4-[4-(Trifluoromethyl)phenoxy]benzaldehyde

Intermediate 52: 4-{[4-(Trifluoromethyl)phenyl]oxy}benzaldehyde; To a solution of the commercially available of 4-(trifluoromethyl)phenol (9.1 g, 56 mmol, 1.2 equiv.) in DMF (100 mL) was added successively cesium carbonate (22.8 g, 70 mmol, 1.5 equiv.) and 4-fluorobenzaldehyde (5 mL, 46.6 mmol) at room temperature. The reaction mixture was then stirred at 85°C for 16h before being cooled and filtered. The resulting filtrate was concentrated to dryness and the crude oil was purified by flash chromatography (SiOTo a homogeneous mixture of 4-(trifluoromethyl)phenol (1.2 g, 7.5 mmol) and 4-fluorobenzaldehyde (0.8 mL, 7.5 mmol) in anhydrous DMF (15 mL), under an argon atmosphere, was added potassium carbonate (1.04 g, 7.5 mmol). The mixture was heated at 150 °C for 4 h before being poured over ice. The resultant precipitate was isolated by vacuum filtration, washed thoroughly with water, dried under vacuum to afford the desired compound (1.4 g, 70percent) as a cream colored solid, which was used without further purification. MS (ESI): 267.1 (M + H)General procedure: Under an argon atmosphere, a Schlenk tube was charged with MCM-41-2N-Cu(OAc)2(46 mg, 0.025 mmol), nitroarene 1 (0.5 mmol), phenol 2 (1.0 mmol), Cs2CO3 (1.0 mmol) and DMF (3 mL). The reaction mixture was stirred at 100 °C for 5 h under Ar. After being cooled to room temperature, the mixture was diluted with ethyl acetate (20 mL) and filtered. The MCM-41-2N-Cu(OAc)2 catalyst was washed with distilled water (2 × 5 mL), DMF (2 × 5 mL) and EtOH (2 × 5 mL) and could be reused in the next run. The filtrate was washed with water (2 × 10 mL) and dried over anhydrous MgSO4. After removal of the solvent under reduced pressure, the residue was purified by column chromatography (EtOAc/hexane) on silica gel to afford the desired product 3.General procedure: Under N4- (4- (trifluoromethyl) phenoxy) benzaldehyde (2.66 g, 10 mmol) and 2-aminopyridine (0.94 g, 10 mmol) were dissolved in 10 mL of dichloromethane, and the reaction was stirred at room temperature for 30 min; The reaction was concentrated under reduced pressure at 90 C for 1h, and then 10 mL of dichloromethane was added and stirred at room temperature for 30min. The reaction was then concentrated under reduced pressure at 90 C for 1h. This cycle was performed three times, and LC-MS was used to detect whether the target product was formed.The title compound was obtained as a crude product (yellow viscous substance, 2.61 g, yield: 75.8%).Sodium borohydride (0.55g, 14mmol) was dissolved in methanol / THF (40mL, v / v = 1: 3), Stir the reaction at room temperature for 10min.A solution of N- (4- (4- (trifluoromethyl) phenoxy) benzylidene) pyridin-2-amine (2.71 g, 7 mmol) in THF (20 mL) obtained by the reaction was slowly dropped into the above boron. In the solution of sodium hydride; after the dropwise addition, the reaction was carried out at room temperature for 10 hours, Slowly add 8mL of hydrochloric acid (1N) and stir for 5min.Then add water (40 mL) and stir vigorously for 10 min.Ethyl acetate was added for extraction, and the organic phase was washed with sodium hydroxide (1N, 30 mL), The organic phase was dried over anhydrous sodium sulfate for 1 h, filtered, and the filtrate was concentrated under reduced pressure, and separated by silica gel column chromatography [petroleum ether / ethyl acetate (v / v) = 5: 1], The title compound was obtained (light yellow oil, 2.3 g, yield: 69.2%).Intermediate 52: 4-{[4-(Trifluoromethyl)phenyl]oxy}benzaldehyde; To a solution of the commercially available of 4-(trifluoromethyl)phenol (9.1 g, 56 mmol, 1.2 equiv.) in DMF (100 mL) was added successively cesium carbonate (22.8 g, 70 mmol, 1.5 equiv.) and 4-fluorobenzaldehyde (5 mL, 46.6 mmol) at room temperature. The reaction mixture was then stirred at 85C for 16h before being cooled and filtered. The resulting filtrate was concentrated to dryness and the crude oil was purified by flash chromatography (SiO2, cyclohexane/ethyl acetate 70/30) to give the title compound (9.0 g, 73% yield) as a colorless oil. 1H NMR (CDCI3) delta 9.97 (s, 1 H), 7.91 (m, 2H), 7.67 (d, J = 8.6 Hz, 2H), 7.20-7.11 (m, 4H). LCMS: (M+H)+ = 267, Rt= 3.53 min.To a homogeneous mixture of 4-(trifluoromethyl)phenol (1.2 g, 7.5 mmol) and 4-fluorobenzaldehyde (0.8 mL, 7.5 mmol) in anhydrous DMF (15 mL), under an argon atmosphere, was added potassium carbonate (1.04 g, 7.5 mmol). The mixture was heated at 150 C for 4 h before being poured over ice. The resultant precipitate was isolated by vacuum filtration, washed thoroughly with water, dried under vacuum to afford the desired compound (1.4 g, 70%) as a cream colored solid, which was used without further purification. MS (ESI): 267.1 (M + H)+.P-fluorobenzaldehyde (2.48g, 20mmol), p-trifluoromethylphenol (3.24g, 20mmol), and potassium carbonate (4.16g, 30mmol) were mixed in 30mL of DMF solution, and heated to 160 C under the protection of nitrogen. The reaction, after the reaction is completed, cool to room temperature, add 30mL of ice water, and stir for 30min to precipitate a solid, suction filter, wash the filter cake with water, The title compound was obtained (light yellow solid, 0.86 g, yield: 16%). A mixture of 4-(trifluoromethyl)phenol (4.86 g, 1 equiv), 4-fluorobenzaldehyde (3.22 mL, 1 equiv), potassium carbonate (4.15 g, 1 equiv) and dimethylformamide (60 mL) was stirred at 150 C. under argon for 3 hours, then poured into ice/water. The precipitate was filtered off, washed with water, then extracted with hot ethanol. Undissolved solid was removed by filtration, and the filtrate evaporated and purified by chromatography on silica. 1H-NMR (CDCl3) delta 7.14 (4H, m), 7.66 (2H, m), 7.90 (2H, m), 9.97 (1H, s); MS (APCI+) found (M+1)=267; C14H9F3O2 requires 266.General procedure: Under an argon atmosphere, a Schlenk tube was charged with MCM-41-2N-Cu(OAc)2(46 mg, 0.025 mmol), nitroarene 1 (0.5 mmol), phenol 2 (1.0 mmol), Cs2CO3 (1.0 mmol) and DMF (3 mL). The reaction mixture was stirred at 100 C for 5 h under Ar. After being cooled to room temperature, the mixture was diluted with ethyl acetate (20 mL) and filtered. The MCM-41-2N-Cu(OAc)2 catalyst was washed with distilled water (2 × 5 mL), DMF (2 × 5 mL) and EtOH (2 × 5 mL) and could be reused in the next run. The filtrate was washed with water (2 × 10 mL) and dried over anhydrous MgSO4. After removal of the solvent under reduced pressure, the residue was purified by column chromatography (EtOAc/hexane) on silica gel to afford the desired product 3.General procedure: Under N2 atmosphere, a Schlenk tube was charged with nitroarenes 1 (0.5 mmol), phenols 2 (1.0 mmol), Cu(OAc)2·H2O (5 mol %), and Cs2CO3 (1.0 mmol) in DMF (3 mL) at room temperature. After that, the mixture was stirred constantly at 100 C (oil bath temperature) for 4 h. After the completion of the reaction, as monitored by TLC and GC-MS analysis, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtrated. The filtrate was concentrated under vacuum, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to afford the desired arylated product 3.Intermediate 56: (4-{r4-(Trifluoromethvl)phenvlloxy}phenvl)methanol (FCAF/U1555/180/1); To a solution of 4-{[4-(Trifluoromethyl)phenyl]oxy}benzaldehyde (Intermediate 52, 9 g, 34 mmol) in THF at 00C was added drop wise LiAIH4 (17 mL, 1 M in THF, 17 mmol, 0.7 equiv.). After the addition was complete, the reaction mixture was allowed to warm to RT for 4h before being quenched with wet Na2SO4. Water was added and the aqueous layer was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (9 g, 99% yield) as a white powder. 1H NMR (CDCI3) delta 7.58 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.6 Hz, 2H), 7.06 (d, J = 8.2 Hz, 2H), 7.05 (d, J = 8.6 Hz, 2H), 4.72 (s, 2H). LCMS : (M-H)= 267, Rt= 3.24 min.

Molecular Weight:266.21
XLogP3:3.8
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:3
Exact Mass:266.05546401
Monoisotopic Mass:266.05546401
Topological Polar Surface Area:26.3
Heavy Atom Count:19
Complexity:288
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes