4-(2-hydroxypropyl)-2-methoxybenzonitrile

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

Procedure: To a stirred solution of 4-(2-hydroxypropyl)-2-methoxybenzonitrile (1.45 g, 7.6 mmol) in dry CH2Cl2 (30 mL) at 0° C. was added Dess-Martin periodinane (4.2 g, 9.8 mmol) in one portion. The mixture was stirred for 12 h at RT and quenched with a 1:1 mixture of saturated Na2S2O3 (20 mL) and saturated NaHCO3 (20 mL). The resulting mixture was diluted with CH2Cl2 (50 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2×50 mL). The combined organic phases were washed with brine, dried (Na2SO4), and concentrated in vacuo to give 2-methoxy-4-(2-oxopropyl)benzonitrile as an oil. The crude residue was used in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 7.55 (dd, 1H, J=1.6 Hz), 6.87 (d, 1H, J=7.8 Hz), 6.83 (s, 1H), 3.96 (s, 3H), 3.79 (s, 2H), 2.25 (s, 3H). quenched with a 1:1 mixture of saturated Na2S2O3 (20 mL) and saturated NaHCO3 (20 mL) The resulting mixture was diluted with CH2Cl2 (50 mL) the layers were separated The aqueous phase was extracted with CH2Cl2 (2×50 mL) The combined organic phases were washed with brine dried (Na2SO4) concentrated in vacuo

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

Procedure: To a stirred solution of 1.48 g (8.47 mmol) of 2-methoxy-4-(2-oxoethyl)benzonitrile in dichloromethane (30 mL) at 0° C. was added 2.82 mL (8.47 mmol) of a 3.0 M solution of methylmagnesium bromide in THF. The reaction mixture was allowed to warm up to RT and stirred for 12 h. The reaction was then quenched by the addition of 10 mL of 1 N hydrochloric acid and extracted with dichloromethane (2×30 mL). The combined organic extracts were dried with magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified on silica (30% EtOAc/hexanes as eluent) to afford 4-(2-hydroxypropyl)-2-methoxybenzonitrile as a clear liquid. 1H NMR (500 MHz, CDCl3) δ 7.47 (d, 1H, J=7.8 Hz), 6.85 (dd, 1H, J=3.4 Hz), 6.82 (s, 1H), 4.05 (m, 1H), 3.93 (d, 2H), 3.91 (s, 3H), 1.25 (d, 2H, J=6.1 Hz). LC-MS (IE, m/z): 192.3 [M+1)+. The reaction was then quenched by the addition of 10 mL of 1 N hydrochloric acid extracted with dichloromethane (2×30 mL) The combined organic extracts were dried with magnesium sulfate filtered concentrated in vacuo The crude residue was purified on silica (30% EtOAc/hexanes as eluent)

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

Procedure: To a stirred solution of 4-(2-hydroxypropyl)-2-methoxybenzonitrile (1.5 g, 7.6 mmol) in dry CH2Cl2 (30 mL) at 0° C. was added Dess-Martin periodinane (4.2 g, 9.9 mmol) in one portion. The mixture was stirred for 12 h at rt and quenched with a 1:1 mixture of saturated Na2S2O3 (20 mL) and saturated NaHCO3 (20 mL). The resulting mixture was diluted with CH2Cl2 (50 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2×50 mL). The combined organic phases were washed with brine, dried (Na2SO4), and concentrated in vacuo to give 2-methoxy-4-(2-oxopropyl)benzonitrile. The crude residue was used in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 7.55 (dd, 1H, J=1.6 Hz), 6.87 (d, 1H, J=7.8 Hz), 6.83 (s, 1H), 3.96 (s, 3H), 3.79 (s, 2H), 2.25 (s, 3H); LCMS: [(M+1)]+=190.32; tR=2.31 min. quenched with a 1:1 mixture of saturated Na2S2O3 (20 mL) and saturated NaHCO3 (20 mL) The resulting mixture was diluted with CH2Cl2 (50 mL) the layers were separated The aqueous phase was extracted with CH2Cl2 (2×50 mL) The combined organic phases were washed with brine dried (Na2SO4) concentrated in vacuo

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

Procedure: To a stirred solution of 2-methoxy-4-(2-oxoethyl)benzonitrile (1.5 g, 8.5 mmol) in dichloromethane (30 mL) at 0° C. was added 2.8 mL (8.5 mmol) of a 3.0 M solution of methylmagnesium bromide in THF. The reaction mixture was allowed to warm up to rt and stirred for 12 h. The reaction was then quenched by the addition of 10 mL of 1 N hydrochloric acid and extracted with dichloromethane (2×30 mL). The combined organic extracts were dried with magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified on silica (30% EtOAc/hexanes as eluent) to afford 4-(2-hydroxypropyl)-2-methoxybenzonitrile. The reaction was then quenched by the addition of 10 mL of 1 N hydrochloric acid extracted with dichloromethane (2×30 mL) The combined organic extracts were dried with magnesium sulfate filtered concentrated in vacuo The crude residue was purified on silica (30% EtOAc/hexanes as eluent)

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

Procedure: To a stirred solution of 4-(2-hydroxypropyl)-2-methoxybenzonitrile (1.5 g, 7.6 mmol) in dry CH2Cl2 (30 mL) at 0° C. was added Dess-Martin periodinane (4.2 g, 9.9 mmol) in one portion. The mixture was stirred for 12 h at rt and quenched with a 1:1 mixture of saturated Na2S2O3 (20 mL) and saturated NaHCO3 (20 mL). The resulting mixture was diluted with CH2Cl2 (50 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2×50 mL). The combined organic phases were washed with brine, dried (Na2SO4), and concentrated in vacuo to give 2-methoxy-4-(2-oxopropyl)benzonitrile. The crude residue was used in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 7.55 (dd, 1H, J=1.6 Hz), 6.87 (d, 1H, J=7.8 Hz), 6.83 (s, 1H), 3.96 (s, 3H), 3.79 (s, 2H), 2.25 (s, 3H); LCMS: [(M+1)]+=190.32; tR=2.31 min. quenched with a 1:1 mixture of saturated Na2S2O3 (20 mL) and saturated NaHCO3 (20 mL) The resulting mixture was diluted with CH2Cl2 (50 mL) the layers were separated The aqueous phase was extracted with CH2Cl2 (2×50 mL) The combined organic phases were washed with brine dried (Na2SO4) concentrated in vacuo

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

Procedure: To a stirred solution of 2-methoxy-4-(2-oxoethyl)benzonitrile (1.5 g, 8.5 mmol) in dichloromethane (30 mL) at 0° C. was added 2.8 mL (8.5 mmol) of a 3.0 M solution of methylmagnesium bromide in THF. The reaction mixture was allowed to warm up to rt and stirred for 12 h. The reaction was then quenched by the addition of 10 mL of 1 N hydrochloric acid and extracted with dichloromethane (2×30 mL). The combined organic extracts were dried with magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified on silica (30% EtOAc/hexanes as eluent) to afford 4-(2-hydroxypropyl)-2-methoxybenzonitrile. 1H NMR (500 MHz, CDCl3) δ 7.47 (d, 1H, J=7.8 Hz), 6.85 (dd, 1H, J=3.4 Hz), 6.82 (s, 1H), 4.05 (m, 1H), 3.93 (d, 2H), 3.91 (s, 3H), 1.25 (d, 2H, J=6.1 Hz); LCMS: [(M+1)]+=192.30; tR=2.39 min. The reaction was then quenched by the addition of 10 mL of 1 N hydrochloric acid extracted with dichloromethane (2×30 mL) The combined organic extracts were dried with magnesium sulfate filtered concentrated in vacuo The crude residue was purified on silica (30% EtOAc/hexanes as eluent)