Wadsworth-Emmons intramolecular

Disubstituted isocoumarins are prepared from ortho-carboxy benzoic acids and a-diazophosphonates via a dirhodium(ll)-mediated O-H insertion followed by a Horner-Wadsworth-Emmons intramolecular cyclization (Scheme 210) <20020L2317>. 

Intramolecular phosphonate-ketone condensation (Homer-Wadsworth-Emmons)... 

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. 

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... 

The same group recently disclosed a related free radical process, namely an efficient one-pot sequence comprising a homolytic aromatic substitution followed by an ionic Homer-Wadsworth-Emmons olefination, for the production of a small library of a,/3-unsaturated oxindoles (Scheme 6.164) [311]. Suitable TEMPO-derived alkoxy-amine precursors were exposed to microwave irradiation in N,N-dimethylformam-ide for 2 min to generate an oxindole intermediate via a radical reaction pathway (intramolecular homolytic aromatic substitution). After the addition of potassium tert-butoxide base (1.2 equivalents) and a suitable aromatic aldehyde (10-20 equivalents), the mixture was further exposed to microwave irradiation at 180 °C for 6 min to provide the a,jS-unsaturated oxindoles in moderate to high overall yields. A number of related oxindoles were also prepared via the same one-pot radical/ionic pathway (Scheme 6.164). 

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>. 

Lin, C.-H., Aristoff, P.A., Johnson, P.D., McGrath, J.P., Timko, J.M., and Robert, A., Benzidine prostaglandins synthesis of optically pure 15-deoxy-U-68,215 and its enantiomer via a modified intramolecular Wadsworth-Emmons-Wittig reaction, /. Org. Chem., 52, 5594, 1987. 

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>. 

D-Camphor-lO-sulfonic acid (CSA) has been utilized to form aj-fused bicyclic acetals from hexopyranosides (Scheme 20) <1997TL849>. A silver terrafluoroborate-promoted cyclization of a series of 3-hydroxyalkyl-2-cyanopiperidines has been used to prepare the octahydropyrano[2,3- ]pyridine of upenamide (Scheme 21) <2004EJ01057>. Related pyranopyr-idines have been prepared using an intramolecular Wadsworth-Emmons cyclization <2003TL8545>. 

B. M. Heron, Heterocycles from Intramolecular Wittig, Homer and Wadsworth-Emmons Reactions, Heterocycles 1995, 41, 2357. 

In this case, the approach involved the construction of two bibenzyl and one biaryl units using Homer-Wadsworth-Emmons and an intramolecular Suzuki-Miyaura reaction. The overall yield for the 11 steps was 10.6%. 

The Homer-Wadsworth-Emmons (HWE) reaction involves the addition of a stabilized phosphonate anion to an aldehyde or ketone to afford an intermediate which undergoes an elimination reaction to form predominately the ( )-alkene. The HWE reaction has been applied inter- and intramolecularly to simple as well as highly functionalized systems. 

A different strategy has been adopted for the transformation of 21a into 335 and 336. In these cases, one carbon atom of the final benzene ring comes from an external phosphonate reagent by means of intramolecular Wadsworth-Emmons reactions. The overall transformations can be classified as C2/C/C6 [84JCS(PI)1035]. 

Tsai, H,-J, Thenappan, A., and Burton, D.J., A novel intramolecular Homer-Wadsworth-Emmons reaction, A simple and general route to a-fluoro-a,P-unsaturated diesters, J. Org. Chem., 59, 7085, 1994. 

Long-chain phosphonylated aldehydes aie generally prepared to achieve the formation of macro-cycles via an intramolecular Homer-Wadsworth-Emmons reaction. The phosphonate group is frequently incorporated at one extremity of the chain by a carbanionic approach. Thus, displacement of iodide of the alkyl chain containing epoxide by the sodium enolate of diethyl l-(ethoxycarbo-nyl)methylphosphonate at 50°C in DMF leads to diethyl l-(ethoxycarbonyl)-4,5-epoxyalkylphos-phonate in 78% yield (Scheme 4.21). 

The last 25 years have seen very signihcant progress in the chemistry of formylphosphonates. - This chapter describes their preparation, their use in intermolecular and intramolecular Horner-Wadsworth-Emmons reactions, and, given their discovery in nature, their importance as precursors for aminophosphonic acids. 

The same strategy has been used to prepare trans bicyclic enones. The protected C5 phosphonylated aldehyde is obtained in 84% yield by a CuBr SMe2-mediated Michael addition of the Grignard reagent derived from 4-chlorobutyraldehyde diethyl acetal to a 5-phosphonylated 2,3-dihydro-4-pyridone in THF. Subsequent room-temperature hydrolysis of the acetal using aqueous oxalic acid in THF affords a near-quantitative yield of the crude aldehyde, which undergoes an intramolecular Homer-Wadsworth-Emmons reaction under treatment with Et3N/LiCl in THF at room temperature (89%). ... 

To date long-chain phosphonylated aldehydes (n > 10) have been prepared exclusively as precursors for the synthesis of 11- to 17-membered macrocycles via intramolecular Homer-Wadsworth-Emmons reactions (Scheme 5.63). This widely used cyclization step provides the best method for preparing macrocycles. 

Gijsen, H.J.M., and Wong, C.-H., Synthesis of a cyclilol via a tandem enzymatic aldol-intramolecular Horner-Wadsworth-Emmons reaction. Tetrahedron Lett., 36, 7057, 1995. 

Comins, D.L., and Olhnger, C.G., Inter- and intramolecular Homer-Wadsworth-Emmons reactions of 5-(diethoxyphosphoryl)-l-acyl-2-alkyl(aryl)-2,3-dihydro-4-pyridones, Tetrahedron Lett., 42, 4115, 2001. 

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