Abstract: Objective To introduce an extremely electronegative fluorine atom into the aromatic structure of 2-hydroxy-2-trifluoromethyl-3-thiophene-5-chromone C₂₃H₂₁BrF₃NO₃S, so as to obtain a target compound with enhanced lipid solubility and stability. Methods In the current study, p-bromobenzaldehyde, dammidone, 4,4,4-trifluoro-1-(thiophen-2-yl)butane-1,3-dione and ammonium acetate were used as raw materials, while a small amount of ethanol was used as the solvent. The target compound was synthesized by the multi-component one-pot method. The crystal structure was verified by ¹H-NMR and¹³C-NMR, IR, HRMS, and X-ray diffraction method and the angle of each surface was analyzed. Results The target product was obtained, that is 2-hydroxy-7,7-dimethy-3-(thiophene-2-carbony)-4-(p-bromophenyl)-2-(trifluoromethyl)-3,4,7,8-tetrahydro-5(6H)-chromone. The crystal structure was verified by ¹H-NMR and¹³C-NMR, IR, and HRMS. According to X-ray diffraction, the crystal structure belonged to the orthorhombic system, and the space group was Pbca. In addition, the direct method was used to analyze the crystal structure, and the atomic parameters corrected by the full matrix least square method showed that the final deviation factor was R=0.0464, and wR=0.113 3. The newly constructed pyridine ring in the molecular structure has a half-chair conformation. Conclusions The trifluoromethyl group was efficiently and conveniently introduced into the chromone framework through a multi-component reaction.