Phosphonate-stabilized carbanion

The ring opening of activated azetidin-2-one 317 by a phosphonate-stabilized carbanion yielded the /3-ketophos-phonate 318 (Equation 109) <2002TL9641>. The Horner-Wadsworth-Emmons alkenylation and subsequent reduction of the latter compound affords a /3-aminoketone, which is used in the synthesis of sphingosine and phytosphingos i ne. 

Fig. 6.38. Preparation of Horner-Wadsworth-Emmons reagents (synthesis applications Section 9.4) by chemoselective acylation of a phosphonate-stabilized carbanion with an ester.

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... 

Milder reaction conditions have been developed for the HWE reaction of phosphonate-stabilized carbanions to increase yields, accommodate sensitive substrates and to minimize undesired side reactions such as double bond migrations, the Cannizzaro reaction, Knoevenagel condensation and Michael addition. For example, a number of different bases have been employed to generate the carbanion. These include sodium hydroxide under phase-transfer conditions, potassium carbonate, barium hydroxide, diisopropylethylamine and l,8-diazabicyclo[5.4.0]undec-7-ene (see Protocol 10).22... 

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. 

An important addition to the Wittig tran -olefination procedure is the introduction of phosphonate-stabilized carbanions as olefin-forming reagents, referred to as the Horner-Wadsworth-Emmons or HWE reaction. The HWE olefination offers several advantages over the Wittig reaction using stabilized ylides ... 

Relatively strong bases are used for the deprotonation of phosphonate reagents, and the phosphonate-stabilized carbanions formed are more basic than the corresponding phosphorane reagents. Such conditions may be incompatible with base-sensitive aldehydes and ketones, causing epimerization of chiral compounds or... 

Wittig type reaction of phosphonate stabilized carbanions with aldehydes or ketones to form olefins (mainly E) (see 1st edition). 

The Homer-Emmons modification is a variation of a Wittig reaction in which a phosphonate-stabilized carbanion in used instead... 

The phosphonate-stabilized carbanion is prepared from an appropriate alkyl halide. This is called ihe, Arbuzov reaction. 

Some of the disadvantages of the Wittig reaction can be overcome by use of the Horner-Wadsworth-Emmons reaction or, in brief, the Horner-Emmons reaction [6,14-16]. The modification of the Wittig process makes use of a phosphonate-stabilized carbanion instead of a phosphorus ylide it is discussed in Section E. 

The Homer-Emmons modification uses a phosphonate-stabilized carbanion in a Wittig reaction. This reagent is an anion that is more nucleophilic than the usual Wittig ylide. The byproduct (R0)2P02 is water-soluble and easily separated from the product. These phosphonate-stabilized carbanions are compatible with carbonyl groups (especially esters) in the reagent. 

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). 

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. 

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. 

The mechanism of the HWE reaction is closely related to that of the Wittig reaction. It is generally accepted that the addition of the phosphonate-stabilized carbanion to the aldehyde gives a mixture of erythro and threo isomeric p-oxido phosphonates under reversible conditions (Scheme 35) [156-160]. The erythro and threo intermediates cyclize to form cis- and trans-oxaphosphetanes, rapid elimination of which affords Z- and -aIkenes, respectively. It should be pointed out that the decomposition of the p-oxido phosphonate intermediate requires an electron-withdrawing group (e.g., ester, acyl, amide, cyano, sulfonyl, vinyl, or aryl) a to the phosphonate moiety. Otherwise, the final product is a p-hydroxy phosphonate... 

Tertiary amines, such as TBD, DBU, and Af-ethylpiperidine, can serve as alternatives to strong ionic bases in the HWE reaction [100], In addition, the HWE reaction can proceed smoothly in the presence of DBU under neat conditions [169, 170]. Recently, Verkade et al. have employed PlNO -BujCHzCHzJsN to promote the HWE reaction at room temperature for the synthesis of a,p-unsaturated esters, ketones, nitriles, and fluorides [171]. In these cases, phosphonate-stabilized carbanions are generated in situ in the presence of aldehydes. 

It is a useful strategy to achieve Z selectivity in the HWE reaction by tuning the electronic and steric properties of the E-substituents of phosphonate-stabilized carbanions. In 1983, Still et al. described the employment of bis(2,2,2-trifluoroethyl)phosphonoacetates in the HWE reaction (Scheme 37) [175]. This modification, together with strongly dissociating conditions (KHMDS and... 

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