Feb 20, 2013 - the synthesis of 2-amino-4H-chromenes under the heterogeneous catalysis ... magnesium oxide in aqueous media in excellent yields at room ...
To appear in: Received date: Revised date: Accepted date:
4-1-2013 20-2-2013 3-3-2013
Please cite this article as: J. Safari, Z. Zarnegar, M. Heydarian, Practical, ecofriendly, and highly efficient synthesis of 2-amino-4H-chromenes using nanocrystalline MgO as a reusable heterogeneous catalyst in aqueous media, Journal of Taibah University for Science (2013), http://dx.doi.org/10.1016/j.jtusci.2013.03.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Practical, ecofriendly, and highly efficient synthesis of 2-amino-4Hchromenes using nanocrystalline MgO as a reusable heterogeneous catalyst in aqueous media
ip t
J. Safari*, Z. Zarnegar, M. Heydarian
Chemistry, University of Kashan, 87317-51167 Kashan, I. R. Iran
cr
Laboratory of Organic Chemistry Research, Department of Organic Chemistry, College of
Abstract: A simple, efficient, and environmentally benign method has been developed for
M
the synthesis of 2-amino-4H-chromenes under the heterogeneous catalysis of nanocrystalline magnesium oxide in aqueous media in excellent yields at room temperature. This method
d
provides a green and improved pathway for the synthesis of chromenes in the terms of
te
excellent yields, short reaction times and reusability catalyst.
Multicomponent coupling reaction (MCR) is a powerful synthetic tool for the synthesis of biologically active compounds [1-3]. Development of such multicomponent coupling reaction strategies in aqueous medium has been of considerable interest, as they provide simple and rapid access to a large number of organic molecules through a sustainable path [4]. One important aspect of green chemistry is the elimination of solvents in chemical processes or the replacement of hazardous solvents with relatively benign solvents. Water being the most environmentally benign, cleanest, cheapest, nonflammable, and naturally occurring solvent 1
Page 1 of 26
having high specific heat capacity is the primary choice. Moreover, in water, significant rate enhancement was observed in many reactions [5], because of hydrophobic interactions that induce a favorable aggregation of polar components in water [6].
ip t
Heterocycles containing the chromene moiety show interesting features that make them attractive targets for MCRs. Among different types of chromene systems, 2-amino-4H-
cr
chromenes are of particular utility as they belong to privileged medicinal scaffolds serving for generation of small-molecule ligands with highly pronounced anticoagulant- , diuretic-,
us
spasmolitic- and antianaphylactic activities [7-12]. The current interest in 2-amino-4H-
an
chromene derivatives arises from their potential application in the treatment of human inflammatory TNFα-mediated diseases, such as psoriatic arthritis and rheumatoid and in
M
cancer therapy [13-15]. Many of the methods reported for the synthesis of these compounds [16-20] are associated with the use of hazardous organic solvents, long reaction time, use of
d
toxic amine-based catalysts, and lack of general applicability. Along with other reaction
te
parameters, the nature of the catalyst plays a significant role in determining yield, selectivity, and general applicability. Thus, development of an inexpensive, mild, general, and reusable
Ac ce p
catalyst for MCRs remains an issue of interest. As a part of our continued interest in catalysis by nanoparticles, recently, we found excellent selectivity of nanocrystalline magnesium oxide for a MCR leading to 2,4,5-trisubstituted imidazole derivatives in high yields without the formation of other byproducts [21] Magnesium oxide (MgO) has many applications as catalyst [22, 23], refractory materials [24], optically transparent ceramic windows [25, 26], etc. Magnesium oxide with large specific surface area is also a potential catalyst support for various reactions and a promising sorbent for chemisorptions and destructive adsorption of a variety of pollutants. In the field of catalysis, MgO has strongly basic properties, which are associated with catalysis by bases in many organic reactions [27]. Nanoscale supports create catalysts with more edges and 2
Page 2 of 26
corners, which can lead to higher performance of the catalyst. In this paper, we report convenient and facile multi-component, one-pot synthesis of 2-amino-4H-chromene in high yields by using nanocrystalline magnesium oxide with high specific surface area of
efficient catalyst in water at room temperature (Scheme 1).
cr
ip t
approximately 116 m2 g-1 and a crystallite size of approximately 12 nm as a novel and
us
an
2. Experimental: 2.1.Materials
M
Chemical reagents in high purity were purchased from the Merck Chemical Company. All materials were of commercial reagent grade.
te
d
2.2. General
Melting points were determined in open capillaries using an Electrothermal Mk3 apparatus
Ac ce p
and are uncorrected. Infrared (IR) spectra were recorded using a Perkin-Elmer FT-IR 550 spectrom-eter. 1H NMR and
13
C NMR spectra were recorded with a Bruker DRX-400
spectrometer at 400 and 100MHz respectively. NMR spectra were obtained in DMSO-d6 solutions. The element analyses (C, H, N) were obtained from a Carlo ERBA Model EA 1108 analyzer carried out on Perkin-Elmer 240c analyzer. XRD analysis was performed with an Xray diffractometer (PANalytical X’Pert-Pro) using a Cu-Ka monochromatic radiation source and an Ni filter.Transmission electron microscopy (TEM) was performed with a Jeol JEM2100UHR, operated at 200 kV. 2.3. Preparation of nanocrystalline MgO 3
Page 3 of 26
Nanocrystalline MgO was prepared by means of a procedure reported elsewhere [28]. In short, poly(vinyl alcohol) (PVA, MW 70,000) was dissolved in water at 90 ºC under vigorous stirring to form a transparent solution. Mg(NO3)2.6H2O was dissolved in water containing
ip t
PVA. The metal ion-to-PVA monomer unit molar ratio (M/PVA) was chosen as 1:3. Aqueous ammonia (25% w/w) was added dropwise at room temperature to the resulting
cr
viscous liquid mixture, with rapid stirring, to achieve careful pH adjustment to 10.5. After precipitation, the slurry was stirred for another 30 min and then heated under reflux at 80 ºC
us
for 20 h under continuous stirring. The mixture was cooled to room temperature, filtered, and
an
washed with hot deionized water for effective removal of the poly(vinyl alcohol). The final product was dried at 80 ºC for 24 h and calcined at 700 ºC.
M
2.4. General procedure for the synthesis of 2-amino-3- cyano-7-hydroxy-4-substituted-4Hchromene derivatives
d
A mixture of resorcinol (1 mmol), aldehyde derivatives (1 mmol), malononitrile (1 mmol),
te
H2O (5ml) and nanocrystalline MgO (0.007 g) was stirred at room temperature for the
Ac ce p
appropriate time.. After completion of the reaction (TLC monitoring), the nanocrystalline MgO was filtered off and the solvent was evaporated. The filtrate was concentrated to dryness, and the crude solid product was crystallized from EtOH to afford the pure 2-amino3-cyano-7-hydroxy-4-substituted-4H-chromene derivatives. 2.5. Spectral data for new compounds 2-Amino-3-cyano-7-hydroxy-4-(3-chlorophenyl)-4Hchromene (4d) IR (KBr): ν (cm−1) 3423 (OH), 3338 (NH2), 2192 (CN), 1656 (C=C vinyl nitrile), 1582 (C=C aromatic); 1H NMR (400 MHz, DMSO-d6): δ 4.739 (s, 1H, H-4), 6.382 (d, 1H, J=3 , H-Ar), 6.457 (dd, 1H, J=3, J=9, H-Ar), 6.591 (d, 1H, J=9, H-Ar), 6.94 (s,2H, NH2) 7.04-7.305 (m, 4
3. Result and discussion: In the preliminary stage of investigation we focused on systematic evaluation of different catalysts for the model reaction of benzaldehyde 1a, malononitrile 2, and resorcinol 3 at room
ip t
temperature in aqueous conditions. A wide variety of catalysts including Nano-Mg/Al2O3, Triethylamine, KOH, bulk MgO and nano MgO were employed to improve the yield for the
cr
specific synthesis of 2-amino-4H-chromene derivative. The results are presented in Table 1.
us
Interestingly, when the reaction was carried out in the presence of (4 mol%) nano MgO; it led to the desired product in 91% yield in 20 min (Table 1, Entry 6). The high efficiency of the
an
nanoparticle oxides is caused not only by their high surface area but also by the high concentration of low-coordinated sites and structural defects on their surface. As the particle
M
size is scaled down to a few nanometers, the constituting atoms have highly defective coordination environments. Most of the atoms have unsatisfied valencies and reside at the
d
surface [28]. The catalytic activity of nano-MgO was evident when no product was obtained
te
in the absence of the catalyst (Table 1, Entry 1).
Ac ce p
The crystallite sizes determined by XRD were between 12.8 and 17.5 nm (determined by use of the Scherrer equation), indicative of the nanocrystalline structure of the prepared MgO. In addition the surface area was approximately 116 m2 g-1. The pore volume and pore size were also calculated from the N2 adsorption result; the pore size was approximately 21.1 nm and the pore volume approximately 0.69 cm3 g-1. The TEM image of MgO is shown in Fig. 1. As can be seen, the sample has a nanocrystalline structure with a plate-like shape [28] < Fig. 1> Subsequent efforts were focused on optimizing conditions for formation of 2-amino-4Hchromene by using different amounts of nanocrystalline MgO to determine their effects on 10
Page 10 of 26
the reaction (Table 2). As indicated, the best result was obtained with 6 mol% nanocrystalline MgO. The reaction yield with increasing amount of nanocrystalline MgO was not substantially increased.
ip t
The efficiency of water as solvent compared to various organic solvents was also examined
cr
(Table 3). In this study, it was found that water is a more efficient and superior solvent (Table
and yield of the desired chromene.
an
us
3, Entry 6) over other organic solvents (Table 3, Entries 1–5) with respect to reaction time
Based on above observations, we conducted the same reactions using various aldehydes 1a-r,
M
malononitrile 2, and resorcinol 3 in the presence of 6 mol% of Nano MgO under similar conditions. As expected, satisfactory results were observed, and the results are summarized in
d
Table 4. Interestingly, a variety of aldehydes including acyclic, aromatic, and heteroaromatic
te
aldehydes participated well in this reaction (Table 4). It is noteworthy that methodology worked well for spatially-hindered aldehydes (Table 4, Entries 6-11).
Ac ce p
Encouraged by this achievement, the versatility of the reaction was explored further by extending the methodology to the synthesis of bis-4H-chromene. When p-phthalaldehyde was treated with two equiv. malononitrile and resorcinol under similar conditions, the reaction proceeded cleanly to give the corresponding bis-4H-chromene (4r) in 97% yield. The order of yield of aldehydes is aromatic- > heteroaromatic- > acyclic aldehydes. The activity of aldehydes with electron-withdrawing groups is higher than that with electron-donating groups. The position of substituent in the benzene rings of aldehyde influences this reaction. The activity of o-aldehyde is lower than p-and m-benzaldehyde.
11
Page 11 of 26
The reactived catalytic reused four consecutive cycles without any significant loss in catalytic activity (Table 5 ).
ip t
A plausible mechanism explaining the aforementioned results and the selectivity is depicted in Scheme 2. The process represents a typical cascade of Knoevenagel condensation, Michael
cr
addition, and a Thorpe-Ziegler type cyclization, which might initiate via two pathways, namely A and B (Scheme 2). Once the three components are mixed, aldehyde 1a undergoes
us
Knoevenagel condensation with malononitrile 2 to afford arylidene (or alkylidene)
an
malononitrile 5, which is subsequently attacked by 3 to furnish the central intermediate 7 (path A). Alternatively, intermediate 7 is likely formed from initial condensation of isatin 1a
M
with 3 to afford 6, followed by nucleophilic addition of malononitrile 2 (path B). The component 7 could undergo cyclization to 8 and subsequently to the more stable tautomer
d
4a.
te
When P- N,N-dimethylaminobenzaldehyde was used as a starting material, component 9 was
Ac ce p
obtained. The structure of this component has been confirmed by physical and spectroscopic data such as; IR, 1H NMR, 13C NMR. In the 1H NMR spectra, the disappearance of aliphatic proton signal around the δ=5 ppm in compounds 4a-r and followed to appear the signals at δ=8.03 ppm [s, 1H, CH(a)], 7.8 ppm [d, J=8 Hz, 2H, 2CH(b)], and 6.8 ppm [d, J=8 Hz, 2H, 2CH(c)], was confirmed the formation of component 9 in this reaction (Fig. 2); therefore A route would be selected as a preferred route. < Fig. 2> 4. Conclusion
12
Page 12 of 26
In summary, we have developed an efficient method for the synthesis of 2-amino-4Hchromene derivatives by means of a three-component reaction between resorcinol, aldehyde and malononitrile using a catalytic amount of nano MgO under neat conditions. This method
ip t
has several advantages including high yields of products, easy experimental workup. The reactived catalytic reused four consecutive cycles without any significant loss in catalytic
cr
activity.
us
Acknowledgment
We gratefully acknowledge the financial support from the Research Council of the University
an
of Kashan.
M
References
[1] R. G.Srivastava, P.S. Venkataramani, Barium Manganate Oxidation in Organic Synthesis:
d
Part III: Oxidation of Schiff'S Bases to Benzimidazoles Benzoxazoles and Benzthiazoles.
te
Synth. Commun. 18 (1988) 1537-1544.
Ac ce p
[2] M. Shen, T.G. Driver, Iron(II) Bromide-Catalyzed Synthesis of Benzimidazoles from Aryl Azides, Org. Lett. 10 (200) 3367-3370. [3] K. Bahrami, M.M. Khodaci, F. Naali, Mild and Highly Efficient Method for the Synthesis of 2-Arylbenzimidazoles and 2-Arylbenzothiazoles, J. Org. Chem. 73 (2008) 6835-6838. [4] R. S. Varma, Solvent-free organic syntheses . using supported reagents and microwave irradiation, Green Chem. 1 (1999) 43-55. [5] D. C. Rideout, R. Breslow, Hydrophobic acceleration of Diels-Alder reactions, J. Am. Chem. Soc. 102 (1980) 7816-7817. [6] S. H. Banitaba, J. Safari, S. D. Khalili. Ultrasound promoted one-pot synthesis of 2amino-4,8-dihydropyrano [3,2-b]pyran-3-carbonitrile scaffolds in aqueous media: A 13
Page 13 of 26
complementary ‘green chemistry’ tool to organic synthesis Ultrason. Sonochem. 20 (2013) 401–407 [7] R. W. DeSimone, K. S. Currie, S. A. Mitchell, J. W. Darrow, D. A. Pippin, Privileged
ip t
structures: applications in drug discovery, Comb. Chem. High Throughput Screen. 7 (2004) 473-494.
cr
[8] J. Safari, Z. Zarnegar, M. Heydarian, Magnetic Fe3O4 Nanoparticles as Efficient and Reusable Catalyst for the Green Synthesis of 2-Amino-4H-chromene in Aqueous Media,
us
Bull. Chem. Soc. Jpn. 85 (2012) 1332-1338.
an
[9] L. Bonsignore, G. Loy, D. Secci, A. Calignano, Eur. J. Med. Chem., 1993, 28, 517. [10] W.O. Foye, Prinicipi di Chemico Farmaceutica; Piccin: Padova, PD. (1991) 416.
M
[11] M.M. Heravi, B. Baghernejad, H.A. Oskooie, A Novel and Efficient Catalyst to One-pot Synthesis of 2-Amino-4H-chromenes by Methanesulfonic Acid, Journal of the Chinese
d
Chemical Society.55 (2008) 659-662
te
[12] L. L. Andreani and E. Lapi, Aspects and orientations of modern pharmacognosy, Boll. Chim. Farm. 99 (1960) 583-586.
Ac ce p
[13] J. Skommer, D. Wlodkowic, M. Matto, M. Eray, J. Pelkonen, HA14-1, a small molecule Bcl-2 antagonist, induces apoptosis and modulates action of selected anticancer drugs in follicular lymphoma B cells, Leukemia Res. 30 (2006) 322-331. [14] W. Kemnitzer, S. Kasibhatla, S. Jiang, H. Zhang, J. Zhao, S. Jia, L. Xu, C. CroganGrundy, R. Denis, N. Barriault, L. Vaillancourt, S. Charron, J. Dodd, G. Attardo, D. Labrecque, S. Lamothe, H. Gourdeau, B. Tseng, J. Drewe, S. X. Cai, Discovery of 4-aryl-4Hchromenes as a new series of apoptosis inducers using a cell- and caspase-based highthroughput screening assay. 2. Structure–activity relationships of the 7- and 5-, 6-, 8positions, Bioorg. Med. Chem. Lett. 15 (2005) 4745-4751.
14
Page 14 of 26
[15] H. Gourdeau, L. Leblond, B. Hamelin, C. Desputeau, K. Dong, I. Kianicka, D. Custeau, C. Bourdeau, L. Geerts, S. X. Cai, J. Drewe, D. Labrecque, S.; Kasibhatla, B. Tseng, Antivascular and antitumor evaluation of 2-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-
ip t
cyano-4H-chromenes, a novel series of anticancer agents, Mol. Cancer Ther. 3 (2004) 13751384.
cr
[16] J. Y.Goujon, F. Zammattio, S. Pagnoncelli, Y. Boursereau, B. Kirschleger, A New and Efficient Synthesis of Substituted 2-Hydroxymethyl-2-methyl-2H-chromenes, Synlet. (2002)
us
322-324.
an
[17] G. W. Kabalka, B. Venkataiah, B. C. Das, Synthesis of 2H-Chromenes in Ionic Liquid Solvents, Synlett. 12 (2004) 2194-2196.
M
[18] S. Makarem, A. A. Mohammadi, A. R. Fakhari, A multi-component electro-organic synthesis of 2-amino-4H-chromenes Tetrahedron Lett. 49 (2008) 7194-7196.
d
[19] A. Shaabani, R. Ghadari, S. Ghasemi, M. Pedarpour, A. H. Rezayan, A. Sarvary, Ng, S.
te
Weng, Novel One-Pot Three- and Pseudo-Five-Component Reactions: Synthesis of Functionalized Benzo[g]- and Dihydropyrano[2,3-g]chromene Derivatives, J. Comb. Chem.
Ac ce p
11 (2009) 956-959.
[20] M.K. Jitender, N. Bhaskara, S. Pooja, DBU: a highly efficient catalyst for one-pot synthesis of substituted 3,4-dihydropyrano[3,2-c]chromenes, dihydropyrano[4,3-b]pyranes, 2-amino-4H-benzo[h]chromenes and 2-amino-4H benzo[g]chromenes in aqueous medium, Tetrahedron. 66 (2010) 5637-5641. [21] J. Safari, S.H Dehghan Khalili, M. Rezaei, S.H.Banitaba, F. Meshkani, Nanocrystalline magnesium oxide: a novel and efficient catalyst for facile synthesis of 2,4,5-trisubstituted imidazole derivatives, Monatsh Chem. 141 (2010) 1339-1345. [22] D. Gulkova, O. Solcova, M. Zdrazil, Preparation of MgO catalytic support in shaped mesoporous high surface area form, Microporous Mesoporous Mater. 76 (2004) 137-149. 15
Page 15 of 26
[23] M.J. Climent, A. Corma, S. Iborra, M. Mifsud, MgO nanoparticle-based multifunctional catalysts in the cascade reaction allows the green synthesis of anti-inflammatory agents, J Catal., 247 (2007) 223-230.
ip t
[24] M.A. Faghihi-Sani, A. Yamaguchi, Oxidation kinetics of MgO–C refractory bricks, Ceram Int. 28 (2002) 835-839.
cr
[25] R. Chaim, Z.J. Shen, M.J. Nygren, Transparent nanocrystalline MgO by rapid and lowtemperature spark plasma sintering, Mater Res. 19 (2004) 2527-2531.
us
[26] D. Chen, E.H. Jordan, M. Gell, Pressureless sintering of translucent MgO ceramics, Scr
[28] F. Meshkani, M. Rezaei, Effect of process parameters on the synthesis of nanocrystalline magnesium oxide with high surface area and plate-like shape by surfactant assisted
Scheme 1. Nanocrystalline MgO catalyzed MCRs leading to 2-amino-4H-chromenes. Fig. 1. TEM image of nanocrystalline MgO
ip t
Table 1. Influence of different catalysts for the reaction of benzaldehyde 1a, malononitrile 2, and resorcinol 3 at room temperature in aqueous medium.
cr
Table 2. Optimizing the reaction conditions.
Table 3. Solvent screening for the reaction between malononitrile, benzaldehyde and
us
resorcinol
an
Table 4. Nanocrystalline MgO catalyzed three component condensations of malononitrile aldehydes and resorcinol to form 2-amino-4H-chromenes.
M
Table 5. The effect of reusability of nanocrystalline MgO on the product 4a yield. Scheme 2. The plasuable mechanism for one-pot synthesis of 2-amino-4H-chromenes.
Ac ce p
te
d
Fig. 2. 1H NMR spectra of P-N,N-dimethylaminobenzylidenmalononitrile (component 9)
17
Page 17 of 26
Tables
d
M
an
us
catalyst amount (2 mol%). Isolated yield of the pure compound.
te
b
Ac ce p
a
cr
ip t
Table 1. Influence of different catalysts for the reaction of benzaldehyde 1a, malononitrile 2, and resorcinol 3 at room temperature in aqueous medium. Entry Catalysta Time(h) Yieldb (%) 1 None 3 2 Nano-Mg/Al2O3 3 Trace 3 Triethylamine 2 70 4 KOH 2 50 5 MgO 1.5 62 6 Nano-MgO 0.3 91
