Wadsworth-Emmons,

Wadsworth-Emmons reactions crown ethers and, 7, 759 Warfarin... 

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.

Retrosynthetic cleavage of the A13,14 double bond in 6 significantly simplifies the side-chain appendage attached to C-l2 and affords aldehyde 7 and ketophosphonate 8 as potential precursors. In the synthetic direction, a Homer-Wadsworth-Emmons reaction10 would appear to provide a very simple means of joining intermediates 7 and 8 with concomitant formation of the requisite trans C13-C14 olefin. Retrosynthetic simplification of aldehyde 7 provides intermediate 9, a molecular assembly commonly known as the Corey lactone. 

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. 

Aldehyde 170 is to serve as the electrophile in an intermolecular Homer-Wadsworth-Emmons (HWE) reaction70 with enantiomeri-cally pure phosphonate 169. Compounds 169 and 170 can in fact be joined efficiently under the mild reaction conditions shown in Scheme 50 to give a,/ -unsaturated imide 206 (96 % yield). The use... 

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

This method, sometimes called the Horner-Emmons, Wadsworth-Emmons, or... 

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

Reactions with phosphonoacetate esters are used frequently to prepare ,[ -unsaturated esters. This reaction is known as the Wadsworth-Emmons reaction and usually leads to the E-isomer. 

Several other methodologies have been developed for control of the stereoselectivity of Wadsworth-Emmons reactions. For example, K2C03 in chlorobenzene with a catalytic amount of 18-crown-6 is reported to give excellent Z-selectivity.261 Another group found that use of excess Na+, added as Nal, improved Z-selectivity for 2-methylphenyl... 

This version of the Wadsworth-Emmons reaction has been used in the scaled-up syntheses of drugs and drug-candidate molecules. For example, it is used to prepare a cinnamate ester that is a starting material for pilot plant synthesis of a potential integrin antagonist.263... 

Scheme 2.18 gives some representative olefination reactions of phosphonate anions. Entry 1 represents a typical preparative procedure. Entry 2 involves formation of a 2,4-dienoate ester using an a, 3-unsaturated aldehyde. Diethyl benzylphosphonate can be used in the Wadsworth-Emmons reaction, as illustrated by Entry 3. Entries 4 to 6 show other anion-stabilizing groups. Intramolecular reactions can be used to prepare cycloalkenes.264... 

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