Wadsworth-Emmons reactions

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

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.

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... 

Intramolecular condensation of phosphonate carbanions with carbonyl groups carried out under conditions of high dilution have been utilized in macrocycle syntheses. Entries 7 and 8 show macrocyclizations involving the Wadsworth-Emmons reaction. Entries 9 to 11 illustrate the construction of new double bonds in the course of a multistage synthesis. The LiCl/amine conditions are used in Entries 9 and 10. 

Visual models, additional information and exercises on the Wadsworth-Emmons Reaction can be found in the Digital Resource available at Springer.com/carey-sundberg. 

Fig. 2.6. Free-energy profile (B3LYP/6-31 + G with ZPE correction) for intermediates and transition structures for Wadsworth-Emmons reactions between the lithium enolate of trimethyl phosphonoacetate anion and formaldehyde in the gas phase and in tetrahydrofuran or ethanol. Adapted from J. Org. Chem., 63, 1280 (1998), by permission of the American Chemical Society.

Scheme 2.19 provides some examples of the Peterson olefination. The Peterson olefination has not been used as widely in synthesis as the Wittig and Wadsworth-Emmons reactions, but it has been used advantageously in the preparation of relatively... 

After the cycloaddition, the thiazole ring was introduced via a Wadsworth-Emmons reaction at Step D, forming the C(17)-C(18) bond. 

The Witting reaction has been investigated in aqueous conditions.305 Wittig olefination reactions with stabilized ylides (known as the Wittig-Homer or Homer-Wadsworth-Emmons reaction) are sometimes performed in an organic/water biphase system.306 Very often, a phase-transfer catalyst is used. Recently, the use of water alone as solvent... 

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... 

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.

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>. 

Although not widely exploited, the use of the phosphonate 148 in Wadsworth-Emmons reactions represents a process of great potential that has been used to access the 3-alkenyl-l,2,4-oxadiazole 149 (Equation 21) <1989J(P1)2047>. 

As shown in Equation (23), the 3-chloromethyl-l,2,4-oxadiazole 159 (X = H) undergoes Arbuzov reaction to give the phosphonate 148 which has been used in Wadsworth-Emmons reactions as shown previously in Equation (21) <1989J(P1)2047>. 

The 4,5-dihydro-l,2,4-oxadiazol-5-one 119 (see also Scheme 12) undergoes Wadsworth-Emmons reaction to give the alkene 190 (Scheme 25). Reduction of the ester with Red-Al and subsequent bromination of the alcohol gave the bromofluoroalkenyl-substituted 4,5-dihydro-l,2,4-oxadiazol-5-one 191, demonstrating the robustness of this ring system <2004T10907>. 

In a process starting with the stereospecific Homer-Wadsworth-Emmons reaction of phosphonoglycinates 99 with 2-iodobenzaldehydes to afford the corresponding (Z)-didehydro-phenylalanine derivatives 100, Brown similarly utilized an intramolecular palladium-catalyzed animation of 100 (Y = 2-chloro-3-pyridyl, Ph, OBn) to form the N-substituted indole carboxylates 101 <00TL1623>. 

Phosphonothiazolylmethanes 40 react with carbonyl compounds to give the expected alkene products via Knoevenagel or Homer-Wadsworth Emmons reactions. When they are treated with oc-haloketones, pyrrolothiazoles 42 are obtained in a two stage process via the quaternary salt 41 <98PSS251>. 

An asymmetric synthesis of phosphonylated thiazolines has been described. The phosphonodithioacetate 46 was aminated with a chiral amino alcohol 47 to give the phosphonylated thioamide 48 in good yield. This was then cyclised using a Mitsunobu procedure to give the chiral thiazoline phosphonate 49 in good yields under mild conditions. Homer-Wadsworth-Emmons reaction of these phosphonylated thiazolines gave chiral vinylic thiazolines 50 <00S1143>. 

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