An expeditious, one-pot method for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones using a mixture of phosphorus pentoxide-methanesulfonic acid (Eaton’s reagent) at room temperature under solvent-free conditions is described. The salient features of this method include short reaction time, green aspects, high yields, and simple procedure.
The widespread interest in 3,4-dihydropyrimidin-2(1H)-ones, Biginelli compounds, has resulted in enormous efforts towards the synthesis of this biologically important moiety. Several methods have been developed for the synthesis of these compounds, but most of these protocols involve expensive reagents, strong acid catalysts, solvents, of prolonged reaction time and even then provide the products in unsatisfactory yields. With the current global awareness of developing environmentally friendly technologies, it is a need to perform a reaction in neat and nonhazardous conditions for providing a green approach towards organic synthesis [
Eaton’s reagent (1 : 10 phosphorus pentoxide in methanesulfonic acid) is an inexpensive and commercially available substance synthesized by Eaton in 1973 and found to be a good alternative to polyphosphoric acid which enables the drawbacks of many traditional catalysts to be overcome, because it has a much lower viscosity, it is easier to handle, and no complex separation procedures need to be employed [
In continuation of our efforts on developing environmentally benign, green methodologies for biologically active organic compounds [
One-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones using Eaton’s reagent.
The synthesis of functionalized 3,4-dihydropyrimidin-2(1H)-one derivatives is the area of interest because a large number of biologically active molecules contain this moiety. Many dihydropyrimidinones and their derivatives are pharmacologically important as they possess antitumor, antibacterial, and antiviral properties; they have also emerged as integral backbones of several calcium-channel blockers, vasorelaxants, antihypertensive, and antimitotic agents [
In our recent study about the synthesis of Bis(indolyl)methanes under mild conditions, we found that reagent works extremely well for the coupling reaction. In this paper, herein we employed the reagent in a multicomponent, one-pot reaction for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones at room temperature. Eaton’s reagent is a colorless, odorless liquid mixture of nonoxidizing methanesulfonic acid and a powerful dehydrating agent phosphorus pentoxide. The addition of phosphorus pentoxide increases the solubility of organic compounds in methanesulfonic acid; this was introduced by Eaton and has been used enormously in organic synthesis.
In order to standardize the reaction conditions for the condensation reaction, it was decided to synthesize 3,4-dihydropyrimidin-2(1H)-one (
Comparison of reaction conditions and yield of product
Entry | Reagent | Condition | Time | Yield (%) | Reference |
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1 | Methanesulfonic acid | Ethanol, reflux | 1 h | 95 | [ |
2 | P2O5 | Ethanol, reflux | 4 h | 91 | [ |
3 | Chlorosulfonic acid | Solvent free, 60°C | 30 min | 93 | [ |
4 | P2O5/SiO2 | Solvent free, 85°C | 2 h | 95 | [ |
5 | ZnCl2 | Solvent free, 80°C | 20 min | 90 | [ |
6 | I2 | Solvent free, 90°C | 15 min | 86 | [ |
7 | CF3COONH4 | Solvent free, 80°C | 10 min | 98 | [ |
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To optimize the reaction condition, the condensation reaction was performed under different conditions (Table
Optimization of reaction conditions for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones (4k) with 4-chlorobenzaldehyde.
Entry | Reagent | Solvent | Condition | Time | Yield (%) |
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1 | Eaton’s reagent | Ethanol | RT, stir | 2.3 h | 60 |
2 | Eaton’s reagent | Ethanol | Reflux | 2 h | 65 |
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To explore the scope and limitations of this reaction, we extended the procedure to various aromatic aldehydes carrying either electron-releasing or electron-withdrawing substituents in the ortho-, meta-, and para-positions. We have also synthesized the compounds with thiourea and methylacetoacetate, and we found that the reaction proceeds very efficiently with all the cases, and the products are obtained in high yields (Table
Expeditious synthesis of 3,4-dihydropyrimidin-2(1H)-ones (4a–4u) using Eaton’s reagent under solvent-free conditionsa.
Entry | R1 | R2 | X | Time (min) | Yieldb (%) | Melting point (°C) | |
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Found | Reported [reference] | ||||||
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C6H5 | C2H5 | O | 5 | 94 | 202–204 | 202–204 [ |
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4-F–C6H4 | C2H5 | O | 5 | 90 | 184–186 | 182-183 [ |
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4-NO2–C6H4 | C2H5 | O | 10 | 89 | 210–212 | 207-208 [ |
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2,3-Cl2–C6H3 | C2H5 | O | 10 | 91 | 248–250 | — |
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2,6-Cl2–C6H3 | C2H5 | O | 10 | 91 | 284–286 | 280–283 [ |
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3-NO2–C6H4 | C2H5 | O | 10 | 89 | 226–228 | 226-227 [ |
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2,4-Cl2–C6H3 | C2H5 | O | 10 | 89 | 252–254 | 249–251 [ |
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4-Br–C6H4 | C2H5 | O | 5 | 92 | 216–218 | 213–215 [ |
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4-OH–C6H4 | C2H5 | O | 15 | 75 | 226–228 | 227-228 [ |
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2-Cl–C6H4 | C2H5 | O | 5 | 85 | 218–220 | 216–219 [ |
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4-Cl–C6H4 | C2H5 | O | 5 | 85 | 214–218 | 213–215 [ |
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4-OCH3–C6H4 | C2H5 | O | 15 | 86 | 202–204 | 201-202 [ |
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2-Cl–C6H4 | CH3 | O | 5 | 90 | 224–228 | 224-225 [ |
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4-F–C6H4 | CH3 | O | 5 | 86 | 208–210 | — |
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C6H5 | CH3 | O | 5 | 92 | 212–214 | 213-214 [ |
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4-Cl–C6H4 | CH3 | O | 5 | 90 | 210–212 | 204–207 [ |
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C6H5 | C2H5 | S | 5 | 96 | 208–209 | 208-209 [ |
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3-NO2–C6H4 | C2H5 | S | 5 | 80 | 202–204 | 202–204 [ |
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4-CH3–C6H4 | C2H5 | S | 10 | 77 | 194–198 | 191–193 [ |
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4-OH–C6H4 | C2H5 | S | 15 | 80 | 196-198 | 195–197 [ |
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4-OCH3–C6H4 | C2H5 | S | 15 | 77 | 140–142 | 140 [ |
aAldehyde (1 mmol), ethyl/methylacetoacetate (1 mmol), urea/thiourea (1.5 mmol), Eaton’s reagent (2 mmol), solvent-free, RT.
bYield refers to isolated product.
Eaton’s reagent (7.7/92.3% by weight of P2O5/MeSO3H) was purchased from Sigma-Aldrich. All melting points were recorded in open capillaries. The purity of the compounds was checked by TLC on silica gel G (Merck). 1H NMR spectra were recorded on Varian 300 MHz instrument, in DMSO
A mixture of aromatic aldehyde
Mp 202–204°C; IR(nujol) cm−1: 3244 (NH), 3108 (NH), 1729 (C=O), 1645 (C=C), 1460 (CH); 1H NMR (300 MHz, DMSO
Mp 248–250°C; IR(nujol) cm−1: 3357 (NH), 3108 (NH), 1696 (C=O), 1646 (C=C), 1459 (CH); 1H NMR (300 MHz, DMSO
Mp 252–254°C; IR(nujol) cm−1: 3359 (NH), 3108 (NH), 1716 (C=O), 1640 (C=C), 1459 (CH); 1H NMR (300 MHz, DMSO
Mp 216–218°C; IR(nujol) cm−1: 3345 (NH), 3110 (NH), 1704 (C=O), 1645 (C=C), 1462 (CH); 1H NMR (300 MHz, DMSO
Mp 226–228°C; IR(nujol) cm−1: 3507 (NH), 3108 (NH), 1682 (C=O), 1645 (C=C), 1460 (CH); 1H NMR (300 MHz, DMSO
Mp 208–210°C; IR(nujol) cm−1: 3326(NH), 3204 (NH), 1695 (C=O), 1666 (C=C), 1460 (CH); 1H NMR (300 MHz, DMSO
Mp 212–214°C; IR(nujol) cm−1: 3334 (NH), 3108 (NH), 1704 (C=O), 1650 (C=C), 1459 (CH); 1H NMR (300 MHz, DMSO
Mp 194–198°C; IR(nujol) cm−1: 3323 (NH), 3165 (NH), 1670 (C=O), 1575 (C=C), 1459 (CH); 1H NMR (300 MHz, DMSO
Mp 196–198°C; IR(nujol) cm−1: 3357 (NH), 3108 (NH), 1670 (C=O), 1644 (C=C), 1459 (CH); 1H NMR (300 MHz, DMSO
Mp 140–142°C; IR(nujol) cm−1: 3311 (NH), 3165 (NH), 1664 (C=O), 1574 (C=C), 1459 (CH); 1H NMR (300 MHz, DMSO
In summary, we have developed an efficient, ecofriendly and solvent-free method for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones
M. N. Patil is thankful to UGC, New Delhi for SAP fellowship under the scheme “Research Fellowship in Sciences for Meritorious Students.” Authors are also thankful to Professor Raghao S. Mali and Dr. Sidhanath V. Bhosale for their constant encouragement.