3-Keto esters metal enolates

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]. 

GL 4] [R 5] [P 5] The rate of the fluorination of y0-keto esters is usually correlated with the enol concentration or the rate of enol formation as this species is actually fluorinated [15, 16]. For the fluorination of ethyl 2-chloroacetoacetate in a micro reactor, much higher yields were found as expected from such relationships and as compared with conventional batch processing which has only low conversion. Obviously, the fluorinated metal surface of the micro channel promotes the enol formation. 

For the synthesis of 2-519, the amines 2-516 were first treated with AlMe3 in benzene at r.t. and after addition of the enol acetates 2-515, easily accessible from 2-513 and 2-514, heated under reflux. Mechanistic investigations using on-line NMR spectroscopy, reveal that a metalated amide 2-517 is formed first. This then leads to a N-acyliminium ion 2-518 which undergoes an electrophilic substitution. Overall, three new bonds are formed selectively in the domino process, and the alkaloid scaffolds 2-519 are provided in very good yields of 79-89%. Interestingly, use of the keto esters 2-513 instead of 2-515 did not lead to the desired products 2-519. 

The primary literature now contains a very large body of kinetic data for the catalysis of enolization and ketonization, not only of ketones and aldehydes but also of )3-diketones, )3-keto esters, and dienones, much of which could be treated by the Kurz approach. Also, data exist for third-order enolization, due to combined general acid and base catalysis, that could also be analysed. Such treatment is beyond the scope the present review. However, one study of metal ion catalysis of enolization is discussed later in this section. 

Hydrolysis and decarboxylation in the usual way lead to keto-esters or keto-acids. Of the more common metals used to form enolates, lithium is the most likely to give good C-acylation as it> like magnesium, forms a strong O-Li bond. It is possible to acylate simple lithium enolates with enoliz-able acid chlorides,... 

Three main types of redox reactions of keto compounds leading to the formation of metal enolates have been reported (i) two-electron reduction of diketones or a,(f-unsaturated ketones or esters (equation 1), (ii) oxidative addition reactions (equation 2) and (iii) threefold deprotonation of diketoamines followed by a two-electron oxidation of the trianion by the metal (equation 3). 

The reductive coupling of carbonyl compounds with formation of C-C double bonds was developed in the early seventies and is now known as McMurry reaction [38, 39]. The active metal in these reactions is titanium in a low-valent oxidation state. The reactive Ti species is usually generated from Ti(IV) or Ti(III) substrates by reduction with Zn, a Zn-Cu couple, or lithium aluminum hydride. A broad variety of dicarbonyl compounds can be cyclized by means of this reaction, unfunctionalized cycloalkenes can be synthesized from diketones, enolethers from ketone-ester substrates, enamines from ketone-amide substrates [40-42], Cycloalkanones can be synthesized from external keto esters (X = OR ) by subsequent hydrolysis of the primary formed enol ethers (Scheme 9). 

In regard to the uiUc ketones, they form the acetates m their enol form equally well io acid medium, the /3-diketones and the /7-keto esters, in the presence cS metals or bases, give compovindR with an acetyl group on the carbon atom of the active methylene group ... 

In many of these cases, both the enolate anion and substrate can exist as (Z) or (E) isomers. With enolates derived from ketones or carboxylic esters. The (E) enolates gave the syn pair of enantiomers (p. 166), while (Z) enolates gave the anti pair. Nitro compounds add to conjugated ketones in the presence of a dipeptide and a piperazine. ° Malonate derivatives also add to conjugated ketones, and keto esters add to conjugated esters.Addition of chiral additives to the reaction, such as metal-salen complexes,proline derivatives, or (—)-sparteine, ... 

The rates of enolization or ionization of certain keto acids in which the carboxylic group is suitably placed to assist the ionization by interaction with the carbonyl oxygen have been found to be considerably higher (factors of up to 2 x 10 ) than those of the corresponding keto esters. If the carbonyl oxygen can be coordinated to a metal ion, a considerable enhancement of the rate of ionization of the active C—H bond would be expected. Pedersen first observed such a rate enhancement for the acetate-catalyzed halogenation of both ethyl acetate and ethyl 2-oxocyclopentanecarboxylate in the presence of Cu". The effects were not large presumably due to only weak complexation between Cu" and the ketones. 

A highly exo-selective asymmetric hetero Diels-Alder reaction was the key step in D.A. Evans total synthesis of (-)-epibatidine. The bicyclic cycloadduct was then subjected to a fluoride-promoted fragmentation that afforded a (f-keto ester, which was isolated exclusively as its enol tautomer. The removal of the ethoxycarbonyl functionality was achieved using the Krapcho decarboxylation. Interestingly, the presence of a metal salt was not necessary in this transformation. Simply heating the substrate in wet DMSO gave rise to the decarboxylated product in quantitative yield. 

An asymmetric synthesis of -formyl -hydroxy esters was also examined by treating the keto aminal 10 a with metal enolates of ethyl acetate. Zinc enolates... 

Alkylation of the metallated enol derived from 52 with m-methoxy-phenylethyl-iodide to afford the tricyclic jj-keto ester 53, followed by cationic cydization of this to furnish the steroid derivative 54, warrants particular attention. Corey and colleagues have recently published another total synthesis of 40 [82], beginning with an enantioselective Diels-Alder reaction between Dane s diene 14 and dienophile 61. An oxazaborolidinium salt (see Section 1.3.2.3) was used as an efficient catalyst (Scheme 1-14). 

In an instructive example from the Widenhoefer group, the hydroalkylative cyclization of unsaturated (3-keto esters was shown to proceed along a pathway of multiple hydro-metallations and p-H-eliminations. Protonolysis of the C-Pd(ll) bond eventually occurred at the a-position to a carbonyl group, facilitated by the strongly polarized palladium(ll) enolate (Scheme 4a) [18]. 

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