Synthesis of coumarins

A synthesis of coumarin has been effected by Meyer, Beer, and Lasch." Ortho-chlorbenzal chloride is heated with glacial acetic acid and potassium acetate—... 

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... 

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). 

The synthesis of Coumarin derivatives can be made cleaner using zeolite H-BEA and even cationic ion-exchange resin like Amberlyst-15 works. Reactions of resorcinol with acrylic/methacrylic acid, maleic anhydride and esters have been studied (Gunnewegh et al., 1996). 

Scheme 7.37. Oxidative twofold rearrangement sequence for the synthesis of coumarin derivatives.

Kosiova I, Janicova A, Kois P (2006) Synthesis of coumarin or ferrocene labeled nucleosides via staudinger ligation. Beilstein J Org Chem 2 2-23... 

Fig. 4 Combinatorial synthesis of coumarin library using Pd-mediated cross-coupling reaction and 3D scatter plot of representative coumarin derivatives according to their excitation, emission wavelength, and quantum yield. All the photophysical properties were measured in ethanol...

Bigi F, Chesini L, Maggi R, Sartori G (1999) Montmorillonite KSF as an inorganic, water stable, and reusable catalyst for the knoevenagel synthesis of coumarin-3-carboxylic acids. J Org Chem 64 1033-1035... 

Appel H (1935) Improved method for the synthesis of coumarins by V Pechmann s method. J Chem Soc. Abstracts 1031... 

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... 

Song A, Wang X, Lam KS (2003) A convenient synthesis of coumarin-3-carboxylic acids via Knoevenagel condensation of Meldrum s acid with ortho-hydroxyaryl aldehydes or ketones. Tetrahedron Lett 44 1755-1758... 

The classical Pechmann approach for the synthesis of coumarins via the micro-wave-promoted reaction [68] has been extended to solvent-free system wherein salicy-... 

Figure 3.4. Synthesis of coumarin and furanocoumarin from p-coumaric acid.

The intermolecular reaction of phenols with propiolic esters occurs in the presence of a Pd(OAc)2 catalyst to afford coumarin derivatives directly.48,48a An exclusive formation of 5,6,7-trimethoxy-4-phenylcoumarin is observed in the Pd(OAc)2-catalyzed reaction of 3,4,5-trimethoxyphenol with ethyl phenylpropiolate in TFA (Equation (46)). Coumarin derivatives are obtained in high yields in the cases of electron-rich phenols, such as 3,4-methylenedioxyphenol, 3-methoxyphenol, 2-naphthol, and 3,5-dimethylphenol. A similar direct route to coumarin derivatives is accomplished by the reaction of phenols with propiolic acids (Equation (47)).49 A similar reaction proceeds in formic acid at room temperature for the synthesis of coumarins.50,50a Interestingly, Pd(0), rather than Pd(n), is involved in this reaction. 

In the preparation described above we have an important means of making fi-arylacrylic acids, and from them, by hydrogenation, fi-arylpropionic acids. The method is used in the investigation of alkaloids and in the synthesis of coumarin from salicylaldehyde. 

Base-catalysed synthesis of coumarins under liquid liquid phase-transfer catalysis... 

A review of Claisen rearrangements in aqueous solution has appeared. The synthesis of natural products utilizing tandem Diels-Alder additions with sigmatropic rearrangement processes has been reviewed, and a brief review of the regioselective synthesis of coumarins, quinolones and thiocoumarins with 3,4-fused pyran or furan ring systems by the Claisen rearrangement has been presented. ... 

A bismuth-catalyzed alkylation of warfarins has not been described, although a bismuth-mediated synthesis of the coumarin core structure 21 starting from phenols 19 and ethyl acetoacetate 20 is known (Scheme 17) [51]. The synthesis of coumarins proceeds in the same way as the above-described indene synthesis. The initial reaction of phenol 19 and ethyl acetoacetate 20 leads to the ester. 

Scheme 17 BiCl3-catalyzed synthesis of coumarin core structures ...

Several reports for the synthesis of coumarins have used lactone formation to erect the tricyclic core (Equation 44) < 1995T3197,1999SC929>. Other approaches to similar coumarins include the ring opening of an epoxide (Equation 45) <2002TA1799>. 

The chemical synthesis of natural flavours started some time ago with the synthesis of coumarin in 1868 and vanillin in 1874 [7]. The development of the petrochemical industry and the availability of cheap oil has meant that most of the plant-derived products are now synthesised from crude oil. In addition, flavours can now be produced using microbial cultures. Thus, to achieve sustainable development plants will have to provide many of the products currently produced from petrochemicals, including flavours. In this chapter the possible use of plant tissue culture techniques and processes in the sustainable production of flavours is outlined and discussed. 

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. 

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...

An indication of the scope of the Knoevenagel synthesis of coumarins is apparent from Table 7, but some further examples utilizing the conventional procedure are worthy of mention partly because some of the products are naturally occurring compounds. Graveolone (375), a benzodipyran, is obtained from the chroman-4-one shown by cyclization of the acrylic acid (Scheme 117) (78IJC(B)570). 

Synthesis of the benzopyran ring has also been performed by microwave-assisted copper-catalysed cross coupling of an aryl iodide with terminal alkynes, in the presence of copper(I) iodide/triphenylphosphine (Scheme 3.35)56. An alternative approach involving microwave heating of mixtures of salicylaldehyde and various derivatives of ethyl acetate in the presence of piperidine has enabled rapid Knoevenagel synthesis of coumarin derivatives (Scheme 3.35)57. 

De la Hoz, A., Moreno, A. and Vazquez, E., Use of microwave irradiation and solid acid catalyst in an enhanced and environmentaly friendly synthesis of coumarin derivatives, Synlett, 1999,608-610. 

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. 

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... 

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