5-fluoro-2-methyl-1H-indole-3-carbaldehyde

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

Procedure: 5-fluoro-2-methyl-1H-indole-3-carbaldehyde (50 mg, 0.28 mmol) was dissolved in 3 mL dry DMF, followed by the addition of N,N-dimethylformamide dimethyl acetal (124 mg, 138 μL, 1.04 mmol). The reaction mixture was heated to 80° C. for 4 h and turned from light yellow to dark red over the course of the reaction. The crude reaction was concentrated in vacuo, dissolved in 0.5 mL DMSO/MeOH, and purified by reverse phase HPLC (5-95% water/acetonitrile gradient over 60 minutes) to obtain 2-((E)-2-(dimethylamino)vinyl)-5-fluoro-1-methyl-1H-indole-3-carbaldehyde as a pale yellow solid (40 mg, 62% yield). 1H NMR (400 mHz, DMSO-d6) δ 9.73 (s, 1H), 7.73 (dd, J=9.8, 2.6 Hz, 1H), 7.39 (m, 2H), 6.96 (dt, J=9.2, 2.6 Hz, 1H), 5.20 (d, J=13.1 Hz, 1H), 3.66 (s, 3H), 2.99 (s, 6H). Mass and purity were confirmed by LC/MS using an acetonitrile gradient with 5 mM ammonium formate pH 6.5. Theoretical (M+H)+ m/z for C14H15FN2O=247.12; Found 247.06. over the course of the reaction The crude reaction was concentrated in vacuo dissolved in 0.5 mL DMSO/MeOH purified by reverse phase HPLC (5-95% water/acetonitrile gradient over 60 minutes)

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

Procedure: 5-fluoro-2-methyl-1H-indole-3-carbaldehyde (50 mg, 0.28 mmol) was dissolved in 3 mL dry DMF, followed by the addition of N,N-dimethylformamide dimethyl acetal (124 mg, 138 μL, 1.04 mmol). The reaction mixture was heated to 80° C. for 4 h and turned from light yellow to dark red over the course of the reaction. The crude reaction was concentrated in vacuo, dissolved in 0.5 mL DMSO/MeOH, and purified by reverse phase HPLC (5-95% water/acetonitrile gradient over 60 minutes) to obtain 2-((E)-2-(dimethylamino)vinyl)-5-fluoro-1-methyl-1H-indole-3-carbaldehyde as a pale yellow solid (40 mg, 62% yield). 1H NMR (400 mHz, DMSO-d6) δ 9.73 (s, 1H), 7.73 (dd, J=9.8, 2.6 Hz, 1H), 7.39 (m, 2H), 6.96 (dt, J=9.2, 2.6 Hz, 1H), 5.20 (d, J=13.1 Hz, 1H), 3.66 (s, 3H), 2.99 (s, 6H). Mass and purity were confirmed by LC/MS using an acetonitrile gradient with 5 mM ammonium formate pH 6.5. Theoretical (M+H)+ m/z for C14H15FN2O=247.12; Found 247.06. over the course of the reaction The crude reaction was concentrated in vacuo dissolved in 0.5 mL DMSO/MeOH purified by reverse phase HPLC (5-95% water/acetonitrile gradient over 60 minutes)

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

Procedure: Dry DMF (0.6 mL) was added slowly to POCl3 (0.9 mL) at room temperature under nitrogen atmosphere, and the mixture stirred for 5 minutes. 5-fluoro-2-methyl-1H-indole (149 mg, 1.0 mmol) was dissolved in 5 mL dry DMF and added slowly to the rapidly stirring mixture to keep the temperature below 35° C. After stirring for 2 h at room temperature, the reaction mixture was poured into 30 mL ice water. The aqueous layer was basified (30 mL 1.0 N NaOH) and extracted into methylene chloride. The organic layer was washed with water (1×50 mL), brine (1×50 mL), and dried over Na2SO4. The solvent was removed in vacuo to yield an off-white solid. The solid was brought up in 1:3 MeOH/methylene chloride and filtered through a short plug of silica to remove colored impurities. The dried-down solid was then washed with dry acetonitrile to provide the product 5-fluoro-2-methyl-1H-indole-3-carbaldehyde as a crystalline white solid (105 mg, 55% yield) after drying. 1H NMR (400 mHz, DMSO-d6) δ 12.10 (s, 1H), 10.03 (s, 1H), 7.72 (dd, J=9.7, 2.6 Hz, 1H), 7.38 (dd, J=8.8, 4.5 Hz, 1H), 7.01 (dt, J=9.2, 2.6 Hz, 1H), 3.34 (s, 1H), 2.68 (s, 3H). added slowly to the rapidly stirring mixture the temperature below 35° C After stirring for 2 h at room temperature extracted into methylene chloride The organic layer was washed with water (1×50 mL), brine (1×50 mL) dried over Na2SO4 The solvent was removed in vacuo to yield an off-white solid filtered through a short plug of silica to remove colored impurities The dried-down solid was then washed with dry acetonitrile