5-bromo-2,3-difluorophenol

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: To an acetone solution (0.1 M, 240 mL) of commercially available 5-bromo-2,3-difluorophenol (5.0 g, 23.93 mmol) was added K2CO3 (9.92 g, 71.77 mmol), and the mixture was heated to reflux for 30 min. After cooling this mixture to RT, (2R)-(−)-glycidyl 3-nitrobenzenesulfonate (6.20 g, 23.93 mmol) was added, and the resulting mixture was heated to reflux overnight. After cooling to RT, the solids were removed by filtration and washed well with ethyl acetate. The filtrate was concentrated and partitioned between ethyl acetate and 1N HCl. The organic portion was washed successively with 5% NaHCO3 and brine, dried (MgSO4), filtered and concentrated to a solid. Purification by FCC (15% ethyl acetate/hexanes) gave the product as a white solid in 97% yield (6.19 g). the mixture was heated to reflux for 30 min the resulting mixture was heated to reflux overnight After cooling to RT the solids were removed by filtration washed well with ethyl acetate The filtrate was concentrated partitioned between ethyl acetate and 1N HCl The organic portion was washed successively with 5% NaHCO3 and brine dried (MgSO4) filtered concentrated to a solid Purification by FCC (15% ethyl acetate/hexanes)

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

実験手順: To an acetone solution (0.1 M, 240 mL) of commercially available 5-bromo-2,3-difluorophenol (5.0 g, 23.93 mmol) was added K2CO3 (9.92 g, 71.77 mmol), and the mixture was heated to reflux for 30 min. After cooling this mixture to RT, (2R)-(−)-glycidyl 3-nitrobenzenesulfonate (6.20 g, 23.93 mmol) was added, and the resulting mixture was heated to reflux overnight. After cooling to RT, the solids were removed by filtration and washed well with ethyl acetate. The filtrate was concentrated and partitioned between ethyl acetate and 1N HCl. The organic portion was washed successively with 5% NaHCO3 and brine, dried (MgSO4), filtered and concentrated to a solid. Purification by FCC (15% ethyl acetate/hexanes) gave the product as a white solid in 97% yield (6.19 g). the mixture was heated to reflux for 30 min the resulting mixture was heated to reflux overnight After cooling to RT the solids were removed by filtration washed well with ethyl acetate The filtrate was concentrated partitioned between ethyl acetate and 1N HCl The organic portion was washed successively with 5% NaHCO3 and brine dried (MgSO4) filtered concentrated to a solid Purification by FCC (15% ethyl acetate/hexanes)

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

実験手順: A solution of DMF (100 mL), 5-bromo-2,3-difluorophenol (10 g, 47.85 mol), and K2CO3 (7.27 g, 52.63 mol) and benzyl bromide (9 g, 52.63 mol) were combined at 0° C. under N2. The solution was allowed to warm to rt and stirred overnight. H2O, Et3N (2 eq) and EtOAc (5000 mL) were added and the organic layer separated. The aqueous layer was washed with EtOAc (2×) and the combined organic fractions were washed with 1M HCl (2×), sat. aq. NaHCO3 (2×), dried, and concentrated. The crude product was purified by Biotage (gradient 100% hexanes-60% EtOAc/hexanes) to afford 10.08 g of product as an oil. were combined at 0° C. under N2 the organic layer separated The aqueous layer was washed with EtOAc (2×) the combined organic fractions were washed with 1M HCl (2×), sat. aq. NaHCO3 (2×) dried concentrated The crude product was purified by Biotage (gradient 100% hexanes-60% EtOAc/hexanes)

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

実験手順: A solution of DMF (100 mL), 5-bromo-2,3-difluorophenol (10 g, 47.85 mol), and K2CO3 (7.27 g, 52.63 mol) and benzyl bromide (9 g, 52.63 mol) were combined at 0° C. under N2. The solution was allowed to warm to rt and stirred overnight. H2O, Et3N (2 eq) and EtOAc (5000 mL) were added and the organic layer separated. The aqueous layer was washed with EtOAc (2×) and the combined organic fractions were washed with 1M HCl (2×), sat. aq. NaHCO3 (2×), dried, and concentrated. The crude product was purified by Biotage (gradient 100% hexanes-60% EtOAc/hexanes) to afford 10.08 g of product as an oil. were combined at 0° C. under N2 the organic layer separated The aqueous layer was washed with EtOAc (2×) the combined organic fractions were washed with 1M HCl (2×), sat. aq. NaHCO3 (2×) dried concentrated The crude product was purified by Biotage (gradient 100% hexanes-60% EtOAc/hexanes)

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 5-bromo-2,3-difluorophenol (20 g 0.0957 mol), ethyl pentenoate (24.53 g, 0.191 mol), N,N-diisopropylamine (66.68 ml, 0.383 mol) and catalytic reagents [Pd(OAc)2=2.15 g, 9.57 mmol; P(O-tol)3=11.65 g, 0.0383 mol] in propionitrile (500 mL) in solution was degassed by bubbling nitrogen. The reactions were heated to 120° C. overnight. The reaction mixtures were filtered through a Celite and washed with CH2Cl2 and filtrates were combined and concentrated. The crude residue was purified by flash column chromatography eluting with 0-10% EtOAc in hexanes to afford the desired product (21.5 g). Subsequent hydrogenation in Parr shaker using Pd/C at 65 psi overnight, followed by filtration, concentration and column chromatography (0-10% ethyl acetate:hexane) afforded the desired product (17.6 g, 71%). was degassed by bubbling nitrogen The reaction mixtures were filtered through a Celite washed with CH2Cl2 and filtrates concentrated The crude residue was purified by flash column chromatography eluting with 0-10% EtOAc in hexanes

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 5-bromo-2,3-difluorophenol (20 g 0.0957 mol), ethyl pentenoate (24.53 g, 0.191 mol), N,N-diisopropylamine (66.68 ml, 0.383 mol) and catalytic reagents [Pd(OAc)2=2.15 g, 9.57 mmol; P(O-tol)3=11.65 g, 0.0383 mol] in propionitrile (500 mL) in solution was degassed by bubbling nitrogen. The reactions were heated to 120° C. overnight. The reaction mixtures were filtered through a Celite and washed with CH2Cl2 and filtrates were combined and concentrated. The crude residue was purified by flash column chromatography eluting with 0-10% EtOAc in hexanes to afford the desired product (21.5 g). Subsequent hydrogenation in Parr shaker using Pd/C at 65 psi overnight, followed by filtration, concentration and column chromatography (0-10% ethyl acetate:hexane) afforded the desired product (17.6 g, 71%). was degassed by bubbling nitrogen The reaction mixtures were filtered through a Celite washed with CH2Cl2 and filtrates concentrated The crude residue was purified by flash column chromatography eluting with 0-10% EtOAc in hexanes

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

実験手順: A second 1 L round-bottomed flask was charged with a stir bar, 5-bromo-2,3-difluorophenol (50.2 g, 240 mmol) and propionitrile (460 mL). The solution was deoxygenated by bubbling nitrogen for 15 minutes. To this solution was added Pd(OAc)2 (5.42 g, 24.1 mmol), P(O-tol)3 (29.3 g, 96.1 mmol), ethyl acrylate (52 mL, 480 mmol) and diisopropylethylamine (167 mL, 959 mmol) sequentially. The flask was immersed into a preheated (120° C.) oil bath. The reaction was heated at this temperature for 22 h. Upon cooling to room temperature, the reaction mixture was filtered through a Celite-plugged filter frit, washed with CH2Cl2, and concentrated. A second 1 L round-bottomed flask was charged with a stir bar The solution was deoxygenated by bubbling nitrogen for 15 minutes was immersed into a preheated (120° C.) oil bath The reaction was heated at this temperature for 22 h the reaction mixture was filtered through a Celite-plugged filter frit washed with CH2Cl2 concentrated

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

実験手順: A second 1 L round-bottomed flask was charged with a stir bar, 5-bromo-2,3-difluorophenol (50.2 g, 240 mmol) and propionitrile (460 mL). The solution was deoxygenated by bubbling nitrogen for 15 minutes. To this solution was added Pd(OAc)2 (5.42 g, 24.1 mmol), P(O-tol)3 (29.3 g, 96.1 mmol), ethyl acrylate (52 mL, 480 mmol) and diisopropylethylamine (167 mL, 959 mmol) sequentially. The flask was immersed into a preheated (120° C.) oil bath. The reaction was heated at this temperature for 22 h. Upon cooling to room temperature, the reaction mixture was filtered through a Celite-plugged filter frit, washed with CH2Cl2, and concentrated. A second 1 L round-bottomed flask was charged with a stir bar The solution was deoxygenated by bubbling nitrogen for 15 minutes was immersed into a preheated (120° C.) oil bath The reaction was heated at this temperature for 22 h the reaction mixture was filtered through a Celite-plugged filter frit washed with CH2Cl2 concentrated

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

実験手順: To an acetone solution (0.1 M, 240 mL) of commercially available 5-bromo-2,3-difluorophenol (5.0 g, 23.93 mmol) was added K2CO3 (9.92 g, 71.77 mmol), and the mixture was heated to reflux for 30 min. After cooling this mixture to RT, (2R)-(−)-glycidyl 3-nitrobenzenesulfonate (6.20 g, 23.93 mmol) was added, and the resulting mixture was heated to reflux overnight. After cooling to RT, the solids were removed by filtration and washed well with ethyl acetate. The filtrate was concentrated and partitioned between ethyl acetate and 1N HCl. The organic portion was washed successively with 5% NaHCO3 and brine, dried (MgSO4), filtered and concentrated to a solid. Purification by FCC (15% ethyl acetate/hexanes) gave the product as a white solid in 97% yield (6.19 g). the mixture was heated to reflux for 30 min the resulting mixture was heated to reflux overnight After cooling to RT the solids were removed by filtration washed well with ethyl acetate The filtrate was concentrated partitioned between ethyl acetate and 1N HCl The organic portion was washed successively with 5% NaHCO3 and brine dried (MgSO4) filtered concentrated to a solid Purification by FCC (15% ethyl acetate/hexanes)