Coumarins Synthesis Essay

Coumarins - Fast Synthesis by the KnoevenagelCondensation under Microwave Irradiation.

Darek Bogdal
Institute of Organic Chemistry, Politechnika Krakowska
ul. Warszawska 24, 31-155 Krakow, Poland;
e-mail: pcbogdal@cyf-kr.edu.pl


Abstract: Condensation of salicylaldehyde or its derivative with various derivatives ofethyl acetate in the presence of piperidine leads to the synthesis of coumarinsby a solvent free reaction under microwave irradiation.
Introduction

Results and Discussion

Experimental

References


Introduction
[first page]

Coumarins are nowadays an important group of organic compounds that are used asadditives to food and cosmetics [1], optical brightening agents [2], anddispersed fluorescent and laser dyes [3]. The derivatives of coumarin usuallyoccur as secondary metabolites present in seeds, root, and leaves of many plantspecies. Their function is far from clear, though suggestions include wasteproducts, plant growth regulators, fungistats and bacteriostats [4]. It istherefore of utmost importance that the synthesis of coumarin and itsderivatives should be achieved by a simple and effective method.

Coumarins can be synthesised by one of such methods as the Claisenrearrangement, Perkin reaction, Pechmann reaction as well as the Knoevenagelcondensation [5]. Some of the industrially important coumarins are the4-methylsubstituted group (e.g., 7-hydroxy-4-methylcoumarin (Coumarin 47 orCoumarin 460) and 7-diethylamino-4-methylcoumarin (Umbelliferon 47)). They canbe prepared by the Pechman reaction, which is just suited to their preparationfrom readily available 1,3-disubstituted compounds and their acetoacetic esters.

It was recently shown that the Pechman reaction could be quickly achieved usingmicrowave irradiation of the reagents in household microwave oven [6]. Since the solvent free phase-transfer catalytic reactions undermicrowave irradiation is the main topic in our lab [7], it has prompted us to present our results ofthe synthesis of coumarins by the Knoevenagel condensation under suchconditions. However, previously both the Knoevenagel reaction [8] and synthesis of coumarin by the Knoevenagelcondensation [9] have been the subject of microwave induced reactions,in the case of coumarins the only example that has been always given is thesynthesis of 3-ethoxycarbonylcoumarin (i.e., ethyl 2H-1-benzopyran-2-oxo-3-carboxylate).

Results and Discussion
[first page]

The aim of the present paper is to show that under the microwave irradiationthe Knoevenagel condensation can be successfully applied to the synthesis of anumber of coumarins, and the scope of the method is much broader. It isreported a very simple, fast and general procedure where the condensation ofsalicylaldehyde or its derivative with various derivatives of ethyl acetate(e.g., R3CH2COEt; R3: CO2Et, COMe, CN, p-C6H4-NO2) in thepresence of piperidine under the solvent-free condition leads to coumarinsynthesis (Fig.1)


Figure 1: Synthesis of coumarinssynthesis by the Knoevenagel condensation under microwaveirradiation.

The solvent-free conditions under microwave irradiation offers severaladvantages [10]: solvents are often expensive, toxic, difficultto remove in the case of aprotic dipolar solvents with high boiling point, andare environment polluting agents. Moreover, liquid-liquid extraction isavoided for the isolation of reaction products, and the absence of solventprevents from the risk of hazardous explosions when the reaction takes place ina microwave oven. The reactions (i.e., the synthesis of coumarins) were usuallycompleted within 1-10 min. and gave improvement yield over conventional methodin a shorter time. Moreover, the work-up procedure is simply reduced to therecrystallization of product from an appropriate solvent. The results from theexperiments are shown in Table 1.

TABLE 1: Results of the coumarins synthesis by the Knoevenagel reactions undermicrowave irradiation.


Compound Power [%] Time [s] Temp.a [C] Yield [%] M.p.e [C]

3ab10101298991-2
3bb2019094120-2
3cb20420176182-4
3db40522085274-5
3eb10101317289-91
3fb--r.t.d90167-9
3gb--r.t.d90224-5
3hc1059078294-6
3ib2062205580-2
3jb20613688152-3
3kb101016580225-6
3lc10612290265-7
4ab20517080117-8
4bb1088775186-8
4cb101010082296-8
4dc20317075297-9

a this is the final temperature reached by thereaction mixture; b a hydroxyaldehyde (100 mmol),carbonyl compound (2) (110 mmol), and piperidine (2.0 mmol); c a hydroxyaldehyde (50 mmol), carbonyl compound (2) (55 mmol), and piperidine (1.0 mmol);d r.t. room temperature (in this case it was unnecessary to applymicrowave power);e melting points, measured on a Boetius-PHMK 05 microscopeplates, are uncorrected.

In summary, the method describes a noticeable improvement in reactionsconditions for the coumarin synthesis by the Knoevenagel condensation and takesadvantage of both solvent free conditions reaction and microwave activation.As it is shown in Table 1, the reaction time is reduced to only a few minutes byusing microwave dielectric heating. The reactions can be run safely in goodyields, and the work-up procedure is reduced to the recrystallization of desiredproducts.

Experimental
[first page]

The reactions were carried out under atmospheric pressure in an open vesseladapted to Synthwave 402 microwave monomode reactor (Prolabo). All thecompounds were identified by GC/MS, IR, NMR and gave satisfactory results incomparison with authentic samples. Melting points are in good agreement withliterature data.

General Procedure - A mixture of a hydroxyaldehyde (100 mmol),carbonyl compound 2 (110 mmol), and piperidine (0.20 g, 2.4 mmol) was irradiatedand heated the microwave reactor with power and by the time indicated inTable 1. At the end of exposure to microwave, the reaction mixture wascooled to room temperature, and the crude product was recrystallised from anappropriate solvent (Table 1) to effort the coumarin 3 or4.

References
[first page]

  1. R. O'Kennedy, R. D. Thornes, Coumarins: Biology, Applications and Mode of Action, Wiley & Sons, Chichester, 1997.
  2. M. Zahradnik, The Production andApplication of Fluorescent Brightening Agents, Wiley & Sons, 1992.
  3. M. Maeda, Laser Dyes, Academic Press, New York, 1994.
  4. R. D. H. Murray, J. Mendez, S. A. Brown, The Natural Coumarins: Occurance,Chemistry and Biochemistry, Wiley & Sons, New York, 1982.
  5. J. D. Hepworth, Ch. D. Gabbut, B. M. Heron, in: Comprehesive inHeterocyclic Chemistry, Pergamon Press, 2nd edition, 1996.
  6. V. Singh, J. Singh, P. Kaur, G. L. Kad, J. Chem. Research (S), 1997, 58.
  7. D. Bogdal, J. Pielichowski, A. Boron, Synlett , 1996, 873; D. Bogdal, J. Pielichowski, K. Jaskot, Heterocycles, 1997, 45, 1997; D. Bogdal, J. Pielichowski, K. Jaskot, Synth. Commun., 1997, 27, 1553.
  8. S. A. Ayoubi and F. Texier-Boullet and D. Hamelin, Synthesis, 1994, 258; S. Y. Kim, P. S. Kwon, T. W. Kwon, Synth. Commun., 1997, 27, 533;J. K. Kim, P. S. Kwon, T. W. Kwon, Synth. Commun., 1996, 26, 535.
  9. A. K. Bose, M. S. Manhas, M. Ghosh, V. S. Raju, K. Tabei, Z. Urbanczyk-Lipkowska,Heterocylces, 1990, 30, 741.
  10. G. Bram, A. Loupy, D.Villemin, in: Solid Supports and Catalysts inOrganic Chemsitry , Ellis Harwood, London, 1992; R. A. Abramovitch, Org. Prep. Proc. Int., 1991, 23, 685; S. Caddick, Tetrahedron , 1995, 51, 10403; G. Majetich, R. Hicks, Radiat. Phys. Chem., 1995, 45, 567; C. R. Strauss, R. W. Trainor, Aust. J. Chem., 1995, 48, 1665,.

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