3,5-二氟-4-甲硫基苯甲醛

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 3,5-difluoro-4-(methylthio)-benzaldehyde (31.3 g, 0.166 mol) in anhydrous THF (200 mL) cooled with a cold water bath was added sodium borohydride (1.6 g, 0.042 mol) in portions over 30 minutes. After stirring 1 hour at room temperature, excess dilute HCl was added, until gas evolution ceased. Water (600 mL) was added and the mixture extracted with dichloromethane (1×500 mL, 1×100 mL). The combined extracts were washed once with water, dried with magnesium sulfate, and concentrated. Purification by silica gel chromatography using 3% ethyl acetate/10% dichloromethane in hexanes initially, and eluting product with 60% ethyl acetate in hexanes gave [3,5-difluoro-4-(methylthio)-phenyl]methanol as a light yellow liquid (24.8 g, 78%). 1H NMR (CDCl3/400 MHz) 6.88-6.93 (m, 2H), 4.65 (s, 2H), 2.42 (s, 3H). HRMS m/z 190.0266 (M+H+, calcd 190.0264). the mixture extracted with dichloromethane (1×500 mL, 1×100 mL) The combined extracts were washed once with water dried with magnesium sulfate concentrated Purification by silica gel chromatography eluting product with 60% ethyl acetate in hexanes

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 3,4,5-trifluorobenzaldehyde (30.0 g, 0.187 mol) in anhydrous THF (400 mL) cooled in a cold water bath was added sodium thiomethoxide (14.4 g, 0.20 mol) in portions over 30 minutes. The mixture was stirred at room temperature for 18 hours, then poured into water and extracted with dichloromethane (1×500 mL, 2×200 mL). The combined extracts were washed with water, dried using magnesium sulfate, and concentrated. Purification of the product by silica gel chromatography using 2% dichloromethane/5% ethyl acetate in hexanes gave the 3,5-difluoro-4-(methylthio)-benzaldehyde as a clear colorless liquid (22.0 g, 62%). 1H NMR (CDCl3/400 MHz) 9.86 (t, J=1.5, 1H), 7.34-7.39 (m, 2H), 2.55 (s, 3H). HRMS m/z 188.0099 (M+, calcd 188.0107). extracted with dichloromethane (1×500 mL, 2×200 mL) The combined extracts were washed with water dried concentrated Purification of the product by silica gel chromatography

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 3,5-difluoro-4-(methylthio)-benzaldehyde (31.3 g, 0.166 mol) in anhydrous THF (200 mL) cooled with a cold water bath was added sodium borohydride (1.6 g, 0.042 mol) in portions over 30 minutes. After stirring 1 hour at room temperature, excess dilute HCl was added, until gas evolution ceased. Water (600 mL) was added and the mixture extracted with dichloromethane (1×500 mL, 1×100 mL). The combined extracts were washed once with water, dried with magnesium sulfate, and concentrated. Purification by silica gel chromatography using 3% ethyl acetate/10% dichloromethane in hexanes initially, and eluting product with 60% ethyl acetate in hexanes gave [3,5-difluoro-4-(methylthio)-phenyl]methanol as a light yellow liquid (24.8 g, 78%). 1H NMR (CDCl3/400 MHz) 6.88-6.93 (m, 2H), 4.65 (s, 2H), 2.42 (s, 3H). HRMS m/z 190.0266 (M+H+, calcd 190.0264). the mixture extracted with dichloromethane (1×500 mL, 1×100 mL) The combined extracts were washed once with water dried with magnesium sulfate concentrated Purification by silica gel chromatography eluting product with 60% ethyl acetate in hexanes

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 3,4,5-trifluorobenzaldehyde (30.0 g, 0.187 mol) in anhydrous THF (400 mL) cooled in a cold water bath was added sodium thiomethoxide (14.4 g, 0.20 mol) in portions over 30 minutes. The mixture was stirred at room temperature for 18 hours, then poured into water and extracted with dichloromethane (1×500 mL, 2×200 mL). The combined extracts were washed with water, dried using magnesium sulfate, and concentrated. Purification of the product by silica gel chromatography using 2% dichloromethane/5% ethyl acetate in hexanes gave the 3,5-difluoro-4-(methylthio)-benzaldehyde as a clear colorless liquid (22.0 g, 62%). 1H NMR (CDCl3/400 MHz) 9.86 (t, J=1.5, 1H), 7.34-7.39 (m, 2H), 2.55 (s, 3H). HRMS m/z 188.0099 (M+, calcd 188.0107). extracted with dichloromethane (1×500 mL, 2×200 mL) The combined extracts were washed with water dried concentrated Purification of the product by silica gel chromatography

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 3,5-difluoro-4-(methylthio)-benzaldehyde (31.3 g, 0.166 mol) in anhydrous THF (200 mL) cooled with a cold water bath was added sodium borohydride (1.6 g, 0.042 mol) in portions over 30 minutes. After stirring 1 hour at room temperature, excess dilute HCl was added, until gas evolution ceased. Water (600 ml) was added and the mixture extracted with dichloromethane (1×500 mL, 1×100 mL). The combined extracts were washed once with water, dried with magnesium sulfate, and concentrated. Purification by silica gel chromatography using 3% ethyl acetate/10% dichloromethane in hexanes initially, and eluting product with 60% ethyl acetate in hexanes gave [3,5-difluoro-4-(methylthio)-phenyl]methanol as a light yellow liquid (24.8 g, 78%). 1H NMR (CDCl3/400 MHz) 6.88-6.93 (m, 2H), 4.65 (s, 2H), 2.42 (s, 3H). HRMS m/z 190.0266 (M+H+, calcd 190.0264). the mixture extracted with dichloromethane (1×500 mL, 1×100 mL) The combined extracts were washed once with water dried with magnesium sulfate concentrated Purification by silica gel chromatography eluting product with 60% ethyl acetate in hexanes

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 3,4,5-trifluorobenzaldehyde (30.0 g, 0.187 mol) in anhydrous THF (400 mL) cooled in a cold water bath was added sodium thiomethoxide (14.4 g, 0.20 mol) in portions over 30 minutes. The mixture was stirred at room temperature for 18 hours, then poured into water and extracted with dichloromethane (1×500 mL, 2×200 mL). The combined extracts were washed with water, dried using magnesium sulfate, and concentrated. Purification of the product by silica gel chromatography using 2% dichloromethane/5% ethyl acetate in hexanes gave the 3,5-difluoro-4-(methylthio)-benzaldehyde as a clear colorless liquid (22.0 g, 62%). 1H NMR (CDCl3/400 MHz) 9.86 (t, J=1.5, 1H), 7.34-7.39 (m, 2H), 2.55 (s, 3H). HRMS m/z 188.0099 (M+, calcd 188.0107). extracted with dichloromethane (1×500 mL, 2×200 mL) The combined extracts were washed with water dried concentrated Purification of the product by silica gel chromatography

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The product from step B was converted to the bromide according to the procedure from intermediate 5 (step A). 1H NMR (500 MHz, CDCl3) δ 7.36 (d, J 7.5 Hz, 2H), 4.82 (s, 2H), 2.88 (s, 3H)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Sodium borohydride (25 mg, 0.66 mmol) was added to a 0° C. slurry of the product of step A (124 mg, 0.659 mmol) in methanol (4.39 mL). After 30 min the reaction mixture was warmed to room temperature, and at 1.5 h the reaction was diluted with DCM and quenched with 0.1 N HCl. The aqueous was extracted with DCM (2×) and then washed with saturated aqueous NaCl (1×). The combined organic layer was dried over Na2SO4, filtered and evaporated in vacuo to yield the title compound. 1H NMR (500 MHz, CDCl3) δ 6.81 (d, J 7.5 Hz, 2H), 4.55 (s, 2H), 3.23 (s, 1H), 2.37 (s, 3H). quenched with 0.1 N HCl The aqueous was extracted with DCM (2×) washed with saturated aqueous NaCl (1×) The combined organic layer was dried over Na2SO4 filtered evaporated in vacuo