PEG₁₀₀₀-Based Dicationic Acidic Ionic Liquid/Solvent-Free Conditions: An Efficient Catalytic System for the Synthesis of Bis(Indolyl)methanes

Abstract

An efficient procedure has been researched for the solvent-free synthesis of bis(indolyl)methanes via a one-pot reaction of indoles and aldehydes or ketones promoted by PEG₁₀₀₀-based dicationic acidic ionic liquid (PEG₁₀₀₀-DAIL). The catalyst PEG₁₀₀₀-DAIL could be reused seven times with excellent results. Furthermore, through this method, a highly chemoselective reaction of benzaldehyde and acetophenone with indole could be achieved.

1. Introduction

Numerous indoles occur in many active medicine compounds for human health [1,2]. In particular, bis(indolyl)methanes possess a wide range of pharmaceutical activities, such as serving as anti-bacterial and anti-fungal agents [3,4,5,6]. Due to their important role in medicine chemistry, many synthetic routes for the bis(indolyl)methanes have been researched by synthetic chemists. The simplest method for the preparation of bis(indolyl)methanes is the reaction of indoles with carbonyl compounds [7,8,9,10,11]. However, most of these synthetic routes require longer reaction times and a toxic organic solvent. Hence, it is desirable to develop improved reaction systems for the synthesis of these compounds.

Nowadays, ionic liquids (ILs) have attracted a great deal of interest because of their special performance including excellent heat stability, ease of operation, unique dissolution properties, and a wide liquid range [12,13,14,15,16,17,18]. Among all the types of developed ILs, PEG-DAILs [19,20,21,22,23,24,25,26,27,28] have been researched as excellent and powerful catalysts for various organic synthetic reactions. To the best of our knowledge, there have been no reports on the application of PEG₁₀₀₀-DAIL as acid catalysts for the synthesis of bis(indolyl)methanes. As part of our ongoing interest in PEG₁₀₀₀-DAIL [23,24,25,26,27,28], we now report, herein, an efficient and simple method for the synthesis of bis(indolyl)methanes using PEG₁₀₀₀-DAIL as a reusable catalyst under solvent-free conditions (Scheme 1).

Scheme 1. PEG₁₀₀₀-based dicationic acidic ionic liquid (PEG₁₀₀₀-DAIL) catalyzed synthesis of bis(indolyl)methanes.

2. Results and Discussion

2.1. Effects of Different Reaction Conditions

To establish the optimum conditions for this reaction, various ratios of PEG₁₀₀₀-DAIL were examined using indole and bezaldehyde as a model reaction. At room temperature, the mixture was ground together in a mortar with a pestle. We found that excellent results were obtained within 3 min when using 3 mol % PEG₁₀₀₀-DAIL (Table 1, entry 4), and there was no superiority to using added PEG₁₀₀₀-DAIL (Table 1, entries 5 and 6).

Table 1. Optimizing reaction conditions.

Entry	PEG1000-DAIL (mol %)	t (min)	Yield (%) a
1	0	20	trace
2	1	20	75
3	2	12	85
4 b	3	3	98, 98, 97, 97, 95, 94, 90
5	4	3	98
6	5	3	98

^a Isolated yields; ^b PEG1000-DAIL was used for seven consecutive cycles.

The recycling performance of PEG₁₀₀₀-DAIL was researched in a condensation reaction of bezaldehyde and indole. The experimental data listed in Table 1 showed that PEG₁₀₀₀-DAIL could be reused seven times with good results (Table 1, entry 4), and only a 6% loss of weight of PEG₁₀₀₀-DAIL was observed after recycling seven times.

2.2. Effects of Different Substrates

To show the efficiency of this method, we researched the versatility of our approach via the reaction of various aromatic aldehydes with several kinds of indoles (Table 2). For all the corresponding reactions, the products of bis(indolyl)methanes (3a–3x) were obtained in excellent yields at room temperature after 25 min. The benzaldehydes with electron-donating groups require longer reaction times than those with electron-withdrawing groups. However, acetophenones and alkyl ketones required longer reaction times (Table 2, entries 21–24), the most likely cause being the steric effects of the -CH₃.

Table 2. PEG₁₀₀₀-DAIL-catalyzed synthesis of bis(indolyl)methanes (3a–3x).

Entry	R1	R2	R3	R4	t (min)	Product	Yield (%) a
1	C6H5	H	H	H	3	3a	98
2	4-ClC6H4	H	H	H	2	3b	98
3	2-ClC6H4	H	H	H	2	3c	98
4	4-CH3C6H4	H	H	H	10	3d	96
5	4-CH3OC6H4	H	H	H	10	3e	95
6	2-CH3OC6H4	H	H	H	8	3f	93
7	4-NO2C6H4	H	H	H	2	3g	98
8	3-NO2C6H4	H	H	H	3	3h	94
9	4-BrC6H4	H	H	H	2	3i	95
10	4-HOC6H4	H	H	H	10	3j	96
11	C6H5	H	CH3	H	3	3k	94
12	4-ClC6H4	H	CH3	H	2	3l	96
13	4-CH3C6H4	H	CH3	H	10	3m	95
14	3-NO2C6H4	H	CH3	H	3	3n	95
15	4-NO2C6H4	H	CH3	H	2	3o	97
16	C6H5	H	H	CH3	4	3p	96
17	4-NO2C6H4	H	H	CH3	3	3q	98
18	4-CH3C6H4	H	H	CH3	10	3r	96
19	CH3(CH2)3	H	H	H	15	3s	92
20	C6H5CH=CH	H	H	H	5	3t	95
21	C6H5	CH3	H	H	25	3u	95
22	4-NO2C6H4	CH3	H	H	18	3v	97
23	CH3	CH3	H	H	50	3w	73
24	(CH2)5		H	H	40	3x	81

^a Isolated yields.

In Table 2, we can see that the acetophenones (Table 2, entries 21 and 22) that react with iodine require longer reaction times than the aldehydes. This provides us a hint that our procedure could be used in the chemoselective reaction of aldehydes and acetophenones. Thus, a mixture of benzaldehyde and acetophenone (mole ratio of 1:1) was allowed to react with indole under the same reaction conditions. The results show that only 3,3′-bisindolyl-phenylmethane was obtained, and the acetophenone did not react with indole and recovered quantitatively (Scheme 2). This result indicates that the presented route is potentially applicable for the chemoselective reaction of aldehyde groups and ketone groups in multi-functional compounds to the desired bis(indolyl)methanes.

Scheme 2. Chemoselective reactions of carbonyl groups with indole.

2.3. Effects of Different Catalysts

In order to show the virtues of PEG₁₀₀₀-DAIL in comparison with other previously reported catalysts, we summarized some of the results in Table 3 (the reaction of benzaldehyde with indole). The results showed that PEG₁₀₀₀-DAIL was a more efficient catalyst with respect to reaction time and yield than other previously reported catalysts at room temperature. For example, in an EtOH solution, the product, 3,3′-bisindolyl-phenylmethane, was obtained in only a 72% yield, in 2.5 h, using Bu₄NBr₃ as a catalyst (Table 3, entry 5).

Table 3. Comparison of the condensation of benzaldehyde with indole with other catalysts.

Entry	Catalysts	Amount (mmol)	Solvents	T (°C)	t (h)	Yield (%)
1	PEG1000-DAIL	0.03	No	r.t.	0.05	98
2	Ascorbic Acid	0.14	EtOH	r.t.	0.5	89 [7]
3	Sulfated Zirconia	0.30	No	r.t.	24	97 [29]
4	BF3∙Et2O	0.15	Et2O	r.t.	2	90 [30]
5	Bu4NBr3	0.08	EtOH	r.t.	2.5	72 [31]
6	Cyclic phosphoric acid	0.01	CH2Cl2	r.t.	2.5	97 [32]

3. Experimental Section

3.1. Materials and Methods

PEG₁₀₀₀-DAIL was synthesized using the route provided in a previously report [19]. All other chemicals are bought from companies (Aladdin Company, Shanghai, China). NMR spectra were recorded on a Bruker Advance DMX400 (Bruker Corporation, Karlsruhe, Germany). All corresponding bis(indolyl)methanes were known compounds and were identified using NMR and mp.

3.2. Typical Procedure for the Synthesis of Bis(indolyl)methanes

At room temperature, a mixture of indole (4 mmol), carbonyl compound (2 mmol), and PEG₁₀₀₀-DAIL (0.092 g, 0.06 mmol) were ground together in a mortar with a pestle for a given amount of time and was monitored using TLC (Aladdin Company, Shanghai, China) (Table 2). After completion of the reaction, the reaction mixture was extracted with Et₂O or EtOAc (15 mL). The upper organic extracts were then washed with water (3 × 5 mL) to remove PEG₁₀₀₀-DAIL. The organic layer was dried over Na₂SO₄. The organic solvent (Et₂O or EtOAc) was evaporated, and the crude product was purified using plate chromatography on silica gel eluted with ethyl acetate/petroleum ether (Aladdin Company, Shanghai, China). After the removal of H₂O under reduced pressure, the PEG₁₀₀₀-DAIL was reused in the next reaction.

4. Conclusions

In conclusion, we have successfully researched an efficient route to synthesize bis(indolyl)methanes. The merits of the present method using PEG₁₀₀₀-DAIL as a catalyst consist in short times, an elimination of metals, high yields of products, and an ease of handing. Furthermore, PEG₁₀₀₀-DAIL can be reused easily for several subsequent cycles, thus making this route more environmentally acceptable.