Ylids, Wittig reactions

Wittig reaction of unstabilized ylid Wittig reaction of stabilized ylid... 

Notice that sulphur ylids behave quite differently from phosphorus ylids, which would of course do the Wittig reaction (ftames 41-43). 

In the Wittig reaction an aldehyde or ketone is treated with a phosphorus ylid (also called a phosphorane) to give an alkene. Phosphorus ylids are usually prepared by treatment of a phosphonium salt with a base, and phosphonium salts are usually prepared from the phosphine and an alkyl halide (10-44) ... 

The overall sequence of three steps may be called the Wittig reaction, or only the final step. Phosphonium salts are also prepared by addition of phosphines to Michael alkenes (hke 15-8) and in other ways. The phosphonium salts are most often converted to the ylids by treatment with a strong base such as butyllithium, sodium amide, sodium hydride, or a sodium alkoxide, though weaker bases can be used if... 

The Wittig reaction has been carried out with polymer-supported ylids (see p. 509). It has also been done on silica gel. " ... 

Ylids are usually prepared from triphenylphosphine, but other triarylpho-sphines, trialkylphosphines, and triphenylarsine " have also been used. The Wittig reaction has also been carried out with other types of ylids, the most important being prepared from phosphonates " ... 

Disconnection (a2) leads to the industrial synthesis as the half aldehyde, hall ester (46) of fumarie acid (100% tpans) is available and the Wittig reaction with unstabilised ylid (45) gives 85% cis geometry in the new double bond. 

The adjustment of the oxidation level is most easily achieved by reducing the protected ester (56) to the alcohol and re-oxidising. The Wittig reaction with a stabilised ylid (55) gives mostly ff-(53). 

Halo-lactonization of ketophosphoranes has been achieved via reaction with cyclic anhydrides and subsequent halogenation. " The products, halo enol lactones (75), are synthetically useful compounds, and an alternative synthesis via incorporation of the halogen at the ylid stage is also described. Mechanistic investigation of the Wittig reactions involved reveals subtle variations in pathway, allowing optimum experimental conditions to be selected to allow for the variation in reactivity of different anhydrides and halides. 

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. 

In practice the low potentials permit a choice of approaches this is illustrated in Scheme 18 for a Wittig reaction in the presence of EGB wherein the desired product, 1,4-diphenylbutadiene, may be formed either from a reactive aldehyde (cinnamaldehyde) and an ylid from a benzylic phosphonium salt, or from a less reactive aldehyde and the ylid from a more acidic phosphonium salt The stereochemical course of the Wittig reaction is particularly sensitive to reaction conditions, especially cations which may be present. This point is partly made in Scheme 18 but deserves further elaboration. 

Alternatively it is possible to have both steps, addition and elimination, occur spontaneously if appropriate reagents are employed. There are two common strategies in use the Wittig reaction and the Wittig-Horner reaction. The Wittig olefination uses a phosphorus-stabilized carbanion (ylid) as a nucleophile and a carbonyl compound as an electrophile. Typically the ylid is generated in situ from a triphenylphosphonium salt and a strong base such as LDA or an alkyl lithium. 

Selective reactions. Wittig reactions of 1 with an aldehyde are possible in the presence of keto, ester, and amino groups.2 Wittig reagents react under normal conditions with acid chlorides. The stabilized ylid I reacts preferentially with the acid chloride group of 4-lormylhcnzoyl chloride (2) lo give 3 as the major product. ... 

Reaction intermediates can be detected by reaction monitoring (i.e. analyses at several reaction times), and their presence may be inferred or even observed more readily at low temperatures. In a Wittig reaction, the ylid 32 in Scheme 2.13 was produced from ethyl-triphenylphosphonium bromide and butyl lithium, and reacted with a small excess of cyclohexanone in THF at —70°C the initial product, the oxaphosphetane 33, was identified by 31P NMR and converted to the alkene product and triphenylphosphine oxide (34) above — 15°C (see also Chapter 9). These results provide relatively direct experimental evidence for the mechanism shown in Scheme 2.13 [23]. 

We have shown that the ylids 3 react with a number of nucleophiles (3). In particular 3a and 3b react quantitatively with the alkylidene phosphoranes 5 to give 3-pyrrolines 6a and 6b as a mixture of diastereoisomers. The cyclisation occurs via an intramolecular Wittig reaction on the carbonyl of an ester group (M. In the same conditions, 2c reacts with 5 to give quantitatively the pyrrolines 7c (two diastereoisomers) as a result of a Wittig reaction on the carbonyl of the keto group in 3c. 

But how are we to make the epoxide 61 The obvious route is by epoxidation of the alkene 63. The alkene 63 could be made by a Wittig reaction (chapter 15) on the ketone 64 or directly by sulfur ylid chemistry (chapter 30). 

As the Wittig reaction forms both tt and cx-bonds, the disconnection is right across the middle of the alkene giving a choice of starting materials. So with the exo-cyclic alkene 26, very difficult to make by elimination methods, we could use formaldehyde or cyclohexanone as the carbonyl component with either phosphonium salt 25 or 28. It is a matter of personal choice whether you draw the ylid, the phosphonium salt or the alkyl halide at this stage. 

An excellent application of the distinction between stabilised and unstabilised ylids is in the synthesis of leukotriene antagonists.10 The intermediate 39 (R is a saturated alkyl group of 6, 11 or 16 carbon atoms) was needed and disconnection of the Z-alkene with a normal Wittig reaction in mind followed by removal of the epoxide exposed a second alkene with the E configuration that could be made from the aldehyde 43 and the stabilised ylid 42. 

PhLi gave the ylid from 55 and the Wittig reaction with 54 did indeed give Z-52. These days we should probably use catalytic OSO4 for the dihydroxylation but his mixtures [1. AgOAc, I2, HOAc, H2O, 2. KOH, EtOH] also gave the diol 51 and TsCl in pyridine gave the bis tosylate 50. This chemistry is explained in the workbook. 

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. 

The pyrrole 19 was made by a Friedel-Crafts reaction on the known and deactivated pyrrole 25. The COiEt group deactivates C-3 and C-5 so reaction occurs at the only unaffected position. The electron-withdrawing CC Et group also makes the pyrrole less susceptible to Lewis acid degradation (chapter 39). The Wittig reaction with the ylid from 20 went in excellent yield but... 

The bulky ligands PPh3 and AsPh3 add to the unsubstituted end of 31 (180,181). The resulting phosphonium salt (32) is deprotonated by butyllith-ium at — 78°C to yield an ylid (33) which reacts with aldehydes in a Wittig reaction. Deprotonation with potassium tert-butoxide followed by addition of aldehyde 34 gives the E isomer (35) only [Eq. (20)] (182). Trimethylphosphite... 

First the normal Wittig reaction, and then a second mol of Wittig reagent must be behaving as a carbene equivalent, just as we hoped the sulphur ylid would (but see Tetrahedron Lett.. 1979, 1511, 1515). 

An acidic proton posed a potential problem during E. J. Corey s synthesis of bergamotene (a component of the fragrance of Earl Grey tea). You met the Wittig reaction in Chapter 14, and phosphonium ylids are another type of basic,... 

You notice that we have drawn the intermediate ylid as an enolate just to emphasize that it is an enolate derivative it can also be represented either as the ylid or as a C=P phosphorane structure. If we look at the details of this sort of Wittig reaction, we shall see that ylid formation is like enolate anion formation (indeed it is enolate anion formation). Only a weak base is needed as the enolate is stabilized by the Ph3P+ group as well. 

The Wittig reactions below were all used in the synthesis of natural products. You will notice that some reactions are Z selective and some are E selective. Look closer, and you see that the stereoselectivity is dependent on the nature of the substituent on the carbon atom of the ylid. 

I hc key intermediates in the synthesis of the E- and the Z-isomers of capsaicin were the E and Z unsaturated esters shown below. By using a Wittig reaction with an unstabilized ylid it was possible to make the Z-isomer selectively, whilst the Julia olefination gave the -isomer. 

How can the Z selectivity in Wittig reactions of unstabilized ylids be explained We have a more complex situation in this reaction than we had for the other eliminations we considered, because we have two separate processes to consider formation of the oxaphosphetane and decomposition of the oxaphosphetane to the alkene. The elimination step is the easier one to explain—it is stereospecific, with the oxygen and phosphorus departing in a syn-periplanar transition state (as in the base-catalysed Peterson reaction). Addition of the ylid to the aldehyde can, in principle, produce two diastere-omers of the intermediate oxaphosphetane. Provided that this step is irreversible, then the stereospecificity of the elimination step means that the ratio of the final alkene geometrical isomers will reflect the stereoselectivity of this addition step. This is almost certainly the case when R is not conjugating or anion-stabilizing the syn diastereoisomer of the oxaphosphetane is formed preferentially, and the predominantly Z-alkene that results reflects this. The Z selective Wittig reaction therefore consists of a kinetically controlled stereoselective first step followed by a stereospecific elimination from this intermediate. 

The female silkworm moth attracts mates by producing a pheromone known as stabilized and unstabilized ylids, respectively, to control the stereochemistry of bombykol. Bombykol is an E.Zdiene, and in this synthesis (dating from 1977) the product, two successive Wittig reactions exploit the stereoselectivity obtained with... 

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