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
