2,6-dibromo-4-fluorobenzaldehyde

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 a solution of 102a (767 mg, 2.72 mmol), 6-tert-butyl-8-fluorophthalazin-1(2H)-one 101h (300 mg, 1.36 mmol) in dioxane (50 mL) was added KOAc (267 mg, 2.72 mmol), CuI (259 mg, 1.36 mmol), and 4,7-dimethoxy-1,10-phenanthroline (327 mg, 1.36 mmol). After bubbling nitrogen through the resulting solution for 30 min, the mixture was stirred at 90 degree for 10 h. It was allowed to cool down to room temperature and H2O (100 mL) was added. The aqueous layer was separated and extracted with ethyl acetate (2×200 mL). The combined organic layers was washed with brine (100 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified on flash column eluting with PE/EA (15:1) to afford 102b (172 mg, 30%). LCMS: [M+H]+ 421. 1H NMR (500 MHz, CDCl3) δ 10.20 (s, 1H), 8.20 (s, 1H), 7.49-7.51 (m, 3H), 7.25 (m, 1H), 1.36 (s, 9H). After bubbling nitrogen through the resulting solution for 30 min H2O (100 mL) was added The aqueous layer was separated extracted with ethyl acetate (2×200 mL) The combined organic layers was washed with brine (100 mL) dried over sodium sulfate The drying agent was removed by filtration the filtrate was concentrated under reduced pressure The residue was purified on flash column eluting with PE/EA (15:1)

反応条件: temp:-19.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 1,3-dibromo-5-fluoro-2-iodobenzene (50 g, 132 mmol) in anhydrous toluene (300 mL) cooled to −35° C. was added the solution of isopropylmagnesium chloride (84 mL, 171 mmol, 2.0 M in diethyl ether) over a period of 30 minutes while maintaining the internal temperature below −25° C. A clear brown solution was obtained. Stirring was continued for 1.5 h. Then anhydrous DMF (34 mL, 436 mmol) was added over a period of 30 minutes. The temperature of the reaction mixture increased to −19° C. The reaction mixture was warmed to 10° C. (room temperature) over 1 h and stirred at this temperature for 1.5 h. The reaction was quenched with saturated aqueous NH4Cl (100 mL), filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography (eluting with petroleum ether/ethyl acetate: from 50:1 to 20:1) to give 102a (20 g, yield 54%) as a yellow solid. while maintaining the internal temperature below −25° C A clear brown solution was obtained The reaction mixture was warmed to 10° C. (room temperature) over 1 h stirred at this temperature for 1.5 h The reaction was quenched with saturated aqueous NH4Cl (100 mL) filtered evaporated under reduced pressure The residue was purified by silica-gel column chromatography (eluting with petroleum ether/ethyl acetate: from 50:1 to 20:1)

反応条件: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 100-mL round bottom flask equipped with a magnetic stirrer and a reflux condenser was charged with 131h (330 mg, 1.5 mmol), 2,6-dibromo-4-fluorobenzaldehyde (1.26 g, 4.5 mmol), CuBr (113 mg, 0.8 mmol), sarcosine (142 mg, 1.6 mmol), K2CO3 (420 mg, 3.0 mmol), and dioxane (20 mL). See FIG. 15. After three cycles of vacuum/argon flush, the mixture was heated at 95° C. for 15 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography 5:1 eluting with petroleum ether/ethyl acetate to 131i as a white solid (380 mg, 60%). MS-ESI: [M+H]+ 420.6 A 100-mL round bottom flask equipped with a magnetic stirrer and a reflux condenser After three cycles of vacuum/argon flush It was then cooled to room temperature filtered The filtrate was concentrated under reduced pressure the resulting residue was purified by silica-gel column chromatography 5:1 eluting with petroleum ether/ethyl acetate to 131i as a white solid (380 mg, 60%)

反応条件: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 100-mL round bottom flask equipped with a magnetic stirrer and a reflux condenser was charged with 131h (330 mg, 1.5 mmol), 2,6-dibromo-4-fluorobenzaldehyde (1.26 g, 4.5 mmol), CuBr (113 mg, 0.8 mmol), sarcosine (142 mg, 1.6 mmol), K2CO3 (420 mg, 3.0 mmol), and dioxane (20 mL). See FIG. 15. After three cycles of vacuum/argon flush, the mixture was heated at 95° C. for 15 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography 5:1 eluting with petroleum ether/ethyl acetate to 131i as a white solid (380 mg, 60%). MS-ESI: [M+H]+ 420.6 A 100-mL round bottom flask equipped with a magnetic stirrer and a reflux condenser After three cycles of vacuum/argon flush It was then cooled to room temperature filtered The filtrate was concentrated under reduced pressure the resulting residue was purified by silica-gel column chromatography 5:1 eluting with petroleum ether/ethyl acetate to 131i as a white solid (380 mg, 60%)

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 127e (450 mg, 2.4 mmol), 2,6-dibromo-4-fluorobenzaldehyde (2.0 g, 7.2 mmol), cesium carbonate (1.6 g, 4.8 mmol), and 1,4-dioxane (50 mL). After bubbling nitrogen through the resulting mixture for 10 minutes, copper(I) iodide (450 mg, 2.4 mmol) and 4,7-dimethoxy-1,10-phenanthroline (571 mg, 2.4 mmol) were added, and the reaction mixture was heated at 90° C. for 12 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was partitioned between methylene chloride (40 mL) and water (40 mL). The aqueous layer was separated and extracted with methylene chloride (3×30 mL). The combined organic layer was washed with brine (50 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:2 ethyl acetate/petroleum ether to afford 127f as a brown solid (251 mg, 31%). MS-ESI: (M+H)+ 390.0. A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser After bubbling nitrogen through the resulting mixture for 10 minutes After this time the reaction was cooled to room temperature filtered The filtrate was partitioned between methylene chloride (40 mL) and water (40 mL) The aqueous layer was separated extracted with methylene chloride (3×30 mL) The combined organic layer was washed with brine (50 mL) dried over sodium sulfate The drying agent was removed by filtration the filtrate was concentrated under reduced pressure The residue was purified by silica-gel column chromatography eluting with 1:2 ethyl acetate/petroleum ether

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 121e (500 mg, 2.66 mmol), 2,6-dibromo-4-fluorobenzaldehyde (1.50 g, 5.32 mmol), and potassium acetate (521 mg, 5.32 mmol). After bubbling argon through the suspension for 30 minutes, 4,7-dimethoxy-1,10-phenanthroline (638.4 mg, 2.66 mmol) and cuprous iodide (506 mg, 2.66 mmol) were added. The system was subjected to three cycles of vacuum/argon flush and then heated at 100° C. for 16 h. It was then cooled to room temperature and filtered. The solid was washed with dichloromethane (2×100 ml). The combined filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (10:1 to 3:1) to afford 121f (510 mg, 49%) as a yellow solid. MS: [M+H]+ 389. A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser After bubbling argon through the suspension for 30 minutes flush It was then cooled to room temperature filtered The solid was washed with dichloromethane (2×100 ml) The combined filtrate was concentrated under reduced pressure the residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (10:1 to 3:1)

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 121e (500 mg, 2.66 mmol), 2,6-dibromo-4-fluorobenzaldehyde (1.50 g, 5.32 mmol), and potassium acetate (521 mg, 5.32 mmol). After bubbling argon through the suspension for 30 minutes, 4,7-dimethoxy-1,10-phenanthroline (638.4 mg, 2.66 mmol) and cuprous iodide (506 mg, 2.66 mmol) were added. The system was subjected to three cycles of vacuum/argon flush and then heated at 100° C. for 16 h. It was then cooled to room temperature and filtered. The solid was washed with dichloromethane (2×100 ml). The combined filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (10:1 to 3:1) to afford 121f (510 mg, 49%) as a yellow solid. MS: [M+H]+ 389. A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser After bubbling argon through the suspension for 30 minutes flush It was then cooled to room temperature filtered The solid was washed with dichloromethane (2×100 ml) The combined filtrate was concentrated under reduced pressure the residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (10:1 to 3:1)

反応条件: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 1,3-dibromo-5-fluoro-2-iodobenzene (50 g, 132 mmol) in anhydrous toluene (300 mL) cooled at −35° C. was added a solution of isopropyl-magnesium chloride (84 mL, 171 mmol, 2.0M in Et2O) over 30 minutes while maintaining the internal temperature below −25° C. A clear brown solution was obtained and the stirring was continued for 1.5 h at −25° C. Then anhydrous DMF (34 mL, 436 mmol) was added over a period of 30 minutes. The reaction mixture was warmed to 10° C. (room temperature) over 1 h and stirred at this temperature for 1.5 h (hours). It was then quenched with 3.0M HCl and followed by the addition of ethyl acetate. The organic layer was separated and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (from 50:1 to 20:1) to give 104k as a white solid (20 g, 54%). 1H NMR (500 MHz, CDCl3) δ 10.23 (s, 1H), 7.48 (d, J=7.5, 2H). while maintaining the internal temperature below −25° C A clear brown solution was obtained It was then quenched with 3.0M HCl followed by the addition of ethyl acetate The organic layer was separated evaporated under reduced pressure The residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (from 50:1 to 20:1)

反応条件: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 1,3-dibromo-5-fluoro-2-iodobenzene (50 g, 132 mmol) in anhydrous toluene (300 mL) cooled at −35° C. was added a solution of isopropyl-magnesium chloride (84 mL, 171 mmol, 2.0M in Et2O) over 30 minutes while maintaining the internal temperature below −25° C. A clear brown solution was obtained and the stirring was continued for 1.5 h at −25° C. Then anhydrous DMF (34 mL, 436 mmol) was added over a period of 30 minutes. The reaction mixture was warmed to 10° C. (room temperature) over 1 h and stirred at this temperature for 1.5 h (hours). It was then quenched with 3.0M HCl and followed by the addition of ethyl acetate. The organic layer was separated and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (from 50:1 to 20:1) to give 104k as a white solid (20 g, 54%). 1H NMR (500 MHz, CDCl3) δ 10.23 (s, 1H), 7.48 (d, J=7.5, 2H). while maintaining the internal temperature below −25° C A clear brown solution was obtained It was then quenched with 3.0M HCl followed by the addition of ethyl acetate The organic layer was separated evaporated under reduced pressure The residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (from 50:1 to 20:1)

反応条件: temp:-19.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 1,3-dibromo-5-fluoro-2-iodobenzene (50 g, 132 mmol) in anhydrous toluene (300 mL) was cooled to −35° C. A solution of isopropylmagnesium chloride (84 mL, 171 mmol, 2.0 M in diethyl ether) over a period of 30 minutes while maintaining the internal temperature below −25° C. See FIG. 1. A clear brown solution was obtained. Stirring was continued for 1.5 h. Then anhydrous DMF (34 mL, 436 mmol) was added over a period of 30 minutes. The temperature of the reaction mixture increased to −19° C. The reaction mixture was warmed to 10° C. (room temperature) over 1 h and stirred at this temperature for 1.5 h. The reaction was quenched with saturated aqueous NH4Cl (100 mL), filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography (eluting with petroleum ether/ethyl acetate:from 50:1 to 20:1) to give 101a (20 g, yield 54%) as a yellow solid. A clear brown solution was obtained The reaction mixture was warmed to 10° C. (room temperature) over 1 h stirred at this temperature for 1.5 h The reaction was quenched with saturated aqueous NH4Cl (100 mL) filtered evaporated under reduced pressure The residue was purified by silica-gel column chromatography (eluting with petroleum ether/ethyl acetate:from 50:1 to 20:1)