SILICA IODIDE CATALYZED ULTRASOUND ASSISTED ONE-POT THREE-COMPONENT SYNTHESIS OF 

3,4-DIHYDROPYRIMIDINE-2-(1H)-ONES/-THIONES 

Amreen Khanumimage, Riyaz-ur-Rahaman Khanimage, Mangalavathiimage, Mohamed Afzal Pasha*image

Department of Chemistry, Jnanabharathi Campus, Bangalore University, Bengaluru-560056, India.

ABSTRACT 

Aim and objective: A single-pot three-component reaction for a competent preparation of biologically active 3,4-dihydropyrimidineones/-thiones using Silica Iodide (SiO2-I) as a reliable and reusable heterogeneous catalyst is developed. 

Methods: The reaction proceeds via condensation of araldehydes, urea/thiourea, ethyl acetoacetate in ethanol under ultrasonic condition to afford the target molecules in best yields. The reaction proceeds in 30 min and SiO2-I has shown high proficiency in performing this single-pot Biginelli reaction.

Results: The use of catalytic SiO2–I (0.1 g) accelerated the reaction and gave the product in excellent yield. Maximum yield of the product was found to be 96% in ethanol

Conclusion: Study concludes the used method has shown many advantages, mild condition, short duration, simple isolation and best yields of products.

Keywords: Araldehydes, 3,4-dihydropyrimidine-2-(1H)-ones/-thiones, ethyl acetoacetate,  silica iodide, ultrasonication, urea/ thiourea.

 

INTRODUCTION

 

Ultrasonication is recognized as a substantial mode for the sustainable synthetic organic processes,1-3 and provides several advantageous like tumbling time, minimization of waste, very high yields of the product by enhancing the rate and yield of the desired products in micro surroundings4-5. The viability of single-pot multicomponent reactions (MCRs) under ultrasonication using the heterogeneous silica iodide (SiO2-I) as a catalyst has shown considerable progress in their efficiency from implementation and environmental points of view6,7. One of the significant, vital and biologically essential heterocyclic scaffolds is pyrimidine, and many natural products possess this motif. Molecules which are having pyrimidine skeleton exhibit unique therapeutic properties, and play essential role in biochemical reactions8. Pyrimidines have occupied a characteristic place in organic and medicinal chemistry and in designing pharmaceutical products since decades9. They exhibit a wide-range of bio activity such as: calcium channel blocking property, as antifungals, antimalarials, antibacterials, antihyperten-sive, anti-inflammatory agents, and inhibit fatty acid transportation, α1a- and neuropeptide Y antagonists and work as mitotic kinesin inhibitors10-14. Marine alkaloids such as: A and B-batzelladines, ptilocaulin and saxitoxin, due to the presence of dihydro-pyrimidine (DHPM) moiety in them are known for inhibiting the binding of HIV gp-120 to CD4 cells in AIDS chemotherapy15. 4-Aryl-5-isopropoxy-carbonyl-6-methyl-3,4-dihydropyrimidin -ones exhibit anti-microbical activity16. 

In 1893, Biginelli synthesized 3,4-dihydropyrimidine-2(1H)-ones via an acid catalysed single-pot three-component reaction of an α, β-ketoester, aldehyde and urea17.  The reported protocol has drawbacks such as: prolonged reaction duration, low yield of products and tolerance of different functional groups throughout the reaction; which led to the growth of single-pot multi-component approaches towards getting the DHPMs and a number of reactions have been reported towards this condensation with a variety of catalysts such as: Lewis acids18, Brønsted acids19, polymer supported materials20, ion-exchange resin21, PTCs19, ionic liquids20, Brønsted bases22, solid phase catalysts23 and heterogeneous reagents24, under microwave irradia-tion25, ultrasonication26, using other green synthetic approaches27, under solvent-less condition28, grindstone technique29, nano ZnO embedded in SBA-1530 and dendrimer attached nano phosphotungstic acid particles immobilized on nano silica31. Many of these protocols involve harsh conditions, tedious work-up, and require long time, use of expensive reagents, non-recoverability of catalysts, strong acidic or basic conditions, environmental contamination, undesirable yields and non-tolerance of certain moieties. Hence, the progress of devising mild and eco-friendly methods which can overcome these drawbacks are of great significance towards the preparation of DHPMs. The ultrasonication method offers copious advantages like: better yield of the target molecules, superior reaction rates, works under mild and energy efficient reaction conditions, and minimization of waste takes place when compared with conventional methods.

 

EXPERIMENTAL

 

Materials and apparatus

Commercially available reagents were used for the reactions. Liquid aldehydes were purified by distillation. Silica gel plates (Merck 60 F250) were used for following the reactions under the UV lamp. Agilent make Cary 630 FT-IR spectrophotometer for IR spectra; Varian Mercury instrument working at 400 MHz for 1H NMR in CDCl3 and Bruker AMX instrument (100 MHz) for 13C NMR spectra in DMSO-d6; Agilent Technologies (1200 series) instrument for LC-MS were used for characterization. SIDILU, Indian make sonic bath was used for sonic reactions (35 kHz at 25°C).  SiO2-I was prepared and characterized by K. B. Ramesh and M. A. Pasha32.

Experimental procedure for the preparation of 4a‒4m  

1 mmol each of araldehyde, urea/thiourea, ethyl acetoacetate, SiO2-I (0.1 g) and ethanol (5 mL) were taken in a 50 mL conical flask and sonicated for 30 min, filtered and the residue was washed with ethanol (5 mL×2). The product present in the filtrate and washings, was recovered by distillation and recrystallized from hot aq. ethanol. The structures were established by spectral analysis, from their melting points or by the comparison on TLC with the standard samples.

Spectral Data

4-(3¢-Methoxyphenyl)-6-methyl-2-oxo-3,4-dihydro-(1H)-pyrimidine-5-ethyl carboxylate (4a):

IR (ATR, υ cm-1): 3237, 3100, 2982, 1700, 1647, 1038;

1H NMR: δ (ppm) = 9.13 (s, 1H, NH), 7.67 (s, 1H, NH), 6.76–7.24 (m, 4H, Ar-H), 5.10 (d, J = 2.4 Hz, 1H, CH), 3.95‒4.00 (q, J = 7.2 Hz, 2H, CH2), 3.70 (s, 3H, CH3), 2.23 (s, 3H, CH3), 1.07–1.11 (t, J = 7.2 Hz, 3H, CH3); 

13C NMR: δ (ppm) = 14.5, 18.2, 53.7, 55.5, 59.6, 106.0, 111.1, 112.1, 119.5, 127.8, 148.4, 152.6, 158.9, 160.8, 167.1; 

Mass (m/e): [M+H]+ 291.1

4-(3¢,4¢-Dimethoxyphenyl)-6-methyl-2-oxo-3,4-dihydro-(1H)-pyrimidine-5-ethyl carboxylate (4b):

IR (ATR, υ cm-1): 3247, 3107, 2955, 1706, 1680, 1024;

1H NMR: δ (ppm) = 9.09 (s, 1H, NH), 7.62 (s, 1H, NH), 6.85–6.88 (d, J = 8.4 Hz, 1H,Ar-H), 6.823 (s, 1H, Ar-H), 6.75–6.77 (d, J = 8.4 Hz, 1H, Ar-H), 5.07 (d, J = 2.8 Hz, 1H,CH), 3.95–4.00 (q, J = 6.8 Hz, 2H, CH2), 3.69 (s, 6H, 2 × OCH3), 2.23 (s, 3H, CH3), 1.07–1.16 (t, J = 6.8 Hz, 3H, CH3); 

13C NMR: δ (ppm) = 14.5, 18.0, 55.9, 59.0, 60.1, 106.0, 111.6, 118.2, 118.3, 136.6, 148.2, 148.3, 149.2, 152.6, 168.5; 

Mass (m/e):  [M+H]+ 321.1

4-(3¢-Nitrophenyl)-6-methyl-2-oxo-3,4-dihydro-(1H)-pyrimidine-5-ethyl carboxylate (4c):

IR (ATR, υ cm-1): 3226, 3105, 2964, 1685, 1636, 1523;

1HNMR: δ (ppm) = 9.32 (s, 1H, NH), 8.10–8.12 (d, J = 7.6 Hz, 1H, Ar-H), 8.06 (s, 1H, Ar-H), 7.85 (s, 1H, NH), 7.61–7.68 (m, 2H, Ar-H), 5.28 (d, J = 2.4 Hz, 1H, CH), 3.96–4.01 (q, J = 6.8 Hz, 2H, CH2), 2.25 (s, 3H, CH3), 1.06–1.09 (t, J = 6.8 Hz, 3H, CH3);

13C NMR: δ (ppm) = 14.2, 17.0, 54.1, 58.0, 59.3, 108.0, 122.6, 123.5, 128.0, 130.5, 145.3, 148.8, 148.9, 150.0, 164.2;

Mass (m/e): [M+H]+ 306.1

4-(4′-Chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-(1H)-pyrimidine-5-ethyl carboxylate (4d):

IR (KBr, υ cm-1): 3329, 1670, 1580, 1540, 1498, 1432, 1335, 1303, 1234, 1199, 1138, 1084, 1025, 928, 877, 752, 690; 

1H NMR: δ (ppm) = 9.32 (s, 1H, NH), 8.19 (d, J = 8.7 Hz, 2H), 7.86 (s, 1H, NH), 7.45 (d, J = 8.7 Hz, 2H), 5.22 (s, 1H), 3.93 (q, J = 7.3 Hz, 2H), 2.22 (s, 3H), 1.05 (t, J = 6.9 Hz, 3H);

13CNMR: δ (ppm) = 14.6, 18.4, 54.2, 59.2, 59.9, 98.2, 123.8, 124.4, 127.8, 128.2, 147.2, 152.3, 152.5, 158.2, 165.5.

4-(4′-Methylphenyl)-6-methyl-2-oxo-3,4-dihydro-(1H)-pyrimidine-5-ethyl carboxylate (4e)33: 

IR (KBr, υ cm-1): 3220, 3100, 1720 (sh), 1700;

1H NMR: δ (ppm) = 9.19 (s, 1H, NH), 7.70 (s, 1H, NH), 7.12 (s, 4H), 5.11 (d, J = 3.0 Hz, 1H), 4.00 (q, J = 7.5 Hz, 2H), 2.28, 2.30 (2 s, 6H, 2 × CH3), 1.12 (t, J = 7.5 Hz, 3H).

4-(2′-Nitrophenyl)-6-methyl-2-oxo-3,4-dihydro-(1H)-pyrimidine-5-ethyl carboxylate (4g)33: 

IR (KBr, υ cm-1): 3230, 3120, 1730, 1710, 1650; 

1H NMR: δ (ppm) = 9.37 (br s, 1H), 8.23 (d, J = 10.0 Hz, 2H), 7.91 (br s, 1H), 7.51 (d, J = 10 Hz, 2 H), 5.29 (d, J = 3.0 Hz, 1H), 4.00 (q, J = 7.5 Hz, 2H), 2.29 (s, 3H), 1.11 (t, J = 7.5 Hz, 3H).

4-(2′-Chlorophenyl)-6-methyl-2-oxo-3,4-dihydro(1H)-pyrimidine-5-ethyl carboxylate (4h)33: 

IR (KBr, υ cm-1): 3240, 3100, 1710, 1650; 

1H NMR: δ (ppm) = 9.39 (br s, 1H), 7.49–7.98 (m, 5H), 5.81 (d, J = 3.0 Hz, 1H), 3.88 (q, J = 7.5 Hz, 2H), 2.30 (s, 1H), 0.94 (t, J = 7.5 Hz, 3H).

4-(2′,3′-Dichlorophenyl)-6-methyl-2-oxo-3,4-dihydro-(1H)-pyrimidine-5-ethyl carboxylate (4i)33: 

IR (KBr, υ cm-1):  3360, 3220, 3100, 1690, 1640; 

1H NMR: δ (ppm) = 9.30 (br s, 1H, NH), 7.72 (br s, 1H, NH), 7.22‒7.46 (m, 4H), 5.67 (d, J = 2.5 Hz, 1H), 3.91 (q, J = 7.5Hz, 2H), 2.32 (s, 3H), 1.08 (t, J = 7.5 Hz, 3H).

4-(2′-Trifluoromethylphenyl)-6-methyl-2-oxo-3,4-dihydro-(1H)-pyrimidine-5-ethyl carboxylate (4j)33: 

 IR (KBr, υ cm-1): 3360, 3100, 1700, 1690, 1640; 

1H NMR: δ (ppm) = 9.32 (br s, 1H, NH), 7.80 (br s, 1H, NH), 7.50–7.61 (m, 1H), 7.25–7.43 (m, 2H), 5.69 (br s, 1H), 3.89 (q, J = 7.5 Hz, 2H), 2.31 (s, 3H), 0.97 (t, J = 7.5 Hz, 3H).

4-Phenyl-6-methyl-2-thioxo-3,4-dihydro-(1H)-pyrimidine-5-ethyl carboxylate (4k)34: 

 IR (KBr, υ cm-1): 3243, 1711, 1627;

1HNMR: δ (ppm) = 10.30 (s, 1H, NH), 9.63 (s, 1H, NH), 7.28 (m, 5H, Ar-H), 5.18 (s, 1H, CH), 4.00 (q, J = 7.0 Hz, 2H, CH2), 2.29 (s, 3H, CH3),  1.10 (t, J = 7.06 Hz, 3H, CH3).

13CNMR: δ (ppm) = 12.2, 15.5, 52.2, 57.8, 99.2, 124.7, 125.8, 126.6, 143.1, 163.4, 172.6; 

Mass (m/e):  [M+H]+ 277.1

4-(4′-Chlorophenyl)-6-methyl-2-thioxo-3,4-dihydro-(1H)-pyrimidine-5-ethyl carboxylate (4l)34: 

IR (KBr, υ cm-1): 3242, 1705, 1638; 

1HNMR: δ (ppm) = 10.58 (s, 1H, NH), 9.75 (s, 1H, NH), 7.45 (d, J = 0.8 Hz, 2H, Ar-H),  7.28 (d, J = 8.6 Hz, 2H, Ar-H), 5.16 (s, 1H, CH), 4.02 (q, J = 7.1 Hz, 2H, CH2), 2.27 (s, 3H, CH3), 1.12 (t, J = 7.1 Hz, 3H, CH3);

Mass (m/e): [M+H]+ 311.06

4-(3′-Nitrophenyl)-6-methyl-2-thioxo-3,4-dihydro-(1H)-pyrimidine-5-ethyl carboxylate (4m)34

IR (KBr, υ cm-1): 3170, 1715, 1661, 1593, 1540; 

1HNMR: δ (ppm) = 10.56 (s, 1H, NH), 9.80 (s, 1H, NH), 8.08 (s, 1H, Ar-H), 7.65–7.73 (m, 2H, Ar-H), 5.36 (s, 1H, CH), 4.04 (q, J = 7.6 Hz, 2H, CH2), 2.34 (s, 3H, CH3), 1.11 (t, J = 7.5 Hz, 3H, CH3);

Mass (m/e): [M+H]+ 322.08

 

RESULTS AND DISCUSSION

 

In order to determine the generality of use of SiO2-I32 assisted ultrasonic single-pot three-component reaction, the influence of reaction medium, temperature, catalyst, amount of the catalyst required and the energy efficiency were examined for enhancing the rate and yield of the products by taking 1 mmol each of 3-methoxybenzaldehyde, urea and ethyl acetoacetate as model substrates. 

Table 1: Effect of various catalysts on the preparation of 4a under ultrasonic condition.

Effect of catalyst

Various catalysts were subjected for screening under different conditions (at 28°C, reflux temperature and ultrasonication) to authenticate the right selection and the results are shown in the Table 1. To study the activity of catalyst, the present reaction was first studied without catalyst to get 20% product (entry 1). The yield of the product hardly enhanced with catalystic NaI, SiO2, TiO2, CeCl3, ZnCl2, K2CO3 and ZnO (entries 2–8). The use of catalytic SiO2–I (0.1 g) accelerated the reaction and gave the product in excellent yield (96%, entry 10) in 30 min. Hence, SiO2–I was therefore, selected under ultrasonication for further studies. 

Table 2: Solvent effect on the SiO2-I catalyzed synthesis of 4a.

Solvent effect

Evaluation of different solvents was taken up and the results are presented in Table 2. To demonstrate the effect of the solvent, the reaction of 1 mmol each of 3-methoxybenzaldehyde, urea and ethyl acetoacetate was first studied under solvent-less condition to get 35% product under ultrasonic condition (entry 1), In nonpolar solvents the yield was very low (entries 2,3), and in polar solvents like 1,4-dioxane, DMSO, DMF and THF, the yields were moderate (entries 4‒7); the most promising enhancement was seen when protic solvents such as: MeOH, H2O and ethanol were used, and the yields were excellent (entries 8−10); and among these three solvents, acceleration of the rate of the reaction (30 min) and yield of the product (96%, entry 10), was found in ethanol. Hence, for further studies, ethanol was used under ultrasonic condition. 

Table 3: Study of catalyst-load on the synthesis of 4a in ethanol.

Catalyst feed ratio

A study on the effect of catalyst-load on the progress of this successful reaction under ultrasonic condition was then taken up; the results are encapsulated in Table 3. From above results, it is evident that, SiO2-I may activate the carbonyl group of the araldehyde and facilitate the attack of urea/thiourea (2) to form an acyl imine.

The active methylene present in ethyl acetoacetate (3) may then attack the intermediate imine to produce ureide. This on subsequent cyclization may lead to the corresponding 2, 3-dihydropyrimidinones/-thiones.

Table 4: SiO2–I catalysed synthesis of 4a–4m.

                                                                            


CONCLUSION

 

In conclusion, a versatile, SiO2-I catalysed, energy efficient, single-pot three-component, green protocol for the synthesis of dihydropyrimidinones/-thiones in ethanol under ultrasonic condition is developed. Such a method has several advantages including: mild condition, short duration, simple isolation and best yields of products.

 

ACKNOWLEDGEMENT

 

Dr. Mohamed Afzal Pasha acknowledges the University Grants Commission, New Delhi for a BSR Faculty Fellowship.

 

AUTHOR’S CONTRIBUTION

 

Preparation and characterization the dihydropyrimidin-thiones was done by Amreen Khanum. Preparation of the dihydropyrimidinones, getting the spectra, characterization of products and drafting of the manuscript was done by Riyaz-ur-Rahaman Khan. Mangalavathi was involved in Purification, getting the spectra and characterization of dihydropyrimidinones. Compilation of data, preparation and editing of the manuscript was performed by supervisor Mohamed Afzal Pasha.

 

CONFLICT OF INTEREST

 

There is no conflict of interest between the authors for publishing this research work.

 

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