Phenols Pechmann coumarin synthesis

The Pechmann coumarin synthesis, also known as the Pechmann condensation or Pechmann reaction, is the Lewis or Bronsted acid-promoted condensation of phenols (1) and P-keto (or other 3-oxo aliphatic) esters (2) to produce coiunarins (2//-chromen-2-ones, 3). ... 

Owing to exceptional sensitivity of the tricyclic phenol (A) to acidic reagents, direct condensation with 2-carbethoxycyclopentane-l,3-dione (i) under von Pechmann coumarin synthesis conditions proved impossible. However, the bromide (ii) readily underwent condensation to give the desired coumarin ring D when zinc carbonate was used both as catalyst and acid scavenger. 

The Pechmann Condensation ( or Coumarin Synthesis) allows the synthesis of coumarins by reaction of phenols with p-keto esters. 

Sinhamahapatra et al. (2011) reported that the microwave-assisted synthesis is the most appropriate method for synthesis of coumarins as it provides improved yield in very less time. Mesoporous zirconium phosphate (m-ZrP) is used as a solid acid catalyst for the synthesis of coumarins via Pechmann condensation reaction. Among the substituted phenols, m-amino phenol is more reactive and 100% yield was obtained in very short time at low temperature due to the presence of ring activating amine group in meta position. The m-ZrP is also active towards phenols for the synthesis of 4-methyl coumarin, where only 57% yield was obtained in conventional heating method. 

For the synthesis of coumarins, the Pechmann reaction [145] is one of the most popular synthetic routes. As the reaction is conventionally carried out at high temperature, two microwave-assisted versions have been recently described. Besson and co-workers described the cyclocondensation of different m-amino phenols 226 with /1-ketoesters 227 on graphite/montmorillonite KIO support (Scheme 83). The use of graphite was crucial in the development of the reaction conditions. In fact, microwave irradiation of the reagents using different conditions gave poor results in terms of yields and purity. The optimized conditions, using a monomode microwave system, employed... 

Alkynoates react with electron rich phenols to give coumarins with good regioselectivity in the presence of formic acid and a Pd-catalyst Yields are good even in instances where the Pechmann synthesis is reported to be unreliable <96JA6305>. 

One of the most reliable and widely used syntheses of coumarins involves the acid-catalyzed reaction between a phenol and a jS-keto ester, the Pechmann reaction (45CRV(36)1, 530R(7)l). An important aspect of the reaction is that it shows a dependency on all three reactants, which can be varied widely, thereby optimizing both the scope and conditions of the synthesis. As a consequence, satisfactory yields of coumarins substituted in either the benzene or pyranone ring or both rings can be obtained from readily accessible starting materials. 

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. 

An improvement in the synthesis of coumarins from phenols and P-keto esters results from the use of Zn to mediate a transesterification <02TL8583> and InCl3 is an efficient catalyst for the Pechmann reaction <02TL9195>. 

The Pechmann synthesis of coumarins via condensation of phenols with / -keto esters also involves an intramolecular hydroxyalkylation, following initial... 

Phenols are convenient substrates for the synthesis of coumarins, but the uncertainty and limited appHcability of the Pechmann reaction is a disadvantage. The effect of substituents on the mode of cyclization has been investigated and n.m.r. spectroscopy has been used to correlate orf/io-proximity effects with those in benzenoid compounds. Some phenols do not react under Pechmann conditions but do so when the keto-ester is replaced by tri-ethyl orthoacrylate (190). ... 

Among polyheterocyclic systems, coumarins are synthesized by many routes, including the Pechmann reaction [51], which involves condensation of phenols with yS-ketoesters. This reaction, which has been the most widely applied method, has recently been studied under the action of MW irradiation by several authors [52], including the GS-MW process for 4-substituted 7-aminocoumarins [53]. Synthesis of methyl 7-aminocoumarin-4-carboxylates (51 and 52) by the Pechmann reaction involves heating a mixture of m-aminophenol and dimethyl oxalate at 130 °C (Scheme 9.17). Under such conditions, however, the yield of the reaction is variable, usually low (36%). Use of graphite as a support led to the expected lactone in slightly better yield (44%). 

In the synthesis of coumarins by the von Pechmann reaction, a spiro-compound (251) was simultaneously formed from 4-chloro-2-methylphenol (and from 2,3,5-trimethylphenol). A possible mechanism for this reaction involves the formation of the lactone (252), which reacts with another molecule of the phenol. The condensation of the dicyano-ester (253) [obtained from malononitrile and ethyl cyanoacetate] with substituted o-hydroxybenzaldehydes yields substituted coumarinimines, e.g. (254).A series of 4,6,7-substituted coumarins have been prepared and assessed for their suitability in fluorescence labelling of polymers. Esters of the type PhCH CRCOaAr react with AICI3 to give coumarins, which are probably formed via dihydrocoumarins (255) by dearylation. ... 

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>. 

CuFc204 nanoparticles are an efficient catalyst for the synthesis of 4-methylcoumarins via Pechmann reaction of phenols with ethyl acetoac-etate in water at room temperature (14SC697). A similar Pechmann reaction of phenols with ethyl 4,4,4-trifluoroacetoacetate catalyzed by molecular iodine affords 4-trifluoromethylcoumarins (14TL6715). Highly functionalized coumarins are formed by an iron(III) chloride-mediated cascade reaction of salicylaldehydes or 2 -hydroxyacetophenones with various activated methylene compounds (14SC1507). 

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... 

The Pechmann condensation also played a key role in the Biichi group s efforts toward the total synthesis of aflatoxin Bi (44). In this work, the central coumarinic ring system of aflatoxin was prepared by condensing the racemic tricyclic phenol 40 with ethyl methyl-3-oxoadipate (41) in methanolic HCl at 5 °C to provide tricycle 42 in 57% yield. The use of methanol as a solvent was crucial to the success of this reaction, as attempts to perform this reaction in sulfuric acid led to the rapid isomerization of 40 to the corresponding benzofuran-3-acetic acid, which could be converted to the analogous coumarin product only in very poor yield. Subsequent cyclization of the pendant ester moieties of 42 afforded pentacyclic lactone 43. Treatment of 43 with disiamylborane resulted in selective reduction of the dihydrofuranone to the corresponding hemiaminal, which was then acetylated and pyrolyzed (240 °C) to provide ( )-aflatoxin Bi (44). 

The Simonis chromone synthesis is the reaction of a phenol la-c with a P-keto ester 2 using an appropriate acid promoter to generate a chromone or benzo-y-pyrone 3 (also called a benzo-l,4-pyrone). While compound 3 is actually a chromenone, for this article, whether the double bond is present or not, the system will be characterized as a chromone. The condensation is related to the Pechmann-Duisberg reaction, which yields coumarins from the condensation of a phenol with a P-keto ester and like its relative, the reaction conditions require the loss of water from the ketone moiety and alcohol from the ester moiety. 

Reddy et al. (2009) documented a novel protocol for a Pechmann reaction involving the synthesis of substituted coumarins from phenols and P-ketoesters catalyzed by sulfuric acid supported on the silica gel surface (Scheme 5.28). The method has several distinct advantages such as a clean reaction profile, operational simplicity, use of nontoxic catalysts, and higher yields in short reaction time and provides a valuable addition to the existing methods for the synthesis of coumarins. 

Retrosynthetic analysis of the target coumarin skeleton provides two major synthetic routes (Figure 10.1). Route A requires an aromatic o-hydroxy carbonyl compound and a two-carbon fragment observed in Knoevenagel and Perkin reactions reflecting the [4h-2] approach for the construction of six-membered heterocycles. Route B represents the reaction between phenols and three carbon fragments associated with the Pechmann cyclization. In recent years, newer synthetic methodologies have also been applied to the synthesis of a variety of coumarins that have avoided the use of concentrated sulfuric acid. The present chapter reviews various... 

Application of montmorillonite clays for the synthesis of coumarins has been systematically investigated. It has been shown that phenols with electron-withdrawing groups such as NO2 and CHO at the para-position do not lead to the expected Pechmann-cyclized product. This method offers easy separation of products, consistent yields and reusability of the clay catalyst (Tong-Shuang et al. 1998). Other solid acid catalysts employed are presented in Table 10.2. 

Tong-Shuang, L., Zhan-Hui, Z., Feng, Y, Cheng-Gaung, F. 1998. MontmorUlonite clay catalysis. Part 7. An environmentally friendly procedure for the synthesis of coumarins via Pechmann condensation of phenols with ethyl acetoacetate. J. Chem. Res. 38-39. 

The Pechmann reaction [96] normally refers to an acid-catalyzed condensation of phenols with p-ketoesters. It is widely applied for the synthesis of coumarins. A large number of reagents were used for this reaction, including sulfuric acid, phosphorus pentoxide, aluminum chloride, trifluoroacetic acid, SnC [97], oxalic acid... 

---