5-fluoro-2-methylbenzaldehyde

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: 5-Fluoro-2-methylbenzaldehyde (40.58 g; 294 mmol) was converted to the ethyl cinnamate according to step 1 of example 1 to yield 40.81 g. of the title compound. to yield 40.81 g

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-fluoro-2-methylbenzaldehyde (50.0 g, 0.382 mol), nitroethane (54.34 g, 0.724 mol), and cyclohexylamine (35.90 g, 0.382 mol) in 300 mL of acetic acid was heated at 80° C. for 5-6 h under an argon atmosphere. After the end of the reaction was established by TLC, the reaction mixture was cooled to rt and the solvent was removed under vacuum. The residue was diluted with water, extracted with ethyl acetate three times. The combined extracts were dried over anhydrous MgSO4, filtered, and concentrated under vacuum. Product was purified by a silica gel chromatography using ethyl acetate and hexanes (1:6 to 1:4) as eluent to afford 62.8 g (89%) of the designed compound as yellow solid. Mass (ESI, positive) m/z 217.9 [M+Na]+. the reaction mixture was cooled to rt the solvent was removed under vacuum The residue was diluted with water extracted with ethyl acetate three times The combined extracts were dried over anhydrous MgSO4 filtered concentrated under vacuum Product was purified by a silica gel chromatography

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-fluoro-2-methylbenzaldehyde (50.0 g, 0.382 mol), nitroethane (54.34 g, 0.724 mol), and cyclohexylamine (35.90 g, 0.382 mol) in 300 mL of acetic acid was heated at 80° C. for 5-6 h under an argon atmosphere. After the end of the reaction was established by TLC, the reaction mixture was cooled to rt and the solvent was removed under vacuum. The residue was diluted with water, extracted with ethyl acetate three times. The combined extracts were dried over anhydrous MgSO4, filtered, and concentrated under vacuum. Product was purified by a silica gel chromatography using ethyl acetate and hexanes (1:6 to 1:4) as eluent to afford 62.8 g (89%) of the designed compound as yellow solid. Mass (ESI, positive) m/z 217.9 [M+Na]+. the reaction mixture was cooled to rt the solvent was removed under vacuum The residue was diluted with water extracted with ethyl acetate three times The combined extracts were dried over anhydrous MgSO4 filtered concentrated under vacuum Product was purified by a silica gel chromatography

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

Procedure: A mixture of acetone (80 ml), sodium hydroxide (3.7 g) and water (100 ml) was treated at room temperature dropwise with a solution of 5-fluoro-2-methylbenzaldehyde (11.5 g) in acetone (30 ml) and stirred at the same temperature for 1 hour. Acetone was distilled off under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and concentrated under reduced pressure to obtain 4-(5-fluoro-2-methylphenyl)-3-buten-2-one (13.4 g). Acetone was distilled off under reduced pressure the mixture was extracted with ethyl acetate The organic layer was washed successively with water and saturated brine concentrated under reduced pressure

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-bromo-4-fluorotoluene (16.0 g) in anhydrous tetrahydrofuran was treated dropwise at −78° C. with a 1.6 M solution of butyllithium in hexane (55.5 ml). At the same temperature, the mixture was stirred and treated dropwise with a solution of dimethylformamide (6.8 g) in tetrahydrofuran (20 ml). After being allowed to warm to 0° C., the reaction mixture was combined with ice-water. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 5-fluoro-2-methylbenzaldehyde (11.5 g) as an oil. The reaction mixture was extracted with ethyl acetate the organic layer was washed successively with water and saturated brine dried over magnesium sulfate The solvent was distilled off under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A mixture of acetone (80 ml), sodium hydroxide (3.7 g) and water (100 ml) was treated at room temperature dropwise with a solution of 5-fluoro-2-methylbenzaldehyde (11.5 g) in acetone (30 ml) and stirred at the same temperature for 1 hour. Acetone was distilled off under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and concentrated under reduced pressure to obtain 4-(5-fluoro-2-methylphenyl)-3-buten-2-one (13.4 g). Acetone was distilled off under reduced pressure the mixture was extracted with ethyl acetate The organic layer was washed successively with water and saturated brine concentrated under reduced pressure

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-bromo-4-fluorotoluene (16.0 g) in anhydrous tetrahydrofuran was treated dropwise at −78° C. with a 1.6 M solution of butyllithium in hexane (55.5 ml). At the same temperature, the mixture was stirred and treated dropwise with a solution of dimethylformamide (6.8 g) in tetrahydrofuran (20 ml). After being allowed to warm to 0° C., the reaction mixture was combined with ice-water. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 5-fluoro-2-methylbenzaldehyde (11.5 g) as an oil. The reaction mixture was extracted with ethyl acetate the organic layer was washed successively with water and saturated brine dried over magnesium sulfate The solvent was distilled off under reduced pressure

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

Procedure: A mixture of 4-amino-benzoic acid ethyl ester (1.65 g, 10 mmol) and 5-fluoro-2-methyl-benzaldehyde (1.38 g, 10 mmol) in ethanol (10 mL) was heated to reflux for 2 hours. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-{[1-(5-fluoro-2-methyl-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (2.0 g, 70%) as a white solid: LC/MS m/e calcd for C17H16FNO2 (M+H)+: 285.3, observed: 286.3. was heated to reflux for 2 hours The solvent was removed in vacuo the residue was washed with ether

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

Procedure: A mixture of 4-amino-benzoic acid ethyl ester (1.65 g, 10 mmol) and 5-fluoro-2-methyl-benzaldehyde (1.38 g, 10 mmol) in ethanol (10 mL) was heated to reflux for 2 hours. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-{[1-(5-fluoro-2-methyl-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (2.0 g, 70%) as a white solid: LC/MS m/e calcd for C17H16FNO2 (M+H)+: 285.3, observed: 286.3. was heated to reflux for 2 hours The solvent was removed in vacuo the residue was washed with ether

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-fluoro-2-methylbenzaldehyde (50.0 g, 0.382 mol), nitroethane (54.34 g, 0.724 mol), and cyclohexylamine (35.90 g, 0.382 mol) in 300 mL of acetic acid was heated at 80° C. for 5-6 h under an argon atmosphere. After the end of the reaction was established by TLC, the reaction mixture was cooled to rt and the solvent was removed under vacuum. The residue was diluted with water, extracted with ethyl acetate three times. The combined extracts were dried over anhydrous MgSO4, filtered, and concentrated under vacuum. Product was purified by a silica gel chromatography using ethyl acetate and hexanes (1:6 to 1:4) as eluent to afford 62.8 g (89%) of the designed compound as yellow solid. Mass (ESI, positive) m/z 217.9 [M+Na]+. the reaction mixture was cooled to rt the solvent was removed under vacuum The residue was diluted with water extracted with ethyl acetate three times The combined extracts were dried over anhydrous MgSO4 filtered concentrated under vacuum Product was purified by a silica gel chromatography