A straightforward, environmentally beneficial synthesis of spiro[diindeno[1,2-b:2′,1′-e]pyridine-11,3′-indoline]-2′,10,12-triones mediated by a nano-ordered reusable catalyst

A library of new spiro[diindeno[1,2-b:2′,1′-e]pyridine-11,3′-indoline]-2′,10,12-trione derivatives has been prepared in an efficient, one-pot pseudo four-component method mediated by a reusable heterogeneous nano-ordered mesoporous SO3H functionalized-silica (MCM-41-SO3H) catalyst. Excellent yields, short reaction times, as well as convenient non-chromatographic purification of the products and environmental benefits such as green and metal-free conditions constitute the main advantages of the developed synthetic methodology. The obtained fused indole-indenone dyes would be of interest to pharmaceutical and medicinal chemistry. Furthermore, due to their sensitivity to pH changes, they could be used as novel pH indicators.

www.nature.com/scientificreports/ MCM-41 is a solid mesoporous nano-ordered silica with a large surface area and a regular structure. The diameter of the MCM-41 pores is distributed between 1.5 and 10 nm. It bears merely weak hydrogen bonding Si-OH sites and therefore at most only slightly acidic 47,48 . Its acidity could be improved, however, by substituting the Si atoms on its surface with Al 49 , B 50 , and Zn 51 , and or by functionalizing the MCM-41 surface with an alkyl sulfonic acid anchoring group 52,53 , succinamic acid 54 , or -SO 3 H [55][56][57] . Due to a large number of silanol groups, anchoring of inorganic -SO 3 H to the MCM-41 surface is very practical 58 . Such a readily accessible compound (MCM-41-SO 3 H) is non-toxic, recyclable, and reusable. Hence, MCM-41-SO 3 H is extensively applied in many chemical processes.   www.nature.com/scientificreports/ As an extension of our continuous studies on the application of heterogeneous catalytic systems to the synthesis of different classes of pharmaceutically important compounds and to the development of green multicomponent reactions (MCRs) 57,59-64 , herein we report a straightforward approach leading to an effective, one-pot pseudo four-components synthesis of spiro[diindenopyridine-indoline]triones. The reaction between 1,3-indandione (1), aromatic amines (2a-g), and isatins (3a-h) in DMF is catalyzed by MCM-41-SO 3 H affording spiro[diindenopyridine-indoline]triones with good to excellent yields (Scheme 1).

Results and discussion
Characterization of the MCM-41-SO 3 H. The MCM-41-SO 3 H was prepared according to our previous reports 57,59,60 and characterized by Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), and Brunauer-Emmett-Teller analysis (BET). The FTIR spectrum of the catalyst has been shown   Fig. 3 and confirm the nanoscale size of the synthesized particles. The size of most particles was in the range of 50-90 nm. As can be seen, the particles are aggregated, due to the strong hydrogen bonding between the acidic moieties. The EDX analysis of the fresh catalyst proved the presence of O, Si, and S atoms in the MCM-41-SO 3 H structure with a uniform distribution of the sulfonic acid groups (Fig. 4).  www.nature.com/scientificreports/ According to the obtained results from the N 2 adsorption-desorption diagram (Fig. 5), the BET and the Langmuir surface area of the MCM-41-SO 3 H were 223 and 303 m 2 g −1 , respectively. The BET adsorption average pore width (4 V/A) was measured to be 7.2 nm. The catalyst surface area and porosity properties are in good agreement with a typical mesoporous material.
The polar aprotic solvent DMF was found to be a solvent of choice in this reaction ( Table 2, entry 1). The solvent-free reaction ran in identical conditions -but without any solvent-with a poor yield, event after a long  www.nature.com/scientificreports/ reaction time ( Table 2, entry 9). On the other hand, the evaluation of the temperature influence on the yield of 4a indicated that higher temperature resulted in an improved yield in a shorter reaction time ( Table 2, entries 1-3).
In comparison with other catalysts used in the similar reaction reported previously (Table 3), the heterogeneous MCM-41-SO 3 H was beneficial, offering higher sustainability and better efficiency in the synthesis of 4a. In addition, the atom economy of the protocol proposed herein and the waste exclusion proved its greenness as well.
In comparison with the EWG-substituted substrates (Table 4, entries 3, 15-18), higher yields and shorter reaction times were observed for EDG-substituted isatins and aromatic amines (Table 4,  The study on catalyst stability and reusability. The possibility of recovering and reusing the catalyst was assessed in four consecutive runs for the benchmark reaction leading to 4a. After each run, the catalyst was filtered off and washed with n-hexane and acetone. Next, it was dried at 60 °C for 0.5 h. The recycled catalyst was then subjected to the next run of the model reaction. A significant maintaining of the catalytic activity of MCM-41-SO 3 H in each run of the reaction was observed (Fig. 6).
The FT-IR spectra of the fresh and the recovered MCM-41-SO 3 H catalyst after the fourth run indicated that its structure remained unchanged (Fig. 7).   www.nature.com/scientificreports/ The UV-Vis spectra of 4a-4y were obtained in methanol and reported in Table 5. They showed a maximum absorption wavelength (λ max ) in the range of 422-435 nm and a molar extinction coefficient (ɛ) of (1.08-2.99) × 10 5 L mol −1 cm −1 .
The Spiro[diindenopyridine indoline]triones with a hydrogen atom at indoline nitrogen may undergo reversible deprotonation and can be used as pH chemo-sensors. The product 4a was examined as a pH indicator and showed a visible color change at pH ca. 11, from red (in the acidic media) to deep blue (in the basic conditions) (Fig. 8). However, the solution of N-substituted isatins (e.g. 4w) showed no remarkable color change in an alkali solution.
The UV-Vis absorption of the compound 4a was measured in the pH range from 3 to 12.5. As shown in Fig. 8, beginning from ca. pH 9, a second absorption peak around 530 nm appears. The spectral data is given in Table 6. Whereas the N-H isatins solution displayed similar behavior, N-substituted isatins showed no color  www.nature.com/scientificreports/ change in a wide range of pH. It seems that the color change in dye 4a is due to the deprotonation of the NH group in the indoline unit (Scheme 3).

Conclusions
To summarize, we have herein reported a straightforward atom-economical method of synthesis of spiro[diindenopyridine indoline]triones mediated by a safe heterogeneous recyclable catalyst MCM-41-SO 3 H, which could be used for at least 4 runs without any significant loss of its activity. Among other advantages of the current protocol, we could emphasize excellent yields, short reaction times, high atom economy as well as simple isolation and purification procedures for both the catalyst and products. The presented approach leading to spiro[diindenopyridine-indoline]triones can be of interest to medicinal and pharmaceutical chemistry. Furthermore, some products exhibit a pH indicator activity proven by a visible color change in the basic pH ranges (Supplementary Information S1).