Wadsworth-Emmons reagents

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. 

Tanaka et al.50 also reported that chiral Horner-Wadsworth-Emmons reagent (S )-51 reacted with an alternative carbonyl group of the meso-a-diketones... 

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... 

Another highlight of the period under review is the report of the total synthesis of the tricyclic alkaloid fawcettimine (22) (Scheme 2).9 Lewis-acid-catalysed Diels-Alder addition of butadiene to 2-allyl-5-methylcyclohex-2-enone provided the ds-octalone (23), which was modified as indicated to give the dialdehyde (24). After considerable experimentation, conditions were defined which led to regioselective ring-closure in the desired direction. The unsaturated aldehyde was treated directly with the Wadsworth-Emmons reagent to provide... 

Fig. 6.48. Preparation of Horner-Wadsworth-Emmons reagents (synthetic applications Section 11.3) by chemoselective acylation of a phosphonatestabilized "carb-anion" with an ester.

The precursors for these Horner-Wadsworth-Emmons reagents are /f-ketophosphomc acid dialkyl esters or a-(alkoxycarbonyl)phosphonic acid dialkyl esters. The first type of compound, i.e., a /3-ketophosphonic acid dialkyl ester is available, for example, by acylation of a metalated phosphonic acid ester (Figure 6.48). The second type of compound, i.e., an a-(alkoxycarbonyl)phosphonic acid dialkyl ester, can be conveniently obtained via the Arbuzov reaction (Figure 11.12). 

Fig. 11.14. Preparation of tmns- or f-configured a,/3-unsaturated esters by the Horner-Wadsworth-Em mons reaction (left) or preparation of their cis- or Z-isomers by the Still-Gennari variant of it (right). 18-Crown-6 is a so-called crown ether containing a saturated 18-membered ring that is made up from six successive —CH2—0—CH2-units. 18-Crown-6 dissociates the K ions of the Horner-Wadsworth-Emmons reagent by way of complexation.

In the example shown the deprotonation of the phosphonate can be achieved under much milder conditions than with the usually employed sodium hydride, which by the way also applies to the standard Horner-Wadsworth-Emmons reagents. Incorporation of the two doubly bound oxygen atoms of the reagent A into sodium chelate B does the trick. Being a cation, B is much more acidic than A and can thus already be deprotonated by an amidine. 

WADSWORTH-EMMONS REAGENT Diethyl l-(methylthio)ethylphospbo-nate. 

The Horner-Wadsworth-Emmons reagent 735 (Scheme 180) prepared through Michaelis-Becker reaction of 4-(chloromethyl)-l-tritylimidazole 734 with lithium diethyl phosphonate reacts with aldehydes or ketones to give 4-vinylimidazoles 736 <2002S1072>. 

Cesium carbonate has also been used as the base used to form the Horner-Wadsworth-Emmons reagent (Scheme 2.25) [41]. Even in fhe presence of an N-H bond in fhe substrate the reaction proceeds with deprotonation of the crucial carbon atom. The transformation gives an a,/ -unsaturated ester wifh an amine substituent. 

Wittig/Homer-Wadsworth-Emmons reagents on a PEG support (Table 8, entry 25) [477] ... 

Kann, N., Rein, T.. Akermark. B., and Helquist, P., New functionalized Homer-Wadsworth-Emmons reagents. Useful building blocks in the synthesis of polyunsaturated aldehydes. A short synthesis of ( )-( , )-coriolic acid.. 1. Org. Chem., 55, 5312, 1990. 

The extra stabilisation makes the ylid rather unreactive and phosphonate esters 91 are often used instead of phosphonium salts in these reactions. Treatment with a base (NaH or RO is often used, BuLi will certainly not do) gives an inherently more reactive enolate anion 92 rather than an ylid. These Horner-Wadsworth-Emmons reagents (H WE as we shall call them, though they go under many other names) react with ketones as well as aldehydes and the product is normally the E-alkcnc16 93. 

A modified Horner-Wadsworth-Emmons reagent with high Z stereoselectivity using trifluoroethyl phosphonates in reaction with saturated, unsaturated or aromatic aldehydes. 

COOEt), whereas the use of the phosphonate (Wadsworth-Emmons) reagent gave large-lythe(Z)-alkenes362 ". 

The Fukuyama indole synthesis involves the intramolecular radical cyclization of 2-alkenylisocyanides, the availability of which often limits the utility of this process. In order to access a wider variety of such substrates, the author prepared the versatile Horner-Wadsworth-Emmons reagent 131 using the Pudovik reaction <01SL1403>. Reaction of 131 with a variety of aldehydes thus provides a convenient and general route to diverse alkenyl precursors 132. Additionally, instead of the standard radical conditions using tri-n-butyltin hydride, Fukuyama now finds that excess thiols arc quite effective for inducing cycliz.ation, whereupon desulfurization of the indoles 133 can be effected with Raney-Ni if desired. 

The preparation of Z-a,/3-unsaturated amides by using Hor-ner-Wadsworth-Emmons reagents, (diphenylphosphono)aceta-mides, has been recently reported. High Z E ratios were observed with aromatic aldehydes and potassium r-butoxide, whereas the best Z-selectivities for aliphatic aldehydes were obtained when NaHMDS was used as base (eq 33). 

Two sulfone-based nucleoside diphosphate isosters (71a,b) has been synthesised and reported by Gervay-Hague to be inhibitors of Neisseria meningitidis CMP-sialic acid synthetase, which is a key enzyme in the biosynthesis of capsular polysaccharides required for bacterial infection. The synthetic methodology includes a condensation reaction of the nucleoside aldehydes with bisphosphonate Horner-Wadsworth-Emmons reagents (Scheme 4). The deprotection sequence was crucial for the appropriate completion of the synthetic targets. 

As a direct route for the constructing carbon-carbon bonds, catalytic asymmetric Michael additions with various carbon-based nucleophiles including malonic esters, cyanide, electron-deficient nitrile derivatives, a-nitroesters, nitroalkanes, Horner-Wadsworth-Emmons reagent, indoles, and silyl enol ethers have attracted considerable attention. 

Scheme 19.28 Asymmetric Michael addition of a Horner-Wadsworth-Emmons reagent to q clic enones catalysed by ALB.

The first example of a catalytic asymmetric Michael addition of a Horner-Wadsworth-Emmons reagent to enones was developed by the Shibasaki group using (J )-ALB ent-18 as the catalyst (Scheme 19.28). When sodium tert-butoxide was used as a base instead of butyllithium, the competitive 1,2-addition could be suppressed and the yield of 1,4-addition product increased. 

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