Pechmann condensation

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). 

Chloroaluminate ILs derived from l-butyl-3-methylimidazolium chloride having two equivalents of aluminum chloride were effective catalysts for the Pechmann condensation of phenol with ethylacetoacetonate, Scheme 26. ... 

Amino acid-modified furocoumarins were prepared by condensation of the T-hydroxysuccinimide ester of 3-(2,3,5-trimethyl-7-oxofuro[3,2-g]chromen-6-yl)propanoic acid 51 with amino acids <2003JPH177>. Ethyl 3-(7-hydroxy-4-methyl-2-oxo-2/7-3-chromenyl)propanoate 49, prepared in 56% yield by Pechmann condensation of resorcinol and diethyl 2-acetylglutarate in the presence of HCl, was condensed with 3-chlorobutan-2-one in the presence of base to give propanoate 50 (Scheme 4). The MacLeod method was then used to fuse a furan ring to the benzopyran-2-one system. Heating 50 with NaOH solution (1 M) readily cyclized it into the corresponding psoralen furocoumarin 51 with simultaneous hydrolysis of the ester. 

Furocoumarins 55a-f were conveniently prepared by the solventless Pechmann condensation of 6-hydroxybenzo-furans 54 with ethyl acetoacetate catalyzed by ZnCl2/Al203 and accelerated by microwave irradiation, as shown in Scheme 6 <2003PS(178)143>. 

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. 

Equation 15.4.1 Pechmann condensation of ethylacetoacetate 38 with resorcinol 37... 

A variation of this reaction involves acylation of a p-keto ester, followed by Friedel-Crafts cyclization of the ketone moiety. The product is a coumarin 43, in what is known as the Pechmann condensation Isolation of esters, such as 42, is not... 

Montmorillonite KIO. Pechmann condensation in an ionic liquid using ethyl acetate has also been reported. 

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

Convenient preparation of (4)ss also was accomplished by the von Pechmann condensation of phloroglucinol dimethyl ether (39)133) with ethyl cyclopentanone-2-carboxylate (40) in acidic media. 

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 regiochemistry of this synthetic coumarin proved to be identical to that of natural aflatoxin Bj (1)132). This preparation was also accomplished in two stages. The first proceeded by the acid catalyzed von Pechmann condensation of phloroglucinol dimethyl ether (59)133) and /3-ketoadipate ester (45)134,13S to give the substituted acyclic coumarin ester (44). This, in turn, underwent55 cyclization to ketocoumarin (6) in polyphosphoric acid media. 

It was felt that the lability of the enol ether was such that it could be adversely affected by the known conditions (vide infra) necessary to effect a von Pechmann condensation for the DE ring system fusion. Therefore, it was allowed that the introduction of this sensitive site would constitute the final step of the synthesis. 

The basic strategy for the formation of the final pentacyclic system via the von Pechmann condensation of an intact ABC system, and a suitable /3-ketoester (or a suitable derivative thereof) was retained, since no obvious difficulty was evident based on prior experiences. Work now was concentrated on the synthesis of the quintessential tricyclic ABC system (94). 

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. 

A difficulty with this synthesis is the low yield in the cyclisation leading to (B). With the objective of finding another route to this ring, the Pechmann condensation of resorcinol with 5,6-dimethoxy-2-methoxycarbonylindan-l-one was examined (ref.114). The latter was... 

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