Preparation of 1,2-substituted benzimidazoles via a copper-catalyzed three component coupling reaction

Abstract

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.

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Introduction

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 1,2-substituted 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 agent¹² (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.

Fig. 1 Some 1,2-substituted benzimidazole drug candidates.

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, H₂SO₄, 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 nucleophiles¹³ 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 o-hydroxy or o-amino electrophiles-containing benzene was the best strategy for the substrates, such as salicylaldehydes/o-hydroxyl-acetophenones,¹⁵ 2-acetyl aniline,¹⁶ phenolic schiffs' bases,¹⁷ α-(ortho-hydroxyphenyl)-α,β-unsaturated ketones/o-hydroxy-phenylpropiolates,¹⁸ o-hydroxybenzonitrile¹⁹ (Scheme 1a) etc. However, two pronucleophiles (Nu–H) simultaneous nucleophilic addition with the ketenimine intermediate is rare.

Scheme 1 MCR of sulfonyl azides and terminal alkynes.

The compounds of above MCRs contain the sulfonyl group, which is stable and difficult to eliminate. Only a few examples could eliminate the sulfonyl group, including the hydrolysis of N-sulfonyl imidates with catalytic amounts of DBU,¹⁹ or N-sulfonyl acetimid amide treated with 2% H₂SO₄ under reflux conditions.²⁰ However, previous studies reported that N-sulfonyl imidates can be hydrolyzed through in situ generated H₂O (Scheme 1b).²¹ Considering these facts, our study developed a novel strategy to eliminate the sulfonyl group through the power of cyclization reaction (Scheme 1c).

Results and discussion

We began our investigation by examining the synthesis of (2-benzyl-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 Et₃N in CHCl₃ at 80 °C for 3.5 h, and 3a was isolated in 73% yield (Table 1, entry 1). Based on this finding, the reaction conditions were screened. Several other solvents were screened first, 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 TsNH₂ (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 Cu-catalysts 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 Et₃N achieved superior results than DMAP, DIPEA, ^tBuONa 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 MsN₃ or PhSO₂N₃ were also suitable for this reaction (Table 1, entries 18).

Table 1 Optimization of catalytic conditions^a

Entry	Cat.	Base	Solvent	Yield^b (%) 3a
a Reaction conditions: 1a (0.5 mmol), Cat. (10 mol%), base (1.2 eq.) in the solvent (3 mL) was added TsN3 (1.2 eq.), 2a (1.2 eq.) stirring at 80 °C for 3.5 h.b Isolated yields.c nd = not detected the target product.d The reaction temperature was 90 °C.e MsN3 or PhSO2N3 was used instead of TsN3.
1	CuI	Et3N	CHCl3	73
2	CuI	Et3N	DCE	90
3	CuI	Et3N	Toluene	31
4	CuI	Et3N	MeCN	95
5	CuI	Et3N	THF	84
6	CuI	Et3N	DMF	15
7	CuBr	Et3N	MeCN	92
8	CuCl	Et3N	MeCN	94
9	CuBr2	Et3N	MeCN	90
10	Cu(OAc)2	Et3N	MeCN	86
11	Cu(OTf)2	Et3N	MeCN	82
12	AgTFA	Et3N	MeCN	nd^c
13	CuI	DMAP	MeCN	15
14	CuI	DIPEA	MeCN	75
15	CuI	Pyridine	MeCN	43
16	CuI	^tBuONa	MeCN	30
17	CuI	Et3N	MeCN	88^d
18	CuI	Et3N	MeCN	95^e

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With the optimized reaction conditions obtained, the substrate diversity with the N-substituted o-phenylenediamines 1 were tested first. As shown in Table 2, the electron effects of the substituents R¹ had slight influences. For example, substrates bearing 4-Me–C₆H₄CO–, 4-OMe–C₆H₄CO–, 4-F–C₆H₄CO–, and 2-thienyl–C₆H₄CO–groups were examined, and 90–86% yield of 3b–3e were obtained. The substrates R¹ bearing the (CH₃)₂CHCO– 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 R² 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 R¹ 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.

Table 2 Substrate scopes^a

a Unless otherwise noted, the reaction conditions were as follow: 1 (0.5 mmol), CuI (10 mol%), Et₃N (1.2 eq.) in the MeCN (3 mL) was added TsN₃ (1.2 eq.), 2 (1.2 eq.) stirring at 80 °C for 3.5 h.

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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 influenced slightly. The electronic effects of substituents had an obvious impact on the efficiency of this transformation. The analogues R³ bearing an electron-withdrawing group (e.g., 4-Cl–C₆H₄– and 4-Br–C₆H₄–) 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

Table 3 Substrate scope of the terminal alkynes 2^a

a Unless otherwise noted, the reaction conditions were as follow: 1a (0.5 mmol), CuI (10 mol%), Et₃N (1.2 eq.) in the MeCN (3 mL) was added TsN₃ (1.2 eq.), 2 (1.2 eq.) stirring at 80 °C for 3.5 h.

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According to the above-mentioned experiments, there was no sulfonyl group in the target product and detected only the side product TsNH₂. In addition, it could not obtain the desired product when test the unsubstituted o-phenylenediamines 1k (Table 2). To confirm 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′-(1,2-phenylene)dibenzamide 1l, which could not detect the target product 3a.

Scheme 2 Control experiments.

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 first by the reaction of TsN₃ 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 TsNH₂ 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 TsNH₂ and N₂.

Scheme 3 Plausible reaction mechanism.

Conclusions

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 TsN₃. TsN₃ 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.

Experimental

General

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 ¹H NMR (400 MHz) and ¹³C NMR (100 MHz) were recorded on a JEOL JNM-ECA 400 spectrometer in DMSO-d₆ or CDCl₃ (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 o-phenylenediamines (1a–1j, see ESI section 1†) were prepared by previously reported methods.²³

Preparation and characterizations of compounds 3a–3x

(2-Benzyl-1H-benzo[d]imidazol-1-yl)(phenyl)methanone (3a). 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), TsN₃ (118 mg, 1.2 mmol), Et₃N (61 mg, 1.2 mmol). After 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 purified via flash 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). ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J = 7.8 Hz, 1H), 7.64–7.60 (m, 1H), 7.56–7.54 (m, 2H), 7.44–7.40 (m, 2H), 7.27–7.17 (m, 5H), 7.15–7.11 (m, 1H), 7.02–7.03 (m, 1H), 6.63 (d, J = 8.6 Hz, 1H), 4.52 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 168.6, 155.1, 142.2, 136.3, 134.1, 133.9, 133.0, 129.8 (2C), 128.80 (2C), 128.77 (2C), 128.4 (2C), 126.8, 123.8, 123.7, 119.9, 113.1, 35.9.

The products 3b–3x were prepared by the similar procedure.

(2-Benzyl-1H-benzo[d]imidazol-1-yl)(p-tolyl)methanone (3b). 147 mg (90%), white solid, mp 104–105 °C. IR (KBr) ν 3048, 2930, 1691, 1451 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J = 8.2 Hz, 1H), 7.48 (d, J = 8.2 Hz, 2H), 7.27–7.17 (m, 7H), 7.15–7.12 (m, 1H), 7.08–7.04 (m, 1H), 6.68 (d, J = 8.2 Hz, 1H), 4.52 (s, 2H), 2.43 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 168.5, 155.2, 145.2, 144.2, 136.4 (2C), 134.2, 130.1 (2C), 129.5 (2C), 128.8 (2C), 128.4 (2C), 126.7, 123.65, 123.62, 119.8, 113.1, 35.8, 21.8; HRMS (ESI-TOF) (m/z). Calcd for C₂₂H₁₈N₂O, [M + H]⁺ 327.1492; found 327.1494.

(2-Benzyl-1H-benzo[d]imidazol-1-yl)(4-methoxyphenyl)methanone (3c). 137 mg (80%), white solid, mp 113–114 °C. IR (KBr) ν 3067, 2935, 2840, 1692, 1450 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.77 (d, J = 8.2 Hz, 1H), 7.56 (d, J = 8.7 Hz, 2H), 7.27–7.16 (m, 5H), 7.14–7.06 (m, 2H), 6.89 (d, J = 8.7 Hz, 2H), 6.75 (d, J = 8.2 Hz, 1H), 4.51 (s, 2H), 3.87 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 167.8, 164.4, 155.1, 144.2, 136.4, 134.4, 132.6 (2C), 128.8 (2C), 128.4 (2C), 126.7, 124.9, 123.6, 123.5, 119.8, 114.1 (2C), 112.9, 55.6, 35.7; HRMS (ESI-TOF) (m/z). Calcd for C₂₂H₁₈N₂O₂, [M + H]⁺ 343.1441; found 343.1444.

(2-Benzyl-1H-benzo[d]imidazol-1-yl)(4-fluorophenyl)methanone (3d). 144 mg (87%), white solid, mp 112–113 °C. IR (KBr) ν 3050, 2836, 2882, 1703, 1426 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.78 (d, J = 8.2 Hz, 1H), 7.61–7.58 (m, 2H), 7.30–7.26 (m, 1H), 7.20–7.18 (m, 4H), 7.16–7.07 (m, 4H), 6.65 (d, J = 8.3 Hz, 1H), 4.52 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 167.3, 166.0 (d, J = 255.5 Hz, 1C), 155.1, 142.2, 136.2, 134.0, 132.6 (d, J = 9.5 Hz, 2C), 129.0 (d, J = 2.8 Hz, 1C), 128.7 (2C), 128.4 (2C), 126.8, 123.82, 123.76, 120.0, 116.1 (d, J = 21.9 Hz, 2C), 112.8, 35.7; HRMS (ESI-TOF) (m/z). Calcd for C₂₁H₁₅FN₂O, [M + H]⁺ 331.1241; found 331.1242.

(2-Benzyl-1H-benzo[d]imidazol-1-yl)(thiophen-2-yl)methanone (3e). 137 mg (86%), white solid, mp 115–117 °C. IR (KBr) ν 3062, 2924, 2520, 1940, 1633, 1378 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.78–7.73 (m, 2H), 7.38–7.37 (m, 1H), 7.29–7.25 (m, 1H), 7.22–7.10 (m, 6H), 7.06–7.02 (m, 2H), 4.49 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 161.7, 154.5, 142.2, 136.2, 136.1, 136.0, 135.8, 134.2, 128.8 (2C), 128.4 (2C), 128.0, 126.7, 123.64, 123.58, 119.8, 112.5, 35.4; HRMS (ESI-TOF) (m/z). Calcd for C₁₉H₁₄N₂OS, [M + H]⁺ 319.0900; found 319.0904.

1-(2-Benzyl-1H-benzo[d]imidazol-1-yl)-2-methylpropan-1-one (3f). 75 mg (54%), white solid, mp 136–137 °C. IR (KBr) ν 3049, 2836, 2683, 1623, 1426 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.80–7.77 (m, 1H), 7.54–7.51 (m, 1H), 7.36–7.31 (m, 2H), 7.27–7.22 (m, 4H), 7.20–7.17 (m, 1H), 4.58 (s, 2H), 3.41–3.36 (m, 1H), 1.10 (s, 3H), 1.08 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 177.1, 155.1, 142.6, 136.4, 132.3, 129.0 (2C), 128.3 (2C), 136.7, 124.4, 124.0, 120.4, 112.8, 36.9, 35.8, 18.6 (2C); HRMS (ESI-TOF) (m/z). Calcd for C₁₈H₁₈N₂O, [M + H]⁺ 279.1492; found 279.1493.

2-Benzyl-1-tosyl-1H-benzo[d]imidazole (3g). 156 mg (86%), yellow solid, mp 142–143 °C (lit.²⁵ 118−120 °C). ¹H NMR (400 MHz, CDCl₃) δ 7.96–7.94 (m, 1H), 7.72–7.69 (m, 1H), 7.37–7.32 (m, 4H), 7.30–7.25 (m, 5H), 7.05 (d, J = 8.2 Hz, 2H), 4.64 (s, 2H), 2.29 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 152.9, 145.5, 141.8, 135.9, 134.9, 132.9, 129.8 (2C), 129.2 (2C), 128.6 (2C), 126.9 (2C), 126.8, 124.8, 124.6, 120.1, 113.6, 35.6, 21.5.

(2-Benzyl-5,6-dimethyl-1H-benzo[d]imidazol-1-yl)(phenyl)methanone (3h). 119 mg (70%), white solid, mp 130–132 °C. IR (KBr) ν 3058, 2854, 1639, 1450 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.64–7.60 (m, 1H), 7.56–7.52 (m, 3H), 7.44–7.40 (m, 2H), 7.20–7.10 (m, 5H), 6.43 (s, 1H), 4.47 (s, 2H), 2.31 (s, 3H), 2.13 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 168.6, 154.2, 140.8, 136.5, 133.7, 133.2, 132.8, 132.7, 132.6, 129.8 (2C), 128.71 (2C), 128.70 (2C), 128.4 (2C), 126.6, 119.9, 113.6, 36.0, 20.4, 20.0; HRMS (ESI-TOF) (m/z). Calcd for C₂₃H₂₀N₂O, [M + H]⁺ 341.1649; found 341.1650.

(2-Benzyl-5,6-dichloro-1H-benzo[d]imidazol-1-yl)(phenyl)methanone (3i). 133 mg (60%), white solid, mp 114–115 °C. IR (KBr) ν 3053, 2925, 2851, 2626, 1630, 1458 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.84 (s, 1H), 7.70–7.66 (m, 1H), 7.55–7.52 (m, 2H), 7.49–7.45 (m, 2H), 7.22–7.12 (m, 5H), 6.89 (s, 1H), 4.44 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 167.8, 167.0, 141.7, 135.6, 134.5, 133.3, 132.2, 129.9 (2C), 129.1 (2C), 128.8 (2C), 128.6 (2C), 128.0, 127.9, 127.0, 121.0, 114.5, 35.9; HRMS (ESI-TOF) (m/z). Calcd for C₂₁H₁₄Cl₂N₂O, [M + H]⁺ 381.0556; found 381.0557.

2-Benzyl-1-methyl-1H-benzo[d]imidazole (3j). 91 mg (82%), white solid, mp 71–73 °C (lit.²⁶ 72 °C). ¹H NMR (400 MHz, CDCl₃) δ 7.78–7.75 (m, 1H), 7.29–7.19 (m, 8H), 4.29 (s, 2H), 3.54 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 153.2, 142.4, 136.0, 135.9, 128.7 (2C), 128.3 (2C), 126.8, 122.2, 121.8, 119.3, 108.9, 34.3, 29.9.

2-(4-Fluorobenzyl)-1-methyl-1H-benzo[d]imidazole (3k). 103 mg (86%), yellow oil. IR (KBr) ν 3054, 2944, 1894, 1602, 1506 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.76–7.73 (m, 1H), 7.26–7.15 (m, 3H), 7.19–7.15 (m, 2H), 6.97–6.92 (m, 2H), 4.24 (s, 2H), 3.53 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 161.6 (d, J = 244.1 Hz, 1C), 152.9, 142.2, 135.8, 131.6 (d, J = 2.9 Hz, 1C), 129.8 (d, J = 8.6 Hz, 2C), 122.3, 121.9, 119.2, 115.5 (d, J = 21.9 Hz, 2C), 109.0, 33.3, 29.8; HRMS (ESI-TOF) (m/z). Calcd for C₁₅H₁₃FN₂, [M + H]⁺ 241.1136; found 241.1137.

2-(4-Chlorobenzyl)-1-methyl-1H-benzo[d]imidazole (3l). 118 mg (92%), white solid, mp 115–116 °C (lit.²⁷ 117−119 °C). ¹H NMR (400 MHz, CDCl₃) δ 7.76–7.74 (m, 1H), 7.26–7.22 (m, 5H), 7.12 (d, J = 8.7 Hz, 2H), 4.22 (s, 2H), 3.51 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 152.5, 142.2, 135.8, 134.4, 132.6, 129.6 (2C), 128.8 (2C), 122.3, 121.8, 119.2, 109.0, 33.4, 29.8.

2-(4-Bromobenzyl)-1-methyl-1H-benzo[d]imidazole (3m). 136 mg (91%), white solid, mp 119−121 °C (lit.²⁸ no report). ¹H NMR (400 MHz, DMSO-d₆) δ 7.58–7.56 (m, 1H), 7.51–7.46 (m, 3H), 7.25–7.14 (m, 4H), 4.28 (s, 2H), 3.69 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 153.1, 142.1, 136.3, 135.8, 131.4 (2C), 131.0 (2C), 121.7, 121.4, 119.7, 118.5, 109.9, 32.3, 29.8.

(2-(4-Methylbenzyl)-1H-benzo[d]imidazol-1-yl)(phenyl)methanone (3n). 142 mg (87%), white solid, mp 164–166 °C. IR (KBr) ν 3049, 2738, 2621, 1624, 1432 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J = 7.8 Hz, 1H), 7.64–7.56 (m, 3H), 7.45–7.41 (m, 2H), 7.27–7.22 (m, 1H), 7.10–6.99 (m, 5H), 6.64 (d, J = 8.2 Hz, 1H), 4.48 (s, 2H), 2.22 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 168.6, 155.4, 142.2, 136.3, 134.1, 133.9, 133.2, 133.1, 129.8 (2C), 129.1 (2C), 128.8 (2C), 128.6 (2C), 123.748, 123.67, 119.8, 113.1, 35.9, 20.9. HRMS (ESI-TOF) (m/z). Calcd for C₂₂H₁₈N₂O, [M + H]⁺ 327.1492; found 327.1495.

(2-(3-Methylbenzyl)-1H-benzo[d]imidazol-1-yl)(phenyl)methanone (3o). 119 mg (89%), white solid, mp 111–113 °C. IR (KBr) ν 3055, 2836, 2684, 1655, 1429 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.78 (d, J = 7.8 Hz, 1H), 7.65–7.61 (m, 1H), 7.58–7.56 (m, 2H), 7.45–7.41 (m, 2H), 7.28–7.24 (m, 1H), 7.10–7.04 (m, 2H), 6.99–6.93 (m, 3H), 6.66 (d, J = 8.2 Hz, 1H), 4.48 (s, 2H), 2.21 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 168.6, 155.2, 142.2, 138.0, 136.1, 134.1, 133.9, 133.0, 129.9 (2C), 129.4, 128.8 (2C), 128.3, 127.5, 125.8, 123.8, 123.7, 119.8, 113.1, 35.9, 20.9. HRMS (ESI-TOF) (m/z). Calcd for C₂₂H₁₈N₂O, [M + H]⁺ 327.1492; found 327.1493.

(2-(4-Fluorobenzyl)-1H-benzo[d]imidazol-1-yl)(phenyl)methanone (3p). 150 mg (91%), white solid, mp 78−79 °C. IR (KBr) ν 3047, 2870, 2616, 1635, 1508 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.77 (d, J = 8.2 Hz, 1H), 7.67–7.63 (m, 1H), 7.59–7.57 (m, 2H), 7.47–7.43 (m, 2H), 7.28–7.24 (m, 1H), 7.22–7.18 (m, 2H), 7.08–7.04 (m, 1H), 6.92–6.87 (m, 2H), 6.62 (d, J = 8.3 Hz, 1H), 4.50 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 168.5, 161.7 (d, J = 244.1 Hz, 1C), 155.0, 142.2, 134.05, 134.00, 132.9, 131.9 (d, J = 2.9 Hz, 1C), 130.4 (d, J = 7.6 Hz, 2C), 129.8 (2C), 128.9 (2C), 123.9, 123.8, 119.9, 115.3 (d, J = 37.7 Hz, 2C), 113.2, 35.1; HRMS (ESI-TOF) (m/z). Calcd for C₂₁H₁₅FN₂O, [M + H]⁺ 331.1241; found 331.1243.

(2-(3-Fluorobenzyl)-1H-benzo[d]imidazol-1-yl)(phenyl)methanone (3q). 140 mg (85%), white solid, mp 71−73 °C.IR (KBr) ν 3060, 2873, 2635, 1653, 1454 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.77 (d, J = 7.8 Hz, 1H), 7.67–7.63 (m, 1H), 7.60–7.58 (m, 2H), 7.48–7.44 (m, 2H), 7.29–7.25 (m, 1H), 7.20–7.15 (m, 1H), 7.09–7.05 (m, 1H), 7.01 (d, J = 7.8 Hz, 1H), 6.96–6.93 (m, 1H), 6.87–6.82 (m, 1H), 6.63 (d, J = 8.3 Hz, 1H), 4.53 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 168.5, 162.7 (d, J = 245.0 Hz, 1C), 154.4, 142.2, 138.7 (d, J = 7.6 Hz, 1C), 134.1, 134.0, 132.9, 129.9, 129.8 (2C), 128.9 (2C), 124.5 (d, J = 2.9 Hz, 1C), 123.95, 123.92, 120.0, 115.8 (d, J = 21.9 Hz, 1C), 113.8 (d, J = 21.0 Hz, 1C), 113.2, 35.6; HRMS (ESI-TOF) (m/z). Calcd for C₂₁H₁₅FN₂O, [M + H]⁺ 331.1241; found 331.1242.

(2-(2-Fluorobenzyl)-1H-benzo[d]imidazol-1-yl)(phenyl)methanone (3r). 139 mg (84%), mp 82−83 °C. IR (KBr) ν 3054, 2738, 2620, 1702, 1451 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.74 (d, J = 8.2 Hz, 1H), 7.66–7.62 (m, 3H), 7.48–7.44 (m, 2H), 7.26–7.13 (m, 3H), 7.09–6.94 (m, 3H), 6.70 (d, J = 8.2 Hz, 1H), 4.52 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 168.5, 160.7 (d, J = 246.0 Hz, 1C), 154.0, 142.3, 134.0, 133.9, 133.0, 130.7 (d, J = 3.8 Hz, 1C), 129.9 (2C), 128.9 (2C), 128.7 (d, J = 8.6 Hz, 1C), 124.11, 124.07, 123.84, 123.80 (d, J = 15.2 Hz, 1C), 119.9, 115.3 (d, J = 21.9 Hz, 1C), 113.2, 29.4 (d, J = 3.8 Hz, 1C); HRMS (ESI-TOF) (m/z). Calcd for C₂₁H₁₅FN₂O, [M + H]⁺ 331.1241; found 331.1244.

(2-(4-Chlorobenzyl)-1H-benzo[d]imidazol-1-yl)(phenyl)methanone (3s). 166 mg (96%), white solid, mp 111–113 °C. IR (KBr) ν 3059, 2744, 2624, 1628, 1491 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J = 7.8 Hz, 1H), 7.66–7.63 (m, 1H), 7.58 (d, J = 7.3 Hz, 2H), 7.47–7.43 (m, 2H), 7.27–7.23 (m, 1H), 7.20–7.16 (m, 4H), 7.08–7.04 (m, 1H), 6.61 (d, J = 8.2 Hz, 1H), 4.49 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 168.4, 154.6, 142.2, 134.8, 134.0, 133.9, 132.9, 132.6, 130.2 (2C), 129.8 (2C), 128.9 (2C), 128.5 (2C), 123.9, 123.8, 119.9, 113.2, 35.3. HRMS (ESI-TOF) (m/z). Calcd for C₂₁H₁₅ClN₂O, [M + H]⁺ 347.0946; found 347.0944.

(2-(4-Bromobenzyl)-1H-benzo[d]imidazol-1-yl)(phenyl)methanone (3t). 156 mg (80%), white solid, mp 91−92 °C. IR (KBr) ν 3089, 2872, 2683, 1657, 1428 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J = 8.2 Hz, 1H), 7.66–7.62 (m, 1H), 7.60–7.57 (m, 2H), 7.47–7.43 (m, 2H), 7.34–7.31 (m, 2H), 7.27–7.23 (m, 1H), 7.12 (d, J = 8.7 Hz, 2H), 7.08–7.03 (m, 1H), 6.61 (d, J = 8.2 Hz, 1H), 4.47 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 168.4, 154.4, 142.1, 135.2, 134.0, 133.9, 132.8, 131.5 (2C), 130.5 (2C), 129.8 (2C), 128.9 (2C), 123.9, 123.8, 120.7, 119.9, 113.2, 35.3. HRMS (ESI-TOF) (m/z). Calcd for C₂₁H₁₅ClN₂O, [M + H]⁺ 391.0441; found 391.0442.

(2-(4-Methoxybenzyl)-1H-benzo[d]imidazol-1-yl)(phenyl)methanone (3u). 157 mg (92%), yellow oil. IR (KBr) ν 3301, 3068, 2836, 2626, 1628, 1512 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J = 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 = 9.1 Hz, 2H), 7.08–7.04 (m, 1H), 6.76–6.73 (m, 2H), 6.64 (d, J = 8.2 Hz, 1H), 4.45 (s, 2H), 3.70 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 168.6, 158.3, 155.6, 142.2, 134.1, 133.9, 133.1, 129.8 (4C), 128.8 (2C), 128.3, 123.8, 123.7, 119.8, 113.8 (2C), 113.1, 55.1, 35.0. HRMS (ESI-TOF) (m/z). Calcd for C₂₂H₁₈N₂O₂, [M + H]⁺ 343.1441; found 343.1443.

(2-Heptyl-1H-benzo[d]imidazol-1-yl)(phenyl)methanone (3v). 123 mg (77%), yellow oil. IR (KBr) ν 3061, 2928, 2626, 1712, 1538 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.77–7.67 (m, 4H), 7.54–7.50 (m, 2H), 7.28–7.22 (m, 1H), 7.08–7.04 (m, 1H), 6.73 (d, J = 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); ¹³C NMR (100 MHz, CDCl₃) δ 168.6, 157.0, 142.3, 133.9, 133.7, 133.3, 129.9 (2C), 128.9 (2C), 123.6, 123.2, 119.5, 113.1, 31.5, 29.8, 29.2, 28.8, 27.8, 22.4, 13.9; HRMS (ESI-TOF) (m/z). Calcd for C₂₁H₂₄N₂O, [M + H]⁺ 321.1962; found 321.1964.

(2-(Cyclohexylmethyl)-1H-benzo[d]imidazol-1-yl)(phenyl)methanone (3w). 92 mg (58%), white solid, mp 77–78 °C. IR (KBr) ν 3056, 2925, 2625, 1711, 1449 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.76–7.67 (m, 4H), 7.54–7.50 (m, 2H), 7.26–7.22 (m, 1H), 7.08–7.04 (m, 1H), 6.73 (d, J = 8.2 Hz, 1H), 2.98 (d, J = 7.3 Hz, 2H), 1.92–1.86 (m, 1H), 1.73–1.60 (m, 5H), 1.26–0.99 (m, 5H); ¹³C NMR (100 MHz, CDCl₃) δ 168.7, 155.8, 142.3, 134.0, 133.8, 133.3, 129.9 (2C), 128.9 (2C), 123.6, 123.3, 119.5, 113.0, 37.4, 36.9, 33.0 (2C), 26.1, 25.9 (2C); HRMS (ESI-TOF) (m/z). Calcd for C₂₁H₂₄N₂O, [M + H]⁺ 321.1962; found 321.1964.

(2-(Cyclopropylmethyl)-1H-benzo[d]imidazol-1-yl)(phenyl)methanone (3x). 94 mg (68%), yellow oil. IR (KBr) ν 3065, 2925, 2623, 1709, 1538 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ7.78–7.74 (m, 3H), 7.70–7.66 (m, 1H), 7.53–7.49 (m, 2H), 7.26–7.22 (m, 1H), 7.07–7.03 (m, 1H), 6.67 (d, J = 8.2 Hz, 1H), 3.05 (d, J = 7.4 Hz, 2H), 13.1–1.26 (m, 1H), 0.57–0.52 (m, 2H), 0.30–0.26 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 168.6, 156.6, 142.3, 134.0, 133.8, 133.2, 129.9 (2C), 128.9 (2C), 123.6, 123.3, 119.6, 113.0, 34.4, 9.3, 4.7 (2C); HRMS (ESI-TOF) (m/z). Calcd for C₁₈H₁₆N₂O, [M + H]⁺ 277.1336; found 277.1337.

All the NMR spectra please see ESI section 3.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

Financial support by Foundation and Applied Basic Research Fund project of Guangdong Province of China (2019A1515110918); Medical Scientific Research Foundation of Guangdong Province (A2020202); Science and Technology Planning Project of Zhanjiang (2019A01018); funds for PhD researchers of Guangdong Medical University in 2019 (B2019015); and the Science and Technology Program of Guangdong Province (2019B090905011).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/d1ra00650a

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