Activated Carbon Supported Hafnium(IV) Chloride as an Efficient, Recyclable, and Facile Removable Catalyst for Expeditious Parallel Synthesis of Benzimidazoles

Abstract

A highly efficient method for parallel synthesis of a diversity of 1,2-disubstituted benzimidazoles from N-substituted phenylenediamines and aldehydes has been developed by using 10 mol% HfCl₄ on activated carbon (HfCl₄/C) as the catalyst. The newly reported HfCl₄/C catalyst not only mediated fast and clean formation of benzimidazoles but also could be easily removed from the reaction solution and reused up to eight times. Scanning electron microscope (SEM) and thermal desorption studies showed that activated carbon could reversibly adsorb and release Hf(IV) in ethanol upon cooling and heating, thereby serving as a thermal-controlled solid support.

1. Introduction

As one of the most important heterocyclic scaffolds, 1,2-disubstituted benzimidazole has been extensively employed in the development of novel pharmaceutical agents and functional materials [1,2,3]. In contemporary drug discovery, a huge number of benzimidazole derivatives have been synthesized and utilized as anti-infective, anti-inflammatory, antihypertensive, antitumor, antiallergic, antidiabetic, analgesic, and proton pump inhibitory agents [4,5,6,7].

In our previous research, we found that the synthesis of 2-aminovinyl benzimidazoles represented a huge challenge to the commonly known synthetic methods for benzimidazoles. To promote the condensation of 1,2-phenylenediamines with N-arylated 3-aminoacroleins, both acidic catalysts (e.g., PPA [8] and BF₃∙Et₂O [9]) and oxidative reagents (e.g., DDQ [10], MnO₂ [11], I₂ [12], and Oxone [13]) were tested. However, none of these methods afforded the desired 2-aminovinyl benzimidazoles, because the conjugation of electron-donating aniline significantly lowered electropositivity of the carbonyl in 3-aminoacroleins. Surprisingly, we found that the non-toxic and inexpensive Group IVB transition metal salts, such as ZrOCl₂∙8H₂O, ZrCl₄ [14], and Cp₂ZrCl₂ [15], exhibited dramatic catalytic effects on the formation of 2-aminovinyl benzimidazoles due to their strong activation capability on carbonyl group. Yin and Gao also reported that the metallocenes of Ti(IV) [16] and Zr(IV) [17] were highly efficient Lewis acids for other carbonyl-transformation reactions. In recent years, HfCl₄, another closely related Group IVB transition metal salt, was revealed to possess even superior activities in many metal Lewis acid-catalyzed reactions [18,19,20], especially those involving carbonyl activation [21,22,23,24]. In addition, it is noteworthy that ZrOCl₂∙8H₂O, ZrCl₄, and HfCl₄ showed high catalytic activity in the synthesis of 2-substituted benzimidazoles from o-phenylenediamines and orthoesters [25]. As equivalents of carboxylic acids, orthoesters are distinct from aldehyde. The condensation of o-phenylenediamines with orthoesters does not require an extra oxidation step to form benzimidazoles as that of o-phenylenediamines with aldehydes. Though aldehydes are more favorable starting materials compared to orthoesters due to their much higher commercial availability, the application of HfCl₄ as a catalyst for the reaction of o-phenylenediamines and aldehydes has never been explored before.

Inspired by these precedent reports, we extended our research to utilize HfCl₄ as a strong carbonyl-activating catalyst to promote the condensation of N-substituted o-phenylenediamines and aldehydes for expeditious synthesis of 1,2-disubstituted benzimidazoles. In this paper, we report the first utilization of HfCl₄ on activated carbon (HfCl₄/C) as a novel, efficient, recyclable, and easily removable catalyst for parallel synthesis of a diversity of 1,2-disubstituted benzimidazoles. The scanning electron microscope (SEM) and thermal desorption data elucidated that HfCl₄ adsorbed on activated carbon could be partially released in refluxing ethanol and efficiently redeposited on activated carbon upon cooling to ambient temperature.

2. Results and Discussion

In the preliminary experiments, N-phenyl-o-phenylenediamine (1{1}) and benzaldehyde (2{1}) in a 1:1 ratio were reacted in the presence or absence of 10 mol% Group IVB metal catalysts in ethanol at room temperature without inert gas protection. The data listed in

Table 1. The effect of catalyst on the synthesis of benzimidazole 3{1,1}.

Entry	Catalyst	Reaction Time (h)	Isolated Yield of 3{1,1} (%)
1	No	120	82
2	TiCl4	20	67
3	ZrOCl2·8H2O	20	89
4	ZrCp2Cl2	20	92
5	ZrCl4	16	90
6	HfCl4	12	96

showed that the control reaction without catalyst was sluggish (96 h) and afforded product 3{1,1} in 81% yield. TiCl₄ shortened the reaction time to 20 h, but the yield of 3{1,1} was low due to the formation of polar byproducts. All Zr(IV)-catalyzed reactions went to completion in 16–20 h with 89%–92% yields of 3{1,1}. This result was in accordance with a previous report on ZrOCl₂∙8H₂O-catalyzed benzimidazole synthesis under solvent-free conditions [26]. Interestingly, HfCl₄-catalyzed reaction was remarkably faster (12 h) and higher-yielding (96%). It is noteworthy that when the amount of HfCl₄ was reduced to 5 mol%, the reaction time was prolonged to 16 h, but the product yield was not affected. Further experiments showed that the catalytic effect was drastically diminished when the amount of HfCl₄ was decreased below 3 mol%.

As expected, increasing temperature significantly accelerated the reaction rate (

Table 2. The effects of temperature and solvent on the synthesis of 3{1,1} with 5 mol% HfCl₄.

Entry	Temperature (°C)	Solvent	Reaction Time (h)	Isolated Yield of 3{1,1} (%)
1	20	EtOH	16	96
2	40	EtOH	12	97
3	60	EtOH	4	97
4	80	EtOH	1	97
5	80	DMF	1	88
6	80	CH3CN	1.5	92
7	80	DCE	24	90
8	70	THF	6	64

, entries 1–4). When the reaction with 5 mol% HfCl₄ was performed in refluxing ethanol, the reaction time was shortened to only 1 h without affecting the yield of 3{1,1}. The solvent effect was also investigated (Table 2, entries 5–8). The HfCl₄-catalyzed reactions proceeded with comparable yields in DMF, CH₃CN, and dichloroethane (DCE) except that the reaction in DCE was much slower. The reaction in THF generated a significant amount of polar byproducts and required 6 h to complete. It was interesting to observe that the reaction solution immediately turned into orange color upon addition of HfCl₄ (Table 2, entry 4). Meanwhile, TLC showed that most of 1{1} and 2{1} starting materials disappeared quickly and were converted into the corresponding colored imine and benzimidazoline intermediates in the presence of HfCl₄. In contrast, the formation of the colored intermediates was much slower without a catalyst. These results indicated that HfCl₄ promoted the formation of both imine and benzimidazoline intermediates, which is similar to the catalytic mechanism of Hf(IV) on the formation of fluorinated benzimidazolines elucidated by NMR tracing data [27]. Subsequently, aerial oxidation of the benzimidazoline intermediate smoothly afforded the desired benzimidazole 3{1,1} as described in many precedent reports [28,29,30].

To test the possibility to recycle the catalyst, we loaded the HfCl₄ onto a series of activated solid supports (5% w/w). Under the optimized reaction conditions, 10 mol% of the supported HfCl₄ was applied as the catalyst. The results listed in

Table 3. The effects of supported HfCl₄ catalysts (10 mol%, 5% w/w) on the synthesis of 3{1,1}.

Entry	Solid Support	Reaction Time 1st/2nd (h)	Isolated Yield of 3{1,1} 1st/2nd (%)
1	SiO2	2/4	92/78
2	activated carbon	1/1	96/96
3	Al2O3	1/4	93/75
4	K-10 montmorillonite	1/4	94/79

showed that the catalytic effects of HfCl₄/C, HfCl₄/Al₂O₃, and HfCl₄/K-10 montmorillonite were similar, where the HfCl₄/SiO₂-catalyzed reaction required a longer reaction time (2 h). However, these supported catalysts exhibited huge differences upon reuse. Compared with the other three supported catalysts whose potencies remarkably decreased in the 2nd round, HfCl₄/C showed consistent catalytic activity in terms of both yield and reaction rate for 4 rounds. As shown in Figure 1, the yields of 3{1,1} with recycled HfCl₄/C catalyst could be maintained (over 95%) up to 8 rounds. However, the reaction time was gradually prolonged from 1 to 2 h in the 5th to 8th rounds.

To determine how much HfCl₄ was released into ethanol as homogeneous catalyst at 80 °C, HfCl₄/C (5% w/w, 500 mg) was added to ethanol (16 mL) and refluxed for 30 min. The solid was filtered while the solution was still at 80 °C. The weight loss data (

Table 4. The ethanol desorption experiments of HfCl₄/C.

Method	Weight Loss (mg)
	1st	2nd	3rd	4th	5th	6th
A a	8	7	5	3	1	0
B b	0	0	0	0	0	1

^a Reflux/hot filtration. ^b Reflux/cooling/cold filtration.

) showed that, in the first use, 30% of HfCl₄ desorbed from the surface of activated carbon and was released into the reaction solution. It took 5 times before the HfCl₄ was completely washed off. If ethanol was cooled to room temperature before filtration, mimicking the reaction workup procedure, the weight loss was almost negligible after 5 rounds. These results indicated that activated carbon could function as an efficient thermal-controlled sponge that enabled reversible adsorption and release of HfCl₄ catalyst in ethanol upon cooling and heating.

As depicted in the scanning electron microscope (SEM) images of HfCl₄/C samples, most HfCl₄ initially loaded onto activated carbon appeared as small crystalline-like solids (Figure 2A). After 5 rounds of hot filtration, the surface of the solid support was as clean as that of pure activated carbon. In contrast, the HfCl₄/C sample, which was filtered after cooling for 5 times still adsorbed Hf(IV) salt as disordered and amorphous solids (Figure 2B). These results were in good accordance with the thermal desorption experiments mentioned above. Meanwhile, the energy dispersive spectrum (EDS) analysis of the samples confirmed that the solids on the surface of activated carbon were hafnium salts (Figure 2). It is worth noting that the Cl element almost disappeared after 5 rounds of refluxing/cooling/filtration, indicating that chloride was gradually exchanged to ethoxide upon repeated use. However, the recyclability of the catalyst suggested that the counter ion had relatively less important effect on the catalytic activity.

Since HfCl₄ was tightly adsorbed on activated carbon at room temperature, we were interested to clarify whether HfCl₄/C could catalyze the formation of benzimidazole 3{1,1} in a heterogeneous manner. The experimental result showed that HfCl₄/C (10 mol%) indeed promoted the formation of 3{1,1} at room temperature. However, as expected, the heterogeneous catalysis (89%, 24 h) was less efficient than the homogeneous catalysis (Table 1, entry 6). These results suggested that, under the refluxing conditions, HfCl₄/C catalyzed the formation of benzimidazole 3{1,1} in a combined homogenous/heterogeneous manner.

Other than the high potency and recyclability of HfCl₄/C, another huge advantage of this novel catalyst was that it could be easily removed from the reaction solution without leaving residual metal Lewis acid in the crude product. Therefore, HfCl₄/C may be applied as an ideal catalyst for expeditious parallel synthesis of benzimidazole derivatives. To prove this point, a diversity of N-substituted o-phenylenediamines (1{1–9}) and aldehydes (2{1–10}) were employed as substrates and total 28 benzimidazoles (3{1–9,1–10}) were prepared on a parallel synthesizer with HfCl₄/C as the catalyst in one single batch. The reactions were heated in tightly capped vials at 80 °C for 1 h. After the reactions were cooled to ambient temperature, HfCl₄/C was removed by centrifuge, and the supernatants were concentrated to afford the crude products in 97%–101% yields. The purity of crude benzimidazoles (3) was determined to be 91.9%–99.0% by analytical HPLC. Further flash chromatography afforded 28 benzimidazoles (3) in excellent isolated yields ranging from 87% to 96% (Figure 3).

3. Materials and Methods

3.1. General Methods

Chemical reagents (Aladdin, Shanghai, China) were obtained from a commercial supplier. Supported catalysts were prepared according to the methods described below. All reactions were performed in commercial analytical reagent (AR) grade solvents (Zhiyuan Chemicals, Tianjin, China) and monitored by thin layer chromatography on plates coated with 0.25 mm silica gel 60 F₂₅₄ (Qingdao Haiyang Chemicals, Qingdao, China). TLC plates were visualized by UV irradiation (254 nm). The parallel synthesis was performed in 28 tightly capped reaction vials (10 mL) on an aluminum reaction heating block with 48 wells. Melting points were determined with a Thomas-Hoover melting point apparatus and uncorrected (Thomas Scientific, Swedesboro, NJ, USA). NMR spectra were obtained with a Bruker AV-400 instrument (Bruker BioSpin, Faellanden, Switzerland) with chemical shifts reported in parts per million (ppm, δ) and referenced to CDCl₃. The NMR spectra of new compounds were provided in Supplementary Materials (Figures S1–S38). IR spectra were recorded on a Bruker Vertex-70 spectrometer (Bruker Optics, Billerica, MA, USA). High-resolution mass spectra were reported as m/z and obtained with a Dalton micrOTOF-Q II spectrometer (Bruker Daltonics, Billerica, MA, USA). HPLC traces were recorded on an analytical Agilent 1260 Infinity II LC instrument (Angilent Technologies, Palo Alto, CA, USA) equipped with a C18 analytical Angilent Zorbax column (4.6 × 150 mm, 5 μm; flow rate = 1.0 mL/min; 70% MeOH in ddH₂O over 15 min; UV detection at 270 nm). The morphology and chemical composition of HfCl₄/C samples were investigated by a Zeiss Sigma field emission scanning electron microscope (Zeiss microscopy, Jena, Germany).

3.2. General Procedure for Preparation of HfCl₄/C Catalyst

Before impregnation of HfCl₄, commercial activated carbon (200 mesh) was pretreated with 30% HNO₃ at 90 °C for 4 h, washed ddH₂O until pH reached 7, and dried at 120 °C for 12 h. HfCl₄ (0.5 g, 5% w/w) was dissolved in absolute ethanol (50 mL). Then, pretreated activated carbon (9.5 g) was added and sonicated for another 30 min at ambient temperature. Ethanol was then removed under reduced pressure to afford HfCl₄/C.

3.3. General Procedure for Preparation of Other Supported HfCl₄ Catalysts

Before impregnation of HfCl₄, commercial silica gel (300–400 mesh), aluminum oxide (200–300 mesh), and K-10 montmorillonite were heated in an oven at 150 °C for 24 h. HfCl₄ (0.5 g, 5% w/w) was dissolved in absolute ethanol (50 mL). Then, pretreated solid supports (9.5 g) was added and stirred for 30 min and sonicated for another 30 min at ambient temperature. Ethanol was then removed under reduced pressure to afford HfCl₄/SiO₂, HfCl₄/Al₂O₃, and HfCl₄/K-10 montmorillonite.

3.4. General Synthetic Procedure and Characterization of Benzimidazoles

To a solution of N-substituted o-phenylenediamines (0.15 mmol) and aldehyde (0.15 mmol) in ethanol (3 mL) was added HfCl₄/C (0.015 mmol, 5% w/w). The reaction was stirred at 80 °C for 1 h. After the reaction was cooled to ambient temperature, HfCl₄/C was removed by centrifuge and supernatant was concentrated under reduced pressure. Flash column chromatography on silica gel (petroleum ether:ethyl acetate = 4:1) afforded benzimidazole in pure form.

1,2-Diphenyl-5-methoxycarbonyl-1H-benzo[d]imidazole (3{2,1}): a white solid; mp 147–148 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.60 (s, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.61–7.47 (m, 5H), 7.38–7.20 (m, 6H), 3.95 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 167.5, 154.1, 142.6, 140.3, 136.5, 130.1, 129.9, 129.5, 129.0, 128.4, 127.3, 125.2, 124.9, 122.2, 110.2, 52.2 ppm; IR: v_max 3058, 2924, 2853, 1721, 1619, 1596, 1496, 1478, 1448, 1024, 982, 924, 892, 827, 804, 778 cm⁻¹; HRMS (ESI+): m/z calcd for C₂₁H₁₇N₂O₂ [M+H]⁺ 329.1285; found 329.1280.

2-(4-Fluorophenyl)-1-phenyl-5-methoxycarbonyl-1H-benzo[d]imidazole (3{2,4}): a white solid; mp 156–157 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.57 (s, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.59–7.47 (m, 5H), 7.29 (d, J = 7.2 Hz, 2H), 7.22 (d, J = 8.2 Hz, 1H), 7.04–6.95 (m, 2H), 3.95 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 167.6, 165.0, 162.5, 153.3, 142.8, 140.5, 136.6, 131.7, 131.6, 130.3, 129.3, 127.9, 125.9, 125.5, 125.2, 122.4, 115.9, 115.7, 110.3, 52.3 ppm; IR: v_max 3062, 2921, 2852, 1709, 1618, 1596, 1523, 1497, 1473, 1437, 1045, 987, 897, 839, 802, 765 cm⁻¹; HRMS (ESI+): m/z calcd for C₂₁H₁₆FN₂O₂ [M+H]⁺ 347.1190; found 347.1187.

2-(Furan-2-yl)-1-phenyl-5-methoxycarbonyl-1H-benzo[d]imidazole (3{2,6}): a light yellow solid; mp 130–131 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.53 (s, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.65–7.56 (m, 3H), 7.52–7.45 (m, 1H), 7.43–7.36 (m, 2H), 7.07 (d, J = 8.6 Hz, 1H), 6.39–6.31 (m, 1H), 6.16–6.11 (m, 1H), 3.92 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 167.5, 145.9, 144.7, 144.1, 142.7, 140.3, 136.0, 130.2, 129.9, 127.9, 125.4, 125.2, 122.2, 113.1, 111.7, 109.9, 52.2 ppm; IR: v_max 3054, 2948, 2825, 1596, 1514, 1481, 1467, 1458, 1043, 995, 976, 928, 785 cm^-1; HRMS (ESI+): m/z calcd for C₁₉H₁₅N₂O₃ [M+H]⁺ 319.1077; found 319.1082.

(E)-1-Phenyl-2-styryl-5-methoxycarbonyl-1H-benzo[d]imidazole (3{2,9}): a white solid; mp 195–196 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.54 (s, 1H), 8.02–7.91 (m, 2H), 7.69–7.55 (m, 3H), 7.51–7.41 (m, 4H), 7.40–7.28 (m, 3H), 7.19 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 15.6 Hz, 1H), 3.96 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 167.7, 152.8, 143.1, 139.9, 138.4, 136.0, 135.4, 130.3, 129.5, 129.4, 129.0, 127.7, 127.6, 125.6, 124.9, 121.9, 113.7, 109.9, 52.2 ppm; IR: v_max 3058, 2955, 2839, 1708, 1611, 1498, 1434, 1015, 797 cm⁻¹; HRMS (ESI+): m/z calcd for C₂₃H₁₉N₂O₂ [M+H]⁺ 355.1441; found 355.1440.

1,2-Diphenyl-5-(trifluoromethyl)-1H-benzo[d]imidazole (3{3,1}): a white solid; mp 145–146 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.06 (s, 1H), 7.53–7.36 (m, 6H), 7.32–7.14 (m, 6H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 154.5, 142.6, 139.3, 136.6, 130.2, 130.1, 129.6, 129.4, 129.2, 128.5, 127.4, 125.6, 123.6, 120.3, 117.7, 111.0 ppm; IR: v_max 3056, 2926, 2845, 1621, 1597, 1500, 1476, 1450, 1435, 1047, 1027, 978, 937, 891, 860, 823, 771 cm⁻¹; HRMS (ESI+): m/z calcd for C₂₀H₁₄F₃N₂ [M+H]⁺ 339.1104; found 339.1109.

2-Cyclohexyl-1-phenyl-5-(trifluoromethyl)-1H-benzo[d]imidazole (3{3,7}): a white solid; mp 93–94 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.06 (s, 1H), 7.65–7.54 (m, 3H), 7.41 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 6.8 Hz, 2H), 7.11 (d, J = 8.4 Hz, 1H), 2.77–2.65 (m, 1H), 1.96–1.62 (m, 6H), 1.38–1.11 (m, 4H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 161.5, 142.3, 138.6, 135.6, 130.3, 129.5, 127.6, 125.2, 119.5, 117.1, 110.5, 36.4, 32.0, 29.8, 26.2, 25.8 ppm; IR: v_max 3045, 2930, 2855, 1727, 1623, 1598, 1506, 1442, 1042, 926, 883, 809, 767 cm⁻¹; HRMS (ESI+): m/z calcd for C₂₀H₂₀F₃N₂ [M+H]⁺ 345.1573; found 345.1566.

2-Pentyl-1-phenyl-5-(trifluoromethyl)-1H-benzo[d]imidazole (3{3,8}): colorless oil; ¹H NMR (400 MHz, CDCl₃): δ 8.05 (s, 1H), 7.69–7.52 (m, 3H), 7.43 (d, J = 8.5, 1H), 7.35 (d, J = 8.1 Hz, 2H), 7.16 (d, J = 8.5 Hz, 1H), 2.78 (t, J = 7.6 Hz, 2H), 1.87–1.72 (m, 2H), 1.34–1.21 (m, 4H), 0.83 (t, J = 6.9 Hz, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 157.7, 142.3, 138.6, 135.6, 130.2, 129.5, 127.4, 119.6, 116.9. 110.4, 31.6, 27.8, 27.5, 22.4, 14.0 ppm; IR: v_max 3064, 2847, 2828, 1586, 1529, 1481, 1475, 1444, 1023, 998, 974, 929, 784 cm⁻¹; HRMS (ESI+): m/z calcd for C₁₉H₂₀F₃N₂ [M+H]⁺ 333.1573; found 333.1574.

1-Benzyl-2-(pyridin-2-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole (3{4,5}): a white solid; mp 160–161 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.75 (d, J = 7.2 Hz, 1H), 8.56 (d, J = 7.6 Hz, 1H), 8.26 (s, 1H), 7.96 (dd, J₁ = J₂ = 7.8 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.49–7.43 (m, 1H), 7.41–7.32 (m, 3H), 7.27 (d, J = 7.6 Hz, 2H), 6.32 (s, 2H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 151.8, 150.0, 148.8, 142.2, 138.7, 137.0, 136.9, 128.7, 127.6, 126.8, 125.8, 124.9, 124.3, 123.5, 120.3, 117.8, 111.2, 49.2 ppm; IR: v_max 3066, 2938, 2854, 1621, 1584, 1492, 1447, 1429, 1045, 994, 974, 930, 895, 840, 792 cm⁻¹; HRMS (ESI+): m/z calcd for C₂₀H₁₅F₃N₃ [M+H]⁺ 354.1213; found 354.1216.

(E)-1-Cyclohexyl-2-styryl-1H-benzo[d]imidazole (3{5,9}): colorless oil; ¹H NMR (400 MHz, CDCl₃): δ 8.01 (d, J = 15.7 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 7.6 Hz, 2H), 7.59 (d, J = 8.1 Hz, 1H), 7.51–7.33 (m, 3H), 7.32–7.16 (m, 3H), 4.51–4.39 (m, 1H), 2.42–2.23 (m, 2H), 2.04 (m, 4H), 1.88 (m, 1H), 1.65–1.22 (m, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 150.0, 143.2, 136.9, 135.7, 133.8, 128.4, 128.3, 126.7, 121.6, 121.5, 119.1, 113.6, 55.6, 31.2, 25.7, 24.9 ppm; IR: v_max 3064, 2937, 2828, 1589, 1532, 1488, 1474, 1456, 1023, 986, 973, 929, 782 cm⁻¹; HRMS (ESI+): m/z calcd for C₂₁H₂₃N₂ [M+H]⁺ 303.1856; found 303.1843.

2-(2-(4-Methoxyphenyl)-1-phenyl-1H-benzo[d]imidazol-5-yl)benzo[d]thiazole (3{6,3}): a light yellow solid; mp 209–210 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.43 (s, 1H), 8.06–7.97 (m, 2H), 7.82 (d, J = 7.8 Hz, 1H), 7.50–7.37 (m, 6H), 7.32–7.17 (m, 4H), 6.76 (d, J = 8.2 Hz, 2H), 3.72 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 168.9, 160.9, 154.4, 153.9, 143.3, 139.3, 136.8, 135.1, 131.0, 130.1, 129.0, 128.9, 127.5, 126.2, 124.9, 123.0, 122.7, 121.9, 121.6, 119.5, 113.9, 110.8, 55.3 ppm; IR: v_max 3062, 2931, 2839, 1719, 1606, 1530, 1501, 1479, 1432, 1020, 908, 835, 792 cm⁻¹; HRMS (ESI+): m/z calcd for C₂₇H₂₀N₃OS [M+H]⁺ 434.1322; found 434.1318.

2-(1-Phenyl-2-(pyridin-2-yl)-1H-benzo[d]imidazol-5-yl)benzo[d]thiazole (3{6,5}): a white solid; mp 128–129 °C. ¹H NMR (400 MHz, D₂O): δ 8.68 (s, 1H), 8.52 (d, J = 4.6 Hz, 1H), 8.28 (d, J = 8.6 Hz, 1H), 8.25–8.17 (m, 2H), 8.03 (d, J = 7.9 Hz, 1H), 7.88 (dd, J₁ = J₂ = 7.8 Hz, 1H), 7.66–7.56 (m, 4H), 7.53–7.42 (m, 4H), 7.40–7.34 (m, 1H) ppm; ¹³C NMR (100 MHz, D₂O): δ 168.7, 154.3, 152.1, 149.1, 149.0, 142.9, 139.6, 137.3, 136.5, 135.1, 129.4, 129.2, 128.4, 127.3, 126.2, 124.9, 124.7, 123.9, 123.4, 123.0, 121.5, 120.1, 111.4 ppm; IR: v_max 3058, 2931, 2856, 1726, 1588, 1496, 1442, 1018, 971, 871, 790 cm⁻¹; HRMS (ESI+): m/z calcd for C₂₅H₁₇N₄S [M+H]⁺ 405.1168; found 405.1154.

2-(2-(Furan-2-yl)-1-phenyl-1H-benzo[d]imidazol-5-yl)benzo[d]thiazole (3{6,6}): a light yellow solid; mp 143–144 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.51 (s, 1H), 8.14–8.03 (m, 2H), 7.89 (d, J = 7.9 Hz, 1H), 7.68–7.57 (m, 3H), 7.55–7.32 (m, 5H), 7.16 (d, J = 8.5 Hz, 1H), 6.41–6.34 (m, 1H), 6.16 (d, J = 3.4 Hz, 1H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 168.1, 153.7, 145.1, 144.0, 143.6, 142.8, 138.6, 134.6, 129.9, 129.6, 128.6, 127.3, 125.7, 124.4, 122.6, 122.4, 121.0, 119.1, 112.4, 111.1, 110.1 ppm; IR: v_max 3052, 2945, 2828, 1620, 1593, 1499, 1470, 1429, 1026, 973, 911, 861, 822, 762 cm⁻¹; HRMS (ESI+): m/z calcd for C₂₄H₁₆N₃OS [M+H]⁺ 394.1009; found 394.1003.

2-(2-Pentyl-1-phenyl-1H-benzo[d]imidazol-5-yl)benzo[d]thiazole (3{6,8}): a light yellow solid; mp 128–129 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.43 (s, 1H), 8.12–8.00 (m, 2H), 7.87 (d, J = 7.8 Hz, 1H), 7.63–7.50 (m, 3H), 7.45 (dd, J₁ = J₂ = 7.6 Hz, 1H), 7.41–7.29 (m, 3H), 7.16 (d, J = 8.4 Hz, 1H), 2.78 (t, J = 7.7 Hz, 2H), 1.88–1.72 (m, 2H), 1.37–1.21 (m, 4H), 0.84 (t, J = 6.8 Hz, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 168.5, 156.6, 153.9, 142.5, 138.1, 135.2, 134.6, 129.5, 128.7, 127.9, 126.8, 125.6, 124.3, 122.4, 121.7, 121.0, 118.6, 109.6, 31.0, 27.3, 26.8, 21.8, 13.4 ppm; IR: v_max 3051, 2934, 2850, 1731, 1619, 1596, 1512, 1498, 1465, 1457, 1441, 1006, 973, 916, 868, 816, 761 cm^-1; HRMS (ESI+): m/z calcd for C₂₅H₂₄N₃S [M+H]⁺ 398.1685; found 398.1694.

2-{2-[(E)-2-(4-Methoxyphenyl)ethenyl]-1-phenyl-1H-benzo[d]imidazol-5-yl}benzo[d]thiazole (3{6,10}): a light yellow solid; mp 212–213 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.47 (s, 1H), 8.15–8.06 (m, 2H), 7.98 (d, J = 15.9 Hz, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.72–7.58 (m, 3H), 7.55–7.34 (m, 6H), 7.27 (d, J = 6.7 Hz, 1H), 6.89 (d, J = 8.5 Hz, 2H), 6.71 (d, J = 15.9 Hz, 1H), 3.83 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 169.0, 160.8, 154.6, 153.1, 143.7, 138.8, 138.0, 135.6, 135.3, 130.2, 129.4, 129.3, 129.1, 128.9, 127.7, 126.3, 125.0,123.2, 122.7, 121.7, 119.2, 114.5, 111.4, 110.6, 55.5 ppm; IR: v_max 3061, 2937, 2838, 1604, 1529, 1500, 1431, 1020, 907, 889, 835, 792 cm⁻¹; HRMS (ESI+): m/z calcd for C₂₉H₂₂N₃OS [M+H]⁺ 460.1478; found 460.1472.

2-(1-(4-Methoxyphenyl)-2-phenyl-1H-benzo[d]imidazol-5-yl)benzo[d]thiazole (3{7,1}): a light yellow solid; mp 187–188 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.55 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H), 8.09 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.63 (d, J = 7.2 Hz, 2H), 7.54–7.45 (m, 1H), 7.44–7.24 (m, 7H), 7.05 (d, J = 8.8 Hz, 2H), 3.91 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 169.0, 159.9, 154.5, 154.2, 143.2, 139.8, 135.3, 129.9, 129.8, 129.6, 129.4, 129.1, 128.7, 128.5, 126.3, 125.0, 123.1, 123.0, 121.7, 119.8, 115.3, 111.1, 55.7 ppm; IR: v_max 3060, 2943, 2829, 1712, 1615, 1516, 1469, 1430, 1024, 914, 894, 842, 796 cm⁻¹; HRMS (ESI+): m/z calcd for C₂₇H₂₀N₃OS [M+H]⁺ 434.1322; found 434.1315.

2-(2-(Furan-2-yl)-1-(4-methoxyphenyl)-1H-benzo[d]imidazol-5-yl)benzo[d]thiazole (3{7,6}): a light yellow solid; mp 153–154 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.49 (s, 1H), 8.09 (d, J = 8.5 Hz, 1H), 8.06 (d, J = 8.1 Hz, 1H),7.90 (d, J = 7.8 Hz, 1H), 7.56–7.52 (m, 1H), 7.48 (dd, J₁ = J₂ = 7.8 Hz, 1H), 7.40–7.31 (m, 3H), 7.19–7.08 (m, 3H), 6.41–6.35 (m, 1H), 6.18 (d, J = 3.4 Hz, 1H), 3.93 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 168.7, 160.4, 154.3, 145.9, 144.5, 144.1, 143.0, 139.4, 135.1, 129.1, 129.0, 128.3, 126.1, 124.9, 123.1, 123.0, 121.5, 119.5, 115.2, 112.9, 111.6, 110.6, 55.6 ppm; IR: v_max 3057, 2956, 2843, 1598, 1534, 1498, 1475, 1456, 1027, 986, 974, 927, 784 cm⁻¹; HRMS (ESI+): m/z calcd for C₂₅H₁₈N₃O₂S [M+H]⁺ 424.1114; found 424.1118.

(E)-2-(1-(4-Methoxyphenyl)-2-styryl-1H-benzo[d]imidazol-5-yl)benzo[d]thiazole (3{7,9}): a light yellow solid; mp 211–212 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.46 (s, 1H), 8.11 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 8.1 Hz, 1H), 8.00 (d, J = 16.0 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.52–7.45 (m, 3H), 7.42–7.31 (m, 6H), 7.24 (d, J = 8.5 Hz, 1H), 7.14 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 16.0 Hz, 1H), 3.95 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 159.1, 153.3, 151.7, 142.3, 137.9, 136.8, 134.8, 134.1, 128.2, 128.0, 127.8, 127.7, 126.6, 126.3, 125.1, 123.8, 121.9, 121.5, 120.5, 118.1, 114.2, 112.5, 109.6, 54.6, 28.6 ppm; IR: v_max 3051, 2957, 2835, 1631, 1514, 1433, 1021, 969, 912, 799 cm⁻¹; HRMS (ESI+): m/z calcd for C₂₉H₂₂N₃OS [M+H]⁺ 460.1478; found 460.1473.

2-(1-Cyclohexyl-2-phenyl-1H-benzo[d]imidazol-5-yl)benzo[d]thiazole (3{8,1}): a light yellow solid; mp 181–182 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.47 (s, 1H), 8.14 (d, J = 12.2 Hz, 1H), 8.08 (d, J = 12.4 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.59–7.51 (m, 3H), 7.49–7.43 (m, 1H), 7.39–7.31 (m, 1H), 4.44–4.32 (m, 1H), 2.39–2.163 (m, 2H), 2.07–1.84 (m, 4H), 1.81–1.70 (m, 1H), 1.41–1.24 (m, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 168.9, 155.3, 154.3, 143.9,136.1, 135.1, 130.6, 129.9, 129.4, 128.7, 128.0, 126.2, 124.8, 122.9, 121.7, 121.5, 120.0, 113.0, 57.2, 31.5, 25.9, 25.2 ppm; IR: v_max 3052, 2948, 2848, 1622, 1518, 1465, 1443, 1020, 983, 931, 874, 924, 809 cm⁻¹; HRMS (ESI+): m/z calcd for C₂₆H₂₄N₃S [M+H]⁺ 410.1685; found 410.1679.

2-(2-Cyclohexyl-1-propyl-1H-benzo[d]imidazol-5-yl)benzo[d]thiazole (3{9,7}): a light yellow solid; mp 164–165 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.37 (s, 1H), 8.13 (d, J = 8.5 Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.46 (dd, J₁ = J₂ = 8.1, 1H), 7.42–7.30 (m, 2H), 4.10 (t, J = 7.3, 2H), 2.89–2.73 (m, 1H), 2.01–1.75 (m, 9H), 1.49–1.35 (m, 3H), 0.99 (t, J =7.5 Hz, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 169.4, 160.8, 154.5, 143.1, 137.1, 135.2, 127.9, 126.2, 124.8, 123.0, 121.6, 121.5, 119.5, 110.0, 45.3, 36.6, 32.2, 26.5, 25.9, 23.6, 11.5 ppm; IR: v_max 3061, 2925, 2846, 1723, 1615, 1502, 1472, 1431, 1015, 982, 918, 869, 819, 799 cm⁻¹; HRMS (ESI+): m/z calcd for C₂₃H₂₆N₃S [M+H]⁺ 376.1842; found 376.1837.

4. Conclusions

In summary, HfCl₄ was identified as a highly efficient transition metal Lewis acid catalyst for the synthesis of benzimidazoles from o-phenylenediamines and aldehydes. Our experimental results showed that activated carbon could serve as an excellent solid support for HfCl₄ with respect to both catalytic activity and recyclability. The SEM images and EDS spectra of HfCl₄/C samples along with the desorption experiments revealed that HfCl₄ was tightly adsorpted on activated carbon at ambient temperature and partially desorpted in refluxing ethanol. Based on the fact that HfCl₄/C could catalyze the formation of benzimidazoles at ambient temperature, the catalytic effect of HfCl₄/C under refluxing conditions should involve both homogeneous and heterogeneous mechanisms. Further application of HfCl₄/C in parallel synthesis of 1,2-disubstituted benzimidazoles well exemplified its advantages in terms of catalytic efficiency and facile removal from reaction.