3-bromo-2-methylbenzaldehyde

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:

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

実験手順: The 3-bromo-2-methyl-benzaldehyde ((Example 6: step c) 813 mg, 4.08 mmol) was dissolved in dry MeOH (50 mL) and trimethyl orthoformate (8 mL). Toluenesulfonic acid (100 mg) was added and the solution was stirred for 6 h at rt. Solid NaHCO3 (200 mg) was added, the solution was stirred for 30 min, and the volatile components were removed in vacuo. The residue was dissolved in dry EtOAc (10 mL), the solution was filtered (45 micron filter), and the solvent was removed in vacuo. 1H NMR analysis of the crude material (918 mg, 92%) revealed approximately a 90% conversion of the starting material to the title compound, which was used without further purification. 1H-NMR (CDCl3): δ 7.47 (dd, 1H, J=1.2, 8.1 Hz), 7.44 (dd, 1H, J=0.9, 7.9 Hz), 6.99 (t, 1H, J=7.9 Hz), 5.37 (s, 1H), 3.25 (s, 6H), 2.37 (s, 3H). the solution was stirred for 30 min the volatile components were removed in vacuo The residue was dissolved in dry EtOAc (10 mL) the solution was filtered (45 micron filter) the solvent was removed in vacuo was used without further purification

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Lithium aluminum hydride (201 mg, 5.31 mmol) was added in one portion to a −78° C. solution of 3-bromo-N-methoxy-2,N-dimethyl-benzamide ((Example 6: step b) 1.1 g, 4.24 mmol) in THF (25 mL). After stirring for 1 h at −78° C., the hydride reagent was quenched with EtOAc (10 mL), and the solution was slowly poured into a vigorously stirred mixture of citric acid (10%, 30 mL) and EtOAc (50 mL). After separating the layers, the organic layer was washed with NaHCO3 (3×20 mL), water (20 mL), and brine (30 mL). The solution was dried (sodium sulfate) and the solvent was removed in vacuo, giving the title compound (813 mg, 96%) as a colorless oil which was used without further purification. 1H-NMR (CDCl3): δ 10.28 (s, 1H), 7.80 (m, 2H), 7.25 (m, 1H), 2.78 (s, 3H). the hydride reagent was quenched with EtOAc (10 mL) the solution was slowly poured into a vigorously stirred mixture of citric acid (10%, 30 mL) and EtOAc (50 mL) After separating the layers the organic layer was washed with NaHCO3 (3×20 mL), water (20 mL), and brine (30 mL) The solution was dried (sodium sulfate) the solvent was removed in vacuo

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Lithium aluminum hydride (201 mg, 5.31 mmol) was added in one portion to a −78° C. solution of 3-bromo-N-methoxy-2,N-dimethyl-benzamide ((Example 6: step b) 1.1 g, 4.24 mmol) in THF (25 mL). After stirring for 1 h at −78° C., the hydride reagent was quenched with EtOAc (10 mL), and the solution was slowly poured into a vigorously stirred mixture of citric acid (10%, 30 mL) and EtOAc (50 mL). After separating the layers, the organic layer was washed with NaHCO3 (3×20 mL), water (20 mL), and brine (30 mL). The solution was dried (sodium sulfate) and the solvent was removed in vacuo, giving the title compound (813 mg, 96%) as a colorless oil which was used without further purification. 1H-NMR (CDCl3): δ 10.28 (s, 1H), 7.80 (m, 2H), 7.25 (m, 1H), 2.78 (s, 3H). the hydride reagent was quenched with EtOAc (10 mL) the solution was slowly poured into a vigorously stirred mixture of citric acid (10%, 30 mL) and EtOAc (50 mL) After separating the layers the organic layer was washed with NaHCO3 (3×20 mL), water (20 mL), and brine (30 mL) The solution was dried (sodium sulfate) the solvent was removed in vacuo

反応条件: temp:82.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Step 2 A solution of 3-bromo-2-methylbenzaldehyde (200 mg, 1.01 mmol) and indolin-2-one (134 mg, 1.01 mmol) in ethanol (10 mL) was treated with piperidine (0.099 mL, 1.01 mmol) and heated at 80-85° C. After 15.25 h, the solution was cooled to rt and concentrated. The residue was purified by column chromatography (eluting with a gradient from 80:20 to 30:70 hexane-ethyl acetate) to provide 3-(3-bromo-2-methylbenzylidene)indolin-2-one as a bright yellow solid (94.9 mg, 30%). 1H NMR (400 MHz, chloroform-d) δ 7.89 (1H, br. s.), 7.85 (1H, s), 7.64 (1H, d, J=7.9 Hz), 7.47 (1H, d, J=7.7 Hz), 7.20 (1H, td, J=7.7, 1.1 Hz), 7.07-7.16 (2H, m), 6.87 (1H, d, J=7.9 Hz), 6.81 (1H, td, J=7.6, 1.0 Hz), 2.43 (3H, s). Mass spectrum m/z 314, 316 (M+H)+. the solution was cooled to rt concentrated The residue was purified by column chromatography ( eluting with a gradient from 80:20 to 30:70 hexane-ethyl acetate)

反応条件: temp:82.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Step 2 A solution of 3-bromo-2-methylbenzaldehyde (200 mg, 1.01 mmol) and indolin-2-one (134 mg, 1.01 mmol) in ethanol (10 mL) was treated with piperidine (0.099 mL, 1.01 mmol) and heated at 80-85° C. After 15.25 h, the solution was cooled to rt and concentrated. The residue was purified by column chromatography (eluting with a gradient from 80:20 to 30:70 hexane-ethyl acetate) to provide 3-(3-bromo-2-methylbenzylidene)indolin-2-one as a bright yellow solid (94.9 mg, 30%). 1H NMR (400 MHz, chloroform-d) δ 7.89 (1H, br. s.), 7.85 (1H, s), 7.64 (1H, d, J=7.9 Hz), 7.47 (1H, d, J=7.7 Hz), 7.20 (1H, td, J=7.7, 1.1 Hz), 7.07-7.16 (2H, m), 6.87 (1H, d, J=7.9 Hz), 6.81 (1H, td, J=7.6, 1.0 Hz), 2.43 (3H, s). Mass spectrum m/z 314, 316 (M+H)+. the solution was cooled to rt concentrated The residue was purified by column chromatography ( eluting with a gradient from 80:20 to 30:70 hexane-ethyl acetate)

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:

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