Ketones 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 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. 

Mikolajczyk, M., Grzejszczak, S., Chefezynska, A., and Zatorski, A., Addition of elemental sulfur to phosphonate carbanions and its application for the synthesis of a-phosphoryl organosulfur compounds. Synthesis of aromatic ketones, J. Org. Chem., 44, 2967, 1979. 

The reaction between a-halo ketones and sodium dialkyl phosphites has been extended to phosphonate carbanions. For example, diisopropyl 1 -lithio-1-fluoromethylphosphonate, generated from diisopropyl fluoromethylphosphonate and LDA, reacts with 3-chloro-2-butanone at low temperature in THF to give diisopropyl l-fluoro-2-nicthyl-2,3-cpoxybutylphosphonate in 46% yield. 33.134... 

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). 

The phosphonylation, via a Michaelis-Becker-type reaction, and the phosphonomethylation, with lithiated phosphonate carbanions, " of protected ketones have been applied to the preparation of 4-oxoalkylphosphonates after acidic hydrolysis. 

Michael addition has been applied to the formation of cyclopropanic systems. Thus, the addition of phosphonate carbanions generated from tetraethyl dichloromethylenediphosphonate by electrochemical techniques to methyl vinyl ketone provides a preparation of tetraethyl 2-acetylcyclopro-pane-l,l-diphosphonate in good yield (75%)." ... 

Whether a Michael or a Horner reaction occurs when an a)3-unsaturated ketone is treated with a phosphonate carbanion depends upon the conditions. Chalcone and the ester phosphonate (135) gave the product of a Horner reaction with sodium hydride in diglyme, but Michael addition occurred with sodamide in ether. 

Lee and oh d d8 employed nitriles in conjunction with lithiated phosphonate carbanions. Careful hydrolysis of the anionic ketimine adducts under acidic conditions gave the (2-oxoalkyl)phosphonic esters, but it was also possible, when the hydrolysis was performed under essentially neutral conditions, to isolate phosphorylated enamines, which themselves are hydrolysable to a corresponding ketone (Scheme 59) the procedure also allows the introduction of other groups into the C(i) position when, for example, R X = PhSCl, PhSSPh, PhSeBr, PhS02Cl or MeSS02Me. ... 

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. 

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... 

Phosphonate carbanions, formed by percolation of a dilute ether solution of the diethyl phos-phonate through a macroporous AER in HO" form, react with carbonyl compounds in Horner-Wittig syntheses of alkenes (Scheme 20). " a,j -Unsaturated nitriles are formed from both aldehydes and ketones, but a,) -unsaturated esters are formed only from aldehydes. The reactions... 

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