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TCI Practical Example: The Z-Selective Horner-Wadsworth-Emmons Reaction Using Ethyl Diphenylphosphonoacetate

We are proud to present the Z-selective Horner-Wadsworth-Emmons reaction of p-tolualdehyde using ethyl diphenylphosphonoacetate (Ando method). Ethyl diphenylphosphonoacetate can be used to easily introduce (Z)-α,β-unsaturated esters.

Used Chemicals

• p-Tolualdehyde [T1073]
• Ethyl Diphenylphosphonoacetate [D2547]
• Sodium Hydride (60%, dispersion in Paraffin Liquid) [S0481]
• THF

Procedure

Sodium hydride (64 mg, 1.6 mmol, 1.6 eq.) was added to a solution of ethyl diphenylphosphonoacetate (481 mg, 1.5 mmol, 1.5 eq.) in dry THF (5 mL) at -78 °C. The mixture was stirred at same temperature for 30 minutes. Then p-tolualdehyde (120 mg, 1.0 mmol) was added to the reaction mixture at -78 °C and stirred 2 hours at same temperature. After that the reaction mixture was quenched with water (15 mL). The solution was extracted with ethyl acetate (15 mL x 3) and the organic layer was washed with 2 mol/L HCl aq. (10 mL), sat. NaHCO₃ aq. (10 mL), and brine (10 mL), dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography (on silica gel, hexane:ethyl acetate = 20:1) to give 1 as a pale yellow oil (157 mg, 83% yield, E:Z = 1 : 3.67).

Experimenter’s Comments

The reaction mixture was monitored by UPLC.
The ratio of E-form and Z-form was estimated from ¹H-NMR.

Analytical Data

Compound 1

¹H NMR (400 MHz, CDCl₃);
1-Z: δ 7.52 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 12.8 Hz, 1H), 5.89 (d, J = 12.8 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 2.36 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H).
1-E: δ 7.62 (d, J = 16 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 1H), 6.40 (d, J = 16.0 Hz, 1H), 4.26 (q, J = 6.8 Hz, 2H), 2.37 (s, 3H), 1.34 (t, J = 6.8 Hz, 3H).

Lead Reference

• Highly Selective Synthesis of Z-Unsaturated Esters by Using New Horner−Emmons Reagents, Ethyl (Diarylphosphono)acetates
  • K. Ando, J. Org. Chem. 1997, 62, 1934.