Efficient Synthesis of Spiro[diindenopyridine-indoline]triones Catalyzed by PEG-OSO3H-H2O and [NMP]H2PO4

Abstract One-pot, three-component synthesis of spiro[diindenopyridine-indoline]triones has been reported via the reaction of 1,3-indandione, aromatic amines, and isatins with (PEG-OSO3H) as an efficient, polymeric acid surfactant–based catalyst in water and also in presence of acidic ionic liquid [NMP]H2PO4, which acts both as a medium and catalyst under conventional heating and ultrasonic irradiation. The reactions were complete in short reaction times with excellent yield of products. Surfactant-based PEG-OSO3H could be recycled and reused several times without any significant loss of activity. The compounds exhibit fluorescence in methanol with large Stokes shift. GRAPHICAL ABSTRACT


INTRODUCTION
The development of synthetic methods that are environmentally benign and yield complex structures from simple and inexpensive starting materials is the main challenge faced by modern organic chemists. [1] Multicomponent reactions (MCRs) have emerged as a powerful synthetic tool to achieve synthetic efficiency, as they have unique advantages such as atom economy and operational simplicity, and have played a significant role in modern synthetic chemistry. The use of ecofriendly, economically viable, recyclable catalysts and reaction media such as water and ionic liquids make the synthetic approach green and efficient. Reactions have been reported in ionic liquids (ILs) [2] and also in task-specific acidic ionic liquids that act as reaction medium and=or catalyst. [3] Development of immobilized catalysts that allow simple workup procedures, easy separation of products, and recyclability of the catalysts is an important process. [4] Sulfuric acid-modified PEG-6000 (PEG-OSO 3 H) is an example of polyethylene glycol-supported catalyst that is functionalized by sulfonic acid groups. It is biodegradable, recyclable, nonvolatile, and noncorrosive organic acid that has been used for the synthesis of heterocyclic compounds. [5] It also acts as a surfactant due to the presence of long chains functionalized by sulfonic acid groups and improves the solubility of the reactants in water by acting as a phase-transfer catalyst. Indenone-fused heterocycles represent an important class of medicinally important compounds. Indenopyridines show biological activities such as cytotoxic, [6] phosphodiesterase inhibitory, [7] adenosine A2a receptor antagonist, [8] anti-inflammatory=antiallergic, [9] coronary dilating, [10] and calcium modulation [11] activities. These compounds have also been investigated for the treatment of hyperlipoproteinemia and arteriosclerosis, [12] as well as neurodegenerative diseases. [13] Our group has been involved in the development of efficient, green, economical, and new methodologies for the synthesis of biologically important heterocycles. [14] The synthesis of indenone-fused pyridines has been reported with p-TSA in acetonitrile under reflux. [15] Therefore, we decided to investigate the synthesis of indenone-fused heterocycles under a variety of green methodologies.
The reaction was then attempted using PEG-OSO 3 H (30 mol%) acid as catalyst in water under reflux. The reaction was much faster and complete in 10 min. After a simple workup, it yielded the desired product 4a in excellent yield of 95% (Table 1, entry 3). The reaction was repeated at 80 C and was also complete in 10 min, giving 97% yield of the product 4a (Table 1, entry 4). However, the reaction was carried out at 60 C under otherwise identical conditions, required longer reaction time, and resulted in poorer yield (Table 1, entry 5). Also, the reaction attempted using lower loading of catalyst (20 mol%) at 80 C required longer time and resulted in slightly poorer yield of the product (Table 1, entry 6). When the reaction was attempted under solvent-free conditions using 30 mol% of PEG-OSO 3 H, the separation of product was not easy and the reaction gave lower yield of the product 4a (Table 1, entry 7). The same reaction when then attempted using ultrasonic irradiation at 40 C and resulted in 95% of 4a (Table 1, entry 8).
It can be inferred from Table 1 that the three-component reaction yielded the product 4a in a rapid reaction with good yield when attempted using 30 mol% of PEG-OSO 3 H as a catalyst in water under conventional heating at 80 C (Table 1, entry 4) and also under ultrasonic irradiation at 40 C ( Table 1, entry 8). One clear advantage of the PEG-OSO 3 H-water combination was that it afforded products that could be obtained by simple filtration. Encouraged by these results, we investigated the scope of this reaction of 1,3-indandione (1) with a range of other aromatic amines (2) having electron-withdrawing and electron-releasing substituents and isatins (3) under conventional heating at 80 C (method A1) ( Table 2, Scheme 1) and also under ultrasonic irradiation at 40 C (method A2). All the products (4a-4n) were obtained in good yield and in short reaction time by both methods as shown in Table 2. The scope of this reaction was further explored by using Brønsted acidic ionic liquid [NMP]H 2 PO 4 , which could be prepared in a single step without the application of organic solvents. [16] Therefore, a model reaction of 1,3-indandione (1) (2.0 mmol), 4-methoxyaniline (2) (1.0 mmol), and isatin (3) (1.0 mmol) was investigated with [NMP]H 2 PO 4 30 mol% at 60 C. The reaction was complete in 15 min and afforded 5-(4-methoxyphenyl)-5H-spiro[diindeno [1,2-b:2 0 ,1 0 -e]pyridine-11,3 0 -indoline]-2 0 ,10,12trione (4a) in 92% yield after a simple workup. The same reaction was then carried out at 80 C and 100 C in the presence of ionic liquid [NMP]H 2 PO 4 (30 mol%). The reactions were complete in 10 min and yielded 95% and 94% of 4a respectively. The reaction was then explored by reducing the catalyst loading (20%). The reaction was complete after 15 min yielding 90% of 4a. When this reaction was attempted in the presence of [NMP]H 2 PO 4 (30 mol%) under ultrasonic irradiation at 40 C, it yielded the product 4a in 94% yield in 5 min.

SPIRO[DIINDENOPYRIDINE-INDOLINE]TRIONES 205
The condensation of the three components in the presence of [NMP]H 2 PO 4 (30 mol%) under conventional heating at 80 C and also under ultrasonic irradiation at 40 C proved to be optimum conditions. These optimized reaction conditions were extended for a range of aromatic amines (2) and different isatins (3) (Scheme 1). All the products were obtained in good yields and in short reaction times by both of these methods (methods B1 and B2) as shown in Table 3.
The possibility of recycling of the catalyst (PEG-OSO 3 H) was also examined using the reaction of 1,3-indandione (1), 4-methoxyaniline (2), and isatin (3) under optimized conditions. Upon completion of reaction, the product was filtered with a suction pump and washed with water. To recover the catalyst, H 2 O was removed under reduced pressure and the resulting liquid was washed with diethyl ether and dried to recover PEG-OSO 3 H. The recovered catalyst could be reused four times, after which there was a significant decrease in the activity of the catalyst (Fig. 1).
All the synthesized compounds 4a-4n were characterized by 1 H NMR, 13 C NMR, and melting point. A plausible mechanism for the synthesis of 4 using PEG-OSO 3 H and [NMP]H 2 PO 4 as catalyst is depicted in Scheme 2.
All the compounds formed are deep red in color. We examined their fluorescent behavior also. We observed that all compounds showed strong fluorescence in methanol when excited at wavelength 268 nm as shown in Fig. 2 The photophysical properties of all molecules are summarized in Table 4. Moreover, the ultraviolet (UV)-visible spectra of these derivatives contain intense absorption maxima in the range of 264-274 nm. These compounds exhibit emission bands in the range of 282-596 nm with Stokes shift in the range of 115-142 nm.

CONCLUSION
We have reported an efficient and green methodology for the synthesis of indenone-fused pyridine heterocycles using PEG-OSO 3 H as a mild, biodegradable, recyclable, nonvolatile, and noncorrosive organic acid in water and also acidic ionic liquid [NMP]H 2 PO 4 , which acts as medium and catalyst under conventional heating and ultrasonic irradiation. All the compounds exhibit strong fluorescence in methanol with large Stokes shift.