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Original article
13 (
12
); 8807-8814
doi:
10.1016/j.arabjc.2020.10.010

Highly efficient and metal-free synthesis of tri- and tetrasubstituted imidazole catalyzed by 3-picolinic acid

, ,
a Department of Chemistry, University of Rajshahi, Rajshahi 6205, Bangladesh
b Organic Material Synthesis Division, Kayrbat Research Institute (KRI), Bogra 5810, Bangladesh

⁎Corresponding author at: Organic Material Synthesis Division, Kayrbat Research Institute (KRI), Bogra 5810, Bangladesh. mazamsarker@gmail.com (Abu Zafar Al Munsur)

Received: , Accepted: ,
© The Author(s) 2020
Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

Abstract

3-Picolinic acid is an efficient organo-catalyst for a one-pot three-component synthesis of 2,4,5-triaryl substituted imidazole. Moreover, the utility of this catalyst has been extended to the four-component synthesis of 1,2,4,5-tetra-substituted imidazole. The pivotal advantages of this process are easy purification, cost-effectiveness, and high yielding, above all environmentally benign protocol.

Keywords

Imidazole
3-Picolinic acid
Metal-free
Organo-catalyst
Green synthesis
1

1 Introduction

Today the synthesis, reactions, and biological properties of substituted imidazole cover a wide area of modern heterocyclic chemistry (Grimmett, 1984). Notably, compounds with imidazole core units have many pharmacological properties and play a vital role in varying biochemical processes (Liverton et al., 1999; Lombardino and Wiseman, 1974). Recent research has uncovered that highly substituted imidazole derivatives endow good photo-physical properties which result in their potential application in materials chemistry (Kulkarni et al., 2004). Moreover, appropriately substituted imidazole are extensively used as glucagon receptors (Black et al., 1974; Khanna et al., 1997), CB1 cannabinoid receptor antagonists (Lee et al., 1994), and in some cases antibacterial (Antolini et al., 1999), antitumor (Wang et al., 2002), and pesticides (Sharma et al., 2020). In the last decade, the advancement of green chemistry and organometallic catalysis have exploited the utility of imidazole as ionic liquids (Tao et al., 2016) and N-heterocyclic carbenes (Kühl, 2007; Kureja et al., 2019). Based on the above facts, lots of synthetic routes are available in the literature to synthesize imidazole analogs including ionic liquids (Akbari, 2016), [Hmim]TFA (MaGee et al., 2013), NH4OAc (Wu et al., 2010), iodine (Kidwai et al., 2006), tons of metal-based heterogeneous catalyst (Daraji et al., 2019; Kerru et al., 2019), and microwave irradiation (Zhou et al., 2010) are most notable. Recently, a metal-free method carried out by pivalic acid (Raj and Singh, 2009) has attracted a lot in condensing three or four components to imidazole instead of benzil with excellent yields.

However, most of these methods are challenged by one or more limitations such as harsh reaction conditions, tedious isolation technique, unsatisfactory yield, limited examples, expensive and detrimental metal catalysts, which limit their use due to the heavy impact on environmentally benign processes. Therefore, the development of mild, economically convenient, and complementary approaches for 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazole derivatives are highly recommendable.

3-Picolinic acid is an important building block of co-enzymes (NAD and NADP) which are essential by all living cells. It has widely used in the fields of medicine, agriculture, and the food industry (Alkayeva et al., 2015).

Nowadays, organocatalysts (D’Souza and Müller, 2007; Dömling, 2006) have drawn much attention in different organic transformations owing to its experimental simplicity, facile handling, cost-effectiveness, and above all excellent solubility in organic solvents or water. Despite that, there are not too many organocatalysts mediated multicomponent reactions for imidazole synthesis being reported to date. By considering the current demands of different tri- and tetrasubstituted imidazole in many aspects, to explore a new organo-catalyst and to forestall possible difficulty of the typical procedures, we herein, reported a convenient multicomponent route (Scheme 1) to condense benzil or benzoin, aldehydes, ammonium acetate, benzylamine, aniline or aniline derivatives mediated by 3-picolinic acid (niacin).

Reaction for three substituted imidazole synthesis.
Scheme 1
Reaction for three substituted imidazole synthesis.

2

2 Result and discussion

This is an extension (Roy et al., 2016) of our earlier attempts in synthesizing biologically active molecules by screening organo-catalyst via a multicomponent scaffold. During flame heating, we observed the charring of the starting materials and the products. To minimize the spoilage of the starting materials and products in this present work we wished to use a little amount of ethanol. Also, our objective was to find a new catalyst with higher efficacy than the earlier catalyst. To this end, we attempted to synthesize substituted imidazoles from benzil, benzaldehyde, and ammonium acetate in ethanol mediated by some small bifunctional molecules (o- & p-aminophenol, 2-picolinic acid, and aspartic acid; Table 1). To carry out the reaction, reacting components were mixed thoroughly with the mentioned small molecules (5–20 mol%) and heated gently over an oil bath at different temperatures with constant speed. But TLC monitoring indicated a tiny conversion of the starting materials, with the exception observed for 2-picolinic acid. The use of 2-picolinic acid afforded the product Entry I 1–50% yield despite the sincere alteration of catalyst, catalyst loading, solvents, and temperatures. Subsequently, by changing the catalyst from 2- to 3-picolinic acid to the same reaction and our delight, full conversions of the starting components were observed in TLC after 2 h reflux at 80 °C into ethanol solvent. Therefore, the feasibility of the reaction was investigated by the changes of catalyst loading and found 10 mol% catalysts are suitable for the desired conversion (Table 1).

Table 1 Tunning of the reaction conditions to synthesize imidazole derivatives.
Entry Catalyst Catalyst Concentration (mol%) Solvent Temperature/°C Time (hour) Yield (%)a
1 Without catalyst – Ethanol RT 48 19
2 Without catalyst – Ethanol 40 48 21
3 Without catalyst – Ethanol 50 48 23
4 Without catalyst – Ethanol 60 48 24
5 Without catalyst – Ethanol 70 48 25
6 Without catalyst – Ethanol Refluxes 48 25
7 Without catalyst – Ethanol 80 48 25
8 o-Aminophenol 5 Ethanol 40 48 18
9 o-Aminophenol 5 Ethanol 50 48 20
10 o-Aminophenol 5 Ethanol 60 48 21
11 o-Aminophenol 5 Ethanol 70 48 22
12 o-Aminophenol 5 Ethanol Reflux 48 23
13 o-Aminophenol 5 Ethanol 80 48 23
14 o-Aminophenol 10 Ethanol 40 48 21
15 o-Aminophenol 10 Ethanol 50 48 23
16 o-Aminophenol 10 Ethanol 60 48 25
17 o-Aminophenol 10 Ethanol 70 48 27
18 o-Aminophenol 10 Ethanol Reflux 48 26
19 o-Aminophenol 10 Ethanol 80 48 27
20 o-Aminophenol 15 Ethanol 40 48 15
21 o-Aminophenol 15 Ethanol 50 48 17
22 o-Aminophenol 15 Ethanol 60 48 22
23 o-Aminophenol 15 Ethanol 70 48 21
24 o-Aminophenol 15 Ethanol Reflux 48 23
25 o-Aminophenol 15 Ethanol 80 48 26
26 o-Aminophenol 20 Ethanol 40 48 20
27 o-Aminophenol 20 Ethanol 50 48 21
28 o-Aminophenolo-Aminophenol 20 Ethanol 60 48 22
29 o-Aminophenol 20 Ethanol 70 48 25
30 o-Aminophenol 20 Ethanol Reflux 48 27
31 o-Aminophenol 20 Ethanol 80 48 26
32 p-Aminophenol 5 Methanol:water (1:1) 40 48 24
33 p-Aminophenol 5 Methanol:water (1:1) 50 48 26
34 p-Aminophenol 5 Methanol:water (1:1) 60 48 28
35 p-Aminophenol 5 Methanol:water (1:1) Reflux 48 30
36 p-Aminophenol 10 Methanol:water (1:1) 40 48 26
37 p-Aminophenol 10 Methanol:water (1:1) 50 48 28
38 p-Aminophenol 10 Methanol:water (1:1) 60 48 31
39 p-Aminophenol 10 Methanol:water (1:1) Reflux 48 35
40 p-Aminophenol 15 Methanol:water (1:1) 40 48 23
41 p-Aminophenol 15 Methanol:water (1:1) 50 48 31
42 p-Aminophenol 15 Methanol:water (1:1) 60 48 36
43 p-Aminophenol 15 Methanol:water (1:1) Reflux 48 43
45 p-Aminophenol 20 Methanol:water (1:1) 40 48 25
46 p-Aminophenol 20 Methanol:water (1:1) 50 48 27
47 p-Aminophenol 20 Methanol:water (1:1) 60 48 30
48 p-Aminophenol 20 Methanol:water (1:1) Reflux 48 41
49 Aspartic acid 5 Methanol 40 48 20
50 Aspartic acid 5 Methanol Reflux 48 25
51 Aspartic acid 10 Methanol 40 48 23
52 Aspartic acid 10 Methanol Reflux 48 28
53 Aspartic acid 15 Methanol 40 48 21
54 Aspartic acid 15 Methanol Reflux 48 30
55 Aspartic acid 20 Methanol 40 48 24
56 Aspartic acid 20 Methanol Reflux 48 29
57 2-Picolinic acid 5 Ethanol:water (1:1) 35 12 20
58 2-Picolinic acid 5 Ethanol:water (1:1) 45 12 24
59 2-Picolinic acid 5 Ethanol:water (1:1) 60 12 23
60 2-Picolinic acid 5 Ethanol:water (1:1) 75 12 25
61 2-Picolinic acid 5 Ethanol:water (1:1) Reflux 12 29
62 2-Picolinic acid 10 Ethanol:water (1:1) 35 12 35
63 2-Picolinic acid 10 Ethanol:water (1:1) 45 12 39
64 2-Picolinic acid 10 Ethanol:water (1:1) 60 12 43
65 2-Picolinic acid 10 Ethanol:water (1:1) 75 12 45
66 2-Picolinic acid 10 Ethanol:water (1:1) Reflux 12 50
67 2-Picolinic acid 15 Ethanol:water (1:1) 35 12 29
68 2-Picolinic acid 15 Ethanol:water (1:1) 45 12 35
69 2-Picolinic acid 15 Ethanol:water (1:1) 60 12 41
70 2-Picolinic acid 15 Ethanol:water (1:1) 75 12 40
71 2-Picolinic acid 15 Ethanol:water (1:1) Reflux 12 45
72 2-Picolinic acid 20 Ethanol:water (1:1) 35 12 31
73 2-Picolinic acid 20 Ethanol:water (1:1) 45 12 35
74 2-Picolinic acid 20 Ethanol:water (1:1) 60 12 38
75 2-Picolinic acid 20 Ethanol:water (1:1) 75 12 42
76 2-Picolinic acid 20 Ethanol:water (1:1) Reflux 12 48
78 3-Picolinic acid 5 Ethanol Reflux at 80 12 70
79 3-Picolinic acid 10 Ethanol Reflux at 80 2 93
80 3-Picolinic acid 15 Ethanol Reflux at 80 12 80
81 3-Picolinic acid 20 Ethanol Reflux at 80 12 80
a Isolated yield.

With the optimized condition, herein, we have explored the scope and limitations with other benzaldehydes and observed aryl chloride & aryl bromide (Entry I and VI in Table 2) were the compatible substrates with the yield of 90% and 88% respectively. Moreover, these two entities could provide convenient access to other products by metal-catalyzed cross-coupling reactions. Heterocyclic aldehydes (Entry IV, VIII, and X in Table 2) were endured under similar reaction conditions to obtain compound 4, 8, and 10 in 94%, 85%, and 87% yield, respectively. A few aldehydes like salicylaldehyde, chloralhydrate, and cinnamaldehyde were reacted but did not produce the expected imidazole. The presence of excess electron pushing functionalities in the benzene ring, accumulation of –ve charge by resonance in cinnamaldehyde, and the presence of three hydrolyzable —Cl atom in chloralhydrate possibly caused such failures (Roy et al., 2013). With the success of a three-component reaction, we wish to extend this methodology to other various substituted imidazole scaffolds by utilizing four-component strategies (Scheme 2).

Table 2 Data table for yield, melting points to the synthesis of trisubstituted imidazole derivatives.
Entry Aldehydes Products Time (hour) Yield (%)a M.p (°C) Reported M.p (°C) Reference
I 2.15 90 195–197 196–198 Maleki et al. (2015)
II 2.10 92 229–231 234 Zhou et al. (2010)
III 2 92 215–217 215 Roy et al. (2013)
IV 2 94 295–297 300 Zhou et al. (2010)
V 2.15 92 269–270 260–261 Kidwai et al. (2006)
VI 2 88 200–201 199–200 Roy et al. (2013)
VII 2 97 259–261 259–260 Zhou et al. (2010)
VIII 1.5 85 181–182 This Work
IX 1.5 97 300 298–301 Maleki et al. (2015)
X 2 87 200–202 199–201 Maleki et al. (2015)
XI No result 48 – – –
XII No result 47 – – –
XIII No result 48 – – –
a Isolated yield.
Reaction for four substituted imidazole synthesis.
Scheme 2
Reaction for four substituted imidazole synthesis.

Under identical reaction conditions, and a stoichiometric amount of different substituted aniline derivatives as the fourth component, the reaction underwent an elegant transformation to various products in good to excellent yield. Moreover, heterocyclic amines (Entry, XXI) or other substituted amines did not create any problems during the product formation shown in Table 3. The reaction mechanism may follow a similar pattern as reported in the literature (Damavandi and Sandaroos, 2016), but in our case, 3-picolinic acid is donating its proton to aldehyde for necessary activation and on the other hand N-atom in pyridine ring abstracts protons to complete the reaction where it is necessary (shown in Fig. 1). In this manner, 3-picolinic acid is assisting the reaction in a dual way both by the rates and the yield of the products. With the same catalyst, twenty-three different tri- (Table 2) and tetrasubstituted imidazole (Table 3) were synthesized successfully without any sophisticated column chromatographic purification techniques.

Table 3 Data table for yield, melting points to the synthesis of tetrasubstituted imidazole derivatives.
Entry Aldehydes Amines Products Time (hour) Yield (%)a Calculated M.p (°C) Reported M.p (°C) Reference
XIV 2 96 162–163 162–165 Kantevari et al. (2007)
XV 2 98 130–132 – This Work
XVI 2 97 180–182 – This Work
XVII 2 98 170–172 – This Work
XVIII 2 96 174–176 177–180 Safari and Zarnegar (2013)
XIX 2 97 247–249 – This Work
XX 2 95 238–240 220–223 Hosseini et al. (2019)
XXI 2 90 254–256 – This Work
XXII 2 92 168–170 – This Work
XXIII 2 95 218–220 – This Work
XXIV 2 91 157–158 – This Work
XXV 2 89 247–249 – This Work
XXVI 2 92 233–235 – This Work
a Isolated yield.
The stepwise mechanistic pathway for the multi-substituted imidazole synthesis via one-pot, three, and four components condensation reaction mediated by 3-picolinic acid.
Fig. 1
The stepwise mechanistic pathway for the multi-substituted imidazole synthesis via one-pot, three, and four components condensation reaction mediated by 3-picolinic acid.

Interestingly, benzoin also reacted in the same fashion and afforded imidazole with high yield and thereby making the reaction path shorter. Besides, the efficiency and reusability of the catalyst activity were verified for the three consecutive reactions, by drying the filtrate solutions and subsequent purifications by column chromatography, whereas two reactions were going on smoothly without any loss of catalyst activity Table 4.

Table 4 Reusability of catalyst 3-Picolinic acid.
Cycle Yield (%) Catalyst recovered (%)
Native 95 86
1st 95 83
2nd 95 85
3rd 94 82

Table 5 compares our results for the synthesis of 2-(4-Chlorophenyl)-1,4,5-triphenyl-1H-imidazole (11). with the results of different catalysts and reaction conditions obtained by other groups.

Table 5 Comparison of the efficiency of various catalysts in the synthesis of 2-(4-Chlorophenyl)-1,4,5-triphenyl-1H-imidazole (11).
Catalyst Conditions Time (min) Yield (%) Reference
SBA-15/TFE TFE/90 °C 180 90 Rostamnia and Zabardasti (2012)
[Poly(AMPS-co-AA)] Solvent-free/110 °C 30 90 Mohammadi et al. (2012)
TFA Glycerol (5 mL) MW(300)/120 °C 10 90 Khalafi-Nezhad et al. (2016)
HClO4–SiO2 Solvent-free/140 °C 8 94 Kantevari et al. (2007)
[bmim]3[GdCl6] Solvent free/120 °C 120 94 Akbari (2016)
3-Picolinic acid Ethanol/80 °C 120 96 This work

Many of the synthesized products are known in the literature, and for such cases, melting points were compared with the literature values.

3

3 Conclusion

In conclusion, the study delineates a rapid, efficient, and convenient synthesis of tri- and tetrasubstituted imidazole in a one-pot, three, and four-components condensation strategy using inexpensive, less toxic, and readily available 3-picolinic acid as an organocatalyst in ethanol. Although 3-picolinic acid is not a familiar organocatalyst in the organic transformation but this report, we have exploited it the first time in an elegant way to construct various substituted imidazole with great ease and in high yield. Some of the products are known in the literature, so far, such cases only melting points were compared with the literature values. We strongly believe that this methodology will be a great strategy annexed to the remaining methods for the synthesis of tri- and tetrasubstituted imidazole.

4

4 Experimental

4.1

4.1 Materials and method

The melting points of the compound were measured on an electrothermal melting point apparatus (Gallenkamp) and the melting points incorporated are uncorrected. Infrared spectra (IR) were recorded on KBr pellets for solids and neat for liquids by FT-IR 8400 PerkinElmer 883 grating spectrometer. 1H NMR spectra were recorded on AC-Bruker 500 MHz spectrometer in D6-DMSO or CDCl3, containing TMS as an internal standard. All ‘J’ values are given in Hz and chemical shifts δ- in ppm units. Reactions were monitored by thin-layer chromatographic (TLC) plates over silica gel (60 GF254. E. Merck).

4.2

4.2 General procedure for the synthesis of 2,4,5-triaryl-1H-imidazoles

A mixture of benzyl/benzoin (1 mmol), aldehyde (1 mmol), ammonium acetate (2.5 mmol), and 3-picolinic acid (12 mg, 10 mol%) in ethanol (2 mL) was stirred at reflux temperature for 2–3 hr. The reaction was monitored by thin-layer chromatography (TLC), the eluent was a mixture of solvent (Hexane & Ethyl acetate). After completion of the reaction, the mixture was cooled to room temperature, neutralized with 5% NaHCO3 solution, diluted with water, and poured on crushed ice. The obtained crude solid product was filtered, dried, and recrystallized from ethanol.

4.2.1

4.2.1 Spectral data for imidazole derivatives

Entry I: 2-(2-Chlorophenyl)-4,5-diphenyl-1H-imidazole (1). Mp: 195–197 °C. 1H NMR (CDCl3, 500 MHz): 10.48 (br.s, 1H, NH), 8.38 (dd, J = 2.5, 8 Hz, 2H, Ar—H), 7.68–7.29 (m, 11H, Ar—H), 2.08 (s, 1H); 13C NMR (300 MHz, DMSO‑d6): 143.3, 130.4, 128.9, 128.5, 128.3, 128.3, 127.8, 127.4, 127, 100; HRMS: calcd. for C21H15ClN2, 330.8123; found: 330.8121.

4.2.2

4.2.2 General procedure for the synthesis of 1,2,4,5-tetra-substituted imidazole:

A mixture of benzyl/benzoin (1 mmol), aldehyde (1 mmol), ammonium acetate (2.5 mmol), amine (1 mmol), and 3-Picolinic acid (12 mg, 10 mol%) in ethanol (2 mL) was stirred at reflux temperature for 2–3 hr. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was cooled to room temperature, neutralized with 5% NaHCO3 solution, diluted with water, and poured on crushed ice. The obtained crude solid product was filtered, dried, and recrystallized from ethanol.

Entry XIV: 2-(4-Chlorophenyl)-1,4,5-triphenyl-1H-imidazole (11): Mp: 162–163 °C. 1H NMR (500 MHz, DMSO‑d6): 7.63–7.57 (m, 4H, Ar—H), 7.38–7.35 (m, 5H, Ar—H), 7.29–7.16 (m, 8H Ar—H), 6.84 (dd, J = 1.5, 8 Hz, 2H), 5.12 (s, 2H) ppm; 13C NMR (300 MHz, DMSO‑d6): 146.9, 138.3, 137.3, 135, 134.3, 131, 130.8, 130.4, 130.3, 129.4, 128.8, 128.8, 128.8, 128.7, 128.1, 127.5, 126.8, 126.5, 125.9, 48.3; HRMS: calcd. for C28H21ClN2, 420.9347; found: 420.93451429.

The rest of the spectral data and spectrum are included in the supporting information file.

Acknowledgment

We gratefully acknowledge the Department of Chemistry, University of Rajshahi, Bangladesh for the facility given during the present work and to the Green Chemistry Laboratory, KRICT for their necessary spectral help.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Appendix A

Supplementary material

Supplementary data to this article can be found online at https://doi.org/10.1016/j.arabjc.2020.10.010.

Appendix A

Supplementary material

The following are the Supplementary data to this article:

Supplementary Data 1

Supplementary Data 1


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