2-chloro-4-ethoxy-1-fluorobenzene

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

Procedure: A mixture of 3-chloro-4-fluorophenol (2.0 g, 13.7 mmol), diethylsulfate (1.58 mL, 17.8 mmol) and K2CO3 (9.4 g, 68.5 mmol) in acetone (20 mL) was heated under refluxed for 3 h. The reaction mixture was filtered and concentrated. The residue was diluted with ethyl acetate (50 mL), washed with water (30 mL) and brine. The organic layer was dried (Na2SO4) and concentrated to give the title compound as a liquid. 1H NMR (CDCl3, 400 MHz): δ=1.39 (t, 3H, J=7.2 Hz), 3.97 (q, 2H, J=7.2 Hz), 6.71-6.74 (m, 1H), 6.89-6.91 (m, 1H), 7.02 (t, 1H, J=8.8 Hz). was heated under refluxed for 3 h The reaction mixture was filtered concentrated The residue was diluted with ethyl acetate (50 mL) washed with water (30 mL) and brine The organic layer was dried (Na2SO4) concentrated

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

Procedure: To a cold (−78° C.) solution of 2-Chloro-4-ethoxy-1-fluorobenzene (5.0 g, 28.6 mmol) in THF (100 mL) was added LDA (1.8 M in THF/heptane/ethylbenzene; 40 mL, 72 mmol). After 7 minutes, DMF (7 mL, 85.8 mmol) was added dropwise while keeping the temperature below −60° C. After 40 minutes, the reaction mixture was quenched with sat. aq. ammonium chloride. The organic layer was separated and the aq. layer was washed with ethyl acetate (2×50 mL). The combined organic layer was washed with water (30 mL) followed by brine. The organic layer was dried (Na2SO4) and concentrated to give a 1:1 mixture of the target compound and a regioisomeric aldehyde. The mixture was purified by column chromatography (5/95, ethyl acetate/hexanes) to give the title compound as a white solid. 1H NMR (CDCl3, 400 MHz): δ=1.46 (t, 3H, J=7.2 Hz), 4.11 (q, 2H, J=7.2 Hz), 6.84-6.86 (m, 1H), 7.25-7.28 (m, 1H), 10.48 (s, 1H). the temperature below −60° C After 40 minutes the reaction mixture was quenched with sat. aq. ammonium chloride The organic layer was separated the aq. layer was washed with ethyl acetate (2×50 mL) The combined organic layer was washed with water (30 mL) The organic layer was dried (Na2SO4) concentrated to give a 1:1 mixture of the target compound The mixture was purified by column chromatography (5/95, ethyl acetate/hexanes)