Pechmann condensation coumarin synthesis

The most important FBAs in the coumarin series are the 7-amino-3-phenylcoumarins which are prepared via the Pechmann coumarin synthesis. For example, m-aminophenol may be condensed with ethyl 3-hydroxy-2-phenylacrylate in the presence of a Lewis acid in nitrobenzene (Scheme 13). 

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. 

Fig. 2 Representative traditional methods for coumarins synthesis, (a) Perkin synthesis (b) Pechmann-type condensation (c) Knoevenagel-type condensation...

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

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

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... 

Potdar, M. K., Mobile, S. S., Salunkhe, M. M. 2001. Coumarin synthesis via Pechmann condensation in Lewis acidic chloroaluminate ionic liquid. Tetrahedron Lett. 42 9285-9287. 

Rajitha, B., Naveen Kumar, V., Someshwar, R, Venu Madhav, J., Narsimha Reddy, P., Thirupathi Reddy, Y. 2006. Dipyridine copper chloride catalyzed coumarin synthesis via Pechmann condensation under conventional heating and microwave irradiation. ARX/VOC 2006(12) 23-27. 

Thirupathi Reddy, Y., Vqayakumar, N. S., Peter, A. C., Pavan, K. D., Narsimha Reddy, R, Rajitha, B. 2008. Ceric ammonium nitrate (CAN) An efficient catalyst for the coumarin synthesis via Pechmann condensation using conventional heating and microwave irradiation. Synth. Commun. 38 2082-2088. 

Soleimani, E. Khodaei, M. M. Batooie, N. Samadi, S. Tetrakis(acetonitrile)copper(I) hexafluorophosphate catalyzed coumarin synthesis via Pechmann condensation under solvent-free condition. J. Heterocycl. Chem. 2012, 49, 409-412. 

Zeolites have been shown to catalyse a variety of related reactions (Downing et al., 1997), e.g. zeolite beta catalyses the synthesis of coumarins via the Pechmann condensation. For example, condensation of resorcinol with ethyl acetoacetate over zeolite beta in refluxing toluene gave methylumbelliferone, a perfumery ingredient, in 70-80% yield (Fig. 2.24) (Gunnewegh ef a/., 1996). 

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... 

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. 

Also used as a spectral comparison model for the elucidation of the B and G aflato-xinsss this compound was prepared in a multi-step synthesis. The von Pechmann condensation of phloroglucinol dimethyl ether (59)133 with diethyl cyclopentane-4,5-dione-l, 3-dicarboxylate (41) in acidic solution afforded the /J-ketoester (42), which readily underwent decarboalkoxylation, in a seperate step, to give the keto-coumarin (5). The beauty of this methodology is illustrated by the use of the symmetrical diketoester (41), which of course, only allows for the formation of a single coumarin (von Pechmann) product (42). The regiochemistry of the final product, however, was demonstrated to be the incorrect isomer insofar as the aflatoxin structures were concerned. 

The classical Pechmann approach for synthesis of coumarins via the microwave-promoted reaction [75] has been extended to a solvent-free system in which salicyl-aldehydes undergo Knoevenagel condensation with a variety of ethyl acetate derivatives in the presence of piperidine to afford coumarins (Scheme 8.23) [76]. 

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 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. 

For example, ethanol clearly stands out as the solvent of choice for the synthesis of quinoxalines derivatives. However, acetonitrile proved to be a better solvent for the preparation of substituted imidazoles, since the reaction time period is shortest in this case. Otherwise, the Pechmann condensation of coumarins performed better when the reaction was carried out under neat conditions and at higher temperatures. None of the reactions proceeded in the absence of the catalyst or with only silica as the catalyst. 

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