Proton transfer lithium enolates

The favourable effect of lithium bromide on facial enantioselective protonation of methyl tetralone enolate by a-sulfinyl alcohols has been attributed to coordination of lithium to both enolate and sulfinyl alcohol followed by competition between diastere-omeric paths involving intramolecular proton transfer the proposed transition-state model is supported by results of PM3 semiempirical calculations. ... 

If this precaution is not followed, partial or complete equilibration of the enolates will occur because of proton transfers between the enolates and the excess un-ionized ketone. In an experiment where a slight excess of ketone was added, the distilled, monoalkylated product (40% yield) contained 77% of the undesired 2,2-isomer and only 23% of the desired 2,6-isomer. However, it is also important in this preparation not to allow a large excess of lithium diisopropylamide to remain in the reaction mixture this base reacts with benzyl bromide to form iraws-stilbene which is difficult to separate from the reaction product. 

Lithium Enolates. The control of mixed aldol additions between aldehydes and ketones that present several possible sites for enolization is a challenging problem. Such reactions are normally carried out by complete conversion of the carbonyl compound that is to serve as the nucleophile to an enolate, silyl enol ether, or imine anion. The reactive nucleophile is then allowed to react with the second reaction component. As long as the addition step is faster than proton transfer, or other mechanisms of interconversion of the nucleophilic and electrophilic components, the adduct will have the desired... 

Under conditions of kinetic control, the mixed Aldol Addition can be used to prepare adducts that are otherwise difficult to obtain selectively. This process begins with the irreversible generation of the kinetic enolate, e.g. by employing a sterically hindered lithium amide base such as LDA (lithium diisopropylamide). With an unsymmetrically substituted ketone, such a non-nucleophilic, sterically-demanding, strong base will abstract a proton from the least hindered side. Proton transfer is avoided with lithium enolates at low temperatures in ethereal solvents, so that addition of a second carbonyl partner (ketone or aldehyde) will produce the desired aldol... 

The models become more complex when they take the structure of the base into account. A simple and very popular hypothesis was proposed for esters by Ireland and coworkers in pioneering work23. This model supposes that a monomeric LDA is the active species and that the lithium-carbonyl interaction leads to a six-membered cyclic Zimmerman-Traxler chair-like transition state24, at which a more-or-less concerted proton transfer occurs. The resulting preference for the E enolate observed in THF and the Z preference in THF-HMPA mixtures, an issue discussed in more detail below, could even be accounted through steric considerations (Scheme 4). 

After the proton transfer completion, the enolates tend to merge in (1 1) mixed aggregates with the excess lithium amide34. These species have so far been the object of relatively little attention48. Then, as the enolization proceeds to completion, the aggregated enolates form at the expense of the mixed dimers. Another aspect to be considered is the interaction between the lithium enolate and the amine released after protonation of the amide49. This phenomenon will be discussed in the section dedicated to the enantios-elective reactions of enolates. 

A preliminary approach to understand the mechanism of the enantioselective protonation and the role of lithium bromide, based on TSs containing one hthium atom, failed to explain the selectivity enhancement by hthium bromide, and the calculated energies of the TSs did not account for the experimentally observed selectivity. Asensio, Domingo and coworkers studied the molecular process associated with the proton transfer at the semiempirical PM3 level . Based on hterature data , they defined the structure of a mixed dimer enolate 234 consisting of a four-membered ring where the bromide anion and the oxygen atom of the enolate were connected by two hthium cations. These bridging... 

Theoretical Study of the Intramolecular Proton Transfer in Lithium-Enolate Amine Complexes. ... 

Ireland s deprotonation model is widely used to rationalize the stereochemistry with various ethyl ketones and bases. " In the absence of additives that solvate the lithium cation such as HMPA, proton transfer occurs via a chair-hke closed transition state. Under these conditions, the (Z)-enolate is disfavored because of the 1,3-diaxial interaction between the Me and the i-Pr group on nitrogen. As the steric requirement of the R group increases, so does the A strain between the R and Me groups in forming the double bond, thus destabilizing the ( )-(0)- relative to the (Z)-(0)-enolate (Table 6.2). 

DME or THF. Clearly, the ratio of the rate of alkylation to the rate of proton transfer is significantly larger for less basic lithium enolates than for their sodium and potassium counterparts. 

An unusual case of internal proton return in a highly chirotopic environment was reported for the L-alanine derivative ( + )-2. On deprotonation with less than one equivalent of LDA in the presence of lithium bromide, and alkylation with iodomethane, 3 is isolated in which the methyl group has entered the ring from the less hindered side (sec also Section 2.1.4.2.). However, complete epimerization of the side chain occurred during this alkylation reaction. Deprotonation first produces the ester enolate. This enolate is selectively reprotonated from the less hindered side by internal proton transfer which produces the starting material for the alkvla-tiony5a. 

Very often lithium enolates, e.g., those produced with lithium diisopropylamide, yield only low levels of deuterated carbonyl compounds when treated with deuterium oxide or deuterated alcohols (see table below). This is due to the fact that the secondary amine formed becomes involved in the protonation162. Deuterated acids, e.g., diisopropyl (2/ ,3/ )-2,3-dihydroxy-<72-butanedioate behave in a similar way, however, the observed enantioselectivities are somewhat higher. The complex from which a deuteron (or proton) is transferred probably contains lithium enolate, amine and the proton source (see also Section 2.1.6.1.2.). 

Mixed condensations in which the nucleophilic enolate is derived from an ester have also been developed. Very strong bases have usually been used for enolate formation. For example, the lithium enolate of ethyl acetate is generated using lithium bis(trimethylsilyl)amide as the base. Condensation with carbonyl compounds proceeds readily (entry 13, Scheme 2.1) without apparent complications from proton-transfer reactions between the ester enolate and carbonyl compound. The dilithium salts of carboxylic acids can also add to carbonyl compounds (entry 14, Scheme 2.1). 

A study of 2-biphenylylcyclohexanone deprotonation by lithium base in THF has established that the unconjugated lithium enolate (existing predominantly as a tetramer) is formed preferentially before converting to a monomer-dimer mixture of the more stable conjugated enolate this occurs by proton transfer from the tertiary carbon, which can then be alkylated. ... 

The catalytic cycle, as proposed by the authors, is also displayed in Scheme 5.120. The reaction of Uthium enolate 478 with the chiral proton source 476 leads to nonracemic ketone 479 and the lithium salt 480. An irreversible proton transfer then occurs from the achiral proton source ArOH to the lithiated imide. Thus, the chiral proton source 476 is regenerated under release of lithium phenolate, and the catalytic cycle closes. 

Martin J, Plaquevent JC, Maddaluno J, Rouden J, Lasne MC. Efficient deracemization of pipecoUc acid amides through enantioselective protonation of their lithium enolates insights into the origin of the transferred proton. Eur. J. Org. Chem. 2009 5414-5422. 

This technique was used to synthesize some cyclohexane derivatives by substitution with electrophiles specifically in the axial or equatorial position. Whereas alkylation with dimethyl sulfate occurred smoothly, alkylation with haloalkanes failed completely. Rather nonstereoselective protonation of the lithium compound, as well as dehydrogenation to enol ethers, occurred. Operation of single electron transfer processes are believed to account for these results27. 

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