Phosphonate carbanions, Wittig reactions

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. 

Important and widely used variants of the Wittig reaction are based on carbanionic organophosphorus reagents, and are known as the Wadsworth-Emmons reaction, Wittig-Horner reaction or Horner-Wadsworth-Emmons reaction. As first reported by Horner, carbanionic phosphine oxides can be used today carbanions from alkyl phosphonates 13 are most often used. The latter are easily prepared by application of the Arbuzov reaction. The reactive carbanionic species—e.g. 14 —is generated by treatment of the appropriate phosphonate with base, e.g. with sodium hydride ... 

Wittig reaction, using dichloromethyl-enetriphenylphosphorane, 45,33 using phosphonate carbanions, 46, 46... 

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... 

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... 

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... 

Unlike the carbanions derived from phosphonate esters, the carbanions of dimethyl methylphosphonate18 and, in some instances phosphine oxides (Homer-Wittig reaction), do not react directly with aldehydes and ketones to give the corresponding alkene.2,3 Rather, the reaction yields an intermediate P-hydroxy derivative that can be isolated and purified to high diastereoisomeric purity. Subsequent reaction then gives the desired alkene with control of stereochemistry (see Schemes 3, 5 and Protocols 7, 8). 

Phosphoranes and phosphonate derived carbanions are also known to react with carbonyl compounds other than aldehydes and ketones, in reactions often referred to as non-classical Wittig reactions.35 Wittig olefination products can be obtained from the reaction of esters, anhydrides and some amides and imides with a range of stabilized and reactive phosphoranes. The reaction of stabilized and semi-stabilized phosphoranes with esters gives alkenes (Scheme 7). However, non-stabilized phosphoranes, such as methylenetriphenylphosphorane, tend to give P-keto phosphoranes on reaction with esters (Scheme 7)—the careful choice of the reaction conditions can also permit the preparation of the alkene in these reactions. 

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. 

The Horner-Wittig reaction of the carbanion generated from the phosphonate 232 with 2,5-diformylthiophene 233 afforded 1,3-dithiole derivatives 234 (Equation 15) <1997TL6107>. 

The 7t-extended 1,3-dithiole 237 containing a cycloproparene moiety was synthesized in the Horner-Wittig reaction involving the phosphonate carbanion derived from 235 and the benzoyl-substituted cycloproparene 236 (Equation 16) <2004EJ0138>. 

Synthesis of fused D-A systems such as 665 involved /-butyldiphenylsilyl protection of 4,7-dihydroxy-l,3-benzo-dithiole-2-thione 661, then the Horner-Wittig reaction of the resulting 662 with the carbanion derived from phosphonate 663 and finally deprotection of the TTF 664 to the required 665, obtained as green crystals (Scheme 94) <2003AG2871, 2004JOC2164>. 

Reports of the use in synthesis of the Wittig reaction, and the related methods involving phosphonate and phosphine oxide carbanions and iminophosphoranes, have, if anything, increased and many of these include useful innovations. New results and speculation on the mechanism of the Wittig reaction continue to be published by groups with well established reputations in the area. 

Anions of a-silyl phosphonates of type (153) also undergo additions to carbonyl compounds. The corresponding addition products, 3-silyl alkoxides, can react with ketones to yield the product of the Peterson alkenation or the Wittig reaction. In practice only the Peterson product (154) is obtained, indicating that loss of OSiMes is faster than elimination of C PPhs (Scheme 68). 72 If the a-silyl carbanion is adjacent to a chlorine atom (155), an internal displacement reaction follows the initial formation of the -silyl alkoxide, and epoxides (156) are formed (Scheme 69). 74... 

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. 

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 ... 

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 carbanion 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. 

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