5-Bromo-2-fluorobenzenemethanol

Preparation Example 4(5-Bromo-2-fluorophenyl)methanolTo a solution of 5-bromo-2-fluorobenzaldehyde (30.0 g, 148 mmol) in EtOH was added sodium borohydride (8.39 g, 222 mmol) at 0 °C. The resulting mixture was stirred with gradual warming to ambient temperature over 15 h, re-cooled to 0 °C, and quenched with aq. saturated NHExample 5, Step 1To a solution of starting aldehyde 5-1 (3.98 g, 19.6 mmol) in MeOH (20 mL) at 0°C was added sodium borohydride (1.48 g, 39.2 mmol). The reaction was stirred at 0°C for 5 mm then warmed up to RT and allowed to stir for an additional 30 mm. The final mixture was diluted with EtOAc and brine, and the organic layer was dried over Na2SO4 and concentrated invacuo to provide 3.92 g (9 8percent) of intermediate 5-2.[0747] BH3-THF (229 mL, 1 M in THF, 5.00 equiv) was added dropwise into a solution of 5-bromo- 2-fluorobenzoic acid (10 g, 45.66 mmol, 1.00 equiv) in tetrahydrofuran (150 mL) at 0°C under nitrogen. The resulting solution was stirred overnight at room temperature, quenched by water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel colunm eluting with ethyl acetate/petroleum ether (1:5) to afford the title compound (9.5 g) as light yellow oil. GCMS mlz = 204, 206.BHPreparation Example 4(5-Bromo-2-fluorophenyl)methanolTo a solution of 5-bromo-2-fluorobenzaldehyde (30.0 g, 148 mmol) in EtOH was added sodium borohydride (8.39 g, 222 mmol) at 0 C. The resulting mixture was stirred with gradual warming to ambient temperature over 15 h, re-cooled to 0 C, and quenched with aq. saturated NH4C1 solution. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over MgS04, filtered and evaporated in vacuo to yield the titled compound (30.3 g, quantitative) as a white sold, which was carried on to the next step without further purification.[M-OH]+ 187.A. 5-Bromo-2-fluoro-benzyl alcohol. To a solution of 5-bromo-2-fluoro-benzaldehyde (6.10 g, 30.0 mmol) in 30 mL of THF at 0 C. is added 5 mL of sodium borohydride (2.0 M solution in triglyme, 10.0 mmol). The reaction mixture is stirred at 0 C. for 25 minutes and then quenched by the addition of 1 N HCl. The mixture is diluted with EtOAc and the layers are separated. The organic layer is washed with H2 O and saturated NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluding with 15% EtOAc/hexanes to afford the title compound (6.00 g, 29.3 mmol). 1 H NMR (CDCl3, 300 MHz) delta7.55 (dd, 1H), 7.36 (m, 1H), 6.89 (t, 1H), 4.71 (d, 2H), 2.11 (bs, 1H). EI MS, [M]+ =204, 206, Br pattern.A. 5-Bromo-2-fluoro-benzyl alcohol To a solution of 5-bromo-2-fluoro-benzaldehyde (6.10 g, 30.0 mmol) in 30 mL of THF at 0 C. is added 5 mL of sodium borohydride (2.0M solution in triglyme, 10.0 mmol). The reaction mixture is stirred at 0 C. for 25 min and then quenched by the addition of 1N HCl. The mixture is diluted with EtOAc and the layers are separated. The organic layer is washed with H2 O and saturated NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluding with 15% EtOAc/hexanes to afford the title compound (6.00 g, 29.3 mmol). 1 H NMR (CDCl3, 300 MHz) delta7.55 (dd, 1H), 7.36 (m, 1H), 6.89 (t, 1H), 4.71 (d, 2H), 2.11 (bs, 1H). EI MS, [M]+ =204, 206, Br pattern.To a solution of 5-bromo-2-fluoro-benzaldehyde [(L.] Oeq. ) in MeOH (0.2M) at [0C] was added portionwise NaBH4 (2. [0EQ.).] The mixture was stirred at rt for [LH, ] poured in HCl (1M) and extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried over [NA2SO4, ] filtered and concentrated to afford the title compound as a white solid.To a cold (0 C) solution of 5-bromo-2-fluorobenzaldehyde (10.0 g, 49.2 mmol) in EtOH (100 mL) was added NaBH4 (2.00 g, 54.2 mmol) and the mixture was stirred at 0 C for 1 h. The reaction was quenched with 1 M aq HCl, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo to give the crude material. To a ice-cold solution of the crude alcohol in DMF (150 mL) were added imidazole (5.00 mL, 73.8 mmol) and tert-butyl(chloro)diphenylsilane (13.9 mL, 54.1 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc = 19/1) to give the title compound (15.7 g, 72% yield) as a pale yellow oil.1H NMR (CDCl3) delta: 1.11 (9H, s), 4.77 (2H, s), 6.85 (1H, t, J = 9.0 Hz), 7.29-7.49 (7H, m), 7.65-7.74 (5H, m). MS (FAB) m/z: 443 (M++H), calcd for C23H24BrFOSi: 442.Step A. 5-Bromo-2-fluoro-phenyl-methanol To a mixture of 5-bromo-2-fluoro-benzaldehyde (25 g, 125 mmol) in THF/MeOH (100 mL / 20 mL) with ice-bath cooling was carefully added NaBH4 (4.75 g, 125 mmol) portionwise and the resulting mixture was stirred at 0 C for 2 hrs. The reaction mixture was added 50 mL of 0 and partitioned with EA. The aqueous phase was extracted with ethyl acetate twice and the combined organic layer was washed with brine, dried over anhydrous Na2S04 and concentrate. The residue was purified by short column chromatography on silica gel (PE/EA=8/1) to give the title compound.Step A. 5-Bromo-2-fluoro-phenyl-methanol To a mixture of 5-bromo-2-fluoro-benzaldehyde (25 g, 125 mmol) in THF/MeOH (100 mL / 20 mL) with ice-bath cooling was carefully added NaBH4 (4.75 g, 125 mmol) portionwise and the resulting mixture was stirred at 0 C for 2 hrs. The reaction mixture was added 50 mL of 0 and partitioned with EA. The aqueous phase was extracted with ethyl acetate twice and the combined organic layer was washed with brine, dried over anhydrous Na2S04 and concentrate. The residue was purified by short column chromatography on silica gel (PE/EA=8/1) to give the title compound.Step B. 4-Bromo-2-bromomethyl-l-fluoro-benzene To a cooled and stirred solution of compound 5-Bromo-2-fluoro-phenyl-methanol (20 g, 100 mmol) in anhydrous DCM (100 mL) was added PBr3 (10.8 g, 40 mmol) dropwise at 0 C and the resulting mixture was stirred at room temperature for 2 hrs. The reaction mixture was diluted with DCM and the organic phase was washed with water and brine, dried over anhydrous Na2S04 and concentrate. The residue was purified by column chromatography on silica gel eluting with PE/EA = 20/1 ~ 10/1 to give the title compound.[0749] DIAD (18.8 g, 92.97 mmol, 2.01 equiv) was added dropwise into a stirred mixture of (5- bromo-2-fluorophenyl)methanol (9.5 g, 46.34 mmol, 1.00 equiv), 2, 3-dihydro-1H-isoindole-1, 3-dion (13.6 g, 92.44 mmol, 2.00 equiv), and PPh3 (24.4 g, 93.03 mmol, 2.Olequiv) in tetrahydrofuran (300 mL) at 0C under nitrogen. The resulting solution was stirred overnight at room temperature and concentrated under vacuum. The residue was purified by a silica gel colunm eluting with ethyl acetate/petroleum ether (1:10) to afford the title compound (9.5 g, 61%) as a white solid. LCMS [M+H] 334; 'H NMR (300 MHz, CDC13) 7.89 - 7.83 (m, 2H), 7.78 - 7.70 (m, 2H), 7.66 - 7.63 (m, 1H), 7.40 - 7.35 (m, 1H), 7.09 - 7.03 (m, 1H), 4.78 (s, 2H).DIAD (18.8 g, 92.97 mmol, 2.01 equiv) was added dropwise into a stirred mixture of (5- bromo-2-fluorophenyl)methanol (9.5 g, 46.34 mmol, 1.00 equiv), 2, 3-dihydro-li7-isoindole-l, 3-dion (13.6 g, 92.44 mmol, 2.00 equiv), and PPh3 (24.4 g, 93.03 mmol, 2.01equiv) in tetrahydrofuran (300 mL) at 0 C under nitrogen. The resulting solution was stirred overnight at room temperature and concentrated under vacuum. The residue was purified by a silica gel column eluting with ethyl acetate/petroleum ether (1 :10) to afford the title compound (9.5 g, 61%) as a white solid. LCMS [M+H+] 334; NMR (300 MHz, CDC13) delta 7.89 - 7.83 (m, 2H), 7.78 - 7.70 (m, 2H), 7.66 - 7.63 (m, 1H), 7.40 - 7.35 (m, 1H), 7.09 - 7.03 (m, 1H), 4.78 (s, 2H).

Molecular Weight:205.02
XLogP3:1.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:203.95861
Monoisotopic Mass:203.95861
Topological Polar Surface Area:20.2
Heavy Atom Count:10
Complexity:110
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes