Hydrated Ferric Sulfate [Fe<sub>2</sub>(SO<sub>4</sub>)<sub>3</sub>·xH<sub>2</sub>O]: An Efficient and Reusable Catalyst for One-Pot Synthesis of 2H-Indazolo[2,1-b]phthalazine-triones
Hydrated Ferric Sulfate [Fe2(SO4)3·xH2O]: An Efficient and Reusable Catalyst for One-Pot Synthesis of 2H-Indazolo[2,1-b]phthalazine-triones
Journal of the Korean Chemical Society. 2015. Aug, 59(4): 280-283
Copyright © 2015, Korean Chemical Society
  • Received : September 02, 2013
  • Accepted : May 20, 2015
  • Published : August 31, 2015
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About the Authors
Abhik Choudhury
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, India
Shahzad Ali
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, India
Abu T. Khan

Hydrated ferric sulfate can be used as an efficient and reusable catalyst for the synthesis of 2 H -indazolo[2,1-b]phthalazine-trione derivatives via one-pot three-component condensation reaction of phthalhydrazide, aromatic aldehydes and cyclic-1,3-diketones in ethanol under reflux conditions.
Hydrated ferric sulfate [Fe 2 (SO 4 ) 3 · x H 2 O] has been found as a catalyst for various organic transformations such as tetrahydropyranlations of alcohols, 1 preparation of acylals from aldehydes, 2 2,3-unsaturated glycosides via Ferrier rearrangement, 3 per-O-acetylation of sugars, 4 synthesis of tetrahydroquinolines 5 through Povarov reaction and synthesis of 1 H -pyrazole-4-carbodithioate 6 using MCRs. The unique solubility of the catalyst in ethanol and insolubility in DCM enables its usage as both homogenous and heterogeneous catalyst; and is recoverable by DCM after the reaction. As a part of our ongoing research work by employing MCRs to synthesize new molecules, 7 we conceived that Fe 2 (SO 4 ) 3 · x H 2 O can be exploited further as a reusable catalyst for the synthesis of heterocycles by employing multicomponent reactions.
The efficient high-throughput synthesis of biologically active organic compounds is one of the most important and challenging endeavors in modern drug discovery. Organic reactions should be fast, neat and clean, and the target products should be easily separable with high purity and good yields. To cover all the above aspects, multicomponent reactions 8 (MCRs) play an important role in combinatorial chemistry because of their ability to synthesize target molecules with greater efficiency, higher atom-economy, structural diversity and complexity in a single step from three or more reactants. These reactions are very effective for synthesizing highly functionalized organic molecules from readily available starting materials.
The synthesis of heterocyclic compounds has gained considerable attention among synthetic organic chemists due to their immense potentiality in pharmaceuticals. Heterocyclic systems are found abundantly in nature as alkaloids, flavonoids and isoflavonoids 9 and they are considered to be essential to life. Among various nitrogen containing heterocycles, phthalazine skeleton is present in many naturally occurring compounds and they exhibit interesting pharmacological properties ( . 1 ). The compounds having fused phthalazines possess many biological activities such as anticonvulsant, 10 cardiotonic, 11 vasorelaxant, 12 antimicrobial, 13 antifungal, 14 anticancer, 15 and anti-inflammatory 16 activities. They are also highly potent inhibitors of vascular endothelial growth factor receptor II (VEGFR-2). 17 19 Furthermore, these compounds might be useful materials for luminescence or fluorescence studies. 20
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Some biologically active compounds having phthalazine skeleton.
The synthesis of 2 H -indazolo[2,1- b ]phthalazine-trione derivatives have been reported involving one-pot condensation of phthalhydrazide, aldehydes and 1,3-diketones using numerous catalysts. 21,22 Though all these protocols are quite useful, still there is a need to develop a new methodology using a reusable catalyst.
In this paper, we have reported hydrated ferric sulfate catalyzed one pot synthesis of 2 H -indazolo[2,1- b ]phthalazine-trione derivatives via three-component condensation reaction of phthalhydrazide, aromatic aldehydes and cyclic 1,3-dicarbonyl compounds in ethanol under reflux conditions as shown in 1 .
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Synthesis of 2H-indazolo[2,1-b]phthalazine-trione derivatives.
- General experimental procedure for the Synthesis of 2H-indazolo[2,1-b]phthalazine-trione derivatives
Hydrated ferric sulfate (0.20 mol, 0.084 g) was added to a mixture of an aromatic aldehyde (1.2 mmol), a cyclic 1,3-dicarbonyl compound (1.0 mmol) and phthalhydrazide (1.0 mmol) in 3 mL of ethanol. The reaction mixture was kept for refluxing in a preheated oil-bath. After completion of the reaction (as monitored by TLC), it was brought to room temperature. The solid product precipitated out after adding 6 mL of water into it and it was filtered off through a Büchner funnel. The precipitate was washed with ethanol (2 mL) and dried in a vacuum pump.
For checking reusability, a reaction mixture of phthalhydrazide (0.810 g, 5.0 mmol), 4-nirobenzaldehyde (0.831 g, 5.5 mmol) and dimedone (0.700 g, 5.0 mmol) in presence of hydrated ferric sulfate (0.418 g, 1 mmol) was refluxed in 10 mL of ethanol. After completion of the reaction, the catalyst was recovered by removing ethanol in a rotatory evaporator followed by addition of 15 mL of CH 2 Cl 2 . The catalyst was precipitated out due to its poor solubility in CH 2 Cl 2 and it was filtered off through a Büchner funnel. The desired product 4h was obtained after concentrating the organic solvent in a rotatory evaporator. The reusability of the recovered catalyst was examined for five consecutive times using the same substrates and the results are summarized in 3 . We have noted that the catalyst can be reused without losing much catalytic activity.
Reusability of the catalyst [Fe2(SO4)3⋅xH2O]
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aThe same set of reaction was performed with phthalhydrazide (5.0 mmol), 4-nirobenzaldehyde (5.5 mmol) and dimedone (5.0 mmol) in each time. bIsolated yield.
To find out suitable reaction conditions, benzaldehyde (1.2 mmol), dimedone (1 mmol), and phthalhydrazide (1 mmol) were chosen as the model substrates. The reactions were examined in presence of various catalysts in different solvent systems and the results are summarized in 1 .
Optimization for one-pot condensation of phthalhydrazide, benzaldehyde and dimedonea
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aThe reactions were carried out using phthalhydrazide (1.0 mmol), benzaldehyde (1.2 mmol) and dimedone (1.0 mmol). bIsolated Yield. X = Fe2(SO4)3xH2O.
It was noted that the reaction did not provide any desired product in absence of catalyst after heating at 80℃ for 10 h either in neat or in ethanol ( 1 , entries 1 and 2). Interestingly, the desired product 4a was isolated in 40% yield ( 1 , entry 4) when the same reaction mixture was heated in presence of 5 mol% hydrated ferric sulfate. Furthermore, we have carried out similar set of reactions in the presence of 10 mol%, 15 mol%, 20 mol% and 25 mol% ( 1 , entries 5-8), respectively. From these observations, we have noted that 20 mol% of the catalyst is the suitable choice to obtain best yield. For scrutinizing a suitable solvent system, the similar reaction was executed with similar boiling range of solvent such as dichloroethane, acetonitrile and water under identical reaction conditions. We found that the maximum yield of product 4a was obtained in ethanol under reflux conditions ( 1 , entry 7). To examine the efficacy of the other catalysts, the similar reactions were performed in presence of FeCl 3 ·6H 2 O, NiCl 2 , SnCl 2 and CH 3 COOH ( 1 , entries 12-15), respectively and we have obtained moderate to good yield. However, we have used hydrated ferric sulfate because of its reusability.
To generalize our protocol, a wide variety of aromatic aldehydes having electron-donating and electron- withdrawing substituents in the aromatic ring were reacted with phthalhydrazide, and dimedone under similar reaction condition and the desired 2 H -indazolo[2,1- b ]phthalazine-trione derivatives ( 4b-o ) were obtained in good yields. Likewise, cyclohexane-1,3-dione also provided the desired 2 H -indazolo[2,1- b ]phthalazine-trione derivatives 4p-u in good yields under identical reaction conditions. It is worthwhile to mention that aromatic aldehydes having electron-withdrawing group require relatively shorter reaction time as well as also provide good yields. Unfortunately, the similar kind of cyclized product was not obtained when the reaction carried out with acyclic 1,3-diketones. All the successful results ( 2 ) clearly demonstrate that hydrated ferric sulfate is an efficient catalyst for this three-component reaction.
Synthesis of 2H-indazolo[2,1-b]phthalazinetriones
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aAll the reactions were carried out using phthalhydrazide (1.0 mmol), aromatic aldehydes (1.2 mmol) and dimedone (1.0 mmol)/cyclohexane-1,3-dione (1.0 mmol) using 0.2 mmol of catalyst. bIsolated yield.
The probable mechanism for the formation of product may be rationalized as follows: Aromatic aldehyde reacts with dimedone to provide Knoevenagel product 2-benzyli-dene-5,5-dimethylcyclohexane-1,3-dione in the presence of hydrated ferric sulfate. Then the intermediate undergoes 1,4-Michael addition with phthalhydrazide followed by concomitant cyclization to give the desired product ( 2 ).
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Probable mechanism for the formation of product.
In view of greener chemistry, efficient recovery and reuse of the catalyst are highly desirable. As a matter of fact, the catalyst Fe 2 (SO 4 ) 3 · x H 2 O was recovered conveniently from the reaction mixture at the end of the reactions and it was reused another four times for the same set of reaction.
In summary, we have shown that hydrated ferric sulfate is an efficient and reusable catalyst for the synthesis of 2 H -indazolo[2,1- b ]phthalazine-trione derivatives via onepot three-component condensation reaction of phthalhydrazide, aromatic aldehydes and cyclic-1,3-diketones in ethanol under reflux conditions.
AC is grateful to CSIR, New Delhi for his research fellowship and SA to UGC for his senior research fellowship. The authors also acknowledge to the Director, IIT Guwahati for providing laboratory facilities in Department of Chemistry. Publication cost of this paper was supported by the Korean Chemical Society.
Li L. , Zhu L. , Zhang X. , Zhang G. , Qu G. 2005 Can. J. Chem. 83 1120 -    DOI : 10.1139/v05-136
Zhang X. , Li L. , Zhang G. 2003 Green Chem. 5 646 -    DOI : 10.1039/b305772k
Zhang G. , Liu Q. , Shi L. , Wang J. 2008 Tetrahedron 64 339 -    DOI : 10.1016/j.tet.2007.10.097
Shi L. , Zhang G. , Pan F. 2008 Tetrahedron 64 2572 -    DOI : 10.1016/j.tet.2008.01.027
Khan A. T. , Das D. K. , Khan M. M. 2011 Tetrahedron Lett. 52 4539 -    DOI : 10.1016/j.tetlet.2011.06.080
Khan A. T. , Ghosh A. , Basha R. S. , Mir M. H. 2012 Asian. J. Org. Chem. 2 126 -
Baxter H. , Moss G. P. 1999 Phytochemical Dictionary - A Handbook of Bioactive Compounds from Plants 2nd eds. Taylor & Francis London: UK
Grasso S. , De Sarro G. , De Sarro A. , Micale N. , Zappala M. , Puia G. , Baraldi M. , De Micheli C. 2000 J. Med. Chem. 43 2851 -    DOI : 10.1021/jm001002x
Nomoto Y. , Obase H. , Takai H. , Teranishi M. , Nakamura J. , Kubo K. 1990 Chem. Pharm. Bull. 38 2179 -    DOI : 10.1248/cpb.38.2179
Watanabe N. , Kabasawa Y. , Takase Y. , Matsukura M. , Miyazaki K. , Ishihara H. , Kodama K. , Adachi H. 1998 J. Med. Chem. 41 3367 -    DOI : 10.1021/jm970815r
El-Sakka S. S. , Soliman A. H. , Imam A. M. 2009 Afinidad 66 167 -
Ryu C.-K. , Park R.-E. , Ma M.-Y. , Nho J.-H. 2007 Bioorg. Med. Chem. Lett. 17 2577 -    DOI : 10.1016/j.bmcl.2007.02.003
Li J. , Zhao Y. F. , Yuan X. Y. , Xu J. X. , Gong P. 2006 Molecules 11 574 -    DOI : 10.3390/11070574
Sinkkonen J. , Ovcharenko V. , Zelenin K. N. , Bezhan I. P. , Chakchir B. A. , Al-Assar F. , Pihlaja K. 2002 Eur. J. Org. Chem. 2046 -
Sung J. S. , Lee H.-J. , Suh M.-E. , Choo H.-Y. P. , Lee S. K. , Park H. J. , Kim C. , Park S. W. , Lee C.-O. 2004 Bioorg. Med.Chem. 12 3683 -    DOI : 10.1016/j.bmc.2004.04.014
Piatnitski E. L. , Duncton M. A. J. , Kiselyov A. S. , KatochRouse R. , Sherman D. , Milligan D. L. , Balagtas C. , Wong W. C. , Kawakami J. , Doody J. F. 2005 Bioorg. Med. Chem. Lett. 15 4696 -    DOI : 10.1016/j.bmcl.2005.07.064
Duncton M. A. J. , Piatnitski E. L. , Katoch-Rouse R. , Smith L. M. , Kiselyov A. S. , Milligan D. L. , Balagtas C. , Wong W. C. , Kawakami J. , Doody J. F. 2006 Bioorg. Med. Chem. Lett. 16 1579 -    DOI : 10.1016/j.bmcl.2005.12.045
Wu H. , Chen X. M. , Wan Y. , Xin H. Q. , Xu H. H. , Ma R. , Yue C. H. , Pang L. L. 2009 Lett. Org. Chem. 6 219 -    DOI : 10.2174/157017809787893127