Ylide reactions, nonstabilized

As in the nonstabilized ylide reactions, benzylides afford alkenes with increasing Z selectivity as the temperature is lowered (lithium-free conditions). However, the inherent selectivity is lower for the benzylides, and the temperature effect is larger. With the exception of the ort/io-methoxybenzalde-hyde and orf/io-chlorobenzaldehyde entries in subset 1, the Z E ratios are similar for a large variety of aromatic aldehydes. There is no simple effect of electron-releasing or electron-withdrawing groups when the temperature variable is controlled. 

Ionic mechanisms based on betaine intermediates or TS are difficult to reconcile with the absence of solvent effects on lithium-free nonstabilized ylide reactions (Table 12) or reactivity-selectivity considerations (15). Also, there is no apparent reason why the reactants should prefer to form a high-energy intermediate such as 93 when the direct conversion to a more stable oxaphosphetane 97 is possible. Orbital symmetry should not interfere with the four-center process since phosphorus can provide 3d orbitals of appropriate symmetry for a 2s - - 2s cycloaddition. Nevertheless, the betaine mechanism has persisted in the literature because there was no direct evidence against the formation of 93 as a transient intermediate until recently (229). 

From the above discussion, P—O bonding lags behind C—C bonding in the TS of nonstabilized ylide reactions, and phosphorus geometry must be close to tetrahedral in an early TS. Carbon rehybridization would be more advanced, but the ylide a-carbon should be closer to tetrahedral geometry than the aldehyde carbon. This conclusion follows from the observation that the ylide a-carbon is partly pyramidalized in the ground state, as deduced from NMR and X-ray evidence discussed earlier. 

Retrosynthetic cleavage of the trans A8,9 disubstituted double bond in intermediate 11, the projected precursor of diketone 10, provides phosphorus ylide 12 and aldehyde 13 as potential precursors. In the forward sense, a Wittig reaction could conceivably achieve a convergent coupling of intermediates 12 and 13 with concomitant formation of the requisite trans C8-C9 olefin. Ordinarily, the union of a nonstabilized ylide, such as 12, with an aldehyde would be expected to afford an alkene with a cis geometry.8 Fortunately, however, the Schlosser modification of the Wittig reaction permits the construction of trans olefins from aldehydes and nonstabilized phosphorus ylides.9... 

Syntheses of (l )-frans-isomers were reported by Crombie [24] and Elliott [25] starting from (1 /t Wran.v-chrysanthemic acid by means of the Wittig reaction. Their method were convenient to obtain (Z)-isomer (Scheme 10, step a) but not appropriate for the synthesis of ( )-isomer because of the (Z)-selective nature of the Wittig reaction in the case of nonstabilized ylides. It was very difficult to separate the pure ( )-isomer out of the (E)- and (Z)-mixture. This problem was overcome by use of the Takai s method (Scheme 10, step b) [26]. The ( )-selectivity of the double bond was fairly high (E Z = 89 11) (Scheme 10). 

The normal Wittig reaction of nonstabilized ylides with aldehydes gives Z-olefms. The Schlosser modification of the Wittig reaction of nonstabilized ylides furnishes f-olefins instead. 

A different approach to synthesize nonstabilized ylide complexes is the reaction of halomethyl-metallic precursors with the corresponding nucleophile EZ . This method is quite general and usually occurs in very mild reaction conditions. Platinum, rhodium, iron, and palladium complexes (21)-(25) (Scheme 8) have been prepared, using phosphines [79-83], amines [84], or sulfides [85] as nucleophiles. Some of the most representative examples are shown in Scheme 8. 

Dodd and co-workers (5) reported the first known synthesis of 11//-indolizino[8,7-h]indoles by the cycloaddition reaction of a nonstabilized ylide 21 and diethylacetylene dicarboxylate (DEAD). The azomethine ylide, formed by the alkylation of the 3,4-dihydro-p-carboline (22) with trimethylsilyl methyl triflate to the triflate salt, followed by in situ desilyation with cesium fluoride, underwent cycloaddition with DEAD at low temperature. The expected major cycloadduct 23 was isolated, along with quantities of a minor product 24, presumed to have been formed by initial reaction of the ylide with 1 equiv of DEAD and the intermediate undergoing reaction with a further equivalent of DEAD before cyclization. Dodd offers no explanation for the unexpected position of the double bond in the newly generated five-membered ring, although it is most likely due to post-reaction isomerization to the thermodynamically more stable p-amino acrylate system (Scheme 3.5). 

Alkylthieno[2,3-4furans 414 and 4-alkylfuro[3,4-, ]furans 416 were obtained as unexpected side products from the reaction of 2-acetyl-5-bromothiophene and 2-acetyl-5-methylfuran with stabilized and nonstabilized ylides, along with the corresponding phosphoranes 415, pyrans 417, and dimeric products 418, respectively (Scheme 45) <2000T7573>. 

Current results indicate that stabilized arsonium ylides such as phenacylide, carbomethoxymethylide, cyanomethylide, fluorenylide, and cyclopentadienylide afford only olefinic products upon reaction with carbonyl compounds. Nonstabilized ylides such as ethylide afford almost exclusively epoxides or rearranged products thereof. However, semi-stabilized arsonium ylides, such as the benzylides, afford approximately equimolar amounts of olefin and epoxide. Obviously, the nature of the carbanion moiety of the arsonium ylide greatly affects the course of the reaction. It is reasonable to suppose that a two-step mechanism is involved in the reaction of heteronium (P, S, and As) ylides with carbonyl compounds (56). 

Nonstabilized ylides react with the aldehyde as soon as they form on the surface of the base, therefore kaolinite does not influence the course of the reaction. 

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. 

A different reaction mode of lithiobetaines is used in the Schlosser variant of the Wittig reaction. Here, too, one starts from a nonstabilized ylide and works under non-salt-free conditions. However, the Schlosser variant is an olefination which gives a pure frans-alkene rather than a trans.cis mixture. The experimental procedure looks like magic at first ... 

Stereogenic Wittig reactions of nonstabilized ylides of the structure Ph3P+—CH —R2 have been studied in-depth in many instances. They give the cis-configured oxaphosphetane rapidly, with the rate constant kcis, and reversibly (Figure 9.7). On the other hand, the same nonstabilized ylide produces the /ran.v-oxaphosphetane slowly, with the rate constant ktrans, and irreversibly. The primary product of the [2+2]-cycloaddition of a nonstabilized P ylide to a substituted aldehyde is therefore a cis-oxaphosphetane. Why this is so has not been ascertained despite the numerous suggestions about details of the mechanism which have been made. 

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. 

Typically, nonstabilized ylides are utilized for the synthesis of (Z)-alkenes. In 1986, Schlosser published a paper summarizing the factors that enhance (Z)-selectivity. Salt effects have historically been defined as the response to the presence of soluble lithium salts. Any soluble salt will compromise the (Z)-selectivity of the reaction, and typically this issue has been resolved by the use of sodium amide or sodium or potassium hexamethyldisilazane (NaHMDS or KHMDS) as the base. Solvent effects are also vital to the stereoselectivity. In general, ethereal solvents such as THF, diethyl ether, DME and t-butyl methyl ether are the solvents of choice." In cases where competitive enolate fomnation is problematic, toluene may be utilized. Protic solvents, such as alcohols, as well as DMSO, should be avoided in attempts to maximize (Z)-selectivity. Finally, the dropwise addition of the carbonyl to the ylide should be carried out at low temperature (-78 C). Recent applications of phosphonium ylides in natural product synthesis have been extensively reviewed by Maryanoff and Reitz. 

Application of the Wittig reaction of a nonstabilized ylide to the synthesis of an ( )-alkene is practically and effectively carried out by the Schlosser modification. Alternatively, the use of a trialkylphos-phonium ylide can produce high ratios of ( )-alkene." Recently, Vedejs has developed a reagent using dibenzophosphole ylides (110) to synthesize ( )-disubstituted alkenes (111) fixnn rddehydes (equation 24). The initial addition of ylide occurs at -78 C, but the intermediate oxaphosphetane must be heated to induce alkene formation. The stereoselectivity in the process is excellent, particularly for aldehydes with branched substitution a to the reacting center. Both the ethyl and butyl yli s have b n utilized. 

This stabilized ylide reacts with aldehydes and ketones to furnish epoxides. The difference in reactivity between dimethylsulfonium methylide and dimethyloxosulfo-nium methylide is apparent when considering their reactions with a, 3-unsaturated ketones. Whereas the nonstabilized ylide yields the epoxide, the stabilized ylide affords a cyclopropane via conjugate addition followed by ring closure and loss of dimethyl sulfoxide. 

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. 

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