Horner-Wadsworth-Emmons and

Asymmetric Horner-Wadsworth-Emmons and Related Reactions... 

Horner-Wadsworth-Emmons Reactions of Phosphonate Anions. - As with the Horner modification of the Wittig reaction, the principal focus of papers that mention the Horner-Wadsworth-Emmons reaction relate to synthetic applications. The use of pressure to induce the synthesis of P-amino esters, p-thioesters and P-thionitriles via tandem Horner-Wadsworth-Emmons and Michael reactions has been reported. The reagent (l-tritylimidazol-4-yl)methylphosphonate (99) has been prepared and, when treated with aldehydes and ketones, affords (E)-vinylimidazoles in high yields. ... 

Kellogg, R. M. Enantioconvergent synthesis by sequential asymmetric Horner-Wadsworth-Emmons and palladium-catalyzed allylic substitution reactions. Chemtracts 2002, 15, 69-73. 

The first part of this chapter deals with the effects of high pressure on cycloaddition reactions, particularly the Diels-Alder reaction, which is the most important cycloaddition reaction. The second part will illustrate applications of pressure to nucleophilic substitutions, condensations and other reactions (miscellaneous reactions), such as Mannich, Heck, ene, SeAr, Wittig, Horner-Wadsworth Emmons and multicomponent Strecker reactions. 

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]. 

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. 

There do not appear to be any simple phosphines that bear a CH2F group. However, fluorine NMR spectra of phosphonates, phosphane oxides, and phosphonium compounds with CH2F and —CHF- bound to phosphorous have been reported. Examples are given in Scheme 3.26, including spectral data for the useful Horner-Wadsworth-Emmons reagent, triethyl 2-fluoro-2-phosphonoacetate. 

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). 

Synthetic routes to the benzocyclazines are analogues of those which lead to the cyclazines themselves. Representatives of the benzoh ]cycl[3.2.2]azine (indolizi no [3,4,5- ] isoindole, 365) ring system result from cycloaddition of, for example, DMAD to pyrido[2,l-tf]isoindole-6-carbonitrile 370 <1986H(24)3071> (Scheme 100). An alternative synthesis, which starts from the cyclazine 371 and involves construction of the additional benzenoid ring by a double Horner-Wadsworth-Emmons type of reaction, apparently gives the tetracyclic product 365 in only very low yields (Scheme 101) <1988H(27)2251>. 

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... 

Similarly, starting from 2,3 5,6-di-0-isopropylidene-D-mannofuranose 72, a one-pot procedure that implies the synthesis of glycosyl sulfones by Horner-Wadsworth-Emmons olefination with phosphonate 73, followed by subsequent Michael addition and Ramberg-Backlund reaction92 gives compound 74 in 78% yield93 (Scheme 24). 

In a different approach, Franck-Neumann et al. [24] utilized the manganese complex 14 (formed by deracemization) to obtain the enantiomerically pure target molecule 12 via Horner-Wadsworth-Emmons olefination and oxidative decomplexation of the intermediate vinylallene complex 15 (Scheme 18.6). 

Syntheses follow a kind of bio-mimetic approach [283, 284] in building up the chain during a sequence of Wittig-type reactions or Horner-Wadsworth-Emmons olefination, adding two carbons to the chain at a time with either methyl- or ethyl-branches. As the final products need to be highly pure (E)-stereoisomers, reaction steps and purification need to be carefully controlled. 

Synthesis of a C(8)-C(18) segment of the larger fragment of lb using the same basic strategy is depicted in Scheme 25. Here, hydroxy ketone 176 was subjected to syn-selective (dr of crude product=90 10) reductive amination [42] with sodium cyanoborohydride and benzylamine followed by tetrahydro-oxazine formation using aqueous formaldehyde. The resulting heterocycle 182 was then converted to unsaturated ester 184 by successive desilylation, oxidation, and entirely (Z)-selective Horner-Wadsworth-Emmons olefination. Re-... 

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]. 

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

Scheme 8 summarizes the introduction of the missing carbon atoms and the diastereoselective epoxidation of the C /C double bond using a Sharpless asymmetric epoxidation (SAE) of the allylic alcohol 64. The primary alcohol 62 was converted into the aldehyde 63 which served as the starting material for a Horner-Wadsworth-Emmons (HWE) reaction to afford an E-configured tri-substituted double bond. The next steps introduced the sulfone moiety via a Mukaiyama redox condensation and a subsequent sulfide to sulfone oxidation. The sequence toward the allylic alcohol 64 was com-... 

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]. 

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