Highly Efﬁcient and Ambient-Temperature Synthesis of Benzimidazoles via Co(III)/Co(II)-Mediated Redox Catalysis

: An efﬁcient method for ambient-temperature synthesis of a variety of 2-substituted and 1,2-disubstituted benzimidazoles from aldehyde and phenylenediamine substrates has been developed by utilizing Co(III)/Co(II)-mediated redox catalysis. The combination of only 1 mol% of Co(acac) 2 and stoichiometric amount of hydrogen peroxide provides a fast, green, and mild access to a diversity of under solvent-free conditions. diamine, 0.01 mmol of catalyst or no catalyst, and 1.2 mmol TBHP (5.5 M in decane) under solvent-free conditions. (Upon mixing of reactants, transparent and homogeneous mixtures were obtained).

Recently, our research group rationally constructed a novel phosphomolybdic acid (PMA)-based catalytic system for benzimidazole synthesis at ambient temperature [34]. Compared to the conventional oxidative methods, insertion of the Mo(VI)/Mo(V) redox cycle between reductive benzimidazoline and oxidative tert-butyl hydroperoxide (TBHP) dramatically accelerated the oxidative dehydrogenation process. Inspired by this method, we further explored the possibility to utilize small molecular multivalent transition metal complexes to catalyze oxidative dehydrogenation. In the paper, we report the development

Results and Discussion
In our initial attempt, MoO 2 (acac) 2 was selected as a multivalent transition metal catalyst to replace PMA Keggin cluster in our previously reported redox catalytic system. The reaction of 1.05 equiv of benzaldehyde, 1 equiv of N-phenyl-o-phenylenediamine, 1 mol% of MoO 2 (acac) 2 , and 1.2 equiv of TBHP (5.5 M in decane) in DMSO yielded the target benzimidazole 1 in 72% yield over 2.5 h without heating. The experimental result proved the possibility to replace large polyoxometalate (POM) cluster catalyst with a small molecular multivalent transition metal complex to catalyze the oxidative dehydrogenation of benzimidazoline. However, it should be noted that the yield and reaction rate of 1 were lower than those of the PMA-mediated redox catalysis due to incomplete oxidation of intermediate. The solvent effects showed that the reaction proceeded much faster in EtOH and CH 3 CN (20-40 min), but the yields of 1 were similar to those in DMSO, THF, and DME. Interestingly, solvent-free conditions significantly promoted the consumption of benzimidazoline intermediate and afforded 1 in 90% yield within 15 min (Table 1). It was observed that the originally yellow-colored reaction mixture of aldehyde and diamine turned green upon addition of MoO 2 (acac) 2 , indicating that Mo(VI) quickly oxidized benzimidazoline and was reduced to blue-colored Mo(V) species. Upon addition of TBHP, Mo(V) was almost instantly oxidized back to Mo(VI) species to complete the redox cycle. The fact that Mo catalyst existed as yellow-colored Mo(VI) state during the reaction process implied that the rate-determining step in the redox cycle was the oxidative dehydrogenation of benzimidazoline by Mo(VI). complexes to catalyze oxidative dehydrogenation. In the paper, we report the development of a Co(acac)2-based redox catalytic system for fast, green, and mild synthesis of a variety of substituted benzimidazoles.

Results and Discussion
In our initial attempt, MoO2(acac)2 was selected as a multivalent transition metal catalyst to replace PMA Keggin cluster in our previously reported redox catalytic system. The reaction of 1.05 equiv of benzaldehyde, 1 equiv of N-phenyl-o-phenylenediamine, 1 mol% of MoO2(acac)2, and 1.2 equiv of TBHP (5.5 M in decane) in DMSO yielded the target benzimidazole 1 in 72% yield over 2.5 h without heating. The experimental result proved the possibility to replace large polyoxometalate (POM) cluster catalyst with a small molecular multivalent transition metal complex to catalyze the oxidative dehydrogenation of benzimidazoline. However, it should be noted that the yield and reaction rate of 1 were lower than those of the PMA-mediated redox catalysis due to incomplete oxidation of intermediate. The solvent effects showed that the reaction proceeded much faster in EtOH and CH3CN (20-40 min), but the yields of 1 were similar to those in DMSO, THF, and DME. Interestingly, solvent-free conditions significantly promoted the consumption of benzimidazoline intermediate and afforded 1 in 90% yield within 15 min (Table 1). It was observed that the originally yellow-colored reaction mixture of aldehyde and diamine turned green upon addition of MoO2(acac)2, indicating that Mo(VI) quickly oxidized benzimidazoline and was reduced to blue-colored Mo(V) species. Upon addition of TBHP, Mo(V) was almost instantly oxidized back to Mo(VI) species to complete the redox cycle. The fact that Mo catalyst existed as yellow-colored Mo(VI) state during the reaction process implied that the rate-determining step in the redox cycle was the oxidative dehydrogenation of benzimidazoline by Mo(VI). On the basis of the solvent-free conditions, we tested the catalytic efficacy of acetylacetonates of different multivalent transition metals. The experimental results listed in Table 2 showed that Ni(acac)2 and Cu(acac)2 were less effective than MoO2(acac)2. VO(acac)2 showed similar effect to MoO2(acac)2, whereas Fe(acac)3, Ce(acac)3, Co(acac)2, and Co(acac)3 exhibited better reactivity than MoO2(acac)2. The Cu(acac)2-catalyzed reaction was ultrafast and finished in only 2 min. After TBHP was added, the reaction mixture turned black immediately and resulted in lowered yield. This is possibly because the complexation of Cu(II) with N-phenyl-o-phenylenediamine promoted its oxidation. Generally, On the basis of the solvent-free conditions, we tested the catalytic efficacy of acetylacetonates of different multivalent transition metals. The experimental results listed in Table 2 showed that Ni(acac) 2 and Cu(acac) 2 were less effective than MoO 2 (acac) 2 . VO(acac) 2 showed similar effect to MoO 2 (acac) 2 , whereas Fe(acac) 3 , Ce(acac) 3 , Co(acac) 2 , and Co(acac) 3 exhibited better reactivity than MoO 2 (acac) 2 . The Cu(acac) 2 -catalyzed reaction was ultrafast and finished in only 2 min. After TBHP was added, the reaction mixture turned black immediately and resulted in lowered yield. This is possibly because the complexation of Cu(II) with N-phenyl-o-phenylenediamine promoted its oxidation. Generally, the catalytic activities of the other metal acetylacetonates are in accordance with the oxidation potentials of their high-valent metal ions with the exception of Ni(acac) 2 . The fact that the catalytic activities of the acetylacetonates of Co(II) and Co(III) are identical implied that the oxidation of Co(II) by TBHP should be very fast. Furthermore, other cobalt(II) salts, including CoCl 2 and Co(OAc) 2 , were also tested for their catalytic activity. The experimental results indicated that Co(acac) 2 is the most efficient catalyst with a TOF value of no less than 1164 h −1 , while the real TOF value based on kinetic experiment was not established and could be even higher. Finally, a control experiment without multivalent transition metal catalyst confirmed their roles in promoting the formation of 1. the catalytic activities of the other metal acetylacetonates are in accordance with the oxidation potentials of their high-valent metal ions with the exception of Ni(acac)2. The fact that the catalytic activities of the acetylacetonates of Co(II) and Co(III) are identical implied that the oxidation of Co(II) by TBHP should be very fast. Furthermore, other cobalt(II) salts, including CoCl2 and Co(OAc)2, were also tested for their catalytic activity. The experimental results indicated that Co(acac)2 is the most efficient catalyst with a TOF value of no less than 1164 h −1 , while the real TOF value based on kinetic experiment was not established and could be even higher. Finally, a control experiment without multivalent transition metal catalyst confirmed their roles in promoting the formation of 1. In the following research, the effects of various peroxide oxidants were tested and listed in Table 3. The experimental results showed that more oxidative aqueous H2O2 resulted in a faster reaction rate. While the reactions with aqueous TBHP and urea hydrogen peroxide (UHP) proceeded slower, the reaction employing mCPBA finished in 5 min but yielded a significant amount of reddish polar byproducts on TLC plate. In addition, the experimental data also showed that 2 mol% Co(acac)2 resulted in more pronounced oxidation of N-phenyl-o-phenylenediamine and lowered yield of 1, whereas 0.5 mol% Co(acac)2 led to prolonged reaction time and decreased TOF. The control experiment showed that the oxidation of benzimidazoline was drastically impeded when H2O2 was replaced with atmospheric oxygen. In the following research, the effects of various peroxide oxidants were tested and listed in Table 3. The experimental results showed that more oxidative aqueous H 2 O 2 resulted in a faster reaction rate. While the reactions with aqueous TBHP and urea hydrogen peroxide (UHP) proceeded slower, the reaction employing mCPBA finished in 5 min but yielded a significant amount of reddish polar byproducts on TLC plate. In addition, the experimental data also showed that 2 mol% Co(acac) 2 resulted in more pronounced oxidation of Nphenyl-o-phenylenediamine and lowered yield of 1, whereas 0.5 mol% Co(acac) 2 led to prolonged reaction time and decreased TOF. The control experiment showed that the oxidation of benzimidazoline was drastically impeded when H 2 O 2 was replaced with atmospheric oxygen.
With optimized reaction conditions, we examined the substrate scope of the Co(III)/Co(II)mediated redox catalytic system. As shown in Table 4, this new method works well with both o-phenylenediamineand N-substituted o-phenylenediamines. It maintained high catalytic activity on various substituted benzaldehydes, heteroaryl aldehydes, and cinnamaldehydes. It is noteworthy that this method exhibited an excellent catalytic effect on nitro-containing substrates, which are known as poor substrates in previous reports. The current method afforded 1,2-disubstituted benzimidazoles 1-18 in 83-97% yields over a period of 5 min-1 h at ambient temperature. The reactions with o-phenylenediamines generally took longer than those with N-substituted o-phenylenediamines. The 2-substituted benzimidazoles 19-30 were isolated in 82-95% yields after 15 min-1.5 h reaction time. As reported in the literature [9][10][11]35], 1,2-disubstituted benzimidazole byproducts could also form when o-phenylenediamine was used. The Co(III)/Co(II)-mediated redox method exhibited high selectivity on desired 2-substituted benzimidazoles over 1,2-disubstituted byproducts. The undesired byproduct was obtainedin 4% yield in the synthesis of 19 (~96% selectivity). In other o-phenylenediamine-based reactions, the amount of 1,2-disubstituted byproduct was neglectable.  With optimized reaction conditions, we examined the substrate scope of the Co(III)/Co(II)-mediated redox catalytic system. As shown in Table 4, this new method works well with both o-phenylenediamineand N-substituted o-phenylenediamines. It maintained high catalytic activity on various substituted benzaldehydes, heteroaryl aldehydes, and cinnamaldehydes. It is noteworthy that this method exhibited an excellent catalytic effect on nitro-containing substrates, which are known as poor substrates in previous reports. The current method afforded 1,2-disubstituted benzimidazoles 1-18 in 83-97% yields over a period of 5 min-1 h at ambient temperature. The reactions with o-phenylenediamines generally took longer than those with N-substituted o-phenylenediamines. The 2-substituted benzimidazoles 19-30 were isolated in 82-95% yields after 15 min-1.5 h reaction time. As reported in the literature [9][10][11]35], 1,2-disubstituted benzimidazole byproducts could also form when o-phenylenediamine was used. The Co(III)/Co(II)-mediated redox method exhibited high selectivity on desired 2-substituted benzimidazoles over 1,2-disubstituted byproducts. The undesired byproduct was obtainedin 4% yield in the synthesis of 19 (~96% selectivity). In other o-phenylenediaminebased reactions, the amount of 1,2-disubstituted byproduct was neglectable.  As seen in Figure 1A, a Co(III)/Co(II) redox cycle-based reaction mechanism was proposed. Similar to what has been observed in our previous research on PMA/PMB-mediated redox catalysis in DMSO [34], N-phenyl-o-phenylenediamine and benzaldehyde quickly formed yellow-colored imine and benzimidazoline intermediates upon mixing. Addition of green-colored Co(acac)3 converted the reaction mixture from yellow to green instantly. However, the green color faded quickly after 5 seconds and the reddish-yellow color remained until the end of the reaction. This result indicated that the green Co(III) quickly oxidized the benzimidazoline intermediate and was reduced to red-colored Co(II). A more apparent green-to-red color change was visualized on TLC plate ( Figure  1B). The UV-Vis absorption data showed that the peak of Co(III) appeared at ~600 nm. Upon addition to the mixture of benzaldehyde and N-phenyl-o-phenylenediamine, the green color faded quickly and the signal at ~600 nm disappeared completely ( Figure S1, SI). This result is in agreement with the color change observed both in glass vial and on TLC plate. In addition, the instant color change from red to green upon addition of aqueous H2O2 to a CH2Cl2 solution of Co(acac)2 proved that H2O2 is capable of oxidizing Co(II) Catalysts 2022, 12, x FOR PEER REVIEW 5 of 9 Table 4. Synthesis of benzimidazoles (1-30) via Co(III)/Co(II)-mediated redox catalysis 1 . 1 The reaction was performed with 1.05 mmol of benzaldehyde, 1.0 mmol of N-phenyl-o-phenylene diamine, 0.01 mmol of Co(acac)2, and 1.2 mmol H2O2 (30% aq.) under solvent-free conditions.
As seen in Figure 1A, a Co(III)/Co(II) redox cycle-based reaction mechanism was proposed. Similar to what has been observed in our previous research on PMA/PMB-mediated redox catalysis in DMSO [34], N-phenyl-o-phenylenediamine and benzaldehyde quickly formed yellow-colored imine and benzimidazoline intermediates upon mixing. Addition of green-colored Co(acac)3 converted the reaction mixture from yellow to green instantly. However, the green color faded quickly after 5 seconds and the reddish-yellow color remained until the end of the reaction. This result indicated that the green Co(III) quickly oxidized the benzimidazoline intermediate and was reduced to red-colored Co(II). A more apparent green-to-red color change was visualized on TLC plate ( Figure  1B). The UV-Vis absorption data showed that the peak of Co(III) appeared at ~600 nm. Upon addition to the mixture of benzaldehyde and N-phenyl-o-phenylenediamine, the green color faded quickly and the signal at ~600 nm disappeared completely ( Figure S1, SI). This result is in agreement with the color change observed both in glass vial and on TLC plate. In addition, the instant color change from red to green upon addition of aqueous H2O2 to a CH2Cl2 solution of Co(acac)2 proved that H2O2 is capable of oxidizing Co(II) 1 The reaction was performed with 1.05 mmol of benzaldehyde, 1.0 mmol of N-phenyl-o-phenylene diamine, 0.01 mmol of Co(acac) 2 , and 1.2 mmol H 2 O 2 (30% aq.) under solvent-free conditions. As seen in Figure 1A, a Co(III)/Co(II) redox cycle-based reaction mechanism was proposed. Similar to what has been observed in our previous research on PMA/PMBmediated redox catalysis in DMSO [34], N-phenyl-o-phenylenediamine and benzaldehyde quickly formed yellow-colored imine and benzimidazoline intermediates upon mixing. Addition of green-colored Co(acac) 3 converted the reaction mixture from yellow to green instantly. However, the green color faded quickly after 5 s and the reddish-yellow color remained until the end of the reaction. This result indicated that the green Co(III) quickly oxidized the benzimidazoline intermediate and was reduced to red-colored Co(II). A more apparent green-to-red color change was visualized on TLC plate ( Figure 1B). The UV-Vis absorption data showed that the peak of Co(III) appeared at~600 nm. Upon addition to the mixture of benzaldehyde and N-phenyl-o-phenylenediamine, the green color faded quickly and the signal at~600 nm disappeared completely ( Figure S1, SI). This result is in agreement with the color change observed both in glass vial and on TLC plate. In addition, the instant color change from red to green upon addition of aqueous H 2 O 2 to a CH 2 Cl 2 solution of Co(acac) 2 proved that H 2 O 2 is capable of oxidizing Co(II) back to Co(III) efficiently ( Figure 1C). The fact that cobalt catalyst existed in red-colored Co(II) state during the reaction process indicated that the rate-limiting step in the redox cycle is the oxidative conversion of Co(II) to Co(III) by H 2 O 2 , which is different from the reaction with MoO 2 (acac) 2 and explains why Co(acac) 2 -based redox catalysis is faster than that based on MoO 2 (acac) 2 .

General Methods
The solvents and chemical reagents used in the current research work were purchased from Leyan-Shanghai Haohong Scientific Co. Ltd., Shanghai, China. All of the reactions were monitored by TLC plates coated with 0.25 mm silica gel 60 F254 and visualized by 254 nm UV. The silica gel used in column chromatography (particle size 32-63 μm) was purchased from Qingdao Haiyang Chemicals, Qingdao, China. 1 H, 13 C, and 19 F NMR spectra were recorded on an AV-400 instrument (Bruker BioSpin, Faellanden, Switzerland) with chemical shifts referenced to DMSO-d6 or CDCl3 and reported in parts per million. Infrared spectra were obtained with a Vertex-70 instrument (Bruker Optics, Billerica, MA, USA). HRMS spectra were acquired with a micrOTOF-Q II instrument (Bruker Daltonics, Billerica, MA, USA) and reported as m/z. Melting points were measuredon an X-4 melting point apparatus and uncorrected (Tech Instrument, Beijing, China).

General Methods
The solvents and chemical reagents used in the current research work were purchased from Leyan-Shanghai Haohong Scientific Co. Ltd., Shanghai, China. All of the reactions were monitored by TLC plates coated with 0.25 mm silica gel 60 F 254 and visualized by 254 nm UV. The silica gel used in column chromatography (particle size 32-63 µm) was purchased from Qingdao Haiyang Chemicals, Qingdao, China. 1 H, 13 C, and 19 F NMR spectra were recorded on an AV-400 instrument (Bruker BioSpin, Faellanden, Switzerland) with chemical shifts referenced to DMSO-d 6 or CDCl 3 and reported in parts per million. Infrared spectra were obtained with a Vertex-70 instrument (Bruker Optics, Billerica, MA, USA). HRMS spectra were acquired with a micrOTOF-Q II instrument (Bruker Daltonics, Billerica, MA, USA) and reported as m/z. Melting points were measuredon an X-4 melting point apparatus and uncorrected (Tech Instrument, Beijing, China).