Wittig reaction example: alkene

With respect to the carbonyl substrate, a variety of additional functional groups is tolerated, e.g. ester, ether, halogen. With compounds that contain an ester as well as a keto or aldehyde function, the latter usually reacts preferentially. Due to its mild reaction conditions the Wittig reaction is an important method for the synthesis of sensitive alkenes, as for example highly unsaturated compounds like the carotinoid 17 shown above. 

The teal value of the Wittig reaction is that it yields a pure alkene of defined structure. The C=C bond in the product is always exactly where the OO group was in the reactant, and no alkene isomers (except E,Z isomers) are formed. For example, Wittig reaction of cyclohexanone with methylenetriphenyl-phosphorane yields only the single alkene product methylenecyclohexane. By contrast, addition of methylmagnesium bromide to cyclohexanone, followed by dehydration with POCI3, yields a roughly 9 1 mixture of two alkenes. 

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. 

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. 

Examples of name reactions can be found by first considering the nature of the starting material and product. The Wittig reaction, for instance, is in Section 199 (Alkenes from Aldehydes) and Section 207 (Alkenes frorm Ketones). The aldol condensation can be found in the chapters on difunctional compounds in Section 324 (Alcohol, Thiol-Aldehyde) and in Section 330 (Alcohol, Thiol-Ketone). 

For the synthesis of alkenes, the Wittig and Horner-Wadsworth-Emmons reactions have become important tools. Triphenylphosphine that is used in the Wittig reaction can be immobilized either on the polymer or can be used in solution for solid-phase chemistry (Scheme 3.18). The Horner-Wadsworth-Emmons reaction for example is used for the synthesis of aldehyde building blocks [261]. 

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. 

Thiiranes that are obtained from the reaction of diazo dipoles with C=S bonds can be transformed into alkenes by desulfurization. This reaction sometimes occurs spontaneously, but more often is achieved by treatment with phosphanes (225). This important methodology represents an alternative for the Wittig reaction and has high merit for the preparation of sterically hindered (226-229) and uncommonly functionalized alkenes (214,216,217,230,231). Some examples are given in... 

Ylides of other elements have been used much less commonly than sulfur ylides in cyclopropanations. Rather, other ylides are better known for their uses in other types of reactions, the best example being the use of phosphonium ylides in the Wittig reaction with carbonyl compounds to give alkenes. Nonetheless, some cases of cyclopropanations have been reported with phosphonium ylides and the related arsenic derivatives. Examples are given in Table 9. 

An example is the study by Lambert9 of the influence of aromatic rings and neighbouring electron-withdrawing groups on Sn2 reactions. He needed the few-tosylate 50. This comes from the diol 51 and now he had a choice. He could epoxidise an -alkene or dihydroxylate a Z-alkene. He chose the latter as Z-52 could be made by a Wittig reaction. 

Silicon-based alkene synthesis is used much less than the analogous phosphorus-based Wittig reaction. In some cases, however, the silicon-based method has proved superior to the phosphorus-based chemistry. For example, a Wittig reaction failed to methylenate the hindered ketone shown in Equation... 

Because the location of the double bond in the product is well defined, the Wittig reaction provides probably the most useful general method for the preparation of alkenes. Some examples are provided in the following equations ... 

As another example, let s consider the synthesis of brevicomin, the aggregation pheromone of the Western pine beetle. First, it is necessary to recognize that brevicomin is an acetal and can be disconnected into a diol and a ketone. The diol can be prepared by hydroxylation of an alkene, and the alkene can be prepared by a Wittig reaction ... 

This C - H activation event is reversible, and is required to achieve catalytic turnover [62], A series of alcohols, mostly secondary benzylic examples, have been oxidized using this catalyst. The catalytic activity does not match that of the Ir examples described above, but it has been used in several tandem reactions that feature both dehydrogenation and hydrogenation steps to achieve interesting transformations. One example is a tandem alcohol oxidation/Wittig reaction/alkene hydrogenation sequence (Scheme 9) [61,62],... 

Phosphonate esters can be deprotonated with sodium hydride or alkoxide anions to give enolate-type anions that react well with aldehydes or ketones to give -alkenes. Alkene-forming reactions with phosphonates are called Horner-Wadsworth-Emmons (or Horner-Emmons, Wadsworth-Emmons, or even Horner-Wittig) reactions. This example is a reaction that was used by some Japanese chemists in the synthesis of polyzonimine, a natural insect repellent produced by millipedes. 

Thefcphosphine oxide can be reduced back to the phosphine (for example, with Cl- SiH) while still bound to the polymer and the polymer-bound reagent can be used again. Separation of Ph3P=0 from alkene products after a Wittig reaction can be quite a nuisance so the ease of work-up alone makes this an attractive procedure. 

One limitation of the Wittig reaction is that a mixture of alkene stereoisomers sometimes forms. For example, reaction of propanal (CH3CH2CHO) with a Wittig reagent forms the mixture of E and Z isomers shown. 

Example What starting materials are needed to synthesize alkene A by a Wittig reaction ... 

For example, two methods can be used to convert cyclohexanone into alkene B (methylenecy-clohexane) a two-step method consisting of Grignard addition followed by dehydration, or a one-step Wittig reaction. 

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