6-bromo-5-fluoro-1H-indole

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

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

Procedure: 6-Bromo-5-fluoro-1H-indole (10 g, 46.7 mmol) was dissolved in DMF (100 mL) and cooled to 0° C. in an ice bath before the addition of sodium hydride, 60% dispersion in mineral oil (3.74 g, 93 mmol) and methyl 2-bromoacetate (8.59 mL, 93 mmol). The ice bath was removed and the reaction mixture was stirred at RT for 1 hour. The reaction mixture was cooled with an ice bath once again then quenched with water (50 mL). The aqueous layer was extracted with DCM (3×200 mL). The organics were combined, passed through a hydrophobic frit and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-40% ethyl acetate in cyclohexane to afford the title compound (10.209 g). LCMS (A): m/z (M+H)+ 286/288, C11H9BrFNO2 requires 285/287 (acidic). The ice bath was removed The reaction mixture was cooled with an ice bath once again quenched with water (50 mL) The aqueous layer was extracted with DCM (3×200 mL) concentrated The residue was purified by column chromatography on silica gel eluting with a gradient of 0-40% ethyl acetate in cyclohexane

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

Procedure: To 6-bromo-5-fluoro-1H-indole (9.4 g, 43.9 mmol) in DMF (50 mL) at −78° C. was added chlorosulfonyl isocyanate (4.6 mL, 53 mmol). After complete addition the mixture was allowed to warm to room temperature and stir for 2 hrs. The reaction mixture was poured into ice water and stirred for 30 minutes. The precipitate was collected on a filter, washed with ice water and dried in a vacuum oven to give 6-bromo-5-fluoro-1H-indole-3-carbonitrile as a light-beige solid (10.5 g, 100%). After complete addition the mixture stirred for 30 minutes The precipitate was collected on a filter washed with ice water dried in a vacuum oven

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 2 L dry round bottom flask was charged with 1-bromo-2-fluoro-4-methyl-5-nitrobenzene (24.5 g, 0.1 mol, 97%), DMF-DIPA (39 g, 0.22 mol), Et3N (16 mL, 0.11 mol) and dry DMF (100 mL). The mixture was stirred at 130° C. for 2 h. After removal of the volatiles the residue was dissolved in a mixture of toluene (650 mL) and acetic acid (390 mL) followed by addition of iron powder (55 g) and silica gel (50 g). The dark red mixture was heated to 100° C. with vigorous stirring. The dark color disappeared after refluxing for 20 min indicating completion of reaction. The mixture was then cooled to 25° C., diluted with EtOAc and filtered. The cake was washed thoroughly with EtOAc. The combined filtrates were washed with sat. aq. Na2S2O5, sat. aq. NaHCO3, and brine, dried over Na2SO4 and concentrated. The residue was purified on a silica gel column eluting with 5/1 hexanes/CH2Cl2 to provide 6-bromo-5-fluoro-1H-indole as a white crystalline solid (16.2 g, 76%). A 2 L dry round bottom flask After removal of the volatiles the residue was dissolved in a mixture of toluene (650 mL) and acetic acid (390 mL) followed by addition of iron powder (55 g) and silica gel (50 g) The dark red mixture was heated to 100° C. with vigorous stirring after refluxing for 20 min completion of reaction The mixture was then cooled to 25° C. filtered The cake was washed thoroughly with EtOAc The combined filtrates were washed with sat. aq. Na2S2O5, sat. aq. NaHCO3, and brine dried over Na2SO4 concentrated The residue was purified on a silica gel column eluting with 5/1 hexanes/CH2Cl2

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 2 L dry round bottom flask was charged with 1-bromo-2-fluoro-4-methyl-5-nitrobenzene (24.5 g, 0.1 mol, 97%), DMF-DIPA (39 g, 0.22 mol), Et3N (16 mL, 0.11 mol) and dry DMF (100 mL). The mixture was stirred at 130° C. for 2 h. After removal of the volatiles the residue was dissolved in a mixture of toluene (650 mL) and acetic acid (390 mL) followed by addition of iron powder (55 g) and silica gel (50 g). The dark red mixture was heated to 100° C. with vigorous stirring. The dark color disappeared after refluxing for 20 min indicating completion of reaction. The mixture was then cooled to 25° C., diluted with EtOAc and filtered. The cake was washed thoroughly with EtOAc. The combined filtrates were washed with sat. aq. Na2S2O5, sat. aq. NaHCO3, and brine, dried over Na2SO4 and concentrated. The residue was purified on a silica gel column eluting with 5/1 hexanes/CH2Cl2 to provide 6-bromo-5-fluoro-1H-indole as a white crystalline solid (16.2 g, 76%). A 2 L dry round bottom flask After removal of the volatiles the residue was dissolved in a mixture of toluene (650 mL) and acetic acid (390 mL) followed by addition of iron powder (55 g) and silica gel (50 g) The dark red mixture was heated to 100° C. with vigorous stirring after refluxing for 20 min completion of reaction The mixture was then cooled to 25° C. filtered The cake was washed thoroughly with EtOAc The combined filtrates were washed with sat. aq. Na2S2O5, sat. aq. NaHCO3, and brine dried over Na2SO4 concentrated The residue was purified on a silica gel column eluting with 5/1 hexanes/CH2Cl2

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

Procedure: The title compound was prepared using the procedure described in Example 3A using 3-fluorobenzyl alcohol and 6-bromo-5-fluoro-1H-indole in place of benzyl alcohol and 6-bromo-1H-indole-3-carbonitrile, respectively. LCMS: 323.8 (M+H)+.

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

Procedure: 6-Bromo-5-fluoro-1H-indole (10 g, 46.7 mmol) was dissolved in DMF (100 mL) and cooled to 0° C. in an ice bath before the addition of sodium hydride, 60% dispersion in mineral oil (3.74 g, 93 mmol) and methyl 2-bromoacetate (8.59 mL, 93 mmol). The ice bath was removed and the reaction mixture was stirred at RT for 1 hour. The reaction mixture was cooled with an ice bath once again then quenched with water (50 mL). The aqueous layer was extracted with DCM (3×200 mL). The organics were combined, passed through a hydrophobic frit and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-40% ethyl acetate in cyclohexane to afford the title compound (10.209 g). LCMS (A): m/z (M+H)+ 286/288, C11H9BrFNO2 requires 285/287 (acidic). The ice bath was removed The reaction mixture was cooled with an ice bath once again quenched with water (50 mL) The aqueous layer was extracted with DCM (3×200 mL) concentrated The residue was purified by column chromatography on silica gel eluting with a gradient of 0-40% ethyl acetate in cyclohexane

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

Procedure: To the solution of 6-bromo-5-fluoro-1H-indole (0.92 g, 4.28 mmol) in dry DMF (10 mL) was added sodium hydride as 60% in oil (0.26 g, 6.41 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min, and then iodomethane (0.32 mL, 5.14 mmol) was added. The mixture was stirred for 1 hour at room temperature, and then quenched with ice and extracted with EtOAc (50 mL). The organic layer was washed with water, brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (EtOAc-hexane, 1:9) give 6-bromo-5-fluoro-1-methyl-1H-indole as a colorless solid (0.97 g, 99%). 1H NMR (CDCl3, 400 MHz): 3.66 (s, 3H), 6.43 (d, J=2.7 Hz, 1H), 7.05 (d, J=2.7 Hz, 1H), 7.34 (d, J=9.3 Hz, 1H), 7.44 (d, J=5.4 Hz, 1H). The mixture was stirred for 1 hour at room temperature quenched with ice extracted with EtOAc (50 mL) The organic layer was washed with water, brine dried over MgSO4 filtered concentrated The residue was purified by column chromatography (EtOAc-hexane, 1:9)

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

Procedure: To the solution of 6-bromo-5-fluoro-1H-indole (0.92 g, 4.28 mmol) in dry DMF (10 mL) was added sodium hydride as 60% in oil (0.26 g, 6.41 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min, and then iodomethane (0.32 mL, 5.14 mmol) was added. The mixture was stirred for 1 hour at room temperature, and then quenched with ice and extracted with EtOAc (50 mL). The organic layer was washed with water, brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (EtOAc-hexane, 1:9) give 6-bromo-5-fluoro-1-methyl-1H-indole as a colorless solid (0.97 g, 99%). 1H NMR (CDCl3, 400 MHz): 3.66 (s, 3H), 6.43 (d, J=2.7 Hz, 1H), 7.05 (d, J=2.7 Hz, 1H), 7.34 (d, J=9.3 Hz, 1H), 7.44 (d, J=5.4 Hz, 1H). The mixture was stirred for 1 hour at room temperature quenched with ice extracted with EtOAc (50 mL) The organic layer was washed with water, brine dried over MgSO4 filtered concentrated The residue was purified by column chromatography (EtOAc-hexane, 1:9)

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

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

Procedure: was prepared from 6-bromo-5-fluoro-1H-indole [259860-08-7] in a similar manner as described for the preparation of (3-carbamoyl-5,6-difluoro-indol-1-yl)-acetic acid. White solid. MS (LC/MS): 315.0 [M+H]+, 631.0 [2M+H]+; tR (HPLC conditions k): 2.79 min. 2.79 min.

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 6-bromo-5-fluoro-1H-indole (0.214 g, 1 mmol), phenylboronic acid (0.171 g, 1.4 mmol), sodium carbonate (1.06 g, 10 mmol), Pd(PPh3)4 (0.116 g, 0.1 mmol), 1,2-dimethoxyethane (5 mL) and water (5 mL) was stirred under nitrogen at 85° C. for 18 h. The mixture was partitioned between water (20 mL) and DCM (2×30 mL) and the combined extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-50% Et2O in petrol) gave 5-fluoro-6-phenyl-1H-indole (0.202 g, 95%) as a pale green solid. MS: [M+H]+=212. A solution of borane in THF (1 M, 1.42 mL) was added to 5-fluoro-6-phenyl-1H-indole (0.20 g, 0.95 mmol) under nitrogen with external cooling using an ice-MeOH bath. The resulting mixture was stirred at 0° C. for 0.5 h, then TFA was added dropwise over 0.1 h. The mixture was stirred at 0° C. for 1 h then a solution of sodium hydroxide (0.8 g, 20 mmol) and water (5 mL) was added dropwise over 0.1 h. The resulting mixture was partitioned between water (20 mL) and DCM (2×30 mL) and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-100% Et2O in petrol) gave the title compound (0.17 g, 85%) as an oil. MS: [M+H]+=214. The mixture was partitioned between water (20 mL) and DCM (2×30 mL) the combined extracts were dried (Na2SO4) evaporated in vacuo to give an oil Chromatography (SiO2; gradient elution with 0-50% Et2O in petrol)