P-Ketoester enolization

The Japp-Klingeraann coupling of aryidiazonium ions with enolates and other nucleophilic alkenes provides an alternative route to arylhydrazones. The reaction has most frequently been applied to P-ketoesters, in which deacylation follow S coupling and the indolization affords an indole-2-carboxylate ester. 

The fluorination of P-diketones and p-ketoesters with N-/luorobis(trifluo-romethanesulfonyl)imide (Table 3a, B) can be controlled to give either mono-fluorination or difluorination. Monofluorination occurs when the strong acid, bis(trifluoromethanesulfonyl)imide, a reaction product, is removed by addition of water, which prevents further enolization and fluormation of the monofluoro adduct [83] (equation 38)... 

The Claisen condensation of t-butyl acetate with a methyl ester is a general route for the preparation of complex P-ketoesters.4 The reaction requires an excess of the enolate of t-butyl acetate to rapidly deprotonate the product and prevent tertiary alcohol formation. Some workers have also used excess LDA or t-butoxide for this purpose. 

The same viewpoint can taken for the ester function in a P-ketoester such as ethyl acetoacetate. Again, acidity of the a-protons is increased because there are two carbonyl groups, and generation of an enolate anion is facilitated. Although mono- or... 

Synthesis of p-Ketoesters by C-Acylation of Preformed Enolates with Methyl Cyanoformate Preparation of (la,4ag,8ao)Methyl 2-Oxo-decahydro-l-naphthoate... 

When two molecules of ester undergo a condensation reaction, the reaction is called a Claisen condensation. Claisen condensation, like the aldol condensation, requires a strong base. However, aqueous NaOH cannot be used in Claisen condensation, because the ester can be hydrolysed by aqueous base. Therefore, most commonly used bases are nonaqueous bases, e.g. sodium ethoxide (NaOEt) in EtOH and sodium methoxide (NaOMe) in MeOH. The product of a Claisen condensation is a P-ketoester. As in the aldol condensation, one molecule of carbonyl compound is converted to an enolate anion when an a-proton is removed by a strong base, e.g. NaOEt. 

The enolate anion attacks the carbonyl carbon of a second molecule of ester and gives a P-ketoester. Thus, the Claisen condensation is a nucleophilic acyl substitution reaction. Eor example, two molecules of ethyl acetate condense together to form the enolate of ethyl acetoacetate, which upon addition of an acid produces ethyl acetoacetate (P-ketoester). 

The enol acetate moiety in diketene can be utilized for cyclopropane formation. Unfortunately, with most diazo compounds, yields are rather moderate 29), and therefore the synthetic value of methods developed on this basis is restricted. As exemplified by the ethyl diazoacetate adduct 44 (Scheme 4) the ring opening of this masked tricarbonyl compound can lead to different classes of acyclic or cyclic products. The outcome of these reactions depends on the conditions employed. They simultaneously transform the P-ketoester unit present in 44 29b). 

Muzart and coworkers have reported a new catalytic enantioselective protonation of prochiral enolic species generated by palladium-induced cleavage of p-ketoesters or enol carbonates of a-alkylated 1-indanones and 1-tetralones [21 ]. Among the various (S)-p-aminocycloalkanols examined, 17 and 18 were effective chiral catalysts for the asymmetric reaction and (J )-enriched a-alkylated 1-indanones and 1-tetralones were obtained with up to 72% ee. In some cases, the reaction temperature affected the ee. 

Cycloaddition reactions can also be pseudopericyclic. Bimey examined a number of these and a few examples involving the reactions of formylketene (91) are covered here. Formylketene reacts with alcohols to produce p-ketoesters from the enols 92. Bimey examined the model reaction of formylketene with water (Reaction 4.6). The reactants first come together to form a hydrogen-bonded complex (93) before passing though the transition state 94 to give the enol product 95. The activation barrier, defined as the energy for the reaction 93 94, is 6.4 kcal... 

More complex equilibria (Fig. 76), also involving chemical modifications, are shown by the aminomethyl derivatives of a-arylidene-P-ketoesters (207), studied as anticancer drugs - these have been found to be in equilibrium with cyclic quaternary ammonium salts, which in turn are characterized by the presence of kcto-enol equilibrium. 

The first step in the mechanism involves the removal of proton from ester by a strong base to generate an enolate at the a-carbon. The enolate can then add to another ester molecule with loss of the alkoxy group to make the P-ketoester (Scheme 3.9). 

Enols (P- ketoesters) Water (Bulk water as suspended droplets or wall films)... 

Fluorination of -Ketoester Enolates. (+)-N-Fluoro-2,10-(3,3-dichlorocamphorsultam) (1) is reactive towards the enolates generated from p-ketoesters. Thus, treatment of the sodium enolate of 8 with (+)-l afforded the desired product 9 in 95% isolated yield and 46% ee with undetermined stereochemistry (eq 4). Reduced yields and enantioselectivities were noted under similar conditions for (-)-N-fluoro-2,10-camphorsultam (28% yield, 25% ee). ... 

After formation of the enolate by deprotonation with LiHMDS, the ester moiety is introduced by reaction with methyl cyanoformate to give P-ketoester 20 in 70 % yield over three steps. Structure 20 represents a 1,3-dicarbonyl compound that preferentially exists in the enol form. 

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