diethyl 2-(2-phenylethyl)propanedioate

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:

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

Procedure: The diethyl benzylmethylmalonate (75 g) was combined with 300 ml of ethanol and a solution of 100 g of potassium hydroxide in 300 ml of water and heated at gentle reflux for 5 hours. After cooling, the mixture was extracted with diethyl ether (2×300 ml). The aqueous layer was then acidified with 120 ml of concentrated hydrochloric acid and extracted with diethyl ether (3×300 ml). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to yield 49.2 g of benzylmethylmalonic acid as a yellow solid (83% yield). at gentle reflux for 5 hours After cooling the mixture was extracted with diethyl ether (2×300 ml) extracted with diethyl ether (3×300 ml) The combined organic extracts were dried over magnesium sulfate filtered concentrated

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

Procedure: The diethyl benzylmethylmalonate (75 g) was combined with 300 ml of ethanol and a solution of 100 g potassium hydroxide in 300 ml of water and heated to a gentle reflux for 5 hours. After cooling, the mixture was extracted with diethyl ether (2×300 ml). The aqueous phase was then acidified with 120 ml concentrated hydrochloric acid, and extracted with diethyl ether (3×300 ml). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to yield 49.2 g of benzylmethylmalonic acid as a yellow solid (83% yield). a gentle reflux for 5 hours After cooling the mixture was extracted with diethyl ether (2×300 ml) extracted with diethyl ether (3×300 ml) The combined organic extracts were dried over magnesium sulfate filtered concentrated

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 diethyl 2-phenylethylmalonate (3.61 g) and potassium hydroxide (1.69 g, 2.5 eq) in water (15 ml) was refluxed for 2 h and cooled to room temperature. The solution was washed with diethyl ether (2×10 ml) and then acidified to pH 2 (5M hydrochloric acid). The aqueous phase was extracted with diethyl ether (2×20 ml). The combined extracts were washed with water (2×20 ml), saturated brine (20 ml), dried (MgSO4) and evaporated to give the title compound as a white solid (1.85 g, 65%); νmax (KBr) 3080(br), 1705 cm-1 ; δH [(CD3)2CO], 2.18 (2H, m, CH2), 2.70 (2H, m, CH2), 3.40 (1H, t, J 7.4 Hz, CH), 7.25 (5H, m, Ph). DCIMS MNH4+ 226. was refluxed for 2 h The solution was washed with diethyl ether (2×10 ml) The aqueous phase was extracted with diethyl ether (2×20 ml) The combined extracts were washed with water (2×20 ml), saturated brine (20 ml) dried (MgSO4) evaporated

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

Procedure: A solution of diethyl malonate (6.07 ml, 40 mmol) in dimethyl formamide (60 ml) at 0° C. was treated portionwise with sodium hydride (1.6 g, 40 mmol, 60% dispersion in oil) and stirred for 0.25 h. 2-Phenylethyl bromide (5.48 ml, 40 mmol) in dimethylformarnmide (30 ml) was added dropwise. The mixture was warmed to room temperature and stirred for 1 h. The mixture was diluted with diethyl ether (300 ml), washed with water (4×200 ml), saturated brine (100 ml), dried (MgSO4) and evaporated. Flash chromatography on silica, eluting with 1% ethyl acetate in hexane, gave the title compound as a colourless oil (7.55 g, 71%); νmax (CH2Cl2), 1726 cm-1 ; stirred for 1 h washed with water (4×200 ml), saturated brine (100 ml) dried (MgSO4) evaporated Flash chromatography on silica, eluting with 1% ethyl acetate in hexane

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

Procedure: A solution of diethyl malonate (6.07 ml, 40 mmol) in dimethyl formamide (60 ml) at 0° C. was treated portionwise with sodium hydride (1.6 g, 40 mmol, 60% dispersion in oil) and stirred for 0.25 h. 2-Phenylethyl bromide (5.48 ml, 40 mmol) in dimethylformarnmide (30 ml) was added dropwise. The mixture was warmed to room temperature and stirred for 1 h. The mixture was diluted with diethyl ether (300 ml), washed with water (4×200 ml), saturated brine (100 ml), dried (MgSO4) and evaporated. Flash chromatography on silica, eluting with 1% ethyl acetate in hexane, gave the title compound as a colourless oil (7.55 g, 71%); νmax (CH2Cl2), 1726 cm-1 ; stirred for 1 h washed with water (4×200 ml), saturated brine (100 ml) dried (MgSO4) evaporated Flash chromatography on silica, eluting with 1% ethyl acetate in hexane

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

Procedure: To a cold suspension (0-5° C.) of 95% sodium hydride (3.53 g, 13.0 mmol) in dry tetrahydrofuran (30 mL) was slowly added diethyl 2-phenylethylmalonate (3.53 g, 13 mmol). The ice bath was removed and the reaction mixture was stirred at rt for 45 minutes. A solution of 2-bromo-1-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)ethanone (4.06 g, 12.0 mmol) in dry tetrahydrofuran (50 mL) was slowly added, and the resulting mixture was stirred at rt for about 70 h. Ethyl acetate (80 mL) and water (20 mL) were added, and the layers were separated. The organic layer was washed with water (2×30 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give a dark, brown oil. This material was purified by flash chromatography (10:90 ethyl acetate/hexane) to give diethyl 2-[2-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)-2-oxoethyl]-2-(2-phenylethyl)malonate as a light yellow oil (5.30 g, 82% yield). LC-MS ret. time 4.01 min, m/z 517.9 (MH+); 1H NMR (CDCl3) δ 1.23-1.35 (m, 6H), 2.41-2.50 (m, 2H), 2.56 (s, 3H), 2.59-2.66 (m, 2H), 3.71 (s, 2H), 4.21-4.32 (m, 4H), 7.13-7.19 (m, 3H), 7.22-7.30 (m, 2H), 7.49-7.55 (m, 2H), 7.73-7.82 (m, 3H), 8.31 (d, 2H). The ice bath was removed the resulting mixture was stirred at rt for about 70 h the layers were separated The organic layer was washed with water (2×30 mL) dried over magnesium sulfate concentrated under reduced pressure to give a dark, brown oil This material was purified by flash chromatography (10:90 ethyl acetate/hexane)

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

Procedure: To a 500 mL 3-neck round-bottom flask equipped with an argon inlet and an addition funnel, was added sodium hydride (95%, 1.40 g, 58.3 mmol) followed by tetrahydrofuran (30 mL). The resulting suspension was then cooled to 0° C. and diethyl 2-(2-phenylethyl)malonate (14.0 g, 53.0 mmol) in tetrahydrofuran (20 mL) was added dropwise over 20 minutes. The cooling bath was removed and the reaction mixture was allowed to warm to rt over 45 minutes. A solution of 2-bromo-1-(4-bromophenyl)ethanone (14.72 g, 58.26 mmol) in tetrahydrofuran (40 mL) was rapidly added and the resulting orange-red mixture was stirred at rt for 16 h. The mixture was carefully poured into 300 mL of 1N hydrochloric acid, and the resulting mixture was stirred for 10 minutes and extracted twice with ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (Biotage flash 75, 10:90 ethyl acetate/hexane) to afford diethyl 2-[2-(4-bromophenyl)-2-oxoethyl]-2-(2-phenylethyl)malonate (14.8 g, 61%). LC-MS ret. time 3.89 min, m/z 461.2 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.26 (t, 6H), 2.41-2.45 (m, 2H), 2.56-2.59 (m, 2H), 3.67 (s, 2H), 4.23 (q, 4H), 7.14-7.22 (m, 3H), 7.22 (d, 2H), 7.61 (d, 2H), 7.79 (d, 2H). To a 500 mL 3-neck round-bottom flask equipped with an argon inlet and an addition funnel The cooling bath was removed to warm to rt over 45 minutes the resulting mixture was stirred for 10 minutes extracted twice with ethyl acetate The combined extracts were dried over anhydrous sodium sulfate concentrated under reduced pressure The resulting residue was purified by flash chromatography (Biotage flash 75, 10:90 ethyl acetate/hexane)