2-bromo-1-fluoro-3-methoxybenzene

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

実験手順: A cooled (−78° C.) solution of commercially available 2-bromo-1-fluoro-3-methoxybenzene (2.642 g; 12.90 mmol) in anh. THF (60 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (8.05 ml; 12.90 mmol). The resulting solution was further stirred at −78° C. for 5 min. A solution of ethyl 4-((tert-butylsulfinyl)imino)-2-methylbutanoate (2.550 g; 10.30 mmol) in anh. THF (20 ml) was then added dropwise to the cooled reaction mixture, and stirring at −78° C. was continued for 45 min. The resulting reaction mixture was treated successively with aq. sat. NH4Cl (75 ml), Et2O (250 ml) and water (75 ml). The separated organic layer was then washed with brine (75 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=30/1) afforded ethyl 4-(1,1-dimethylethylsulfinamido)-4-(2-fluoro-6-methoxyphenyl)-2-methylbutanoate as a yellow oil. LC-MS (conditions A): tR=0.81 min. and [M+H]+: 374.02 g/mol; tR=0.83 min. and [M+H]+: 374.34 g/mol (mixture of diastereoisomers). stirring at −78° C. was continued for 45 min The resulting reaction mixture The separated organic layer was then washed with brine (75 ml) dried over anh. MgSO4 filtered concentrated to dryness under reduced pressure Purification by FC (DCM/MeOH=30/1)

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

実験手順: A cooled (−78° C.) solution of commercially available 2-bromo-1-fluoro-3-methoxybenzene (2.642 g; 12.90 mmol) in anh. THF (60 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (8.05 ml; 12.90 mmol). The resulting solution was further stirred at −78° C. for 5 min. A solution of ethyl 4-((tert-butylsulfinyl)imino)-2-methylbutanoate (2.550 g; 10.30 mmol) in anh. THF (20 ml) was then added dropwise to the cooled reaction mixture, and stirring at −78° C. was continued for 45 min. The resulting reaction mixture was treated successively with aq. sat. NH4Cl (75 ml), Et2O (250 ml) and water (75 ml). The separated organic layer was then washed with brine (75 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=30/1) afforded ethyl 4-(1,1-dimethylethylsulfinamido)-4-(2-fluoro-6-methoxyphenyl)-2-methylbutanoate as a yellow oil. LC-MS (conditions A): tR=0.81 min. and [M+H]+: 374.02 g/mol; tR=0.83 min. and [M+H]+: 374.34 g/mol (mixture of diastereoisomers). stirring at −78° C. was continued for 45 min The resulting reaction mixture The separated organic layer was then washed with brine (75 ml) dried over anh. MgSO4 filtered concentrated to dryness under reduced pressure Purification by FC (DCM/MeOH=30/1)

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

実験手順: 2-Bromo-3-fluoro anisole (10 g, 48.77 mmol) was dissolved in DCM (200 mL) and cooled to about −78° C. To the solution was added BBr3 (11.53 mL, 121.9 mmol) in one portion. The mixture was warmed to r.t. and stirred overnight. The mixture was partitioned between water and DCM (50 mL), and the aqueous layer was back extracted with DCM (200 mL). The combined organics were dried (NaSO4), filtered and concentrated to give about 9.32 g of the product as a dark oil. MS found 188.9 (M−1) The mixture was warmed to r.t. The mixture was partitioned between water and DCM (50 mL) the aqueous layer was back extracted with DCM (200 mL) The combined organics were dried (NaSO4) filtered concentrated

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

実験手順: The 3-fluoro anisole (15 g, 119 mmol) was placed in THF (300 mL) and cooled to about −78° C., and then n-BuLi (89 mL 1.6 M in hexanes) was added while maintaining the temperature at around −70° C. The mixture was stirred for about 15 minutes, and bromine (18.9 g, 119 mmol) was added over 10 minutes. The mixture was warmed to r.t. and stirred overnight. The mixture was quenched with water, diluted with ether (500 mL) and partitioned between water/ether (1/1 300 mL). The water layer was back extracted with ether (250 mL), and the combined organic fractions were dried, filtered and concentrated. The dark residue was distilled under house vacuum (product 115–130° C.) to recover about 13.8 g of the product as a gray oil (57%). while maintaining the temperature at around −70° C The mixture was warmed to r.t. stirred overnight The mixture was quenched with water diluted with ether (500 mL) partitioned between water/ether (1/1 300 mL) The water layer was back extracted with ether (250 mL) the combined organic fractions were dried filtered concentrated The dark residue was distilled under house vacuum (product 115–130° C.) to recover about 13.8 g of the product as a gray oil (57%)

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

実験手順: The 3-fluoro anisole (15 g, 119 mmol) was placed in THF (300 mL) and cooled to about −78° C., and then n-BuLi (89 mL 1.6 M in hexanes) was added while maintaining the temperature at around −70° C. The mixture was stirred for about 15 minutes, and bromine (18.9 g, 119 mmol) was added over 10 minutes. The mixture was warmed to r.t. and stirred overnight. The mixture was quenched with water, diluted with ether (500 mL) and partitioned between water/ether (1/1 300 mL). The water layer was back extracted with ether (250 mL), and the combined organic fractions were dried, filtered and concentrated. The dark residue was distilled under house vacuum (product 115–130° C.) to recover about 13.8 g of the product as a gray oil (57%). while maintaining the temperature at around −70° C The mixture was warmed to r.t. stirred overnight The mixture was quenched with water diluted with ether (500 mL) partitioned between water/ether (1/1 300 mL) The water layer was back extracted with ether (250 mL) the combined organic fractions were dried filtered concentrated The dark residue was distilled under house vacuum (product 115–130° C.) to recover about 13.8 g of the product as a gray oil (57%)

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

実験手順: 2-Bromo-1-fluoro-3-methoxybenzene (200 mg, 0.975 mmol), 1,2-thiazinane 1,1-dioxide (264 mg, 1.951 mmol), copper (62 mg, 0.975 mmol) and potassium carbonate (270 mg, 1.95 1 mmol) were combined and heated to 170 C for 5 hours. After this time, the mixture was suspended in methanol (15 ml) and vortexed for 18 hours. This mixture was filtered through Gelman Acrodisc and evaporated in vacuo. The resulting residue was partitioned between EtOAc (2×10 ml) and aq NH4Cl (5 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. This residue was purified by column chromatography eluting with a 0-10% EtOAc/CH2Cl2 to give 2-(2-fluoro-6-methoxyphenyl)-1,2-thiazinane 1,1-dioxide. Low resolution mass spectrometry: (M+H+)=260.1. 1H NMR (400 MHz, CDCl3) δ 7.21 (dt, 1H, J=8.1 and 4.3 Hz), 6.69-6.77 (m, 21), 3.88 (s, 3H), 3.75-8.74 (m, 1H), 3.65 (dq, 1H, J=4.6, 6.0 and 14 Hz), 3.24 (dd, 2H, J=5.6 and 7.4 Hz), 3.27 (quin, 2H, J=6.1 Hz) and 1.78-1.90 (m, 2H) ppm. heated to 170 C for 5 hours This mixture was filtered through Gelman Acrodisc evaporated in vacuo The resulting residue was partitioned between EtOAc (2×10 ml) and aq NH4Cl (5 ml) The combined organic extracts were dried over MgSO4 filtered concentrated in vacuo This residue was purified by column chromatography eluting with a 0-10% EtOAc/CH2Cl2

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2-bromo-3-fluoroanisol (5.00 g, 24.4 mmol) in trifluoroacetic acid (25 mL) was heated to 80° C. and then a solution of hexamethylenetetramine (6.83 g, 48.8 mmol) in trifluoroacetic acid (25 mL) was added dropwise over 1.5 h. Upon completion of the addition, the reaction was stirred at 80° C. for 1 h under nitrogen. The excess trifluoroacetic acid was removed under vacuum, and the pH was adjusted to 7.5-8.0 by addition of saturated aqueous potassium carbonate (˜100 mL). The white solid that formed was filtered to give I-30 which was used without additional purification. Upon completion of the addition The excess trifluoroacetic acid was removed under vacuum the pH was adjusted to 7.5-8.0 by addition of saturated aqueous potassium carbonate (˜100 mL) The white solid that formed was filtered to give I-30 which was used without additional purification

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

実験手順: In a 3-necked 250 mL round-bottomed flask equipped with nitrogen lines and a stir bar was placed 2-bromo-1-fluoro-3-methoxy-benzene (I-29, 2.0 g, 9.75 mmol) and dichloromethane (48 mL). The solution was cooled in an ice water bath for 15 minutes and then titanium tetrachloride (5.02 mL, 45.8 mmol) and dichloromethyl methyl ether (1.32 mL, 14.6 mmol) were added and the reaction mixture was allowed to warm to room temperature and react for 2 hours. The reaction mixture was slowly added to ice water (250 mL) and extracted with dichloromethane (2×100 mL). The organic portions were combined, washed with a saturated sodium bicarbonate solution (75 mL), water (75 mL) and brine (75 mL), dried (MgSO4) and concentrated. The crude material was triturated with hexanes (15 mL) to produce 1.67 g of 3-bromo-2-fluoro-4-methoxy-benzaldehyde (I-30) as an off-white solid in 74% yield. MS (ESI+): 233.2 (M+) In a 3-necked 250 mL round-bottomed flask equipped with nitrogen lines and a stir bar The solution was cooled in an ice water bath for 15 minutes react for 2 hours extracted with dichloromethane (2×100 mL) washed with a saturated sodium bicarbonate solution (75 mL), water (75 mL) and brine (75 mL) dried (MgSO4) concentrated The crude material was triturated with hexanes (15 mL)

反応条件: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 2-bromo-3-fluoroanisole (1.0 g, 4.88 mmol), 3-chlorophenylboronic acid (0.91 g, 5.88 mmol), PPh3 (0.64 g, 2.44 mmol), K2CO3 (0.27 g, 1.95 mmol) and Pd(OAc)2 (0.13 g, 0.58 mmol) was added dioxane (8 mL), and EtOH—H2O (1:1, 4 mL). Ar gas was bubbled through the stirred reaction for 5 min. The reaction was heated at 180° C. using microwave oven (Biotage Intiator II) for 20 min. The reaction was cooled to room temperature, combined with another 0.5 g scale run, concentrated. The residue was purified by silica gel column chromatography using 1:1 dichloromethane-hexanes to afford 1.33 g (77%) 3′-chloro-6-fluoro-2-methoxy-biphenyl (I-16, R1═CH3, R2═Cl, Y═F) as a viscous liquid. Ar gas was bubbled through the stirred reaction for 5 min for 20 min The reaction was cooled to room temperature concentrated The residue was purified by silica gel column chromatography

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

実験手順: A cooled (−78° C.) solution of commercially available 2-bromo-1-fluoro-3-methoxybenzene (2.642 g; 12.90 mmol) in anh. THF (60 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (8.05 ml; 12.90 mmol). The resulting solution was further stirred at −78° C. for 5 min. A solution of ethyl 4-((tert-butylsulfinyl)imino)-2-methylbutanoate (2.550 g; 10.30 mmol) in anh. THF (20 ml) was then added dropwise to the cooled reaction mixture, and stirring at −78° C. was continued for 45 min. The resulting reaction mixture was treated successively with aq. sat. NH4Cl (75 ml), Et2O (250 ml) and water (75 ml). The separated organic layer was then washed with brine (75 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=30/1) afforded ethyl 4-(1,1-dimethylethylsulfinamido)-4-(2-fluoro-6-methoxyphenyl)-2-methylbutanoate as a yellow oil. LC-MS (conditions A): tR=0.81 min. and [M+H]+: 374.02 g/mol; tR=0.83 min. and [M+H]+: 374.34 g/mol (mixture of diastereoisomers). stirring at −78° C. was continued for 45 min The resulting reaction mixture The separated organic layer was then washed with brine (75 ml) dried over anh. MgSO4 filtered concentrated to dryness under reduced pressure Purification by FC (DCM/MeOH=30/1)

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

実験手順: 2-Bromo-3-fluoro anisole (10 g, 48.77 mmol) was dissolved in DCM (200 mL) and cooled to about −78° C. To the solution was added BBr3 (11.53 mL, 121.9 mmol) in one portion. The mixture was warmed to r.t. and stirred overnight. The mixture was partitioned between water and DCM (50 mL), and the aqueous layer was back extracted with DCM (200 mL). The combined organics were dried (NaSO4), filtered and concentrated to give about 9.32 g of the product as a dark oil. MS found 188.9 (M−1) The mixture was warmed to r.t. The mixture was partitioned between water and DCM (50 mL) the aqueous layer was back extracted with DCM (200 mL) The combined organics were dried (NaSO4) filtered concentrated

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

実験手順: The 3-fluoro anisole (15 g, 119 mmol) was placed in THF (300 mL) and cooled to about −78° C., and then n-BuLi (89 mL 1.6 M in hexanes) was added while maintaining the temperature at around −70° C. The mixture was stirred for about 15 minutes, and bromine (18.9 g, 119 mmol) was added over 10 minutes. The mixture was warmed to r.t. and stirred overnight. The mixture was quenched with water, diluted with ether (500 mL) and partitioned between water/ether (1/1 300 mL). The water layer was back extracted with ether (250 mL), and the combined organic fractions were dried, filtered and concentrated. The dark residue was distilled under house vacuum (product 115–130° C.) to recover about 13.8 g of the product as a gray oil (57%). while maintaining the temperature at around −70° C The mixture was warmed to r.t. stirred overnight The mixture was quenched with water diluted with ether (500 mL) partitioned between water/ether (1/1 300 mL) The water layer was back extracted with ether (250 mL) the combined organic fractions were dried filtered concentrated The dark residue was distilled under house vacuum (product 115–130° C.) to recover about 13.8 g of the product as a gray oil (57%)