key: cord-1033345-01jfpe8m
authors: Yang, Weiguang; Zhao, Yu; Zhou, Zitong; Li, Li; Cui, Liao; Luo, Hui
title: Preparation of 1,2-substituted benzimidazoles via a copper-catalyzed three component coupling reaction
date: 2021-02-25
journal: RSC advances
DOI: 10.1039/d1ra00650a
sha: 066640c166f9c9e2f65485c9c8f693bf3417eb4a
doc_id: 1033345
cord_uid: 01jfpe8m

1,2-Substituted benzimidazoles were prepared by simply stirring a mixture of copper catalysts, N-substituted o-phenylenediamines, sulfonyl azides and terminal alkynes. Particularly, the intermediate N-sulfonylketenimine occurred with two nucleophilic addition and the sulfonyl group was eliminated via cyclization. In a way, sulfonyl azides and copper catalysts activated the terminal alkynes to synthesize benzimidazoles.

Owing to their diverse biological activity and clinical applications, 1 benzimidazole derivatives are the potential candidates for a diverse set of biological activities including antiviral, 2 antifungal, 3 antibacterial, 4 antiamoebic, 5 anti-HIV, 6 antiulcer, 4,7 antihypertensive. 8, 9 One subset of such compounds are 1,2substituted benzimidazole derivatives, such as 5-nitrobenzimidazoles (I) that exhibit antitumor activity against melanoma and breast cancer, 10 telmisartan (II) that acts as AT1 receptor antagonists and tentative angiotensin receptor blocker therapeutic for COVID -19, 11 and bendamustine (III) that acts as an antileukemia agent 12 (Fig. 1) . The observed activity depends upon the functional group attached to the moiety. In order to obtain novel effective chemotherapeutic agents, more synthetic methods and routes are required.

Classical types of reactions have focused on the preparation of benzimidazole structural frameworks, such as metal catalysed reaction, metal-free catalysed/reagent-based reaction, green synthesis and photocatalyzed reaction. 1a,1b The main synthesis reaction of benzimidazole drug candidates is the condensation of o-phenylenediamine with aldehydes, acyl chloride, carboxylic acids and esters. 1a,1b However, most of these protocols suffer from strong acidic conditions (HCl, H 2 SO 4 , or polyphosphoric acid), readily oxidized or unstable substrate, or presence of numerous oxidative catalytic reagents. Therefore, a catalytic approach without using oxidant and stable substrate would overcome the above-mentioned disadvantages.

Previous studies reported that the multicomponent reactions (MCRs) of Cu I -catalyzed terminal alkyne, sulfonyl azide, and nucleophiles 13 were applied to synthesize numerous oxygen-containing and nitrogen-containing heterocyclic compounds. 14 The ketenimine intermediate generated by copper-catalyzed terminal alkyne and sulfonyl azide could be take reaction simultaneous employing of pronucleophiles (Nu-H) and electrophiles (E) by designing the substrates. The ohydroxy or o-amino electrophiles-containing benzene was the best strategy for the substrates, such as salicylaldehydes/ohydroxyl-acetophenones, 15 2-acetyl aniline, 16 phenolic schiffs' bases, 17 a-(ortho-hydroxyphenyl)-a,b-unsaturated ketones/ohydroxy-phenylpropiolates, 18 20 However, previous studies reported that Nsulfonyl imidates can be hydrolyzed through in situ generated H 2 O (Scheme 1b). 21 Considering these facts, our study 

We began our investigation by examining the synthesis of (2benzyl-1H-benzo[d]imidazol-1-yl)(phenyl)methanone 3a via N-(2-aminophenyl)benzamide 1a, tosylazide and ethynylbenzene 2a. The reaction was carried out in the presence of CuI and Et 3 N in CHCl 3 at 80 C for 3.5 h, and 3a was isolated in 73% yield ( Table 1 , entry 1). Based on this nding, the reaction conditions were screened. Several other solvents were screened rst, and a lower or comparable yield was obtained when toluene, THF, DMF, DCE were used as solvents, while the MeCN gave 3a the highest yield of 95% and the side product TsNH 2 (Table 1 , entries 2-6). Thus, the optimal solvent was determined to be MeCN. Encouraged by this promising result, numerous catalysts were screened. Among the copper catalysts used, most Cucatalysts exhibited high catalytic reactivity in this reaction whether Cu I -catalysts or Cu II -catalysts (Table 1, entries 7-11). Other catalysts such as AgTFA failed to produce the desired product (Table 1 , entry 12). The effects of different bases were evaluated. Screening results revealed that the use of Et 3 N achieved superior results than DMAP, DIPEA, t BuONa and other bases ( Table 1 , entries 13-16). When the reaction temperature was changed to 90 C, the reaction yield decreased and produced side-products (Table 1 , entries 17). It is worth noting that the other sulfonyl azides such as MsN 3 or PhSO 2 N 3 were also suitable for this reaction ( Table 1 , entries 18).

With the optimized reaction conditions obtained, the substrate diversity with the N-substituted o-phenylenediamines 1 were tested rst. As shown in Table 2 , the electron effects of the substituents R 1 had slight inuences. For example, substrates bearing 4-Me-C 6 H 4 CO-, 4-OMe-C 6 H 4 CO-, 4-F-C 6 H 4 CO-, and 2-thienyl-C 6 H 4 CO-groups were examined, and 90-86% yield of 3b-3e were obtained. The substrates R 1 bearing the (CH 3 ) 2 CHCO-and p-tosyl (Ts-) groups also can obtain 3f in moderate yield of 54% and 3g in good yield of 86%. Next, the scope and limitation of substrates R 2 were examined by employing 3,4-dimethyl and 3,4-dichloro groups, which provided the corresponding benzimidazole derivatives, 3h and 3i, in moderate yield of 65% and 60%. It is noteworthy to mention that when R 1 was changed for methyl instead of electron-withdrawing group acyl, the reaction also could smoothly obtain corresponding methyl-substituted products 3j-3m. However, interestingly, unsubstituted o-phenylenediamines 1k could not obtain the desired product and gave complex compounds. Finally, the scope and limitation of terminal alkynes 2 were examined. As shown in Table 3 , the steric effects were clearly observed for two groups of products, namely 3n-3o and 3p-3r, in which both the substituents led to high yields and got inuenced slightly. The electronic effects of substituents had an obvious impact on the efficiency of this transformation. The analogues R 3 bearing an electron-withdrawing group (e.g., 4-Cl-C 6 H 4and 4-Br-C 6 H 4 -) and strong electron-donating group (e.g., -OMe) substituents produced a good yield of 3s, 3t and 3u. The aliphatic alkynes were also suitable for this reaction obtaining 3v, 3w, 3x in moderate yields of 77%, 58% and 68%, respectively. However, the other functional groups of terminal ynones such as the ethyl propiolate, propiolamide, propiolic acid made the reactions less effective, which obtained complex compounds or no corresponding desired products because the terminal ynones undergo self-condensation under the alkaline conditions. 22 According to the above-mentioned experiments, there was no sulfonyl group in the target product and detected only the side product TsNH 2 . In addition, it could not obtain the desired product when test the unsubstituted o-phenylenediamines 1k ( Table 2) . To conrm the effects of tosylazide and elucidate the mechanism of eliminating the sulfonyl group, few control experiments were performed under the standard conditions. As shown in Scheme 2, the reaction of 1a and 2a, without tosylazide under the standard conditions was performed, and the corresponding products 3a failed to generate. Other test was carried out using the reactant of N,N 0 -(1,2-phenylene)dibenzamide 1l, which could not detect the target product 3a.

On the basis of these above experimental results, a possible reaction pathway for the synthesis of (2-benzyl-1H-benzo[d] imidazol-1-yl)(phenyl)methanone 3a was proposed (Scheme 3). According to the previous proposal, ketenimine A was generated rst by the reaction of TsN 3 and 2a. Then, similar to the published work by Wang, 20 ketenimine A was attacked by the nucleophile to generate intermediate B. Subsequently, intermediate B underwent an intramolecular cascade addition to form intermediate C. At last, the desired product 3a and side product TsNH 2 were obtained by the cyclization of intermediate C. Irrespective of change in the conditions, intermediates B and C could not be detected. Therefore, the procedure from B to 3a was fast and almost simultaneous. The sulfonyl group was eliminated via cyclization and activated the terminal alkynes to decompose into TsNH 2 and N 2 .

We developed a novel and an effective three-component coupling approach to synthesize 1,2-substituted benzimidazoles in the presence of N-substituted o-phenylenediamines, terminal alkynes, copper catalyst and TsN 3 . TsN 3 activated the terminal alkynes to generate ketenimine, took two nucleophilic addition in the process, and eliminated through cyclization. Nonetheless, we expect that this methodology could be applied to build more 1,2-substituted benzimidazole block facility.

All the melting points were determined on a Yanaco melting point apparatus and were uncorrected. IR spectra were recorded as KBr pellets on a Nicolet FT-IR 5DX spectrometer. All the spectra of 1 H NMR (400 MHz) and 13 C NMR (100 MHz) were recorded on a JEOL JNM-ECA 400 spectrometer in DMSO-d 6 or Table 3 Substrate scope of the terminal alkynes 2 a CDCl 3 (otherwise as indicated) with TMS was used as an internal reference and J values are given in Hz. HRMS were obtained on a Bruker micrOTOF-Q II spectrometer. All the ophenylenediamines (1a-1j, see ESI section 1 †) were prepared by previously reported methods. 23 Preparation and characterizations of compounds 3a-3x

To a solution of N-(2-aminophenyl)benzamide (1a, 106 mg, 0.5 mmol) and CuI (9.5 mg, 0.05 mmol) in MeCN (3 mL) was added ethynylbenzene (2a, 61 mg, 1.2 mmol), TsN 3 (118 mg, 1.2 mmol), Et 3 N (61 mg, 1.2 mmol). Aer the mixture was stirred at room temperature for 10 min, and then at 80 C for 3.5 h (monitored by TLC), the solvent was removed. The residue was puried via ash chromatography (silica gel, 9% EtOAc in petroleum ether) to give 148 mg (95%) of product 3a as a white solid, mp 88-89 C (lit. 24 308-310 C). 1 The products 3b-3x were prepared by the similar procedure. 

Calcd for C 15 H 13 FN 2

mg (92%), white solid, mp 115-116 C (lit. 27 117À119 C)

400 MHz, CDCl 3 ) d 7.76-7.74 (m, 1H), 7.26-7.22 (m, 5H)

mg (91%), white solid, mp 119À121 C (lit. 28 no report). 1 H NMR (400 MHz, DMSO-d 6 ) d 7.58-7.56 (m, 1H), 7.51-7.46 (m, 3H)

1432 cm À1 ; 1 H NMR (400 MHz

HRMS (ESI-TOF) (m/z). Calcd for C 22 H 18 N 2 O

93 (m, 3H), 6.66 (d, J ¼ 8.2 Hz, 1H), 4.48 (s, 2H), 2.21 (s, 3H); 13 C NMR (100 MHz

140 mg (85%), white solid, mp 71À73 C.IR (KBr) n 3060, 2873, 2635, 1653, 1454 cm À1 ; 1 H NMR (400 MHz

Calcd for C 21 H 15 FN 2 O

white solid, mp 111-113 C. IR (KBr) n 3059, 2744, 2624, 1628, 1491 cm À1 ; 1 H NMR (400 MHz

-(4-Bromobenzyl)-1H-benzo[d]imidazol-1-yl)(phenyl) methanone (3t)

) (m/z). Calcd for C 21 H 15 ClN 2 O

1512 cm À1 ; 1 H NMR (400 MHz, CDCl 3 ) d 7.76 (d, J ¼ 8.3 Hz, 1H), 7.66-7.61 (m, 1H), 7.58-7.56 (m, 2H), 7.46-7.42 (m, 2H), 7.27-7.23 (m, 1H), 7.12 (d, J ¼ 9.1 Hz, 2H)

(m, 1H), 6.73 (d, J ¼ 8.2 Hz, 1H), 3.08-3.04 (m, 2H), 1.90-1.82 (m, 2H), 1.40-1.26 (m, 8H), 0.87-0.84 (m, 3H); 13 C NMR (100 MHz

Hz, 2H), 1.92-1.86 (m, 1H), 1.73-1.60 (m, 5H), 1.26-0.99 (m, 5H)

HRMS (ESI-TOF) (m/z)

Calcd for C 21 H 24 N 2 O

1538 cm À1 ; 1 H NMR (400 MHz

Hz, 2H), 13.1-1.26 (m, 1H)

All the NMR spectra please see ESI section 3. † Notes and references

13 (a) Review and Recent work

There are no conicts to declare.