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TCI Practical Example: Addition of Phosphoric Ester Group Using Di-tert-butyl Chloromethyl Phosphate

We are proud to introduce the addition of phosphate ester moiety to the hydroxy group of 4-hydroxybenzaldehyde.

Used Chemicals

• Di-tert-butyl Chloromethyl Phosphate [D5835]
• 4-Hydroxybenzaldehyde [H0198]
• Sodium Hydride (60%, dispersion in Paraffin Liquid) [S0481]
• Potassium Iodide [P1721]
• DMF

Procedure

Sodium hydride (60%, dispersion in paraffin liquid) (0.12 g, 3.1 mmol) was added to a solution of 4-hydroxybenzaldehyde (0.25 g, 2.0 mmol) in DMF (5 mL) and stirred for 30 minutes at room temperature. Di-tert-butyl chloromethyl phosphate (0.58 g, 2.3 mmol) and potassium iodide (1.0 g, 6.1 mmol) were added to the mixture and stirred for 25 hours. The mixture was poured into iced water (20 mL) and then saturated ammonium chloride aqueous solution (5 mL) was added. The mixture was extracted with diethyl ether and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate:hexane = 2:8 - 4:6 on silica gel) to give compound 1 (0.27 g, 38% yield) as a colorless oil.

Experimenter’s Comments

The reaction mixture was monitored by TLC (ethyl acetate:hexane = 1:1, Rf = 0.33).

Analytical Data

Compound 1

¹H NMR (400 MHz, CDCl₃); δ 9.92 (s, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 5.70 (d, J = 12.0 Hz, 2H), 1.46 (18H, s).

Lead Reference

• Synthesis and Characterization of a Phosphate Prodrug of Isoliquiritigenin
  • K. Boyapelly, M.-A. Bonin, H. Traboulsi, A. Cloutier, S. C. Phaneuf, D. Fortin, A. M. Cantin, M. V. Richter, E. Marsault, J. Nat. Prod. 2017, 80, 879.