* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
[2-(2-Bromo-3-methyl-6-nitro-phenyl)-vinyl]-dimethyl-amine (10 g) was dissolved in AcOH /H2O(100mL:25mL), cooled to 0°C and treated with Zn (30 g) added slowly in portions. After complete addition, the reaction mixture was heated at 110°C overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2S0 and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to afford the title compound (1.4 g, 20 percent) 1H NMR CDCI3400 MHz δ 2.47 (m, 3H), 6.50-6.51 (m, 1H), 6.97-6.99 (m, 1 H), 7.12- 7.18(m, 2H), 8.12 (s, 1 H)
1.4 g
With acetic acid; zinc In water at 0 - 110℃;
2-(2-Bromo-3-methyl-6-nitro-phenyl)vinyl]-dimethyl-amine (10 g) was dissolved in AcOH/H2O (100 mL:25 mL), cooled to 0° C. and treated with Zn (30 g) added slowly in portions. After complete addition, the reaction mixture was heated at 110° C. overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to afford the title compound (1.4 g, 20percent) 1H NMR CDCl3 400 MHz δ 2.47 (m, 3H), 6.50-6.51 (m, 1H), 6.97-6.99 (m, 1H), 7.12-7.18 (m, 2H), 8.12 (s, 1H)
Stage #1: With pyrrolidine In 1,4-dioxane at 100℃; for 18 h; Inert atmosphere Stage #2: at 110℃; for 4 h;
ep 2: A mixture of 298 (3.0 g, 13.04 mmol), pyrrolidine (926 mg, 13.04 mmol), and DMF-DMA (7.76 g, 65.22 mmol) in 1,4-dioxane (20 mL) under nitrogen atmosphere was heated at 100 °C for 18 h. The reaction was concentrated under to dryness in vacuo and to the residue was added iron (3.65 g, 65.22 mmol) and HO Ac (40 mL). The resulting mixture was heated at 110 °C for 4 h, cooled to RT and filtered. The filtrate was concentrated in vacuo. The crude was purified by S1O2 chromatography eluting with petroleum ether/EtOAc (10:1) to afford 150 mg (5.5percent) of 4-bromo-5-methyl-lH-indole (300) as a yellow solid: MS (ESI) m/z = 210.1 (M+l).
Bredereck's reagent (tert-butoxybis (dimethylamino) methane (16 g, 91 mmol) is added to a solution of 2, 6-dimethyl-3-nitrobromobenzene (20 g, 87 mmol) in anhydrous DMF (120 mL) at room temperature. 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 used in 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 hours. 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 as a light purple oil.
A solution of <strong>[610794-15-5]4-bromo-5-methylindole</strong> (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-78C for 1 hour. Tributylborate (3.1 mL, 11.4 mmol) is slowly added and the reaction mixture is stirred for 1 hour at-78C 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).
To a suspension of potassium hydride (143 mg, 1.07 mmol) in anhydrous diethyl ether (2 mL) at 0 0C is added a solution of <strong>[610794-15-5]4-bromo-5-methylindole</strong> (186 mg, 0.89 mmol) in diethyl ether (2 mL). The reaction mixture is cooled to -78 0C prior to dropwise addition of tert-butyllithium (1.56 mL of a 1.7 M solution in hexane, 2.7 mmol). The resulting mixture is stirred for 40 min prior to slow addition of tributylborate (980 muL, 3.54 mmol) and the reaction mixture is allowed to slowly warm to ambient temperature. After stirring for 18 h the reaction is quenched by the addition of phosphoric acid (IM) and extraction with diethyl ether. The organic layer is back-extracted with aqueous sodium hydroxide (IM) and the resulting aqueous layer is acidified with phosphoric acid (IM) and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Trituration with hexane affords the desired 5- methylindole-4-boronic acid as a beige gum.
A solution of <strong>[610794-15-5]4-bromo-5-methylindole</strong> (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 rert-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 h. Tributylborate (3.1 mL, 11.4 mmol) is slowly added and the reaction mixture is stirred for 1 h 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 x 3) and the combined extracts are extracted with 1 N sodium hydroxide (20 mL x 4). The combined base extracts are cooled with an ice bath, acidified with 1 M phosphoric acid and extracted with EtOAc (20 mL x 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.
A solution of <strong>[610794-15-5]4-bromo-5-methylindole</strong> (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 x 3) and the combined extracts are extracted with 1 N sodium hydroxide (20 mL x 4). The combined base extracts are cooled with an ice bath, acidified with 1 M phosphoric acid and extracted with EtOAc (20 mL x 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.
Fuming nitric acid (>90% yellow fuming HN03) is slowly added to a solution of 2-bromo-m-xylene (20 g, 150 mmol) in acetic acid (100 mL) cooled in an ice bath (above freezing point). The resulting mixture is allowed to warm to room temperature, stirred for 1 h, and heated at 80 C for 2 h or until the reaction is complete by GC/MS analysis following micro-scale base work-up. The reaction mixture is cooled to room temperature and poured into ice/water with stirring. The resulting yellow precipitates are collected by suction filtration and air dried to obtain 2,6-dimethyl-3-nitrobromobenzene. Bredereck's reagent (tert-butoxybis(dimethylamino)methane (16 g, 91 mmol) is added to a solution of 2,6-dimethyl-3-nitrobromobenzene (20 g, 87 mmol) in anhydrous DMF (120 mL) at room temperature. The reaction mixture is heated at 120-125 C under N2 for 5 h 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 x 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 used in 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 x 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 <strong>[610794-15-5]4-bromo-5-methylindole</strong> as a light purple oil. A solution of <strong>[610794-15-5]4-bromo-5-methylindole</strong> (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 h. Tributylborate (3.1 mL, 11.4 mmol) is slowly added and the reaction mixture is stirred for 1 h 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 x 3) and the combined extracts are extracted with 1 N sodium hydroxide (20 mL x 4). The combined base extracts are cooled with an ice bath, acidified with 1 M phosphoric acid and extracted with ethyl acetate (20 mL x 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.
To 2,6-dimethyl-3-nitrobromobenzene (2.31 g, 10.0 mmol) in anhydrous DMF (15 mL) is added Bredereck's reagent (tert-butoxybis(dimethylamino)methane) (4.35 mL, 21.1 mmol) and the resultant solution is heated at 125 0C for 5h. Upon cooling to ambient temperature, the reaction mixture is diluted with water and extracted with methylene chloride. The organic layer is isolated, dried (Na2SO4), filtered and concentrated in vacuo to give a dark brown oil. The crude mixture is dissolved in acetic acid/water (12 mL of 4:1) and <n="63"/>cooled to 0 C prior to portion-wise addition of zinc dust (6.56 g, 100.4 mmol) over 2 h. On completion of the addition the reaction mixture is stirred at ambient temperature for 1 h prior to heating at 110 0C for 2 h. The resultant reaction mixture is passed through a pad of Celite eluting with methylene chloride. The filtrate was extracted with methylene chloride and the organic layer is isolated, dried (Na2SO4), filtered and concentrated in vacuo. The crude product is purified by silica gel column chromatography eluting with ethyl acetate/heptane to give 4-bromo-5-niethylindole as a dark brown oil which solidified on standing.
STEP A. SYNTHESIS OF 4-BROMO-5-METHYLINDOLE Fuming nitric acid (>90% yellow fuming HNO3) is slowly added to a solution of 2- bromo-m-xylene (20 g, 150 mmol) in acetic acid (100 ml) cooled in an ice bath (above freezing point). The resulting mixture is allowed to warm to room temperature, stirred for 1 hour, and heated at 80C for 2 hours or until the reaction is shown to be complete by GC/MS analysis following micro-scale base work-up. The reaction mixture is cooled to room temperature and poured into ice/water with stirring. The resulting yellow precipitates are collected by suction filtration and air dried to obtain 2,6-dimethyl-3-nitrobromobenzene. 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 x 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 0C 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 4h. Zinc is removed by filtration through a celite pad and the filtrate is extracted with dichloromethane (100 ml x 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.
Fuming nitric acid (>90% yellow fuming HN03) is slowly added to a solution of 2-bromo-m-xylene (20 g, 150 mmol) in acetic acid (100 mL) cooled in an ice bath (above freezing point). The resulting mixture is allowed to warm to room temperature, stirred for 1 h, and heated at 80 C for 2 h or until the reaction is complete by GC/MS analysis following micro-scale base work-up. The reaction mixture is cooled to room temperature and poured into ice/water with stirring. The resulting yellow precipitates are collected by suction filtration and air dried to obtain 2,6-dimethyl-3-nitrobromobenzene. Bredereck's reagent (tert-butoxybis(dimethylamino)methane (16 g, 91 mmol) is added to a solution of 2,6-dimethyl-3-nitrobromobenzene (20 g, 87 mmol) in anhydrous DMF (120 mL) at room temperature. The reaction mixture is heated at 120-125 C under N2 for 5 h 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 x 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 used in 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 x 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 as a light purple oil. 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 h. Tributylborate (3.1 mL, 11.4 mmol) is slowly added and the reaction mixture is stirred for 1 h 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 x 3) and the combined extracts are extracted with 1 N sodium hydroxide (20 mL x 4). The combined base extracts are cooled with an ice bath, acidified with 1 M phosphoric acid and extracted with ethyl acetate (20 mL x 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.
With acetic acid; zinc; In water; at 0 - 110℃; for 4h;
Bredereck's reagent (tert-butoxybis(dimethylamino)methane (16 g, 91 mmol) is added to1 a solution of 2,6-dimethyl-3-nitrobromobenzene (20 g, 87 mmol) in anhydrous DMF (120 mL) at room temperature. The reaction mixture is heated at 120-125 C under N2 for 5 h 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 x 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 used in 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 x 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 as a light purple oil.
With acetic acid; zinc; In water; at 0 - 110℃; for 4h;
B. 5-Methy.-4-bromo indole; EPO <DP n="45"/>The crude mixture from examp,e 21 A was dissolved in acetic acid/water (250 mL, 4/1), cooled to 0 0C and treated with zinc dust (5.7 g, 87 mmol) added in small portions. After the addition, the reaction mixture was heated at 110 0C for 4 h. Zinc was removed through a pad of celite and the filtrate was extracted in dichloromethane (100 ml X 3). The combined extracts were dried over sodium sulfate, concentrated and puried by column chromatography using 10% ethyl acetate/methanol.
[2-(2-Bromo-3-methyl-6-nitro-phenyl)-vinyl]-dimethyl-amine (10 g) was dissolved in AcOH /H2O(100mL:25mL), cooled to 0C and treated with Zn (30 g) added slowly in portions. After complete addition, the reaction mixture was heated at 110C overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2S0 and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to afford the title compound (1.4 g, 20 %) 1H NMR CDCI3400 MHz delta 2.47 (m, 3H), 6.50-6.51 (m, 1H), 6.97-6.99 (m, 1 H), 7.12- 7.18(m, 2H), 8.12 (s, 1 H)
1.4 g
With acetic acid; zinc; In water; at 0 - 110℃;
2-(2-Bromo-3-methyl-6-nitro-phenyl)vinyl]-dimethyl-amine (10 g) was dissolved in AcOH/H2O (100 mL:25 mL), cooled to 0 C. and treated with Zn (30 g) added slowly in portions. After complete addition, the reaction mixture was heated at 110 C. overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to afford the title compound (1.4 g, 20%) 1H NMR CDCl3 400 MHz delta 2.47 (m, 3H), 6.50-6.51 (m, 1H), 6.97-6.99 (m, 1H), 7.12-7.18 (m, 2H), 8.12 (s, 1H)
With acetic anhydride; zinc; In water; at 110℃; for 4h;
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 x 3) and the combined extracts are extracted with 1 N sodium hydroxide (20 mL x 4). The combined base extracts are cooled with an ice bath, acidified with 1 M phosphoric acid and extracted with EtOAc (20 mL x 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.
NaH (60% in oil, 81.4 mg, 3.39 mmol) is added to a RT solution of 4-bromo-5-methyl-1 H-indole (500 mg,2.26 mmol) in DMF (5 mL). It is stirred at RT for 20 min and iodomethane (0.156 mL, 2.49 mmol) is added. The RM is stirred at RT for 3h. Water is added, and the mixture is extracted twice with EtOAc. Combined organic layers are washed with brine, dried (MgSCXi), filtered and concentrated under reduced pressure. The residue is purified by FC (heptane:EtOAc, 1 :0 to 7:3), affording the title compound as a beige solid (464 mg, 92%). LC-MS B: tR = 1.02 min; [M+H]+ = 226.2.
STEP B. PREPARATION OF 4-BROMO-1, 5-DIMETHYL-lH-INDOLE A solution of <strong>[610794-15-5]4-bromo-5-methylindole</strong> (3.55g, 16. 9mmol) (21) in 10 ml of anhydrous DMF is added to a suspension of sodium hydride (l. Olg, 60% in mineral oil, 25.3 mmol, 1.5 eq. ) in 10 ml of DMF under nitrogen at 0C. The resulting mixture is stirred at 0C 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 0C. Iodomethane (2.40g, 18.6mmol, 1.1 eq. ) is added dropwise, the mixture is stirred at 0C for 2 hours, and then is warmed to 50C and stirred for an additional 2 hours. The reaction mixture is poured into 100ml of ice-water, extracted with ethyl acetate (30 ml x 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 3.75g of pure compound.'H NMR (400 MHz, CDC13) 8 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+).
With 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); zinc; In 1-methyl-pyrrolidin-2-one; at 145℃; for 18h;
step 3: 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 x 3). The combined extracts were dried (MgS04), filtered, and concentrated to dryness. The crude was purified by S1O2 chromatography eluting with petroleum ether/EtOAc (3:1) to afford54 mg (48.5%) 5-methyl-lH-indole-4-carbonitrile (302) as yellow solid: MS (ESI) m/z = 157.1 (M+l).
ep 2: A mixture of 298 (3.0 g, 13.04 mmol), pyrrolidine (926 mg, 13.04 mmol), and DMF-DMA (7.76 g, 65.22 mmol) in 1,4-dioxane (20 mL) under nitrogen atmosphere was heated at 100 C for 18 h. The reaction was concentrated under to dryness in vacuo and to the residue was added iron (3.65 g, 65.22 mmol) and HO Ac (40 mL). The resulting mixture was heated at 110 C for 4 h, cooled to RT and filtered. The filtrate was concentrated in vacuo. The crude was purified by S1O2 chromatography eluting with petroleum ether/EtOAc (10:1) to afford 150 mg (5.5%) of 4-bromo-5-methyl-lH-indole (300) as a yellow solid: MS (ESI) m/z = 210.1 (M+l).
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