Cyclization of o-phenylenediamines by CO₂ in the presence of H₂ for the synthesis of benzimidazoles

Abstract

The cyclization of o-phenylenediamines by CO₂ in the presence of H₂ was presented to directly synthesize benzimidazoles, and a series of benzimidazoles were obtained in excellent yields using RuCl₂(dppe)₂ as the catalyst.

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Introduction

The chemical conversion of carbon dioxide (CO₂) into value-added chemicals such as formic acid, methanol, carbonates, amides and so on has attracted much attention in recent years since CO₂ is an economical, abundant and nontoxic renewable C1 resource and its utilization is of significance for sustainable development.^1,2 However, CO₂ is chemically inert, and a large energy input or special catalysts are usually required for its chemical transformation. For example, in the hydrogenation of CO₂ to formic acid or its derivatives, a base and catalysts (e.g., RuCl₂(dppe)₂, RuCl₂(PPh₃)₃, Ru₃(CO)₁₂) are necessary.³ Therefore, to activate a CO₂ multi-component reaction system in which each component has a synergistic effect on CO₂ conversion may be promising candidates for efficient CO₂ chemical transformation and designing such systems is highly desirable.

Catalytic C–N bond formation reactions between the N-containing compounds with CO₂ are important in both industry and academia because they offer economical and environmental advantages.⁴ Benzimidazoles are important intermediates in the synthesis of pharmaceutical compounds, and heterocycles with a benzimidazole structure are omnipresent in biologically active compounds.^5,6 The conventional methods to synthesize benzimidazoles are based on the condensation reactions of 1,2-diaminobenzenes with formic acid or its derivatives (imidates, esters, orthoesters, or nitriles) under strong acidic conditions at high temperature⁷ or under microwave irradiation.⁸ Recently, benzimidazoles have been reported to be synthesized from aldehydes instead of carboxylic acids in the presence of different oxidants.⁹ Although much progress has been made in the synthesis of benzimidazoles, it is still highly desirable to develop simple and green routes using clean and renewable materials instead of harmful compounds, which is of paramount importance from a standpoint of green chemistry and sustainable development.

Herein, we proposed a new route to directly synthesize benzimidazoles via the cyclization of o-phenylenediamines by CO₂ in the presence of H₂ and a catalyst under the solvent-free condition, as illustrated in eqn (1). A series of benzimidazoles were obtained in excellent yields by cyclizing the corresponding o-phenylenediamines with CO₂ under reductive conditions using RuCl₂(dppe)₂ as the catalyst. Though benzimidazoles have been synthesized using various starting materials via different routes,¹⁰ this is the first example to synthesize benzimidazoles directly from renewable carbon resource CO₂ to the best of our knowledge. This strategy is very appealing due to the following obvious advantages: (1) using CO₂ instead of harmful compounds as the starting material; (2) water is the only byproduct. More importantly, it opens a new route for CO₂ fixation.

Results and discussion

The reaction of o-phenylenediamine with CO₂ and H₂ was first investigated in detail, and the results are listed in Table 1. All reactions were performed at 120 °C since o-phenylenediamine is in liquid state and can dissolve CO₂ and H₂. A blank test was performed in the absence of catalyst, and no benzimidazole was obtained (Table 1, entry 1), while in the presence of the RuCl₂(dppe)₂ catalyst benzimidazole was successfully achieved. This suggests that RuCl₂(dppe)₂ catalyzed the formation of benzimidazole. We explored the influence of system pressures on this reaction. It was found that the conversion of o-phenylenediamine increased with pressure remarkably, approaching 100% at 20 MPa under the other identical conditions (Table 1, entries 2–5). The isolated yields of benzimidazole increased with pressure, and a high product yield of 87% was obtained at a pressure of 20 MPa and a catalyst amount of 0.06 mol% (Table 1, entry 5). The catalyst amount considerably affected the conversion of the substrate. For example, increasing the catalyst amount from 0.06 to 0.20 mol%, o-phenylenediamine was completely converted under the same conditions, affording a 92% isolated yield of benzimidazole (2a) (Table 1, entries 4 and 6). It is noteworthy that a byproduct, 2-hydroxybenzimidazole (3), identified by ¹H and ¹³C NMR (see ESI, Fig. S3 and S4†), was detectable with a trace amount accompanied with benzimidazole. The formation of this byproduct was proved to be the sole product of o-phenylenediamine reacting with CO₂ (see ESI†). The maximum isolated yield of this byproduct was 7% at 20 MPa and a catalyst amount of 0.06%. The above experiments indicate that controlling the system pressure and the catalyst amount can tune the competing reactions among o-phenylenediamine, CO₂ and H₂, and benzimidazole could be obtained in excellent yield.

Table 1 Synthesis of benzimidazole under different conditions^a

Entry	Catalyst	mol%	P/MPa	Conv./%^b	Isolated yield/%^c
a Reaction conditions: o-phenylenediamine, 5.0 mmol; 120 °C; 40 h. b Conversion is defined as the percentage of the converted substrate, which was calculated based on the results analyzed by LC. c The isolated yield of the product is the percentage of the obtained amount divided by the theoretical value of the product.
1	—	—	15	0	0
2	RuCl2(dppe)2	0.06	5	7	4
3	RuCl2(dppe)2	0.06	10	29	24
4	RuCl2(dppe)2	0.06	15	81	74
5	RuCl2(dppe)2	0.06	20	>99	87
6	RuCl2(dppe)2	0.20	15	>99	92
7	RuCl2(PPh3)3	0.06	15	67	63
8	PdCl2(dppe)2	0.06	15	19	15

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Two other homogeneous catalysts, RuCl₂(PPh₃)₃ and PdCl₂(dppe)₂, which show high reactivity in the CO₂ hydrogenation were selected to catalyze the cyclization of o-phenylenediamine with CO₂ in the presence of H₂. It was demonstrated that these catalysts could also catalyze this reaction, and the product yields were 63% and 15% using RuCl₂(PPh₃)₃ and PdCl₂(dppe)₂, respectively (Table 1, entries 7 and 8). From these results, it may be deduced that the catalysts effective in the CO₂ hydrogenation can catalyze the production of benzimidazoles from o-phenylenediamines reacting with CO₂ and H₂.

Encouraged by the initial success in production of benzimidazole, to investigate the general scope and versatility of this strategy in the synthesis of substituted benzimidazoles, we examined the cyclization of a variety of structurally different phenylenediamines possessing functional groups containing both electron-donating and electron-withdrawing groups (1a–k) by CO₂ in the presence of H₂ catalyzed by RuCl₂(dppe)₂ (0.2 mol%). Excitingly, the corresponding substituted benzimidazole derivatives were successfully obtained (see ESI,†¹H and ¹³C NMR data), and the results are listed in Table 2. From this table, it can be observed that most of the substituted benzimidazoles were obtained in excellent yields no matter if the substituents were electron-donating (Table 2, entries 2 and 3) or electron-withdrawing groups (Table 2, entries 3–9), similar to benzimidazole (Table 2, entry 1). These findings indicate that most of the substituted groups in the phenyl ring of diamines had little influence on the cyclization of the substrates by CO₂ in the presence of H₂. However, the CF₃ group was an exception, which had a considerable effect on the yield of the corresponding benzimidazole (Table 2, entry 10). It was demonstrated that the competing reaction of 5-trifluoromethylphenylenediamine with CO₂ resulted in the reduction in 5-trifluoromethylbenzimidazole yield. In addition, the steric hindrance of N-phenyl-o-phenylenediamine (1k) seemed not to hamper the cyclization by CO₂, confirmed by the fact that N-phenyl-benzimidazole (2k) was produced in 92% yield (Table 2, entry 11). It is worth noticing that the dehalogenation (Table 2, entries 4, 5) and the ketone reduction (Table 2, entry 8) of the substituted diamines did not occur under the experimental conditions, which is important for the production of these kinds of benzimidazoles. It should be pointed out that in all the above reactions the corresponding byproducts from the reactions of diamine substrates with CO₂ were detectable, most with a trace amount.

Table 2 Scope of the ruthenium-catalyzed synthesis of benzimidazoles^a

Entry	Substrate	Product	Isolated yield/%
a Reaction conditions: substrate, 5.0 mmol; RuCl2(dppe)2, 0.2 mol%; 120 °C; pressure of mixed gas of CO2 and H2, 15 MPa; 40 h. The conversions of the substrates were >99%.
1			92
2			95
3			93
4			91
5			90
6			91
7			93
8			92
9			87
10			73
11			92

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It is noteworthy that when 2′-aminoacetanilide (1l) was used as the diamine substrate under similar conditions, neither the desired product (i.e., N-acetyl benzimidazole) nor byproduct (i.e., 2-hydroxybenzimidazole) was obtained. Instead, 2-methyl benzimidazole (2l) was obtained in a yield of 98% (Scheme 1), which may be attributed to the good tendency of 2′-aminoacetanilide to undergo cyclization under the experimental conditions (Scheme 1).

Scheme 1 Reaction of 2′-aminoacetanilide with H₂ and CO₂.

To explore the reaction mechanism of the benzimidazole production, a control experiment, the hydrogenation of 2-hydroxybenzimidazole, was performed in the presence of RuCl₂(dppe)₂ under similar conditions, and no benzimidazole was obtained. This indicates that 2-hydroxybenzimidazole was not the intermediate of the final product, benzimidazole. We checked the reaction solution at the o-phenylenediamine conversion around 30%. Unfortunately, no intermediates, such as formic acid and formamide, were detectable, implying the formation of benzimidazole was very fast. We performed the reaction of o-phenylenediamine with formic acid without RuCl₂(dppe)₂. It was found that o-phenylenediamine could react with formic acid to form benzimidazole within 1 min at 120 °C, and even at room temperature the reaction could occur. From these findings, it can be deduced that the ruthenium catalyst was not involved in the formation of the intermediate product in this work. To get information about the intermediate from the reaction of o-phenylenediamine with formic acid, in situ¹³C NMR investigations were performed on the reaction solution as the reaction proceeded, and the results are shown in Fig. 1. In the ¹³C NMR spectra of Fig. 1b and 1c, the signals at δ = 161.8, 132.9, 131.0, 127.5 126.4, 121.3, and 117.3 ppm are attributed to the intermediate formamide (4), while the signals at δ = 141.9, 135.9, 124.1, 115.7 ppm to the final product benzimidazole. Moreover, as the reaction proceeded, the ¹³C NMR signal intensity of benzimidazole gradually increased, and the intensity of the intermediate declined until disappearing. This indicates that benzimidazole was produced via the formation of the intermediate formamide (4) from o-phenylenediamine reacting with formic acid. Considering that CO₂ can be hydrogenated to formic acid catalyzed by RuCl₂(dppe)₂ with the assistance of a base³ and benzimidazole can be produced via the reaction of o-phenylenediamine with formic acid^7,8, we proposed the reaction pathway of benzimidazole production from o-phenylenediamine cyclization by CO₂ in the presence of H₂, as depicted in Scheme 2. The reaction may in principle proceed in two steps. In step 1, the aromatic diamine serves as a base to promote the CO₂ hydrogenation to formic acid catalyzed by RuCl₂(dppe)₂, and subsequently formamide (4) may form fast via dehydration from the diamine with formic acid in step 2, followed by quick intramolecular cyclization to the final product benzimidazole (2a). The process in which CO₂ hydrogenation is combined with further formation of the imidazole ring takes place in several steps wherein each product becomes the substrate for the next reaction. According to this possible reaction pathway, o-phenylenediamines should be completely converted into corresponding benzimidazoles. However, due to the presence of the competing reaction of o-phenylenediamines with CO₂, byproducts are inevitably formed in small amounts.

Fig. 1 ¹³C NMR spectra (D₆-DMSO) of the reaction solution of o-phenylenediamine with HCOOH at different reaction times, (a) 0 min, (b) 40 min, (c) 60 min.

Scheme 2 Proposed reaction pathway for benzimidazole production.

Conclusions

The cyclization of o-phenylenediamines by CO₂ was achieved in the presence of H₂, producing benzimidazoles. The catalyst RuCl₂(dppe)₂ is highly active and selective for the production of a series of benzimidazoles in excellent yields. In addition, the reactions can be performed under solvent-free conditions, rendering the strategy to synthesize benzimidazoles from CO₂ highly valuable from both environmental and economical points of view. The present synthetic route of benzimidazoles starting from CO₂ represents a novel alternative to the traditional routes, and opens a new way for the CO₂ utilization as well.

Experimental section

Hydrogen (99.99%) and CO₂ (99.99%) were provided by Beijing Analytical Instrument Company. o-Phenylenediamine (1a: 98%), 3,4-diaminotoluene(1b: 97%), 4,5-dimethyl-o-phenylenediamine (1c: 98%), 4-chloro-o-phenylenediamine (1d: 97%), 4-bromo-o-phenylenediamine (1e: 97%), 4-fluoro-o-phenylenediamine (1f: 97%), ethyl-3,4-diaminobenzoate (1g: 97%), 3,4-diaminobenzophenone (1h: 97%), 4-nitro-o-phenylenediamine (1i: 98%), 4-trifluoromethyl-o-phenylenediamine (1j: 98%), N-phenyl-o-phenylenediamine (1k: 98%), 2′-aminoacetanilide (1l: 98%) were purchased from Alfa Aesar and used without further purification. RuCl₂(dppe)₂ (dppe = 1,2-bis(diphenylphosphino)-ethane) was prepared according to a reported procedure.³

¹H (400 MHz) and ¹³C (100 MHz) NMR spectra were collected in CDCl₃ or (CD₃)₂SO on a Bruker Avance NMR (400 MHz) at ambient temperature, and chemical shifts were recorded relative to tetramethylsilane (TMS). ¹H and ¹³C NMR chemical shifts are reported in ppm downfield from tetramethylsilane. Abbreviations used in the NMR follow-up experiments: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet. Melting points of new products were recorded using an XT4 microscopy melting point determinator. The quantity analysis of the products was conducted on an HPLC (Shimadzu, LC-15C) with a UV detector set at a wavelength of 254 nm.

Procedure for the synthesis of benzimidazoles from o-phenylenediamines and CO₂

The cyclization of o-phenylenediamines by CO₂ in the presence of H₂ was carried out in a Teflon-lined stainless steel reactor of 22 mL coupled with a magnetic stirrer. In a typical experiment to synthesize benzimidazole, o-phenylenediamine (5.0 mmol) and RuCl₂(dppe)₂ were loaded into the reactor, and moved subsequently to an oil bath of 120 °C, which was controlled by a Haake-D3 temperature controller. Then the mixed gas of CO₂ and H₂ (the molar ratio of CO₂ to H₂ was 3 : 2) was charged into the reactor up to the desired pressure (e.g., 5, 10, 15, 20 MPa), and the stirrer started. After the reaction, the reactor was cooled in ice water and the gas inside was slowly vented. The reaction mixture was dissolved in methanol and transferred into a volumetric flask. The quantitative analysis was conducted by HPLC using a Shimadzu LC-20AT pump, a Hypersil ODS2 5 μm column, and a Soma UV-Vis LC-830 detector at 282 nm. A methanol–water (50 : 50 V/V) solution was used as the mobile phase with a flow rate of 0.8 mL min⁻¹. The pure products were obtained via column chromatography separation. The pure products were identified by ¹H and ¹³C NMR. Similarly, substituted benzimidazoles were obtained using the corresponding o-phenylenediamines as the substrates.

Acknowledgements

We are grateful to the National Natural Science Foundation of China (Nos. 21125314, 21021003, 21073202) and the Chinese Academy of Sciences (KJXC2-YW-H30) for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Detailed experimental procedures and full compound characterization. See DOI: 10.1039/c2gc36517k

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