methyl 2-(4-cyano-3-fluorophenyl)acetate

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: LiBH4 (1.94 mL, 3.88 mmol, 2 M in THF) was added to a stirred solution of methyl(4-cyano-3-fluorophenyl)acetate (0.50 g, 2.59 mmol) in THF (25 ml) at 0° C. The resulting solution was stirred for 12 h. Water (10 ml) was added, and the resulting solution was extracted with dichloromethane (2×50 ml). The combined organic layers were dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography eluting with EtOAc-Hexanes (7:3→1:1) to give the product as colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.60 (dd, J=7.4, J=7.1 Hz, 1H), 7.30 (s, 1H), 7.18 (dd, J=7.3, J=9.1 Hz, 1H), 3.95 (t, J=6.2 Hz, 2H), 2.93 (t, J=6.3 Hz, 2H). the resulting solution was extracted with dichloromethane (2×50 ml) The combined organic layers were dried over MgSO4 filtered evaporated under reduced pressure The residue was purified by column chromatography eluting with EtOAc-Hexanes (7:3→1:1)

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

Procedure: LiBH4 (1.94 mL, 3.88 mmol, 2 M in THF) was added to a stirred solution of methyl(4-cyano-3-fluorophenyl)acetate (0.50 g, 2.59 mmol) in THF (25 ml) at 0° C. The resulting solution was stirred for 12 h. Water (10 ml) was added, and the resulting solution was extracted with dichloromethane (2×50 ml). The combined organic layers were dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography eluting with EtOAc-Hexanes (7:3→1:1) to give the product as colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.60 (dd, J=7.4, J=7.1 Hz, 1H), 7.30 (s, 1H), 7.18 (dd, J=7.3, J=9.1 Hz, 1H), 3.95 (t, J=6.2 Hz, 2H), 2.93 (t, J=6.3 Hz, 2H). the resulting solution was extracted with dichloromethane (2×50 ml) The combined organic layers were dried over MgSO4 filtered evaporated under reduced pressure The residue was purified by column chromatography eluting with EtOAc-Hexanes (7:3→1:1)

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

Procedure: (4-Cyano-3-fluoro-phenyl)-acetic acid methyl ester (3.06 g, 15.84 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL) and cooled in a dry ice-acetone bath. Lithium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 17.42 mL) was added under a nitrogen atmosphere. The solution was stirred for 1 h, at which point methyliodide (4.91 mL) was added dropwise. The reaction was allowed to warm to ambient temperature while stirring. Upon reaction completion satd. aq. ammonium chloride (100 mL) was added and the bulk of the tetrahydrofuran evaporated under a nitrogen stream. The aqueous layer was then extracted with ethyl acetate (3×300 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude was purified by silica gel chromatography with ethyl acetate:hexanes (3:17) to give the title compound (1.73 g). cooled in a dry ice-acetone bath was added dropwise Upon reaction completion the bulk of the tetrahydrofuran evaporated under a nitrogen stream The aqueous layer was then extracted with ethyl acetate (3×300 mL) The combined organics were dried over magnesium sulfate filtered concentrated in vacuo The crude was purified by silica gel chromatography with ethyl acetate:hexanes (3:17)

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (60% dispersion in mineral oil, 0.360 g) was suspended in anhydrous tetrahydrofuran (60 mL) under nitrogen. 1,2-Dibromoethane (2.0 mL) was added to the suspension, followed by (4-cyano-3-fluoro-phenyl)-acetic acid methyl ester (0.499 g). After the rate of gas evolution slowed, the reaction mixture was transferred to an oil bath and heated to 75° C. for 15 min. The reaction mixture was allowed to cool to ambient temperature and quenched with excess saturated ammonium chloride. The organic layer was separated and the remaining aqueous layer extracted with ethyl acetate (5×60 mL). The combined organics were dried with magnesium sulfate, filtered, and concentrated in vacuo. The crude product (0.637 g) was purified by silica gel chromatography (ethyl acetate:hexanes=2:3) yielding the title compound (0.500 g). the reaction mixture was transferred to an oil bath to cool to ambient temperature quenched with excess saturated ammonium chloride The organic layer was separated the remaining aqueous layer extracted with ethyl acetate (5×60 mL) The combined organics were dried with magnesium sulfate filtered concentrated in vacuo The crude product (0.637 g) was purified by silica gel chromatography (ethyl acetate:hexanes=2:3)