ethyl cyclopentanecarboxylate

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

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

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

Procedure: To an ice cold solution of diisopropylamine (56 mL, 0.396 mol) in THF 85 (mL) was added n-butyl lithium in hexane solution (240 mL, 1.6 M, 0.393 mol) over 20 min. The mixture was stirred at 0° C. for 30 min, cooled to a bath temperature of −65° C. and ethyl cyclopentane carboxylate (37.4 g, 0.263 mol) in THF (50 mL) was added over 20 min. After 1 hr, a solution of 1,2-dibromoethane (47 mL, 0.545 mol) in THF (50 mL) was added, the mixture was held at −65° C. for 3 hr and allowed to warm to room temperature overnight. The reaction was quenched by addition of saturated ammonium chloride solution (200 mL), the layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined extracts were washed with 1:1 brine:water (250 mL) and were dried (Na2SO4). The solution was filtered and concentrated, diluted with toluene (100 mL) and concentrated. The dilution and concentration was repeated twice to give ethyl 1-(2-bromoethyl)cyclopentane carboxylate (52.5 g). was added over 20 min After 1 hr the mixture was held at −65° C. for 3 hr to warm to room temperature overnight The reaction was quenched by addition of saturated ammonium chloride solution (200 mL) the layers were separated the aqueous layer was extracted with ethyl acetate (100 mL) The combined extracts were washed with 1:1 brine water (250 mL) and were dried (Na2SO4) The solution was filtered concentrated diluted with toluene (100 mL) concentrated The dilution and concentration

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

Procedure: A solution of diisopropylamine (58 mL, 0.44 mol) in THF 400 mL was cooled to below 0° C. and n-butyl lithium in hexane (170 mL, 2.5 N, 0.43 mol) was added dropwise maintaining the temperature below 0° C. Upon completion of the addition, ethyl cyclopentylcarboxylate (55 g, 0.39 mol) in THF (175 mL) was added dropwise maintaining the internal temperature between −60 and −70° C. Upon completion of the addition, the internal temperature was allowed to rise to −40° C. and was held there for 20 min and lowered back to −70° C. A solution of 4-methoxybenzyl bromide (75 g, 0.48 mol) in 175 mL of THF was added dropwise and the mixture was allowed to warm to room temperature overnight. A solution of 20% ammonium chloride in water (225 mL) was added followed by 450 mL of ethyl acetate, the layers were separated, the aqueous layer was extracted with ethyl acetate (450 mL) and the combined organic layers were washed with saturated brine (2×450 mL) and were dried (MgSO4). The crude product was chromatographed on silica gel, eluting with 1-5% ether in hexane to give 1-[(4-methoxyphenyl)methyl]cyclo-pentane carboxylic acid ethyl ester (80.8 g, 79%) as an oil. maintaining the temperature below 0° C was added dropwise maintaining the internal temperature between −60 and −70° C Upon completion of the addition to rise to −40° C. lowered back to −70° C the layers were separated the aqueous layer was extracted with ethyl acetate (450 mL) the combined organic layers were washed with saturated brine (2×450 mL) were dried (MgSO4) The crude product was chromatographed on silica gel eluting with 1-5% ether in hexane

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

Procedure: A solution of diisopropylamine (1.0 mL, 7.7 mmol) in 20 mL of dry THF was cooled to −78° C. in a dry ice-acetone bath under argon. n-Butyl lithium in hexanes (2.5 M, 3.6 mL, 7.7 mmol) was added all at once and the mixture was stirred for 0.5 hour and transferred to a precooled (−30° C.) solution of 1.0 g (7.0 mmol) of ethyl cyclopentane carboxylate in 10 mL of THF. After a further 45 min, benzyl bromide (0.92 mL, 7.7 mmol) was added and the mixture was allowed to warm to room temperature over night. The resulting mixture was concentrated, and the residue was taken up in 70 mL of ether, washed with water, 1 N HCl, water, saturated brine and was dried (MgSO4). The residue obtained after filtration and evaporation was purified by flash chromatography over 100 g of silica gel, eluting with 3% ethyl acetate-hexane to give 1-benzylcyclopentane carboxylic acid ethyl ester (0.80 g, 45%) as a colorless oil. After a further 45 min The resulting mixture was concentrated washed with water, 1 N HCl, water, saturated brine was dried (MgSO4) The residue obtained after filtration and evaporation was purified by flash chromatography over 100 g of silica gel eluting with 3% ethyl acetate-hexane

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

Procedure: 3-(4-Phenyl-benzyl)-7-trifluoromethylsulfonyloxy-4-chromanone (35.0 g, 91.0 mmole, prepared from the product of Example 2C with biphenyl aldehyde using the procedures of Example 2D and Example 2E, was dissolved in a mixture of dimethylformamide (230 mL) and dimethoxyethane (230 mL). To this solution was added in the following order, tris(2-methylphenyl)phosphine (7.48 g, 24.6 mmole), bis(benzonitrile)palladium (II) chloride (2.44 g, 6.37 mmole), the trimethylsilyl ketene acetal of ethyl cyclopentanecarboxylate (29.26 g, 136.5 mmole), and a 1.0M ethereal solution of zinc chloride (25 mL, 25 mmole). The resulting clear yellow solution was refluxed for about 1 hour. Additional trimethylsilyl ketene acetal (9.75 g, 45.5 mmole) was added at this point and the reflux continued for about another 1 hour. The cooled mixture was diluted with water (1 L) and extracted with ether. The combined ether extracts were washed with water (1 L) and then dried over magnesium sulfate. Filtration and concentration of the extract gave a yellow oil which was chromatographed on silica gel (8:92 ethyl acetate/hexane). This yielded 22.13 g (64%) of the title compound of this Example 5A as a white solid; m.p. 50-56 ° C.; 1H NMR (CDCl3): 1.23 (3H, t, J=7.0), 1.75 (4H, m), 1.9 (2H, m), 2.6 (2H, m), 2.70 (1H, dd, J=10.5, 13.8), 2.9 (1H, m), 3.26 (1H, dd, J=4.3, 13.8), 4.08 (2H, d, J=7.0), 4.15 (1H, dd, J=8.2, 11.5), 4.35 (dd, J=4.3, 11.5), 6.95 (1H, d, J=1.7), 7.02 (1H, dd, J=1.7, 8.3), 7.2-7.4 (5H, m) 7.84 (1H, d, J=8.3). The resulting clear yellow solution was refluxed for about 1 hour continued for about another 1 hour extracted with ether The combined ether extracts were washed with water (1 L) dried over magnesium sulfate Filtration and concentration of the extract gave a yellow oil which was chromatographed on silica gel (8:92 ethyl acetate/hexane)

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

Procedure: A solution of ethyl cyclopentanecarboxylate (prepared by esterification of commercially available cyclopentantecarboxylic acid, 30 g, 0.21 mol) and acetonitrile (10.1 g, 0.25 mol) in dry THF (80 mL) was added dropwise to a suspension of NaH (12.5 g, 0.31 mol) in dry THF (80 mL) and the resulting mixture was refluxed overnight. The reaction mixture was concentrated under reduced pressure and partitioned between water and EtOAc. The aqueous layer was separated, adjusted to pH 8 and extracted with EtOAc. The combined extracts were washed with brine, dried (MgSO4), and concentrated to give 3-cyclopentyl-3-oxopropanenitrile (26 g, 90% yield), which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ 4.06 (s, 2 H), 2.92 (m, 1 H), 1.41-1.77 (m, 8 H). the resulting mixture was refluxed overnight The reaction mixture was concentrated under reduced pressure partitioned between water and EtOAc The aqueous layer was separated extracted with EtOAc The combined extracts were washed with brine dried (MgSO4) concentrated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of nBuLi in hexanes (242 mL, 387 mmol) was added to a −78° C. solution of diisopropylamine (39.1 g, 387 mmol) in anhydrous THF (300 mL) and the resultant mixture was stirred for 30 min at −78° C. A solution of ethyl cyclopentanecarboxylate (50 g, 352 mmol) in anhydrous THF (150 mL) was added dropwise into the mixture and the reaction mixture was stirred at −78° C. for 1 h. Iodomethane (79.2 g, 558 mmol) was added dropwise and the resulting mixture was warmed to RT and stirred overnight. The mixture was poured into water and extracted with ethyl ether. The combined extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to give ethyl 1-methylcyclopentanecarboxylate (47 g, 85%). 1H NMR (300 MHz, DMSO-d6): δ 4.03 (q, J=7.2 Hz, 2 H), 1.37-2.03 (m, 8 H), 1.15-1.12 (m, 6 H). the resulting mixture was warmed to RT stirred overnight extracted with ethyl ether The combined extracts were washed with brine dried (MgSO4) concentrated in vacuo

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

Procedure: To an ice cold solution of diisopropylamine (56 mL, 0.396 mol) in THF (85 mL) was added n-butyl lithium in hexane solution (240 mL, 1.6 M, 0.393 mol) over 20 min. The mixture was stirred at 0° C. for 30 min, cooled to a bath temperature of −65° C. and ethyl cyclopentanecarboxylate (37.4 g, 0.263 mol) in THF (50 mL) was added over 20 min. After 1 h, a solution of 1,2-dibromoethane (47 mL, 0.545 mol) in THF (50 mL) was added, the mixture was held at -65 ° C for 3 h and then was allowed to warm to room temperature overnight. After the reaction was quenched by addition of saturated ammonium chloride solution (200 mL), the layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined extracts were washed with 1:1 brine:water (250 mL) and were dried (Na2SO4). The solution was filtered, concentrated in vacuo then the residue was diluted with toluene (100 mL) and concentrated. The dilution and concentration cycle was repeated twice to give ethyl 1-(2-bromoethyl)cyclopentanecarboxylate (52.5 g). was added over 20 min After 1 h the mixture was held at -65 ° C for 3 h to warm to room temperature overnight After the reaction was quenched by addition of saturated ammonium chloride solution (200 mL) the layers were separated the aqueous layer was extracted with ethyl acetate (100 mL) The combined extracts were washed with 1:1 brine water (250 mL) and were dried (Na2SO4) The solution was filtered concentrated in vacuo the residue was diluted with toluene (100 mL) concentrated The dilution and concentration cycle

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

Procedure: 3-(4-Phenyl-benzyl)-7-trifluoromethylsulfonyloxy-4-chromanone (35.0 g, 91.0 mmole, prepared from the product of Example 2C with biphenyl aldehyde using the procedures of Example 2D and Example 2E, was dissolved in a mixture of dimethylformamide (230 mL) and dimethoxyethane (230 mL). To this solution was added in the following order, tris(2-methylphenyl)phosphine (7.48 g, 24.6 mmole), bis(benzonitrile)palladium (II) chloride (2.44 g, 6.37 mmole), the trimethylsilyl ketene acetal of ethyl cyclopentanecarboxylate (29.26 g, 136.5 mmole), and a 1.0M ethereal solution of zinc chloride (25 mL, 25 mmole). The resulting clear yellow solution was refluxed for about 1 hour. Additional trimethylsilyl ketene acetal (9.75 g, 45.5 mmole) was added at this point and the reflux continued for about another 1 hour. The cooled mixture was diluted with water (1 L) and extracted with ether. The combined ether extracts were washed with water (1 L) and then dried over magnesium sulfate. Filtration and concentration of the extract gave a yellow oil which was chromatographed on silica gel (8:92 ethyl acetate/hexane). This yielded 22.13 g (64%) of the title compound of this Example 5A as a white solid; m.p. 50-56 ° C.; 1H NMR (CDCl3): 1.23 (3H, t, J=7.0), 1.75 (4H, m), 1.9 (2H, m), 2.6 (2H, m), 2.70 (1H, dd, J=10.5,13.8), 2.9 (1H, m), 3.26 (1H, dd, J =4.3, 13.8), 4.08 (2H, d, J=7.0), 4.15 (1H, dd, J=8.2, 11.5), 4.35 (dd, J=4.3, 11.5), 6.95 (1H, d, J=1.7), 7.02 (1H, dd, J=1.7, 8.3), 7.2-7.4 (5H, m), 7.84 (1H, d, J=8.3). The resulting clear yellow solution was refluxed for about 1 hour continued for about another 1 hour extracted with ether The combined ether extracts were washed with water (1 L) dried over magnesium sulfate Filtration and concentration of the extract gave a yellow oil which was chromatographed on silica gel (8:92 ethyl acetate/hexane)

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

Procedure: 3-(4-Phenyl-benzyl)-7-trifluoromethylsulfonyloxy-4-chromanone (35.0 g, 91.0 mmole, prepared from the product of Example 2C with biphenyl aldehyde using the procedures of Example 2D and Example 2E, was dissolved in a mixture of dimethylformamide (230 mL) and dimethoxyethane (230 mL). To this solution was added in the following order, tris(2-methylphenyl)phosphine (7.48 g, 24.6 mmole), bis(benzonitrile)palladium (II) chloride (2.44 g, 6.37 mmole), the trimethylsilyl ketene acetal of ethyl cyclopentanecarboxylate (29.26 g, 136.5 mmole), and a 1.0M ethereal solution of zinc chloride (25 mL, 25 mmole). The resulting clear yellow solution was refluxed for about 1 hour. Additional trimethylsilyl ketene acetal (9.75 g, 45.5 mmole) was added at this point and the reflux continued for about another 1 hour. The cooled mixture was diluted with water (1 L) and extracted with ether. The combined ether extracts were washed with water (1 L) and then dried over magnesium sulfate. Filtration and concentration of the extract gave a yellow oil which was chromatographed on silica gel (8:92 ethyl acetate/hexane). This yielded 22.13 g (64%) of the title compound of this Example 5A as a white solid; m.p. 50-56 ° C.; 1H NMR (CDCl3): 1.23 (3H, t, J=7.0), 1.75 (4H, m), 1.9 (2H, m), 2.6 (2H, m), 2.70 (1H, dd, J=10.5,13.8), 2.9 (1H, m), 3.26 (1H, dd, J =4.3, 13.8), 4.08 (2H, d, J=7.0), 4.15 (1H, dd, J=8.2, 11.5), 4.35 (dd, J=4.3, 11.5), 6.95 (1H, d, J=1.7), 7.02 (1H, dd, J=1.7, 8.3), 7.2-7.4 (5H, m), 7.84 (1H, d, J=8.3). The resulting clear yellow solution was refluxed for about 1 hour continued for about another 1 hour extracted with ether The combined ether extracts were washed with water (1 L) dried over magnesium sulfate Filtration and concentration of the extract gave a yellow oil which was chromatographed on silica gel (8:92 ethyl acetate/hexane)

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

Procedure: To an ice cold solution of diisopropylamine (56 mL, 0.396 mol) in THF (85 mL) was added n-butyl lithium in hexane solution (240 mL, 1.6 M, 0.393 mol) over 20 min. The mixture was stirred at 0° C. for 30 min, cooled to a bath temperature of −65° C. and ethyl cyclopentanecarboxylate (37.4 g, 0.263 mol) in THF (50 mL) was added over 20 min. After 1 h, a solution of 1,2-dibromoethane (47 mL, 0.545 mol) in THF (50 mL) was added, the mixture was held at −65° C. for 3 h and then was allowed to warm to room temperature overnight. After the reaction was quenched by addition of saturated ammonium chloride solution (200 mL), the layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined extracts were washed with 1:1 brine:water (250 mL) and were dried (Na2SO4). The solution was filtered, concentrated in vacuo then the residue was diluted with toluene (100 mL) and concentrated. The dilution and concentration cycle was repeated twice to give ethyl 1-(2-bromoethyl)cyclopentanecarboxylate (52.5 g). was added over 20 min After 1 h the mixture was held at −65° C. for 3 h to warm to room temperature overnight After the reaction was quenched by addition of saturated ammonium chloride solution (200 mL) the layers were separated the aqueous layer was extracted with ethyl acetate (100 mL) The combined extracts were washed with 1:1 brine water (250 mL) and were dried (Na2SO4) The solution was filtered concentrated in vacuo the residue was diluted with toluene (100 mL) concentrated The dilution and concentration cycle