Ketones kinetic deprotonation

For cyclic ketones conformational factors also come into play in determining enolate composition. 2-Substituted cyclohexanones are kinetically deprotonated at the C(6) methylene group, whereas the more-substituted C(2) enolate is slightly favored... 

Hydrazones can also be deprotonated to give lithium salts that are reactive toward alkylation at the (3-carbon. Hydrazones are more stable than alkylimines and therefore have some advantages in synthesis.119 The A N-dimcthyl hydrazones of methyl ketones are kinetically deprotonated at the methyl group. This regioselectivity is independent... 

The requirement that an enolate have at least one bulky substituent restricts the types of compounds that give highly stereoselective aldol additions via the lithium enolate method. Furthermore, only the enolate formed by kinetic deprotonation is directly available. Whereas ketones with one tertiary alkyl substituent give mainly the Z-enolate, less highly substituted ketones usually give mixtures of E- and Z-enolates.7 (Review the data in Scheme 1.1.) Therefore efforts aimed at increasing the stereoselectivity of aldol additions have been directed at two facets of the problem (1) better control of enolate stereochemistry, and (2) enhancement of the degree of stereoselectivity in the addition step, which is discussed in Section 2.1.2.2. 

Enolate anion 68, which was generated by kinetic deprotonation of ketone 67, produced CF3 ketone 70 almost exclusively, while enolate anion 69, generated by thermodynamic deprotonation, gave a 3 4 mixture of 70 and 71 (Eq. 36). 

In general, this effect is sufficient to allow selective kinetic deprotonation of methyl ketones, that is, where the distinction is between Me and alkyl. In this example, unusually, MeLi is used as a base LDA was probably tried but perhaps gave poorer selectivity. The first choice for getting kinetic enolate formation should always be LDA. 

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]. 

Galatsis group [14] reported a study on an NARC sequence involving (i) aldol reactions of enolates derived from the kinetic deprotonation of unsaturated esters, such as 25 and 28, to ketones (Fig. 9) and aldehydes (Fig. 10) followed by (ii) endo-cyclisation via intramolecular iodoetherification. As the enolates used in the study were racemic and the aldol reactions stereorandom, it would be interesting to repeat this work using a chiral auxiliary (e.g. a chiral amide). This should ensure high levels of enantio- and diastereo-selectivity. 

Regioselective enolate formation using kinetic deprotonation of an unsymmetri-cal ketone has been discussed in Section 1.1.1. The specihc enolate can react with aldehydes to give the aldol product, initially formed as the metal chelate in aprotic solvents such as THF or EtiO. Thus, 2-pentanone, on deprotonation with lithium diisopropylamide (LDA) and reaction of the enolate with butanal, gave the aldol product 44 in reasonable yield (1.56). 

In general, this effect is sufficient to allow selective kinetic deprotonation of methyl ketones, that is, where the distinction is between Me and alkyl ... 

A large part of carbonyl chemistry is concerned with enolization. Kinetic deprotonation of ketones suggests the following preference CH3CO >CH2CO >CHCO. On considering the carbanions as acid-base complexes it becomes clear that the primary complex is better stabilized than the secondary one, which is, in turn, more stable than the tertiary complex. 

Kinetic deprotonation of a,/S-unsaturated ketones usually occurs preferentially adjacent to the carbonyl group. The electron-withdrawing inductive effect of the carbonyl group is probably responsible for the faster rate of deprotonation at this position. 

The requirement that an enolate have at least one bulky substituent restricts the types of compounds which can be expected to give highly stereoselective aldol condensations. Furthermore, only the enolate formed by kinetic deprotonation is directly available. Ketones with one tertiary alkyl substituent give mainly the Z-enolate. 

Kinetically controlled deprotonation also leads to the lower substituted alkali enolates of acyclic ketones, as illustrated by selected examples in Scheme 2.5 2-heptanone [27], 3-methyl-2-butanone [26a], and 2-methyl-3-pentanone [23]. Under the conditions of kinetic deprotonation with LDA, a-alkoxy-substituted ketones behave similar to their alkyl-substituted counterparts giving predominantly the less substituted enolate, as illustrated for 2-methoxycyclohexanone [28] in Scheme 2.5. a-Dialkylamino ketones also follow this tendency. In M-carbamato-substituted ketones, however, regioselectivity is reversed, and enolization predominantly occurs toward the nitrogen atom - a result that might be caused by the electron-withdrawing nature of the urethane moiety this effect becomes even more dominant when the enolate is formed under thermodynamic control (LiHMDS, equilibrating conditions) [29]. 

Applying this protocol, enantioselective aldol reactions became feasible under reasonable conditions with fair chemical yields of P-hydroxy ketones 286 in up to 93% ee (Scheme 5.81) [142a]. For the unbranched aliphatic ketone butanone, the control of regiochemistry in favor of the formation of the less substituted enolate - without preceding kinetic deprotonation step - is remarkable. When applied to a-hydroxyacetophenone, nfi-configured aldol adducts 287 formed as the major diastereomers, the enantiomeric excess amounting to 90-95%. 

Control of Regioselectivity and Stereoselectivity. The recognition by Ireland and co-workers that Hexamethylphosphoric Triamide has a profound effect on the stereochemistry of lithium enolates has led to the examination of the effects of other additives, as the ability to control enolate stereochemistry is of utmost importance for the stereochemical outcome of aldol reactions. Kinetic deprotonation of 3-pentanone with Lithium 2,2,6,6-Tetramethylpiperidide at 0 C in THF containing varying amounts of HMPA or TMEDA was found to give predominantly the (Z)-enolate at a base ketone additive ratio of ca. 1 1 1, whereas with a base.ketone.additive ratio 1 0.25 1, formation of the ( )-enolate was favored (Table I). This remarkable result contrasts with those cases where HMPA base ratios were varied towards larger amounts of HMPA, which favored formation of the (Z)-enolate. ... 

Structural effects on the rates of deprotonation of ketones have also been studied using veiy strong bases under conditions where complete conversion to the enolate occurs. In solvents such as THF or DME, bases such as lithium di-/-propylamide (LDA) and potassium hexamethyldisilylamide (KHMDS) give solutions of the enolates in relative proportions that reflect the relative rates of removal of the different protons in the carbonyl compound (kinetic control). The least hindered proton is removed most rapidly under these... 

A number of studies of the acid-catalyzed mechanism of enolization have been done. The case of cyclohexanone is illustrative. The reaction is catalyzed by various carboxylic acids and substituted ammonium ions. The effectiveness of these proton donors as catalysts correlates with their pK values. When plotted according to the Bronsted catalysis law (Section 4.8), the value of the slope a is 0.74. When deuterium or tritium is introduced in the a position, there is a marked decrease in the rate of acid-catalyzed enolization h/ d 5. This kinetic isotope effect indicates that the C—H bond cleavage is part of the rate-determining step. The generally accepted mechanism for acid-catalyzed enolization pictures the rate-determining step as deprotonation of the protonated ketone ... 

A further improvement utilizes the compatibility of hindered lithium dialkylamides with TMSC1 at —78 °C. Deprotonation of ketones and esters with lithium dialkylamides in the presence of TMSC1 leads to enhanced selectivity (3) for the kinetically generated enolate. Lithium t-octyl-t-butyl-amide (4) appears to be superior to LDA for the regioselective generation of enolates and in the stereoselective formation of (E) enolates. 

Scheme 1.1 shows data for the regioselectivity of enolate formation for several ketones under various reaction conditions. A consistent relationship is found in these and related data. Conditions of kinetic control usually favor formation of the less-substituted enolate, especially for methyl ketones. The main reason for this result is that removal of a less hindered hydrogen is faster, for steric reasons, than removal of a more hindered hydrogen. Steric factors in ketone deprotonation are accentuated by using bulky bases. The most widely used bases are LDA, LiHMDS, and NaHMDS. Still more hindered disilylamides such as hexaethyldisilylamide9 and bis-(dimethylphenylsilyl)amide10 may be useful for specific cases. 

Write the structures of all possible enolates for each ketone. Indicate which you expect to be favored in a kinetically controlled deprotonation. Indicate which you would expect to be the most stable enolate. 

It has been suggested that the kinetic preference for formation of (3,y-unsaturated ketones results from an intramolecular deprotonation, as shown in the mechanism above.51 The carbonyl-ene and alkene acylation reactions have several similarities. Both reactions occur most effectively in intramolecular circumstances and provide a useful method for ring closure. Although both reactions appear to occur through highly polarized TSs, there is a strong tendency toward specificity in the proton abstraction step. This specificity and other similarities in the reaction are consistent with a cyclic formulation of the mechanism. 

Kinetic enolates. Alkyllithium reagents have the advantage over lithium amides for deprotonation of ketones in that the co-product is a neutral alkane rather than an amine. This bulky lithium reagent is useful for selective abstraction of the less-hindered a-proton of ketones with generation of the less-stable enolate, as shown previously for a hindered lithium dialkylamide (LOBA,12,285). Thus reaction of benzyl methyl ketone (2) with 1 and ClSifCH,), at - 50° results mainly in the less-stable enolate (3), even though the benzylic protons are much more acidic than those of the methyl group, the less hindered ones. Mesityllithium shows... 

Although there is a kinetic barrier to the direct deprotonation of tertiary amines, Ahlbrecht and Dollinger showed in 1984 that the Schlosser superbase, i c-BuLi/f-BuOK, can deprotonate A-methylpiperidine selectively on the methyl group (Scheme 3). This superbase probably yields an a-amino-organopotassium species (and f-BuOLi), but treatment with LiBr effects transmetalation to the more nucleophilic, and less basic, a-amino-organolithium species. Electrophilic quench with several aldehydes and ketones gives substitution products in good yields as typified by the example in Scheme 3. Similarly,... 

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