
==== Front
RSC Adv
RSC Adv
RA
RSCACL
RSC Advances
2046-2069
The Royal Society of Chemistry

39239291
d4ra03939d
10.1039/d4ra03939d
Chemistry
Metal-free approach for imidazole synthesis via one-pot N-α-C(sp3)–H bond functionalization of benzylamines†
† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4ra03939d

https://orcid.org/0000-0001-7286-093X
Y-1897-2019
Kadu Vikas D. a
Thokal Machhindra S. a
Godase Rajkumar K. a
Kotali Bhagyashree C. a
Wadkar Pooja S. a
a School of Chemical Sciences, Punyashlok Ahilyadevi Holkar Solapur University Solapur 413255 Maharashtra India vikaskadu1@gmail.com

5 9 2024
4 9 2024
5 9 2024
14 39 2833228339
28 5 2024
11 8 2024
This journal is © The Royal Society of Chemistry
2024
The Royal Society of Chemistry
https://creativecommons.org/licenses/by-nc/3.0/ This article is licensed under a Creative Commons Attribution-Non Commercial 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given and it is not used for commercial purposes.
A metal-free one-pot method is established for the synthesis of tetrasubstituted imidazoles from the reaction of arylmethylamines and 1,2-dicarbonyls/benzoin. The N-α-C(sp3)–H bond functionalization of arylmethylamines using a catalytic amount of AcOH afforded polysubstituted imidazoles under aerobic conditions in significant yields of up to 95%.

A metal-free one-pot method is established for the synthesis of tetrasubstituted imidazoles from the reaction of arylmethylamines and 1,2-dicarbonyls/benzoin.

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pmcIntroduction

The ever-growing influence of nitrogen heterocycles in pharmaceuticals has positioned these heterocycles in drug development and medicinal chemistry as key therapeutic agents.1–4 In particular, azole heterocycles have significant representation in different biological applications.5 Especially, five-membered imidazoles have a wide diversity of pharmaceutical importance.6–11 In addition, imidazole-based drug molecules such as apoptozole, eprosartan, losartan and olmesartan have attracted the attention of chemists for designing bioactive molecules (Fig. 1).12–15 Furthermore, imidazole heterocycles have demonstrated various biological activities such as antifungal,16 antitumor,17 analgesic,18 antibacterial,19 anthelmintic,20 anti-tuberculosis,21 and anti-inflammatory.22 Zeolite imidazole frameworks act as prominent materials and are exposed to potential applications such as host–guest chemistry, catalysis, luminescence, gas separation, gas sorption and magnetism.23,24 Moreover, they have anion and/or cation selectively functioning in different applications in asymmetric catalysis.25,26 In addition, these imidazoles have significant photophysical properties.27,28

Fig. 1 Imidazole containing drug molecules.

The traditional method for the synthesis of imidazoles is carried out through condensation of carbonyl molecules with ammonium salts. Different substrates such as aldehydes, nitriles, imines, amides, isocyanides, amidines, amino acids and benzylamines are used for the synthesis of trisubstituted imidazoles.29–34 Unfortunately, there are limited reports on tetrasubstituted imidazole synthesis. In particular, aldehyde, benzil, amine and NH4OAc with acid catalysts were used for the synthesis of tetrasubstituted imidazole.35,36 Later, the condensation of amidine and α-halo ketones was developed for tetrasubstituted imidazole synthesis using IBX as a strong oxidant.37 Subsequently, Kevin Nguyen et al. demonstrated the synthesis of tetrasubstituted imidazoles from CF3CO2NH4 and N-(2-oxo)-amide substrates at higher temperatures of up to 150 °C for the reaction.38 Next, the sulphur-catalyzed cyclization reaction between ketones and aliphatic amines with a reaction time of up to 36 h was reported for tetrasubstituted imidazole synthesis.39 Moreover, there are some methods for the synthesis of polysubstituted imidazoles constructed from benzils/benzoins and arylmethylamines using catalysts such as Mo-ZnIn2S4 photocatalysts,40 NiCl2·6H2O/Ni(OAc)2·4H2O41 and Ag2CO3.42 Earlier, 2,4,5-trisubstituted and tetrasubstituted imidazole synthesis was achieved using CuI and FeCl3 catalysts.34,43,44 Biswadip Banerji et al. synthesized a series of tetrasubstituted imidazoles using excess K2CO3 (3.0 equiv.) as an additive and a I2 catalyst.45 As a result of a few shortcomings, such as the use of excess catalyst as well as the tedious process for catalyst design and product separation, the progress of a competent protocol is greatly providential for the synthesis of polysubstituted imidazoles.

In recent years, the utility of benzylic α-(sp3)C–N bond functionalization has led to one of the most attractive strategies for the construction of complex molecules for preclinical research and discovery.46 Moreover, amines play a crucial role in N-heterocycle design as a key building block.43,44,47–52 Herein, the AcOH-catalysed synthesis of tetrasubstituted imidazoles from benzylamines and 1,2-dicarbonyl/benzoin substrates using molecular oxygen as an oxidant was developed.

Results and discussion

At the outset, the reaction optimization commenced with benzylamine 1 (2.1 mmol) and benzil 2a (1.0 mmol) substrates in the presence of AcOH (30 mol%) under air oxygen (O2) (Table 1). Initially, different polar solvents such as BuOH, EtOH and MeOH were examined considering green chemistry principles in which the tetrasubstituted imidazole product 3a was obtained in 78%, 65% and 55% yields (Table 1, entries 1–3). From these results, further study was carried out with polar aprotic solvents such as CH3CN, 1,4-dioxane, ethyl acetate, DMF and DMSO where the anticipated product 3a was accomplished in yields of 60%, 62%, 15%, 75% and 72%, respectively (Table 1, entries 4–8). The reaction was further performed using non-polar solvents (such as toluene, o-xylene, chlorobenzene and 1,2-dichlorobenzene), affording lower yields of the desired product (Table 1, entries 9–12). After screening of polar and non-polar solvents, the reaction was examined at 140 °C under solvent-free conditions where the formation of product 3a was observed to be significant up to 91% of yield (Table 1, entry 13). Then, the same product 3a was furnished in lower yields when the temperature study was carried out at 120 °C and 100 °C (Table 1, entries 14–15). Furthermore, the reaction investigation was performed with catalyst loadings such as 20 mol% and 15 mol% of AcOH under solvent-free conditions, in which product 3a was obtained in slightly lower yields of 88% and 85%, respectively (Table 1, entries 16–17). At last, the product furnished up to 69% yield under anaerobic conditions, whereas the trace amount of the product obtained under N2 conditions recognized the role of air oxygen in the reaction for the product formation (Table 1, entries 18–19). Finally, the best-optimized conditions for the formation of product 3a under solvent-free conditions are benzylamine 1 (2.1 mmol) and benzil 2a (1.0 mmol), AcOH (30 mol%) under air O2 at 140 °C.

Optimization of reaction conditionsa

	
Entry	Solvent	Temp (°C)	Time (h)	Yieldb (%)	
1	BuOH	100	8	78	
2	EtOH	80	8	65	
3	MeOH	60	8	55	
4	CH3CN	80	8	60	
5	1,4-Dioxane	100	8	62	
6	Ethyl acetate	78	8	15	
7	DMF	140	8	75	
8	DMSO	140	8	72	
9	Toluene	110	8	30	
10	o-Xylene	130	8	56	
11	Chlorobenzene	130	8	52	
12	1,2-Dichlorobenzene	140	8	35	
13	Neat	140	3	91	
14	Neat	120	4	80	
15	Neat	100	4	69	
16c	Neat	140	4	88	
17d	Neat	140	4	85	
18e	Neat	140	4	69	
19f	Neat	140	4	Trace	
a Reaction conditions: 1a (2.1 mmol), 2a (1.0 mmol), AcOH (30 mol%), and solvent (1 mL) in air O2.

b Isolated yield.

c Reaction was carried out at 20 mol%.

d Reaction was carried out at 15 mol%.

e Reaction was carried out without air.

f Under an N2 atmosphere.

By using the optimized conditions, the finding of the reaction scope was broadly explored with substituted benzylamines and 1,2-dicarbonyls for the synthesis of polysubstituted imidazoles (Table 2). Initially, the reaction of benzil 2a was studied with para-substituted benzylamies of electron-donating and electron-withdrawing functional groups, where the products 3a, 3b, 3c, 3d and 3e were obtained in the yields of 91%, 95%, 94%, 84% and 89%, respectively. Then, ortho-substituted benzyalmines were examined with benzil 2a and afforded products 3f (87%), 3g (86%) and 3h (82%) in excellent yields. After that, the disubstituted arylmethylamines were used to prepare tetrasubstituted products that were achieved in yields of 3i (85%) and 3j (88%). Also, the optimized conditions with heteroaryl benzylamines were found feasible for the synthesis of imidazoles as 3k (83%), 3l (81%) and 3m (86%). Additionally, the substrate scope was further explored with substituted arylmethylamines using 9,10-phenanthrenequinone 2b where the analogous products formed (3n: 83%, 3o: 85% and 3p: 86%) were in excellent yields. After that, heteroaryl methylamines were screened with 9,10-phenanthrenequinone 2b and products were obtained (3q: 80% and 3r: 87%) in significant yields (Table 2). There are a number of methods available for the synthesis of imidazoles using 1,2-diketones (benzil) but not from α-hydroxy ketone. Due to this, the optimized reaction conditions were tested against α-hydroxy ketones (benzoin) with different substituted arylmethylamines for the synthesis of imidazole, achieved in good to excellent yields as illustrated in Table 3. Here, the improved method has the utility to synthesize these polyfunctionalized imidazoles from both α-hydroxy ketone (benzoin) and 1,2-diketones (benzil) substrates by reacting with different arylmethylamines.

Substrate scope of arylmethylamines with 1,2-dicarbonylsa

	
a Reaction conditions: 1 (2.1 mmol, 2.1 equiv.), 2 (1.0 mmol, 1.0 equiv.), AcOH (30 mol%), open air at 140 °C under neat condition for 3–6 h.

Substrate scope of arylmethylamines with benzoina

	
a Reaction conditions: 1 (2.1 mmol, 2.1 equiv.), 2c (1.0 mmol, 1.0 equiv.), AcOH (30 mol%), open air at 140 °C under neat condition for 3–6 h.

The mechanism of the reaction is proposed on the basis of literature and experimental results (Scheme 1).43,44,47 At first, the condensation of 1,2-diketone 2 with arylmethylamine 1 takes place, which gives intermediate I in the presence of a catalytic amount of AcOH. On the other hand, α-hydroxy ketone (benzoin) 2c and arylmethylamine 1 condensation leads to the formation of intermediate IV, which is further converted into intermediate V to produce a similar intermediate I in the presence of an AcOH catalyst under aerobic conditions. Afterward, the 1,5-H shift of intermediate I produces intermediate II, which further cyclizes into III in the presence of AcOH. Lastly, the aerobic oxidation of intermediate III affords the anticipated product 3.51,53

Scheme 1 The possible reaction mechanism.

Conclusions

In conclusion, the facile and convenient metal-free approach demonstrated the synthesis of polyfunctionalized imidazoles from simple starting materials. The formation of all products was achieved with good functional group tolerance, leading to further investigation towards designing different organic scaffolds.

Experimental section

General information

The distilled solvents were used for performing reactions. The physical constants were recorded using the Buchi melting point apparatus and are uncorrected. By using silica gel plates (0.25 mm), thin-layer chromatography (TLC) was performed to study the reaction progress under a UV lamp. The synthesised compounds were analysed by NMR (1H NMR at 400 MHz and 13C NMR at 100 MHz) on a JEOL NMR spectrometer and mass on 6530 Accurate-Mass Q-TOF LC/MS of Agilent Technologies.

General procedure for synthesis of tetrasubstituted imidazoles (3)

Arylmethylamine 1 (2.1 mmol), 1,2-diketone/benzoin 2 (1.0 mmol), and AcOH (30 mol%) were stirred at 140 °C temperature under solvent-free aerobic conditions in a 25 mL round bottom flask. The progress of the reaction was monitored by thin-layer chromatography (TLC). After completion of the reaction, the reaction mixture was cooled and poured into crushed ice. After that, the mixture was stirred and filtered to obtain the crude imidazole product 3. The purified imidazole product 3 was achieved by column chromatography using hexane/ethyl acetate as eluent.

Analysis data of the synthesised tetrasubstituted imidazoles

1-Benzyl-2,4,5-triphenyl-1H-imidazole (3a)

M.P.: 165–166 °C; (Lit.43 163–166 °C); white solid; 1H-NMR (400 MHz, DMSO-D6) δ 7.62 (d, J = 4.3 Hz, 2H), 7.41 (q, J = 6.7 Hz, 8H), 7.27–7.14 (m, 8H), 6.72 (d, J = 6.7 Hz, 2H), 5.13 (s, 2H) ppm; 13C-NMR (400 MHz, DMSO-D6) δ 147.6, 137.8, 137.4, 135.1, 131.4, 131.1, 130.7, 129.5, 129.4, 129.1, 128.6, 127.7, 126.8, 126.6, 126.2, 48.2 ppm.

1-(4-Methoxybenzyl)-2-(4-methoxyphenyl)-4,5-diphenyl-1H-imidazole (3b)

M.P.: 155–157 °C; (Lit.43 153–155 °C); off-white solid; 1H-NMR (400 MHz, CDCl3): δ1H-NMR (400 MHz, DMSO-D6) δ 7.55 (d, J = 8.6 Hz, 2H), 7.41–7.37 (m, 5H), 7.25 (d, J = 3.7 Hz, 2H), 7.16 (t, J = 7.6 Hz, 2H), 7.08 (t, J = 7.3 Hz, 1H), 6.97 (d, J = 8.6 Hz, 2H), 6.72 (d, J = 8.6 Hz, 2H), 6.62 (d, J = 8.6 Hz, 2H), 5.02 (s, 2H), 3.75 (s, 3H), 3.62 (s, 3H) ppm; 13C-NMR (400 MHz, DMSO-D6) δ 160.1, 158.8, 147.5, 137.1, 135.2, 131.4, 130.5, 130.3, 129.8, 129.4, 129.3, 128.6, 127.4, 126.6, 123.7, 114.6, 114.5, 55.8, 55.5, 47.6 ppm.

1-(4-Methylbenzyl)-4,5-diphenyl-2-p-tolyl-1H-imidazole (3c)

M.P.: 131–134 °C (Lit.43 132–134 °C); white solid; 1H-NMR (400 MHz, DMSO-D6) δ 7.51 (d, J = 7.9 Hz, 2H), 7.42–7.38 (m, 5H), 7.26–7.15 (m, 6H), 7.09 (t, J = 7.0 Hz, 1H), 6.97 (d, J = 7.3 Hz, 2H), 6.61 (d, J = 7.9 Hz, 2H), 5.06 (s, 2H), 2.29 (s, 3H), 2.16 (s, 3H) ppm; 13C-NMR (100 MHz, DMSO-D6) δ 147.6, 138.8, 137.3, 136.8, 135.2, 135.0, 131.4, 131.2, 130.6, 129.7, 129.6, 129.4, 129.3, 128.9, 128.6, 128.5, 126.7, 126.6, 126.0, 47.9, 21.4, 21.1 ppm.

1-(4-Fluorobenzyl)-2-(4-fluorophenyl)-4,5-diphenyl-1H-imidazole (3d)

M.P.: 161–163 °C (Lit.43 159–162 °C); white solid; 1H-NMR (400 MHz, DMSO-D6) δ 7.68–7.64 (m, 2H), 7.41 (d, J = 9.2 Hz, 5H), 7.26 (t, J = 8.6 Hz, 4H), 7.17 (t, J = 7.6 Hz, 2H), 7.10 (t, J = 7.0 Hz, 1H), 6.97 (t, J = 8.6 Hz, 2H), 6.73 (t, J = 6.4 Hz, 2H), 5.08 (s, 2H) ppm; 13C-NMR (100 MHz, DMSO-D6) δ 164.1, 162.9, 161.6, 160.5, 146.7, 137.4, 134.9, 133.8, 131.4, 131.3, 131.0, 130.7, 129.5, 129.5, 128.6, 128.4, 128.3, 127.8, 127.8, 126.8, 126.6, 116.3, 116.0, 116.0, 115.8, 47.6 ppm.

1-(4-Chlorobenzyl)-2-(4-chlorophenyl)-4,5-diphenyl-1H-imidazole (3e)

M.P.:158–160 °C (Lit.43 159–162 °C); white solid; 1H-NMR (400 MHz, DMSO-D6) δ 7.64 (d, J = 7.9 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 7.43–7.39 (m, 5H), 7.28 (d, J = 3.7 Hz, 1H), 7.23–7.16 (m, 4H), 7.11 (t, J = 7.3 Hz, 1H), 6.75 (d, J = 8.6 Hz, 2H), 5.11 (s, 2H) ppm; 13C-NMR (100 MHz, DMSO-D6) δ 146.4, 137.7, 136.6, 134.8, 134.2, 132.3, 131.3, 131.0, 130.9, 130.7, 130.0, 129.6, 129.3, 129.1, 128.6, 128.1, 126.9, 126.6, 47.7 ppm.

1-(2-Methylbenzyl)-2-(2-methylphenyl)-4,5-diphenyl-1H-imidazole (3f)

M.P.: 178–180 °C; brown solid; 1H-NMR (400 MHz, DMSO-D6) δ 7.42 (d, J = 7.3 Hz, 2H), 7.37–7.33 (m, 4H), 7.29–7.25 (m, 4H), 7.17 (t, J = 7.3 Hz, 3H), 7.09 (t, J = 7.3 Hz, 1H), 7.03–6.96 (m, 2H), 6.88 (d, J = 7.3 Hz, 1H), 6.47 (d, J = 6.7 Hz, 1H), 4.84 (s, 2H), 2.21 (s, 3H), 1.75 (s, 3H) ppm; 13C-NMR (100 MHz, DMSO-D6) δ 147.4, 138.4, 136.9, 135.9, 135.2, 134.5, 131.2, 130.9, 130.5, 130.2, 129.7, 129.4, 129.2, 128.6, 127.4, 126.7, 126.5, 126.1, 125.8, 45.5, 20.0, 18.7 ppm; HRMS: m/z [M + H]+ calcd for C30H26N2: 415.2096; found: 415.2182.

1-(2-Methoxybenzyl)-2-(2-methoxyphenyl)-4,5-diphenyl-1H-imidazole (3g)

M.P.: 135–136 °C; (Lit.43 132–134 °C); yellow solid; 1H-NMR (400 MHz, DMSO-D6) δ 7.37 (d, J = 12.2 Hz, 7H), 7.21–6.94 (m, 8H), 6.69 (d, J = 6.7 Hz, 2H), 6.40 (d, J = 6.1 Hz, 1H), 4.82 (s, 2H), 3.71 (s, 3H), 3.48 (s, 3H) ppm; 13C-NMR (100 MHz, DMSO-D6) δ 157.6, 156.0, 145.8, 137.1, 135.3, 132.6, 131.4, 131.4, 131.2, 129.9, 129.4, 129.1, 128.7, 128.6, 127.0, 126.5, 125.5, 120.9, 120.6, 112.0, 110.8, 55.9, 55.7, 43.1 ppm.

1-(2-Chlorobenzyl)-2-(2-chlorophenyl)-4,5-diphenyl-1H-imidazole (3h)

M.P.: 143–145 °C (Lit.43 142–144 °C); white solid; 1H-NMR (400 MHz, DMSO-D6) δ 7.55 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 7.3 Hz, 1H), 7.46–7.33 (m, 6H), 7.28 (d, J = 6.7 Hz, 2H), 7.20–7.09 (m, 7H), 6.64 (d, J = 7.3 Hz, 1H), 4.95 (s, 2H) ppm; 13C-NMR (100 MHz, DMSO-D6) δ 145.2, 137.3, 134.8, 134.3, 134.0, 133.0, 131.9, 131.2, 131.2, 130.7, 130.3, 130.2, 130.0, 129.6, 129.5, 128.7, 128.2, 127.9, 127.8, 126.9, 126.5, 45.8 ppm.

2-(Benzo[d][1,3]dioxol-5-yl)-1-(benzo[d][1,3]dioxol-5-ylmethyl)-4,5-diphenyl-1H-imidazole (3i)

M.P.: 178–180 °C (Lit.43 175–177 °C); white solid; 1H-NMR (400 MHz, DMSO-D6) δ 7.44–7.34 (m, 6H), 7.29–7.24 (m, 2H), 7.18–7.14 (m, 3H), 7.10 (t, J = 7.0 Hz, 1H), 6.96 (d, J = 7.9 Hz, 1H), 6.69 (d, J = 7.9 Hz, 1H), 6.24 (s, 1H), 6.13 (d, J = 7.9 Hz, 1H), 6.04 (s, 2H), 5.89 (s, 2H), 4.99 (s, 2H) ppm; 13C-NMR (100 MHz, DMSO-D6) δ 148.3, 147.9, 147.3, 146.8, 137.1, 135.1, 131.7, 131.3, 131.2, 130.4, 129.5, 129.4, 128.7, 128.6, 126.7, 126.6, 125.1, 123.2, 119.5, 109.4, 109.0, 108.7, 106.7, 101.9, 101.6, 47.9 ppm.

1-(3,4-Dichlorobenzyl)-2-(3,4-dichlorophenyl)-4,5-diphenyl-1H-imidazole (3j)

M.P.: 160–163 °C (Lit.43 158–161 °C); white solid; 1H-NMR (400 MHz, DMSO-D6) δ 7.87 (d, J = 1.2 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.59 (dd, J = 7.9, 1.8 Hz, 1H), 7.43–7.41 (m, 6H), 7.28 (d, J = 3.7 Hz, 2H), 7.18 (t, J = 7.3 Hz, 2H), 7.12 (t, J = 7.3 Hz, 1H), 6.98 (s, 1H), 6.70 (d, J = 8.6 Hz, 1H), 5.14 (s, 2H) ppm; 13C-NMR (100 MHz, DMSO-D6) δ 145.1, 138.5, 137.9, 134.6, 132.3, 132.0, 131.7, 131.5, 131.4, 131.3, 130.8, 130.6, 130.5, 129.7, 129.7, 129.0, 128.7, 128.7, 127.1, 126.7, 47.5 ppm.

2-(4,5-Diphenyl-1-(pyridin-2-ylmethyl)-1H-imidazole-2-yl)pyridine (3k)

M.P.: 166–168 °C (Lit.43 165–167 °C); light yellow solid; 1H-NMR (400 MHz, DMSO-D6) δ 8.94–8.87 (m, 1H), 8.81 (d, J = 8.6 Hz, 1H), 8.60 (d, J = 7.9 Hz, 1H), 8.45 (d, J = 7.9 Hz, 1H), 8.36 (d, J = 7.3 Hz, 1H), 8.08 (d, J = 7.9 Hz, 1H), 7.81–7.68 (m, 3H), 7.64–7.50 (m, 1H), 7.22–7.17 (m, 2H), 7.05 (d, J = 7.9 Hz, 1H), 6.79–6.72 (m, 1H), 6.46 (d, J = 7.9 Hz, 1H), 6.16–6.11 (m, 1H), 6.09–6.03 (m, 1H), 5.95 (s, 1H), 5.78 (s, 2H) ppm; 13C-NMR (100 MHz, DMSO-D6) δ 152.9, 148.5, 148.1, 147.2, 137.5, 131.4, 130.0, 129.0, 128.3, 127.8, 127.5, 126.8, 126.2, 125.6, 124.3, 124.1, 122.7, 121.8, 121.1, 119.1, 110.0, 109.1, 107.2, 106.6, 102.2, 50.3 ppm.

3-(4,5-Diphenyl-1-(pyridin-3-ylmethyl)-1H-imidazole-2-yl)pyridine (3l)

M.P.: 190–192 °C; faint yellow solid; 1H-NMR (400 MHz, DMSO-D6) δ 8.85 (s, 1H), 8.58 (d, J = 3.7 Hz, 1H), 8.30 (d, J = 3.1 Hz, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.91 (s, 1H), 7.44–7.31 (m, 8H), 7.21–7.11 (m, 5H), 5.14–5.28 (2H) ppm; 13C-NMR (100 MHz, DMSO-D6) δ 150.3, 149.5, 149.1, 147.9, 144.9, 138.0, 136.4, 134.7, 134.2, 133.0, 131.3, 131.3, 130.7, 129.7, 128.7, 127.3, 127.0, 126.7, 124.2, 46.2 ppm; HRMS: m/z [M + H]+ calcd for C26H20N4: 389.1688; found: 389.1774.

4,5-Diphenyl-2-(thiophen-2-yl)-1-(thiophen-2-ylmethyl)-1H-imidazole (3m)

M.P.: 170–173 °C (Lit.43 169–171 °C); white solid; 1H-NMR (400 MHz, DMSO-D6) δ 7.62 (d, J = 6.1 Hz, 1H), 7.44–7.36 (m, 10H), 7.17–6.83 (m, 4H), 6.55 (d, J = 5.5 Hz, 1H), 5.36 (s, 2H) ppm; 13C-NMR (100 MHz, DMSO-D6) δ 141.5, 140.0, 137.6, 134.6, 133.1, 131.5, 130.7, 130.5, 129.7, 129.6, 128.7, 128.5, 128.3, 127.6, 127.0, 126.7, 126.5, 126.3, 125.8, 44.1 ppm.

1-(2-Chlorobenzyl)-2-(2-chlorophenyl)-1H-phenanthro[9,10-d]imidazole (3n)

M.P.: 185–187 °C; dark brown solid; 1H-NMR (400 MHz, DMSO-D6) δ 8.96–8.91 (m, 1H), 8.85 (d, J = 6.7 Hz, 2H), 8.58 (d, J = 7.9 Hz, 1H), 8.31 (t, J = 7.9 Hz, 1H), 7.87 (d, J = 8.6 Hz, 1H), 7.66 (t, J = 7.9 Hz, 2H), 7.60 (t, J = 6.4 Hz, 2H), 7.47 (t, J = 6.1 Hz, 2H), 7.36–7.29 (m, 1H), 7.23 (t, J = 7.9 Hz, 1H), 7.08 (d, J = 8.6 Hz, 1H), 6.56 (d, J = 7.9 Hz, 1H), 5.72 (s, 2H) ppm; 13C-NMR (100 MHz, DMSO-D6) δ 141.8, 133.9, 131.4, 130.9, 130.6, 129.6, 128.5, 127.8, 127.8, 127.3, 126.9, 126.9, 126.6, 126.2, 126.1, 125.3, 124.8, 124.5, 124.4, 123.5, 123.2, 42.4; HRMS: m/z [M + H]+ calcd for C28H18Cl2N2: 453.0847; found: 453.0925.

1-(4-Methoxybenzyl)-2-(4-methoxyphenyl)-1H-phenanthro[9,10-d]imidazole (3o)

M.P.: 123–125 °C (Lit.42 122–124 °C); white solid; 1H-NMR (400 MHz, DMSO-D6) δ 8.87–8.61 (m, 4H), 8.26–8.08 (m, 1H), 7.71–7.47 (m, 5H), 7.06–6.86 (m, 6H), 5.82 (s, 2H), 3.79 (s, 3H), 3.65 (s, 3H) ppm; 13C-NMR (100 MHz, DMSO-D6) δ 158.2, 157.5, 153.9, 137.6, 132.3, 131.2, 129.4, 129.4, 129.3, 129.3, 127.5, 127.5, 127.4, 127.4, 127.2, 127.1, 126.1, 122.5, 115.1, 114.9, 114.9, 114.8, 114.7, 55.9, 55.6, 45.3 ppm; HRMS: m/z [M + H]+ calcd for C30H24N2O2: 445.1838; found: 445.1919.

2-(Benzo[d][1,3]dioxol-5-yl)-1-(benzo[d][1,3]dioxol-5-ylmethyl)-1H-phenanthro[9,10-d]imidazole (3p)

M.P.: 270–272 °C; brown solid; 1H-NMR (400 MHz, DMSO-D6) δ 9.48 (d, J = 1.2 Hz, 1H), 8.93 (t, J = 9.5 Hz, 1H), 8.89 (s, 1H), 8.82 (d, J = 8.6 Hz, 1H), 8.78 (d, J = 3.7 Hz, 1H), 8.71 (d, J = 4.3 Hz, 1H), 8.63 (d, J = 7.3 Hz, 1H), 8.48 (d, J = 7.9 Hz, 1H), 8.43–8.38 (m, 1H), 8.11 (d, J = 7.3 Hz, 1H), 7.84–7.71 (m, 3H), 7.68–7.63 (m, 1H), 7.58–7.55 (m, 1H), 7.50 (t, J = 7.3 Hz, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.27 (dd, J = 7.3, 4.9 Hz, 1H), 6.00 (s, 2H) ppm; 13C-NMR (100 MHz, DMSO-D6) δ 152.4, 151.1, 150.2, 149.4, 148.3, 147.9, 137.4, 134.8, 134.0, 133.1, 128.5, 128.0, 127.9, 127.7, 127.3, 126.5, 126.0, 124.9, 124.6, 124.3, 124.2, 122.9, 121.7, 121.4, 48.6 ppm; HRMS: m/z [M + H]+ calcd for C30H20N2O4: 473.1423; found: 473.1517.

2-(Pyridin-4-yl)-1-(pyridin-4-ylmethyl)-1H-phenanthro[9,10-d]imidazole (3q)

M.P.: 210–212 °C; brown solid; 1H-NMR (400 MHz, DMSO-D6) δ 8.90 (t, J = 9.5 Hz, 2H), 8.36 (d, J = 7.3 Hz, 2H), 8.20 (d, J = 6.7 Hz, 2H), 7.76–7.70 (m, 9H), 7.01 (s, 2H) ppm; 13C-NMR (100 MHz, DMSO-D6) δ 146.9, 144.4, 142.0, 134.1, 133.6, 129.1, 128.9, 128.8, 128.4, 128.3, 127.2, 127.1, 126.8, 125.9, 125.5, 125.0, 124.8, 124.6, 122.7, 120.9, 120.8, 118.1, 45.6 ppm; HRMS: m/z [M + H]+ calcd for C26H18N4: 387.1531; found: 387.1625.

2-(Thiophen-2-yl)-1-(thiophen-2-ylmethyl)-1H-phenanthro[9,10-d]imidazole (3r)

M.P.: 258–262 °C; brown solid; 1H-NMR (400 MHz, DMSO-D6) δ 8.95–8.89 (m, 1H), 8.81 (d, J = 8.6 Hz, 1H), 8.57 (d, J = 7.9 Hz, 1H), 8.31–8.26 (m, 1H), 7.80 (d, J = 4.3 Hz, 1H), 7.77–7.68 (m, 1H), 7.65 (d, J = 7.3 Hz, 1H), 7.62–7.55 (m, 3H), 7.45 (t, J = 5.2 Hz, 1H), 7.21 (t, J = 4.3 Hz, 1H), 6.97 (t, J = 4.0 Hz, 2H), 6.21 (s, 2H) ppm; 13C-NMR (100 MHz, DMSO-D6) δ 140.2, 139.1, 129.9, 129.0, 128.8, 128.3, 128.2, 128.1, 128.0, 127.7, 127.2, 126.9, 126.5, 126.5, 125.9, 125.7, 125.0, 124.1, 122.9, 122.8, 122.5, 121.8, 121.1, 47.3 ppm; HRMS: m/z [M + H]+ calcd for C24H16N2S2: 397.0755; found: 397.0839.

Data availability

The data supporting this article have been included as part of the ESI.†

Conflicts of interest

There are no conflicts to declare.

Supplementary Material

RA-014-D4RA03939D-s001
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References

Vitaku E. Smith D. T. Njardarson J. T. J. Med. Chem. 2014 57 10257 10274 10.1021/jm501100b 25255204
Kerru N. Gummidi L. Maddila S. Gangu K. K. Jonnalagadda S. B. Molecules 2020 25 1909 10.3390/molecules25081909 32326131
Jampilek J. Molecules 2019 24 3839 10.3390/molecules24213839 31731387
Heravi M. M. Zadsirjan V. RSC Adv. 2020 10 44247 44311 10.1039/D0RA09198G 35557843
Kabi A. K. , Sravani S. , Gujjarappa R. , Garg A. , Vodnala N. , Tyagi U. , Kaldhi D. , Velayutham R. , Gupta S. and Malakar C. C. , in Materials Horizons: From Nature to Nanomaterials, 2022, pp. 79–99
De Luca L. Curr. Med. Chem. 2006 13 1 23 16457636
Rulhania S. Kumar S. Nehra B. Gupta G. D. Monga V. J. Mol. Struct. 2021 1232 129982 10.1016/j.molstruc.2021.129982
Alghamdi S. S. Suliman R. S. Almutairi K. Kahtani K. Aljatli D. Drug Des., Dev. Ther. 2021 15 3289 3312 10.2147/DDDT.S307113 34354342
Chopra P. N. Sahu J. K. Curr. Drug Discovery Technol. 2020 17 574 584 10.2174/1570163816666190320123340 30894111
Zhang L. Peng X. M. Damu G. L. V. Geng R. X. Zhou C. H. Med. Res. Rev. 2014 34 340 437 10.1002/med.21290 23740514
Gaba M. Mohan C. Med. Chem. Res. 2016 25 173 210 10.1007/s00044-015-1495-5
Evans L. E. Cheeseman M. D. Yahya N. Jones K. PLoS One 2015 10 e0140006 10.1371/journal.pone.0140006 26458144
Plosker G. L. Drugs 2009 69 2477 2499 10.2165/11203980-000000000-00000 19911859
Al-Majed A. R. A. , Assiri E. , Khalil N. Y. and Abdel-Aziz H. A. , in Profiles of Drug Substances, Excipients and Related Methodology, Academic Press, 2015, vol. 40 , pp. 159–194
Kourlaba G. Gialama F. Tsioufis K. Maniadakis N. Int. J. Cardiol. 2016 221 60 74 10.1016/j.ijcard.2016.06.115 27404671
Rani N. Sharma A. Gupta G. K. Singh R. Mini-Rev. Med. Chem. 2013 13 1626 1655 10.2174/13895575113139990069 23815583
Wang L. Woods K. W. Li Q. Barr K. J. McCroskey R. W. Hannick S. M. Gherke L. Credo R. B. Hui Y. H. Marsh K. Warner R. Lee J. Y. Zielinski-Mozng N. Frost D. Rosenberg S. H. Sham H. L. J. Med. Chem. 2002 45 1697 1711 10.1021/jm010523x 11931625
Uçucu Ü. Karaburun N. G. Işikdag I. Farmaco 2001 56 285 290 10.1016/S0014-827X(01)01076-X 11421256
Antolini M. Bozzoli A. Ghiron C. Kennedy G. Rossi T. Ursini A. Bioorg. Med. Chem. Lett. 1999 9 1023 1028 10.1016/S0960-894X(99)00112-2 10230632
Rocha J. A. Andrade I. M. Véras L. M. C. Quelemes P. V. Lima D. F. Soares M. J. S. Pinto P. L. S. Mayo S. J. Ivanova G. Rangel M. Correia M. Mafud A. C. Mascarenhas Y. P. Delerue-Matos C. de Moraes J. Eaton P. Leite J. R. S. A. Phytother. Res. 2017 31 624 630 10.1002/ptr.5771 28111828
Gupta P. Hameed S. Jain R. Eur. J. Med. Chem. 2004 39 805 814 10.1016/j.ejmech.2004.05.005 15337293
Silva V. G. Silva R. O. Damasceno S. R. B. Carvalho N. S. Prudeîncio R. S. Aragão K. S. Guimarães M. A. Campos S. A. Véras L. M. C. Godejohann M. Leite J. R. S. A. Barbosa A. L. R. Medeiros J. V. R. J. Nat. Prod. 2013 76 1071 1077 10.1021/np400099m 23734744
Kouser S. Hezam A. Khadri M. J. N. Khanum S. A. J. Porous Mater. 2022 29 663 681 10.1007/s10934-021-01184-z
Zhu X. W. Luo D. Zhou X. P. Li D. Coord. Chem. Rev. 2022 455 214354 10.1016/j.ccr.2021.214354
Molina P. Tárraga A. Otón F. Org. Biomol. Chem. 2012 10 1711 1724 10.1039/C2OB06808G 22281703
Wang M. Zhang Z. Zhang W. Acc. Chem. Res. 2022 55 2708 2727 10.1021/acs.accounts.2c00455 36043467
Al Sharif O. F. Nhari L. M. El-Shishtawy R. M. Asiri A. M. Mater. Today Chem. 2023 29 101453 10.1016/j.mtchem.2023.101453
Lin Y. D. Tsai W. W. Lu C. W. Chem.–Eur. J. 2023 29 e202203040 10.1002/chem.202203040 36593580
Zhang B. Wan C. Wang Q. Zhang S. Zha Z. Wang Z. Acta Chim. Sin. 2012 70 2408 2411 10.6023/A12090651
Huang H. Ji X. Wu W. Jiang H. Adv. Synth. Catal. 2013 355 170 180 10.1002/adsc.201200582
Cao J. Zhou X. Ma H. Shi C. Huang G. RSC Adv. 2016 6 57232 57235 10.1039/C6RA08174F
Salfeena C. T. F. Jalaja R. Davis R. Suresh E. Somappa S. B. ACS Omega 2018 3 8074 8082 10.1021/acsomega.8b01017 31458944
Yang Z. Zhang J. Hu L. Li A. Li L. Liu K. Yang T. Zhou C. J. Org. Chem. 2020 85 5952 5958 10.1021/acs.joc.0c00316 32279501
Kadu V. D. Mali G. A. Khadul S. P. Kothe G. J. RSC Adv. 2021 11 21955 21963 10.1039/D1RA01767E 35480836
Heravi M. M. Derikvand F. Bamoharram F. F. J. Mol. Catal. A: Chem. 2007 263 112 114 10.1016/j.molcata.2006.08.048
Sadeghi B. Mirjalili B. B. F. Hashemi M. M. Tetrahedron Lett. 2008 49 2575 2577 10.1016/j.tetlet.2008.02.100
Donohoe T. J. Kabeshov M. A. Rathi A. H. Smith I. E. D. Org. Biomol. Chem. 2012 10 1093 1101 10.1039/C1OB06587D 22159268
Claiborne C. F. Liverton N. J. Nguyen K. T. Tetrahedron Lett. 1998 39 8939 8942 10.1016/S0040-4039(98)02058-9
Chen X. Wang Z. Huang H. Deng G. J. Adv. Synth. Catal. 2018 360 4017 4022 10.1002/adsc.201800765
Wang M. Li L. Lu J. Luo N. Zhang X. Wang F. Green Chem. 2017 19 5172 5177 10.1039/C7GC01728F
Samanta S. Roy D. Khamarui S. Maiti D. K. Chem. Commun. 2014 50 2477 2480 10.1039/C3CC48437H 24457458
Sarkar R. Mukhopadhyay C. Eur. J. Org. Chem. 2015 2015 1246 1256 10.1002/ejoc.201403465
Kadu V. D. Khadul S. P. Kothe G. J. Mali G. A. Asian J. Org. Chem. 2022 11 e202200162 10.1002/ajoc.202200162
Kadu V. D. Sankala N. C. Hublikar M. G. Bansode S. I. Bhosale R. B. Synth. 2023 56 2277 2283 10.1055/s-0043-1763690
Adhikary S. Majumder L. Pakrashy S. Srinath R. Mukherjee K. Mandal C. Banerji B. ACS Omega 2020 5 14394 14407 10.1021/acsomega.0c00934 32596577
Zhang Y. Zhang T. Das S. Chem 2022 8 3175 3201
Kadu V. D. ChemistrySelect 2022 7 e202104028 10.1002/slct.202104028
Liu S. Zhao Z. Wang Y. Chem.–Eur. J. 2019 25 2423 2441 10.1002/chem.201803960 30357981
Tashrifi Z. Khanaposhtani M. M. Larijani B. Mahdavi M. Tetrahedron 2021 84 131990 10.1016/j.tet.2021.131990
Kadu V. D. Patil A. A. Shendage P. R. J. Mol. Struct. 2022 1267 133502 10.1016/j.molstruc.2022.133502
Kadu V. D. Chandrudu S. N. Hublikar M. G. Raut D. G. Bhosale R. B. RSC Adv. 2020 10 23254 23262 10.1039/D0RA03221B 35520337
Kadu V. D. Gund M. S. Godage A. S. ChemistrySelect 2021 6 11954 11960 10.1002/slct.202102628
Zhang X. Wang Z. Xu K. Feng Y. Zhao W. Xu X. Yan Y. Yi W. Green Chem. 2016 18 2313 2316 10.1039/C5GC02747K
