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Convenient on water synthesis of novel derivatives of dicoumarol as functional vitamin K depleter by Fe3O4 magnetic nanoparticles
⁎Corresponding authors. Address: Department of Chemistry, Yasouj University, P.O. Box 353, Yasouj 75918-74831, Iran (S. Khodabakhshi). Tel.: +98 7412223048; fax: +98 7412242167. saeidkhm@yahoo.com (Saeed Khodabakhshi), karami@mail.yu.ac.ir (Bahador Karami)
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Received: ,
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This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Peer review under responsibility of King Saud University.
Abstract
Abstract
The Fe3O4 nanoparticles were successfully prepared and characterized by X-ray diffraction (XRD), Fourier transform-infrared (FT-IR), and transmission electron microscopy (TEM). The magnetic property of the prepared nanoparticles was investigated by magnetization analysis and the measured magnetization of NPs was found to be considerably lower than the values measured from bulk magnetite. The catalytic efficiency of the prepared nanoparticles was subsequently investigated as a magnetically recyclable and safe catalyst for the green synthesis of new dicoumarols via the one-pot condensation of 4-hydroxycoumarin with aryl glyoxals on water. Catalyst loadings can be as low as 2 mol% to give good yields of the corresponding products. This present method has many advantages, such as the high product yield, avoidance of toxic organic solvents, and simple work-up procedure.
Keywords
Fe3O4 nanoparticles
Dicoumarols
Recyclable
Green synthesis
1 Introduction
Dicoumarol, a derivative of coumarin, is a naturally occurring anticoagulant that functions like warfarin as a vitamin K antagonist. Dicoumarols are the bridge substituted dimers of 4-hydroxycoumarin which have been employed for the prevention and treatment of thrombosis. They are also used in biochemical experiments as inhibitor of reductases (Link, 1941). According to the importance of some compounds containing coumarin nucleus in pharmaceutical research, the chemistry of this class of compounds has recently attracted the attention of chemists (Barzegar et al., 2011; Karami et al., 2012a, 2013a; Litinas et al., 2011). Although dicoumarol was firstly discovered in mouldy wet sweet-clover hay, several methods have been described in the literature to synthesize its derivatives such as, total synthesis of dicoumarols starting from salicylaldehyde and formaldehyde (Cherkupally and Mekala, 2008), biosynthesis of dicoumarol employing micro-organisms such as Penicillium jenseni (Bellis et al., 1967), and Knoevenagel condensation of 4-hydroxycoumarins with carbonyls using several catalysts (Hamdi et al., 2008; Kolos et al., 2007; Siddiqui and Farooq, 2011; Ziarani and Hajiabbasi, 2013).
To develop environmentally benign reaction conditions and media for organic transformations with excellent efficiency and selectivity, water has been shown to be a useful solvent or media (Karami et al., 2012b). Recently, organic synthesis on water was reviewed by Fokin and co-workers (Chanda and Fokin, 2009). Magnetically recyclable nanocatalyst systems for the organic reactions have also attracted considerable attention. In this context, we report the use of Iron oxide nanoparticles (Fe3O4 NPs) as an eco-friendly and efficient catalyst for the synthesis of some new and known dicoumarols containing an aryloyl group. Fe3O4 NPs were extensively applied as a powerful catalyst for organic transformations (Karami et al., 2012c,d). Moreover, the composite containing Fe2O3 and Fe3O4 NPs (Ahmad, 2013) have been used for the cellular separation (Roveimiab et al., 2012), bioadsorbents of biotin (Fartani et al., 2007), and potential solid support for recyclable biocatalysts (Rahman et al., 2013).
2 Experimental
All chemicals were purchased from Merck and Aldrich. Aryl gloxals were synthesized in accord with our previous method (Karami et al., 2011). The reactions were monitored by thin layer chromatography (TLC; silica-gel 60 F254, n-hexane: ethyl acetate). IR spectra were recorded on a FT-IR JASCO-680 and the 1H NMR spectra were obtained on a Bruker-Instrument DPX-400 and 300 MHz Avance 2 model. The varioEl CHNS Isfahan Industrial University was used for elemental analysis. The powder X-ray diffraction (XRD) pattern was obtained by a Bruker AXS (D8, Avance) instrument employing the reflection Bragg–Brentano geometry with CuKα radiation. Transmission electron microscopy (TEM) images were taken with a Philips CM-10 TEM microscope operated at 100 kV. The structures and purity of the obtained products were deduced from their IR, elemental analysis, and NMR spectral data.
2.1 Preparation of Fe3O4 NPs
FeCl3·6H2O (6.1 g, 0.02 mol) and FeCl2·4H2O (2.35 g, 0.01 mol) were dissolved in 100 mL de-ionized H2O under magnetic stirring for 10 min, then, the solution was heated to 90 °C under nitrogen atmosphere. Subsequently, the ammonium hydroxide solution (10 mL, 25%) was added drop by drop to the reaction mixture and was allowed to continue for about 1 h. The reaction mixture was cooled to room temperature and black precipitate separated in a magnetic field from the reaction mixture, repeatedly washed with de-ionized H2O for several times to remove the impurities.
2.2 Preparation of dicoumarols 3
A mixture of 4-hydroxycoumarin 1 (2 mmol), aryl glyoxals 2 (1 mmol) and Fe3O4 NPs (2 mol%) in H2O (10 mL) was heated at 80 °C for an appropriate time. The progress of the reaction was monitored by TLC. Upon completion, the mixture was poured on ice. After formation of precipitate, the solid was filtered off, dried and dissolved in a hot mixture of EtOH/THF (2:1). Fe3O4 NPs were separated by a magnet and pure product obtained by recrystallization from solvent. In some cases, column chromatography is needed.
2.3 Spectral data of new compounds
4-Flouro-benzoyl[bis(4-hydroxycoumarin-3-yl)]methane (3b): M.p. 235–237 °C; IR (KBr) = 3500–3300, 3066.26, 2887, 1695, 1650, 1619, 1600, 1567, 1271, 1225, 1107 cm−1; 1H NMR (CDCl3, 300 MHz): δ = 11.15 (s, 2H), 7.89 (dd, 2H, J1 = 8.2, J2 = 1.6 Hz), 7.79–7.75 (m, 2H), 7.56–7.50 (m, 2H), 7.33–7.24 (m, 4H), 6.94 (t, 2H, J = 8.6 Hz).
13C NMR (CDCl3, 75 MHz): δ = 192.91, 165.40, 152.41, 133.27, 132.00, 130.77, 130.65, 125.08, 124.56, 116.75, 116.35, 115.97, 115.68, 42.80.
4-Methoxy-benzoyl[bis(4-hydroxycoumarin-3-yl)]methane (3e): M.p. 265–267 °C; IR (KBr) = 3500–3300, 3076, 2978, 1684, 1650, 1620, 1601, 1571, 1263 cm−1; 1H NMR (CDCl3, 300 MHz): δ = 11.22 (s, 2H), 8.00 (dd, 2H, J = 8.2, 1.6 Hz), 7.77–7.72 (m, 2H), 7.55–7.49 (m, 2H), 7.32–7.24 (m, 4H), 6.77–6.72 (m, 2H), 6.00 (s, 1H), 3.71 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ = 193.13, 165.22, 163.55, 152.40, 133.08, 130.48, 128.30, 124.94, 124.57, 116.68, 116.48, 113.88, 55.46, 42.62.
3-Methoxy-benzoyl[bis(4-hydroxycoumarin-3-yl)]methane (3f): M.p. 205–207 °C; IR (KBr) = 3500–3300, 1693, 1655, 1619, 1602, 1567, 1273, 1427 cm−1; 1H NMR (CDCl3, 300 MHz): δ = 11.16 (s, 1H), 8.00 (dd, 2H, J = 8.2, 1.6 Hz), 7.55–7.49 (m, 2H), 7.34–7.24 (m, 6H), 7.12 (t, 1H, J = 8.2 Hz), 6.94–6.90 (m, 1H), 6.00 (s, 1H), 3.69 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ = 194.21, 165.28, 159.72, 152.40, 136.93, 133.17, 129.42, 125.03, 124.52, 120.26, 120.15, 116.73, 116.42, 112.46, 42.91.
4-Chloro-benzoyl[bis(4-hydroxycoumarin-3-yl)]methane (3g): M.p. 250–252 °C; IR (KBr) = 3500–3300, 3080, 2884, 1713, 1665, 1650, 1614, 1564, 1266, 1090, 767 cm−1; 1H NMR (DMSO-d6, 400 MHz): δ = 11.10 (s, 2H), 7.85 (d, 2H, J = 6.0 Hz), 7.72 (d, 2H, J = 5.2 Hz), 7.62–7.52 (m, 4H), 7.31–7.25 (m, 4H), 6.28 (s, 1H); 13C NMR (DMSO-d6, 100 MHz): δ = 196.16, 165.92, 163.33, 152.27, 135.90, 131.66, 131.24, 129.32, 125.94, 123.83, 123.45, 118.09, 115.87, 101.64, 42.92.
2-Naphthoyl[bis(4-hydroxycoumarin-3-yl)]methane (3h): M.p. 255–257 °C; IR (KBr) = 3550–3300, 1694, 1653, 1617, 1565, 1454, 1280 cm−1; 1H NMR (CDCl3, 300 MHz): δ = 11.24 (s, 2H), 8.27 (s, 1H), 8.01 (dd, 2H, J1 = 8.2, J2 = 1.6 Hz), 7.83–7.72 (m, 4H), 7.54–7.43 (m, 4H), 7.33–7.23 (m, 4H), 6.19 (s, 1H). 13C NMR (DMSO-d6, 75 MHz): δ = 177.38, 166.60, 163.65, 152.32, 134.48, 134.38, 131.82, 131.50, 129.13, 127.95, 127.54, 126.70, 124.15, 123.90, 123.33, 118.50, 115.78, 101.67, 43.14.
3 Results and discussion
The Fe3O4 NPs, homogeneous in size and composition, were prepared according to previous methods (Liu et al., 2008) by modification and characterized by X-ray diffraction (XRD), Fourier transform-infrared (FT-IR), and transmission electron microscopy (TEM).
Fig. 1. shows the powder X-ray diffraction (XRD) pattern for the Fe3O4 NPs. Although, the laboratory XRD diffractometers do not allow discriminating between the two possible cubic spinel phases of γ-Fe2O3 and magnetite (Fe3O4) due to their structural similarities (Cozzoli et al., 2006; Petkov et al., 2009; Buonsanti et al., 2010; Levy et al., 2011), our reaction conditions (Fe3O4 prepared under N2 atmosphere) supplied Fe3O4 nanoparticles that were considered in literatures (Park et al., 2004). The γ-Fe2O3 particles could prepare at high temperature in air (Kang et al., 1996). A number of prominent Bragg reflections by their indices (2 2 0), (3 1 1), (4 0 0), (4 2 2), (5 1 1) and (4 4 0) reveal that the resultant magnetic NPs were Fe3O4 and structure is that of an inverse spinel (Park et al., 2004). The size of the magnetic NPs was also determined from X-ray line broadening by the use of Debye–Scherrer formula (D = 0.9λ/β cos θ, where D is the average crystalline size, λ is the X-ray wavelength used, β is the angular line width at half maximum intensity, and θ is the Bragg’s angle). For the (3 1 1) reflection the average size of the Fe3O4 NPs was estimated to be around 11 nm.
The powder X-ray diffraction pattern of the Fe3O4 NPs.
The Fourier transform-infrared (FT-IR) spectrum of Fe3O4 NPs is shown in Fig. 2. The absorbance band at 583.3 cm−1 can be ascribed to Fe+2–O−2, which is consistent with the reported IR spectra for Fe3O4 NPs (Hoseini et al., 2013).
FT-IR spectra of Fe3O4 NPs.
The morphology and microstructure of the NPs were further investigated by TEM analysis. Fig. 3A and B show TEM images that reveal spherical Fe3O4 NPs with an average size of 10–15 nm (Fig. 3C).
TEM images (A and B) show spherical Fe3O4 NPs with 10–15 nm and (C) the Histogram of particle size distribution.
Fig. 4 shows the results for magnetization as a function of applied field at room temperature obtained for dry powder of Fe3O4 NPs. Magnetic measurement indicates magnetic behavior at room temperature for Fe3O4 NPs with no hysteresis behavior. For Fe3O4 NPs, the saturation magnetization value (Ms) is 57.8 emu/g while the reported value, Ms is 84 emu/g for the bulk Fe3O4 particles (Zhang and Wan, 2003). The measured magnetization of NPs was found to be considerably lower than the values measured from bulk magnetite.
Room-temperature magnetization curve of magnetic Fe3O4 NPs.
Following our efforts to develop green methods in organic synthesis (Karami et al., 2013b,c; Khodabakhshi and Karami, 2012), we turned our attention toward the condensation of 4-hydroxycoumarin (1) and aryl glyoxals 2 in the presence of catalytic amounts of Iron oxide nanoparticles (Fe3O4 NPs) to produce dicoumarol derivatives 3 (Scheme 1).
Synthesis of dicoumarol derivatives.
To identify the suitable reaction conditions for the synthesis of 3 using Fe3O4 NPs, the reaction of 4-hydroxycoumarin (1) and phenyl glyoxal (2a) was selected as a model (Scheme 2).
Model reaction for optimization of conditions.
As can be seen in Table 1, we found that in the absence of the catalyst, the reaction was not completed, even at long reaction times.
Entry
Catalyst
Time (min)
Yield (%)
1
–
360
25
2
Fe3O4 NPs (1 mol%)
100
77
3
Fe3O4 NPs (2 mol%)
40
75
4
Fe3O4 NPs (5 mol%)
40
73
5
Fe3O4 powder (2 mol%)
70
65
A higher loading of catalyst did not affect a marked influence on the product yield or reaction rate. Furthermore, in order to compare the Fe3O4 nanoparticles with bulk case, an experiment was also investigated. However, it was found that the model reaction proceeded slowly in the presence of Fe3O4 powder as bulk case (it needs 140 min to be completed).
In another experiment, in order to show the effect of solvent or media on the reaction progress, we employed several solvents for which the results have been shown in Table 2. It can be concluded that protonic solvents such as EtOH, MeOH, and H2O can accelerate the condensation reaction.
Entry
Solvent
Time (min)
Yield (%)
1
–
360
10
1
MeOH
40
77
2
EtOH
40
75
3
THF
45
73
4
CH2Cl2
360
50
5
EtOH/H2O (1:1)
35
75
6
H2O
40
75
It should be also noted that 4-hydroxycoumarin is soluble in alcohol, acetone and ether, but it has low solubility in water. Through screening, we found that this reaction was efficiently completed using Fe3O4 NPs (2 mol%) under reflux in H2O about 40 min (entry 6). Subsequently, in order to prove the general applicability of this method, different aryl glyoxals were employed in the reaction with 1 (Table 3).
Entry
Ar
Time (min)
Yielda (%)
Mp (°C)
3a
C6H5
40
75
177–175
3b
4-F-C6H4
35
73
273–235
3c
4-Br-C6H4
30
80
262–264
3d
4-NO2-C6H4
30
86
270–272
3e
4-MeO-C6H4
35
75
265–267
3f
3-MeO-C6H4
40
70
205–207
3g
4-Cl-C6H4
45
75
250–252
3h
40
85
255–257
The nature of the Ar group showed no significant effect on the reaction rate or product yield. The use of water instead of organic solvents is more reasonable because of its safety and cheapness.
Mechanistically, the Scheme 3 shows a suggested mechanism to synthesize by Fe3O4. Making an active leaving group on aryl glyoxal by a Lewis acid such as iron (II, III) may be a reasonable start for the Knoevenagel condensation with 4-hydroxycoumarin (1). Subsequently, 1,4-addition of next 4-hydroxycoumarin to the formed α,β-unsaturated ketone can produce target molecule. This mechanism also shows the recyclability of Fe3O4 NPs.
Suggested mechanism for the synthesis of dicoumarol using Fe3O4 Nps.
Nano-magnetite (Fe3O4) as a support for recyclable catalysts in the development of sustainable methodologies has been recently reviewed by Gawande and co-workers (Gawande et al., 2013). To investigate the reusability of Fe3O4 NPs in the synthesis of dicoumarols 3, this magnetically recyclable catalyst was reused 3 times (Fig. 5).
Recyclability of Fe3O4 NPs in synthesis of 3a. Reaction time: 40 min.
The results show that these magnetic nanoparticles are usable for 3 times without appreciable loss in catalytic activity and it is likely to be slowly aggregated after cycle 3 according to Fe3O4 NP aggregation in aqueous media (Butter et al., 2003). It should be noted that, here, we investigated the catalytic efficiency in a constant time (40 min) and the reaction was efficiently completed after 60 min for the cycle 4. Despite an observable decrease of catalytic activity in cycle 4, it is separable from the reaction mixture and reusable for the next step, but, acts like Fe3O4 powder. Totally, avoidance of organic solvents and use of separable catalysts are important factors in agreement with green chemistry principles.
4 Conclusions
In summary, we have described the preparation, characterization, and a new application of Fe3O4 nanoparticles as a magnetically recyclable catalyst in a condensation reaction to produce new dicoumarol containing an aroyl group. This reaction can be also regarded as a new approach for the preparation of pharmaceutically relevant heterocyclic systems. This method includes some important aspects such as use of environmentally friendly and recyclable catalyst, good productivity, short reaction times, and use of water as a clean media, which make this protocol in accord with green and sustainable chemistry.
Acknowledgements
We gratefully acknowledge the Yasouj University Research Council for their support. We are also grateful to the Iranian Nanotechnology Initiative Council for financial support.
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Appendix A
Supplementary data
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.arabjc.2014.05.030.
Appendix A
Supplementary data
Supplementary data
Supplementary data