Dimethyl 2-(4-bromobenzyl)malonate

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of dimethyl 2-(4-bromobenzyl)malonate (22 g, 73.33 mmol, 1.00 equiv) and potassium hydroxide (12.3 g, 219.64 mmol, 3.00 equiv) in ethanol (140 mL) and water (140 mL) was stirred at 60° C. overnight. The resulting solution was diluted with 300 mL of ice and water then extracted with 1×500 mL of ethyl acetate. The organic layer was washed with 2×150 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 18.2 g (91%) of 2-(4-bromobenzyl)malonic acid as a white solid. then extracted with 1×500 mL of ethyl acetate The organic layer was washed with 2×150 mL of brine dried over anhydrous sodium sulfate concentrated under vacuum

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of dimethyl malonate (42.6 g, 322.73 mmol, 4.00 equiv) and potassium carbonate (22.3 g, 161.59 mmol, 2.00 equiv) in N,N-dimethylformamide (200 mL) was stirred for 30 min at 50° C. A solution of 1-bromo-4-(bromomethyl)benzene (20 g, 80.65 mmol, 1.00 equiv) in N,N-dimethylformamide (80 mL) was then added dropwise with stirring to the reaction mixture. The resulting solution was stirred at 50° C. for 2 h. Water (100 mL) was added and the mixture was extracted with 1×400 mL of ethyl acetate. The organic layer was washed with 2×100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 22 g (91%) of dimethyl 2-(4-bromobenzyl)malonate as a white solid. LC-MS: (ES, m/z): 301 [M+H]+, 126, 120. with stirring to the reaction mixture The resulting solution was stirred at 50° C. for 2 h the mixture was extracted with 1×400 mL of ethyl acetate The organic layer was washed with 2×100 mL of brine dried over anhydrous sodium sulfate concentrated under vacuum

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of dimethyl 2-(4-bromobenzyl)malonate (4.2 g), 1-(bromomethyl)-4-(diethoxymethyl)benzene (4 g) in DMF (50 mL) was treated with NaH (0.8 g, 60% in mineral oil). The mixture was stirred for 2 h at 60° C., and then quenched with 100 mL of 50% saturated NH4Cl. The product was extracted with 200 mL of 2:1 hexane/EtOAc. The extract was dried over Na2SO4 and concentrated, and dried under vacuum to give the title compound which was used without further purification. quenched with 100 mL of 50% saturated NH4Cl The product was extracted with 200 mL of 2:1 hexane/EtOAc The extract was dried over Na2SO4 concentrated dried under vacuum

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

Procedure: A solution of dimethyl malonate (13.2 g), 4-bromobenzylbromide (5.4 g) in DMF (200 mL) was treated with NaH (4 g, 60% in mineral oil). The mixture was stirred for 5 min at 0° C. and 20 min at room temperature and then quenched with 10 mL of AcOH slowly. The mixture was concentrated under vacuum and the residue was dissolved in 200 mL of 1:1 EtOAc/hexane, and filtered through a pad of silica gel. The filtrate was concentrated and the excess dimethyl malonate was removed under vacuum at 70° C. to provide the title compound as a yellow oil. quenched with 10 mL of AcOH slowly The mixture was concentrated under vacuum the residue was dissolved in 200 mL of 1:1 EtOAc/hexane filtered through a pad of silica gel The filtrate was concentrated the excess dimethyl malonate was removed under vacuum at 70° C.

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

Procedure: A solution of dimethyl malonate (13.2 g), 4-bromobenzylbromide (5.4 g) in DMF (200 mL) was treated with NaH (4 g, 60% in mineral oil). The mixture was stirred for 5 min at 0° C. and 20 min at room temperature and then quenched with 10 mL of AcOH slowly. The mixture was concentrated under vacuum and the residue was dissolved in 200 mL of 1:1 EtOAc/hexane, and filtered through a pad of silica gel. The filtrate was concentrated and the excess dimethyl malonate was removed under vacuum at 70° C. to provide the title compound as a yellow oil. quenched with 10 mL of AcOH slowly The mixture was concentrated under vacuum the residue was dissolved in 200 mL of 1:1 EtOAc/hexane filtered through a pad of silica gel The filtrate was concentrated the excess dimethyl malonate was removed under vacuum at 70° C.

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of dimethyl 2-(4-bromobenzyl)malonate (22 g, 73.33 mmol, 1.00 equiv) and potassium hydroxide (12.3 g, 219.64 mmol, 3.00 equiv) in ethanol (140 mL) and water (140 mL) was stirred at 60° C. overnight. The resulting solution was diluted with 300 mL of ice and water then extracted with 1×500 mL of ethyl acetate. The organic layer was washed with 2×150 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 18.2 g (91%) of 2-(4-bromobenzyl)malonic acid as a white solid. then extracted with 1×500 mL of ethyl acetate The organic layer was washed with 2×150 mL of brine dried over anhydrous sodium sulfate concentrated under vacuum

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of dimethyl malonate (42.6 g, 322.73 mmol, 4.00 equiv) and potassium carbonate (22.3 g, 161.59 mmol, 2.00 equiv) in N,N-dimethylformamide (200 mL) was stirred for 30 min at 50° C. A solution of 1-bromo-4-(bromomethyl)benzene (20 g, 80.65 mmol, 1.00 equiv) in N,N-dimethylformamide (80 mL) was then added dropwise with stirring to the reaction mixture. The resulting solution was stirred at 50° C. for 2 h. Water (100 mL) was added and the mixture was extracted with 1×400 mL of ethyl acetate. The organic layer was washed with 2×100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 22 g (91%) of dimethyl 2-(4-bromobenzyl)malonate as a white solid. LC-MS: (ES, m/z): 301 [M+H]+, 126, 120. with stirring to the reaction mixture The resulting solution was stirred at 50° C. for 2 h the mixture was extracted with 1×400 mL of ethyl acetate The organic layer was washed with 2×100 mL of brine dried over anhydrous sodium sulfate concentrated under vacuum

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of dimethyl 2-(4-bromobenzyl)malonate (22 g, 73.33 mmol, 1.00 equiv) and potassium hydroxide (12.3 g, 219.64 mmol, 3.00 equiv) in ethanol (140 mL) and water (140 mL) was stirred at 60° C. overnight. The resulting solution was diluted with 300 mL of ice and water then extracted with 1×500 mL of ethyl acetate. The organic layer was washed with 2×150 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 18.2 g (91%) of 2-(4-bromobenzyl)malonic acid as a white solid. then extracted with 1×500 mL of ethyl acetate The organic layer was washed with 2×150 mL of brine dried over anhydrous sodium sulfate concentrated under vacuum

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of dimethyl malonate (42.6 g, 322.73 mmol, 4.00 equiv) and potassium carbonate (22.3 g, 161.59 mmol, 2.00 equiv) in N,N-dimethylformamide (200 mL) was stirred for 30 min at 50° C. A solution of 1-bromo-4-(bromomethyl)benzene (20 g, 80.65 mmol, 1.00 equiv) in N,N-dimethylformamide (80 mL) was then added dropwise with stirring to the reaction mixture. The resulting solution was stirred at 50° C. for 2 h. Water (100 mL) was added and the mixture was extracted with 1×400 mL of ethyl acetate. The organic layer was washed with 2×100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 22 g (91%) of dimethyl 2-(4-bromobenzyl)malonate as a white solid. LC-MS: (ES, m/z): 301 [M+H]+, 126, 120. with stirring to the reaction mixture The resulting solution was stirred at 50° C. for 2 h the mixture was extracted with 1×400 mL of ethyl acetate The organic layer was washed with 2×100 mL of brine dried over anhydrous sodium sulfate concentrated under vacuum

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of dimethyl 2-(4-bromobenzyl)malonate (4.2 g), 1-(bromomethyl)-4-(diethoxymethyl)benzene (4 g) in DMF (50 mL) was treated with NaH (0.8 g, 60% in mineral oil). The mixture was stirred for 2 h at 60° C., and then quenched with 100 mL of 50% saturated NH4Cl. The product was extracted with 200 mL of 2:1 hexane/EtOAc. The extract was dried over Na2SO4 and concentrated, and dried under vacuum to give the title compound which was used without further purification. quenched with 100 mL of 50% saturated NH4Cl The product was extracted with 200 mL of 2:1 hexane/EtOAc The extract was dried over Na2SO4 concentrated dried under vacuum

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

Procedure: A solution of dimethyl malonate (13.2 g), 4-bromobenzylbromide (5.4 g) in DMF (200 mL) was treated with NaH (4 g, 60% in mineral oil). The mixture was stirred for 5 min at 0° C. and 20 min at room temperature and then quenched with 10 mL of AcOH slowly. The mixture was concentrated under vacuum and the residue was dissolved in 200 mL of 1:1 EtOAc/hexane, and filtered through a pad of silica gel. The filtrate was concentrated and the excess dimethyl malonate was removed under vacuum at 70° C. to provide the title compound as a yellow oil. quenched with 10 mL of AcOH slowly The mixture was concentrated under vacuum the residue was dissolved in 200 mL of 1:1 EtOAc/hexane filtered through a pad of silica gel The filtrate was concentrated the excess dimethyl malonate was removed under vacuum at 70° C.