Homer-Wadsworth-Emmons reaction phosphonate carbanion

Condensations between aldehydes and metalated phosphonic acid dialkyl esters other than those mentioned previously are also referred to as Homer-Wadsworth-Emmons reactions. Nevertheless, in these esters, too, the carbanionic center carries a substituent with a pi electron withdrawing group, for example, an alkenyl group, a polyene or a C=N group. The Homer-Wadsworth-Emmons reactions of these reagents are also stereoselective and form the new C=C double bond /ra/ ,v-selectively. 

The use of anions derived from a phosphine oxide (132) or a diethyl phosphonate (133) to form al-kenes was originally described by Homer.Although these papers laid the foundations for the use of phosphoryl-stabiliz carbanions for alkene synthesis, it was not until Wadsworth and Emmons published a more detailed account of the general applicability of the reaction that phosphonates bet e widely used. Since the work of Wadsworth and Emmons was significant and crucial to the acceptance of this methodology, the reaction of a phosphonate caibanion with a carbonyl derivative to form an alkene is referred to as a Homer-Wadsworth-Emmons reaction (abbreviated HWE). The phosphine oxide variation of the Wittig alkenation is called the Homer reaction. 

Long-chain phosphonylated aldehydes aie generally prepared to achieve the formation of macro-cycles via an intramolecular Homer-Wadsworth-Emmons reaction. The phosphonate group is frequently incorporated at one extremity of the chain by a carbanionic approach. Thus, displacement of iodide of the alkyl chain containing epoxide by the sodium enolate of diethyl l-(ethoxycarbo-nyl)methylphosphonate at 50°C in DMF leads to diethyl l-(ethoxycarbonyl)-4,5-epoxyalkylphos-phonate in 78% yield (Scheme 4.21). 

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). 

Addition of charged nucleophiles to diethyl 1-cy anovinyl phosphonate leads to the generation of a-substituted cyanomethylphosphonate carbanions. In the presence of carbonyl compounds, they undergo Homer-Wadsworth-Emmons reaction to produce the a,p-unsaturated nitriles in fair to good yields as a mixture of ( )- and (Z)-isomers. ... 

The use of the phosphonate ester (Homer-Wadsworth-Emmons reaction) allows much easier separation of the product alkene, since the sodium phosphate byproduct is water soluble the byproduct of fhe Wiffig reaction, tri-phenylphosphine oxide, is not water soluble. In the Horner-Wadsworth-Emmons modification, a conjugated, or electron-withdrawing, substituent (such as a phenyl or carbonyl group) on the nucleophilic carbon is used to assist in the stabilization of the carbanion. This modification (Experiment [19B]) maybe used as an alternative to Experiment [19A] for the preparation of (E)-stilbene. The "instant-ylide" Wittig reaction yields predominantly the E isomer of... 

Ylids are also convenient sources of carbanions and they react with aldehydes and ketones to give alkenes. With a suitable reactant, alkenyl amino acids can be prepared using this approach. One example used a phosphonate ester ylid in a Homer-Wadsworth-Emmons reaction 12 with amino aldehyde 1.189. The product... 

The commonly accepted mechanism for the Homer-Wadsworth-Emmons reaction is as depicted in Scheme 1.6. Here, reaction of the phosphonate stabilized carbanion with an aldehyde forms the oxyanion intermediates 4 under reversible conditions. Rapid decomposition of 4, via the four-centered intermediates 5, then affords alkenes 6. 

The stereochemical outcome of the Homer-Wadsworth-Emmons reaction is primarily dependent on the nature of the phosphonate used. In general, bulky substituents at both the phosphoms and the carbon adjacent to the carbanion favor formation of the -alkene. This selectivity has been rationalized in terms of a lowering of steric strain in intermediate SB as compared to intermediate SA. Z-Selectivity in HWE reactions can, however, be achieved using the Still-Gennari modification [20]. Here, the use of a (2,2,2-trifluoroethyl) phosphonate enhances the rate of elimination of the originally formed adduct SA (Scheme 1.6) relative to equilibration of the intermediates 4 and S. An example of the Still-Gennari modification is illustrated in Scheme 1.7. 

One of the first variations of the Wittig reaction was initially reported by Homer and coworkers and rapidly followed by an initial report by Wadsworth and Emmons. These examples made use of phosphine oxide/phosphonate derivatives of the ylides first reported by Wittig and are now collectively known as the Homer-Wadsworth-Emmons reaction (HWE). Ylide formation occurs upon deprotonation of dialkoxy phosphonate 31 and alkene 32 is formed from carbonyl compound 30 with loss of the corresponding phosphate derivative 33. The use of this variation has advantages over the eonventional version a) phosphonate carbanions are known to be more nucleophilic due to decreased stabilization by valence shell expansion of the phosphorous atom, thus are able to react with a wider diversity of carbonyl compounds, b) the phosphorous-based product of the reaction, a water-soluble phosphate, allows for a greater ease of reaction work-up. c) the enhanced reactivity of the phosphonate permits direct derivitization of the reagent, d) the Arbuzov reaction allows for ready preparation of the desired phosphonate. 

Alternatives to the standard Wittig reaction have been developed, including the Homer-Wadsworth-Emmons (HWE) reaction which involves the reaction of a phosphonate stabilized carbanion with a carbonyl compound (Scheme 2). These carbanions are generally more reactive than the traditional phosphoranes and they will often react with ketones that are unreactive to stabilized phosphoranes.2 3,8... 

Whereas the Wittig reaction gives exclusively ( )-isomers, the Homer-Wadsworth-Emmons procedure gives predominantly (Z)-isomers. This result is contrary to expectation because phosphonate carbanions usually give better (/j-spccilicity than phosphoranes. " ... 

The formation of alkene 2 from phosphine oxide carbanion and aldehydes is referred to as the Homer reaction. When using phosphonate carbanion, the reaction is known as the Homer-Wadsworth-Emmons (HWE) reaction. ... 

A very useful modification of the Wittig reaction involves the reaction of phosphonate-stabilized carbanions with aldehydes or ketones, which is known as the Homer-Wadsworth-Emmons (HWE) reaction [7, 151,152], This reaction was originally described by Homer et al. [153, 154] and further defined by Wadsworth and Emmons [155]. Phosphonate-stabilized carbanions are more nucleophilic and more basic than phosphonium ylides. They are prepared by the addition of suitable bases to the corresponding alkylphosphonates, which are readily accessible through the Michaelis-Arbuzov reaction of trialkyl phosphites with alkyl halides (usually a-halo carbonyl compounds) [143]. In contrast to the Wittig reaction, the HWE reaction yields phosphate salt byproducts that are water-soluble and hence are readily separated from the desired alkene products by simple extraction. 

An important modification to the Wittig reaction is the use of stabilized phosphonate carbanions in olefin synthesis. This reaction, originally discovered by Homer but developed by Wadsworth and Emmons, is used extensively for transformation of a carbonyl... 

Wadsworth-Emmons olefination, or in brief, the Homer-Emmons reaction, a phosphonate carbanion 7, produced by deprotonating a phosphonate 8, reacts with a carbonyl compound 9 to give an olefin 10 and a dialkyl phosphate anion 11 (Scheme 2). 

The disadvantages of the Wittig reaction described in Section A led to the development of modified olefination methods based on phosphoryl-stabilized carbanions. The most important modification of the Wittig reaction in the field of carotenoid synthesis is olefination by means of phosphonate carbanions, as introduced by Homer [55] and by Wadsworth and Emmons [56]. 

Because the Wittig reaction is so useful for the preparation of alkenes, chemists have explored several variations of it. One of the most useful of these, known as the Homer-Emmons-Wadsworth modification, uses a phosphonate ester derived from an a-haloester or a ketone to generate the Wittig carbanion. 

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