Addition of Phosphorus Ylides The Wittig Reaction

Another useful reagent in nucleophilic additions contains a carbanion that is stabilized by an adjacent, positively charged phosphorus group. Such a species is called a phosphorus ylide, and its attack on aldehydes and ketones is called the Wittig reaction. The Wittig reaction is a powerful method for the selective synthesis of alkenes from aldehydes and ketones. 

Deprotonation of phosphonium salts gives phosphorus ylides 

Phosphorus ylides are most conveniently prepared from haloalkanes by a two-step sequence the first step is the nucleophihc displacement of halide by triphenylphosphine to furnish an alkyltriphenylphosphonium salt. 

The positively charged phosphorus atom renders any neighboring proton acidic. In the second step, deprotonation by bases, such as alkoxides, sodium hydride, or butyllithium, gives the ylide. Ylides can be isolated, although they are usually only generated in solutions that are subsequently treated with other reagents. 

Notice that we may formulate a second resonance structure for the ylide by delocalizing the negative charge onto the phosphorus. In this form, the valence shell on phosphorus has been expanded and a carbon-phosphorus double bond is present. 

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Nucleophilic Addition of Phosphorus Ylides The Wittig Reaction 721... 

Nucleophilic Addition of Phosphorus Ylide The Wittig Reaction... 

Addition of Hydrogen Halides to an Alkene Section 11.2 Addition of a Nitrogen Nucleophile to an Aldehyde or a Ketone Section 18.8 Figure 18.3 Addition of Phosphorus Ylides to an Aldehyde or a Ketone (The Wittig Reaction) Section 18.7 Figure 18.2... 

Very recently, Zhu and Cheng reported an organocatalytic Michael-type addition of phosphorus ylides 93 to a,(i-unsaturated ketones 94 using a chiral dual organo-catalyst system composed of 9-amino-(9-deoxy)-epi-quinine with Boc-L-proline (Scheme 43.20) [31]. The Michael-type/Wittig reactions proceeded smoothly to provide chiral a-methylene-6-ketoesters 95 with good to excellent enantioselectivi-ties (up to 95% ee). 

The Julia-Lythgoc olefination operates by addition of alkyl sulfone anions to carbonyl compounds and subsequent reductive deoxysulfonation (P. Kocienski, 1985). In comparison with the Wittig reaction, it has several advantages sulfones are often more readily available than phosphorus ylides, and it was often successful when the Wittig olefination failed. The elimination step yields exclusively or predominantly the more stable trans olefin stereoisomer. 

Heating a-hydroxy amides 135 in xylene with the cumulated phosphoms ylide 134 gives the 2(3//)-oxazolones 140. The reaction proceeds via an addition-cyclization-intermolecular-Wittig olefination sequence, which imphes three different types of phosphorus ylides, 134,136, and 137, respectively, of increasing ylide activity (Fig. 5.33 Table 5.7, Figs. 5.34, 5.35). 

This variation of the Wittig reaction uses ylides prepared from phosphonates.12 The Horner-Wadsworth-Emmons method has several advantages over the use of phosphoranes. These ylides are more reactive than the corresponding phosphoranes, especially when substituted with an electron withdrawing group. In addition the phosphorus product is a phosphate ester and soluble in water - unlike the Ph3PO product of the Wittig reaction - which makes it easy to separate from the olefin product. Phosphonates are also cheaper than phosphonium salts and can easily be prepared by the Arbuzov reaction from phosphanes and halides. 

Dimsylsodium (24) functions as a highly basic sulfur ylide. It can be used to convert phosphonium salts to phosphorus ylides for use in the Wittig reaction. Dimsylsodium also reacts with aldehydes and ketones by nucleophilic addition to form epoxides and with esters by nucleophilic substitution to yield p-ketosulfoxides (25) (Scheme 11). The p-ketosulfoxides (25) contain acidic a-hydrogens which can be readily removed to allow alkylation, and the products (26) suffer reductive desulfuration on treatment with aluminium amalgam to yield ketones (27) (Scheme 11) This procedure can, for instance, be applied to the conversion of ethyl benzoate to propiophenone (28) (Scheme 12). 

Abstract Phosphacumulene ylides of the general formula Ph3P=C=C=X [X=0, S, NR, (0R)2] are versatile C2-building blocks. They can act either as C-nudeophiles-only in a manner typical of phosphorus ylides, or as cumulenes undergoing [2 + n -cycloadditions with other cumulenes such as CO2, COS, RNCO etc. Most prominent is their tandem addition-Wittig alkenation of hydroxy- or amino-substituted carbonyl compounds. With aptly chosen reaction partners all these pathways may lead to heterocyclic products. Some recent applications of these methods to the syntheses of azetidines, five-membered lactams, lactones, tetramates, tetronates and pyrroles as well as to six-membered quinolones and to macrolides are delineated. 

The role of steric interactions on anomalous stereoselectivity in the Wittig reaction has been examined. " DFT calculations combined with a distortion/interaction energy analysis show that the anomalous Z selectivity observed in Wittig reactions of o-substituted benzaldehydes is not caused by phosphorus-heteroatom interactions in the addition transition state but is predominantly steric in nature. The calculations reproduced correctly the stereoselectivity preferences for a wide range of reactant pairs as well as relative reactivities for different substituent types. An efficient synthesis of olefins by the coupling of stabilized, semi-stabilized, and non-stabilized phosphorus ylides with various carbonyl compounds in the presence of silver carbonate has been reported. Wittig olefination of aromatic, heteroaromatic, and aliphatic aldehydes (yields up to 97%) and a ketone (yield 42%) was demonstrated. 

The first step in the Wittig reaction is nucleophihc attack of the negatively charged carbon atom of the ylide on the carbonyl group to give an adduct called a betaine that rapidly converts to an oxaphosphetane. The exact course of the reaction may depend on the type of groups bonded to the carbonyl carbon atom and the type of ylide. Nevertheless, the direction of the addition of the yhde to the carbonyl atoms is the same as for other addition reactions studied in this chapter. The electrophilic carbon atom of the ylide forms a bond to the carbonyl carbon atom and the phosphorus bonds to the oxygen atom. 

The employment of phosphorus-stabilized carbon nucleophiles for alkene synthesis was initiated by the discovery of the Wittig reaction [10], which provides a convenient method for the preparation of a wide variety of polysubstituted alkenes with complete positional selectivity and generally high levels of geometrical control. Moreover, the phosphonium ylides used in the Wittig reaction are readily formed by the addition of suitable bases to the corresponding phosphonium salts, which are commonly prepared by treating alkyl halides with phosphines. 

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