Regioselective Ylide Formation on Acetal-Functionalized Trialkyl Phosphonium Salts: Extending the Scope of Carbonyl Homologation

Dedicated to Professor Victor Snieckus on the occasion of his 80^th birthday

Abstract

The discovery of a complex-induced proximity effect and scope of regioselective ylide formation on acetal- and ketal-functionalized trialkylphosphine-derived phosphonium salts is explored as a route to homologated unsaturated carbonyl derivatives.

Key words

olefination - vinyl ethers - homologation - Wittig reaction - carbonyl chemistry

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• 12 Wittig Reaction General Procedure A A microwave reaction tube equipped with a stir bar was charged with the corresponding aldehyde (1 equiv, 0.54 mmol) and the phosphonium salt 1d (1.1 equiv, 0.59 mmol). To the tube, base and H₂O (1 mL) were added. The tube was sealed and heated at 110 °C overnight. The tube was cooled to r.t. and 5 mL of water was added. The aqueous solution was extracted with EtOAc (2 × 5 mL). The organic layers were combined, dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crude residue was purified by silica gel column chromatography using EtOAc/hexanes (40:1) to afford the homologated product. Wittig Reaction General Procedure C A two-neck flask equipped with a magnetic stirring bar, glass stopper, adapter to a two-line Schlenk manifold, was charged with salt 1e (85 mg, 0.20 mmol), purged under vacuum for 0.5 h then filled with N₂. The glass stopper was quickly exchanged with a rubber septum under rapid N₂ flow and the solvent (1.0 mL) was added via syringe then the septum was quickly replaced with a glass stopper. The mixture was stirred until a solution was formed then cooled to 0 °C. To the cooled solution base (0.26 mmol) was quickly added under rapid N₂ flow. Upon stirring for 0.5 h, 4-chlorobenzaldehyde (25 mg, 0.18 mmol) was quickly added, and the reaction was allowed to warm to r.t. overnight. The reaction was quenched with the addition of NH₄Cl (10 mg), solvent was removed under reduced pressure, and the pot residue was extracted with Et₂O (3 × 1 mL). The combined extract was washed with sat. NH₄Cl (2 ml), water (2 mL), brine (2 mL), dried with MgSO₄, and solvent was removed under reduced pressure to give a crude extract as a yellow oil that was subject to ¹H NMR analysis.