Emmons reaction

The reaction has been extended to include carbanions generated from phosphonates. This is often referred to as the Horner-Wittig or Homer-Emmons reaction. The Horner-Emmons reaction has a number of advantages over the conventional Wittig reaction. It occurs with a wider variety of aldehydes and ketones under relatively mild conditions as a result of the higher nucleophilicity of the phosphonate carbanions. The separation of the olefinic product is easier due to the aqueous solubility of the phosphate by-product, and the phosphonates are readily available from the Arbusov reaction. Furthermore, although the reaction itself is not stereospecific, the majority favor the formation of the trans olefin and many produce the trans isomer as the sole product. 

Triethylphosphonoacetic acid [867-13-0] (PEPA) is a useful olefination reagent for Homer-Emmons reactions in organic synthesis. 

Homofolic acid, 5,11-methenyl-tetrahydro-biological activity, 3, 327 Homofolic acid, tetrahydro-biological activity, 3, 327 Homoisoflavanones occurrence, 3, 722 thermoisomerization, 3, 722 thermolysis, 3, 728 Homolytic reactions heterocyclic compounds reviews, 1, 74 Homophthalic acid isocoumarins synthesis from, 3, 830 synthesis, 3, 830 Homophthalic anhydride isochroman-l-one synthesis from, 3, 860 20a-Homoporphyrin nomenclature, 1, 30 Homopterocarpin isolation, 4, 998 ( )- D- Homotestosterone synthesis, 1, 453 Homer-Emmons reaction chromene synthesis by, 3, 749 Hortiacine isolation, 3, 149 Hortiamine isolation, 3, 149... 

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.

Alkylation of cyanohydrin acetonide 79 with the iodide 78 proceeded smoothly to give pentaacetonide 80 in 70% yield (Scheme 10). This represents the entire polyol framework of roflamycoin. An eight-step sequence involving installation of the polyene, macrocyclization via Horner-Emmons reaction, and protecting group machinations, completed the first total synthesis of roflamycoin. 

The synthetic P-o-glucopyranoside 30 was converted to the cyanoglucoside rho-diocyanoside A (38a), which was isolated from the underground part of Rhodiola quadrifida (Pall.) Fisch. et Mey. (Crassulaceae) and found to show antiallergic activity in a passive cutaneous anaphylaxis test in rat. Acetylation of 30 gave an acetate (98% yield) which was subjected to ozonolysis to afford the aldehyde 39. The Horner-Emmons reaction of 39 using diethyl (l-cyanoethyl)phosphonate furnished (Z)-40a (32% yield from 30) and ( )-40b (10% yield from 30). The physical... 

The synthetic 31 was converted to the cyanoglucoside osmaronin (41a) which was isolated from a methanolic extract of the leaves of Osmaronia cerasi-formis. Acetylation of 31 gave an acetate (99% yield) which was subjected to ozonolysis to afford a ketone 42. The Horner-Emmons reaction of 42 using diethyl cyanomethylphosphonate furnished (Z)-43a (22% yield from the acetate of 31) and ( )-43b (10% yield from the acetate of 31). Deprotection of (Z)-43a and ( )-43b gave the (3-D-glucosides 41a (83% yield) and 41b (94% yield), respectively. The spectral data of the synthetic 41a were identical with those ( H- and C-NMR) of the natural osmaronin (41a) (Fig. 5). 

Then the synthetic 32 was converted to the cyanoglucoside sutherlandin (44) which was isolated from leaves of Acacia sutherlandii. Acetylation of a diastereomeric mixture of 32 gave the corresponding acetate which was subjected to the hydrogenation and the subsequent oxidation to yield the a-acetoxyl ketone (45, 84% overall yield from the acetate of 32). The Homer-Emmons reaction of 45 using diethyl cyanomethylphosphonate furnished (Z)-46a (33% yield from 45) and ( )-46b (31% yield from 45). Deprotection of the presumably desired (Z)-46a afforded (Z)-44 (76% yield), whose C-NMR spectra were identical with those of the natural sutherlandin (44) (Fig. 6). 

OS 79] ]R 17] ]no protocol] 4-Methoxybenzaldehyde and methyl diethoxyphos-phonoacetate were reacted by means of the Wittig-Horner-Emmons reaction [85] (see a more detailed description in [42]). A modified micro reaction system consisting of two mixers, for deprotonation of the phosphonates and introduction of the aldehyde, connected to an HPLC capillary of 0.8 m length and 0.25 mm diameter was employed. The micro reactor showed higher yields than laboratory batch synthesis. 

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. 

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