The Horner-Wadsworth-Emmons Reaction

Diphenyl phosphite-ester-aldehyde substrates (83) undergo a Z-selective intramolecular Homer-Wadsworth-Emmons (HWE) reaction to give macrocyclic ene-lactones (84). Terminal placement of the ester in the substrate gives a macrocyclic alkene with 

An unexpected alkenylphosphonate product has arisen in an HWE reaction, but it can be suppressed by bulking up the aldehyde or ester reactant.  

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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. 

Scheme 5.1-32 The Horner-Wadsworth-Emmons reaction in an ionic liquid.

Application of the Horner-Wadsworth-Emmons reaction to the functionalization of dendrimers allows one to prepare amino acid terminated macromolecules. Such a reaction conducted with dendrimers 10-[G ], 10-[G 3], lO-fG ] and phosphonates unsubstituted at the carbon a to the phosphoryl group affords in moderate yield dendrimers bearing various a, / unsaturated functional groups on the surface [18]. (Schemes 17 and 18). 

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]. 

Applicable to base-sensitive aldehydes and phosphonates for the Horner-Wadsworth-Emmons reaction... 

Furo[3,4-f]pyranones are produced by an intramolecular hetero-Diels-Alder reaction of a,/3-unsaturated 7-keto esters, 81. The Horner-Wadsworth-Emmons reaction of phosphonates with a-diketones is used to assemble compounds 81 (Scheme 17) <2004TL4297>. 

The enantioselective desymmetrization of prochiral ketones of type 75 by means of the Horner-Wadsworth-Emmons reaction [76, 77] is an elegant means of synthe-... 

We have already seen the bishydroxylation using 0s04 and NMO this time lead tetraacetate is used to cleave the diol and yield the aldehyde. The phosphorane (Me0)2P(0)CHN2 is named the Gilbert-Seyferth reagent. 8 It basically behaves like the phosphoranes in the Horner-Wadsworth-Emmons reaction described above, except that the olefin subsequently loses nitrogen, creating the desired triple bond (also see Chapter 10). 

Some stabilized ylides are too stable to be very reactive. In this case phosphonates are used instead of phosphonium salts. For the Horner-Wadsworth-Emmons-reaction see Chapter 2. 

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... 

Synthesis of OPV3 38 by the Horner-Wadsworth-Emmons reaction To a solution of aldehyde 6 (7.77 g, 40 mmol) and diphosphonate 37 (7.57 g, 20 mmol) in THF (200 mL) cooled in an ice-bath was added t-BuOK (4.94 g, 44 mmol) in small portions during 10 min. After stirring for 6 h at room temperature under a nitrogen atmosphere, the mixture was poured into H20 (300 mL). The yellow precipitate was filtered off, washed with H20 and dried. The product was dissolved in a minimum amount of boiling THF containing I2 (0.1 mM). The mixture was refluxed for 12 h and then slowly cooled to room temperature. The pure trans-stilbene 38 crystallized [10a]. 

The Ando variant is an alternative to the Still-Gennari variant of the Horner-Wadsworth-Emmons reaction. Here, phosphonates are employed that contain two aryloxy residues, for example, the ortho-tolyloxy residues of the phosphonate A. The Ar-O groups in this reaction... 

Although the Horner-Wadsworth-Emmons reaction is not an ylide reaction, it represents methodologically such an important supplement to the Wittig reaction discussed in Figure 9.3 that we include its discussion here. 

Condensations between aldehydes and metallated phosphonic acid dialkyl esters other than those mentioned previously are also referred to as Horner-Wadsworth-Emmons reactions. Nevertheless, in these esters, too, the carbanionic center carries a substituent with a M effect, for example, an alkenyl group, a polyene or a C=N group. The Horner-Wadsworth-Emmons reactions of these reagents are also stereoselective and form the new C—C double bond fraus-selectively. 

Fig. 9.15. Preparation of trans- or -configured a,/3-unsaturated esters by the Horner-Wadsworth-Emmons reaction (left) or preparation of their ns- or Z-isomers by the Still-Gennari variant of it (right). 18-Crown-6 is a so-called crown ether and contains a saturated 18-membered ring containing six successive —CH2—O—CH2-units. 18-Crown-6 dissociates the K+ ions of the Horner-Wadsworth-Emmons reagent by way of complexation.

Protocol 2 produces the protected fi-formylphosphonate 12 f)-ketophospho-nates may also be synthesized by other methods,23 however, they may not be prepared in unprotected form by the Michaelis-Arbuzov reaction because the Perkow reaction, in which an a-haloaldehyde or ketone and a trialkyl phosphite yield an enol phosphate (e.g. 13, Scheme 5,24 i.e. [P—O] bond formation), competes and frequently dominates (see Section 4). Conversely halocarboxylic acid derivatives (e.g. see Table 7.1, entry 3) and acyl halides (see Protocol 3) react well in the Michaelis-Arbuzov reaction to yield useful functionalized phosphonates. fi-Ketophosphonates are useful reagents for the synthesis of a,fi-unsaturated carbonyl compounds by the Horner-Wadsworth-Emmons reaction,3,4 25 and have other applications.23... 

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. ... 

Sano, s., Yokoyama, K., Fukushima, M., Yagi, T., Nagao, Y. New reaction mode of the Horner-Wadsworth-Emmons reaction using Sn(OS02CF3)2 and N-ethylpiperidine. Chem. Common. 1997, 559-560. 

Brandt, P., Norrby, P.-O., Martin, I., Rein, T. A Quantum Chemical Exploration of the Horner-Wadsworth-Emmons Reaction. J. Org. Chem. 1998, 63, 1280-1289. 

Ando, K. A Mechanistic Study of the Horner-Wadsworth-Emmons Reaction Computational Investigation on the Reaction Pass and the Stereochemistry in the Reaction of Lithium Enolate Derived from Trimethyl Phosphonoacetate with Acetaldehyde. J. Org. Chem. 1999, 64, 6815-6821. 

Motoyoshiya, J., Kusaura, T., Kokin, K., Yokoya, S. i., Takaguchi, Y., Narita, S., Aoyama, H. The Horner-Wadsworth-Emmons reaction of mixed phosphonoacetates and aromatic aldehydes geometrical selectivity and computational investigation. Tetrahedron 2001, 57, 1715-1721. 

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. 

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