Ester lithium enolates deprotonation

The most useful method is reaction of ketone (and ester) lithium enolates, usually prepared by deprotonation of ketones with LD A, with either Ce H5 SeBr or Ce Hj SeCl. Enol acetates can be converted into a-phenylseleno ketones by reaction with phenylselenenyl trifluoroacetate, prepared in situ by treatment of CeHsSeCl or CgHsSeBr with silver trifluoroacetate or by conversion to the lithium e late and reaction with CeHsSeBr. It is sometimes possible to obtain isomeric a-phenylseleno ketones by use of these two methods (equations I and II). 

All aldehydes, ketones, and carboxylic esters can be deprotonated quantitatively to enolates with lithium amides. The same substrates and alkoxides give only small amounts of enolate in equilibrium reactions, but even these small amounts of enolate may be large enough to allow for enolate reactions. 

The best base for making lithium enolates is usually LDA, made from diisopropylamine (i-P NH) and BuLi. LDA will deprotonate virtually all ketones and esters that have an acidic proton to form the corresponding lithium enolates rapidly, completely, and irreversibly even at the low temperatures (about -78°C) required for some of these reactive species to survive. 

Another successful tactic is to make the group R as large as possible to discourage attack at the carbonyl group. Tertiary butyl esters are particularly useful in this regard, because they are readily made, f-butyl is extremely bulky, and yet they can can still be hydrolysed in aqueous acid under mild conditions by the method discussed on pp. 652-3. In this example, deprotonation of f-butyl acetate with LICA (lithium isopropylcyclohexylamide) gives a lithium enolate that reacts with butyl iodide as the reaction mixture is warmed to room temperature. 

An alternative to the direct a-deprotonation of a ketone is the conversion of its enol ether (in particular, TMS enol ethers) or ester (in particular, acetates) into the corresponding lithium enolate. The advantage of this detour is that the enol ethers and esters can either be prepared as a single isomer or the mixture of isomers can be separated by distillation or chromatography108, while their conversion into enolates takes place in a regio-and stereospecific manner. 

The original system considered by this group involved the lithium enolate and a chiral diether. The results suggest that the presence of an excess of the achiral lithium amide used to deprotonate the ester improves the induction level (Scheme 134)618. Remarkably, employing substoichiometric amounts (20 mol%) of the chiral ligand led to a marginal decrease in the e.e. value. The authors proposed that the formation of an intermediate ternary complex between the enolate, the excess lithium amide and the chiral diether could be responsible for the observed enantiomeric excesses. 

First the hydroxy group is protected as the TBS ether. In the second step lithium diisopropylamine (EDA) is used to deprotonate the a-carbon and the resulting lithium enolate is trapped as trifluoro-methanesulfonic acid ester. In the last reaction, palladium catalysis is used to introduce the carbon monoxide. In the presence of methanol this intermediate directly yields the methyl ester. 

Nozaki and coworkers reported that diethylaluminum 2,2,6,6-tetramethylpiperidine (DATMP) is capable of producing diethylaluminum enolates by deprotonation of ketones or esters at -23°C in THF (Scheme 6.23) [43]. Unlike the instabih-ty of the corresponding lithium enolate, the aldol reaction of the aluminum enolate of t-butyl acetate prevails over the alkoxy ehmination that produces the ketene species, even at -23 °C. 

Cyclic cobalt-acyl complexes can be deprotonated, and subsequent reaction of these enolates with aldehydes gives predominantly the anti/threo product (Scheme 63). Rhenium-acyl complexes can be deprotonated in the same manner. These lithium enolates can be alkylated or can react with [M(CO)5(OTf)] (M = Re, Mn) to give the corresponding enolates (Scheme Many transition metal enolates of type (21) or (22) are known, - but only a few have shown normal enolate behavior , e.g. aldol reaction, reaction with alkyl halides, etc. Particularly useful examples have been developed by Molander. In a process analogous to the Reformatsky reaction, an a-bromo ester may be reduced with Smia to provide excellent yields of condensation products (Scheme 65) which are generated through intermediacy of a samarium(III) enolate. ... 

One of these important bases, diisopropylaminomagnesium bromide, was first introduced by Frostick and Hauser in 1949 as a catalyst for the Claisen condensation. However, the most generally useful base has turned out to be lithium diisopropylamide (LDA), which was first used by Hamell and Levine for the same purpose in 1950 (equation 3). After the introduction of LDA, it was more than 10 years before it was used by Wittig for the stoichiometric deprotonation of aldimines in what has come to be known as the Wittig directed aldol condensation.In a seminal paper in 1970, Rathke reported that the lithium enolate of ethyl acetate is formed by reaction of the ester with lithium hexamethyldisilazane in THF. - Rathke found that THF solutions of the lithium enolate are stable indefinitely at -78 °C, and that the enolate reacts smoothly with aldehydes and ketones to give p-hydroxy esters (equation 4). 

Zinc ester enolates may also be obtained by the addition of ZnX2 to lithium or sodium enolates as first described by Hauser and Puterbaugh (equation 6)P This approach has so far received little attention but similar reactions have been used to obtain zinc ketone enolates. In this regard, it should be noted that Heathcock and coworkers have shown that deprotonation reactions of ketones with zinc dialkylamide bases reach equilibrium at only about 50% conversion (equation 7). This result implies that attempts to prepare zinc enolates from solutions of amide-generated lithium enolates will be successful only when the lithium enolate is made amine-free. 

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