SUCCINIMIDE-N-SULFONIC ACID AS AN EFFICIENT RECYCLABLE CATALYST FOR THE SYNTHESIS OF SOME FUSED INDOLO PYRANO PYRIMIDINONE DERIVATIVES

A new, simple, thermally efficient and solvent-free condensation of 2-amino-4,5-dihydro-4phenylpyrano[3,2-b]indole-3-carbonitrile derivatives with coumarin-3-carboxylic acid employing succinimide-Nsulfonic acid (SuSA) as catalyst for the synthesis of a series of 5,6-dihydro-2-(2-oxo-2H-chromen-3-yl)-5-phenylindolo[2',3':5,6]pyrano[2,3-d]pyrimidin-4(3H)-one derivatives is described. This method has the advantages of high yield, simple methodology, and short reaction time, as well as being green in terms of avoiding the use of toxic catalysts and solvents. Furthermore, the catalyst could be recycled and reused four times without significant loss of activity. Thiourea dioxide (TUD) catalyzed efficient three-component coupling reactions of aromatic aldehydes, 3-hydroxyindole and malononitrile in water at 70 oC was described as the preparation of 2-amino-4,5dihydro-4-phenylpyrano[3,2-b]indole-3-carbonitrile derivatives.


INTRODUCTION
Coumarins are secondary heterocyclic metabolites composed of fused benzene and α-pyrone rings, and they occur widely in different parts of plants, such as roots, seeds, nuts, flowers and fruits [1].The pharmacological and biochemical properties and therapeutic applications of coumarins depend upon the pattern of substitution and have attracted intense interest in recent years because of their diverse pharmacological properties [2].The coumarin derivatives have demonstrated significant potential for use in a wide range of biological applications such as antioxidant [3], anticancer [4,5], anti-proliferative [6], anti-tuberculosis [7] and antimicrobial activities [8].Some novel coumarin-3-carboxamide derivatives linked to N-benzylpiperidine scaffold were synthesized and evaluated as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors [9].Osteoporosis is a progressive skeletal disorder, due to the unequal coupling between osteoclast mediated bone resorption and osteoblast mediated bone formation [10,11].Anti-osteoporotic effects of the newly synthesized coumarine pyridine hybrids were evaluated in primary cultures of rat calvarial osteoblasts in vitro [12].The observed interesting biological properties of this class of compounds impelled us to synthesize new examples.
In view of the pharmaceutical importance of heterocyclic compounds containing coumarin moiety, various approaches toward the synthesis of this class of compounds have been explored [13][14][15][16][17].Although these methods are quite satisfactory, most of these methods suffer from extended reaction times, low yields, use of costly reagents, vigorous reaction conditions and also requirement of tedious work-up procedures.Therefore, development of a simple, efficient, inexpensive and environment friendly process for the synthesis of coumarins is highly desirable.
The principles of green chemistry have been introduced to eliminate or reduce the use of hazardous materials [18].Solvent-free organic reactions have attracted much interest particularly from the viewpoint of green chemistry.Implementation of organic transformations under solvent-free reaction conditions have gained in popularity in recent years because of their simple workup procedure, high efficiency, mild conditions, environmental friendliness, cleanliness, low cost, handling, and economical friendliness [19,20].In addition the growing concern for the influence of the chemical reagents on the environment as well as on human body, recovery and reusability of the chemical reagents has attracted the attention of synthetic organic chemists.More importantly pharmaceutical industry has given more importance towards recovery and reuse of chemical reagents to reduce the cost of a product as well as the environmental burden.

Apparatus and analysis
Chemicals were purchased from Merck, Fluka and Aldrich Chemical Companies.All yields refer to isolated products unless otherwise stated. 1 H NMR (500 MHz) and 13 C NMR (125 MHz) spectra were obtained using Bruker DRX-500 Avance at ambient temperature, using TMS as internal standard.FT-IR spectra were obtained as KBr discs on Shimadzu spectrometer.Mass spectra were determined on a Varion -Saturn 2000 GC/MS instrument.Elemental analysis was measured by means of Perkin Elmer 2400 CHN elemental analyzer flowchart.
The remaining solution was washed with warm ethanol (3 × 5 mL) in order to separate organocatalyst.After cooling, the crude products were precipitated.The remaining aqueous thiourea dioxide was collected and reused without any further processing for subsequent runs.The reaction products were identified by comparing their physical and spectral data (i.e., IR, 1 H and 13 C NMR and MS) with those reported in the literature for the same compounds.The crude products were purified by recrystallization from ethanol (95%) to give 4a-j.
Our initial work started with screening of solvent and catalyst loading so as to identify optimal reaction conditions for the synthesis of pyranoindole derivatives.To evaluate the effect of solvent, we studied the reaction of benzaldehyde, 3-hydroxyindole and malononitrile in the presence of catalytic amount of TUD (0.1 mmol).A range of solvents like acetonitrile, 1,4-dioxane, CHCl 3 , MeOH, EtOH and water were examined (Table 1, Entries 1-6).The reaction without any solvent at 70 ºC was not very successful (Table 1, Entry 5).The reaction was more facile and proceeded to give highest yield, in the presence of water as solvent (Table 1, Entry 6).Furthermore, the effect of reaction temperature was examined and the reaction proceeded smoothly at 70 ºC (Table 1, Entry 6).The model reaction was conducted in a range of different temperatures, including room temperature, 50, 60, 70 and 80 ºC, in the presence of 0.1 mmol TUD catalyst in water (Table 1, Entries 6-10).As can be concluded from Table 1, the reaction proceeded slowly at room temperature.With increasing temperature to 70 ºC, reaction yield was increased and time of reaction was decreased, when the reaction was heated above 70 ºC, so high temperatures did not further improved yield and decrease time of reaction.The greatest yield in the shortest reaction time was obtained in water at 70 ºC (Table 1, Entry 6).We also evaluated the amount of TUD required for the reaction.Catalyst loadings in the range of 0.00-0.15mmol were tested (Table 1, Entries 6 and 11-14).The best result was obtained with 0.1 mmol of TUD in water at 70 ºC (Table 1, Entry 6).Among the different catalysts tested, including KF/Al 2 O 3 , triphenyl phosphine (PPh 3 ) , tetrabutylammonium bromide (TBAB), p-toluene sulfonic acid and TUD, TUD was found to be the most efficient in terms of the reaction time and yield of the product (Table 1, Entries 6 and 15-18).
At these optimise conditions (solvent-free, 80 ºC, 0.05 mmol of SuSA) we synthesized various indolo pyrano pyrimidinones 6a-j (Table 4, Entries 1-10).All the synthesized compounds were confirmed by their analytical and spectroscopic data.The possible mechanism for the synthesis of 5,6-dihydro-2-(2-oxo-2H-chromen-3-yl)-5phenyl-indolo[2',3':5,6]pyrano [2,3-d]pyrimidin-4(3H)-one derivatives in the presence of SuSA as a solid catalyst is shown in Scheme 4. SuSA activates the coumarin-3-carboxylic acid by protonation to form a cation intermediate (a).In continue, the formation of (b) resulting from the amidation of (a) with 4a was established.In the next step, the protonation of nitrile group of intermediate (b) following by a cyclo-addition reaction was occurred to form the intermediate (c).In continue the addition reaction of -SO 3 -followed by ring opening of the (c) to the intermediate (d) and (e) followed by ring closure of intermediate (e) results in the formation of intermediate (f) that convert to the (6a) as product by the de-protonation reaction.Interestingly, the formation of compound 6a, obtained from the condensation of coumarin-3-carboxylic acid with 4a, confirms the mechanism of the reaction which was rarely described in the literature as Dimroth rearrangement [35,36].
The reusability of the catalyst is one of the most important green aspects by avoiding toxic catalyst [37].One of the most important advantages of heterogeneous catalysis over the homogeneous counterpart is the possibility of reusing the catalyst by simple filtration, without loss of activity [38][39][40].We have studied the recyclability and reusability of the catalyst.After completion of the reaction as indicated TLC, the insoluble crude product was dissolved in hot ethanol and the SuSA was filtered off.The filtrate was concentrated to dryness, and the crude product was purified by recrystallization from ethanol.The recovered catalyst was, washed with acetone, dried and reused for subsequent reactions without significant loss in its activity.The catalyst was recycled for four runs without loss of its activity (Figure 1).This method tolerates most of the substrates, and the catalyst can be reused at least four times without significant loss of activity.