| 67% |
With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 23.4h;Inert atmosphere; |
A solution of <strong>[176548-70-2]3-bromo-5-fluorobenzoic acid</strong> (2.74 g, 12.5 mmol) in tetrahydrofuran (6 mL), at 0C under nitrogen, was treated with borane-tetrahydrofuran complex (1 M, 15 mL, 15 mmol) in small portions over 12 min, and the reaction was then stirred at 0C for 70 minutes, and at room temperature for 22 h. The reaction was quenched by addition of methanol (10 mL), and the methanolic mixture was stirred at room temperature for 3 h, and then evaporated in vacuo, with co-evaporation from methanol, then from ethyl acetate, to give the crude product. The material was dissolved in ethyl acetate (200 mL), and the solution was washed with 0.5M aqueous sodium hydroxide (200 mL), and with saturated aqueous sodium chloride (100 mL); then dried over sodium sulfate; filtered and evaporated in vacuo to give 3-bromo-5- fluorobenzyl alcohol (1.79 g, 67%). 1H NMR (400 MHz, CDCI3): delta 7.29 (s, 1 H), 7.15 (ddd, JHF = 8.2 Hz, JHH = 2.2, 1.8 Hz, 1 H), 7.00-7.02 and 7.02-7.04 (dm, JHF = 9.2 Hz, JHH = unresolved, 1 H), 4.66 (s, 2H), 2.04 (br s, 1 H); 19F NMR (377 MHz, CDCI3): delta -111.05 (dd, JHF = 9.3, 8.0 Hz, 1 F); 13C NMR (101 MHz, CDCI3): delta 162.87 (d, JCF = 250.6 Hz), 145.42 (d, JCF = 6.9 Hz), 125.45 (d, JCF = 3.1 Hz), 122.69 (d, JCF = 9.2 Hz), 118.01 (d, JCF = 24.6 Hz), 112.51 (d, JCF = 21.5 Hz), |
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With borane; In tetrahydrofuran; at 0 - 25℃; for 12.5h; |
Method 42; (3-Bromo-5-fluorophenyl)methanol ?>A solution of <strong>[176548-70-2]3-bromo-5-fluorobenzoic acid</strong> (1.14 g, 5.21 mmol) in THF (10 ml) was treated with BH3 (1.0 M in THF, 8.0 ml, 8.0 mmol, 1.5 equiv) dropwise under Ar at 0 C. The mixture was stirred at 0 0C for 30 min then allowed to warm to 25 0C and stirred for 12 h. The reaction was quenched with 10% HCl and extracted with EtOAc. The organic layer was washed with 10% NaOH and then dried with NaCl(Sat) and Na2SO4(S). The solvents were removed under reduced pressure and the resulting product was used without further purification, m/z 284. |
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With sodium borohydrid; In diethylene glycol dimethyl ether; |
Referential Example 16 Production of 3-Bromo-5-fluorobenzyl Alcohol Sodium borohydride (1.68 g) was added to diethylene glycol dimethyl ether (40 ml). While the mixture was stirred at room temperature, <strong>[176548-70-2]3-bromo-5-fluorobenzoic acid</strong> (9.72 g) was added portionwise (six portions). After the crystals were completely dissolved, trifluoroborane ether complex (8.40 g) in diethylene glycol dimethyl ether (10 ml) was added dropwise thereto. The mixture was stirred for 5 hours, and poured into ice/water. The mixture was extracted with ether (200 ml), and washed with water, followed by drying over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1?5:1), to thereby yield a mixture of the target compound and diethylene glycol dimethyl ether. The thus-obtained mixture was analyzed by NMR to determine the content of diethylene glycol dimethyl ether. The content and the yield of the target compound as determined by NMR were 7.70 g and 84.6%, respectively. 1H-NMR (CDCl3, ppm); 1.87 (1H, t, J=5.94 Hz), 4.69 (2H, d, J=5.94 Hz), 7.04 (1H, brd), 7.16 (1H, dt, J=7.83 Hz, 1.89 Hz), 7.31 (1H, brs). |
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General Procedure 1: Preparation of Benzyl Alcohols from Benzoic AcidsAt RT, 1.3 eq. of triethylamine and then 1.2 eq. of methyl chloroformate were added to a 0.5 M solution of the benzoic acid in question in toluene, and the mixture was stirred at RT overnight. The resulting suspension was then filtered through Celite and the residue was washed with toluene. The filtrate was concentrated, and the residue of the filtrate was dissolved in THF (1.5 ml/mmol) and then added dropwise to a suspension, cooled to -78 C., of 1.2 eq. of lithium aluminum hydride in THF (1 ml/mmol). After 1.5 h at -78 C., the reaction mixture was warmed to RT, and stirring was continued overnight. The resulting suspension was poured into 5% strength aqueous sodium hydroxide solution (5 ml/mmol), and the mixture was filtered through Celite and the filter cake was washed with ethyl acetate. The filtrate was extracted repeatedly with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. |
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General Procedure 1: Preparation of Benzyl Alcohols from Benzoic Acids; At RT, 1.3 eq. of triethylamine and then 1.2 eq. of methyl chloroformate were added to a 0.5 M solution of the benzoic acid in question in toluene. The mixture was stirred at RT overnight. The suspension formed was then filtered through Celite and the residue was washed with toluene. The filtrate was concentrated, and the filtrate residue was dissolved in THF (1.5 ml/mmol) and then added dropwise to a suspension, cooled to -78 C., of 1.2 eq. of lithium aluminium hydride in THF (1 ml/mmol). After 1.5 h at -78 C., the reaction mixture was warmed to RT, and stirring was continued overnight. The suspension formed was poured into 5% strength aqueous sodium hydroxide solution (5 ml/mmol), the mixture was filtered through Celite and the residue was washed with ethyl acetate. The filtrate was extracted repeatedly with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. |
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With borane-THF; In tetrahydrofuran; at 0 - 20℃; |
Step 1. (3-bromo-5-fluorophenyl)methanol To a suspension of <strong>[176548-70-2]3-bromo-5-fluorobenzoic acid</strong> (4.51 g, 20.59 mmol) in THF (41.2 mL) at 0 C., BH3.THF (41.2 mL, 41.2 mmol) was added dropwise over 30 min, the reaction mixture was then allowed to return to room temperature and stirred at room temperature overnight. Methanol (40 mL) was added slowly and stirred at room temperature for 1 h. THF and Methanol was removed in vacuo. The residue was then extracted by EtOAc, and washed with sat.NaHCO3, The organic was dried and concentrated. The crude product was used in next step reaction without purification. LCMS (m/z): 187.2 (MH+-18), 0.66 min. 1H NMR (400 MHz, CDCl3) delta ppm 7.32 (s, 1H), 7.19-7.14 (m, 1H), 7.05 (tdd, J=0.7, 1.5, 9.1 Hz, 1H), 4.70 (br. s., 2H), 1.78 (br. s., 1H). |
| 966 mg |
With borane-THF; In tetrahydrofuran;Cooling with ice; |
(1) Borane-tetrahydrofuran complex (0.98 mol/L tetrahydrofuran solution, 9.3 mL) was added to a solution of <strong>[176548-70-2]3-bromo-5-fluorobenzoic acid</strong> (1.0 g) in tetrahydrofuran (23 mL) under ice cooling, the ice bath was removed, and the mixture was stirred overnight. Water was added to the reaction solution under ice cooling, the mixture was extracted with chloroform, and the organic layer was separated by a phase separator. The obtained organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform/methanol = 99:1 to 47:3) to give (3-bromo-5-fluorophenyl)methanol (966 mg) as a colorless oily substance. |
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