Introduction

The synthesis, reactions, and biological properties of substituted imidazoles constitute a significant part of modern heterocyclic chemistry. Multi-substituted imidazoles, an important class of pharmaceutical compounds, have a wide spectrum of biological activity [1–3]. They have emerged as an integral part of many biological systems [4], viz. histidine, histamine, and biotin [5], and an active backbone in drugs such as losartan, eprosartan [6], and trifenagrel [7]. They also have a variety of bioactive effects, for example fungicidal [8, 9], herbicidal [10], antitumor [11], anti-inflammatory [12], anti-allergic [13], analgesic [14], and antibacterial [15]. Some substituted imidazoles are selective antagonists of the glucagons receptor [16], inhibitors of p38 MAP kinase [17], B-Raf kinase [18], transforming growth factor β1 (TGF-β1) type 1 activin receptor-like kinase (ALK5) [19], cyclooxygenase-2 (COX-2) [20], and biosynthesis of interleukin-1 (IL-1) [21].

Several methods are used for synthesis of multi-substituted imidazoles [22–33]. Recently, one-pot condensations of an aldehyde and ammonium acetate with an α-hydroxy ketone, an α-keto oxime, or a 1,2-diketone have been achieved by using a variety catalysts, for example Zr(acac)4 [34], Yb(OTf)3 [35], Yb(OPf)3 [36], InCl3·3H2O [37], I2 [38], NiCl2·6H2O/Al2O3 [39], ZrCl4 [40], silica sulfuric acid (SSA) [41, 42], boric acid [43], ionic liquids [44–47], heteropolyacid [48], ceric ammonium nitrate (CAN) [49, 50], sodium bisulfite [51], potassium aluminum sulfate (alum) [52], polymer-supported ZnCl2 [53], phosphomolybdic acid [54], ZrOCl2·8H2O [55], l-proline [56], PEG-400 medium [57], and scolecite [58]. Despite their potential utility, some of these methods are not environmentally friendly and suffer from one or more disadvantages, for example hazardous reaction conditions, complex work-up and purification, strongly acidic conditions, high temperature, use of toxic metal catalysts, poor yields, occurrence of side reactions, and long reaction time. Therefore, the development of a mild general method to overcome these shortcomings remains a challenge for organic chemists in the synthesis of highly substituted imidazoles. Magnesium oxide (MgO) has many applications as catalyst [59, 60], refractory materials [61], optically transparent ceramic windows [62, 63], etc. Magnesium oxide with large specific surface area is also a potential catalyst support for various reactions and a promising sorbent for chemisorption and destructive adsorption of a variety of pollutants. In the field of catalysis, MgO has strongly basic properties, which are associated with catalysis by bases in many organic reactions [64]. Nanoscale supports create catalysts with more edges and corners, which can lead to higher performance of the catalyst. Herein, we report convenient and facile multi-component, one-pot synthesis of 2,4,5-trisubstituted imidazoles in high yields by using nanocrystalline magnesium oxide with high specific surface area of approximately 116 m2 g−1 and a crystallite size of approximately 12 nm as a novel and efficient catalyst (Scheme 1).

Scheme 1
scheme 1

 

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Results and discussion

In an initial study, for examination of catalytic activity of different catalysts such as CaO, BaO, and MgO in this condensation reaction, 1 mmol benzaldehyde was first reacted with 1 mmol benzil and 2 mmol ammonium acetate for 30 min at 100 °C in the presence of each catalyst (2 mol%) separately. In the course of this study we found that MgO was the most effective catalyst (Table 1). In the absence of catalyst, yield of the product was found to be very low. Therefore, we decided to use nanocrystalline MgO with a high specific surface area as a catalyst with higher activity and better controlled selectivity.

Table 1 Synthesis of 2,4,5-triphenyl-1H-imidazole in the presence of metal oxide catalysts
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The crystallite sizes determined by XRD were between 12.8 and 17.5 nm (determined by use of the Scherrer equation), indicative of the nanocrystalline structure of the prepared MgO. In addition the surface area was approximately 116 m2 g−1. The pore volume and pore size were also calculated from the N2 adsorption result; the pore size was approximately 21.1 nm and the pore volume approximately 0.69 cm3 g−1. The theoretical particle size was also calculated from surface area, assuming spherical particles, from the equation:

$$ D_{BET} = \left( {{\frac{6,000}{\rho \times S}}} \right) $$
(1)

where D BET is the equivalent particle diameter in nanometers, ρ is the density of the material in g cm−3, and S is the specific surface area in m2 g−1. The particle size calculated from Eq. 1 was 14.4 nm, which confirmed the nanostructure of the MgO sample [66]. The TEM image of MgO is shown in Fig. 1. As can be seen, the sample has a nanocrystalline structure with a plate-like shape.

Fig. 1
figure 1

TEM image of nanocrystalline MgO

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Subsequent efforts were focused on optimizing conditions for formation of 2,4,5-triphenylimidazole by using different amounts of nanocrystalline MgO and different temperatures to determine their effects on the reaction (Table 2). As indicated, the best result was obtained at 100 °C with 5 mol% nanocrystalline MgO. The reaction yield with increasing amount of nanocrystalline MgO and temperature was not substantially increased.

Table 2 Optimization of reaction conditions for synthesis of 2,4,5-triphenyl-1H-imidazole
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Results from nanocrystalline magnesium oxide-catalyzed condensation reaction of 1,2-diketones (benzil, 1a, 4,4′-difluorobenzil, 1b) with different aromatic aldehydes and ammonium acetate at 100 °C under solvent-free conditions are given in Table 3. As shown, these conditions proved to be general for the reacting aldehyde. Aldehydes bearing either electron-withdrawing or electron-donating groups perform equally well in the reaction and all imidazoles were obtained in high yields.

Table 3 Nanocrystalline MgO-catalyzed synthesis of 2,4,5-trisubstituted imidazoles at 100 °C under solvent-free conditions
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The high efficiency of the nanoparticle oxides is caused not only by their high surface area but also by the high concentration of low-coordinated sites and structural defects on their surface. As the particle size is scaled down to a few nanometers, the constituting atoms have highly defective coordination environments. Most of the atoms have unsatisfied valencies and reside at the surface [65]. Nanocrystalline MgO also acts as a mild Lewis acid that catalyzes three-component, one-pot synthesis of 2,4,5-trisubstituted imidazoles.

The structure of compounds 4a–4v was deduced from their high-field 1H NMR, 13C NMR, IR, and UV spectral data. Also, their melting points were compared with literature reports. The 1H NMR spectra of all the products contained a singlet at approximately δ = 12.50–12.80 ppm. IR spectra contained a distinguishing peak at 3,400–3,440 cm−1 for NH. In 13C NMR spectra of fluorinated derivatives, C–F couplings were observed with coupling constants of 1 J C–F = 241–244 Hz, 2 J C–F = 21–22 Hz, 3 J C–F = 7–8 Hz, and 4 J C–F = 2 Hz. For example, the 13C NMR spectrum of compound 4t is indicated in Fig. 2.

Fig. 2
figure 2

13C NMR spectrum of compound 4t

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In summary, we describe a facile, eco-friendly, and green procedure for synthesis of biologically active 2,4,5-trisubstituted imidazoles via condensation of representative 1,2-diketones with a variety of aromatic aldehydes and ammonium acetate in the presence of nanocrystalline magnesium oxide with high surface area as a novel, efficient, and recyclable catalyst under solvent-free and conventional heating conditions. The approach has several benefits, for example low waste, easy work up, short reaction time, and high yields.

Experimental

Materials

Chemical reagents in high purity were purchased from the Merck Chemical Company. All materials were of commercial reagent grade.

Apparatus

Melting points were determined in open capillaries using an Electrothermal Mk3 apparatus. Infrared spectra were recorded using a Perkin–Elmer FTIR 550 spectrometer. 1H NMR and 13C NMR spectra were recorded with a Bruker DRX-400 spectrometer at 400 and 100 MHz, respectively. NMR spectra were obtained in DMSO-d 6 solutions and are reported as parts per million (ppm) downfield from tetramethylsilane as internal standard. The abbreviations used are: singlet (s), doublet (d), triplet (t), and multiplet (m). Elemental analysis (C, H, N) was performed with a Carlo Erba model EA 1108 analyzer or a Perkin–Elmer 240c analyzer, and results agreed favorably with calculated values. UV spectra were recorded on a Hitachi 200-20 spectrophotometer using spectrophotometric grade chloroform (Baker). The N2 adsorption/desorption analysis (BET) was performed at −196 °C using an automated gas adsorption analyzer (Tristar 3000, Micromeritics). XRD analysis was performed with an X-ray diffractometer (PANalytical X’Pert-Pro) using a Cu-Kα monochromatic radiation source and an Ni filter. Transmission electron microscopy (TEM) was performed with a Jeol JEM-2100UHR, operated at 200 kV.

Preparation of nanocrystalline MgO

Nanocrystalline MgO was prepared by means of a procedure reported elsewhere [66]. In short, poly(vinyl alcohol) (PVA, MW 70,000) was dissolved in water at 90 °C under vigorous stirring to form a transparent solution. Mg(NO3)2·6H2O was dissolved in water containing PVA. The metal ion-to-PVA monomer unit molar ratio (M/PVA) was chosen as 1:3. Aqueous ammonia (25% w/w) was added dropwise at room temperature to the resulting viscous liquid mixture, with rapid stirring, to achieve careful pH adjustment to 10.5. After precipitation, the slurry was stirred for another 30 min and then heated under reflux at 80 °C for 20 h under continuous stirring. The mixture was cooled to room temperature, filtered, and washed with hot deionized water for effective removal of the poly(vinyl alcohol). The final product was dried at 80 °C for 24 h and calcined at 700 °C.

Preparation of 2,4,5-trisubstituted imidazoles by use of nanocrystalline magnesium oxide

A mixture of 1,2-diketone (1 mmol), 0.15 g ammonium acetate (2 mmol), aldehyde (1 mmol), and 0.008 g nanocrystalline magnesium oxide (5 mol%) was stirred at 100 °C for 30 min. The progress of the reaction was monitored by TLC (petroleum ether–ethyl acetate 7:3). After cooling, the reaction mixture was dissolved in acetone and filtered. The filtrate was concentrated on a rotary evaporator under reduced pressure and the solid product obtained was washed with water and recrystallized from acetone–water 9:1 (v/v). Pure products were obtained in excellent yields, as summarized in Table 3. Most of the products are known and were identified by comparison of their physical and spectral data with those of authentic samples.

2-(3-Methoxyphenyl)-4,5-diphenyl-1H-imidazole (4f, C22H18N2O)

Colorless powder; yield 93%; m.p.: 259–262 °C; 1H NMR (400 MHz, DMSO-d 6): δ = 12.70 (s, 1H, NH), 6.80–7.80 (m, 14H, Ar–H), 3.80 (s, 3H, OMe) ppm; 13C NMR (100 MHz, DMSO-d 6): δ = 160.00, 145.86, 137.63, 135.60, 132.15, 130.27, 129.20, 128.86, 127.70, 118.13, 114.70, 110.70, 55.70 ppm; IR (KBr): \( \bar{\nu } \) = 3,432 (N–H), 1,591 (C=C), 1,513 (C=N) cm−1; UV (CDCl3): λ max = 314, 240 nm.

2-(2-Naphthyl)-4,5-diphenyl-1H-imidazole (4l, C25H18N2)

Colorless powder; yield 94%; m.p.: 273–276 °C; 1H NMR (400 MHz, DMSO-d 6): δ = 12.80 (s, 1H, NH), 8.61 (s, 1H, Ar–H), 8.25 (d, 1H, 3 J = 8.0 Hz, Ar–H), 7.92–8.02 (m, 3H, Ar–H), 7.53–7.61 (m, 6H, Ar–H), 7.46 (t, 2H, 3 J = 7.9 Hz, Ar–H), 7.39 (t, 1H, 3 J = 7.6 Hz, Ar–H), 7.32 (t, 2H, 3 J = 7.9 Hz, Ar–H), 7.24 (t, 1H, 3 J = 7.6 Hz, Ar–H) ppm; 13C NMR (100 MHz, DMSO-d 6): δ = 146.00, 137.90, 135.60, 133.50, 132.20, 131.50, 129.10, 129.00, 128.90, 128.70, 128.60, 128.30, 128.20, 127.60, 127.10, 127.00, 126.80, 124.10, 123.90 ppm; IR (KBr): \( \bar{\nu } \) = 3,429 (N–H), 1,601 (C=C), 1,510 (C=N) cm−1; UV (CDCl3): λ max = 330, 288 nm.

2-(3,5-Dimethoxyphenyl)-4,5-diphenyl-1H-imidazole (4q, C23H20N2O2)

Colorless powder; yield 94%; m.p.: 254–256 °C; 1H NMR (400 MHz, DMSO-d 6): δ = 12.70 (s, 1H, NH), 7.30–7.54 (m, 9H, Ar–H), 7.28 (d, 2H, 4 J = 2.0 Hz, Ar–H), 7.22 (t, 1H, 3 J = 7.8 Hz, Ar–H), 6.52 (t, 1H, 4 J = 2.0 Hz, Ar–H), 3.81 (s, 6H, OMe) ppm; 13C NMR (100 MHz, DMSO-d 6): δ = 161.21, 145.76, 137.51, 135.56, 132.59, 131.52, 129.14, 128.98, 128.65, 128.30, 127.56, 127.01, 103.54, 101.10, 55.83 ppm; IR (KBr): \( \bar{\nu } \) = 3,429 (N–H), 1,601 (C=C), 1,533 (C=N) cm−1; UV (CDCl3): λ max = 310, 245 nm.

5-(4,5-Diphenyl-1H-imidazol-2-yl)-2-methoxyphenol (4r, C22H18N2O2)

Ash-gray powder; yield 96%; m.p.: 215–216 °C; 1H NMR (400 MHz, DMSO-d 6): δ = 12.50 (s, 1H, NH), 9.11 (s, 1H, OH), 7.46–7.55 (m, 6H, Ar–H), 7.42 (t, 2H, 3 J = 7.6 Hz, Ar–H), 7.34 (t, 1H, 3 J = 7.2 Hz, Ar–H), 7.28 (t, 2H, 3 J = 7.6 Hz, Ar–H), 7.20 (t, 1H, 3 J = 7.2 Hz, Ar–H), 7.00 (d, 1H, 3 J = 8.4 Hz, Ar–H), 3.81 (s, 3H, OMe) ppm; 13C NMR (100 MHz, DMSO-d 6): δ = 148.58, 146.99, 146.31, 137.17, 135.86, 131.71, 129.05, 128.82, 128.62, 128.02, 127.51, 126.84, 123.94, 117.01, 113.31, 112.55, 56.09 ppm; IR (KBr): \( \bar{\nu } \) = 3,409 (N–H), 3,260 (O–H), 1,596 (C=C), 1,510 (C=N) cm−1; UV (CDCl3): λ max = 310, 244 nm.

2-(3-Methoxyphenyl)-4,5-bis(4-fluorophenyl)-1H-imidazole (4s, C22H16F2N2O)

Off-white powder; yield 94%; m.p.: 251–253 °C; 1H NMR (400 MHz, DMSO-d 6): δ = 12.71 (s, 1H, NH), 7.65 (d, 1H, 3 J = 7.6 Hz, Ar–H), 7.62 (s, 1H, Ar–H), 7.50–7.55 (m, 4H, Ar–H), 7.38 (t, 1H, 3 J = 8.0 Hz, Ar–H), 7.30 (t, 2H, 3 J = 8.8 Hz, Ar–H), 7.15 (t, 2H, 3 J = 8.8 Hz, Ar–H), 6.94 (d, 1H, 3 J = 8.0 Hz, Ar–H), 3.82 (s, 3H, OMe) ppm; 13C NMR (100 MHz, DMSO-d 6): δ = 162.20 (C–F, d, 1 J = 243.0 Hz), 161.57 (C–F, d, 1 J = 243.0 Hz), 160.05, 145.90, 136.74, 132.04, 131.94, 131.09 (d, 3 J = 7.0 Hz), 130.26, 129.37 (d, 3 J = 7.0 Hz), 127.83, 127.58, 118.11, 116.15 (d, 2 J = 21.0 Hz), 115.56 (d, 2 J = 22.0 Hz), 114.68, 110.74, 55.61 ppm; IR (KBr): \( \bar{\nu } \) = 3,441 (N–H), 1,600 (C=C), 1,520 (C=N) cm−1; UV (CDCl3): λ max = 315, 245 nm.

2-(3-Bromophenyl)-4,5-bis(4-fluorophenyl)-1H-imidazole (4t, C21H13BrF2N2)

Colorless powder; yield 95%; m.p.: 287–290 °C; 1H NMR (400 MHz, DMSO-d 6): δ = 12.70 (s, 1H, NH), 8.26 (s, 1H, Ar–H), 8.06 (d, 1H, 3 J = 8.0 Hz, Ar–H), 7.52–7.55 (m, 5H, Ar–H), 7.44 (t, 1H, 3 J = 8.0 Hz, Ar–H), 7.30 (t, 2H, 3 J = 8.4 Hz, Ar–H), 7.15 (t, 2H, 3 J = 8.4 Hz, Ar–H) ppm; 13C NMR (100 MHz, DMSO-d 6): δ = 162.25 (C–F, d, 1 J = 244.0 Hz), 161.62 (C–F, d, 1 J = 242.0 Hz), 144.34, 137.01, 132.85, 131.69 (d, 4 J = 2.0 Hz), 131.37 (d, 3 J = 8.0 Hz), 131.09, 131.01, 129.42 (d, 3 J = 8.0 Hz), 128.09, 127.98, 127.56 (d, 4 J = 2.0 Hz), 124.50, 122.62, 116.22 (d, 2 J = 22.0 Hz), 115.64 (d, 2 J = 21.0 Hz) ppm; IR (KBr): \( \bar{\nu } \) = 3,437 (N–H), 1,604 (C=C), 1,516 (C=N) cm−1; UV (CDCl3): λ max = 310, 245 nm.

2-(3,4-Dimethoxyphenyl)-4,5-bis(4-fluorophenyl)-1H-imidazole (4u, C23H18F2N2O2)

Off-white powder; yield 96%; m.p.: 207–208 °C; 1H NMR (400 MHz, DMSO-d 6): δ = 12.50 (s, 1H, NH), 7.48–7.63 (m, 6H, Ar–H), 7.30 (t, 2H, 3 J = 8.0 Hz, Ar–H), 7.14 (t, 2H, 3 J = 8.0 Hz, Ar–H), 7.05 (d, 1H, 3 J = 8.0 Hz, Ar–H), 3.80 (s, 3H, OMe), 3.83 (s, 3H, OMe) ppm; 13C NMR (100 MHz, DMSO-d 6): δ = 162.11 (C–F, d, 1 J = 243.0 Hz), 161.47 (C–F, d, 1 J = 241.0 Hz), 149.59, 149.27, 146.17, 136.36, 132.04, 131.06 (d, 3 J = 8.0 Hz), 129.30 (d, 3 J = 8.0 Hz), 128.02, 127.00, 123.55, 118.38, 116.18 (d, 2 J = 21.0 Hz), 115.56 (d, 2 J = 21.0 Hz), 112.27, 109.26, 56.03, 55.98 ppm; IR (KBr): \( \bar{\nu } \) = 3,424 (N–H), 1,599 (C=C), 1,524 (C=N) cm−1; UV (CDCl3): λ max = 310, 243 nm.

5-[4,5-Bis(4-fluorophenyl)-1H-imidazol-2-yl]-2-methoxyphenol (4v, C22H16F2N2O2)

Silver powder; yield 97%; m.p.: 218–220 °C; 1H NMR (400 MHz, DMSO-d 6): δ = 12.50 (s, 1H, NH), 9.13 (s, 1H, OH), 7.40–7.60 (m, 6H, Ar–H), 7.27 (t, 2H, 3 J = 8.8 Hz, Ar–H), 7.13 (t, 2H, 3 J = 8.8 Hz, Ar–H), 7.00 (d, 1H, 3 J = 8.4 Hz, Ar–H), 3.81 (s, 3H, OMe) ppm; 13C NMR (100 MHz, DMSO-d 6): δ = 162.06 (C–F, d, 1 J = 244.0 Hz), 161.47 (C–F, d, 1 J = 242.0 Hz), 148.66, 147.02, 146.34, 136.32, 132.17, 130.96 (d, 3 J = 8.0 Hz), 129.31 (d, 3 J = 8.0 Hz), 128.00, 126.91, 123.84, 117.05, 116.08 (d, 2 J = 21.0 Hz), 115.53 (d, 2 J = 21.0 Hz), 113.32, 112.56, 56.08 ppm; IR (KBr): \( \bar{\nu } \) = 3,437 (N–H), 3,298 (O–H), 1,594 (C=C), 1,521 (C=N) cm−1; UV (CDCl3): λ max = 310, 242 nm.