Methylenation of Ketoesters

Many efforts have been made to find optimal synthetic routes of a-methylene carbonyl compounds. These simple but interesting molecules are used in a variety of applications, such as synthetic intermediates 14], to mimic biologically active natural products [15] and as potential antitumor drugs [16]. 

Direct infusion ESI( + )-MS(/MS) was used to monitor Mannich-type a-methy-lenation of a-, [ -, and y-ketoesters, and the results guided development of a convenient one-pot method for the efficient preparation of their a-methylene 

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ESI Monitoring Mannich-type a-methylenation of ketoesters, mechanistic study Milagreefa/. [293]... 

M.N. Eherlin Probing the mechanism of direct Mannidi-type OL-methylenation of ketoesters [232]... 

Scheme 3.9 summarizes the catalytic cycle proposed from the ESI-MS(/MS) data for direct Mannich-type a-methylenation of ketoester 21, which forms the a-methylene ketoester 22 in the presence of 23. This cycle is based on previous mechamstic interpretations [19] but now shows authentic cationic intermediates (24, 25 and 26) that have been properly detected and characterized via ESI( + )-MS(/MS) momtoring. 

Scheme 3.9 Catalytic cycle for a-methylenation of p-ketoesters in glacial acetic acid medium based on data from ESI-MS(/MS) monitoring.

Very recently, Zhu and Cheng reported an organocatalytic Michael-type addition of phosphorus ylides 93 to a,(i-unsaturated ketones 94 using a chiral dual organo-catalyst system composed of 9-amino-(9-deoxy)-epi-quinine with Boc-L-proline (Scheme 43.20) [31]. The Michael-type/Wittig reactions proceeded smoothly to provide chiral a-methylene-6-ketoesters 95 with good to excellent enantioselectivi-ties (up to 95% ee). 

The most convenient synthesis of 6-hydroxy-2-pyridones is by the condensation of a P-ketoester, eg, ethyl acetoacetate, with an active methylene compound, eg, malonic ester, cyanoacetic ester, and an amine. The amine can be omitted if an acetamide is used and in some cases this modification results in a higher yield. 

The methylene hydrogens between the two carbonyls are the most acidic, so this is where enolate anion formation occurs. Now follows an Sn2 reaction with the dibromide reagent. It is soon apparent that this sequence of enolate anion formation and Sn2 displacement can be repeated, since the substrate still contains an acidic hydrogen. We soon end up with an alkylated ketoester. 

Activated methylene components like malonic esters and P-ketoesters can be coupled anodically using small amounts of potassium iodide as redox catalyst (Table 4, No. 4-7) i45-i5n -pj g cathodically formed metallic potassium is used to deprotonate the methylene component generating the oxidizable carbanion. The combination of this reaction with the cathodic hydrodimerization of acrylic esters has been studied several times (Table 4, No. 7) Thus both electrode reac-... 

Haddadin and Issidorides first reported an elegant method for the synthesis of quinoxaline 1,4-dioxides (47) from the reaction of benzofurazan 1-oxide (46) and an enamine or an active methylene compound, such as a /J-diketone or a /J-ketoester, in the presence of base.46 47 Quinoxaline 1,4-dioxide formation formally involves loss of secondary amine in the enamine reaction and loss of water when an active methylene compound of the type R CH2CORJ is used. This reaction is now commonly referred to as the Beirut reaction. The isolation of the dihydroquinoxaline 1,4-dioxide 48 from the reaction of 46 and NJV-dimethylisobutenylamine (Me2C=CHNMe2), which is unable to aromatize by amine loss, suggests that 2,3-dihydroquinoxalines are likely intermediates in all these reactions.48... 

The enedione (283) is a useful starting material for a two-step synthesis of 2,3,4,5-tetrasubstituted furans which are not otherwise readily accessible (81JCS(P1)2398). Michael addition of an active methylene compound, e.g. (284), to the enedione (283) led to the two regioisomeric adducts (285) and (286) which could then be cyclized to furans (287) and (288) under mild conditions (Scheme 75). The formation of Michael adducts was successful with both j8-ketoesters (284) and cyclic 1,3-diones. Normal routes to furans require much more drastic conditions the Michael addition allowed the preparation of 1,4-diones particularly activated by the presence of an easily enolizable group. This is a useful synthetic pathway because alternative routes for the preparation of complex furans are not at present available. 

N, N-Dimethylformamide diethyl acetal (DMFDEA) is a interesting reagent, since it can be used to form alkylaminopropenones or alkylaminopropenoates when reacted with compounds having activated methylene groups such as (3-ketoesters, acetophenone and N-acylglycine. These alkylaminopropenones or alkylaminopropenoates can subsequently be reacted with dinucleophiles to form a variety of heterocycles. Westman and co-workers32 have used DMFDEA for the synthesis of propenoates and propenones, which were used directly without intermediate purification for the formation of a number of heterocycles in a combinatorial fashion. Some examples are outlined in Scheme 5.16. The reactions were performed in a two-step one-pot procedure, which in this case were more suitable for combinatorial synthesis. 

Scheme 12 shows a series of reactions between 2-bromomethyl-pyridine and compounds containing active methylene groups the sequence 12(a) may be varied by using derivatives of acetylacetone or malonic ester instead of a j8-ketoester.40 Reactions 12(b) and 12(c) provide useful routes to 3-hydroxy and 3-amino compounds, which are noted for their instability in air (although 62 was stable in air for several weeks).30... 

What is the effect of the stoichiometric amount of strong base that allows the Claisen condensation to proceed to completion The /3-ketoester C, which occurs in the equilibrium, is an active-methylene compound and rather C,H-acidic. Therefore, its reaction with the alkoxide to form the ester-substituted enolate D occurs with considerable driving force. This driving force is strong enough to render the deprotonation step C —> D essentially irreversible. Consequently, the overall condensation also becomes irreversible. In this way, all the substrate is eventually converted into enolate D. The neutral /3-ketoester can be isolated after addition of one equivalent of aqueous acid during workup. 

Moreno-Manas et al. [98] reported on a similar effect of triphenylphosphine for the Michael addition of active methylene compounds to n-acceptor olefins such as methyl vinyl ketone, acrylonitrile, and 2-vinylpyridine and dialkyl azodi-carboxylates. They compared the reactivity of RuH2(PPh3)4, RuCl2(PPh3)3, and PPh3 and concluded that for /5-diketones, ketoesters, and ketoamides, triphenylphosphine released from the ruthenium complexes contributes totally or partially to the catalysis. 

The reactions of arylation of heterocyclic /3-ketoesters were employed in the synthesis of a number of isoflavanones and isoflavones.27,28 cr-Methylene cr-arylketones can be easily and selectively obtained by arylation of allyl /3-ketoesters which are eventually deprotected by the Tsuji s procedures. a Deallyloxycarbonylation was performed by treatment of the allyl cr-aryl-/3-ketoesters with catalytic amounts of palladium(n) acetate, triethylammo-nium formate and triphenylphosphane in THF at room temperature and afforded the a-arylketones in 75-97% yield.27 Deallyloxycarbonylation-dehydrogenation can be realized with the same allyl esters by treatment with catalytic amounts of palladium(n) acetate and l,2-bis(diphenylphosphino)ethane (DPPE) in acetonitrile under reflux and affords the ct-aryl cr,/3-unsaturated ketones in 60-90% yield (Scheme 4).28 In particular, this reaction was used in a direct convergent synthesis of 2 -hydroxyisoflavones involving arylation of an appropriate allyl /3-ketoester with the MOM-protected (2-methoxymethoxyphenyl)lead triacetate derivative (Scheme 4). The reaction of the isomeric... 

Reactions of unsymmetrical methylene 1,3-dicarbonyl compounds with enol ethers have been investigated by Yamauchi et al. [137]. As we have mentioned earlier, the a,/ -unsaturated ketone moiety in alkylidene-/ -ketoesters reacts exclusively as the oxabutadiene. However, high regioselectivity is also observed with mixed alkyl-phenyl-1,3-diketones with exclusive reaction of the aliphatic carbonyl group, whereas in alkylidene-1,3-dicarbonyl compounds bearing an aldehyde and a keto-moiety, the a,/J-unsaturated aldehyde reacts preferentially as oxabutadiene, but not exclusively [130a]. 

This loses one of the carboxylates on heating in the presence of toluene-sulfonic acid to afford the (B-ketoester (82). Reaction of this intermediate with ethylorthoformate then adds a carbon atom to the activated methylene. Heating that compound with cyclopropylamine in effect exchanges the ethoxy group with the amine to afford enamine (84). Treatment 84 with sodium fluoride leads to displacement of one of the ring fluoro groups by the basic nitrogen on the side chain. This step concludes the formation... 

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