2-bromo-1,5,6,7-tetrahydroindol-4-one

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

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

Procedure: A solution of 2-bromo-6,7-dihydro-1H-indol-4(5H)-one (303a) (222 mg, 1.04 mmol), hydroxylamine hydrochloride (80 mg, 1.14 mmol), and sodium acetate (94 mg, 1.14 mmol) in MeOH (28 mL) was stirred under argon at 50° C. for 22 h. The reaction mixture was then concentrated in vacuo, and the residue was partitioned between saturated aq. NaHCO3 (40 mL) and EtOAc (60 mL). The organic layer was separated, and the aq. layer was extracted with EtOAc (60 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo to provide 2-bromo-6,7-dihydro-1H-indol-4(5H)-one oxime (273 mg) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm: (˜2:1 mixture of oxime isomers) Major isomer: 7.99 (1H, br. s.), 6.36 (1H, br. s.), 2.71 (2H, br. s.), 2.63 (2H, br. s.), 1.89-1.98 (2H, m). Minor isomer: 1H NMR (400 MHz, CDCl3) δ ppm 8.14 (1H, br. s.), 6.97 (1H, br. s.), 2.67-2.75 (2H, m), 2.47 (2H, br. s.), 1.99 (2H, br. s.). m/z (ESI, +ve) 228.9/231.1 (M+H)+. The reaction mixture was then concentrated in vacuo the residue was partitioned between saturated aq. NaHCO3 (40 mL) and EtOAc (60 mL) The organic layer was separated the aq. layer was extracted with EtOAc (60 mL) The combined extracts were dried over Na2SO4 filtered concentrated in vacuo

Conditions: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-(tert-butyl)-3-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxalin-2-amine (174b) (222.6 mg, 0.652 mmol), 2-bromo-6,7-dihydro-1H-indol-4(5H)-one (303a; 209 mg, 0.978 mmol), K2PO4 (415 mg, 1.957 mmol), (Strem Chemicals, Inc., 31.1 mg, 0.065 mmol), and Pd2dba3 (Aldrich, 29.9 mg, 0.033 mmol) in a mixture of dioxane (4.5 mL) and water (0.900 mL) was heated under argon at 105° C. for 1 h. The reaction mixture was subsequently cooled to RT and diluted with water (30 mL). The resulting mixture was extracted with 5% MeOH/DCM (3×30 mL), and the combined extracts were dried over Na2SO4, filtered, and concentrated onto silica gel. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes) furnished 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-indol-4(5H)-one (175 mg, 0.502 mmol, 77% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 12.52 (1H, br. s.), 7.96 (1H, dd, J=7.6, 1.0 Hz), 7.73 (1H, d, J=7.8 Hz), 7.40 (1H, t, J=7.8 Hz), 7.08 (1H, d, J=2.0 Hz), 4.89 (1H, s), 2.93 (2H, t, J=6.2 Hz), 2.60 (3H, s), 2.51-2.57 (2H, m), 2.23 (2H, quin, J=6.3 Hz), 1.68 (9H, s). m/z (ESI, +ve) 349.2 (M+H)+. The reaction mixture was subsequently cooled to RT The resulting mixture was extracted with 5% MeOH/DCM (3×30 mL) the combined extracts were dried over Na2SO4 filtered concentrated onto silica gel Chromatographic purification (silica gel, 0-100% EtOAc/hexanes)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,3-Dibromo-5,5-dimethylhydantoin (Fluka, St. Louis, Mo.) (532 mg, 1.86 mmol) was added to a solution of 6,7-dihydro-1H-indol-4(5H)-one (Aldrich) (503.0 mg, 3.72 mmol) in DMF (13 mL) at 60° C. and the resulting mixture was stirred at 60° C. for 10 min. The mixture was then concentrated in vacuo (65° C., 24 Torr), and the residual oil was chromatographically purified (silica gel, 0-80% EtOAc/hexanes). The isolated product was taken up in EtOAc (100 mL) and sequentially washed with saturated aq. NaHCO3 (3×40 mL) and brine (40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to provide 2-bromo-6,7-dihydro-1H-indol-4(5H)-one (664 mg, 3.10 mmol, 83% yield) as a white solid: 1H NMR (400 MHz, CDCl3) δ ppm 8.43 (1H, br. s.), 6.51 (1H, d, J=2.3 Hz), 2.79 (2H, t, J=6.2 Hz), 2.48 (2H, t, J=6.6 Hz), 2.15 (2H, quin, J=6.3 Hz). m/z (ESI, +ve) 214.1/216.1 (M+H)+. The mixture was then concentrated in vacuo (65° C., 24 Torr) the residual oil was chromatographically purified (silica gel, 0-80% EtOAc/hexanes) sequentially washed with saturated aq. NaHCO3 (3×40 mL) and brine (40 mL) The organic layer was dried over Na2SO4 filtered concentrated in vacuo

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,3-Dibromo-5,5-dimethylhydantoin (Fluka, St. Louis, Mo.) (532 mg, 1.86 mmol) was added to a solution of 6,7-dihydro-1H-indol-4(5H)-one (Aldrich) (503.0 mg, 3.72 mmol) in DMF (13 mL) at 60° C. and the resulting mixture was stirred at 60° C. for 10 min. The mixture was then concentrated in vacuo (65° C., 24 Torr), and the residual oil was chromatographically purified (silica gel, 0-80% EtOAc/hexanes). The isolated product was taken up in EtOAc (100 mL) and sequentially washed with saturated aq. NaHCO3 (3×40 mL) and brine (40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to provide 2-bromo-6,7-dihydro-1H-indol-4(5H)-one (664 mg, 3.10 mmol, 83% yield) as a white solid: 1H NMR (400 MHz, CDCl3) δ ppm 8.43 (1H, br. s.), 6.51 (1H, d, J=2.3 Hz), 2.79 (2H, t, J=6.2 Hz), 2.48 (2H, t, J=6.6 Hz), 2.15 (2H, quin, J=6.3 Hz). m/z (ESI, +ve) 214.1/216.1 (M+H)+. The mixture was then concentrated in vacuo (65° C., 24 Torr) the residual oil was chromatographically purified (silica gel, 0-80% EtOAc/hexanes) sequentially washed with saturated aq. NaHCO3 (3×40 mL) and brine (40 mL) The organic layer was dried over Na2SO4 filtered concentrated in vacuo

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

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

Procedure: was prepared using a literature procedure (Remers et al., J. Org. Chem., 36:1241-1247 (1971) (“Remers”), which is hereby incorporated by reference). To a 100 mL round bottom flask charged with a magnetic stir bar was added 1,5,6,7-tetrahydro-4H-indol-4-one (1.2 g, 8.8 mmole) and dry THF (20 mL). Stirring was commenced, and a solution of phenyltrimethylammonium tribromide (3.33 g, 8.8 mmole) in 15 mL of dry THF was added dropwise over 10 minutes at ambient temperature. After the addition was complete, the reaction mixture was stirred for an additional 2 hours and then filtered to remove the precipitate. The filtrate was concentrated in vacuo and the residue treated with dichloromethane (30 mL) and 5% aqueous Na2CO3 solution (30 mL). The layers were separated and the dichloromethane layer was then washed with brine (30 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to give the crude product as a white solid which was directly used without further purification. 1H NMR data matched the literature values exactly (“Remers”, which is hereby incorporated by reference). was prepared To a 100 mL round bottom flask charged with a magnetic stir bar After the addition the reaction mixture was stirred for an additional 2 hours filtered to remove the precipitate The filtrate was concentrated in vacuo the residue treated with dichloromethane (30 mL) and 5% aqueous Na2CO3 solution (30 mL) The layers were separated the dichloromethane layer was then washed with brine (30 mL) dried over anhydrous MgSO4 filtered concentrated in vacuo

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

Procedure: A solution of 2-bromo-6,7-dihydro-1H-indol-4(5H)-one (303a) (222 mg, 1.04 mmol), hydroxylamine hydrochloride (80 mg, 1.14 mmol), and sodium acetate (94 mg, 1.14 mmol) in MeOH (28 mL) was stirred under argon at 50° C. for 22 h. The reaction mixture was then concentrated in vacuo, and the residue was partitioned between saturated aq. NaHCO3 (40 mL) and EtOAc (60 mL). The organic layer was separated, and the aq. layer was extracted with EtOAc (60 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo to provide 2-bromo-6,7-dihydro-1H-indol-4(5H)-one oxime (273 mg) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm: (˜2:1 mixture of oxime isomers) Major isomer: 7.99 (1H, br. s.), 6.36 (1H, br. s.), 2.71 (2H, br. s.), 2.63 (2H, br. s.), 1.89-1.98 (2H, m). Minor isomer: 1H NMR (400 MHz, CDCl3) δ ppm 8.14 (1H, br. s.), 6.97 (1H, br. s.), 2.67-2.75 (2H, m), 2.47 (2H, br. s.), 1.99 (2H, br. s.). m/z (ESI, +ve) 228.9/231.1 (M+H)+. The reaction mixture was then concentrated in vacuo the residue was partitioned between saturated aq. NaHCO3 (40 mL) and EtOAc (60 mL) The organic layer was separated the aq. layer was extracted with EtOAc (60 mL) The combined extracts were dried over Na2SO4 filtered concentrated in vacuo

Conditions: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-(tert-butyl)-3-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxalin-2-amine (174b) (222.6 mg, 0.652 mmol), 2-bromo-6,7-dihydro-1H-indol-4(5H)-one (303a; 209 mg, 0.978 mmol), K2PO4 (415 mg, 1.957 mmol), (Strem Chemicals, Inc., 31.1 mg, 0.065 mmol), and Pd2dba3 (Aldrich, 29.9 mg, 0.033 mmol) in a mixture of dioxane (4.5 mL) and water (0.900 mL) was heated under argon at 105° C. for 1 h. The reaction mixture was subsequently cooled to RT and diluted with water (30 mL). The resulting mixture was extracted with 5% MeOH/DCM (3×30 mL), and the combined extracts were dried over Na2SO4, filtered, and concentrated onto silica gel. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes) furnished 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-indol-4(5H)-one (175 mg, 0.502 mmol, 77% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 12.52 (1H, br. s.), 7.96 (1H, dd, J=7.6, 1.0 Hz), 7.73 (1H, d, J=7.8 Hz), 7.40 (1H, t, J=7.8 Hz), 7.08 (1H, d, J=2.0 Hz), 4.89 (1H, s), 2.93 (2H, t, J=6.2 Hz), 2.60 (3H, s), 2.51-2.57 (2H, m), 2.23 (2H, quin, J=6.3 Hz), 1.68 (9H, s). m/z (ESI, +ve) 349.2 (M+H)+. The reaction mixture was subsequently cooled to RT The resulting mixture was extracted with 5% MeOH/DCM (3×30 mL) the combined extracts were dried over Na2SO4 filtered concentrated onto silica gel Chromatographic purification (silica gel, 0-100% EtOAc/hexanes)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,3-Dibromo-5,5-dimethylhydantoin (Fluka, St. Louis, Mo.) (532 mg, 1.86 mmol) was added to a solution of 6,7-dihydro-1H-indol-4(5H)-one (Aldrich) (503.0 mg, 3.72 mmol) in DMF (13 mL) at 60° C. and the resulting mixture was stirred at 60° C. for 10 min. The mixture was then concentrated in vacuo (65° C., 24 Torr), and the residual oil was chromatographically purified (silica gel, 0-80% EtOAc/hexanes). The isolated product was taken up in EtOAc (100 mL) and sequentially washed with saturated aq. NaHCO3 (3×40 mL) and brine (40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to provide 2-bromo-6,7-dihydro-1H-indol-4(5H)-one (664 mg, 3.10 mmol, 83% yield) as a white solid: 1H NMR (400 MHz, CDCl3) δ ppm 8.43 (1H, br. s.), 6.51 (1H, d, J=2.3 Hz), 2.79 (2H, t, J=6.2 Hz), 2.48 (2H, t, J=6.6 Hz), 2.15 (2H, quin, J=6.3 Hz). m/z (ESI, +ve) 214.1/216.1 (M+H)+. The mixture was then concentrated in vacuo (65° C., 24 Torr) the residual oil was chromatographically purified (silica gel, 0-80% EtOAc/hexanes) sequentially washed with saturated aq. NaHCO3 (3×40 mL) and brine (40 mL) The organic layer was dried over Na2SO4 filtered concentrated in vacuo