Ketenes lithium ester enolates

The third type of C = CX2 olefin examined from the point of view of structure correlation was the ester enolate. Three crystal structures of lithium ester enolates, obtained in the course of synthetic studies by Seebach et al., provided a total of four fragments depicted in Scheme 6.13 [108]. The variation in the C-O bond lengths and bond angles provides a picture of the incipient stages of elimination of an alkoxy ion (alcoholate OR), yielding a ketene. The C-OR bond length varies between 1.379(3) and 1.412(5) A, and the C = C-0 angle increases from 125.4 to 128.2° (d and / i in Scheme 6.14), i.e. the picture is similar to the enamine one. The other... 

Similarly, a qualitative relation between the chemical behavior and the distortion from ideal C2v symmetry was suggested for a series of lithium ester enolates (Scheme 6.13) [108]. Enolate 1, furthest along the reaction coordinate to ketene, had to be handled at temperatures below -50°C and decomposed rapidly at temperatures higher than -30°C. The two other enolates, 2 and 3, were found to survive in crystalline form at 0°C and at room temperature, respectively. The decomposition occurs most likely through a ketene-like intermediate, whose transient existence was demonstrated by cleaving the lithium enolate of 2,6-di-/ert-butyl-4-methylphenyl-2-methylpropanoate at room temperature in the presence of excess -BuLi. 

In the seminal paper of 1972, Ireland first described the low temperature enolization of ester 97 with lithium isopropylcyclohexylamide followed by trapping with trimethylsilylchloride to efficiently generate silyl ketene acetal 99. Unlike the behavior of the initial lithium ester enolate, 99 did not participate in side reactions upon warming to ambient temperature, and smoothly rearranged to 100 which yielded 101 upon treatment with mild acid. 

Alternate Name ethyl 2-(methyldiphenylsilyl)propionate. Physical Data clear to pale yellow liquid 1.5407. Preparative Method whereas the direct silylation of the lithium enolate of an ester normally results in the formation of a mixture of the a-silyl ester and the corresponding silyl ketene acetal, the reaction of lithium ester enolates with methyldiphenylchlorosi-lane gives exclusively the a-methyldiphenylsilyl ester. This direct C-sUylation is the best general route to a-sUyl esters. Purification can be purified by silica gel chromatography, eluting with ethyl acetate/hexane (2 98 v/v), or by short path distUlation. 

The enolates of other carbonyl compounds can be used in mixed aldol reactions. Extensive use has been made of the enolates of esters, thiol esters, amides, and imides, including several that serve as chiral auxiliaries. The methods for formation of these enolates are similar to those for ketones. Lithium, boron, titanium, and tin derivatives have all been widely used. The silyl ethers of ester enolates, which are called silyl ketene acetals, show reactivity that is analogous to silyl enol ethers and are covalent equivalents of ester enolates. The silyl thioketene acetal derivatives of thiol esters are also useful. The reactions of these enolate equivalents are discussed in Section 2.1.4. 

Similar effects were observed in the structures of the lithium salts of ester enolates [43] studied by Seebach et al. (1985). Here too systematic differences in angles are observed compared with amide and ketone enolates, and there is a correlation between the bond angles and the difference in the two C-O bond lengths at the reaction centre for three compounds [43], consistent with incipient elimination of t-butoxide to give the ketene [44] (Ferretti et al., 1991). 

After examining the feasibility of an asymmetric [2 + 2] ketene-imine cycloaddition route and an asymmetric ester enolate-imine cyclocondensation route, we chose the latter route for the efficient asymmetric synthesis of (3/ ,4Sj-3-hydroxy-4-phenylazetidin-2-one and (2R,35)-/V-benzoyl-3-phenylisoserine. The cyclocondensation of the lithium enolate of (-)-(1 / ,2S)-2-phenyl-1 -cyclohexyltriiso-propylsiloxyacetate (5a P = (i-Pr)3Si (TIPS) and R = (-)-(lR,2S)-2-phenyl-1 -cyclohexyl) with A-trimethylsilylbenzaldimine (6a R1 = Ph) in THF at -78 °C gives (3/ ,4S)-3-triisopropylsiloxy-4-phenylazetidin-2-one (7a P = TIPS and R1 = Ph)... 

The reaction of thiol esters with lithium ynolates (equation 67) takes place by a route different than the one shown in equation 65 for alcohol esters. Thiol esters (162) undergo a two-carbon homologation to S-keto thiol esters 165 in good yield. Intermediates 163 undergo a two-step rearrangement to a S-keto thiol ester enolate (165), via elimination of lithium thiolate to yield a ketene (164), followed by the nucleophilic attack of the thiolate on 164. Finally, the homologated S-keto thioester (165 ) is obtained on acidification of the reaction mixture . ... 

In 1972, a further brilliant improvement on the Claisen rearrangement was realized by Ireland and co-woikers. Ester enolization wiA lithium dialkylamide bases, followed by silylation with TMS-Cl, generated reactive silyl ketene acetals at -78 °C or lower temperatures. Sigmatropic rearrangement to easily hydrolyzable 7,8-unsaturated silyl esters occurred at ambient tempontures (15 16 17 equa-... 

Icetene VII from doing so Besides the molecular diffusion that would reduce the local concentration of methoxy, no other nucleophile, least of all the bulky lithium base, would be available to compete for this ketene. Furthermore, the incorporation of methoxy would result in a new ester enolate XI whose addition to formaldehyde would yield II (see Scheme 36.3). 

A successful trapping reaction of a cyclopropyl ester enolate with trimethylsilyl chloride (TMSC) was first performed by Ainsworth and coworkers . In the reaction of 232 with lithium diisopropyl amide at — 78°C, followed by addition of TMSC, the ketene acetal 233 was formed in 10% yield as well as the silylated cyclopropane 234 (40%). Ketene acetals other than 233 are formed in yields > 90 %. 

In contrast, the formation of an ester enolate with LDA in a mixture of THF and DMPU provides the Z-ester enolate which is then converted to the corresponding Z-silyl ketene acetal 12. The reason for this is the high degree of solvation of the lithium cation by DMPU which prevents the formation of a closed six-membered transition state. Therefore, it is assumed that the deprotonation can proceed via the open transition states C and D. Owing to the steric interaction between the methyl group and the ester group in 15, transition state D is disfavored resulting in the formation of the Z-ester enolate. 

Seebach has also studied the utility of esters in organometallic acylation. In this case, preformed ester enolates of 2,6-di(t-butyl)-4-methylphenyl esters (BHT esters) were slowly warmed above -20 C to form the corresponding ketene. If this was done in the presence of an ad tional equivalent of alkyl-lithium the ketene was trapped to give a ketone enolate in high yield. The same reaction failed to give any product when simple esters such as methyl, ethyl or Nbutyl were uscd. Scheme 17 is illustrative of the method. 

Azodicarboxylate esters are the reagents of choice for electrophilic N-amino amination leading to hydrazine derivatives. Besides Grignard reagents and alkyl or aryl lithium compounds,enolates and silyl enol ethersderived from ketones have been aminated by this method. In particular, di-r-butyl azodicarboxylate has been reacted with a variety of chiral enolates (Scheme I9)i03->o and chiral silyl ketene acetds (Schemes 20 and to afford a-hydrazino acid derivatives with high dia-... 

The first example of catalytic enantioselective protonation of metal enolates was achieved by Fehr and coworkers (Scheme 3) [44]. They found the enantioselective addition of a lithium thiolate to ketene 41 in the presence of an equimolar amount of (-)-iV-isopropylephedrine (23) with up to 97% ee. Based on the results, they attempted the catalytic version for example, slow addition of p-chlo-rothiophenol to a mixture of ketene 41 (1 equiv) and lithium alkoxide of (-)-N-isopropylephedrine 23-Li (0.05 equiv) gave thiol ester 43 with 90% ee. First, the thiol is deprotonated by 23-Li to generate lithium p-chlorothiophenoxide and 23. The thiophenoxide adds to the ketene 41 leading to Z-thiol ester enolate which is presumed to react with the chiral amino alcohol 23 via a four-membered cyclic transition state 42 to form the product 43 and 23-Li. The hthium alkoxide 23-Li is reused in the catalytic cycle. The key to success in the catalytic process is that the rate of introduction of thiophenol to a mixture of the ketene 41 and 23-Li is kept low, avoiding the reaction of the thiol with the intermediate hthium enolate. 

The standard Ireland conditions for the ester enolate rearrangement (lithium diisopropylamine, tetrahydrofuran) give a retro-Michael addition product in this ease. However, silyl ketene acetal 15 is successfully obtained by the silyl triflate/triethylamine protocol539 for the preparation of ketene acetals which proceeds via a silyladon and then deprotonation mechanism560-563. 

Lithium diisopropylamide. 13, 163-164 15, 188-189 16, 196-197 17, 165-167 Ester enolates. Procedures for the preparation of ( )- and (Z)-ketene silyl acetals are well developed. Enolates have been generated from conjugate esters by way of Michael addition, and when a remote halide is present, they are quenched by cyclization. Chiral Michael donors such as carbanions of the SAMP/RAMP hydra-zones initiate formation of trani-2-(2 -oxoalkyl)cycloalkanecarboxylic esters with excellent diastereomer excess and enantiomer excess. 

Nucleophiles relevant for this chapter are hydride ion, O-atom- and N-atom-centered nucleophiles and C-nucleo-philes like organometallic compounds, ketene acetals, and ester enolates as well as electron-rich heterocycles. Reductions of 1,2,3-triazines and 2-methyl-l,2,3-triazin-2-ium salts by sodium borohydride in methanol and lithium alanate in ether to yield 2,5-dihydro-l,2,3-triazines have been reviewed in CHEC(1984) and CHEG-II(1996). The reaction is explained by nucleophilic attack of the hydride ion at C-5. Borohydride reductions of 1,2,3-triazine... 

In 1972, Ireland and Mueller reported the transformation that has come to be known as the Ireland-Claisen rearrangement (Scheme 4.2) [1]. Use of a lithium dialkylamide base allowed for efficient low temperature enolization of the allyUc ester. They found that sUylation of the ester enolate suppressed side reactions such as decomposition via the ketene pathway and Claisen-type condensations. Although this first reported Ireland-Claisen rearrangement was presumably dia-stereoselective vide infra, Section 4.6.1), the stereochemistry of the alkyl groups was not an issue in its application to the synthesis of dihydrojasmone. 

Ester enolates formed from carbohydrate esters, e.g. 2, display peculiar properties. Thus, the ester enolate 3 of the 3-0-propionyl-diisopylidene-glucofuranose 2 slowly decomposes even at -70 C to give the ketene 4 and the alcoholate 5. This effect obviously arises from the intramolecular complexation of the lithium ion in the carbohydrate ester enolate which renders the carbohydrate a good leaving group. 

Silyl Ketene Acetals. The lithium enolates of esters may be trapped with TBDMSCl to prepare the corresponding ketene silyl acetals. The resulting TBDMS ketene acetals are more stable than the corresponding TMS ketene acetals and have a greater preference for O- vs. C-silylation products. When TMSCl was used to trap the enolate of methyl acetate, a 65 35 ratio of O- to C-silated products was obtained. In addition, O-(TMS) sUyl ketene acetals are thermally and hydrolytically unstable. However, similar treatment of lithium enolates with TBDMSCl provided the corresponding O-(TBDMS) silyl ketene acetals exclusively (eq 3). The 0-TBDMS ketene acetals generally survive extraction from cold aqueous acid, lithium diisopropylamide was found to be satisfactory for the preparation of the ester enolates. The lower reactivity of TBDMSCl requires that the enol silation be performed at 0 °C with added HMPA. ... 

Very potent carbon nucleophiles formally equivalent to ester enolates are generated by the interaction of TASF(Me) with unhindered trialkylsilyl ketene acetals. In contrast to lithium enolates, these TAS enolates add 1,4 (nonstereoselectively) to a,fi-unsaturated ketones. These adducts can be alkylated in situ to form two new C-C bonds in one pot, or they can be hydrolyzed to give 1,5-dicarbonyl compounds (eq 5). ... 

Among alkali metal enolates, those derived from ketones are the most robust one they are stable in etheric solutions at 0 C. The formation of aldehyde enolates by deprotonation is difficult because of the very fast occurring aldol addition. Whereas LDA has been reported to be definitely unsuitable for the generation preformed aldehyde enolates [15], potassium amide in Hquid ammonia, potassium hydride in THE, and super active lithium hydride seem to be appropriate bases forthe metallation of aldehydes [16]. In general, preformed alkali metal enolates of aldehydes did not find wide application in stereoselective synthesis. Ester enolates are very frequently used, although they are more capricious than ketone enolates. They have to be formed fast and quantitatively, because otherwise a Claisen condensation readily occurs between enolate and ester. A complication with ester enolates originates from their inherent tendency to form ketene under elimination... 

As an alternative to lithium enolates. silyl enolates or ketene acetals may be used in a complementary route to pentanedioates. The reaction requires Lewis acid catalysis, for example aluminum trifluoromethanesulfonate (modest diastereoselectivity with unsaturated esters)72 74 antimony(V) chloride/tin(II) trifluoromethanesulfonate (predominant formation of anti-adducts with the more reactive a,/5-unsaturated thioesters)75 montmorillonite clay (modest to good yields but poor diastereoselectivity with unsaturated esters)76 or high pressure77. 

The ester 7-1 gives alternative stereoisomers when subjected to Claisen rearrangement as the lithium enolate or as the silyl ketene acetal. Analyze the respective transition structures and develop a rationale to explain these results. 

Silyl enol ethers have also been used as a trap for electrophilic radicals derived from a-haloesters [36] or perfluoroalkyl iodides [32]. They afford the a-alkylated ketones after acidic treatment of the intermediate silyl enol ethers (Scheme 19, Eq. 19a). Similarly, silyl ketene acetals are converted into o -pcriluoroalkyl esters upon treatment with per fluoro alkyl iodides [32, 47]. The Et3B/02-mediated diastereoselective trifluoromethylation [48,49] (Eq. 19b) and (ethoxycarbonyl)difluoromethylation [50,51] of lithium eno-lates derived from N-acyloxazolidinones have also been achieved. More recently, Mikami [52] succeeded in the trifluoromethylation of ketone enolates... 

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