Aldehydes phosphonate carbanions

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. 

An important complement to the Wittig reaction is the reaction of phosphonate carbanions with carbonyl compounds.151 The alkylphosphonate esters are made by the reaction of an alkyl halide, preferably primary, with a phosphite ester. Phosphonate carbanions are more nucleophilic than an analogous ylide, and even when R is a carbanion-stabilizing substituent, they react readily with aldehydes and ketones to give alkenes. Phosphonate carbanions are generated by treating alkylphosphonate esters with bases such as sodium hydride, w-butyllithium, or sodium ethoxide. Alumina coated with KF or KOH has also found use as the base.152... 

The reaction of aldehydes or ketones with stabilized phosphorus ylides (phosphonate carbanions) leads to olefins with excellent E-selectivity. 

The phosphonates stabilized by an adjacent electron-withdrawing substituent, such as the carboxylate group or nitrile group, are particularly suitable. The phosphonate carbanions are very readily formed, even with aqueous alkali, and, in contrast to the triphenylalkylenephosphoranes stabilized by carbonyl groups, react not only with aldehydes but also with ketones. 

The nature of the substituents on a stabilized phosphonate carbanion is known to influence the stereochemical outcome of their reactions with aldehydes. For example, a bis(2,2,2-trifluoroethyl) substituent reverses the normal preference for (E) alkenes in a sequence referred to as the Still modification of the HWE reaction (see Protocol ll).24 This substituent is thought to favour formation of the (Z)-isomeric alkene by greatly enhancing the rate of the elimination of the phosphine oxide to give the alkene, which then suppresses equilibration to the thermodynamic product. 

Olefination of aldehydes with a-silyl- and a-stannyl-stabilized phosphonate carbanions derived from cyclo-[L-AP4-D-Val] allow a (Z)-selective access to a,p-substituted vinyl phosphonates (343) that have been transformed into enantiomerically pure 4-alkylidene 4PA derivatives (344) (Figure 54). " Electrophilic fluorination of lithiated bis-lactim ethers derived from cyclo-[L-AP4-D Val] (345) with commercial NFSi allow direct access to a-monofluor-inated phosphonate mimetics of naturally occurring phosphoserine (346) and phosphothreonine (347), in enantiomerically pure form and suitably protected for solid-phase peptide synthesis (Figure 55). ... 

The HWE reaction can be carried out on a ketone, but often the stereoselectivity is not as good as the reaction of a substituted phosphonate carbanion with the corresponding aldehyde. Because of the greater reactivity of the phosphonate reagent relative to the phosphonium carbanion, the HWE reaction has proven to be effective with hindered ketones that were unreactive toward classical Wittig ylides. 

Phosphonate carbanions are more nucleophilic than phosphonium ylides. Thus, they can be used in condensations with ketones as well as with aldehydes under mild conditions. 

Al-Badri, H.. About-Jaudet. E., and Collignon, N., Reaction of in situ generated a-silylated allylic phosphonate carbanions with aldehydes. An unexpected cyclization reaction, J. Chem. Soc., Perkin Trans. 1, 931. 1996. 

Le Menu, J.-C., Sarrazin, J., and Tallec, A., Electrochemically generated phosphonate carbanions. Formation and reactivity towards aldehydes. Can. J. Chem., 67, 1332, 1989. 

An added and valuable advantage found in this attractive and mild approach to dialkyl cyanoalkylphosphonates is the possibility of trapping the phosphonate carbanions in situ by reaction with an aldehyde or ketone when the desired product is the olefin resulting from the Homer-Wadsworth-Emmons reaction (Scheme 6.6). 

Danion, D., and Carrie, R., Comparative study of intramolecular O-phosphorylations during the condensation of aldehydes with phosphonate carbanions having several nucleophilic sites, Tetrahedron Lett., 12, 3219, 1971. 

Sato has reported a new route to allylic sulphides through the reaction of a-sulphenyl aldehydes (35) with phosphonium ylides or phosphonate carbanions.25 Similar reactions have been used to achieve a two-carbon... 

Ultimately, those factors which influence the outcome of the WEH reaction are linked to, and are a measure of, the stability of the phosphorus-carbon bond in equilibria between carbanion and carbonyl reactant. In general, dialkyl phosphonate carbanions (162 R = EtO) in their reactions with either aliphatic or aromatic aldehydes yield (E)-alkenes, whereas carbanions based on the l,3,2-dioxaphosph(V)olane 163 (X = O) or the 1,3,2-dioxaphosphorinane ring 164 (X = O) mav reverse the relative amounts of the (Z)- and (E)-alkenes, in this case from ca 1 2 to ca 2 1 no reaction at all was observed in this instance... 

Reactive ylides must be produced in the absence of oxygen and moisture, whereas stable ylides can be isolated as solid substances which are relatively insensitive to hydrolysis. Ylides which are stabilized by a carbonyl group generally only react with aldehydes if need be, they can be made to react with ketones under relatively drastic conditions [3]. In these cases, the Horner-Emmons reaction is the method of choice because of the greater nucleophilicity of the phosphonate carbanions in comparison to phosphorus ylides [6] (see Section E). 

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). 

Closely related to the Wittig reaction is the Horner-Wadsworth-Emmons reaction, where a stabilized phosphonate carbanion reacts with an aldehyde or ketone to yield an olefin. 

A simple protocol for the highly ( )-selective (E/Z =180 1 in some cases) Horner-Wittig reactions of alkyl diethylphosphonoacetates and a range of straight-chain and branched aliphatic, substituted aromatic, and base-sensitive aldehydes in the presence of MeMgBr, as a base generating the corresponding phosphonate carbanions, has been reported (Scheme 67) ... 

The intramolecular cyclization of a stabilized phosphonate carbanion onto an aldehyde has proved to be an effective method for the synthesis of brefeldin polyene macrolides, and in a formal synthesis of carbomycin Pyrenophorin has been synthesized using a pent-3-enoic acid d reagent two other routes to the racemic compound have also appeared. Macrocyclic polyether macrolides have been prepared by cyclization, and by ozonolysis of a furan crown-ether compound. 

When R is a simple alkyl group, addition of the phosphonate carbanion to the carbonyl compound occurs but the intermediate does not undergo elimination. Since the reaction sequence results in the conversion of an aldehyde or ketone to an alkene, as does the Wittig reaction, but works well when electron-withdrawing... 

The synthetic utility of carbonyl olefination reactions can be expanded beyond alkene synthesis through the use of functionalized ylides and functionalized phosphonate carbanions. Thus, methoxymethylene and phenoxymethylene ylides lead to vinyl ethers which can be readily hydrolyzed to aldehydes. 

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