Alum-Catalyzed One-Pot Synthesis of Dihydropyrano [ 3 , 2-b ] chromenediones

The rapid assembly of molecular diversity is an important goal of synthetic organic chemistry and one of the key paradigms of modern drug discovery. One approach to address this challenge involves the development of multicomponent reactions (MCR), in which three or more reactants are combined together in a single reaction flask to generate a product. In addition to the intrinsic atom economy and selectivity underlying such reactions, simpler procedures and equipment, time and energy savings, as well as environmental friendliness have all led to a sizable effort to design and implement MCR in both academia and industry. Kojic acid derivatives, one of the important kind of fused heterocyclic compounds, possess significant bioactivities such as antifungal, anti-neoplastic, antiproliferative, antiHIV, anticonvulsant, anti-inflammatory, antioxidative, antibacterial, anticonvulsant, and tyrosinase inhibitory activities. Therefore, the synthesis of kojic acid derivatives has aroused great interest in the organic and medicinal communities. Recently Reddy et al. reported the synthesis of 2-(hydroxymethyl)-7,7-dimethyl-10-aryl-7,8-dihydropyrano[3,2-b]chromene-4,9(6H,10H)-diones using InCl3 as a catalyst. However, this method is associated with one or more disadvantages such as the use of an expensive, waterintolerant and non recyclable catalyst and higher reaction temperature. Thus, there is still need of a simple and general procedure for the one-pot synthesis of 2-(hydroxymethyl)7,7-dimethyl-10-aryl-7,8-dihydropyrano[3,2-b]chromene4,9(6H,10H)-dione under mild conditions. Alum (KAl(SO4)2·12H2O), which is relatively nontoxic and inexpensive catalyst, has emerged as an efficient alternative catalyst for a variety of prominent organic transformations, such as the Biginelly and Pechmann reactions and also used for the synthesis of 1,8-dioxo-octahydroxanthenes, isoquinolonic acids, trisubstituted imidazoles, 1’H-spiro[isoindoline-1,2’quinazoline]-3,4’(3’H)-diones, 1,3,4-oxadiazoles and 1,5-benzodiazepines. In this paper, we wish to report a rapid and highly efficient method for the synthesis of 2-(hydroxymethyl)-7,7-dimethyl-10-aryl-7,8dihydropyrano[3,2-b] chromene-4,9(6H,10H)-dione in the presence of alum under solvent-free conditions (Scheme 1).


Introduction
The rapid assembly of molecular diversity is an important goal of synthetic organic chemistry and one of the key paradigms of modern drug discovery.One approach to address this challenge involves the development of multicomponent reactions (MCR), in which three or more reactants are combined together in a single reaction flask to generate a product.In addition to the intrinsic atom economy and selectivity underlying such reactions, simpler procedures and equipment, time and energy savings, as well as environmental friendliness have all led to a sizable effort to design and implement MCR in both academia and industry. 1ojic acid derivatives, one of the important kind of fused heterocyclic compounds, possess significant bioactivities such as antifungal, 2 anti-neoplastic, 3 antiproliferative, 4 anti-HIV, 5 anticonvulsant, 6 anti-inflammatory, 7 antioxidative, 8 antibacterial, 9 anticonvulsant, 10 and tyrosinase inhibitory activities. 11Therefore, the synthesis of kojic acid derivatives has aroused great interest in the organic and medicinal communities.

Results and Discussion
To choose optimum conditions, first, the effect of temperature on the rate of the reaction was studied for the preparation of the three-component condensation reaction of kojic acid, benzaldehyde, and dimedone in presence of 10 mol% alum under solvent-free conditions (Table 1).At 100 o C, the reaction proceeded smoothly and gave short reaction time and high yield.Therefore, we kept the reaction temperature at 100 °C.
Next, in the study set out to determine optimal amount of alum, the reaction was carried out by varying the amount of the catalyst ( in the mentioned reaction did not has any significant effect on the product yield. In order to extend the above reaction (Scheme 1) to a library system, various kinds of arylaldehydes 2 (Table 3) were subjected to react with 1 and 3 to give the   3.All of 1 gave the expected products in high yields, either bearing electron-withdrawing groups (such as halide, nitro) or electron-donating groups (such as alkyl group) under the same reaction condition.To further demonstrate the scope and limitation of the substrates, aliphatic aldehydes, such as phenylacetaldehyde, propionaldehyde, n-butylaldehyde and n-heptaldehyde, were used as reactants to react with kojic acid and dimedone.However, the desired products were not found and obtained successfully.All of the structures were characterized by IR, 1 H NMR, 13 C NMR, MS and elemental analysis.In the 1 H NMR spectra, there was a missing proton, which was possibly OH.When 1 H NMR spectra were determined using DMSO-d 6 instead of CDCl 3 as solvent, there appeared a broad peak at d 5.54-5.36,so that proved that our supposition was correct.We also checked the reusability of the catalyst by recovering the alum and using it for new runs and found that the catalyst could be reused several times without any decrease in the product yield.An example is shown for the reaction of kojic acid with benzaldehyde (Table 3, 4a) and dimedone.The catalyst can be removed from the aqueous phase by removing the water under vacuum then washing with EtOH and drying at rt.
The formation of products 4a-4k can be rationalized by initial formation of heterodiene 5 by standard Knoevenagel condensation of dimedone 3 and aromatic aldehyde 2 in the presence of a catalytic amount of alum.Subsequent Diels Alder-type addition of kojic acid 1 to the heterodienes 5 followed by dehydration afford the corresponding products 4a-4k (Scheme 2).

Conclusions
In conclusion, an efficient protocol for the one-pot preparation of 2-(hydroxymethyl)-7,7-dimethyl-10-aryl-7,8-dihydropyrano[3,2-b]chromene-4,9(6H,10H)-diones from the three-component condensation reaction of kojic acid, aromatic aldehydes, and dimedone employing alum as reusable catalyst was described.The reactions were carried out under thermal solvent-free in short reaction time and produced the corresponding products in good to excellent yields.Also, the catalyst could be successfully recovered and recycled at least for three runs without significant loss in activity.

Experimental
IR spectra were determined on an FTS-40 infrared spectrometer; NMR spectra were determined on Bruker AV-400 spectrometer at room temperature using TMS as internal standard, coupling constants (J) were measured in Hz.Mass spectra were recorded on a Finnigan LCQ Advantage mass spectrometer.Elemental analyses were performed by a Vario-III elemental analyzer.Melting points were determined on a XT-4 binocular microscope and were uncorrected.Commercially available reagents were used throughout without further purification unless otherwise stated.

Table 2 )
. Maximum yield was obtained with 10 mol% of the catalyst.Further increase in amount of alumVol.22, No. 11, 2011

Table 2 .
The b Isolated yield.