Regioselectivity of enol 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. 

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. 

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. 

Another interesting way of controlling the regioselectivity of enolate formation is the internal delivery of the base. This is shown in Scheme 3.64 [104]. 

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. 

Full exploitation of the synthetic potential of enolates requires control over the regioselectivity of their formation. Although it may not be possible to direct deprotonation so as to form one enolate to the exclusion of the other, experimental conditions can often be chosen to favor one of the regioisomers. The composition of an enolate mixture can be governed by kinetic or thermodynamic factors. The enolate ratio is governed... 

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... 

There are also procedures in which the enolate is generated quantitatively and allowed to react with a halogenating agent. Regioselectivity can then be controlled by the direction of enolate formation. Among the sources of halogen that have been used under these conditions are bromine,125 (V-chlorosuccinimide,126 trifluoromethanesul-fonyl chloride,127 and hexachloroethane.128... 

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. 

All the procedures outlined in this section present no dilemma in regioselection, since they may take advantage of the well-documented regiocontrol of enolate formation. 

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... 

A good example of enolate control comes in Stork s synthesis of abietic acid.32 The first two reactions each involve regioselectivity of enolates in the formation of 115 and 117. 

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. 

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. 

It is noteworthy that these results constitute a complete reversal of the regioselectivity in enolate formation and the 99° angle of the Cj - H bond with the carbonyl group is a clearly convincing explanation of the high acidity. 

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, and irreversible. This- ideal is approached experimentally by using a very strong base such as lithium diisopropylamide or triphenylmethyllithium in an aprotic solvent in the absence of excess ketone. Lithium as the counterion is better than sodium or potassium for regioselective generation of the kinetic enolate. Protic solvents promote enolate equilibration by allowing protonation-deprotonation pathways to operate on the isomeric enolates. Excess ketone seems to catalyze equilibration in much the same way by acting as a proton source. 

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