1-(3-bromo-4-chlorophenyl)ethanone

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 solution of (R)-1-(3-chlorophenyl)ethanamine 107 (0.701 g, 4.50 mmol), 1-(3-bromo-4-chlorophenyl)ethanone 106 (1.00 g, 4.29 mmol), and triethylamine (1.79 mL, 12.9 mmol) in dry DME was chilled to −78° C. in a dry ice bath. Via syringe, titanium(IV) chloride (4.50 mL, 4.50 mmol) was added dropwise to the reaction mixture. The reaction was warmed to ambient temperature and it was stirred under N2 for 10 h. A solution of sodium cyanoborohydride (0.674 g, 10.7 mmol) in 4 mL of MeOH was then added slowly to the reaction mixture and the reaction solution was stirred for another 3 h. The reaction was quenched by the addition of saturated NH4Cl. The solution was diluted with ether and water, and the mixture was extracted with water (2×) and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography using a 3% to 30% gradient of EtOAc in hexanes as the eluent. The desired fractions were combined and concentrated to give 1-(3-bromo-4-chlorophenyl)-N—((R)-1-(3-chlorophenyl)ethyl)ethanamine 108 (1.04 g, 65.0% yield) as a colorless oil. the reaction solution was stirred for another 3 h The reaction was quenched by the addition of saturated NH4Cl The solution was diluted with ether and water the mixture was extracted with water (2×) and brine The organic layer was dried over MgSO4 filtered concentrated in vacuo The crude material was purified by silica gel chromatography concentrated

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3-bromo-4-chloro-N-methoxy-N-methylbenzamide 105 (2.04 g, 7.3 mmol), was dissolved in 30 mL of dry THF. The solution was chilled to −5° C. in a salt bath under N2. Via syringe, methylmagnesium bromide (2.7 mL, 8.1 mmol) was added slowly to the solution. The solution was stirred for 2 h at −5° C., and then it was warmed to room temperature where it was stirred for another 1 h. The reaction was quenched with saturated NH4Cl, and it was diluted with ether and water. The organic solution was extracted with water and brine. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was then filtered through a bed of silica and the filtrate was concentrated to give 1-(3-bromo-4-chlorophenyl)ethanone 106 (1.55 g, 91% yield) as a white solid. it was warmed to room temperature where it was stirred for another 1 h The reaction was quenched with saturated NH4Cl, and it was diluted with ether and water The organic solution was extracted with water and brine The organic phase was dried over MgSO4 filtered concentrated in vacuo The crude material was then filtered through a bed of silica the filtrate was concentrated

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

Procedure: 5-Bromo-2-methoxytoluene (6.4 g, 0.032 mol) was dissolved in tetrahydrofuran (100 mL) and 5 mL of the solution was added to a stirred mixture of magnesium turnings (0.90 g, 0.037 mol) and iodine (a catalytic amount) in tetrahydrofuran (10 mL). The mixture was heated to vigorous reflux until some of the iodine colour was lost. The flask was removed from the heat and the remainder of the bromide was added so as to maintain a gentle reflux. The flask was then returned to the heat and stirred at reflux for 2 hours. The flask was removed from the heat and a solution of 1-(3-bromo-4-chlorophenyl)-ethanone (7.1 g, 0.030 mol) in tetrahydrofuran (100 mL) was added so as to maintain a gentle reflux. The reaction mixture was returned to the heat and stirred at reflux for 3 hours then cooled to room temperature and poured into ice-water (300 mL). The mixture was stirred for 5 minutes then concentrated to remove tetrahydrofuran. The aqueous residue was diluted with aqueous ammonium chloride (100 mL), extracted with ethyl acetate (3 200 mL) and the combined organic extracts were washed with water (100 mL) and brine (100 mL), dried (sodium sulfate) and concentrated to give the crude product as a red oil which was purified by flash chromatography (5 to 10% ethyl acetate/hexane) to give the desired alcohol as a bright yellow oil (6.7 g, 71%). 1H NMR (300 MHz; CDCl3) 7.72 (1H, d, J 2.1, Ar), 7.35 (1H, d, 8.5, Ar), 7.23-7.13 (3H, m, Ar), 6.76 (1H, d, J 8.5, Ar), 3.82 (3H, s, OMe), 2.19 (3H, s, Me), 2.11 (1H, s, OH), 1.88 (3H, s, Me). The mixture was heated The flask was removed from the heat the remainder of the bromide was added so as to maintain a gentle reflux heat at reflux for 2 hours The flask was removed from the heat to maintain a gentle reflux heat stirred at reflux for 3 hours The mixture was stirred for 5 minutes then concentrated to remove tetrahydrofuran The aqueous residue was diluted with aqueous ammonium chloride (100 mL) extracted with ethyl acetate (3 200 mL) the combined organic extracts were washed with water (100 mL) and brine (100 mL) dried (sodium sulfate) concentrated to give the crude product as a red oil which was purified by flash chromatography (5 to 10% ethyl acetate/hexane)