2,8-Bis(trifluoromethyl)-4-quinolinol

Chemical Properties

light grey powder

Uses

2,8-Bis(trifluoromethyl)-4-quinolinol is a simplified quinine derivative that exhibits the highest antifungal activity among its series and serves as a lead compound for further structural modification[6]. This compound acts as a starting material for synthesizing quinoline derivatives with various substitutions at the 4-OH position, including specific series such as compounds 4g–i[7-8]. It reacts with methyl chloroacetate in DMF using K2CO3 to form intermediates, and undergoes conversion to yield 4-bromo-2,8-bis(trifluoromethyl)quinoline[6].

Synthesis

2-(Trifluoromethyl)aniline (0.54 mL, 4.3 mmol) and ethyl 4,4,4-trifluoro-3-oxobutanoate (0.62 mL, 4.3 mmol) were mixed in a round-bottomed flask fitted with a large oval stir bar. Subsequently, polyphosphoric acid (4.0 g) was added to the reaction system. The reaction mixture was stirred at 120 °C for 3 h under nitrogen protection. Upon completion of the reaction, the reaction was quenched with ice water (50 mL) to give a golden-brown sticky substance. Extraction was carried out with dichloromethane (2 x 20 mL) and the organic layers were combined and dried over anhydrous magnesium sulfate. After filtration, the organic phase was concentrated under reduced pressure to give a beige solid product that did not require further purification (0.27 g, 23% yield).

References

[1] European Journal of Medicinal Chemistry,  2010,  vol. 45,  # 8,  p. 3374 - 3383
[2] Indian Journal of Chemistry, Section B:  Organic Chemistry Including Medicinal Chemistry,  2012,  vol. 51,  # 9,  p. 1411 - 1416,6
[3] Monatshefte fur Chemie,  2008,  vol. 139,  # 2,  p. 179 - 181
[4] Bioorganic and Medicinal Chemistry Letters,  2014,  vol. 24,  # 23,  p. 5466 - 5469
[5] CrystEngComm,  2018,  vol. 20,  # 16,  p. 2316 - 2323
[6] Chen, Y.-J., Ma, K.-Y., Du, S.-S., Zhang, Z.-J., Wu, T.-L., Sun, Y., Liu, Y.-Q., Yin, X.-D., Zhou, R., Yan, Y.-F., Wang, R.-X., He, Y.-H., Chu, Q.-R., Tang, C. (2021). Antifungal Exploration of Quinoline Derivatives against Phytopathogenic Fungi Inspired by Quinine Alkaloids. Journal of Agricultural and Food Chemistry, 69(41), 12156–12170. https://doi.org/10.1021/acs.jafc.1c05677
[7] Qin, L.-L., Yang, L., Zhang, Z.-J., Zhang, L.-J., Zhang, W., Jin, Y.-R., Luo, X.-F., Li, F.-P., Zhang, S.-Y., Bian, Q., Mou, G.-L., Dai, T.-L., Ma, L., Liu, Y.-Q. (2024). Design, Synthesis, and Biological Evaluation of Novel Quinoline Derivatives against Phytopathogenic Bacteria Inspired from Natural Quinine Alkaloids. Journal of Agricultural and Food Chemistry. https://doi.org/10.1021/acs.jafc.4c05509
[8] Bhagat, S., Arfeen, M., Das, G., Ramkumar, M., Khan, S. I., Tekwani, B. L., Bharatam, P. V. (2019). Design, synthesis and biological evaluation of 4-aminoquinoline-guanylthiourea derivatives as antimalarial agents. Bioorganic Chemistry, 91, 103094. https://doi.org/10.1016/j.bioorg.2019.103094