The chemistry of indoles has been and continues to be one of the most active areas of heterocyclic chemistry [1, 2]. Various indole derivatives are pharmacologically and biologically active compounds [3, 4, 5, 6, 7]. For example, topsentin A (Fig. 1) is a 3,3′-bisindole derivative originating from natural sources like the marine sponge Topsentina genitrix [8] that acts as an antitumor agent [9].
In recent years, many studies have focused on the functionalization of indoles at the C-3 position because it is the most nucleophilic site. A large number of 3-substituted indoles, especially 3,3′-bis(indolyl)methanes, have been reported [10, 11, 12, 13, 14]. However, little attention has been paid to the reactions that involve more than one nucleophilic center, namely C-3, C-2 and N, of the indole ring system. Some exciting reports on this subject include Jiang’s work on multicomponent domino reactions resulting in polyfunctionalized indoles [15, 16, 17]. Our involvement in the study of indoles and solid acid catalysts [18, 19, 20], along with a recent report on three-component formation of bis-indole derivatives by Tu’s group [21], prompted us to investigate the use of functionalized magnetic nanoparticles in their protocol to overcome its associated limitations such as acidic media and need for specialized instruments, and the obtained results were satisfying. Functionalized magnetic nanoparticles were selected because they could be easily separated from the reaction mixture by an external magnet. Herein, we report sulfuric acid-functionalized MCM-48 coated on magnetite nanoparticles with a core-shell structure (Fe3O4@MCM- 48-OSO3H, where Fe3O4 nanoparticles serve as a core for a mesoporous MCM-48 shell functionalized with sulfuric acid) as an efficient solid acid nanocatalyst for three-component reaction of indoles, phenylglyoxal monohydrates and N- arylenaminones under mild reaction conditions (Scheme 1).
Fe3O4 nanoparticles were synthesized according to our previous report [22]. To synthesize Fe3O4@MCM-48, the as-prepared Fe3O4 nanoparticles (1.5 g) and ammonia solution (5 mL, 25%) were mixed with distilled water (50 mL) in a glass reactor and sonicated for 2 min at 40 °C. Tetraethylorthosilicate (10.0 mL), NaOH (0.90 g) and NaF (0.19 g) were added and then the mixture was stirred for 2 h. Cetyltrimethylammonium bromide (7.0 g) was added to the mixture, and it was stirred at 40 °C for 2 h. The magnetic composite was then hydrothermally treated at 120 °C for 48 h in an autoclave. The resulting solid was filtered, washed with distilled water and dried at 60 °C. Finally, the template was removed by calcination of the synthesized particles for 3 h at 300 °C. SO3H functionalization of Fe3O4@MCM-48 was carried out according to the method of Kiasat et al. [23]. Fe3O4@MCM-48 (2.0 g) was charged into a suction flask equipped with a constant-pressure dropping funnel, and dispersed in CH2Cl2 (75 mL) by ultrasound for 10 min. Chlorosulfonic acid (2.92 g, 25 mmol) in CH2Cl2 (20 mL) was added dropwise over a period of 30 min at room temperature. The mixture was then stirred for 1.5 h, and evolved HCl was removed by suction. Fe3O4@MCM-48-OSO3H was then separated from the reaction mixture using an external magnet, washed several times with CH2Cl2, and then dried under vacuum at 60 °C. The calculated sulfonic acid loading was 2.3 mmol SO3H per g of catalyst according to a literature method [23].
Powder X-ray diffraction (XRD) measurements were performed on a Philips diffractometer with monochromatized Cu Kα radiation. Fourier transform infrared (FT-IR) spectra were recorded on a Shimadzu FTIR-8400S spectrometer. 1H NMR spectra were obtained on a Bruker DRX-400 Advance spectrometer and 13C NMR spectra were recorded on a Bruker DRX-100 Advance spectrometer. Chemical shifts of 1H and 13C NMR spectra were expressed in ppm downfield from tetramethylsilane. Melting points were measured on a Büchi Melting Point B-540 instrument and were not corrected. Elemental analyses were performed using a Carlo-Erba EA1110 CNNO-S analyzer and agreed with the calculated values. TEM images were obtained on a transmission electron microscope (TEM; PHILIPS MC 10) with an acceleration voltage of 80 kV. Vibrating sample magnetometry (VSM) curves were obtained on a vibrating sample magnetometer (JDM-13) at room temperature. Analytical gas chromatographic (GC) evaluations of product mixtures were carried out on a Varian CP-3800 chromatograph using a split/splitless injector, CP Sil 8CB column, and FID assembly.
In a three-necked round-bottom flask equipped with a reflux condenser, indole (1.00 mmol), phenylglyoxal monohydrate (1.00 mmol), and N-arylenaminone (1.00 mmol) were dissolved in refluxing ethanol (10 mL). Fe3O4@MCM-48-OSO3H (0.1 g) was added and the resulting mixture was mechanically stirred until the starting indole completely disappeared (monitored by TLC). After completion of the reaction, the catalyst was removed by an external magnet. The resulting hot solution was quenched with water. The solidified product was filtered, rinsed with a cold mixture of ethanol and water (70:30) and then dried under high vacuum overnight to provide pure product. The recovered catalyst was washed three times with CH2Cl2 and then dried under vacuum at 60 °C overnight.
White solid, Yield 80%; m.p. 255-256 °C; FT-IR (KBr): υmax = 3275, 1640, 1598, 1498, 1460, 1366, 1123, 1075, 787, 739, 706 cm-1. 1H NMR (400 MHz, DMSO-d6, 25 °C) δ = 10.72 (s, 1H, NH), 7.36-7.43 (m, 3H, ArH), 7.28 (s, 2H, ArH), 7.18 (d, J = 7.6 Hz, 1H, ArH), 6.87-6.97 (m, 5H, ArH), 6.71-6.77 (m, 3H, ArH), 2.65 (d, J = 16.8 Hz, 1H, CH2), 2.58 (d, J = 16.9 Hz, 1H, CH2), 2.28 (s, 2H, CH2), 1.90 (s, 3H, CH3), 1.09 (s, 3H, CH3), 1.08 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6, 25 °C) δ = 193.3, 143.7, 137.9, 135.5, 133.8, 133.0, 131.9, 130.0, 129.3, 129.1, 128.0, 127.6, 126.2, 125.9, 120.3, 119.7, 119.2, 118.8, 113.2, 110.1, 106.1, 53.1, 35.0, 29.1, 28.3, 12.4; Anal. Calc for C31H22N2O (%): C 83.75, H 6.35, N 6.30; Found (%): C 83.81, H 6.39, N 6.29.
All of the other products are known compounds, and their spectroscopic and physical data were identical to those described in the literature [21].
Mesoporous MCM-48 was selected as the shell for Fe3O4 magnetite nanoparticles because of its three-dimensional channel system and numerous external hydroxyl groups. Deposition of the shell onto the surface of Fe3O4 nanoparticles was performed by a simple, low-cost method. Subsequent treatment of the core-shell nanocomposite with chlorosulfonic acid in dichloromethane provided the solid acid catalyst Fe3O4@MCM-48-OSO3H, which was characterized by FT-IR spectroscopy, TEM, XRD and VSM. In the FT-IR spectrum of Fe3O4@MCM-48-OSO3H nanoparticles (Fig. 2(2)), basic characteristic vibrations of Fe-O at 588 cm-1 and Si-O-Si asymmetric stretching, symmetric stretching and bending vibrations at 1072, 795 and 453 cm-1, respectively, were observed. Characteristic bands of the sulfonyl groups were observed at 1229 and 1120 cm-1, along with simultaneous disappearance of the Si-OH peak of Fe3O4@MCM-48 at 900 cm-1 [23].
The XRD pattern of Fe3O4@MCM-48-OSO3H (Fig. 3(b)(2)) contained peaks that could be indexed to both mesoporous structure and Fe3O4 nanoparticles. The Fe3O4 nanoparticles exhibited peaks at 2θ = 29.72°, 35.57°, 43.17°, 57.15° and 62.77°, consistent with pure magnetite (Fig. 3(b)(1)) and matched well with the standard XRD pattern of Fe3O4 (JCPDS No. 19-692) [24]. The siliceous mesoporous structure exhibited four peaks at 2θ = 1.5°-10° (Fig. 3(a)(2)) from the (211), (220), (420) and (332) planes, which are characteristic peaks of MCM-48.
The nanoscale size of the composite was confirmed by TEM observation, as shown in Fig. 4(a). An average particle size of 20 nm was determined for Fe3O4@MCM-48-OSO3H according to a particle size distribution analysis (Fig. 4(b)). TEM image indicated that the surface of Fe3O4@MCM-48-OSO3H consisted of an agglomeration of many ultrafine spherical particles with dark magnetite cores each surrounded by a mesoporous shell.
The magnetic hysteresis curves of the Fe3O4@MCM-48- OSO3H magnetic nanoparticles were also obtained. Bare Fe3O4 and Fe3O4@MCM-48-OSO3H nanoparticles exhibited typical superparamagnetic behavior. The large saturation magnetization of bare Fe3O4 decreased from 82 to 49 emu/g for the Fe3O4@MCM-48-OSO3H nanoparticles because of their non-magnetic mesoporous shell (Fig. 5).
The porosity of the Fe3O4@MCM-48-OSO3H nanoparticles was evaluated by N2 adsorption-desorption isotherm measurements, which showed a characteristic type-IV curve (Fig. 6). This curve exhibited a distinct hysteresis loop in the relative pressure (p/p0) range of 0.6-0.9, indicating the presence of mesopores with a narrow size distribution. Other physicochemical properties of the Fe3O4@MCM-48-OSO3H nanoparticles determined from the N2 adsorption-desorption measurements are a Brunauer-Emmett-Teller surface area of 412.5 m2/g (calculated in the p/p0 = 0-0.5), mean Barrett-Joyner- Halenda pore diameter of 2.6 nm, total pore volume of 0.417 cm3/g and mean pore volume of 0.401 cm3/g.
Thermogravimetric (TG) analysis of the as-synthesized product (Fig. 7) contained distinct parts: (1) loss of physisorbed water from 80 to 180 °C, which corresponded to the water molecules adsorbed on the external surface and those hosted in the pores, (2) loss of template molecules from 200 to 350 °C and (3) collapse of the -SO3H functional groups or condensation of silanol groups from 350 to 600 °C. The TG analysis reveals that the obtained catalyst has sufficient thermal stability to endure recycling processes or harsh reaction conditions up to 300 °C.
The characterized catalyst was then used in one-pot three-component condensation reactions of indoles, phenylglyoxal monohydrates and N-arylenaminones. To optimize the reaction conditions with respect to catalyst type and loading, and examine the effect of solvent and temperature on the reaction yield, 2-methylindole, phenylglyoxal monohydrate and 5,5-dimethyl-3-(phenylamino)cyclohex-2-enone were used as model substrates and their reactions were carried out under different conditions. The results of these reactions are summarized in Table 1.
Table 1 shows that in the absence of catalyst, the desired product was not formed (entry 1). Although far from giving the maximum yield, it was proved that the optimum loading of Fe3O4@MCM-48-OSO3H under ambient conditions was 0.1 g per mmol of indole (entry 5). The same loading of MCM-48 sulfuric acid (entry 4) was also tested under ambient conditions and gave a comparable yield. However, Fe3O4@MCM-48- OSO3H has the advantage over MCM-48 sulfuric acid in terms of easy recycling. It was found that elevated temperature had a powerful effect on the reaction yield, and an excellent yield of 80% was obtained under reflux (entry 6). Meanwhile, higher loads of the catalyst did not have a considerable effect on yield (entry 8). To evaluate the effect of particle size on catalyst performance, larger Fe3O4@MCM-48-OSO3H nanoparticles with a diameter of about 50 nm (Fig 8) were synthesized by manipulation of the hydrothermal synthesis conditions (140 °C, 4 d). However, under the same reaction conditions, the larger particle size of the new catalyst had only a moderate effect on the reaction yield (73% vs 80%). This may be because the -SO3H functionality plays the main role in this catalytic system. It is noteworthy that the yield of the product depended on solvent, and the highest yields were obtained using ethanol and methanol. Ethanol was selected as the solvent because it is less toxic than methanol.
After determining the optimum reaction conditions (Scheme 1), a series of 2-substituted indoles, phenylglyoxal monohydrates and N-arylenaminones were used to investigate the generality and scope of the reaction. As shown in Table 2, the results are satisfying, because the same regioselectivity toward 3,3′-bisindoles was observed in each case.
Table 2 reveals that various indoles, phenylglyoxal monohydrates and N-arylenaminones participated in the reaction, and this catalytic system tolerated different functional groups. With regard to substituents, the electron-releasing nature of the aryl moiety in N-arylenaminones favors the formation of products. However, 1-methylindole did not yield the desired product. These observations may be explained by the following proposed reaction mechanism (Scheme 2).
In general, after activation of the phenylglyoxal monohydrate by the solid Brӧnsted acid catalyst, nucleophilic attack from the C-3 carbon atom of indole gives intermediates I. The next steps are nucleophilic attacks by the β-C atom of β-enaminone to give intermediate II and NH group of β-enaminone resulting in C-C and C-N bond formation via [3+2] cyclization to provide intermediate III, which then dehydrates to form the product.
To evaluate reusability of the catalyst, the reaction of 2-methylindole, phenylglyoxal monohydrate and 5,5-dimethyl- 3-(phenylamino)cyclohex-2-enone was carried out in the presence of the recycled catalyst in successive runs. For reaction runs 1, 2, 3, 4, 5 and 6, the yields were 80%, 80%, 77%, 70%, 63% and 38%, respectively. Therefore, after five runs, the efficiency of the catalyst decreased by 17%. This result shows that Fe3O4@MCM-48-OSO3H can be used as a recyclable catalyst for the formation of 3,3′-bisindoles under moderate conditions. To confirm heterogeneity of the catalyst, the sulfonic acid loading was determined for the recycled catalyst used in the third run. The calculated value was 2.3 mmol SO3H/g, similar to that of the unused catalyst, which confirmed that considerable leaching did not occur during the course of the reaction. To further strengthen this assumption, the reaction of 2-methylindole, phenylglyoxal monohydrate and 5,5- dimethyl-3-(phenylamino)cyclohex-2-enone was interrupted halfway during the normal reaction period (after 12.5 min) and the catalyst was removed by an external magnet. The reaction was then continued for the rest of the time (up to 25 min). At the end of this period, the yield was only 39%, and no considerable change in the concentration of residual 2-methylindole was observed according to GC analysis of the reaction mixture.
We developed a convenient method for one-pot three- component reaction of indoles, phenylglyoxal monohydrates and N-arylenaminones under mild conditions. Highlights of the present work are regioselective one-pot formation of two C-C and one C-N bonds in a smooth cascade, recyclable catalyst, which promises minimization of waste, ease of work-up and good efficiency in terms of solvent, temperature and yield. Further manipulation of this reaction is currently underway in our laboratory.
2015, Vol. 36 Issue (5): 778-784
PDF (636 KB)
2015, Vol. 36 Issue (5): 778-784
PDF (636 KB)