5-oxohexanenitrile

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:; See reaction.notes.procedure_details.

Procedure: The Grignard reagent of 3,5-dichlorophenyl iodide was prepared by the reaction of 20.0 grams (0.073 mole) of 3,5-dichlorophenyl iodide and 1.8 grams (0.073 mole) of magnesium turnings in 350 mL of diethyl ether. The reaction mixture was heated at reflux for about three hours and then allowed to cool to ambient temperature. To the Grignard reagent, with stirring, was added dropwise during a 15 minute period a solution of 8.4 mL (0.073 mole) of 5-oxohexanenitrile in 25 mL of diethyl ether. The exothermic reaction caused the reaction mixture temperature to rise to about 30 ° C. Upon completion of addition, the reaction mixture was stirred for one hour and then was poured into 400 mL of water. The mixture was made acidic with about 80 mL of aqueous 2N hydrochloric acid and extracted with two 200 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chroma-tography on silica gel, using 5% diethyl ether in methylene chloride as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 8.4 grams of 5-hydroxy-5-(3,5-dichlorophenyl)hexanenitrile. The NMR spectrum was consistent with the proposed structure. The reaction mixture was heated at reflux for about three hours The exothermic reaction to rise to about 30 ° C Upon completion of addition extracted with two 200 mL portions of diethyl ether The combined extracts were dried with magnesium sulfate filtered The filtrate was concentrated under reduced pressure to a residue concentrated under reduced pressure

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

Procedure: The Grignard reagent of 3,5-dichlorophenyl iodide was prepared by the reaction of 20.0 grams (0.073 mole) of 3,5-dichlorophenyl iodide and 1.8 grams (0.073 mole) of magnesium turnings in 350 mL of diethyl ether. The reaction mixture was heated at reflux for about three hours and then allowed to cool to ambient temperature. To the Grignard reagent, with stirring, was added dropwise during a 15 minute period a solution of 8.4 mL (0.073 mole) of 5-oxohexanenitrile in 25 mL of diethyl ether. The exothermic reaction caused the reaction mixture temperature to rise to about 30 ° C. Upon completion of addition, the reaction mixture was stirred for one hour and then was poured into 400 mL of water. The mixture was made acidic with about 80 mL of aqueous 2N hydrochloric acid and extracted with two 200 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chroma-tography on silica gel, using 5% diethyl ether in methylene chloride as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 8.4 grams of 5-hydroxy-5-(3,5-dichlorophenyl)hexanenitrile. The NMR spectrum was consistent with the proposed structure. The reaction mixture was heated at reflux for about three hours The exothermic reaction to rise to about 30 ° C Upon completion of addition extracted with two 200 mL portions of diethyl ether The combined extracts were dried with magnesium sulfate filtered The filtrate was concentrated under reduced pressure to a residue concentrated under reduced pressure

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

Procedure: Under a nitrogen atmosphere a stirred solution of 7.5 grams (0.025 mole) of 3-(4-trifluoromethylphenyl)phenyl bromide in 100 mL of tetrahydrofuran was cooled to about -78 ° C., and 10.0 mL (0.025 mole) of n-butyllithium (2.5 molar in hexane) was added dropwise. Upon completion of addition, the reaction mixture was stirred at -78 ° C. for about one hour. After this time a solution of 2.8 grams (0.025 mole) of 5-oxohexanenitrile in 10 mL of tetrahydrofuran was added dropwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature as it stirred for about 18 hours. After this time the reaction mixture was diluted with diethyl ether and partitioned between an aqueous dilute solution of hydrochloric acid and diethyl ether. The organic layer was separated and dried with sodium sulfate. The mixture was filtered and concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, using 1:1 ethyl acetate and hexane as the eluant. The product-containing fractions were concentrated under reduced pressure, yielding about 3.0 grams of 5-hydroxy-5-[3-(4-trifluoromethylphenyl)phenyl]hexanenitrile. The NMR spectrum was consistent with the proposed structure. This reaction was repeated. Upon completion of addition Upon completion of addition to warm to ambient temperature as it stirred for about 18 hours partitioned between an aqueous dilute solution of hydrochloric acid and diethyl ether The organic layer was separated dried with sodium sulfate The mixture was filtered concentrated under reduced pressure to a residue The product-containing fractions were concentrated under reduced pressure

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

Procedure: Under a nitrogen atmosphere a stirred solution of 7.5 grams (0.025 mole) of 3-(4-trifluoromethylphenyl)phenyl bromide in 100 mL of tetrahydrofuran was cooled to about -78 ° C., and 10.0 mL (0.025 mole) of n-butyllithium (2.5 molar in hexane) was added dropwise. Upon completion of addition, the reaction mixture was stirred at -78 ° C. for about one hour. After this time a solution of 2.8 grams (0.025 mole) of 5-oxohexanenitrile in 10 mL of tetrahydrofuran was added dropwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature as it stirred for about 18 hours. After this time the reaction mixture was diluted with diethyl ether and partitioned between an aqueous dilute solution of hydrochloric acid and diethyl ether. The organic layer was separated and dried with sodium sulfate. The mixture was filtered and concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, using 1:1 ethyl acetate and hexane as the eluant. The product-containing fractions were concentrated under reduced pressure, yielding about 3.0 grams of 5-hydroxy-5-[3-(4-trifluoromethylphenyl)phenyl]hexanenitrile. The NMR spectrum was consistent with the proposed structure. This reaction was repeated. Upon completion of addition Upon completion of addition to warm to ambient temperature as it stirred for about 18 hours partitioned between an aqueous dilute solution of hydrochloric acid and diethyl ether The organic layer was separated dried with sodium sulfate The mixture was filtered concentrated under reduced pressure to a residue The product-containing fractions were concentrated under reduced pressure

Conditions: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 7.0 mL (0.05 mole) of 3-trifluoromethylphenyl bromide, 1.2 grams (0.05 mole) of magnesium and a crystal of iodine in about 70 mL of tetrahydrofuran was warmed to 35° C. to initiate the formation of the Grignard reagent. Upon formation of the Grignard reagent, the reaction mixture was cooled to ambient temperature and, with stirring, a solution of 5.8 mL (0.05 mole) of 5-oxohexanenitrile in 10 mL of tetrahydrofuran was added dropwise. The reaction mixture temperature increased to about 35° C., at which time the rate of addition was slowed to keep the reaction mixture temperature at about 35°-40° C. The complete addition required about 15 minutes. Upon completion of the addition, the reaction mixture was allowed to warm to ambient temperature, where it was stirred for 2 hours. After this time, the reaction mixture was poured into 200 mL of water and was acidified with aqueous 2N hydrochloric acid. The mixture was then extracted with two 150 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 6.3 grams of 5-hydroxy-5-(3-trifluoromethylphenyl)hexanenitrile. The NMR spectrum was consistent with the proposed structure. the rate of addition at about 35°-40° C The complete addition required about 15 minutes Upon completion of the addition to warm to ambient temperature where it was stirred for 2 hours The mixture was then extracted with two 150 mL portions of diethyl ether The combined extracts were dried with magnesium sulfate filtered The filtrate was concentrated under reduced pressure to a residual oil Elution concentrated under reduced pressure

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a flame dried round-bottomed flask equipped with a magnetic stir bar and a Dean-Stark apparatus and under inert atmosphere (N2), 5-oxo-hexanenitrile (1.69 g, 15.2 mmol) was dissolved in dry toluene (10 mL). Ethylene glycol (4.24 mL, 76.0 mmol) and p-TsOH (289 mg, 1.5 mmol) were added and the reaction mixture stirred at 120° C. for 5 h. The reaction mixture was then cooled down to rt and sat. aq. NaHCO3 was added. The layers were separated and the aq. layer extracted with CH2Cl2 (2×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as a pale yellow oil. LC-MS-conditions 02: tR=0.94 min. In a flame dried round-bottomed flask equipped with a magnetic stir bar The reaction mixture was then cooled down to rt The layers were separated the aq. layer extracted with CH2Cl2 (2×) The combined organic extracts were dried over Na2SO4 filtered concentrated under reduced pressure

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a flame dried round-bottomed flask equipped with a magnetic stir bar and a Dean-Stark apparatus and under inert atmosphere (N2), 5-oxo-hexanenitrile (1.69 g, 15.2 mmol) was dissolved in dry toluene (10 mL). Ethylene glycol (4.24 mL, 76.0 mmol) and p-TsOH (289 mg, 1.5 mmol) were added and the reaction mixture stirred at 120° C. for 5 h. The reaction mixture was then cooled down to rt and sat. aq. NaHCO3 was added. The layers were separated and the aq. layer extracted with CH2Cl2 (2×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as a pale yellow oil. LC-MS-conditions 02: tR=0.94 min. In a flame dried round-bottomed flask equipped with a magnetic stir bar The reaction mixture was then cooled down to rt The layers were separated the aq. layer extracted with CH2Cl2 (2×) The combined organic extracts were dried over Na2SO4 filtered concentrated under reduced pressure

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

Procedure: A mixture of 5-oxo-hexanenitrile (5 mL, TCI-US), 2-amino-3-formylpyridine (7 g, J. Org. Chem. 1983, vol.48, p3401) and ethanol (100 mL) was heated to reflux for 12 hours. Following evaporation of the solvent, the residue was chromatographed (silica gel, ethyl acetate) to give 4-[1,8]naphthyridin-2-yl-butyronitirile and the title product as colorless solids. 1H (CDCl3) δ 2.29 (3H, s); 2.83 (2H, t); 3.18 (2H, t); 7.48 (1H, dd); 8.04 (1H, s); 8.20 (1H, dd); 9.03 (1H, dd). Step 2 was heated to reflux for 12 hours evaporation of the solvent the residue was chromatographed (silica gel, ethyl acetate) to give 4-[1,8]naphthyridin-2-yl-butyronitirile

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

Procedure: A mixture of 5-oxo-hexanenitrile (5 mL, TCI-US), 2-amino-3-formylpyridine (7 g, J. Org. Chem. 1983, vol.48, p3401) and ethanol (100 mL) was heated to reflux for 12 hours. Following evaporation of the solvent, the residue was chromatographed (silica gel, ethyl acetate) to give 4-[1,8]naphthyridin-2-yl-butyronitirile and the title product as colorless solids. 1H (CDCl3) δ 2.29 (3H, s); 2.83 (2H, t); 3.18 (2H, t); 7.48 (1H, dd); 8.04 (1H, s); 8.20 (1H, dd); 9.03 (1H, dd). Step 2 was heated to reflux for 12 hours evaporation of the solvent the residue was chromatographed (silica gel, ethyl acetate) to give 4-[1,8]naphthyridin-2-yl-butyronitirile