Abstract
Ordered mesoporous siliceous material has been identified as one of the key elements of the catalysis concept. Here we report an efficient Friedel-Crafts reaction of indoles with isatins catalyzed by PWA/MCM-41, which got the di(indolyl)indolin-2-ones derivatives with high yield. Moreover, the catalysts were characterized by XRD and SEM/EDS, the EDS spectrum indicated that the catalyst used in this reaction also contains tungsten, and the proposed mechanism for the synthesis of 3,3-di(indolyl)indolin-2-ones was also discussed. Finally, the catalyst can be reused repeatedly for several times without obvious loss of activity.
1. Introduction
Friedel-Crafts reaction is a fundamental transformation for C-C bonds formation in organic synthesis [1]. Among the Friedel-Crafts reaction substrate of aromatic compounds, indoles and indole derivatives have received more and more attention [2] because of their privileged structure and quite pervasiveness in nature [3] as well as their excellent biological activities [4]. Isatin is one of the most important derivatives of indole with significant bioactive scaffold, containing double adjacent carbonyls with an indole unit and a -lactam moiety, which endows isatin with an amount of interesting synthetic applications [5].
The carbonyl group in 3-position of isatins readily makes isatins undergo electrophilic condensation reactions with indoles to produce 3,3-di(indolyl)indolin-2-ones, which also show excellent bioactivities [6–8]. Some literature sources revealed that the synthesis of 3,3-diaryloxindole skeleton can be achieved by coupling of indoles and isatins with acid [9, 10], I2 [11], metal salts [12], ionic liquids [13], CAN [14], -CD [15], Amberlyst-15 [16], and nanomaterials [17]. Despite these important contributions, developing and searching for a highly effective catalytic system is still challenging.
In the last few years, ordered mesoporous siliceous material supporting catalysts have been paid much attention because of their high surface areas, large pores, and ordered arrangement of structures [18]. Phosphotungstic acid (PWA) supported on heterogeneous materials has been widely used for Friedel-Crafts reaction [19, 20]. As a continuation of our interest in catalyst of supported mesoporous material in the organic synthesis [21, 22], herein, we reported isatins as the electrophiles to react with indoles using PWA/MCM-41 as catalyst at room temperature for the synthesis of 3,3-di(indolyl)indolin-2-ones.
2. Experimental
The purity of compounds was checked by thin layer chromatography (TLC) using ethyl acetate/petroleum ether (v/v) as eluent; IR spectrum was recorded on a Bruker Equinox 55 FT-IR spectrophotometer as KBr discs. The 1H NMR and 13C NMR spectra were recorded on an INOVA (400 MHz) FT-NMR spectrometer in CDCl3 using TMS as an internal standard. The prepared catalysts were characterized by XRD, SEM, and EDS.
Indoles (0.20 mmol), isatins (0.10 mmol), and 60 wt% PWA/MCM-41 catalyst (0.0050 g) were stirred in THF (0.3 mL) at room temperature for 2.5 h and monitored by TLC. The product were purified by column chromatography on silica gel using petroleum ether/ethyl acetate (20 : 1, 10 : 1, 5 : 1, 2 : 1, 1 : 1) as the eluent. All compounds (3a–3o) were characterized by 1H and 13C NMR (400 MHz) spectral analysis. The catalyst was separated from the reaction mixture by centrifugalization, dried at 473 K for 4 h after washing with ethanol, then continued to be reused for the next reaction.
3. Results and Discussion
Initially, as a continuation of our work on the applications of mesoporous siliceous material catalysts for organic reaction, to optimize the reaction condition of the Friedel-Crafts reaction of indoles with isatins, we utilized isatin (0.10 mmol) and indole (0.20 mmol) as model substrates (Scheme 1), and the results are shown in Table 1. MCM-41 or PMoA as catalysts led to lower yields than PWA as catalyst (Table 1, entries (1)–(3)). To our delight, the yield was significantly improved with PWA/MCM-41 catalyzing the model reaction and the 60 wt% PWA/MCM-41 being the optimized catalyst that contrasted with (40–80) wt% and obtained up to 86% yield (Table 1, entries (4)–(8)). With the ratio of PWA/MCM-41 exceeding 60 wt%, the yields of the 3,3-di(indolyl)indolin-2-one decreased, because the MCM-41 pores might be blocked by the excessive amounts of PWA. Comparative experiments indicated that the pores indeed facilitated the Friedel-Crafts reaction [21].
The optimal catalyst was established, and further screening of the reaction conditions was focused on solvents, catalyst quantity, solvent quantity, and reaction time. The results revealed that the use of THF as a reaction medium was superior to other solvents (Table 1, entry (6) versus entries (9)–(15)). And with the amount of catalyst reduced from 0.0050 g to 0.0030 g, the yield of the reaction was significantly decreased (Table 1, entries (16) and (17)). However, the amount of solvent obviously influenced the formation of the 3,3-di(indolyl)indolin-2-one and the best outcome was obtained with 0.3 mL THF at 0.1 mmol scale of isatin (Table 1, entry (18)). To our delight, the reaction time was slightly decreased to 2.5 h and could also successfully deliver the desired product in excellent yield up to 99% (Table 1, entry (19)). Therefore, (0.005 g) 60 wt% PWA/MCM-41 catalyzed (0.10 mmol) isatins with (0.20 mmol) indoles with (0.3 mL) THF at room temperature for 2.5 h, which proved to be a robust method to build up the 3,3-di(indolyl)indolin-2-ones scaffold.
General procedure for synthesis of catalysts was exhibited in supporting information (see SI 2.1 S1). The catalysts were characterized using SEM equipped with EDS and XRD. The EDS spectrum and elemental contents of some zones are shown in Figure 1. It can be seen that the optimal catalyst (B zone in Figure 1(b)) in this system contains rich tungsten (X-ray energy 1.774 keV) compared with the pure MCM-41 [23] (A zone in Figure 1(a)). Meanwhile, the EDS spectrum indicated that the catalyst used in this reaction also contains tungsten and the catalyst could be used repeatedly.
(a)
(b)
(c)
(d)
(e)
(f)
The bands in the X-ray diffraction patterns (Figure 2) of pure MCM-41 (a), as well as the catalyst of PWA supported on MCM-41 (b) and the used catalyst PWA/MCM-41 (c) in the range of 1°–8° (Figure 2(a)), suggest that the hexagonal pore arrangement was kept [24]. The catalyst of 60 wt% PWA/MCM-41 exhibited clear diffractions at 10.2°, 20.7°, 22.5°, 29.6°, and 34.9° compared with pure MCM-41 that was associated with PWA (Figure 2(b)) [25], suggesting that PWA was supported on MCM-41 and the catalyst of PWA remained after catalyzing this reaction.
(a)
(b)
With the optimized parameters established, the substrate scope was investigated (Scheme 2) and the results were listed in Table 2. When the phenyl ring of indoles or isatins interacts with methyl substituent, the desired products 3b–3d and 3k are obtained in a moderate to good yield (Table 2, entries (2)–(4), (11)). However, product 3l, the yield of 5-methyl-3,3-di(indolyl) oxindole, was excellent (Table 2, entry (12)). Wherever -F and -Cl groups are located in indoles or isatins of aromatic rings, they all could be tolerated well and gave the desired product derivatives 3e–3h, 3m, and 3o in excellent yields (Table 2, entries (5)–(8), (13), and (15)). However, the benzene ring of indoles or isatins bearing sterically demanding groups, such as -Br and -NO2, could only give corresponding products with lower yields, respectively (Table 2, entries (9), (10), and (14)). All compounds (3a–3o) were characterized by 1H and 13C NMR (400 MHz) spectral analysis (for all physical data of compounds, see SI 3 S2–S11).
On the basis of previous studies [9] and above results, a mechanism for this reaction was proposed. The first step is the activation of the 3-position carbonyl group of isatin (2) by 60 wt% PWA/MCM-41, which facilitates nucleophilic addition of indole (1) to form corresponding 3-hydroxy-3-indolyl oxindole (5). Then, hydrogen of indolyloxindole transferred to hydroxyl group and gave the intermediate (6), followed by its dehydration to (7). Finally, another indole reacted with (7) to provide the desired product 3,3-di(indolyl)indolin-2-one (3) and regenerate the catalyst for the next catalytic cycle (Scheme 3).
The study of reusability of catalytic is an important aspect of green chemistry. To investigate it, we used the above model reaction and optimized condition. After completion of the reaction, the catalyst was separated from the reaction mixture by centrifugalization, then washed with ethanol, and dried at 473 K for 4 h. The recovered catalyst was used for five consecutive reactions with no significant loss of activity (Figure 3) (for general cyclic procedure, see SI 2.3 S2).
4. Conclusion
In summary, we developed an efficient heterogeneous PWA/MCM-41 catalyzed Friedel-Crafts reaction of isatins with indoles, delivering a series of 3,3-di(indolyl)indolin-2-ones. The catalytic reaction could be carried out under mild conditions with broad substrate scope, good efficiency, and well functional group compatibility. Furthermore, the catalyst keeps the basic hexagonal pore arrangement and the components of PWA. The recovered catalyst was reused for five consecutive reactions with no significant loss of activity. Further investigation focusing on the scope of the currently synthetic applications is being conducted in our group.
Conflicts of Interest
All authors declare no conflicts of interest.
Acknowledgments
The authors acknowledge the National Natural Science Foundation of China (nos. 21362036 and 21162026) and the Thousand Talents Plan for financial support, Xinjiang University Analytical & Testing Center for instrumental analyses, and Adamas-beta Chemical Co. for all chemical reagents.
Supplementary Materials
Supplementary data and general procedure for synthesis of catalyst PWA/MCM-41 associated with this article can be found in the attached file. These data include NMR (1H and 13C), IR, melting point, and yield of the synthesized compounds (3a–3o). (Supplementary Materials)