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. 2022 Dec 2;7(49):45678–45687. doi: 10.1021/acsomega.2c06554

Facile Synthesis of Benzimidazoles via N-Arylamidoxime Cyclization

Hongjian Qin †,§, Abdullajon Odilov ‡,§, Emmanuel Mintah Bonku ‡,§, Fuqiang Zhu ∥, Tianwen Hu ∥, He Liu ∥, Haji A Aisa †,§,*, Jingshan Shen ‡,§,*
PMCID: PMC9753192  PMID: 36530318

Abstract

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A facile synthesis of benzimidazoles was described by a one-pot process containing acylation–cyclization of N-arylamidoxime. This method provided an alternative synthesis of benzimidazoles with a certain diversity of substituted groups in acceptable yields (up to 96%). More importantly, the construction of bis-benzimidazole (8), the key intermediate for making telmisartan, was achieved by adopting this method that enabled avoiding the undesired nitration with nitric/sulfuric acid and the cyclization in polyphosphoric acid in the existing operations.

Introduction

Benzimidazole is an important class of N-containing heterocycles that widely exists in a variety of bioactive compounds1−7 and pharmaceutical active ingredients, such as telmisartan8,9 and candesartan cilexetil,10,11 and esomeprazole12 (Figure 1). Benzimidazole compounds have attracted great interest of researchers, and many synthetic methods were developed due to their various biological activities and wide applications in the past several decades. Generally, benzimidazole compounds were most often constructed by condensation of o-phenylenediamines with carboxylic acid derivatives13−17 as well as aldehydes,18−20 ketones,21 primary aliphatic amines,22 and alcohols23,24 (Scheme 1A). Additionally, the synthesis of benzamidines from amidines through metal-catalyzed or oxidative cyclization was also explored (Scheme 1B).25−29 Recently, benzimidazoles were generated from N-phenylamidoxime esters with the iridium photocatalyst.30N-Arylamidoximes have been previously used to prepare various types of heterocycles, such as benzoxazoles,31 1,2,4-thiadiazole-5-thiones,32 1,2,4-oxadiazole-5-(4H)-thiones,33 and fulleroimidazole derivatives.34 Nevertheless, the synthesis of benzimidazoles with N-arylamidoxime was rarely reported,35,36 and the functional group scope was rather narrow. Herein, we report a “one-pot” acylation–cyclization method for the synthesis of benzimidazoles with various functional groups from N-aryl amidoxime (Scheme 1C). In addition, this method provided an improved approach for making telmisartan, avoiding the undesired nitration with nitric/sulfuric acid and the cyclization with polyphosphoric acid in the existing operations.37,38

Figure 1.

Figure 1

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Representative benzimidazole-containing drugs.

Scheme 1. (A,B) Previous Methods and (C) This Method for the Synthesis of Benzimidazoles through One-Pot Acylation–Cyclization of N-Arylamidoxime.

Scheme 1

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Results and Discussion

We started our investigations by screening the cyclization reaction conditions with N-arylamidoxime 1 as the model substrate (Table 1). First, N-arylamidoxime 1 was acylated by various leaving groups to afford compound 2, which was then treated with alkaline solution to produce benzimidazole 3. The types of leaving groups and bases were screened. In the initial screening, N-arylamidoxime 1 (1 mmol) was treated with a p-TsCl leaving group (1 eq) and N,N-diisopropylethylamine (DIPEA, 2.5 eq) in acetonitrile (MeCN) to produce benzimidazole 3 in 85% yield (entry 1). Upon replacement with other leaving groups such as p-nitrobenzoyloxy, benzoyloxy, and acetoxy, only a trace of benzimidazole 3 was observed (Table 1, entries 2–4, respectively). Furthermore, increasing the reaction temperature showed an ineffective conversion of intermediate 2 (Table 1, entries 5–7).

Table 1. Optimization of the Cyclization Reaction for Benzimidazole 3.

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a

The reactions were performed on the scale of 1 mmol of 1 under the conditions: 1 equiv of acylation reagent, 4 equiv of base.

b

The reactions were performed on the scale of 1 mmol of 1 under the conditions: 1 equiv of acylation reagent, 2.5 equiv of base.

c

The yields were given as isolated yields.

As an alternative, the reactions were carried out with potassium hydroxide (KOH) to replace DIPEA in acetonitrile, and benzimidazole 3 was obtained in 57–70% yield (Table 1, entries 8–13, respectively). In addition, the reaction in chlorobenzene (PhCl) with DIPEA at 25 °C showed only a trace of benzimidazole 3 (Table 1, entries 14–16, respectively), whereas the conversion of intermediate 2 to product 3 occurred with over 50% of unreacted 2 remaining at 100 °C (Table 1, entries 17–19). When the reaction temperature was raised to the refluxing temperature of chlorobenzene (132 °C) in the presence of DIPEA, the desired benzimidazole 3 was achieved with moderate isolated yields (Table 1, entries 20 and 21, respectively). In fact, when 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was used instead of DIPEA, the desired product 3 was obtained with significantly increased isolated yields of over 89% (Table 1, entries 22 and 23, respectively). Thus, we chose our acylation–cyclization process using AcCl as an acylation reagent with DBU as the base in PhCl at refluxing temperature (132 °C) (Table 1, entry 22) as the optimum reaction condition for further studies.

With reliable conditions in hand, we then investigated the scope and generality of the cyclization process (Table 2). It was found that both methyl- and ester-substituted phenyl moieties of N-arylamidoxime (1a–1c, 1f, 1k, 1o) underwent the reactions smoothly, generating the desired benzimidazoles (3a–3c, 3f, 3k, 3o(39)) in comparable yields (65–90%). In addition, electronic effects of the substituents on the phenyl moiety were observed. Methoxy-substituted phenyl substrates (1d–1e, 1v) well participated in the “one-pot” acylation–cyclization reaction, leading to benzimidazoles (3d–3e, 3v) in 85–95% yields, and the chloro- or fluoro-substituted phenyl moiety (1g–1h) also resulted in high reaction outcomes (3g, 92% yield, 3h, 85% yield). Furthermore, unsubstituted phenyl moiety substrates (1, 1x) were compatible with this reaction to afford benzimidazole products (3, 3x) with excellent yields (92–96%). In contrast, when an electron-withdrawing substituent such as a nitro group (1l, 1m) and nitrile (1n) reacted, the yields of the corresponding products (3l, 3m, 3n) were decreased (43–75% yield). The yield of benzimidazole 3l (75% yield) was higher than that of 3m (55% yield) or 3n (43% yield), due to the substituent of the amidoxime moiety which was swapped from n-propyl to conjugation substituent phenyl. In addition, a series of benzimidazole products could be delivered using substrates bearing substituents on an amidoxime moiety. For example, the ethoxyl or methylthio group at the amidoxime moiety was well tolerated, in which the corresponding products (3p–3r, 3s,393t, 3u,403w) were furnished in 35–75% yields. Notably, substrates carrying the 1-naphthyl moiety (1i) and pyridyl moiety (1j) were applicable in this protocol, giving rise to 3i (90% yield) and 3j (70% yield), demonstrating broad applicability of the present reaction to the synthesis of invaluable imidazole derivatives.

Table 2. Substrate Scope of the Cyclization Reaction for Benzimidazolesa.

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a

The reactions were performed on the scale of 1 mmol of 1, 1a–1x, under the conditions: 1.2 equiv of acylation reagent, 2.5 equiv DBU, PhCl as a solvent, 132 °C. The yields were given as isolated yields.

b

Ratio of regioisomeric products. See the Supporting Information for the structure of the minor isomers.

c

Tautomers were obtained. See the Supporting Information for the structure of the tautomer.

Next, we demonstrated the utility of our cyclization approach by applying it to construct the key intermediate bis-benzimidazole 8 for telmisartan (Scheme 2). First, aniline 4 could be easily synthesized in two steps in 96% yield from 3x through N-methylation of the imidazole moiety and catalytic hydrogenation of the nitro group. Subsequently, N-arylamidoxime 6 was prepared via the displacement of hydroxylamine with N-arylbutyrimidate 5, which was obtained by the condensation of aniline 4 with trimethylorthobutyrate in total 93% yield. N-Arylamidoxime 6 further converted to bis-benzimidazole 8 using our optimized conditions with an isolated yield of 96%.

Scheme 2. Postapplication for the Synthesis of Bis-Benzimidazole (8).

Scheme 2

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Based on the references34 and above-mentioned experimental facts, the plausible mechanism for the cyclization of N-arylamidoxime is depicted in Scheme 3. First, N-arylamidoxime 1 reacts with acetyl chloride to afford 2 which is to form an acetoxy leaving group. Afterward, the deacetoxylation of 2 promoted by a base would follow path 1 to produce the nitrene intermediate A, which in turn undergoes electrocyclization or C–H insertion to form the intermediate B and involves two sequential proton transfer steps to provide benzimidazole 3. In addition, an alternative pathway via the direct cyclization to generate the intermediate B was also plausible (Path 2).

Scheme 3. Plausible Mechanism for the Cyclization Step.

Scheme 3

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Conclusions

In summary, the synthesis of benzimidazoles by one-pot acylation–cyclization of N-arylamidoxime was developed in acceptable yields and exhibited good substituent tolerance. The precious metal, expensive ligands, and harsh reaction conditions were excluded in this approach, and the nitration and subsequent reduction steps required for the preparation of o-phenylenediamine were eliminated. In addition, the utility of the method was demonstrated in the synthesis of the key intermediate bis-benzimidazole (8) for telmisartan without using nitric acid, sulfuric acid, and polyphosphoric acid. Further extension of this N-arylamidoxime cyclization approach is ongoing in our laboratory.

Experimental Section

General Methods

1H NMR and 13C NMR spectra were recorded on a Bruker 400, 500, or 600 Hz instrument. Data for 1H NMR were presented as the chemical shift in ppm, and multiplicities were denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. Data for 13C NMR were reported as the chemical shift. The ESI mass spectra were determined on a Thermo Fisher FINNIGAN LTQ instrument. All high-resolution mass spectra (HRMS) results were obtained on an Agilent 1290-6545 UHPLC-QTOF LC/MS spectrometer. Thin-layer chromatography was performed on silica gel plates (GF-254). DCM refers to dichloromethane. Flash column chromatography was carried out using commercially available 200–300 mesh under pressure unless otherwise indicated. All commercially available chemicals and solvents were directly used without further purification unless otherwise noted.

General Procedure

Synthesis of Benzimidazoles 3, 3a–3w

To a mixture of 1, 1a–1w (1 mmol) and DBU (2.5 mmol) in chlorobenzene (3 mL) was added acetyl chloride (1.2 mmol), and the mixture was stirred for 60 min at 5 °C. Afterward, the reaction mixture was stirred for 1–5 h at 132 °C. Then the reaction mixture was cooled to 25 °C and quenched with water. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica-gel column chromatography to give 3, 3a–3w.

Benzimidazoles 3

Following the general procedure, 3 was obtained from 1 (180 mg, 1.0 mmol). The residue was purified by silica-gel column chromatography (DCM/MeOH = 100/1 to 30/1) to give 3(42) (147 mg, 92%) as a light yellow solid; m.p. 155–157 °C; 1H NMR (500 MHz, CDCl3) δ 7.92 (brs, 1H), 7.56 (dd, J = 6.0, 3.2 Hz, 2H), 7.35–7.16 (m, 2H), 2.93 (t, J = 7.6 Hz, 2H), 1.95–1.86 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 155.59, 138.54, 122.09, 114.58, 31.21, 21.77, 13.85; HRMS (ESI) m/z [M + H]+ calcd for C10H13N2 161.1073, found 161.1071.

Benzimidazoles 3a

Following the general procedure, 3a was obtained from 1a (251 mg, 1.0 mmol). The crude product was purified by silica-gel column chromatography (DCM/MeOH = 100/1 to 20/1) to afford the title compound 3a(37) (210 mg, 90%) as a white solid; m.p. 143–145 °C; 1H NMR (400 MHz, CDCl3) δ 8.87 (brs, 1H), 8.11 (s, 1H), 7.77 (s, 1H), 3.91 (s, 3H), 2.93 (t, J = 7.6 Hz, 2H), 2.57 (s, 3H), 1.94–1.83 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.08, 157.34, 141.81, 137.53, 124.64, 124.21, 124.06, 114.28, 52.06, 31.30, 21.76, 17.10, 13.82; HRMS (ESI): m/z [M + H]+ calcd for C13H17N2O2 233.1285, found: 233.1281.

Benzimidazoles 3b

Following the general procedure, compound 3b(43) was obtained from 1b (271 mg, 1.0 mmol). The crude product was purified by silica-gel column chromatography (DCM/MeOH = 100/1 to 20/1) to afford the title compound 3b (235 mg, 93%) as a white solid; m.p. 125–128 °C; two sets of 1H NMR data representing two isomers (10:9) were observed as indicative of the presence of tautomerism; 1H NMR (400 MHz, DMSO-d6, major isomer) δ 12.30 (s, 1H), 7.51 (s, 1H), 7.08 (s, 1H), 2.77 (t, J = 7.1 Hz, 2H), 2.45 (s, 3H), 1.78 (dt, J = 14.3, 7.2 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6, major isomer) δ 156.78, 144.90, 130.26, 124.78, 118.41, 113.43, 111.35, 30.90, 21.44, 17.09, 14.16; 1H NMR (400 MHz, DMSO-d6, minor isomer) δ 12.24 (s, 1 H), 7.40 (s, 1H), 7.08 (s, 1H), 2.77 (t, J = 7.1 Hz, 2H), 2.48 (s, 3H), 1.78 (dt, J = 14.3, 7.2 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6, minor isomer) δ 155.65, 142.30, 135.39, 133.59, 124.22, 123.20, 113.85, 30.98, 21.44, 16.75, 14.16; HRMS (ESI): m/z [M + H]+ calcd for C11H14BrN2 253.0335, found: 253.0332.

Benzimidazoles 3c

Following the general procedure, compound 3c was obtained from 1c (223 mg, 1.0 mmol). The crude product was purified by silica-gel column chromatography (DCM/MeOH = 100/1 to 20/1) to afford the title compound 3c(44) (175 mg, 85%) as a white solid; m.p. 172–174 °C; 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.98 (dd, J = 8.5, 1.4 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 2.70 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H). 13C {1H}NMR (100 MHz, CDCl3) δ 167.38, 153.70, 142.37, 138.15, 124.60, 123.89, 114.26, 60.98, 15.13, 14.38.

HRMS (ESI): m/z [M + H]+ calcd for C11H13N2O2 205.0972, found: 205.0969.

Benzimidazoles 3d

Following the general procedure, compound 3d(45) was obtained from 1d (208 mg, 1.0 mmol). The crude product was purified by silica-gel column chromatography (DCM/MeOH = 100/1 to 20/1) to afford the title compound 3d (181 mg, 95%) as a white solid; m.p. 82–84 °C; 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.7 Hz, 1H), 6.97 (d, J = 1.3 Hz, 1H), 6.83–6.74 (m, 1H), 3.73 (s, 3H), 2.82 (t, J = 7.5 Hz, 2H), 1.86–1.72 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 156.44, 154.53, 137.99, 132.47, 115.19, 111.86, 97.54, 55.87, 30.91, 21.61, 13.79; HRMS (ESI): m/z [M + H]+ calcd for C11H15N2O 191.1179, found: 191.1177.

Benzimidazoles 3e

Following the general procedure, compound 3e(46) was obtained from 1e (208 mg, 1.0 mmol). The crude product was purified by silica-gel column chromatography (DCM/MeOH = 100/1 to 20/1) to afford the title compound 3e (175 mg, 92%) as a white solid; m.p. 130–131 °C; 1H NMR (400 MHz, CDCl3) δ 7.22–7.07 (m, 2H), 6.67 (dd, J = 7.5, 1.2 Hz, 1H), 3.94 (s, 3H), 2.90 (t, J = 7.4 Hz, 2H), 2.03–1.76 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.02, 148.38, 139.72, 128.69, 122.60, 107.48, 102.62, 55.50, 31.11, 21.70, 13.85; HRMS (ESI): m/z [M + H]+ calcd for C11H15N2O 191.1179, found: 191.1176.

Benzimidazoles 3f

Following the general procedure, compound 3f was obtained from 1f (206 mg, 1.0 mmol). The crude product was purified by silica-gel column chromatography (DCM/MeOH = 100/1 to 20/1) to afford the title compound 3f (170 mg, 90%) as a white solid; m.p. 170–171 °C; 1H NMR (400 MHz, CD3OD) δ 7.34 (s, 1H), 7.20 (s, 1H), 3.16–3.12 (m, 2 H), 2.59 (s, 3H), 2.49 (s, 3H), 2.07–1.86 (m, 2H), 1.07 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ 153.34, 136.78, 131.05, 128.62, 127.96, 123.66, 110.13, 27.87, 20.61, 20.14, 15.14, 12.36; HRMS (ESI): m/z [M + H]+ calcd for C12H17N2189.1386, found: 189.1383.

Benzimidazoles 3g

Following the general procedure, compound 3g was obtained from 1g (280 mg, 1.0 mmol). The crude product was purified by silica-gel column chromatography (DCM/MeOH = 100/1 to 20/1) to afford the title compound 3g (241 mg, 92%) as a foamy solid. 1H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 7.52 (s, 1H), 2.84 (t, J = 7.5 Hz, 2H), 1.87–1.75 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ 159.62, 132.68, 131.23, 130.70, 128.14, 119.37, 117.78, 29.65, 22.65, 13.94; HRMS (ESI): m/z [M + H]+ calcd for C10H10Cl3N2262.9904, found: 262.9898.

Benzimidazoles 3h

Following the general procedure, compound 3h(47) was obtained from 1h (170 mg, 1.0 mmol). The crude product was purified by silica-gel column chromatography (DCM/MeOH = 100/1 to 20/1) to afford the title compound 3h (128 mg, 85%) as a white solid m.p. 194–196 °C; two sets of 1HNMR data representing two isomers (3:1) were observed as indicative of the presence of tautomerism; 1H NMR (400 MHz, DMSO-d6, major isomer) δ 12.47 (s, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.13–7.03 (m, 1H), 6.99–6.84 (m, 1H), 2.49 (s, 3H). 1HNMR (400 MHz, DMSO-d6, minor isomer) δ 12.71 (s, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.13–7.03 (m, 1H), 7.01–6.89 (m, 1H), 2.49 (s, 3H). 13C{1H} NMR (100 MHz, DMSO-d6) δ 152.98 (d, J = 247.7 Hz), 152.37, 138.08 (d, J = 9.4 Hz), 132.11 (d, J = 16.2 Hz), 122.28 (d, J = 7.2 Hz), 107.59, 106.71 (d, J = 17.6 Hz), 15.01; HRMS (ESI): m/z [M + H]+ calcd for C8H8FN2151.0666, found: 151.0662.

Benzimidazoles 3i

Following the general procedure, compound 3i(48) was obtained from 1i (230 mg, 1.0 mmol). The crude product was purified by silica-gel column chromatography (DCM/MeOH = 100/1 to 20/1) to afford the title compound 3i (190 mg, 90%) as a white solid; m.p. 90–93 °C; 1H NMR (400 MHz, CD3OD) δ 8.36–8.28 (m, 1H), 8.09–8.01 (m, 1H), 7.97–7.89 (m, 1H), 7.78–7.67 (m, 2H), 7.67–7.60 (m, 1H), 3.22 (t, J = 7.7 Hz, 2H), 2.08–1.95 (m, 2H), 1.11 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (100 MHz, CD3OD) δ 153.08, 132.64, 132.61, 130.30, 129.33, 129.26, 128.69, 127.91, 122.09, 121.98, 113.12, 29.28, 22.13, 13.82; HRMS (ESI): m/z [M + H]+ calcd for C14H15N2 211.1230, found: 211.1226.

Benzimidazoles 3j

Following the general procedure, compound 3j was obtained from 1j (180 mg, 1.0 mmol). The crude product was purified by silica-gel column chromatography (DCM/MeOH = 100/1 to 20/1) to afford the title compound 3j (113 mg, 70%) as a foamy solid; 1H NMR (400 MHz, CD3OD) δ 9.37 (s, 1H), 8.69 (d, J = 6.5 Hz, 1H), 8.24 (d, J = 6.5 Hz, 1H), 3.18 (t, J = 7.6 Hz, 1H), 2.05–1.94 (m, 2H), 1.10 (t, J = 7.4 Hz, 1H). 13C{1H} NMR (100 MHz, CD3OD) δ 164.72, 145.00, 135.15, 134.63, 131.58, 111.27, 29.86, 20.43, 12.52; HRMS (ESI): m/z [M + H]+ calcd for C9H12N3 162.1026, found: 162.1023.

Benzimidazoles 3k

Following the general procedure, compound 3k(49) was obtained from 1k (250 mg, 1.0 mmol). The crude product was purified by silica-gel column chromatography (DCM/MeOH = 100/1 to 20/1) to afford the title compound 3k (205 mg, 88%) as a foamy solid; 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 0.7 Hz, 1H), 8.26 (dd, J = 8.6, 1.4 Hz, 1H), 7.86 (d, J = 8.6 Hz, 1H), 4.46 (q, J = 7.1 Hz, 2H), 3.59 (dt, J = 14.0, 7.0 Hz, 1H), 1.60 (d, J = 7.0 Hz, 6H), 1.45 (t, J = 7.1 Hz, 4H); 13C{1H} NMR (100 MHz, CD3OD) δ 166.80, 162.56, 135.29, 132.19, 129.90, 128.26, 116.50, 114.89, 62.83, 29.08, 20.38, 14.61; HRMS (ESI): m/z [M + H]+ calcd for C13H17N2O2 233.1285, found: 233.1282.

Benzimidazoles 3l

Following the general procedure, compound 3l was obtained from 1l (316 mg, 1.0 mmol). The crude product was purified by silica-gel column chromatography (DCM/MeOH = 100/1 to 20/1) to afford the title compound 3l (224 mg, 75%) as a light yellow solid; m.p. 154–156 °C; 1H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.09–7.90 (m, 2H), 7.69 (d, J = 1.1 Hz, 1H), 7.60–7.44 (m, 1H), 7.37–7.18 (m, 1H), 7.00 (dd, J = 8.1, 1.0 Hz, 1H), 2.08 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 167.95, 152.83, 150.48, 142.18, 135.22, 134.51, 134.47, 133.49, 133.47, 128.11, 127.06, 125.82, 125.27, 125.07, 19.72; HRMS (ESI): m/z [M + H]+ calcd for C14H14N4O4 299.0775, found: 299.0772.

Benzimidazoles 3m

Following the general procedure, compound 3m(50) was obtained from 1m (223 mg, 1.0 mmol). The crude product was purified by silica-gel column chromatography (DCM/MeOH = 100/1 to 20/1) to afford the title compound 3m (113 mg, 55%) as a light yellow solid; m.p. 160–162 °C; 1H NMR (400 MHz, CD3OD) δ 8.66 (d, J = 1.9 Hz, 1H), 8.46 (dd, J = 9.0, 2.1 Hz, 1H), 7.97 (d, J = 9.0 Hz, 1H), 3.28–3.20 (m, 2H), 2.07–1.95 (m, 2H), 1.12 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (100 MHz, CD3OD) δ 158.86, 145.89, 134.82, 130.75, 121.08, 114.31, 110.08, 28.32, 20.12, 12.39; HRMS (ESI): m/z [M + H]+ calcd for C10H12N3O2 206.0924, found: 206.0921.

Benzimidazoles 3n

Following the general procedure, compound 3n was obtained from 1n (223 mg, 1.0 mmol). The crude product was purified by silica-gel column chromatography (DCM/MeOH = 100/1 to 20/1) to afford the title compound 3n (113 mg, 55%) as a light yellow solid; m.p. 168–169 °C. 1H NMR (400 MHz, CD3OD) δ 8.12 (d, J = 8.3 Hz, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.75 (t, J = 8.0 Hz, 1H), 3.24 (t, J = 7.7 Hz, 2H), 2.12–1.93 (m, 2H), 1.13 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (100 MHz, CD3OD) δ 157.02, 131.81, 131.62, 130.56, 126.08, 118.79, 113.97, 97.97, 28.09, 20.48, 12.40; HRMS (ESI): m/z [M + H]+ calcd for C11H12N3 186.1026, found: 186.1024.

Benzimidazoles 3k and 3o

Following the general procedure, compounds 3k and 3o were obtained from 1o (250 mg, 1.0 mmol). The crude product was purified by silica-gel column chromatography (DCM/MeOH = 100/1 to 50/1) to afford compound 3o (151 mg, 65%) as a foamy solid and silica-gel column chromatography (DCM/MeOH = 50/1 to 20/1) to afford 3k (50 mg, 22%); for compound 3o1H NMR (400 MHz, CD3OD) δ 8.22 (d, J = 7.7 Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.76–7.68 (m, 1H), 4.57 (q, J = 7.1 Hz, 1H), 3.72 (dd, J = 14.0, 7.0 Hz, 1H), 1.59 (d, J = 7.0 Hz, 1H), 1.48 (t, J = 7.1 Hz, 1H); 13C{1H} NMR (100 MHz, CD3OD) δ 165.82, 162.51, 134.81, 131.80, 128.38, 126.46, 120.40, 117.97, 62.93, 28.87, 21.01, 14.72; HRMS (ESI): m/z [M + H]+ calcd for C13H17N2O2 233.1285, found: 233.1283.

Benzimidazoles 3p

Following the general procedure, compound 3p was obtained from 1p (210 mg, 1.0 mmol). The crude product was purified by silica-gel column chromatography (DCM/MeOH = 100/1 to 20/1) to afford the title compound 3p (144 mg, 75%) as a foamy solid; 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 2.4 Hz, 1H), 6.75 (dd, J = 8.7, 2.4 Hz, 1H), 4.58 (d, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 158.11, 155.72, 137.01, 130.44, 113.82, 109.54, 98.52, 66.28, 56.02, 14.73; HRMS (ESI): m/z [M + H]+ calcd for C10H13N2O2 193.0982, found: 193.0979.

Benzimidazoles 3q

Following the general procedure, compound 3q was obtained from 1q (210 mg, 1.0 mmol). The crude product was purified by silica-gel column chromatography (DCM/MeOH = 100/1 to 20/1) to afford the title compound 3q (124 mg, 65%) as a foamy solid; 1H NMR (400 MHz, CDCl3) δ 7.03 (s, 1H), 6.77 (s, 1H), 4.57 (q, J = 7.1 Hz, 2H), 2.42 (s, 3H), 2.38 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 157.87, 136.76, 133.17, 131.02, 123.54, 122.45, 111.60, 65.88, 21.49, 16.83, 14.62; HRMS (ESI): m/z [M + H]+ calcd for C11H15N2O 191.1179, found: 191.1176.

Benzimidazoles 3r

Following the general procedure, compound 3r was obtained from 1r (184 mg, 1.0 mmol). The crude product was purified by silica-gel column chromatography (DCM/MeOH = 100/1 to 20/1) to afford the title compound 3r (97 mg, 55%) as a foamy solid; 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 7.5 Hz, 1H), 7.05 (t, J = 7.7 Hz, 1H), 6.94 (d, J = 7.5 Hz, 1H), 4.60 (q, J = 7.1 Hz, 2H), 2.51–2.42 (m, 3H), 1.43 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 157.96, 136.87, 135.00, 131.13, 122.34, 121.45, 111.70, 66.02, 16.86, 14.62; HRMS (ESI): m/z [M + H]+ calcd for C10H13N2O 177.1022, found: 177.1020.

Benzimidazoles 3s and 3w

Following the general procedure, compound 3s(51) and 3w were obtained from 1s (252 mg, 1.0 mmol). The crude product was purified by silica-gel column chromatography (DCM/MeOH = 80/1 to 50/1) to afford compound 3s (82 mg, 35%) as a foamy solid and silica-gel column chromatography (DCM/MeOH = 50/1 to 20/1) to afford 3w (28 mg, 12%) as a foamy solid; for compound 3s1H NMR (400 MHz, CDCl3) δ 9.56 (brs, 1H), 7.78–7.64 (m, 2H), 7.30–7.04 (m, 1H), 4.62 (q, J = 7.1 Hz, 2H), 4.49–4.36 (m, 2H), 1.54–1.40 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.34, 153.28, 136.56, 127.97, 117.21, 117.05, 115.73, 107.10, 61.08, 55.77, 9.35, 9.17; HRMS (ESI): m/z [M + H]+ calcd for C12H15N2O3 235.1077, found: 235.1073; for compound 3w1HNMR data representing two isomers (1:1) were observed as indicative of the presence of tautomerism for 3w. 1H NMR (400 MHz, DMSO-d6, two isomer mixture) δ 12.22 (s, 0.5H), 12.16 (s, 0.5H), 7.96 (s, 0.5H), 7.81 (s, 0.5H), 7.72 (dd, J = 8.3, 1.6 Hz, 1H), 7.44 (d, J = 8.3 Hz, 0.5H), 7.31 (d, J = 8.3 Hz, 0.5H), 4.60–4.45 (m, 2H), 4.30 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, DMSO-d6, two isomer mixture) δ 166.87, 166.70, 160.81, 159.98, 145.74, 141.28, 137.16, 132.97, 122.97, 122.80, 122.70, 122.40, 118.40, 116.83, 111.39, 110.01, 66.24, 66.11, 60.74, 14.92, 14.73; HRMS (ESI): m/z [M + H]+ calcd for C12H15N2O3 235.1077, found: 235.1074.

Benzimidazoles 3t

Following the general procedure, compound 3t was obtained from 1t (205 mg, 1.0 mmol). The crude product was purified by silica-gel column chromatography (DCM/MeOH = 100/1 to 20/1) to afford the title compound 3t (71 mg, 38%) as a foamy solid; 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.9 Hz, 1H), 7.45 (dd, J = 7.7, 0.5 Hz, 1H), 7.20 (t, J = 7.9 Hz, 1H), 4.68 (q, J = 7.1 Hz, 2H), 1.50 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 160.51, 143.36, 133.70, 125.30, 121.24, 118.04, 115.25, 98.87, 66.65, 14.89; HRMS (ESI): m/z [M + H]+ calcd for C10H10N3O 188.0818, found: 188.0815.

Benzimidazoles 3u

Following the general procedure, compound 3u was obtained from 1u (212 mg, 1.0 mmol). The crude product was purified by silica-gel column chromatography (DCM/MeOH = 100/1 to 20/1) to afford the title compound 3u (68 mg, 35%) as a foamy solid; 1H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 7.33 (d, J = 8.7 Hz, 1H), 6.97 (s, 1H), 6.74 (dd, J = 8.7, 2.4 Hz, 1H), 3.77 (s, 3H), 2.67 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 155.16, 150.19, 139.83, 134.63, 114.44, 110.06, 96.98, 55.37, 13.90; HRMS (ESI): m/z [M + H]+ calcd for C9H11N2OS 195.0587, found: 195.0585.

Benzimidazoles 3v

Following the general procedure, compound 3v(52) was obtained from 1v (164 mg, 1.0 mmol). The crude product was purified by silica-gel column chromatography (DCM/MeOH = 100/1 to 30/1) to give 3v (110 mg, 75%) as a light yellow solid; m.p. 168–169 °C; 1H NMR (500 MHz, Acetone-d6) δ 8.28 (s, 1H), 7.33 (d, J = 4.2 Hz, 1H), 7.17 (t, J = 7.9 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 3.99 (s, 1H); 13C{1H}NMR (125 MHz, acetone-d6) δ 150.94, 142.66, 131.52, 127.09, 124.84, 110.13, 105.04, 57.02; HRMS (ESI) m/z [M + H]+ calcd for C8H9N2O 149.0709, found 149.0708.

Benzimidazoles 3w

Following the general procedure, compound 3w was obtained from 1w (252 mg, 1.0 mmol). The crude product was purified by silica-gel column chromatography (DCM/MeOH = 100/1 to 30/1) to give 3w (106 mg, 45%) as a foamy solid; 1H NMR data representing two isomers (1:1) were observed as indicative of the presence of tautomerism for 3w. 1H NMR (400 MHz, DMSO-d6, two isomer mixture) δ 12.22 (s, 0.5 H), 12.16 (s, 0.5 H), 7.96 (s, 0.5H), 7.81 (s, 0.5H), 7.72 (dd, J = 8.3, 1.6 Hz, 1H), 7.44 (d, J = 8.3 Hz, 0.5H), 7.31 (d, J = 8.3 Hz, 0.5H), 4.60–4.45 (m, 2H), 4.30 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, DMSO-d6, two isomer mixture) δ 166.87, 166.70, 160.81, 159.98, 145.74, 141.28, 137.16, 132.97, 122.97, 122.80, 122.70, 122.40, 118.40, 116.83, 111.39, 110.01, 66.24, 66.11, 60.74, 14.92, 14.73; HRMS (ESI): m/z [M + H]+ calcd for C12H15N2O3 235.1077, found: 235.1074.

Synthesis of Compound 3x

Acetyl chloride (2.06 g, 26.25 mmol) was added to a flask containing 1x (6.8 g, 25 mmol), DBU (9.45 g, 62.5 mmol), and chlorobenzene (75 mL) at 5 °C. Then, the resulting mixture was stirred for 30 min at 5 °C. After being refluxed for 1 h, the reaction mixture was cooled to 25 °C and then quenched by water. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica-gel column chromatography (DCM/MeOH = 100/1 to 30/1) to give 3x (6.0 g, 96%) as a light yellow solid; m.p. 221–223 °C; 1H NMR (400 MHz, DMSO-d6) δ 13.33 (s, 1H), 8.31 (s, 1H), 8.25–8.16 (m, 2H), 7.66 (dd, J = 5.9, 3.2 Hz, 2H), 7.32–7.23 (m, 2H), 2.64 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 149.46, 149.35, 139.93, 134.75, 134.18, 130.85, 130.75, 125.83, 125.31, 123.24, 115.90, 20.34; HRMS (ESI) m/z [M + H]+ calcd for C14H12N3O2 254.0924, found 254.0919.

Synthesis of Compound S2

Dimethyl sulfate (2.62 g, 20 mmol) was added to a flask containing 3x (5.06 g, 20 mmol), sodium methanolate (2.16 g, 40 mmol), and dry acetonitrile (50 mL) at 5 °C. After being stirred for 3 h at 25 °C and then quenched by water, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica-gel column chromatography (DCM/MeOH = 100/1 to 30/1) to give S2(28) (5.24 g, 98%) as a yellow solid; m.p. 186–188 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 8.5 Hz, 1H), 8.03 (d, J = 0.9 Hz, 1H), 7.96 (dd, J = 8.4, 1.7 Hz, 1H), 7.70 (dd, J = 19.3, 7.9 Hz, 2H), 7.41–7.25 (m, 2H), 3.94 (s, 3H), 2.64 (s, 3H). 13C{1H} NMR (100 MHz, DMSO-d6) δ 150.88, 149.16, 142.37, 136.73, 134.56, 133.39, 133.28, 127.92, 124.76, 123.02, 122.33, 119.30, 110.84, 31.81, 19.49. HRMS (ESI) m/z [M + H]+ calcd for C15H14N3O2 268.1081, found 268.1079.

Synthesis of Compound 4

S2 (5.34 g, 20 mmol) was reduced with Raney nickel (0.1 g) and hydrogen (5 bar) in ethanol (100 mL) 30 °C for 12 h. The insoluble substances were filtered away, and the filtrate was removed by a rotary evaporator to give 4(28,29) (4.65 g, 98%) as a white solid; m.p. 148–150 °C. 1H NMR (400 MHz, DMSO-d6) δ 7.60 (dd, J = 4.5, 3.7 Hz, 1H), 7.50 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.2 Hz, 1H), 7.27–7.14 (m, 2H), 6.77 (d, J = 8.2 Hz, 1H), 5.37 (s, 2H), 3.83 (s, 3H), 2.17 (s, 3H). 13C{1H} NMR (100 MHz, DMSO-d6) δ 154.74, 148.76, 143.15, 137.13, 131.60, 128.30, 121.94, 121.91, 121.28, 118.77, 117.61, 113.86, 110.46, 32.20, 17.92. HRMS (ESI) m/z calcd for C15H16N3 [M + H]+: 238.1339, found 238.1336.

Synthesis of Compound 5

To a suspension of 4 (4.22 g, 17.8 mmol) in toluene (20 mL) were added trimethyl orthobutyrate (2.9 g, 19.6 mmol) and acetic acid (1.06 g, 17.8 mol). The resulting mixture was heated for 3 h at 60 °C and concentrated in vacuo to give 5 (5.8 g, 100%) which was used for the next step without further purification; 1H NMR (600 MHz, CDCl3) δ 7.80–7.77 (m, 1H), 7.61 (s, 1H), 7.47 (dd, J = 8.0, 1.8 Hz, 1H), 7.36–7.33 (m, 1H), 7.27 (dd, J = 5.9, 3.0 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 2.16 (s, 3H), 2.12–2.06 (m, 2H), 1.53 (m, 2H), 0.83 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (150 MHz, CDCl3) δ 163.18, 153.71, 148.58, 142.35, 136.06, 131.07, 128.98, 127.02, 123.92, 121.99, 121.82, 120.30, 119.06, 109.01, 52.80, 31.39, 31.26, 18.96, 17.45, 13.38; HRMS (ESI) m/z [M + H]+ calcd for C20H23N3O 322.1914, found 322.1911.

Synthesis of Compound 6

Sodium acetate (2.9 g, 35.6 mmol) was added to a flask containing hydroxylamine hydrochloride (2.46 g, 35.8 mmol) and isopropyl alcohol (40 mL) under an ice bath, and the mixture was stirred for 30 min at 0–5 °C. To the reaction mixture was added a solution of 5 (5.8 g, 17.8 mmol) in isopropyl alcohol (5 mL) at 0–5 °C. After being stirred for 16 h at 25 °C, the reaction mixture offered a viscous solid. The viscous solid was filtered, and the wet cake was washed with isopropyl alcohol (5 mL). The wet cake was suspended in water (20 mL) and stirred at 20–25 °C for 2 h. The precipitated solid was filtered and dried in a vacuum at 50 °C, affording 6 (5.34 g, 93%) as a white solid; m.p. 153–155 °C; 1HNMR (400 MHz, CDCl3) δ 7.89–7.81 (m, 1H), 7.72 (d, J = 1.3 Hz, 1H), 7.58 (dd, J = 8.1, 1.8 Hz, 1H), 7.43–7.38 (m, 1H), 7.37–7.29 (m, 2H), 7.24 (d, J = 8.2 Hz, 1H), 7.00 (br, 1H), 3.91 (s, 3H), 2.39 (s, 3H), 2.35–2.28 (m, 2H), 1.50–1.38 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.25, 153.21, 142.68, 138.92, 136.53, 133.34, 132.06, 127.58, 126.90, 125.24, 122.90, 122.62, 119.75, 109.62, 31.81, 30.94, 19.51, 17.98, 13.64; HRMS (ESI) m/z [M + H]+ calcd for C19H23N4O 323.1866, found 323.1863.

Synthesis of Compound 8

Acetyl chloride (412 mg, 5.25 mmol) was added to a flask containing 6 (1.6 g, 5 mmol), DBU (1.89 g, 12.5 mmol), and chlorobenzene (15 mL) at 5 °C. Then the resulting mixture was stirred for 30 min at 5 °C. After being refluxed for 1 h, the reaction mixture was cooled to 25 °C and then quenched by water. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica-gel column chromatography (DCM/MeOH = 100/1 to 30/1) to give 8(37) (1.43 g, 96%) as a white solid; m.p. 130–132 °C; 1HNMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.44 (s, 1H), 7.33–7.18 (m, 2H), 3.90 (s, 3H), 2.85 (t, J = 7.5 Hz, 2H), 2.59 (s, 3H), 1.89–1.78 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6): δ 156.20, 154.33, 142.49, 138.87, 136.60, 124.14, 123.13, 122.88, 121.90, 121.70, 118.61, 113.38, 110.29, 31.71, 30.58, 21.04, 16.79, 13.71; HRMS (ESI): m/z [M + H]+ calcd for C19H21N4 305.1761, found: 305.1756.

Acknowledgments

This work was supported financially by the West Light Foundation of The Chinese Academy of Sciences (Grant No. 2018-XBYJRC-001) and 2020 ANSO Collaborative Research Project (number: ANSO-CR-SP-2020-03).

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.2c06554.

  • Experimental details and compound characterization data (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao2c06554_si_001.pdf (5.5MB, pdf)

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