4-fluoro-2,6-dimethoxybenzaldehyde

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

Procedure: Phosphorous oxychloride (1.8 mL, 19.3 mmol) was added slowly to a well-stirred mixture of 1-fluoro-3,5-dimethoxy benzene (2.6 mL, 19.25 mmol) and N,N-dimethylformamide (2.5 mL, 20 mmol) while temperature was kept below −5° C. Stirring was continued at room temperature for 1.5 h and at 60° C. for another 2 h. Reaction completion was monitored by TLC. The reaction mixture was cooled and hydrolyzed with ice-water (60 mL). The resulting suspension was neutralized by addition of 5N NaOH, extracted with ethyl acetate (2×30 mL), the aqueous phase was adjusted to pH 10 by 5N NaOH and re-extracted with ethyl acetate (2×30 mL). The combined organic phases were washed with saturated aqueous NaHCO3 solution (30 mL) and brine (30 mL) and dried over anhydrous sodium sulfate. The dried solution was concentrated to get the crude product which on purification by column chromatography afforded a colorless pure product. Yield: 75%; white solid mp 79-81° C. 1H NMR: δ 3.85 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 6.25 (S, 2H, Ar—H), 10.24 (s, 1H, CHO). Anal. Calcd for C18H19FO5S: C, 58.70, H, 4.92. Found: C, 58.64, H, 4.91. was kept below −5° C Reaction completion extracted with ethyl acetate (2×30 mL) re-extracted with ethyl acetate (2×30 mL) The combined organic phases were washed with saturated aqueous NaHCO3 solution (30 mL) and brine (30 mL) dried over anhydrous sodium sulfate The dried solution was concentrated

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

Procedure: Phosphorous oxychloride (1.8 mL, 19.3 mmol) was added slowly to a well-stirred mixture of 1-fluoro-3,5-dimethoxy benzene (2.6 mL, 19.25 mmol) and N,N-dimethylformamide (2.5 mL, 20 mmol) while temperature was kept below −5° C. Stirring was continued at room temperature for 1.5 h and at 60° C. for another 2 h. Reaction completion was monitored by TLC. The reaction mixture was cooled and hydrolyzed with ice-water (60 mL). The resulting suspension was neutralized by addition of 5N NaOH, extracted with ethyl acetate (2×30 mL), the aqueous phase was adjusted to pH 10 by 5N NaOH and re-extracted with ethyl acetate (2×30 mL). The combined organic phases were washed with saturated aqueous NaHCO3 solution (30 mL) and brine (30 mL) and dried over anhydrous sodium sulfate. The dried solution was concentrated to get the crude product which on purification by column chromatography afforded a colorless pure product. Yield: 75%; white solid mp 79-81° C. 1H NMR: δ 3.85 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 6.25 (S, 2H, Ar—H), 10.24 (s, 1H, CHO). Anal. Calcd for C18H19FO5S: C, 58.70, H, 4.92. Found: C, 58.64, H, 4.91. was kept below −5° C Reaction completion extracted with ethyl acetate (2×30 mL) re-extracted with ethyl acetate (2×30 mL) The combined organic phases were washed with saturated aqueous NaHCO3 solution (30 mL) and brine (30 mL) dried over anhydrous sodium sulfate The dried solution was concentrated

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

Procedure: A cooled (−5° C.) mixture of commercially available 1-fluoro-3,5-dimethoxybenzene (500 mg; 3.20 mmol; 1.0 equiv.) and DMF (4.680 g; 64.03 mmol; 20.0 equiv.) was treated dropwise with POCl3 (2.454 g; 16.01 mmol; 5.0 equiv.). This mixture was further stirred at rt for 1.5 h, and was then heated to 60° C. for 3 h. After cooling to rt, ice-water (50 ml) and a solution of 2.5 M aq. NaOH (24 ml) were successively added. After extractions with AcOEt (3×30 ml), the mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=1/1) afforded 4-fluoro-2,6-dimethoxybenzaldehyde as a yellow solid. LC-MS (conditions A): tR=0.50 min.; [M+H]+: 185.10 g/mol. According to 1H-NMR (CDCl3; 400 MHz), this product also contained 19% of the regioisomer 2-fluoro-4,6-dimethoxybenzaldehyde. This minor regioisomer could be advantageously removed after further chemical transformations of the isomeric mixture. A cooled was then heated to 60° C. for 3 h After cooling to rt After extractions with AcOEt (3×30 ml) the mixed organic layers were dried over anh. MgSO4 filtered concentrated to dryness under reduced pressure Purification by FC (heptane/AcOEt=1/1)

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

Procedure: Phosphorous oxychloride (1.8 mL, 19.3 mmol) was added slowly to a well-stirred mixture of 1-fluoro-3,5-dimethoxy benzene (2.6 mL, 19.25 mmol) and N,N-dimethylformamide (2.5 mL, 20 mmol) while temperature was kept below −5° C. Stirring was continued at room temperature for 1.5 h and at 60° C. for another 2 h. Reaction completion was monitored by TLC. The reaction mixture was cooled and hydrolyzed with ice-water (60 mL). The resulting suspension was neutralized by addition of 5N NaOH, extracted with ethyl acetate (2×30 mL), the aqueous phase was adjusted to pH 10 by 5N NaOH and re-extracted with ethyl acetate (2×30 mL). The combined organic phases were washed with saturated aqueous NaHCO3 solution (30 mL) and brine (30 mL) and dried over anhydrous sodium sulfate. The dried solution was concentrated to get the crude product which on purification by column chromatography afforded a colorless pure product. Yield: 75%; white solid mp 79-81° C. 1H NMR: δ 3.85 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 6.25 (S, 2H, Ar—H), 10.24 (s, 1H, CHO). Anal. Calcd for C18H19FO5S: C, 58.70, H, 4.92. Found: C, 58.64, H, 4.91. was kept below −5° C Reaction completion extracted with ethyl acetate (2×30 mL) re-extracted with ethyl acetate (2×30 mL) The combined organic phases were washed with saturated aqueous NaHCO3 solution (30 mL) and brine (30 mL) dried over anhydrous sodium sulfate The dried solution was concentrated

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

Procedure: A cooled (−5° C.) mixture of commercially available 1-fluoro-3,5-dimethoxybenzene (500 mg; 3.20 mmol; 1.0 equiv.) and DMF (4.680 g; 64.03 mmol; 20.0 equiv.) was treated dropwise with POCl3 (2.454 g; 16.01 mmol; 5.0 equiv.). This mixture was further stirred at rt for 1.5 h, and was then heated to 60° C. for 3 h. After cooling to rt, ice-water (50 ml) and a solution of 2.5 M aq. NaOH (24 ml) were successively added. After extractions with AcOEt (3×30 ml), the mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=1/1) afforded 4-fluoro-2,6-dimethoxybenzaldehyde as a yellow solid. LC-MS (conditions A): tR=0.50 min.; [M+H]+: 185.10 g/mol. According to 1H-NMR (CDCl3; 400 MHz), this product also contained 19% of the regioisomer 2-fluoro-4,6-dimethoxybenzaldehyde. This minor regioisomer could be advantageously removed after further chemical transformations of the isomeric mixture. A cooled was then heated to 60° C. for 3 h After cooling to rt After extractions with AcOEt (3×30 ml) the mixed organic layers were dried over anh. MgSO4 filtered concentrated to dryness under reduced pressure Purification by FC (heptane/AcOEt=1/1)