Coumarins Pechmann reaction

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... 

Biswas GK, Basu K, Barua AK, Bhattacharyya P (1992) Montmorillonite clay as condensing agent in Pechmann reaction for the synthesis of coumarin derivatives. Indian J Chem 31B 628-628... 

Among polyheterocyclic systems, coumarins are synthesized by many routes, including the Pechmann reaction, which involves condensation of phenols with /fke-toesters [51]. This reaction, which has been the most widely applied method, has re-... 

Some 7-aminocoumarins-4-carboxylates [60 a] were synthesized by the Pechmann reaction, by microwave irradiation of the reactants on solid supports (graphite-K10) (Scheme 8.41). Synthesis of unsubstituted coumarins (C-4 position) has been also reported [60 b]. 

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%). 

Until the late 1890s, coumarin was obtained commercially only from natural sources by extraction from tonka beans. Synthetic methods of preparation and industrial manufacturing processes were developed starting principally from ortho-creso (Raschig process), phenol (Pechmann reaction) and salicylaldehyde (Perkin reaction). Various methods can be used to obtain coumarin from each of these starting materials. In order to be suitable for perfumery uses, synthetic coumarin must be highly pure (Bauer et al., 1988 Boisde Meuly, 1993). 

The formation of 2-oxopyran-5 -carboxylic acid (coumalic acid) from 2-hydroxybutanedioic acid (malic acid) is described in detail (63OSC(4)20l) and involves the decarbonylation and dehydration of the hydroxy acid. The formylacetic acid so formed then undergoes selfcondensation. This synthesis is an example of the Pechmann reaction usually associated with the synthesis of coumarins (benzopyran-2-ones). It will be observed that this route leads to pyran-2-ones which carry identical substituents at the 4- and 6-positions. 

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. 

Both fumaric and maleic acid give rise to coumarins on reaction with phenols. Initially, this route was considered different from the Pechmann reaction, but experimental evidence has been accumulated which suggests that it is simply a variant (73AJC899). Under the acidic conditions, the unsaturated acid could well produce some malic acid, which would then lose carbon monoxide and water as usual. Generally yields in the two approaches to coumarins are much the same. 

The Pechmann reaction is thought to proceed through electrophilic aromatic substitution of the phenol. The resulting /3-hydroxy ester then cyclizes and dehydrates to the coumarin, although of course dehydration may occur earlier in the sequence (Scheme 113). Indeed, the observation that 2-hydroxycinnamic acids readily yield coumarins in sulfuric acid (32JCS1681) renders these compounds or their esters plausible intermediates in the reaction. 

The vigorous conditions which are necessary serve to detract from the value of the Perkin synthesis, leading to the production of tarry material which adversely affects the yield of coumarin. Difficulties encountered in the synthesis of substituted o-hydroxybenzaldehydes also limit the application of this route. The obvious advantages of the method are that there are no doubts about the orientation of the product and that, unlike the Pechmann reaction, formation of the isomeric chromones is not possible. 

Aryl acetoacetates, which may be obtained by the reaction of phenols with diketene, are cyclized on treatment with sulfuric acid (54JCS854). The yields of coumarins are similar to those obtained by a Pechmann reaction on the phenol. 

There has been some controversy about the mechanisms of the Simonis and Pechmann reactions, which still remain in doubt. It has been suggested (50BSF1132) that the condensations proceed through a common oxonium ion (467). Dehydration to the phenoxyacrylic ester (468) is followed by cyclization to the chromone whilst a rearrangement to the substituted phenol (469) subsequently affords the coumarin (Scheme 171). 

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

Coumarins are readily accessed via the Pechmann condensation of phenols and 1,3-dicarbonyl compounds, which proceeds via electrophilic aromatic substitution of the phenol followed by dehydration and lactonization <1984CHEC, 1996CHEC-II>. In this manner, the amino acid bearing coumarins 676 are formed by a Pechmann condensation of phenols and 2-amino-6-ethoxy-4,6-dioxohexanoic acid 677 (Scheme 161) <2004AGE3432>. The popularity of this approach results from the wide range of readily available substrates (phenols and 1,3-dicarbonyl compounds). However, a major drawback is that electron withdrawing groups on the phenolic component dramatically reduces the yield of a Pechmann reaction. 

A popular variant of the Pechmann reaction involves the use of propynoic acids as a 1,3-dicarbonyl equivalent. Cation-exchange resins under microwave irradiation <1999SL608>, PtCl2-AgOTf <2005TL3823> and Pd(OAc)2 <2000JOC7516, 2004S1466> can effectively promote the reaction of phenols with propynoic acids to afford coumarins (Equation 275). 

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>. 

Coumarins are an important family of fragrance chemicals with herbaceous, haylike odors. The conventional methods for coumarin synthesis require drastic conditions. For example, 4-methyl-7-hydroxycoumarin 39 (Eq. 15.4.1) is prepared via the Pechmann reaction by stirring a mixture of resorcinol 37 and ethyl acetoacetate 38 in H2SO4 for 12-14 h (63). 

The short and efficient stereospecific synthesis of the dimer-selective retinoid X receptor modulator was carried out in the laboratory of L.G. Hamann. The synthetic sequence began with the von Pechmann reaction between tetramethyltetrahydronaphthol and ethyl acetoacetate in 75% sulfuric acid solution. The desired coumarin was formed regioselectively and isolated in high yield. 

P-keto ester substituted coumarin von Pechmann reaction... 

Wang, L., Xia, J., Tian, H., Qian, C., Ma, Y. Synthesis of coumarin by Yb(OTf)3 catalyzed Pechmann reaction under the solvent-free conditions. Indian J. Chem., Sect. B2003, 42B, 2097-2099. 

Smitha, G., Sanjeeva Reddy, C. ZrCl4-Catalyzed Pechmann Reaction Synthesis of Coumarins Under Solvent-Free Conditions. Synth. Commun. 2004, 34, 39974003. 

Subhas Bose, D., Rudradas, A. P., Hari Babu, M. The indium(lll) chloride-catalyzed von Pechmann reaction a simple and effective procedure forthe synthesis of 4-substituted coumarins. Tetrahedron Lett. 2002, 43, 9195-9197. 

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