Oxalic Acid-Catalyzed Coumarin Synthesis via Pechmann Condensation Under Microwave Irradiation

Synthesis, Pages 4 (808 words)

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Abstract

This study presents an energy-efficient protocol for synthesizing coumarin through Pechmann condensation catalyzed by oxalic acid under microwave irradiation, eliminating the need for solvents. This novel approach provides a clean, fast, and convenient alternative for synthesizing coumarin derivatives, yielding products in significantly reduced time compared to traditional methods.

Introduction

Coumarin derivatives continue to be investigated over the years due to their importance in organic and medicinal chemistry because of their biological activities. Coumarin and its derivatives are associated with various biological activities viz.

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anti-inflammatory, anti-convulsant, anti-viral, anticoagulant, antioxidant, antibacterial, antifungal, anti-HIV, anti-carcinogenic material, and antihistamine. They are attracting attention of chemists as a large number of natural products contain this heterocyclic nucleus. Commercially, they are widely used as food additives, perfumes, cosmetics, pharmaceutical, optical brightenrs in dispersed fluorescent and laser dyes.

Microwave induced organic reaction enhancement. (MORE) is a technique realized in 1986 played a pivotal role in synthetic organic chemistry. MWI offers selective, instantaneous heat energy to a material providing faster and safer reactions.

Consequently, microwave irradiations often provide higher reaction yields in short time of span and simplify cumbersome purification processes. Applications of MORE chemistry finds useful in organic chemistry in alkylations, acylation, nucleophilic substitution, condensation, protection and deprotection, cycloaddition, oxidation andorganometallic reactions. In literature coumarin synthesis has been achieved by employing various methods like Von-Pechmann, Knoevenagel, Perkin, Reformatsy, and Wittig reaction.

In general, a valuable method for the synthesis of coumarin is the Von-Pechmann reaction. It is simple and straight reaction employingethyl acetoacetate and substituted phenol together with an acid catalyst.

Literature prevalence suggested that acids like H2SO4 TFA, etc. have been widely utilized for this conversion into coumarin synthesis. In addition, some other catalysts were also reported viz P2O5, AlCl3, Ionic liquid, Sulfated zircona[, Indiumhalides, and palladium, dipyridine copper chloride.

However, most of the reported synthetic protocols require high temperatures, prolonged reaction times, harsh reaction conditions, lower yield and the use of hazardous and often expensive acid catalysts. Another major drawback associated with reported procedures was that catalyst used in stoichiometric excess and recovery of catalyst was not possible during usual work-up processes.

Herein we report oxalic acid as a catalyst for coumarin synthesis under solvent free conditions using microwave irradiation. Oxalic acid has emerged as a promising acid catalyst during recent years and reported to catalyze some organic reactions. The catalyst used is inert, inexpensive and environmentally benign allowing various reaction conditions to be employed.

Experimental Section

The synthesis involved reacting phenols with ethyl acetoacetate in the presence of oxalic acid, utilizing microwave irradiation for energy input. The reaction's progress was monitored by TLC, and products were characterized using IR, ^1H NMR, and Mass spectroscopy. This method demonstrated the capability to synthesize various coumarin derivatives with high yields in a short duration, showcasing the versatility and efficiency of the protocol.

Results and Discussion

A mixture of phenol (1 mmol) and ethyl acetoacetate (1 mmol) in presence of oxalic acid (20mol %) was irradiated in microwave oven at 180 watt and the reaction was monitored by TLC. After completion of reaction, the product was extracted in dichloromethane and the solvent was distilled off on rotary evaporator. The compound obtained was then recrystallised from ethanol. The cellulose sulphuric acid gave comparatively high yields in shorter reaction period of 0.5-3 min and the products are characterized by IR, 1H NMR, and Mass.

C14H10O2,Mw=210, mp=154-153 οC, (1HNMR, 400MHz, DMSO-d6):2.52(s, 3H, Me) 6.374 (1H,C=CH) 6.63–7.43, m (6H, C=CH ArH).IR KBr (cm–1) 2987, 1715, 1602, , Mass:- 210(M+).

C10H8O3,Mw=177,mp=182οC,(1H,NMR,400MHz,DMSO-d6):2.34(s,3H,Me),6.01(s,1H),6.68(d,1H),6.76-6.79(dd,1H,)10.47(s,1H Phenolic -OH). IR KBr (cm–1) 3127,1682,1620. Mass:-177 (M+)

In order to investigate the synthetic utility of catalyst, a model reaction between ethyl acetoacetate (1mmol) and α-Naphthol (1mmol) in MWI under solvent free condition gave coumarin derivative 6 in 92% yield in 3 min.

To study the generality of the reaction different examples were studied. Phenols such as α-naphthol, resorcinol, 2-methyl resorcinol, m- nitro phenol, mcresol, 3-methoxy phenol, 1,2,3 trihydroxy phenol etc. efficiently reacted with ethyl acetoacetate to give corresponding coumarin derivatives in excellent yields (>90%) (Table 1). Unfortunately, the β-naphthol and p-nitro phenols did not undergo the reaction. The effect of catalyst concentration was also studied. The use of 20 mol% of catalyst was sufficient to catalyze the reaction at 180 Watt. It was observed that higher concentration of catalyst didn’t give the high yields (Table 2) indicating best results were obtained by using 20 mol% catalyst in standard reaction under solvent free and microwave irradiation conditions. After completion of the reaction, the product was isolated from organic solvent by extraction.

Conclusion

The efficient protocol for the synthesis of coumarin derivatives via Pechmann condensation has been developed. Various substituted phenols reacts with ethyl acetoacetate using oxalic acid as a catalyst under solvent free and microwave irradiation conditions to get the desired product in excellent yield.