Efficient Green Approach for the Synthesis of Spiro[indoline-3,4′-pyrazolo[3,4-b]quinoline]diones Using [NMP]H2PO4 and Solvatochromic and pH Studies

Abstract A mild and efficient protocol for the synthesis of spiro[indoline-3,4′-pyrazolo[3,4-b]quinoline]diones via a one-pot, three-component condensation of isatins, 1,3-dicarbonyls, and 5-amino-1-phenyl-3-methylpyrazole using [NMP]H2PO4 as a catalyst in EtOH/H2O is described. The catalyst could be recycled and reused four times without significant loss of activity. Spiro[indoline-3,4′-pyrazolo[3,4-b]quinoline]diones with stabilized zwitter ionic resonance structures showed feasible application as new fluorescent probes and pH indicators. These chemosensors have a good wavelength shift and showed excellent sensitivity in the range of pH from 11 to 13. GRAPHICAL ABSTRACT


INTRODUCTION
Multicomponent reactions (MCRs) provide unmatched opportunities for the enhancement of complexity and diversity in synthetic outcomes [1] by the facile formation of several new covalent bonds in a one-pot transformation. [2] Synthesis of quinolines and indoles via MCRs has paved the way for diverse classes of heterocycles. [3] Significantly, 3-spiroheterocyclic 2-oxindole cores have been found in a number of natural products, such as alstonisine, [4] tabernoxidine, [5] and medicinally important NITD 609. [6] 3-Spiroheterocyclic 2-oxindoles show significant biological activities [7] and have emerged as potential fluorescent materials. [8] Isatin is a privileged lead molecule for designing potential bioactive agents, and its derivatives have been shown to possess a broad spectrum of bioactivities, such as anti-HIV, [9] antiviral, [10] antitumor, [11] antifungal, [12] and anticonvulsant [13] activities. Oxindoles have also been shown to possess mechanism-specific antiproliferative, antibacterial, antiprotozoal, and anti-inflammatory activities. [14][15][16][17] The combination of green chemistry and MCRs offers very efficient protocols for the synthesis of complex heterocycles from both economic and environmental perspectives. The ionic liquids (ILs) have emerged as green solvents for synthesis and catalysis. [18][19][20][21] There are only a few reports about the synthesis of spirooxindole derivatives [22][23][24][25] in ionic liquid medium. We have been working on the applications of task-specific ionic liquid [NMP]H 2 PO 4 as this can be prepared in one step without the use of organic solvents. We have attempted synthesis of spiro-oxindole derivatives.
Encouraged by these results, we investigated the scope of the reaction of 5-amino-1-phenyl-3-methylpyrazole (2) with different isatins (1) and 1-3-dicarbonyls (3) under optimized reaction conditions (Scheme 2). All the reactions were complete in 15-30 min and gave the corresponding products in good yields by a simple workup.
All the products were characterized using 1 H NMR, 13 C NMR, infrared (IR), and meltin point (mp). A proposed mechanism for the synthesis of 4 using [NMP] H 2 PO 4 is depicted in Scheme 3.
The possibility of recycling the catalyst [NMP]H 2 PO 4 was also examined using the reaction of isatin (1), 5-amino-3-methyl-1-phenyl-pyrazole (2), and dimedone (3a) under optimized conditions. Upon completion of the reaction, the product was filtered at the suction pump and washed with water. To recover the catalyst, H 2 O and ethanol were removed under reduced pressure, and the resulting liquid was washed with diethyl ether and dried to recover [NMP]H 2 PO 4 . The recovered Table 1. Optimization conditions for the synthesis of 3 0 ,7 0 ,7 0 -trimethyl-  (1)

SYNTHESIS OF OXINDOLES USING [NMP]H 2 PO 4
catalyst could be reused four times after which there was a significant decrease in the activity of the catalyst (Fig. 1).

Photophysical Studies
The design and synthesis of new fluorescent probes has attracted considerable attention for a variety of applications [29][30][31] such as telecommunications, optical

Absorption and Emission Characteristics
The spectral properties of all the compounds (4a-4k) were measured in methanol. The 1.0 × 10 À6 mol L À1 solution of all compounds showed single absorption band in the region of 319-358 nm (Fig. 2). Moreover, when these compounds were excited at 320 nm, they exhibited strong photoluminescent emissions with the emission maxima ranging from 412 to 437 nm (Fig. 3). The spectrophotometric properties of the compounds such as absorption maxima (k max ), emission maxima (k em ), and Stokes shift (Dn) are reported in Table 3. The large magnitude of Stokes shift was observed for all the compounds (4a-4k), which indicates that the excited state geometry could be different from that of the ground state.

Effects of Solvent Polarity on Absorption and Emission Spectra
The effect of solvent polarities on photophysical properties of 4d was investigated in nine solvents of varying polarity. Effects of solvent polarity on absorption and emission spectra of this compound are shown in Figs. 4 and 5, respectively and are summarized in Table 4. It is clear from Table 4 that compound 4d showed

Effects of Different pH Values on Absorption and Emission Spectra
The effects of different pH values on absorption and emission spectra of compound 4d were also investigated by adding different amounts of HCl and KOH to the solutions of compound 4d (1.0 × 10 À6 M in methanol). The absorption spectra of compound 4d is not sensitive to the addition of acid, but the absorption spectra is sensitive to the addition of base, although not at all the examined pH values. The absorption band did not show any shift at low basic pH values (7.6, 8.3, 9.6, 10.2) but it showed a large bathochromic shift of 48 nm from k max of 314 nm to k max of 362 nm at high basic pH values (>10.2) (Fig. 7). These results suggest that tautomeric form of compound 4d in methanol changes to another tautomeric form on addition of base.
The effects of acid and base on emission spectra of compound 4d in methanol (1.0 × 10 À6 M) was also investigated (Fig. 8). Emission spectra of compound 4d showed a slight bathochromic shift of 7 nm at high acidic pH value and no effect was observed at less acidic pH values. Also a bathochromic shift of 21 nm from

CONCLUSION
We have developed a simple, one-pot, three-component procedure for the preparation of biologically interesting oxindole derivatives using ionic liquid [NMP]H 2 PO 4 in H 2 O=EtOH (4:1 v=v) as reaction medium. Effects of solvent polarity on absorption and emission spectra of compound 4d showed that absorbance and fluorescence spectra depend on solvent polarity and showed good correlation to Lippert-Mataga plot. It has been observed that absorption and emission spectra show high bathochromic shift at pH range of 11.4-13.2.

EXPERIMENTAL
Structures of all of the compounds were identified by their spectroscopic data. Silica gel 60 F 254 (precoated aluminum plates) from Merck were used to monitor the reaction progress. Melting points were determined on a Tropical labequip apparatus and are uncorrected. IR (KBr) spectra were recorded on a Perkin-Elmer FTIR spectrophotometer and the values are expressed as n max in cm À1 . The NMR ( 1 H and 13 (20 mol%) in H 2 O=EtOH (4:1 v=v) was placed in a 100-ml round-bottomed flask, which was stirred at 80°C on a preheated oil bath for an appropriate time as shown in Table 2.
After completion of the reaction as confirmed by thin-layer chromatography (TLC; ethyl acetate=petroleum ether, 40:60 v=v), the reaction mixture was cooled to room temperature. The precipitated product was filtered at pump, washed with water=ethanol (1:1), and dried. It was recrystallized from ethanol to afford the pure products (4a-4k) in excellent yield. All the products were characterized using 1 H NMR, 13 C NMR, IR, and mass spectra.