5-bromo-3-formyl-1H-indole-6-carbonitrile

反応条件: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of 5-bromo-3-formyl-1H-indole-6-carbonitrile (250 mg, 1.00 mmol), 1-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]cyclobutanol (300 mg, 1.16 mmol) and 2M aqueous potassium carbonate solution (1.26 mL, 2.51 mmol) in toluene (2.1 mL) and ethanol (1.25 mL) was degassed with nitrogen for 10 minutes, then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73.2 mg, 0.1 mmol) and heated to 85° C. for 1 hour, at which point the reaction mixture was treated with a solution of 1-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]cyclobutanol (40 mg) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 mg) in DMF (0.6 mL). After 3.5 hours, the clear red reaction mixture was cooled to room temperature and poured into half-diluted ammonium chloride solution (100 mL). The product was extracted with ethyl acetate (6×70 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified using flash chromatograph eluting with heptanes/ethyl acetate (with 0.2% formic acid) (9:1 to 1:9) to give the title compound (223 mg, 70%) as an off-white solid. MS (ES−) 315.2 (M−H)−. 1H NMR (500 MHz, DMSO-d6) δ 12.62 (br. s., 1H), 10.02 (s, 1H), 8.59 (s, 1H), 8.21 (s, 1H), 8.13 (s, 1H), 7.64 (d, J=8.3 Hz, 2H), 7.56 (d, J=8.3 Hz, 2H), 5.59 (s, 1H), 2.48-2.43 (m, 2H), 2.32-2.25 (m, 2H), 2.01-1.92 (m, 1H), 1.77-1.67 (m, 1H). was degassed with nitrogen for 10 minutes the clear red reaction mixture was cooled to room temperature The product was extracted with ethyl acetate (6×70 mL) The combined organic layers were dried over sodium sulfate filtered evaporated The crude product was purified eluting with heptanes/ethyl acetate (with 0.2% formic acid) (9:1 to 1:9)

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

実験手順: Phosphorus oxychloride (1.39 mL, 14.9 mmol) was added dropwise over 5 minutes to DMF (10 mL) with stirring. The clear mixture was stirred at room temperature for 10 minutes. A solution of 5-bromo-1H-indole-6-carbonitrile (1.10 g, 4.97 mmol) in DMF (1.5 with 0.5 mL wash) was added to the clear red solution, and the reaction mixture was stirred at room temperature for 5 min. The resulting grey suspension was heated to 80° C. under nitrogen for 25 min, and then allowed to cool to room temperature. The reaction mixture was treated slowly with water (30 mL) and aqueous 1N NaOH (30 mL) at room temperature. The resulting thick suspension was then heated to 85° C. for five minutes with vigorous stirring. The reaction mixture was allowed to cool to room temperature over 5 minutes, and the solids were collected by filtration. The solids were dried in vacuo for 16 hours at 55° C. to afford the title compound (1.15 g, 92%) as a cream-colored solid. MS (ES−) 247.1 (M−H)−. 1H NMR (500 MHz, DMSO-d6) δ 12.76 (br. s., 1H), 9.99 (s, 1H), 8.60 (s, 1H), 8.43 (s, 1H), 8.18 (s, 1H). The clear mixture was stirred at room temperature for 10 minutes the reaction mixture was stirred at room temperature for 5 min to cool to room temperature The resulting thick suspension was then heated to 85° C. for five minutes with vigorous stirring to cool to room temperature over 5 minutes the solids were collected by filtration The solids were dried in vacuo for 16 hours at 55° C.

反応条件: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of 5-bromo-3-formyl-1H-indole-6-carbonitrile (250 mg, 1.00 mmol), 1-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]cyclobutanol (300 mg, 1.16 mmol) and 2 M aqueous potassium carbonate solution (1.26 mL, 2.51 mmol) in toluene (2.1 mL) and ethanol (1.25 mL) was degassed with nitrogen for 10 minutes, then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73.2 mg, 0.1 mmol) and heated to 85° C. for 1 hour, at which point the reaction mixture was treated with a solution of 1-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]cyclobutanol (40 mg) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 mg) in DMF (0.6 mL). After 3.5 hours, the clear red reaction mixture was cooled to room temperature and poured into half-diluted ammonium chloride solution (100 mL). The product was extracted with ethyl acetate (6×70 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified using flash chromatograph eluting with heptanes/ethyl acetate (with 0.2% formic acid) (9:1 to 1:9) to give the title compound (223 mg, 70%) as an off-white solid. MS (ES−) 315.2 (M−H)−. 1H NMR (500 MHz, DMSO-d6) δ 12.62 (br. s., 1 H), 10.02 (s, 1 H), 8.59 (s, 1 H), 8.21 (s, 1 H), 8.13 (s, 1 H), 7.64 (d, J=8.3 Hz, 2 H), 7.56 (d, J=8.3 Hz, 2 H), 5.59 (s, 1 H), 2.48-2.43 (m, 2 H), 2.32-2.25 (m, 2H), 2.01-1.92 (m, 1H), 1.77-1.67 (m, 1H). was degassed with nitrogen for 10 minutes the clear red reaction mixture was cooled to room temperature The product was extracted with ethyl acetate (6×70 mL) The combined organic layers were dried over sodium sulfate filtered evaporated The crude product was purified eluting with heptanes/ethyl acetate (with 0.2% formic acid) (9:1 to 1:9)

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

実験手順: Phosphorus oxychloride (1.39 mL, 14.9 mmol) was added dropwise over 5 minutes to DMF (10 mL) with stirring. The clear mixture was stirred at room temperature for 10 minutes. A solution of 5-bromo-1H-indole-6-carbonitrile (1.10 g, 4.97 mmol) in DMF (1.5 with 0.5 mL wash) was added to the clear red solution, and the reaction mixture was stirred at room temperature for 5 min. The resulting grey suspension was heated to 80° C. under nitrogen for 25 min, and then allowed to cool to room temperature. The reaction mixture was treated slowly with water (30 mL) and aqueous 1 N NaOH (30 mL) at room temperature. The resulting thick suspension was then heated to 85° C. for five minutes with vigorous stirring. The reaction mixture was allowed to cool to room temperature over 5 minutes, and the solids were collected by filtration. The solids were dried in vacuo for 16 hours at 55° C. to afford the title compound (1.15 g, 92%) as a cream-colored solid. MS (ES−) 247.1 (M−H)−. 1H NMR (500 MHz, DMSO-d6) δ 12.76 (br. s., 1H), 9.99 (s, 1H), 8.60 (s, 1H), 8.43 (s, 1H), 8.18 (s, 1H). The clear mixture was stirred at room temperature for 10 minutes the reaction mixture was stirred at room temperature for 5 min to cool to room temperature The resulting thick suspension was then heated to 85° C. for five minutes with vigorous stirring to cool to room temperature over 5 minutes the solids were collected by filtration The solids were dried in vacuo for 16 hours at 55° C.

反応条件: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of 5-bromo-3-formyl-1H-indole-6-carbonitrile (250 mg, 1.00 mmol), 1-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]cyclobutanol (300 mg, 1.16 mmol) and 2M aqueous potassium carbonate solution (1.26 mL, 2.51 mmol) in toluene (2.1 mL) and ethanol (1.25 mL) was degassed with nitrogen for 10 minutes, then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73.2 mg, 0.1 mmol) and heated to 85° C. for 1 hour, at which point the reaction mixture was treated with a solution of 1-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]cyclobutanol (40 mg) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 mg) in DMF (0.6 mL). After 3.5 hours, the clear red reaction mixture was cooled to room temperature and poured into half-diluted ammonium chloride solution (100 mL). The product was extracted with ethyl acetate (6×70 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified using flash chromatograph eluting with heptanes/ethyl acetate (with 0.2% formic acid) (9:1 to 1:9) to give the title compound (223 mg, 70%) as an off-white solid. MS (ES−) 315.2 (M−H)−. 1H NMR (500 MHz, DMSO-d6) δ 12.62 (br. s., 1H), 10.02 (s, 1H), 8.59 (s, 1H), 8.21 (s, 1H), 8.13 (s, 1H), 7.64 (d, J=8.3 Hz, 2H), 7.56 (d, J=8.3 Hz, 2H), 5.59 (s, 1H), 2.48-2.43 (m, 2H), 2.32-2.25 (m, 2H), 2.01-1.92 (m, 1H), 1.77-1.67 (m, 1H). was degassed with nitrogen for 10 minutes the clear red reaction mixture was cooled to room temperature The product was extracted with ethyl acetate (6×70 mL) The combined organic layers were dried over sodium sulfate filtered evaporated The crude product was purified eluting with heptanes/ethyl acetate (with 0.2% formic acid) (9:1 to 1:9)

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

実験手順: Phosphorus oxychloride (1.39 mL, 14.9 mmol) was added dropwise over 5 minutes to DMF (10 mL) with stirring. The clear mixture was stirred at room temperature for 10 minutes. A solution of 5-bromo-1H-indole-6-carbonitrile (1.10 g, 4.97 mmol) in DMF (1.5 with 0.5 mL wash) was added to the clear red solution, and the reaction mixture was stirred at room temperature for 5 min. The resulting grey suspension was heated to 80° C. under nitrogen for 25 min, and then allowed to cool to room temperature. The reaction mixture was treated slowly with water (30 mL) and aqueous 1N NaOH (30 mL) at room temperature. The resulting thick suspension was then heated to 85° C. for five minutes with vigorous stirring. The reaction mixture was allowed to cool to room temperature over 5 minutes, and the solids were collected by filtration. The solids were dried in vacuo for 16 hours at 55° C. to afford the title compound (1.15 g, 92%) as a cream-colored solid. MS (ES−) 247.1 (M−H)−. 1H NMR (500 MHz, DMSO-d6) δ 12.76 (br. s., 1H), 9.99 (s, 1H), 8.60 (s, 1H), 8.43 (s, 1H), 8.18 (s, 1H). The clear mixture was stirred at room temperature for 10 minutes the reaction mixture was stirred at room temperature for 5 min to cool to room temperature The resulting thick suspension was then heated to 85° C. for five minutes with vigorous stirring to cool to room temperature over 5 minutes the solids were collected by filtration The solids were dried in vacuo for 16 hours at 55° C.

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

実験手順: Phosphorus oxychloride (1.39 mL, 14.9 mmol) was added dropwise over 5 minutes to DMF (10 mL) with stirring. The clear mixture was stirred at room temperature for 10 minutes. A solution of 5-bromo-1H-indole-6-carbonitrile (1.10 g, 4.97 mmol) in DMF (1.5 with 0.5 mL wash) was added to the clear red solution, and the reaction mixture was stirred at room temperature for 5 min. The resulting grey suspension was heated to 80° C. under nitrogen for 25 min, and then allowed to cool to room temperature. The reaction mixture was treated slowly with water (30 mL) and aqueous 1N NaOH (30 mL) at room temperature. The resulting thick suspension was then heated to 85° C. for five minutes with vigorous stirring. The reaction mixture was allowed to cool to room temperature over 5 minutes, and the solids were collected by filtration. The solids were dried in vacuo for 16 hours at 55° C. to afford the title compound (1.15 g, 92%) as a cream-colored solid. MS (ES−) 247.1 (M−H)−. 1H NMR (500 MHz, DMSO-d6) δ 12.76 (br. s., 1H), 9.99 (s, 1H), 8.60 (s, 1H), 8.43 (s, 1H), 8.18 (s, 1H). The clear mixture was stirred at room temperature for 10 minutes the reaction mixture was stirred at room temperature for 5 min to cool to room temperature The resulting thick suspension was then heated to 85° C. for five minutes with vigorous stirring to cool to room temperature over 5 minutes the solids were collected by filtration The solids were dried in vacuo for 16 hours at 55° C.

反応条件: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of 5-bromo-3-formyl-1H-indole-6-carbonitrile (250 mg, 1.00 mmol), 1-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]cyclobutanol (300 mg, 1.16 mmol) and 2 M aqueous potassium carbonate solution (1.26 mL, 2.51 mmol) in toluene (2.1 mL) and ethanol (1.25 mL) was degassed with nitrogen for 10 minutes, then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73.2 mg, 0.1 mmol) and heated to 85° C. for 1 hour, at which point the reaction mixture was treated with a solution of 1-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]cyclobutanol (40 mg) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 mg) in DMF (0.6 mL). After 3.5 hours, the clear red reaction mixture was cooled to room temperature and poured into half-diluted ammonium chloride solution (100 mL). The product was extracted with ethyl acetate (6×70 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified using flash chromatograph eluting with heptanes/ethyl acetate (with 0.2% formic acid) (9:1 to 1:9) to give the title compound (223 mg, 70%) as an off-white solid. MS (ES−) 315.2 (M−H)−. 1H NMR (500 MHz, DMSO-d6) δ 12.62 (br. s., 1 H), 10.02 (s, 1 H), 8.59 (s, 1 H), 8.21 (s, 1 H), 8.13 (s, 1 H), 7.64 (d, J=8.3 Hz, 2 H), 7.56 (d, J=8.3 Hz, 2 H), 5.59 (s, 1 H), 2.48-2.43 (m, 2 H), 2.32-2.25 (m, 2H), 2.01-1.92 (m, 1H), 1.77-1.67 (m, 1H). was degassed with nitrogen for 10 minutes the clear red reaction mixture was cooled to room temperature The product was extracted with ethyl acetate (6×70 mL) The combined organic layers were dried over sodium sulfate filtered evaporated The crude product was purified eluting with heptanes/ethyl acetate (with 0.2% formic acid) (9:1 to 1:9)

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

実験手順: Phosphorus oxychloride (1.39 mL, 14.9 mmol) was added dropwise over 5 minutes to DMF (10 mL) with stirring. The clear mixture was stirred at room temperature for 10 minutes. A solution of 5-bromo-1H-indole-6-carbonitrile (1.10 g, 4.97 mmol) in DMF (1.5 with 0.5 mL wash) was added to the clear red solution, and the reaction mixture was stirred at room temperature for 5 min. The resulting grey suspension was heated to 80° C. under nitrogen for 25 min, and then allowed to cool to room temperature. The reaction mixture was treated slowly with water (30 mL) and aqueous 1 N NaOH (30 mL) at room temperature. The resulting thick suspension was then heated to 85° C. for five minutes with vigorous stirring. The reaction mixture was allowed to cool to room temperature over 5 minutes, and the solids were collected by filtration. The solids were dried in vacuo for 16 hours at 55° C. to afford the title compound (1.15 g, 92%) as a cream-colored solid. MS (ES−) 247.1 (M−H)−. 1H NMR (500 MHz, DMSO-d6) δ 12.76 (br. s., 1H), 9.99 (s, 1H), 8.60 (s, 1H), 8.43 (s, 1H), 8.18 (s, 1H). The clear mixture was stirred at room temperature for 10 minutes the reaction mixture was stirred at room temperature for 5 min to cool to room temperature The resulting thick suspension was then heated to 85° C. for five minutes with vigorous stirring to cool to room temperature over 5 minutes the solids were collected by filtration The solids were dried in vacuo for 16 hours at 55° C.

反応条件: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of 5-bromo-3-formyl-1H-indole-6-carbonitrile (250 mg, 1.00 mmol), 1-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]cyclobutanol (300 mg, 1.16 mmol) and 2M aqueous potassium carbonate solution (1.26 mL, 2.51 mmol) in toluene (2.1 mL) and ethanol (1.25 mL) was degassed with nitrogen for 10 minutes, then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73.2 mg, 0.1 mmol) and heated to 85° C. for 1 hour, at which point the reaction mixture was treated with a solution of 1-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]cyclobutanol (40 mg) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 mg) in DMF (0.6 mL). After 3.5 hours, the clear red reaction mixture was cooled to room temperature and poured into half-diluted ammonium chloride solution (100 mL). The product was extracted with ethyl acetate (6×70 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified using flash chromatograph eluting with heptanes/ethyl acetate (with 0.2% formic acid) (9:1 to 1:9) to give the title compound (223 mg, 70%) as an off-white solid. MS (ES−) 315.2 (M−H)−. 1H NMR (500 MHz, DMSO-d6) δ 12.62 (br. s., 1H), 10.02 (s, 1H), 8.59 (s, 1H), 8.21 (s, 1H), 8.13 (s, 1H), 7.64 (d, J=8.3 Hz, 2H), 7.56 (d, J=8.3 Hz, 2H), 5.59 (s, 1H), 2.48-2.43 (m, 2H), 2.32-2.25 (m, 2H), 2.01-1.92 (m, 1H), 1.77-1.67 (m, 1H). was degassed with nitrogen for 10 minutes the clear red reaction mixture was cooled to room temperature The product was extracted with ethyl acetate (6×70 mL) The combined organic layers were dried over sodium sulfate filtered evaporated The crude product was purified eluting with heptanes/ethyl acetate (with 0.2% formic acid) (9:1 to 1:9)

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

実験手順: Phosphorus oxychloride (1.39 mL, 14.9 mmol) was added dropwise over 5 minutes to DMF (10 mL) with stirring. The clear mixture was stirred at room temperature for 10 minutes. A solution of 5-bromo-1H-indole-6-carbonitrile (1.10 g, 4.97 mmol) in DMF (1.5 with 0.5 mL wash) was added to the clear red solution, and the reaction mixture was stirred at room temperature for 5 min. The resulting grey suspension was heated to 80° C. under nitrogen for 25 min, and then allowed to cool to room temperature. The reaction mixture was treated slowly with water (30 mL) and aqueous 1N NaOH (30 mL) at room temperature. The resulting thick suspension was then heated to 85° C. for five minutes with vigorous stirring. The reaction mixture was allowed to cool to room temperature over 5 minutes, and the solids were collected by filtration. The solids were dried in vacuo for 16 hours at 55° C. to afford the title compound (1.15 g, 92%) as a cream-colored solid. MS (ES−) 247.1 (M−H)−. 1H NMR (500 MHz, DMSO-d6) δ 12.76 (br. s., 1H), 9.99 (s, 1H), 8.60 (s, 1H), 8.43 (s, 1H), 8.18 (s, 1H). The clear mixture was stirred at room temperature for 10 minutes the reaction mixture was stirred at room temperature for 5 min to cool to room temperature The resulting thick suspension was then heated to 85° C. for five minutes with vigorous stirring to cool to room temperature over 5 minutes the solids were collected by filtration The solids were dried in vacuo for 16 hours at 55° C.