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TCI Practical Example: Formylation of Aromatic Compound Using the Vilsmeier Reagent

We are proud to present the formylation of indole using the Vilsmeier reagent.

Used Chemicals

• Vilsmeier Reagent [C1545]
• Indole [I0021]
• DMF

Procedure

Indole (500 mg, 4.27 mmol) was added to a solution of Vilsmeier reagent (1.09 g, 8.54 mmol, 2.0 eq.) in DMF (8.5 mL) at 0 °C and the solution was stirred for 2.5 hours at room temperature. The reaction mixture was quenched with 1 mol/L NaOH aq. (13 mL) and diluted with water (12 mL). The solution was poured into ice-cooled water (25 mL) and stirred for 1 hour at the same temperature. The precipitation was collected by filtration, washed with water (3 x 3 mL), and dried under reduced pressure to give indole-3-carbaldehyde as a pale yellow solid (529 mg, 77% yield).

Experimenter's Comments

The reaction mixture was monitored by TLC (ethyl acetate:hexane = 1:1, Rf = 0.32).
Since Vilsmeier reagent has hydroscopicity, it was quickly weighed and used.

Analytical Data

Indole-3-carboxaldehyde

¹H NMR (270 MHz, DMSO-d₆); δ 12.11 (brs, 1H), 9.94 (s, 1H), 8.27 (s, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.29-7.19 (m, 2H).

Other Reference

• Discovery and synthesis of novel indole derivatives-containing 3-methylenedihydrofuran-2(3H)-one as irreversible LSD1 inhibitors
  • H.-M. Liu, F.-Z. Suo, X.-B. Li, Y.-H. You, C.-T. Lv, C.-X. Zheng, G.-C. Zhang, Y.-J. Liu, W.-T. Kang, Y.-C. Zheng, H.-W. Xu, Eur. J. Med. Chem. 2019, 175, 357.