Deprotonation silyl enol ethers

Addition of alkyllithium to cyclobutanones and transmetallation with VO(OEt)Cl2 is considered to give a similar alkoxide intermediates, which are converted to either the y-chloroketones 239 or the olefinic ketone 240 depending on the substituent of cyclobutanones. Deprotonation of the cationic species, formed by further oxidation of the radical intermediate, leads to 240. The oxovanadium compound also induces tandem nucleophilic addition of silyl enol ethers and oxidative ring-opening transformation to produce 6-chloro-l,3-diketones and 2-tetrahydrofurylidene ketones. (Scheme 95)... 

The use of /i-ketocstcrs and malonic ester enolates has largely been supplanted by the development of the newer procedures based on selective enolate formation that permit direct alkylation of ketone and ester enolates and avoid the hydrolysis and decarboxylation of ketoesters intermediates. Most enolate alkylations are carried out by deprotonating the ketone under conditions that are appropriate for kinetic or thermodynamic control. Enolates can also be prepared from silyl enol ethers and by reduction of enones (see Section 1.3). Alkylation also can be carried out using silyl enol ethers by reaction with fluoride ion.31 Tetraalkylammonium fluoride salts in anhydrous solvents are normally the... 

Bromide 280 (derived by bromination of silyl enol ether 270) undergoes both zinc- and cerium-mediated cleavage under mild and essentially neutral conditions, and was used to prepare the nucleoside-containing C-glycoside 282 (Scheme 73) [ 112,113], The aldehyde 281 used in this transformation was exceptionally sensitive to basic conditions which completely precluded use of a conventional enolate obtained by deprotonation of ketone 265 (Sect. 4.3.1). 

The feasibility of a deprotonation of cyclohexanone derivatives bearing a chiral heterocyclic substituent in the 4-position with the C2-symmetric base lithium bis[(/f)-l-phenylethyl]amide with internal quenching of the lithium enolate formed with chlorotrimethylsilane is shown in entries 32 and 33 of Table 229,25a. The silyl enol ethers are obtained in a diastereomeric ratio of 79.5 20.5. By using lithium bis[(1S)-l-phenylethyl]amide the two diastereomers are formed in a ratio of 20 80 indicating that the influence of the chirality of the substituent is negligible. 

Enantioselective deprotonation can also be successfully extended to 4,4-disubstituted cyclohexanones. 4-Methyl-4-phenylcyclohexanone (3) gives, upon reaction with various chiral lithium amides in THF under internal quenching with chlorotrimethylsilane, the silyl enol ether 4 having a quaternary stereogenic carbon atom. Not surprisingly, enantioselectivities are lower than in the case of 4-tm-butylcyclohexanone. Oxidation of 4 with palladium acetate furnishes the a./i-unsaturated ketone 5 whose ee value can be determined by HPLC using the chiral column Chiralcel OJ (Diacel Chemical Industries, Ltd.)59c... 

The preparation of silyl enol ethers and enol acetates may afford mixtures of isomers, however, these can be separated prior to cleavage. Usually the preparation of silyl enol ethers or enol acetates proceeds via one of the base-catalyzed deprotonations described previously and conditions can be applied which favor the formation of one isomer (vide supra). Thus, regio- and stereoselectivity can be achieved. An extensive review of the synthetic uses, including the preparation and reactions, of silyl enol ethers is available32. 

The functionalized silyl enol ethers 156 are useful synthetic intermediates since electrophiles can now be introduced either directly in the P-position by known methodology 55) or in the opposition after deprotonation with LDA to an allyl anion (Eq. 70)61>. Both pathways should enormously widen the scope of specifically substituted y-oxoesters and their derivatives obtained via siloxycyclopropanes. 

Accordingly, trimethylsilyl enol ethers are enolate precursors (Figure 10.16). Fortunately, they can be prepared in many ways. For instance, silyl enol ethers are produced in the silylation of ammonium enolates. Such ammonium enolates can be generated at higher temperature by partial deprotonation of ketones with triethylamine (Figure 10.18). The incompleteness of this reaction makes this deprotonation reversible. Therefore, the regioselectivity of such deprotonations is subject to thermodynamic control and assures the preferential formation of the more stable enolate. Consequently, upon... 

Deprotonation of 4-f-butyl cyclohexanone 28 with chiral lithium amide 39 (30 mol%) and bulk base 107 (240 mol%) in the presence of HMPA (240 mol%) and DABCO (150 mol%), under external quench conditions, resulted in 79% ee of the silyl enol ether 29 (Scheme 79)121. This stereoselectivity is only slightly lower than that of the stoichiometric reaction (81% ee). 

The kinetic reprotonation by a series of carbonyl-based acids, of the lithium enolate obtained from 2,4-dimethyltetralone either by LDA-mediated deprotonation or by cleavage of its silyl enol ether, was studied by Eames (Scheme 71)352. The diastereoselective ratio, close to the thermodynamic value, obtained with methanol (pKa = 29 in DMSO) is probably due to equilibration. The difference observed in the presence of an additive was interpreted as the result of a fine balance between the coordinating ability, the intrinsic acidity, and probably the concentration of the enolic form of the cyclic and linear dicarbonyl acidic compounds. 

We also observed similar phenomena in the reaction of silyl enol ethers with cation radicals derived from allylic sulfides. For example, oxidation of allyl phenyl sulfide (3) with ammonium hexanitratocerate (CAN) in the presence of silyl enol ether 4 gave a-phenylthio-Y,5-un-saturated ketone 5. In this reaction, silyl enol ether 4 reacts with cation radical of allyl phenyl sulfide CR3 to give sulfonium intermediate C3, and successive deprotonation and [2,3]-Wittig rearrangement affords a-phenylthio-Y,6-unsaturated ketone 5 (Scheme 2). Direct carbon-carbon bond formation is so difficult that nucleophiles attack the heteroatom of the cation radicals. 

Since Scheme 4 implies formation of a-carbonyl radicals after deprotonation of enol radical cations, the same oxidation chemistry should potentially be accessible from various enol derivatives as enolates, silyl enol ethers and enol esters (Scheme 5). On the other hand, enol ether radical cations do not fit in this systematization since they are attacked by nucleophiles at the double bond faster than providing a-carbonyl radical intermediates through O-C bond cleavage (Sect. 4.3). 

Similar to the deprotonation of enol radical cations, silyl enol ether radical cations can undergo loss of trialkylsilyl cations (most likely not as ionic silicenium ions [190]). Based on photoinduced electron transfer (PET), Gass-man devised a strategy for the selective deprotection of trimethylsilyl enol ethers in the presence of trimethylsilyl ethers [191]. Using 1-cyanonapthalene (1-CN) ( = 1.84 V) in acetonitrile/methanol or acetonitrile/water trimethylsilyl enol ether 93 ( j = 1.29 V) readily afforded cyclohexanone 64 in 60%. Mechanistically it was proposed that the silyl enol ether radical cation 93 undergoes O-Si bond cleavage, most likely induced by added methanol [192-194], and that radical 66 abstracts a hydrogen from methanol. Alternatively, back electron transfer from 1-CN - to 66 would yield the enolate of cyclohexanone which should be readily protonated by the solvent. 

The two main problems in the preparation of silyl enol ethers are control of regios-electivity, kinetic and thermodynamic, and stereoselectivity, (E) and (Z). Although many useful procedures are now available for the kinetic deprotonation of ketones by use of alkali metal dialkylamides, there are few practical procedures for thermodynamic deprotonation. Recently, the author and Yamamoto et al. found that the regio- and stereoselective isomerization of a kinetic silyl enol ether to a thermodynamic ether was catalyzed by LBA [138]. 

For a discussion of enantioselective deprotonation to form chiral silyl enol ethers, see Carswell, E.L. Hayes, D. Henderson, K.W. Kerr, W.J. Russell, C.J. Synlett 2003, 1017. 

Alkylation reactions of ester derivatives of l,2 5,6-di-0-isopropylidene-D-gulofiiranose were investigated by Mulzer et al. [154]. The deprotonation of the ester 207 with LDA or LTMP and trapping of the enolate with trimethylchlorosilane furnished the silyl enol ether 208 with a very high ( )-selectivity (95 5), whereas the enol ether obtained by deprotonation with LHMDS was formed without any ( )/(Z)-selectivity (Scheme 10.68). 

In the first step of the reaction silyl enol ether 23 is formed. The use of bulky bases like NaHMDS at -78 °C ensures the formation of the so-called kinetic enolate 22, which is obtained by deprotonation of the ketone at the less-hindered a-position. Afterwards, 22 is protected by trimethylsilyl chloride (TMSCl), yielding TMS-enol ether 23. TMS ethers are often unstable under acidic and basic conditions and barely survive the simplest chemical transformation. TMS-enol ethers of this type are often used in Mukaiyama aldol reactions with catalytic amounts of Lewis acids. 

Chiral lithium amide bases have been used successfully in the asymmetric deprotonation of prochiral ketones [55, 56]. WUliard prepared polymer-supported chiral amines from amino acid derivatives and Merrifield resin [57]. The treatment of cis-2,6-dimethylcyclohexanone with the polymer-supported chiral lithium amide base, followed by the reaction with TMSCl, gave the chiral silyl enol ether. By using polymeric base 96, asymmetric deprotonation occurred smoothly in tetrahydrofuran to give the chiral sUyl enol ether (, S )-102 in 94% with 82% ee (Scheme 3.28). 

With ketones we come to the problem of regioselectivity, and the situation from chapter 3 is that methyl ketones 98 and ketones with one primary and one secondary alkyl group, particularly cyclic ketones such as 103 give the less substituted lithium enolate 97 or 102 by kinetically controlled deprotonation with LDA, and the more substituted silyl enol ether 99 or 104 on silylation under equilibrium conditions. Either derivative (lithium enolate or silyl enol ether) may be used to make the other, e.g. 96 and 100. 

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