1,2-difluoro-4,5-dimethoxybenzene

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:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 1,2-difluoro-4,5-dimethoxybenzene (3.48 g, 20 mmol) in 10 mL of anhydrous THF was slowly added to a cooled at −78° C. solution of sec-BuLi in THF/cyclohexane (1.4M in cyclohexane, 15 mL, 21 mmol mixed with 80 mL of THF). The mixture was stirred at −70° C. for 10 min, then a solution of R-(+)-propylene oxide (1.51 g, 1.8 mL, 26 mmol) in 15 mL of THF was added dropwise at −100° C. to −90° C., then the mixture was cooled to −105° C. and a 46.5% solution of BF3 in diethyl ether (4.18 mL, 30 mmol) was added dropwise. The mixture was stirred at −100° C. to −90° C. for 2 h, then the reaction was quenched with 20 mL of sat. aq. NH4Cl at −90° C. The mixture was stirred and warmed to 0° C. overnight. Then 20 mL of water was added and mixture was extracted with EtOAc (2×60 mL), the extract was dried over Na2SO4 and evaporated to give crude oil, which was purified by column (silica gel, EtOAc/hexane 1:9, Rf=0.29 in EtOAc/hexane 3:7) to give (2R)-1-(2,3-difluoro-5,6-dimethoxyphenyl)propan-2-ol (883 mg, 19%) as pale oil. 1H NMR (300 MHz, CDCl3): δ 6.65 (m, 1H), 4.06 (m, 1H), 3.83 (s, 3H), 3.82 (s, 3H), 2.87 (m, 2H), 2.05 (d, J=4.71 Hz, 1H), 1.25 (d, J=6.24 Hz, 3H). the mixture was cooled to −105° C. The mixture was stirred at −100° C. to −90° C. for 2 h the reaction was quenched with 20 mL of sat. aq. NH4Cl at −90° C The mixture was stirred warmed to 0° C. overnight Then 20 mL of water was added mixture was extracted with EtOAc (2×60 mL) the extract was dried over Na2SO4 evaporated to give crude oil, which was purified by column (silica gel, EtOAc/hexane 1:9, Rf=0.29 in EtOAc/hexane 3:7)

反応条件: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 1,2-difluoro-4,5-dimethoxybenzene (3.48 g, 20 mmol) in 10 mL of anhydrous THF was slowly added to a cooled at −78° C. solution of sec-BuLi in THF/cyclohexane (1.4M in cyclohexane, 15 mL, 21 mmol mixed with 80 mL of THF). The mixture was stirred at −70° C. for 10 min, then a solution of R-(+)-propylene oxide (1.51 g, 1.8 mL, 26 mmol) in 15 mL of THF was added dropwise at −100° C. to −90° C., then the mixture was cooled to −105° C. and a 46.5% solution of BF3 in diethyl ether (4.18 mL, 30 mmol) was added dropwise. The mixture was stirred at −100° C. to −90° C. for 2 h, then the reaction was quenched with 20 mL of sat. aq. NH4Cl at −90° C. The mixture was stirred and warmed to 0° C. overnight. Then 20 mL of water was added and mixture was extracted with EtOAc (2×60 mL), the extract was dried over Na2SO4 and evaporated to give crude oil, which was purified by column (silica gel, EtOAc/hexane 1:9, Rf=0.29 in EtOAc/hexane 3:7) to give (2R)-1-(2,3-difluoro-5,6-dimethoxyphenyl)propan-2-ol (883 mg, 19%) as pale oil. 1H NMR (300 MHz, CDCl3): δ 6.65 (m, 1H), 4.06 (m, 1H), 3.83 (s, 3H), 3.82 (s, 3H), 2.87 (m, 2H), 2.05 (d, J=4.71 Hz, 1H), 1.25 (d, J=6.24 Hz, 3H). the mixture was cooled to −105° C. The mixture was stirred at −100° C. to −90° C. for 2 h the reaction was quenched with 20 mL of sat. aq. NH4Cl at −90° C The mixture was stirred warmed to 0° C. overnight Then 20 mL of water was added mixture was extracted with EtOAc (2×60 mL) the extract was dried over Na2SO4 evaporated to give crude oil, which was purified by column (silica gel, EtOAc/hexane 1:9, Rf=0.29 in EtOAc/hexane 3:7)

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Sodium thiomethoxide (0.4 g) was added to a solution of 1,2-difluoro-4,5-dimethoxybenzene (1.0 g) in DMF (10 ml) at RT, then heated at 100° C. for 4 h. A further 0.8 g of sodium thiomethoxide was added, the mixture heated for a further 2 h. The mixture was cooled, partitioned between ethylacetate/2M hydrochloric acid, the organics dried and evaporated under reduced pressure, yield 1.05 g the mixture heated for a further 2 h The mixture was cooled partitioned between ethylacetate/2M hydrochloric acid the organics dried evaporated under reduced pressure, yield 1.05 g

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

実験手順: To a solution of 1,2-difluoro-4,5-dimethoxybenzene (2.61 g, 15 mmol) in N,N-dimethylformamide (20 ml) was added sodium thiomethoxide (95%, 1.11 g, 15 mmol). The reaction was allowed to reflux for 3 hours and then was cooled to room temperature. The mixture was poured into 200 ml ice-water and neutralized with 2 N HCl. The aqueous layer was extracted with ethyl ether (2×100 ml), washed with water, dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum to afford a mixture of the two title products. to reflux for 3 hours The aqueous layer was extracted with ethyl ether (2×100 ml) washed with water dried over anhydrous sodium sulfate filtered The solvent was removed under vacuum to afford a mixture of the two title products

反応条件: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 1,2-difluoro-4,5-dimethoxybenzene (3.48 g, 20 mmol) in 10 mL of anhydrous THF was slowly added to a cooled at −78° C. solution of sec-BuLi in THF/cyclohexane (1.4M in cyclohexane, 15 mL, 21 mmol mixed with 80 mL of THF). The mixture was stirred at −70° C. for 10 min, then a solution of R-(+)-propylene oxide (1.51 g, 1.8 mL, 26 mmol) in 15 mL of THF was added dropwise at −100° C. to −90° C., then the mixture was cooled to −105° C. and a 46.5% solution of BF3 in diethyl ether (4.18 mL, 30 mmol) was added dropwise. The mixture was stirred at −100° C. to −90° C. for 2 h, then the reaction was quenched with 20 mL of sat. aq. NH4Cl at −90° C. The mixture was stirred and warmed to 0° C. overnight. Then 20 mL of water was added and mixture was extracted with EtOAc (2×60 mL), the extract was dried over Na2SO4 and evaporated to give crude oil, which was purified by column (silicagel, EtOAc/hexane 1:9, Rf=0.29 in EtOAc/hexane 3:7) to give (2R)-1-(2,3-difluoro-5,6-dimethoxyphenyl)propan-2-ol (883 mg, 19%) as pale oil. 1H NMR (300 MHz, CDCl3): 6.65 (m, 1H), 4.06 (m, 1H), 3.83 (s, 3H), 3.82 (s, 3H), 2.87 (m, 2H), 2.05 (d, J=4.71 Hz, 1H), 1.25 (d, J=6.24 Hz, 3H). the mixture was cooled to −105° C. The mixture was stirred at −100° C. to −90° C. for 2 h the reaction was quenched with 20 mL of sat. aq. NH4Cl at −90° C The mixture was stirred warmed to 0° C. overnight Then 20 mL of water was added mixture was extracted with EtOAc (2×60 mL) the extract was dried over Na2SO4 evaporated to give crude oil, which was purified by column (silicagel, EtOAc/hexane 1:9, Rf=0.29 in EtOAc/hexane 3:7)

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Sodium thiomethoxide (0.4 g) was added to a solution of 1,2-difluoro-4,5-dimethoxybenzene (1.0 g) in DMF (10 ml) at RT, then heated at 100° C. for 4 h. A further 0.8 g of sodium thiomethoxide was added, the mixture heated for a further 2 h. The mixture was cooled, partitioned between ethylacetate/2M hydrochloric acid, the organics dried and evaporated under reduced pressure, yield 1.05 g the mixture heated for a further 2 h The mixture was cooled partitioned between ethylacetate/2M hydrochloric acid the organics dried evaporated under reduced pressure, yield 1.05 g

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

実験手順: To a solution of 1,2-difluoro-4,5-dimethoxybenzene (5 g, 28.71 mmol, Aldrich) in methylene chloride (300 mL) cooled to 0° C. was added aluminum chloride (14.16 g, 106.2 mmol, Fluka) in several portions. At the end of the addition, the ice bath was removed and the reaction mixture was stirred at room temperature for 12 hours. Water was added to quench the reaction. Diethyl ether (200 mL) was added and the layers were separated. The aqueous layer was extracted with diethyl ether (50 mL). The combined organic layers were washed with water, brine and dried over anhydrous magnesium sulfate. The solids were filtered off and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, 60 Å silica gel, eluting with 10% ethyl acetate in hexanes) yielded 4,5-difluoro-2-methoxy-phenol as dark oil (3.75 g, 82%). At the end of the addition the ice bath was removed Water was added to quench the reaction the layers were separated The aqueous layer was extracted with diethyl ether (50 mL) The combined organic layers were washed with water, brine dried over anhydrous magnesium sulfate The solids were filtered off the filtrate was concentrated in vacuo Purification of the crude residue by flash chromatography (Biotage system, 60 Å silica gel, eluting with 10% ethyl acetate in hexanes)

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

実験手順: To a solution of 1,2-difluoro-4,5-dimethoxybenzene (5 g, 28.71 mmol, Aldrich) in methylene chloride (300 mL) cooled to 0° C. was added aluminum chloride (14.16 g, 106.2 mmol, Fluka) in several portions. At the end of the addition, the ice bath was removed and the reaction mixture was stirred at room temperature for 12 hours. Water was added to quench the reaction. Diethyl ether (200 mL) was added and the layers were separated. The aqueous layer was extracted with diethyl ether (50 mL). The combined organic layers were washed with water, brine and dried over anhydrous magnesium sulfate. The solids were filtered off and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, 60 Å silica gel, eluting with 10% ethyl acetate in hexanes) yielded 4,5-difluoro-2-methoxy-phenol as dark oil (3.75 g, 82%). At the end of the addition the ice bath was removed Water was added to quench the reaction the layers were separated The aqueous layer was extracted with diethyl ether (50 mL) The combined organic layers were washed with water, brine dried over anhydrous magnesium sulfate The solids were filtered off the filtrate was concentrated in vacuo Purification of the crude residue by flash chromatography (Biotage system, 60 Å silica gel, eluting with 10% ethyl acetate in hexanes)