4-bromo-5-methyl-1H-indole

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

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-bromo-5-methylindole (800 mg, 3.8 mmol) in anhydrous ether (8 mL) is added with stirring to a suspension of potassium hydride (560 mg, 4.2 mmol, 30% dispersion in mineral oil) in anhydrous ether at 0° C. under argon. The resulting mixture is cooled to −78° C. and tert-butyllithium (4.9 ml, of 1.7 M in pentane, 8.4 mmol) is slowly added. The resulting cream-colored mixture is stirred at −78° C. for 1 hour. Tributylborate (3.1 mL, 11.4 mmol) is slowly added and the reaction mixture is stirred for 1 hour at −78° C. before being allowed to slowly warm to room temperature. More anhydrous ether is added to facilitate stirring. After stirring for 24 hours, the resulting sticky mixture is diluted with ether and transferred in portions with stirring to a precooled solution of 1 M phosphoric acid (50 mL). After stirring for 30 minutes, the acidic mixture is extracted with diethyl ether (75 mL×3) and the combined extracts are extracted with 1 N sodium hydroxide (20 ml×4). The combined base extracts are cooled with an ice bath, acidified with 1 M phosphoric acid and extracted with ethyl acetate (20 ml×3). The combined extracts are washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a beige residue. The residue is triturated with hexane to obtain the desired 5-methylindole-4-boronic acid as a beige gum (230 mg). the reaction mixture is stirred for 1 hour at −78° C. to slowly warm to room temperature to facilitate stirring After stirring for 24 hours After stirring for 30 minutes the acidic mixture is extracted with diethyl ether (75 mL×3) the combined extracts are extracted with 1 N sodium hydroxide (20 ml×4) The combined base extracts are cooled with an ice bath extracted with ethyl acetate (20 ml×3) The combined extracts are washed with brine (20 mL) dried over anhydrous sodium sulfate filtered concentrated to obtain a beige residue The residue is triturated with hexane

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-bromo-5-methylindole (800 mg, 3.8 mmol) in anhydrous ether (8 mL) is added with stirring to a suspension of potassium hydride (560 mg, 4.2 mmol, 30% dispersion in mineral oil) in anhydrous ether at 0° C. under argon. The resulting mixture is cooled to −78° C. and tert-butyllithium (4.9 ml, of 1.7 M in pentane, 8.4 mmol) is slowly added. The resulting cream-colored mixture is stirred at −78° C. for 1 hour. Tributylborate (3.1 mL, 11.4 mmol) is slowly added and the reaction mixture is stirred for 1 hour at −78° C. before being allowed to slowly warm to room temperature. More anhydrous ether is added to facilitate stirring. After stirring for 24 hours, the resulting sticky mixture is diluted with ether and transferred in portions with stirring to a precooled solution of 1 M phosphoric acid (50 mL). After stirring for 30 minutes, the acidic mixture is extracted with diethyl ether (75 mL×3) and the combined extracts are extracted with 1 N sodium hydroxide (20 ml×4). The combined base extracts are cooled with an ice bath, acidified with 1 M phosphoric acid and extracted with ethyl acetate (20 ml×3). The combined extracts are washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a beige residue. The residue is triturated with hexane to obtain the desired 5-methylindole-4-boronic acid as a beige gum (230 mg). the reaction mixture is stirred for 1 hour at −78° C. to slowly warm to room temperature to facilitate stirring After stirring for 24 hours After stirring for 30 minutes the acidic mixture is extracted with diethyl ether (75 mL×3) the combined extracts are extracted with 1 N sodium hydroxide (20 ml×4) The combined base extracts are cooled with an ice bath extracted with ethyl acetate (20 ml×3) The combined extracts are washed with brine (20 mL) dried over anhydrous sodium sulfate filtered concentrated to obtain a beige residue The residue is triturated with hexane

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-bromo-5-methylindole (800 mg, 3.8 mmol) in anhydrous ether (8 mL) is added with stirring to a suspension of potassium hydride (560 mg, 4.2 mmol, 30% dispersion in mineral oil) in anhydrous ether at 0° C. under argon. The resulting mixture is cooled to −78° C. and tert-butyllithium (4.9 mL of 1.7 M in pentane, 8.4 mmol) is slowly added. The resulting cream-colored mixture is stirred at −78° C. for 1 hour. Tributylborate (3.1 mL, 11.4 mmol) is slowly added and the reaction mixture is stirred for 1 hour at −78° C. before being allowed to slowly warm to room temperature. More anhydrous ether is added to facilitate stirring. After stirring for 24 h, the resulting sticky mixture is diluted with ether and transferred in portions with stirring to a precooled solution of 1 M phosphoric acid (50 mL). After stirring for 30 min, the acidic mixture is extracted with diethyl ether (75 mL×3) and the combined extracts are extracted with 1 N sodium hydroxide (20 mL×4). The combined base extracts are cooled with an ice bath, acidified with 1 M phosphoric acid and extracted with EtOAc (20 mL×3). The combined extracts are washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a beige residue. The residue is triturated with hexane to obtain the desired 5-methylindole-4-boronic acid as a beige gum. the reaction mixture is stirred for 1 hour at −78° C. to slowly warm to room temperature to facilitate stirring After stirring for 24 h After stirring for 30 min the acidic mixture is extracted with diethyl ether (75 mL×3) the combined extracts are extracted with 1 N sodium hydroxide (20 mL×4) The combined base extracts are cooled with an ice bath extracted with EtOAc (20 mL×3) The combined extracts are washed with brine (20 mL) dried over anhydrous sodium sulfate filtered concentrated to obtain a beige residue The residue is triturated with hexane

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-bromo-5-methylindole (800 mg, 3.8 mmol) in anhydrous ether (8 mL) is added with stirring to a suspension of potassium hydride (560 mg, 4.2 mmol, 30% dispersion in mineral oil) in anhydrous ether at 0° C. under argon. The resulting mixture is cooled to −78° C. and tert-butyllithium (4.9 mL of 1.7 M in pentane, 8.4 mmol) is slowly added. The resulting cream-colored mixture is stirred at −78° C. for 1 hour. Tributylborate (3.1 mL, 11.4 mmol) is slowly added and the reaction mixture is stirred for 1 hour at −78° C. before being allowed to slowly warm to room temperature. More anhydrous ether is added to facilitate stirring. After stirring for 24 h, the resulting sticky mixture is diluted with ether and transferred in portions with stirring to a precooled solution of 1 M phosphoric acid (50 mL). After stirring for 30 min, the acidic mixture is extracted with diethyl ether (75 mL×3) and the combined extracts are extracted with 1 N sodium hydroxide (20 mL×4). The combined base extracts are cooled with an ice bath, acidified with 1 M phosphoric acid and extracted with EtOAc (20 mL×3). The combined extracts are washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a beige residue. The residue is triturated with hexane to obtain the desired 5-methylindole-4-boronic acid as a beige gum. the reaction mixture is stirred for 1 hour at −78° C. to slowly warm to room temperature to facilitate stirring After stirring for 24 h After stirring for 30 min the acidic mixture is extracted with diethyl ether (75 mL×3) the combined extracts are extracted with 1 N sodium hydroxide (20 mL×4) The combined base extracts are cooled with an ice bath extracted with EtOAc (20 mL×3) The combined extracts are washed with brine (20 mL) dried over anhydrous sodium sulfate filtered concentrated to obtain a beige residue The residue is triturated with hexane

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

Procedure: A solution of 4-bromo-5-methylindole (3.55 g, 16.9 mmol) (21) in 10 ml of anhydrous DMF is added to a suspension of sodium hydride (1.01 g, 60% in mineral oil, 25.3 mmol, 1.5 eq.) in 10 ml of DMF under nitrogen at 0° C. The resulting mixture is stirred at 0° C. for 30 minutes, and then warmed to room temperature. After stirring at room temperature for an additional 2 hours, the reaction mixture is cooled to 0° C. Iodomethane (2.40 g, 18.6 mmol, 1.1 eq.) is added dropwise, the mixture is stirred at 0° C. for 2 hours, and then is warmed to 50° C. and stirred for an additional 2 hours. The reaction mixture is poured into 100 ml of ice-water, extracted with ethyl acetate (30 ml×3), washed with water and brine dried over anhydrous sodium sulfate. The solvent is evaporated and the product (22) is taken to dryness under high vacuum to give 3.75 g of pure compound. 1H NMR (400 MHz, CDCl3) δ 7.17 (1H, d, J=8.4 Hz), 7.08 (1H, d, J=8.4 Hz), 7.05 (1H, 4, J=3.2 Hz), 650 (1H, dd, J=0.4, 2.8 Hz), 3.77 (3H, 3), 2.51 (3H, s); MS (+VE) m/z 224 (M+). warmed to room temperature After stirring at room temperature for an additional 2 hours the reaction mixture is cooled to 0° C the mixture is stirred at 0° C. for 2 hours is warmed to 50° C. stirred for an additional 2 hours extracted with ethyl acetate (30 ml×3) washed with water and brine dried over anhydrous sodium sulfate The solvent is evaporated

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

Procedure: A solution of 4-bromo-5-methylindole (3.55 g, 16.9 mmol) (21) in 10 ml of anhydrous DMF is added to a suspension of sodium hydride (1.01 g, 60% in mineral oil, 25.3 mmol, 1.5 eq.) in 10 ml of DMF under nitrogen at 0° C. The resulting mixture is stirred at 0° C. for 30 minutes, and then warmed to room temperature. After stirring at room temperature for an additional 2 hours, the reaction mixture is cooled to 0° C. Iodomethane (2.40 g, 18.6 mmol, 1.1 eq.) is added dropwise, the mixture is stirred at 0° C. for 2 hours, and then is warmed to 50° C. and stirred for an additional 2 hours. The reaction mixture is poured into 100 ml of ice-water, extracted with ethyl acetate (30 ml×3), washed with water and brine dried over anhydrous sodium sulfate. The solvent is evaporated and the product (22) is taken to dryness under high vacuum to give 3.75 g of pure compound. 1H NMR (400 MHz, CDCl3) δ 7.17 (1H, d, J=8.4 Hz), 7.08 (1H, d, J=8.4 Hz), 7.05 (1H, 4, J=3.2 Hz), 650 (1H, dd, J=0.4, 2.8 Hz), 3.77 (3H, 3), 2.51 (3H, s); MS (+VE) m/z 224 (M+). warmed to room temperature After stirring at room temperature for an additional 2 hours the reaction mixture is cooled to 0° C the mixture is stirred at 0° C. for 2 hours is warmed to 50° C. stirred for an additional 2 hours extracted with ethyl acetate (30 ml×3) washed with water and brine dried over anhydrous sodium sulfate The solvent is evaporated

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

Procedure: Bredereck's reagent (tert-butoxybis(dimethylamino)methane—16 g, 91 mmol) is added at room temperature to a solution of 2,6-dimethyl-3-nitrobromobenzene (20 g, 87 mmol) in anhydrous DMF (120 ml). The reaction mixture is heated at 120–125° C. under N2 for 5 hours or until starting material is mostly consumed according to TLC. The reaction mixture is allowed to cool to room temperature, poured into water (300 ml), and extracted with dichloromethane (100 ml×3). The combined extracts are dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture of enamines as a dark brown oil. This material is carried on to the next step without purification. The crude mixture is dissolved in acetic acid/water (250 ml of 4:1), cooled to 0° C. and treated with zinc dust (57 g, 870 mmol) added slowly in portions. After complete addition, the reaction mixture is heated at 110° C. for 4 h. Zinc is removed by filtration through a celite pad and the filtrate is extracted with dichloromethane (100 ml×3). The combined extracts are dried over anhydrous sodium sulfate, concentrated and purified by flash chromatography on silica gel (EtOAc/Hexane 1:20) to obtain 4-bromo-5-methylindole (5.3 g) (21) as a light purple oil. The reaction mixture is heated at 120–125° C. under N2 for 5 hours is mostly consumed poured into water (300 ml) extracted with dichloromethane (100 ml×3) The combined extracts are dried over anhydrous sodium sulfate filtered concentrated to obtain This material is carried on to the next step without purification The crude mixture is dissolved in acetic acid/water (250 ml of 4:1) cooled to 0° C. added slowly in portions After complete addition the reaction mixture is heated at 110° C. for 4 h Zinc is removed by filtration through a celite pad the filtrate is extracted with dichloromethane (100 ml×3) The combined extracts are dried over anhydrous sodium sulfate concentrated purified by flash chromatography on silica gel (EtOAc/Hexane 1:20)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-bromo-5-methylindole (800 mg, 3.8 mmol) in anhydrous ether (8 mL) is added with stirring to a suspension of potassium hydride (560 mg, 4.2 mmol, 30% dispersion in mineral oil) in anhydrous ether at 0° C. under argon. The resulting mixture is cooled to −78° C. and tert-butyllithium (4.9 mL of 1.7 M in pentane, 8.4 mmol) is slowly added. The resulting cream-colored mixture is stirred at −78° C. for 1 hour. Tributylborate (3.1 mL, 11.4 mmol) is slowly added and the reaction mixture is stirred for 1 hour at −78° C. before being allowed to slowly warm to room temperature. More anhydrous ether is added to facilitate stirring. After stirring for 24 hours, the resulting sticky mixture is diluted with ether and transferred in portions with stirring to a precooled solution of 1 M phosphoric acid (50 mL). After stirring for 30 minutes, the acidic mixture is extracted with diethyl ether (75 mL×3) and the combined extracts are extracted with 1 N sodium hydroxide (20 mL×4). The combined base extracts are cooled with an ice bath, acidified with 1 M phosphoric acid and extracted with ethyl acetate (20 mL×3). The combined extracts are washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a beige residue. The residue is triturated with hexane to obtain the desired 5-methylindole-4-boronic acid as a beige gum (230 mg). the reaction mixture is stirred for 1 hour at −78° C. to slowly warm to room temperature to facilitate stirring After stirring for 24 hours After stirring for 30 minutes the acidic mixture is extracted with diethyl ether (75 mL×3) the combined extracts are extracted with 1 N sodium hydroxide (20 mL×4) The combined base extracts are cooled with an ice bath extracted with ethyl acetate (20 mL×3) The combined extracts are washed with brine (20 mL) dried over anhydrous sodium sulfate filtered concentrated to obtain a beige residue The residue is triturated with hexane

Conditions: temp:145.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 300 (150 mg, 0.714 mmol), Pd2(dba)3 (131 mg, 0.143 mmol), dppf (159 mg, 0.286 mmol), Zn(CN)2 (84 mg, 0.714 mmol), and zinc (4.6 mg, 0.0714 mmol) in NMP (10 mL) under nitrogen atmosphere was heated at 145° C. for 18 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (20 mL×3). The combined extracts were dried (MgSO4), filtered, and concentrated to dryness. The crude was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (3:1) to afford 54 mg (48.5%) 5-methyl-1H-indole-4-carbonitrile (302) as yellow solid: MS (ESI) m/z=157.1 (M+1). extracted with EtOAc (20 mL×3) The combined extracts were dried (MgSO4) filtered concentrated to dryness The crude was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (3:1)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-bromo-5-methylindole (800 mg, 3.8 mmol) in anhydrous ether (8 mL) is added with stirring to a suspension of potassium hydride (560 mg, 4.2 mmol, 30% dispersion in mineral oil) in anhydrous ether at 0° C. under argon. The resulting mixture is cooled to −78° C. and tert-butyllithium (4.9 ml, of 1.7 M in pentane, 8.4 mmol) is slowly added. The resulting cream-colored mixture is stirred at −78° C. for 1 hour. Tributylborate (3.1 mL, 11.4 mmol) is slowly added and the reaction mixture is stirred for 1 hour at −78° C. before being allowed to slowly warm to room temperature. More anhydrous ether is added to facilitate stirring. After stirring for 24 hours, the resulting sticky mixture is diluted with ether and transferred in portions with stirring to a precooled solution of 1 M phosphoric acid (50 mL). After stirring for 30 minutes, the acidic mixture is extracted with diethyl ether (75 mL×3) and the combined extracts are extracted with 1 N sodium hydroxide (20 ml×4). The combined base extracts are cooled with an ice bath, acidified with 1 M phosphoric acid and extracted with ethyl acetate (20 ml×3). The combined extracts are washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a beige residue. The residue is triturated with hexane to obtain the desired 5-methylindole-4-boronic acid as a beige gum (230 mg). the reaction mixture is stirred for 1 hour at −78° C. to slowly warm to room temperature to facilitate stirring After stirring for 24 hours After stirring for 30 minutes the acidic mixture is extracted with diethyl ether (75 mL×3) the combined extracts are extracted with 1 N sodium hydroxide (20 ml×4) The combined base extracts are cooled with an ice bath extracted with ethyl acetate (20 ml×3) The combined extracts are washed with brine (20 mL) dried over anhydrous sodium sulfate filtered concentrated to obtain a beige residue The residue is triturated with hexane

Conditions: temp:122.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Bredereck's reagent (tert-butoxybis(dimethylamino)methane—16 g, 91 mmol) is added at room temperature to a solution of 2,6-dimethyl-3-nitrobromobenzene (20 g, 87 mmol) in anhydrous DMF (120 ml). The reaction mixture is heated at 120-125° C. under N2 for 5 hours or until starting material is mostly consumed according to TLC. The reaction mixture is allowed to cool to room temperature, poured into water (300 ml), and extracted with dichloromethane (100 ml×3). The combined extracts are dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture of enamines as a dark brown oil. This material is carried on to the next step without purification. The crude mixture is dissolved in acetic acid/water (250 ml of 4:1), cooled to 0° C. and treated with zinc dust (57 g, 870 mmol) added slowly in portions. After complete addition, the reaction mixture is heated at 110° C. for 4 h. Zinc is removed by filtration through a celite pad and the filtrate is extracted with dichloromethane (100 ml×3). The combined extracts are dried over anhydrous sodium sulfate, concentrated and purified by flash chromatography on silica get (EtOAc/Hexane 1:20) to obtain 4-bromo-5-methylindole (5.3 g) (21) as a light purple oil. is mostly consumed to cool to room temperature poured into water (300 ml) extracted with dichloromethane (100 ml×3) The combined extracts are dried over anhydrous sodium sulfate filtered concentrated to obtain This material is carried on to the next step without purification The crude mixture is dissolved in acetic acid/water (250 ml of 4:1) cooled to 0° C. added slowly in portions After complete addition the reaction mixture is heated at 110° C. for 4 h Zinc is removed by filtration through a celite pad the filtrate is extracted with dichloromethane (100 ml×3) The combined extracts are dried over anhydrous sodium sulfate concentrated purified by flash chromatography on silica get (EtOAc/Hexane 1:20)