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

: A highly e ﬃ cient 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% HfCl 4 on activated carbon (HfCl 4 / C) as the catalyst. The newly reported HfCl 4 / 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.

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 BF 3 ·Et 2 O [9]) and oxidative reagents (e.g., DDQ [10], MnO 2 [11], I 2 [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 ZrOCl 2 ·8H 2 O, ZrCl 4 [14], and Cp 2 ZrCl 2 [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, HfCl 4 , 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 ZrOCl 2 ·8H 2 O, ZrCl 4 , and HfCl 4 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 HfCl 4 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 HfCl 4 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 HfCl 4 on activated carbon (HfCl 4 /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 HfCl 4 adsorbed on activated carbon could be partially released in refluxing ethanol and efficiently redeposited on activated carbon upon cooling to ambient temperature.

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 showed that the control reaction without catalyst was sluggish (96 h) and afforded product 3{1,1} in 81% yield. TiCl 4 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 ZrOCl 2 ·8H 2 O-catalyzed benzimidazole synthesis under solvent-free conditions [26]. Interestingly, HfCl 4 -catalyzed reaction was remarkably faster (12 h) and higher-yielding (96%). It is noteworthy that when the amount of HfCl 4 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 HfCl 4 was decreased below 3 mol%. 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.

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 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, 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 As expected, increasing temperature significantly accelerated the reaction rate ( Table 2, entries 1-4). When the reaction with 5 mol% HfCl 4 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 HfCl 4 -catalyzed reactions proceeded with comparable yields in DMF, CH 3 CN, 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 HfCl 4 ( 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 HfCl 4 . In contrast, the formation of the colored intermediates was much slower without a catalyst. These results indicated that HfCl 4 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 HfCl 4 onto a series of activated solid supports (5% w/w). Under the optimized reaction conditions, 10 mol% of the supported HfCl 4 was applied as the catalyst. The results listed in Table 3 showed that the catalytic effects of HfCl 4 /C, HfCl 4 /Al 2 O 3 , and HfCl 4 /K-10 montmorillonite were similar, where the HfCl 4 /SiO 2 -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, HfCl 4 /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 HfCl 4 /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.  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 To determine how much HfCl 4 was released into ethanol as homogeneous catalyst at 80 • C, HfCl 4 /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) showed that, in the first use, 30% of HfCl 4 desorbed from the surface of activated carbon and was released into the reaction solution. It took 5 times before the HfCl 4 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 HfCl 4 catalyst in ethanol upon cooling and heating. As depicted in the scanning electron microscope (SEM) images of HfCl 4 /C samples, most HfCl 4 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 HfCl 4 /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. 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. Since HfCl 4 was tightly adsorbed on activated carbon at room temperature, we were interested to clarify whether HfCl 4 /C could catalyze the formation of benzimidazole 3{1,1} in a heterogeneous manner. The experimental result showed that HfCl 4 /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, HfCl 4 /C catalyzed the formation of benzimidazole 3{1,1} in a combined homogenous/heterogeneous manner.
Other than the high potency and recyclability of HfCl 4 /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, HfCl 4 /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 HfCl 4 /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, HfCl 4 /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).
Catalysts 2020, 10, x FOR PEER REVIEW 5 of 11 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).

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 F 254 (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 CDCl 3 . 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 ddH 2 O over 15 min; UV detection at 270 nm). The morphology and chemical composition of HfCl 4 /C samples were investigated by a Zeiss Sigma field emission scanning electron microscope (Zeiss microscopy, Jena, Germany).

General Procedure for Preparation of HfCl 4 /C Catalyst
Before impregnation of HfCl 4 , commercial activated carbon (200 mesh) was pretreated with 30% HNO 3 at 90 • C for 4 h, washed ddH 2 O until pH reached 7, and dried at 120 • C for 12 h. HfCl 4 (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 HfCl 4 /C.

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 HfCl 4 /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, HfCl 4 /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.

Conclusions
In summary, HfCl 4 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 HfCl 4 with respect to both catalytic activity and recyclability. The SEM images and EDS spectra of HfCl 4 /C samples along with the desorption experiments revealed that HfCl 4 was tightly adsorpted on activated carbon at ambient temperature and partially desorpted in refluxing ethanol. Based on the fact that HfCl 4 /C could catalyze the formation of benzimidazoles at ambient temperature, the catalytic effect of HfCl 4 /C under refluxing conditions should involve both homogeneous and heterogeneous mechanisms. Further application of HfCl 4 /C in parallel synthesis of 1,2-disubstituted benzimidazoles well exemplified its advantages in terms of catalytic efficiency and facile removal from reaction.