Aldol condensation ketone reaction with enolates

Recently, Trost et al. reported the vanadium-catalyzed addition reaction of 2,3-allenols [180], Here the oxygen in 401 served as an intramolecular nucleophile to attack the center carbon atom of allene to form a vanadium enolate 402. Aldol condensation of 402 with an aldehyde afforded (2-hydroxy)alkyl vinylic ketones 403. 

Carbonyl activation and deactivation.1 Aldehydes, but not ketones, undergo aldol condensation with silyl enol ethers at —78° in the presence of dibutyltin bistriflate. In contrast, the dimethyl acetals of ketones, but not of aldehydes, can undergo this condensation (Mukaiyama reaction) with silyl enol ethers at -78° with almost complete discrimination, which is not observed with the usual Lewis-acid catalysts. Thus dibutyltin bistriflate activates aldehydes, but deactivates acetals of... 

Stereoselective aldol condensation. Heathcock and Buse have previously employed 2-methyl-2-trimethylsiloxy-3-pentanone (1) in a highly stereoselective route to 3-hydroxy-2-methylcarboxylic acids (8, 295). Aldol condensation of the lithium enolate derived from 1 with a chiral aldehyde yields ery//iro-aldols, which are cleaved with periodic acid to -hydroxy carboxylic acids. However, when 1 is condensed with a chiral aldehyde such as 2, two eryt/iro-products (3 and 4) are produced. Heathcock and co-workers now report that the 1,2-diastereoselectivity of these aldol condensations can be enhanced by use of the ketone 5. Reaction of racemic 5 with racemic aldehyde 2 furnishes a single (racemic) adduct 6. 

Cp 2La CH(SiMe3)2 reacts with 3-pentanone to form the solvated enolate, Cp 2La —O—C(Et)=CHMe Et2CO (equation 9a), while with acetone it forms a chelate (equation 9b) after intramolecular aldol condensation. The reaction of the precursor bistrimethylsi-lyhnethyl organometallic with hydroxyketone, preformed from the pentanone, yields the enolate ketone solvate. This difference between acetone and 3-pentanone presumably reflects the difference in strain in the condensation product because the ethyl groups in 3-pentanone are rather much bigger than the methyl groups in acetone. 

The synthesis of methyl ketone 281 began with the reaction between the tetra-substituted allylborane 279 and 2,3-0-isopropylidene-D-glyceraldehyde 48. The resulting homoallylic alcohol 280, obtained in 73% yield and excellent selectivity (exact ratio not defined) [231], was converted in two steps to the methyl ketone 281. Aldol condensation between the lithium enolate of 281 and aldehyde 278 (structure shown in Scheme 11-12) gave, after protection of the initial adduct, the Felkin diastereomer 282 as the only reported product in 54% yield. This adduct... 

When an aldehyde or ketone and its enolate are both present in solution they can react with each other in what is called an aldol condensation. Such reactions are an important part of this chapter. The aldol condensation will be discussed in Sections 20.3 and 20.4. 

The enols and enolates are capable of undergoing many reactions at the a position, among them exchange, racemization, halogenation, alkylation, addition to ketones or aldehydes, and addition to esters. The aldol condensation involves reaction of the enolate, a strong nucleophile, with the electrophilic carbonyl compound, or of the less strongly nucleophilic enol with the powerful electrophile, the protonated carbonyl. 

Aldol Condensation with Enol Silyl Ethers. The first example of an aldol condensation between an unactivated enolate and an electrophilically activated carbonyl substrate was accomplished using enol silyl ethers and acetals or orthoesters in conjunction with a catalytic amount of Trimethykilyl Trifluoromethanesul-fonate. The reaction proceeds very readily at —78 C and affords the eo /W-aldol product with high stereoselectivity. The use of 2,2-dimethoxypropane in this reaction affords p-methoxy ketones (eq 10). 

In practice this reaction is difficult to carry out with simple aldehydes and ketones because aldol condensation competes with alkylation Furthermore it is not always possi ble to limit the reaction to the introduction of a single alkyl group The most successful alkylation procedures use p diketones as starting materials Because they are relatively acidic p diketones can be converted quantitatively to their enolate ions by weak bases and do not self condense Ideally the alkyl halide should be a methyl or primary alkyl halide... 

In contrast, fluorinated ketones have been used as both nucleophilic and electrophilic reaction constituents The (Z)-lithium enolate of 1 fluoro 3,3-di-methylbutanone can be selectively prepared and undergoes highly diastereoselec-tive aldol condensations with aldehydes [7] (equation 8) (Table 4)... 

The mixed Claisen condensation of two different esters is similar to the mixed aldol condensation of two different aldehydes or ketones (Section 23.5). Mixed Claisen reactions are successful only when one of the two ester components has no a hydrogens and thus can t form an enolate ion. For example, ethyl benzoate and ethyl formate can t form enolate ions and thus can t serve as donors. They can, however, act as the electrophilic acceptor components in reactions with other ester anions to give mixed /3-keto ester products. 

The first step of the Robinson annulation is simply a Michael reaction. An enamine or an enolate ion from a jS-keto ester or /3-diketone effects a conjugate addition to an a-,/3-unsaturated ketone, yielding a 1,5-diketone. But as we saw in Section 23.6,1,5-diketones undergo intramolecular aldol condensation to yield cyclohexenones when treated with base. Thus, the final product contains a six-membered ring, and an annulation has been accomplished. An example occurs during the commercial synthesis of the steroid hormone estrone (figure 23.9). 

The coupling of a secondary alcohol 1 with a primary alcohol 2 is achieved by the temporary removal of from each substrate which generates the ketone 3 and aldehyde 4 intermediates. A crossed aldol condensation occurs under the reaction conditions by the enolate derived from ketone 3 undergoing nucleophilic addition... 

In the general context of donor/acceptor formulation, the carbonyl derivatives (especially ketones) are utilized as electron acceptors in a wide variety of reactions such as additions with Grignard reagents, alkyl metals, enolates (aldol condensation), hydroxide (Cannizzaro reaction), alkoxides (Meerwein-Pondorff-Verley reduction), thiolates, phenolates, etc. reduction to alcohols with lithium aluminum hydride, sodium borohydride, trialkyltin hydrides, etc. and cyloadditions with electron-rich olefins (Paterno-Buchi reaction), acetylenes, and dienes.46... 

Three tactical approaches were surveyed in the evolution of our program. As outlined in Scheme 2.7, initially the aldol reaction (Path A) was performed direcdy between aldehyde 63 and the dianion derived from tricarbonyl 58. In this way, it was indeed possible to generate the Z-lithium enolate of 58 as shown in Scheme 2.7 which underwent successful aldol condensation. However, the resultant C7 P-hydroxyl functionality tended to cyclize to the C3 carbonyl group, thereby affording a rather unmanageable mixture of hydroxy ketone 59a and lactol 59b products. Lac-tol formation could be reversed following treatment of the crude aldol product under the conditions shown (Scheme 2.7) however, under these conditions an inseparable 4 1 mixture of diastereomeric products, 60 (a or b) 61 (a or b) [30], was obtained. This avenue was further impeded when it became apparent that neither the acetate nor TES groups were compatible with the remainder of the synthesis. 

The most direct route to the 1,4-dicarbonyl equivalent required for the aldol condensation would be to couple the enol ether of an aldehyde with the enol ether of a ketone. However, this sequence proved impractical due to the hydrolytic instability of the ketone enol ether. Even after an extensive effort, the substrate for the electrolysis reaction could not be reproducibly prepared in high yield. These problems were readily avoided with the use of an allylsilane based... 

Aldol addition and condensation reactions involving two different carbonyl compounds are called mixed aldol reactions. For these reactions to be useful as a method for synthesis, there must be some basis for controlling which carbonyl component serves as the electrophile and which acts as the enolate precursor. One of the most general mixed aldol condensations involves the use of aromatic aldehydes with alkyl ketones or aldehydes. Aromatic aldehydes are incapable of enolization and cannot function as the nucleophilic component. Furthermore, dehydration is especially favorable because the resulting enone is conjugated with the aromatic ring. 

Deprotonation of the A -acyl substituent of benzothiazines gives a nucleophile that reacts by deacylation with a second molecule of starting material (Equation 46) < 1980TL3001 >. Such anions also react with ketones in an erythro-selective aldol condensation (Equation 47) <1983TL3883>. The selectivity is due to the formation of a Z-enolate and the reaction was also extended to A -acylphenothiazines. 

One of the most important reactions of aldehydes and ketones is the Aldol condensation. In this reaction, an enolate anion is formed from the reaction between an aldehyde or a ketone and an aqueous base, e.g. NaOH. The enolate anion reacts with another molecule of aldehyde or ketone to give (3-hydroxyaldehyde or (3-hydroxyketone, respectively (see Section 5.3.2). 

Aldol reaction. The reagent (I) adds in a 1,4-fashion to an a,/J-unsaturated ketone lo give an aluminum enolate, which undergoes aldol condensation with an aldehyde. The adduct is converted into an a-substituted-a./l-unsaturated ketone on sulfoxide elimination.1... 

Stereoselective aldol-type condensation.1 Enol silyl ethers do not undergo aldol condensation with aldehydes or ketones in the presence of this triflate,. but the reaction occurs at —78° (4-12 hours) with the corresponding acetals or ketals (and certain orthoesters). Moreover the erythro-aldol is formed with high stereoselectivity. 

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