ethyl 2-ethyl-4-oxocyclopentane-1-carboxylate

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:

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: A round-bottom flask was charged with ethyl 2-ethyl-4-oxocyclopentanecarboxylate (95.9 g, 521 mmol) and DCE (1.8 L). The solution was cooled to about 0° C. and AcOH (45 mL, 780 mmol) and dibenzylamine (120 mL, 625 mmol) were added drop-wise, resulting in the formation of a thick suspension. The reaction mixture was warmed to about 10° C. by removing the cooling bath and additional DCE (500 mL) was added. Sodium triacetoxyborohydride (166 g, 781 mmol) was added portion-wise and the reaction mixture was stirred at room temperature for about 20 h. The reaction mixture was slowly poured into saturated aqueous NaHCO3 (1.5 L) with stirring followed by the portion-wise addition of solid NaHCO3 (175 g, 2083 mmol). The mixture was stirred for about 2 h and the organic layer was separated, dried over anhydrous Na2SO4, and concentrated to dryness under reduced pressure. The crude yellow oil was purified by flash column chromatography using EtOAc/heptane as eluant (0-20% EtOAc) to yield ethyl 4-(dibenzylamino)-2-ethylcyclopentanecarboxylate (136.6 g, 72%) as a white solid: LC/MS (Table 2, Method a) Rt=3.26 min; MS m/z: 366 (M+H)+. resulting in the formation of a thick suspension The reaction mixture was warmed to about 10° C. by removing the cooling bath and additional DCE (500 mL) was added with stirring The mixture was stirred for about 2 h the organic layer was separated dried over anhydrous Na2SO4 concentrated to dryness under reduced pressure The crude yellow oil was purified by flash column chromatography

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

Procedure: A round-bottom flask was charged with 10% palladium on carbon (10 g, 9.4 mmol). The flask was cooled to about 0° C. and EtOAc (400 mL) was added under a nitrogen atmosphere. The cooling bath was removed and ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate (47.8 g, 263 mmol) was added. Hydrogen gas was bubbled through the mixture for about 5 min and the mixture was then stirred under a hydrogen atmosphere for about 48 h at ambient temperature. The hydrogen source was removed, the mixture was bubbled with nitrogen for about 5 min and was filtered through a pad of Celite®. The filter cake was rinsed with EtOAc (400 mL). The filtrate was concentrated under reduced pressure to give ethyl 2-ethyl-4-oxocyclopentanecarboxylate (about 9:1 mixture cis:trans) (48.0 g, 99%) as a yellow liquid: 1H NMR (CDCl3) δ 4.23-4.10 (m, 2H), 3.22 (m, 1H), 2.59-2.50 (m, 1H), 2.44-2.28 (m, 3H), 2.26-2.16 (m, 1H), 1.58-1.46 (m, 1H), 1.41-1.30 (m, 1H), 1.30-1.23 (m, 3H), 1.02-0.91 (m, 3H). The cooling bath was removed Hydrogen gas was bubbled through the mixture for about 5 min The hydrogen source was removed the mixture was bubbled with nitrogen for about 5 min was filtered through a pad of Celite® The filter cake was rinsed with EtOAc (400 mL) The filtrate was concentrated under reduced pressure

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

Procedure: A round-bottom flask was charged with ethyl 2-ethyl-4-oxocyclopentanecarboxylate (95.9 g, 521 mmol) and DCE (1.8 L). The solution was cooled to about 0° C. and glacial AcOH (45 mL, 780 mmol) and dibenzylamine (120 mL, 625 mmol) were added drop-wise, resulting in formation of a thick suspension. The reaction mixture was warmed to about 10° C. by removing the cooling bath and additional DCE (500 mL) was added. Sodium triacetoxyborohydride (166 g, 781 mmol) was added portion-wise and the reaction mixture was stirred at room temperature for about 20 h. The reaction mixture was slowly poured into stirred saturated aqueous NaHCO3 (1.5 L), followed by the portion-wise addition of solid NaHCO3 (175 g, 2083 mmol). The mixture was stirred for about 2 h and the organic layer was separated, dried over anhydrous Na2SO4, and concentrated to dryness under reduced pressure. The crude yellow oil was purified on silica gel column chromatography eluting with a gradient of 0-20% EtOAc/heptane. The solvent was removed under reduced pressure to yield ethyl 4-(dibenzylamino)-2-ethylcyclopentanecarboxylate (136.6 g, 72%) as a white solid: LC/MS (Table 2, Method a) Rt=3.26 min; MS m/z: 366 (M+H)+. resulting in formation of a thick suspension The reaction mixture was warmed to about 10° C. by removing the cooling bath and additional DCE (500 mL) was added The reaction mixture was slowly poured The mixture was stirred for about 2 h the organic layer was separated dried over anhydrous Na2SO4 concentrated to dryness under reduced pressure The crude yellow oil was purified on silica gel column chromatography eluting with a gradient of 0-20% EtOAc/heptane The solvent was removed under reduced pressure

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

Procedure: A round-bottom flask was charged with 10% palladium on carbon (10 g, 9.4 mmol). The flask was cooled to about 0° C. and EtOAc (400 mL) was added under a nitrogen atmosphere. The cooling bath was removed and ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate (47.8 g, 263 mmol) was added. Hydrogen gas was bubbled through the mixture for about 5 min and the mixture was then stirred under a hydrogen atmosphere for about 48 h. The hydrogen source was removed, the mixture was bubbled with nitrogen for about 5 min and was filtered through a pad of Celite®. The filter cake was rinsed with EtOAc (400 mL). The filtrate was concentrated under reduced pressure to give ethyl 2-ethyl-4-oxocyclopentanecarboxylate (48.0 g, 99%) as a yellow liquid: 1H NMR (CDCl3) δ 4.23-4.10 (m, 2H), 3.22 (m, 1H), 2.59-2.50 (m, 1H), 2.44-2.28 (m, 3H), 2.26-2.16 (m, 1H), 1.58-1.46 (m, 1H), 1.41-1.30 (m, 1H), 1.30-1.23 (m, 3H), 1.02-0.91 (m, 3H). The cooling bath was removed Hydrogen gas was bubbled through the mixture for about 5 min The hydrogen source was removed the mixture was bubbled with nitrogen for about 5 min was filtered through a pad of Celite® The filter cake was rinsed with EtOAc (400 mL) The filtrate was concentrated under reduced pressure

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

Procedure: A round-bottom flask was charged with ethyl 2-ethyl-4-oxocyclopentanecarboxylate (95.9 g, 521 mmol, Preparation #DD.1) and DCE (1.8 L). The solution was cooled to about 0° C. and AcOH (45 mL, 780 mmol) and dibenzylamine (120 mL, 625 mmol) were added drop-wise, resulting in formation of a thick suspension. The reaction mixture was warmed to about 10° C. and additional DCE (500 mL) was added. Sodium triacetoxyborohydride (166 g, 781 mmol) was added portion-wise and the reaction mixture was stirred at room temperature for about 20 h. The reaction mixture was slowly poured into stirred saturated aqueous NaHCO3 (1.5 L), followed by the portion-wise addition of solid sodium bicarbonate (175 g). The mixture was stirred for about 2 h and the organic layer was separated, dried over anhydrous Na2SO4, and concentrated to dryness under reduced pressure. The crude yellow oil was purified by silica gel chromatography using EtOAc/heptane as eluant (0-20% EtOAc in heptane). The solvent was removed under reduced pressure to yield ethyl 4-(dibenzylamino)-2-ethylcyclopentanecarboxylate (136.6 g, 72%) as a white solid: LC/MS (Table 2, Method a) Rt=3.26 min; MS m/z: 366 (M+H)+ resulting in formation of a thick suspension The reaction mixture was warmed to about 10° C. The reaction mixture was slowly poured The mixture was stirred for about 2 h the organic layer was separated dried over anhydrous Na2SO4 concentrated to dryness under reduced pressure The crude yellow oil was purified by silica gel chromatography The solvent was removed under reduced pressure