Horner-Wadsworth Emmons

HORNER - WADSWORTH - EMMONS Olelination Wittig type reaction of ptwsptionale stabilized carbanions with aldehydes or ketones to form olefins... 

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 first examples of Horner-Wadsworth-Emmons reactions have been reported by Kitazume and Tanaka [60]. Here the ionic liquid [EDBU][OTf] was used in the synthesis of a-fluoro-a,P-unsaturated esters (Scheme 5.1-32). It was found that when K2CO3 was used as a base, the E isomer was the major product and that when DBU was used as a base, the Z isomer was the major product. The reaction was also performed in [EMIM][BF4] and [EMIM][PFgj, but gave lower yields than with [EDBU][OTf] [60]. 

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

Horner-Wadsworth-Emmons double bond reduction... 

Carboximide 160, the C35-C42 fragment, can be traced retro-synthetically to phosphonate 169 and aldehyde 170. In the synthetic direction, the C35-C36 bond in 160 could be constructed by an intermolecular Horner-Wadsworth-Emmons (HWE)70 coupling of intermediates 169 and 170. Reduction of the unsaturated coupling product and exchange of silyl protecting groups would then furnish compound 160. 

Intramolecular phosphonate-ketone condensation (Horner- Wadsworth-Emmons)... 

Scheme 21 Higher order Horner-Wadsworth-Emmons olefination via hexacoordinated intermediates 67...

A tandem enzymatic aldol-intramolecular Homer-Wadsworth-Emmons reaction has been used in the synthesis of a cyclitol.310 The key steps are illustrated in Scheme 8.33. The phosphonate aldehyde was condensed with dihydroxyacetone phosphate (DHAP) in water with FDP aldolase to give the aldol adduct, which cyclizes with an intramolecular Horner-Wadsworth-Emmons reaction to give the cyclo-pentene product. The one-pot reaction takes place in aqueous solution at slightly acidic (pH 6.1-6.8) conditions. The aqueous Wittig-type reaction has also been investigated in DNA-templated synthesis.311... 

There do not appear to be any simple phosphines that bear a CH2F group. However, fluorine NMR spectra of phosphonates, phosphane oxides, and phosphonium compounds with CH2F and —CHF- bound to phosphorous have been reported. Examples are given in Scheme 3.26, including spectral data for the useful Horner-Wadsworth-Emmons reagent, triethyl 2-fluoro-2-phosphonoacetate. 

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). 

Scheme 2.66. Domino Corey-Kwiatkowski /Horner-Wadsworth-Emmons reaction.

Several other anionic/pericyclic domino processes use a Horner-Wadsworth-Emmons (HWE) or a Wittig olefmation as the first step. 

Horner-Wadsworth-Emmons or Horner-Wittig-Emmons 2-iodoxybenzoic acid... 

Synthetic routes to the benzocyclazines are analogues of those which lead to the cyclazines themselves. Representatives of the benzoh ]cycl[3.2.2]azine (indolizi no [3,4,5- ] isoindole, 365) ring system result from cycloaddition of, for example, DMAD to pyrido[2,l-tf]isoindole-6-carbonitrile 370 <1986H(24)3071> (Scheme 100). An alternative synthesis, which starts from the cyclazine 371 and involves construction of the additional benzenoid ring by a double Horner-Wadsworth-Emmons type of reaction, apparently gives the tetracyclic product 365 in only very low yields (Scheme 101) <1988H(27)2251>. 

Pyridylidenehydantoins such as 139, obtained from pyridinecarbaldehydes by Horner-Wadsworth-Emmons reactions, are cyclized under acidic conditions to tricycles of the type 140 (Scheme 39) <2004TL553>. Similar benzannulated ring systems can be prepared by the reaction of 2-benzimidazolylacetonitriles and, for example, 2-chloronicotinic esters or 2-chloronicotinamides under basic conditions (Equation 32) <1996JHC1147, 1997JHC397>. 

Tanaka et al.50 also reported that chiral Horner-Wadsworth-Emmons reagent (S )-51 reacted with an alternative carbonyl group of the meso-a-diketones... 

The catalytic asymmetric Horner-Wadsworth-Emmons reaction was realized by use of the quaternary ammonium salts 7 derived from cinchonine as a phase transfer catalyst.1631 Thus, tert-butylcyclo-hexanone 85 reacted with triethyl phosphonoacet-ate 86 together with RbOH-H20 in the presence of the ammonium salts 7, and then the product 87 was isolated after reesterification by treatment with acidic ethanol, as shown in Scheme 27 Among the... 

S. Arai, S. Hamaguchi, T. Shioiri, Catalytic Asymmetric Horner-Wadsworth-Emmons Reaction under Phase-Transfer-Catalyzed Conditions , Tetrahedron Lett 1998, 39,2997-3000. 

Similarly, starting from 2,3 5,6-di-0-isopropylidene-D-mannofuranose 72, a one-pot procedure that implies the synthesis of glycosyl sulfones by Horner-Wadsworth-Emmons olefination with phosphonate 73, followed by subsequent Michael addition and Ramberg-Backlund reaction92 gives compound 74 in 78% yield93 (Scheme 24). 

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