Lewis acidic ionic liquids of crown ether complex cations: preparation and applications in organic reactions

Abstract

A range of Lewis acidic ionic liquids composed of crown ether complex cations were designed, synthesised and characterised by Raman, MS, FT-IR, thermogravimetric differential thermal analysis (TGA-DSC) and elemental analysis. These Lewis acidic ionic liquids were utilized as catalysts to prepare 2-phenyl-1H-benzo[d]imidazole using the same amount of aldehyde and o-phenylenediamine under air atmosphere and 1-benzyl-2-phenyl-1H-benzo[d]imidazole using two equivalents of aldehyde and one equivalent of o-phenylenediamine in argon. These ionic liquids were also found to be good catalysts to synthesize bis(indolyl)methane derivatives under mild conditions. In addition, the plausible mechanisms of the above reactions in the presence of ionic liquids as catalysts are suggested and discussed.

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Introduction

In the past decades, ionic liquids (ILs) have attracted much attention in the area of organic reactions¹ due to their special features, such as negligible vapour pressure, non-flammability, high ionic conductivity, good tunable solubility, and excellent thermal and chemical stability.^2–5 Nowadays, researchers are attracted by the ‘air and water stable’ ionic liquids, but the investigation and application of the Lewis acidic ionic liquids are still the main interest.⁶ In the early 1950s, the [AlCl₄]⁻ anion was paired with suitable cations to get the first record of Lewis acidic ionic liquids or molten salts.⁷ Since then, a lot of similar anions have been exploited such as [FeCl₄]⁻ and [ZnCl₃]⁻.⁸

To extend the ILs family, our group defined a novel type of ionic liquid containing crown ether complex cations with various anions that were utilized to catalyse various organic reactions.^9–12 Recently, a calix[4]arene-chelated potassium salt was also reported as an efficient catalyst for organometallic reactions,¹³ which is similar to our ILs. Pursuant to our previous study, a series of Lewis acidic crown ether complex cation ionic liquids were devised, synthesized and applied to Friedel–Crafts alkylation reaction^14,15 and the synthesis of benzimidazole derivatives.

The benzimidazole derivatives are well known for their various biological and pharmaceutical activities.^16–18 Although different catalysts have been reported for the synthesis of these heterocycles,^19–21 tedious workup procedures, drastic reaction conditions, low yields and co-occurrence of several side reactions have limited their practical applications. Therefore, new methods are necessary to be developed. Herein, a new IL of [18-C-6K][FeCl₄] was utilized to prepare benzimidazole derivatives as an efficient catalyst.

Bis(indolyl)methane derivatives are well known for their vast biological activity, and many methods of their synthesis have been reported, such as Lewis acids, Brønsted acids, and ionic liquids.^22–24 Herein, a new IL of [18-C-6K][FeCl₄] showed an excellent catalytic efficiency in the reaction of an aldehyde and indole to give bis(indolyl)methane derivatives.

Experimental

Materials and methods

All commercially available reagents were used without further purification unless otherwise mentioned. Reactions were monitored by thin layer chromatography (TLC). All the yields of isolated products were calculated after purification, using column chromatography and recrystallization. Products were analysed and characterized via Varian 300/400 spectrometer using DMSO-d₆ as an internal standard solvent for ¹H-NMR and ¹³C-NMR measurements. Infrared spectra were collected on a Nicolet NEXUS670 FT-IR spectrometer using a KBr pellet. MS (ESI) was carried out on a Bruker APEX II mass spectrometer. Raman spectra were collected using Raman microscopy system with a laser wavelength of 628 nm. Melting points were examined using a TGA/DSC/NETZS CH STA449C instrument heated from 30 °C to 800 °C (heating rate of 10 °C min⁻¹, under N₂).

Preparation of Lewis acidic ionic liquid of crown ether complex cations

Following our previous studies, we attempted to prepare a novel type of Lewis acidic ionic liquid. Inorganic potassium or sodium chloride salt (10 mmol) was mixed with 18-crown-6 (10 mmol, 2.6432 g) or 15-crown-5 (10 mmol, 2.2026 g) in water (15 mL). The mixture was stirred for 12 h at room temperature. After completion of the reaction, excess water was evaporated under reduced pressure. Then, the obtained solid and AlCl₃/FeCl₃·6H₂O/ZnCl₂ (10 mmol) were refluxed in ethanol. After stirring for 12 h, the solvent was removed under reduced pressure. The residue was dried in vacuum to generate the desired product in 100% yield (Fig. 1).

Fig. 1 The structures of Lewis acidic crown ether complex cation ionic liquids.

General procedure for synthesis of 1-substituted benzimidazole derivatives

The catalytic reactions were performed with arylaldehyde (1 mmol), 1,2-phenylenediamine (1.0 mmol) and ionic liquid (0.05 mmol) in ethanol (5 mL). The mixture was stirred for a proper time in air at room temperature and the reaction progress was monitored by TLC. After completion of the reaction, the mixture was evaporated under reduced pressure to get the crude product, which was purified by column chromatography using petroleum ether/ethyl acetate/dichloromethane (2 : 1 : 1) as eluent to give pure target product.

General procedure for synthesis of 1,2-disubstituted benzimidazole derivatives

The reactions were carried out with arylaldehydes (2 mmol), 1,2-phenylenediamine (1.0 mmol) and ionic liquid (0.05 mmol) in ethanol (5 mL). The mixture was stirred for a certain time under argon atmosphere at room temperature. After completion of the reaction, the mixture was evaporated under reduced pressure to get the crude product, which was then purified by column chromatography using petroleum ether/ethyl acetate/dichloromethane (2 : 1 : 1) as eluent to yield pure product.

Typical procedure for the synthesis of bis-(indolyl)methanes derivatives

The portion of indole (2.0 mmol), arylaldehydes (1.0 mmol), methanol (5 mL) and ionic liquid (0.1 mmol) were added to a 10 mL round-bottom flask equipped with a magnetic stir bar at room temperature. After completion of the reaction, which was monitored by TLC, 10 mL water was added to the mixture and extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to give the desired product, which was then purified by flash column chromatography.

Results and discussion

It is important to identify the anion speciation of Lewis acidic ionic liquids. Raman/ESI-MS was used to authenticate the formation of the anion (Fig. 2) due to their symmetric structures. The Raman spectra of the five ILs appear in the range of 200–500 cm⁻¹ and are consistent with the literature report.^25–27 On the basis of the principles of Raman spectroscopy, the Stokes line is attributed to the symmetric stretching vibration of metal chloride clusters. The Stokes line of the triangular structure of ZnCl₃⁻ that has a weak interaction with cation appeared at 287 cm⁻¹ in both C and E ILs.

Fig. 2 Raman spectra of five Lewis acidic ILs.

The Stokes line of the tetrahedron structure of FeCl₄⁻ that has a strong interaction with cation appeared at 335 and 341 cm⁻¹ in B and D, respectively. The obtained ionic liquids were of high purity and gave sharp melting points. The melting points of the ILs were in the range of 91–158 °C (Table 1) and significantly lower than that of the homologous metal chlorates, due to different ions in ILs. Moreover, the good thermodynamic stabilities were demonstrated by TGA-DSC analysis, in which their decomposition points were in the range of 205–280 °C (Table 1). All the ionic liquids exhibit relatively low melting point that match our new definition for ionic liquids.⁹

Table 1 The properties of new Lewis acidic ILs

Entry	ILs	Colour	Mp^a (°C)	T d ^a (°C)
a All melting points and decomposed temperatures (Td) were measured by XT-4 instrument and also determined by TGA-DSC, heating at 10 °C min^−1 under N2.
1	A	White	120	210
2	B	Green	109	233
3	C	White	91	280
4	D	Green	117	205
5	E	White	158	218

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Currently, Lewis acidic ionic liquids have immense diversity in applications, such as acting as catalysts in synthesis chemistry, providing transitional improvements in electroplating, supplying new gas scrubbing processes and preparing new inorganic semiconductor materials. Similarly, our Lewis acidic ionic liquids of crown ether complex cations also showed efficient catalytic ability in organic reactions.

In this study, we wish to use the ILs as catalysts for the preparation of benzimidazole derivates. With this purpose in mind, we firstly choose o-phenylenediamine (1.0 mmol) and benzaldehyde (1.0 mmol) as the model substrates in order to synthesize benzimidazole under different reaction conditions. Fortunately, [18-C-6K][FeCl₄] (B) can initiate the desired reaction to proceed efficiently in air atmosphere, solely producing 2-phenyl-1H-benzo[d]imidazole in 90% yield (Table 2, entry 2). For comparison, low yields of products could be afforded under the same reaction conditions in the presence of [18-C-6K][AlCl₄], [18-C-6K][ZnCl₃], [15-C-5Na][FeCl₄], and [15-C-5Na][ZnCl₃] (Table 2, entries 1, 3–5). Then, the solvent effect was also investigated. The results show that protic solvents give better yield (Table 2, entries 6, 10, 2) than aprotic solvents under similar conditions (Table 2, entries 7–9). Thus, 82% yield can be obtained using B as a catalyst in ethanol within 1 hour (Table 2, entry 10).

Table 2 Catalyst screening and optimization of reaction conditions^a

Entry	IL	Solvent	Time (h)	Yield^b (%)
a Reaction conditions: benzaldehyde (1 mmol), 1,2-phenylenediamine (1 mmol), catalyst (10 mol%), solvent (5 mL). b Isolated yield.
1	A	CH3CH2OH	4	78
2	B	CH3CH2OH	2	90
3	C	CH3CH2OH	4	62
4	D	CH3CH2OH	2	56
5	E	CH3CH2OH	4	64
6	B	CH3OH	2	73
7	B	THF	2	72
8	B	CH2Cl2	2	70
9	B	CH3CN	2	69
10	B	CH3CH2OH	1	82

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Under optimized conditions, the scope of the reaction was investigated, in which, o-phenylenediamine was reacted with various aldehydes to generate corresponding products. The results are summarized in Table 3. The substituted benzaldehydes with electron-withdrawing groups show better activity (Table 3, entries 2, 4, 7) than those with electron-donating groups (Table 3, entries 4, 10, 12) owing to the more electropositive nature of carbon in carbonyl. Even 2-nitrobenzene formaldehyde with a large steric hindrance can also react with o-phenylenediamine to produce target product in moderate yield under these reaction conditions (Table 3, entry 3).

Table 3 The synthesis of 1-substituted benzimidazole derivatives^a

Entry	–R	Product	Time (h)	Yield^b (%)
a Reaction conditions: 1 (1 mmol), 2 (1 mmol), catalyst (B, 10 mol%), ethanol (5 mL). b Isolated yield.
1	H	3a	2	90
2	4-NO2	3b	2	99
3	2-NO2	3c	2	67
4	3-NO2	3d	2	99
5	4-Cl	3e	2	85
6	2-Cl	3f	2	88
7	2,4-Cl	3g	2	92
8	4-CH3	3h	2	85
9	3-OCH3	3i	2	94
10	2-OCH3	3j	2	72
11	2-OH	3k	2	86
12	4-OH	3l	2	57

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Surprisingly, when two equivalents of benzaldehyde (2.0 mmol) reacted with one equivalent of o-phenylenediamine (1.0 mmol) under argon atmosphere at room temperature, 1-benzyl-2-phenyl-1H-benzo[d]imidazoles was obtained in high yield without any by-product (Table 4). The synthesis of 1,2-disubstituted benzimidazoles was also investigated with five types of Lewis acidic ionic liquids (Table 4, entries 1–5). [18-C-6K][FeCl₄] (B) was still a good choice for obtaining 1,2-disubstituted benzimidazoles in ethanol at the room temperature. To further extend the scope of this reaction, aromatic aldehydes possessing different substituents were applied in this reaction. We found that benzaldehydes with electron-donating groups or weak electron-withdrawing groups could react with o-phenylenediamine to generate the desired 1,2-disubstituted benzimidazoles (Table 4, entries 6–13) and benzaldehydes with strong electron-withdrawing groups showed no reactivity, because the corresponding intermediate was too stable to dehydrate (vide infra).

Table 4 The synthesis of 1,2-disubstituted benzimidazole derivatives^a

Entry	IL	R	Product	Time (h)	Yield^b (%)
a Reaction conditions: 1 (2 mmol), 2 (1 mmol), catalyst 10 mol%, ethanol (5 mL). b Isolated yield.
1	A	H	4a	4	70
2	B	H	4a	2	87
3	C	H	4a	3	71
4	D	H	4a	2	82
5	E	H	4a	3	72
6	B	2-OCH3	4b	2	72
7	B	2-Cl	4c	2	80
8	B	3-CH3	4d	2	69
9	B	3-OH	4e	2	59
10	B	2,4-Cl	4f	2	67
11	B	2,5-OCH3	6g	20	97
12	B	2-OCH3	6h	30	99
13	B	2,4-Cl	6i	60	95

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To understand the difference the syntheses of 1-substituted benzimidazole and 1,2-disubstituted benzimidazole, a possible mechanism is carefully proposed in Fig. 3. It can be seen that the amino-groups of the reactant are activated by cations of ILs and aldehydes are activated simultaneously by anions of ILs, which accelerate the rates of the reactions. When the imines of intermediate (i) were formed by the activated reactants, a key zwitterionic-type intermediate (ii) of cyclization was easily produced by the aid of IL. After 1,3-H shift of (ii), the most important intermediate (iii) was generated. When air was involved in the reaction, intermediate (iii) was oxidized and dehydrated to yield 1-substituted benzimidazole, which is similar to the literature.²⁸ In argon atmosphere, the intermediate (iii), stabilized in protic solvent, could react continuously with excess benzaldehyde to produce another zwitterionic-type intermediate (iv). When the proton reacted with (iv), intermediate (v) was formed via a dehydration process. Finally the 1,2-disubstituted benzimidazole could be obtained by an intramolecular rearrangement and deprotonation.

Fig. 3 Proposed mechanism for the reaction of o-phenylenediamine and benzaldehyde in the presence of ILs.

It is well known that Friedel–Crafts alkylation reaction is one of the most powerful methods to synthesize optically functionalized aromatic compounds. This reaction is carried out between an aromatic substrate and an acyl component in the presence of an acid catalyst. Herein, a series of Lewis acidic ionic liquids were utilized to synthesize bis(indolyl)alkane with indole and aldehyde. The results are summarized in Table 5. Among the ILs, [18-C-6K][FeCl₄] showed the best activity in ethanol (Table 5, entry 2 vs. 1, 3–5). To extend the scope of this reaction, various substituted benzaldehydes were reacted with indole to generate the corresponding products under optimal reaction conditions. Fortunately, all reactions proceeded smoothly and generated target products in high yields in a proper time. It is clear that benzaldehydes with electron-donating groups show better yield in shorter reaction times (Table 5, entries 9–12) than those with electron-withdrawing groups (Table 5, entries 6–8, 13).

Table 5 The synthesis of bis(indolyl)alkane^a

Entry	IL	R	Product	Time (min)	Yield^b (%)
a Reaction conditions: 1 (1 mmol), 5 (2 mmol), catalyst (10%), ethanol (5 mL). b Isolated yield.
1	A	H	6a	120	76
2	B	H	6a	60	99
3	C	H	6a	120	81
4	D	H	6a	100	87
5	E	H	6a	120	74
6	B	4-NO2	6b	150	90
7	B	2-NO2	6c	50	98
8	B	4-Cl	6d	40	97
9	B	4-OH	6e	50	99
10	B	4-CH3	6f	50	98
11	B	2,5-OCH3	6g	20	97
12	B	2-OCH3	6h	30	99
13	B	2,4-Cl	6i	60	95

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Finally, the probable mechanism for the synthesis of bis(indolyl)methane reaction was proposed (Fig. 4). First, the anion [FeCl₄]⁻ activates the carbonyl group of the aldehyde, while a molecule of indole attacks the aldehyde to generate intermediate I. After the loss of H₂O to afford intermediate II, another molecule of indole reacts with intermediate II to afford intermediate III. Simultaneously, with the leaving of cation [18 C-6K]⁺, the bis(indolyl)methane 6a is finally formed. Meanwhile, the catalyst of ionic liquid [18-C-6K][FeCl₄] is regenerated for the next catalytic cycle.

Fig. 4 Proposed mechanism for the reaction of indole and benzaldehyde in the presence of ILs.

Conclusions

In summary, we designed and synthesized five new Lewis acidic ionic liquids of crown ether complex cations that were applied to the synthesis of benzimidazole derivatives as catalysts. By controlling reaction conditions, various substituted products could be obtained in high yields under mild reaction conditions. Furthermore, these new ionic liquids showed good catalytic abilities for the synthesis of bis(indolyl)alkanes. Their excellent catalytic activities might be attributed to the Lewis acidity of metal complex anions and crown ether alkali cations that can activate substrates and stabilize the intermediates, which were revealed in the proposed mechanisms. Further investigation on other applications of these type of ionic liquids is in progress in our laboratory.

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (NSFC 21173106), the Fundamental Research Funds for the Central University (lzujbky-2016-K09) and the Foundation of State Key Laboratory of Coal Conversion (Grant No. J16-17-913).

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Footnotes

† Electronic supplementary information (ESI) available: The characterization data of Lewis acidic ionic liquids and target compounds, the data of FT-IR, MS, TGA-DSC of Lewis acidic ionic liquids, and ¹H NMR of target compounds. See DOI: 10.1039/c6ra21947k

‡ Contribution equally.

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