6-溴-2,2-二甲基-4-二氢色原酮

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: N,N,N′,N′-tetramethylmethanediamine (4.8 g, 47 mmol) was added to a solution of 6-bromo-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (3.0 g, 12 mmol) and acetic acid (0.67 ml, 12 mmol) in tetrahydrofuran (43 ml), and the mixture was stirred at 70° C. for 24 hours. To the mixture was added acetic anhydride (4.4 ml, 47 mmol), and the mixture was stirred at 70° C. for 4 hours and concentrated in vacuo. The residue was directly purified by silica gel column chromatography (hexane/ethyl acetate=20:1) to afford 6-bromo-2,2-dimethyl-3-methylene-2,3-dihydro-4H-chromen-4-one (2.8 g). the mixture was stirred at 70° C. for 4 hours concentrated in vacuo The residue was directly purified by silica gel column chromatography (hexane/ethyl acetate=20:1)

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: N,N,N′,N′-tetramethylmethanediamine (4.8 g, 47 mmol) was added to a solution of 6-bromo-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (3.0 g, 12 mmol) and acetic acid (0.67 ml, 12 mmol) in tetrahydrofuran (43 ml), and the mixture was stirred at 70° C. for 24 hours. To the mixture was added acetic anhydride (4.4 ml, 47 mmol), and the mixture was stirred at 70° C. for 4 hours and concentrated in vacuo. The residue was directly purified by silica gel column chromatography (hexane/ethyl acetate=20:1) to afford 6-bromo-2,2-dimethyl-3-methylene-2,3-dihydro-4H-chromen-4-one (2.8 g). the mixture was stirred at 70° C. for 4 hours concentrated in vacuo The residue was directly purified by silica gel column chromatography (hexane/ethyl acetate=20:1)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of 6-bromo-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (1.00 g, 3.92 mmol) and dioxane (10 mL) were added formaldehyde (37 wt. % in water, 2.95 mL, 39.2 mmol) and Na2CO3 (831 mg, 7.84 mmol) at room temperature. After stirring overnight at the same temperature, the reaction mixture was filtered. The filtrate was diluted with CHCl3, washed with 1M aqueous HCl and water, dried over MgSO4 and filtered. The filtrate was concentrated at reduced pressure, and the residue was purified with column chromatography on silica gel (hexane-EtOAc, a linear gradient of EtOAc from 0 to 50%) to afford 6-bromo-3,3-bis(hydroxymethyl)-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (1.07 g). the reaction mixture was filtered The filtrate was diluted with CHCl3 washed with 1M aqueous HCl and water dried over MgSO4 filtered The filtrate was concentrated at reduced pressure the residue was purified with column chromatography on silica gel (hexane-EtOAc

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of piperidine (2,83 g, 33.25 mmol) in 45 mL benzene was added trifluoroacetic acid (344.6 mg, 3.02 mmol) as a solution in 4.0 mL of benzene. Acetone (8.78 g, 151.3 mmol) was added followed by 2-hydroxy-5-bromoacetophenone (Compound 259, 6.50 g, 30.23 mmol). The resulting solution was heated to reflux in a flask fitted with a Dean-Stark trap. After 24 hours, an additional 2.5 equivalents of acetone and 0.1 equivalents of trifluoroacetic acid were added. After a total of 43 hours the reaction was cooled to room temperature and diluted with EtOAc. The solution was washed with 1M aqueous HCl, H2O, and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. Distillation of the residual oil (bulb-to-bulb) afforded 4.80 g (62%) of the title compound as a clear yellow oil, bp 105-115° C./5 mm. The reaction conditions here are a moderate modification of the synthesis of the title compound described by Buckle et al. in J. Med. Chem. 1990 3028-3034. 1H NMR (300 MHz, CDCl3) δ: 7.97 (1H, d, J=2.6 Hz), 7.54 (1H, dd, J=2.6, 8.7 Hz), 6.84 (1H, d, J=8.8 Hz), 2.72 (2H, s), 1.46 (6H, s). The resulting solution was heated to reflux in a flask fitted with a Dean-Stark trap The solution was washed with 1M aqueous HCl, H2O, and saturated aqueous NaCl before being dried (MgSO4) concentrated under reduced pressure Distillation of the residual oil (bulb-to-bulb)

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: N,N,N′,N′-tetramethylmethanediamine (4.8 g, 47 mmol) was added to a solution of 6-bromo-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (3.0 g, 12 mmol) and acetic acid (0.67 ml, 12 mmol) in tetrahydrofuran (43 ml), and the mixture was stirred at 70° C. for 24 hours. To the mixture was added acetic anhydride (4.4 ml, 47 mmol), and the mixture was stirred at 70° C. for 4 hours and concentrated in vacuo. The residue was directly purified by silica gel column chromatography (hexane/ethyl acetate=20:1) to afford 6-bromo-2,2-dimethyl-3-methylene-2,3-dihydro-4H-chromen-4-one (2.8 g). the mixture was stirred at 70° C. for 4 hours concentrated in vacuo The residue was directly purified by silica gel column chromatography (hexane/ethyl acetate=20:1)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of 6-bromo-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (1.00 g, 3.92 mmol) and dioxane (10 mL) were added formaldehyde (37 wt. % in water, 2.95 mL, 39.2 mmol) and Na2CO3 (831 mg, 7.84 mmol) at room temperature. After stirring overnight at the same temperature, the reaction mixture was filtered. The filtrate was diluted with CHCl3, washed with 1M aqueous HCl and water, dried over MgSO4 and filtered. The filtrate was concentrated at reduced pressure, and the residue was purified with column chromatography on silica gel (hexane-EtOAc, a linear gradient of EtOAc from 0 to 50%) to afford 6-bromo-3,3-bis(hydroxymethyl)-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (1.07 g). the reaction mixture was filtered The filtrate was diluted with CHCl3 washed with 1M aqueous HCl and water dried over MgSO4 filtered The filtrate was concentrated at reduced pressure the residue was purified with column chromatography on silica gel (hexane-EtOAc

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of 6-bromo-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (1.00 g, 3.92 mmol) and dioxane (10 mL) were added formaldehyde (37 wt. % in water, 2.95 mL, 39.2 mmol) and Na2CO3 (831 mg, 7.84 mmol) at room temperature. After stirring overnight at the same temperature, the reaction mixture was filtered. The filtrate was diluted with CHCl3, washed with 1M aqueous HCl and water, dried over MgSO4 and filtered. The filtrate was concentrated at reduced pressure, and the residue was purified with column chromatography on silica gel (hexane-EtOAc, a linear gradient of EtOAc from 0 to 50%) to afford 6-bromo-3,3-bis(hydroxymethyl)-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (1.07 g). the reaction mixture was filtered The filtrate was diluted with CHCl3 washed with 1M aqueous HCl and water dried over MgSO4 filtered The filtrate was concentrated at reduced pressure the residue was purified with column chromatography on silica gel (hexane-EtOAc

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a cold (-78° C.) solution of 2-methylthiophene (820 mg, 8.3 mmol) in THF (16 mL) was added n-BuLi in hexane (1.6M, 4.4 mL, 8.5 mmol). The mixture was warmed to ambient temperature and stirred for 15 minutes. This solution was added to a flask containing cold (-78° C.) solution of 2,2-dimethyl-6-bromo-chroman-4-one (1.08 g, 4.2 mmol) in THF (4 mL). The mixture was stirred and allowed to gradually warm to ambient temperature over 8 hours, and then stirred for an additional 4 hours at ambient temperature. The mixture was diluted with ethyl acetate (200 mL), washed with 10% HCl, brine (20 mL), dried and the solvent was removed by evaporation. The product was purified by chromatography on a silica gel column to afford the title compound as a colorless off. This solution was added to a flask The mixture was stirred to gradually warm to ambient temperature over 8 hours stirred for an additional 4 hours at ambient temperature washed with 10% HCl, brine (20 mL) dried the solvent was removed by evaporation The product was purified by chromatography on a silica gel column

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir: