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TCI Practical Example: The Z-Preferential Horner-Wadsworth-Emmons Reaction Using Ethyl Di-o-tolylphosphonoacetate

We are proud to present the Z-preferential Horner-Wadsworth-Emmons reaction (Ando method) using ethyl di-o-tolylphosphonoacetate and p-Tolualdehyde. This reagent can be used to easily introduce (Z)- α,β-unsaturated esters.

Used Chemicals

• p-Tolualdehyde [T1073]
• Ethyl Di-o-tolylphosphonoacetate [D2548]
• Sodium Hydride (60%, dispersion in Paraffin Liquid) [S0481]
• THF

Procedure

To a solution of ethyl di-o-tolylphosphonoacetate (523 mg, 1.5 mmol, 1.5 eq.) in dry THF (5 mL) was added sodium hydride (64 mg, 1.6 mmol, 1.6 eq.) at −78 °C and the mixture was stirred 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 the solution was quenched with water (15 mL), it 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, toluene:diethyl ether = 40:1) to give 1 as a colorless oil (175 mg, 91% yield, E:Z = 1:1.29).

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.