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Article

Ultrasound-Promoted One-Pot, Four-Component Synthesis of Pyridin-2(1H)-One Derivatives

1
School of Pharmacy, Yancheng Teachers University, Yancheng 224051, Jiangsu, China
2
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, Jiangsu, China
3
Hainan Chuntch Pharmaceutical Company Limited, Haikou 570216, Hainan, China
4
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Perkin Union, Medical College, Beijing 100050, China
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Molecules 2013, 18(12), 14519-14528; https://doi.org/10.3390/molecules181214519
Submission received: 30 September 2013 / Revised: 19 November 2013 / Accepted: 19 November 2013 / Published: 25 November 2013
(This article belongs to the Special Issue Combinatorial Synthesis)

Abstract

:
An efficient one-pot synthesis of 1,6-diamino-2-oxo-1,2,3,4-tetrahydro- pyridine-3,5-dicarbonitrile derivatives by four-component piperidine-catalyzed reactions of a ketone, malononitrile, ethyl cyanoacetate and hydrazine hydrate under ultrasound irradiation is described. This method provides several advantages such as shorter reaction times, excellent yields, and a simple workup procedure.

Graphical Abstract

1. Introduction

Multi-component reactions (MCRs) have been designed to produce elaborate biologically active compounds and have become an important area of research in organic, combinatorial, and medicinal chemistry [1,2,3,4]. MCRs offer a wide range of possibilities for the efficient construction of highly complex molecules in a single procedure, thus avoiding the complicated purification operations and allowing savings of both solvents and reagents, making them perfectly amenable to automation for combinatorial synthesis. In the past decade there have been tremendous developments in MCRs and great efforts continue to be made to develop new MCRs [5,6,7,8,9].
Nitrogen-containing heterocyclic compounds are widespread in natural products and medicinal agents [10], and their applications in biologically active pharmaceuticals, agrochemicals, and functional materials are becoming more and more important [11,12]. Among them, pyridinone derivatives have been received considerable attention as a result of their biological activities and as an interesting template for medicinal chemistry [13,14,15,16]. The conventional method for the synthesis of pyridinones is ammonization of pyranone at a high temperature or in a sealed tube [17,18]. Recently, a number of improved methods have been reported in the literatures for the synthesis of this heterocyclic system [19,20,21]. However, most of these methodologies suffer from disadvantages such as multi-step procedures, long reaction times, unsatisfactory yields, and the use of organic solvents or toxic reagents. These facts prompted us towards further investigation in search for a more efficient methods for the preparation of this kind of compounds.
Ultrasound irradiation has been increasingly used in organic synthesis in recent years. A large number of organic reactions can be carried out in a higher yield, shorter reaction time and under milder reaction conditions under ultrasonication. Compared with traditional methods, this method is more convenient and can be easily controlled [22]. Nevertheless, the use of ultrasound in heterocyclic systems has not been fully explored [23,24]. As a consequence of our interest in the synthesis of heterocyclic compounds under ultrasound irradiation [25,26,27,28,29,30], we report herein for the first time a facile one-pot synthesis of pyridin-2(1H)-one derivatives via four-component reactions of a ketone, malononitrile, ethyl cyanoacetate and hydrazine catalyzed by piperidine under ultrasound irradiation.

2. Results and Discussion

Initially, the four-component reaction of acetone (1a), malononitrile (2), ethyl cyanoacetate (3) and hydrazine hydrate (4) as a simple model was investigated to establish the feasibility of the strategy and to optimize the reaction conditions (Scheme 1). The effects of solvents and catalysts were evaluated for this model reaction, and the results are summarized in Table 1. It was found that when the reaction was carried out without any catalysts only traces of product were detected, even after 10 h under ultrasound irradiation (Table 1, entry 1). To improve the yields, we examined this reaction using different bases (Table 1, entries 2–6). Based on the reaction times and the yields, piperidine was identified as the optimal catalyst with 5a being isolated in 93% yield (Table 1, entry 2). In order to further improve the product yields, we tried to perform the reaction in higher temperatures under ultrasound irradiation, but the yield did not increase (Table 1, entries 7–8). Subsequently, we turned to testing the effect of solvents. MeOH, CH3CN, THF, and water showed no superiority to EtOH (Table 1, entries 9–12). Therefore, EtOH is the solvent of choice for this reaction. To optimize the catalyst loading, 5, 10, 15, 20 and 25 mol% of piperidine was tested, respectively (Table 1, entries 13, 2, 14–16). A 10 mol% loading of piperidine was sufficient to push the reaction forward and 5 mol% of piperidine was not enough. Higher amounts of piperidine did not lead to a significant changes in the reaction yields.
Scheme 1. The model reaction.
Scheme 1. The model reaction.
Molecules 18 14519 g002
Table 1. Optimization of reaction conditions a.
Table 1. Optimization of reaction conditions a.
EntrySolventTemperature (°C)CatalystTime (min)Isolated Yield (%)
1EtOHrtNo catalyst600trace
2EtOHrtPiperidine (10%)3093
3EtOHrtNaOH (10%)24080
4EtOHrtKOH (10%)18078
5EtOHrtNa2CO3 (10%)36062
6EtOHrtEtONa (10%)24083
7EtOH40Piperidine (10%)3089
8EtOH50Piperidine (10%)3085
9MeOHrtPiperidine (10%)4085
10CH3CNrtPiperidine (10%)12065
11THFrtPiperidine (10%)9079
12WaterrtPiperidine (10%)120trace
13EtOHrtPiperidine (5%)6086
14EtOHrtPiperidine (15%)6090
15EtOHrtPiperidine (20%)3091
16EtOHrtPiperidine (25%)3089
a Reaction conditions: acetone (1 nmol), malononitrile (1 nmol), ethyl cyanoacetate (1 nmol), hydrazine hydrate (1 nmol) and piperidine (0.1 nmol) in solvent (10 mL) under ultrasonic waves and the ultrasonic power 250 W, irradiation frequency 40 kHz.
Using the optimal conditions, we investigated the substrate scope of the transformation (Scheme 2). The results are summarized in Table 2. As shown in Table 2, aliphatic chain ketones and cyclic ketones were well tolerated under the reaction conditions, leading to the final products in satisfactory yields. However, when the aromatic ketones (such as acetophenone, 4-bromoacetophenone, and 4-methylacetophenone) and aromatic aldehyde (such as benzaldehyde) were used, only traces of products were detected.
Scheme 2. The synthesis of pyridin-2(1H)-one derivatives 5.
Scheme 2. The synthesis of pyridin-2(1H)-one derivatives 5.
Molecules 18 14519 g003
Table 2. Synthesis of pyridin-2(1H)-one derivatives 5.
Table 2. Synthesis of pyridin-2(1H)-one derivatives 5.
EntryKetoneProductWith USWithout US
Time (min)Yield (%)Time (min)Yield (%)
1 Molecules 18 14519 i001 Molecules 18 14519 i002309412072
2 Molecules 18 14519 i003 Molecules 18 14519 i004309212069
3 Molecules 18 14519 i005 Molecules 18 14519 i006309318070
4 Molecules 18 14519 i007 Molecules 18 14519 i008309218060
5 Molecules 18 14519 i009 Molecules 18 14519 i010359218065
6 Molecules 18 14519 i011 Molecules 18 14519 i012409118067
7 Molecules 18 14519 i013 Molecules 18 14519 i014409018062
8 Molecules 18 14519 i015 Molecules 18 14519 i016409124059
9 Molecules 18 14519 i017 Molecules 18 14519 i018408930060
10 Molecules 18 14519 i019 Molecules 18 14519 i020358830060
11 Molecules 18 14519 i021 Molecules 18 14519 i022358918064
The structures of 5 were characterized using IR, 1H-NMR, and 13C-NMR spectroscopies, and HRMS analysis. Compound 5a exhibited characteristic IR stretching frequencies in the 3415, 3346, 3305, 2175, 1702, and 1632 cm−1 regions for NH2, CN, C=O, and C=C, respectively. In the 1H-NMR spectrum of compound 5a the amino group protons show two singlets at δ 6.61 and 5.15. The methyl group protons show two singlets at δ 1.20 and 1.04 due to the two methyl groups. A singlet appearing at δ 4.50 was assigned to the C-3 proton of the pyridine ring. In addition, HRMS analyses were consistent with the structures. The structure of 5a was further confirmed by X-ray diffraction. The molecular structure of 5a is shown in Figure 1.
Figure 1. The crystal structure of compound 5a.
Figure 1. The crystal structure of compound 5a.
Molecules 18 14519 g001
In this tetrahydropyridine ring, because of the existence of conjugation, the distance C4–N4 [1.338(3) Å] is significantly shorter than the typical Csp2–N bond distance (1.426 Å) [31]. The tetrahydropyridine ring adopts a distorted boat conformation, atoms C3, N1, C4 and C5 are coplanar, while C1 and C2 deviate from the plane by 0.4358(39) and −0.3639(38) Å, respectively.
Although the detailed mechanism of this reaction has not yet been clarified, the formation of compounds 5 can be explained by the possible mechanism presented in Scheme 3. First, a Knoevenagel condensation of ketone 1 with malononitrile 2 is proposed to give the intermediate A. A condensation of ethyl cyanoacetate 3 with hydrazine hydrate 4 is also proposed to give the intermediate B. Michael addition of intermediate B to A catalyzed by piperidine should then occur to provide intermediate C, which undergoes intramolecular cyclization to give intermediate D. In the last step, the intermediate D is tautomerized to afford the product 5.
Scheme 3. The proposed mechanism for the synthesis of compound 5.
Scheme 3. The proposed mechanism for the synthesis of compound 5.
Molecules 18 14519 g004

3. Experimental

3.1. General Information

Melting points are uncorrected. IR spectra were recorded on Varian F-1000 spectrometer in KBr with absorptions in cm−1. All 1H-NMR data were determined on a Varian Inova-400 MHz but the 13C-NMR spectra had been run on the Varian Inova-300 MHz instrument, J values are in Hz. Chemical shifts are expressed in ppm downfield from internal standard TMS. HRMS analyses were carried out using a Bruker microTOF-Q instrument. X-ray diffraction was recorded on a Smart-1000 CCD diffractometer. Ultrasonication was performed in a KQ-250E medical ultrasound cleaner with a frequency of 40 kHz and an output power of 250 W. The reaction flask was located at the maximum energy area in the cleaner, and the surface of the reactions was placed slightly lower than the level of the water. Observation of the surface of the reaction solution during vertical adjustment of vessel depth will show the optimum position by the point at which maximum surface disturbance occurs. The reaction temperature was controlled by addition or removal of water from the ultrasonic bath.

3.2. General Procedure for the Synthesis of 1,6-Diamino-2-oxo-1,2,3,4-Tetrahydro-Pyridine-3,5-Dicarbonitrile Derivatives 5

A 100 mL flask was charged with ketone 1 (1 mmol), malononitrile 2 (1 mmol), ethyl cyanoacetate 3 (1 mmol), hydrazine hydrate 4 (1 mmol) and piperidine (10 mol%, 0.1 mmol) in ethanol (10 mL). The mixture was sonicated in the water bath of an ultrasonic cleaner at 25–30 °C. After the completion of the reaction (monitored by TLC), the reaction mixture was concentrated in vacuo to remove the solvent. The residue was quenched with water and then filtered. The crude products were purified by recrystallization from ethanol to afford the pure products 5.
1,6-Diamino-4,4-dimethyl-2-oxo-1,2,3,4-tetrahydropyridine-3,5-dicarbonitrile (5a). White solid, 147.7 mg, 72% yield; m.p.: 198–200 °C. IR (KBr, cm−1): 3415, 3346, 3305, 2175, 1702, 1632, 1569, 1428, 1340, 1218, 917, 858; 1H-NMR (400 MHz, DMSO-d6,): δ (ppm) 1.04 (s, 3H, CH3), 1.20 (s, 3H, CH3), 4.50 (s, 1H, CH), 5.15 (s, 2H, NH2), 6.61 (s, 2H, NH2). 13C-NMR (75 MHz, DMSO-d6): δ (ppm) 24.6, 27.0, 33.0, 47.9, 62.4, 115.8, 119.8, 153.8, 162.8; HRMS: calculated for C9H10N5O [M−H]+: 204.0885, found 204.0867.
1,6-Diamino-4-methyl-2-oxo-4-propyl-1,2,3,4-tetrahydropyridine-3,5-dicarbonitrile (5b). Black solid, 160.9 mg, 69% yield; m.p.: 136–138 °C. IR (KBr, cm1): 3426, 3318, 2999, 2187, 1709, 1641, 1582, 1418, 1326, 1200, 942, 878, 785; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 0.85–0.86 (m, 3H, CH3), 1.10–1.27 (m, 7H, 2 × CH2,CH3), 4.65 (s, 1H, CH), 5.21 (s, 2H, NH2), 6.66 (s, 2H, NH2); 13C-NMR (75 MHz, DMSO-d6): δ (ppm) 13.7, 16.4, 23.9, 34.7, 43.9, 47.0, 59.1, 114.7, 119.5, 152.9, 162.0; HRMS: calculated for C11H14N5O [M−H]+: 232.1198, found 232.1186.
1,6-Diamino-4,4-diethyl-2-oxo-1,2,3,4-tetrahydropyridine-3,5-dicarbonitrile (5c). White solid, 163.3 mg, 70% yield; m.p.: 170–172 °C. IR (KBr, cm1): 3445, 3317, 2988, 2195, 1707, 1645, 1576, 1418, 1369, 1206, 989, 886, 736; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 0.83 (t, J = 7.2 Hz, 3H, CH3), 0.91 (t, J = 7.2 Hz, 3H, CH3), 1.33–1.39 (m, 2H, CH2), 1.48–1.55 (m, 1H, CH), 1.78–1.82 (m, 1H, CH), 4.19 (s, 1H, CH), 5.20 (s, 2H, NH2), 6.72 (s, 2H, NH2); 13C-NMR (75 MHz, DMSO-d6): δ (ppm) 8.4, 8.9, 28.6, 30.8, 40.0, 43.7, 57.4, 115.4, 120.5, 155.0, 163.3; HRMS: calculated for C11H14N5O [M−H]+: 232.1198, found 232.1186.
1,6-Diamino-4-cyclopropyl-4-methyl-2-oxo-1,2,3,4-tetrahydropyridine-3,5-dicarbonitrile (5d). Gray solid, 138.6 mg, 60% yield; m.p.: 181–182 °C. IR (KBr, cm1): 3624, 3446, 2880, 2189, 1713, 1637, 1565, 1431, 1284, 1224, 1166, 940, 839, 691; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) −0.04–0.02 (m, 1H, CH), 0.10–0.16 (m, 1H, CH), 0.31–0.40 (m, 2H, CH2), 0.84–0.91 (m, 1H, CH), 1.32 (s, 3H, CH3), 4.72 (s, 1H, CH), 5.23 (s, 2H, NH2), 6.72 (s, 2H, NH2); 13C-NMR (75 MHz, DMSO-d6): δ (ppm) −0.7, 0.6, 16.1, 24.8, 34.8, 47.2, 54.9, 114.8, 119.6, 153.9, 161.9; HRMS: calculated for C11H12N5O [M−H]+: 230.1042, found 230.1039.
2,3-Diamino-4-oxo-3-azaspiro[5.5]undec-1-ene-1,5-dicarbonitrile (5e). White solid, 159.4 mg, 65% yield; m.p.: 156–158 °C. IR (KBr, cm1): 3499, 3296, 2899, 2169, 1699, 1632, 1561, 1400, 1376, 1258, 914, 864, 681; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 1.04–1.07 (m, 1H, CH), 1.20–1.36 (m, 1H, CH), 1.45–1.70 (m, 8H, 4 × CH2), 4.52 (s, 1H, CH), 5.26 (s, 2H, NH2), 6.71 (s, 2H, NH2); 13C-NMR (75 MHz, DMSO-d6): δ (ppm) 21.4, 21.6, 25.3, 33.4, 34.2, 35.4, 45.8, 60.8, 115.9, 121.0, 154.8, 162.4; HRMS: calculated for C12H14N5O [M−H]+: 244.1198, found 244.1172.
2,3-Diamino-9-methyl-4-oxo-3-azaspiro[5.5]undec-1-ene-1,5-dicarbonitrile (5f). White solid, 173.6 mg, 67% yield; m.p.: 175–176 °C. IR (KBr, cm1): 3426, 3318, 2164, 1709, 1626, 1538, 1410, 1299, 1148, 902, 836, 687; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 0.89 (d, J = 6.4 Hz, 3H, CH3), 1.14–1.22 (m, 1H, CH), 1.26–1.41 (m, 2H, CH2), 1.45–1.61 (m, 4H, 2 × CH2), 1.64–1.77 (m, 2H, CH2), 4.49 (s, 1H, CH), 5.23 (s, 2H, NH2), 6.68 (s, 2H, NH2); 13C-NMR (75 MHz, DMSO-d6): δ (ppm) 22.5, 30.4, 30.5, 31.6, 32.8, 34.1, 34.9, 48.8, 59.4, 115.8, 121.7, 155.2, 163.0; HRMS: calculated for C13H16N5O [M−H]+: 258.1335, found 258.1336.
2,3-Diamino-9-ethyl-4-oxo-3-azaspiro[5.5]undec-1-ene-1,5-dicarbonitrile (5g). White solid, 169.5 mg, 62% yield; m.p.: 184–186 °C. IR (KBr, cm1): 3418, 3216, 2186, 1712, 1656, 1566, 1432, 1240, 1121, 956, 812, 662; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 0.86 (t, J = 6.4 Hz, 3H, CH3), 1.10–1.25 (m, 4H, 2 × CH2), 1.37 (t, J = 8.0 Hz, 1H, CH), 1.50–1.70 (m, 5H, 2 × CH2, CH), 1.77 (d, J = 9.6 Hz, 1H, CH), 4.50 (s, 1H, CH), 5.24 (s, 2H, NH2), 6.68 (s, 2H, NH2); 13C-NMR (75 MHz, DMSO-d6): δ (ppm) 11.7, 28.1, 29.4, 32.8, 34.1, 35.3, 38.2, 48.8, 59.4, 107.9, 115.8, 121.7, 155.2, 163.0; HRMS: calculated for C14H18N5O [M−H]+: 272.1511, found 272.1484.
2,3-Diamino-9-benzyl-4-oxo-3,9-diazaspiro[5.5]undec-1-ene-1,5-dicarbonitrile (5h). Yellow solid, 198.5 mg, 59% yield; m.p.: 114–116 °C. IR (KBr, cm1): 3602, 3425, 3330, 2932, 2174, 1715, 1625, 1561, 1427, 1345, 1229, 1078, 985, 795, 740; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 1.68 (s, 4H, 2 × CH2), 2.28–2.60 (m, 4H, 2 × CH2), 3.48 (s, 2H, NCH2), 4.57 (s, 1H, CH), 5.25 (s, 2H, NH2), 6.78 (s, 2H, NH2), 7.25–7.35 (m, 5H, ArH); 13C-NMR (75 MHz, DMSO-d6): δ (ppm) 33.1, 33.7, 33.8, 46.3, 48.9, 49.2, 59.6, 62.5, 115.7, 121.2, 127.4, 128.6, 129.2, 138.8, 155.2, 162.5; HRMS: calculated for C18H19N6O [M−H]+: 335.1620, found 335.1619.
tert-Butyl-8,9-diamino-7,11-dicyano-10-oxo-3,9-diazaspiro[5.5]undec-7-ene-3-carboxylate (5i). White solid, 207.8 mg, 60% yield; m.p.: 222–224 °C. IR (KBr, cm1): 3422, 3315, 3216, 2971, 2189, 1703, 1672, 1635, 1571, 1479, 1170, 897, 858, 769, 665; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 1.36–1.42 (m, 9H, C(CH3)3), 1.43–1.44 (m, 2H, CH2), 1.55–1.68 (m, 6H, 3 × CH2), 4.65 (s, 1H, CH), 5.24 (s, 2H, NH2), 6.86 (s, 2H, NH2); 13C-NMR (75 MHz, DMSO-d6): δ (ppm) 28.4, 32.7, 33.3, 33.9, 45.9, 58.6, 79.5, 115.5, 121.0, 154.3, 162.2; HRMS: calculated for C16H21N6O3 [M−H]+: 345.1675, found 345.1683.
8,9-Diamino-10-oxo-3-thia-9-azaspiro[5.5]undec-7-ene-7,11-dicarbonitrile (5j). Yellow solid, 158.0 mg, 60% yield; m.p.: 165–167 °C. IR (KBr, cm1): 3427, 3340, 3041, 2926, 2179, 1725, 1633, 1552, 1430, 1349, 1064, 945, 829, 795; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 1.75–1.91 (m, 5H, 2 × CH2 and CH), 2.58–2.66 (m, 3H, CH2 and CH), 4.64 (s, 1H, CH), 5.20 (s, 2H, NH2), 6.18 (s, 2H, NH2); 13C-NMR (75 MHz, DMSO-d6): δ (ppm) 22.2, 22.3, 33.6, 33.7, 34.1, 44.6, 58.6, 114.6, 120.1, 154.1, 161.1; HRMS: calculated for C11H12N5OS [M−H]+: 262.0763, found 262.0741.
2,3-Diamino-4-oxo-3-azaspiro[5.6]dodec-1-ene-1,5-dicarbonitrile (5k). Gray solid, 165.9 mg, 64% yield; m.p.: 179–181 °C. IR (KBr, cm1): 3356, 3189, 2198, 1703, 1686, 1589, 1453, 1256, 1141, 988, 852, 701; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 1.10 (s, 1H, CH), 1.26 (s, 1H, CH), 1.34–1.90 (m, 10H, 5 × CH2), 4.46 (s, 1H, CH), 5.24 (s, 2H, NH2), 6.67 (s, 2H, NH2); 13C-NMR (75 MHz, DMSO-d6): δ (ppm) 22.5, 23.0, 27.0, 30.3, 33.0, 35.8, 38.5, 47.8, 63.0, 116.3, 121.1, 154.2, 162.7; HRMS: calculated for C13H16N5O [M−H]+: 258.1355, found 258.1328.

4. Conclusions

In conclusion, we have described a novel approach to exploit the use of ultrasound irradiation for the synthesis of pyridin-2(1H)-one derivatives in ethanol solution at room temperature within 30–40 min. Compared with traditional methods, the procedure offers several advantages, including excellent yields, shorter reaction times, and a simple workup procedure.

Acknowledgments

We gratefully acknowledge the support from the National Natural Science Foundation of China (81102817), the Natural Science Foundation of the Jiangsu Province (BK2011422), and the Key Laboratory of Organic Synthesis of Jiangsu Province (JSK1112).

Conflicts of Interest

The authors declare no conflict of interest.

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  • Sample Availability: Samples of the compounds 5ak are available from the authors.

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MDPI and ACS Style

Yang, J.; Li, Q.; Zhang, J.; Lin, W.; Wang, J.; Wang, Y.; Huang, Z.; Shi, D. Ultrasound-Promoted One-Pot, Four-Component Synthesis of Pyridin-2(1H)-One Derivatives. Molecules 2013, 18, 14519-14528. https://doi.org/10.3390/molecules181214519

AMA Style

Yang J, Li Q, Zhang J, Lin W, Wang J, Wang Y, Huang Z, Shi D. Ultrasound-Promoted One-Pot, Four-Component Synthesis of Pyridin-2(1H)-One Derivatives. Molecules. 2013; 18(12):14519-14528. https://doi.org/10.3390/molecules181214519

Chicago/Turabian Style

Yang, Jinming, Qiang Li, Juanjuan Zhang, Wei Lin, Juxian Wang, Yucheng Wang, Zhibin Huang, and Daqing Shi. 2013. "Ultrasound-Promoted One-Pot, Four-Component Synthesis of Pyridin-2(1H)-One Derivatives" Molecules 18, no. 12: 14519-14528. https://doi.org/10.3390/molecules181214519

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