Horner synthesis esters

A suspension of NaH in abs. tetrahydrofuran stirred and treated portionwise at 0° with diethyl methoxycarbonylmethylphosphonate, after completion of the Hg-evolution a soln. of cortexone in abs. tetrahydrofuran added whereupon the temp, rises to 40-50° then drops to ca. 30°, the product isolated after 35 min. stirring crude butenolide. Y 90.1%. F. e. s. W. Fritsch, U. Stache, and H. Ruschig, A. 699, 195 (1966) a, -ethylenecarboxyiic acid esters from ketones, labeled compounds, s. W. M. Walter, Jr., J. Labelled Compds. 3, 54 (1967) a,/ -ethylenephosphonic from methylenediphosphonic acid esters s. T. L. Hular, Tetrah. Let. 1967, 4921 a,y -ethylenealdehydes from oxo compounds by Horner synthesis cf. W. Nagata and Y. Hayase, Tetrah. Let. 1968, 4359. 

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]. 

The synthesis in Scheme 13.21 starts with a lactone that is available in enantiomer-ically pure form. It was first subjected to an enolate alkylation that was stereocontrolled by the convex shape of the cis ring junction (Step A). A stereospecific Pd-mediated allylic substitution followed by LiAlH4 reduction generated the first key intermediate (Step B). This compound was oxidized with NaI04, converted to the methyl ester, and subjected to a base-catalyzed conjugation. After oxidation of the primary alcohol to an aldehyde, a Wittig-Horner olefination completed the side chain. 

A Michaelis-Arbusov rearrangement followed by a Wittig-Horner reaction is involved in preparation of the distyrylbenzene derivative 11.37, as shown in Scheme 11.15. Precautions must be taken in the first stage to minimise formation of the carcinogenic by-product bis(chloromethyl) ether 11.16. The stilbene bis-ester 11.38 can be made by a similar procedure, or alternatively by the reaction of ethyl acrylate with 4,4 -dibromostilbene in the presence of a palladium-based catalyst (Scheme 11.16), a synthesis that yields the required trans form of the brightener. 

Sharpless asymmetric dihydroxylation procedure was applied to the synthesis of the side chain of azinomycin A (equation 26)43. Horner-Emmons condensation of phospho-nate 36 with a /J-aziridine substituted acrolein afforded dehydroamino acid diene 37. Treatment of the diene with catalytic amounts of an osmium reagent and dihydroquini-dine (DHQD) p-chlorobenzoate resulted in asymmetric dihydroxylation, producing diol 38. Diol 38 was further converted to the naphthyl ester. 

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-... 

An improved Horner-Wadsworth-Emmons preparation of a-methyl or a-ethyl-a, P Unsaturated esters from aldehydes, which are useful intermediates in the synthesis of insect pheromones, has been reported. ... 

An interesting example of biocatalysis and chemical catalysis is the synthesis of a derivative of y-aminobutyric acid (GABA) that is an inhibitor for the treatment of neuropathic pain and epilepsy (Scheme 10.4). The key intermediate is a racemic mixture of cis- and trons-diastereoisomer esters obtained by a hydrogenation following a Horner-Emmons reaction. The enzymatic hydrolysis of both diaste-reoisomers, catalyzed by Candida antarctica lipase type B (CALB), yields the corresponding acid intermediate of the GABA derivative. It is of note that both cis- and trans-diastereoisomers of the desired enantiomer of the acid intermediate can be converted into the final product in the downstream chemistry [10]. 

Various methods have been used to lengthen a carbon side chain, in the syntheses of quinuclidyl-3-acetic acid (113) (Scheme 1). The lowest yield is in the sodiomalonic ester synthesis (13.4% ).125 Much better results are afforded by the Reformatsky reaction (40%)125 and Knoevenagel condensation (65-70%).129 The best yield (nearly quantitative) may be obtained by application of the Wittig-Horner reaction.155... 

Butenolides. The fmnal steps in a synthesis of jolkinolide E (4) involve formation of the butenolide ring by reaction of the a-hydroxy ketone 1 with the mixed anhydride of trichloroacetic acid amd a-(diethylphosphono)propionic acid (2) with catalysis by DMAP. The ester 3 undergoes an intramolecular Wittig-Horner reaction in the presence of NaH to give 4. ... 

Fig. 6.38. Preparation of Horner-Wadsworth-Emmons reagents (synthesis applications Section 9.4) by chemoselective acylation of a phosphonate-stabilized carbanion with an ester.

An intramolecular cycloaddition reaction is also a vital feature of Oppolzer s synthesis (Scheme 5).336 Here the cycloaddition reaction occurs on an unsaturated nitrone ester (39) (not isolated). Again, the aldehyde derived from oxidation of the diol (40) gave entirely the ( )-olefin on reaction with crystalline a-methoxy-carbonylethylidenetriphenylphosphorane, which allowed the synthesis of (+)-chanoclavine I (34) to be completed in an overall yield of 14% from indole-4-aldehyde. In contrast, the Horner-Emmons reaction on the aldehyde from... 

Phosphonate esters can be deprotonated with sodium hydride or alkoxide anions to give enolate-type anions that react well with aldehydes or ketones to give -alkenes. Alkene-forming reactions with phosphonates are called Horner-Wadsworth-Emmons (or Horner-Emmons, Wadsworth-Emmons, or even Horner-Wittig) reactions. This example is a reaction that was used by some Japanese chemists in the synthesis of polyzonimine, a natural insect repellent produced by millipedes. 

The Wittig-Horner reaction of protected 3-formylindazoles with iV-(benzyloxycarbonyl)-a-phosphonoglycine trimethyl ester has been developed as a new practical synthesis of dehydro 2-azatryptophans and amino acid derivatives <2007TL2457>. Nucleophilic addition of Grignard or lithiated reagents of 3-A -methoxy-A -methyl-amides of indazole afforded a library of 3-keto and 3-formylindazoles <2007T419>. 

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. ... 

DIBAL-H is the reducing agent of choice for regioselective reduction of oc,(3-unsat-urated esters to allylic alcohols. Horner-Wadsworth-Emmons olefmation (see Section 8.3b) followed by DIBAL-H reduction provides a tandem synthesis of ( )-allylic alcohols. ... 

Still, W. C., Gennari, C. Direct synthesis of Z-unsaturated esters. A useful modification of the Horner-Emmons oiefination. Tetrahedron Lett. 1983, 24, 44054408. 

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