Copper-Promoted One-Pot Approach: Synthesis of Benzimidazoles.

A facile, one-pot, and proficient method was developed for the production of various 2-arylaminobenzimidazoles. This methodology is based for the first time on a copper catalyst promoted domino C–N cross-coupling reaction for the generation of 2-arylaminobenzimidazoles. Mechanistic investigations revealed that the synthetic pathway involves a copper-based desulphurization/nucleophilic substitution and a subsequent domino intra and intermolecular C–N cross-coupling reactions. Some of the issues typically encountered during the synthesis of 2-arylaminobezimidazoles, including the use of expensive catalytic systems and the low reactivity of bromo precursors, were addressed using this newly developed copper-catalyzed method. The reaction procedure is simple, generally with excellent substrate tolerance, and provides good to high yields of the desired products.

Very recently, 2-phenylaminobenzimidazoles have been reported from thiourea using cobalt catalysis [37];however, they have failed to develop from bromo precursors. Therefore, in continuation of our research towards the development of efficient methodologies for the synthesis of heterocycles [38,39], herein, we developed a methodology for the synthesis of 2-phenylamino benzimidazoles from molecules having a bromo moiety, under moderate reaction conditions using copper catalysis. Another advantage of our method is the use of copper, which is cheaper, more airstable and more easily available than cobalt.

Results and Discussion
In this context, 2-phenylaminobenzimidazoles were prepared from thiourea through an approach consisting of consecutive desulphurization/nucleophilic substitution and C-N crosscoupling.Thiourea reacted with 2-bromoaniline at room temperature using copper salt as a catalyst to give N-(2-bromophenyl)-guanidine, which further underwent a domino intra and intermolecular C-N cross-coupling reaction with aryliodide to yield the desired product 2- Thus, enormous efforts have been focused on the preparation of benzimidazole structural frameworks. Classical methods may involve (i) the inter cyclocondensation of 2-aminophenylaniline precursors with either carboxylic acids or aldehydes followed by oxidation [12], (ii) the diazotization on 1-benzimidazolylidenehydrazine [13], (iii) the cyclocondensation of esters with diaminobenzene under microwave irradiation [14], (iv) the reductive cyclization of o-nitroaniline with aldehyde using sodium dithionite [15] and (v) a solid-phase route [16]. However, most of these protocols suffer from major shortcomings such as limited suitable substituents for diverse synthesis, strong alkaline conditions, troublesome management of the chemical process, and elevated temperature. Therefore, we reasoned that a catalytic approach involving C-N bond formation would overcome the abovementioned disadvantages.
Very recently, 2-phenylaminobenzimidazoles have been reported from thiourea using cobalt catalysis [37]; however, they have failed to develop from bromo precursors. Therefore, in continuation of our research towards the development of efficient methodologies for the synthesis of heterocycles [38,39], herein, we developed a methodology for the synthesis of 2-phenylamino benzimidazoles from molecules having a bromo moiety, under moderate reaction conditions using copper catalysis. Another advantage of our method is the use of copper, which is cheaper, more air-stable and more easily available than cobalt.

Results and Discussion
In this context, 2-phenylaminobenzimidazoles were prepared from thiourea through an approach consisting of consecutive desulphurization/nucleophilic substitution and C-N cross-coupling. Thiourea reacted with 2-bromoaniline at room temperature using copper salt as a catalyst to give N-(2-bromophenyl)-guanidine, which further underwent a domino intra and intermolecular C-N cross-coupling reaction with aryliodide to yield the desired product 2-phenylaminobenzimidazole 1a (Scheme 1). Optimization was achieved by taking thiourea and bromoaniline as model substrates and using various solvents, bases, ligands, and copper salts at different temperatures. We were pleased to observe that thiourea gave 2-bromoguanidine in quantitative conversion using NaOAc as a base and both copper (I) and copper (II) salts in the presence of DMSO/DMF at room temperature. The reaction was further continued at room temperature using K 2 CO 3 (2 equiv) as a base, Cu salt (20 mol%), ligand L4 (20 mol%) for 18 h. Unfortunately, no target product was observed ( Table 1, entry 1). Later, the reaction was performed at 50 • C, however, no product formed (Table 1, entry 2). In contrast, target product 1a was observed in 15% yield when the reaction was carried out at 80 • C ( Table 1, entry 3). The yield of the product increased to 52% when the reaction was conducted at 100 • C ( Table 1, entry 4). Very interestingly, the reaction provided the desired product 1a quantitatively at 120 • C ( Table 1, entry 5).
Molecules 2020, 25, x FOR PEER REVIEW 3 of 12 phenylaminobenzimidazole 1a (Scheme 1). Optimization was achieved by taking thiourea and bromoaniline as model substrates and using various solvents, bases, ligands, and copper salts at different temperatures. We were pleased to observe that thiourea gave 2-bromoguanidine in quantitative conversion using NaOAc as a base and both copper (I) and copper (II) salts in the presence of DMSO/DMF at room temperature. The reaction was further continued at room temperature using K2CO3 (2 equiv) as a base, Cu salt (20 mol%), ligand L4 (20 mol%) for 18 h. Unfortunately, no target product was observed ( Table 1, entry 1). Later, the reaction was performed at 50 °C, however, no product formed ( Table 1, entry 2). In contrast, target product 1a was observed in 15% yield when the reaction was carried out at 80 °C (Table 1, entry 3). The yield of the product increased to 52% when the reaction was conducted at 100 °C (Table 1, entry 4). Very interestingly, the reaction provided the desired product 1a quantitatively at 120 °C ( By lowering the quantity of the copper source (10 mol%) or of the base (1.0 equiv), the reaction led to N-arylation, affording a lower amount of the target product (Table 1, entries [17][18]. Control experiments also confirmed that the reaction could not yield the target product in the absence of a catalyst, and the intermediate 2-bromophenylguanidine was recovered intact (Table 1, entry 19). This control experiments demonstrated that the reaction requires a catalyst. Despite the similar catalytic activity of all the copper salts tested, considering the cost effectiveness of CuSO 4 ·5H 2 O over the other examined catalysts, the authors chosen CuSO 4 ·5H 2 O as a reasonable copper source for both step 1 and step 2 in Scheme 1. Finally, the total outcome of the above optimization studies is presented in Scheme 2. Bases like K2CO3 and Cs2CO3 were found to be effective for the reaction ( By lowering the quantity of the copper source (10 mol%) or of the base (1.0 equiv), the reaction led to N-arylation, affording a lower amount of the target product ( Step-1 Step-2 1a (96%) Scheme 2. Optimized synthetic pathway for the synthesis of 2-phenylaminobenzimidazole from thiourea.
The compound 1a was further confirmed based on spectral data, for example, the appearance of characteristic peaks at 1542(m), 1478(s), 1413(s) cm −1 , clearlyshowing Ar-C=C stretching, a peak at 3098(w) cm −1 showing aromatic =CH stretching, and peak at 3294(s) cm −1 indicating -N-H stretching. In the 1 H NMR spectrum of compound 1a, adoublet at δ 7.78 ppm and amultiplet at δ 7.26-7.11 ppm were assigned to aromatic protons, and a broad singlet at δ 6.12 ppm (br s, 1H) to a -N-H proton. This spectral data allowed determining the structure of compound 1a as N-Phenyl-1Hbenzo[d]imidazol-2-amine, which was further confirmed by its 13 C NMR spectrum which exposed 11 signals between δ 139.2 and 110.8 ppm, indicates the existence of 11 different carbons in the compound. Further, the formation of compound 1a was supported by the molecular ion peak at 210.10[M + H] + in its mass spectrum (EI). The compound 1a was further confirmed based on spectral data, for example, the appearance of characteristic peaks at 1542(m), 1478(s), 1413(s) cm −1 , clearlyshowing Ar-C=C stretching, a peak at 3098(w) cm −1 showing aromatic =CH stretching, and peak at 3294(s) cm −1 indicating -N-H stretching. In the 1 H NMR spectrum of compound 1a, adoublet at δ 7.78 ppm and amultiplet at δ 7.26-7.11 ppm were assigned to aromatic protons, and a broad singlet at δ 6.12 ppm (br s, 1H) to a -N-H proton. This spectral data allowed determining the structure of compound 1a as N-Phenyl-1H-benzo[d]imidazol-2-amine, which was further confirmed by its 13 C NMR spectrum which exposed 11 signals between δ 139.2 and 110.8 ppm, indicates the existence of 11 different carbons in the compound. Further, the formation of compound 1a was supported by the molecular ion peak at 210.10[M + H] + in its mass spectrum (EI).
Next, to validate the efficiency of the protocol, we investigated the substrate scope towards the production of 15 more 2-arylaminobenzimidazoles 1b-1p under optimized conditions, and the results are indicated in Figure 2. N-(2-bromophenyl)-guanidine was reacted with various derivatives of aryl iodide having 2-CH 3 , 3-CH 3 , 4-CH 3 , 4-OCH 3 , 4-COOCH 3 , 4-Cl, 2,4-DiCH 3 , 2,6-DiCH 3 and naphthyl to obtain the final products 1b-1j in 62-97% yields. Similarly, the reaction of 2-bromoaniline holding substituents such as 2-Me, 3-Me, 4-Me, 4-CN readily provided the desired products 1k-1n in 56-96% yields. In addition, several substrates were tested to understand the reactivity of aryl halides. For example, thiourea reacted with 4-chloro-2-bromoaniline to provide guanidine which consecutively underwent a C-N cross-coupling reaction with 4-methyliodobenzene and 4-nitroiodobenzene to afford the target products 1o and 1p in 79% and 62% yields respectively. The above mentioned results clearly confirmed that the substrates having electron-donating and electron-withdrawing groups are compatible with this process, affording the substituted 2-aminobenzimidazoles in moderate to excellent yield. All the spectroscopic and analytical data of the synthesized compounds were in full agreement with the anticipated structures. The reaction of aryl halides was next examined under optimized reaction conditions. Iodobenzene afforded the target product 1a in 96% yield (Equation (1)). On the other hand, bromobenzene led to the target product 1a in 12% yield and to the product 2-aminobenzimidazole B in 81% yield (Equation (2)). However, no target product could be obtained when using chlorobenzene, which provided 2-aminobenzimidazole B in 97% yield (Equation (3)). In addition, we also examined the activity of different haloanilines. It was observed that 2-iodoaniline readily reacted with thiourea to give iodoguanidine C, which required a shorter reaction time than bromoguanidine to undergo a domino C-N cross-coupling reaction with iodobenzene, affording the desired product 1a in 96% yield (Equation (4)). However, 2-chloroaniline gave the intermediate chloroguanidine D in complete conversion, but no domin O C-N cross-coupled product was observed with iodobenzene under optimized reaction conditions (Equation (5)).
To reveal the mechanism, control experiments were conducted. The reaction was performed in (4) (5) To reveal the mechanism, control experiments were conducted. The reaction was performed in the absence of aryl iodide and resulted inthe intramolecular C-N cyclized product 2aminobenzimidazole B in 97% yield (eq 6) under optimized reaction conditions. Furthermore, 2aminobenzimidazole readily reacted with iodobenzene under optimized conditions to afford the target product 1a in 96% yield (eq 7).
The above results clearly suggested that thiourea treated with 2-bromoaniline to provide N-(2bromophenyl)-guanidine A gave first the intramolecular C-N cyclised product 2-amino benzimidazole B, which reacted with iodobenzene to providethe final product 1a by an intermolecular C-N cross-coupling reaction.
Moreover, the formation of the key intermediate B was confirmed based on its spectral data. In fact, in the IR spectrum of compound B, thepeaks at 3421(w) and 3396(w) cm −1 corresponds to N-H stretching, the peak at 3063(w) cm −1 represents -C=C-H stretching, the peaks at 1626(s), 1530(s), 1444(s) cm −1 correspond to Ar-C=C stretching; 1 H-NMR analysis showed a broad signal at δ 5.62(2H) ppm, indicating amino protons and signals between δ7.58 and 7.09 ppm representing aromatic To reveal the mechanism, control experiments were conducted. The reaction was performed in the absence of aryl iodide and resulted inthe intramolecular C-N cyclized product 2-aminobenzimidazole B in 97% yield (Equation (6)) under optimized reaction conditions. Furthermore, 2-aminobenzimidazole readily reacted with iodobenzene under optimized conditions to afford the target product 1a in 96% yield (Equation (7)).
To reveal the mechanism, control experiments were conducted. The reaction was performed in the absence of aryl iodide and resulted inthe intramolecular C-N cyclized product 2aminobenzimidazole B in 97% yield (eq 6) under optimized reaction conditions. Furthermore, 2aminobenzimidazole readily reacted with iodobenzene under optimized conditions to afford the target product 1a in 96% yield (eq 7).
The above results clearly suggested that thiourea treated with 2-bromoaniline to provide N-(2bromophenyl)-guanidine A gave first the intramolecular C-N cyclised product 2-amino benzimidazole B, which reacted with iodobenzene to providethe final product 1a by an intermolecular C-N cross-coupling reaction.
Moreover, the formation of the key intermediate B was confirmed based on its spectral data. In fact, in the IR spectrum of compound B, thepeaks at 3421(w) and 3396(w) cm −1 corresponds to N-H stretching, the peak at 3063(w) cm −1 represents -C=C-H stretching, the peaks at 1626(s), 1530(s), 1444(s) cm −1 correspond to Ar-C=C stretching; 1 H-NMR analysis showed a broad signal at δ 5.62(2H) ppm, indicating amino protons and signals between δ7.58 and 7.09 ppm representing aromatic (4) To reveal the mechanism, control experiments were conducted. The reaction was performed in the absence of aryl iodide and resulted inthe intramolecular C-N cyclized product 2aminobenzimidazole B in 97% yield (eq 6) under optimized reaction conditions. Furthermore, 2aminobenzimidazole readily reacted with iodobenzene under optimized conditions to afford the target product 1a in 96% yield (eq 7).
The above results clearly suggested that thiourea treated with 2-bromoaniline to provide N-(2bromophenyl)-guanidine A gave first the intramolecular C-N cyclised product 2-amino benzimidazole B, which reacted with iodobenzene to providethe final product 1a by an intermolecular C-N cross-coupling reaction.
Moreover, the formation of the key intermediate B was confirmed based on its spectral data. In fact, in the IR spectrum of compound B, thepeaks at 3421(w) and 3396(w) cm −1 corresponds to N-H stretching, the peak at 3063(w) cm −1 represents -C=C-H stretching, the peaks at 1626(s), 1530(s), 1444(s) cm −1 correspond to Ar-C=C stretching; 1 H-NMR analysis showed a broad signal at δ 5.62(2H) ppm, indicating amino protons and signals between δ7.58 and 7.09 ppm representing aromatic The above results clearly suggested that thiourea treated with 2-bromoaniline to provide N-(2-bromophenyl)-guanidine A gave first the intramolecular C-N cyclised product 2-amino benzimidazole B, which reacted with iodobenzene to providethe final product 1a by an intermolecular C-N cross-coupling reaction.
Moreover, the formation of the key intermediate B was confirmed based on its spectral data. In fact, in the IR spectrum of compound B, thepeaks at 3421(w) and 3396(w) cm −1 corresponds to N-H stretching, the peak at 3063(w) cm −1 represents -C=C-H stretching, the peaks at 1626(s), 1530(s), 1444(s) cm −1 correspond to Ar-C=C stretching; 1 H-NMR analysis showed a broad signal at δ 5.62(2H) ppm, indicating amino protons and signals between δ7.58 and 7.09 ppm representing aromatic protons. Moreover, in the 13 C NMR spectrum, seven signals between δ167.0 and 118.2 ppm also confirmed that compound B is 1H-benzo[d]imidazol-2-amine. Finally, the structure of B was confirmed by the appearanceof a peak at m/z 134.07 [M + H] + in its mass spectrum (EI).

General Procedure for the Synthesis of 2-(N-arylamino)Benzimidazole
To a stirred solution of DMSO (2-3 mL), thiourea (1 mmol, 76 mg) was added slowly, followed by the addition of NaOAc (1 mmol, 82 mg) and a copper source (50 mol%) at room temperature. The whole reaction mixture was stirred for 1 h (until a black-colored solution was obtained) at room temperature. To this, 2-bromoaniline (2 mmol, 344 mg) was added. After completion of the reaction (monitored by TLC), the reaction mixture was transferred into tubes and the mixture was centrifuged for 10 min. A black solid was then recovered from the tubes, and to this a clear solution of iodobenzene (1 mmol, 204 mg), K 2 CO 3 (2 mmol, 277 mg), Cu(SO) 4 .5H 2 O (20 mol%, 50 mg), and 1,10-phenanthroline (20 mol%, 36 mg) was added slowly in several minutes, and the reaction mixture was then allowed to stir for 18 h at 120 • C. Progress of the reaction was monitored by TLC, using ethyl acetate and hexane (1:4). After completion of the reaction, the reaction mixture was cooled to room temperature. Then, the solution was washed with ethyl acetate (7 mL) and water (3 mL) for 5 times. The organic layer was evaporated, and the crude reaction mixture was purified on asilica gel (60-120 mesh) column by chromatography to obtain the final product 2-(N-arylamino)benzimidazole, which was characterized by NMR ( 1 H and 13 C), IR, and mass spectral data.

Conclusions
In conclusion, we have developed a methodology for the synthesis of substituted 2-aminophenyl benzimidazoles from thiourea through a multistep reaction. This methodology involves consecutive a desulphurization/nucleophilic substitution and domino intra and inter molecular C-N cross-coupling reaction. Control experiments were performed to understand themechanism. Many researchers have reported reactions for the generationof benzimidazoles; however, the simplicity, environmental acceptability, and cost effectiveness of copper makes this method more practical. Although the single yields look moderate, considering that the reaction consists of multiple processes, the yields are in fact good to high.