1-(3-bromophenyl)-N-methylmethanamine

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

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

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

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 7-bromo-4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline (500 mg, 1.35 mmol) which was prepared following similar method described in Steps A to C of Example 1 starting from 2-bromo-1-(3,4-dichlorophenyl)ethanone and 1-(3-bromophenyl)-N-methylmethanamine, pyridin-2-ol (154 mg, 1.62 mmol), N,N′-dimethylethylene diamine (58 μl, 0.54 mmol), and potassium phosphate (572 mg, 2.69 mmol) in 1,4-dioxane (5 mL) was added copper(1) iodide (51 mg, 0.27 mmol). The mixture was degassed with argon and then heated to 110° C. for 17 hours. The reaction mixture was diluted with water (20 mL) and extracted with methylene chloride (2×25 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was partially purified by column chromatography (methylene chloride to 90:9:1 methylene chloride/methanol/ammonium hydroxide) to give 1-(4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridin-2(1H)-one (37 mg, 7%): ESI MS m/z 385 [M+H]+. was prepared The mixture was degassed with argon The reaction mixture was diluted with water (20 mL) extracted with methylene chloride (2×25 mL) The combined organics were dried over sodium sulfate filtered concentrated in vacuo The residue was partially purified by column chromatography (methylene chloride to 90:9:1 methylene chloride/methanol/ammonium hydroxide)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 7-bromo-4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline (500 mg, 1.35 mmol) which was prepared following similar method described in Steps A to C of Example 1 starting from 2-bromo-1-(3,4-dichlorophenyl)ethanone and 1-(3-bromophenyl)-N-methylmethanamine, pyridin-2-ol (154 mg, 1.62 mmol), N,N′-dimethylethylene diamine (58 μl, 0.54 mmol), and potassium phosphate (572 mg, 2.69 mmol) in 1,4-dioxane (5 mL) was added copper(1) iodide (51 mg, 0.27 mmol). The mixture was degassed with argon and then heated to 110° C. for 17 hours. The reaction mixture was diluted with water (20 mL) and extracted with methylene chloride (2×25 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was partially purified by column chromatography (methylene chloride to 90:9:1 methylene chloride/methanol/ammonium hydroxide) to give 1-(4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridin-2(1H)-one (37 mg, 7%): ESI MS m/z 385 [M+H]+. was prepared The mixture was degassed with argon The reaction mixture was diluted with water (20 mL) extracted with methylene chloride (2×25 mL) The combined organics were dried over sodium sulfate filtered concentrated in vacuo The residue was partially purified by column chromatography (methylene chloride to 90:9:1 methylene chloride/methanol/ammonium hydroxide)

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

Procedure: To a solution of (3-bromo-benzyl)-methyl-amine (3.0 g, 15.0 mmol) in methylene chloride (60 mL) was added diisopropylethylamine (5.2 mL, 30.0 mmol). The reaction mixture was cooled to 0° C. and treated with 2-bromo-1-p-tolyl-ethanone (3.19 g, 15.0 mmol) portionwise over a period of 10 minutes. The reaction mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was washed with water (3×), dried over sodium sulfate, filtered, and the solvent was evaporated to afford 2-((3-bromobenzyl)(methyl)amino)-1-p-tolylethanone (4.89 g, 98%) as a viscous, orange oil: 1H NMR (CDCl3, 500 MHz) δ 7.85 (d, J=8.2 Hz, 2H), 7.51 (br s, 1H), 7.38 (d, J=7.9 Hz, 1H), 7.28-7.23 (m, 3H), 7.17 (t, J=7.8 Hz, 1H), 3.78 (s, 2H), 3.63 (s, 2H), 2.41 (s, 3H), 2.35 (s, 3H). The reaction mixture was warmed to room temperature The reaction mixture was washed with water (3×) dried over sodium sulfate filtered the solvent was evaporated

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

Procedure: To a solution of (3-bromo-benzyl)-methyl-amine (3.0 g, 15.0 mmol) in methylene chloride (60 mL) was added diisopropylethylamine (5.2 mL, 30.0 mmol). The reaction mixture was cooled to 0° C. and treated with 2-bromo-1-p-tolyl-ethanone (3.19 g, 15.0 mmol) portionwise over a period of 10 minutes. The reaction mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was washed with water (3×), dried over sodium sulfate, filtered, and the solvent was evaporated to afford 2-((3-bromobenzyl)(methyl)amino)-1-p-tolylethanone (4.89 g, 98%) as a viscous, orange oil: 1H NMR (CDCl3, 500 MHz) δ 7.85 (d, J=8.2 Hz, 2H), 7.51 (br s, 1H), 7.38 (d, J=7.9 Hz, 1H), 7.28-7.23 (m, 3H), 7.17 (t, J=7.8 Hz, 1H), 3.78 (s, 2H), 3.63 (s, 2H), 2.41 (s, 3H), 2.35 (s, 3H). The reaction mixture was warmed to room temperature The reaction mixture was washed with water (3×) dried over sodium sulfate filtered the solvent was evaporated

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

Procedure: 1-(3-Bromophenyl)-N-methylmethanamine (0.100 g, 0.5 mmol) in DCM (5 mL) was added TEA (0.139 mL, 1.000 mmol) and 3-(chlorosulfonyl)benzoic acid (0.110 g, 0.500 mmol). The resulting mixture was stirred at room temperature for 0.5 h. The reaction was quenched with HCl (1 N), concentrated and redissolved in EtOAc (10 mL) which was washed with H2O (2×3 mL), brine (3 mL), then dried with Na2SO4. It was then filtered and concentrated to afford the title compound (0.1505 g, 78%). LC-MS m/z 384 (M+H)+. The reaction was quenched with HCl (1 N) concentrated redissolved in EtOAc (10 mL) which was washed with H2O (2×3 mL), brine (3 mL) dried with Na2SO4 It was then filtered concentrated

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

Procedure: To a DMF (0.1 M) solution of 3-bromo-N-methylbenzylamine (1 eq.), Hunig's base (3 eq) and 4-(dimethylamino)pyridine (5% loading) was added acetyl chloride (1.5 eq). The resulting reaction mixture was stirred at RT for 16 h. After quenching the reaction with sat. aq. NaHCO3, the mixture was extracted with EtOAc. The organic extract was washed with 10% aq. HCl, sat. aq. NaHCO3, and brine. Drying over Na2SO4, filtration and concentration of the filtrate in vacuo afforded the crude product as a yellow oil. Purification by way of flash chromatography (SiO2, 4:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a yellow oil. The resulting reaction mixture After quenching the reaction with sat. aq. NaHCO3 the mixture was extracted with EtOAc The organic extract was washed with 10% aq. HCl, sat. aq. NaHCO3, and brine Drying over Na2SO4, filtration and concentration of the filtrate in vacuo afforded the crude product as a yellow oil Purification by way of flash chromatography (SiO2, 4:1 (v/v) Hex:EtOAc→EtOAc)

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

Procedure: To a solution of 1-benzyl-4-oxo-pyrrolidine-2-carboxylic acid methyl ester (1 mmol), (3-bromo-benzyl)-methyl-amine (1 mmol) in 2 mL of CH2Cl2 were added NaBH(OAc)3 (2 mmol) and 5 drops of AcOH, and the resulting mixture was stirred for 3 h. The mixture was treated with aq. NaHCO3, extracted by CH2Cl2 (3×5 mL), and the combined extracts were washed by brine (10 mL), dried over Na2SO4, and concentrated to give 261.3 mg of crude product in 65% yield. extracted by CH2Cl2 (3×5 mL) the combined extracts were washed by brine (10 mL) dried over Na2SO4 concentrated

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

Procedure: To a solution of 1-benzyl-4-oxo-pyrrolidine-2-carboxylic acid methyl ester (1 mmol), (3-bromo-benzyl)-methyl-amine (1 mmol) in 2 mL of CH2Cl2 were added NaBH(OAc)3 (2 mmol) and 5 drops of AcOH, and the resulting mixture was stirred for 3 h. The mixture was treated with aq. NaHCO3, extracted by CH2Cl2 (3×5 mL), and the combined extracts were washed by brine (10 mL), dried over Na2SO4, and concentrated to give 261.3 mg of crude product in 65% yield. extracted by CH2Cl2 (3×5 mL) the combined extracts were washed by brine (10 mL) dried over Na2SO4 concentrated

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