A Green Protocol for One-Pot Biginelli Condensation Catalyzed by Para Toulene Sulfonic Acid under Microwave Irradiation


Kundan Lal, Lalitmohan J. Paliwal and Mahendra B. BagadePages 255-262 (8)


An environmentally benign protocol for the synthesis of some new 3, 4-dihydropyrimidin- 2-(1H)-ones and thiones promoted by p-Toulene Sulfonic Acid (PTSA) efficiently catalyzes the three component condensation reaction of formylchromone, substituted acetophenones and urea/thiourea under microwave irradiation (MWI). Compared to the classical Biginelli reaction conditions, this new methodology consistently has the advantage of giving good yields, require less reaction time, mild conditions with simple workup procedure. Newly synthesized compounds show moderate to good antimicrobial properties against some gram positive and gram negative bacteria.

Background: During recent years, dihydropyrimidinones have emerged as a vital compound with diverse biological and pharmacological applications. P. Biginelli in 1893 was the first chemist to report the three component condensation, using ethylacetoacetate with different aldehydes and urea for the synthesis of dihydropyrimidine under acidic condition. However, serious drawback of this reaction has been the low yields obtained in the case of substituted aromatic and aliphatic aldehydes. Several improved procedures for the synthesis of dihydropyrimidines have been recently reported to enhance the efficiency of the Biginelli reaction, using various catalysts. Inspite of their potential utility many of the existing methods suffer from some drawbacks, such as the use of strong acidic conditions, long reaction times, tedious workup procedures, posing environmental hazards, and low yield of the products. The present work describes a novel approach toward the solvent-free one-pot synthesis of some novel dihydropyrimidine derivatives using formylchromone, substituted acetophenones and urea/thiourea under Microwave Irradiation (MWI) as well as by conventional method using p- toulene sulfonic acid (PTSA) as catalyst.

Objective: To develop an environment friendly method to get high yield and purity for the one-pot synthesis of some novel 3,4-Dihydropyrimidine derivatives. Also, incorporation of various functional groups along with other heterocyclic ring like chromone nucleus has been introduced to increase the efficacy of antimicrobial properties.

Methods: Conventional Method: A mixture of 2.24g (0.01mol) 4-Oxo-4-H-benzo[h]chromene-3-carbaldehyde (1) was refluxed for 12-14 h with substituted Acetophenones (0.01mol) (2a: 1.2 mL), m-Nitroacetophenone (2b:1.65 g), p-Chloro acetophenone(2c:1.54 g), p-Hydroxy acetophenone, (2d:1.36 g), p-Bromo acetophenone (2e:1.99 g) and p- Nitroacetophenone(2f:1.65 g) and (0.01mol) of urea(0.60 g)/ thiourea(0.76 g) (3) in presence of p-toulene sulphonic acid (PTSA) (7-10 mol %, 13.3-19 g) as catalyst in 1,4 dioxane (30 mL). After the completion of reaction, the reaction mixture was poured into the cold water, filtered, washed with water, dried and was recrystallized using ethanol: acetic acid (2:1). Microwave Irradiation Method: A mixture of 0.22 g (1 mmol) 4-Oxo-4-H-benzo[h]chromene-3-carbaldehyde (1), substituted acetophenones(1 mmol) (2a:0.12 mL), m-Nitro acetophenone(2b:0.165 g), p-Chloro acetophenone(2c:0.154 g), p- Hydroxy acetophenone(2d:0.136 g), p-Bromo acetophenone(2e:0.199 g) and p- Nitro acetophenone(2f:0.165 g) and (1 mmol) of urea (0.06 g)/ thiourea (0.076 g) (3) in presence of p-toulene sulphonic acid (PTSA) (1-3 mol %, 1.9-6.7 g) was irradiated at 300 W, 120°C for 15-20 min to get 4-(4-Oxo-4H-benzo[h]chromen-3-yl)-6-substituted phenyl-3,4- dihydropyrimidin-2(1H)-one. After the completion of reaction, the reaction mixture was poured into the cold water, filtered, washed with water, dried and was recrystallized using ethanol: acetic acid (2:1).

Results: 4-(4-Oxo-4H-benzo[h]chromen-3-yl)-6-substituted phenyl-3,4-dihydropyrimidin-2(1H)-one: 4(a-f) and 3-(6- Substituted phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-4yl)-4H-benzo[h]chromen-4-one 5(a-f) were obtained by one-pot three component condensation of 4-Oxo-4-H-benzo[h]chromene-3-carbaldehyde(1), substituted acetophenones 2(a-f) and Urea / Thiourea (3) in presence of p-toulene sulphonic acid (PTSA) as a catalyst under microwave irradiation in solventfree condition. The present method has given excellent yields as compared to conventional method (Table 1). The schematic representation has been shown in Scheme 1. Under these conditions, the time for completion of reaction has been reduced dramatically and completed within 15-20 min as compared with the conventional method consuming 12-14 h to get the desired product. Different substituted acetophenones have been employed in this reaction successfully which showed large scope of this reaction for the synthesis of dihydropyrimidine derivatives. The newly dihydropyrimidines were synthesized by corresponding acetophenones, 4-Oxo-4-H-benzo[h]chromene-3-carbaldehyde and urea/thiourea in 1,4-dioxane using conventional method as well as by green approach under microwave irradiation in solvent free conditions (Scheme 1). The percentage yield has been found to be drastically increased in case of solvent free condition under microwave irradiation. Synthesized compounds have been characterized on the basis of various spectroscopic techniques such as FTIR, HRMS, 1H and 13C NMR. HRMS of the compounds 4c and 5c showed two peaks of M+ Na in a ratio of 3:1 and confirmed the existence of chloro group. Similarly compounds, 4e and 5e showed two peaks of M+ Na peak in a ratio of 100:97.3 nearly 1:1 ratios which confirmed the existence of bromo group. 1H and 13C NMR also gave various corresponding peaks confirming the formation of various DHPMs.

To investigate and evaluate the catalytic efficacy of different Lewis acids in this reaction, some other combinations have also been tried (Table 2). It is clear from these data (Table 2) the catalyst PTSA used in this reaction has been found to be most effective in synthesis of dihydropyrimidines with a better yield of the products in a very short reaction time. Other catalysts such as AlCl3.6H2O and ZnCl2 did not give the desired product. This protocol is practically general and several functionalities like nitro, chloro, hydroxyl and bromo were not affected during the course of reaction and were of special interest in the synthesis of dihydropyrimidines in a single step with high yield. An amount of (1-3 mol %) PTSA was found to be very effective under MWI and the use of less than that was not optimal. All the synthesized dihydropyrimidine derivatives 4(a-f) and 5(a-f) were tested for their in vitro antibacterial study against different strains of bacterial species such as S.aureus, B.subtillis, E.coli and K.aerogenes using well diffusion method. Antibacterial results have been summarized in (Table 3), which indicated that the most of the synthesized compounds exhibited moderate to good antibacterial properties against all bacterial strains and compared with standard drug Amoxicillin. Compounds 4b, 4c, 4d, 4e and 5f have exhibited excellent activity against E.coli species. Similarly compounds, 5b and 5f have showed excellent activity against S.aureus and compound 4e showed good activity against B.subtilis. All these compounds showed their activity at the concentration of 100μl. Remaining compounds exhibited moderate antibacterial activity as compared to the standard drug (Amoxicillin).

Conclusion: In the course of our study an environment friendly, solvent-free, mild and efficient protocol for the synthesis of some new dihydropyrimidinones and thiones catalyzed by PTSA in MWI have been found to be of several advantages. It may be of high interest for a synthetic chemist for its simple and environmentally safe procedure. It has an easy workup with mild conditions, solvent-free, short reaction times (15-20 min) and produced excellent yields (80-95%). Furthermore, this series may provide new classes of biologically active compounds. The newly synthesized DHPM’s showed moderate to good antimicrobial properties. Therefore, we expect our protocol will find its way to endow the requirements of pharmaceutical industries and institutions towards the invention of broad range of dihydropyrimidones and open a new pathway in the field of green chemistry which is the need of hour.


Biginelli reaction, dihydropyrimidines (DHPM), formylchromone, microwave Irradiation (MWI), p-toulene sulfonic acid (PTSA), substituted acetophenones, thiourea, urea.


Department of Chemistry, Faculty of Science, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, 440 033, Nagpur, Maharashtra, India.

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