Michael/Horner-Wadsworth-Emmons reaction

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. ... 

Tandem Michael and Horner-Wadsworth-Emmons Reactions... 

Tandem reactions have emerged as promising procedures for the synthesis of highly functionalised compounds in a single step. Horner-Wadsworth-Emmons reactions have been coupled with 1,4-Michael additions to prepare 6-substituted a,p-unsaturated carboxylic acids derivatives, and with Diels-Alder reactions, which utilised sugar-derived phosphonate (176) to prepare enantiomerically pure bicyclo[4.3.0]nonanes. ... 

Meanwhile, 3-functionalized sulfoxides 20 can be easily obtained by Michael addition to a,p-unsaturated sulfoxides. The a,p-unsaturated sulfoxide starting materials 19 can be prepared by the oxidation of vinyl sulfides 21 and also by the Horner-Wadsworth-Emmons reaction, using commercially available sulfoxy phosphonates 18 fScheme 20.6a). Alternatively, cross... 

Aziridine-2-phosphonates spiro-fused with 2-oxindole (790) have been prepared by a straightforward Horner-Wadsworth-Emmons reaction of ethyl 7V- [(4-nitrophenyl)sulfonyl]oxy -carbamate (791) and 3-(phosphoryl-methylene)oxindoles (792) in the presence of calcium oxide. Oxindoles (792) were also transformed into novel oxirane-2-phosphonates (793), as oxygen analogues of (790), by reaction with H202/Na0H (Scheme 201). " Cinchonine-based thiourea (797) catalysed asymmetric Michael addition of simple p-oxo-alkyl phosphonates (794) to nitro olefins (795), which afforded valuable a-substituted p-oxo phosphonates (796) in satisfactory yields with good to excellent enantioselectivities (up to 98% ee) (Scheme 202). ... 

The one-pot, organocatalytic Hayashi sequential reaction (HSR) of p-nitroacrylate (806), aldehyde (807), toluenethiol (808), and vinylphosphonate (805) allowed the synthesis of highly functionaKsed cyclohexanes (809) with very high enantioselectivity (up to 99 % ee). The one-pot synthesis consisted of the tertiary amine modified diarylprolinol silyl ether (810)-mediated asymmetric Michael reaction, a domino Michael reaction/the Horner-Wadsworth Emmons reaction, and a sulfa-Michael reaction (Scheme 205). ... 

Shibasaki made several improvements in the asymmetric Michael addition reaction using the previously developed BINOL-based (R)-ALB, (R)-6, and (R)-LPB, (R)-7 [1]. The former is prepared from (R)-BINOL, diisobutylaluminum hydride, and butyllithium, while the latter is from (R)-BINOL, La(Oz -Pr)3, and potassium f-butoxide. Only 0.1 mol % of (R)-6 and 0.09 mol % of potassium f-butoxide were needed to catalyze the addition of dimethyl malonate to 2-cy-clohexenone on a kilogram scale in >99% ee, when 4-A molecular sieves were added [15,16]. (R)-6 in the presence of sodium f-butoxide catalyzes the asymmetric 1,4-addition of the Horner-Wadsworth-Emmons reagent [17]. (R)-7 catalyzes the addition of nitromethane to chalcone [18]. Feringa prepared another aluminum complex from BINOL and lithium aluminum hydride and used this in the addition of nitroacetate to methyl vinyl ketone [19]. Later, Shibasaki developed a linked lanthanum reagent (R,R)-8 for the same asymmetric addition, in which two BINOLs were connected at the 3-positions with a 2-oxapropylene... 

Both regioselectivity and enantioselectivity are efficiently controlled by ALB in the Michael addition of Horner-Wadsworth-Emmons reagents 17 with enones (Scheme 8D.12) [29]. Although the reaction catalyzed by ALB itself did not afford the product, the use of a combination of ALB (10 mol %) and NaC/Bu (0.9 equiv. to ALB) gave the Michael adduct of 17 to cyclohexenone in 64% yield and 99% ee. The reaction of cyclohexenone with 17 promoted by standard bases such as NaO Bu and BuLi gave the 1,2-adduct in only 8-9% yield. The adduct... 

Scheme 20 A selection of the reactions investigated by Miyake and Kitazume (2003) for the incorporation of fluorine into small organic molecules (a) Michael addition and (b) Horner-Wadsworth-Emmons.

Tandem Horner-Wadsworth-Emmons and Michael Reactions... 

Phosphonates are useful nucleophiles in the Michael addition. The presence of the phosphonate group enables subsequent Horner-Wadsworth-Emmons (HWE) reaction. In this way, initial Michael adducts were transformed into biologically relevant 8-lactams and 5-lactones (Scheme 8.12). Transformation involved reduction of the aldehyde moiety, cyclisation and Horner-Wadsworth-Emmons (HWE) reaction with formaldehyde. 

The starting material for iloprost is the enantiomerically pure Corey lactone, which is treated with the lithium salt of ethyl acetate. After oxidation, treatment with l,5-diazabicyclo[4.3.0]non-5-ene (DBN) leads to an exceptionally interesting rearrangement. Presumed cleavage of the cyclic ether generates an enolate, which adds to the cyclopentenone in a Michael reaction. Decarbethoxylation is achieved with l,5-diazabicyclo[2.2.2]octane (DABCO), and the w-chain is constructed under Horner-Wadsworth-Emmons conditions. The subsequent reduction leads to a mixture of allyl alcohols, which can be purified by chromatography, and the alcohol from the less polar product then be released by trans-esterification. Both alcohol functions are then protected as THP-ethers. The... 

Michael reaction and Michael-Wittig (Horner-Wadsworth-Emmons) Cascade Process... 

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