Meglumine sulfate catalyzed solvent-free one-pot synthesis of coumarins under microwave and thermal conditions

ABSTRACT A convenient method has been developed for the Pechmann reaction of phenols and β-keto esters catalyzed by meglumine sulfate. Solvent-free conditions, inexpensive catalyst, short reaction times, high yield, and ease of purification of the products are the advantages of this protocol. This novel catalytic system is expected to contribute to the development of more benign Pechmann condensation reactions of phenols with β-keto esters. GRAPHICAL ABSTRACT


Introduction
Coumarins, some of the most important of natural products, are fragrant organic compounds in the benzopyrone chemical class. They have been widely used in pharmaceuticals, [1] efficient laser dyes and optical brightening agents, [2] and additives in With attention to the importance of acidic catalyst, initially, we prepared sulfated meglumine (MS) in a simple route (Scheme 1). In continuation of our research, we try to develop a truly catalytic method for the formation of 4-substituted coumarins in the presence of a catalytic amount of MS as a high efficient acidic catalyst. The solvent-free condensation reaction of substituted phenols (2.5 mmol) and dicarbonyl compounds (2.5 mmol) in the presence of MS as a high efficient catalyst under thermal condition has been investigated (Scheme 2).
To optimize the reaction conditions such as temperature, time of reaction, and catalyst amounts, we considered the reaction between resorcinol and ethylacetoacetate as a model reaction. The results are summarized in Table 1. As shown in this table, in the presence of 0.01 g of catalyst, any product was obtained at room temperature (Table 1, entry 1). On the other hand, the yield and time were found to be more favorable when the reaction temperature increased to 100 °C (using 0.01 g of catalyst). Also, with increasing the catalyst amount from 0.01 to 0.04 g, the reaction moved faster with higher yield (Table 1, entry 9).
According to these results, we conducted the same reactions using ethylacetoacetate and a variety of substituted phenols in the presence of 0.04 g of MS under similar conditions. As expected, satisfactory results were obtained ( Table 2). As shown in Table 2, in all cases, the products have high yields, but in some cases the reaction times are longer because of the hindrance in phenol or β-ketoester structures; on the other hand, when the reaction was performed with inactive phenols, no product was achieved. In fact, starting materials remained intact even after prolonged heating (entry 3k). All products were characterized in detailed using physical and spectroscopic data (melting point, FT-IR, 1 H and 13 C NMR, and elemental analysis), consistent in comparison with authentic samples. [33][34][35][36][37][38][39] In next step, the model reaction performed under microwave irradiation with optimized power. Table 3 contains results of the coumarin synthesis in thermal and MW conditions.   The comparison between the yield and times of reactions show that the yields of products are high to excellent in both conditions but reactions in MW condition were performed in short times (6-8 min) as one of the important MW advantages in comparison with the thermal method.
Comparison of the activity of various catalysts in Pechmann condensation of resorcinol and ethyl acetoacetate in a ratio of 1:1 (model reaction) is depicted in Table 4. Data show that excellent yields of product were obtained when meglumine sulfate was used as a highly efficient catalyst both in thermal and microwave conditions.

Proposed reaction mechanism
A possible mechanistic pathway has been proposed for the condensation reaction for the synthesis of 7-hydroxy-4-methyl coumarin. It is based on proton transfer to keto group    of ethylacetoacetate from acid sites of catalyst followed by the nucleophilic attack of the resorcinol, resulting an intermediate that rapidly undergoes cyclization (through acidcatalyzed intramolecular condensation), yielding 7-hydroxy-4-methyl coumarin (Scheme 3).

Materials and methods
Chemical reagents and solvents were purchased from the Merck and Aldrich companies. Fourier transform infrared (FTIR) spectra were recorded using a Perkin-Elmer FT-IR 550 spectrometer. Melting points were determined in open capillaries using an Electrothermal MK3 apparatus. 1 H NMR and 13 C NMR spectra were recorded with a Bruker Avance DRX-400 spectrometer at 400 and 100 MHz, respectively. The elemental analyses were obtained from a Carlo ERBA model EA 1108 analyzer carried out on Perkin-Elmer 240c analyzer. Microwave-assisted reactions were performed with a Milestone ETHOS EZ apparatus, keeping irradiation power fixed and monitoring the internal reaction temperature.

Preparation of meglumine sulfate
A mixture of meglumine (1 g) and dry chloroform (20 ml) was poured in a two-necked, 100-ml, round-bottom flask equipped with ice bath in 0 °C and mixed for awhile. Chlorosulfonic acid (0.6 ml) was added dropwise to the mixture during 60 min and stirred for 6 h. After that, the product was filtered, washed with ethanol (5 times), and separated meglumine sulfate was dried at 90 °C for 4 h (Scheme 2). The yield of the obtained catalyst was about 90%. The concentration of H þ on the meglumine sulfate was about 3.5 mmol/g from acid-base titration. Also elemental analysis (CHNS) demonstrated that meglumine was sulfated successfully (C: 24%, H: 5.3%, N: 4.3%, S: 17%).

Synthesis of 3a as general procedure for solvent-free, one-pot preparation of coumarins using MS under thermal and microwave conditions
Resorcinol (2.5 mmol), ethylacetoacetate (2.5 mmol), and a catalytic amount of meglumine sulfate (0.04 g) were mixed and heated at 100 °C in thermal conditions. In microwave conditions, the reaction mixture subjected to microwave irradiation at power of 600 W and 60-70 °C for 6 min. The progress of the reaction was monitored by thin-layer chromatography (TLC). After the completion of reaction, the reaction mixture was cooled to room temperature and 10 ml of EtOH was added. Then, obtained mixture poured into crushed ice and stirred for 10 min. The crude product was collected by filtration, washed with icecold distilled water, and recrystallized from hot ethanol to afford pure corresponding pure product 3a (Scheme 1, Table 2

Conclusion
A convenient method has been developed for the Pechmann reaction of phenols and β-keto esters catalyzed by meglumine sulfate. Use of solvent-free conditions, inexpensive catalyst, short reaction times, high yield, and ease of purification of the products are the advantages of this protocol. The pronounced advantage of this novel catalytic system is expected to contribute to the development of more benign Pechmann condensation reactions of phenols with β-keto esters.