3-(4-bromophenyl)-1-cyclohexylpropan-1-one

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: To a solution of 2.84 g 3-(4-bromophenyl)-1-cyclohexylpropan-1-one from Step B above in 50 mL anhydrous THF was added 1.15 g 60% sodium hydride followed by one 6.2 mL and five 3.2 mL portions of ethyl formate over one day. The resulting mixture was stirred at room temperature under nitrogen for another day. The solvent was removed under reduced pressure and the residue was partitioned between cold 0.1 N HCl and ether. The combined ether extract was washed with water (2×), 5% NaHCO3 (3×), water, and saturated brine, dried over anhydrous Na2SO4, and evaporated to give crude product as orange solid. It was purified on silica gel using 10˜15% EtOAc in hexanes to give the title compounds as pink oily solid. 1H NMR (CDCl3, 500 MHz) δ 15.43 (d, J=7.1 Hz, 1H), 8.01 (d, J=7.1 Hz, 1H), 7.43˜7.45 (m, 2H), 7.07 (d, J=8.3 Hz, 2H), 3.52 (s, 2H), 2.32 (tt, J=11.5 & Hz, 1H), 1.73˜1.77 (m, 2H), 1.63˜1.68 (m, 1H), 1.49˜1.53 (m, 2H), 1.39˜1.47 (m, 2H), 1.07˜1.25 (m, 4H). The solvent was removed under reduced pressure the residue was partitioned between cold 0.1 N HCl and ether The combined ether extract was washed with water (2×), 5% NaHCO3 (3×), water, and saturated brine dried over anhydrous Na2SO4 evaporated to give crude product as orange solid It was purified on silica gel using 10˜15% EtOAc in hexanes

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

Procedure: To a solution of 25.02 g 3-(4-Bromophenyl)-N-methoxy-N-methylpropanamide from Step A above in 500 mL anhydrous ether cooled in an ice bath was added 115 mL 2 M cyclohexylmagnesium bromide in ether over 30 minutes. The cooling bath was removed after finishing addition. After 75 minutes, an additional 30 mL 2 M cyclohexylmagnesium bromide in ether was added. The reaction mixture was stirred for 40 minutes and poured into a mixture containing 500 mL ether, 500 mL cold water, 200 mL saturated brine, and 175 mL 2 N HCl. The layers were separated. The aqueous layer was extracted with 4×75 mL ether. The combined ether solution was washed with 200 mL 1:1 5% NaHCO3 and saturated brine followed by 200 mL saturated brine, dried over anhydrous Na2SO4, and evaporated to give a crude product. It was purified on silica gel using 20-100% EtOAc in hexanes and re-purified using 5-10% EtOAc in hexanes to give the title compound as yellow oil. 1H NMR (CDCl3, 500 MHz) δ 7.39˜7.42 (m, 2H), 7.06˜7.09 (m, 2H), 2.84˜2.87 (m, 2H), 2.74˜2.78 (m, 2H), 2.32 (tt, J=3.3 & 11.3 Hz, 1H), 1.76˜1.84 (m, 4H), 1.65˜1.70 (m, 1H), 1.15˜1.36 (m, 5H). The cooling bath was removed addition an additional 30 mL 2 M cyclohexylmagnesium bromide in ether was added poured into a mixture containing 500 mL ether, 500 mL cold water, 200 mL saturated brine, and 175 mL 2 N HCl The layers were separated The aqueous layer was extracted with 4×75 mL ether The combined ether solution was washed with 200 mL 1:1 5% NaHCO3 and saturated brine dried over anhydrous Na2SO4 evaporated to give a crude product It was purified on silica gel using 20-100% EtOAc in hexanes re-purified

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

Procedure: To a solution of 2.84 g 3-(4-bromophenyl)-1-cyclohexylpropan-1-one from Step B above in 50 mL anhydrous THF was added 1.15 g 60% sodium hydride followed by one 6.2 mL and five 3.2 mL portions of ethyl formate over one day. The resulting mixture was stirred at room temperature under nitrogen for another day. The solvent was removed under reduced pressure and the residue was partitioned between cold 0.1 N HCl and ether. The combined ether extract was washed with water (2×), 5% NaHCO3 (3×), water, and saturated brine, dried over anhydrous Na2SO4, and evaporated to give crude product as orange solid. It was purified on silica gel using 10˜15% EtOAc in hexanes to give the title compounds as pink oily solid. 1H NMR (CDCl3, 500 MHz) δ 15.43 (d, J=7.1 Hz, 1H), 8.01 (d, J=7.1 Hz, 1H), 7.43˜7.45 (m, 2H), 7.07 (d, J=8.3 Hz, 2H), 3.52 (s, 2H), 2.32 (tt, J=11.5 & Hz, 1H), 1.73˜1.77 (m, 2H), 1.63˜1.68 (m, 1H), 1.49˜1.53 (m, 2H), 1.39˜1.47 (m, 2H), 1.07˜1.25 (m, 4H). The solvent was removed under reduced pressure the residue was partitioned between cold 0.1 N HCl and ether The combined ether extract was washed with water (2×), 5% NaHCO3 (3×), water, and saturated brine dried over anhydrous Na2SO4 evaporated to give crude product as orange solid It was purified on silica gel using 10˜15% EtOAc in hexanes

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

Procedure: To a solution of 25.02 g 3-(4-Bromophenyl)-N-methoxy-N-methylpropanamide from Step A above in 500 mL anhydrous ether cooled in an ice bath was added 115 mL 2 M cyclohexylmagnesium bromide in ether over 30 minutes. The cooling bath was removed after finishing addition. After 75 minutes, an additional 30 mL 2 M cyclohexylmagnesium bromide in ether was added. The reaction mixture was stirred for 40 minutes and poured into a mixture containing 500 mL ether, 500 mL cold water, 200 mL saturated brine, and 175 mL 2 N HCl. The layers were separated. The aqueous layer was extracted with 4×75 mL ether. The combined ether solution was washed with 200 mL 1:1 5% NaHCO3 and saturated brine followed by 200 mL saturated brine, dried over anhydrous Na2SO4, and evaporated to give a crude product. It was purified on silica gel using 20˜100% EtOAc in hexanes and re-purified using 5˜10% EtOAc in hexanes to give the title compound as yellow oil. 1H NMR (CDCl3, 500 MHz) δ 7.39˜7.42 (m, 2H), 7.06˜7.09 (m, 2H), 2.84˜2.87 (m, 2H), 2.74˜2.78 (m, 2H), 2.32 (tt, J=3.3 & 11.3 Hz, 1H), 1.76˜1.84 (m, 4H), 1.65˜1.70 (m, 1H), 1.15˜1.36 (m, 5H). The cooling bath was removed addition an additional 30 mL 2 M cyclohexylmagnesium bromide in ether was added poured into a mixture containing 500 mL ether, 500 mL cold water, 200 mL saturated brine, and 175 mL 2 N HCl The layers were separated The aqueous layer was extracted with 4×75 mL ether The combined ether solution was washed with 200 mL 1:1 5% NaHCO3 and saturated brine dried over anhydrous Na2SO4 evaporated to give a crude product It was purified on silica gel using 20˜100% EtOAc in hexanes re-purified