Enolate formation from

Our experience to this point has been that C—H bonds are not very acidic Com pared with most hydrocarbons however aldehydes and ketones have relatively acidic protons on their a carbon atoms pA s for enolate formation from simple aldehydes and ketones are m the 16 to 20 range... 

Further studies by Bode and co-workers have shown that enolate formation from a-chloroaldehydes and subsequent reaction with 4-oxo-enoates or unsaturated a-ketoesters 232 generates dihydropyranones 233 in excellent diastereo- and enantio-selectivities, and with impressively low catalyst loadings [90], This work has been extended to the generation of enolate equivalents from bisulfite adducts of a-haloaldehydes 234 under aqueous conditions (Scheme 12.50) [91]. 

NHC-promoted enolate formation from an enal, followed by a desymmetrising aldol event to generate P-lactones and loss of CO, has been exploited by Scheidt and co-workers to generate functionalised cyclopentenes 240 in high ee from enal substrates 238 (Scheme 12.52) [94]. Interestingly, the use of alkyl ketones in this reaction manifold allows the isolation of the p-lactone intermediates with acyclic diketones, P-lactones 239 are formed with the R group anti- to the tertiary alkox-ide, while with cyclic diketones the P-lactone products have the R group with a syn relationship to the alkoxide [95]. 

The high selectivity of the catalyst in forming ( )-alkenes can be used in interesting ways (eq. 1). For example, in acetone-iie solution, within 15 min at room temperature allyl alcohol is converted to nearly pure enol (E)-26. Under these mild conditions, the product slowly isomerizes to the more stable aldehyde tautomer. We know of one other report of rapid enol formation from allyl alcohol, using a Rh... 

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

Because of their usefulness in aldol additions and other synthetic methods (see especially Section 6.5.2), there has been a good deal of interest in the factors that control the stereoselectivity of enolate formation from esters. For simple esters such as ethyl propanoate, the /r-enolate is preferred under kinetic conditions using a strong base such as LDA in THF solution. Inclusion of a strong cation solvating co-solvent, such as HMPA or tetrahydro-1,3 -dimethyl-2(1 Z/)p y r i m i d o nc (DMPU) favors the Z-enolate.13... 

The effect of the steric and electronic nature of lithium amide bases (71-74) on highly stereoselective kinetic enolate formation from six ketones (70a-f) in THF has been investigated. The results in general can be rationalized with respect to the cyclic... 

A zinc-bis(BINOL) complex has been employed to effect chemoselective enolate formation from an a-hydroxy ketone (in the presence of an isomerizable imine) to give a Mannich-type product in high ee 1... 

A Et2Zn-(5, S)-linked-BINOL (21) complex has been found suitable for chemos-elective enolate formation from a hydroxy ketone in the presence of isomerizable aliphatic iV-diphenylphosphinoylimines.103 The reaction proceeded smoothly and /9- alkyl-yS-amino-a-hydroxy ketones were obtained in good yield and high enantioselectivity (up to 99% ee). A titanium complex derived from 3-(3,5-diphenylphenyl)-BINOL (22) has exhibited an enhanced catalytic activity in the asymmetric alkylation of aldehydes, allowing the reduction of the catalyst amount to less than 1 mol% without deterioration in enantioselectivity.104... 

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... 

Silyl ketene acetals from esters.1 Ireland has examined various factors in the enolization and silylation of ethyl propionate (1) as a model system. As expected from previous work (6, 276-277), use of LDA (1 equiv.) in THF at —78 -+ 25° results mainly in (E)-2, formed from the (Z)-enolate. The stereoselectivity is markedly affected by the solvent. Addition of TMEDA results in a 60 40 ratio of (Z)- and (E)-2 and lowers the yield significantly. Use of THF/23% HMPA provides (Z)- and (E)-2 in the ratio of 85 15 with no decrease in yield. This system has been widely used for (E)-selective lithium enolate formation from esters and ketones. Highest stereoselectivity is observed by addition of DMPU, recently introduced as a noncar-... 

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... 

In 1993, Enholm described the Sml2-mediated aldol reactions of ot-benzoyl lactones derived from carbohydrates with ketones.153 For example, treatment of lactone 136 with Sml2 in the presence of (+ )-dihydrocarvone 137 gave aldol adduct 138 in good yield and in high diastereoisomeric excess (Scheme 5.97). In this example, HMPA is used as an additive to increase the reduction potential of Sml2 and thus to facilitate Sm(III) enolate formation from the ot-benzoyl lactone.153... 

TABLE 1. Conditions for the kinetic or thermodynamic control of enolate formation from 2-methylcyclohexanone ... 

In both cases we must consider the danger of enolate formation from the ketone. In the first case the alcohol might displace the bromide or attack the ketone and in the second the allylic bromide might be attacked at the alkene though this makes no difference as the allylic system is symmetrical. The first approach is easier as the bromoketone is easily made from acetone (Chapter 21) and the allylic halide in the second approach would probably be made from the alcohol used in the firs synthesis. 

With saUcylaldehyde, the second example, the OH group will exist as an oxyanion under reaction conditions. Alkylation with the chloroketone allows enolate formation from the proci leading to an intramolecular aldol reaction. 

The deprotonation of an unsymmetrically substituted ketones having both a and a -hydrogens furnishes two regioisomeric enolates. Much effort has been devoted to uncover methods to control the regiochemistry of enolate formation from such ketones. 

Aldol reactions Enolate formation from ketones and subsequent aldol reaction give yyn-aldols stereoselectively. 

The same type of reaction was also found for a y-diketone (eq 11) but, in this case, the product is a six-membered ring system (17) and the reaction proceeds at a much slower rate. It is interesting to note that this y-ketone also appears to react via enol formation from the terminal CH3 group rather than from the internal CH2 moiety. 

A more conventional analysis, using the aldol disconnection 22a, leads to a strategy similar to that used for 12 and we must decide which half of the 1,4-keto-aldehyde 27 should have the natural, and which the unnatural polarity. The two methyl groups help as they do not hinder chemoselective enol formation from Me2CH.CHO, but would make the a2 reagent sterically less reactive towards an SN2 reaction. 

Enamines are the nitrogen analogues of enols but their formation from imines is thermodynamically more favourable than enol formation from ketones (Table 1). The equilibrium constant for enol formation is ca. 10 compared with a value of 10 for enamine formation. However, at pH 7 half of the imine exists as the iminium ion and the proportion of enamine present is 10 -fold greater than the proportion of enolate anion. In general, this implies that loss of an electrophile from... 

The last two ketones have two different a-positions so there is a good chance of controlling enol formation from the parent ketone. But the first ketone has two primary a-positions and the difference appears only in the two p-positions. The obvious solution is conjugate addition and trapping (described in the textbook on p. 603). The thermodynamic enol is needed from the second ketone and direct silylation is a good bet. The third requires kinetic enolate formation and LD A is a good way to do that. 

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