Wittig reactions oxaphosphetane intermediate

The Wittig reaction is one that IS still undergoing mech anistic investigation An other possibility is that the oxaphosphetane intermedi ate IS formed by a two step process rather than the one step process shown in Figure 17 13... 

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... 

Olefination Reactions Involving Phosphonium Ylides. The synthetic potential of phosphonium ylides was developed initially by G. Wittig and his associates at the University of Heidelberg. The reaction of a phosphonium ylide with an aldehyde or ketone introduces a carbon-carbon double bond in place of the carbonyl bond. The mechanism originally proposed involves an addition of the nucleophilic ylide carbon to the carbonyl group to form a dipolar intermediate (a betaine), followed by elimination of a phosphine oxide. The elimination is presumed to occur after formation of a four-membered oxaphosphetane intermediate. An alternative mechanism proposes direct formation of the oxaphosphetane by a cycloaddition reaction.236 There have been several computational studies that find the oxaphosphetane structure to be an intermediate.237 Oxaphosphetane intermediates have been observed by NMR studies at low temperature.238 Betaine intermediates have been observed only under special conditions that retard the cyclization and elimination steps.239... 

The pentacoordinate oxazaphosphetidines 53 (Tip = tri(isopropyl)phenyl) are related to intermediates in the aza-Wittig reaction. Thermolysis of 53 shows that the compound displays two types of reactivity as an azaphosphetidine to give 51 and 52 and as an oxaphosphetane to yield 54 and 55 <00TL5237>. 

The stereochemical outcome of the Wittig reaction can depend on the presence or absence of lithium salts. This may be due to a betaine intermediate stabilized by lithium cation. A stable adduct of this type has now been observed during a Wittig reaction. When Ph3P=CH2 is treated with 2,2 -dipyridyl ketone, P NMR shows the formation of an oxaphosphetane (72) and addition of lithium bromide gives the chelation-stabilized betaine lithium adduct (73). 

Oxaphosphetanes (121 P-CiV = 5) have been isolated as intermediates of the Wittig reaction when special conditions are observed (79AG(E)876, 79CC1072, 79AG(E)633). 

In the first step a Wittig reaction" is used to transform the aldehyde into a terminal olefin. This requires initial preparation of a quaternary phosphonium salt. The latter is then deprotonated with sodium amide to give phosphorus ylide 46, which after nucleophilic attack on aldehyde 12 leads to the oxaphosphetane intermediate 47. This intermediate in turn decomposes into olefin 48 and triphenylphosphine oxide. 

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]. 

With phosphorus ylides as used for the Wittig Reaction, the phosphorus atom forms a strong double bond with oxygen. This leads the mechanism in a different direction, to effect olefination instead of epoxidation through intermediate oxaphosphetanes. 

Addition of the ylide to the carbonyl is postulated to lead first to the zwitterionic intermediate betaine, which would then close to form a four-membered cyclic intermediate, an oxaphosphetane. The existence of the betaine hasn t been fully established, although its intermediacy plays an important role in the Schlosser Modification. Betaines may be stabilized by lithium salts leading to side products therefore, suitable bases in the Wittig Reaction are for example NaH, NaOMe, NEt3). 

Quantum mechanical calculations in the gas phase and DMSO solution at different temperatures can highlight the hazards of standard 0 K gas-phase calculations.259 For the Wittig reaction, a small barrier in the potential energy curve is transformed into a significant entropic barrier in the free energy profile, and the formally neutral oxaphosphetane intermediate is displaced in favour of the zwitterionic betaine in the presence of DMSO. 

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. 

The acid-catalyzed Peterson olefination is presumably an E2-elimination, that is, a one-step reaction. On the other hand, the base-induced Peterson olefination probably takes place via an intermediate. In all probability, this intermediate is a four-membered heterocycle with a pentavalent, negatively charged Si atom. This heterocycle probably decomposes by a [2+2]-cycloreversion just like the oxaphosphetane intermediate of the Wittig reaction (Section 4.7.3). 

Beware of thinking that the occurrence of the lithiobetaines A and B must have stereochemical implications. Until fairly recently, lithium /ree betaines were incorrectly considered intermediates in the Wittig reaction. Today, it is known that lithima-containing betaines are formed in a dead-end side reaction. They must revert back to an oxaphosphetane—which occurs with retention of the configuration—before the actual Wittig reaction can continue. 

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 first step is a simple Wittig reaction with an unstabilized ylid (Chapter 31), which we expect to favour the Z-alkene. It does but, as is common with Wittig reactions, an E/Z mixture is formed but not separated as both isomers eventually give the same compound. The reaction is kinetically controlled and the decomposition of the oxaphosphetane intermediate is in some ways like a fragmentation. 

The stereochemistry of the alkene product in Wittig reactions is thought to be influenced by the reversibility of formation of the isomeric threo and erythro oxaphosphetanes (or betaines) which undergo stereospecific loss of triphenyl-phosphine oxide to give the trans (E) and cis (Z) alkenes, respectively (Scheme 4). Factors that enhance the reversibility of this initial step favour the threo intermediate and hence the (E) alkene. Stabilized phosphoranes give a predominance of the (E) alkene while non-stabilized phosphoranes give the (Z) alkene. In general, stabilized phosphoranes react readily with aldehydes (see Protocol 4) while non-stabilized phosphoranes will react with aldehydes, hemiacetals (see Protocol 5) and ketones.2,3... 

The.l,2-A -oxaphosphetanes 58 and 68 can be considered stable intermediates of the Wittig reaction. Pyrolysis of the parent compounds yields the corresponding olefins and oxophosphoranes, respectively, which have been reported in several publications 204, 220, 221, 226). 

Protic solvents shift the alkene E)j Z) ratio in the direction of the (E)-form. The alkene [E)I Z) ratio of salt-free Wittig reactions is thus influenced not only by the electronic character of R, but also by the solvent and the stereochemistry of the formation of the 1,2-oxaphosphetane in the first rate-determining step. According to Eq. (5-48), the thermodynamically less stable (Z)-l,2-oxaphosphetane is formed in the first activation step. A conformational analysis of the activated complex leading to the 1,2-oxaphosphetane intermediate provides a reasonable explanation for this unexpected cis-selectivity [143, 556]. 

Currently accepted mechanism of the Wittig reaction of aldehydes with non-stabilized ylides involves the formation of oxaphosphetanes through a [2-I-2]-cycloaddition-like reaction . The oxaphosphetanes are thermally unstable and collapse to alkene and phosphine oxide below room temperature. Under salt-free conditions there is no formation of betaine intermediates. The salt-free ylides can be prepared by the reaction of phosphines with carbenes generated in situ. Vedejs etal proposed a puckered 4-centre cyclic transition state I for sy -oxaphosphetane and planar structure J for anff-oxaphosphetane. In general, the flnfi-oxaphosphetane J is more stable than the syn-oxaphosphetane I, and under equilibrium conditions (when stabilized ylides are used) the E-alkene product is favoured (Scheme 4.24). However, kinetic control conditions, which appear to dominate when non-stabilized ylides are used, would lead to Z-alkene. 

Oxaphosphetane (Section 21.10B) An intermediate in the Wittig reaction consisting of a four-membered ring containing a phosphorus-oxygen bond. 

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