4-bromo-1-fluoro-2-iodobenzene

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

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

Procedure: A solution of 4-bromo-1-fluoro-2-iodobenzene (5.0 g, 116 mmol, (1), Aldrich) in THF (60 ml) under nitrogen atmosphere was cooled to −78° C. A solution of n-BuLi (2.5M in hexanes; 7.31 ml, 18.28 mmol, Aldrich) was added drop wise and the reaction was stirred at −78° C. for one hour. Ethyl monofluoroacetate (2.1 g, 19.94 mmol, Aldrich) was added drop wise and the reaction was stirred at −78° C. for one hour. The reaction was quenched with aqueous saturated ammonium chloride solution and allowed to warm to RT. The reaction was diluted with water and EtOAc. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The material was purified via silica gel flash chromatography using a gradient of 0-20% EtOAc in Hexanes to afford the title compound as an off white solid. (2.45 g, 10.42 mmol, 63% yield). MS m/z=234.9 M+. Calculated for C8H5BrF2O: 235.03 the reaction was stirred at −78° C. for one hour The reaction was quenched with aqueous saturated ammonium chloride solution to warm to RT The reaction was diluted with water and EtOAc The organic layer was separated washed with brine dried over magnesium sulfate concentrated under reduced pressure The material was purified via silica gel flash chromatography

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

Procedure: A solution of 4-bromo-1-fluoro-2-iodobenzene (5.0 g, 116 mmol, (1), Aldrich) in THF (60 ml) under nitrogen atmosphere was cooled to −78° C. A solution of n-BuLi (2.5M in hexanes; 7.31 ml, 18.28 mmol, Aldrich) was added drop wise and the reaction was stirred at −78° C. for one hour. Ethyl monofluoroacetate (2.1 g, 19.94 mmol, Aldrich) was added drop wise and the reaction was stirred at −78° C. for one hour. The reaction was quenched with aqueous saturated ammonium chloride solution and allowed to warm to RT. The reaction was diluted with water and EtOAc. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The material was purified via silica gel flash chromatography using a gradient of 0-20% EtOAc in Hexanes to afford the title compound as an off white solid. (2.45 g, 10.42 mmol, 63% yield). MS m/z=234.9 M+. Calculated for C8H5BrF2O: 235.03 the reaction was stirred at −78° C. for one hour The reaction was quenched with aqueous saturated ammonium chloride solution to warm to RT The reaction was diluted with water and EtOAc The organic layer was separated washed with brine dried over magnesium sulfate concentrated under reduced pressure The material was purified via silica gel flash chromatography

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

Procedure: A 1.6 M hexanes solution of n-butyl lithium (25.4 mL, 40.6 mmol) is added drop wise to a −78° C. solution of 4-bromo-1-fluoro-2-iodobenzene (12.22 g, 40.6 mmol) in tetrahydrofuran (60 mL) to give a yellow solution that is stirred at −78° C. for 15 minutes. Boron trifluoride etherate (5.14 mL, 40.6 mmol) is added to a separate −78° C. solution of benzyl 3,3a,4,6-tetrahydropyrrolo[3,4-c]isoxazole-5-carboxylate (5 g, 20.3 mmol) in tetrahydrofuran (60 mL) and the mixture is stirred at −78° C. for 5 minutes. This solution is added to the previously prepared −78° C. organolithium mixture via cannula. The combined mixture is stirred for 30 minutes at −78° C. The mixture is quenched with saturated aqueous ammonium chloride and warmed to room temperature. The mixture is extracted with ethyl acetate (3×) and the organic extracts are combined, dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude product is purified over silica gel with a 35 minute 5% to 100% ethyl acetate in hexanes gradient to give the title compound (2.27 g, 27%). ES/MS (m/e): (79Br/81Br) 421/423 (M+H). to give a yellow solution that the mixture is stirred at −78° C. for 5 minutes The combined mixture is stirred for 30 minutes at −78° C The mixture is quenched with saturated aqueous ammonium chloride warmed to room temperature The mixture is extracted with ethyl acetate (3×) dried over sodium sulfate filtered the solvent removed in vacuo The crude product is purified over silica gel with a 35 minute 5% to 100% ethyl acetate in hexanes gradient

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

Procedure: Scheme 1, steps C and D: To 4-bromo-1-fluoro-2-iodobenzene (0.95 equiv.) in THF (4.6 mL/g) at 0° C. is added isopropylmagnesium chloride (1.0 equiv, 20 weight percent in THF). After about 60 minutes at 0° C., a solution of 2-(allyloxy)-N-methoxy-N-methylacetamide (1.0 equiv.) (Volumes for this stage are in mL/g of this compound) in THF (2.2 mL/g) is added over about 60 minutes. The reaction mixture is quenched into a solution of NH4Cl (4.3 equiv.) in water (5.8 mL/g) at 0° C. Heptanes (7.2 mL/g) is added as the mixture is warmed to room temperature, and the layers are separated. The organic layer is washed with water (7.2 mL/g). The organic layer is concentrated while additional heptanes (4 mL/g) is added to remove water and THF. The intermediate, 2-allyloxy-1-(5-bromo-2-fluoro-phenyl)ethanone is obtained as a solution in heptanes (approximately 20-25 weight %). is added over about 60 minutes the layers are separated The organic layer is washed with water (7.2 mL/g) The organic layer is concentrated while additional heptanes (4 mL/g) is added to remove water and THF

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

Procedure: In the atmosphere of argon, 22.7 g of 2-ethoxynaphthalene-1-boronic acid, 30.0 g of 2-fluoro-5-bromoiodobenzene, 2.31 g of tetrakistriphenylphosphine palladium (0), 300 mL of toluene and 150 mL of an aqueous 2M solution of sodium carbonate were placed in a flask, and the resulting mixture was stirred with heating under reflux for 8 hours. After cooling to room temperature, the reaction solution was extracted with toluene. An aqueous phase was removed, and then, an organic phase was washed with saturated saline. The organic phase was dried with magnesium sulfate, and concentrated. Residues were purified by means of silica gel column chromatography, whereby 24.1 g (yield: 70%) of 2-ethoxy-1-(2-fluoro-5-bromophenyl)naphthalene was obtained. with heating under reflux for 8 hours the reaction solution was extracted with toluene An aqueous phase was removed an organic phase was washed with saturated saline The organic phase was dried with magnesium sulfate concentrated Residues were purified by means of silica gel column chromatography

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

Procedure: In the atmosphere of argon, 15.2 g of 2′-fluoro-2,3-dimethoxybiphenyl-4-boronic acid, 16.5 g of 2-fluoro-5-bromoiodobenzene, 1.27 g of tetrakistriphenylphosphine palladium (0), 180 mL of toluene and 90 mL of an aqueous 2M sodium carbonate solution were placed in a flask. The resulting solution was stirred with heating under reflux for 8 hours. After cooling to room temperature, the reaction solution was extracted with toluene. An aqueous phase was removed, and an organic phase was washed with saturated saline. The organic phase was dried with magnesium sulfate, and concentrated. Residues were purified by means of silica gel column chromatography, whereby 17.8 g (yield: 80%) of 5-bromo-2-fluoro-2′,3′-dimethoxy-2″-fluoro-p-terphenyl was obtained. with heating under reflux for 8 hours the reaction solution was extracted with toluene An aqueous phase was removed an organic phase was washed with saturated saline The organic phase was dried with magnesium sulfate concentrated Residues were purified by means of silica gel column chromatography

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

Procedure: In the atmosphere of argon, 22.7 g of 2-ethoxynaphthalene-1-boronic acid, 30.0 g of 2-fluoro-5-bromoiodobenzene, 2.31 g of tetrakistriphenylphosphine palladium (0), 300 mL of toluene and 150 mL of an aqueous 2M solution of sodium carbonate were placed in a flask, and the resulting mixture was stirred with heating under reflux for 8 hours. After cooling to room temperature, the reaction solution was extracted with toluene. An aqueous phase was removed, and then, an organic phase was washed with saturated saline. The organic phase was dried with magnesium sulfate, and concentrated. Residues were purified by means of silica gel column chromatography, whereby 24.1 g (yield: 70%) of 2-ethoxy-1-(2-fluoro-5-bromophenyl)naphthalene was obtained. with heating under reflux for 8 hours the reaction solution was extracted with toluene An aqueous phase was removed an organic phase was washed with saturated saline The organic phase was dried with magnesium sulfate concentrated Residues were purified by means of silica gel column chromatography

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

Procedure: In the atmosphere of argon, 15.2 g of 2′-fluoro-2,3-dimethoxybiphenyl-4-boronic acid, 16.5 g of 2-fluoro-5-bromoiodobenzene, 1.27 g of tetrakistriphenylphosphine palladium (0), 180 mL of toluene and 90 mL of an aqueous 2M sodium carbonate solution were placed in a flask. The resulting solution was stirred with heating under reflux for 8 hours. After cooling to room temperature, the reaction solution was extracted with toluene. An aqueous phase was removed, and an organic phase was washed with saturated saline. The organic phase was dried with magnesium sulfate, and concentrated. Residues were purified by means of silica gel column chromatography, whereby 17.8 g (yield: 80%) of 5-bromo-2-fluoro-2′,3′-dimethoxy-2″-fluoro-p-terphenyl was obtained. with heating under reflux for 8 hours the reaction solution was extracted with toluene An aqueous phase was removed an organic phase was washed with saturated saline The organic phase was dried with magnesium sulfate concentrated Residues were purified by means of silica gel column chromatography

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

Procedure: In the atmosphere of argon, 15.2 g of 2′-fluoro-2,3-dimethoxybiphenyl-4-boronic acid, 16.5 g of 2-fluoro-5-bromoiodobenzene, 1.27 g of tetrakistriphenylphosphine palladium (0), 180 mL of toluene and 90 mL of an aqueous 2M sodium carbonate solution were placed in a flask. The resulting solution was stirred with heating under reflux for 8 hours. After cooling to room temperature, the reaction solution was extracted with toluene. An aqueous phase was removed, and an organic phase was washed with saturated saline. The organic phase was dried with magnesium sulfate, and concentrated. Residues were purified by means of silica gel column chromatography, whereby 17.8 g (yield: 80%) of 5-bromo-2-fluoro-2′,3′-dimethoxy-2″-fluoro-p-terphenyl was obtained. with heating under reflux for 8 hours the reaction solution was extracted with toluene An aqueous phase was removed an organic phase was washed with saturated saline The organic phase was dried with magnesium sulfate concentrated Residues were purified by means of silica gel column chromatography

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-(cis-4-hydroxycyclohexyl)-2,8-diazaspiro[4.5]decan-1-one (0.50 g, 2.0 mmol), 4-bromo-1-fluoro-2-iodobenzene (0.894 g, 2.97 mmol), copper(I) iodide (0.0586 g, 0.308 mmol), potassium phosphate (1.26 g, 0.596 mmol) and 1,2-ethanediol (0.23 mL, 4.1 mmol) in 1-butanol (2.5 mL) was heated at 100° C. overnight. The reaction mixture was treated with water, extracted with ether. The combined organic layers were washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column with ethyl acetate in hexane (gradient: 0 to 50%) to give the desired product (0.59 g, 70%). LCMS: (M+H)+=425.0/427.0. extracted with ether The combined organic layers were washed with brine dried over MgSO4 filtered The filtrate was concentrated under reduced pressure The residue was purified on a silica gel column with ethyl acetate in hexane (gradient: 0 to 50%)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-(cis-4-hydroxycyclohexyl)-2,8-diazaspiro[4.5]decan-1-one (0.50 g, 2.0 mmol), 4-bromo-1-fluoro-2-iodobenzene (0.894 g, 2.97 mmol), copper(I) iodide (0.0586 g, 0.308 mmol), potassium phosphate (1.26 g, 0.596 mmol) and 1,2-ethanediol (0.23 mL, 4.1 mmol) in 1-butanol (2.5 mL) was heated at 100° C. overnight. The reaction mixture was treated with water, extracted with ether. The combined organic layers were washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column with ethyl acetate in hexane (gradient: 0 to 50%) to give the desired product (0.59 g, 70%). LCMS: (M+H)+=425.0/427.0. extracted with ether The combined organic layers were washed with brine dried over MgSO4 filtered The filtrate was concentrated under reduced pressure The residue was purified on a silica gel column with ethyl acetate in hexane (gradient: 0 to 50%)