bicyclo[3.1.0]hexan-2-one

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

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

Procedure: In this preparation 10 ml. of acetonitrile is stirred in 300 ml. of anhydrous tetrahydrofuran, under nitrogen, and cooled to -70° C. 62.5 Ml. (0.1 mole) of 1.6 M butyllithium, in hexane, is added dropwise at a controlled rate such that the temperature of the mixture does not exceed -50° C. The mixture is then stirred for 5 minutes and 0.1 mole of bicyclo[3.1.0]hexan-2-one (J. Org. Chem., v. 22, 1146 (1957)) in 60 ml. of anhydrous tetrahydrofuran is added dropwise and the mixture then allowed to warm to room temperature. The mixture is then evaporated, under vacuum, to remove the tetrahydrofuran solvent and then 300 ml. of ethyl acetate is added and the mixture washed twice with water. The organic layer is dried with anhydrous magnesium sulfate and filtered. The filtrate is evaporated to dryness, under vacuum, affording 2-hydroxy-2-(bicyclo[3.1.0]hex-2-yl)acetonitrile. In this preparation 10 ml does not exceed -50° C The mixture is then evaporated, under vacuum to remove the tetrahydrofuran solvent of ethyl acetate is added the mixture washed twice with water The organic layer is dried with anhydrous magnesium sulfate filtered The filtrate is evaporated to dryness, under vacuum

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

Procedure: In this preparation 10 ml. of acetonitrile is stirred in 300 ml. of anhydrous tetrahydrofuran, under nitrogen, and cooled to -70° C. 62.5 Ml. (0.1 mole) of 1.6 M butyllithium, in hexane, is added dropwise at a controlled rate such that the temperature of the mixture does not exceed -50° C. The mixture is then stirred for 5 minutes and 0.1 mole of bicyclo[3.1.0]hexan-2-one (J. Org. Chem., v. 22, 1146 (1957)) in 60 ml. of anhydrous tetrahydrofuran is added dropwise and the mixture then allowed to warm to room temperature. The mixture is then evaporated, under vacuum, to remove the tetrahydrofuran solvent and then 300 ml. of ethyl acetate is added and the mixture washed twice with water. The organic layer is dried with anhydrous magnesium sulfate and filtered. The filtrate is evaporated to dryness, under vacuum, affording 2-hydroxy-2-(bicyclo[3.1.0]hex-2-yl)acetonitrile. In this preparation 10 ml does not exceed -50° C The mixture is then evaporated, under vacuum to remove the tetrahydrofuran solvent of ethyl acetate is added the mixture washed twice with water The organic layer is dried with anhydrous magnesium sulfate filtered The filtrate is evaporated to dryness, under vacuum

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 bicyclo[3.1.0]hexan-2-one (9.24 g, 96.1 mmol) and diethyl oxalate (14.7 g, 101 mmol) in EtOH (250 mL) at rt under N2 was added a solution of KOt-Bu in THF (106 mL of a 1M solution, 106 mmol). The reaction was stirred for 3.5 h at which time hydrazine hydrochloride (7.90 g, 115 mmol) in H2O (40 mL) was added. The reaction mixture was stirred for 20 h at rt and acidified to pH ˜3 by the addition of HCl (6N aq.). The volatiles were removed in vacuo and the resulting solid was diluted with EtOAc (500 mL) and H2O (500 mL). The layers were separated and the aqueous phase was back-extracted with EtOAc (300 mL). The combined organics were washed with brine (400 mL), dried over MgSO4, filtered, and concentrated to a crude oil that was determined to be approximately 75-80% pure (wt./wt.) ester by 1H NMR. The title compound was used directly in the next reaction (aminolysis) without further purification. 1H NMR (400 MHz, CDCl3): δ 10.55 (1H, bs), 4.32 (2H, q, J=6.8 Hz), 2.96 (1H, dd, J=16.8, 6.0 Hz), 2.80 (1H, d, J=17.2 Hz), 2.23-2.13 (2H, m), 1.35 (3H, t, J=7.2 Hz), 1.15 (1H, m), 0.34 (1H, m). 13C APT NM (partial) (100 MHz, CDCl3): δ up: 127.4, 61.2, 26.8, 16.8; down: 23.0, 15.4, 14.5. HPLC/MS: Discovery® C18 column (5 μ, 50×2.1 mm), 5% v/v CH3CN (containing 1% v/v TFA) in H2O (containing 1% v/v TFA) gradient to 99% v/v CH3CN in H2O, 0.75 mL/min, tr=1.62 min, ESr =193.1 (M+H). was added The volatiles were removed in vacuo the resulting solid was diluted with EtOAc (500 mL) and H2O (500 mL) The layers were separated the aqueous phase was back-extracted with EtOAc (300 mL) The combined organics were washed with brine (400 mL) dried over MgSO4 filtered concentrated to a crude oil that The title compound was used directly in the next reaction (aminolysis) without further purification

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

Procedure: To a solution of bicyclo[3.1.0]hexan-2-one (9.24 g, 96.1 mmol) and diethyl oxalate (14.7 g, 101 mmol) in EtOH (250 mL) at rt under N2 was added a solution of KOt-Bu in THF (106 mL of a 1M solution, 106 mmol). The reaction was stirred for 3.5 h at which time hydrazine hydrochloride (7.90 g, 115 mmol) in H2O (40 mL) was added. The reaction mixture was stirred for 20 h at rt and acidified to pH ˜3 by the addition of HCl (6N aq.). The volatiles were removed in vacuo and the resulting solid was diluted with EtOAc (500 mL) and H2O (500 mL). The layers were separated and the aqueous phase was back-extracted with EtOAc (300 mL). The combined organics were washed with brine (400 mL), dried over MgSO4, filtered, and concentrated to a crude oil that was determined to be approximately 75–80% pure (wt./wt.) ester by 1H NMR. The title compound was used directly in the next reaction (aminolysis) without further purification. 1H NMR (400 MHz, CDCl3): δ 10.55 (1H, bs), 4.32 (2H, q, J=6.8 Hz), 2.96 (1H, dd, J=16.8, 6.0 Hz), 2.80 (1H, d, J=17.2 Hz), 2.23–2.13 (2H, m), 1.35 (3H, t, J=7.2 Hz), 1.15 (1H, m), 0.34 (1H, m). 13C APT NMR (partial) (100 MHz, CDCl3): δ up: 127.4, 61.2, 26.8, 16.8; down: 23.0, 15.4, 14.5. HPLC/MS: Discovery® C18 column (5μ, 50×2.1 mm), 5% v/v CH3CN (containing 1% v/v TFA) in H2O (containing 1% v/v TFA) gradient to 99% v/v CH3CN in H2O, 0.75 mL/min, tr=1.62 min, ESI+=193.1 (M+H). was added The volatiles were removed in vacuo the resulting solid was diluted with EtOAc (500 mL) and H2O (500 mL) The layers were separated the aqueous phase was back-extracted with EtOAc (300 mL) The combined organics were washed with brine (400 mL) dried over MgSO4 filtered concentrated to a crude oil that The title compound was used directly in the next reaction (aminolysis) without further purification

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

Procedure: In this preparation 10 ml. of acetonitrile is stirred in 300 ml. of anhydrous tetrahydrofuran, under nitrogen, and cooled to -70° C. 62.5 Ml. (0.1 mole) of 1.6 M butyllithium, in hexane, is added dropwise at a controlled rate such that the temperature of the mixture does not exceed -50° C. The mixture is then stirred for 5 minutes and 0.1 mole of bicyclo[3.1.0]hexan-2-one (J. Org. Chem., v. 22, 1146 (1957)) in 60 ml. of anhydrous tetrahydrofuran is added dropwise and the mixture then allowed to warm to room temperature. The mixture is then evaporated, under vacuum, to remove the tetrahydrofuran solvent and then 300 ml. of ethyl acetate is added and the mixture washed twice with water. The organic layer is dried with anhydrous magnesium sulfate and filtered. The filtrate is evaporated to dryness, under vacuum, affording 2-hydroxy-2-(bicyclo[3.1.0]hex-2-yl)acetonitrile. In this preparation 10 ml does not exceed -50° C The mixture is then evaporated, under vacuum to remove the tetrahydrofuran solvent of ethyl acetate is added the mixture washed twice with water The organic layer is dried with anhydrous magnesium sulfate filtered The filtrate is evaporated to dryness, under vacuum