Classic Wittig reaction

The spectral parameters of 15a and other silicon-organophosphorus betaines described henceforth in Section 2.2.2 allowed us to show reliably that the reaction of phosphorus ylides with thiocarbonyl compounds, unlike the classical Wittig reaction, occurs through the intermediate formation of betaines (17)11 (Scheme 9). Erker and coworkers performed a more detailed... 

P. J. Murphy, S. E. Lee, Recent Synthetic Applications of the Non-Classical Wittig Reaction, J. Chetn. Soc.-Perkin Trans 1 1999, 3049-3066. 

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. 

Phosphoranes and phosphonate derived carbanions are also known to react with carbonyl compounds other than aldehydes and ketones, in reactions often referred to as non-classical Wittig reactions.35 Wittig olefination products can be obtained from the reaction of esters, anhydrides and some amides and imides with a range of stabilized and reactive phosphoranes. The reaction of stabilized and semi-stabilized phosphoranes with esters gives alkenes (Scheme 7). However, non-stabilized phosphoranes, such as methylenetriphenylphosphorane, tend to give P-keto phosphoranes on reaction with esters (Scheme 7)—the careful choice of the reaction conditions can also permit the preparation of the alkene in these reactions. 

These non-classical Wittig reactions of esters have been used to prepare a number of oxygen-containing heterocycles.35 Phosphonate stabilized carbanions, for example, those derived from dimethyl methylphophonate, also react with esters to give, in this case, a P-keto phophonate which can react further with aldehydes and ketones. 

The strategy described here should find considerable use as a method for the stereoselective synthesis of alkenes. Although this olefination strategy involves one more step than the classic Wittig reaction, in many cases it may prove to be the more practical method. Finally, the scope, overall efficiency, and stereoselectivity of the 0-lactone route compares favorably to the Wittig, Julia-Lythgoe, and related established strategies for the synthesis of tri- and tetrasubstituted alkenes. 

Low reactivity of ot,(B-unsaturated ketones and sterically hindered ketones as well as separation of reaction products from phosphine oxide are a few disadvantages of the classical Wittig reaction. Phosphonate anions are stronger nucleophiles than related phosphoranes thus, alkenate hindered ketones under mild conditions. The dialkylphosphate (R2PO4), the other product of the HWE reaction, can easily be removed from the reaction mixture because it is soluble in water. 

The mechanism of the HWE reaction is similar to that of the classic Wittig reaction. 

The general representation of the classic Wittig reaction is presented in equation (21). The ( )- and (Z)-selectivity may be controlled by the choice of the type of ylide (95), the carbonyl derivative (94), the solvent and the counterion for ylide formation. As a general rule, the use of a nonstabilized ylide (95 X and Y are H or alkyl substituents and is phenyl) and salt-free conditions in a nonprotic, polar solvent favors the formation of the (Z)-alkene isomer (96) in reactions with an aldehyde. A stabilized ylide with strongly conjugating substituents such as an ester, nitrile or sulfone forms predominantly the (f -alkene. 

It is sometimes desirable to avoid the use of alkoxide during the formation of C—C double bonds in the synthesis of / -lactams [3324]. An iminophosphorane (formed in situ from an azide and triphenylphosphine) reacts with a carboxylic ester group in a neighbouring malonylidene side-chain to form this ring [3792]. The classic Wittig reaction has been extended to the synthesis of 2-vinylindoles [3603], and other indoles have been obtained from isothiocyanato phosphoranes [3297]. 

Table I, examination of which provides ample support for the generality of the process. It is noteworthy that increased branching at the carbon a to the imine function leads to decreased yields of the desired adducts (12) the reason for this failure has not been addressed, but reversion by retroaldolization is one likely possibility. The base that was typically employed to effect the deprotonation of the intermediate aldimines was lithium diisopropylamide, since alkyllithiums were found to add to the carbon-nitrogen double bond of the aldimines. Wittig observed in a number of instances that the overall yields of a,3-un-saturated carbonyl compounds obtained according to this procedure were better than by the corresponding classical Wittig reaction. Interestingly, the anion derived from the r-butylimine of isobutyraldehyde reacts with selected a,3-unsaturated ketones to give 1,4-adducts, whereas the corresponding hydrazone anions add to such ketones to provide the 1,2-adducts. ...

The Wittig condensation has a wide range of applicability. The most suitable carbonyl components are generally aliphatic, alicyclic or aromatic aldehydes, but reactive phosphorus ylides also react with ketones, and even esters, amides and anhydrides can be reacted with phosphorus ylides in so-called non-classical Wittig reactions [13]. 

Its principle use in organic synthesis has been as a substitute for methylene triphenylphosphorane, Ph3P= CH2, in cases where the classical Wittig reaction is too basic and causes side reactions. It is also used for the... 

Tab. 1.1. Factors that influence the E/Z ratio in the classic" Wittig reaction.

Mechanistically, this variation is similar to the classical Wittig reaction. The only departure stems from the physico-chemical nature of the intermediates. The addition of ylide 34 to carbonyl compound 3 occurs as before to set up a mixture of erythro 35 and threo 37 adducts. Now the betaines are more acidic, which facilitates the interconversion of 35 and 37. Deprotonation of 35, in situ, produces 36. Kinetic protonation occurs from the least sterically hindered face, as shown in 38. With the equilibration to... 

Nicolaou also made use of the Wittig reaction in his synthesis of brevetoxin B 136. The western 133 and eastern 134 portions of the molecule were linked in 75% yield using a classical Wittig reaction to generate 135. 

The classical Wittig reaction can equally be employed to transform enals into fluorinated dienes, for instance. Thus, reacting an ot-fluoro enal and an a-fluoro phosphonium ylide, difluoro-2,4-dienoates were easily obtained in fine yields and generally good selectivities [205]. 

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