Alkenes by the Wittig reaction

There are many other reactions that make C-C bonds using only one functional group. Among the most important involve alkynes by alkylation 73 (chapter 16), alkenes by the Wittig reaction 74 (chapter 15) and nitro compounds by alkylation 75 (chapter 22). Disconnections of alkenes outside the double bond 76 and especially disconnections of dienes between the double bonds 77 use palladium chemistry and are discussed extensively in Strategy and Control. 

We have expanded our collection of stereoselective reactions even more in the making of alkenes by the Wittig reaction (chapter 15), from acetylenes (chapter 16), by thermodynamic control in enone synthesis (chapters 18 and 19) and in sigmatropic rearrangements (chapter 35). We have seen that such E- or Z-alkenes can be transformed into three-dimensional stereochemistry by the Diels-Alder reaction (chapter 17), by electrophilic addition (chapters 23 and 30), by carbene insertion (chapter 30) and by cycloadditions to make four-membered rings (chapters 32 and 33). 

This work showed how easy it was to make strained alkenes by the Wittig reaction (W. G. Dauben and J. Ipaktschi, J. Am. Chem. Soc., 1973, 95, 5088). 

With a-monosubstituted ylides the oxidation results in the formation of alkenes (by subsequent Wittig reaction on the intermediate aldehyde). A recent example of such synthesis is found in the preparation of all-(Z)-cyclododecate-traene by oxidation of the appropriate bis-ylide [33]. It must be pointed out that an approach of the same macrocycle based on ring closing metathesis was found ineffective. 

Transformation of [4- F]fluorobenzaldehydes into [4- F]fluorophenyl-alkenes using the Wittig reaction has been relatively unexplored. Examples are shown in Scheme 35. It requires the in situ generation of the ylid [171] by reaction of the phosphonium bromide with propylenoxide [172]. These conditions, successfully used in carbon-11 chemistry [173], have however the drawback of leading to a mixture of Z and E stereoisomers. 

The synthesis of alkenes through the Wittig reaction has generated an impressive understanding of the chemistry of organophosphorus compounds. The generated car-banions stabilized by a phosphoryl moiety can be considered as ylide anions, and the... 

The ketone behaves in its normal fashion, first undergoing nucleophilic addition from the ylide to form a betaine (pronounced "bay -tuh-ene"). However, the betaine is unstable and quickly breaks down to a triphcnylphosphine oxide and the alkene. When possible, a mixture of both cis and trans isomers are formed by the Wittig reaction. 

The simplest sulfur ylids are formed from sulfonium salts 69 by deprotonation in base. These ylids react with carbonyl compounds to give epoxides.18 Nucleophilic attack on the carbonyl group 70 is followed by elimination 71 of dimethylsulfide 72 and formation of the epoxide 73. You should compare diagram 71 with diagram 23 in chapter 15. The phosphonium ylid reacted by formation of a P-0 bond and an alkene in the Wittig reaction. The sulfonium compound reacts by formation of a C-O bond 71 as the S-O bond is much weaker than the P-0 bond. The sulfonium salt 69 can be reformed by reaction of 72 with Mel. 

Planning a Wittig Synthesis The Wittig reaction is a valuable synthetic tool that converts a carbonyl group to a carbon-carbon double bond. A wide variety of alkenes may be synthesized by the Wittig reaction. To determine the necessary reagents, mentally divide the target molecule at the double bond and decide which of the two components should come from the carbonyl compound and which should come from the ylide. 

The main interest in unsaturated sugars prepared by the Wittig reaction (and described in this Section) has concerned their synthetic utilization. The pathways of the latter depend on the structure of the unsaturated precursor. In the case of C-glycosylated alkenes, addition to the double bond (mainly hydration and hydrogenation) leads to a branched-chain or long-chain sugar, although correct choice of the reactant to be added may provide a variety of derivatives. 

The reaction between a phosphonium ylidc derived from a fluorotrihalomcthane and an acetyl halide leads to the ylide acylation product 9 and the salt 10 by the Wittig reaction. This has been used to obtain alkenes 11 from acyl halides. ... 

The Wittig alkenation has found widespread application in synthetic organic chemistry, and numerous papers and reviews have detailed the progress of the Wittig reaction. A principal advantage of alkene synthesis by the Wittig reaction is that the location of the double bond is absolutely fixed in contrast to the mixture often produced by alcohol dehydration. With simple substituted ylides Z-alkenes are favoured. 

Mono-, di- and trisubstituted alkenes can all be prepared in good yield by the Wittig reaction. A large variety of ketones and aldehydes are effective in the reaction, although carboxylic acid derivatives such as esters fail to react usefully. The carbonyl compound can tolerate several groups such as OH, OR, aromatic nitro and even ester groups. 

The methylenation of ketones and aldehydes by the Wittig reaction is a well-established and selective methodology. Unlike addition-elimination methods of alkene formation, the Wittig proceeds in a defined sense, producing an alkene at the original site of the carbonyl. The Wittig reaction is not considered here, but is used as the standard by which the methods discussed are measured. The topics covered in the methylenation sections include the Peterson alkenation, the Johnson sulfoximine approach, the Tebbe reaction and the Oshima-Takai titanium-dihalomethane method. 

The Peterson reaction, as shown in equation (70), has been applied to the synthesis of alkenes that are hindered and difficult to form by the Wittig reaction. In the case of trisubstituted alkenes (311) in which R and are components of a ring or are identical, the reaction may prove to be the method of choice. 

Phosphorus ylides are very important because of their use in the well-known Wittig reaction (1954) for the synthesis of alkenes. In the Wittig reaction, a phosphorus ylide (1) reacts with an aldehyde or ketone to yield the corresponding alkene (16) (Scheme 7). The reaction involves nucleophilic attack by the ylide (1) on the electrophilic carbonyl carbon atom to yield the betaine intermediate, which then collapses with elimination of the phosphine oxide and formation of the alkene (16). The driving force of the Wittig reaction is the production of the very strong phosphorus-oxygen double bond in the phosphine oxide (Scheme 7). 

Z)- Trisubstituted alfylic alcohols.1 The conditions used by Bestmann et at. (7, 329) for preparation of (Z)-disubstituted alkenes via the Wittig reaction also can provide a stereoselective route to (Z)-trisubstituted allylic alcohols. An example is the reaction of ethylidenetriphenylphosphorane with the THP ether of hydroxy-acetone (equation I). The stereoselectivity is decreased with other protecting... 

A further aldehyde linker has been constructed using Wittig chemistry [82] (Scheme 33). The alkene 71 created by the Wittig reaction was deaved by ozonol-ysis, and subsequent work-up with dimethyl sulfide yielded the aldehyde 72. The feasibility of this principle was demonstrated in the synthesis of a library of peptide aldehydes. 

Substituted alkenes, e.g. (13>, can be made by the Wittig reaction the more reactive phosphonate ester (14) is often used when there is a stabilising group present. 

Cross-metathesis of two different alkenes to give an acyclic alkene is complicated by the possible formation of not only the desired cross-metathesis product, but also self-metathesis products, each as a mixture of alkene isomers. However, some alkenes are amenable to efficient cross-metathesis to give the desired substituted alkene. This is particularly the case with alkenes that are slow to homod-imerize, such as a, -unsaturated carbonyl compounds or alkenes bearing bulky substituents. Hence, cross-metathesis of methyl acrylate with an alkene proceeds efficiently (2.116). The ruthenium catalyst reacts preferentially with the more electron-rich alkene 98, which then undergoes cross-metathesis with the acrylate or self-metathesis with another molecule of the alkene 98. The latter reaction is reversible and hence a high yield of the desired substituted acrylate results over time. The use of 1,1-disubstituted alkenes as partners in cross-metathesis provides a route to trisubstituted alkenes. This chemistry is therefore a useful alternative to conventional syntheses of alkenes, such as by the Wittig reaction. 

Reaction of the ylide formed in part (g) with benzaldehyde gives the desired alkene by a Wittig reaction. 

Polvstvrvlmethvlltriphenvlphosphonium Ions. The phosphonium ions used for formation of alkenes on cross-linked polystyrenes by the Wittig reaction have been prepared by reaction of triphenylphosphine with chloromethylated polystyrene in chlorobenzene at reflux (25). More highly nucleophilic phosphines such as tri- -butylphos-phine require only 80-100 °C to form phosphonium salts with chloromethylated... 

The mixed phosphonium-iodonium ylides (Section 2.1.10.1), such as the tosylate 796, represent a useful class of reagents that combine in one molecule the synthetic advantages of a phosphonium ylide and an iodonium salt [1091-1100]. Specifically, phosphorane-derived phenyliodonium tosylate 796 reacts with soft nucleophiles, such as iodide, bromide, benzenesulfinate and thiophenolate anions, to form selectively the respective a-functionalized phosphonium ylides 797 (Scheme 3.315), which can be further converted into alkenes (e.g., 798) by the Wittig reaction with aldehydes [1092]. The analogous arsonium-iodonium ylides have a similar reactivity toward nucleophiles [1091, 1094, 1101]. 

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