6-BROMO-1-METHYL-1H-INDOLE 97

A 1 -round-bottom flask was charged with 6-bromo-lH-indole (14.88 g, 76 mmol) and THF (150 ml) to give a dark maroon solution. The flask was put under a 2 sweep, and sodium hydride (60 wtpercent) (3.64 g, 91 mmol) was added in several portions over 15 min. The resulting mixture was stirred for 20 min, then iodomethane (5.94 ml, 95 mmol) was added via syringe. Within a few minutes, an exotherm was observed. After stirring for 20 min, the mixture was concentrated in vacuo, and the residue was taken up in saturated aq. sodium bicarbonate solution and extracted with DCM (3x). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (0 to 40percent EtO Ac/Heptane) to afford 6-bromo-l -methyl- lH-indole (14.44 g, 68.7 mmol, 91 percent yield) as a lightly colored oil. To a solution of 6-bromo-1H-indole (3.00 g, 15.3 mmol) in DMF (30 mL), NaH (60percent, 734 mg, 18.4 mmol) was added in an ice-water bath, and the mixture was stirred at this temperature for 20 minutes. Then a solution of MeI (1.14 mL, 18.4 mmol) in DMF (10 mL) was added dropwise, and the mixture was stirred at this temperature for 30 minutes. 100 mL of water was added, and the reaction solution was extracted with EtOAc. The EtOAc phase was washed several times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: pure PE) to obtain the title compound 6-bromo-1-methyl-1H-indole (2.70 g, 84 percent).To a suspension of 60percent NaH (3.61 g, 90.3 mmol) in dry DMF (150 mE) was added 6-bromoindole (11.8 g, 60.191 mmol) at 0° C. in portions. Caution: gas evolved. The inner temperature rose to 7° C. The mixture was re-cooled to 0° C. To the resulting red suspension was stirred at 0° C. for 3 h. CH3I (3.26 g, 23 mmol) was added dropwise at 0° C.-5° C. The reaction suspension was stirred at room temperature (25° C.) for 2 h. TEC (petroleum ether/EtOAc=8/i) showed most of the starting material was consumed and a good spot was formed. The mixture was poured into ice water (200 mE) and extracted with petroleum ether (100 mEx3). The extract was washed with brine (100 mE), dried over Na2 SO4 and concentrated in vacuo to dryness to afford crude (15 g). The crude was purified by silica gel chromatography eluted with EtOAc in petroleum ether from 0 to 10percent to afford J-2 (10 g, 79.1percent) as a slight yellow oil. ‘H NMR (400 MHz, CDC13) ö ppm 7.49-7.47 (m, 2H), 7.22 (d, 1H), 7.03 (d, 1H), 6.46 (d, 1H), 3.76 (s, 3H).A mixture of 6-bromo-1H-indole (5 g, 25.50 mmol, 1.00 equiv), Ka) 6-bromo-l -methyl- lH-indoleA solution of 6-bromo-l H-indole (1.530 mmol) in dimethyl sulfoxide (10 mL) was treated with potassium carbonate (4.59 mmol) and was stirred at room temperature for 30 min. The solution was then treated with methyl iodide (1.683 mmol) and was stirred at room temperature overnight. The solution was diluted with water (100 mL) and was extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (hexanes) to provide the titlecompound as a yellow oil (62percent). 1H NMR (400 MHz, DMSO-dExample 29 A 1 -round-bottom flask was charged with 6-bromo-lH-indole (14.88 g, 76 mmol) and THF (150 ml) to give a dark maroon solution. The flask was put under a 2 sweep, and sodium hydride (60 wt%) (3.64 g, 91 mmol) was added in several portions over 15 min. The resulting mixture was stirred for 20 min, then iodomethane (5.94 ml, 95 mmol) was added via syringe. Within a few minutes, an exotherm was observed. After stirring for 20 min, the mixture was concentrated in vacuo, and the residue was taken up in saturated aq. sodium bicarbonate solution and extracted with DCM (3x). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (0 to 40% EtO Ac/Heptane) to afford 6-bromo-l -methyl- lH-indole (14.44 g, 68.7 mmol, 91 % yield) as a lightly colored oil. .H NMR (400MHz, CDC13) delta = 7.51 - 7.46 (m, 2 H), 7.24 - 7.19 (m, 1 H), 7.03 (d, J = 3.1 Hz, 1 H), 6.47 (dd, J = 0.9, 3.1 Hz, 1 H), 3.77 (s, 3 H).To a solution of 6-bromo-1H-indole (3.00 g, 15.3 mmol) in DMF (30 mL), NaH (60%, 734 mg, 18.4 mmol) was added in an ice-water bath, and the mixture was stirred at this temperature for 20 minutes. Then a solution of MeI (1.14 mL, 18.4 mmol) in DMF (10 mL) was added dropwise, and the mixture was stirred at this temperature for 30 minutes. 100 mL of water was added, and the reaction solution was extracted with EtOAc. The EtOAc phase was washed several times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: pure PE) to obtain the title compound To a suspension of 60% NaH (3.61 g, 90.3 mmol) in dry DMF (150 mE) was added 6-bromoindole (11.8 g, 60.191 mmol) at 0 C. in portions. Caution: gas evolved. The inner temperature rose to 7 C. The mixture was re-cooled to 0 C. To the resulting red suspension was stirred at 0 C. for 3 h. CH3I (3.26 g, 23 mmol) was added dropwise at 0 C.-5 C. The reaction suspension was stirred at room temperature (25 C.) for 2 h. TEC (petroleum ether/EtOAc=8/i) showed most of the starting material was consumed and a good spot was formed. The mixture was poured into ice water (200 mE) and extracted with petroleum ether (100 mEx3). The extract was washed with brine (100 mE), dried over Na2 SO4 and concentrated in vacuo to dryness to afford crude (15 g). The crude was purified by silica gel chromatography eluted with EtOAc in petroleum ether from 0 to 10% to afford J-2 (10 g, 79.1%) as a slight yellow oil. 'H NMR (400 MHz, CDC13) oe ppm 7.49-7.47 (m, 2H), 7.22 (d, 1H), 7.03 (d, 1H), 6.46 (d, 1H), 3.76 (s, 3H).A mixture of 6-bromo-1H-indole (5 g, 25.50 mmol, 1.00 equiv), K2CO3 (7 g, 50.65 mmol, 2.00 equiv), and CH3I (7.3 g, 51.43 mmol, 2.00 equiv) in acetone (100 mL) was stirred for 16 h at 55 C., then cooled to rt, diluted with 100 mL H2O, and extracted with 2×200 mL of EtOAc. The combined organic layers were washed with 100 mL of brine, dried over Na2SO4, concentrated under vacuum, and purified with silica gel chromatography using EtOAc/petroleum ether (1:10) to afford 3.4 g (63%) of the title compound as a yellow oil. LC-MS: (ES, m/z): 208. 1H NMR (300 MHz, DMSO-d6) delta 7.69 (dt, J=1.6, 0.7 Hz, 1H), 7.49 (dd, J=8.4, 0.6 Hz, 1H), 7.34 (d, J=3.1 Hz, 1H), 7.13 (dd, J=8.4, 1.8 Hz, 1H), 6.43 (dd, J=3.1, 0.9 Hz, 1H), 3.77 (s, 3H).a) 6-bromo-l -methyl- lH-indoleA solution of 6-bromo-l H-indole (1.530 mmol) in dimethyl sulfoxide (10 mL) was treated with potassium carbonate (4.59 mmol) and was stirred at room temperature for 30 min. The solution was then treated with methyl iodide (1.683 mmol) and was stirred at room temperature overnight. The solution was diluted with water (100 mL) and was extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (hexanes) to provide the titlecompound as a yellow oil (62%). 1H NMR (400 MHz, DMSO-d6) delta ppm 7.70 (s, 1 H) 7.50 (d, J=8.34 Hz, 1 H) 7.35 (d, J=3.03 Hz, 1 H) 7.14 (dd, J=8.34, 1.77 Hz, 1 H) 6.44 (d, J=3.03 Hz, 1 H) 3.78 (s, 3 H).Step 1 6-Bromo-1-methyl-1H-indole A solution of 6-bromo-1H-indole (2.34 g, 11.9 mmol) in dry THF (25 mL) was cooled in an ice bath. Sodium hydride (1.12 g of 60% dispersion in oil, 28.0 mmol) was added. The mixture was stirred for 30 minutes under nitrogen at room temperature, then cooled in an ice bath. Iodomethane (1.6 mL, 26 mmol) was added. The reaction mixture was stirred for 2 hours at room temperature, poured into excess water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was purified by flash chromatography using hexane as an eluant to yield (a) 6-Bromo-1-methylindole STR25 Sodium hydride (4.10 g of a 60% dispersion in paraffin wax) was added to a stirred solution of 6-bromoindole (10 g, 51.3 mmol) in tetrahydrofuran (10 ml) at 0 C. under a nitrogen atmosphere. After 1 hour iodomethane (6.38 ml, 102.6 mmol) was added and the cooling bath removed. After 12 hours methanol was added dropwise until effervescence ceased and then the solvent was removed in vacuo. The thick residue was diluted with dichloromethane and washed first with water then with brine. The organic layer was dried (magnesium sulphate) and concentrated in vacuo to give a dark yellow oil. Filtration through a plug of silica with 90% hexane/10% ethyl acetate as eluant gave the subtitle compound as a pale yellow oil (10.5 g). 1 H NMR (300 MHz, CDCl3): delta=3.75 (d, 3 H), 6.40 (d, 1 H), 7.00 (d, 1 H), 7.20 (d, 1 H), 7.50 (d, 1 H), 7.45 (s, 1 H). LRMS (Thermospray): 209.7 (MH+)To a stirred suspension of 60% sodium hydride (4.88 g, 122 mmol) in tetrahydrofuran (1 50 mL) was added 6-bromoindole (1 5.0 g, 76.5 mmol) portionwise, followed by methyl iodide (1 1.9 g, 83.8 mmol) dropwise and the mixture stirred at room temperature for 16 h. After this time, the reaction was poured into ice-cold water and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed sequentially with water, then brine and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate concentrated under reduced pressure to afford 6-bromo-l -methyl -1 H-indole as a pale red solid: NMR (400 MHz, CDC13) d 7.49 (m, 2H), 7.22 (dd, J = 8.0, 1.6 Hz, 1 H), 7.04 (d, J = 3.2 Hz, 1 H), 6.47 (d, J = 3.2 Hz, 1 H), 3.77 (s, 3H).Preparation of General procedure: To a solution of indoles 1a-i (10mmol) in dry tetrahydrofuran (THF; 25mL), NaH (30mmol) was added. After the mixture was stirred 30min, CH3I (30mmol) in 5mL THF was added dropwise under 0C. The reaction mixture was stirred at room temperature for 12h in the dark. Then the reaction mixture was cooled to room temperature, diluted with 30mL saturated NH4Cl solution, and extracted with EtOAc (3×30mL). The organic layer dried over anhydrous MgSO4 and concentrated in vacuo. The pure products 2a-i was obtained by column chromatography on silica gel (Petroleum ether/EtOAc=20:1) with yield of 90%-99%.General procedure: To a solution of indole (1.17 g, 10 mmol) and potassium hydroxide (2.8 g, 50 mmol) in anhydrous DMF (20 ml) was added iodomethane (2.13 g, 15 mmol). The reaction mixture was stirred at room temperature for 2 h. Then H2O was added to the mixture. The water layer was extracted with EtOAc (50 ml * 3). The organic layer was combined and dried over Na2SO4. After filtration and evaporation, the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 8/1) to afford N-methyl-1H-indole (1.24 g, 94%).

Molecular Weight:210.07
XLogP3:3.4
Exact Mass:208.98401
Monoisotopic Mass:208.98401
Topological Polar Surface Area:4.9
Heavy Atom Count:11
Complexity:149
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes