Wittig reaction using phosphonate esters,

The Horner-Wadsworth-Emmons reaction (or HWE reaction) is the reaction of stabilized phosphonate carbanions with aldehydes (or ketones) to produce predominantly -alkenes. In 1958, Horner published a modified Wittig reaction using phosphonate-stabilized carbanions [32]. Wadsworth and Emmons further defined the reaction [33]. Compared to phosphonium ylides used in the Wittig reaction, phosphonate-stabilized carbanions are more nucleophilic and more basic. Likewise, phosphonate-stabilized carbanions can be alkylated, unlike phosphonium ylides. The dialkylphosphate salt by-product is easily removed by aqueous extradion. A reliable and versatile synthesis of a stilbene derivative, 2,2-aryl-substituted cinnamic acid esters, using the Wittig reaction was reported [34—36] (Figure 1.3). 

A modification of the above reaction, known as the Wittig-Homer reaction or Homer-Wadsworth-Emmons reaction uses phosphonate esters. Thus, the reaction of ethyl bromoacetate with triphenylphosphite gives the phosphonate ester, which on treatment with base (NaH) and reaction with cyclohexanone... 

This variation of the Wittig reaction uses ylides prepared from phosphonates.12 The Horner-Wadsworth-Emmons method has several advantages over the use of phosphoranes. These ylides are more reactive than the corresponding phosphoranes, especially when substituted with an electron withdrawing group. In addition the phosphorus product is a phosphate ester and soluble in water - unlike the Ph3PO product of the Wittig reaction - which makes it easy to separate from the olefin product. Phosphonates are also cheaper than phosphonium salts and can easily be prepared by the Arbuzov reaction from phosphanes and halides. 

The protected methyl glycoside 3 is converted to the corresponding aldehyde by Swern oxidation using oxalyl chloride activated DMSO. Further reaction with triethyl phosphonoacetate and sodium hydride -known as the Horner-Wadsworth-Emmons reaction - provides selectively the trans et /Tun saturated ester 4 in 72 % yield. This valuable alternative to the Wittig olefination protocol uses phosphonate esters as substrates which are readily available from alkyl halides and trialkyl phosphites via the Arbuzov rearrangement.9 co2Et Reaction of the phosphonate with a suitable base gives the... 

A.iu. Phosphine Oxides and Phosphonate Esters. Many extensions of the Wittig reaction have been introduced that improve or modify the reactivity and/or stereoselectivity of the ylid. Horner et al. showed that a-lithiophosphine oxides such as that derived from 552 react with aldehydes or ketones to give a p-hydroxy phosphine oxide (553) as an isolable species. Subsequent treatment with base liberates the alkene, (554). Wadsworth and Emmons modified the Horner reaction to use phosphonate ester derivatives such as... 

The formation of an alkene and the loss of phosphorus are typical of a Wittig reaction but the formation of an unsaturated carbonyl compound using an enolate is very hke an aldol reaction. The phosphonate ester reagent is also like a 1,3-dicarbonyl compound, with P replacing C. The very weak base used shows how stable the enolate must be. The enolate attacks the aldehyde, perhaps to form an intermediate oxyanion. 

The Wadsworth-Emmons modification [56] of the Wittig reaction uses the phosphonate esters to form a,p-unsaturated esters in which the ( )-alkene is favored (Eq. 7.33) [57]. In situ alkylation is also possible (Eq. 7.34) [56]. The phosphonoesters are prepared by treating the a-bromoesters with triethyl phosphite (Arbuzov reaction) [58]. The diethyl phosphate by-product is water-soluble and easily removed. 

Olefination Reactions Involving Phosphonate Anions. An important complement to the Wittig reaction involves the reaction of phosphonate carbanions with carbonyl compounds 253 The alkylphosphonic acid esters are made by the reaction of an alkyl halide, preferably primary, with a phosphite ester. Phosphonate carbanions are generated by treating alkylphosphonate esters with a base such as sodium hydride, n-butyllithium, or sodium ethoxide. Alumina coated with KF or KOH has also found use as the base.254... 

Derivatives of the general formula (7) in Table 6 have been successfully used as probases and their properties in this context are being further explored. In common with the azobenzenes and ethenetetracarboxylate esters, the fluoren-9-ylidene derivatives usually display two reversible one-electron peaks in cyclic voltammetric experiments. Although disproportionation is possible (cf. Scheme 12) it is the dianions which are the effective bases. It was shown early on that the radical-anions of such derivatives are long-lived in relatively acidic conditions (e.g. in DMF solution the first reduction peak of Ph C -.QCN) remains reversible in the presence of a 570-fold molar excess of acetic acid, at 0.1 V s ). Even the dianions are relatively weak bases, useful mainly for ylid formation from phosphonium and sulphonium salts (pKj s 11-15) they are not sufficiently basic to effect the Wittig-Homer reaction which involves deprotonation of phosphonate esters... 

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. 

These non-classical Wittig reactions of esters have been used to prepare a number of oxygen-containing heterocycles.35 Phosphonate stabilized carbanions, for example, those derived from dimethyl methylphophonate, also react with esters to give, in this case, a P-keto phophonate which can react further with aldehydes and ketones. 

Horner-Wadsworth-Emmons Reactions of Phosphonate Anions. - As with the Horner modification of the Wittig reaction, the principal focus of papers that mention the Horner-Wadsworth-Emmons reaction relate to synthetic applications. The use of pressure to induce the synthesis of P-amino esters, p-thioesters and P-thionitriles via tandem Horner-Wadsworth-Emmons and Michael reactions has been reported. The reagent (l-tritylimidazol-4-yl)methylphosphonate (99) has been prepared and, when treated with aldehydes and ketones, affords (E)-vinylimidazoles in high yields. ... 

Wittig (74) and Wittig-Homer (75) reagents of 1,3-dichalcogenoles are useful starting materials, and they have been used extensively for synthesis of extended fulvenes in the sulfur series as well as for their selenium analogues. As expected, the phosphonate esters are more reactive nucleophiles in these reactions as compared to the phosphoranes. 

A device for getting extended enolates of esters to combine with aldehydes and ketones in the y position is to use a Wittig approach. The bromo-ester 28 is commercially available. Reaction with a trialkyl phosphite gives the phosphonate ester 29 that gives dienes such as 30 with aldehydes.11 Phosphonium salts can also be used.12... 

Substituted alkenes, e.g. (13>, can be made by the Wittig reaction the more reactive phosphonate ester (14) is often used when there is a stabilising group present. 

The use of trialkyl phosphites in the Michaelis-Arbuzov reaction has been so widespread during the decades following its discovery that it is almost impossible to select individual examples worthy of separate comment. Some examples of the preparation of benzylic phosphonic diesters may be noted these are of some interest since they are useful reactants in the Wadsworth-Emmons modification of the Wittig reaction, and are extensively used in the synthesis of alkenes It may also be noted that when the phosphite ester possesses different alkyl groups, some selectivity of reaction is possible. ... 

The Wittig reaction involves the interaction of an aldehyde or ketone with a phosphorus-containing carbanionic species, in which the phosphorus is bonded directly to the carbanionic site. At the time of discovery of the reaction, that specification described the triphenylphosphonium alkylides 343 later developments employed the anions from tert-phosphine oxides, the use of which has been described elsewhere in this series and also from a wide variety of phosphonic and phosphinic esters. This latter application will be considered more fully in Chapter 6. An early application of the reaction to the synthesis of alkenephosphonic acids, and which involved an ylide, employed the stable compound 344, generated from 345 by the action of a strong base. Reactions between 344 and aliphatic or aromatic aldehydes at 100 °C in toluene or dmso gave the diphenyl esters of (alk-1-enyl)phosphonic acids or (2-arylethenyl)phosphonic acids. ... 

Yet another way to obtain a 1 -monohalogenated alkylphosphonic diester is based on the application of the Wadsworth-Emmons adaptation of the Wittig reaction (Scheme 10). Here, the anion from tetraisopropyl (fluoromethyl)bisphosphonate reacts with a carbonyl compound to give the (l-fluoroalk-l-enyl)phosphonic esters 126 as an E-Z mixture (80-95 20-5) hydrogenolysis of these mixtures yields (l-fluoroalkyl)phosphonic esters. In a review of the literature the authors pointed out the widely different results experienced by other workers in their attempts to alkylate carbanions derived from fluorinated alkylphosphonic diesters and, as a result of their own work, advocated the use of alkyl triflates, which appear to react with lithiated carbanions very quickly and cleanly. 

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