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An unexpected synthesis and application of ethyl 2,4-bis(chloromethyl)-6-iodoquinoline-3-carboxylate

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Abstract

An unexpected and direct synthesis of ethyl 2,4-bis(chloromethyl)-6-iodoquinoline-3-carboxylate (3) from the chlorotrimethylsilane (TMSCl)-promoted Friedländer reaction between 1-(2-amino-5-iodophenyl)ethanone (2) and ethyl 4-chloro-3-oxobutanoate has been disclosed. As a versatile and attractive building block, a synthetic application of the poly-functionalized quinoline 3 in the successive Williamson ether synthesis with various phenols and in situ ester hydrolysis reaction has been achieved and the corresponding 2,4-bis(aroxymethyl)quinoline-3-carboxylic acids (5a-k) were obtained in good yields of 71–86%.

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Notes

  1. The yields, physical properties and spectral data for ethyl 2-(chloromethyl)-6-iodo-4-methyl quinoline-3-carboxylate: White solid, yield 27%, m.p. 113–115 °C; 1H NMR (CDCl3, 400 MHz) (δ, ppm): 1.54 (t, J = 7.6 Hz, 3H, CH2CH3), 2.85 (s, 3H, CH3), 4.63 (q, J = 7.6 Hz, 2H, CH2CH3), 5.15 (s, 2H, CH2Cl), 7.82 (dd, J = 8.8, 2.0 Hz, 1H, Quino-H), 8.03 (d, J = 2.0 Hz, 1H, Quino-H), 8.05 (d, J = 8.8 Hz, 1H, Quino-H).

  2. The yields, physical properties and spectral data for ethyl 6-bromo-2,4-bis(chloromethyl)quinoline-3-carboxylate: Yellow solid, yield 67%, m.p. 144–145 °C; 1H NMR (CDCl3, 400 MHz) (δ, ppm): 1.48 (t, J = 7.6 Hz, 3H, CH2CH3), 4.50 (q, J = 7.6 Hz, 2H, CH2CH3), 4.86 (s, 2H, CH2Cl), 5.28 (s, 2H, CH2Cl), 7.91 (dd, J = 8.8, 1.6 Hz, 1H, Quino-H), 8.05 (d, J = 8.8 Hz, 1H, Quino-H), 8.10 (d, J = 1.6 Hz, 1H, Quino-H); 13C NMR (CDCl3, 100 MHz) (δ, ppm): 15.17, 39.35, 48.24, 67.71, 129.69, 132.58, 132.86, 136.45, 138.56, 139.38, 145.48, 152.13, 161.51, 168.42; for ethyl 6-chloro-2,4-bis(chloromethyl)quinoline-3-carboxylate: Yellow, solid, yield 61%, m.p. 149–151 °C; 1H NMR (CDCl3, 400 MHz) (δ, ppm): 1.50 (t, J = 7.6 Hz, 3H, CH2CH3), 4.51 (q, J = 7.6 Hz, 2H, CH2CH3), 4.94 (s, 2H, CH2Cl), 5.27 (s, 2H, CH2Cl), 7.78 (dd, J = 8.8, 2.0 Hz, 1H, Quino-H), 7.91 (d, J = 2.0 Hz, 1H, Quino-H), 8.08 (d, J = 8.4 Hz, 1H, Quino-H); 13C NMR (CDCl3, 100 MHz) (δ, ppm): 14.17, 37.81, 45.90, 62.18, 119.40, 122.11, 127.76, 130.38, 130.57, 135.71, 140.11, 146.29, 155.95, 165.06.

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Acknowledgements

The authors would like to thank the Doctoral Start-up Foundation of Liaoning Province (Grant No. 2019-BS-004) and the Scientific Research Foundation of the Education Department of Liaoning Province (Grant No. LQ2019006).

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Authors and Affiliations

  1. Institute of Superfine Chemicals, Bohai University, Jinzhou, 121000, People’s Republic of China

    Yang Li, Shiyu Dong & Bingyue Tang

  2. College of Land and Environmental Science, Shenyang Agricultural University, Shenyang, 110866, People’s Republic of China

    Hongtao Zou

  3. College of Life Science, Yan’an University, Yan’an, 712100, People’s Republic of China

    Wenting Jiang

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  1. Yang Li
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Li, Y., Dong, S., Tang, B. et al. An unexpected synthesis and application of ethyl 2,4-bis(chloromethyl)-6-iodoquinoline-3-carboxylate. Res Chem Intermed 46, 2215–2228 (2020). https://doi.org/10.1007/s11164-020-04088-w

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