Regioselectivity ketone enolate formation

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. 

Ketone imine anions can also be alkylated. The prediction of the regioselectivity of lithioenamine formation is somewhat more complex than for the case of kinetic ketone enolate formation. One of the complicating factors is that there are two imine stereoisomers, each of which can give rise to two regioisomeric imine anions. The isomers in which the nitrogen substituent R is syn to the double bond are the more stable.114... 

Another important contribution is to the regioselectivity of enolate formation from unsym-metrical ketones. As we established in chapter 13, ketones, particularly methyl ketones, form lithium enolates on the less substituted side. These compounds are excellent at aldol reactions even with enolisable aldehydes.15 An application of both thermodynamic and kinetic control is in the synthesis of the-gingerols, the flavouring principles of ginger, by Whiting.16... 

The regioselectivity of enolate formation is governed by the usual factors so that methyl benzyl ketone forms the more stable enolate with sodium metal. This undergoes smooth and rapid conjugate addition to acrylonitrile, which is unsubstituted at the P position and so very reactive. 

With the ketone, there is a question of regioselectivity in enolate formation, but the aldol product can lose water only if the enolate from the methyl group is the nucleophile. If we draw both enolates and combine them with the ketone in an aldol reaction, it is clear that one can dehydrate as it has two enolizable H atoms but the other cannot dehydrate as it has no H atoms on the vital carbon atom (in grey). The mechanism is the same as the one with the aldehyde and the elimination in both cases is by the ElcB mechanism. 

When starting with an unsymmetrical ketone such as 2-butanone, deprotonation at either alpha carbon will result in two possible enolates. Varying the reaction conditions can control the regioselectivity of enolate formation. When LDA is used at a low temperature, the irreversible deprotonation is controlled by kinetics, and the least sterically hindered proton is removed to form the so-called kinetic enolate. 

The composition of the silyl enol ether mixture is then determined by NMR spectroscopy or by gas chromatography. Table 1.2 shows data for the regioselectivity of enolate formation for several ketones under various reaction conditions. 

The enantiomeric /1-hydroxy ketones are available in an analogous way using the corresponding enantiomeric borinates. The reaction is plagued by low regioselectivity in the formation of the boron enolates, except when R1 is phenyl or isobutyl53,57. 

Regioselectivity and Stereoselectivity in Enolate Formation from Ketones and Esters... 

The regio- and stereoselectivity of enolate formation are essential for the control of alkylation reactions. The regioselectivity of ketone deprotonation has been extensively investigated and this important step in alkylation reactions has been discussed in many reviews (e.g., refs 1-4, 71) and textbooks (e.g., refs 5, 6). Therefore, this topic will be discussed here only in general terms. 

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. 

Fig. 13.24. O-Phosphoryla-tion of a ketone enolate to afford an enol phosphonamide (see Figure 13.13, bottom row, regarding the regioselectivity of the enolate formation) ...

In constrast, kinetic regioselectivity does not usually correspond to the thermodynamic stability ratio between the two enolates. Indeed, when the ketone is ionised in protic solvents which make equilibration possible, the more substituted enolate is formed (e.g. [45] and [46] are in the ratios 10 90 and 40 60 for the lithium and sodium ion pairs, respectively, in dimethyl ether) (House, 1972). This means that the hyperconjugative effect, which is predominant in the enolate, is less important than inductive and steric effects in the transition state, a result which is in agreement with the carbanion character. The regioselectivity of preparative enolate formation in organic solvents has been reviewed by D Angelo (1976). 

II. C-C BOND FORMATION BYa-SUBSTITUTION OF KETONE ENOLATES A. Control of Stereo- and Regioselectivity in Enolate Preparation... 

The regio- and stereoselectivity of enolate formation has been discussed in many reviews . In general, the stereo- and regioselectivity of ketone deprotonation can be thermodynamically or kinetically controlled. Conditions for the kinetic control of enolate formation are achieved by slow addition of the ketone to an excess of strong base in an aprotic solvent at low temperature. In this case the deprotonation occurs directly, irreversibly and with high regioselectivity (equation 1). By using a proton donor (solvent or excess of ketone) or a weaker base, an equilibration between the enolates formed may... 

One of the most useful methods for the transformation of ketones into alkenes is conversion of the ketone, via enolate formation, into a vinyl-OR derivative and subsequent reductive cleavage of the sp oxygen bond. Because there are a number of ways to generate either the kinetic or thermodynamic enolate selectively, this route offers one of the most important ways of introducing the alkenic double bond with excellent control of regioselectivity. 

Matsuda, I., Okada, H., Sato, S., Izumi, Y. A regioselective enolate formation of trimethylsilylmethyl ketones. Application to the (E)-selective synthesis of a,P-unsaturated ketones. Tetrahedron Lett. 1984, 25, 3879-3882. 

The original Mannich reaction is the acid-catalyzed aminomethylation of enohz-able ketones with non-enolizable aldehydes and ammonia, primary amines, or secondary amines, which involves nucleophilic addition of ketone enols to iminium salts generated in situ from the aldehydes and the nitrogen compounds [183]. This three-component coupling reaction provides a powerful tool for carbon-carbon bond formation and introduction of nitrogen functionality. The classical Mannich reaction has some drawbacks in reaction efficiency, regioselectivity, and appli-... 

If the electrophile is a vinyl triflate, it is essential to add LiCl to the reaction so that the chloride may displace triflate from the palladium o-complex. Transmetallation takes place with chloride on palladium but not with triflate. This famous example illustrates the similar regioselectivity of enol triflate formation from ketones to that of silyl enol ether formation discussed in chapter 3. Kinetic conditions give the less 198 and thermodynamic conditions the more highly substituted 195 triflate. 

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