Next Article in Journal
Effects of Phlomis umbrosa Root on Longitudinal Bone Growth Rate in Adolescent Female Rats
Next Article in Special Issue
Green Technique-Solvent Free Microwave Synthesis and Antimicrobial Evaluation of New Thiopyridine Arabinosides
Previous Article in Journal
Antimicrobial Diterpenoids of Wedelia trilobata (L.) Hitchc
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 21
Issue 4
10.3390/molecules21040462
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

New Efficient Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones Catalyzed by Benzotriazolium-Based Ionic Liquids under Solvent-Free Conditions

by
Zhiqing Liu
1,†,
Rong Ma
1,†,
Dawei Cao
1 and
Chenjiang Liu
1,2,*
1
Key Laboratory of Oil and Gas Fine Chemicals of Ministry of Education, School of Chemistry and Chemical Engineering, Xinjiang University, Urumqi 830046, China
2
Physics and Chemistry Detecting Center, Xinjiang University, Urumqi 830046, China
*
Author to whom correspondence should be addressed.
†
The two authors contributed equally to this paper.
Molecules 2016, 21(4), 462; https://doi.org/10.3390/molecules21040462
Submission received: 13 March 2016 / Revised: 30 March 2016 / Accepted: 5 April 2016 / Published: 7 April 2016
(This article belongs to the Special Issue Organic Reaction in Green Solvents)
Browse Figures
Versions Notes

Abstract

:
An efficient synthesis of novel 3,4-dihydropyrimidin-2(1H)-ones (DHPMs) and their derivatives, using Brønsted acidic ionic liquid [C2O2BBTA][TFA] as a catalyst, from the condensation of aryl aldehyde, β-ketoester and urea was described. Reactions proceeded smoothly for 40 min under solvent-free conditions and gave the desirable products with good to excellent yields (up to 99%). The catalyst could be easily recycled and reused with similar efficacies for at least six cycles.

Graphical Abstract

1. Introduction

In recent years, 3,4-dihydropyrimidin-2(1H)-ones (DHPMs) and their derivatives have received much attention because they are important substructures in both biologically active compounds and several marine alkaloids involving the DHPM core units [1]. A simple and direct approach for their synthesis involves the conjugate addition of aryl aldehyde, β-ketoester and urea in the presence of either protic or Lewis acids. In recent years, several improved methods have been reported for the preparation of these compounds using various catalysts such as p-TsOH·H2O [2], H3BO3 [3], [Al(H2O)6](BF4)3 [4], thiamine hydrochloride [5], l-(+)-tartaric acid-dimethylurea [6], imidazole-1–yl-acetic acid [7], HClO4-SiO2 [8], polyvinylsulfonic acid [9], SnCl2·2H2O [10], NaCl [11], SrCl2·6H2O [12], Al-planted MCM-41 [13], (NH4)2CO3 [14], CeCl3·7H2O [15], CaCl2 [16], Ce(NH4)2(NO3)6 [17] and Fe(OTs)3·6H2O [18]. However, several of these reported procedures suffer from some drawbacks such as strong acidic conditions, long reaction times, use of expensive or hazardous reagents, complex handling and low yields of products. Moreover, most of these methods employ organic solvents as the reaction medium. Hence, new, efficient and environmentally friendly procedures are still strongly demanded in organic transformations such as condensation reactions.
Currently, ionic liquids (ILs) have been widely used as environmentally benign reaction media and catalysts in organic synthesis owing to their unique properties of non-volatility, excellent solubility, high thermal stability and recyclability [19,20]. In particular, the synthesis of task-specific ILs (TSIL) with special functions according to the requirement of a specific reaction has become an attractive field. Extensive effort has been focused on the elucidation of the mechanism of Lewis acid–catalyzed Biginelli reactions in ionic liquids [21]. Sharma et al. [22] reported highly recyclable amino acid ionic liquids as a catalyst, particularly glycine nitrate, for the one-pot, three-component Biginelli condensation under microwave irradiation (MW). Recently, Kandasamy and co-workers realized the synthesis of 1-alkyl triazolium triflate room temperature ionic liquids and their catalytic studies in a multi-component Biginelli reaction [23]. In continuation of our interest in the Biginelli reaction [24,25,26], herein we employ Brønsted acid ionic liquid 1-butyl-3-carboxymethyl-benzotriazolium trifluoroacetate [C2O2BBTA][TFA] as a catalyst to study the possibility of synthesizing DHPMs under solvent-free conditions (Scheme 1).

2. Results and Discussion

The catalytic activity of [C2O2BBTA][TFA] was investigated in a one-pot Biginelli condensation of aryl aldehyde, β-ketoester and urea. The results are presented in Table 1. The best result was achieved by carrying out the reaction at 90 °C for 40 min in the presence of 10% catalytic amount of [C2O2BBTA][TFA] without any solvent (Table 1, entry 8). Inspired by Clark’s work [27], we explored the relationship between the catalyst and solvents (Table 1, entries 1–8). When molecular solvents, such as H2O, MeOH, CH3CN or toluene, were employed, the reaction afforded a mixture of benzaldehyde, ethyl acetoacetate and urea under similar conditions, and DHPMs were obtained only in a very low yield (<19%). When no catalyst was used in this reaction system, the reaction did not give the desired product. This showed that ionic liquid plays a very important role in the reaction system (Table 1, entry 9). The influence of the reaction time on the yield was also investigated as shown in Table 1, entries 8, 15–19. It turned out that although the reaction time was increased to 40 min, the yield did not change significantly (Table 1, entry 8). For the purpose of saving energy, we chose 40 min as the reaction time. Hence, the best conditions employed a 0.1:2:2:3 mole ratio of [C2O2BBTA][TFA], aryl aldehyde, β-ketoester, and urea at 90 °C for 40 min under solvent-free conditions.
The recycling performance of TSIL [C2O2BBTA][TFA] was one of its most important benefits, which was also investigated in the reaction of aryl aldehyde, β-ketoester and urea. After separation of the product, the filtrate containing catalyst was vacuumed to remove water and the resulting catalyst was reused directly for the next run. As shown in Table 1, Brønsted acidic ionic liquid [C2O2BBTA][TFA] can be recycled at least six times without showing a significant decrease in catalytic activity, and the yields ranged from 96% to 92% (Table 1, entry 8). This indicated that ionic liquid [C2O2BBTA][TFA] was an efficient and recyclable catalyst for the preparation of 3,4-dihydropyrimidin-2(1H)-ones derivatives.
In order to explore the scope and limitations of this reaction, we extended the procedure to various aryl-substituted aldehydes carrying either electron-donating or -withdrawing groups in the ortho, meta, and para positions. In general, the reaction proceeded easily under the best conditions and the adducts were isolated in excellent yields and high purity. In addition, compared to the reported synthetic method of 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Table 2, entry 3a) by using HCl as a catalyst and ethonal as a solvent [28], our strategy has the advantages of higher yield (96% vs. 78%) and shorter reaction time (40 min vs. 3 h). The obtained results indicated that the electron-donating or -withdrawing groups at the aryl ring did not seem to affect the reaction significantly in terms of yield (Table 2, entries 3a–3o). Thiourea has been used with similar success to provide the corresponding S-dihydropyrimidinones analogues, which are also of interest due to their biological activities (Table 2, entries 3p–3t). The use of different substituted β-ketoester as a 1,3-dicarbonyl moiety in place of ethyl acetoacetate also gave similar results, as shown in Table 2 (entries 3u–3ab).

3. Experimental Section

All melting points were determined using a Büchi B-540 instrument. All melting points are uncorrected. All new compounds were characterized by IR, 1H- and 13C-NMR spectra. The IR spectra were obtained as potassium bromide pellets with a FTS-40 spectrometer (BIO-RAD, Hercules, CA, USA). The 1H-NMR spectra were measured on a Varian Inova-400 spectrometer (at 400 and 100 MHz, respectively) using TMS as an internal standard in CDCl3 or DMSO-d6.

3.1. General Procedure for the Synthesis of 1-Butyl-3-carboxymethyl-benzotriazolium Trifluoroacetate

[C2O2BBTA][TFA]: benzotriazole (0.2 mol) and chlorobutane (0.24 mol) were dissolved in 30% aqueous solution of sodium hydroxide (100 mL). Tetrabutylammonium bromide (1 g) was added and the solution was stirred 24 h at 80 °C until two phases formed. The top organic phase and bottom water phase were separated with separating funnel. Any remaining water in the organic phase was removed by decompressing Ratovapor at 70 °C [46]. The 1-butylbenzotriazole (0.1 mol) and chloroacetic acid (0.1 mol) were added to a 50 mL round bottom flask fitted with a reflux condenser. The solution was stirred for 36 h at 90 °C. Then the mixture was washed at least three times with diethyl ether and acetone. The product ([C2O2BBTA][Cl]) precipitated as a white solid and then was collected by filtration and dried in vacuo for 24 h. The [C2O2BBTA][Cl] (0.05 mol) was transferred to a 25 mL round bottom flask and trifluoroacetic acid (TFA, 0.06 mol) was added dropwise, then stirred 24 h at 80 °C. Finally, any remaining TFA was removed by decompressing Ratovapor at 90 °C for 1 h and dried in vacuo for 24 h (Scheme 2).

3.2. General Procedure for the Synthesis of 3,4-Dihydropyrimidin-2(1H)-(thio)ones

A mixture of aryl aldehyde (2 mmol), β-ketoester (2 mmol), urea (2 mmol) and [C2O2BBTA][TFA] (0.2 mmol) were heated at 90 °C under solvent-free conditions for 40 min with stirring (Scheme 1). After cooling, the reaction mixture was poured onto crushed ice (30 g) and stirred for 10 min. The separated solid was filtered under suction, washed with cold water (30 mL) and then recrystallized from ethanol to afford the pure product. The resulting precipitate was filtered under suction. The results are summarized in Table 2. All products (except 3l–3m, 3y–3ab) are known compounds, which were characterized by IR, 1H and 13C-NMR spectra.
1-Butyl-3-carboxymethyl-benzotriazolium Trifluoroacetate [C2O2BBTA][TFA]: brown liquid; 1H-NMR (DMSO-d6, 400 MHz, TMS): δ 0.93 (t, 3H, CH3), 1.31–1.41 (m, 2H, CH2), 2.00–2.07 (m, 2H, CH2), 5.11 (t, 2H, CH2), 6.13 (s, 2H, CH2), 8.00–8.53 (m, 4H, Ar-H); 13C-NMR (DMSO-d6, 100 MHz, ppm): δ 166.4, 158.3 (q, COCF3), 135.0, 134.3, 131.4, 130.9, 115.6 (q, CF3), 114.1, 114.0, 51.9, 51.2, 30.2, 18.7, 13.0 ppm; IR (KBr, ν/cm−1): 3106, 2967, 2940, 2879, 2511, 1738, 1505, 1471, 1364, 1190, 1141, 1029, 754, 718, 643, 599; ESI-MS: m/z (%) = 234.1 (100) [M]+, 113.0 (100) [M]−.
5-Ethoxycarbonyl-6-methyl-4-(2-chloro-4-fluorophenyl)-3,4-dihydropyrimidin-2(1H)-thione (3l): white solid; 1H-NMR (400 MHz, DMSO-d6), δ: 1.00 (t, 3H, OCH2CH3), 2.29 (s, 3H, CH3 ), 3.89 (q, 2H, OCH2), 5.59 (s, 1H, CH), 7.20 (t, 1H, Ar-H), 7.32–7.39 (dd, 2H, Ar-H), 7.73 (s, 1H, NH), 9.30 (s, 1H, NH); 13C-NMR (100 MHz, DMSO-d6), δ: 13.80, 17.56, 39.07, 39.59, 50.90, 58.98, 97.61, 115.53, 131,26, 138.24, 138.27, 149.28, 151.08, 159,52, 162.98, 164.74; IR (KBr, ν/cm−1): 3346, 3225, 3112, 2976, 1697, 1644, 1223, 1093, 903, 805.
5-Ethoxycarbonyl-6-methyl-4-(3-bromo-4-fluorophenyl)-3,4-dihydropyrimidin-2(1H)-thione (3y): white solid; 1H-NMR (400 MHz, DMSO-d6), δ: 1.09 (t, 3H, OCH2CH3), 2.25 (s, 3H, CH3 ), 3.99 (q, 2H, OCH2), 5.15 (s, 1H, CH), 7.24–7.27 (m, 1H, Ar-H), 7.33–7.37 (t, 1H, Ar-H), 7.48–7.50 (dd, 1H, Ar-H), 7.79 (s, 1H, NH), 9.29 (s, 1H, NH); 13C-NMR (100 MHz, DMSO-d6), δ: 13.92, 17.72, 52.97, 59.20, 98.41, 112.13, 127.44, 131.19,142.88, 148.95, 151.66, 156.05, 158.49, 164.99; IR (KBr, ν/cm−1): 3342, 3203, 3100, 2984, 1702, 1658, 1232, 1099, 895, 804.
5-Isopropoxycarbonyl-6-methyl-4-(3-methoxyphenyl)-3,4-dihydropyrimidin-2(1H)-thione (3z): white solid; 1H-NMR (400 MHz, DMSO-d6), δ: 1.01 (d, 3H, CH3), 1.16 (d, 3H, CH3CH), 2.23 (s, 3H, CH3C), 3.72 (s, 3H, MeO), 4.82 (m, 1H, CHCH3), 5.10 (s, 1H, CH), 6.76–6.83 (m, 3H, Ar-H), 7.24 (t, H, Ar-H), 7.70 (s, 1H, NH), 9.15 (s, 1H, NH); 13C-NMR (100 MHz, DMSO-d6), δ: 17.60, 21.54, 53.73, 54.86, 66.24, 99.34, 112.16, 118.19, 129.37, 146.34, 148.05, 152.07, 159.07, 164.73; IR (KBr, ν/cm−1): 3234, 3106, 2981, 2948, 1721, 1652, 1599, 1463, 1431, 1374, 1282, 1232, 1092, 1073, 788.
5-Isopropoxycarbonyl-6-methyl-4-(4-hydroxyphenyl)-3,4-dihydropyrimidin-2(1H)-thione (3z): orange solid; 1H-NMR (400 MHz, DMSO-d6), δ: 1.00 (d, 3H, CH3), 1.15 (d, 3H, CH3CH), 2.22 (s, 3H, CH3C), 4.80 (m, 1H, CHCH3), 5.02 (s, 1H, CH), 6.68 (d, 2H, Ar-H), 7.02 (d, 2H, Ar-H), 9.07 (s, 1H, NH), 9.31 (s, 1H, OH); 13C-NMR (100 MHz, DMSO-d6), δ: 17.56, 21.39, 21.69, 53.44, 66.09, 99.91, 114.79, 114.79, 127.35, 127.35, 135.46, 147.35, 152.02, 156.39, 164.79; IR (KBr, ν/cm−1): 3289, 3227, 3109, 2979, 2808, 1706, 1686, 1651, 1511, 1448, 1371, 1282, 1226, 1173, 1086, 783, 680.
5-Tert-Butoxycarbonyl-6-methyl-4-(4-fluorophenyl)-3,4-dihydropyrimidin-2(1H)-thione (3aa): faint yellow solid; 1H-NMR (400 MHz, DMSO-d6), δ: 1.28 (s, 9H, (CH3)3C), 2.21 (s, 3H, CH3C), 5.07 (s, 1H, CH), 7.13–7.18 (m, 2H, Ar-H), 7.22–7.26 (m, 2H, Ar-H), 7.66 (s, 1H, NH), 9.09 (s, 1H, NH); 13C-NMR (100 MHz, DMSO-d6), δ: 17.56, 27.72, 27.72, 53.60, 79.09, 100.25, 114.92, 128.12, 128.20, 141.12, 141.15, 147.43, 151.81, 159.96, 162.38, 164.61; IR (KBr, ν/cm−1): 3230, 3107, 2975, 2930, 1697, 1644, 1507, 1452, 1366, 1292, 1230, 1164, 1090, 1035, 837, 798, 759, 658.
5-Tert-Butoxycarbonyl-6-methyl-4-(3-methoxyphenyl)-3,4-dihydropyrimidin-2(1H)-thione (3ab): faint yellow solid; 1H-NMR (400 MHz, DMSO-d6), δ: 1.29 (s, 9H, (CH3)3C), 2.21 (s, 3H, CH3C), 2.27 (s, 3H, CH3C), 5.07 (s, 1H, CH), 7.01–7.06 (m, 3H, Ar-H), 7.18–7.22 (t, 1H, Ar-H), 7.63 (s, 1H, NH), 9.05 (s, 1H, NH); 13C-NMR (100 MHz, DMSO-d6), δ: 17.56, 21.01, 27.72, 27.72, 27.72, 54.20, 78.99, 100.50, 123.22, 126.79, 127.67, 128.12, 137.07, 144.89, 147.04, 152.05, 164.73; IR (KBr, ν/cm−1): 3226, 3099, 2977, 2935, 1699, 1647, 1489, 1438, 1366, 1294, 1232, 1165, 1087, 859, 813, 774, 745, 697, 670, 599.

4. Conclusions

In summary, we have reported an efficient and convenient method for the synthesis of a series of novel dihydropyrimidin-2(1H)-ones using aryl aldehyde, β-ketoester and urea as substrates and employing Brønsted acidic ionic liquid [C2O2BBTA][TFA] as a catalyst. This method offers several advantages including high yields, short reaction times, and a simple work-up procedure. It also has the ability to tolerate a wide variety of substituted groups in all three components, which is lacking in existing procedures.

Acknowledgments

The authors are grateful to Key Laboratory of Xinjiang Uyghur Autonomous Region (2015KL014), NSFC (21572195, 21262035, and 21162025), the Program for Outstanding Youth Science and Technology Innovation Talents Training in Xinjiang Uygur Autonomous Region (2014721004), and Natural Science Foundation of Xinjiang University (BS110133 and BS150230) for financial support of this research.

Author Contributions

Zhiqing Liu and Rong Ma contributed equally to this paper. Chenjiang Liu conceived the idea of this piece of research; Zhiqing Liu, Rong Ma and Chenjiang Liu designed the experiments; Zhiqing Liu, Rong Ma, and Dawei Cao performed the chemical experiments; Zhiqing Liu and Rong Ma performed the performed the spectra analyses; Zhiqing Liu, Rong Ma and Chenjiang Liu wrote the paper.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Tayebee, R.; Amini, M.M.; Ghadamgahi, M.; Armaghan, M. H5PW10V2O40/Pip-SBA-15: A novel reusable organic-inorganic hybrid material as potent Lewis acid catalyst for one-pot solvent-free synthesis of 3,4-dihydropyrimidinones. J. Mol. Catal. A Chem. 2013, 366, 266–274. [Google Scholar]
  2. Shaabani, A.; Seyyedhamzeh, M.; Maleki, A.; Hajishaabanha, F. Diketene as an alternative substrate for a new Biginelli-like multicomponent reaction: One-pot synthesis of 5-carboxamide substituted 3,4-dihydropyrimidine-2(1H)ones. Tetrahedron 2010, 66, 4040–4042. [Google Scholar] [CrossRef]
  3. Ismaili, L.; Nadaradjane, A.; Nicod, L.; Guyon, C.; Xicluna, A.; Robert, J.F.; Refouvelet, B. Synthesis and antioxidant activity evaluation of new hexahydropyrimido[5,4-c]quinoline-2,5-diones and 2-thioxohexahydropyrimido[5,4-c]quinoline-5-ones obtained by Biginelli reaction in two steps. Eur. J. Med. Chem. 2008, 43, 1270–1275. [Google Scholar] [CrossRef] [PubMed]
  4. Litvic, M.; Vecenaj, I.; Ladisic, Z.M.; Lovric, M.; Vinkovic, V.; Filipan-Litvic, M. First application of hexaaquaaluminium(III) tetrafluoroborate as a mild, recyclable, non-hygroscopic acid catalyst in organic synthesis: A simple and efficient protocol for the multigram scale synthesis of 3,4-dihydropyrimidinones by Biginelli reaction. Tetrahedron 2010, 66, 3463–3471. [Google Scholar] [CrossRef]
  5. Mandhane, P.G.; Joshi, R.S.; Nagargoje, D.R.; Gill, C.H. An efficient synthesis of 3,4-dihydropyrimidin-2(1H)-ones catalyzed by thiamine hydrochloride in water under ultrasound irradiation. Tetrahedron Lett. 2010, 51, 3138–3140. [Google Scholar] [CrossRef]
  6. Gore, S.; Baskaran, S.; Koenig, B. Efficient synthesis of 3,4-dihydropyrimidin-2-ones in low melting tartaric acid-urea mixtures. Green Chem. 2011, 13, 1009–1013. [Google Scholar] [CrossRef]
  7. Kargar, M.; Hekmatshoar, R.; Mostashari, A.; Hashemi, Z. Efficient and green synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones using imidazol-1-yl-acetic acid as a novel, reusable and water-soluble organocatalyst. Catal. Commun. 2011, 15, 123–126. [Google Scholar] [CrossRef]
  8. Narahari, S.R.; Reguri, B.R.; Gudaparthi, O.; Mukkanti, K. Synthesis of dihydropyrimidinones via Biginelli multi-component reaction. Tetrahedron Lett. 2012, 53, 1543–1545. [Google Scholar] [CrossRef]
  9. Rahmatpour, A. Polyvinylsulfonic acid: An efficient, water-soluble and reusable bronsted acid catalyst for the three-component synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones in water and ethanol. Catal. Lett. 2012, 142, 1505–1511. [Google Scholar] [CrossRef]
  10. Ashok, M.; Holla, B.S.; Kumari, N.S. Convenient one pot synthesis of some novel derivatives of thiazolo[2,3-b]dihydropyrimidinone possessing 4-methylthiophenyl moiety and evaluation of their antibacterial and antifungal activities. Eur. J. Med. Chem. 2007, 42, 380–385. [Google Scholar] [CrossRef] [PubMed]
  11. Kolosov, M.A.; Orlov, V.D.; Beloborodov, D.A.; Dotsenko, V.V. A chemical placebo: NaCl as an effective, cheapest, non-acidic and greener catalyst for Biginelli-type 3,4-dihydropyrimidin-2(1H)-ones (-thiones) synthesis. Mol. Div. 2009, 13, 5–25. [Google Scholar] [CrossRef] [PubMed]
  12. Chitra, S.; Devanathan, D.; Pandiarajan, K. Synthesis and in vitro microbiological evaluation of novel 4-aryl-5-isopropoxycarbonyl-6-methyl-3,4-dihydropyrimidinones. Eur. J. Med. Chem. 2010, 45, 367–371. [Google Scholar] [CrossRef] [PubMed]
  13. Murata, H.; Ishitani, H.; Iwamoto, M. Highly ordered aluminium-planted mesoporous silica as active catalyst for Biginelli reaction and formyl C-H insertion reaction with diazoester. Phys. Chem. Chem. Phys. 2010, 12, 14452–14455. [Google Scholar] [CrossRef] [PubMed]
  14. Tamaddon, F.; Rami, Z.; Jafari, A.A. Synthesis of 3,4-dihydropyrimidin-2(1H)-ones and 1,4-dihydropyridines using ammonium carbonate in water. Tetrahedron Lett. 2010, 51, 1187–1189. [Google Scholar] [CrossRef]
  15. Zych, A.J.; Wang, H.-J.; Sakwa, S.A. Synthesis and Suzuki-Miyaura reactions of 5-halo-3,4-dihydropyrimidin-2(1H)-ones. Tetrahedron Lett. 2010, 51, 5103–5105. [Google Scholar] [CrossRef]
  16. Akhaja, T.N.; Raval, J.P. 1,3-Dihydro-2H-indol-2-ones derivatives: Design, synthesis, in vitro antibacterial, antifungal and antitubercular study. Eur. J. Med. Chem. 2011, 46, 5573–5579. [Google Scholar] [CrossRef] [PubMed]
  17. Karade, H.N.; Acharya, J.; Kaushik, M.P. An efficient and rapid dehydrogenation of 4-aryl-3,4-dihydropyrimidin-2(1H)-ones (DHPMs) using CAN/HCl. Tetrahedron Lett. 2012, 53, 5541–5543. [Google Scholar] [CrossRef]
  18. Starcevich, J.T.; Laughlin, T.J.; Mohan, R.S. Iron(III) tosylate catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones via the Biginelli reaction. Tetrahedron Lett. 2013, 54, 983–985. [Google Scholar] [CrossRef]
  19. Hallett, J.P.; Welton, T. Room-temperature ionic liquids: Solvents for synthesis and catalysis. 2. Chem. Rev. 2011, 111, 3508–3576. [Google Scholar] [CrossRef] [PubMed]
  20. Welton, T. Room-temperature ionic liquids. Solvents for Synthesis and catalysis. Chem. Rev. 1999, 99, 2071–2084. [Google Scholar] [CrossRef] [PubMed]
  21. Ramos, L.M.; Ponce de Leon y Tobio, A.Y.; dosSantos, M.R.; de Oliveira, H.C.B.; Gomes, A.F.; Gozzo, F.C.; de Oliveira, A.L.; Neto, B.A.D. Mechanistic studies on lewis acid catalyzed biginelli reactions in ionic liquids: Evidence for the reactive intermediates and the role of the reagents. J. Org. Chem. 2012, 77, 10184–10193. [Google Scholar] [CrossRef] [PubMed]
  22. Sharma, N.; Sharma, U.K.; Kumar, R.; Richa; Sinha, A.K. Green and recyclable glycine nitrate (GlyNO3) ionic liquid triggered multicomponent Biginelli reaction for the efficient synthesis of dihydropyrimidinones. RSC Adv. 2012, 2, 10648–10651. [Google Scholar] [CrossRef]
  23. Nagarajan, S.; Shaikh, T.M.; Kandasamy, E. Synthesis of 1-alkyl triazolium triflate room temperature ionic liquids and their catalytic studies in multi-component Biginelli reaction. J. Chem. Sci. 2015, 127, 1539–1545. [Google Scholar] [CrossRef]
  24. Liu, C.J.; Wang, J.D. Ultrasound-assisted synthesis of novel 4-(2-pheny-1,2,3-triazol-4-yl)-3,4-dihydropyrimidin-2(1H)-(thio)ones catalyzed by Sm(ClO4)3. Molecules 2010, 15, 2087–2095. [Google Scholar] [CrossRef] [PubMed]
  25. Liu, C.J.; Wang, J.D. Copper(II) sulfamate: an efficient catalyst for the one-pot synthesis of 3,4-dihydropyrimidine-2(1H)-ones and thiones. Molecules 2009, 14, 763–770. [Google Scholar] [CrossRef] [PubMed]
  26. Zhang, Y.H.; Wang, B.; Zhang, X.M.; Huang, J.B.; Liu, C.J. An efficient synthesis of 3, 4-dihydropyrimidin-2(1H)-ones and thiones catalyzed by a novel Brønsted acidic ionic liquid under solvent-free conditions. Molecules 2015, 20, 3811–3820. [Google Scholar] [CrossRef] [PubMed]
  27. Clark, J.H.; Macquarrie, D.J.; Sherwood, J. The combined role of catalysis and solvent effects on the Biginelli reaction: Improving efficiency and sustainability. Chem. Eur. J. 2013, 19, 5174–5182. [Google Scholar] [CrossRef] [PubMed]
  28. Folkers, K.; Harwd, H.J.; Johnson, T.B. Researches on pyrimidines. Cxxx. synthesis of 2-keto-l,2,3,4-tetrahydropymidin. J. Am. Chem. Soc. 1932, 54, 3751–3758. [Google Scholar] [CrossRef]
  29. Rao, G.B.D.; Acharya, B.N.; Verma, S.K.; Kaushik, M.P. N,N'-Dichlorobis(2,4,6-trichlorophenyl) urea (CC-2) as a new reagent for the synthesis of pyrimidone and pyrimidine derivatives via Biginelli reaction. Tetrahedron Lett. 2011, 52, 809–812. [Google Scholar] [CrossRef]
  30. Gholap, A.R.; Venkatesan, K.; Daniel, T.; Lahoti, R.J.; Srinivasan, K.V. Ionic liquid promoted novel and efficient one pot synthesis of 3,4-dihydropyrimidin-2-(1H)-ones at ambient temperature under ultrasound irradiation. Green Chem. 2004, 6, 147–150. [Google Scholar] [CrossRef]
  31. Boumoud, T.; Boumoud, B.; Mosset, P.; Debache, A. Gypsum-catalyzed one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones under solvent-free conditions. Eur. J. Chem. 2011, 8, 312–318. [Google Scholar] [CrossRef]
  32. Yadav, J.S.; Reddy, B.V.S.; Sridhar, P.; Reddy, J.S.S.; Nagaiah, K.; Lingaiah, N.; Saiprasad, P.S. Green protocol for the Biginelli three-component reaction: Ag3PW12O40 as a novel, water-tolerant heteropolyacid for the synthesis of 3,4-dihydropyrimidinones. Eur. J. Org. Chem. 2004, 3, 552–557. [Google Scholar] [CrossRef]
  33. Li, W.M.; Zhou, G.B.; Zhang, P.F.; Lai, Y.F.; Xu, S.F. One-pot synthesis of dihydropyrimidiones via environmentally friendly enzyme-catalyzed Biginelli reaction. Heterocycles 2011, 83, 2067–2077. [Google Scholar] [CrossRef]
  34. Boumoud, T.; Boumoud, B.; Rhouati, S.; Belfaitah, A.; Debache, A.; Mosset, P. An efficient and recycling catalyst for the one-pot three-component synthesis of substituted 3,4-dihydropyrimidin-2(1H)-ones. Eur. J. Chem. 2008, 5, 688–695. [Google Scholar] [CrossRef]
  35. Murata, H.; Ishitani, H.; Iwamoto, M. Synthesis of Biginelli dihydropyrimidinone derivatives with various substituents on aluminium-planted mesoporous silica catalyst. Org. Biomol. Chem. 2010, 8, 1202–1211. [Google Scholar] [CrossRef] [PubMed]
  36. Pasunooti, K.K.; Chai, H.; Jensen, C.N.; Gorityala, B.K.; Wang, S.; Liu, X.W. A microwave-assisted, copper-catalyzed three-component synthesis of dihydropyrimidinones under mild conditions. Tetrahedron Lett. 2011, 52, 80–84. [Google Scholar] [CrossRef]
  37. Da Silva, D.L.; Fernandes, S.A.; Sabino, A.A.; de Fatima, A. p-Sulfonic acid calixarenes as efficient and reusable organocatalysts for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones/-thiones. Tetrahedron Lett. 2011, 52, 6328–6330. [Google Scholar] [CrossRef]
  38. Hajipour, A.R.; Khazdooz, L.; Zarei, A. Brønsted acidic ionic liquid–catalyzed one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones and thiones under solvent-free conditions. Synth. Commun. 2011, 41, 2200–2208. [Google Scholar] [CrossRef]
  39. Nath, J.; Chaudhuri, M.K. Borax: An ecofriendly and efficient catalyst for one-pot synthesis of 3,4-dihydropyrimidine-2(1H)-ones under solvent-free conditions. Synth. Commun. 2010, 40, 2976–2982. [Google Scholar] [CrossRef]
  40. Chandak, H.S.; Lad, N.P.; Upare, P.P. Recyclable amberlyst-70 as a catalyst for Biginelli reaction: An efficient one-pot green protocol for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones. Catal Lett. 2009, 131, 469–473. [Google Scholar] [CrossRef]
  41. Wang, Y.Y.; Yu, J.P.; Yang, H.H.; Miao, Z.W.; Chen, R.Y. Solvent-free Biginelli reaction: A green method for the synthesis of 3,4-dihydropyrimidin-2-ones catalyzed by protic acids in large-scale. Lett. Org. Chem. 2011, 8, 264–267. [Google Scholar] [CrossRef]
  42. Khabazzadeh, H.; Saidi, K.; Sheibani, H. Microwave-assisted synthesis of dihydropyrimidin-2(1H)-ones using graphite supported lanthanum chloride as a mild and efficient catalyst. Bioorg. Med. Chem. Lett. 2008, 18, 278–280. [Google Scholar] [CrossRef] [PubMed]
  43. Dallinger, D.; Kappe, C.O. Automated generation of a dihydropyrimidine compound library using microwave-assisted processing. Nat. Protoc. 2007, 2, 1713–1721. [Google Scholar] [CrossRef] [PubMed]
  44. Dilmaghani, K.A.; Zeynizadeh, B.; Yari, M. One-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones and their sulfur derivatives with H2SO4 supported on silica gel or alumina. Phosphorus Sulfur Silicon Related Elem. 2009, 184, 1722–1728. [Google Scholar] [CrossRef]
  45. Jiang, C.; You, Q.D. An efficient and solvent-free one-pot synthesis of dihydropyrimidinones under microwave irradiation. Chin. Chem. Lett. 2007, 18, 647–650. [Google Scholar] [CrossRef]
  46. Zhang, S.; Hou, Y.; Huang, W.; Shan, Y. Preparation and characterization of novel ionic liquid based on benzotriazolium cation. Electrochim. Acta 2005, 50, 4097–4103. [Google Scholar] [CrossRef]
  • Sample Availability: All samples are available from the authors.
Molecules 21 00462 sch001 550
Scheme 1. Condensation of aryl aldehyde, β-ketoester and urea in the presence of [C2O2BBTA][TFA].
Scheme 1. Condensation of aryl aldehyde, β-ketoester and urea in the presence of [C2O2BBTA][TFA].
Molecules 21 00462 sch001
Molecules 21 00462 sch002 550
Scheme 2. Synthesis of [C2O2BBTA][TFA].
Scheme 2. Synthesis of [C2O2BBTA][TFA].
Molecules 21 00462 sch002
Table
Table 1. Effect of catalyst [C2O2BBTA][TFA] under different conditions for the reaction of aryl aldehyde, β-ketoester and urea a.
Table 1. Effect of catalyst [C2O2BBTA][TFA] under different conditions for the reaction of aryl aldehyde, β-ketoester and urea a.
EntrySolventIL (mol %)Time (min)Yield (%) b
1H2O10405
2MeOH10403
3EtOH104010
4CH2Cl2104016
5CH3CN104019
6DMF1040NR
7Toluene10405
8 csolvent-free104096, 95, 95, 94, 93, 92
9solvent-freeNone40NR
10solvent-free14081
11solvent-free2.54084
12solvent-free54085
13solvent-free154095
14solvent-free204093
15solvent-free101075
16solvent-free102091
17solvent-free103094
18solvent-free105091
19solvent-free106093
a Reaction conditions: benzaldehyde (2 mmol), ethyl acetoacetate (2 mmol), urea (3 mmol) and catalyst in solvent (5 mL) or solvent-free, 90 °C; b Isolated yield; c catalyst was recycled six times.
Table
Table 2. The [C2O2BBTA][TFA]-catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-ones a.
Table 2. The [C2O2BBTA][TFA]-catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-ones a.
EntryR1R2XYields b (%)Mp (°C) c
FoundReported (lit.)
3aC6H5EtOO96201–202200–202 [29]
3b2-F-C6H4EtOO96236–237235–237 [30]
3c3-F-C6H4EtOO97209–211209–211 [31]
3d4-F-C6H4EtOO98175–176175–177 [32]
3e2-Cl-C6H4EtOO93211–213211–213 [33]
3f2-Br-C6H4EtOO93204–205205–207 [30]
3g3-Br-C6H4EtOO94190–191190–192 [26]
3h3-Me-C6H4EtOO92228–230228–230 [34]
3i4-Me-C6H4EtOO97209–211209–212 [35]
3j3,4-(MeO)2-C6H3EtOO98171–172172–174 [36]
3k3-MeO-C6H4EtOO93219–221219–220 [37]
3l2-Cl-4-F-C6H3EtOO88195–197
3m3-Br-4-F-C6H3EtOO85193–195
3n3,4-(HO)2-C6H3EtOO89232–234233–235 [37]
3o4-N(CH3)2-C6H4EtOO89249–251249–250 [38]
3pC6H5EtOS83202–204202–204 [39]
3q4-F-C6H4EtOS86192–193191–192 [40]
3r3-Me-C6H4EtOS86193–195194–195 [41]
3s4-Me-C6H4EtOS90184–186185–186 [42]
3t3-MeO-C6H4EtOS93140–142141–143 [37]
3u4-F-C6H4MeOO98188–189188–190 [43]
3v4-Me-C6H4MeOO96202–203202–204 [44]
3w3-MeO-C6H4MeOO92206–208204–206 [29]
3x4-OH-C6H4MeOO99231–233231–233 [45]
3y3-MeO-C6H4i-PrOO94196–198
3z4-OH-C6H4i-PrOO98192–194
3aa4-F-C6H4t-BuOO99147–149
3ab3-MeO-C6H4t-BuOO95212–214
a Reaction conditions: benzaldehyde (2 mmol), ethyl acetoacetate (2 mmol), urea (3 mmol) and catalyst in solvent-free, 90 °C; b Isolated yield; c Melting points are uncorrected.

Share and Cite

MDPI and ACS Style

Liu, Z.; Ma, R.; Cao, D.; Liu, C. New Efficient Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones Catalyzed by Benzotriazolium-Based Ionic Liquids under Solvent-Free Conditions. Molecules 2016, 21, 462. https://doi.org/10.3390/molecules21040462

AMA Style

Liu Z, Ma R, Cao D, Liu C. New Efficient Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones Catalyzed by Benzotriazolium-Based Ionic Liquids under Solvent-Free Conditions. Molecules. 2016; 21(4):462. https://doi.org/10.3390/molecules21040462

Chicago/Turabian Style

Liu, Zhiqing, Rong Ma, Dawei Cao, and Chenjiang Liu. 2016. "New Efficient Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones Catalyzed by Benzotriazolium-Based Ionic Liquids under Solvent-Free Conditions" Molecules 21, no. 4: 462. https://doi.org/10.3390/molecules21040462

Article Metrics

Back to TopTop