The Wittig and related reactions

Introduction As noted in the preceding section, the ability of the carbonyl group to increase the 

The Homer-Wadsworth-Emmons reaction is an important variant of the Wittig reaction and involves using a phosphonate ester in place of a phosphonium salt. Like the phase-transfer Wittig reaction just discussed, these reactions may be easily performed in the undergraduate laboratory. In one of the procedures that follows, the phosphonate ester 12 is deprotonated with potassium tert-butoxide in the polar, aprotic solvent N,N-dimethylformamide, (CH3)2NCHO (DMF), to provide the resonance-stabilized, nucleophilic phosphonate anion 13 (Eq. 18.7). 

By obtaining spectral data for your product, you will be able to determine which of the stilbenes is produced. An explanation of why the Wadsworth-Emmons reaction mainly yields a single diastereomer of stilbene is beyond the scope of this discussion. 

The classic Wittig reaction is carried out under relatively mild conditions and is very general in that the starting carbonyl compound and phosphorane can contain a variety of substituents. The other real synthetic advantage of this reaction is that the position of the carbon-carbon double bond in the product is not in doubt. 

Caution All procedures should be carried out in a well-ventilated fume-hood, and chemical resistant gloves and safety glasses should be worn at all times. 

In a two-necked round-bottomed flask (100 mL) equipped with a magnetic stirrer, rubber septum and under a nitrogen atmosphere, dissolve triphenylphosphine (14.0 g, 53.4 mmol) in toluene (25 mL). 

Add a solution of ethyl bromoacetate (9.5 g, 6.33 mL, 56.8 mmol) in toluene (25 mL). Shake the solution vigorously and then let it stand overnight. 

Filter off precipitate, washing with additional toluene (50 mL) followed by pentane (50 mL). Allow to dry. 

The stability of phosphorus ylides can be ascribed, in part, to resonance of these two structures. NMR spectroscopic studies ( H, and P), however, are more consistent with the dipolar ylide structure and suggest only a minor contribution from the ylene structure. Theoretical calculations support this view also.  

The synthetic potential of phosphorus ylides was initially developed by G. Wittig and his associates at the University of Heidelberg. The reaction of a phosphorus ylide with an aldehyde or ketone introduces a carbon-carbon double bond in place of the carbonyl bond  

The mechanism originally proposed is an addition of the nucleophilic ylide carbon to the carbonyl group to yield a dipolar intermediate (a betaine), followed by elimination of a phosphine oxide. The elimination is presumed to occur after formation of a four-membered oxaphosphetane intermediate. An alternative mechanism might involve direct formation of the oxaphosphetane. There have been several theoretical studies of these intermediates. Oxaphosphetane intermediates have been observed by NMR studies at low temperature, but direct evidence for the betaine intermediates is less clear.  

CHAPTER 2 REACTIONS OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS 

Phosphorus ylides are usually prepared by deprotonation of phosphonium salts. The phosphonium salts that are used most often are alkyltriphenylphosphonium halides, which can be prepared by the reaction of triphenylphosphine and an alkyl halide  

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The Wittig and Related Reactions of Phosphorus-Stabilized Carbon Nucleophiles... 

SECTION 2.4. THE WITTIG AND RELATED REACTIONS OF PHOSPHORUS-STABILIZED CARBON NUCLEOPHILES... 

Abell, A. D. Edmonds, M. K. The Wittig and Related Reactions. In Organophosphorus Reagents Murphy, P. J., Ed. Oxford University Press Oxford, 2004 pp 99-127. 

The Wittig and related reactions have been reviewed in the context of natural product synthesis 120 mechanistic studies of the Wittig reaction have also been reviewed with particular reference to asymmetric induction.121... 

Tervalent phosphorus has a high affinity for oxygen and the P=0 bond once formed is very strong. This fact, which also provides the driving force for the Wittig and related reactions, has led to the widespread use of P(III) compounds for direct deoxygenation of epoxides, ozonides, carbonyl compounds, and both N- and 5-oxides.2... 

The versatility of the Wittig, and related reactions, has resulted in examples being used as key steps in many organic syntheses of complex natural products.2,3... 

The Wittig, and related reactions, have also found application in the synthesis of peptidomimetics—mimics of natural peptides that possess modified biological properties such as increased bioavailability, biostability, bioselectivity, and bioefficiency relative to the parent peptide. As an example, the phenylalanine-based HWE reagent shown in Protocol 13 reacts with aldehydes to give a modified amino acid that can be used as a building block for the construction of extended peptidomimetics. 

Aldehydes.- A recent review of the Wittig and related reactions includes information on the development and use of new Wittig reagents and cyclizations using intramolecular Wittig reactions. 

Nicolaou, K. C., Harter, M. W., Gunzner, J. L., Nadin, A. The Wittig and related reactions in natural product synthesis. Liebigs Annalen/Recueil 1997,1283-1301. 

Other Reactions at the Carbonyl Carbon Atom.—A new method for converting ketones into methylene compounds is claimed to be successful even in cases where the Wittig and related reactions fail. Treatment of the ketone (e.g. 271) with phenylthiomethyl-lithium (270) gives a derivative (272), which may be acetylated or benzoylated in situ. Reduction of the ester (273) with lithium-NH3 gives the methylene compound (274) in good yield. The conversion of cholest-5-en-3-one into 3-methylenecholest-5-ene contrasts with the lability of the 5-en-3-one to the basic conditions required for the Wittig reaction. Even many hindered ketones appear to be reactive. 

The Wittig and related reactions or by conducting the reaction at a higher temperature. 

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