Synthesis of some Novel Imidazoles Catalyzed by

Send Orders for Reprints to [email protected] Combinatorial Chemistry & High Throughput Screening, 2018, 21, 1-10

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RESEARCH ARTICLE

Synthesis of some Novel Imidazoles Catalyzed by Co3O4 Nanoparticles and Evaluation of their Antibacterial Activities Mohammad Ali Ghasemzadeh*, Mohammad Hossein Abdollahi-Basir and Zahra Elyasi Department of Chemistry, Qom Branch, Islamic Azad University, Qom, I.R. Iran Abstract: Aim and objective: The multi-component condensation of benzil, primary amines, ammonium acetate and various aldehydes was efficiently catalyzed using cobalt oxide nanoparticles under ultrasonic irradiation. This approach describes an effective and facile method for the synthesis of some novel 1,2,4,5-tetrasubstituted imidazole derivatives with several advantages such as high yields and short reaction times and reusability of the catalyst. Moreover, the prepared heterocyclic compounds showed high antibacterial activity against some pathogenic strains.

ARTICLE HISTORY Received: March 4, 2017 Revised: March 22, 2018 Accepted: March 26, 2018 DOI: 10.2174/1386207321666180330164942

Material and method: The facile and efficient approaches for the preparation of Co3O4 nanoparticles were carried out by one step method. The synthesized heterogeneous nanocatalyst was characterized by spectroscopic analysis including EDX, FE-SEM, VSM, XRD and FT-IR analysis. The as-synthesized cobalt oxide nanoparticles showed paramagnetic behaviour in magnetic field. In addition, the catalytic influence of the nanocatalyst was examined in the one-pot reaction of primary amines, benzil, ammonium acetate and diverse aromatic aldehydes under ultrasonic irradiation. All of the 1,2,4,5-tetrasubstituted imidazoles were investigated and checked with m.p., 1H NMR, 13C NMR and FT-IR spectroscopy techniques. The antibacterial properties of the heterocycles were evaluated in vitro by the disk diffusion against pathogenic strains such as Escherichia Coli (EC), Bacillus subtillis (BS), Staphylococcus aureus (SA), Salmonellatyphi (ST) and Shigella dysentrae (SD) species. Results: In this research cobalt oxide nanostructure was used as a robust and green catalyst in the some novel imidazoles. The average particle size measured from the FE-SEM image is found to be 20-30 nm which confirmed to the obtained results from XRD pattern. Various electron-donating and electron-withdrawing aryl aldehydes were efficiently reacted in the presence of Co3O4 nanoparticles. The role of the catalyst as a Lewis acid is promoting the reactions with the increase in the electrophilicity of the carbonyl and double band groups. To investigate the reusability of the catalyst, the model study was repeated using recovered cobalt oxide nanoparticles. The results showed that the nanocatalyst could be reused for five times with a minimal loss of its activity. Conclusion: We have developed an efficient and environmentally friendly method for the synthesis of some tetrasubstituted imidazoles via three-component reaction of benzil, primary amines, ammonium acetate and various aldehydes using Co3O4 NPs. The present approach suggests different benefits such as: excellent yields, short reaction times, simple workup procedure and recyclability of the magnetic nanocatalyst. The prepared 1,2,4,5-tetrasubstituted imidazoles revealed high antibacterial activities and can be useful in many biomedical applications.

Keywords: Ultrasound, imidazole, Co3O4, nanoparticles, multi-component reaction, antibacterial.

Imidazole is a vital heterocyclic nucleus which is wellknown for its wide biological profile. Imidazole skeleton is a unique structure fragment in clinical medicine [1]. Imidazole has attracted attention for various medicinal applications such as anticancer [2], anti-inflammatory [3, 4], anticoagulants [5] antibacterial [6-9], antiviral [10], antitubercular [11], and ACE inhibitor [12]. Therefore,

medicinal chemists are encouraged to synthesize novel series of the imidazole derivative drugs with exquisite chemotherapeutic agents [13]. 1,2,4-triazole rings have great recognition due to their biological activities including antifungal [14-16], antibacterial [17-20], antioxidant [21, 22] and anticancer [23, 24]. Also, these compounds have enormous applications in industrial settings [25]. Due to above-mentioned facts, in this work, we prepared some novel 1,2,4,5-tetrasubstituted imidazoles and evaluated their antibacterial activities.

*Address correspondence to this author at the Department of Chemistry, Qom Branch, Islamic Azad University, Qom, I.R. Iran; Tel/Fax: +98-2537780001; E-mail: [email protected]

Today, the ultrasonication technique based on the effects of cavitations which lead to mass transfer betterment is widely used in organic synthesis and has a prodigious effect

1. INTRODUCTION

1386-2073/18 $58.00+.00

© 2018 Bentham Science Publishers

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Combinatorial Chemistry & High Throughput Screening, 2018, Vol. 21, No. 4

on the way of chemists approach parallel synthesis. The reduction of reaction times, mild reaction conditions, improved yields and diminishing the side products, are advantages of this technology [26, 27].

Ghasemzadeh et al.

as solvents using TMS as an internal standard. FT-IR spectrum was recorded on Magna-IR, spectrometer 550. The (C, H, N) elemental analyses were obtained from a Carlo ERBA Model EA 1108 analyzer. Microscopic morphology of products was visualized by SEM (LEO 1455VP). The elemental analysis was performed by energy dispersive analysis of X-ray (EDX, Kevex, Delta Class I). Powder Xray diffraction (XRD) was carried out on a Philips diffractometer of X’pert Company with mono chromatized Cu Kα radiation (λ = 1.5406 Å). Magnetic properties were obtained on a BHV-55 vibrating sample magnetometer (VSM) made by MDK-I.R.Iran.

Multi-component reactions (MCRs) are synthetically beneficial organic reactions which have been often used as a facile approach to synthesize a variety of compounds [28]. In this context, 1,2,4,5-tetrasubstituted imidazoles are one of these compounds which show a great potential to be prepared via MCRs under ultrasound irradiation. Four-component condensation of 1,2-diketones, aldehydes, amines and ammonium acetate has been reported using different catalysts such as silica gel or Zeolite HY [29], molecular iodine [30], silica gel/NaHSO4 [31], K5CoW12O40.3H2O [32], hetropolyacids [33], InCl3.3H2O [34], HClO4-SiO2 [35], BF3/SiO2 [36] and L-proline [37]. Some of these reactions have disadvantages such as using the hazardous substances, expensive catalysts, harsh reaction conditions, significant amounts of waste materials, low yields and long reaction times. The method applied in this work has various advantages including short reaction times, excellent yields and recoverability of the catalyst. Herein, we introduce an environmentally friendly method to synthesize the novel 1,2,4,5-tetrasubstituted imidazoles in the presence of Co3O4 nanoparticles as a catalyst (Scheme 1).

2.2. Preparation of Co3O4 nanoparticles Co3O4 NPs were prepared by Vela et al. procedure with some corrections [38]. Cobalt (II) nitrate hexa hydrate (8.60 g) was dispersed in ethanol (100 mL) under vigorously stirring. Then, the reaction mixture was heated to 50oC for 30 min. In the last step, oxalic acid (2.14 g) was added to the mixtures and the solution was stirred for 2 h at 50°C. The formed precipitate was gathered by centrifuges and finally, the prepared powder was calcined at 400oC for 2 h. In order to check the morphology and structure of the catalyst, we characterized the Co3O4 nanoparticles using FESEM, EDX, VSM, XRD and FT-IR spectroscopy. Evaluation of size and morphology were determined by scanning electron microscopy (SEM). The FE-SEM image of the Co3O4 NPs is represented in Fig. (1). The average particle size measured from the scanning electron microscopy image is found to be 20-30 nm.

2. EXPERIMENTAL SECTION 2.1. Chemicals and apparatus Chemicals were purchased from the Sigma-Aldrich and Merck in high purity. All of the materials were of commercial reagent grade and were used without further purification. All melting points are uncorrected and were determined in the capillary tube on Boetius melting point microscope. 1H NMR and 13C NMR spectra were obtained on Bruker 400 MHz spectrometer with CDCl3 and DMSO-d6

The chemical purity of these samples was checked by EDX study. The only element which can be noted from EDX spectrum of Co3O4 wasCo and O indicating the absence of impurities (Fig. 2).

S S H2N

N H

O N H

NH2

HN N

OH

N

NH2

Melt Cl

3 Cl N

S O O

O R

R

HN

N

HN

N

NH2

NH4OAc

H

4 1

2

3

Cl

Co3O4 NPs )))))), r.t Ethanol

N

S

Cl HN

N

5(a-h)

5a; R = phenyl, 5b; R = 4-chlorophenyl, 5c; R = 4-bromophenyl, 5d; R = 4-nitrophenyl, 5e; R = 4-cyanophenyl, 5f; R = 4-fluorophenyl, 5g; R = 4-methylphenyl, 5h; R = 4-methoxyphenyl

Scheme 1. Preparation of 1,2,4,5-tetrasubstituted imidazoles in the presence of Co3O4 NPs as catalyst under ultrasonic irradiation.

Co3O4 Catalyzed Synthesis of Imidazoles


Fig. (1). FE-SEM image of Co3O4 nanoparticles.

3

Fig. (3). VSM magnetization curve of the Co3O4 NPs.

Fig. (4). XRD spectrum of Co3O4 NPs Fig. (2). EDX spectrum of Co3O4 nanoparticles.

Fig. (3) shows the magnetization measurement for the synthesized cobalt oxide nanoparticles using a vibrating sample magnetometer (VSM) at room temperature. The magnetization curves of the Co3O4 nanoparticles indicate paramagnetic properties which confirm no hysteresis, coercivity or remanence in the prepared nanoparticles. Moreover, the saturation magnetization value of the magnetic nanocatalyst was found 47.1 emu/g. The crystal structure of the nanocatalyst was further characterized using XRD. Fig. (4) shows the XRD pattern of Co3O4 nanoparticles (JCPDS File No. 74-1656). The major reflection indicated that the average size of Co3O4 nanoparticles was 18.8 nm. No peak for impurities was observed in the XRD patterns of sheets of Co3O4. Fig. (5) shows the FT-IR spectrum of the Co3O4 nanoparticles. As shown the vibration bands at 565 and 662 cm-1are the typical IR absorbance of Co-O vibration.

Synthesis of 4-amino-5-(4-chlorophenyl)-2,4-dihydro-3H1,2,4-triazole-3-thione(3): A mixture of 4-chlorobenzoic acid (0.01mol) and thiocarbohydrazide (0.015mol) was heated in a roundbottomed flask until the compound was melted. Then, the product was cooled down and sodium bicarbonate solution was added in order to neutralize any unreactive carboxylic acid. Finally, the residue was washed with water and separated by filtration. The product was recrystallized with ethanol to afford the desired compound. General procedure for synthesis of 1,2,4,5-tetrasubstituted imidazole derivatives (5a-5h): A mixture of benzil (1 mmol), aldehyde (1 mmol), ammonium acetate (1 mmol), and 4-amino-5-(4chlorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (1 mmol) was added to a 50 mL flask containing ethanol (5 mL). The reaction mixture was sonicated under 30 kHz at room temperature in the presence of Co3O4 nanoparticles

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Ghasemzadeh et al.

Fig. (5). FT-IR spectrum of Co3O4 nanoparticles.

(0.03g). After completion of the reaction as indicated by TLC, the reaction mixture was dissolved in dichloromethane and the catalyst was removed by an external magnet. The pure product was obtained after evaporation of the solvent and then recrystallized from ethanol. All the products were investigated and checked with m.p., 1H NMR, 13C NMR and FT-IR spectroscopy techniques. Spectral data of the new products are given below. 5-(4-chlorophenyl)-4-(2,4,5-triphenyl-1H-imidazol-1-yl)2,4-dihydro-3H-1,2,4-triazole-3-thione (5a). Yellow solid; m.p. 179-181°C.1H NMR (400 MHz, DMSO-d6) δ: 6.60-6.61(d, J=7.8 Hz, 2H), 7.10-7.20(m, 9H), 7.23-7.28(m, 6H), 7.43-7.44(d, J=7.8 Hz, 2H), 9.61(s, 1H, NH).13C NMR (100 MHz, DMSO-d6) δ: 125.65, 126.34, 126.40, 127.00, 127.15, 127.27, 127.32, 127.36, 127.41, 127.79, 127.83, 128.00, 128.07, 128.16, 130.05, 135.94, 136.52, 145.10. FT-IR (KBr) v: 3198, 1644, 1566, 1480, 1184 cm-1. MS (EI) (m/z): 505.11 (M+). Anal. Calcd. for: C29H20ClN5S (Mr= 506.02): C 68.83, H 3.98, N 13.84. Found: C 68.89, H 3.95, N 13.91. 5-(4-chlorophenyl)-4-(2-(4-chlorophenyl)-4,5-diphenyl1H-imidazol-1-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (5b). Yellow solid; m.p. 190-192°C.1H NMR (400 MHz, CDCl3) δ: 6.66-6-67(d,J=7.6 Hz, 2H), 7.07-7.11(m, 4H), 7.13-7.13(t, 1H), 7.19-7.28(m, 9H), 7.46-7.48(d, J=7.6 Hz, 2H), 9.65(s, 1H, NH).13C NMR (100 MHz, CDCl3) δ: 125.77, 126.31, 126.37, 126.95, 127.03, 127.11, 127.20, 127.36, 127.38, 127.56, 128.13, 128.26, 129.31, 130.06, 131.36, 135.94, 141.66. FT-IR (KBr) v: 3149, 1642, 1555, 1479, 1182 cm-1. MS (EI) (m/z): 539.07 (M+). Anal. Calcd. for: C29H19Cl2N5S (Mr= 540.47): C 64.45, H 3.54, N 12.96. Found: C 64.40, H 3.58, N 12.92. 4-(2-(4-bromophenyl)-4,5-diphenyl-1H-imidazol-1-yl)-5(4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (5c). Yellow solid; m.p. 138-140°C.1H NMR (400 MHz, CDCl3) δ: 6.99-7.08 (m, 4H), 7.16-7.17 (d, J=8.2 Hz, 2H), 7.24-7.34 (m, 8H), 7.44-7.46 (d, J=8.2 Hz, 2H), 7.60-7.63

(m, 2H) 9.66(s, 1H, NH). 13C NMR (100 MHz, CDCl3) δ: 115.165, 115.39, 125.77, 126.32, 127.19, 127.48, 127.94, 128.01, 128.12, 128.99, 129.07, 129.22, 130.05, 131.95, 133.03, 136.78, 159.75, 162.23. FT-IR (KBr) v: 3191, 1646, 1560, 1480, 1181 cm-1. MS (EI) (m/z): 583.02 (M+). Anal. Calcd. for: C29H19BrClN5S (Mr= 584.92): C 59.55, H 3.27, N 11.97. Found: C 59.67, H 3.18, N 11.94. 5-(4-chlorophenyl)-4-(2-(4-nitrophenyl)-4,5-diphenyl-1Himidazol-1-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (5d). Yellow solid; m.p. 183-185°C.1H NMR (400 MHz, CDCl3) δ: 7.00-7.02 (d, J=7.6 Hz, 2H), 7.05 (d, 2H), 7.13 (dd, 2H), 7.19–7.27 (m, 8H), 7.34 (d, 2H), 7.59-7.61 (d, J=7.6 Hz, 2H), 9.69(s, 1H, NH). 13C NMR (100 MHz, CDCl3) δ: 125.57, 126.28, 126.43, 126.55, 126.92, 127.14, 127.31, 127.40, 127.42, 127.53, 128.02, 129.58, 129.76, 130.08, 133.40, 136.04, 141.68, 145.84, 146.26, 153.15. FTIR (KBr) v: 3198, 1651, 1562, 1480, 1185 cm-1. MS (EI) (m/z): 550.10 (M+). Anal. Calcd. for: C29H19ClN6O2S (Mr= 551.02): C 63.21, H 3.48, N 15.25. Found: C 63.37, H 3.35, N 15.20. 4-(1-(3-(4-chlorophenyl)-5-thioxo-1,5-dihydro-4H-1,2,4triazol-4-yl)-4,5-diphenyl-1H-imidazol-2-yl)benzonitrile (5e). Yellow solid; m.p. 201-203°C.1H NMR (400 MHz, CDCl3) δ: 6.93-6.94 (d, J=7.8 Hz, 2H), 7.11–7.17 (m, 4H), 7.20–7.35 (m, 8H), 7.41 (d, 2H), 7.60–7.62 (d, J=7.8 Hz, 2H), 9.85(s, 1H, NH). 13C NMR (100 MHz, CDCl3) δ: 121.06, 121.58, 125.64, 126.37, 127.14, 127.51, 127.88, 127.96, 128.56, 128.91, 129.35, 129.44, 130.10, 131.13, 131.25, 133.27, 135.27, 137.42, 146.04. FT-IR (KBr) v: 3189, 2187, 1649, 1558, 1485, 1181 cm-1. MS (EI) (m/z): 530.11 (M+). Anal. Calcd. for: C30H19ClN6S (Mr= 531.03): C 67.85, H 3.61, N 15.83. Found: C 67.81, H 3.67, N 15.97. 5-(4-chlorophenyl)-4-(2-(4-fluorophenyl)-4,5-diphenyl1H-imidazol-1-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (5f). Yellow solid; m.p. 141-143°C.1H NMR (400 MHz, CDCl3) δ: 6.96–7.00 (d, J=7.6 Hz, 2H), 7.03–7.07 (m, 2H),



7.11-7.13 (d, J=7.8 Hz, 2H), 7.14–7.17 (m, 2H), 7.21–7.32 (m, 6H). 7.33-7.35 (d, J=7.6 Hz, 2H), 7.62-7.64 (d, J=7.8 Hz, 2H), 9.68(s, 1H, NH). 13C NMR (100 MHz, CDCl3) δ: 114.95, 115.17, 125.58, 126.32, 126.41, 127.01, 127.12, 127.41, 127.79, 127.88, 128.99, 129.08, 129.50, 129.58, 130.07, 132.19, 133.30, 137.16, 137.31, 146.12, 159.59, 162.06. FT-IR (KBr) v: 3190, 1650, 1557, 1485, 1188 cm-1. MS (EI) (m/z): 523.10 (M+). Anal. Calcd for: C29H19ClFN5S (Mr= 524.01): C 66.47, H 3.65, N 13.37. Found: C 66.31, H 3.76, N 13.39. 5-(4-chlorophenyl)-4-(4,5-diphenyl-2-(p-tolyl)-1Himidazol-1-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (5g). Yellow solid; m.p. 190-192°C.1H NMR (400 MHz, CDCl3) δ: 2.36 (s, 3H, CH3), 6.95-6.96 (d, J=8 Hz, 2H), 7.10-7.11 (d, J=7.6 Hz, 2H), 7.16–7.18 (d, J=8 Hz, 2H), 7.21–7.30 (m, 8H), 7.41–7.43 (d, J=7.6 Hz, 2H), 7.61–7.63 (m, 2H), 9.72(s, 1H, NH). 13C NMR (100 MHz, CDCl3) δ: 20.14, 119.77, 125.60, 126.30, 126.95, 126.99, 127.13, 127.29, 127.31, 128.10, 128.82, 129.03, 129.50, 130.05, 130.17, 133.15, 133.21, 133.31, 137.41, 144.74. FT-IR (KBr) v: 3187, 1655, 1554, 1481, 1183 cm-1. MS (EI) (m/z): 519.13 (M+). Anal. Calcd. for: C30H22ClN5S (Mr= 520.05): C 69.29, H 4.26, N 13.47. Found: C 69.78, H 4.21, N 13.29.

mmol) and ammonium acetate (1 mmol) as a model reaction (Scheme 2). In order to study the effects of Co3O4 nanocatalyst and compare it with homogeneous catalysts under ultrasonication; catalytic behaviour of MgSO4, HCl, CuSO4, H2SO4 were examined and compared with Co3O4 nanoparticles in model reaction (Table 1). The results demonstrate that the best results were obtained in the presence of Co3O4 nanoparticles . It is noteworthy to mention that when the reaction was carried out without catalyst, the synthesis did not progress at all. In addition, the summarized results in Table 1 indicate that 0.12 mmol (0.03g) of Co3O4 nanoparticle is the optimum amount of the catalyst. Table 1.

5-(4-chlorophenyl)-4-(2-(4-methoxyphenyl)-4,5-diphenyl1H-imidazol-1-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (5h). Yellow solid; m.p. 164-166°C.1H NMR (400 MHz, CDCl3) δ: 2.32 (s, 3H, OCH3), 6.93–6.95 (d, J=8 Hz, 1H), 7.05 (t, 1H), 7.07-7.09 (d, J=7.8 Hz, 2H), 7.12–7.27 (m, 10H), 7.31-7.33 (d, J=7.8 Hz, 2H),7.58–7.60 (d, J=8 Hz, 2H), 9.71(s, 1H, NH). 13C NMR (100 MHz, CDCl3) δ: 20.27, 125.64, 125.77, 126.24, 126.33, 127.14, 127.15, 127.47, 127.58, 127.78, 127.95, 128.92, 129.31, 130.05, 133.21, 133.48, 137.33, 137.45, 146.00. FT-IR (KBr) v: 3186, 1655, 1555, 1481, 1183 cm-1. MS (EI) (m/z): 535.12 (M+). Anal. Calcd. for: C30H22ClN5OS (Mr= 536.05): C 67.22, H 4.14, N 13.07. Found: C 67.38, H .4.01, N 12.96. RESULTS AND DISCUSSIONS The Main key to a successful synthesis is choosing the appropriate reaction medium. Therefore, first, we optimized different reaction conditions for the preparation of 1,2,4,5tetrasubstituted imidazoles by the multi-component reaction of benzyl (1 mmol), benzaldehyde (1 mmol), 4-amino-5-(4chlorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (1

Optimization of the model reaction using various catalysts under ultrasonic irradiation.a

Entry

Catalyst (mmol)

Time (min)

Yield (%)b

1

MgSO4 (0.2)

90

45

2

HCl (0.2)

70

30

3

CuSO4 (0.2)

60

75

4

H2SO4 (0.2)

60

80

5

Co3O4NPs(0.2)

20

95

6

Co3O4NPs (0.12)

20

95

7

Co3O4NPs(0.04)

20

90

a

Reactionconditions: benzyl (1mmol), benzaldehyde(1mmol), 4-Amino-5-(4chlorophenyl)-2,4- dihydro-3H-1,2,4-triazole-3-thione (1mmol) and ammonium acetate (1mmol) in ethanol at r.t. under sonication b Isolated yield.

Further, we test the effect of diverse solvents such as CH3OH, CH3CH2OH, CH3CN, CH2Cl2, CHCl3 as well as solvent-free conditions in the model reaction at room temperature. The results are summarized in Table 2. The use of 0.03g of Co3O4NPs in ethanol was yielded 95% of the desired product. Therefore, ethanol was chosen as the best solvent in this research. For a demonstration of the efficiency of the present approach and to illustrate the role of ultrasound, the preparation of heterocyclic compounds were compared under reflux conditions (method A) and ultrasonic irradiation (method B) (Table 3). Long reaction times and low yields are some pitfalls of reactions under reflux conditions, while the same reaction under ultrasonic irradiation obtained much better yields in short reaction times. Likewise, as compared

N

S O O

HN

O

N

N

N

NH2

NH4OAc

H

5

Co3O4 NPs )))))), r.t EtOH

Cl

Scheme 2.The model reaction for the synthesis of 1,2,4,5-tetrasubstituted imidazole.

N

S

Cl HN

N

6


dissolved in dichloromethane and then the nanocatalyst was separated magnetically [43]. Afterwards, the separated catalyst was washed three times with dichloromethane and methanol and then dried at 50 oC for 10 h. To investigate the level of reusability of the Co3O4 NPs, the model reaction was performed several times using recovered nanocatalyst. The results of these experiments showed that the catalytic activity of Co3O4 NPs did not decrease significantly even after five catalytic cycles (Table 4).

Table 2. Synthesis of 5-(4-chlorophenyl)-4-(2,4,5-triphenyl-1Himidazol-1-yl)-2,4-dihydro-3H-1,2,4-triazole 3-thione 5a in different solvent.a Entry

Solvent

Time (min)

Yield (%)b

1

CH3OH

35

75

2

CH3CH2OH

20

95

3

CH3CN

35

70

4

CH2Cl2

70

45

5

CHCl3

90

30

6

Solvent-free

90

20

Ghasemzadeh et al.

Table 4.

a

Reaction conditions :Reaction of benzyl (1mmol), benzaldehyde (1mmol), 4-amino-5(4-chlorophenyl)-2,4- dihydro-3H-1,2,4-triazole-3-thione (1mmol) and ammonium acetate (1mmol) in various solvents at r.t. in the presence of Co3O4 NPs (0.03 g) under ultrasonic irradiation. b Isolated yield.

a

The catalyst reusability for the synthesis of 1,2,4,5tetra-substituted imidazoles

Cycle

First

Second

Third

Fourth

Fifth

Yield (%)a

95

93

93

89

87

Yields refer to the isolated pure product

Proposed Mechanism with contractual method [39], this approach is more environmentally friendly, especially when considering the green chemistry.

The obtained results as well as some previous reports suggest a mechanism shown in Scheme 3 for the preparation of 1,2,4,5-tetrasubstituted imidazoles in the presence of Co3O4 NPs [44, 45]. Co3O4 NPs increase the electrophilicity of the carbonyl and double band groups as a Lewis acid. Evidently, in this scheme, the catalyst activates the carbonyl group of aldehyde to form an intermediate hydroxylamine [A], which is dehydrated, to imine [B]. Nucleophilic attack of amino group of 4-amino-5-(4-chlorophenyl)-2,4-dihydro3H-1,2,4-triazole-3-thione yields intermediate diamine [C]. Consequent nucleophilic attack of [C] on activated benzil [D] gaines [E] which releases water to form [F]. Intramolecular nucleophilic attack in [F] which leads to the cyclization of [G]. The nanocatalyst from this stage can be utilized for another cycle. Subsequently, dehydration of [G] gives the 2,4,5-tetrasubstituted imidazoles product.

Cavitation as the origin of sonochemistry is a physical process vaporous or gaseous cavities can form and collapse in an irradiated liquid, which leads to an increase in the mass transfer and helping chemical reactions to occur. The bubbles are tiny and can collapse quickly; also they act as microreactors which can speed in some reactions [40-42]. The recoverability of a catalyst is a crucial issue in organic synthesis. In this work the possibility of the recycling and reusing of the cobalt oxide nanoparticles was studied in the reaction of benzil, aldehydes, 4-amino-5-(4chlorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione and ammonium acetate under optimized conditions. When the model reaction was complete, the reaction mixture was

HOAc

NH4OAc

H

OH

O

NH2 Ar

H

NH3

Ar

NHR

H2O NH

Ar

H A

NH2

RNH2 Ar

H C

B

O

Ph D

O

Ph

H

H

Ar

Ar H N

Ar

Ph

N

Ar

NHR Ph

HN

NHR

HO

Ph

O

Ph

N

N R

N

Ph

Ph

R

HO G

Ph

O

Ph F

H2O

E

Co3O4 NPs =

Scheme 3. The proposed mechanism for the synthesis of 1,2,4,5-tetrasubstituted imidazolescatalyzed by Co3O4 NPs.


Table 3. Entry


7

Synthesis of 1,2,4,5-tetrasubstituted imidazoles under reflux conditions and sonication (method A and B). Method Aa

Product

1

Method Bb

Time(min)

Yieldc(%)

Time(min)

Yieldc(%)

130

80

20

95

120

84

12

97

120

82

12

94

150

78

25

91

150

77

28

91

140

79

16

93

5a 2

5b 3

5c 4

5d 5

5e 6

5f (Table 4) Contd….

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Combinatorial Chemistry & High Throughput Screening, 2018, Vol. 21, No. 4 Entry

Ghasemzadeh et al. Method Aa

Product

7

Method Bb c

Time(min)

Yield (%)

Time(min)

Yieldc(%)

180

81

18

95

145

80

22

92

5g 8

5h a

Reaction conditions: Reaction of benzil and aromatic aldehydes in the presence of 4-amino-5-(4-chlorophenyl)-2,4- dihydro-3H-1,2,4-triazole-3-thione and ammonium acetate in water under reflux conditions. b Reaction conditions: Reaction of benzil and aromatic aldehydes in the presence of 4-amino-5-(4-chlorophenyl)-2,4- dihydro-3H-1,2,4-triazole-3-thione and ammonium acetate in ethanol at room temperature under ultrasonic irradiation. c Yields of isolated products.

Antibacterial Activity

CONCLUSION

The products were screened using E. Coli (EC), S. aureus (SA) B. subtillis (BS) S. typhi (ST) and S. dysentrae (SD) bacteria. The activities of these compounds were tested using disc diffusion method in DMSO (150 ppm concentration) using 5 mm filter papers disc. The area of zone of inhibition was measured using tetracycline drug as a standard compound [46].

In summary, an extremely efficient approach has been reported for the preparation of some novel 1,2,4,5tetrasubstituted imidazole compounds in the presence of Co3O4 NPs under ultrasonic irradiation at room temperature. The quick reaction, simple workup, neutral conditions, and high yields are the advantages of this methodology which can help chemists to synthesize1,2,4,5-tetrasubstituted imidazoles.

The compounds 5c, 5f and 5h showed the highest antibacterial activity against all bacteria. Compound 5a showed the highest activity against the bacillus Bacillussubtillis organism. Compound 5g showed the highest activity against the Salmonella dysentrae organism. The other remaining compounds showed moderate to poor activities (Table 5). Table 5.

Antibacterial activities of compounds studied.

CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise.

Zone of inhibition in mm

ACKNOWLEDGEMENTS

NO

EC

SA

BS

ST

SD

5a

5

10

12

5

7

5b

5

4

6

3

2

5c

14

10

12

17

15

5d

9

8

6

6

4

REFERENCES

5e

8

4

2

7

7

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5f

15

11

14

16

14

5g

4

6

7

9

10

5h

12

10

14

18

16

tetracycline

16

14

15

17

15

This work was supported by the Islamic Azad University, Qom Branch, Qom, I. R. Iran, followed by [grant number 2014-13929]

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