Deprotonation kinetically controlled

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... 

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. 

Kinetically controlled deprotonation of a,p-unsaturated ketones usually occurs preferentially at the a -carbon adjacent to the carbonyl group. The polar effect of the carbonyl group is probably responsible for the faster deprotonation at this position. 

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. 

Aldol Reactions of Lithium Enolates. Entries 1 to 4 in Scheme 2.1 represent cases in which the nucleophilic component is a lithium enolate formed by kinetically controlled deprotonation, as discussed in Section 1.1. Lithium enolates are usually highly reactive toward aldehydes and addition occurs rapidly when the aldehyde is added, even at low temperature. The low temperature ensures kinetic control and enhances selectivity. When the addition step is complete, the reaction is stopped by neutralization and the product is isolated. 

The comparatively unreactive complex Mn(CO)3(C5H5BMe) (14) with MeCOCl/AlCl3 produces the 2-acetyl derivative 84 and small amounts of [Mn(CO)3(PhMe)]+ (27). The product ratio is rather insensitive to reaction conditions. It is reasonable to assume a common intermediate 85 (of unspecified stereochemistry at C-6) which under kinetic control may either irreversibly deprotonate to 84 or undergo a rearrangement ultimately leading to the ring-member substitution product (27). 

Providing the deprotonation reaction is kinetically controlled, meaning the intermediates 6 and epi-6 do not interconvert (path A), the enantiomeric ratio Hepi-1 (e.r.) of the trapping products reflects the ratio ks/kg. This is exactly true, if the deprotonation is irreversible and if the reactions of both epimers are complete and stereospecific and proceed with identical yields. (—)-Sparteine 11 proved to be a powerful ligand for the... 

A conscientious investigation of the stereochemical features was undertaken, including Li and NMR studies of the lithium intermediates . The epimeric ratio is kinetically controlled in the deprotonation step by a high preference for the 1-pro-R-H in 398a, and the stereocentre is configurationally stable at —78°C. The ratio of l-endo-399 and its epimer (Li behind the plane) was found to be 96 4. The interconversion of the E/Z-isomers l-endo-399 and l-exo-399 at — 78°C is slower than the rate of alkylation with... 

The nitrile 153 similarly can be formed below - 105°C by a kinetically controlled deprotonation with LDA, but on warming above -100°C it readily rearranges to the thermodynamically more stable vinyllithium derivative 154 [77AG(E)853]. In contrast the morpholino derivative 155 is... 

By adjusting the conditions under which an enolate mixture is formed from a ketone, it is possible to establish either kinetic or thermodynamic control. Ideal conditions for kinetic control of enolate formation are those in which deprotonation is rapid, quantitative,... 

Kinetic control can be achieved by slow addition of the ketone to an excess of strong base in an aprotic solvent. Kinetic control requires a rapid, quantitative and irreversible deprotonation reaction 2-6. The use of a very strong, sterically hindered base, such as lithium diisopropylamide or triphenylmethyllithium (trityllithium), at low temperature (— 78 °C) in an aprotic solvent in the absence of excess ketone has become a general tool for kinetic control in selective enolate formation. It is important to note that the nature of the counterion is sometimes important for the regioselectivity. Thus, lithium is usually better than sodium and potassium for the selective generation of enolates by kinetic control. 

In the case of 3-pentanone, evidence has been presented27-28 for thermodynamic control during formation of the (Z)-enolates and for kinetic control during formation of the ( )-eno-lates in the presence or absence of HMPA. Ester enolates are preferentially ( ), when prepared with LDA (THF), and (Z) when prepared with LDA in the presence of HMPA. In contrast, dialkylamides are deprotonated (LDA/THF) preferentially to give the (Z)-enolates. The role of HMPA in the above case is still not quite clear6-29. 

A new method of kinetically controlled generation of the more substituted enolate from an unsymmetrical ketone involves precomplexation of the ketone with aluminium tris(2,6-diphenylphenoxide) (ATPH) at —78°C in toluene, followed by deprotonation with diisopropylamide (LDA) highly regioselective alkylations can then be performed.22 ATPH has also been used, through complexation, as a carbonyl protector of y./)-unsaturated carbonyl substrates during regioselective Michael addition of lithium enolates (including dianions of /i-di carbonyl compounds).23... 

At low temperature (-78 °C) deprotonation with the bulky silyl amide KHMDS runs under kinetic control - enolization takes place regio-and stereoselectively at the terminal methyl group of ketone 4. The sterically less hindered enolate is transformed to enol triflate 22, which has all-trans configuration. 

The regioseledivity of the last reaction in Scheme 5.13 is not only because of the greater acidity of the methylene group, but also because some secondary and tertiary amides (e.g. /3-arylamides, /3-vinylamides, or /3-(phenylthio)amides, or borane complexes of /3-phosphino propionamides [132, 133]) are deprotonated at the /3 position under kinetic control to yield chelate-stabilized carbanions [58, 134], Illustrative examples of such remarkable metalations are shown in Scheme 5.14. 

For other polysubstituted arenes or heteroarenes, deprotonation at different sites can compete and yield product mixtures. The first reaction in Scheme 5.46 is an example of kinetically controlled carbanion formation, which shows that for some substrates regioselective metalations might be achieved by careful control of the reaction conditions. 

The kinetically controlled deprotonation of allylic carbamate esters (29) by n-BuLi-(—)-sparteine has preferentially removed the pro-S proton, leading to the lithium intermediate (S)-(30) (Scheme 14).85 Trapping experiments with chlorotrimethylsilane has afforded the a-substitution products, with R-configuration. 

The relative power of DMG (Table 1), established by experiments at low temperature and short reaction times and thus crudely representative of kinetic control conditions, may vary with inter- and intramolecular competition, conditions, and sometimes results are conflicting. Nevertheless, for synthetic practice this hierarchy follows a qualitative order consistent with CIPE and serves as a useful predictive chart. For thermodynamic control conditions, the pchart of Fraser of 12 DMG [27], determined by equilibrium deprotonation using LiTMP (pka=37.8), is a guide for lithium dialkylamide DoM reactions. 

For example, 2-phenylcyclohexanone can be deprotonated regioselectively with LDA (Figure 13.11). This reaction is most successful at -78 °C in THF because the reaction is irreversible under these conditions as long as a small excess of LDA is employed. Hence, the reaction is kinetically controlled and proceeds via the most stable transition state. The standard transition state of all enolate formations from C,H acids with LDA is thought to be cyclic, six-membered, and preferentially in the chair conformation (A and B in Figure 13.11). To be as... 

Significantly higher stereoselectivities were observed in the Lewis acid-promoted 1,4-additions. Kinetically controlled deprotonation/silylation of esters 33 followed by treatment of the resulting crude ketene silyl acetals 35 with TiCl4/Ti(Oi-Pr)4 (2 1) and DTBAD (1.25 equiv.) at -78 °C, gave the adducts 34 in good yields and excellent diastereoselectivities (Scheme 15 Table 3.2). 

The reason for the increased regioselectivity is that with tertiary alcohols as substrates there is no longer exclusively kinetic control. This is because the regioisomeric olefins are no longer formed irreversibly. Instead they can be reprotonated, deprotonated again, and thereby finally equilibrated. In this way, the greatest part of the initially formed Hofmann product is converted to the more stable Saytzeff isomer. Product formation is thus... 

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