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With boron tribromide In dichloromethane at -20 - 20℃; for 12 h;
To a stirred solution of l-bromo-2,3-difluoro-4-methoxybenzene (3 g, 13.45 mmol) in DCM (30 mL) at -20 °C was added 1M BBr3 in DCM (26.9 mL, 26.9 mmol) dropwise over 10 min. The cold bath was removed and the reaction mixture was stirred at RT for 12 h. The reaction mixture was cooled to 10 °C and quenched with saturated aqueous sodium bicarbonate solution (100 mL). The mixture was diluted with DCM (150 mL). The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to afford 4-bromo-2,3- difiuorophenol (2 g, 9.47 mmol, 70percent yield) as a dark red oil. NMR (400 MHz, CHLOROFORM-cf): δ 7.15-7.21 (m, 1H), 6.69-6.76 (m, 1H), 5.30-5.31 (m, 1H) ppm.
With potassium carbonate In N,N-dimethyl-formamide for 72 h;
Methyl iodide (1.56 mL, 25.1 mmol, 1.5 equ) was added dropwise to a suspension of 4-bromo- 2,3-difluorophenol (3.5 g, 16.7 mmol) and potassium carbonate (2.77 g, 20.0 mmol, 1.2 equ) in N,N-dimethylformamide (30 mL) and the mixture was stirred for 3 days. The precipitate was removed by filtration and the filtrate was concentrated to dryness in vacuo. Dichloromethane and water were added and the product was extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to give l-bromo-2,3- difluoro-4-methoxybenzene as a white crystalline solid (3.8 g, quantitative).
With bromine; triethylamine; In dichloromethane; at 0 - 20℃; for 1.33333h;
Step 2) 2.Og 3-Isobutoxy-4,5,6,6a-tetrahydro-3aH-pentalen-l -one was dissolved in 40 ml DCM. 2.47g Br2 was added drop wise and the mixture was stirred at rt for 20 min. The reaction mixture was cooled to O0C and 3.12 g TEA was slowly added. The cooling bath was removed and the mixture was stirred at rt for 1 h. Filtration and concentration gave a crude product which was purified on silica using 2% MeOH in DCM to produce 2.26 g l-Bromo-2,3-difluoro-4-methoxy-benzene.
Step 3 ) n-BuLi (1.1 eq) was added to a solution of 40 mg l-Bromo-2,3-difluoro-4-methoxy-benzene in 5 ml dry ether at -78C under N2. 440 mg (1.61 mmol) 2-Bromo-3-isobutoxy-4,5,6,6a-tetrahydro-3aH- pentalen-1-one dissolved in 5 ml dry ether and cooled to -78C was added drop wise. The mixture was stirred under N2 and the temperature was slowly raised overnight. The reaction was quenched with 10 ml water followed by 10 ml HCl (2N). The aqueous mixture was extracted with ether 3x and the combined organic layers were washed with brine and dried over Na2SO4. Concentration followed by purification on silica using a ether/n-heptane (1 :9-2:8) gradient afforded 390 mg 2-Bromo-3-(2,3-difluoro-4-methoxy- phenyl)-4,5,6,6a-tetrahydro-3aH-pentalen-l-one as a clear oil which solidified after a while.
(2,3-difluoro-4-methoxyphenyl)boronic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A 1.6M solution of tert-butyl lithium in pentane (23.4 mL, 37.5 mmol, 2.2 equ) was added dropwise under nitrogen at -78C to a solution of l-bromo-2,3-difluoro-4-methoxybenzene (3.8 g, 17.0 mmol) in anhydrous tetrahydrofuran (40 mL) and the resulting yellow/red solution was stirred for 45 min. at -78 C before the addition of trimethyl borate (5.69 mmol, 51.0 mmol, 3 equ). The resulting pale yellow solution was stirred for 16 h and the reaction was quenched with 3N HC1. The mixture was stirred for 2 h and water was added. The product was extracted with diethyl ether and the combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The product was triturated with hexane, filtered and dried under suction to give the title compound as an off-white solid (2.53 g, 79% yield).<¾ (DMSO-d6): 8.16 (2H, s (br)), 7.31-7.36 (1H, ddd, J=8.6, 6.6, 2.3), 6.96-7.00 (1H, ddd, J=8.6, 7.3, 1.5), 3.87 (3H, s).Note: The estimated purity of the product as determined by NMR was 80% and the product was used without further purification in the next step.
With potassium carbonate; In N,N-dimethyl-formamide; for 72h;
Methyl iodide (1.56 mL, 25.1 mmol, 1.5 equ) was added dropwise to a suspension of 4-bromo- 2,3-difluorophenol (3.5 g, 16.7 mmol) and potassium carbonate (2.77 g, 20.0 mmol, 1.2 equ) in N,N-dimethylformamide (30 mL) and the mixture was stirred for 3 days. The precipitate was removed by filtration and the filtrate was concentrated to dryness in vacuo. Dichloromethane and water were added and the product was extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to give l-bromo-2,3- difluoro-4-methoxybenzene as a white crystalline solid (3.8 g, quantitative).
8-(2,3-difluoro-4-methoxyphenyl)-1,4-dioxa-8-azaspiro[4.5]decane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
600 mg
With sodium t-butanolate; In 1,4-dioxane; at 100℃;Inert atmosphere;
To a flask containing <strong>[406482-22-2]1-bromo-2,3-difluoro-4-methoxy-benzene</strong> (500 mg, 2.25 mmol) and1,4-dioxa-8-azaspiro[4.5]decane (355 mg, 2.48 mmol) in dioxane (10 mL) was added t-BuONa (432 mg, 4.5 mmol) under N2. After being heated with stirring at 100 C overnight, the resulting reaction mixture was cooled to rt, diluted with H20 (30 mL) and extracted with EA (30 mL) for three times. The combined organic layer was washed with brine (30 mL), dried over anhydrousNa2SO4 and concentrated in vacuo to afford 8-(2,3-difluoro-4-methoxy-phenyl)-1,4-dioxa-8- azaspiro[4.5]decane (600 mg), which was used in the next step without further purification.
2,3-difluoro-4,4''-bis(methoxy)-1,1’:4’,1’’-terphenyl[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In methanol; water; for 12h;Reflux; Inert atmosphere;
1,4-phenylene diboronic acid (1.0 g, 6.03 mmol)1,2-Dimethoxyethanol (100 mL)And methanol (10 mL) was addedAfter dissolution,4-Bromoanisole (1.24 g, 6.64 mmol) and <strong>[406482-22-2]2,3-difluoro-4-bromoanisole</strong> (1.48 g, 6.64 mmol) were added dropwise to the mixed solution,2 M aqueous potassium carbonate solution (20 mL) was added and degassed.To the mixed solution, palladium tetrakis (triphenylphosphine)(349 mg, 0.30 mmol), and the mixture was refluxed under nitrogen atmosphere for 12 hours.An excessive amount of distilled water was added to the reaction solution to terminate the reaction,After extraction with dichloromethane, the solvent was concentrated under reduced pressure,The residue was purified by column chromatography to give the desired compound (827 mg, 42%) as a white solid.
2-(2,3-difluoro-4-methoxyphenyl)thiophene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
4.4 g
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In methanol; Dimethyl ether; water; for 11h;Reflux;
2-thiophene boronic acid pinacol ester(5.0 g, 23.8 mmol) was dissolved in dimethyl ether (150 ml) and MeOH (70 ml) and degassed for 30 minutes. To the mixed solution was added a potassium carbonate aqueous solution (K2CO3, 2M, 20 ml) and <strong>[406482-22-2]4-bromo-2,3-difluoroanisole</strong> (6.4 g, 28.6 mmol). After degassing again for 30 minutes, tetrakis (triphenylphosphine) palladium(Pd (PPh3) 4, 2.8 g, 2.4 mmol) was added and the mixture was degassed for 1 hour, then the temperature was raised, and the mixture was refluxed with stirring. Next, the reaction mixture was poured into excess water to complete the reaction, followed by extraction with dichloromethane, drying, and passing through a silica gel column to obtain a colorless liquid crude product (4.4 g).
With boron tribromide; In dichloromethane; at -20 - 20℃; for 12h;
To a stirred solution of l-bromo-2,3-difluoro-4-methoxybenzene (3 g, 13.45 mmol) in DCM (30 mL) at -20 C was added 1M BBr3 in DCM (26.9 mL, 26.9 mmol) dropwise over 10 min. The cold bath was removed and the reaction mixture was stirred at RT for 12 h. The reaction mixture was cooled to 10 C and quenched with saturated aqueous sodium bicarbonate solution (100 mL). The mixture was diluted with DCM (150 mL). The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to afford 4-bromo-2,3- difiuorophenol (2 g, 9.47 mmol, 70% yield) as a dark red oil. NMR (400 MHz, CHLOROFORM-cf): delta 7.15-7.21 (m, 1H), 6.69-6.76 (m, 1H), 5.30-5.31 (m, 1H) ppm.
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