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DOI: 10.1055/a-2102-1192
One-Pot Telescopic Approach to Synthesize Disubstituted Benzimidazoles in Deep Eutectic Solvent
K.C. would like to thank the administration of the Vellore Institute of Technology for offering seed money as a research grant.
Abstract
An ongoing challenge in the pharmaceutical sector is the need to find and implement novel synthetic approaches because traditional methods sometimes violate the principles of green chemistry. While benzimidazoles are of great importance as building blocks for the creation of molecules having pharmacological activity, the development of methods for their sustainable synthesis has been a challenge for organic synthesis. Herein, we have carried out a one-pot telescopic approach to the synthesis of disubstituted benzimidazole derivatives in a deep eutectic solvent (DES) medium to investigate an alternate synthetic technique. Starting with methyl 4-fluoro-3-nitrobenzoate, SNAr reaction, reduction, and cyclization were performed with choline chloride/glycerol/H2O as DES medium, which gave the best performance out of the five DESs examined. We report the synthesis of disubstituted benzimidazoles via one-pot telescopic approach.
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Key words
deep eutectic solvent - benzimidazole - sustainable organic synthesis - telescopic approachHeterocyclic compounds, which are crucial to life, can be found across the natural world. Heterocyclic molecules serve an important part in the cellular metabolism of all known organisms.[1] Almost one third of marketed drugs constitute heterocyclics as a pharmacophore.[2] Also, they have outstanding photophysical properties, which make them useful in interdisciplinary research projects such as bioimaging. Recently, we evaluated a number of chemical synthesis techniques for heterocyclic compounds that may be of biological interest, including nanoparticle catalyzed synthesis,[3] ionic liquid mediated synthesis,[4] microwave-assisted, and water assisted synthesis.[5] Of all nitrogen-based heterocyclic compounds, the five-membered heterocyclic ring attached to a benzene moiety has a special significance, whether they are natural or man-made. Benzimidazole stands out for its significant biological and industrial applications. In recent decades, there has been intense interest in eco-friendly ways for synthesizing benzimidazole derivatives because of their diverse pharmacological properties, which includes anticancer, antihypertensive, anti-inflammatory, antimicrobial, antidiabetic, antidepressant, and antiviral activities.[6] Commercial drugs such as pantoprazole (A), thiabendazole (B), omeprazole (C), bendamustine (D), and rabeprazole (E), contain benzimidazole as privileged scaffolds, as depicted in Figure [1].[7]
In 2017, we published an extensive review of the various synthetic methodologies for the synthesis of benzimidazoles, which include conventional, solid-phase, and green synthetic approaches.[8] Subsequently, in 2018, Dipankar et al. reported the synthesis of benzimidazoles using a manganese complex.[9a] Sanzhong and his group also demonstrated the synthesis of benzimidazoles by using o-quinone as catalyst.[9b] In 2018, Xu et al. reported the synthesis of benzimidazole derivatives using nickel catalyst.[9c] Recently, Yun and his group accomplished the formation of benzimidazoles by using DMSO as carbon source.[9d] However, most of the synthetic routes used toxic solvents, transition-metal catalyst, high temperature conditions, and suffered from a lack of diversity. As part of our research program on the development of a new generation of heterocyclic scaffolds employing green synthetic techniques,[10] herein we report for the first time a one-pot telescopic approach to synthesize benzimidazole derivatives using deep eutectic solvent (DES) as reaction medium. Recently, numerous research groups have focused on sustainable synthesis of heterocyclic molecules in DES as reaction medium.[11]
Hydrogen-bond acceptors (HBAs) and hydrogen-bond donors (HBDs), both of which are often naturally occurring and biodegradable, complex together to form deep eutectic systems. Hence, it is anticipated that DES will be biodegradable and will exhibit lower toxicity compared to other solvents. Low melting points, non-flammable nature, chemical and thermal stability, low vapor pressure, polarity, high solubility, low volatility, and miscibility are some of the benefits of this unique class of solvents.[12] Sreekumar et al. reported the synthesis of benzimidazoles from o-phenylene diamine (o-PDA) in DES (ZrCl2·8H2O:urea) medium (Figure [2a]).[13] Procopio et al. accomplished the synthesis of benzimidazole derivatives from o-phenylene diamine in DES (Ch. Cl.: urea) (Figure [2b]).[14]
Throughout the years, the versatility of a one-pot telescopic approach for the preparation of heterocyclic compounds or medicines has become well-established.[15] The main advantage of a one-pot process is that it avoids the separation and purification of intermediates and, instead, uses a high yielding, time-saving method. In order to avoid complex synthetic processes and prolonged reaction periods, mild and environmentally friendly reactions are in high demand nowadays. We recently achieved the one-pot telescopic synthesis of complex heterocycles from the 2-amino pyridine moiety.[16] Excited by the outcome, we planned to use DES as reaction medium for the one-pot telescopic method to produce structural and diversified benzimidazole derivatives.
We started our study by a benchmark reaction between methyl 4-fluoro-3-nitro benzoate (1) and cychexenylethnylamine (2a) as model reaction for the aromatic nucleophilic substitution (SNAr) reaction (Scheme [1]).
a The reaction was performed using 1 (1 equiv) and 2a (1 equiv).
b The reaction was performed at 60 °C.
c Isolated yield of compound 3a.
As expected, using choline chloride/ethylene glycol as DES medium, product 3a was obtained in 81% yield in 60 min at 60 °C (Table [1], entry 1). Further, when the same reaction was performed in choline chloride/urea as DES medium, no dramatic increase in the product yield was observed (entry 2). However, by use of choline chloride/glucose as reaction medium for 55 min at the same temperature, the yield of the product decreased to 79% (entry 3). Subsequently, using choline chloride/glycerol as reaction medium, 93% yield was recorded for the product 3a (entry 4). Interestingly, when choline chloride/glycerol/water (1:2:3) was used as the reaction medium, the yield of the product rose to 96% within 40 min (entry 5).
Once we had achieved the synthesis of product 3a, our next target was to reduce the nitro group in compound 3a to generate the diamine moiety for heterocyclization. For this purpose, we used Zn dust/HCl as the reducing agent. In the reduction step, we utilized a variety of DES to optimize the reduction conditions, as shown in Scheme [2].
The reduction of the nitro group in compound 3a was first carried out in choline chloride/ethylene glycol as DES medium at 60 °C for 35 min, which resulted in 74% yield of the product 4a (Table [2], entry 1). Subsequently, we found that switching from choline chloride/ethylene glycol to choline chloride/urea, resulted in a modest drop in yield (entry 2). The yield dropped to 70% when choline chloride/glucose was used as DES medium (entry 3). Choline chloride/glycerol was similarly effective as DES medium and yielded 81% of the product 4a (entry 4). However, to enhance the product yield, using choline chloride/glycerol/water as reaction medium dramatically increased the yield of product 4a up to 84% in 20 min (entry 5). Once we obtained the diamine intermediate 4a, our next step of the synthetic manipulation involved the creation of five-membered benzimidazole frameworks using aromatic aldehydes, as depicted in Scheme [3]. For this cyclization, we examined the key factors and optimized reaction conditions as depicted in Table [3].
a The reaction was performed using 4a (1 equiv), Zn (3 equiv) and HCl (1.5 equiv).
b The reaction was performed at 60 °C.
c Isolated yield of compound 4a.
a The reaction was performed using 4a (1 equiv) and 5a (1.1 equiv).
b The reaction was performed at 60 °C.
c Isolated yield of compound 6a.
The reaction of diamine intermediate 4a with benzaldehyde 5a in choline chloride/ethylene glycol (1:2) as solvent medium at 60 °C resulted in the generation of benzimidazole 6a in 82% yield (Table [3], entry 1). The use of choline chloride/urea (1:2) as reaction medium did not improve the yield of product 6a (entry 2). However, the use of choline chloride/glucose (1:2 ratio) as reaction medium raised the yield of the product to 78% (entry 3).
The most dramatic increase in yield of product 6a was observed (up to 95%) when using choline chloride/glycerol/water (1:2:3) as reaction medium (Table [3], entry 4). Therefore, we choose the choline chloride/glycerol/water (1:2:3) as reaction medium for the heterocyclization reaction.
Further, to establish the formation of product 6a, we performed a proton NMR spectroscopic study as shown in Figure [3]. In spectra A, it was found that three protons, Ha, Hb, and Hc, appeared at δ = 8.91, 8.10, and 6.85 ppm, respectively, whereas the peak at δ = 8.35 ppm corresponds to the NH proton. After reduction of the NO2 group in compound 3a, all aromatic protons moved to upfield positions as shown in spectra B. In spectra C, we observed the peak at δ = 8.55 ppm corresponding to Ha proton, whereas the peaks at δ = 8.05 and 7.40 ppm correspond to Hb and Hc protons, respectively. Other aromatic protons appeared at usual positions.
After successfully executing the benzimidazole ring formation to access 6a, our next target was to achieve the synthetic manipulation in a one-pot telescoped pathway. For this reason, we executed the one-pot telescoped reaction of methyl 4-fluoro-3-nitro benzoate (1) and substituted amines 2 in choline chloride/glycerol/water (1:2:3) as reaction medium at 60 °C for 40 min, which resulted in the formation of intermediate 3. Instead of isolating the intermediate product 3, the same reaction mixture was charged with Zn dust/HCl as reducing agent for the generation of diamine intermediate 4 under the same reaction conditions for 20 min. After successful reduction of the nitro group as determined by TLC, the reaction mixture was centrifuged to remove the Zn dust followed by the addition of substituted aromatic aldehydes 5 under same reaction conditions for 8 h to obtain the desired benzimidazole derivatives 6, as depicted in Scheme [4].
Upon successful execution of the reaction, the 1H NMR spectrum of the synthesized compound showed the formation of pure benzimidazole 6 in excellent yield. Next, we expanded the substrate scope to different amines and substituted aldehydes with both electron-donation and electron-withdrawing moieties. As depicted in Scheme [5], no noticeable changes in the yield of final benzimidazole derivatives 6 were observed for different aliphatic amines and substituted aldehydes. Finally, the corresponding benzimidazole derivatives 6 were successfully produced after the telescoped reaction in excellent yields. This was followed by straightforward work-up procedures that included the removal of solvent under reduced pressure, extraction, and solvent evaporation. Finally, the pure products were obtained after purification through column chromatography, which was followed by the spectroscopic analysis of the pure compounds using 1H, 13C NMR, and IR spectroscopy, and high-resolution mass (HRMS) spectrometry.
In conclusion, to create a diverse set of benzimidazole derivatives, choline chloride/glycerol/water (1:2:3) DES was used as the reaction medium. The synthetic scheme comprises the one-pot telescopic synthesis of diverse benzimidazoles via SNAr reaction, NO2 group reduction, followed by heterocyclization with aldehyde in DES medium. This is the first report of the one-pot telescopic synthesis of diverse benzimidazoles in DES medium. The key features of our method are its high reaction yield, selectivity, simplicity in solvent preparation, economy, short reaction time, and lack of chromatographic purification in each step. This approach could be used to make diverse benzimidazole derivatives of potential biological interest on a large scale, because it uses simple, environmentally friendly chemicals with low toxicity. The one-pot telescopic approach satisfies the criteria set out in the twelve principles of green chemistry.
Unless otherwise noted, all standard chemicals and solvents were used as purchased from commercial vendors without further purification. A Bruker DRX400 spectrometer was used to record 1H (400 MHz) and 13C (100 MHz) NMR spectra. Chemical shifts are reported in parts per million (ppm) relative to the internal solvent peak. Coupling constants J are given in hertz. Peak multiplicities are labeled as d (doublet), m (multiplet), s (singlet), and t (triplet). HRMS were recorded with a XEVO-G2-XS–QTOF from Waters. IR spectra were recorded with a Thermo Nicolet iS50 with inbuilt ATR from Thermo Fisher.
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Deep Eutectic Solvent (DES) Preparation
All the DESs were prepared by the heating of two or three components at 90 °C under magnetic stirring.[17] After 30–40 min, a homogeneous solution was obtained. All the DES were prepared according to the corresponding mol ratio given in the optimization tables (Table [1], Table [2], Table [3]).
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Synthesis of Disubstituted Benzimidazole
Initially, to a round-bottomed flask containing DES (choline chloride/glycerol/water 1:2:3, 3 g), methyl 4-fluoro-3-nitrobenzoate 1 (1 equiv) and 2-(cyclohex-1-en-1-yl)ethan-1-amine 2a (1 equiv) were added. The reaction mixture was then heated at 60 °C for 40 min. After completion of the reaction as monitored by TLC, Zn dust (3 equiv) and HCl (1.5 equiv) were added and the reaction mixture was heated for 20 min at 60 °C. After completion of the reaction, as monitored by TLC, Zn dust was removed by centrifuge followed by the addition of benzaldehyde 5a (1.1 equiv) and the reaction mixture was heated for 8 h. After completion of the reaction as monitored by TLC the reaction mixture was cooled and extracted with EtOAc (4 × 30 mL). The organic layer was then passed through Na2SO4 and dried under reduced pressure. The crude material was purified by column chromatography on silica gel (60–120 mesh; EtOAc/hexane) to obtained 6a.
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Methyl 1-(2-(Cyclohex-1-en-1-yl)ethyl)-2-phenyl-1H-benzo[d]imidazole-5-carboxylate (6a)
Yield: 342 mg (95%); off-white solid; mp 108–110 °C.
IR (KBr): 2933, 2851, 1608, 1695, 1445, 1081, 694 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.52 (d, J = 1.0 Hz, 1 H), 8.04 (dd, J = 8.5, 1.5 Hz, 1 H), 7.73–7.71 (m, 2 H), 7.54–7.52 (m, 3 H), 7.43 (d, J = 8.2 Hz, 1 H), 5.19 (s, 1 H), 4.33 (t, J = 7.3 Hz, 2 H), 3.95 (s, 3 H), 2.36 (t, J = 7.3 Hz, 2 H), 1.83 (s, 2 H), 1.74 (s, 2 H), 1.46–1.41 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 167.6, 155.4, 142.2, 138.6, 132.9, 130.1, 129.8, 129.3, 128.8, 124.7, 124.6, 124.2, 122.1, 109.9, 52.0, 43.7, 37.7, 28.1, 25.0, 22.5, 21.8.
HRMS (ESI): m/z [M + H]+ calcd for C23H25N2O2: 361.1916; found: 361.1922.
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Methyl 2-(4-Chlorophenyl)-1-(2-(cyclohex-1-en-1-yl)ethyl)-1H-benzo[d]imidazole-5-carboxylate (6b)
Yield: 366 mg (93%); brown solid; mp 128–130 °C.
IR (KBr): 2951, 2922, 2856, 1716, 1615, 1302, 1090, 658 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.44 (d, J = 1.0 Hz, 1 H), 7.98 (dd, J = 8.5, 1.5 Hz, 1 H), 7.62 (d, J = 8.5 Hz, 2 H), 7.46 (d, J = 8.5 Hz, 2 H), 7.37 (d, J = 8.5 Hz, 1 H), 5.14 (s, 1 H), 4.25 (t, J = 7.3 Hz, 2 H), 3.89 (s, 3 H), 2.30 (t, J = 7.3 Hz, 2 H), 1.77 (s, 2 H), 1.70 (s, 2 H), 1.42–1.35 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 167.6, 157.8, 142.6, 136.4, 132.9, 130.6, 129.2, 128.7, 128.5, 124.9, 124.7, 124.5, 122.1, 109.9, 52.0, 43.7, 37.7, 28.1, 25.0, 22.5, 21.8.
HRMS (ESI): m/z [M + H]+ calcd for C23H24ClN2O2: 395.1526; found: 395.1531.
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Methyl 1-(2-(Cyclohex-1-en-1-yl)ethyl)-2-(4-fluorophenyl)-1H-benzo[d]imidazole-5-carboxylate (6c)
Yield: 351 mg (93%); brown solid; mp 93–95 °C.
IR (KBr): 2934, 2860, 1707, 1298, 1217, 835, 755, 513 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.44 (d, J = 1.0 Hz, 1 H), 7.98 (dd, J = 8.5, 1.5 Hz, 1 H), 7.67–7.64 (m, 2 H), 7.36 (d, J = 8.5 Hz, 1 H), 7.16 (d, J = 8.5 Hz, 2 H), 5.13 (s, 1 H), 4.26–4.22 (m, 2 H), 3.89 (s, 3 H), 2.29 (t, J = 7.3 Hz, 2 H), 1.77 (s, 2 H), 1.69 (s, 2 H), 1.41–1.36 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 167.6, 156.0 (d, 1 J C–F = 155.8 Hz), 142.5, 131.4 (d, 3 J C–F = 8.6 Hz), 128.2, 124.9, 124.4, 123.0, 122.3, 116.9 (d, 2 J C–F = 21.9 Hz), 116.0, 115.9, 110.5, 109.9, 102.6, 52.1, 43.8, 37.8, 28.2, 22.5, 21.8.
HRMS (ESI): m/z [M + H]+ calcd for C23H24FN2O2: 379.1822; found: 379.1832.
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Methyl 2-(2-Bromophenyl)-1-(2-(cyclohex-1-en-1-yl)ethyl)-1H-benzo[d]imidazole-5-carboxylate (6d)
Yield: 336 mg (89%); brown viscous liquid.
IR (KBr): 3015, 2927, 2853, 1707, 1613, 1298, 1210, 658 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.47 (s, 1 H), 8.00 (dd, J = 8.5, 1.5 Hz, 1 H), 7.65 (d, J = 7.8 Hz, 1 H), 7.46–7.34 (m, 4 H), 5.10 (s, 1 H), 4.04 (t, J = 7.3 Hz, 2 H), 3.88 (s, 3 H), 2.20 (t, J = 7.3 Hz, 2 H), 1.75 (s, 2 H), 1.60 (s, 2 H), 1.43–1.33 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 167.5, 153.8, 142.3, 137.7, 133.0, 132.9, 132.3, 131.7, 131.6, 127.5, 124.6, 124.5, 124.4, 123.5, 122.5, 110.0, 60.3, 52.0, 43.7, 37.7, 28.0, 25.0, 22.5.
HRMS (ESI): m/z [M + H]+ calcd for C23H24BrN2O2: 379.1822; found: 379.1832.
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Methyl 2-(2-Bromophenyl)-1-hexyl-1H-benzo[d]imidazole-5-carboxylate (6e)
Yield: 360 mg (87%); brown viscous liquid.
IR (KBr): 3954, 2927, 2847, 1707, 1613, 1432, 1304, 1210, 668 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.48 (d, J = 1.0 Hz, 1 H), 7.99 (dd, J = 8.5, 1.5 Hz, 1 H), 7.65 (dd, J = 7.9, 1.0 Hz, 1 H), 7.45–7.33 (m, 4 H), 3.97 (t, J = 7.3 Hz, 2 H), 3.88 (s, 3 H), 1.61–160 (m, 2 H), 1.12–1.03 (m, 6 H), 0.71 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 167.5, 153.8, 142.1, 137.7, 133.9, 132.9, 132.2, 131.7, 127.5, 124.6, 124.5, 123.6, 122.4, 110.0, 52.0, 44.7, 30.9, 29.3, 26.1, 22.2, 13.8.
HRMS (ESI): m/z [M + H]+ calcd for C21H24BrN2O2: 415.1021; found: 415.1034.
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Methyl 1-(2-(Cyclohex-1-en-1-yl)ethyl)-2-(4-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylate (6f)
Yield: 354 mg (91%); brown solid; mp 106–108 °C.
IR (KBr): 3015, 2941, 2833, 1707, 1613, 1435, 1258, 1204, 658 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.43 (d, J = 1.0 Hz, 1 H), 7.95 (dd, J = 8.5, 1.5 Hz, 1 H), 7.60 (d, J = 8.8 Hz, 2 H), 7.33 (d, J = 8.5 Hz, 1 H), 6.98 (d, J = 8.8 Hz, 2 H), 5.15 (s, 1 H), 4.24 (t, J = 7.4 Hz, 2 H), 3.88 (s, 3 H), 3.82 (s, 3 H), 2.30 (t, J = 7.4 Hz, 2 H), 1.77 (s, 2 H), 1.71 (s, 2 H), 1.41–1.36 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 167.7, 161.0, 155.4, 142.5, 138.8, 133.0, 130.7, 124.6, 124.4, 124.0, 122.3, 122.0, 114.2, 109.7, 91.9, 55.4, 52.0, 43.8, 37.8, 36.6, 28.2, 25.1, 22.5.
HRMS (ESI): m/z [M + H]+ calcd for C24H27N2O3: 391.2021; found: 391.2043.
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Methyl 1-(2-(Cyclohex-1-en-1-yl)ethyl)-2-(3-fluorophenyl)-1H-benzo[d]imidazole-5-carboxylate (6g)
Yield: 336 mg (87%); brown solid; mp 94–96 °C.
IR (KBr): 2934, 2860, 1707, 1298, 1217, 835, 755, 513 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.35 (s, 1 H), 7.89 (d, J = 8.5 Hz, 1 H), 7.35–7.33 (m, 3 H), 7.25–7.08 (s, 1 H), 7.06 (t, J = 9.4 Hz, 1 H), 5.02 (s, 1 H), 4.17 (t, J = 7.1 Hz, 2 H), 3.79 (s, 3 H), 2.20 (t, J = 7.1 Hz, 2 H), 1.67 (s, 2 H), 1.59 (s, 2 H), 1.29–1.28 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 167.5, 163.9 (d, 1 J C–F = 246.3 Hz), 154.5, 142.6, 138.8, 132.8, 132.3, 132.2, 130.5 (d, 3 J C–F = 8.21 Hz), 128.5, 125.0, 124.9, 124.8, 124.5, 122.5, 117.1 (dd, 2 J C–F = 52.1 Hz, 20.9 Hz), 52.0, 43.9, 37.8, 28.2, 25.0, 22.5, 21.8.
HRMS (ESI): m/z [M + H]+ calcd for C23H24FN2O2: 379.1822; found: 379.1832.
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Methyl 1-(2-(Cyclohex-1-en-1-yl)ethyl)-2-(3,4,5-trimethoxyphenyl)-1H-benzo[d]imidazole-5-carboxylate (6h)
Yield: 396 mg (88%); brown viscous liquid.
IR (KBr): 3015, 2931, 2846, 1706, 1609, 1433, 1300, 1215, 663 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.50 (s, 1 H), 8.02 (d, J = 8.5 Hz, 1 H), 7.41 (d, J = 8.5 Hz, 1 H), 6.93 (s, 2 H), 5.23 (s, 1 H), 4.35 (t, J = 7.0 Hz, 2 H), 3.94 (s, 3 H), 3.91 (s, 9 H), 2.40 (t, J = 7.0 Hz, 2 H), 1.84 (s, 2 H), 1.78 (s, 2 H), 1.48–1.44 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 167.6, 155.3, 153.5, 142.5, 139.8, 138.8, 133.1, 125.4, 124.6, 124.6, 124.2, 122.2, 109.8, 106.7, 61.0, 56.3, 52.1, 43.9, 38.0, 28.3, 25.1, 22.5, 21.9.
HRMS (ESI): m/z [M + H]+ calcd for C26H31N2O5: 451.2233; found: 451.2261.
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Methyl 1-(2-(Cyclohex-1-en-1-yl)ethyl)-2-(2-hydroxy-3-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylate (6i)
Yield: 361 mg (89%); brown solid; mp 106–108 °C.
IR (KBr): 2994, 2927, 2847, 1714, 1613, 1458, 1251, 1076, 748 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.48 (s, 1 H), 8.06 (d, J = 8.5 Hz, 1 H), 7.43 (d, J = 8.5 Hz, 1 H), 7.28 (d, J = 8.0 Hz, 1 H), 7.01 (d, J = 8.0 Hz, 1 H), 6.94 (t, J = 8.0 Hz, 1 H), 5.29 (s, 1 H), 4.49 (t, J = 7.4 Hz, 2 H), 3.96 (s, 6 H), 2.48 (t, J = 7.4 Hz, 2 H), 1.89–1.87 (m, 4 H), 1.52–1.44 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 167.6, 153.4, 149.5, 149.3, 149.0, 140.6, 138.5, 133.1, 125.2, 124.8, 121.5, 119.1, 118.8, 113.8, 113.7, 109.9, 56.4, 52.3, 45.0, 37.9, 28.6, 25.3, 22.8, 22.1.
HRMS (ESI): m/z [M + H]+ calcd for C24H27N2O4: 407.1971; found: 407.1978.
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Methyl 1-Butyl-2-(2-hydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylate (6j)
Yield: 301 mg (93%); brown solid; mp 95–97 °C.
IR (KBr): 2961, 2920, 2874, 1700, 1291, 1217, 741 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.47 (s, 1 H), 8.06 (d, J = 8.5 Hz, 1 H), 7.64 (d, J = 8.0 Hz, 1 H), 7.44–7.37 (m, 2 H), 7.17 (d, J = 8.5 Hz, 1 H), 6.99 (t, J = 8.0 Hz, 1 H), 4.42 (t, J = 7.5 Hz, 2 H), 3.96 (s, 3 H), 2.03–1.92 (quint, J = 7.5 Hz, 2 H), 1.49–1.47 (m, 2 H), 1.02 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 167.3, 159.1, 152.9, 140.1, 138.4, 131.9, 126.4, 125.2, 124.8, 121.1, 118.8, 118.4, 112.8, 109.5, 52.1, 45.8, 31.8, 20.0, 13.6.
HRMS (ESI): m/z [M + H]+ calcd for C19H21N2O3: 325.1552; found: 325.1554.
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Methyl 1-Butyl-2-(thiophen-2-yl)-1H-benzo[d]imidazole-5-carboxylate (6k)
Yield: 270 mg (86%); yellowish brown viscous liquid.
IR (KBr): 2967, 2860, 1720, 1291, 1204, 842, 755 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.45 (s, 1 H), 7.99 (d, J = 8.5 Hz, 1 H), 7.62 (s, 1 H), 7.36 (d, J = 8.6 Hz, 1 H), 7.22 (d, J = 3.4 Hz, 1 H), 6.61 (d, J = 1.6 Hz, 1 H), 4.46 (t, J = 7.4 Hz, 2 H), 3.92 (s, 3 H), 1.87–1.79 (m, 2 H), 1.43–1.33 (m,, 2 H), 0.94 (t, J = 7.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 167.5, 145.6, 145.2, 144.1, 142.5, 138.8, 124.7, 124.4, 122.0, 113.3, 112.1, 109.3, 52.09, 45.0, 32.2, 20.0, 13.6.
HRMS (ESI): m/z [M + H]+ calcd for C17H19N2O2S: 315.1167; found: 315.1163.
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Methyl 1-Butyl-2-(4-fluorophenyl)-1H-benzo[d]imidazole-5-carboxylate (6l)
Yield: 290 mg (89%); brown viscous liquid.
IR (KBr): 2967, 2860, 1720, 1291, 1204, 842, 755 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.53 (s, 1 H), 8.06 (d, J = 8.5 Hz, 1 H), 7.73 (t, J = 6.8 Hz, 2 H), 7.44 (d, J = 8.4 Hz, 1 H), 7.27 (d, J = 9.2 Hz, 2 H), 4.24 (t, J = 7.5 Hz, 2 H), 3.97 (s, 3 H), 1.85–1.75 (m, 2 H), 1.34–1.25 (m, 2 H), 0.89 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 167.5, 165.3 (d, 1 J C–F = 270.9 Hz), 154.4, 142.6, 138.8, 131.3 (d, 3 J C–F = 8.5 Hz), 126.3, 124.7, 124.4, 122.3, 116.1 (d, 2 J C–F = 21.7 Hz), 109.7, 52.0, 44.7, 31.8, 19.8, 13.4.
HRMS (ESI): m/z [M + H]+ calcd for C19H20FN2O2: 327.1509; found: 327.1505.
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Methyl 1-Cyclohexyl-2-(2-hydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylate (6m)
Yield: 329 mg (94%); white solid; mp 188–190 °C.
IR (KBr): 2936, 2846, 2670, 1718, 1439, 1288, 1227, 1233, 663 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.46 (s, 1 H), 7.99 (d, J = 8.7 Hz, 1 H), 7.71 (d, J = 8.7 Hz, 1 H), 7.41–7.38 (m, 2 H), 7.19 (d, J = 8.7 Hz, 1 H), 7.01 (t, J = 7.6 Hz, 1 H), 4.74–4.67 (m, 1 H), 3.96 (s, 3 H), 2.41–2.33 (m, 2 H), 2.04–1.98 (m, 4 H), 1.50–1.35 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 167.3, 158.3, 155.5, 141.7, 136.0, 131.8, 127.5, 124.7, 123.9, 121.6, 119.1, 118.3, 113.4, 112.7, 57.9, 52.1, 31.4, 25.9, 25.2.
HRMS (ESI): m/z [M + H]+ calcd for C21H23N2O3: 351.1708; found: 351.1718.
#
#
Conflict of Interest
The authors declare no conflict of interest.
Acknowledgment
The authors are grateful to the Vellore Institute of Technology’s Chancellor and Vice Chancellor for providing the chance to conduct this research.
Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2102-1192.
- Supporting Information
-
References
- 1 Kerru N, Gummidi L, Maddila S, Gangu KK, Jonnalagadda SB. Molecules 2020; 25: 1909
- 2a Dawoud NT. A, El-Fakharany EM, Abdallah AE, El-Gendi H, Lotfy DR. Sci. Rep. 2022; 12: 3424 ; and references cited therein
- 2b Blakemore DC, Castro L, Churcher I, Rees DC, Thomas AW, Wilson DM, Wood A. Nat. Chem. 2018; 10: 383
- 3 Das S, Chanda K. ChemNanoMat 2022; 8: e202200375
- 4 Ahmad MG, Chanda K. Coord. Chem. Rev. 2022; 472: 214769
- 5 Rao NR, Jena S, Mukherjee M, Maiti B, Chanda K. Environ. Chem. Lett. 2021; 19: 3315
- 6a Aca Çevik U, Sağlık BN, Korkut B, Özkay Y, Ilgın S. J. Heterocycl. Chem. 2018; 55: 138
- 6b Wu Z, Xia M.-B, Bertsetseg D, Wang Y.-H, Bao X.-L, Zhu W.-B, Tao Xu, Chen P.-R, Tang H.-S, Yan Y.-J, Chen Z.-L. Bioorg. Chem. 2020; 101: 104042
- 6c El-Gohary NS, Shaaban MI. Eur. J. Med. Chem. 2017; 131: 255
- 6d Sharma R, Bali A, Chaudhari BB. Bioorg. Med. Chem. Lett. 2017; 27: 3007
- 6e Shingalapur RV, Hosamani KM, Keri RS, Hugar MH. Eur. J. Med. Chem. 2010; 45: 1753
- 6f Tantray MA, Khan I, Hamid H, Alam MS, Dhulap A, Kalam A. RSC Adv. 2016; 6: 43345
- 6g Tonelli M, Paglietti G, Boido V, Sparatore F, Marongiu F, Marongiu E, La Colla P, Loddo R. Chem. Biodivers. 2008; 5: 2386
- 6h Salahuddin, Shaharyar M, Mazumder A. Arabian J. Chem. 2017; 10: S157
- 7 Yadav S, Narasimhan B, Kaur H. Anti-Cancer Agents Med. Chem. 2016; 16: 1403
- 8 Rajasekhar S, Maiti B, Balamurali MM, Chanda K. Curr. Org. Synth. 2017; 14: 40
- 9a Das K, Mondal A, Srimani D. J. Org. Chem. 2018; 83: 9553
- 9b Zhang R, Qin Y, Zhang L, Luo S. Org. Lett. 2017; 19: 5629
- 9c Ke F, Peng Z, Xu Y, Lin X, Lin J, Lin C, Xu J. Synlett 2018; 29: 2722
- 9d Zhu X, Zhang F, Kuang D, Deng G, Yang Y, Yu J, Liang Y. Org. Lett. 2020; 22: 3789
- 11 Di Carmine G, Abbott AP, D’Agostino C. React. Chem. Eng. 2021; 6: 582
- 12a Alonso DA, Baeza A, Chinchilla R, Guillena G, Pastor IM, Ramón DJ. Eur. J. Org. Chem. 2016; 612
- 12b Rente D, Paiva A, Duarte AR. Molecules 2021; 26: 2336
- 13 Shaibuna M, Hiba K, Shebitha AM, Kuniyil MJ. K, Sherly mole PB, Sreekumar K. Curr. Res. Green Sustainable Chem. 2022; 5: 100285
- 14 Di Gioia ML, Cassano R, Costanzo P, Cano NH, Maiuolo L, Nardi M, Nicoletta FP, Oliverio M, Procopio A. Molecules 2019; 24: 2885
- 15 Ishikawa H, Suzuki T, Hayashi Y. Angew. Chem. Int. Ed. 2009; 48: 1304
- 16a Padmaja RD, Balamurali MM, Chanda K. J. Org. Chem. 2019; 84: 11382
- 16b Saikia AA, Rao RN, Maiti B, Balamurali MM, Chanda K. ACS Comb. Sci. 2020; 22: 630
- 17 Delaye PO, Pénichon M, Boudesocque-Delaye L, Enguehard-Gueiffier C, Gueiffier A. SynOpen 2018; 2: 306
Corresponding Author
Publication History
Received: 04 March 2023
Accepted after revision: 26 May 2023
Accepted Manuscript online:
26 May 2023
Article published online:
03 July 2023
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-
References
- 1 Kerru N, Gummidi L, Maddila S, Gangu KK, Jonnalagadda SB. Molecules 2020; 25: 1909
- 2a Dawoud NT. A, El-Fakharany EM, Abdallah AE, El-Gendi H, Lotfy DR. Sci. Rep. 2022; 12: 3424 ; and references cited therein
- 2b Blakemore DC, Castro L, Churcher I, Rees DC, Thomas AW, Wilson DM, Wood A. Nat. Chem. 2018; 10: 383
- 3 Das S, Chanda K. ChemNanoMat 2022; 8: e202200375
- 4 Ahmad MG, Chanda K. Coord. Chem. Rev. 2022; 472: 214769
- 5 Rao NR, Jena S, Mukherjee M, Maiti B, Chanda K. Environ. Chem. Lett. 2021; 19: 3315
- 6a Aca Çevik U, Sağlık BN, Korkut B, Özkay Y, Ilgın S. J. Heterocycl. Chem. 2018; 55: 138
- 6b Wu Z, Xia M.-B, Bertsetseg D, Wang Y.-H, Bao X.-L, Zhu W.-B, Tao Xu, Chen P.-R, Tang H.-S, Yan Y.-J, Chen Z.-L. Bioorg. Chem. 2020; 101: 104042
- 6c El-Gohary NS, Shaaban MI. Eur. J. Med. Chem. 2017; 131: 255
- 6d Sharma R, Bali A, Chaudhari BB. Bioorg. Med. Chem. Lett. 2017; 27: 3007
- 6e Shingalapur RV, Hosamani KM, Keri RS, Hugar MH. Eur. J. Med. Chem. 2010; 45: 1753
- 6f Tantray MA, Khan I, Hamid H, Alam MS, Dhulap A, Kalam A. RSC Adv. 2016; 6: 43345
- 6g Tonelli M, Paglietti G, Boido V, Sparatore F, Marongiu F, Marongiu E, La Colla P, Loddo R. Chem. Biodivers. 2008; 5: 2386
- 6h Salahuddin, Shaharyar M, Mazumder A. Arabian J. Chem. 2017; 10: S157
- 7 Yadav S, Narasimhan B, Kaur H. Anti-Cancer Agents Med. Chem. 2016; 16: 1403
- 8 Rajasekhar S, Maiti B, Balamurali MM, Chanda K. Curr. Org. Synth. 2017; 14: 40
- 9a Das K, Mondal A, Srimani D. J. Org. Chem. 2018; 83: 9553
- 9b Zhang R, Qin Y, Zhang L, Luo S. Org. Lett. 2017; 19: 5629
- 9c Ke F, Peng Z, Xu Y, Lin X, Lin J, Lin C, Xu J. Synlett 2018; 29: 2722
- 9d Zhu X, Zhang F, Kuang D, Deng G, Yang Y, Yu J, Liang Y. Org. Lett. 2020; 22: 3789
- 11 Di Carmine G, Abbott AP, D’Agostino C. React. Chem. Eng. 2021; 6: 582
- 12a Alonso DA, Baeza A, Chinchilla R, Guillena G, Pastor IM, Ramón DJ. Eur. J. Org. Chem. 2016; 612
- 12b Rente D, Paiva A, Duarte AR. Molecules 2021; 26: 2336
- 13 Shaibuna M, Hiba K, Shebitha AM, Kuniyil MJ. K, Sherly mole PB, Sreekumar K. Curr. Res. Green Sustainable Chem. 2022; 5: 100285
- 14 Di Gioia ML, Cassano R, Costanzo P, Cano NH, Maiuolo L, Nardi M, Nicoletta FP, Oliverio M, Procopio A. Molecules 2019; 24: 2885
- 15 Ishikawa H, Suzuki T, Hayashi Y. Angew. Chem. Int. Ed. 2009; 48: 1304
- 16a Padmaja RD, Balamurali MM, Chanda K. J. Org. Chem. 2019; 84: 11382
- 16b Saikia AA, Rao RN, Maiti B, Balamurali MM, Chanda K. ACS Comb. Sci. 2020; 22: 630
- 17 Delaye PO, Pénichon M, Boudesocque-Delaye L, Enguehard-Gueiffier C, Gueiffier A. SynOpen 2018; 2: 306