Coumarins Knoevenagel reaction

The Knoevenagel reaction between o-hydroxyaryl aldehydes and ketones and substituted acetonitriles affords high yields of 3-substituted coumarins in aqueous alkaline media <96H(43)1257>, whilst 4-hydroxycoumarins have been elaborated to pyrano [3,2-c]benzopyran-5-ones by reaction with aromatic aldehydes and malononitiile <96P148>. The imine (10) resulting from the complex reaction of o-hydroxyacetophenone with malononitrile undergoes a 1,5-tautomeric shift in solution <96JCS(P1)1067>. 

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>. 

Use of the Knoevenagel reaction (67OR(l5)204), in which a benzaldehyde reacts with an activated methylene compound in the presence of an amine, goes some way to overcoming the inherent difficulties of the Perkin synthesis of coumarins (see later). In order to obtain the coumarin rather than the usual cinnamic acid, a 2-hydroxy substituent must be present... 

Table 7 Synthesis of Coumarins by a Knoevenagel Reaction on Salicylaldehyde...

Two mechanisms have been proposed for the Knoevenagel reaction. In one, the role of the amine is to form an imine or iminium salt (378) which subsequently reacts with the enolate of the active methylene compound. Under normal circumstances elimination of the amine would give the cinnamic acid derivative (379). However, when an o-hydroxy group is present in the aromatic aldehyde intramolecular ring closure to the coumarin can occur. The timing of the various steps may be different from that shown (Scheme 118). 

Salicylaldehydes and some o-hydroxyaryl ketones react with Meldrum s acid to give coumarin-3-carboxylic acids <03TL1755>. 3-Cyanocoumarins, and thus the 3-carboxylic acids, are available in high yield from a Knoevenagel reaction between salicylaldehydes and malononitrile in water <0382331>. 3-Chlorocoumarins result from the cathodic reduction of trichloroacetyl esters of o-hydroxyacetophenones <03T9161>. 

The ability of L-Pro to promote the Knoevenagel reaction has been harnessed in domino reaction sequences for the preparation of important target products. Several bicyclic and polycyclic systems have been obtained by these means. As an example, coumarines were prepared by the one-pot condensation reaction of o-hydroxybenzaldehydes with active methylene compounds (Scheme 2.8). In a related procedure, flavanones were synthesised from aromatic (3-ketoesters and aldehydes (Scheme 2.8). The domino sequence comprises in this case, a proline-catalysed Knoevenagel condensation and an intramolecular Michael addition. 

Valizadeh, H., Vaghefi, S. 2009. One-pot Wittig and Knoevenagel reactions in ionic liquid as convenient methods for the synthesis of coumarin derivatives. Synth. Commun. 39 1666-1678. 

Verdia, P., Santamarta, R, Tojo, E. 2011. Knoevenagel reaction in [MMlmlfMSOJ synthesis of coumarins. Molecules 16 4379-4388. 

Moussaoui, Y. Ben Salem, R. Catalyzed Knoevenagel reactions on inorganic solid supports Application to the synthesis of coumarin compounds. C. R. Chim. 2007,10,1162-1169. 

In order to study any chemoselectivity influences of microwave irradiation on the domino Knoevenagel/hetero-Diels-Alder process (the so-called Tietze reaction), Raghunathan and coworkers [31a] investigated the transformation of 4-hydroxy coumarins (10-85) with benzaldehydes 10-86 in EtOH to afford pyrano[2,3-c]cou-marin 10-87 and pyrano[2,3-b]chromone derivatives 10-88. Normal heating of 10-85a and 10-86a at reflux for 4h gave a 68 32 mixture of 10-87a and 10-88 in 57% yield, whereas under microwave irradiation a 97 7 mixture in 82% yield was obtained. Similar results were found using the benzo-annulated substrates 10-85b and 10-86b. 

In the second investigation [34], involving a coumarin synthesis by Knoevenagel condensation, supported by rate constant measurements and activation energy calculations, it was found that the effect of MW was more important when the reaction was conducted in xylene - it was noticeably reduced in ethanol (Eq. (5) and Tab. 3.3). 

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