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With sodium tetrahydroborate In methanolCooling with ice
1008551 Step A: Preparation of (3 -fluoro-4-(trifluoromethyl)phenyl)methanol: Charged a round bottomed flask plus stir bar with 3-fluoro-4-(trifluoromethyl)benzaldehyde (2.0 g, 10 mmol) and anhydrous MeOH (20 mL). The flask was chilled in an ice bath and sodium borohydride (0.47 g, 12 mmol) was added in portions. Removed ice bath and allowed reaction to warm to ambient temperature. Added saturated NH4C1 (2 mL) and concentrated mixture in vacuo. The residue was diluted with additional saturated NH4C1 (30 mE) and extracted with EtOAc (3 x 30 mL). The combined organic phases were dried (MgSO4), filtered, and concentrated. Yield: 1.8 g (80percent). Product carried forward without purification.
With thionyl chloride; In chloroform; for 4h;Heating / reflux;
To a solution of <strong>[230295-16-6]3-fluoro-4-(trifluoromethyl)benzyl alcohol</strong> (10 g, 52 mmol) in chloroform (20 ml) was added thionyl chloride (18.5 ml, 257 mmol) and the mixture was heated under reflux for 4 hrs. The reaction solution was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 3-fluoro-4-(trifluoromethyl)benzyl chloride (9.52 g, 87%). IR nu maxKBrcm-1: 1634, 1589, 1512, 1435.1H-NMR (CDCl3) delta: 4.58 (2H, s), 7.20-7.32 (2H, m), 7.60 (1H, t, J = 7.6 Hz).
3-fluoro-4-(trifluoromethyl)benzoic acid[ No CAS ]
[ 230295-16-6 ]
Yield
Reaction Conditions
Operation in experiment
94%
To a solution of 3-fluoro-4-(trifluoromethyl)benzoic acid (10.5 g, 50.7 mmol) in tetrahydrofuran (30 ml) was added a 1M tetrahydrofuran solution of borane (63 ml, 63 mmol) and the mixture was stirred at room temperature for 8 hrs. 1N Hydrochloric acid (100 ml) was added to the reaction solution and the mixture was extracted with ethyl acetate (300 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give 3-fluoro-4-(trifluoromethyl)benzyl alcohol (10.3 g, purity 90%, 94%).1H-NMR (CDCl3)delta: 1.91 (1H, t, J = 5.4 Hz), 4.78 (2H, d, J = 5.4 Hz), 7.16-7.30 (2H, m), 7.59 (1H, t, J = 7.6 Hz).
With borane; In tetrahydrofuran; at 20℃;Inert atmosphere;
Step 1: Into a 500-mL 4-necked round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed a solution of 3-fluoro-4-(trifluoromethyl)benzoic acid(50 g, 240.26 mmol) in tetrahydrofuran (200 mL). This was followed by the addition of borane (300 g, 216.84 mmol) dropwise with stirring at room temperature over 2 hours. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 1 M aqueous HC1 (500 mL). The resulting solution was dilutedwith water (500 mL) and extracted with ethyl acetate (3 x 600 mL). The organic layers were combined, washed with water (600 mL) and brine (600 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in [3-fluoro-4- (trifluoromethyl)phenyl]methanol as yellow oil.
1008561 Step B: Preparation of 2-fluoro-4-(methoxymethyl)- 1-(trifluoromethyl)benzene: Charged a dry round bottomed flask plus stir bar with (3-fluoro-4- (trifluoromethyl)phenyl)methanol (1.6 g, 8.24 mmol) and anhydrous DMF (25 mL). Cooled in an ice bath under N2, and added sodium hydride (0.659 g, 16.5 mmol; 60% wt. in mineral oil) in portions over a 20 mm period. Removed ice bath and stirred at ambient temperature for 20 minutes. The reaction mixture was again cooled in an ice bath and iodomethane was added (1.55 mE, 24.7 mmol) dropwise. Removed from ice bath and stirred for 30 mm. Quenched reaction by careful addition of saturated aqueous NH4C1 (50 mL). Then extracted product with EtOAc (50 mE, then 30 mL). Washed combined organics with water (50 mL), brine (30 mE), dried (MgSO4), filtered, and concentrated. Yield: 1.8 g (84%). The product carried forward without purification.
With sodium tetrahydroborate; In methanol;Cooling with ice;
1008551 Step A: Preparation of (3 -fluoro-4-(trifluoromethyl)phenyl)methanol: Charged a round bottomed flask plus stir bar with 3-fluoro-4-(trifluoromethyl)benzaldehyde (2.0 g, 10 mmol) and anhydrous MeOH (20 mL). The flask was chilled in an ice bath and sodium borohydride (0.47 g, 12 mmol) was added in portions. Removed ice bath and allowed reaction to warm to ambient temperature. Added saturated NH4C1 (2 mL) and concentrated mixture in vacuo. The residue was diluted with additional saturated NH4C1 (30 mE) and extracted with EtOAc (3 x 30 mL). The combined organic phases were dried (MgSO4), filtered, and concentrated. Yield: 1.8 g (80%). Product carried forward without purification.
4-(bromomethyl)-2-fluoro-1-(trifluoromethyl)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogen bromide; for 2h;Reflux;
Step2: A mixture of <strong>[230295-16-6][3-fluoro-4-(trifluoromethyl)phenyl]methanol</strong> (230 g, 1.18 mol) andHBr (1200 mL, 40%) was heated to reflux for 2 hours. The resulting solution was cooledand diluted with 2 L of water. The resulting solution was extracted with dichloromethane (3 x 1 L). The organic layers were combined, washed with water (1 L), aqueous sodium bicarbonate (1 L) and brine (1 L), dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 4-(bromomethyl)-2-fluoro-1-(trifluoromethyl)benzene asyellow oil.
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