4-bromo-2,6-dimethoxyphenol

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:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 500 mL flask fitted with a condenser, 2,6-dimethoxyphenol (10 g, 64.86 mmol) and 80 mL of anhydrous CHCl3 was added. The solution was cooled to −40° C. and NaH (60% dispersion in mineral oil, 26 mg, 0.65 mmol) was added. Another 20 mL of anhydrous CHCl3 was added followed by rapid addition of N-bromo-succinimide (12.77 g, 71.35 mmol). The reaction mixture was stirred for 1 hour at −35° C., heated to room temperature over the next 30 minutes and heated to reflux for another 30 minutes. The solvent was evaporated under vacuum overnight. The tan solid was stirred with 100 mL ether, the mixture was filtered, and the residue was washed with ether. The solvent was evaporated under vacuum to yield a tan solid, which was then dissolved in boiling hexanes. The solution was decanted from the brown oil and filtered through a pre-heated celite pad into a heated flask. The light yellow solution was allowed to cool at room temperature for 3 hours. White wooly needles were filtered off and dried to yield 217 (3.22 g, 22%). 1H NMR (CDCl3) δ 6.72 (s, 2H), 5.44 (s, 1H), 3.88 (s, 6H); 13C NMR (CDCl3) 147.47, 133.93, 110.88, 108.38, 56.33. To a 500 mL flask fitted with a condenser heated to room temperature over the next 30 minutes heated to reflux for another 30 minutes The solvent was evaporated under vacuum overnight The tan solid was stirred with 100 mL ether the mixture was filtered the residue was washed with ether The solvent was evaporated under vacuum to yield a tan solid, which was then dissolved The solution was decanted from the brown oil filtered through a pre-heated celite pad into a heated flask to cool at room temperature for 3 hours White wooly needles were filtered off dried

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

実験手順: 5-Bromo-2-(difluoromethoxy)-1,3-dimethoxybenzene was synthesized from 4-bromo-2,6-dimethoxyphenol according to the procedure of Zafrani, Y. Tetrahedron 2009, 65, 5278 as follows. To a solution of 4-bromo-2,6-dimethoxyphenol (1.08 g, 4.6 mmol) in MeCN (27 mL) was added a solution of KOH (5.0 g, 89 mmol) in H2O (27 mL). The mixture was immediately cooled over a −78° C. bath and diethyl(bromodifluoromethyl)phosphonate (1.6 mL, 8.9 mmol) was added. The flask was sealed with a septum and the cold bath was removed. The mixture was stirred for a total of 3.5 hrs during which time the septum was ejected from the flask. The reaction was diluted with EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organics were washed with 1 M NaOH, H2O and brine then dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (0-30% EtOAc-hexanes) provided 5-bromo-2-(difluoromethoxy)-1,3-dimethoxybenzene as a white solid (0.808 g, 62% yield). The flask was sealed with a septum the cold bath was removed The reaction was diluted with EtOAc the layers were separated The aqueous layer was extracted with EtOAc the combined organics were washed with 1 M NaOH, H2O and brine then dried over Na2SO4 concentrated in vacuo Purification by chromatography (0-30% EtOAc-hexanes)

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

実験手順: 5-Bromo-2-(difluoromethoxy)-1,3-dimethoxybenzene was synthesized from 4-bromo-2,6-dimethoxyphenol according to the procedure of Zafrani, Y. Tetrahedron 2009, 65, 5278 as follows. To a solution of 4-bromo-2,6-dimethoxyphenol (1.08 g, 4.6 mmol) in MeCN (27 mL) was added a solution of KOH (5.0 g, 89 mmol) in H2O (27 mL). The mixture was immediately cooled over a −78° C. bath and diethyl(bromodifluoromethyl)phosphonate (1.6 mL, 8.9 mmol) was added. The flask was sealed with a septum and the cold bath was removed. The mixture was stirred for a total of 3.5 hrs during which time the septum was ejected from the flask. The reaction was diluted with EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organics were washed with 1 M NaOH, H2O and brine then dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (0-30% EtOAc-hexanes) provided 5-bromo-2-(difluoromethoxy)-1,3-dimethoxybenzene as a white solid (0.808 g, 62% yield). The flask was sealed with a septum the cold bath was removed The reaction was diluted with EtOAc the layers were separated The aqueous layer was extracted with EtOAc the combined organics were washed with 1 M NaOH, H2O and brine then dried over Na2SO4 concentrated in vacuo Purification by chromatography (0-30% EtOAc-hexanes)

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

実験手順: 4-Bromo-2,6-dimethoxyphenol (Lee, H.; et al. Tetrahedron Letters, 2004, 45, 1019) was coupled with 2-furylboronic acid according to the procedure used in the synthesis of Example 21. Purification by chromatography (20-40% EtOAc-hexanes) gave 4-(furan-2-yl)-2,6-dimethoxyphenol as a light orange solid (1.95 g, 79% yield). used in the synthesis of Example 21 Purification by chromatography (20-40% EtOAc-hexanes)

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

実験手順: 4-Bromo-2,6-dimethoxyphenol (Lee, H.; et al. Tetrahedron Letters, 2004, 45, 1019) was coupled with 2-furylboronic acid according to the procedure used in the synthesis of Example 21. Purification by chromatography (20-40% EtOAc-hexanes) gave 4-(furan-2-yl)-2,6-dimethoxyphenol as a light orange solid (1.95 g, 79% yield). used in the synthesis of Example 21 Purification by chromatography (20-40% EtOAc-hexanes)

反応条件: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 74 g (0.32 mol) of 4-bromo-2,6-dimethoxy-phenol 17 and 32 g (0.8 mol) of NaOH in 850 ml of H2O was cooled to 10° C. and 45 ml (0.48 mmol) of dimethyl sulfate was added. The mixture was refluxed for 3 h and an equal amount of dimethyl sulfate (total 0.96 mol) was then added. The mixture was refluxed for another 3 h. Upon cooling overnight, the gray product solidified and was filtered off and dissolved in 1.2 l of ether. The ether solution was filtered to remove insoluble impurity and washed sequentially with 5% NaOH solution (200 ml), water (2×200 mL), and brine (200 mL). The ether phase was dried over Na2SO4 to give a off-white solid, which was recrystallized in hexane (300 ml) to give 62.3 g (79%) of 18. The mixture was refluxed for 3 h The mixture was refluxed for another 3 h Upon cooling overnight was filtered off dissolved in 1.2 l of ether The ether solution was filtered to remove insoluble impurity washed sequentially with 5% NaOH solution (200 ml), water (2×200 mL), and brine (200 mL) The ether phase was dried over Na2SO4 to give a off-white solid, which was recrystallized in hexane (300 ml)

反応条件: temp:-45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 2 liter flask equipped with a magnetic stirrer, thermometer, and nitrogen inlet, was added 77 g (0.5 mol) of pyrogallol 1,3-dimethyl ether, 5.8 ml of MeOH, and 750 ml of CH2Cl2. To this solution was added 126 mg (5 mmol) of NaH (95%). The solution was stirred while cooling to −45° C. with a dry-ice acetone bath. 94 g (0.53 mol) of powdered N-bromosuccinimide was added rapidly. The reaction mixture was then stirred for 1 hour at −35° C., heated to room temperature over next 30 min, and finally refluxed for 30 min. The CH2Cl2 was removed under reduced pressure and the residue solidified. The tan solid was broken up and stirred well with 1 liter of ether. This was filtered and the residue was washed well with ether. The ether was evaporated under reduced pressure to yield a tan solid. The solid was placed in a 5 liter flask with 3 liters of ligroin (bp: 90-110° C.) and heated with stirring to 80° C. The hot solution was decanted from the brown oil and the hot yellow solution was allowed to cool at room temperature for 3 hr. The white needles was filtered off and dried to yield 74 g (63%) of 17. To a 2 liter flask equipped with a magnetic stirrer The reaction mixture was then stirred for 1 hour at −35° C. heated to room temperature over next 30 min finally refluxed for 30 min The CH2Cl2 was removed under reduced pressure stirred well with 1 liter of ether This was filtered the residue was washed well with ether The ether was evaporated under reduced pressure to yield a tan solid heated with stirring to 80° C The hot solution was decanted from the brown oil to cool at room temperature for 3 hr The white needles was filtered off dried

反応条件: temp:-45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 2 liter flask equipped with a magnetic stirrer, thermometer, and nitrogen inlet, was added 77 g (0.5 mol) of pyrogallol 1,3-dimethyl ether, 5.8 ml of MeOH, and 750 ml of CH2Cl2. To this solution was added 126 mg (5 mmol) of NaH (95%). The solution was stirred while cooling to −45° C. with a dry-ice acetone bath. 94 g (0.53 mol) of powdered N-bromosuccinimide was added rapidly. The reaction mixture was then stirred for 1 hour at −35° C., heated to room temperature over next 30 min, and finally refluxed for 30 min. The CH2Cl2 was removed under reduced pressure and the residue solidified. The tan solid was broken up and stirred well with 1 liter of ether. This was filtered and the residue was washed well with ether. The ether was evaporated under reduced pressure to yield a tan solid. The solid was placed in a 5 liter flask with 3 liters of ligroin (bp: 90-110° C.) and heated with stirring to 80° C. The hot solution was decanted from the brown oil and the hot yellow solution was allowed to cool at room temperature for 3 hr. The white needles was filtered off and dried to yield 74 g (63%) of 17. To a 2 liter flask equipped with a magnetic stirrer The reaction mixture was then stirred for 1 hour at −35° C. heated to room temperature over next 30 min finally refluxed for 30 min The CH2Cl2 was removed under reduced pressure stirred well with 1 liter of ether This was filtered the residue was washed well with ether The ether was evaporated under reduced pressure to yield a tan solid heated with stirring to 80° C The hot solution was decanted from the brown oil to cool at room temperature for 3 hr The white needles was filtered off dried

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

実験手順: 4-bromo-2,6-dimethoxyphenol (500 mg, 0.002 mol), phenylboronic acid (0.65 g, 0.0054 mol), TEA (1.8 mL, 0.013 mol), cupric acetate (0.62 g, 0.0034 mol) and DCM (30 mL, 0.4 mol) were added to a 100 mL oven dried flask and the reaction was stirred at rt for 48 h. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=3.77 (s, 6H), 6.82 (s, 2H), 6.86 (d, J=7.83 Hz, 2H), 6.96-7.04 (m, 1H), 7.22-7.27 (m, 2H). dried flask Reaction mixture was then filtered through celite The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography eluting with 5% EtOAc in hexane