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TCI Practical Example: Z-Stereoselective Horner-Wadsworth-Emmons Olefination via Still-Gennari Method

We are proud to present the Z-selective olefination using bis(2,2,2-trifluoroethyl) (methoxycarbonylmethyl)phosphonate.

Used Chemicals

• p-Tolualdehyde [T1073]
• Bis(2,2,2-trifluoroethyl) (Methoxycarbonylmethyl)phosphonate [B1714]
• Potassium tert-Butoxide [P1008]
• 18-Crown 6-Ether [C0860]
• THF

Procedure

Potassium tert-butoxide (236 mg, 2.1 mmol, 2.1 eq.) in dry THF (5 mL) was added dropwise to a solution of p-tolualdehyde (120 mg, 1.0 mmol), bis(2,2,2-trifluoroethyl) (methoxycarbonylmethyl)phosphonate (636 mg, 2.0 mmol, 2.0 eq.) and 18-crown-6-ether (793 mg, 3.0 mmol, 3.0 eq.) in dry THF (5 mL) at -78 °C. The mixture was stirred for 2 hours at -78 °C and then stirred at room temperature for overnight. The reaction was quenched with water (15 mL) and the aqueous layer was extracted with ethyl acetate (15 mL x 3). The combined 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 pale yellow liquid (138 mg, 78% yield, E:Z = 1:15.5).

Experimenter’s Comments

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

Analytical Data

Compound 1

¹H NMR (400 MHz, CDCl₃);
1-Z: δ 7.53 (d, J = 7.6 Hz, 2H), 7.17 (d, J = 7.6 Hz, 2H), 6.91 (d, J = 12.8 Hz, 1H), 5.90 (d, J = 12.8 Hz, 1H), 3.72 (s, 3H), 2.36 (s, 3H).
1-E: δ 7.67 (d, J = 16.0 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 6.40 (d, J = 16.0 Hz, 1H), 3.80 (s, 3H), 2.37 (s, 3H).

Lead References

• Direct synthesis of Z-unsaturated esters. A useful modification of the horner-emmons olefination.
• • W. C. Still, C. Gennari, Tetrahedron Lett. 1983, 24, 4405.