Enolate anions, kinetic addition

Addition of a silylating reagent such as Me3SiCl to the reaction mixture traps the enolate anions and produces two silyl enol ethers in a ratio which reflects the ratio of the enolate anions. Thus if 2-methylcyclohexanone is added to the hindered base LDA at -78 °C and the mixture stirred for 1 hour at -78 °C and quenched with MeySiCl, then the major product is the silyl enol ether derived from the kinetic enolate. In contrast, heating 2-methylcyclohexanone, triethylamine, and Me3SiCl at 130 °C for 90 hours... 

With the 1,4-dimethoxynaphthalene ligand, cyano-stabilized anions (including cyanohydrin acetal anions) and ester enolates equilibrate even at low temperature and strongly favor addition at the a-position (C-5). The kinetic site of addition is also generally C-a. However, the 2-lithio-l,3-dithiane anion and phenyllithium do not equilibrate over the temperature range -78 to 0°C. The sulfur-stabilized anions favor addition at C-/3 (equation 119) 134,190 phenyllithium... 

The a-protons that are less sierically hindered are most rapidly removed by a bulky base. Thus, addition of an unsymmetrical ketone to an excess of lithium diisopropy-lamide (LDA) gives the enolate anion on the less substituted side as the result of kinetic control. 2-Methylcyclohe anone has been specifically benzylated in the (3-position in this manner [4],... 

The intermediate AD is a 1,5-diketone and as such accessible by means of a Michael addition of D (as an enolate anion) to A (in a yield of 52%). It is a characteristic of the photochemical synthesis of 123b that the kinetical-ly favored cw-orientation of the ethyl and vinyl groups on the five-membered ring of the Michael adduct AD ensures the thermodynamically disfavored fran -fusion of rings C and D in the Diels-Alder adduct of type ABCD. The overall yield of 123b, based on D, amounts to 11% ). The achiral building block A is accessible by conventional means [118d]. 

Alkylation of unsymmetrical ketones bearing a-alkyl substituents generally leads to mixtures containing both a-alkylated products. The relative amount of the two products depends on the structure of the ketone and may also be influenced by experimental factors, such as the nature of the cation and the solvent (see Table 1.2). In the presence of the ketone or a protic solvent, equilibration of the two enolate anions can take place. Therefore, if the enolate is prepared by slow addition of the base to the ketone, or if an excess of the ketone remains after the addition of base is complete, the equilibrium mixture of enolate anions is obtained, containing predominantly the more-substituted enolate. Slow addition of the ketone to an excess of a strong base in an aprotic solvent, on the other hand, leads to the kinetic mixture of enolates under these conditions the ketone is converted completely into the anion and equilibration does not occur. 

Enolate anions react as nucleophiles. They give nucleophilic acyl addition reactions with aldehydes and ketones. The condensation reaction of an aldehyde or ketone enolate with another aldehyde or ketone is called an aldol condensation. Selfcondensation of symmetrical aldehydes or ketones leads to a single product under thermodynamic conditions. Condensation between two different carbonyl compounds gives a mixture of products under thermodynamic conditions, but can give a single product under kinetic control conditions. 

Once an ester enolate is generated, it can react with another ester in a Claisen condensation however, it may also react with the carbonyl of an aldehyde or ketone. The ester enolate anion is a nucleophile and it reacts with an aldehyde or ketone via acyl addition. Kinetic control conditions are the most suitable for this reaction in order to minimize Claisen condensation of the ester with itself (self-condensation). If ester 74 (ethyl propanoate, in green in the illustration) is treated first with LDA and then with butanal (21, in violet), for example, the initial acyl addition product is 78. The new carbon-carbon bond is marked in blue and treatment with dilute aqueous acid converts the alkoxide to an alcohol in the final product of this sequence, 79. Compound 79 is a P-hydroxy ester, which is the usual product when an ester enolate reacts with an aldehyde or a ketone. Ester enolate anions react with ketones in the same way that they react with aldehydes. 

The a-proton of an aldehyde or ketone is less acidic as more carbon substituents are added. As more electron-withdrawing groups are added, the a-proton becomes more acidic, so a 1,3-diketone is more acidic than a ketone. The more acidic proton of an unsymmetrical ketone is the one attached to the less substituted carbon atom 8,12,13,14,22,23,28,30, 77,81,86,89,93. Enolate anions react as nucleophiles. They give nucleophilic acyl addition reactions with aldehydes and ketones. The condensation reaction of an aldehyde or ketone enolate with another aldehyde or ketone is called an aldol condensation. Selfcondensation of symmetrical aldehydes or ketones leads to a single product under thermodynamic conditions. Condensation between two different carbonyl compounds gives a mixture of products under thermodynamic conditions, but can give a single product under kinetic control conditions 5, 9, 11, 15, 16, 17, 18,19,20,21,23,29,30,31,32,33,34,40,41,42,43,44,45,46,49,91, 92, 94,102,114,115,123,134. 

A remarkable kinetic resolution was observed recently by Feringa and coworkers when 2-silyloxyfuran was reacted with the racemic unsymmetrical allylic substrate 86, catalyzed by the palladium complex of Trost s ligand (/ ,/ )-14, as illustrated in Scheme 5.28. The acetate anion liberated upon oxidative addition of palladium(O) is assumed to cleave the silyl protecting group, so that the enolate anion forms aside from TMSOAc. After allylic alkylation of that enolate, double bond migration leads to butenolide (R)-87 isolated in 47%, if the reaction was run with 52% conversion. Not only the product 87 but also the recovered acetate... 

These observations showed that the reaction can be simplified by preformation of the indanone enolate in toluene/50% NaOH and subsequent addition of catalyst and CH3CI (Figure 12). This eliminates the "induction period and most importantly the high sensitivity of rate and ee to the catalyst/indanone ratio. Detailed kinetic measurements on this preformed enolate methylation in toluene/50% NaOH determined that the reaction is 0.55 order in catalyst. This is consistent with our finding that the catalyst goes into solution as a dimer which must dissociate prior to com-plexation with the indanone anion. If the rate has a first order dependence on the monomer, the amount of monomer is very small, and the equilibration between dimer and monomer is fast, then the order in catalyst is expected to be 0.5. The 0.5 order in catalyst is not due to the preformation of solid sodium indanone enolate but is a peculiarity of this type of chiral catalyst. Vlhen Aliquat 336 is used as catalyst in this identical system the order in catalyst is 1. Finally, in the absence of a phase transfer catalyst less than 2% methylation was observed in 95 hours. 

The conjugate addition of unstabilized enolates to various acceptors was conceptually recognized by early researchers however, complications were encountered depending on the enolates and acceptors employed. Reexamination of this strategy was made possible by the development of techniques for kinetic enolate formation. This discussion is divided into three enolate classes (a) aldehyde and ketone enolates, azaenolates or equivalents, (b) ester and amide enolates, dithioenolates and dienolates and (c) a,0-carboxylic dianions and a-nitrile anions, in order to emphasize the differential reactivity of various enolates with various acceptors."7 The a-nitrile anions are included because of their equivalence to the hypothetical a-carboxylic acid anion. 

While the addition-oxidation and the addition-protonation procedures are successful with ester enol-ates as well as more reactive carbon nucleophiles, the addition-acylation procedure requires more reactive anions and the addition of a polar aptotic solvent (HMPA has been used) to disfavor reversal of anion addition. Under these conditions, cyano-stabilized anions and ester enolates fail (simple alkylation of the carbanion) but cyanohydrin acetal anions are successful. The addition of the cyanohydrin acetal anion (71) to [(l,4-dimethoxynaphthalene)Cr(CO)3] occurs by kinetic control at C-P in THF-HMPA and leads to the a,p-diacetyl derivative (72) after methyl iodide addition, and hydrolysis of the cyanohydrin acetal (equation 50).84,124-126... 

Directed lithiations of a,3- and -y.b-unsaturated amides " have been extensively studied. Illustrative examples are shown in Scheme 44. Prior complexation of the alkyllithium base with the amide carbonyl oxygen directs the base to the thermodynamically less acidic -position in a,3-unsaturated amide (31), which adds to benzophenone and subsequently lactonizes. Analysis of the NMR spectrum reveals that the organolithium added the benzophenone in the equatorial position. A Afferent kinetic deprotonation is seen in y,8-unsaturated amide (32), where -lithiation to form an allylic anion predominates over a-lithiadon to form an enolate. > Addition of the lithium anion to acetone affords poor regioselectivity, but transmetalation to magnesium before carbonyl addition yields a species which adds exclusively at the 8-position. ... 

Metallation of the arylsulfinyl-N-methoxyacetimidate (49), which may be prepared in two steps from commercially available V-hydroxyacetimidate, followed by reaction with aldehydes provides adducts that after sequential desulfurization and hydrolysis may be converted into -hydroxy esters with 280% enantiomeric excess (Scheme 20). Thus, under kinetic conditions the reaction of the anion derived from (49) with aldehydes gives mixtures of the syn and anti products, (50) and (51) respectively, in nearly equal amounts. Under thermodynamic conditions, however, the more stable anti adducts (51) dominate, and after desulfurization and hydrolysis the P-hydroxy esters (53) are obtained in 75-94% enantiomeric excess. When the zinc enolate derived from (49) is condensed with aldehydes, the anti adducts (51) are again the major products and the p-hydroxy esters (53) can be isolated in 76-86% enantiomeric excess. On the other hand, the reaction of the zirconium enolate of (49), which is obtained by the addition of Cp2ZrCl2 to the corresponding lithium enolate, with aldehydes followed by desulfurization gives p-hy-... 

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