Tungstosilicic acid as an efficient catalyst for the one-pot multicomponent synthesis of triazolo[1,2-a]indazole-1,3,8-trione derivatives under solvent-free conditions

1 Introduction

Multicomponent reactions (MCRs) are important for the achievement of high levels of diversity, as they allow more than two building blocks to be combined in practical, time-saving one-pot operations, giving rise to complex structures by simultaneous formation of two or more bonds, according to the domino principle (Zhu and Bienayme, 2005). MCRs contribute to the requirements of an environmentally friendly process by reducing the number of synthetic steps, energy consumption and waste production. Researchers have transformed this powerful technology into one of the most efficient and economic tools for combinatorial and parallel synthesis (Zhu and Bienayme, 2005; Domling and Ugi, 2000; Domling, 2006).

Among a large variety of nitrogen-containing heterocyclic compounds, heterocycles containing an urazole moiety are of interest because they constitute an important class of natural and non-natural products, many of which exhibit useful biological activities and clinical applications (Lei et al., 2005; Kiriazis et al., 2007; Boatman et al., 2003; Kolb et al., 1994; Izydore et al., 1990). Urazole derivatives also exhibit anticonvulsant (Jacobson et al., 1972) or fungicidal activity (Shgematsu et al., 1977) as well as catalytic activity in radical polymerization (Baumgartner et al., 1990). Novel methods for preparing heterocycles containing a urazole moiety have attracted much interest in recent years (Lei et al., 2005; Kiriazis et al., 2007; Boatman et al., 2003; Boldi et al., 1999; Tanaka et al., 1994; Arroya et al., 2004; Deghati et al., 1998; Meehan and Little, 1997; Menard et al., 2003; Bazgir et al., 2007; Hasaninejad et al., 2011; Chari et al., 2010). Only few methods being available for the synthesis of heterocycles containing an triazolo[1,2-a]indazole-1,3,8-trione (Bazgir et al., 2007; Hasaninejad et al., 2011; Chari et al., 2010). These compounds are synthesized by the condensation of dimedone, urazole, and aromatic aldehydes using catalysts such as p-toluene sulfonic acid (Bazgir et al., 2007), sulfonated polyethylene glycol (Hasaninejad et al., 2011) or mesoporous aluminosilicate (Chari et al., 2010). These protocols have limitations such as requirement of huge amounts of catalyst, regeneration of the catalyst, the separation of the product from the reaction mixtures, purification of the products by column chromatography and the use of toxic organic solvent. Therefore, the search continues for a better catalyst for the synthesis of indazole-1,3,8-trione ring fragment.

In recent years, solid acids have found increased application in organic synthesis, as they may be easily recovered and recycled. Heteropolyacids (HPAs) are strong solid acids, harmless to the environment, and highly stable toward humidity, with flexibility in modifying acid strength (Wang et al., 2010; Ueda and Kotsuki, 2008). Moreover, solvent-free reactions often provide clean, efficient, and high-yielding organic processes in heterocyclic synthesis (Martins et al., 2009). In continuation of our efforts to develop new, green chemistry methods (Mosaddegh and Hassankhani, 2011), herein we describe a simple synthesis of triazolo[1,2-a]indazole-1,3,8-triones by three-component condensation reaction of urazole, aromatic aldehydes, and dimedone under solvent-free conditions using catalytic amount of tungstosilicic acid as a recyclable catalyst at 100 °C (Scheme 1).

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Scheme 1

Synthesis of triazolo[1,2-a]indazole-1,3,8-triones under solvent-free conditions using tungstosilicic acid.

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2 Experimental

Chemicals were purchased from Fluka, Merck and Aldrich. Melting points were determined in open capillary tubes and are uncorrected. IR measurements were carried out using KBr pellets in FTIR spectrometer. The NMR was run on Bruker-400 MHz instruments CDCl₃. All of the products are known and were characterized by their spectral and physical data. The monitoring of the progress of all reactions was carried out by TLC. TLC was runned using TLC aluminum sheets silica gel 60 F₂₅₄ (Merck).

3 Results and discussion

Keggin-type HPAs such as H₃PW₁₂O₄₀ (PWA), H₃PMo₁₂O₄₀ (PMoA), or H₄SiW₁₂O₄₀ (SiWA) are often employed as efficient and green catalysts in many organic transformations (Kozhevnikov, 1998, 2009; Firouzabadi and Jafari, 2005; Firouzabadi et al., 2005; Yang et al., 2008; Rafiee and Jafari, 2006; Wang et al., 2008a,b, 2009; Kozhevnikov et al., 2003; Heydari et al., 2008). This prompted us to use SiWA to survey the three-component reaction of urazole, aromatic aldehydes, and dimedone. To compare the efficiency as well as capacity of the solvent-free conditions with respect to solution conditions, various solvents were examined. The results presented in Table 1 indicate that solvents affected the efficiency of the catalyst. Yields were lower in acetonitrile, ethanol, chloroform, ethyl acetate, and water (Table 1, entries 1–5). However, the best result was obtained under solvent-free conditions at 100 °C (Table 1, entry 9). Next, the optimum amount of SiWA was evaluated. The highest yield was obtained with 3.5 mol% of the catalyst. A further increase in the amount of SiWA did not have any significant effect on the product yield. In order to establish the true effectiveness of the catalyst, reaction of 4-chlorobenzaldehyde, dimedone, and urazole was performed at 100 °C without catalyst under solvent-free conditions. It was found that no conversion to triazolo[1,2-a]indazole-1,3,8-trione occurred after 60 min of heating.

The reusability of the catalyst was examined in the synthesis of triazolo[1,2-a]indazole-1,3,8-trione derivatives. When the reaction was completed, water was added and the solid product was filtered. The aqueous solution was evaporated under reduced pressure, and the obtained powder was washed with diethyl ether, dried, and reused for the same reaction again. It was found that the catalyst could be reused three times with slight decreasing in catalytic activity, 75%, 74% and 72% (Table 2, entry 2). The generality of this reaction was examined using different aldehydes having electron-donating as well as electron-withdrawing groups. Substituents on the aromatic ring had no obvious effect on yield or reaction time under the above optimal conditions. In all cases, the reactions gave the corresponding products in good yields and short reaction times (Table 2). This method offers significant improvements with regard to the scope of the transformation, simplicity and green aspects by avoiding toxic solvents.

A possible mechanism for the formation of the products is shown in Scheme 2. The reaction occurs via initial formation of heterodiene 5 by standard Knoevenagel condensation of aldehyde 1 and dimedone 2. Subsequent Michael-type addition of the urazole 3 to 5 followed by cyclization affords the corresponding product 4 (Scheme 2).

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Scheme 2

Suggested mechanism for the formation of triazolo[1,2-a]indazole-1,3,8-triones.

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4 Conclusion

We have developed a simple, efficient, one-pot and green protocol for the synthesis of triazolo[1,2-a]indazole-1,3,8-trione derivatives using SiWA as a reusable heterogeneous catalyst under solvent-free conditions. The short reaction times, mild reaction conditions, simple work-up in isolation of the products in good yields and high purity are features of this new procedure.