3-(Benzyloxy)propionitrile

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

Procedure: To generate indolizidine alcohol and aldehyde intermediates useful in the synthesis of pumiliotoxin B, it is necessary to assemble a chiral silylalkyne from esters of (S)-5-(benzyloxy)-1-trimethyl-silyl-1-pentyn-3-ol. This involves the reduction of 3-(benzyloxy)propanitrile, the latter reagent being prepared from acrylonitrile and benzyl alcohol as described by Gaiffe and Launay in Academy of Science, Serial C, Pages 1379-1380 (1968), with i-Bu2AlH to give 3-benzyloxy propanal which is condensed with ethynyllithium, prepared as described by Midland in the Journal of Organic Chemistry, Volume 40, Page 2250 (1975), to yield the racemic propargylic alcohol in about 50% yield following distillation. Reaction of the propargylic alcohol with R-(+)-2-methylbenzylamine gives the corresponding diastereomeric carbamates that upon chromatographic separation and carbamate cleavage with Cl3SiH as described by Pirkle in the Journal of Organic Chemistry, Volume 42, Page 2781 (1971) yields the (S)-alcohol and (R)-alcohol derivatives in yields of about 20%.

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

Procedure: To a solution of 3-(benzyloxy)propanenitrile (16.9 g 105 mmol) in diethyl ether (400 mL) were added titanium isopropoxide (35.7 mL, 115 mmol) and ethyl magnesium bromide (210 mL, 1 M in diethyl ether) successively at room temperature. After being stirred for 0.5 hour, boron trifluoride etherate (27 mL, 525 mmol) was added. After stirring for another 0.5 hour, 10% aqueous solution of sodium hydroxide (ca. 5.5 mL) was introduced to the above mixture. The resulting mixture was acidified with 1N hydrochloric acid to pH 3, and then washed with dichloromethane. The aqueous layer was basified with 5% aqueous solution of sodium hydroxide to pH 8˜9 and extracted with dichloromethane (100 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo to afford 11 g of 1-[2-(benzyloxy)ethyl]cyclopropanamine (yield was 55%). After stirring for another 0.5 hour washed with dichloromethane extracted with dichloromethane (100 mL) The organic layer was washed with brine (100 mL) dried over sodium sulfate concentrated in vacuo

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

Procedure: To a mixture of benzyl alcohol (108 g, 1 mol) and 40% aqueous solution of sodium hydroxide (10 mL) was added prop-2-enenitrile (58.3 g, 1.1 mol) and the mixture was stirred for 6 hours at room temperature. The mixture was neutralized with 1 N hydrochloric acid, and extracted with dichloromethane (300 mL). The organic layer was washed with 5% solution of sodium hydroxide (300 mL) and brine (300 mL), dried over sodium sulfate and concentrated in vacuo to afford 150 g of the desired compound (yield was 93%). extracted with dichloromethane (300 mL) The organic layer was washed with 5% solution of sodium hydroxide (300 mL) and brine (300 mL) dried over sodium sulfate concentrated in vacuo

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

Procedure: To a mixture of benzyl alcohol (108 g, 1 mol) and 40% aqueous solution of sodium hydroxide (10 mL) was added prop-2-enenitrile (58.3 g, 1.1 mol) and the mixture was stirred for 6 hours at room temperature. The mixture was neutralized with 1 N hydrochloric acid, and extracted with dichloromethane (300 mL). The organic layer was washed with 5% solution of sodium hydroxide (300 mL) and brine (300 mL), dried over sodium sulfate and concentrated in vacuo to afford 150 g of the desired compound (yield was 93%). extracted with dichloromethane (300 mL) The organic layer was washed with 5% solution of sodium hydroxide (300 mL) and brine (300 mL) dried over sodium sulfate concentrated in vacuo

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

Procedure: To a mixture of the compound (24.7 g) obtained in step (1) above, tetraisopropyl orthotitanate (49.4 mL) and methoxycyclopentane (306 mL), ethyl magnesium bromide (about 3 mol/L, solution in diethyl ether, 102 mL) was added at 0° C. and thereafter the mixture was stirred at room temperature for 3 hours. After adding boron trifluoride/diethylether complex (38.8 mL) at 0° C., the mixture was stirred at room temperature for 1.5 hours. After adding water at 0° C., pH was adjusted to 12 by adding a solution of 10% sodium hydroxide in water. The reaction mixture was extracted with chloroform three times. The combined organic layers were washed with saturated brine and then passed through a phase separator and concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (n-hexane:ethyl acetate=100:0-5:95) and further purified by silica gel column chromatography (n-hexane:ethylacetate=90:10-5:95, then chloroform:methanol=100:0-90:10) to give 1-[2-(benzyloxy)ethyl]cyclopropaneamine as a pale yellow oil (12.5 g). was added at 0° C. After adding boron trifluoride/diethylether complex (38.8 mL) at 0° C. the mixture was stirred at room temperature for 1.5 hours The reaction mixture was extracted with chloroform three times The combined organic layers were washed with saturated brine concentrated under reduced pressure The resulting residue was purified by NH silica gel column chromatography (n-hexane:ethyl acetate=100:0-5:95) further purified by silica gel column chromatography (n-hexane

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

Procedure: To a suspension of sodium hydride (60% dispersion in mineral oil; 14.6 g) in tetrahydrofuran (281 mL), ethylene cyanohydrin (21.0 mL) was added dropwise at 0° C. and the mixture was stirred at that temperature for 40 minutes. After adding benzyl bromide (44.4 mL) to the reaction mixture, the resulting mixture was stirred overnight as it was brought to room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate three times. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (n-hexane:ethyl acetate=100:0-70:30) to give 3-(benzyloxy)propanenitrile as a colorless oil (24.7 g). was added dropwise at 0° C. the resulting mixture was stirred overnight as it was brought to room temperature was then extracted with ethyl acetate three times The combined organic layers were washed with saturated brine dried over anhydrous magnesium sulfate The desiccant was removed by filtration the filtrate was concentrated under reduced pressure The resulting residue was purified by NH silica gel column chromatography (n-hexane:ethyl acetate=100:0-70:30)

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

Procedure: To generate indolizidine alcohol and aldehyde intermediates useful in the synthesis of pumiliotoxin B, it is necessary to assemble a chiral silylalkyne from esters of (S)-5-(benzyloxy)-1-trimethyl-silyl-1-pentyn-3-ol. This involves the reduction of 3-(benzyloxy)propanitrile, the latter reagent being prepared from acrylonitrile and benzyl alcohol as described by Gaiffe and Launay in Academy of Science, Serial C, Pages 1379-1380 (1968), with i-Bu2AlH to give 3-benzyloxy propanal which is condensed with ethynyllithium, prepared as described by Midland in the Journal of Organic Chemistry, Volume 40, Page 2250 (1975), to yield the racemic propargylic alcohol in about 50% yield following distillation. Reaction of the propargylic alcohol with R-(+)-2-methylbenzylamine gives the corresponding diastereomeric carbamates that upon chromatographic separation and carbamate cleavage with Cl3SiH as described by Pirkle in the Journal of Organic Chemistry, Volume 42, Page 2781 (1971) yields the (S)-alcohol and (R)-alcohol derivatives in yields of about 20%.

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

Procedure: To a solution of 3-(benzyloxy)propanenitrile (16.9 g 105 mmol) in diethyl ether (400 mL) were added titanium isopropoxide (35.7 mL, 115 mmol) and ethyl magnesium bromide (210 mL, 1 M in diethyl ether) successively at room temperature. After being stirred for 0.5 hour, boron trifluoride etherate (27 mL, 525 mmol) was added. After stirring for another 0.5 hour, 10% aqueous solution of sodium hydroxide (ca. 5.5 mL) was introduced to the above mixture. The resulting mixture was acidified with 1N hydrochloric acid to pH 3, and then washed with dichloromethane. The aqueous layer was basified with 5% aqueous solution of sodium hydroxide to pH 8˜9 and extracted with dichloromethane (100 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo to afford 11 g of 1-[2-(benzyloxy)ethyl]cyclopropanamine (yield was 55%). After stirring for another 0.5 hour washed with dichloromethane extracted with dichloromethane (100 mL) The organic layer was washed with brine (100 mL) dried over sodium sulfate concentrated in vacuo

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

Procedure: To a mixture of benzyl alcohol (108 g, 1 mol) and 40% aqueous solution of sodium hydroxide (10 mL) was added prop-2-enenitrile (58.3 g, 1.1 mol) and the mixture was stirred for 6 hours at room temperature. The mixture was neutralized with 1 N hydrochloric acid, and extracted with dichloromethane (300 mL). The organic layer was washed with 5% solution of sodium hydroxide (300 mL) and brine (300 mL), dried over sodium sulfate and concentrated in vacuo to afford 150 g of the desired compound (yield was 93%). extracted with dichloromethane (300 mL) The organic layer was washed with 5% solution of sodium hydroxide (300 mL) and brine (300 mL) dried over sodium sulfate concentrated in vacuo