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With hydrogenchloride; n-butyllithium; In tetrahydrofuran;
Example I 2-Fluoro-4-trifluoromethoxybenzeneboronic Acid To a solution of n-butyllithium (2.5 M solution in hexanes, 14.1 mL) in THF (30 mL) at -98 C. was added a solution of 4-bromo-3-fluorotrifluoromethoxy-benzene in THF (3 mL). After stirring for 10 min. at -98 C., triisopropyl borate (4.88 mL, 3.98 g, 21 mmol) was added at a rate needed to keep the temperature below -97 C. The reaction mixture was allowed to warm to -30 C. over 30 minutes, re-cooled to -78 C. and stirred at this temperature for 30 min. Concentrated hydrochloric acid (2 mL) was added and the reaction mixture was concentrated under reduced pressure. Dilute hydrochloric acid (0.2 N, 15 mL) was added and the mixture was extracted with ether (3*20 mL). The combined ethereal layers were extracted with dilute sodium hydroxide (0.02 N, 3*30 mL). The combined aqueous extracts were cooled to 0 C., acidified to pH 3.5 using concentrated hydrochloric acid and extracted with ether (3*30 mL). The combined ethereal layers were then washed with water (15 mL) and brine (15 mL), dried over magnesium sulphate and concentrated under reduced pressure to leave 2.3 g of yellow solid. Recrystallisation from hexane afforded pink needles (1.25 g, 41%): mp 89-93 C.; 1H NMR (CDCl3) δ 7.89 (t, 1H), 7.07 (d, 1H), 6.94 (d, 1H), 5.11 (d, 2H); EI/MS 223 m/e (M-1).
43 g
With n-butyllithium; In tetrahydrofuran; toluene; at -78 - -70℃; for 4h;
Tripropan-2-yl borate (43.6 g, 232 mmol) was added to a solution of 4-bromo-3-fluorophenyl trifluoromethyl ether (50.0 g, 193 mmol) in toluene (400 mL) and tetrahydrofuran (100 mL), and the mixture was cooled to -78 C. n-Butyllithium (2.5 M solution; 92.7 mL, 232 mmol) was then added drop-wise, at a rate that maintained the reaction temperature below -60 C., and the reaction mixture was stirred at -70 C. for 4 hours. After the reaction mixture had been warmed to -20 C., it was quenched via addition of aqueous hydrochloric acid (2 M, 200 mL), and then stirred at room temperature (20 C.) for 40 minutes. The aqueous layer was extracted with ethyl acetate (3×50 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford the product (43 g) as a white solid, which was carried directly to the next step.
With copper(l) iodide; sodium iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 110℃;Inert atmosphere;
General procedure: 5-Bromo-2-tert-butylpyridine (500 mg; 2.34 mmol) is dissolved in 5 ml_ of dioxane. Copper iodide (89 mg, 0.47 mmol) is added and the mixture is placed under argon atmosphere. Sodium iodide is added and the mixture is stirred for a few minutes under argon atmosphere. N,N?-dimethylethylenediamine (100 mI_, 0.93 mmol) is added and the mixture is stirred at 130C over night. The mixture is allowed to cool to room temperature before being diluted with ethyl acetate and extracted with saturated aqueous solution of sodium bicarbonate twice. The organic layer is dried over magnesium sulfate, filtered and concentrated.Yield: 610 mg (95 % of theory)Mass spectrometry (ESI+): m/z = 262 [M+H]+HPLC (Method 3): Retention time = 1.176 min.
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