Tetrahedron Letters 59 (2018) 1924–1927

Contents lists available at ScienceDirect

Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet

Catalyst-free synthesis of 1,2,4,5-tetrasubstituted imidazoles from

arylamins, benzonitriles, arylglyoxals, and Meldrum’s acid
Hossein Mehrabi ⇑, Farzaneh Alizadeh-Bami, Reza Ranjbar-Karimi
Department of Chemistry, Vali-e-Asr University of Rafsanjan, 77176 Rafsanjan, Iran

a r t i c l e i n f o a b s t r a c t

Article history: An efficient and catalyst-free for the synthesis of 1,2,4,5-tetrasubstituted imidazoles has been developed
Received 16 January 2018 using a one-pot, two-step reaction of arylamins, benzonitriles, arylglyoxals, and Meldrum’s acid. All the
Revised 29 March 2018 products were obtained in good to excellent yields and their structures were established from their spec-
Accepted 30 March 2018
troscopic data.
Available online 31 March 2018
Ó 2018 Elsevier Ltd. All rights reserved.

Keywords:
Tetrasubstituted imidazoles
Arylamine
Benzonitrile
Arylglyoxal
Meldrum’s acid

Imidazoles are one of the most important five-membered ring solvents, longer reaction times, tedious work-up procedure, expen-
heteroaromatic nitrogen-bearing compounds that show a broad sive reagents, and large amounts of catalysts which would eventu-
range of pharmaceutical and industrial applications. Imidazole ally result in the generation of large amounts of toxic waste.
derivatives have a various biological activity such as antitumor,1 It is known that the arylglyoxals undergoes multicomponent
antibacterial,2 anti-HIV,3 antiviral,4 anti-allergic,5 antioxidant,6 domino reactions have played an important role in the total syn-
anti-inflammatory,7 antifungal,8 and antiparasitic,9 which have thesis of natural products. To illustrate this point, Jiang et al. have
indicated them as new candidates in cancer therapy.10 Moreover, discovered a novel ABC2 type domino reaction of arylglyoxal with
they can be found in many important drugs such as Omeprazole, electron-rich pyrazol-5-amines and aromatic amines, leading to
Eprosartan, and Trifenagrel having functionalized imidazole the formation of pyrazolo[40 ,30 :6,7]azepino[5,4,3-cd]indoles and
motif.11 Therefore, a broad utility range has made imidazoles pyrazolo[3,4-b]-pyridines under microwave heating.26 Also, they
prime synthetic targets thereby accentuating the need to develop were synthesized pyrazolo[3,4-b]pyridine derivatives from aryl-
newer synthetic routes for imidazole derivatives. glyoxals, pyrazol-5-amines, aromatic amines, 4-hydroxy-6-
A number of methods have been developed for the synthesis of methyl-2H-pyran-2-one, and cyclohexane-1,3-diones,27 or
1,2,4,5-tetrasubstituted imidazoles. These compounds are gener- synthesis of pyrazolo-fused 1,7-naphthyridines, 1,3-diazocanes,
ally synthesized in a four-component condensations of a 1,2-dike- and pyrroles from arylglyoxals and pyrazol-5-amines,28 and syn-
tone derivative with an aldehyde, primary amine, and ammonium thesis of oxazolo[5,4-b]indoles by using arylglyoxals with cyclic
acetate using Cu(II) nitrate impregnated zeolite,12 FeCl3
6H2O,13 enaminones and amino acids.29 In addition, bi-electrophilic centers
SiO2:BF3,14 SiO2:NaHSO4,15 CAN,16 p-toluene sulfonic acid,17 molec- of arylglyoxals were simultaneously utilized for the synthesis of
ular iodine,18 heteropolyacid,19 SiO2:SnO2,20 bioglycerol-based car- biologically active compounds. For examples, synthesis of
bon,21 and the magnetic ionic liquid.22 In addition, they can also be functionalized quinoxalines by the cyclocondensation of
accessed by the condensation of a 1,2-diketone with an aryl nitrile bi-electrophilic centers of arylglyoxals and aryl 1,2-diamine via a
and primary amine under microwave irradiation,23 by hetero-Cope oxidation process using BiCl3/SiO2,30 PVPP
OTf,31 magnetic Fe3O4
rearrangement,24 and by N-alkylation of trisubstituted imida- nanoparticles,32 iodine-catalyzed,33 Pd(OAc)2 or RuCl2(PPh3)3-
zoles.25 However, many of these procedures are associated with TEMPO,34 and MnO2.35 With this background in mind, we describe
one or more disadvantages such as the use of hazardous organic in this study a one-pot, two-step synthesis of 1,2,4,5-tetrasubsti-
tuted imidazoles from the reaction of arylamins, benzonitriles,
⇑ Corresponding author. Meldrum’s acid with arylglyoxals under catalyst-free conditions
E-mail address: mehraby_h@yahoo.com (H. Mehrabi). (Table 1).

https://doi.org/10.1016/j.tetlet.2018.03.093
0040-4039/Ó 2018 Elsevier Ltd. All rights reserved.
 H. Mehrabi et al. / Tetrahedron Letters 59 (2018) 1924–1927 1925

Table 1 The first step reaction was started using 4-methylaniline 1a,
Optimization of the reaction conditionsa. and benzyl cyanide 2a for construction of the corresponding inter-
mediate at 120 °C for 1 h under solvent-free conditions. After cool-
ing the reaction medium to room temperature at the second step,
NH2 O
Cl O ethanol (5.0 mL), 4-chlorophenylglyoxal 3a, and Meldrum’s acid 4
CN O
were added to the intermediate. The reaction mixture was then
H3C + O
1a 2a 120 oC to r.t. H
stirred at room temperature. After completion of the reaction
O N during 1 h, the reaction furnished the desired product, 5-(2-ben-
2h. N
H O O zyl-5-(4-chlorophenyl)-1-(p-tolyl)-1H-imidazol-4-yl)-6-hydroxy-
O O O
2,2-dimethyl-4H-1,3-dioxin-4-one 5a. Therefore, the best reaction
Cl Me
conditions for the synthesis of 1,2,4,5-tetrasubstituted imidazole
3a 4 5a
5a was found to be an one-pot, two-step reaction of 4-methylani-
line (1.2 mmol), benzyl cyanide (1.0 mmol), 4-chlorophenylglyoxal
(1.5 mmol), and Meldrum’s acid (1.0 mmol) at ambient tempera-
ture in ethanol for the second step and the product 5a was
Entry Solvent Temp. (°C) Yield (%)b
obtained in 96% yield after 2 h (Table 1, entry 8).
Second step First step/Second step Under the optimized reaction conditions, a series of 1,2,4,5-
1 MeOH 120/r.t. 30
tetrasubstituted imidazole derivatives 5a–m were synthesized
2 H2O 120/r.t. 40 (Table 2). To explore the scope of this novel transformation, then
3 MeCN 120/r.t. 50 various arylamins 1, benzonitriles 2, arylglyoxals 3, and Meldrum’s
4 DMF 120/r.t. 58 acid 4 were utilized under the same reaction conditions. From the
5 H2O:EtOH (1:1) 120/r.t. 60
results shown in Table 2, we could see that all of the reactions pro-
6 EtOH r.t./r.t. 55
7 EtOH 80/r.t. 70 ceeded smoothly to afford the corresponding products 5a–m in
8 EtOH 120/r.t. 96 excellent yields.
9 EtOH 120/r.t. 90c All the synthesized compounds were unknown to the best of
a
Reaction conditions: 1a (1.2 mmol), 2a (1.0 mmol), 3a (1.5 mmol), 4 (1.0 our knowledge and were characterized by 1H and 13C NMR, IR,
mmol), and reaction time was 2 h. CHN analysis and melting points. For instance, the 1H NMR spec-
b
Isolated yields. trum of the compound 5a consisted of two singlet at d = 0.96 and
c
Reaction time was 6 h. 1.38 ppm for the methyl groups in the Meldrum’s acid. The methyl
and the methylene group protons were discernible as a singlet at d
= 2.36 and 4.19 ppm respectively. The aromatic protons resonated
To find the optimized conditions, we studied the synthesis of 5- in the region d = 6.96–7.71 ppm, and a broad singlet that integrated
(2-benzyl-5-(4-chlorophenyl)-1-(p-tolyl)-1H-imidazol-4-yl)-6- for one hydrogen was observed at d = 14.76 ppm for the hydroxy
hydroxy-2,2-dimethyl-4H-1,3-dioxin-4-one 5a from the reaction proton. The 13C NMR spectrum of compound 5a exhibited 22 dis-
of 4-methylaniline 1a (1.2 mmol), benzyl cyanide 2a (1.0 mmol), tinct signals in agreement with the proposed structure. In the IR
4-chlorophenylglyoxal 3a (1.5 mmol), and Meldrum’s acid 4 (1.0 spectrum, the hydroxyl and the carbonyl lactone absorption were
mmol) under a variety of conditions without any catalyst (Table 2). observed at 3448 and 1674 cm1. Partial assignments of these

Table 2
Synthesis of 1,2,4,5-tetrasubstituted imidazoles in ethanol at room temperature.

O
O
O O
NH2 CN H O O 120 oC to r.t. Ar2 O
+ + Ar2 + H
Ar1 R EtOH N
O O O N
1 2 Ar1
3 4 5a-m R

Entry Product Ar1 R Ar2 Time (h) Yield (%)a

1 5a 4-CH3C6H4 CH2C6H5 4-ClC6H4 2 96
2 5b 4-CH3C6H4 CH2C6H5 4-CH3C6H4 2 80
3 5c 4-CH3C6H4 CH2C6H5 C6H5 3 83
4 5d 4-CH3C6H4 CH2C6H5 4-NO2C6H4 2 87
5 5e 4-CH3C6H4 CH2C6H5 4-CH3OC6H4 3 82
6 5f 4-CH3OC6H4 2-ClC6H4 4-ClC6H4 1.5 96
7 5g 4-CH3OC6H4 2-ClC6H4 4-CH3C6H4 2 82
8 5h 4-CH3C6H4 CH2C6H5 4-BrC6H4 1.5 90
9 5i C6H5 2-ClC6H4 4-ClC6H4 2 92
10 5j C6H5 2-ClC6H4 4-CH3C6H4 3 81
11 5k 4-ClC6H4 2-ClC6H4 4-CH3OC6H4 3 78
12 5l 4-CH3C6H4 2-ClC6H4 4-BrC6H4 1.5 94
13 5m 4-CH3C6H4 C6H5 4-ClC6H4 1.5 91
a
Isolated yields.
1926 H. Mehrabi et al. / Tetrahedron Letters 59 (2018) 1924–1927

Table 3
Synthesis of 1,2,4,5-tetrasubstituted imidazoles in ethanol at reflux conditions.

O CH2CO2Et
NH2 120 oC to reflux Ar2
CN H O O
+ + Ar2 + EtOH, 24h
Ar1 R N
O O O - CH3COCH3 N
- CO2 Ar1
1 2 3 4 6a-e R

Entry Product Ar1 R Ar2 Yield (%)a

1 6a 4-CH3C6H4 CH2-C6H5 4-ClC6H4 75
2 6b 4-CH3C6H4 2-ClC6H4 4-ClC6H4 71
3 6c C6H5 2-ClC6H4 4-CH3OC6H4 65
4 6d 4-ClC6H4 2-ClC6H4 C6H5 60
5 6e 4-ClC6H4 2-ClC6H4 4-CH3C6H4 63
a
Isolated yields.

H
NH2 CN N NH
+ 120 oC, 1h Ar1 O O
Ar1 R
Solvent-free
O O
1 2 AR
H Ar2
O O N
H O O EtOH Ar2 O
Ar2 + O R N
O O O O Ar1
O O
3 4 B C
Ar2
Ar1 O
N O

O O
5 N
O EtOH/r.t.
R H O O
- H2O Ar2 OH H
Ar2 CH2CO2Et Ar2 N
O
Ar1 O N
O EtOH/reflux Ar1
N
Ar1
N N - H2O R
- CH3COCH3
N O
- CO2 R D
6 O
R EtOH

Scheme 1. Proposed mechanism of the reaction.

resonances for the other products are given in the experimental between the arylglyoxal and Meldrum’s acid. Then, Michael addi-
section. tion of amidine A (as Michael donor) to a,b-unsaturated c-dicar-
We also investigate the initial reaction between arylamine 1, bonyl compound B (as Michael acceptor) provides intermediate
and benzonitrile 2 under the same as above reaction conditions. C, which subsequently undergoes intramolecular nucleophilic
But in continuation, ethanol (5.0 mL), arylglyoxal 3, and addition to form intermediate D. Consequently, tetrasubstituted
Meldrum’s acid 4 were added to the intermediate under reflux imidazole 5 is formed by elimination of molecule of H2O and
conditions. After completion of the reaction during 24 h, 1,2,4,5- intramolecular H-shift in ethanol at room temperature. But, tetra-
tetrasubstituted imidazoles 6 were obtained in 60–75% yields substituted imidazole 6 is formed by elimination of molecule of
(Table 3). H2O and then ethanolysis of Meldrum’s acid ring by elimination
As can be seen from Tables 2 and 3, the temperature effect is of acetone and CO2 in ethanol at reflux conditions.
difference on the above reactions and the type of products. When In summary, we have developed an efficient and simple method
the reaction is done at room temperature the product 5 is stable, for the synthesis of 1,2,4,5-tetrasubstituted imidazole derivatives
but at reflux conditions Meldrum’s acid ring on the product 5 is by treatment of arylamines, benzonitriles, arylglyoxals, and Mel-
decomposed using ethanol by elimination of acetone and CO2 to drum’s acid under catalyst-free conditions in ethanol at ambient
produce the product 6. temperature. The present reaction show the following salient char-
The possible mechanism for the synthesis of 1,2,4,5-tetrasubsti- acteristics: (1) avoiding the use of any catalyst, (2) low cost of the
tuted imidazoles 5 and 6 is illustrated in Scheme 1. At first, inter- starting materials, (3) suitable reaction rates which enable to be
mediate A is formed by the addition of the arylamine to the completed within 1.5–3 h in ethanol at room temperature, and
benzonitrile at 120 °C for 1 h under solvent-free conditions. Also, (4) convenient workup requiring only simple filtration from prod-
intermediate B is formed by means of a Knoevenagel condensation ucts precipitate.
 H. Mehrabi et al. / Tetrahedron Letters 59 (2018) 1924–1927 1927

Acknowledgments 9. (a) Cuckler AC, Chapin LR, Malanga CM, et al. Proc Soc Exp Biol Med.
1958;98:167–170;
(b) Jarrad AM, Debnath A, Miyamoto Y, et al. Eur J Med Chem.
We are thankful to the Office of Graduate Studies of Vali-e-Asr 2016;120:353–362.
University of Rafsanjan for partial support of this work. 10. (a) King AJ, Patrick DR, Batorsky RS, et al. Cancer Res. 2006;66:11100–11105;
(b) Narasimhan B, Sharma D, Kumar P. Med Chem Res. 2011;20:1119–1140;
(c) Liu J, Liu H, Huesca M, Young A, Allen C. Cancer Chemother Pharmacol.
A. Supplementary data 2006;58:306–318.
11. Chowdhury S, Mohan RS, Scott JL. Tetrahedron. 2007;63:2363–2389.
12. Sivakumar K, Kathirvel A, Lalitha A. Tetrahedron Lett. 2010;51:3018–3021.
Supplementary data associated with this article can be found, in 13. Heravi MM, Derikvand F, Haghighi M. Monatsh Chem. 2008;139:31–33.
the online version, at https://doi.org/10.1016/j.tetlet.2018.03.093. 14. Sadeghi B, Mirjalili BF, Hashemi MM. Tetrahedron Lett. 2008;49:2575–2577.
15. Karimi AR, Alimohammadi Z, Azizian J, Mohammadi AA, Mohammadizadeh
MR. Catal Commun. 2006;7:728–732.
References 16. Sangshetti JN, Kokare ND, Kotharkara SA, Shinde DB. J Chem Sci.
2008;120:463–467.
1. (a) Hranjec M, Kralj M, Piantanida I, et al. J Med Chem. 2008;51:4899–4910; 17. Khodaei MM, Bahrami K, Kavianinia I. J Chinese Chem Soc. 2007;54:829–833.
(b) Hranjec M, Piantanida I, Kralj M, Suman L, Pavelic K, Karminski-Zamola. J 18. Kidwai M, Mothsra P, Bansal V, et al. J Mol Catal A: Chem. 2007;265:177–182.
Med Chem. 2007;50:5696–5711. 19. (a) Heravi MM, Derikvand F, Bamoharram FF. J Mol Catal A: Chem.
2. (a) Aridoss G, Balasubramanian S, Parthiban P, Kabilan S. Eur J Med Chem. 2007;263:112–114;
2006;41:268–275; (b) Nagarapu L, Apuri S, Kantevari S. J Mol Catal A: Chem. 2007;266:104–108.
(b) Heerding DA, Chan G, DeWolf Jr WE, et al. Bioorg Med Chem Lett. 20. Borhade AV, Tope DR, Gite SG. Arab J Chem. 2017;10:S559–S567.
2001;11:2061–2065. 21. Ramesh K, Murthy SN, Karnakar K, et al. Tetrahedron Lett. 2012;53:1126–1129.
3. Badaway E, Kappe T. Eur J Med Chem. 1995;30:327–332. 22. Akbari A. Tetrahedron Lett. 2016;57:431–434.
4. (a) Lhassani M, Chavignon O, Chezal JM, et al. Eur J Med Chem. 23. Balalaie S, Hashemi MM, Akhbari M. Tetrahedron Lett. 2003;44:1709–1711.
1999;34:271–274; 24. Lantos I, Zhang WY, Shui X, Eggleston DS. J Org Chem. 1993;58:7092–7095.
(b) Sharma D, Narasimhan B, Kumar P, et al. Eur J Med Chem. 25. Davidson D, Weiss M, Jelling M. J Org Chem. 1937;2:319–327.
2009;44:2347–2353. 26. Jiang B, Ye Q, Fan W, Wang SL, Tu SJ, Li G. Chem Commun. 2014;50:6108–6111.
5. (a) Nakano H, Inoue T, Kawasaki N, et al. Bioorg Med Chem. 2000;8:373–380; 27. Tu XJ, Hao WJ, Ye Q, et al. J Org Chem. 2014;79:11110–11118.
(b) Nakano H, Inoue T, Kawasaki N, et al. Chem Pharm Bull. 1999;47:1573–1578. 28. Jiang B, Fan W, Sun MY, et al. J Org Chem. 2014;79:5258–5268.
6. (a) Abdel-Wahab BF, Awad GEA, Badria FA. Eur J Med Chem. 29. Wang L, Shi LX, Liu L, et al. J Org Chem. 2017;82:3605–3611.
2011;46:1505–1511; 30. Aghapoor K, Mohsenzadeh F, Shakeri A, Darabi HR, Ghassemzadeh M,
(b) Reddy PR, Seenaiah D, Padmaja A, Padmavathi V, Krishna NS. Med Chem Res. Neumüller B. J Organomet Chem. 2013;743:170–178.
2015;24:86–98. 31. Khaksar S, Tajbakhsh M, Gholami M, Rostamnezhad F. Chin Chem Lett.
7. (a) Achar KCS, Hosamani KM, Seetharamareddy HR. Eur J Med Chem. 2014;25:1287–1290.
2010;45:2048–2054; 32. Lu HY, Yang SH, Deng J, Zhang ZH. Aust J Chem. 2010;63:1290–1296.
(b) Nath M, Saini PK, Kumar A. J Organomet Chem. 2010;695:1353–1362; 33. Bandyopadhyay D, Mukherjee S, Rodriguez RR, Banik BK. Molecules.
(b) Trujillo JI, Kiefer JR, Huang W, et al. Bioorg Med Chem Lett. 2009;19:908–911. 2010;15:4207–4212.
8. (a) Souto EB, Muller EH. Original Articles. 2006;61:431–437; 34. Robinson RS, Taylor RJK. Synlett. 2005;6:1003–1005.
(b) Rodrigues AD, Gibson GG, Ioannides C, Parke DV. Biochem Phwnuzcoiqy. 35. Raw SA, Wilfred CD, Taylor RJK. Org Biomol Chem. 2004;2:788–796.
1987;36:4277–4281;
(c) Borelli D, Bran JL, Fuentes J, et al. Postgrad Med J. 1979;55:657–661.