1-bromo-2-(bromomethyl)-4-chlorobenzene

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

Procedure: A mixture of 2-bromo-5-chloro-toluene (2.00 g, 9.75 mmol), NBS (2.08 g, 11.7 mmol) and catalytic amount of AIBN in carbon tetrachloride (50 ml) was stirred under refluxing conditions for 4 h. TLC (EtOAc:hexane=5:95) showed no starting material. The mixture was filtered and the filtrate was concentrated. The title compound was obtained as a white solid after flash column using EtOAc:hexane=5:95 as the elute. 1H NMR (CDCl3, 500 MHz) δ 7.53 (d, J=9.0 Hz, 1H), 7.47 (d, J=2.5 Hz, 1H), 7.18 (dd, J=8.5, 2.5 Hz, 1H), 4.60 (s, 2H). The mixture was filtered the filtrate was concentrated

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N,N-bis(tert-butoxycarbonyl)-2-bromo-5-chlorobenzylamine: To 1-bromo-4-chloro-2-methylbenzene (3.3 g, 16.06 mmol) in CCl4 (30 mL) were added NBS (3.43 g, 19.27 mmol) and benzoyl peroxide (10 mg, 0.041 mmol). The reaction was heated 80° C. overnight, then filtered and purified by flash chromatography to give 1-bromo-2-bromomethyl-4-chloro-benzene (4.5 g). 1HNMR (400 MHz, CDCl3) δ: 4.53 (s, 2 H) 7.15 (dd, J=8.59, 2.27 Hz, 1 H), 7.40-7.47 (m, 1 H), 7.49 (d, J=8.59 Hz, 1 H). This intermediate was combined with di-tert-butyl imidodicarbonate (3.49 g, 16.06 mmol) and cesium carbonate (5.23 g, 16.06 mmol) in DMF (16 mL) and stirred overnight. The reaction was partitioned with EtOAc/water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (MgSO4), and evaporated. The resulting residue was purified by flash chromatography to give 126A (3.4 g). 1HNMR (400 MHz, CDCl3) δ: 1.43-1.51 (m, 18 H), 4.82 (s, 2 H), 7.08-7.18 (m, 1 H), 7.39-7.53 (m, 2 H). filtered purified by flash chromatography

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N,N-bis(tert-butoxycarbonyl)-2-bromo-5-chlorobenzylamine: To 1-bromo-4-chloro-2-methylbenzene (3.3 g, 16.06 mmol) in CCl4 (30 mL) were added NBS (3.43 g, 19.27 mmol) and benzoyl peroxide (10 mg, 0.041 mmol). The reaction was heated 80° C. overnight, then filtered and purified by flash chromatography to give 1-bromo-2-bromomethyl-4-chloro-benzene (4.5 g). 1HNMR (400 MHz, CDCl3) δ: 4.53 (s, 2 H) 7.15 (dd, J=8.59, 2.27 Hz, 1 H), 7.40-7.47 (m, 1 H), 7.49 (d, J=8.59 Hz, 1 H). This intermediate was combined with di-tert-butyl imidodicarbonate (3.49 g, 16.06 mmol) and cesium carbonate (5.23 g, 16.06 mmol) in DMF (16 mL) and stirred overnight. The reaction was partitioned with EtOAc/water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (MgSO4), and evaporated. The resulting residue was purified by flash chromatography to give 126A (3.4 g). 1HNMR (400 MHz, CDCl3) δ: 1.43-1.51 (m, 18 H), 4.82 (s, 2 H), 7.08-7.18 (m, 1 H), 7.39-7.53 (m, 2 H). filtered purified by flash chromatography

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

Procedure: To a stirred solution of 7-hydroxy-1-tetralone (13.9 g, 85.7 mmol) and 1-bromo-2-(bromomethyl)-4-chlorobenzene (25.6 g, 90.0 mmol) in dimethylformamide (850 mL) was added potassium carbonate (24 g, 172 mmol). The reaction was stirred under argon for 18 hours then diluted with ethyl acetate (1 L). The organics were washed three times with water and once with brine. The organic layer was then dried with magnesium sulfate, filtered and concentrated. To the resulting oil was added methanol (500 mL) and the suspension was agitated for thirty minutes. 7-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one (27.8 g, 89% yield) was isolated by filtration. The organics were washed three times with water The organic layer was then dried with magnesium sulfate filtered concentrated To the resulting oil was added methanol (500 mL) the suspension was agitated for thirty minutes

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 1-bromo-2-(bromomethyl)-4-chlorobenzene (1.70 g, 6 mmol) in ACN (10.0 mL) was added p-methoxybenzyl amine (0.91 g, 6.6 mmol) and potassium carbonate (2.08 g, 15.0 mmol) and the overall mixture was stirred at 80° C. overnight. After cooling, the reaction mixture was diluted with water (10 mL) and diluted with EtOAc (15 mL). The separated aqueous layer was extracted with EtOAc (10 mL×2) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a crude residue which was washed with hexanes to obtain the desired product N-(4-methoxybenzyl)(2-bromo-5-chlorophenyl)methanamine as a pale yellow solid. MS m/e 340 (M+H)+. After cooling The separated aqueous layer was extracted with EtOAc (10 mL×2) the combined organic layers were washed with brine dried over Na2SO4 concentrated to give a crude residue which was washed with hexanes

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 1-bromo-2-(bromomethyl)-4-chlorobenzene (1.70 g, 6 mmol) in ACN (10.0 mL) was added p-methoxybenzyl amine (0.91 g, 6.6 mmol) and potassium carbonate (2.08 g, 15.0 mmol) and the overall mixture was stirred at 80° C. overnight. After cooling, the reaction mixture was diluted with water (10 mL) and diluted with EtOAc (15 mL). The separated aqueous layer was extracted with EtOAc (10 mL×2) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a crude residue which was washed with hexanes to obtain the desired product N-(4-methoxybenzyl)(2-bromo-5-chlorophenyl)methanamine as a pale yellow solid. MS m/e 340 (M+H)+. After cooling The separated aqueous layer was extracted with EtOAc (10 mL×2) the combined organic layers were washed with brine dried over Na2SO4 concentrated to give a crude residue which was washed with hexanes

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

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Bromo-5-chlorobenzyl bromide prepared from 2-bromo-5-chlorotoluene (50 g), N-bromosuccinimide and N,N′-azobisisobutyronitrile, and ethyl 1-cyclohexyl-2-(4-hydroxyphenyl)benzimidazole-5-carboxylate (50 g) obtained in Example 3 were suspended in dimethylformamide (300 ml). Potassium carbonate (38 g) was added and the mixture was stirred for 1 hr at 80° C. with heating. The reaction mixture was allowed to cool and then added to a mixed solvent of water-ethyl acetate. The precipitated crystals were collected by filtration to give the title compound (50 g, yield 64%). with heating to cool The precipitated crystals were collected by filtration

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

Procedure: To a stirred solution of 5-hydroxy-1-tetralone (2.0 g, 12.3 mmol) and 1-bromo-2-(bromomethyl)-4-chlorobenzene (3.6 g, 12.7 mmol) in dimethylformamide (125 mL) was added potassium carbonate (3.5 g, 25.1 mmol). The reaction was stirred under argon for 1 hour then diluted with ethyl acetate (1 L). The organics were washed three times with water and once with brine. The organic layer was then dried with magnesium sulfate, filtered and concentrated. To the resulting oil was added methanol (100 mL) and the suspension was agitated for thirty minutes. 5-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1 (2H)-one (4.25 g, 94% yield) was isolated by filtration. The organics were washed three times with water The organic layer was then dried with magnesium sulfate filtered concentrated To the resulting oil was added methanol (100 mL) the suspension was agitated for thirty minutes