Enolates formation from ketones

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

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

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... 

Base Catalyzed Reactions. TMEDA can be monoprotonated (pATa 8.97) anddiprotonated (pATa 5.85). Titanium enolate formation from ketones and acid derivatives has been achieved by using Titanium(IV) Chloride and tertiary amines including TMEDA in dichloromethane at 0 °C. The reactive species, whieh is likely to be a complex with the tertiary amine, undergoes aldol reaction with aldehydes to form syn adducts with high stereoselectivity (eq 13). 

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... 

Thus the product in such cases can exist as two pairs of enantiomers. In a di-astereoselective process, one of the two pairs is formed exclusively or predominantly as a racemic mixture. Many such examples have been reported. In many of these cases, both the enolate and substrate can exist as (Z) or (E) isomers. With enolates derived from ketones or carboxylic esters, (E) enolates gave the syn pair of enantiomers (p. 146), while (Z) enolates gave the anti pair. Addition of chiral additives to the reaction, such as proline derivatives, or (—)-sparteine lead to product formation with good-to-excellent asynunetric induction. Ultrasound has also been used to promote asymmetric Michael reactions. Intramolecular versions of Michael addition are well known. ... 

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]. 

A similar preference for formation of the syn aldol is found for other Z-enolates derived from ketones in which one of the carbonyl substituents is bulky. Ketone enolates with less bulky substituents show a decreasing stereoselectivity in the order r-butyl > i-propyl > ethyl.2c This trend parallels a decreasing preference for stereoselective formation of the Z-enolate. 

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-... 

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... 

High diastereoselecivities are normally observed in the alkylation of five-membered ring enolates (eqnations 7 and 8), implying that the alkylation is mainly controlled by steric factors. Thus, with 3-substituted cyclopentanones formation of only the frawi-product (23 and 25, respectively) is preferred. Representative examples are the alkylations of lithium enolates derived from ketones 22 and 24 . Before the electrophiles were added, the enolate solutions were stirred at higher temperature for a longer time to secure the... 

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. 

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. 

Enolate anions from ketones, and carbanions from other compoimds containing activated hydrogen such as dimethyl sulphoxide and fluorene, can also donate one electron to suitable acceptors (e.g., nitrobenzene and phenylglyoxal) (Russell and Janzen, 1962 Russell et al., 1962 Russell et al., 1966a). One example is the generation of the p-nitrotoluene radical-anion fromp-nitrotoluene in base the formation... 

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. 

Regioselective olefin formation from ketones has been exploited. Conversion of ketones to the corresponding enol diphenylphosphates and subsequent coupling of... 

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. 

The enolates of other carbonyl compounds can be used in mixed aldol condensations. Extensive use has been made of the enolates of esters, thioesters, and amides. Of particular importance are several modified amides, such as those derived from oxazolidinones, that can be used as chiral auxiliaries. The methods for formation of these enolates are similar to those for ketones. Lithium, boron, tin, and titanium derivatives have all been used. Because of their usefulness in aldol additions and other synthetic methods (see especially Section 6.4.2.3, Part B), 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 E-enolate is preferred under kinetic conditions using a strong base such as EDA in THE solution. Inclusion of a... 

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. 

Formation of Silyl Enol Ethers. TMS-I in combination with Triethylamine is a reactive silylating reagent for the formation of silyl enol ethers from ketones (eq 22). TMS-I with Hexam-ethyldisilazane has also been used as an effective silylation agent, affording the thermodynamic silyl enol ethers. For example, 2-methylcyclohexanone gives a 90 10 mixture in favor of the tetra-substituted enol ether product. The reaction of TMS-I with... 

Reaction with Imines. Imines react with TMS-I to form N-silylenamines, in a process analogous to the formation of silyl enol ethers from ketones. ... 

The factors that govern the direction of enolate formation from such unsymmetrical ketones are numerous, but can be organized using the concept of kinetic versus thermodynamic control. 

The acylation of enolates derived from ketones with esters is an important tool for enhancing reactivity and selectivity in synthetic modification of ketones. Some representative examples are given in Scheme 2.7. The most common example of this is the formylation of ketone enolates by formate esters ... 

Ester enolates usually exist as mixtures oiE- andZ-isomers (see Chapter 9, Section 9.4.3). An example is the enolate anion generated from ethyl propano-ate, where the two priority groups (see Chapter 9, Section 9.3.1) of the C=C unit are the methyl group on one sp carbon and the OEt group on the other sp carbon atom. When the priority groups are on opposite sides, as in 64, this is an E-enolate anion. The other enolate anion is 65, the Z-isomer. Methods are available for the reaction that will lead to selectivity in the formation of E- or Z-isomers, but those methods are not discussed. Assume that both 64 and 65 are present in the reaction. Assume also that formation of this mixture has no influence on the subsequent reaction. This is not entirely correct because there may be stereochemical issues in the product, but it simplifies the fundamental concepts. As mentioned in Section 22.4.2, enolate anions from ketones may also exist as E- and Z-isomers. Enolate anion 39 in that section is drawn as the Z-isomer, but both are formed. 

However, when 2-methylcyclohexanone is treated under the same conditions, two regioisomeric cyclohexanone enolates are expected (Equation 9.66). The issue of regioselectivity is extant in enol formation from any unsymmetricaUy substituted ketone and must be addressed in order to control the site of the alkylation in the next step. 

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