Efficient microwave-assisted synthesis of N-(2-alkyl/aryl-4-phenyl-1 H-imidazol-1-yl)-2-phenylacetamides

Article abstract of DOI:10.1080/00397911.2014.895382

An easy, efficient, and environmentally friendly method for the synthesis of N-(2-alkyl/aryl-4-phenyl-1H-imidazol-1-yl)-2-phenylacetamides from the reaction of phenyl acylbromides and phenylacetohydrazide derivatives has been presented. Shorter reaction t

Full text of DOI:10.1080/00397911.2014.895382

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Efficient Microwave-Assisted Synthesis of
N-(2-Alkyl/aryl-4-phenyl-1H-imidazol-1-
yl)-2-phenylacetamides
Emre Menteşe a & Fatih Yılmaz a
a Department of Chemistry , Recep Tayyip Erdogan University , Rize ,
Turkey
Accepted author version posted online: 15 Apr 2014.Published
online: 13 Jun 2014.
To cite this article: Emre Menteşe & Fatih Yılmaz (2014) Efficient Microwave-Assisted Synthesis
of N-(2-Alkyl/aryl-4-phenyl-1H-imidazol-1-yl)-2-phenylacetamides, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:16, 2348-2354,
DOI: 10.1080/00397911.2014.895382
To link to this article: http://dx.doi.org/10.1080/00397911.2014.895382
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Synthetic Communications1, 44: 2348–2354, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.895382
EFFICIENT MICROWAVE-ASSISTED SYNTHESIS
OF N-(2-ALKYL/ARYL-4-PHENYL-1H-IMIDAZOL-
1-YL)-2-PHENYLACETAMIDES
Emre Mentes¸e and Fatih Yılmaz
Department of Chemistry, Recep Tayyip Erdogan University, Rize, Turkey
GRAPHICAL ABSTRACT
Abstract An easy, efficient, and environmentally friendly method for the synthesis of
N-(2-alkyl/aryl-4-phenyl-1H-imidazol-1-yl)-2-phenylacetamides from the reaction of
phenyl acylbromides and phenylacetohydrazide derivatives has been presented. Shorter
reaction times, simple workup procedure, no catalyst requirement, and use of small
quantities of organic solvent are the most obvious advantages of this protocol.
Keywords Catalyst-free reaction; imidazoles; microwave irradiation; phenylacetohydra-
zide; phenylacyl bromide
INTRODUCTION
Imidazole ring is an important structure in modern drug discovery.[1–4] The
imidazole derivatives with different biological activities, including antimicrobial,[5]
Received November 28, 2013.
Address correspondence to Emre Mentes¸e, Department of Chemistry, Recep Tayyip Erdogan
University, Rize, Turkey. E-mail: emre.mentese@erdogan.edu.tr
2348

MICROWAVE-ASSISTED SYNTHESIS OF IMIDAZOLES
2349
Figure 1. Structures of clonidine, idazoxan, and napamazole.
anticonvulsant,[6] anticancer,[7,8] and antiviral,[9] are present in the literature.
Also, many of today’s drugs include imidazole skeleton in their structure such as
Clonidine (a2 adrenergicagonist), Idazoxan, and Napamazole (antidepressant)[3,10,11]
(Fig. 1).
Because of their important biological properties, many imidazole derivatives
have been synthesized extensively and various synthetic protocols have been
developed by organic chemists.[12–15] However, there are only a few protocols found
in literature for the synthesis of N-(2-alkyl=aryl-4-phenyl-1H-imidazol-1-yl)-2-phe-
nylacetamides. These protocols require catalyst and hard purification methods.[16–
18]
Therefore, there is a need for an environmental and ecofriendly method for the
synthesis of N-(2-alkyl=aryl-4-phenyl-1H-imidazol-1-yl)-2-phenylacetamides.
Microwave-assisted organic synthesis is an important development for organic
chemistry in the 21st century. When comparing it to the conventional heating
methods, it has many advantages, such as reducing reaction times, providing greater
yield and purity, and requiring less energy. One of the biggest advantages
of microwave heating is that it supplies environmentally friendly conditions for
organic reactions. Many organic reactions can be performed in dry media instead
of in organic solvent by using microwave heating.[19–21]
In literature, the general reaction conditions of imidazoles include using
a considerable amount of organic solvent, some kinds of catalysts, and harsh
reaction conditions.[22–24] In this study, a novel, practical, and efficient method
is developed for the synthesis of N-(2-alkyl=aryl-4-phenyl-1H-imidazol-1-yl)-2-
phenylacetamides by using microwave irradiation. This new method has some
advantages on previously reported procedures because it provides greater yield and
requires a small quantity of organic solvent.
RESULTS AND DISCUSSION
In this study, a convenient method for the synthesis of N-(2-alkyl=aryl-
4-phenyl-1H-imidazol-1-yl)-2-phenylacetamides has been achieved by using micro-
wave irradiation and catalyst-free conditions. Iminoester hydrochlorides (1a–g) have
been synthesized according to the literature.[25] Treatment of compounds 1a–g with
phenylacetic hydrazide in the presence of NaOEt gave the hydrazide derivatives
2a–g.[16,17] The compounds 2a–g were reacted with phenyl acylbromide and
4-chlorophenyl acylbromide, separately, with 1 mL of acetonitrile under microwave

˙
E. MENTES¸E AND F. YILMAZ
2350
Scheme 1. Synthetic route for compounds 3a–g and 4a–g.
irradiation (Scheme 1). Also, the compounds 3a–g and 4a–g have been synthesized
with conventional heating procedure and results were compared to microwave
heating (Table 1).
The microwave heating has provided greater yields, around 10%, compared to
classical heating for the synthesis of compounds 3a–g and 4a–g (except for com-
pound 3b). The classical heating techniques are rather slow, and a temperature gradi-
ent can develop within the sample. In addition, local overheating can cause substrate
and reagent decomposition. In contrast, the microwave energy is introduced into the
chemical reactor and direct access by the energy source to the reaction vessel is
obtained. The microwave radiation passes through the walls of the vessel and heats
only the reactants and solvent, not the reaction vessel itself. If the apparatus is
properly designed, the temperature increase will be the same throughout the sample,
which can lead to fewer by-products and=or decomposition products.[26]
Syntheses of compounds 3a–g and 4a–g were tried under solvent-free con-
ditions but have not succeeded because of decomposition of reagents. In dry-media
Table 1. Comparison of conventional and microwave heating procedure for compounds 3a–g and 4a–g
Microwave heating
Conventional heating
Compound Time (min) Yield (%) Acetonitrile (mL) Time (h) Yield (%) Acetonitrile (mL)
3a
3b
3c
3d
3e
3f
5 ꢀ 4
5 ꢀ 4
5 ꢀ 4
5 ꢀ 4
5 ꢀ 4
5 ꢀ 4
5 ꢀ 4
5 ꢀ 4
5 ꢀ 4
5 ꢀ 4
5 ꢀ 4
5 ꢀ 4
5 ꢀ 4
5 ꢀ 4
72
47
69
66
71
76
65
78
56
67
72
76
78
67
1
1
1
1
1
1
1
1
1
1
1
1
1
1
3
3
3
3
3
3
3
3
3
3
3
3
3
3
64
62
52
45
68
64
53
67
52
60
63
68
61
56
5
5
5
5
5
5
5
5
5
5
5
5
5
5
3g
4a
4b
4c
4d
4e
4f
4g

MICROWAVE-ASSISTED SYNTHESIS OF IMIDAZOLES
2351
Table 2. Reaction condition for compound 3a
Solvent
Microwave temperature (ꢁC) Microwave power (W) Reaction time (min) Yield (%)
Ethanol
Ethanol
100
100
100
95
200
150
100
200
150
100
100
200
100
100
150
100
100
5 ꢀ 5
5 ꢀ 4
5 ꢀ 4
5 ꢀ 5
5 ꢀ 5
5 ꢀ 5
5 ꢀ 6
5 ꢀ 3
5 ꢀ 3
5 ꢀ 3
5 ꢀ 4
5 ꢀ 4
5 ꢀ 5
35
37
41
38
40
16
18
42
59
67
63
72
68
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
95
95
90
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
100
100
95
90
90
85
reaction, the homogeneity cannot be fully guaranteed. Therefore, formation of unde-
sirable and decomposed products decreased the reaction yield.[27] However, these
compounds have been synthesized using only 1 mL of organic solvent (acetonitrile)
under microwave irradiation. Even when using small quantities of organic solvent,
the polarity and homogeneity for the microwave interaction have been provided.
At the same time, the microwave power and the reaction temperature were very
important parameters on the yield of the compounds 3a–g and 4a–g. More micro-
wave power and temperature caused decomposition of the starting compounds,
which is why we abstained from using greater microwave power and reaction tem-
perature. The reaction conditions, tried for compound 3a, have been given in Table 2.
Our literature survey has revealed that acetamidrazones have shown amide
hydrazone (A)-hydrazide imide (B) tautomerism and they could exist as E and Z
[28]
1
=
isomers because of the C N bond (Scheme 2).
When we investigated H NMR
and 13C NMR spectra of compounds 2a–g, some proton and carbon atoms have
two set of signals coming from this tautomerism. In 1H NMR spectra of compounds
2a–g, the signals between 10.44 and 9.43 ppm had NH protons and those between
6.68 and 6.19 ppm have NH2 protons (amide hydrazone A). In 13C NMR spectra
=
of compounds 2a–g, C O and C N carbons have signals at about 170 and
=
152 ppm, respectively.
1H NMR and 13C NMR spectra of compounds 3a–g and 4a–g have given com-
patible signals with the proposed structures. NH and CH2 protons have been
=
=
observed at 13.53–11.26 ppm and 4.27–3.51 ppm and C O and C N carbons
have been seen at about 170 and 148 ppm, respectively. The aromatic carbons of
Scheme 2. Amidehydrazone (A) and hydrazide imide (B) structures.

˙
E. MENTES¸E AND F. YILMAZ
2352
compounds 3a–g and 4a–g were observed between 142.2 and 113.8 ppm. In our
previously works, it has been proved that the compounds that have CO-NH single
bond could exist in cis=trans amide conformer. That is why, when aromatic carbons
of compounds 3a–g and 4a–g have been compared with their structures, the number
of these aromatic carbons could be seen more than proposed.[29]
EXPERIMENTAL
All the chemicals were supplied from Merck, Aldrich, and Fluka. Melting
points were taken on capillary tubes on a Buchi oil heated melting-point apparatus
¨
and are uncorrected. 1H NMR and 13C NMR spectra were recorded on a
Varian-Mercury 400-MHz spectrophotometer (solvent DMSO-d6, tetramethylsilane
[TMS] as internal standard). The mass spectra were recorded on Thermo Scientific
Quantum Access max liquid chromatography–mass spectrometry (LC-MS) instru-
ment. A monomode CEM-Discover Microwave was used in the standard configur-
ation as delivered, including proprietary software. All experiments were carried out
in microwave process vials (30 mL) with control of the temperature by infrared
detection temperature sensor. It was monitored by a computer and maintained con-
stant at a constant value by a discrete modulation of delivered microwave power.
After completion of the reaction, the vial was cooled to 60 ꢁC via air jet cooling.
Synthesis of N-(2-Alkyl/aryl-4-phenyl-1H-imidazol-1-yl)-
2-phenylacetamides (3a–g and 4a–g)
Conventional method. A solution of compounds 2a–g (0.01 mol) in acetoni-
trile (5 mL) and phenylacyl bromide or 4-chlorophenylacyl bromide (0.013 mol) was
placed in a round-bottom flask. The mixture was refluxed for 3 h. After the
completion of the reaction, (monitored by thin-layer chromatography [TLC], ethyl
acetate=hexane, 3:2), the mixture was cooled to room temperature. The formed
gel-like mixture was extracted with acetone (4 ꢀ 5 mL) and filtered off. Then, diethyl
ether was added to the filtrate to precipitate the desired products 3a–g and 4a–g.
Microwave method. A mixture of compounds 2a–g (0.01 mol), phenylacyl
bromide or 4-chlorophenyl acylbromide (0.013 mol), and acetonitrile (1 mL) was taken
in a microwave process vial and irradiated in microwave at 90 ꢁC for 5 ꢀ 4 min at
100 W. After the completion of the reaction, (monitored by TLC, ethyl acetate=
hexane, 3:2), the mixture was extracted with acetone (4 ꢀ 5 mL) and filtered off. Then,
diethyl ether was added the filtrate to precipitate the desired product 3a–g and 4a–g.
N-(2-Methyl-4-phenyl-1H-imidazol-1-yl)-2-phenylacetamide
(3a). Mp
228–226 ꢁC. 1H NMR (400 MHz, DMSO-d6) d ppm: 11.59 (1H, br, NH); 7.74
(2H, d, J ¼ 7.6, Ar-H); 7.62 (1H, s, Ar-H); 7.38–7.19 (8H, m, Ar-H); 3.67 (2H, s,
13
=
CH2); 2.12 (3H, s, CH3). C NMR (100 MHZ, DMSO-d6), d ppm: 169.8 (C O);
=
145.1 (C N); 137.1; 135.3; 134.6; 130.1; 129.6; 128.9; 127.3; 126.7; 124.5; 117.2
(Ar-C); 40.5 (CH2); 11.8 (CH3). LC-MS: 292 [MþH]þ.
N-[4-(4-Chlorophenyl)-2-methyl-1H-imidazol-1-yl]-2-phenylacetamide
1
(4a). Mp 241–242 ꢁC. H NMR (400 MHz, DMSO-d6) d ppm: 11.60 (1H, s, NH);

MICROWAVE-ASSISTED SYNTHESIS OF IMIDAZOLES
2353
7.78 (2H, d, J ¼ 6.8, Ar-H); 7.69 (1H, s, Ar-H); 7.40–7.36 (7H, m, Ar-H); 3.67 (2H, s,
13
=
CH2); 2.11 (3H, s, CH3). C NMR (100 MHZ, DMSO-d6), d ppm: 169.9 (C O);
=
145.3 (C N); 135.9; 135.2; 133.4; 131.6; 131.0; 129.8; 129.5; 129.0; 128.9; 127.3;
126.2; 117.8 (Ar-C); 40.6 (CH2); 11.8 (CH3). LC-MS: 328=326 [MþH]þ.
CONCLUSION
A series of some novel imidazole derivatives (3a–g and 4a–g) have been synthe-
sized from the reaction of phenylacetohydrazide and phenyl acylbromide derivatives
by using microwave irradiation. The microwave irradiation technique has been first used
for the synthesis of N-(2-alkyl=aryl-4-phenyl-1H-imidazol-1-yl)-2-phenylacetamides
(3a–g and 4a–g). This technique has provided some advantages on yields and reaction
times. The use of a low amount of organic solvent is very important for this reaction
to ensure homogeneous reaction medium. We strongly believe that this novel technique
will have a wide range of applications and we have high expectations for the synthesis of
bioactive imidazole derivatives.
FUNDING
This study was funded by the Turkish Scientific and Technological Research
Institute (TUBITAK, Project No. 212T183).
SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher’s website.
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