Oxaphosphetanes, Wittig reaction

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... 

Monocyclic Phosphoranes. - Further studies on the mechanism and stereochemistry of the Wittig reaction have been conducted by a combination of 1H, 13C and 3 P n.m.r.2k 25. The results show that at -18°C both ois and trans diastereomeric oxaphosphetans (e.g. 17 and 18) may be observed and their decomposition to alkenes monitored by n.m.r. Evidence was presented to suggest that during this process oxaphosphetan equilibration involving the siphoning of (17) into (18) occurred in competition with alkene formation. 

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. 

The photochemical fragmentation of vinyl-substituted 1,2k5-oxaphosphetanes, representing a step of a photochemical variant of the Wittig reaction with methyl-eneoxophosphoranes, has been examined as a model in the case of 22b20). Photolysis of this compound in methanol affords the 1,3-diene 24b as well as the highly reactive dioxophosphorane 23 which is trapped by the solvent subsequent esterification of the half-ester 62, formed as a primary product, with diazomethane to give the diester 63 was undertaken solely for preparative reasons 20). 

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). 

The preferential formation of ( )-alkene on Wittig reaction of phenyl 3-pyridyl ketones (bearing an oxazole carboxamide group at the / -position of the phenyl ring) with Ph3P=CH(CH2)4C02 K+ has been attributed to interaction between the amide (rather than oxazole) moiety and the carboxyl terminus during oxaphosphetane formation. ... 

Spectroscopic evidence for formation of a betaine lithium salt adduct during the course of a Wittig reaction has been reported for the first time. The ylide Ph3P=CH2 formed oxaphosphetane (71) on treatment with 2,2 -dipyridyl ketone at -60 °C in... 

Recent detailed discussions229,283,284,286,289,290 of the bonding in phosphoranes has usually taken for granted the three-centre, four-electron bond model described above and have concentrated on other related issues of importance in these systems, viz. apicophilicity, pseudorotation and the oxaphosphetanes involved in the Wittig reaction. 

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. 

The Wittig reaction is a very important method for olefin formation. The stereochemistry about the new carbon-carbon double bond is the Z (or less stable) isomer. This unusual stereoselectivity indicates that product formation is dominated by kinetic control during formation of the oxaphosphetane. 

By adding a strong base to the cold solution of the oxaphosphetane before it eliminates, die oxaphosphetane equilibrates to die more stable anti isomer and die E olefin is produced upon elimination. This so-called Schlosser modification in conjunction with the normal Wittig reaction enables either the Z or E isomer of the olefin to be prepared selectively. 

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). 

Next again a Wittig reaction succeeds. Aldehyde 55 is directly converted to a 3 1 mixture of E- and Z-enynes 16 upon exposure to the in situ generated Wittig salt 15. The E-isomer is built as main product, passing the anti-configurated oxaphosphetane 56. 

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. 

Oxaphosphetane (24) has been successfully isolated for the first time as stable crystals in the typical Wittig reaction of cyclopropylidenetriphenylphosphorane with activated carbonyl compounds.61 X-ray analysis of (24) showed that the phosphorus atom is at the centre of a slightly distorted trigonal bipyramidal structure. 

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). 

We have a fairly detailed knowledge of the mechanism of the Wittig reaction (Figure 11.3). It starts with a one-step [2+2]-cycloaddition of the ylide to the aldehyde. This leads to a heterocycle called an oxaphosphetane. The oxaphosphetane decomposes in the second step—which is a one-step [2+2]-cycloreversion—to give triphenylphosphine oxide and an alkene. This decomposition takes place stereoselectively (cf. Figure 4.44) a cw-disubstituted oxaphosphetane reacts exclusively to give a cis-alkene, whereas a fraws-disubstituted oxaphosphetane gives only a trans-alkene. The reaction is stereospecific. 

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