Wittig reactions 1,2-oxaphosphetane from

Betaine precipitates have been isolated in certain Wittig reactions, but these are betaine-lithium halide adducts, and might just as well have been formed from the oxaphosphetane as from a true betaine. However, there is one report of an observed betaine lithium salt during the course of a Wittig reaction. In contrast, there is much evidence for the presence of the oxaphosphetane intermediates, at least... 

This accounts for the considerable discrepancy between the alkene Z/E ratio found on work-up and the initial oxaphosphetan ais/trans ratio. By approaching the problem from the starting point of the diastereomeric phosphonium salts (19) and (20), deprotonation studies and crossover experiments showed that the retro-Wittig reaction was only detectable with the erythreo isomer (19) via the cis-oxaphosphetan (17). Furthermore, it was shown that under lithium-salt-free conditions, mixtures of (19) and (20) exhibited stereochemical drift because of a synergistic effect (of undefined mechanism) between the oxaphosphetans (17) and (18) during their decomposition to alkenes. 

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]. 

The effects of the solvent and finite temperature (entropy) on the Wittig reaction are studied by using density functional theory in combination with molecular dynamics and a continuum solvation model.21 The introduction of the solvent dimethyl sulfoxide causes a change in the structure of the intermediate from the oxaphosphetane structure to the dipolar betaine structure. 

Under salt-free conditions, the cw-oxaphosphetanes formed from nonstabilized ylides can be kept from participating in the stereochemical drift and left intact until they decompose to give the alkene in the terminating step. This alkene is then a pure ci.s-isomer. In other words, salt-free Wittig reactions of nonstabilized ylides represent a stereoselective synthesis of cis-alkenes. 

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. 

Keglevich et al. have reported a series of papers on the mechanistic aspects of what they term inverse Wittig reactions , i.e. the preparation of phosphoranes from the [2-f2] cycloadditions of phosphine oxides and acetylenedicar-boxylates, an example of which is given in Scheme 1. A raft of spectroscopic and structural evidence, coupled with theoretical calaculations, indicate that these reactions proceed via oxaphosphetane intermediates (16). ... 

This is a Wittig reaction. The stable ylide is prepared from 29 prior to the reaction. Only the ketone reacts to form the corresponding olefin via the oxaphosphetane intermediate, as the Weinreb amide is not reactive enough. Owing to the use of a stable phosphonium ylide, only the product with the -configured double bond is obtained in 90 % yield ( /Z 99 1). 

You have met epoxides being formed by intramolecular substitution reactions, but the oxidation of aikenes is a much more important way of making them. Their alternative name derives from a systematic way of naming rings ox for the 0 atom, 1r for the three-membered ring, and ane forfull saturation. You may meet oxetane (remember the oxaphosphetane in the Wittig reaction, Chapter 14, p. 000) and, whileTHFis never called oxolane, dioxolane is another name for five-membered cyclic... 

Schlosser Modification. Almost pure tran -olefins are obtained from nonstabilized ylides by the Schlosser modification of the Wittig reaction (Wittig-Schlosser reaction). For example, treatment of the (cij )-oxaphosphetane intermediate A with n-BuLi or PhLi at -78 °C results in lithiation of the acidic proton adjacent to phosphoras to produce the P"Oxido phosphonium ylide B. Protonation of B with f-BuOH leads to the trans-1,2-disubstituted alkene C. 

In 1970, a review entitled The Stereochemistry of the Wittig Reaction was published in Topics of Stereochemistry by M. Schlosser (1). This review was a milestone in early attempts to understand the Wittig mechanism based on a stepwise, ionic process (Scheme 1) (1,2). The reaction of ylides with aldehydes was believed to involve a partly reversible nucleophilic addition step to generate a betaine intermediate (1 or 2). Subsequent decomposition to the alkene was attributed to the formation of oxaphosphetanes 3 or 4, structures that were assumed to be intermediates of higher energy leading from the betaine to the alkene. 

The last item (S) may explain why the independent betaine generation control experiments gave contradictory results. If betaines are high-energy species that lie above the saddle point leading from the ylide to the oxaphosphetane, then experiments that deliberately generate betaines (Schemes 3-5) may encounter pathways for stereochemical equilibration that are not accessible to typical Wittig reactions. 

Methods A, D, and E suffer from the inherent limitation that they deliberately generate a betaine as the precursor of the oxaphosphetane. Since there is no assurance that the reaction of an ylide with an aldehyde would involve the same ionic intermediate (19,21) these control experiments may provide opportunities for stereochemical equilibration that may not be available to the corresponding Wittig reactions. If the oxaphosphetane generated by methods A or E is stable enough to observe directly, then it is usually possible to distinguish between oxaphosphetane equilibration, betaine equilibration, and other mechanisms for loss of stereochemistry (21 c). However, this is not possible for oxaphosphetanes that contain unsaturated substituents at Cj because oxaphosphetane decomposition is fast at — 78°C (21c). In these examples, method A (like method D or E) can only establish an upper limit for equilibration of all of the conceivable intermediates betaines, betaine lithium halide adducts, oxaphosphetanes, and so on. 

Tables 6 and 7 summarize results from stereochemical equilibration studies performed over the past decade by MaryanofT et al. (22,23), and Vedejs et al. (20, 21c, 39-42). A few other convincing examples are included to expand the scope of the systems covered. Table 6 lists those examples where control experiments establish at least 90% retention of stereochemistry from intermediates-to alkene products. As already discussed, the percentage of equilibration represents the upper limit for loss of stereochemistry from all possible pathways in the control experiments. No attempt has been made to determine whether the minor levels of stereochemical leakage in Table 6 occur at the stage of oxaphosphetanes, betaines, or other potential intermediates. Table 6 includes entries corresponding to all of the principal families of Wittig reagents nonstabilized ylides (entries 1-12, 24, 25, 29, and 30), benzylic ylides (entries 13-17 and 28), allylic ylides (entries 22, 23, 26, and 27), and ester-stabilized ylides (entries 18-21). The corresponding Wittig reactions must take place under dominant kinetic control.

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