Applications of microwave technology to rapid synthesis of substituted imidazoles on silica-supported SbCl₃ as an efficient heterogeneous catalyst

Peer review under responsibility of Taibah University

Abstract

One-pot cyclo-condensation of benzil, aldehydes, ammonium acetate and primary amines were used to synthesize 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted-1H-imidazole derivatives under microwave irradiation with silica-supported SbCl₃ (SbCl₃/SiO₂) as a heterogeneous catalyst. The operational simplicity, practicability and applicability of this protocol to various substrates make it an interesting alternative to previous procedures. From the environmental stand-point, this eco-friendly, green catalyst is stable, highly active, easy to prepare and handle.

Keywords:

• SbCl₃/SiO₂
• Lewis acid
• Heterogeneous catalyst
• Imidazoles
• Microwave irradiation
• Solvent-free condition

1 Introduction

Microwave-assisted organic synthesis results in spectacular acceleration of many chemical reactions as a consequence of three-dimensional heating of the reaction mass, which cannot be reproduced by classical heating methods. High yields, simple work-up, improved selectivity and clean reaction pathways are additional advantages of this synthetic technique [1]. Moreover, even reactions that do not occur with conventional heating can be performed with microwave irradiation. In most cases, microwave irradiation coupled with solvent-free techniques represents a powerful, eco-friendly, green alternative to conventional synthesis. Theoretical calculations also suggest that reactions with high activation energies can be performed under microwave conditions without the use of harsh organic solvents [2].

Numerous important heterocycle compounds have been synthesized under solvent-free conditions accelerated by microwave technology. Nitrogen-containing heterocyclics are widespread in nature, and their applications in agrochemicals, pharmaceuticals and functional materials are gaining importance [3,4]. A wide variety of N-containing heterocyclic imidazole ring systems have received considerable attention because of their pharmacological properties and roles in biochemical processes [4,5].

Multi-substituted imidazoles are known to possess NO synthase inhibition and antifungal, antibacterial, antiulcerative, antibiotic, antitumour, antimycotic, and CB1 receptor antagonistic activities [6,7]. Various substituted imidazoles act as inhibitors of p38 MAP kinase [8] and B-Raf kinase [9], glucagon receptors [10], plant growth regulators [11] and pesticides [12]. Accordingly, a number of synthetic methods have been reported for the construction of substituted imidazoles.

In 1882, Radziszewski and Japp [13,14] reported the first synthesis of a highly substituted imidazole from a 1,2-dicarbonyl compound, aldehydes and ammonia. A number of synthetic processes have also been developed for the synthesis of 1,2,4,5-tetrasubstituted imidazole and 2,4,5-trisubstituted imidazole derivatives. Syntheses of 1,2,4,5-tetrasubstituted imidazoles are carried out by four-component cyclo-condensation of a 1,2-diketone/α-hydroxyketone with various aldehydes, primary amine and ammonium acetate with molecular HBF₄-SiO₂ [15], FePO₄ [16], BF₃·SiO₂ [17], sulfuric acid ([3-(3-silicapropyl)sulfanyl]propyl] ester [18], cyclic phosphoric acid [19], silica-supported Wells–Dawson acid [20], heteropolyacid [21,22], ionic liquids [23,24], SBA-15/2,2,2-trifluoroethanol [25] and clay-supported titanium [26]. 1,2,4,5-Tetrasubstituted imidazoles can also be obtained by condensation of a 1,2-diketone, aryl nitrile and primary amine under microwave conditions [27], by N-alkylation of trisubstituted imidazoles and by hetero-cope rearrangement [5]. 2,4,5-Trisubstituted imidazole derivatives are generally synthesized by three-component condensation of a 1,2-diketone/α-hydroxyketone with various aldehydes and ammonium acetate, including ionic liquids [28], refluxing in acetic acid [29], silica-immobilized sulfuric acid [30], InCl₃·3H₂O [31], ceric ammonium nitrate [32], NiCl₂·6H₂O/Al₂O₃ [33] and microwave irradiation [34].

Although these protocols are suitable for certain synthetic conditions, many have one or more disadvantages, such as long reaction times, expensive reagents and catalysts, low selectivity, tedious work-up procedure and large amounts of catalysts, which eventually results in the generation of large amounts of toxic waste.

Use of Lewis acids supported on “inert” carriers as catalysts has received considerable interest for organic synthesis [35]. The features of supported Lewis acids, such as ease of handling, enhanced reaction rates, greater selectivity, simple workup and recoverability of catalysts make them attractive alternatives to conventional reagents [36]. Although there is a large variety of supported Lewis acids, silica-supported antimony (III) chloride is a recoverable, reusable heterogeneous catalyst in organic synthesis [36–39], making the processes truly eco-friendly, green methods [35]. SbCl₃ has been studied for its catalytic activity in only one study [35], while this compound is not only commercially available and inexpensive, but is also easier to handle than other metal halides. Reports on the safety of SbCl₃, however, show that it is highly toxic. Therefore, immobilized antimony (III) chloride has recently received considerable importance. This catalyst can be easily separated from the reaction products by simple filtration and recovered quantitatively in the active form. Supported SbCl₃ can be recycled, making the preparation of sophisticated fine chemicals less expensive and, at the same time, avoiding contamination of the products by trace amounts of catalyst [40].

In this context and in continuation of our studies on the applications of new catalysts for the synthesis of heterocyclic compounds [41–43] and to extend them to cleaner processes, we herein report a facile, efficient synthetic strategy for obtaining multi-substituted imidazoles in excellent yield with SbCl₃/SiO₂ under microwave irradiation and solvent-free conditions. Although the use of various solid heterogeneous catalysts has been reported in literature, silica-supported heterogeneous Lewis acid catalysts like SbCl₃/SiO₂, have not yet been explored for the preparation of imidazoles under solvent-free conditions and microwave irradiation (Scheme 1).

Scheme 1 Synthesis of substituted imidazoles by SbCl₃/SiO₂ catalyst under solvent-free conditions.

2 Experimental

2.1 Chemicals and apparatus

Chemical reagents of high purity were purchased from Merck, and all materials were of commercial reagent grade. Melting-points were determined in open capillaries on an Electrothermal Mk3 apparatus and are uncorrected. ¹H nuclear magnetic resonance (NMR) and ¹³C NMR spectra were recorded on a Bruker DRX-400 spectrometer at 400 and 100 MHz, respectively, and are reported as parts per million (ppm) downfield from tetramethylsilane as the internal standard. Fourier transform (FT)–infrared (IR) spectra were obtained with potassium bromide pellets in the range 400–4000 cm⁻¹ on a Perkin-Elmer 550 spectrometer. A domestic microwave oven (Bajaj, ET–B at 2450 MHz, 100% power, 1300 W) was used in all experiments.

2.2 Preparation of SbCl₃/SiO₂ catalyst

The catalyst was prepared as reported elsewhere [35]. Thus, 20 g of silica gel (80–200 mesh) were activated by refluxing with 150 mL of 6 mol/L hydrochloric acid under stirring for 24 h. The activated silica gel was filtered and washed with double-distilled water to neutral and dried overnight at 70 °C under vacuum to give preconditioned silica gel. Antimony trichloride (1.99 g) was added to a suspension of activated silica gel (1.54 g) in ethanol (50.0 mL), and the mixture was stirred at room temperature for 1 h. The solvent was removed, and the residue was washed three times with absolute ethanol and heated at 100 °C under vacuum for 5 h to furnish silica-supported antimony (III) chloride (2.83 g) as a white, free-flowing powder (Scheme 2).

Scheme 2 Reaction of SbCl₃ with silica gel to form a highly active catalyst.

2.3 General synthesis for the preparation of 1,2,4,5-tetrasubstituted imidazoles

SbCl₃/SiO₂ (0.1 g), an efficient catalyst, was added to the mixture of benzil (1 mmol), benzaldehyde (1 mmol), NH₄OAc (4 mmol) and primary aliphatic and aromatic amine (4 mmol). The resulting mixture was heated in a microwave oven at 850 W or in an oil bath (at 120 °C) for the appropriate time until the reaction was complete. After thin-layer chromatography (eluent, petroleum ether:ethyl acetate: 9:1) indicated disappearance of the starting materials, the reaction was cooled to room temperature. The resulting solid was dissolved in acetone and filtered. The solid product obtained was washed with water and recrystallized from acetone:water 9:1 (v/v) to provide pure 1,2,4,5-tetrasubstituted imidazole derivatives as colourless crystals.

2.4 General synthesis for the preparation of 2,4,5-trisubstituted imidazoles

In a 50-mL round-bottom flask, a mixture of benzil (1 mmol), benzaldehyde (1 mmol), ammonium acetate (4 mmol) and SbCl₃/SiO₂ (0.1 g) was stirred under microwave irradiation at 850 W or in an oil bath (at 120 °C) in solvent-free conditions. Pure 2,4,5-trisubstituted imidazole derivatives were obtained by a method similar to that for 1,2,4,5-tetrasubstituted imidazoles.

3 Results and discussion

Synthesis of tri- and tetra-substituted imidazoles by cyclo-condensation of aldehyde, benzil, ammonium acetate and amine in refluxing acetic acid for a few hours is a well-established protocol [44]. The drawbacks of this procedure include low yields, long reaction time, tedious workup and drastic reaction conditions. An improved method for the synthesis of multi-substituted imidazoles, using silica gel, zeolite and acidic alumina under microwave irradiation, has been described [45,46]; however, this technique does not meet the definition of ‘no solvent’, as it requires the use of an appreciable amount of solvent at the reaction stages. We modified the supported Lewis acid technique to make it an environmentally friendly green synthesis, in which the reaction is carried out in the absence of solvent and solid support by a microwave technique.

In an initial study, we considered cyclo-condensation of benzaldehyde with aniline, benzil and ammonium acetate under microwave irradiation and solvent-free conditions a model reaction. We screened various common SbCl₃/SiO₂ for their ability to catalyze the four-component cyclo-condensation at 30 W under microwave irradiation. The results are summarized in Table 1. Use of 0.1 g SbCl₃/SiO₂ afforded a 95% yield of the desired product. A physical mixture of silica and SbCl₃ showed lower activity. Thus, SbCl₃/SiO₂ presumably acts in a synergistic fashion to catalyze this reaction. The experimental results show that the reaction times are shorter and the yields of the products higher under microwave conditions. In the absence of catalyst, the yield of product was low (30%), showing that the catalyst is necessary for synthesis of 1,2,4,5-tetrasubstituted imidazoles.

Table 1 Optimization of catalyst amount in synthesis of 1,2,4,5-tetrasubstituted imidazole derivatives under microwave irradiation.

Entry	Catalyst (g)	Time (min)	Yield (%)
1	0.02 (SbCl3/SiO2)	15	40
2	0.04 (SbCl3/SiO2)	15	52
3	0.06 (SbCl3/SiO2)	15	70
4	0.08 (SbCl3/SiO2)	15	83
5	0.09 (SbCl3/SiO2)	15	90
6	0.1 (SbCl3/SiO2)^a	15	95
7	0.1 (SbCl3/SiO2)^b	20	90
8	0.11 (SbCl3/SiO2)	15	95
9	0.1 (SiO2)	15	80
10	0.1 (1.99 g SbCl3 and 1.54 g SiO2)	15	85
11	–	25	30

a The best yield of product.

b Under heating condition at 120 °C.

1,2,4,5-Tetrasubstituted imidazole was synthesized by reacting benzil, aliphatic and aromatic amines and ammonium acetate with various aromatic aldehydes and various functional groups under microwave conditions and classical heating. The aromatic aldehydes and aliphatic and aromatic amines were converted to the corresponding products in good yields and in short time (Table 2). The reactions were also performed with conventional heating, with similar reaction conditions. Direct heating of the reactants without solvent took longer to complete the reactions and gave high yields. The yields obtained were good to excellent with no formation of side products such as 2,4,5-trisubstituted imidazoles, oxidized products of anilines or aldehydes, which are usually observed under the influence of strong acids.

Table 2 Synthesis of 1,2,4,5-tetrasubstituted imidazole derivatives catalyzed by SbCl₃/SiO₂.

R	Amine	Product	Time (min) (MW)/(120 °C)	Yield (%) (MW)/(120 °C)	Melting-point (°C) [References]
H	Ph-NH2	5a	15/45	95/87	216–218 [47]
4-Me	Ph-NH2	5b	17/60	90/80	186–188 [47]
4-Cl	Ph-NH2	5c	12/35	97/92	160–163 [48]
2-OH	Ph-NH2	5d	18/70	76/73	252–254 [48]
2-F	Ph-NH2	5e	10/30	96/92	165–168 [49]
3,4-(OMe)2	Ph-NH2	5f	23/75	85/75	178–180 [50]
4-Br	Ph-NH2	5g	13/35	96/90	207–211 [48]
4-OMe	Ph-NH2	5h	20/65	87/78	177–180 [47]
H	n-Pr-NH2	5i	10/40	96/90	87–89 [50]
4-Cl	n-Pr-NH2	5j	6/35	96/93	85–87 [50]
4-Me	n-Pr-NH2	5k	15/50	91/82	78–83 [50]
4-OMe	n-Pr-NH2	5l	15/65	90/78	76–80 [50]

In order to explore the applicability of this method, the same reaction conditions were used for synthesis of 2,4,5-trisubstituted imidazoles via a one-pot, cyclo-condensation of 1,2-diketone (1 mmol), aldehyde (1 mmol) and ammonium acetate (4 mmol). Good to excellent yields and a short reaction time were found with SbCl₃/SiO_2. Therefore, application of SbCl₃ dispersed on dry silica gel not only affords excellent yield but also avoids the problems of catalyst cost, handling, safety and pollution. This ecofriendly, green catalyst is a heterogeneous acid that can be easily separated from the reaction mixture simply by filtration (Table 3).

Table 3 Synthesis of 2,4,5-trisubstituted imidazole derivatives catalyzed by SbCl₃/SiO₂.

R	Product	Yield (%) (MW)/(120 °C)	Time (min) (MW)/(120 °C)	Melting-point (°C)^a
H	6a	10/35	95/87	272–273
4-Me	6b	10/40	90/80	226–227
4-OMe	6c	10/43	88/78	227–228
4-Cl	6d	10/25	97/94	272–273
3-Cl	6e	10/15	97/92	226–227
2-OMe	6f	10/45	86/73	227–228
3-NO2	6g	10/20	93/95	259–261
2-OH	3h	2/45	85/70	282–284
3-Cl	6i	10/20	92/93	207–209
3,5-(OMe)2	6j	12/45	90/80	269–271
4-Br	6k	10/25	98/92	203–205
4-N(Me)2	6l	10/40	88/77	260–261

a From Ref. [49].

The probable mechanism for the synthesis of multi-substituted imidazoles in the presence of SbCl₃/SiO₂ is outlined in Scheme 3. The reaction proceeds via the diamine intermediate [A], which is formed by activation of the aldehyde carbonyl group by Lewis acids on the surface of the silica gel. Condensation of diamine with 1,2-diketone, followed by dehydration and then rearrangement through the imino intermediate [B], yielded the desired product. The Lewis acid site on silica-supported antimony (III) chloride acts as a highly efficient catalyst, even for low-activity substrates, in the preparation of imidazole derivatives. The higher catalytic activity of SbCl₃/SiO₂ is due to good dispersion of SbCl₃ over the large surface area of the silica support. The results indicated that dispersed SbCl₃ coordinates with surface hydroxyl groups, leading to formation of O–Sb–Cl as stable Lewis acid sites under the reaction condition [35].

Scheme 3 Proposed mechanism for the formation of substituted imidazoles in the presence of SbCl₃/SiO₂.

We also examined the possibility of recycling the catalyst in the model reaction. When the reaction was complete, ethyl acetate was added to the reaction mixture, the mixture was stirred, and the SbCl₃/SiO₂ was filtered off, washed with ethyl acetate and activated by heating for 2 h at 110 °C. The recovered catalyst was used in another reaction with the same substrates with no significant loss of activity after five cycles (from 95% in the first run to 90% in the fifth run).

In order to show the advantages of this catalyst over other reported catalysts, we compared the reactions of SbCl₃/SiO₂ with ionic liquid [EMIM] OAc, Zr(acac)₄, zinc (II) [tetra(4-methylphenyl)] porphyrin and BO₃H₃ for the preparation of imidazole (6a in Table 4). SbCl₃/SiO₂ was a better catalyst with respect to reaction times and yields of products. Furthermore, SbCl₃/SiO₂ provides products of high purity in a short reaction time and is also cheap, speedy, facile and eco-friendly throughout the course of the reaction.

Table 4 Comparison of SbCl₃/SiO₂ with other catalysts reported in the literature for the synthesis of imidazoles.

Catalyst	Time	Yield^a (%)	References
Ionic liquid [EMIM]OAc	1.5 h	95	[39]
Zr(acac)4	45 min	88	[27]
Zinc (II) [tetra(4-methylphenyl)] porphyrin	70 min	94	[36]
BO3H3	30 min	98	[40]
SbCl3/SiO2	10 min	95	This work

Benzil (1 mmol), aldehyde (1 mmol), NH₄OAc (5 mmol).

a Isolated yields.

4 Conclusion

In conclusion, SbCl₃/SiO₂ can catalyze the one-pot synthesis of a large number of multi-substituted imidazoles at moderate temperature under microwave conditions very efficiently. Microwave-promoted solvent-free solid acid reactions are environmentally benign methods, usually with improved selectively, enhanced reaction rates, cleaner products and manipulative simplicity. SbCl₃/SiO₂ is also an excellent catalyst for microwave-assisted organic synthesis. We expect that this method will find extensive applications in the fields of combinatorial chemistry, diversity-oriented synthesis, heterogeneous catalytic systems and drug development.

Acknowledgement

This work was financially supported by a grant (No. 256722/19) from the research foundation of the University of Kashan.

Notes

Peer review under responsibility of Taibah University