Abstract
Two new Zn(II) and Cd(II) MOFs have been synthesized. These MOFs have been applied as heterogeneous catalysts for the green synthesis of a variety of dihydropyrimidinone derivatives through the Biginelli reaction and the desired products were obtained in high yields with short reaction time under mild solvent- free conditions. Moreover, the MOF catalysts may be readily recovered after the reaction and reused for many cycles.
Keywords: Metal-organic framework, Biginelli reaction, Heterogeneous catalyst, Solvent- free conditions, Green reactions
Heterogenization of homogeneous catalysts has been of great academic and industrial importance, because the heterogenized catalysts have the advantages to be recoverable, reusable and environmentally friendly. Although a variety of heterogenization approaches such as anchoring catalysts onto porous inorganic materials, organic polymers, dendrimers supports and metal-organic frameworks (MOFs) have been explored; most heterogenized catalysts suffer from the reduced catalytic activity and efficiency.1,2
The Biginelli reaction,3 the three-component reaction between aldehydes, urea, and acetoacetate, is one of the most efficient ways to synthesize dihydropyrimidinone derivatives, which are important pharmacological compounds.4 Although a few lanthanide-containing MOF catalysts have been explored for this reaction, the yields are usually very low (<69%) even with a large loading of the catalysts (up to 20 mol %).5 Moreover, the reaction time has been quite long while the recyclability of these catalysts has been very poor or not established. The fact that these reported MOF catalysts are not comparable to their homogeneous Lewis acid counterparts6 in terms of the catalytic activity indicates that there is a great need to realize highly efficient heterogeneous catalysts for this important three-component reaction. It has been known that some simple zinc(II) and cadmium(II) salts, such as ZnCl2 and CdCl2, are good homogeneous catalysts for the Biginelli reaction,7 we thus intended to develop zinc and cadmium-based MOFs as the heterogeneous catalysts for the Biginelli reaction. Herein we report the synthesis and structures of two new iso-structural Zn- and Cd-based MOFs M(4,4′-bpe)2(H2O)4·(m-BDS) (M = Zn2+ and Cd2+; 4,4′-bpe = 1,2-bis(4-pyridyl)ethylene; m-BDS = 1,3-benzenedisulfonic acid) and their application as robust and green catalysts for the Biginelli reaction.
The Zn- and Cd-MOFs were readily synthesized from hydrothermal reactions from their corresponding metal salts and organic linkers 4,4′-bpe and m-BDS as single crystals in high yield.8 Their crystal structures were characterized by single x-ray diffraction and purity of the phases were confirmed by powder XRD.9 Zn- and Cd-MOFs are iso-structural. As shown in Figure S1,9 the Cd ion is coordinated by two 4,4′-bpe and four water molecules in octahedral coordination geometry. These Cd(4,4′-bpe)2(H2O)4 moieties are bridged by the free m-BDS molecules by hydrogen bonding to form two-dimensional hydrogen bonded framework (Figure 1).
Figure 1.
Part of the single crystal structure of Cd-MOF Cd(4,4′-bpe)2(H2O)4·(m-BDS) indicating the 2D framework and hydrogen bonding.
Using benzaldehyde (1a), acetoacetate (2a), and urea (3a) as the model substrates, the Biginelli reaction was studied with these two catalysts, and the results are summarized in Table 1.
Table 1.
Reaction condition optimizations and catalyst recycling studya
| 1a | 2a | 3a | 4a | |||
|---|---|---|---|---|---|---|
| Entry | MOF | T (°C) |
Cycle | Catalyst recovery (%) |
Time (min) |
Yield (%)b |
| 1c | none | reflux | 480 | 0 | ||
| 2c | Cd | reflux | 480 | 66 | ||
| 3 | Cd | 80 | 110 | 92 | ||
| 4 | Zn | 80 | 110 | 92 | ||
| 5 | Cdd | 80 | I | 92 | 120 | 96 |
| 6 | Cdd | 80 | II | 90 | 130 | 96 |
| 7 | Cde | 80 | III | 89 | 130 | 94 |
| 8 | Cdf | 80 | IV | 89 | 140 | 96 |
| 9 | Cd | 80 | V | 88 | 140 | 92 |
| 10 | Znd | 80 | I | 97 | 110 | 94 |
| 11 | Znd | 80 | II | 96 | 110 | 90 |
| 12 | Zne | 80 | III | 96 | 115 | 88 |
| 13 | Znf | 80 | IV | 95 | 115 | 88 |
| 14 | Zn | 80 | V | 95 | 120 | 87 |
| 15 | Zng | 80 | 180 | 90 | ||
| 16 | Znh | 80 | 360 | 86 | ||
Unless otherwise specified, all reactions were carried out with 1a (1.0 mmol), 2a (1.0 mmol), and 3a (1.0 mmol) and the MOF catalyst (0.025 mmol, 2.5 mol %) under neat conditions.
Yield of the isolated product after recrystallization from EtOH.
Carried out in EtOH.
The scale of this reaction was 5.0 mmol.
The scale of this reaction was 3.0 mmol.
The scale of this reaction was 2.0 mmol.
Carried out with 1.0 mol % of the catalyst.
Carried out with 0.5 mol % of the catalyst.
Without catalyst, no product was obtained after 6 h of reflux in EtOH (entry 1). When 2.5 mol % of the Cd-MOF was added, 66% of the desired product 4a was obtained under similar conditions (entry 2). This discovery encouraged us to further explore green reaction conditions without the usage of the organic solvent for this reaction.10 To our pleasure, the reaction goes much faster under these conditions, and a high yield of 92% of the product was obtained in about 2 h (entry 3). Under these conditions, the Zn-MOF also leads to similar results (entry 4). Unlike molecular Zn2+ and Cd2+ Lewis acid catalysts, 5 these two catalysts are not soluble in the reaction mixture and the reaction system is heterogeneous.
After the reaction, the catalyst can be readily recovered by a simple filtration followed by washing.
To demonstrate the advantage of these heterogeneous MOF catalysts, we studied the recyclability of these catalysts. As shown by the data collected in Table 1, both catalysts may be recovered in high yields after the reaction and reused for five cycles with almost no loss of the catalytic activity (entries 5-14). The catalyst loading of the Zn-MOF may also be reduced to 1.0 mol % or 0.5 mol % without affecting the product yield (entries 15-16), although slightly longer reaction time is necessary with the lower catalyst loadings.
With these promising results, we next studied the scope of this reaction. The results are summarized in Table 2. With the Zn-MOF, high yields (≥86%) of the corresponding dihydropyrimidinone derivatives 4 may be obtained within 2 h of reaction for aromatic aldehydes that bear both an electron-withdrawing and an electron-donating group on the phenyl ring (entries 1-8). A high yield (91%) may also be obtained for the products of thiourea (entry 9) and acetoacetone (entry 10). An aliphatic aldehyde may also be applied in this reaction and the reaction of hexanal gave the desired product in 71% yield in 8 h (entry 11). The Cd-MOF was found to have similar reactivity and substrate scope (entries 12-22).
Table 2.
Biginelli Reaction Catalyzed by Zn-MOF and Cd-MOFa
| 1 | 2 | 3 | 4 | |||
|---|---|---|---|---|---|---|
| Entry | MOF catalyst |
R1 | R2 | X | Time (min) |
Yield (%)b |
| 1 | Zn | Ph | OEt | O | 110 | 94 |
| 2 | Zn | 4-FC6H4 | OEt | O | 110 | 91 |
| 3 | Zn | 4-ClC6H4 | OEt | O | 115 | 90 |
| 4 | Zn | 4-BrC6H4 | OEt | O | 120 | 90 |
| 5 | Zn | 4-CNC6H4 | OEt | O | 140 | 87 |
| 6 | Zn | 4-NO2C6H4 | OEt | O | 140 | 86 |
| 7 | Zn | 4-MeC6H4 | OEt | O | 115 | 90 |
| 8 | Zn | 4-MeOC6H4 | OEt | O | 115 | 91 |
| 9 | Zn | Ph | OEt | S | 120 | 91 |
| 10 | Zn | Ph | Me | O | 110 | 91 |
| 11 | Zn | n-C5H11 | OEt | O | 480 | 71 |
| 12 | Cd | Ph | OEt | O | 110 | 93 |
| 13 | Cd | 4-FC6H4 | OEt | O | 110 | 91 |
| 14 | Cd | 4-ClC6H4 | OEt | O | 115 | 90 |
| 15 | Cd | 4-BrC6H4 | OEt | O | 120 | 89 |
| 16 | Cd | 4-CNC6H4 | OEt | O | 150 | 86 |
| 17 | Cd | 4-NO2C6H4 | OEt | O | 140 | 87 |
| 18 | Cd | 4-MeC6H4 | OEt | O | 115 | 91 |
| 19 | Cd | 4-MeOC6H4 | OEt | O | 115 | 90 |
| 20 | Cd | Ph | OEt | S | 120 | 90 |
| 21 | Cd | Ph | Me | O | 110 | 91 |
| 22 | Cd | n-C5H11 | OEt | O | 480 | 73 |
Unless otherwise specified, all reactions were carried out with 1 (1.0 mmol), 2 (1.0 mmol), and 3 (1.0 mmol) and the MOF catalyst (0.025 mmol, 2.5 mol %) under neat conditions.
Yield of the isolated product after recrystallization from EtOH.
In summary, we have demonstrated that the newly synthesized Zn and Cd-MOFs are highly efficient heterogeneous catalysts for the Biginelli reaction. High yields of the desired products may be obtained in short reaction times. These cheap and readily available catalysts have high stability under the reaction conditions and may be easily recycled and reused without loss of reactivity. Furthermore, no organic solvent is necessary for the synthesis, which makes the synthesis really green. It is very unusual for such hydrogen bonded frameworks to have such a high stability that are even much superior to a lot of traditional MOFs during the catalytic reaction.11 It is expected that the sulfonic groups significantly enforce the frameworks by their hydrogen interactions with the coordination water molecules. We are now exploring chiral sulfonic derivatives and incorporating them into enantiopure MOFs for their heterogeneous asymmetric catalysis.
Supplementary Material
Acknowledgments
BC thanks the financial support of this research from the Welch Foundation (Grant No. AX-1730). CGZ thanks the generous financial support of this research from the National Institutes of Health-National Institute of General Medical Sciences (Grant no. SC1GM082718) and the Welch Foundation (Grant No. AX-1593).
Footnotes
Supplementary data Supplementary data (detailed experimental procedures and characterization data of the MOFs and the Biginelli products) associated with this article can be found, in the online version at doi:.
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References and notes
- 1(a).Leadbeater NE, Marco M. Chem. Rev. 2002;102:3217–3274. doi: 10.1021/cr010361c. [DOI] [PubMed] [Google Scholar]; (b) Song CE, Lee S. Chem. Rev. 2002;102:3495–3524. doi: 10.1021/cr0103625. [DOI] [PubMed] [Google Scholar]; (c) van Heerbeek R, Kamer PCJ, van Leeuwen PWNM, Reek JNH. Chem. Rev. 2002;102:3717–3756. doi: 10.1021/cr0103874. [DOI] [PubMed] [Google Scholar]; (d) Corma A, Garcia H, Llabres i Xamena FX. Chem. Rev. 2010;110:4606–4655. doi: 10.1021/cr9003924. [DOI] [PubMed] [Google Scholar]
- 2(a).Ma L, Abney C, Lin W. Chem. Soc. Rev. 2009;38:1248–1256. doi: 10.1039/b807083k. [DOI] [PubMed] [Google Scholar]; (b) Lee JY, Farha OK, Roberts J, Scheidt KA, Nguyen SBT, Hupp JT. Chem. Soc. Rev. 2009;38:1450–1459. doi: 10.1039/b807080f. [DOI] [PubMed] [Google Scholar]; (c) Ma L, Lin W. Top. Curr. Chem. 2010;293:175–205. doi: 10.1007/128_2009_20. [DOI] [PubMed] [Google Scholar]; (d) Jiang H-L, Xu Q. Chem. Commun. 2011;47:3351–3370. doi: 10.1039/c0cc05419d. [DOI] [PubMed] [Google Scholar]
- 3(a).Biginelli P. Chem. Ber. 1891;24:1317–2962. [Google Scholar]; (b) Biginelli P. Chem. Ber. 1893;26:447. [Google Scholar]; (c) Biginelli P. Gazz. Chim. Ital. 1893;23:360–416. [Google Scholar]
- 4(a).For reviews, see: Kappe CO. Eur. J. Med. Chem. 2000;35:1043–1052. doi: 10.1016/s0223-5234(00)01189-2. Heys L, Moore CG, Murphy PJ. Chem. Soc. Rev. 2000;29:57–67.
- 5(a).Bao S-S, Ma L-F, Wang Y, Fang L, Zhu C-J, Li Y-Z, Zheng L-M. Chem. Eur. J. 2007;13:2333–2343. doi: 10.1002/chem.200601097. [DOI] [PubMed] [Google Scholar]; (b) Yang T-H, Zhou K, Bao S-S, Zhu C-J, Zheng L-M. Inorg. Chem. Commun. 2008;11:1075–1078. [Google Scholar]; (c) Wang C-M, Wu Y-Y, Chang Y-M, Lii K-H. Chem. Mater. 2008;20:2857–2859. [Google Scholar]; (d) Wang C-M, Wu Y-Y, Hou C-H, Chen C-C, Lii K-H. Inorg. Chem. 2009;48:1519–1523. doi: 10.1021/ic801817e. [DOI] [PubMed] [Google Scholar]; (e) MacNeill CM, Day CS, Marts A, Lachgar A, Noftle RE. Inorg. Chim. Acta. 2010:196–203. [Google Scholar]; (f) MacNeill CM, Day CS, Marts A, Lachgar A, Noftle RE. Inorg. Chim. Acta. 2011;365:196–203. [Google Scholar]; (g) Wang M, Xie M-H, Wu C-D, Wang Y-G. Chem. Commun. 2009:2396–2398. doi: 10.1039/b823323c. [DOI] [PubMed] [Google Scholar]
- 6.For a review, see: Kappe CO, Stadler A. Org. React. 2004;63:1–116.
- 7(a).Sun Q, Wang Y-Q, Ge Z-M, Cheng T-M, Li R-T. Synthesis. 2004:1047–1051. [Google Scholar]; (b) Narsaiah AV, Basak AK, Nagaiah K. Synthesis. 2004:1253–1256. [Google Scholar]; (c) Yu Y, Liu D, Liu C, Jiang H, Luo G. Prep. Biochem. Biotech. 2007;37:381–387. doi: 10.1080/10826060701593290. [DOI] [PubMed] [Google Scholar]; (d) Xue S, Shen Y-C, Li Y-L, Shen X-M, Guo Q-X. Chin. J. Chem. 2002;20:385–389. [Google Scholar]; (e) Xu H, Wang Y-G. Chin. J. Chem. 2003;21:327–331. [Google Scholar]; (f) Wang M, Jiang H, Wang Z. J. Chem. Res. 2005:691–693. [Google Scholar]
- 8.For the synthesis of these two MOFs, please see the Supplementary Data.
- 9.For details, please see the Supplementary Data.
- 10.Anastas PT, Warner JC. Green Chemistry: Theory and Practice. Oxford University Press; New York: 1998. [Google Scholar]
- 11(a).For examples, see: Gedrich K, Heitbaum M, Notzon A, Senkovska I, Froehlich R, Getzschmann J, Mueller U, Glorius F, Kaskel S. Chem. Eur. J. 2011;17:2099–2106. doi: 10.1002/chem.201002568. Shi L-X, Wu C-D. Chem. Commun. 2011;47:2928–2930. doi: 10.1039/c0cc05074a.
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