tert-butyl N-cyclopent-3-en-1-ylcarbamate

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

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

Procedure: In a dry round-bottomed flask, N-1-Boc-amino-3-cyclopentene (1.0 g, 5.46 mmol) was dissolved in THF (7 ml). The solution was cooled to 0° C. and borane tetrahydrofuran complex (1.0M in THF, 6.0 ml, 6.0 mmol) was added dropwise. The reaction was stirred at 0° C. for 1 h then warmed to room temperature overnight. The mixture was cooled back to 0° C. and water (2 ml) was added. Then 10% aqueous sodium hydroxide (8 ml, 20.0 mmol) was added dropwise followed by dropwise addition of hydrogen peroxide (30% solution in water, 5.0 ml, 49 mmol). After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was extracted with ethyl acetate (2×). The combined organic layers were washed with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-60% EtOAc) to afford 330 mg (30%) of (cis-3-hydroxy-cyclopentyl)-carbamic acid tert-butyl ester as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 5.12 (br. s., 1H), 4.39 (m, 1H), 4.03 (br. s., 1H), 1.95-2.17 (m, 2H), 1.78 (d, J=2.6 Hz, 3H), 1.64 (d, J=12.5 Hz, 1H), 1.44 (s, 9H). Also isolated 99 mg (9%) of (trans-3-hydroxy-cyclopentyl)-carbamic acid tert-butyl ester as a white solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 4.35-4.51 (m, 2H), 4.15 (br. s, 1H), 2.15-2.30 (m, 1H), 1.98-2.10 (m, 2H), 1.45 (s, 9H), 1.34-1.72 (m, 3H). then warmed to room temperature overnight The mixture was cooled back to 0° C. After the addition the ice bath was removed the reaction mixture was stirred at room temperature for 5 h The reaction mixture was extracted with ethyl acetate (2×) The combined organic layers were washed with brine then dried over sodium sulfate filtered concentrated The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-60% EtOAc)

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

Procedure: In a dry round-bottomed flask, N-1-Boc-amino-3-cyclopentene (1.0 g, 5.46 mmol) was dissolved in THF (7 ml). The solution was cooled to 0° C. and borane tetrahydrofuran complex (1.0M in THF, 6.0 ml, 6.0 mmol) was added dropwise. The reaction was stirred at 0° C. for 1 h then warmed to room temperature overnight. The mixture was cooled back to 0° C. and water (2 ml) was added. Then 10% aqueous sodium hydroxide (8 ml, 20.0 mmol) was added dropwise followed by dropwise addition of hydrogen peroxide (30% solution in water, 5.0 ml, 49 mmol). After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was extracted with ethyl acetate (2×). The combined organic layers were washed with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-60% EtOAc) to afford 330 mg (30%) of (cis-3-hydroxy-cyclopentyl)-carbamic acid tert-butyl ester as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 5.12 (br. s., 1H), 4.39 (m, 1H), 4.03 (br. s., 1H), 1.95-2.17 (m, 2H), 1.78 (d, J=2.6 Hz, 3H), 1.64 (d, J=12.5 Hz, 1H), 1.44 (s, 9H). Also isolated 99 mg (9%) of (trans-3-hydroxy-cyclopentyl)-carbamic acid tert-butyl ester as a white solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 4.35-4.51 (m, 2H), 4.15 (br. s, 1H), 2.15-2.30 (m, 1H), 1.98-2.10 (m, 2H), 1.45 (s, 9H), 1.34-1.72 (m, 3H). then warmed to room temperature overnight The mixture was cooled back to 0° C. After the addition the ice bath was removed the reaction mixture was stirred at room temperature for 5 h The reaction mixture was extracted with ethyl acetate (2×) The combined organic layers were washed with brine then dried over sodium sulfate filtered concentrated The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-60% EtOAc)

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

Procedure: To a solution of 3-cyclopentene-1-carboxylic acid (J.-P. Depres and A. E. Greene, J. Org. Chem. 1984, 49:928-931; 29.71 g, 0.261 mole), triethylamine (36.4 mL) in t-butanol (1 L) was added diphenylphosphoryl azide, Aldrich, 97%, 74.0 g, 0.261 mmole). The solution was maintained at 60--C. for 4 hours. Cuprous chloride (1.3 g) was added and stirring continued at ambient temperature for 18 hours. Volatiles were evaporated and the residue was dissolved in methylene chloride (1250 mL) and washed with 10 % aqueous sodium carbonate (2×250 mL) and dried (magnesium sulfate). Volatiles were evaporated and the residue was chromatographed on a silica gel column. Title compound was eluted with chloroform as white crystals, from hexanes (22.63 g, 47%), m.p. 68-70° C. The solution was maintained at 60 continued at ambient temperature for 18 hours Volatiles were evaporated the residue was dissolved in methylene chloride (1250 mL) washed with 10 % aqueous sodium carbonate (2×250 mL) dried (magnesium sulfate) Volatiles were evaporated the residue was chromatographed on a silica gel column Title compound was eluted with chloroform as white crystals, from hexanes (22.63 g, 47%), m.p. 68-70° C.

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

Procedure: In a dry round-bottomed flask, N-1-Boc-amino-3-cyclopentene (1.0 g, 5.46 mmol) was dissolved in THF (7 ml). The solution was cooled to 0° C. and borane tetrahydrofuran complex (1.0M in THF, 6.0 ml, 6.0 mmol) was added dropwise. The reaction was stirred at 0° C. for 1 h then warmed to room temperature overnight. The mixture was cooled back to 0° C. and water (2 ml) was added. Then 10% aqueous sodium hydroxide (8 ml, 20.0 mmol) was added dropwise followed by dropwise addition of hydrogen peroxide (30% solution in water, 5.0 ml, 49 mmol). After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was extracted with ethyl acetate (2×). The combined organic layers were washed with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-60% EtOAc) to afford 330 mg (30%) of (cis-3-hydroxy-cyclopentyl)-carbamic acid tert-butyl ester as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 5.12 (br. s., 1H), 4.39 (m, 1H), 4.03 (br. s., 1H), 1.95-2.17 (m, 2H), 1.78 (d, J=2.6 Hz, 3H), 1.64 (d, J=12.5 Hz, 1H), 1.44 (s, 9H). Also isolated 99 mg (9%) of (trans-3-hydroxy-cyclopentyl)-carbamic acid tert-butyl ester as a white solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 4.35-4.51 (m, 2H), 4.15 (br. s, 1H), 2.15-2.30 (m, 1H), 1.98-2.10 (m, 2H), 1.45 (s, 9H), 1.34-1.72 (m, 3H). then warmed to room temperature overnight The mixture was cooled back to 0° C. After the addition the ice bath was removed the reaction mixture was stirred at room temperature for 5 h The reaction mixture was extracted with ethyl acetate (2×) The combined organic layers were washed with brine then dried over sodium sulfate filtered concentrated The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-60% EtOAc)

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

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

Procedure: To a stirred solution cooled in an ice-water bath of the above crude product, (tert-butoxycarbonyl-cyclopent-3-enyl-amino)-oxo-acetic acid ethyl ester, (3.80 g) in THF (35 mL) was added a solution of LiOH (0.0765 mol) in water (35 mL). The mixture was stirred in the ice-water bath for 3 h. The organic material was extracted with CH2Cl2 (30 mL×3), the organic layers were combined and washed with brine (30 mL×2), and the solvent was removed in vacuo. The residue was purified by column chromatography (silica gel, 100% dichloromethane) to obtain white crystals of pure product (53%). The organic material was extracted with CH2Cl2 (30 mL×3) washed with brine (30 mL×2) the solvent was removed in vacuo The residue was purified by column chromatography (silica gel, 100% dichloromethane)

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

Procedure: To a stirred solution cooled in an ice-water bath of the above crude product, (tert-butoxycarbonyl-cyclopent-3-enyl-amino)-oxo-acetic acid ethyl ester, (3.80 g) in THF (35 mL) was added a solution of LiOH (0.0765 mol) in water (35 mL). The mixture was stirred in the ice-water bath for 3 h. The organic material was extracted with CH2Cl2 (30 mL×3), the organic layers were combined and washed with brine (30 mL×2), and the solvent was removed in vacuo. The residue was purified by column chromatography (silica gel, 100% dichloromethane) to obtain white crystals of pure product (53%). The organic material was extracted with CH2Cl2 (30 mL×3) washed with brine (30 mL×2) the solvent was removed in vacuo The residue was purified by column chromatography (silica gel, 100% dichloromethane)

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

Procedure: To a stirred solution cooled in an ice-water bath of the above crude product, (tert-butoxycarbonyl-cyclopent-3-enyl-amino)-oxo-acetic acid ethyl ester, (3.80 g) in THF (35 mL) was added a solution of LiOH (0.0765 mol) in water (35 mL). The mixture was stirred in the ice-water bath for 3 h. The organic material was extracted with CH2Cl2 (30 mL×3), the organic layers were combined and washed with brine (30 mL×2), and the solvent was removed in vacuo. The residue was purified by column chromatography (silica gel, 100% dichloromethane) to obtain white crystals of pure product (53%). The organic material was extracted with CH2Cl2 (30 mL×3) washed with brine (30 mL×2) the solvent was removed in vacuo The residue was purified by column chromatography (silica gel, 100% dichloromethane)

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

Procedure: A solution of cyclopent-3-enecarboxylic acid (2.25 g), diphenylphosphoryl azide (4.7 mL), and triethylamine (2.8 mL) in 25 mL toluene was refluxed for 7 h. The mixture was cooled to rt and treated with 10 mL of tert-butanol. The resulting mixture was refluxed for an additional 16 h. The solvents were evaporated and the crude residue was chromatographed with silica gel (1:10 ethyl acetate:hexanes) to give Cyclopent-3-enylcarbamic acid tert-butyl ester (racemic): (2.37 g). Borane-tetrahydrofuran (1.5 M in THF, 20 mL) was added dropwise to a solution of cyclopent-3-enylcarbamic acid tert-butyl ester (1.83 g) in tetrahydrofuran (30 mL) at 0° C. The solution was gradually warmed to rt and stirred for 16 h. The reaction solution was cooled to 0° C. and sodium hydroxide (1 N, 33 mL) was slowly added followed by 30% hydrogen peroxide (33 mL). The resulting mixture was stirred at rt for an additional 5 h and diluted with ethyl acetate (70 mL). The aqueous layer was separated and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated via rotary evaporator. Silica gel chromatography (1:1 ethyl acetate:hexanes) provided 0.25 g of cis-(3-hydroxycyclopentyl)carbamic acid tert-butyl ester (racemic) followed by 1.07 g of the trans isomer. A solution of cis-(3-hydroxycyclopentyl)-carbamic acid tert-butyl ester (201 mg) in dimethylformamide (3 mL) was treated with sodium hydride (60% in mineral oil, 95 mg) at 0° C. After gas evolution had ceased, the mixture was stirred for 30 min at rt. Iodoethane (88 μL) was added to the mixture and the reaction was stirred at rt for 16 h. The excess sodium hydride was destroyed at 0° C. by the careful addition of aqueous ammonium chloride. The resulting mixture was partitioned between ethyl acetate and ammonium chloride and the organic layer was separated and washed with brine. The organic layer was dried over Na2SO4 and concentrated via rotary evaporator. Silica gel chromatography (1:4 ethyl acetate:hexanes) provided cis-(3-ethoxycyclopentyl)carbamic acid tert-butyl ester (racemic) (102 mg). Cis-(3-ethoxycyclopentyl)carbamic acid tert-butyl ester was stirred in 1:1 trifluoroacetic acid:dichloromethane for 0.5 h. The solvent was removed by evaporation to provide cis-3-ethoxycyclopentylamine (racemic). The reaction solution was cooled to 0° C. The resulting mixture was stirred at rt for an additional 5 h The aqueous layer was separated extracted with ethyl acetate (30 mL×3) The combined organic layers were washed with water and brine dried over Na2SO4 concentrated via rotary evaporator

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

Procedure: A solution of cyclopent-3-enecarboxylic acid (2.25 g), diphenylphosphoryl azide (4.7 mL), and triethylamine (2.8 mL) in 25 mL toluene was refluxed for 7 h. The mixture was cooled to rt and treated with 10 mL of tert-butanol. The resulting mixture was refluxed for an additional 16 h. The solvents were evaporated and the crude residue was chromatographed with silica gel (1:10 ethyl acetate:hexanes) to give Cyclopent-3-enylcarbamic acid tert-butyl ester (racemic): (2.37 g). Borane-tetrahydrofuran (1.5 M in THF, 20 mL) was added dropwise to a solution of cyclopent-3-enylcarbamic acid tert-butyl ester (1.83 g) in tetrahydrofuran (30 mL) at 0° C. The solution was gradually warmed to rt and stirred for 16 h. The reaction solution was cooled to 0° C. and sodium hydroxide (1 N, 33 mL) was slowly added followed by 30% hydrogen peroxide (33 mL). The resulting mixture was stirred at rt for an additional 5 h and diluted with ethyl acetate (70 mL). The aqueous layer was separated and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated via rotary evaporator. Silica gel chromatography (1:1 ethyl acetate:hexanes) provided 0.25 g of cis-(3-hydroxycyclopentyl)carbamic acid tert-butyl ester (racemic) followed by 1.07 g of the trans isomer. A solution of cis-(3-hydroxycyclopentyl)-carbamic acid tert-butyl ester (201 mg) in dimethylformamide (3 mL) was treated with sodium hydride (60% in mineral oil, 95 mg) at 0° C. After gas evolution had ceased, the mixture was stirred for 30 min at rt. Iodoethane (88 μL) was added to the mixture and the reaction was stirred at rt for 16 h. The excess sodium hydride was destroyed at 0° C. by the careful addition of aqueous ammonium chloride. The resulting mixture was partitioned between ethyl acetate and ammonium chloride and the organic layer was separated and washed with brine. The organic layer was dried over Na2SO4 and concentrated via rotary evaporator. Silica gel chromatography (1:4 ethyl acetate:hexanes) provided cis-(3-ethoxycyclopentyl)carbamic acid tert-butyl ester (racemic) (102 mg). Cis-(3-ethoxycyclopentyl)carbamic acid tert-butyl ester was stirred in 1:1 trifluoroacetic acid:dichloromethane for 0.5 h. The solvent was removed by evaporation to provide cis-3-ethoxycyclopentylamine (racemic). The resulting mixture was refluxed for an additional 16 h The solvents were evaporated the crude residue was chromatographed with silica gel (1:10 ethyl acetate:hexanes)

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

Procedure: To a stirred solution cooled in an ice-water bath of the above crude product, (tert-butoxycarbonyl-cyclopent-3-enyl-amino)-oxo-acetic acid ethyl ester, (3.80 g) in THF (35 mL) was added a solution of LiOH (0.0765 mol) in water (35 mL). The mixture was stirred in the ice-water bath for 3 h. The organic material was extracted with CH2Cl2 (30 mL×3), the organic layers were combined and washed with brine (30 mL×2), and the solvent was removed in vacuo. The residue was purified by column chromatography (silica gel, 100% dichloromethane) to obtain white crystals of pure product (53%). The organic material was extracted with CH2Cl2 (30 mL×3) washed with brine (30 mL×2) the solvent was removed in vacuo The residue was purified by column chromatography (silica gel, 100% dichloromethane)