2-bromo-4-fluoro-1-methoxybenzene

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

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

Procedure: A microwave vial was charged with 2-bromo-4-fluoro-1-methoxybenzene (500 mg, 2.44 mmol), 1-cyclopentenylboronic acid (273 mg, 2.44 mmol), and Pd(dppf)Cl2 (199 mg, 0.24 mmol). The solids were dissolved in acetonitrile (7 mL) and 2 M Na2CO3 (5 mL) and the mixture heated under microwave irradiation for 20 min at 110° C. The reaction was diluted with dichloromethane (50 mL) and the layers separated. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (10-30% ethyl acetate/hexane) provided 2-cyclopentenyl-4-fluoro-1-methoxybenzene (231 mg, 49% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.01 (dd, J=3.1, 10.0 Hz, 1H), 6.92-6.82 (m, 1H), 6.54 (dd, J=2.4, 6.5 Hz, 1H), 6.54 (s, 1H), 3.87 (s, 3H), 2.78-2.73 (m, 2H), 2.62-2.57 (m, 2H), 2.03-1.95 (m, 2H). the layers separated The organic layer was washed with brine dried over Na2SO4 filtered concentrated Purification by silica gel chromatography (10-30% ethyl acetate/hexane)

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of iso-propylmagnesium chloride in tetrahydrofuran (2M, 130 ml) was added dropwise over 30 minutes to a stirred solution of 2-bromo-4-fluoroanisole (34.2 ml) in anhydrous tetrahydrofuran (400 ml) at 30° C. under nitrogen. After a further 16 hours at 30° C., copper(I) bromide dimethyl sulphide complex (0.4 g) was added followed by a solution of 1-oxa-6-azaspiro[2.5]octane-6-carboxylic acid, 1,1-dimethylethyl ester (56.2 g) in anhydrous tetrahydrofuran (I 10 ml). After a further 3 hours at 30° C., the solution was cooled to 20° C., diluted with water (600 ml) and extracted with tert.-butyl methyl ether (600 ml) then ethyl acetate (600 ml). Combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give crude sub-title compound (86 g) as a solid. copper(I) bromide dimethyl sulphide complex (0.4 g) was added After a further 3 hours at 30° C. extracted with tert.-butyl methyl ether (600 ml) Combined organic extracts were dried over anhydrous magnesium sulphate filtered evaporated under reduced pressure

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of iso-propylmagnesium chloride in tetrahydrofuran (2M, 130 ml) was added dropwise over 30 minutes to a stirred solution of 2-bromo-4-fluoroanisole (34.2 ml) in anhydrous tetrahydrofuran (400 ml) at 30° C. under nitrogen. After a further 16 hours at 30° C., copper(I) bromide dimethyl sulphide complex (0.4 g) was added followed by a solution of 1-oxa-6-azaspiro[2.5]octane-6-carboxylic acid, 1,1-dimethylethyl ester (56.2 g) in anhydrous tetrahydrofuran (I 10 ml). After a further 3 hours at 30° C., the solution was cooled to 20° C., diluted with water (600 ml) and extracted with tert.-butyl methyl ether (600 ml) then ethyl acetate (600 ml). Combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give crude sub-title compound (86 g) as a solid. copper(I) bromide dimethyl sulphide complex (0.4 g) was added After a further 3 hours at 30° C. extracted with tert.-butyl methyl ether (600 ml) Combined organic extracts were dried over anhydrous magnesium sulphate filtered evaporated under reduced pressure

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

Procedure: To a stirred solution of 2-bromo-4-fluoro anisole (3.24 mL, 25 mmol) in anhydrous THF (40 mL) cooled to —78° C. and maintained under argon was added n-butyl lithium (17.2 mL of 1.6 M solution in hexanes, 27.5 mmol). After stirring at −78° C. for 45 minutes, the reaction mixture was treated with a solution of cuprous iodide in dimethyl sulfide (4.76 g in 15 mL, 25 mmol) and stirred for 15 minutes at −78° C. Then chlorotrimethylsilane (6.4 mL, 50 mmol) was added, followed by a solution of mesityl oxide (2.9 mL, 25 mmol) in anhydrous THF (5 mL). The reaction was stirred at −78° C. to −60° C. for 4 hours and then quenched with a saturated solution of ammonium chloride and extracted with three 50 mL portions of methylene chloride. The combined extracts were washed with three 25 mL portions of water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one as a light brown liquid (85% yield) which was used in the next reaction without further purification. maintained under argon stirred for 15 minutes at −78° C The reaction was stirred at −78° C. to −60° C. for 4 hours quenched with a saturated solution of ammonium chloride extracted with three 50 mL portions of methylene chloride The combined extracts were washed with three 25 mL portions of water dried over anhydrous sodium sulfate concentrated in vacuo

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

Procedure: To a stirred solution of 2-bromo-4-fluoro anisole (4.1 g, 20 mmol) in anhydrous THF (40 mL) cooled to −78° C. and maintained under an atmosphere of argon was added n-butyl lithium (8.8 mL of 2.5 M solution in hexanes, 22 mmol). After stirring at −78° C. for 45 minutes, the reaction mixture was treated with anhydrous acetone (5 mL). After 15 minutes, the reaction mixture was quenched with a saturated solution of ammonium chloride and extracted with three 50 mL portions of methylene chloride. Combined extracts were washed with three 25 mL portions of water, dried over anhydrous sodium sulfate, and the solvent was evaporated to give 2-(5-fluoro-2-methoxyphenyl)propan-2-ol as a light brown thick oil (85% yield) which solidified on standing. The crude product was used for the next reaction without further purification. maintained under an atmosphere of argon After 15 minutes the reaction mixture was quenched with a saturated solution of ammonium chloride extracted with three 50 mL portions of methylene chloride Combined extracts were washed with three 25 mL portions of water dried over anhydrous sodium sulfate the solvent was evaporated

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

Procedure: 2-Bromo-4-fluoroanisole (20 g, 10 mmol, 1 equiv) and carbazole (18.4 g, 11 mmol, 1.1 equiv) were dissolved in 1,4-dioxane (200 mL). Potassium phosphate tribasic hydrate (46 g, 20 mmol, 2 equiv), copper(I) iodide (1 g, 0.5 mmol, 0.05 equiv) and 1,2-diaminopropane (1 mL, 1.3 mmol, 0.13 equiv) were added and the reaction was refluxed for 18 hours. The reaction was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified over silica gel (250 g), eluting with gradient of 0 to 10% ethyl acetate in heptanes to give compound 1 (7.6 g, 26% yield) as an off white solid that was contaminated with carbazole. This material was used subsequently. the reaction was refluxed for 18 hours filtered through celite The filtrate was concentrated under reduced pressure the residue was purified over silica gel (250 g) eluting with gradient of 0 to 10% ethyl acetate in heptanes

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

Procedure: 2-Bromo-4-fluoroanisole (20 g, 10 mmol, 1 equiv) and carbazole (18.4 g, 11 mmol, 1.1 equiv) were dissolved in 1,4-dioxane (200 mL). Potassium phosphate tribasic hydrate (46 g, 20 mmol, 2 equiv), copper(I) iodide (1 g, 0.5 mmol, 0.05 equiv) and 1,2-diaminopropane (1 mL, 1.3 mmol, 0.13 equiv) were added and the reaction was refluxed for 18 hours. The reaction was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified over silica gel (250 g), eluting with gradient of 0 to 10% ethyl acetate in heptanes to give compound 1 (7.6 g, 26% yield) as an off white solid that was contaminated with carbazole. This material was used subsequently. the reaction was refluxed for 18 hours filtered through celite The filtrate was concentrated under reduced pressure the residue was purified over silica gel (250 g) eluting with gradient of 0 to 10% ethyl acetate in heptanes

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 2-bromo-4-fluoro-1-methoxybenzene (4.10 g) and titanium tetrachloride (4.4 mL), dichloromethyl methyl ether (3.5 mL) was added under ice cooling, and then the reaction mixture was stirred at 0° C. for 2.5 hours. To the reaction mixture was added chloroform, and the reaction mixture was poured into ice water, and then stirred at room temperature for 1 hour. The organic layer was separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was added hexane and the produced solid was filtered to give the titled compound (1.61 g) as a white solid. was added under ice cooling stirred at room temperature for 1 hour The organic layer was separated dried over anhydrous sodium sulfate filtered the filtrate was concentrated under reduced pressure The obtained residue was added hexane the produced solid was filtered

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-[4-fluoro-3-(tert-butoxycarbonyl -amino)phenyl]-2-methyl-1-propanone (0.11 g), 2-bromo-4-fluoroanisole (0.057 mL), palladium(II) acetate (4.5 mg), tri(tert-butyl)phosphine tetrafluoroborate (5.8 mg) and sodium tert-butoxide (96 mg) in tetrahydrofuran (1 mL) was stirred at 70° C. under an argon atmosphere for 3 days. To the reaction mixture was added water, and the mixture was stirred for 10 minutes. The mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1) to give 1-[4-fluoro-3-(tert-butoxycarbonylamino)phenyl]-2-(5-fluoro -2-methoxyphenyl)-2-methyl-1-propanone (45 mg). This material was dissolved in hydrochloric acid (4 mol/L ethyl acetate solution, 3 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on aminopropylated silica gel (eluent: n-hexane/ethyl acetate=4/1 -3/1) to give the title compound (25 mg). the mixture was stirred for 10 minutes the resulting mixture was extracted with ethyl acetate The extract was washed with water and brine successively dried over anhydrous sodium sulfate The solvent was removed under reduced pressure the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1)

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

Procedure: A microwave vial was charged with 2-bromo-4-fluoro-1-methoxybenzene (500 mg, 2.44 mmol), 1-cyclopentenylboronic acid (273 mg, 2.44 mmol), and Pd(dppf)Cl2 (199 mg, 0.24 mmol). The solids were dissolved in acetonitrile (7 mL) and 2 M Na2CO3 (5 mL) and the mixture heated under microwave irradiation for 20 min at 110° C. The reaction was diluted with dichloromethane (50 mL) and the layers separated. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (10-30% ethyl acetate/hexane) provided 2-cyclopentenyl-4-fluoro-1-methoxybenzene (231 mg, 49% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.01 (dd, J=3.1, 10.0 Hz, 1H), 6.92-6.82 (m, 1H), 6.54 (dd, J=2.4, 6.5 Hz, 1H), 6.54 (s, 1H), 3.87 (s, 3H), 2.78-2.73 (m, 2H), 2.62-2.57 (m, 2H), 2.03-1.95 (m, 2H). the layers separated The organic layer was washed with brine dried over Na2SO4 filtered concentrated Purification by silica gel chromatography (10-30% ethyl acetate/hexane)

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

Procedure: To a stirred solution of 2-bromo-4-fluoro anisole (3.24 mL, 25 mmol) in anhydrous THF (40 mL) cooled to −78° C. and maintained under argon was added n-butyl lithium (17.2 mL of 1.6 M solution in hexanes, 27.5 mmol). After stirring at −78° C. for 45 minutes, the reaction mixture was treated with a solution of cuprous iodide in dimethyl sulfide (4.76 g in 15 mL, 25 mmol) and stirred for 15 minutes at −78° C. Then chlorotrimethylsilane (6.4 mL, 50 mmol) was added, followed by a solution of mesityl oxide (2.9 mL, 25 mmol) in anhydrous THF (5 mL). The reaction was stirred at −78° C. to −60° C. for 4 hours and then quenched with a saturated solution of ammonium chloride and extracted with three 50 mL portions of methylene chloride. The combined extracts were washed with three 25 mL portions of water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one as a light brown liquid (85% yield) which was used in the next reaction without further purification. maintained under argon stirred for 15 minutes at −78° C The reaction was stirred at −78° C. to −60° C. for 4 hours quenched with a saturated solution of ammonium chloride extracted with three 50 mL portions of methylene chloride The combined extracts were washed with three 25 mL portions of water dried over anhydrous sodium sulfate concentrated in vacuo