Silicotungstic acid (H₄SiW₁₂O₄₀): An efficient Keggin heteropoly acid catalyst for the synthesis of oxindole derivatives

1 Introduction

Isatin (2,3-dioxindole) identified as an endogenous compound in humans that has a range of biological properties including actions in the brain and offering protection against certain type of infections (Pandeya et al., 2005). Various derivatives of isatin are key motifs of natural product structures for example Convolutamydine A is an alkaloid which is isolated from marine bryozoan amathia convoluta has exhibited potent activity in differentiation of HL-60 human promyelocytic leukemic cells (Kamano et al., 1995). A well-known category of isatins are oxindoles which possess anti-convulsant natures including antibacterial, anti-inflammatory, antiprotozoal and mechanism-specific antiproliferative properties and also patented as PR (progesterone receptors) agonists (Pajouhesh et al., 1983). They can also be used as laxatives (Garrido et al., 1975). Much attention has been devoted to the preparation of oxindole rings because their systems are the core structures of many pharmacological agents. For example, Spiro[indole-thiazolidinones] possess antifungal activities against pathogens (Dandia et al., 2006) and Spirotryprostatine B as a natural alkaloid, showed anti-mitotic properties to get it in great interest as an anti-cancer drug (Sebahar and Williams, 2000). Isatins possess a reactive carbonyl group at 3-position that readily made them good electrophilic candidates to undergo condensation reactions with indoles to form 3,3-bis(indolyl)oxindole derivatives. The synthesis of natural 3,3-bis(indolyl)oxindole (3a) was first reported by Seidel in 1950. 3,3-Bis(indolyl)indoline-2-ones (3,3-bis(indolyl)oxindoles) showed anti-cancer properties (Kamal et al., 2010). During recent years some methods have been reported for the condensation of some electron-rich heteroaromatics such as indoles and pyrroles with isatins using catalysts such as silica sulfuric acid (SSA) (Azizian et al., 2006), KAl(SO₄)₂.12H₂O (Azizian et al., 2004), ceric ammonium nitrate (CAN) (Wang and Ji, 2006), phosphotungstic acid (H₆P₂W₁₈O₆₂) (Alimohammadi et al., 2008), montmorillonite K10 clay (Chakrabarty et al., 2005), KSF (Nikpasand et al., 2010), ionic liquids (Karimi et al., 2011 and Rad-Moghadam et al., 2010), FeCl₃ (Kamal et al., 2010) and I₂ (Paira et al., 2009) to prepare the corresponding, 3,3-bis(3-indolyl)- and, 3,3-bis(2-pyrrolyl)oxindoles. Some of these strategies have shortcomings such as cost, reaction time, operational parameters and yield. Due to these deficiencies and also the significance of this class of compounds, offering new and efficient methods for their synthesis is still in demand. Heteropoly acids (HPAs) have been pointed out lately as versatile, environmentally benign, water tolerate, stable and green heterogeneous and homogenous catalysts for a variety of organic reactions (Okuhara, 2002). They contain lewis and strong bronsted acidity (Nandhini et al., 2004). Solid HPAs have discrete ionic structures that contain heteropolyanion (polyoxometalate) units and countercations that are H⁺ (Kozhevnikov, 1998). This special structure exhibits high proton mobility while heteropolyanions stabilize cationic intermediates (Izumi et al., 1992). The best known HPAs are the Keggin type H_8−nXM₁₂O₄₀, where X is he central atom, n is the oxidation state of X and M is the metal ion. In the Keggin type HPAs, protons take part in the formation of the crystal structure by linking the neighboring polyoxometalate units (Kozhevnikov, 1998). Also HPAs possess bronsted acidity, but found to be efficient in catalyzing some reactions that conventionally use lewis acids such as Friedel–Crafts alkylation (Kamakshi and Reddy, 2007). Silicotungstic acid H₄W₁₂SiO₄₀ is one of the well-known Keggin types of HPAs. It has been used as an acid catalyst in some transformations such as bis(indolyl)methane synthesis (Rafiee et al., 2011), alkylation of benzene with olefins (Sawant and Halligudi, 2005), production of acrolein from glycerol (Tsukuda et al., 2007), indole Michael addition (Murugan et al., 2005) and 1,2-dihydroquinones (Kamakshi and Reddy, 2007). We wish now to report a new usage of silicotungstic acid as an impressive, inexpensive and easily handling acid catalyst for the synthesis of 3,3-bisoxindole derivatives via the condensation reaction of various isatins with indoles and pyrrole at room temperature.

2 Materials and methods

Isatins, indoles, pyrrole, STA and solvents were purchased from Merck, Aldrich and Alfa Aesar and used without further purification. N-Benzylisatin is synthesized from isatin according to the reported procedure (Azizian et al., 2003). Melting points were determined using a Stuart Scientific SMP2 capillary apparatus and are uncorrected. IR spectra were recorded from KBr disks on a Shimadzu IR-435. ¹H NMR spectra were recorded with a Bruker drx 500 (500 MHz) machine. Mass spectra were obtained on a Platform II spectrometer from Micromass; EI mode at 70 eV. Preparative layer chromatography (PLC) was carried out on 20 × 20 cm² plates, coated with a 1 mm layer of Merck silica gel PF₂₅₄, prepared by applying the silica as slurry and drying in air.

3 Results and discussion

To investigate the solvent nature on the reaction rate, the model condensation of indole and isatin was performed in various solvents and conditions. According to the data presented in Table 1, it seems that the polarity of the solvent is necessary, as the reaction in n-Hexane, a non-polar solvent candidate, did not progress (entry 1). Using polar solvents like CHCl₃, EtOAc, MeOH and EtOH, the model reaction promoted obviously. These observations lead that the solubility of the substrates is essential in reaction promotion. The polarity, dipole moment, and hydrogen bonding of a solvent are determining factors for the solvation of a substrate. Methanol as a polar protic solvent with the highest dielectric constant and dipole moment can solve indole and isatin almost completely. So the best result is gained in MeOH (entry 4). Temperature did not affect the results (entry 6). STA is also solvable in almost polar protic solvents. But this factor is not as important as a substrate solvation .This assumption is confirmed by adding H₂O to EtOH that did not promote the reaction more than as utilizing the polar organic solvent lonely (entry 7). It is parallel to this fact that STA as a heteropolyacid can apply its catalytic influence both heterogeneously and homogeneously. So, methanol at room temperature has been chosen as the best condition for this purpose.

Using the reaction of isatin with indole in methanol as test experiment, the consumption of catalyst amount has been optimized. Due to Fig. 1 using 10 mol% (0.1 mmol) of STA showed the best result.

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Figure 1

Optimization of catalyst amount.

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Under optimized reaction conditions, the reactions of various isatins 1(a–e) with indoles 2(a–d) were carried out until maximum progression of the reactions (Scheme 1). The results are given in Table 2.

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Scheme 1

Synthesis of 3,3-bis(indolyl)oxindoles.

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As can be seen a wide range of electron-rich and electron-deficient indoles and isatins performed the reaction. The summarized results confirmed the faster reaction of 2-methylindole rather than 1-methylindole with isatin (entries 3b and 3c). The study also revealed the faster reaction of 2-methylindole with electron-donating isatins in comparison with indole (entries 3e–3h). All the products were characterized by recording IR, ¹HNMR and MS spectra and also by comparison of their spectral data with those of authentic samples. Under the reaction conditions, skatole (3-methylindole) 4 and pyrrole 5 underwent the condensation with isatin to form their corresponding 3,3-bis(2-indolyl)oxindole (6) and 3,3-bis(2-pyrrolyl)oxindole (7) respectively (Scheme 2). These results revealed the efficacy of the catalyst, as it can condense other heterocycles rather than indoles with isatin. The condensation of 3-methylindole at its 2-position, where its 3-moeity is blocked, with isatin, is another highlighted point in protocol feasibility.

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Scheme 2

Synthesis of 3,3-bis(2-indolyl)oxindole and 3,3-bis(2-pyrrolyl)oxinole.

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On the basis of forgoing results we reported a proposed mechanism for this condensation with the involvement of H₄SiW₁₂O₄₀ in the rate determining step (Scheme 3):

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Scheme 3

Proposed mechanism of the reaction.

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Due to conjugation of the nitrogen lone pair with the carbonyl group at 2-position, this moiety is uncreative and the complexation of STA returns to the substrates (Scheme 3, A). The attack of STA as a solid acid to the reactive ketonic carbonyl group of isatin at 3-position, forms B which is stabilized by resonance structures IB–IIB. Nucleophilic attack of indole to this structure gave the intermediate C that dehydrated to D. Subsequent nucleophilic addition of another indole to D forms 3,3-bis(indolyl)oxindole as the main product.

4 Conclusion

In this report we have demonstrated the application of silicotungstic acid (STA) as a very effective, eco-friendly and inexpensive commercial-available catalyst in the synthesis of symmetrical 3,3-bis(heteroaryl)oxindoles at room temperature. Simple experimental procedure associated with high yield, short reaction time makes this protocol interesting for organic chemists.