Ethyl acetoacetate, reaction with phenols

The Pechmaim reaction has found extensive appHcations for the synthesis of numerous coumarin derivatives (39). Coumarin derivatives substituted in the pyrone ring can be obtained by condensing phenol with beta-ketoesters. For example, 4-methylcoumarin (3) is obtained with ethyl acetoacetate... 

Coumarin can also be formed by the reaction of phenol with diketene (40). Similarly, diphenols can react with hydroxycarboxyUc acids or beta-ketoesters to give hydroxycoumaria derivatives. The reaction of resorciaol with malic acid produces umbeUiferone (7-hydroxycoumaria) and its reaction with ethyl acetoacetate gives beta-methylumbeUiferone (7-hydroxy-4-methylcoumaria). 

A -acetyl groups attached to the aniline have been shown to withstand the Conrad-Limpach reaction. Phenols and alcohols also survived unless in proximity to a reactive center. Jaroszewski reported the formation of 64 by reaction of aniline 63 with ethyl acetoacetate (5). Cyclization under thermal conditions in paraffin gave a mixture of quinolone 65 and quinoline 66. 

Constitution of the Esters of the (3-Ketocarboxylic Acids and of the P-Diketones.—Ethyl acetoacetate is taken as example. It reacts like a ketone with phenylhydrazine, bisulphite, and other ketone reagents on the other hand it shows an acid reaction, it dissolves in alkalis, and gives the colour reaction with ferric chloride characteristic of ends and also of phenols. From this double behaviour it was formerly concluded that it was either purely ketonic or purely enolic and that the reactions in the other form were to be attributed to a rearrangement caused by the reagents used. The true state of affairs was first disclosed by... 

While this reaction to form coumarin derivatives can be completed in mineral acids, research shows that the reaction was much faster in ILs even at room temperature. The same group used l-butyl-3-methylimidazolium hexafluoro-phosphate IL at high temperatures without employing any acid catalyst. The yields were comparable to chloroaluminate ILs with catalytic amounts of acid at room temperature. They also concluded that Bronsted acidity (produced by HF when [bmimJIPF ] contacts water) was not responsible for the observed activity. Singh et al have used l-butyl-3-methylimidazolium hydrogen sulfate IL in combination with microwave irradiation. They were able to synthesize coumarins in quantitative yields with drastic reduction in reaction times. Soares et al have used [bmim][NbCl6] IL to perform the Pechmann reaction using various phenols with ethyl acetoacetate to produce coumarin in moderate yields (-35%). 

Methylcoumarins bearing hydroxy and other electron-donating groups can be synthesized from the corresponding phenols by reaction with ethyl acetoacetate in the presence of sulfuric acid. Hydrolysis of the ester group in the product then allows the lactone ring of the coumarin to form (Scheme 5.6). 

The Pechmann and Knoevenagel reactions have been widely used to synthesise coumarins and developments in both have been reported. Activated phenols react rapidly with ethyl acetoacetate, propenoic acid and propynoic acid under microwave irradiation using cation-exchange resins as catalyst <99SL608>. Similarly, salicylaldehydes are converted into coumarin-3-carboxylic acids when the reaction with malonic acid is catalysed by the montmorillonite KSF <99JOC1033>. In both cases the use of a solid catalyst has environmentally friendly benefits. Methyl 3-(3-coumarinyl)propenoate 44, prepared from dimethyl glutaconate and salicylaldehyde, is a stable electron deficient diene which reacts with enamines to form benzo[c]coumarins. An inverse electron demand Diels-Alder reaction is followed by elimination of a secondary amine and aromatisation (Scheme 26) <99SL477>. 

Although earlier investigations suggested that a Pechmann reaction on 3-substituted or 3,4-disubstituted phenols yielded only one product, it is now clear that this is not always the case (81T2021). The failure of earlier workers to isolate a second product is readily understood from the data in Table 6. As yet, it is not known whether this behaviour is a general feature of m-substituted phenols. The lack of formation of the 5- or 5,6-isomer in the reactions with ethyl acetoacetate may be a result of steric hindrance by the 4-methyl substituent. 

A mixture of phenol 1 (10 mmol) and a,/ -unsaturated carboxylic derivative 2, 4 or ethyl acetoacetate 6 (15-20 mmol) supported on 1 g of solid acid support (by dissolving the mixture in 5 mL of diethyl ether followed by evaporation of the solvent) was exposed to microwave irradiation in a focused microwave reactor (Prolabo MX350). For isolation of the compounds, the solid support was removed by extraction with ethanol (for reactants 2 and 6) or acetonitrile (reactions of 4). After solvent evaporation, the products were purified by column chromatography on silica gel (hexane-ethyl acetate, 3 1). 

A more general synthesis of coumarins involves the interaction of a phenol with a /1-ketoester in the presence of an acid condensing agent (the Pechmann reaction). In the case of 4-methylcoumarin (117) appropriate disconnection reveals ethyl acetoacetate and phenol. 

The use of ethyl [2-13C]acetoacetate instead of diethyl [2-t3CJmafonafe in the condensation reaction with 4H-pyran-4-one afforded ethyl 4-hydroxy[1 -13C]benzoate in 87% yield. In this case, 1.1 equiv of 4H-pyran-4-one and 1.1 equiv of potassium tert-butoxide were optimal. The addition of catalytic amounts of the base was not satisfactory. Ethyl [2-13C]acetoacetate was prepared from ethyl (2-13C]acetate as described for diethyl [2-13C]matonate.16 The maximum yield for this reaction on a 10-mmol scale was only 70% after distillation. 4H-Pyran-4-one reacted with nitromethane and potassium tert-butoxide (each 1.1 equiv) to afford 4-nitrophenol in 75% yield after purification by flash chromatography. This gives easy access to 4-nitro[4-13C]phenol. With 2,4-pentanedione, the condensation with 4H-pyran-4-one under the same reaction conditions gave 4-hydroxyacetophenone in 45-50% yield after purification. 

Another route to coumarins is the Pechmann condensation of phenols with (3-ketoesters. The reaction proceeds via transesterification and intramolecular hydroxyalkylation, followed by dehydration, and is conventionally conducted using sulfuric acid as catalyst. Resorcinol and ethyl acetoacetate reacted sol vent-free over H-beta at 150 °C to give 7-hydroxy-4-methylcoumarin (78 % isolated yield) [85J. This is another perfumery ingredient which is also an intermediate for the insecticide I Iymecromone. 

Polymer bound acrylic ester is reacted in a Baylis-Hillman reaction with aldehydes to form 3-hydroxy-2-methylidenepropionic acids or with aldehydes and sulfonamides in a three-component reaction to form 2-methylidene-3-[(arylsulfonyl)amino]propionic acids. In order to show the possibility of Michael additions, the synthesis of pyrazolones was chosen. The Michael addition was carried out with ethyl acetoacetate and BEMP as base to form the resin bound p-keto ester. This was then transformed into the hydrazone with phenylhydrazine hydrochloride in the presence of TMOF and DIPEA [28]. The polymer bound phenol was readily coupled to a variety of allyl halides by using the Pl- Bu to generate a reactive phenoxide [29]. 

The long-established Pechmann synthesis of coumarins has been revisited. The reaction of phenols with ethyl acetoacetate (EAA) occurs in better yield at lower temperatures and milder conditions in ionic liquids which act as both solvent and Lewis acid catalyst <01TL9285> and in solvent free reactions catalysed by 4-TsOH <01CL110>. Microwave irradiation of aminophenols and EAA on a solid support of graphite and montmorillonite KIO rapidly gives good yields of 4-substituted 7-aminocoumarins <01TL2791>. 

The Pechmann synthesis of coumarins via condensation of phenols with keto esters also involves an intramolecular hydroxyalkylation, following initial transesterification, and subsequent dehydration. It was found that H-Beta could successfully replace the sulfuric acid conventionally used as catalyst. For example, reaction of resorcinol with ethyl acetoacetate afforded methylumbelliferone (Figure 11.9), a perfumery ingredient and insecticide... 

Phosphorus oxychloride (POCI3) has proven useful as a promoter in a range of Pechmann condensations employing sterically encumbered 3-keto ester coupling partners and electronically deactivated phenols, reactions which fail using sulfuric acid as a promoter. Thus POCI3 has been found to successfully promote the condensation of a-benzylacetoacetate and 1-naphthol as well as the reaction of ethyl acetoacetate with 4-acyl-resorcinols. ... 

Shinde et al. (2008) have prepared silica gel-supported sodium hydrogen sulfate and demonstrated its application in the synthesis of coumarins. The reactions were conducted in acetonitrile and the reaction time in most of the cases was 1 h, which included the weakly reactive naphthols. Application of nanocrystalline sulfated zirconia in the reaction of meta-substituted phenols has also been investigated (Tyagi et al. 2007) under different conditions. In view of the slow reaction rates observed in nitrobenzene and toluene, the solvent-free conditions were adopted under MW irradiation to obtain high yields (95%-99%), of 7-amino- and 7-hydroxy-4-methylcoumarins in the reaction of m-amino and m-hydroxy phenols with ethyl acetoacetate. A low percentage of catalyst is required and its reusability has been claimed as a novel feature of this synthesis. 

The catalytic ability of niobate ionic liquids generated in combination with 1-butyl-3-methylimidazolium chloride and niobium pentachloride was tested in Pechmann cyclizations. The reaction of phenols and ethyl acetoacetate, leading to the formation of coumarins, was conducted in an acidic mixture of 60 mol% (Soares et al. 2007). 

Amberlyst 15 has also been used in the von Pechmann coupling of ethyl acetoacetate to a variety of substituted phenols, such as resorcinol (8), to give substituted hydroxycoumarins such as 9 (eq 17). This reaction appears to occur efficiently with a substo-ichlometiic amount of Amberlyst 15 (25% w/w). 

Potdar et al. (2005) employed neutral ILs such as [bmimjPFa or [bmim]BF4 with catalytic amount of acid for synthesis of coumarin via Pechmann condensation of phenols and ethyl acetoacetate (EAA) under ambient conditions. They also carried out the reaction at high temperature in IL [bmimJPFe, without the use of any acid catalyst and investigated the recycling of the ILs for reuse. 

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