Other Keto Esters

Reductions of keto esters to esters are not very frequent. Both Clemmensen and Wolff-Kizhner reductions can hardly be used. The best way is desulfurization of thioketals with Raney nickel (p. 130). Thus ethyl acetoacetate was reduced to ethyl butyrate in 70% yield, methyl benzoylformate (phenylglyoxy-late) to methyl phenylacetate in 79% yield, and other keto esters gave equally high yields (74-77%) [82J]. 

Keto acids and 2-alkyl- or 2-arylmalonic acids readily decarboxylate, and acylations with these proceed satisfactorily only at low temperatures. An alternative to direct acylation with /3-keto acids is thermolysis of acyl Meldrum s add (to generate an acylketene) in the presence of a nucleophile (Scheme 7.7). Esters of /J-keto acids can also be conveniently prepared from other keto esters by transesterification [27, 28],... 

No 0-allylation is observed in formation of the six-membered ring compound 79 by intramolecular allylation of the /3-keto ester 78(15,57]. Intramolecular allylation is useful for lactone fonnation. On the other hand, exclusive formation of the eight-membered ring lactone 81 from 80 may be in part derived from the preference for the nucleophile to attack the less substituted terminus of the allyl system[58]. 

The 1.3-allylic diacetate 135 can be used for the formation of the methy-lenecyclopentane 137 with the dianionic compound 136(86]. The cyclohexa-none-2-carboxylate 138 itself undergoes a similar annulation with the 1,3-allylic diacetate 135 to form the methylenecyclohexane derivative 139(90]. The reaction was applied as a key step in the synthesis of huperzin A[91]. On the other hand. C- and 0-allylations of simple J-dikctones or. 1-keto esters take place, yielding a dihydropyran 140(92]. 

The decarboxylation of allyl /3-keto carboxylates generates 7r-allylpalladium enolates. Aldol condensation and Michael addition are typical reactions for metal enolates. Actually Pd enolates undergo intramolecular aldol condensation and Michael addition. When an aldehyde group is present in the allyl fi-keto ester 738, intramolecular aldol condensation takes place yielding the cyclic aldol 739 as a main product[463]. At the same time, the diketone 740 is formed as a minor product by /3-eIimination. This is Pd-catalyzed aldol condensation under neutral conditions. The reaction proceeds even in the presence of water, showing that the Pd enolate is not decomposed with water. The spiro-aldol 742 is obtained from 741. Allyl acetates with other EWGs such as allyl malonate, cyanoacetate 743, and sulfonylacetate undergo similar aldol-type cycliza-tions[464]. 

Keto esters are obtained by the carbonylation of alkadienes via insertion of the aikene into an acylpalladium intermediate. The five-membered ring keto ester 22 is formed from l,5-hexadiene[24]. Carbonylation of 1,5-COD in alcohols affords the mono- and diesters 23 and 24[25], On the other hand, bicy-clo[3.3.1]-2-nonen-9-one (25) is formed in 40% yield in THF[26], 1,5-Diphenyl-3-oxopentane (26) and 1,5-diphenylpent-l-en-3-one (27) are obtained by the carbonylation of styrene. A cationic Pd-diphosphine complex is used as the catalyst[27]. 

Even though ketones have the potential to react with themselves by aldol addition recall that the position of equilibrium for such reactions lies to the side of the starting materials (Section 18 9) On the other hand acylation of ketone enolates gives products (p keto esters or p diketones) that are converted to stabilized anions under the reaction conditions Consequently ketone acylation is observed to the exclusion of aldol addition when ketones are treated with base m the presence of esters... 

The carbon-carbon bond forming potential inherent m the Claisen and Dieckmann reac tions has been extensively exploited m organic synthesis Subsequent transformations of the p keto ester products permit the synthesis of other functional groups One of these transformations converts p keto esters to ketones it is based on the fact that p keto acids (not esters ) undergo decarboxylation readily (Section 19 17) Indeed p keto acids and their corresponding carboxylate anions as well lose carbon dioxide so easily that they tend to decarboxylate under the conditions of their formation... 

The condensation of P-keto esters with hydroxylamine can occur in two directions to give either isoxazolin-3-ones [which exist predominately as 3-hydroxyisoxazoles (2)] or isoxazolin-5-ones (3). Early work by Claisen, Hantzch, and others showed that the products from 2-unsubstituted P-keto esters were isoxazolin-5-ones. In the early 1960 s, Katritzky found that 2-substituted analogues give 3-hydroxyisozaoles. Jacquier later showed that both types of products could be produced from both types of keto esters depending on the precise pH variation during the reaction workup. ... 

General Conditions for each step and selectivity of m-substituted anilines As previously mentioned, Hauser and Reynolds reported on factors governing the first step of the Conrad-Limpach reaction but they tvere by no means exhaustive. Other than the conditions reported above for the first step, HClAleOH, CHCI3 or CHCI2 (neat or with acid catalyst), PhMe or PhH with removal of water with or without acid catalyst, or EtOH/AcOH/CaS04 were reported to provide the desired enamino-ester from an aryl amine and 3-keto-ester. Hauser and Reynolds also noted that o-nitroaniline and o-nitro-p-methoxyaniline failed to form the desired enamino-ester under conditions which they reported. 

In the 1880s, Pinner found that the amidine derivative 2 reacted with acetoacetic ester (4) to furnish 2-substituted-6-hydroxy-4-methylpyrimidine 5. The condensation of amidine derivative 2 with other (l-keto esters, malonic esters, and (l-diketones proceeded similarly (see the following pages for examples). ... 

Esters, like aldehydes and ketones, are weakly acidic. When an ester with an a- hydrogen is treated with 1 equivalent of a base such as sodium ethoxide, a reversible carbonyl condensation reaction occurs to yield a /3-keto ester. For example, ethyl acetate yields ethyl acetoacetate on base treatment. This reaction between two ester molecules is known as the Claisen condensation reaction. (We ll use ethyl esters, abbreviated "Et," for consistency, but other esters will also work.)... 

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 mechanism of the Dieckmann cyclization, shown in Figure 23.6, is the same as that of the Claisen condensation. One of the two ester groups is converted into an enolate ion, which then carries out a nucleophilic acyl substitution on the second ester group at the other end of the molecule. A cyclic /3-keto ester product results. 

The best Michael reactions are those that take place when a particularly stable enolate ion such as that derived from a /i-keto ester or other 1,3-dicarbonyl compound adds to an unhindered a,/3-unsaturated ketone. Tor example, ethyl acetoacetate reacts with 3-buten-2-one in the presence of sodium ethoxide to yield the conjugate addition product. 

The reaction described is of general synthetic utility for the preparation of a variety of cyclic /3-keto esters from the corresponding ketones. Using this procedure the 2-carbethoxy-cycloalkanones have been prepared from cyclononanone, cyclo-decanone, and cyclododecanone in yields of 85%, 95%, and 90%, respectively. The procedure is simpler and gives much higher yields than other synthetic routes to these systems. 

Reaction of a-phenylsulfinyl acetate or ethyl a-(t-butylsulfmyl)acetate with one equivalent of ethylmagnesium bromide or iodide was shown to give the corresponding Grignard reagent 129 or 132, which upon reaction with carbonyl compounds afforded the corresponding adducts. Thus Nokami and coworkers prepared ethyl / -hydroxycarboxylates 130167, jS-keto esters 131168, a,/J-unsaturated esters 133169 and other derivatives by this method. 

The present method9 affords the methyl ester directly in high yields from 2-pyrazolin-5-ones, which are readily prepared in nearly quantitative yields from readily accessible, /3-keto-esters. In addition, the reaction is simple to carry out, conditions are mild, and the product is easily isolated in a high state of purity. A limitation of the reaction is that only the methyl ester can be made, as other alcohols have been found to give poor yields and undesirable mixtures of products. Table I illustrates other examples of the reaction.10... 

Bisulfite addition products are formed from aldehydes, methyl ketones, cyclic ketones (generally seven-membered and smaller rings), a-keto esters, and isocyanates, upon treatment with sodium bisulfite. Most other ketones do not undergo the reaction, probably for steric reasons. The reaction is reversible (by treatment of the addition product with either acid or base ) and is useful for the purification of the starting compounds, since the addition products are soluble in water and many of the impurities are not. ... 

A somewhat different type of coupling is observed when salts of (i-keto esters, arylacetonitriles (ArCH2CN), and other compounds of the form ZCH2Z are treated with an oxidizing agent such as iodine," " or Cu(II) salts." Arylmethanesulfonyl chlorides (ArCH2S02Cl) couple to give ArCH=CHAr when treated with Et N." ... 

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