2-chloro-6-ethoxy-3-fluorobenzaldehyde

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)

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

Procedure: A solution of 2-Chloro-6-ethoxy-3-fluorobenzaldehyde (2.0 g, 9.8 mmol), 5-bromo-7-azaindole (1.8 g, 8.9 mmol) and KOH (797 mg, 14.2 mmol) in methanol (30 mL) was stirred for 48 h at room temperature. The reaction mixture was concentrated to dryness and diluted with saturated aq. ammonium chloride. The aq. layer was extracted with ethyl acetate (2×30 mL). The combined organic layers were dried (Na2SO4) and concentrated to give a residue that was purified by column chromatography (5/95, methanol/DCM) to give the title compound as foamy solid. 1H NMR (CDCl3, 400 MHz): δ=1.35 (t, 3H, J=7.2 Hz), 3.43 (s, 3H), 4.0 (q, 1H, J=7.2 Hz), 4.07 (q, 1H, J=7.2 Hz), 6.39 (s, 1H), 6.81 (dd, 1H, J=4.0, 9.2 Hz), 7.01 (t, 1H, J=8.4 Hz), 8.06 (d, 1H, J=2.0 Hz), 8.29 (d, 1H, J=2.0 Hz), 9.49 (s, 1H). The reaction mixture was concentrated to dryness diluted with saturated aq. ammonium chloride The aq. layer was extracted with ethyl acetate (2×30 mL) The combined organic layers were dried (Na2SO4) concentrated to give a residue that was purified by column chromatography (5/95, methanol/DCM)