6-Chloro-5-fluoroindole

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: Tetra-n-butylammonium hydrogensulfate (0.1 g, 0.33 mmol), powdered sodium hydroxide (1.3 g, 33 mmol) and 6-chloro-5-fluoroindole (1.4 g, 8.3 mmol) were stirred at room tempera in acetonitrile (40 mL) for 1 h. 2-Chloroethylamine hydrochloride (1.45 g, 12.5 mmol) was then added in 1 portion and the reaction was heated to reflux and stirred for 36 h. After allowing to cool to room temperature the mixture was poured into water (100 mL) and extracted with ethyl acetate (3×70 mL). The combined organic extracts were washed with brine (1×100 mL), dried (magnesium sulfate), filtered and the solvent removed under vacuo to leave a crude oil. The oil was purified by flash column chromatography [SiO2; ethyl acetate-methanol-ammonium hydroxide, (90:9:1)] to give the product as an orange oil (1.4 g, 80%). IR νmax (film)/cm−1 3377, 3104, 2937, 2868, 1675, 1568, 1505, 1479, 1449, 1400, 1357, 1327, 1291, 1236, 1143, 1090, 1030, 994, 862, 817, 753, 717, 698, 678, 646, 633, 596 and 579; NMR δH (400 MHz; DMSO-d6) 7.79 (1H, d, J 7 Hz), 7.51 (1H, d, J 10 Hz), 7.50 (1H, d, J 3.5 Hz), 6.46 (1H, m), 4.13 (2H, t, J 6.3 Hz), 2.86 (2H, t, J 6.3 Hz), 1.52 (1H, br. s). the reaction was heated to reflux extracted with ethyl acetate (3×70 mL) The combined organic extracts were washed with brine (1×100 mL) dried (magnesium sulfate) filtered the solvent removed under vacuo to leave a crude oil The oil was purified by flash column chromatography [SiO2; ethyl acetate-methanol-ammonium hydroxide, (90:9:1)]

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

実験手順: Tetra-n-butylammonium hydrogensulfate (0.1 g, 0.33 mmol), powdered sodium hydroxide (1.3 g, 33 mmol) and 6-chloro-5-fluoroindole (1.4 g, 8.3 mmol) were stirred at room temperature in acetonitrile (40 mL) for 1 h. 2-Chloroethylamine hydrochloride (1.45 g, 12.5 mmol) was then added in 1 portion and the reaction was heated to reflux and stirred for 36 h. After allowing to cool to room temperature the mixture was poured into water (100 mL) and extracted with ethyl acetate (3×70 mL). The combined organic extracts were washed with brine (1×100 mL), dried (magnesium sulfate), filtered and the solvent removed under vacuum to leave a crude oil. The oil was purified by flash column chromatography [SiO2; ethyl acetate-methanol-ammonium hydroxide, (90:9:1)] to give the product as an orange oil (1.4 g, 80%). IR νmax (film)/cm−1 3377, 3104, 2937, 2868, 1675, 1568, 1505, 1479, 1449, 1400, 1357, 1327, 1291, 1236, 1143, 1090, 1030, 994, 862, 817, 753, 717, 698, 678, 646, 633, 596 and 579; NMR δH (400 MHz; DMSO-d6) 7.79 (1H, d, J 7 Hz), 7.51 (1H, d, J 10 Hz), 7.50 (1H, d, J 3.5 Hz), 6.46 (1H, m), 4.13 (2H, t, J 6.3 Hz), 2.86 (2H, t, J 6.3 Hz), 1.52 (1H, br. s). the reaction was heated to reflux extracted with ethyl acetate (3×70 mL) The combined organic extracts were washed with brine (1×100 mL) dried (magnesium sulfate) filtered the solvent removed under vacuum to leave a crude oil The oil was purified by flash column chromatography [SiO2; ethyl acetate-methanol-ammonium hydroxide, (90:9:1)]

反応条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: N,N-Dimethylformamide dimethylacetal (6.3 ml, 45 mmol) was added in one portion to a stirred solution of 3-chloro-4-fluoro-6-methylnitrobenzene (7.0 g, 37 mmol) in N,N-dimethylformamide (30 mL) at 130° C. under Ar. The mixture was stirred at 130° C. for 2 h, cooled to room temperature, concentrated in vacuo and partitioned between ethyl acetate and water and the aqueous was extracted with ethyl acetate (2×). The combined organic extracts were washed with brine, dried (magnesium sulfate), concentrated in vacuo, dissolved in methanol/tetrahydrofuran (1:1; 100 mL) and Raney Nickel®, 50% wt. in water, (5 g) was added. The mixture was cooled to 0° C. and hydrazine hydrate (3 mL, 59 mmol) was added dropwise over 2 min. The mixture was warmed to room temperature, stirred for 1 h then cooled to 0° C. and hydrazine hydrate (1.5 mL) was added over 2 min. The mixture was warmed to room temperature, stirred for 1 h and filtered through celite®. The filter-cake was washed with tetrahydrofuran and the filtrate was concentrated in vacuo and purified by column chromatography [SiO2; heptane-dichloromethane (4:1)] to give the product (3.2 g, 51%) as an off-white solid. An analytical sample was recrystallised (heptane) to give a white solid: mp 105-107° C.; NMR δH (400 MHz, CDCl3) 8.01 (1H, br. s), 7.40 (1H, d, J 6 Hz), 7.35 (1H, d, J 9.4 Hz), 7.25 (1H, t, J 2.8 Hz), 6.50-6.51 (1H, m). cooled to room temperature concentrated in vacuo partitioned between ethyl acetate and water the aqueous was extracted with ethyl acetate (2×) The combined organic extracts were washed with brine dried (magnesium sulfate) concentrated in vacuo dissolved in methanol/tetrahydrofuran (1:1; 100 mL) Raney Nickel®, 50% wt. in water, (5 g) was added The mixture was cooled to 0° C. The mixture was warmed to room temperature stirred for 1 h then cooled to 0° C. The mixture was warmed to room temperature stirred for 1 h filtered through celite® The filter-cake was washed with tetrahydrofuran the filtrate was concentrated in vacuo purified by column chromatography [SiO2; heptane-dichloromethane (4:1)]

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

実験手順: To a solution of 6-chloro-5-fluoroindole (1.8 g, 10.8 mmol) and Ac2O (10 mL) in AcOH (30 mL) was added L-serine (2.2 g, 20.9 mmol), the mixture was heated to 80° C. After TLC indicated the reaction was complete, the mixture was cooled to 0° C., neutralized to pH 11, and washed with MTBE. The aqueous phase was acidified to pH 2 and extracted with EtOAc. The combined organic layers were washed with water and brine, dried with Na2SO4, filtered, and concentrated. The residue was purified with chromatography (Petroleum ether/EtOAc 1:1) to give 2-acetylamino-3-(6-chloro-5-fluoro-1H-indol-3-yl)-proprionic acid as a light yellow solid (1.2 g, 37% yield). the mixture was cooled to 0° C. washed with MTBE extracted with EtOAc The combined organic layers were washed with water and brine dried with Na2SO4 filtered concentrated The residue was purified with chromatography (Petroleum ether/EtOAc 1:1)

反応条件: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: POCl3 (2.43 mL, 26.53 mmol) was added dropwise to N,N-dimethylformamide (15.0 mL) at −20° C. and stirred below −5° C. for one hour. A solution of 6-chloro-5-fluoroindole (3.0 g, 17.69 mmol) in dimethylformamide (5.0 mL) was added dropwise to the above reaction mixture at −20° C. The salt-ice bath was removed and the reaction mixture was warmed to 35° C., After one hour, the reaction was poured onto ice and basified by solid sodium bicarbonate and extracted with ethyl acetate. The combined organic layer was washed with water and then concentrated to give 6-chloro-5-fluoro-1H-indole-3-carbaldehyde (3.4 g, 97%) as a light brown solid. 1H NMR (500 MHz, CDCl3): δ 10.02 (s, 1 H), 8.10 (d, 1H, J=9.5 Hz), 7.87 (s, 1 H), 7.49 (d, 1H, J=5.5 Hz). The salt-ice bath was removed the reaction was poured onto ice extracted with ethyl acetate The combined organic layer was washed with water concentrated

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

実験手順: Tetra-n-butylammonium hydrogensulfate (0.1 g, 0.33 mmol), powdered sodium hydroxide (1.3 g, 33 mmol) and 6-chloro-5-fluoroindole (1.4 g, 8.3 mmol) were stirred at room tempera in acetonitrile (40 mL) for 1 h. 2-Chloroethylamine hydrochloride (1.45 g, 12.5 mmol) was then added in 1 portion and the reaction was heated to reflux and stirred for 36 h. After allowing to cool to room temperature the mixture was poured into water (100 mL) and extracted with ethyl acetate (3×70 mL). The combined organic extracts were washed with brine (1×100 mL), dried (magnesium sulfate), filtered and the solvent removed under vacuo to leave a crude oil. The oil was purified by flash column chromatography [SiO2; ethyl acetate-methanol-ammonium hydroxide, (90:9:1)] to give the product as an orange oil (1.4 g, 80%). IR νmax (film)/cm−1 3377, 3104, 2937, 2868, 1675, 1568, 1505, 1479, 1449, 1400, 1357, 1327, 1291, 1236, 1143, 1090, 1030, 994, 862, 817, 753, 717, 698, 678, 646, 633, 596 and 579; NMR δH (400 MHz; DMSO-d6) 7.79 (1H, d, J 7 Hz), 7.51 (1H, d, J 10 Hz), 7.50 (1H, d, J 3.5 Hz), 6.46 (1H, m), 4.13 (2H, t, J 6.3 Hz), 2.86 (2H, t, J 6.3 Hz), 1.52 (1H, br. s). the reaction was heated to reflux extracted with ethyl acetate (3×70 mL) The combined organic extracts were washed with brine (1×100 mL) dried (magnesium sulfate) filtered the solvent removed under vacuo to leave a crude oil The oil was purified by flash column chromatography [SiO2; ethyl acetate-methanol-ammonium hydroxide, (90:9:1)]

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

実験手順: Tetra-n-butylammonium hydrogensulfate (0.1 g, 0.33 mmol), powdered sodium hydroxide (1.3 g, 33 mmol) and 6-chloro-5-fluoroindole (1.4 g, 8.3 mmol) were stirred at room tempera in acetonitrile (40 mL) for 1 h. 2-Chloroethylamine hydrochloride (1.45 g, 12.5 mmol) was then added in 1 portion and the reaction was heated to reflux and stirred for 36 h. After allowing to cool to room temperature the mixture was poured into water (100 mL) and extracted with ethyl acetate (3×70 mL). The combined organic extracts were washed with brine (1×100 mL), dried (magnesium sulfate), filtered and the solvent removed under vacuo to leave a crude oil. The oil was purified by flash column chromatography [SiO2; ethyl acetate-methanol-ammonium hydroxide, (90:9:1)] to give the product as an orange oil (1.4 g, 80%). IR νmax (film)/cm−1 3377, 3104, 2937, 2868, 1675, 1568, 1505, 1479, 1449, 1400, 1357, 1327, 1291, 1236, 1143, 1090, 1030, 994, 862, 817, 753, 717, 698, 678, 646, 633, 596 and 579; NMR δH (400 MHz; DMSO-d6) 7.79 (1H, d, J 7 Hz), 7.51 (1H, d, J 10 Hz), 7.50 (1H, d, J 3.5 Hz), 6.46 (1H, m), 4.13 (2H, t, J 6.3 Hz), 2.86 (2H, t, J 6.3 Hz), 1.52 (1H, br. s). the reaction was heated to reflux extracted with ethyl acetate (3×70 mL) The combined organic extracts were washed with brine (1×100 mL) dried (magnesium sulfate) filtered the solvent removed under vacuo to leave a crude oil The oil was purified by flash column chromatography [SiO2; ethyl acetate-methanol-ammonium hydroxide, (90:9:1)]

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: A suspension of 0.11 g of sodium hydride dispersion in 15 ml of tetrahydrofuran was treated with 0.5 g of 6-chloro-5-fluoroindole at 0° and stirred at this temperature for 1 hour. After the addition of 0.42 ml of (R)-methyloxirane the reaction mixture was stirred at room temperature for 85 hours and subsequently treated with is water. The mixture was diluted with ether, washed with water and with saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 25 g of silica gel with toluene/ethyl acetate (19:1). There was obtained 0.51 g (74.6%) of (R)-1-(6-chloro-5-fluoro-indol-1-yl)-propan-2-ol as white crystals (m.p. 104°-105°.) was stirred at room temperature for 85 hours subsequently treated washed with water and with saturated sodium chloride solution the organic phase was dried over sodium sulfate After removal of the solvent the residue was chromatographed over 25 g of silica gel with toluene/ethyl acetate (19:1)

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

実験手順: A suspension of 0.11 g of sodium hydride dispersion in 15 ml of tetrahydrofuran was treated with 0.5 g of 6-chloro-5-fluoroindole at 0° and stirred at this temperature for 1 hour. After the addition of 0.42 ml of (S)-methyloxirane the reaction mixture was stirred at room temperature for 85 hours and subsequently treated with water. The mixture was diluted with ether, washed with water and with saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 25 g of silica gel with toluene-ethyl acetate (19:1). There was obtained 0.54 g (79%) of (S)-1-(6-chloro-5-fluoro-indol-1-yl)-propan-2-ol as beige crystals (m.p. 99°-101°). was stirred at room temperature for 85 hours washed with water and with saturated sodium chloride solution the organic phase was dried over sodium sulfate After removal of the solvent the residue was chromatographed over 25 g of silica gel with toluene-ethyl acetate (19:1)

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

実験手順: A suspension of 0.11 g of sodium hydride dispersion in 15 ml of tetrahydrofuran was treated with 0.5 g of 6-chloro-5-fluoroindole at 0° and stirred at this temperature for 1 hour. After the addition of 0.42 ml of (S)-methyloxirane the reaction mixture was stirred at room temperature for 85 hours and subsequently treated with water. The mixture was diluted with ether, washed with water and with saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 25 g of silica gel with toluene-ethyl acetate (19:1). There was obtained 0.54 g (79%) of (S)-1-(6-chloro-5-fluoro-indol-1-yl)-propan-2-ol as beige crystals (m.p. 99°-101°). was stirred at room temperature for 85 hours washed with water and with saturated sodium chloride solution the organic phase was dried over sodium sulfate After removal of the solvent the residue was chromatographed over 25 g of silica gel with toluene-ethyl acetate (19:1)