Wittig and Horner-Wadsworth-Emmons Reactions

For the synthesis of alkenes, the Wittig and Horner-Wadsworth-Emmons reactions have become important tools. Triphenylphosphine that is used in the Wittig reaction can be immobilized either on the polymer or can be used in solution for solid-phase chemistry (Scheme 3.18). The Horner-Wadsworth-Emmons reaction for example is used for the synthesis of aldehyde building blocks [261]. 

Oxaphosphetane Fragmentation, Last Step of Wittig and Horner-Wadsworth-Emmons Reactions... 

Scheme 1. Schematic representation of the Wittig and Horner-Wadsworth-Emmons reactions. LG = leaving group.

Introduction The extended enolate problem Kinetic and thermodynamic control Wittig and Horner-Wadsworth-Emmons Reactions Extended Aza-Enolates Extended Lithium Enolates of Aldehydes Summary a-Alkylation of Extended Enolates Reaction in the y-Position Extended Enolates from Unsaturated Ketones Diels-Alder Reactions Extended Enolates from Birch Reductions The Baylis-Hillman Reaction The Synthesis of Mniopetal F... 

Formation of C-N bond has raised of interest in the scientific community in the last 10 years. In this context, the formation of enamides is a valuable protocol. In addition to conventional approaches that include condensation of amides and aldehydes, addition of amides to alkynes, acylation of imines, Curtius rearrangement of a,jS-unsaturated acyl azides, amide Peterson olefination, and Wittig and Horner-Wadsworth-Emmons reactions, several transition metal-catalyzed methods have been developed that allow the synthesis of enamides.Inspired by the analogous arylation of amines catalyzed by palladium or copper complexes (Buchwald-Hartwig reaction), a new approach for the synthesis of enamides has been published recently, which allows to prepare enamides from readily available starting materials (amides and vinyl halides) proceeding under very mild conditions. Thus, we decided to test the Porco-Buchwald amidation of vinyl halides in our synthesis [144-146]. 

The past year has seen continued interest in the structural nature of phosphorus ylides with the aim of gaining greater insight into their stabilities, electronic distributions and conformations, which ultimately affect the reactivities of these species. However, there have been fewer mechanistic studies of the Wittig reaction itself although several studies into the closely related aza-Wittig and Horner-Wadsworth-Emmons modifications have appeared. 

In 1990, Gorgues and coworkers [60,61] reported the earliest studies of extended TTFs by acetylene scaffolding 61, in order to decrease on-site Coulomb repulsion. The symmetrically substituted acetylenic analog 61 was prepared from a very reactive aldehyde (58) [62] by Wittig or Horner-Wadsworth-Emmons reactions (Scheme 8.8). The CV of 61 exhibited reversible one two-electron redox pan-corresponding to 61/61 . This behavior is different from the TTFVs series of 2, which is linked by an ethylene spacer, due to lack of electronic communication through the acetylenic bond in 61 ". ... 

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 ... 

The (Horner-)Wadsworth-Emmons reaction generally is superior to the Wittig reaction, and has found application in many cases for the synthesis of a ,/3-unsaturated esters, a ,/3-unsaturated ketones and other conjugated systems. Yields are often better then with the original Wittig procedure. However the Wadsworth-Emmons method is not suitable for the preparation of alkenes with simple, non-stabilizing alkyl substituents. 

The protected methyl glycoside 3 is converted to the corresponding aldehyde by Swern oxidation using oxalyl chloride activated DMSO. Further reaction with triethyl phosphonoacetate and sodium hydride -known as the Horner-Wadsworth-Emmons reaction - provides selectively the trans et /Tun saturated ester 4 in 72 % yield. This valuable alternative to the Wittig olefination protocol uses phosphonate esters as substrates which are readily available from alkyl halides and trialkyl phosphites via the Arbuzov rearrangement.9 co2Et Reaction of the phosphonate with a suitable base gives the... 

Horner-Wadsworth-Emmons Reactions of Phosphonate Anions. - As with the Horner modification of the Wittig reaction, the principal focus of papers that mention the Horner-Wadsworth-Emmons reaction relate to synthetic applications. The use of pressure to induce the synthesis of P-amino esters, p-thioesters and P-thionitriles via tandem Horner-Wadsworth-Emmons and Michael reactions has been reported. The reagent (l-tritylimidazol-4-yl)methylphosphonate (99) has been prepared and, when treated with aldehydes and ketones, affords (E)-vinylimidazoles in high yields. ... 

Starting from (+)-diethyl tartrate (2), bromobutenolide 18 was obtained in nine steps. Three of the four C=C double bonds were built up using a Wittig reaction (11—>12), an Ando- y Q Horner-Wadsworth-Emmons reaction (13— 15) and (3-elimination (16 18). From (-)-actinol (3) stannane 23 and sulfone 24 were synthesized in 9 and 13 steps, respectively. Their common intermediate, alkyne 22, was synthesized using methoxycarbonylation. Sharpless asymmetric epoxidation and Ci-elongation with lithio trimethylsilyldiazomethane. Stannane 23 was obtained upon hydrostannylation and TBS deprotection. Sulfone 24 was obtained after addition to methyl tetrolate, reduction, Mukaiyama redox condensation, acetylation and catalytic oxidation. 

Wittig reactions, and Horner-Wadsworth-Emmons olefmation... 

The format of this chapter is similar to that used in previous volumes. The first section deals with methylene phosphoranes and their Wittig reactions, the second looks at the Horner-Wadsworth-Emmons reaction of phosphonate anions and the third the structure and reaction of lithiated phosphine oxides - an area which continues to receive particular attention. The majority of reports concerning ylides relate to their use in synthesis and in the final section some of these applications are reviewed. 

Rehwinkel, H., Skupsch, J., and Vorbrtiggen, H., E- or Z-selective Homer-Wittig reactions of suhsti-tuted bicyclo[3.3.0]octane-3-ones with chiral phosphonoacetates. Tetrahedron Lett., 29, 1775, 1988. Tiillis, J.S., Vares, L., Kann, N., Norrby, P.-O., and Rein, T., Reagent control of geometric selectivity and enantiotopic group preference in asymmetric Horner-Wadsworth-Emmons reactions with meso-dialdehydes, J. Org. Chem., 63, 8284, 1998. 

The Horner-Wadsworth-Emmons modification of the Wittig reaction continues to find wide application in contemporary organic synthesis. Two reviews, looking at different aspects of the stereoselectivity of this procedure, have been published. One considers approaches to improve the Z-selectivity of the Horner-Wadsworth-Emmons reaction, and the other the use of heteroatoms to improve the stereoselectivity of the Horner-Wadsworth-Emmons reaction. A combined experimental and computational study of the selectivity of the Horner-Wadsworth-Emmons reaction of a series of phosphonoacetates (172) has... 

Other y-bromoesters such as 31 can be made by radical bromination13 with NBS (this too is a y reaction ) and used in similar Horner-Wadsworth-Emmons reactions. It does not matter if some reaction occurs at the y position of 29 or 33 as the Wittig elimination cannot occur on such an intermediate and it reverses. The products of these aldol reactions are dienes 30 and 34 and are usually made for use in Diels-Alder reactions. We shall return to this subject later in this chapter. 

You saw in the last section that the preparation of allylic sulfides by displacement of, say, a halide from an allylic system is likely to give the more stable allylic sulfide whichever allylic halide is used and that the corresponding allylic sulfoxides are made by oxidation of the sulfide. The same is true of phosphorus compounds 73 used in chapter 15 to make dienes of fixed configuration. If R = OR, 73 is an allylic phosphonate for the Horner-Wadsworth-Emmons reaction but if R = Ph, 73 is a phosphine oxide for the Wittig-Horner reaction. 

Where applicable, the Horner-Wadsworth-Emmons reaction is generally superior to the Wittig reaction with resonance-stabilized phosphonium ylides and it is employed widely in the preparation of a,(3-unsaturated esters and other conjugated systems. It often gives better yields than the Wittig reaction, the phosphonate esters are readily available and it has the practical advantage that the phosphate... 

Universal methods for coupling of the synthetic building blocks are the Wittig reaction, the Horner-Wadsworth-Emmons reaction, the sulfone coupling by Julia s procedure, the enol ether condensation (Miiller-Cunradi-Pieroh reaction), and the Saucy-Marbet rearrangement. Since in very many cases mixtures... 

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 Wittig synthesis of alkenes and variations of it, such as the Horner-Wadsworth-Emmons reaction, are now regarded as among the classic reactions of organic chemistry. Such reactions are of enormous importance because they produce alkenes of predictable structure under mild conditions. In performing some of the experiments in this chapter, you may be executing a functional group transformation that earned its discoverer a Nobel Prize in Chemistry (Sec. 18.2). 

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