphere at 80 °C, and the progress of the fluorination was monitored by TLC. Upon complete consumption of 1, the reaction was cooled to room temperature. Volatile solvent and reagents were removed by rotary evaporation, and the residue was purified by silica gel flash chromatography using PE/EtOAc (100:1 to 20:1) to afford fluorinated product 2. N-(5-Fluoroquinolin-8-yl)-4-methylbenzamide (2a) 45% yield, white solid. 1H NMR (600 MHz, chloroform-d): δ = 10.52 (s, 1 H), 8.94–8.85 (m, 2 H), 8.47 (dd, J = 8.4, 1.7 Hz, 1 H), 8.01–7.94 (m, 2 H), 7.56 (dd, J = 8.4, 4.2 Hz, 1 H), 7.40–7.33 (m, 2 H), 7.30–7.27 (m, 1 H), 2.46 (s, 3 H). 13C NMR (151 MHz, chloroform-d): δ = 165.48 , 153.87 (d, J = 250.7 Hz), 149.22, 142.55, 139.09 (d, J = 3.0 Hz), 132.28, 131.35 (d, J = 3.0 Hz), 129.98 (d, J = 3.0 Hz), 129.62, 127.37, 121.87 (d, J = 3.0 Hz), 119.00 (d, J = 3.0 Hz), 116.09 (d, J = 7.6 Hz), 110.72 (d, J = 19.6 Hz), 21.71. 19F NMR (565 MHz, chloroform-d): δ = –129.22. HRMS (ESI): m/z calcd for C17H14ON2F [M + H]+: 281.1090; found: 281.1086. 4-Fluoro-N-(5-fluoroquinolin-8-yl)benzamide (2g) 38% yield, white solid. 1H NMR (600 MHz, chloroform-d): δ = 10.50 (s, 1 H), 8.91 (dd, J = 4.2, 1.6 Hz, 1 H), 8.87 (dd, J = 8.6, 5.3 Hz, 1 H), 8.48 (dd, J = 8.4, 1.7 Hz, 1 H), 8.12–8.06 (m, 2 H), 7.57 (dd, J = 8.4, 4.2 Hz, 1 H), 7.30–7.23 (m, 3 H). 13C NMR (151 MHz, chloroform-d): δ = 165.83, 164.23, 164.16, 153.89 (d, J = 252.2 Hz), 149.16, 138.92 (d, J = 3.0 Hz), 131.16 (d, J = 3.0 Hz), 130.96 (d, J = 4.5 Hz), 129.95 (d, J = 4.5 Hz), 129.64 (d, J = 9.1 Hz), 121.82 (d, J = 1.5 Hz), 118.90 (d, J = 18.1 Hz), 116.07 (d, J = 9.1 Hz), 115.97 (d, J = 22.6 Hz), 110.59 (d, J = 19.6 Hz). 19F NMR (565 MHz, chloroform-d): δ = –107.51, –128.74. HRMS (ESI): m/z calcd for C16H11ON2F2 [M + H]+: 285.0839; found: 285.0833. N-(5-Fluoroquinolin-8-yl)-2,6-dimethoxybenzamide (2i) 34% yield, white solid. 1H NMR (600 MHz, chloroform-d): δ = 10.10 (s, 1 H), 8.99 (dd, J = 7.6, 1.3 Hz, 1 H), 8.78 (dd, J = 4.2, 1.7 Hz, 1 H), 8.18 (dd, J = 8.2, 1.7 Hz, 1 H), 7.61 (t, J = 7.9 Hz, 1 H), 7.56 (dd, J = 8.3, 1.4 Hz, 1 H), 7.45 (dd, J = 8.2, 4.2 Hz, 1 H), 7.14 (dd, J = 11.2, 9.1 Hz, 1 H), 6.64 (dd, J = 9.2, 3.3 Hz, 1 H), 4.01 (d, J = 1.9 Hz, 3 H), 3.83 (s, 3 H). 13C NMR (151 MHz, chloroform-d): δ = 162.92 (d, J = 3.0 Hz), 153.18 (d, J = 3.0 Hz), 150.80 (d, J = 241.6 Hz), 148.35, 145.77 (d, J = 12.1 Hz) 138.60, 136.44, 134.76, 128.10, 127.60, 121.97, 121.73, 117.79 (d, J = 21.1 Hz), 117.01, 106.10 (d, J = 7.6 Hz), 62.32 (d, J = 4.5 Hz), 56.49. 19F NMR (565 MHz, chloroform-d): δ = –139.30, –139.33. HRMS (ESI): m/z calcd for C18H16O3N2F [M + H]+: 327.1145; found: 327.1140. 2,3,4,5,6-Pentafluoro-N-(5-fluoroquinolin-8-yl)benzamide (2j) 23% yield, white solid. 1H NMR (600 MHz, chloroform-d): δ = 10.19 (s, 1 H), 8.87 (ddd, J = 4.7, 3.0, 1.7 Hz, 1 H), 8.83 (ddd, J = 8.9, 5.3, 3.8 Hz, 1 H), 8.48 (ddd, J = 8.4, 4.2, 1.7 Hz, 1 H), 7.58 (ddd, J = 8.5, 4.2, 2.9 Hz, 1 H), 7.32–7.27 (m, 1 H). 13C NMR (151 MHz, chloroform-d): δ = 155.23, 154.61 (d, J = 253.7 Hz), 149.49, 145.35 (m), 143.66 (m), 141.81 (m), 138.65 (m), 136.98 (m), 130.07 (m), 122.08, 118.90 (dd, J = 18.4, 3.6 Hz), 116.99 (d, J = 9.1 Hz), 116.94 (m), 110.51(dd, J = 19.6, 2.8 Hz). 19F NMR (565 MHz, chloroform-d): δ = –126.79, –139.92 (d, J = 19.0 Hz), –149.94 (d, J = 20.9 Hz), –149.99, –159.64 (t, J = 19.2 Hz). HRMS (ESI): m/z calcd for C16H7ON2F6 [M + H]+: 357.0463; found: 357.0457.