Phosphonium ylides alkene synthesis

Typically, nonstabilized ylides are utilized for the synthesis of (Z)-alkenes. In 1986, Schlosser published a paper summarizing the factors that enhance (Z)-selectivity. Salt effects have historically been defined as the response to the presence of soluble lithium salts. Any soluble salt will compromise the (Z)-selectivity of the reaction, and typically this issue has been resolved by the use of sodium amide or sodium or potassium hexamethyldisilazane (NaHMDS or KHMDS) as the base. Solvent effects are also vital to the stereoselectivity. In general, ethereal solvents such as THF, diethyl ether, DME and t-butyl methyl ether are the solvents of choice." In cases where competitive enolate fomnation is problematic, toluene may be utilized. Protic solvents, such as alcohols, as well as DMSO, should be avoided in attempts to maximize (Z)-selectivity. Finally, the dropwise addition of the carbonyl to the ylide should be carried out at low temperature (-78 C). Recent applications of phosphonium ylides in natural product synthesis have been extensively reviewed by Maryanoff and Reitz. 

It has been found that nonstabilized ylides derived from the tetrahydro-phosphole nucleus (90 or 91) afford oxaphosphetanes that decompose at room temperature. Sin( 89, the phosphonium salt precursor of 90, contains only one alkyl group, BTP ylide 90 can be recommended for E-selective alkene synthesis in cases where the alkyl substituent must be used efficiently. Since the phosphorus environment in 90 is relatively expensive, this family of reagents will not provide a practical solution for large-scale synthesis of... 

The Wittig reaction has been used widely in organic synthesis. For example, a number of steps in a synthesis of the neurotoxin brevetoxin B make use of the Wittig reaction with both stabilized and non-stabilized phosphonium ylides, two of which are shown in Scheme 2.74. This synthesis also uses a Wittig reaction in a later, key step to combine two large fragments using a non-stabilized phosphonium ylide to prepare a Z-alkene. 

The Horner-Wadsworth-Emmons reaction (or HWE reaction) is the reaction of stabilized phosphonate carbanions with aldehydes (or ketones) to produce predominantly -alkenes. In 1958, Horner published a modified Wittig reaction using phosphonate-stabilized carbanions [32]. Wadsworth and Emmons further defined the reaction [33]. Compared to phosphonium ylides used in the Wittig reaction, phosphonate-stabilized carbanions are more nucleophilic and more basic. Likewise, phosphonate-stabilized carbanions can be alkylated, unlike phosphonium ylides. The dialkylphosphate salt by-product is easily removed by aqueous extradion. A reliable and versatile synthesis of a stilbene derivative, 2,2-aryl-substituted cinnamic acid esters, using the Wittig reaction was reported [34—36] (Figure 1.3). 

An unprecedented protocol for the stereoselective synthesis of stracturally diverse electron-deflcient alkenes in moderate to excellent yields from readily accessible A-sulfonyl imines and stabilized phosphonium ylides has been reported. The oleflna-tion reaction of (V-sulfonyl imines with nitrile-stabilized phosphonium ylides affords an array of a./S-unsaturated nitriles with high Z selectivity, and the reactions with ester-, amide-, and ketone-stabilized phosphonium ylides afford a,)3-unsaturated esters, amides, and ketones with high E selectivity, respectively (Scheme 3). 

The reaction is most often used for epoxide synthesis via methylene transfer. An important point concerns the difference in reactivity of sulfonium versus phosphonium ylides. The former gives three-membered rings the latter gives alkenes via the Wittig reaction. Thermodynamics is believed to account for a good deal of this difference the P+-0 bond in a phosphine oxide (BDE 544 kJ/mol) is much stronger than the S+-0 bond in DMSO (BDE for DMSO DMS + O 389 kJ/mol), which would form if the sulfonium ylide reaction resulted in an alkene. 

Since, the ionic liquids under study were completely dried, the most likely proton source was claimed to originate from the phosphonium cation after a-proton abstraction by superoxide anion in analogy with the Witting alkene synthesis to yield a phosphorous ylide with the general structure R3P = CHR. ... 

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. 

Intermediates 18 and 19 are comparable in complexity and complementary in reactivity. Treatment of a solution of phosphonium iodide 19 in DMSO at 25 °C with several equivalents of sodium hydride produces a deep red phosphorous ylide which couples smoothly with aldehyde 18 to give cis alkene 17 accompanied by 20 % of the undesired trans olefin (see Scheme 6a). This reaction is an example of the familiar Wittig reaction,17 a most powerful carbon-carbon bond forming process in organic synthesis. 

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