Horner-Wadsworth-Emmons Reaction

What Is Horner-Wadsworth-Emmons Reaction?

In the Horner-Wadsworth-Emmons (HWE) reaction, phosphonates are substituted for the phosphonium salt in the Wittig reaction, and olefins are synthesized by the reaction of the phosphonate α-carbanion with an aldehyde. Trans olefins are usually produced instead of cis olefins.

Phosphonates can be conveniently prepared by the reaction of trialkylphosphites with organic halides (generally bromocarbons) (Michaelis-Arbuzov reaction). If methyl/ethyl phosphites are used, the byproducts are volatile methyl bromide or ethyl bromide, and the products can be obtained directly by distillation. The HWE reaction usually uses NaH as the base and ethylene glycol dimethyl ether (DME) or tetrahydrofuran as the solvent.

Advantages of HWE Reaction

Compared with the Witig reaction, the HWE reaction has the following advantages:

• The phosphonate α-carbanion is highly reactive and can react with ketones.
• The byproduct is water-soluble O,O-diethyl sodium phosphate, which is easily removed by extraction.
• The reaction exhibits (E)-stereoselectivity and is therefore widely used in the synthesis of natural products.

Fig 1. HWE reaction and its mechanism. [1]

Improvements and Conditions of HWE Reaction

• Sometimes the stereoselectivity of the reaction is not high, and many improved methods and conditions have been developed for this purpose. For example, the stereoselectivity of the reaction can be adjusted by changing the R group on the phosphorus. For example, in one step of the total synthesis of the natural product (-)-Bafilomycin A1, if dimethyl phosphonate is used, the (Z,E:E,E)-stereoselectivity is only 2:1, while if diisopropyl phosphonate is used (Paterson conditions), the (Z,E:E,E)-stereoselectivity can reach 95:5.
• Schlosser conditions can also be used to improve the stereoselectivity of HWE reactions. For example, in the total synthesis of the pentacyclopropane antifungal agent FR-900848, Barrett used Schlosser conditions to construct the diene unit to obtain a higher (E/Z)-selectivity.
• The reaction of β-carbonylphosphonates can be carried out with the base system DBU-LiCl (Masamune-Roush conditions). This is a convenient method for synthesizing the (E)-isomer.

Mechanism of HWE Reaction

The reaction mechanism closely resembles that of the Wittig Reaction. Steric approach control determines the stereochemistry, with the carbanion approaching the carbonyl carbon in an antiperiplanar fashion favored by the smaller aldehydic hydrogen eclipsing the bulky phosphoranyl moiety. This results in the ester group being syn to the aldehyde R group, while the alkene assumes an E-orientation of these groups after rotation to form the oxaphosphetane. The resulting phosphate byproduct can be easily separated from the desired products by washing with water.

Application Examples of HWE Reaction

• Example 1: In the synthesis of permethylated viniferifuran analogues, indole 15b was easily synthesized by quantitative methylation of 5a with MeI and NaH followed by HWE reaction. [2]
• Example 2: Debobrata Paul et al. reported the first asymmetric total synthesis of cytotoxic macrolides pestalotioprolides E and F. In this synthetic strategy, an intramolecular HWE reaction was involved to form a 14-membered lactone. [3]

Fig 2. Synthetic examples via HWE reaction.

Related Products

CAS No.	Structure	Product
100-10-7		4-(Dimethylamino)benzaldehyde
10031-82-0		4-Ethoxybenzaldehyde
100-83-4		3-Hydroxybenzaldehyde
100980-82-3		4'-Hydroxy(1,1'-biphenyl)-4-carboxaldehyde
101093-56-5		2-Methyl 4-benzyloxybenzaldehyde
186393-22-6		Rel-(3R,4S)-tert-butyl 3,4-dihydroxypyrrolidine-1-carboxylate
20235-78-3		Uridine, 2-thio-
21193-75-9		D-Galactal
2140-61-6		5-Methylcytidine
2140-67-2		2-(Dimethylamino)guanosine

References

1. Li, Jie Jack. Name Reactions: A Collection of Detailed Reaction Mechanisms, 2006, 262-264.
2. Adrian Krzyzanowski, et al. Organic letters, 2018, 20(21), 6650-6654.
3. Debobrata Paul, et al. Organic letters, 2018, 20(15), 4606-4609.