Wittig and Homer - Wadsworth - Emmons Reactions

Acylphosphonates are suilable carbonyl substrates for Wittig and Homer-Wadsworth-Emmons reactions, but with certain limitations. 5° These limitations are the result of competing side reactions involving proton iransfer or acylation. Homer-Wadsworth-Emmons reactions fail with... 

SeeNicolaou,K.C. Hartner,M.W. Gunzner,J.L. Nadin, A. LieWgi Ann. Chem. 1997,1283-1301, fOT a review of the Wittig and Homer-Wadsworth-Emmons reactions. 

A convenient procedure to effect the Wittig and Homer-Wadsworth-Emmons reactions employing guanidine TBD and MTBD as base promoters was developed. Mild reaction conditions highly efficiently facflitated isolation of the final products (Figurel.5) [38]. Further developments oftheWittigreactionhavebeenreported [39,40]. 

In addition to the Wittig- und Homer-Wadsworth-Emmons reactions, we know a third alkene-forming reaction between carbonyl and phosphororganic compounds, i.e. the Wittig-Homer reaction. In Section 11.2, you will learn that in the course of this reaction a. syn-elim-ination of Ph2P(=0)0 takes places, i.e. another / elimination of I let1/I let2. 

The Homer-Wadsworth-Emmons reaction is also a useful option for producing olefins in the solid phase. Supported stabilized phosphonoactates, as they are more acidic than phosphonium salts, can readily give the corresponding ylides with weak bases such as DBU, DIPEA, EtaN. One still has to make sure that these reaction conditions are chemoselective. Both types of reactions, Wittig and Homer-Wadsworth-Emmons, have been successfully used in cyclative and/or functionalizing cleavage. 

The (Homer-)Wadsworth-Emmons reaction generally is superior to the Wittig reaction, and has found application in many cases for the synthesis of a,/l-unsaturated esters, a,/l-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 Homer-Wadsworth-Emmons reaction represents a methodologically more important and more commonly used supplement to the Wittig reaction (cf. Section 11.1.3) than the Wittig-Homer reaction (Section 11.2). 

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. 

A variation of the Wittig reaction that can overcome problems with the stereochemical outcome is the Homer-Wittig reaction with phosphine oxides. The oxides are obtained by quatemization of triphenylphosphine and hydrolysis of the phosphonium salt, or by reaction of hthiodiphenylphosphide with an alkyl halide or sulfonate and oxidation of the resulting phosphine with hydrogen peroxide. The derived hthio species react with aldehydes or ketones to give p-hydroxy phosphine oxides, which ehminate on treatment with a base such as sodium hydride or potassium hydroxide to form the alkene. In common with the Homer-Wadsworth-Emmons reaction, the phosphorus by-product is water soluble and easily removed from the product. 

Addition reactions such as addition of enolates to carbonyl compounds, photochemical cydoaddition, radical addition and elimination reactions such as dehydration can be carried out in microflow reactors. Addition-elimination reactions such as Wittig reaction, Homer-Wadsworth-Emmons reaction, Baylis-Hillman reaction. 

The Homer-Wadsworth-Emmons reaction is an important variant of the Wittig reaction and involves using a phosphonate ester in place of a phosphonium salt. Like the phase-transfer Wittig reaction just discussed, these reactions may be easily performed in the undergraduate laboratory. In one of the procedures that follows, the phosphonate ester 12 is deprotonated with potassium tert-butoxide in the polar, aprotic solvent N,N-dimethylformamide, (CH3)2NCHO (DMF), to provide the resonance-stabilized, nucleophilic phosphonate anion 13 (Eq. 18.7). 

A modification of the above reaction, known as the Wittig-Homer reaction or Homer-Wadsworth-Emmons reaction uses phosphonate esters. Thus, the reaction of ethyl bromoacetate with triphenylphosphite gives the phosphonate ester, which on treatment with base (NaH) and reaction with cyclohexanone... 

There are many carbanion and ylid derivatives that also contain an acid moiety, an ester or an acid sutrogate. Ester and acid enolates, for example, react with a variety of electrophilic reagents to produce new acid or ester derivatives. If the electrophile contains an amine or an amine surrogate, amino acids are produced as the final product. In addition, ylids bearing an acid or ester moiety react with aldehydes or ketones bearing an amine moiety via a Wittig reaction or a Homer-Wadsworth-Emmons reaction to give alkenyl amino acids. 

Once an aldehyde such as 5.62 is formed, other reactions can be done, as seen in previous sections. One is an oleflnation reaction (here using a Homer-Wadsworth-Emmons reaction see 5.7 in section 5.1.A) with 5.62 to generate methyl 4S-(N-Cbz amino)-6-methylhept-2-enoate, 5.65.32 Using a similar strategy, a Wittig reaction33 with 5.66 gave 5.67 and this was converted to dipeptide 5.68. Subsequent reaction... 

Syntheses of the five possible dihydro derivatives of all-7ra/i -retinoic acid (3) are summarized in the equations below. In each case, a conventional coupling technique for the synthesis of retinoids was employed this was based on a Wittig reaction for (517) and on Homer-Wadsworth-Emmons reactions for (513), (514), (515), and (516) (Pawson et al., 1977). 

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. 

Also for the Wittig reaction, the product may be formed as a mixture of Z- and ii-isomers, but each of these may be improved by applying appropriate reaction conditions. Studies on modifications on the Homer-Wadsworth-Emmons reaction done by StiU and Gennari [38] and Ando [39] have resulted in improved Z-selective reactions. As of today, these reactions are limited to phosphonate esters. 

Aldehyde 123 was then reacted in a stereoselective Homer-Wadsworth-Emmons reaction with the sodium salt of phosphonate 124 to produce enone 125 (Scheme 3.31). Chemo- and stereoselective rednction of enone 125 with zinc borohydride provided secondary alcohol 126 as a 1 1 mixture of C-15 epimers, which could be separated by chromatography. Next, solvolysis of the acetate in 126 with basic methanol was followed by protection of the two alcohols with dihydropyran in the presence of a catalytic amount of para-toluenesulfonic acid. Reduction with DIBAL-H then provided lactol 127. Wittig reaction of 127 with the nonsta-bilized ylide 128 and snbsequent deprotection produced ( )-prostaglandin F (113). 

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