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Article

Aqueous Synthesis of 1-H-2-Substituted Benzimidazoles via Transition-Metal-Free Intramolecular Amination of Aryl Iodides

by
Chunxia Chen
1,2,
Chen Chen
1,
Bin Li
1,2,*,
Jingwei Tao
1 and
Jinsong Peng
1,*
1
Department of Chemistry and Chemical Engineering, College of Science, Northeast Forestry University, Harbin 150040, China
2
Post-Doctoral Mobile Research Station of Forestry Engineering, Northeast Forestry University, Harbin 150040, China
*
Authors to whom correspondence should be addressed.
Molecules 2012, 17(11), 12506-12520; https://doi.org/10.3390/molecules171112506
Submission received: 25 September 2012 / Revised: 17 October 2012 / Accepted: 21 October 2012 / Published: 24 October 2012
(This article belongs to the Section Organic Chemistry)
Browse Figures
Versions Notes

Abstract

:
A straightforward method has been developed for the synthesis of the benzimidazole ring system through a carbon-nitrogen cross-coupling reaction. In the presence of 2.0 equiv. of K2CO3 in water at 100 °C for 30 h, the intramolecular cyclization of N-(2-iodoaryl)benzamidine provides benzimidazole derivatives in moderate to high yields. Remarkably, the procedure occurs exclusively in water and doesn’t require the use of any additional reagent/catalyst, rendering the methodology highly valuable from both environmental and economical points of view.

1. Introduction

Benzimidazoles are an important class of heterocycles that are frequently used in drug and agrochemical discovery programs. For examples, the benzimidazole core structure is found in a variety of commercial drugs such as Atacand, Nexium, Micardis, Protonix, and Vermox (Figure 1). Recent medicinal chemistry applications of benzimidazole analogs include antibacterial and antifungal agents [1,2,3], anthelmintic agents [4], HIV-1-induced cytopathic inhibitor [5], anti-inflammatory and antiulcer agents [6], cytotoxic and antitumor agents [7,8], DNA binding agents [9], enzyme and receptor agonists or antagonists [10]. Other applications of benzimidazoles include their use as organic ligands [11,12], fluorescent whitening agent dyes [13] and functional materials [14,15]. Therefore, the construction of these heterocycles has always been of great interest to organic and medicinal chemists and has consequently received much attention [16].
Molecules 17 12506 g001 550
Figure 1. Structures of some pharmacologically important benzimidazoles.
Figure 1. Structures of some pharmacologically important benzimidazoles.
Molecules 17 12506 g001
The classical and most common methods to assemble benzimidazoles involve the condensation of benzene-1,2-diamines with aldehydes, carboxylic acids, or their derivatives (Scheme 1, route a) under strong acid/high temperature conditions or using a stoichiometric oxidant [17,18,19,20]. Although these transformations are widely used owing to their inherent simplicity, this method is restricted to the available starting materials and involves harsh reaction conditions [17,18,19,20]. Furthermore, this methodology is not suitable for the regioselective synthesis of N-substituted benzimidazoles, as both syntheses result in regioisomers and disubstituted products from the 1,2-diaminoarene. To circumvent these restrictions, the transition-metal-catalyzed amination approach is a viable strategy to construct the benzimidazole ring regiospecifically. Among the different catalysts, palladium- [21,22,23,24,25], copper- [26,27,28,29,30,31,32,33], nickel- [34], iron- [35], and cobalt-based [36] complexes are generally employed for this coupling reaction (Scheme 1, routes b–e). Despite these recent advances, transition-metal-catalyzed methods are often expensive and require especially designed ligands. Another disadvantage is the need to find ways to remove metal-related impurities from products, an important issue in the synthesis of pharmaceutical compounds.
Transition-metal-free N-arylation reactions [37,38,39,40,41,42,43,44] are also known to occur either by nucleophilic aromatic substitutions [45] or aryne-type intermediates [46,47,48,49,50] in the presence of a base. The former usually requires dipolar aprotic solvents (such as DMF, NMP and DMSO) and sometimes high reaction temperatures; the latter method requires strongly basic reaction conditions (generally potassium amide in liquid ammonia or n-BuLi in hexane). Both synthetic procedures have some drawbacks: harsh reaction conditions, inconvenient handling and workup, or a relatively narrow scope of substrates. Green reaction conditions in synthetic processes have been advocated, and extensive efforts have been devoted to finding sustainable reaction media. Notably the use of water as solvent has attracted much attention in recent years [51,52,53,54]. In parallel with our efforts to develop metal-free synthetic protocols for the production of pharmaceutical and agrochemical heterocyclic compounds [55,56], we envisaged the application of more sustainable protocol to the aqueous synthesis of the benzimidazole framework under transition metal-free conditions.
Molecules 17 12506 g002 550
Scheme 1. Available methods to assemble benzimidazole derivatives.
Scheme 1. Available methods to assemble benzimidazole derivatives.
Molecules 17 12506 g002
As shown in Scheme 2, we propose the synthesis of benzimidazole derivatives 2 through a direct base-mediated intramolecular N-arylation reaction in water, starting from the corresponding N-(2-haloaryl) amidine 1.
Molecules 17 12506 g003 550
Scheme 2. Proposed approach to the synthesis of benzimidazoles 2.
Scheme 2. Proposed approach to the synthesis of benzimidazoles 2.
Molecules 17 12506 g003
N-(2-Halophenyl) benzamidines 1a–a" were selected as model substrates for this N-arylation reaction. In fact, our recently reported copper-catalyzed amination [28] showed that 2-iodoarylbenzamidine 1a (with a concentration of 0.67 mol/L on a 1 mmol scale) can be transformed into the corresponding product in 19% yield with K2CO3 in water at 100 °C for 30 h. The use of Cu2O/DMEDA as the catalyst could efficiently promote this transformation giving 98% yield. Based on the above observations, we wondered whether this copper-free chemical reaction can be improved by changing heterogeneity, oil-water interface, and modes of aggregation “on” the surface of water or in water [57,58]. Further investigations showed that using a relatively low concentration (about 0.1 mol/L on a 0.25 mmol scale), benzimidazole can be obtained in moderate to high yields with vigorous stirring in water.

2. Results and Discussion

Optimization of other reaction conditions such as base, temperature and time is shown in Table 1. At first, the control experiment of 1a was examined in the absence of a base (entry 1, Table 1), and the desired product was not observed. The intramolecular carbon-nitrogen cross-coupling reaction of N-(2-iodophenyl)benzamidine (1a) using potassium carbonate (K2CO3, 2.0 equiv.) as the base in water at 100 °C for 30 h was then examined. To our delight, benzimidazole 2a was smoothly obtained in 80% yield (entry 2, Table 1).
Table
Table 1. Optimization of base-mediated intramolecular C–N cross-coupling of benzamidine 1a–c in water [a]. Molecules 17 12506 i001
Table 1. Optimization of base-mediated intramolecular C–N cross-coupling of benzamidine 1a–c in water [a]. Molecules 17 12506 i001
EntrySubstrateBaseTemperature (°C)Time (h)Yield (%) [b]
11a―100300
21aK2CO31003080
31aKOH1003063
41aK3PO410030trace
51aNaOH100300
61aNaHCO3100300
71aNa2CO3100300
81aCs2CO31003084
91aEt3N100300
101aPyridine100300
11 [c]1aK2CO38030trace
121aK2CO3903060
131aK2CO31002050
141aK2CO31004874
15 [d]1aK2CO31203078
16 [d]1aK2CO31503066
171a'K2CO3100300
181a''K2CO3100300
[a] The reaction was carried out with N-(2-halophenyl)benzamidine (0.25 mmol) and base (0.5 mmol) in water (2.0 mL) with vigorous stirring at 80–150 °C for 20–48 h; [b] Isolated yield after column chromatography; [c] Complete recovery of starting material; [d] Decomposition product o-bromoaniline was also obtained under the given reaction conditions.
Recent research has revealed that metal impurities in commercially available reagents might potentially affect their reactions [59,60,61,62]. To eliminate this possibility, different sources of K2CO3 and purified K2CO3 with high purities (99.9%) were used with new glassware, and metal reagents were avoided in synthetic steps wherever possible, and almost the same yields were obtained. Furthermore, based on the data from entries 2 to 10 in Table 1, we concluded that the presence of trace metal impurities weren’t involved in this carbon-nitrogen bond formation reaction [63]. The nature of base was very important to the reaction outcome. KOH and Cs2CO3 were also effective in promoting this C–N bond formation in water, and the following yields were obtained: 63% (KOH) and 84% (Cs2CO3). Surprisingly, other bases such as NaOH, NaHCO3, K3PO4, Na2CO3, Et3N and pyridine gave no product. The reactions performed at 100 °C gave the best result, because at lower temperature the conversions remained incomplete (entries 11 and 12, Table 1), at higher temperature the undesired decomposition of substrate to o-iodoaniline happened (entries 15 and 16, Table 1). The ortho-substituted halogen on the aniline moiety was very important to this intramolecular carbon-nitrogen cross-coupling reaction. Aryl chloride and aryl bromide, which were expected to be more reactive than their iodo analogues in a substitution reaction proceeding by the SNAr mechanism [64,65], gave no product. Obviously an aromatic nucleophilic substitution process is inconsistent with our experimental results (entries 17 and 18, Table 1), so this reaction presumably occurred by an aryne-type intermediate in the presence of a base.
With the optimized reaction conditions in hand, the generality of the aniline moiety in the amination process was explored first. As shown in Table 2, (o-iodoaryl)benzamidines can smoothly be converted to the desired products in moderate to high yields, however, the use of aryl bromides to effect such transformations afforded none of the desired products (entries 3 and 9, Table 2). For aryl iodides, a variety of substituents such as F, Cl, Br, Me and MeO can be used. It is worth noting that reaction conditions compatible with C–Br or C–Cl combinations are particularly appealing, since these substituents offer great opportunity for further synthetic manipulations (entries 4 and 21, Table 2). 3-Iodo-2-aminopyridine substrate 1g can be transformed into the corresponding benzimidazole in 44% yield (entry 8, Table 2), however, 2-iodo-3-aminopyridine substrate 1h gave no product (entry 10, Table 2) that probably attributed to failure to generate an aryne intermediate by ortho-deprotonations followed by iodide elimination. These results as well as the order of reactivity of aryl halides (entries 2, 17 and 18. Table 1) further pointed to the involvement of aryne-type intermediates.
The scope and limitation of the nitrile moiety were next studied (Table 3). Obviously, the electronic nature of the benzonitrile motifs had a great effect on the yields. Substrates bearing various electron-donating substituents such as Me–, MeO– and Me2N– can be converted smoothly into the desired products in moderate to high yields (entries 1–6, Table 3). Furthermore, the steric hindrance of ortho substituents on the benzonitrile moiety seemed not to hamper N-arylation reaction, the benzimidazoles could be obtained in similar yields (entries 1–4, Table 2). However, the presence of relatively electron-withdrawing or stronger electron-withdrawing functional groups completely held back intramolecular amination process. Other electron-rich aromatic and heteroaromatic substrates such as 1q, 1r and 1s could be efficiently transformed into the corresponding benzimidazoles in satisfactory yields (entries 9–11, Table 3). In addition, N′-phenylated alkylamidine substrate 1u could also be converted to the desired product 2u under these conditions (entry 13, Table 3). In contrast to electron-rich aromatic substituents, N-(2-iodophenyl)amidine with an aliphatic functional group (Me–) provided a trace amount of the product (entry 12, Table 3), the most of the starting materials were unchanged and recovered from the reaction mixture.
Table
Table 2. Direct weak base-mediated synthesis of 2-phenylbenzimidazole derivatives in water [a]. Molecules 17 12506 i002
Table 2. Direct weak base-mediated synthesis of 2-phenylbenzimidazole derivatives in water [a]. Molecules 17 12506 i002
EntrySubstrateProductYield (%) [b]
1 Molecules 17 12506 i003 1a Molecules 17 12506 i004 2a80
2 Molecules 17 12506 i005 1b Molecules 17 12506 i006 2b77
3c Molecules 17 12506 i007 1b' Molecules 17 12506 i008 2b0
4 Molecules 17 12506 i009 1c Molecules 17 12506 i010 2c66
5 Molecules 17 12506 i011 1d Molecules 17 12506 i012 2d54
6 Molecules 17 12506 i013 1e Molecules 17 12506 i014 2e67
7 Molecules 17 12506 i015 1f Molecules 17 12506 i016 2f67
8 Molecules 17 12506 i017 1g Molecules 17 12506 i018 2g44
9 [c] Molecules 17 12506 i019 1g' Molecules 17 12506 i020 2g0
10 [c] Molecules 17 12506 i021 1h Molecules 17 12506 i022 2h0
[a] Reaction conditions: 1.0 equiv. of N-(2-haloaryl)benzamidine (0.25 mmol) and 2.0 equiv. of K2CO3 in water (2.0 mL) at 100 °C with vigorous stirring for 30 h; [b] Isolated yield after column chromatography; [c] Complete recovery of starting material.
Table
Table 3. Synthesis of 2-arylbenzimidazole derivatives in water [a]. Molecules 17 12506 i023
Table 3. Synthesis of 2-arylbenzimidazole derivatives in water [a]. Molecules 17 12506 i023
EntrySubstrateProductYield (%) [b]
1 Molecules 17 12506 i024 1i Molecules 17 12506 i025 2i60
2 Molecules 17 12506 i026 1j Molecules 17 12506 i0272j63
3 Molecules 17 12506 i028 1k Molecules 17 12506 i029 2k58
4 Molecules 17 12506 i030 1l Molecules 17 12506 i031 2l64
5 Molecules 17 12506 i032 1m Molecules 17 12506 i0332m70
6 Molecules 17 12506 i034 1n Molecules 17 12506 i035 2n50
7 [c] Molecules 17 12506 i036 1o Molecules 17 12506 i037 2o0
8 [c] Molecules 17 12506 i038 1p Molecules 17 12506 i039 2p0
9 Molecules 17 12506 i040 1q Molecules 17 12506 i041 2q48
10 Molecules 17 12506 i042 1r Molecules 17 12506 i043 2r60
11 Molecules 17 12506 i044 1s Molecules 17 12506 i045 2s48
12 [c] Molecules 17 12506 i046 1t Molecules 17 12506 i047 2t0
13 Molecules 17 12506 i048 1u Molecules 17 12506 i049 2u33
[a] Reaction conditions: 1.0 equiv. of N-(2-iodophenyl)amidine (0.25 mmol) and 2.0 equiv. of K2CO3 in water (2.0 mL) at 100 °C with vigorous stirring for 30 h; [b] Isolated yield after column chromatography; [c] Complete recovery of starting material.

3. Experimental

3.1. General

Chemicals and solvents were all purchased from commercial supplies and used without further purification. Amidines were prepared through the addition of an aniline to a nitrile according to known procedures [20,21,22,23,24]. Silica gel (100 mesh) was used for chromatographic separation. Silica gel G was used for TLC. Petroleum ether refers to the fraction boiling between 60 °C and 80 °C. All reactions were carried out in dried glassware. 1H-NMR spectra were recorded on a Bruker-400 MHz spectrometer and 13C-NMR spectra were recorded at 100 MHz using tetramethylsilane (TMS) as the internal standard in DMSO-d6. Chemical shifts (δ) are given in parts per million (ppm) downfield relative to TMS (1H-NMR: TMS at 0.00 ppm, DMSO at 2.50 ppm; 13C-NMR: DMSO at 40.0 ppm). Yields refer to isolated yields of compounds estimated to be >95% pure as determined by 1H-NMR. Melting points were determined by use of a Buchi melting point apparatus and not corrected. High-resolution mass spectra were recorded on a Bruker BIO TOF Q mass spectrometer.

3.2. Chemistry

3.2.1. General Procedure for the Preparation of Benzimidazoles 2a–u

A 10 mL Schlenk tube equipped with a magnetic stirring bar was charged with the (o-iodoaryl)-benzamidine substrate (0.25 mmol, 1.0 equiv.) and K2CO3 (69 mg, 0.5 mmol, 2.0 equiv.), then H2O (2.0 mL) was added via syringe at room temperature. The tube was sealed and put into a pre-heated oil bath at 100 °C for 30 h. The reaction mixture was cooled to room temperature, quenched with water (3 mL), and diluted with ethyl acetate (5 mL). The layers were separated and the aqueous layer was extracted with (2 × 5 mL) ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was then purified by flash chromatography on silica gel (H), eluting with 5–10% ethyl acetate/petroleum ether.
2-Phenyl-1H-benzo[d]imidazole (2a). White solid; m.p. 293–295 °C; yield: 80%. 1H-NMR: δ 12.92 (br s, 0.19H), 8.21–8.19 (d, 2H, J = 7.6 Hz), 7.69–7.67 (d, 1H, J = 6.8 Hz), 7.58–7.48 (m, 4H), 7.24–7.22 (d, 2H, J = 6.8 Hz). 13C-NMR: δ 151.55, 144.23, 135.30, 130.57, 130.32, 129.42, 126.89, 123.02, 122.15, 119.34, 111.75. HRMS-ESI (m/z): [M+Na]+ calcd. for C13H10N2Na 217.0742; found 217.0745.
5-Fluoro-2-phenyl-1H-benzo[d]imidazole (2b). White solid; m.p. 243–244 °C; yield: 77%. 1H-NMR: δ 13.06 (br s, 0.14H), 8.18–8.16 (d, 2H, J = 8.0 Hz), 7.69–7.31 (m, 5H), 7.12–7.04 (m, 1H). 13C-NMR: δ 160.15, 153.33, 140.91, 130.60, 130.28, 126.95, 120.19, 111.19, 110.44, 104.90, 98.28. HRMS-ESI (m/z): [M+Na]+ calcd. for C13H9FN2Na 235.0647; found 235.0649.
5-Chloro-2-phenyl-1H-benzo[d]imidazole (2c). White solid; m.p. 209–211 °C; yield: 66%. 1H-NMR: δ 13.13 (br s, 0.18H), 8.20–8.18 (d, 2H, J = 7.2 Hz), 7.74–7.51 (m, 5H), 7.26–7.24 (d, 1H, J = 8.0 Hz). 13C-NMR: δ 152.55, 144.63 (142.48), 135.52 (133.60), 130.15, 129.56, 128.94, 126.50, 122.53 (122.08), 120.02, 118.18, 112.53 (110.92). HRMS-ESI (m/z): [M+Na]+ calcd. for C13H9ClN2Na 251.0352; found 251.0356.
5-Bromo-2-phenyl-1H-benzo[d]imidazole (2d). White solid; m.p. 202–203 °C; yield: 54%. 1H-NMR: δ 13.09 (br s, 0.26H), 8.18–8.16 (d, 2H, J = 8.0 Hz), 7.87–7.50 (m, 5H), 7.37–7.33 (m, 1H). 13C-NMR: δ 145.20, 142.82, 130.27, 129.54, 129.01, 126.57, 125.21, 124.70, 114.71, 113.87, 113.07. HRMS-ESI (m/z): [M+Na]+ calcd. for C13H9BrN2Na 294.9847; found 294.9849.
5-Methyl-2-phenyl-1H-benzo[d]imidazole (2e). White solid; m.p. 242–243 °C; yield: 67%. 1H-NMR: δ 12.80 (br s, 0.22H), 8.20 (m, 2H), 7.55 (m, 5H), 7.05 (m, 1H), 2.45 (s, 3H). 13C-NMR: δ 150.80, 141.94, 135.08, 131.53, 130.24, 129.59, 128.84, 128.01, 126.26, 123.51, 118.29, 110.86, 21.27. HRMS-ESI (m/z): [M+Na]+ calcd. for C14H12N2Na 231.0898; found 231.0896.
5-Methoxy-2-phenyl-1H-benzo[d]imidazole (2f). White solid; m.p. 148–150 °C; yield: 67%. 1H-NMR: δ 13.07 (br s, 0.13H), 8.29–8.13 (m, 2H), 7.58-7.48 (m, 4H), 7.25–7.08 (m, 1H), 7.02–7.01 (m, 1H), 3.83–3.82 (s, 3H). 13C-NMR: δ 156.8, 151.4, 137.4, 136.2, 130.4 (130.1), 129.4 (129.2), 127.5, 126.8, 114.2, 112.4, 94.99 (94.94), 56.4. HRMS-ESI (m/z): [M+Na]+ calcd. for C14H12N2NaO 247.0847; found 247.0849.
2-Phenyl-3H-imidazo[4,5-b]pyridine (2g). White solid; m.p. 283–284 °C; yield: 44%. 1H-NMR δ 13.48 (br s, 1H), 8.34 (dd, J = 4.8, 1.5 Hz, 1H), 8.25−8.21 (m, 2H), 8.02 (d, J = 7.5 Hz, 1H), 7.61−7.51 (m, 3H), 7.25 (dd, J = 8.1, 4.8 Hz, 1H). 13C-NMR: δ 152.32, 143.75, 135.57, 130.52, 129.57, 129.00, 126.70, 126.27, 119.16, 118.09. HRMS-ESI (m/z): [M+Na]+ calcd. for C12H9N3Na 218.0694; found 218.0697.
2-p-Tolyl-1H-benzo[d]imidazole (2i). White solid; m.p. 276–278 °C; yield: 60%. 1H-NMR: δ 12.83 (br s, 0.15H), 8.09–8.07 (d, 2H, J = 7.6 Hz), 7.65–7.53 (m, 2H), 7.37–7.35 (d, 2H, J = 8.0 Hz), 7.20 (m, 2H), 2.39 (s, 3H). 13C-NMR: δ 151.17, 143.71, 139.49, 134.74, 129.42, 127.31, 126.30, 122.23, 121.50, 118.62, 111.04, 20.87. HRMS-ESI (m/z): [M+Na]+ calcd. for C14H12N2Na 231.0898; found 231.0895.
2-(4-Methoxyphenyl)-1H-benzo[d]imidazole (2j). White solid; m.p. 221–223 °C; yield: 63%. 1H-NMR: δ 12.76 (br s, 0.11H), 8.14–8.12 (d, 2H, J = 8.8 Hz), 7.57 (m, 2H), 7.20–7.17 (m, 2H), 7.13–1.11 (d, 2H, J = 8.8 Hz), 3.85 (s, 3H). 13C-NMR: δ 160.59, 151.25, 143.73, 134.97, 127.98, 122.61, 122.07, 121.74, 118.43, 114.34, 111.05, 55.29. HRMS-ESI (m/z): [M+Na]+ calcd. for C14H12N2NaO 247.0847; found 247.0851.
2-o-Tolyl-1H-benzo[d]imidazole (2k). White solid; m.p. 206–208 °C; yield: 58%. 1H-NMR δ 12.64 (br s, 0.11H), 7.76–7.74 (d, 1H, J = 6.8 Hz), 7.62 (m, 2H), 7.39–7.37 (m, 3H), 7.23–7.21 (m, 2H), 2.62 (s, 3H). 13C-NMR δ 151.73, 136.91, 131.15, 129.94, 129.33, 129.22, 125.85, 121.78, 20.90. HRMS-ESI (m/z): [M+Na]+ calcd. for C14H12N2Na 231.0898; found 231.0901.
2-(2-Methoxyphenyl)-1H-benzo[d]imidazole (2l). White solid; m.p. 181–182 °C; yield: 64%. 1H-NMR δ 12.13 (br s, 0.22H), 8.35–8.32 (dd, 1H, J = 7.6, 1.6 Hz), 7.66–7.62 (m, 2H), 7.52–7.47 (m, 1H), 7.27–7.25 (d, 1H, J = 8.0 Hz), 7.21–7.19 (m, 2H), 7.15–7.11 (m, 1H), 4.04 (s, 3H). 13C-NMR δ 156.74, 152.87, 141.72, 141.68, 131.25, 129.70, 122.02, 129.33, 121.50, 120.85, 118.45, 117.93, 112.07, 55.74. HRMS-ESI (m/z): [M+Na]+ calcd. for C14H12N2NaO 247.0847; found 247.0849.
4-(1H-Benzo[d]imidazol-2-yl)-N,N-dimethylaniline (2m). White solid; m.p. 272–274 °C; yield: 70%. 1H-NMR: δ 12.57 (br s, 0.29H), 8.01 (d, 2H, J = 8.0 Hz), 7.57–7.46 (m, 2H), 7.15–7.13 (dd, 2H, J = 6.0, 2.8 Hz), 6.85–6.83 (d, 2H, J = 8.0 Hz), 3.00 (s, 6H). 13C-NMR: δ 152.12, 151.22, 144.01, 134.78, 127.52, 121.48, 121.16, 117.99, 117.31, 111.81, 110.60, 41.07. HRMS-ESI (m/z): [M+Na]+ calcd. for C15H15N3Na 260.1164; found 260.1168.
2-(m-Tolyl)-1H-benzo[d]imidazole (2n). White solid; m.p. 213–215 °C; yield: 50%. 1H-NMR: δ 12.88 (br s, 0.21H), 8.03 (s, 1H), 7.98–7.96 (d, 1H, J = 8.0 Hz), 7.65–7.54 (m, 2H), 7.47–7.43 (t, 1H, J = 8.0 Hz), 7.33–7.31 (d, 1H, J = 8.0 Hz), 7.22–7.21 (m, 2H), 2.43 (s, 3H). 13C-NMR: δ 151.13, 143.26, 138.15, 130.47, 129.92, 129.86, 128.83, 126.96, 123.55, 122.46, 121.64, 118.78, 111.22, 21.02. HRMS-ESI (m/z): [M+Na]+ calcd. for C14H12N2Na 231.0898; found 231.0899.
2-(Naphthalen-2-yl)-1H-benzo[d]imidazole (2q). White solid; m.p. 206–207 °C; yield: 48%. 1H-NMR: δ 13.11 (br s, 0.29H), 8.76 (s, 1H), 8.34 (d, 1H, J = 8.0 Hz), 8.11–8.05 (m, 2H), 8.01–7.99 (m, 1H), 7.73–7.71 (m, 1H), 7.64–7.59 (m, 3H), 7.25 (m, 2H). 13C-NMR: δ 151.23, 143.87, 134.96, 133.45, 132.79, 128.54, 128.42, 127.77, 127.53, 127.10, 126.91, 125.79, 123.91, 122.67, 121.76, 118.88, 111.31. HRMS-ESI (m/z): [M+Na]+ calcd. for C17H12N2Na 267.0898; found 267.0899.
2-(Thiophen-2-yl)-1H-benzo[d]imidazole (2r). White solid; m.p. 341–343 °C; yield: 60%. 1H-NMR: δ 12.94 (br s, 0.24H), 7.83 (dd, J = 3.6, 0.8 Hz, 1H), 7.72 (dd, J = 4.8, 0.8 Hz, 1H), 7.62−7.60 (m, 1H), 7.50 (dd, J = 6.9, 2.1 Hz, 1H), 7.25−7.16 (m, 3H). 13C-NMR: δ 146.86, 143.54, 134.49, 133.59, 128.73, 128.25, 126.67, 122.61, 121.74, 118.51, 111.02. HRMS-ESI (m/z): [M+Na]+ calcd. for C11H8N2NaS 223.0306; found 223.0304.
2-(Furan-2-yl)-1H-benzo[d]imidazole (2s). White solid; m.p. 285–286 °C; yield: 48%. 1H-NMR: δ 12.92 (br s, 0.26H), 7.95 (dd, J = 1.8, 0.9 Hz, 1H), 7.55 (br s, 2H), 7.24−7.20 (m, 3H), 6.73 (dd, J = 3.3, 1.8 Hz, 1H). 13C-NMR: δ 145.5, 144.6, 143.5, 134.3, 122.3, 121.6, 118.7, 112.3, 111.4, 110.5. HRMS-ESI (m/z): [M+Na]+ calcd. for C11H8N2NaO 207.0534; found 207.0536.
2-Methyl-1-phenyl-1H-benzo[d]imidazole (2u). White solid; m.p. 127–129 °C; yield: 33%. 1H-NMR: δ 7.67–7.63 (m, 3H), 7.59–7.53 (m, 3H), 7.24–7.12 (m, 3H), 2.43 (s, 3H). 13C-NMR δ 143.2, 136.1, 134.3, 130.4, 129.2, 127.3, 124.5, 122.8, 122.4, 118.9, 110.3, 14.6. HRMS-ESI (m/z): [M+Na]+ calcd. for C14H12N2Na 231.0898; found 231.0896.

4. Conclusions

In summary, a straightforward weak base-mediated protocol had been developed for the intramolecular C–N bond formation to provide benzimidazole derivatives in moderate to high yields. Particularly interesting, the use of water as a benign and accessible solvent should render the methodology described herein economical and environmentally attractive, providing an alternative synthetic protocol for potential industrial applications without the addition of any exogenous transition metal catalysts.

Acknowledgments

We are grateful for the funding support from the Fundamental Research Funds for the Central Universities (DL12DB03), China Postdoctoral Science Foundation (20110491013, 2012T50319) and Heilongjiang Postdoctoral Grant (LBH-Z11251).

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  • Sample Availability: Samples of the compounds are available from the authors.

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Chen, C.; Chen, C.; Li, B.; Tao, J.; Peng, J. Aqueous Synthesis of 1-H-2-Substituted Benzimidazoles via Transition-Metal-Free Intramolecular Amination of Aryl Iodides. Molecules 2012, 17, 12506-12520. https://doi.org/10.3390/molecules171112506

AMA Style

Chen C, Chen C, Li B, Tao J, Peng J. Aqueous Synthesis of 1-H-2-Substituted Benzimidazoles via Transition-Metal-Free Intramolecular Amination of Aryl Iodides. Molecules. 2012; 17(11):12506-12520. https://doi.org/10.3390/molecules171112506

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Chen, Chunxia, Chen Chen, Bin Li, Jingwei Tao, and Jinsong Peng. 2012. "Aqueous Synthesis of 1-H-2-Substituted Benzimidazoles via Transition-Metal-Free Intramolecular Amination of Aryl Iodides" Molecules 17, no. 11: 12506-12520. https://doi.org/10.3390/molecules171112506

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