Methyl 4-fluorocinnamate

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-bromo-4-fluorobenzene (10 g, 57 mmol), methyl acrylate (4.5 g, 52 mmol), tetraethylammonium chloride (8.6 g, 52 mmol), N-cyclohexyl-N-methylcyclohexanamine (15 g, 78 mmol), and palladium (II) acetate (0.35 g, 1.6 mmol) in dimethylacetamide (200 mL) was heated to 100° C. under an argon atmosphere. The reaction was allowed to proceed until the aryl halide was consumed. The reaction mixture was then cooled to room temperature, diluted with Et2O, and washed three times with water. The separated organic phase was dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with EtOAc/hexanes to afford 8.5 g (91% yield) of the title compound. was consumed The reaction mixture was then cooled to room temperature diluted with Et2O washed three times with water The separated organic phase was dried over MgSO4 concentrated in vacuo The crude product was purified by flash column chromatography on silica gel eluting with EtOAc/hexanes

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

Procedure: Trifluoroacetic acid (38.9 mL, 0.505 mmol) was added to a solution of the product of step B (1.03 g, 5.05 mmol) and methyl (2E)-3-(4-fluorophenyl)prop-2-enoate (1.00 g, 5.05 mmol) in methylene chloride (10 mL) at ambient temperature. After 18 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted three times with methylene chloride. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification of the crude residue by medium pressure liquid chromatography on silica gel (gradient elution; 0–9% methanol (containing 10% v/v ammonium hydroxide)/methylene chloride as eluent) furnished the title compound as a colorless liquid (1.06 g). extracted three times with methylene chloride The combined organic extracts were washed with brine dried (Na2SO4) concentrated in vacuo Purification of the crude residue by medium pressure liquid chromatography on silica gel (gradient elution; 0–9% methanol (containing 10% v/v ammonium hydroxide)/methylene chloride as eluent)

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

Procedure: Dimethyl malonate (14.7 g, 111 mmol) was added dropwise to the mixture of sodium methoxide in methanol (methanol solution 28%, 19.3 g, 100 mmol) and methanol (30 ml) under ice cooling and stirred for 15 minutes. To the mixture was added a solution of methyl (2E)-3-(4-fluorophenyl)-2-propenoate (10.0 g, 55.5 mmol) obtained in Reference Example 1 in THF (50 ml) under ice cooling and the mixture was refluxed for 12 hours. The resulting mixture was concentrated under reduced pressure, and the residue was diluted with water. The aqueous layer was acidified with dilute hydrochloric acid, extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (hexane/ethyl-acetate=8/1) to obtain 12.7 g (yield 73%) of 2-(4-fluorophenyl)-1,1,3-trimethoxy carbonyl propane via recrystallization (ethyl acetate-hexane). mp. 75–76° C. the mixture was refluxed for 12 hours The resulting mixture was concentrated under reduced pressure the residue was diluted with water extracted with ethyl acetate The organic layer was washed with water and saturated aqueous sodium chloride dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-bromo-4-fluorobenzene (10 g, 57 mmol), methyl acrylate (4.5 g, 52 mmol), tetraethylammonium chloride (8.6 g, 52 mmol), N-cyclohexyl-N-methylcyclohexanamine (15 g, 78 mmol), and palladium (II) acetate (0.35 g, 1.6 mmol) in dimethylacetamide (200 mL) was heated to 100° C. under an argon atmosphere. The reaction was allowed to proceed until the aryl halide was consumed. The reaction mixture was then cooled to room temperature, diluted with Et2O, and washed three times with water. The separated organic phase was dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with EtOAc/hexanes to afford 8.5 g (91% yield) of the title compound. was consumed The reaction mixture was then cooled to room temperature diluted with Et2O washed three times with water The separated organic phase was dried over MgSO4 concentrated in vacuo The crude product was purified by flash column chromatography on silica gel eluting with EtOAc/hexanes