Ketones 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... 

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]. 

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

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... 

This reagent readily reduces esters in toluene, hexanes, THF or CH2CI2 solutions, etc. The reaction is especially useful for the preparation of allylic alcohols from a,3-unsaturated esters. 3-Keto esters have been selectively reduced to 3-hydroxy ketones via ketone enolate formation and AIH3 reduction. 

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. 

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. 

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... 

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. 

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. 

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. 

The chemoselective enolate formation from hydroxyketone (245) and isomerizable aliphatic Ai-Dpp imines (246) has been described. The Et2Zn/linked-BINOL complex (247) effectively promoted the Mannich-type reaction, affording P-alkyl-P-amino-a-hydroxy ketones (248) in high enantioselectivity and good yield (Scheme 100). ... 

First, 11 was converted into the ketone 10 through deprotection of the TBS group with TBAF followed by PCC oxidation. At this stage, regioselective methylation of the enolate of 10 was highly desirable, though the selectivity of the enolate formation from 10 might well be toward the less substituted... 

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). 

Another preparative method for the enone 554 is the reaction of the enol acetate 553 with allyl methyl carbonate using a bimetallic catalyst of Pd and Tin methoxide[354,358]. The enone formation is competitive with the allylation reaction (see Section 2.4.1). MeCN as a solvent and a low Pd to ligand ratio favor enone formation. Two regioisomeric steroidal dienones, 558 and 559, are prepared regioselectively from the respective dienol acetates 556 and 557 formed from the steroidal a, /3-unsaturated ketone 555. Enone formation from both silyl enol ethers and enol acetates proceeds via 7r-allylpalladium enolates as common intermediates. 

Hydroperoxides have been obtained from the autoxidation of alkanes, aralkanes, alkenes, ketones, enols, hydrazones, aromatic amines, amides, ethers, acetals, alcohols, and organomineral compounds, eg, Grignard reagents (10,45). In autoxidations involving hydrazones, double-bond migration occurs with the formation of hydroperoxy—azo compounds via free-radical chain processes (10,59) (eq. 20). 

The idea of kinetic versus thermodynamic control can be illustrated by discussing briefly the case of formation of enolate anions from unsymmetrical ketones. This is a very important matter for synthesis and will be discussed more fully in Chapter 1 of Part B. Most ketones, highly symmetric ones being the exception, can give rise to more than one enolate. Many studies have shown tiiat the ratio among the possible enolates that are formed depends on the reaction conditions. This can be illustrated for the case of 3-methyl-2-butanone. If the base chosen is a strong, sterically hindered one and the solvent is aptotic, the major enolate formed is 3. If a protic solvent is used or if a weaker base (one comparable in basicity to the ketone enolate) is used, the dominant enolate is 2. Enolate 3 is the kinetic enolate whereas 2 is the thermodynamically favored enolate. 

Enamines behave in much the same way as enolate ions and enter into many of the same kinds of reactions. In the Stork reaction, for example, an enamine adds to an aqQ-unsaturated carbonyl acceptor in a Michael-like process. The initial product is then hydrolyzed by aqueous acid (Section 19.8) to yield a 1,5-dicarbonyi compound. The overall reaction is thus a three-step sequence of (11 enamine formation from a ketone, (2) Michael addition to an a,j3-unsaturated carbonyl compound, and (3) enamine hydrolysis back to a ketone. 

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