Reaction Horner-Wadsworth-Emmons

Horner-Wadsworth-Emmons reaction of glycine phosphonate. 

Olefin formation from aldehydes and phosphonates. Workup is more advantageous than the corresponding Wittig reaction because the phosphate by-product can be washed away with water. 

Acid-catalyzed acylation of phenols as well as phenolic ethers using nitriles. 

Hoesch, K. Ber. Dtsch. Chem. Ges. 1915, 48, 1122. Kurt Hoesch (1882-1932) was bom in Krezau, Germany. He studied at Berlin under Emil Fischer. During WWI, Hoesch was Professor of Chemistry at the University of Istanbul, Turkey. After the war he gave up his scientific activities to devote himself to the management of a family business. 

---

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.

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>. 

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. 

For the synthesis of alkenes, the Wittig and Horner-Wadsworth-Emmons reactions have become important tools. Triphenylphosphine that is used in the Wittig reaction can be immobilized either on the polymer or can be used in solution for solid-phase chemistry (Scheme 3.18). The Horner-Wadsworth-Emmons reaction for example is used for the synthesis of aldehyde building blocks [261]. 

An asymmetric Horner-Wadsworth-Emmons reaction has been developed which uses an external chiral ligand to avoid the need to prepare chiral phosphonate derivatives. ... 

Applicable to base-sensitive aldehydes and phosphonates for the Horner-Wadsworth-Emmons reaction... 

Other examples of Ugi reactions combined with RCM have been described in the literature. Hebach and Kazmaier reported the synthesis of conformationally fixed cyclic peptides [70] and Beck and Domling synthesized biaryl-containing natural product-like macrocycles using this method [41]. The same group also reported combination of Passerini and Horner-Wadsworth-Emmons reactions to obtain butenolides [67] and another variation for the combinatorial synthesis of thiazoles [69]. 

The stereoselective Horner-Wadsworth-Emmons reaction of aldehydes with 2-fluoro-2-diethylphosphonoacetic acid utilizing isopropyl magnesium bromide afforded (Z)-a-fluoro-a,j8-unsaturated carboxylates (42) as the major products in 81-98% yield [58] (Scheme 14). 

Furo[3,4-f]pyranones are produced by an intramolecular hetero-Diels-Alder reaction of a,/3-unsaturated 7-keto esters, 81. The Horner-Wadsworth-Emmons reaction of phosphonates with a-diketones is used to assemble compounds 81 (Scheme 17) <2004TL4297>. 

Cyclopropanation, Horner-Wadsworth Emmons Reaction, and Darzens Condensation Although induction in the cyclopropanation of alkenes was reported early, this work was disputed [49]. Other reports of cyclopropanations have yielded, at best, low asymmetric inductions [llh,50]. The first example of a catalytic asymmetric Horner-Wadsworth Emmons reaction, which is promoted by a chiral quaternary ammonium salt, was reported recently by the Shioiri group (Scheme 10.10) [51]. The reaction of the prochiral ketone 74 gives optically active a,P-unsaturated ester 76 with 57% ee. 

The enantioselective desymmetrization of prochiral ketones of type 75 by means of the Horner-Wadsworth-Emmons reaction [76, 77] is an elegant means of synthe-... 

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. 

For reviews about the asymmetric Horner-Wadsworth-Emmons reaction, see (a) T. Rein, L. Vares,... 

For selected asymmetric Horner-Wadsworth-Emmons reactions using stoichiometric amount of a chiral auxiliary, see (a) B. M. Trost, D. P. Curran,/. Am. Chem. Soc. 1980, 102, 5699-5700 (b) S. Hanessian, S. Beaudoin, Tetrahedron Lett. 1992, 33, 7659-7662 (c) N. Kann, T. Rein,... 

Thus the primary allylic alcohol 5 is transformed into an aldehyde, which can now be used in a Horner-Wadsworth-Emmons reaction. In this reaction the dienoate moiety was obtained in a Z,E E,E-selectivity of 95 5. 

We have already seen the bishydroxylation using 0s04 and NMO this time lead tetraacetate is used to cleave the diol and yield the aldehyde. The phosphorane (Me0)2P(0)CHN2 is named the Gilbert-Seyferth reagent. 8 It basically behaves like the phosphoranes in the Horner-Wadsworth-Emmons reaction described above, except that the olefin subsequently loses nitrogen, creating the desired triple bond (also see Chapter 10). 

---