2-Bromo-1-fluoro-3-iodobenzene

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cooled (−78° C.) solution of 2-bromo-1-fluoro-3-iodo-benzene (10.5 g, 35 mmol) in THF (100 mL) under nitrogen was added LDA (2.0 M, 21 mL, 42 mmol). The mixture was stirred for 1 h at −78° C. and then DMF (4.0 mL, 52 mmol) was added slowly. The reaction mixture was stirred for a further 1 h and then saturated aqueous ammonium chloride (50 mL) was added slowly and the mixture was warmed to RT. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×60 mL). The combined organic fractions were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. Purification of the residue by flash chromatography (5% ethyl acetate:hexanes) afforded 2.3 g (20%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.43 (dd, J=9.0, 6.6 Hz, 1H), 7.69 (dd, J=9.0, 1.5 Hz, 1H), 10.08 (d, J=0.9 Hz, 1H); 19F NMR (282 MHz, CDCl3): δ−109.18 (d, J=7.3 Hz, 1F). The reaction mixture was stirred for a further 1 h the mixture was warmed to RT The layers were separated the aqueous layer was extracted with ethyl acetate (2×60 mL) The combined organic fractions were washed with brine (100 mL) dried over anhydrous sodium sulfate concentrated Purification of the residue by flash chromatography (5% ethyl acetate:hexanes)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (2-fluoro-6-iodo-phenyl)-carbamic acid tert-butyl ester (22.5 g, 67 mmol) in ethanol (100 mL) and 48% aqueous hydrobromic acid (100 mL) was stirred at RT. After 1 h the solvent was removed under reduced pressure and the residue was resuspended in 48% aqueous hydrobromic acid (100 mL). The suspension was heated to 60° C. for 10 min followed by cooling to 0° C. in an ice-water bath. A solution of sodium nitrite (4.9 g, 70 mmol) in water (25 mL) was added dropwise keeping the internal temperature below 5° C. The resulting suspension was stirred for 15 min at 0° C. followed by addition of copper (I) bromide (2.93 g, 20 mmol). The mixture was heated to 80° C. for 1 h and subsequently cooled to RT. The mixture was extracted with dichloromethane (2×250 mL) and the organic layer was washed with brine (150 mL), 10% aqueous sodium hydroxide solution (250 mL), brine (250 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (5% ethyl acetate:hexanes) to afford 10.5 g (50%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.01-7.05 (m, 1H), 7.08-7.12 (m, 1H), 7.67 (d, J=4.8 Hz); 13C NMR (100 MHz, CDCl3): δ 102.5, 115.9 (d, J=22 Hz), 117.6 (d, J=21 Hz), 129.8 (d, J=14 Hz), 135.4 (d, J=21 Hz), 158.7 (d, J=250 Hz); 19F NMR (282 MHz, CDCl3): δ−96.3 (m, 1F). After 1 h the solvent was removed under reduced pressure by cooling to 0° C. in an ice-water bath the internal temperature below 5° C The mixture was heated to 80° C. for 1 h subsequently cooled to RT The mixture was extracted with dichloromethane (2×250 mL) the organic layer was washed with brine (150 mL), 10% aqueous sodium hydroxide solution (250 mL), brine (250 mL) dried over anhydrous sodium sulfate filtered concentrated The residue was purified by flash column chromatography (5% ethyl acetate:hexanes)

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cooled (−78° C.) solution of 2-bromo-1-fluoro-3-iodo-benzene (10.5 g, 35 mmol) in THF (100 mL) under nitrogen was added LDA (2.0 M, 21 mL, 42 mmol). The mixture was stirred for 1 h at −78° C. and then DMF (4.0 mL, 52 mmol) was added slowly. The reaction mixture was stirred for a further 1 h and then saturated aqueous ammonium chloride (50 mL) was added slowly and the mixture was warmed to RT. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×60 mL). The combined organic fractions were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. Purification of the residue by flash chromatography (5% ethyl acetate:hexanes) afforded 2.3 g (20%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.43 (dd, J=9.0, 6.6 Hz, 1H), 7.69 (dd, J=9.0, 1.5 Hz, 1H), 10.08 (d, J=0.9 Hz, 1H); 19F NMR (282 MHz, CDCl3): δ−109.18 (d, J=7.3 Hz, 1F). The reaction mixture was stirred for a further 1 h the mixture was warmed to RT The layers were separated the aqueous layer was extracted with ethyl acetate (2×60 mL) The combined organic fractions were washed with brine (100 mL) dried over anhydrous sodium sulfate concentrated Purification of the residue by flash chromatography (5% ethyl acetate:hexanes)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (2-fluoro-6-iodo-phenyl)-carbamic acid tert-butyl ester (22.5 g, 67 mmol) in ethanol (100 mL) and 48% aqueous hydrobromic acid (100 mL) was stirred at RT. After 1 h the solvent was removed under reduced pressure and the residue was resuspended in 48% aqueous hydrobromic acid (100 mL). The suspension was heated to 60° C. for 10 min followed by cooling to 0° C. in an ice-water bath. A solution of sodium nitrite (4.9 g, 70 mmol) in water (25 mL) was added dropwise keeping the internal temperature below 5° C. The resulting suspension was stirred for 15 min at 0° C. followed by addition of copper (I) bromide (2.93 g, 20 mmol). The mixture was heated to 80° C. for 1 h and subsequently cooled to RT. The mixture was extracted with dichloromethane (2×250 mL) and the organic layer was washed with brine (150 mL), 10% aqueous sodium hydroxide solution (250 mL), brine (250 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (5% ethyl acetate:hexanes) to afford 10.5 g (50%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.01-7.05 (m, 1H), 7.08-7.12 (m, 1H), 7.67 (d, J=4.8 Hz); 13C NMR (100 MHz, CDCl3): δ 102.5, 115.9 (d, J=22 Hz), 117.6 (d, J=21 Hz), 129.8 (d, J=14 Hz), 135.4 (d, J=21 Hz), 158.7 (d, J=250 Hz); 19F NMR (282 MHz, CDCl3): δ−96.3 (m, 1F). After 1 h the solvent was removed under reduced pressure by cooling to 0° C. in an ice-water bath the internal temperature below 5° C The mixture was heated to 80° C. for 1 h subsequently cooled to RT The mixture was extracted with dichloromethane (2×250 mL) the organic layer was washed with brine (150 mL), 10% aqueous sodium hydroxide solution (250 mL), brine (250 mL) dried over anhydrous sodium sulfate filtered concentrated The residue was purified by flash column chromatography (5% ethyl acetate:hexanes)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (2-fluoro-6-iodo-phenyl)-carbamic acid tert-butyl ester (22.5 g, 67 mmol) in ethanol (100 mL) and 48% aqueous hydrobromic acid (100 mL) was stirred at RT. After 1 h the solvent was removed under reduced pressure and the residue was resuspended in 48% aqueous hydrobromic acid (100 mL). The suspension was heated to 60° C. for 10 min followed by cooling to 0° C. in an ice-water bath. A solution of sodium nitrite (4.9 g, 70 mmol) in water (25 mL) was added dropwise keeping the internal temperature below 5° C. The resulting suspension was stirred for 15 min at 0° C. followed by addition of copper (I) bromide (2.93 g, 20 mmol). The mixture was heated to 80° C. for 1 h and subsequently cooled to RT. The mixture was extracted with dichloromethane (2×250 mL) and the organic layer was washed with brine (150 mL), 10% aqueous sodium hydroxide solution (250 mL), brine (250 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (5% ethyl acetate:hexanes) to afford 10.5 g (50%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.01-7.05 (m, 1H), 7.08-7.12 (m, 1H), 7.67 (d, J=4.8 Hz); 13C NMR (100 MHz, CDCl3): δ 102.5, 115.9 (d, J=22 Hz), 117.6 (d, J=21 Hz), 129.8 (d, J=14 Hz), 135.4 (d, J=21 Hz), 158.7 (d, J=250 Hz); 19F NMR (282 MHz, CDCl3): δ−96.3 (m, 1F). After 1 h the solvent was removed under reduced pressure by cooling to 0° C. in an ice-water bath the internal temperature below 5° C The mixture was heated to 80° C. for 1 h subsequently cooled to RT The mixture was extracted with dichloromethane (2×250 mL) the organic layer was washed with brine (150 mL), 10% aqueous sodium hydroxide solution (250 mL), brine (250 mL) dried over anhydrous sodium sulfate filtered concentrated The residue was purified by flash column chromatography (5% ethyl acetate:hexanes)

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cooled (−78° C.) solution of 2-bromo-1-fluoro-3-iodo-benzene (10.5 g, 35 mmol) in THF (100 mL) under nitrogen was added LDA (2.0 M, 21 mL, 42 mmol). The mixture was stirred for 1 h at −78° C. and then DMF (4.0 mL, 52 mmol) was added slowly. The reaction mixture was stirred for a further 1 h and then saturated aqueous ammonium chloride (50 mL) was added slowly and the mixture was warmed to RT. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×60 mL). The combined organic fractions were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. Purification of the residue by flash chromatography (5% ethyl acetate:hexanes) afforded 2.3 g (20%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.43 (dd, J=9.0, 6.6 Hz, 1H), 7.69 (dd, J=9.0, 1.5 Hz, 1H), 10.08 (d, J=0.9 Hz, 1H); 19F NMR (282 MHz, CDCl3): δ−109.18 (d, J=7.3 Hz, 1F). The reaction mixture was stirred for a further 1 h the mixture was warmed to RT The layers were separated the aqueous layer was extracted with ethyl acetate (2×60 mL) The combined organic fractions were washed with brine (100 mL) dried over anhydrous sodium sulfate concentrated Purification of the residue by flash chromatography (5% ethyl acetate:hexanes)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (2-fluoro-6-iodo-phenyl)-carbamic acid tert-butyl ester (22.5 g, 67 mmol) in ethanol (100 mL) and 48% aqueous hydrobromic acid (100 mL) was stirred at RT. After 1 h the solvent was removed under reduced pressure and the residue was resuspended in 48% aqueous hydrobromic acid (100 mL). The suspension was heated to 60° C. for 10 min followed by cooling to 0° C. in an ice-water bath. A solution of sodium nitrite (4.9 g, 70 mmol) in water (25 mL) was added dropwise keeping the internal temperature below 5° C. The resulting suspension was stirred for 15 min at 0° C. followed by addition of copper (I) bromide (2.93 g, 20 mmol). The mixture was heated to 80° C. for 1 h and subsequently cooled to RT. The mixture was extracted with dichloromethane (2×250 mL) and the organic layer was washed with brine (150 mL), 10% aqueous sodium hydroxide solution (250 mL), brine (250 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (5% ethyl acetate:hexanes) to afford 10.5 g (50%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.01-7.05 (m, 1H), 7.08-7.12 (m, 1H), 7.67 (d, J=4.8 Hz); 13C NMR (100 MHz, CDCl3): δ 102.5, 115.9 (d, J=22 Hz), 117.6 (d, J=21 Hz), 129.8 (d, J=14 Hz), 135.4 (d, J=21 Hz), 158.7 (d, J=250 Hz); 19F NMR (282 MHz, CDCl3): δ−96.3 (m, 1F). After 1 h the solvent was removed under reduced pressure by cooling to 0° C. in an ice-water bath the internal temperature below 5° C The mixture was heated to 80° C. for 1 h subsequently cooled to RT The mixture was extracted with dichloromethane (2×250 mL) the organic layer was washed with brine (150 mL), 10% aqueous sodium hydroxide solution (250 mL), brine (250 mL) dried over anhydrous sodium sulfate filtered concentrated The residue was purified by flash column chromatography (5% ethyl acetate:hexanes)