(3-bromo-2-methylphenyl)methanol

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Step 1 A mixture of (3-bromo-2-methylphenyl)methanol (prepared according to the procedures reported in US Pat. Appl. 2006/0173183, 500 mg, 2.49 mmol) in THF (20 mL) was stirred at rt and treated with 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martin periodinane, 1.58 g, 3.73 mmol). After 2 h, the mixture was diluted with ether (ca. 100 mL) and washed with 5% aqueous sodium bisulfite, NaHCO3 (aq) and brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from hexane to 55:45 hexane-EtOAc) to provide 3-bromo-2-methylbenzaldehyde as a colorless oil (343 mg, 70%). 1H NMR (400 MHz, chloroform-d) δ 10.26 (1H, s), 7.78 (2H, ddd, J=9.7, 8.0, 1.2 Hz), 7.20-7.27 (1H, m), 2.75 (3H, s). prepared washed with 5% aqueous sodium bisulfite, NaHCO3 (aq) and brine dried concentrated The residue was purified by column chromatography ( eluting with a gradient from hexane to 55:45 hexane-EtOAc)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a flask charged with (3-bromo-2-methylphenyl)methanol (6.0 g, 30 mmol) was added a 1M trifluoroacetic acid solution of thallium trifluoroacetate (16.2 g, 29.8 mmol). The mixture was stirred at room temperature overnight. The solvent was removed under vacuum, and the residue was pumped under high vacuum for 30 minutes to ensure complete removal of TFA. To the residue was then added palladium(II) chloride (529 mg, 2.98 mmol), lithium chloride (2.53 g, 59.7 mmol), magnesium oxide (2.41 g, 59.7 mmol), and methanol (150 mL). The reaction was flushed with CO twice, and kept under CO at room temperature. Analysis by LC showed a big product spot within 2 hours. To this solution was added ethyl acetate to precipitate the salts. The black solution was filtered through a Celite® diatomaceous earth pad, washed with EtOAc, adsorbed onto silica and purified by silica gel chromatography to afford 5-bromo-4-methyl-2-benzofuran-1(3H)-one. The solvent was removed under vacuum the residue was pumped under high vacuum for 30 minutes removal of TFA The reaction was flushed with CO twice kept under CO at room temperature within 2 hours To this solution was added ethyl acetate to precipitate the salts The black solution was filtered through a Celite® diatomaceous earth pad washed with EtOAc purified by silica gel chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 3-bromo-2-methyl benzoic acid (35 g, 160 mmol) in THF (200 mL) was added borane THF complex (1.0 M, 210 mL, 210 mmol). The mixture was allowed to stir for 24 hours. The reaction was quenched with water. The solvent THF was removed under reduced pressure. The resulting solid was dissolved in ethyl acetate (500 mL), washed with 1N hydrochloric acid, saturated sodium bicarbonate, and brine. The combined organic layers were dried over sodium sulfate and concentrated to afford (3-bromo-2-methylphenyl)methanol. The reaction was quenched with water The solvent THF was removed under reduced pressure The resulting solid was dissolved in ethyl acetate (500 mL) washed with 1N hydrochloric acid, saturated sodium bicarbonate, and brine The combined organic layers were dried over sodium sulfate concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 3-bromo-2-methyl benzoic acid (35 g, 160 mmol) in THF (200 mL) was added borane THF complex (1.0 M, 210 mL, 210 mmol). The mixture was allowed to stir for 24 hours. The reaction was quenched with water. The solvent THF was removed under reduced pressure. The resulting solid was dissolved in ethyl acetate (500 mL), washed with 1N hydrochloric acid, saturated sodium bicarbonate, and brine. The combined organic layers were dried over sodium sulfate and concentrated to afford (3-bromo-2-methylphenyl)methanol. The reaction was quenched with water The solvent THF was removed under reduced pressure The resulting solid was dissolved in ethyl acetate (500 mL) washed with 1N hydrochloric acid, saturated sodium bicarbonate, and brine The combined organic layers were dried over sodium sulfate concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ethyl 3-bromo-2-methylbenzoic acid was reduced as follows: Add 5 equivalents of borane tetrahydrofuran complex, via syringe, to 10 mmol ethyl 3-bromo-2-methylbenzoic acid in tetrahydrofuran (5 mL). The mixture was refluxed for two hours, then cooled in an ice bath. Methanol (10 mL) was added dropwise, followed by 1 N HCl (50 mL). The solvent was removed and the mixture partitioned between ethyl acetate and water. The yield was 90%. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) 67.5 (d, 1H) 7.2 (d, 1H) 7.1 (t, 1H), 4.6 (s, 2H) 2.3 (s, 3H). Add 5 equivalents of borane tetrahydrofuran complex The mixture was refluxed for two hours cooled in an ice bath The solvent was removed the mixture partitioned between ethyl acetate and water

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ethyl 3-bromo-2-methylbenzoic acid was reduced as follows: Add 5 equivalents of borane tetrahydrofuran complex, via syringe, to 10 mmol ethyl 3-bromo-2-methylbenzoic acid in tetrahydrofuran (5 mL). The mixture was refluxed for two hours, then cooled in an ice bath. Methanol (10 mL) was added dropwise, followed by 1 N HCl (50 mL). The solvent was removed and the mixture partitioned between ethyl acetate and water. The yield was 90%. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) 67.5 (d, 1H) 7.2 (d, 1H) 7.1 (t, 1H), 4.6 (s, 2H) 2.3 (s, 3H). Add 5 equivalents of borane tetrahydrofuran complex The mixture was refluxed for two hours cooled in an ice bath The solvent was removed the mixture partitioned between ethyl acetate and water

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (3-bromo-2-methylphenyl)methanol was oxidized as follows: The alcohol (15 mmol) was dissolved in methylene chloride (30 mL). 10 equivalents of activated manganese oxide (IV) was added and the mixture stirred at room temperature for 24 hours. The mixture was filtered through a bed of celite and the solvent removed in-vacuo to leave yellow solid. Product was used crude in next step without further purification. The yield was 93%. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 9.8 (s, 1H) 8.1 (d, 1H) 7.7 (d, 1H), 7.2 (t, 1H), 2.4 (s, 3H). The mixture was filtered through a bed of celite the solvent removed in-vacuo to leave yellow solid without further purification

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ethyl 3-bromo-2-methylbenzoic acid was reduced as follows: Add 5 equivalents of borane tetrahydrofuran complex, via syringe, to 10 mmol ethyl 3-bromo-2-methylbenzoic acid in tetrahydrofuran (5 mL). The mixture was refluxed for two hours, then cooled in an ice bath. Methanol (10 mL) was added dropwise, followed by 1 N HCl (50 mL). The solvent was removed and the mixture partitioned between ethyl acetate and water. The yield was 90%. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ7.5 (d, 1H) 7.2 (d, 1H) 7.1 (t, 1H), 4.6 (s, 2H) 2.3 (s, 3H). Add 5 equivalents of borane tetrahydrofuran complex The mixture was refluxed for two hours cooled in an ice bath The solvent was removed the mixture partitioned between ethyl acetate and water

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ethyl 3-bromo-2-methylbenzoic acid was reduced as follows: Add 5 equivalents of borane tetrahydrofuran complex, via syringe, to 10 mmol ethyl 3-bromo-2-methylbenzoic acid in tetrahydrofuran (5 mL). The mixture was refluxed for two hours, then cooled in an ice bath. Methanol (10 mL) was added dropwise, followed by 1 N HCl (50 mL). The solvent was removed and the mixture partitioned between ethyl acetate and water. The yield was 90%. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ7.5 (d, 1H) 7.2 (d, 1H) 7.1 (t, 1H), 4.6 (s, 2H) 2.3 (s, 3H). Add 5 equivalents of borane tetrahydrofuran complex The mixture was refluxed for two hours cooled in an ice bath The solvent was removed the mixture partitioned between ethyl acetate and water