Efficient synthesis of 9,10-dihydropyrano[2,3-h]chromene-2,8-dione derivatives in ionic liquid and the study of their antioxidant activity

Abstract Ionic liquid N,N,N′,N′-tetramethylguanidinium trifluoroacetate (TMGT) has been applied as a green and reusable catalyst for the one-pot synthesis of 10-aryl substituted-9,10-dihydropyrano[2,3-h]chromene-2,8-diones via reaction of various aromatic aldehydes, 5,7-dihydroxycoumarin derivatives and Meldrum’s acid. The reactions were rapid, clean and the products were prepared in good yield. The ionic liquid was stable during the reaction process and reused without significant loss of its activity. The synthesised compounds were evaluated for their antioxidant activity by a 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay. Lasemi et al. ‘Efficient synthesis of 9,10-dihydropyrano[2,3-h]chromene-2,8-dione derivatives in ionic liquid and the study of their antioxidant activity’


Introduction
The use of environmentally benign reagents and solvents as well as efficient and cleanly reusable catalysts represents one of the more powerful green chemical technology procedures (Wilkes 2002). Ionic liquids have attracted considerable attention as eco-friendly solvents, catalysts and reagents in organic transformations, because of their interesting properties such as low volatility, non-flammability, high-thermal stability and ability to dissolve a wide range of materials (Kirchner 2009).
Pyranochromenes are an important class of structural motif of many natural products and synthetic compounds exhibiting a broad spectrum of biological activities including diuretic, analgesic, anti-HIV, anticancer, antifungal, antimicrobial, antiviral, antioxidant, anticoagulant, antidiabetic and anti-inflammatory (Tomoda et al. 1994;Uckun et al. 2000). In addition, they are also useful for the treatment of neurodegenerative disorders, including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease and Parkinson's disease (Bonsignore et al. 1993). Considering the importance of pyran derivatives, several methods have been reported for their synthesis (shaabani et al. 2005, 2009Yavari et al. 2008;Wang et al. 2010;Chen et al. 2011;Khan et al. 2011;Pratap et al. 2011;Karami et al. 2012;Miya et al. 2012;Rad-Moghadam et al. 2012;Li et al. 2013;Rad-Moghadam et al. 2013;eshghi et al. 2014;Pal et al. 2015). Despite the efficiency of these procedures, some suffer from drawbacks like the use of toxic solvent or catalyst, long reaction times, harsh reaction conditions and use of a non-reusable catalyst. Therefore, the development of a facile, efficient, and environmentally benign method for the preparation of pyranochromenes has become an interesting challenge.

Chemistry
TMGT was easily synthesised according to a reported procedure in the literature (Rahmati 2010), from N,N,N′,N′-tetramethyl guanidine and trifluoro acetic acid. To assess the catalytic activity of TMGT in the synthesis of coumarin-fused dihydropyran-2-ones, the three-component condensation of 4-chlorobenzaldehyde (1 mmol), Meldrum's acid (1 mmol), and 5,7-dihydroxy-4-methyl coumarin (1 mmol) was selected as a model reaction (scheme 2). In this regard, we attempted to determine the optimum conditions by examining the influence of ionic liquid at a variety of temperature (25, 50, 80°C) and different amounts of TMGT (0.5, 0.7, 1, 1.5, 2 mL) under solvent-free conditions on progress of the reaction.
The TMGT-catalyzed reaction was also carried out in various solvents such as etOH, H 2 O, MeCN and DMF. The best result was obtained using 1 mL of TMGT as catalyst at 80°C under solvent-free conditions.
To explore the substrate scope of this reaction, the condensation of various aromatic aldehydes with Meldrum's acid and 5,7-dihydroxy-4-methyl coumarin or 5,7-dihydroxy-4-trifluoromethyl coumarin in the presence of TMGT were examined for the preparation of 10-aryl substituted-9,10-dihydropyrano[2,3-h] chromene-2,8-dione derivatives (4) under optimum reaction conditions (Table 1). In all cases, aromatic aldehyde substituted with either electron-donating or electron-withdrawing groups underwent the reaction smoothly and gave desired products in excellent yields (Table 1, entries 1-4, 6, 7 and 9-10). The results in Table  1 indicate that the substituents on the pyranone ring have not substantial effect in terms of reaction time or product yields (Table 1, entries 5 and 8). Having these data in hand, we decided to apply this method for heterocyclic benzaldehydes. Furan-2-carbaldehyde and nicotinaldehyde reacted with Meldrum's acid and 5,7-dihydroxy-4-methyl coumarin under optimum reaction conditions and were found to produce the corresponding products 4 in high yields (Table 1, entries 11-12). The structure of products was determined on the basis of their elemental analysis, 1 H and 13 C NMR, IR and mass spectral data.
We also investigated the reusability of the ionic liquid. After completion of the model reaction under optimum reaction conditions, TMGT was separated from the reaction medium by washing the residue with cold water and the solvent evaporated under vacuum, then Scheme 1. Preparation of 10-aryl substituted-9,10-dihydropyrano[2,3-h]chromene-2,8-diones in tMGt.

Scheme 2. Model reaction for the optimisation of reaction conditions.
TMGT reused for the subsequent reactions at least four times without noticeable drop in the product yield and its catalytic efficiency (Table 1, entry 4). This reusability demonstrates the high stability and turnover of TMGT ionic liquid under operating conditions.

Antioxidant activity evaluation
In vitro antioxidant activity for coumarin fused dihydropyran-2-ones 4a-l was evaluated by use of the DPPH radical-scavenging method (Blois 1958); the results are presented in Figure 1. Antioxidant compounds scavenge DPPH radicals by the process of either hydrogen or electron donation and the purple color from the DPPH radical assay solution becomes light yellow which can be quantified by its decrease of absorbance at a wavelength 517 nm (Nabavi et al. 2012). The synthesised compounds 4a-l showed moderate to good antioxidant activity (27-57%), this can be attributed to their hydroxyl and benzyl hydrogens (Kumar et al. 2010;Kadhum et al. 2011). As illustrated in Figure 1, compounds 4c, 4i, 4j and 4k exhibited a high percent inhibition of DPPH radical activity (48.5% ± 0.8%, 51.7% ± 0.6%, 57.2% ± 1.1% and 53.4% ± 1.2%, respectively) and were the most effective DPPH radical scavengers.

Experimental
experimental section (experimental procedure and proposed mechanism for the synthesis of pyranochromenes 4 using TMGT, characterisation data and antioxidant assay) is available in supplementary material.

Conclusion
In summary, an efficient and green one-pot procedure for the synthesis of 10-aryl substituted-9,10-dihydropyrano[2,3-h]chromene-2,8-diones derivatives, potential antioxidants, using ionic liquid TMGT has been described. TMGT could be reused several times without loss of its catalytic activity. High yield, short reaction time, simple work-up, easy removal and recyclability of catalyst are the important features of this atom economical protocol.  Figure 1. antioxidant activity of coumarin-fused dihydropyran-2-ones 4a-l (1 mg ml −1 ). each value represents mean ± sd (n = 3).