One-Pot, Fluoride-Promoted Wittig Reaction

Abstract

A one-pot, fluoride-promoted Wittig reaction was developed. The reactions of ethyl α-bromoacetate with aliphatic, aromatic, and heteroaromatic aldehydes in the presence of tri-n-butylphosphine and tetrabutylammonium fluoride produced α,β-unsaturated esters in good to excellent yields and E-stereoselectivity. Under the same conditions, reactions of ethyl α-bromopropionate, α-bromo acetonitrile, and α-bromoacetophenone with aliphatic and aromatic aldehydes in the presence of tri-n-butylphosphine and tetrabutylammonium fluoride produced the expected α,β-unsaturated derivatives in good E-stereoselectivity. The protocol was extended to semistabilized ylides and applied to the synthesis of some combretastatin analogs.

Keywords:

• Tetra-n-butylammonium fluoride
• α,β-unsaturated compounds
• Wittig reaction

ACKNOWLEDGMENTS

Universitá degli Studi di Milano and MIUR (Ministero dell' Istruzione, dell’ Universitá e della Ricerca) are acknowledged for financial support.

Notes

^a Conditions: 1a/n-Bu₃P/2/n-Bu₄NF = 1:1:1.1:1.2 molar ratio; THF at room temperature.

^b 1a/n-Bu₃P/2/n-Bu₄NF = 1:1:0.5:1.2 molar ratio.

^c1H NMR yields of the crude reaction mixture.

^d Reaction also carried out at 70°C; after 16 h, 32% yield by ¹H NMR of the crude reaction mixture.

^e E/Z determined by ¹H NMR.

^f Reaction carried out also with PPh₃ in 86% yield and unchanged diastereoisomeric ratio.

^g Mixture of E and Z isomers.

^h Both E and Z isomers were isolated and characterized.

ⁱ When TBDMS protects the hydroxylic functionality, the reaction yield is 87%.

^j SDS: sodium dodecyl sulphate; Ref. 10a.

^a Conditions: 1/n-Bu₃P/2/n-Bu₄NF = 1:1:1.1:1.2; THF at room temperature.

^b E/Z determined by ¹H NMR.

^c The reported yield concerns the E isomer only. By ¹H NMR, the crude mixture contains 95% yield of E/Z (72:28) isomers: the E isomer only was purified.

^a Conditions:1/n-Bu₃P/2/n-Bu₄NF = 1:1.1:1.1:1.

^b Both E and Z isomers were isolated and characterized.