Wittig reaction, Horner-Emmons

Earlier it was shown that by the use of cyclic phosphonates it is possible to modify the steric course of the Horner-Emmons-Wittig reaction. Treatment of diethyl ben-zoylphosphonate with an acyclic and a five-membered cyclic phosphonate led to the formation of vinylphosphonates of opposite stereochemistry (equation 65). ... 

The synthesis of quadrupolar chromophores has also been achieved from 2,6-DTT-dicarboxaldehyde 117. Push-push (i.e., bis-donor) compound 118 was prepared via a double Wittig reaction carried out under solid-liquid phase transfer conditions. Pull-pull (i.e., bis-acceptor) compounds 119 were obtained from a symmetrical bis-aldehydes via a double Horner-Emmons-Wittig condensation (Scheme 9) <2002SM17, 1999CC2055>. 

The reaction has been extended to include carbanions generated from phosphonates. This is often referred to as the Horner-Wittig or Homer-Emmons reaction. The Horner-Emmons reaction has a number of advantages over the conventional Wittig reaction. It occurs with a wider variety of aldehydes and ketones under relatively mild conditions as a result of the higher nucleophilicity of the phosphonate carbanions. The separation of the olefinic product is easier due to the aqueous solubility of the phosphate by-product, and the phosphonates are readily available from the Arbusov reaction. Furthermore, although the reaction itself is not stereospecific, the majority favor the formation of the trans olefin and many produce the trans isomer as the sole product. 

Important and widely used variants of the Wittig reaction are based on carbanionic organophosphorus reagents, and are known as the Wadsworth-Emmons reaction, Wittig-Horner reaction or Horner-Wadsworth-Emmons reaction. As first reported by Horner, carbanionic phosphine oxides can be used today carbanions from alkyl phosphonates 13 are most often used. The latter are easily prepared by application of the Arbuzov reaction. The reactive carbanionic species—e.g. 14 —is generated by treatment of the appropriate phosphonate with base, e.g. with sodium hydride ... 

The (Horner-)Wadsworth-Emmons reaction generally is superior to the Wittig reaction, and has found application in many cases for the synthesis of a ,/3-unsaturated esters, a ,/3-unsaturated ketones and other conjugated systems. Yields are often better then with the original Wittig procedure. However the Wadsworth-Emmons method is not suitable for the preparation of alkenes with simple, non-stabilizing alkyl substituents. 

OS 79] ]R 17] ]no protocol] 4-Methoxybenzaldehyde and methyl diethoxyphos-phonoacetate were reacted by means of the Wittig-Horner-Emmons reaction [85] (see a more detailed description in [42]). A modified micro reaction system consisting of two mixers, for deprotonation of the phosphonates and introduction of the aldehyde, connected to an HPLC capillary of 0.8 m length and 0.25 mm diameter was employed. The micro reactor showed higher yields than laboratory batch synthesis. 

The final example of a domino process under high pressure, to be discussed in this chapter, is a combination of a Horner-Wittig-Emmons (HWE) reaction with a Michael addition developed by Reiser and coworkers [5]. Hence, reaction of a mixture of an aldehyde such as 10-18, a phosphonate 10-19 and a nucleophile 10-20 in the presence of triethylamine at 8 kbar led to 10-21. By this method, (3-amino esters, 3-thio esters and 3-thio nitriles can be prepared in high yield (Scheme 10.4). Many of these transformations do not occur under standard conditions, thereby underlining the importance of high pressure in organic chemistry. 

An intramolecular cycloaddition also occurred with 3-ylidenepiperazine-2,5-diones such as 124 or 125, obtained by Wittig-Horner-Emmons reaction from phosphonate 121 and aldehydes 122 or 123, respectively. The products of the Diels-Alder reaction are the bridged bicyclo[2.2.2]diazaoctane rings 126 and 127 that have been found in biologically active secondary metabolite such as VM55599 and brevianamide A. The different type of structures employed in this case requires a chemoselective reaction in order to produce the expected products as single diastereoisomers after 20 days (Scheme 18) <2001JOC3984>. 

For the synthesis of alkenes, the Wittig and Horner-Wadsworth-Emmons reactions have become important tools. Triphenylphosphine that is used in the Wittig reaction can be immobilized either on the polymer or can be used in solution for solid-phase chemistry (Scheme 3.18). The Horner-Wadsworth-Emmons reaction for example is used for the synthesis of aldehyde building blocks [261]. 

Other commonly used synthetic routes to alkenes are also affected by crown ethers. The Wittig (80TL4831), Wittig-Horner and Wadsworth-Emmons (81S117) reactions all give pure trans- alkene products in higher yields in the presence of crown ethers. 

This method, sometimes called the Horner-Emmons, Wadsworth-Emmons, or Wittig-Hor-ner reaction,658 has several advantages over the use of phosphoranes.659 These ylides are more reactive than the corresponding phosphoranes, and when R is an electron-withdrawing group, these compounds often react with ketones that are inert to phosphoranes. In addition, the phosphorus product is a phosphate ester and hence soluble in water, unlike PhjPO, which makes it easy to separate it from the olefin product. Phosphonates are also cheaper than phosphonium salts and can easily be prepared by the Arbuzov reaction ... 

THE HORNER-EMMONS OR WADSWORTH-EMMONS MODIFICATION OF THE WITTIG REACTION... 

Step 1 (3-keto phosphonates often are used for olefmation of ketones (Horner-Wadsworth-Emmons modification of the Wittig reaction). Steps 2 + 3 The cuprate-mediated 1,4-addition and subsequent Lemieux-Johnson oxidation of a vinyl group are excellent procedures for the introduction of the p-formyl group. 

Although the Horner-Wadsworth-Emmons reaction is not an ylide reaction, it represents methodologically such an important supplement to the Wittig reaction discussed in Figure 9.3 that we include its discussion here. 

Thus far, the aldol condensation was presented as a method for adding carbon atoms adjacent to carbonyl groups, and the Friedel-Crafts acylation was presented as useful for the addition of carbon atoms to aromatic rings. In addition to these reactions, the Wittig reaction (Scheme 8.13) and the Horner-Emmons reaction (Scheme 8.14) were... 

When considering the Horner-Emmons reaction, it is important to recognize that the mechanism and products are similar to those observed during a Wittig reaction. In fact, the Horner-Emmons reaction is a recognized and viable alternative to the Wittig reaction. 

Phosphonate esters can be deprotonated with sodium hydride or alkoxide anions to give enolate-type anions that react well with aldehydes or ketones to give -alkenes. Alkene-forming reactions with phosphonates are called Horner-Wadsworth-Emmons (or Horner-Emmons, Wadsworth-Emmons, or even Horner-Wittig) reactions. This example is a reaction that was used by some Japanese chemists in the synthesis of polyzonimine, a natural insect repellent produced by millipedes. 

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