Homer—Wadsworth—Emmons reaction

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). 

1 Horner-Wadsworth-Emmons Reactions Between Achiral Substrates 

Condensations between aldehydes and metalated phosphonic acid dialkyl esters other than those mentioned previously are also referred to as Homer-Wadsworth-Emmons reactions. Nevertheless, in these esters, too, the carbanionic center carries a substituent with a pi electron withdrawing group, for example, an alkenyl group, a polyene or a C=N group. The Homer-Wadsworth-Emmons reactions of these reagents are also stereoselective and form the new C=C double bond /ra/ ,v-selectively. 

11 Conversion of Phosphorus- or Sulfur-Stabilized C Nucleophiles with Carbonyl Compounds 

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 

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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... 

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>. 

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 first examples of Homer-Wadsworth-Emmons reactions have been reported by Kitazume and Tanaka [60]. Here the ionic liquid [EDBU][OTfj 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 2 isomer was the major product. The reaction was also performed in [EMIMJjBFJ and [EMIMjjPFg], but gave lower yields than with [FDBU][OTf] [60]. 

Homer-Wadsworth-Emmons reactions of ketones and aldehydes with phosphono-acetate esters, (R20)2P(=0)CH2C02R1, produce E/Z mixtures of a, /Tunsaturated esters. Use of the conventional reagent, sodium hydride, gives some selectivity. The combination of tin(II) triflate and A -cthylpipcndine enhances—and sometimes also reverses—the selectivity in most cases studied.71 Six-membered oxo-coordinated tin intermediates are proposed to control the selectivities observed. A similarly selective synthesis of trisubstituted exocyclic alkenes from cyclic ketones has been reported.72... 

The first example of a catalytic asymmetric Horner-Wadsworth-Emmons reaction was recently reported by Arai et al. [78]. It is based on the use of a chiral quaternary ammonium salt as a phase-transfer catalyst, 78, derived from cinchonine. Catalytic amounts (20 mol%) of organocatalyst 78 were initially used in the Homer-Wadsworth-Emmons reaction of ketone 75a with a variety of phospho-nates as a model reaction. The condensation products of type 77 were obtained in widely varying yields (from 15 to 89%) and the enantioselectivity of the product was low to moderate (< 43%). Although yields were usually low for methyl and ethyl phosphonates the best enantioselectivity was observed for these substrates (43 and 38% ee, respectively). In contrast higher yields were obtained with phosphonates with sterically more demanding ester groups, e.g. tert-butyl, but ee values were much lower. An overview of this reaction and the effect of the ester functionality is given in Scheme 13.40. 

You will learn about the reaction of a-metalated phosphonic acid esters with aldehydes in Section 11.3 in connection with the Homer-Wadsworth-Emmons reaction. This reaction also seems to give a Irans-con figured oxaphosphetane (Figure 4.46). Again, a. vyn-selective /3-elim-ination of a compound with P=0 double bond should occur. One of the elimination products is (EtO)2P(=O)O0. As a second product an alkene is produced that is predominantly or exclusively irans-configured. 

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. 

Fig. 4.46. A Het /Het2 elimination from the presumed oxaphosphetane intermediate of a Homer-Wadsworth-Emmons reaction.

Homer-Wadsworth-Emmons reactions are C=C-forming condensation reactions between the Li, Na, or K salt of a /1-koto- or an a-(alkoxycarbonyl )phosphomc acid dialkyl ester and a carbonyl compound (see Figure 4.46). These reactions furnish a,/3-unsaturated ketones or 0 ,/3-unsaturated esters, respectively, as the desired products and a phosphoric acid diester anion as a water-soluble by-product. In general, starting from aldehydes, the desired compounds are produced /ra/ov-selectively or, in the case of alkenes with trisubstituted C=C double bonds, -selectively. 

The mechanism of Homer-Wadsworth-Emmons reactions has not been definitively established. A contemporary rationalization is shown in Figure 11.13 for the reaction between an... 

Johnson CR, Zhang B, Solid phase synthesis of alkenes using the Homer-Wadsworth-Emmons reaction and monitoring by gel phase (31)P NMR,... 

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