Bases for enolate formation

Stoichiometric, irreversible formation of enolates from ketones or aldehydes is usually performed by addition of the carbonyl compound to a cold solution of LDA. Additives and the solvent can strongly influence the rate of enolate formation [23]. The use of organolithium compounds as bases for enolate formation is usually not a good idea, because these reagents will add to ketones quickly, even at low temperatures. Slightly less electrophilic carbonyl compounds, for example some methyl esters [75], can, however, be deprotonated by BuLi if the reactants are mixed at low temperatures (typically -78 °C), at which more metalation than addition is usually observed. A powerful lithiating reagent, which can sometimes be used to deproto-nate ketones at low temperatures, is tBuLi [76],... 

Sterically Hindered Base for Enolate Formation. Like other metal dialkylamide bases, sodium bis(trimethylsilyl)amide is sufficiently basic to deprotonate carbonyl-activated carbon acids and is sterically hindered, allowing good initial kinetic vs. thermodynamic deprotonation ratios. The presence of the sodium counterion also allows for subsequent equilibration to the thermodynamically more stable enolate. More recently, this base has been used in the stereoselective generation of enolates for subsequent alkylation or oxidation in asymmetric syntheses. As shown in eq 1, NaHMDS was used to selectively generate a (Z)-enolate alkylation with lodomethane proceeded with excellent diastereoselectivity. In this case, use of the sodium enolate was preferred as it was more reactive than the corresponding lithium enolate at lower temperatures. 

The stereochemistry of the silyl ketene acetal can be controlled by the conditions of preparation. The base that is usually used for enolate formation is lithium diisopropyl-amide (LDA). If the enolate is prepared in pure THF, the F-enolate is generated and this stereochemistry is maintained in the silyl derivative. The preferential formation of the F-enolate can be explained in terms of a cyclic TS in which the proton is abstracted from the stereoelectronically preferred orientation perpendicular to the carbonyl plane. The carboxy substituent is oriented away from the alkyl groups on the amide base. 

The [1,4]-Wittig rearrangement is potentially useful not only for the carbon-carbon bond formation but also for enolate formation. However, synthetic applications have been rather limited, because of the low yields and restricted range of substrates. Schlosser s group have developed a practical approach to aldehydes based on a [1,4]-rearrangement/ enolate trapping sequence. In contrast, standard aqueous workup gave poor yield of aldehyde. This protocol was employed as the key step in a synthesis of pheromone (102) from 99 via 100 and 101 (equation 56f. ... 

Catalysis of the enolization of indan-2-one (96 pKa = 12.2) by a-, j8-, y-, and modified cyclodextrins (of similar pKa) indicate that the latter act as general bases.139 There is also an inclusion component to the catalysis saturation kinetics consistent with 1 1 binding are observed for enolate formation. 

On alkylation of 2-(aminomethyl)oxazolines (42) and (43), stereochemical induction is evident for the tertiary carbamates (43), but not the tertiary amines (42) this is apparently a consequence of prior complexation of the carbamate carbonyl group to the base and kinetic preference for ( )-enolate formation on deprotonation 47 4-Alkenylamides (44) having a /1-cliiral centre have been found to undergo syn-selective a-iodination with iodine to give syn-a-iodoalkcnamidcs, via an intermediate... 

Compounds with one carbonyl group next to the stereogenic centre can be made but care still needs to be taken. The a amino acids, the component parts of proteins, are like this. They are perfectly stable and do not racemize in aqueous acid or base. In base they exist as carboxylate anions that do not enolize, as explained above. Enolization in acid is prevented by the NHlj group, which inhibits the second protonation necessary for enol formation. 

Najera and coworkers introduced a new class of cyclic alanine templates (227, equation 59), the structure of which was anchored on Schollkopf s bislactim ether . Palladium-catalyzed allylations of the chiral pyrazinone derivative 227 with allylic carbonates (228) as substrates led to the formation of y,i5-unsaturated amino acids (229a-c) under very mild and neutral reaction conditions, whereas the required base for enolate preparation has been generated in situ from the allylic carbonate during jr-allyl complex formation. With this protocol in hand, the alkylated pyrazinones 229 were obtained with excellent regio- and diastereoselectivities (>98% ds). Finally, hydrolysis with 6 N aqueous HCl under relatively drastic conditions (150 °C) led to the free amino acids. 

It is a useful base for effecting formation of potassium enolates. It was used for methylation of isobutyrophenone to give pivalophenone in 767 yield. ... 

Conjugate addition reactions, including the Robinson annulation, which make use of reactive Michael acceptors such as methyl vinyl ketone, can suffer from low yields of the desired adduct. The basic conditions required for enolate formation can cause polymerization of the vinyl ketone. Further difficulties arise from the fact that the Michael adduct 42 and the original cyclohexanone have similar acidities and reactivities, such that competitive reaction of the product with the vinyl ketone can ensue. These problems can be minimized by the use of acidic conditions. Sulfuric acid is known to promote the conjugate addition and intramolecular aldol reaction of 2-methylcyclohexanone and methyl vinyl ketone in 55% yield. Alternatively, a silyl enol ether can be prepared from the ketone and treated with methyl vinyl ketone in the presence of a Lewis acid such as a lanthanide triflate" or boron tri fluoride etherate (BF3 OEt2) and a proton source to effect the conjugate addition (followed by base-promoted aldol closure). 

In a study on the electrophilic azide transfer to chiral enolates, Evans found that the use of potassium bis(trimethylsilyl)amide was crucial for this process. The KN(TMS)2 played a dual role in the reaction as a base, it was used for the stereoselective generation of the (Z)-enolate (1). Reaction of this enolate with trisyl azide gave an intermediate triazene species (2) (eq 4). The potassium counterion from the KN(TMS)2 used for enolate formation was important for the decomposition of the triazene to the desired azide. Use of other hindered bases such as Lithium Hexamethyldisilazide allowed preparation of the intermediate triazene however, the lithium ion did not catalyze the decomposition of the triazene to the azide.This methodology has been utilized in the synthesis of cyclic tripeptides. 

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). 

Another feature of target 58 will complicate any chemical reaction chosen in a disconnection. If the disconnection requires an acyl addition reaction of a Grignard reagent (Chapter 18, Section 18.4) or formation of an enolate anion (Chapter 22, Sections 22.2, 22.4), there is a problem. Both Grignard reagents and enolate anions will react with an alcohol in an acid-base reaction that will interfere with the desired carbon-carbon bond-forming reaction (see Chapter 22, Section 22.2). Further, there are two sites for reaction. An aldehyde will undergo acyl addition or reaction with an enolate anion, but so will the ketone unit. Both the a-carbon of the aldehyde and the a-carbon of the ketone are candidates for enolate formation, which further complicates any reaction. 

The beginning point for almost all of the reactions in this chapter, from which almost everything else is derived, is enolate formation in base or enol formation in acid. 

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