Mechanism of the Wittig Reaction

The Wittig reaction occurs by nucleophilic attack of an ylide carbanion 2 at the carbonyl carbon of an aldehyde 21 (or ketone) to form what was assumed to be 'betaine' 22. This intermediate cyclises to the unstable oxaphosphetane system (or OPT) 23 and subsequently breaks down to the corresponding olefin 38 and phosphane oxide (see Scheme 16). However, there has been much debate whether the betaine or oxaphosphetane intermediates actually exist and if so, how they influence the stereochemical course of the reaction.

In the 1960's, just after the discovery of the Wittig reaction, it was believed that both betaines^[25,29] and OPT's^[25a] were likely intermediates. Although some 10 years later, more emphasis was placed on the dipolar betaine intermediate due to experimental data attempting to prove its existence^[25,30]. Oxaphosphetanes (OPT's) were not considered 'true' intermediates but simply transition states from the betaine 'en route' to the final products. But in the late 70's, betaines were abandoned as likely intermediates because they could not be isolated but only trapped as salts^[25,30] and the emphasis was redirected towards OPT's, which were isolatable. The 'betaine' proposal could not justify the stereoselectivity of various Wittig reactions.

Therefore, the general mechanism in Scheme 16 is not an up-to-date description of the Wittig mechanism, but modern chemists rely more on a proposal put forward by Vedejs^[31]. This consists of a four-centred transition state, the geometry of which is believed to govern the geometry of the subsequently formed OPT, in turn determining the stereochemistry of the Wittig products.

Non-stabilised, reactive ylides form 'early' transition states with non-planar or 'puckered' geometries and a close to tetrahedral phosphorus, see 39i. The aldehyde molecule takes up a pseudo-equitorial orientation in relation to the ylide and the alkyl group attached to the ylidic carbon assumes a pseudoaxial position. As a result of this geometry, there is maximum separation between the aldehyde and ylide (both the

phosphorus and C^α) substituents. 1,3-interactions dominate in this structure favouring a cis-selective reaction; the intermediate is more stable as the cis-oxaphosphetane 39i and the Z-alkene product is favoured. Formation of an intermediate with planar geometry 39ii is not favoured due to severe methyl-alkyl interactions. The Z-selectivity of this reaction is reduced by using unbranched aldehydes.

P

Fig.3 39i: non-planar geometry of cis-arranged 'early' transition state 39ii: unfavourable planar cis geometry.

On the contrary, stabilised ylides form late, product-like, planar transition states with an almost trigonal bipyramidal phosphorus atom (39iii):

P

Fig.4 39iii: planar geometry of E-arranged 'late' transition state, 39iv: unfavourable non-planar trans geometry.

Here, 1,2-interactions dominate, promoting a trans-selective reaction and favouring formation of the E-alkene. 1,3-interactions which destabilise 39iii depend on the aldehyde substituents e.g. an aldehyde bearing an α-hydrogen could orientate itself so the hydrogen points towards the PPh3 group, reducing these 1,3-interactions and stabilising the structure. The alternative trans-selective geometry 39iv is not favoured due to steric repulsion between Ph¹ and an α-methyl group of the aldehyde.

In conclusion, the 1,2- and 1,3-interactions which greatly influence the cis/trans-selectivity of the Wittig reaction can be enhanced or reduced by careful choice of both the ylide and aldehyde substituents^{[30, 32]}.

Factors affecting the stereochemistry of the Wittig reaction

In general, stabilised ylides^[33] such as ester ylides promote a E-selective Wittig reaction, semi-stabilised ylides show no preference, while non-stable, reactive ylides^[34] e.g. alkyl ylides, favour production of the thermodynamically less stable Z-olefins. However, there are exceptions to this rule.

The ylide phosphorus substituents affect the reactivity of the ylide and have little or no influence on the stereochemical outcome of the Wittig reaction. However, replacement of one or more phenyl ligands of a triphenylphosphonium ylide with a 2-methoxy-phenyl group enhances the stereoselectivity of the reaction^[35]. Trialkyl phosphorus ylides have also been known to promote high E-stereoselectivity^[36].

The carbonyl compound used in the Wittig reaction greatly affects the rate of the reaction and can also improve the stereoselectivity of the reaction^[37] e.g. non-stabilised ylides react with bulky, aliphatic aldehydes such as (CH3)3CCHO, exhibiting improved Z-alkene stereoselectivity in comparison to less bulky, unbranched aldehydes.

Lithium salts are known to exert a profound effect on the stereochemistry of the Wittig reactione.g. reactive ylides promote E-selectivity in the presence of lithium salts in comparison to the 'normal' Z-selectivity^[38]. Dilution of the reaction mixture, use of solvents which solvate the lithium cation or other complexation possibilities for the lithium cation e.g. addition of alcohols or crown ethers^[39], can significantly reduce this effect.

Wittig reactions of unstable ylides, without organolithium bases, produce high ratios of Z:E-isomer products e.g. the reaction of triphenyl-propylylide and hexanal produced a Z:E olefin ratio of 96:4 in the presence of NaN(SiMe3)3 and only a 50:50 ratio when n-BuLi was used^[40]. Therefore, the preparation of ylides using 'salt-free' methods i.e. the use of a base which is not an organolithium one, are highly beneficial and have attracted much interest.

The choice of solvent used in Wittig reactions can also affect the stereoselectivity of the reaction. The reaction of unstable ylides in aprotic solvents such as THF, are Z-selective^[30,41], while use of polar aprotic solvents such as DMF, give a 50:50 mixture of the olefinic products^[39,42].

In summation, the stereoselectivity of the Wittig reaction may be optimised by careful choice of the ylide, carbonyl compound and reaction conditions.

1.5.3 'Non-classical' Wittig Reactions

The reaction between a phosphorane 2 and a carboxylate derivative 40 such as a carboxylic ester, an amide etc, generates a heterosubstituted alkene 41 and is known as a 'non-classical' Wittig reaction^[43]:

R¹

1.5.3.1 Wittig Reactions with carboxylic esters

Carboxylic esters and phosphoranes undergo intermolecular or intramolecular Wittig reactions generating acyclic, carbocyclic or heterocyclic products e.g. the reaction of 2d with a simple ester 40a yields β-ketophosphorane 42a^[43a,44]:

PPh₃

But when the propyl residue of 2d is substituted with a strong electron-withdrawing group, Wittig products i.e. the phosphorus-free alkene and phosphine oxide are produced. However, this concept is not clear-cut. It has been shown that variation of the temperature or the presence of alkali salts can produce a mixture of both the β-ketophosphorane and olefin products^[44].

Reaction of keteneylidenetriphenylphosphorane 1a and α-hydroxy ester 43 generates ester ylide 44, which undergoes an intramolecular Wittig cyclisation to the corresponding tetronate 46^[45] and phosphane oxide:

R'

The reaction described above is generally not stereoselective, although there are some exceptions^[45]. This reaction has also been applied to the synthesis of thiotetronatesand tetramates^[46], benzofurans and chromenes^[47], dihydrofurans^[48] and bicyclic heterocycles^[49].

When R = allyl, a Claisen rearrangement to C-3 of 46 takes place yielding the α,γ-disubstituted tetronic acid^[45]. This reaction is temperature dependent.

1.5.3.2 Wittig Reactions with amides

Amides are much less susceptible to nucleophilic attack than esters and only the more reactive ylides can alkenate them, typically in an intramolecular process. Pyrroles 48 were synthesised by an intramolecular Wittig condensation of 47^[43]:

N O PPh₃

Ar NC

R

Ph Ar N Ph

R

heat, DMF, 20 - 24 h.

47 48

- HCN - Ph₃P=O

Scheme 20

The cyanide residue adjacent to the amide functionality of 47 influences the conjugation of the nitrogen lone pair across the amide, thus increasing amide reactivity for reaction with the ylide residue. There are no reports of intramolecular Wittig reactions with simple, less substituted amides.

1.5.3.3 Wittig Reactions with thiol esters

The 'non-classical' intermolecular Wittig reaction of thiol esters is of limited use as β-ketophosphoranes are generally formed over the olefinic products^[50]. But the intramolecular reaction has attracted some interest, especially in the synthesis of penem and carbapenem antibiotics^[51] e.g.:

N

R S

O PPh₃

Bu^tO₂C O

N R S

O CO₂^tBu

heat, toluene

49 50

- Ph₃P=O

Scheme 21