A new more atom-efficient multi-component approach to tetrasubstituted imidazoles: One-pot condensation of nitriles, amines and benzoin

Article abstract of DOI:10.1039/c6ra11171h

A new more atom-efficient multi-component approach for the synthesis of tetrasubstituted imidazoles via the one-pot condensation of nitriles, primary amines and benzoin has been described. Using this method, a wide range of structurally diverse nitriles and primary amines were successfully condensed with benzoin in glycerol in the presence of TFA under microwave irradiation at 120 °C and all the products were obtained in good to excellent yields with higher atom efficiencies in comparison with the commonly used four-component condensation of aldehydes, ammonium acetate, primary amines and benzil.

Full text of DOI:10.1039/c6ra11171h

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A new more atom-efficient multi-component approach to tetrasubstituted
imidazoles: One-pot condensation of nitriles, amines and benzoin
Ali Khalafi-Nezhad *, a, Mohsen Shekouhy a, Hashem Sharghi a, Jasem Aboonajmi a, Abdolkarim Zare b
a Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran
b Department of Chemistry, Payame Noor University, PO Box 19395-3697, Tehran, Iran
Abstract
A new more atom-efficient multi-component approach for the synthesis of tetrasubstituted imidazoles
via the one-pot condensation of nitriles, primary amines and benzoin has been described. Using this
method, a wide range of structurally diverse nitriles and primary amines were successfully condensed
with benzoin in glycerol in the presence of TFA under microwave irradiation at 120 oC and all products
were obtained in good to excellent yields with higher atom efficiencies in comparison with the
commonly used four-component condensation of aldehydes, ammonium acetate, primary amines and
benzil.
Introduction
Between various kinds of heterocyclic compounds, imidazoles occupied a special place because of
their unique biological properties such as anti-inflammatory1, inhibition of p38 MAP kinase1, anti-
allergic2 and analgesic activity.3 Their presence in so many natural products and biological active
compounds such as histidine and histamine (two human body essential amino acids) and their versatile
applications as sensitizers of multi-drug-resistant cancer cells4, pesticides5, antibiotics6 and sodium
channel modulators7a,b have been caused to increased importance of these molecules. Moreover,
imadazoles are the main backbone of some commercial drugs such as ketoconazole7c as an antifungal
and losartan7d as an anti-hypertension agent. In addition to their biological and pharmaceutical
applications, these compounds have been attracted much attention in benign organic synthesis due to
1

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their application as more green solvents by means of imidazolium-based ionic liquids8 and in
organometallic chemistry as N-heterocyclic carbenes.9 From the first report about the preparation of
imidazoles in 185810 to now, various synthetic strategies have been applied for the synthesis of these
compounds.11 Although there are a wide variety of synthetic routes toward imidazoles, only a few
studies exist for the synthesis of 1,2,4,5-tetrasubstituted imidazoles which are mostly performed via
multi step routes1d, 1f-g, 12 or via a trisubstituted 1H-imidazole in which the nitrogen is substituted in the
final step.3, 13 Nowadays, the most commonly used synthetic route to tetrasubstituted imidazoles is a
one-pot four-component reaction of benzil, aldehydes, primary amines and ammonium acetate (Scheme
1) under various reaction condition.14
Ph
O
O
Ph
Ph
Ph
N
N
R
+ 3H2O
+ HOAc
R' NH2
R CHO
NH4OAC
R'
Scheme 1. The one-pot four-component route to tetrasubstituted imidazoles.
In spite of the fact that the application of this method is in combination with advantages of multi-
component synthesis, unfortunately, it has the fatal problem of low atom efficiency due to the waste of
three molecules of water and one molecule of acetic acid (Scheme 1). So, despite the available one-pot
four-component method, there still exists a demand for the devising a more atom-efficient and
environmentally benign route which allows the simple and fast synthesis of tetrasubstituted imidazoles.
Based on the above facts and as a part of our recent studies in the development of more benign
procedures for the synthesis of heterocyclic compounds15, we herein report a new and more atom-
efficient three-component reaction for the synthesis of tetrasubstituted imidazols via a one-pot
condensation of nitriles (1), primary amines (2) and benzoin (3) in the presence of catalytic amounts of
trifluoroacetic acid (TFA) under microwave irradiation. (Scheme 2)
Experimental
2

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All chemicals were purchased from Merck, Fluka and Aldrich chemical companies and used without
further purification. 1H (250 and 300 MHz) and 13C-NMR (62.5 and 75 MHz) spectra were recorded on
Bruker Avance 250 and Bruker Avance 300 spectrometers in DMSO-d6 solution with tetramethylsilane
(TMS) as an internal standard. Microanalysis was performed on a Perkin-Elmer 240-Bmicroanalyzer.
Mass spectra were recorded on a Shimadzu GC MS-QP 1000 EX apparatus. Melting points were
determined in open capillary tubes with a Barnstead Electro-thermal 9100 BZ circulating oil melting
point apparatus. The reaction monitoring was accomplished by TLC on silica gel PolyGram
SILG/UV254 plates. All reactions were carried out using a laboratory microwave oven (MicroSYNTH,
Milestone Company, Italy). The reactions were performed in a glass tube sealed with a septum. The
reported reaction temperature was monitored using a calibrated infrared temperature control mounted
under the reaction vessel. The reaction mixture was magnetically stirred. All reactions were performed
three times and the average amount of isolated yields and reaction times were reported.
General procedure for the condensation of benzoin, nitriles and primary amines
A solution of nitrile (1) (1 mmol), primary amine (2) (1 mmol), benzoin (3) (1 mmol) and TFA (0.1
mmol, 0.01 g) in glycerol (5 mL) was placed in a pressure-resistance microwave glass tube sealed with
a septum. The mixture was stirred for 5 min at room temperature and exposed to microwave irradiation
o
o
(300 W) at 120 C (The microwave instrument was set to increase the temperature to 120 C during 1
min.) and the progress of reaction was monitored by TLC (In order to check the progress of the
reaction, the microwave irradiation was stopped each one minute, the reaction mixture was cooled to
room temperature and the TLC analysis was taken place. If the reaction was not completed, the reaction
vessel has been sealed and the reaction temperature was increased to 120 oC during 1 minutes and after
this, the microwave irradiation was taken place for another one minute. These steps were repeated until
the reaction became completed. Then, the reaction time was calculated as the sum of each one minute
of microwave irradiations. After this, a new mixture of the same starting materials was continuously
irradiated with microwave irradiation for calculated time and the completion of the reaction was
checked at the end. In all cases, obtained results were the same.). After the completion of reaction, the
mixture was cooled to room temperature, water (20 mL) was added and resulting solids were filtered
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off and washed with hot water (10 mL) and dried under reduced pressure. Purer products were obtained
with recrystallization from hot ethanol.
Selected Spectral Data
1-(4-isopropylphenyl)-2,4,5-triphenyl-1H-imidazole (4b)
1
White powder, H NMR (250 MHz, DMSO-d6) δ (ppm) 1.09 (d, J= 6.8 Hz, 6H), 2.82 (m, 1H), 7.13-
7.46 (m, 19H). 13C NMR (62.5 MHz, DMSO-d6) δ (ppm) 22.9, 32.4, 123.5, 124.3, 126.9, 127.2, 127.4,
128.0, 128.5, 128.6, 129.0, 129.4, 129.5, 130.0, 130.2, 130.8, 132.9, 133.2, 135.9, 144.7, 146.2. Anal.
Calcd. for C30H26N2: C, 86.92; H, 6.32; N, 6.76 (%). Found: C, 86.97; H, 6.24; N, 6.83 (%). MS (m/z):
414 (M+).
1-benzyl-2,4,5-triphenyl-1H-imidazole (4d)
1
White powder, H NMR (250 MHz, DMSO-d6) δ (ppm) 5.12 (s, 2H), 6.70-7.63 (m, 20H). 13C NMR
(62.5 MHz, DMSO-d6) δ (ppm) 50.4, 126.9, 127.3, 127.4, 127.9, 128.5, 128.6, 128.8, 128.9, 129.2,
129.4, 129.7, 129.9, 130.3, 131.4, 132.4, 132.9, 136.7, 142.3, 150.9. Anal. Calcd. for C28H22N2: C,
87.01; H, 5.74; N, 7.25 (%). Found: C, 86.91; H, 5.83; N, 7.30 (%). MS (m/z): 386 (M+).
1-(4-methoxyphenyl)-2,4,5-triphenyl-1H-imidazole (4e)
1
White powder, H NMR (250 MHz, DMSO-d6) δ (ppm) 3.67 (s, 3H), 6.80-7.36 (m, 19H). 13C NMR
(62.5 MHz, DMSO-d6) δ (ppm) 53.4, 114.3, 123.4, 127.3, 128.1, 128.4, 128.6, 128.8, 129.1, 129.4,
129.7, 130.1, 130.4, 130.7, 131.0, 133.0, 133.52, 133.59, 146.2, 158.4. Anal. Calcd. for C28H22N2O: C,
83.56; H, 5.51; N, 6.96 (%). Found: C, 83.45; H, 5.49; N, 7.08 (%). MS (m/z): 402 (M+).
4-(1-benzyl-4,5-diphenyl-1H-imidazol-2-yl)phenol (4p)
White powder, 1H NMR (250 MHz, DMSO-d6) δ (ppm) 5.08 (s, 2H), 6.71-7.46 (m, 19H), 9.83 (s, 1H).
13C NMR (62.5 MHz, DMSO-d6) δ (ppm) 49.9, 116.5, 123.9, 126.9, 127.4, 127.7, 128.3, 128.74,
128.79, 128.9, 129.01, 129.03, 129.5, 129.8, 132.3, 134.5, 137.0, 141.8, 150.9, 158.7. Anal. Calcd. for
C28H22N2O: C, 83.56; H, 5.51; N, 6.96 (%). Found: C, 83.61; H, 5.60; N, 7.09 (%). MS (m/z): 402 (M+).
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4-(1,4,5-triphenyl-1H-imidazol-2-yl)phenol (4q)
White powder, 1H NMR (250 MHz, DMSO-d6) δ (ppm) 6.60-6.65 (m, 2H), 7.13-7.47 (m, 17H), 9.77 (s,
1H). 13C NMR (62.5 MHz, DMSO-d6) δ (ppm) 116.2, 123.9, 125.8, 127.2, 127.9, 128.0, 128.8, 128.9,
129.0, 129.3, 129.5, 129.8, 130.5, 133.0, 133.4, 136.1, 141.9, 158.9. Anal. Calcd. for C27H20N2O: C,
83.48; H, 5.19; N, 7.21 (%). Found: C, 83.36; H, 5.05; N, 7.39 (%). MS (m/z): 388 (M+).
4-(1-(4-methoxyphenyl)-4,5-diphenyl-1H-imidazol-2-yl)phenol (4r)
White powder, 1H NMR (250 MHz, DMSO-d6) δ (ppm) 3.79 (s, 3H), 6.79 (d, J= 8.7 Hz, 2H), 6.94 (d,
J= 8.7 Hz, 2H), 7.22-7.61 (m, 14H), 9.67 (br, 1H). 13C NMR (62.5 MHz, DMSO-d6) δ (ppm) 54.9,
114.9, 115.9, 124.4, 126.0, 126.9, 128.3, 128.8, 129.0, 129.3, 129.4, 129.7, 131.0, 132.9, 133.03,
133.09, 149.0, 158.5, 159.4. Anal. Calcd. for C28H22N2O2: C, 80.36; H, 5.30; N, 6.69 (%). Found: C,
80.47; H, 5.24; N, 6.73 (%). MS (m/z): 418 (M+).
4-(1-(4-chlorophenyl)-4,5-diphenyl-1H-imidazol-2-yl)phenol (4s)
1
White powder, H NMR (250 MHz, DMSO-d6) δ (ppm) 6.67-6.70 (m, 2H), 7.19-7.46 (m, 16H), 9.67
(br, 1H). 13C NMR (62.5 MHz, DMSO-d6) δ (ppm) 116.3, 123.9, 125.6, 126.9, 128.8, 128.9, 129.1,
129.3, 129.4, 129.5, 129.8, 130.0, 130.6, 133.0, 133.1, 134.0, 136.4, 147.2, 158.7. Anal. Calcd. for
C27H19ClN2O: C, 76.68; H, 4.53; N, 6.62 (%). Found: C, 76.55; H, 4.62; N, 6.74 (%). MS (m/z): 422
(M+).
1-benzyl-2-(4-methoxyphenyl)-4,5-diphenyl-1H-imidazole (4t)
White powder, 1H NMR (250 MHz, DMSO-d6) δ (ppm) 2.28 (s, 3H), 5.11 (s, 2H), 6.69-7.52 (m, 19H).
13C NMR (62.5 MHz, DMSO-d6) δ (ppm) 47.8, 53.1, 112.3, 123.4, 127.0, 127.3, 127.5, 128.60, 128.61,
128.7, 129.0, 129.2, 129.4, 129.7, 131.0, 132.5, 132.9, 137.3, 140.9, 152.2, 160.5. Anal. Calcd. for
C29H24N2O: C, 83.63; H, 5.81; N, 6.73 (%). Found: C, 83.72; H, 5.70; N, 6.76 (%). MS (m/z): 416 (M+).
2-(4-tert-butylphenyl)-1-benzyl-4,5-diphenyl-1H-imidazole (4u)
White powder, 1H NMR (250 MHz, DMSO-d6) δ (ppm) 1.25 (s, 9H), 5.11 (s, 2H), 6.72-7.55 (m, 19H).
13C NMR (62.5 MHz, DMSO-d6) δ (ppm) 29.9, 33.8, 28.1, 124.0, 125.9, 126.3, 126.4, 127.3, 127.4,
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127.5, 127.6, 128.3, 128.5, 128.6, 128.7, 131.4, 131.8, 135.3, 140.5, 150.1, 150.3. Anal. Calcd. for
C32H30N2: C, 86.84; H, 6.83; N, 6.33 (%). Found: C, 86.76; H, 6.94; N, 6.27 (%). MS (m/z): 442 (M+).
2-(4-bromophenyl)-4,5-diphenyl-1-p-tolyl-1H-imidazole (4v)
1
White powder, H NMR (250 MHz, DMSO-d6) δ (ppm) 2.25 (s, 3H), 7.09-7.51 (m, 18H). 13C NMR
(62.5 MHz, DMSO-d6) δ (ppm) 21.0, 119.9, 124.8, 127.5, 128.3, 128.4, 129.0, 129.3, 129.5, 130.1,
131.1, 132.3, 132.5, 133.3, 136.3, 141.3, 148.6. Anal. Calcd. for C28H21BrN2: C, 72.26; H, 4.55; N, 6.02
(%). Found: C, 72.33; H, 4.69; N, 5.93 (%). MS (m/z): 464 (M+).
1-(4-isopropylphenyl)-2-(4-nitrophenyl)-4,5-diphenyl-1H-imidazole (4w)
1
White powder, H NMR (250 MHz, DMSO-d6) δ (ppm) 1.11 (d, J= 6.7 Hz, 6H), 2.82 (m, 1H), 7.10-
7.44 (m, 14H), 7.86 (d, J= 7.0 Hz, 2H), 8.29 (d, J= 7.0 Hz, 2H). 13C NMR (62.5 MHz, DMSO-d6) δ
(ppm) 22.9, 32.4, 124.6, 124.8, 126.0, 126.9, 127.2, 128.3, 128.5, 128.8, 129.3, 129.6, 129.7, 130.0,
130.5, 131.9, 132.5, 137.1, 143.5, 148.4, 148.6. Anal. Calcd. for C30H25N3O2: C, 78.41; H, 5.48; N, 9.14
(%). Found: C, 78.33; H, 5.59; N, 9.25 (%). MS (m/z): 459 (M+).
2-(4-(1-benzyl-4,5-diphenyl-1H-imidazol-2-yl)phenyl)-1H-benzo[d]imidazole (4x)
1
White powder, H NMR (250 MHz, DMSO-d6) δ (ppm) 6.52 (s, 2H), 6.80-7.65 (m, 23H), 12.92 (s,
1H). 13C NMR (62.5 MHz, DMSO-d6) δ (ppm) 46.9, 113.2, 115.3, 120.6, 120.7, 124.7, 125.22, 125.29,
125.3, 125.9, 126.1, 126.2, 126.3, 126.5, 126.6, 127.12, 127.16, 127.3, 127.5, 130.2, 130.7, 134.2,
138.9, 139.4, 149.2, 153.4. Anal. Calcd. for C35H26N4: C, 83.64; H, 5.21; N, 11.15 (%). Found: C,
83.57; H, 5.30; N, 11.01 (%). MS (m/z): 502 (M+).
4,5-bis(4-chlorophenyl)-2-(4-methoxyphenyl)-1-phenyl-1H-imidazole (4ab)
White powder, 1H NMR (300 MHz, DMSO-d6) δ (ppm) 3.79 (s, 3H), 7.08 (d, J= 7.5 Hz, 2H), 7.43-7.51
(m, 6H), 7.58-7.63 (m, 3H), 7.73-7.78 (m, 4H), 7.91 (d, J= 7.5 Hz, 2H). 13C NMR (75 MHz, DMSO-d6)
δ (ppm) 54.8, 113.8, 124.3, 124.9, 127.5, 128.0, 128.9, 129.6, 130.8, 131.0, 131.25, 131.29, 132.9,
134.8, 135.3, 135.9, 136.1, 138.9, 150.0, 160.7. Anal. Calcd. for C28H20Cl2N2O: C, 71.34; H, 4.28; N,
5.94; (%). Found: C, 71.28; H, 4.31; N, 5.99 (%). MS (m/z): 471 (M+).
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1,2-diphenyl-4,5-di-p-tolyl-1H-imidazole (4af)
White powder, 1H NMR (300 MHz, DMSO-d6) δ (ppm) 2.17 (s, 6H), 7.09 (d, J= 7.5 H, 4H), 7.39-7.58
(m, 12H), 7.81 (d, J= 7.5 Hz, 2H). 13C NMR (75 MHz, DMSO-d6) δ (ppm) 20.5, 123.7, 127.5, 127.8,
127.91, 127.99, 129.0, 129.3, 129.4, 129.6, 129.9, 130.0, 130.2, 131.0, 134.0, 136.1, 136.5, 138.9,
139.4, 150.1. Anal. Calcd. for C29H24N2: C, 86.97; H, 6.04; N, 6.99; (%). Found: C, 86.89; H, 6.12; N,
6.83 (%). MS (m/z): 400 (M+).
4-(1-benzyl-4,5-diphenyl-1H-imidazol-2-yl)benzonitrile (6a)
White powder, m.p= 197-199 oC. 1H NMR (250 MHz, DMSO-d6) δ (ppm) 5.18 (s, 2H), 7.01-7.29 (m,
15H), 7.66 (d, J= 7.8 Hz, 2H), 7.93 (d, J= 7.8 Hz, 2H). 13C NMR (62.5 MHz, DMSO-d6) δ (ppm) 49.1,
111.5, 117.6, 126.8, 127.1, 127.8, 128.3, 128.7, 128.9, 129.0, 129.7, 129.8, 129.9, 130.2, 131.3, 132.9,
133.5, 135.9, 140.9, 152.0. Anal. Calcd. for C29H21N3: C, 84.64; H, 5.14; N, 10.21 (%). Found: C,
84.57; H, 5.23; N, 10.10 (%). MS (m/z): 411 (M+).
1-benzyl-2-(4-(1-benzyl-4,5-diphenyl-1H-imidazol-2-yl)phenyl)-4,5-diphenyl-1H-imidazole (6b)
1
White powder, m.p.= 289-292 (dec.). H NMR (250 MHz, DMSO-d6) δ (ppm) 5.66 (s, 2H), 7.00-7.75
(m, 34H). 13C NMR (62.5 MHz, DMSO-d6) δ (ppm) 49.9, 127.7, 128.2, 128.3, 129.1, 129.2, 129.3,
129.5, 130.1, 130.3, 130.4, 130.5, 133.2, 133.7, 137.2, 142.4, 152.2. Anal. Calcd. for C50H38N4: C,
86.42; H, 5.51; N, 8.06 (%). Found: C, 86.50; H, 5.38; N, 8.10 (%).
1,2-diphenyl-2-(phenylamino)ethanone (8a)
Yellowish powder, m.p.= 167-168 oC. 1H NMR (250 MHz, CDCl3) δ (ppm) 4.94 (s, 1H), 5.49 (s, 1H),
6.34 (d, J= 6.5 Hz, 2H), 6.43 (t, J= 7.5 Hz, 1H), 6.75 (t, J= 7.5 Hz, 2H), 7.11-7.40 (m, 8H), 7.55 (d, J=
7.5 Hz, 2H). 13C NMR (62.5 MHz, CDCl3) δ (ppm) 64.1, 112.1, 117.2, 126.2, 126.9, 127.1, 127.4,
127.7, 131.7, 134.8, 135.1, 144.3, 192.2. Anal. Calcd. for C20H17NO: C, 83.59; H, 5.96; N, 4.87 (%).
Found: C, 83.67; H, 5.83; N, 4.90 (%).
(Z)-N'-phenylbenzamidine (9a)
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o
o
1
Yellowish powder, m.p.= 112-113 C (110-111 C)18. H NMR (250 MHz, CDCl3) δ (ppm) 4.87 (s,
2H), 6.95 (d, J= 6.6 Hz, 2H), 7.06 (t, J= 6.6 Hz, 1H), 7.30 (t, J= 6.6 Hz, 2H), 7.39 (t, J= 6.2 Hz, 2H),
7.50 (t, J= 6.2 Hz, 1H), 7.85 (d, J= 6.2 Hz, 2H). 13C NMR (62.5 MHz, CDCl3) δ (ppm) 121.8, 123.6,
126.1, 128.7, 130.2, 136.2, 150.5, 154.8. Anal. Calcd. for C13H12N2: C, 79.56; H, 6.16; N, 14.27 (%).
Found: C, 79.49; H, 6.21; N, 14.40 (%).
Results and Discussion
In the first step, we focused on the search of a catalytic system for the condensation reaction between
nitriles, primary amines and benzoin. For this purpose, the condensation reaction between benzonitrile
(1 mmol), aniline (1 mmol) and benzoin (1 mmol) for the synthesis of compound (4a) was selected as a
model reaction and the yield of product and the time of reaction were monitored in the presence of
different catalytic systems under various reaction conditions and obtained results were summarized in
Table 1.
Table 1. The condensation reaction of benzonitrile (1 mmol), aniline (1 mmol) and benzoin (1 mmol) in
the presence of various catalysts under different reaction conditions.
Entry Catalyst (quantity)
Reaction Conditions
Solvent-free, 140 oC
140 oC
Time
Yield (%)a
No reaction
Trace
35b
1
-
24 (h)
24 (h)
18 (h)
24 (h)
24 (h)
2
[Bmim]Br (0.5 g)
[Bmim]HSO4 (10 mol%)
PEG-OSO3H (10 mol%)
Silica sulfuric acid (0.5 g)
3
Solvent-free, 140 oC
Solvent-free, 140 oC
Solvent-free, 140 oC
4c
5d
30
38
SiO2/P2O5 - 5% w/w (0.5
g)
6
Solvent-free, 140 oC
24 (h)
30
7
8
9
NaHSO4.SiO2 (10 mol%)
Zn(OAc)2 (10 mol%)
Ni(OAc)2 (10 mol%)
Solvent-free, 140 oC
Solvent-free, 140 oC
Solvent-free, 140 oC
24 (h)
24 (h)
24 (h)
Trace
Trace
Trace
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10
11
12
13
14
15
16
17
18
19
20
21
HOAc (5 mL)
TFA (10 mol%)
TFA (2 mol%)
TFA (5 mol%)
TFA (15 mol%)
TFA (10 mol%)
TFA (10 mol%)
TFA (10 mol%)
TFA (10 mol%)
TFA (10 mol%)
TFA (10 mol%)
TFA (10 mol%)
Reflux
12 (h)
8 (h)
61
71
51
58
71
40
38
62
25
70
71
Solvent-free, 140 oC
Solvent-free, 140 oC
24 (h)
16 (h)
8 (h)
Solvent-free, 140 oC
Solvent-free, 140 oC
Ethanol (5 mL), Reflux
Methanol (5 mL), Reflux
DMF (5 mL), Reflux
THF (5 mL), Reflux
24 (h)
24 (h)
15 (h)
24 (h)
14 (h)
8 (h)
Solvent-free, 120 oC
Solvent-free, 150 oC
Glycerol (5mL), 80 oC, MW (300 w)
20 (min) 75
14 (min) 88
o
Glycerol (5 mL), 100 C, MW (300
22
23
24
25
26
TFA (10 mol%)
w)
o
Glycerol (5 mL), 120 C, MW (300
TFA (10 mol%)
TFA (10 mol%)
10 (min) 89
20 (min) 72
20 (min) 82
10 (min) 89
w)
o
Glycerol (5 mL), 120 C, MW (100
w)
o
TFA (10 mol%)
TFA (10 mol%)
Glycerol (5 mL), 120 C, MW (200
w)
o
Glycerol (5 mL), 120 C, MW (400
w)
o
Glycerol (5 mL), 140 C, MW (300
27
28
TFA (10 mol%)
TFA (10 mol%)
10 (min) 88
20 (min) 83
w)
Solvent-free, 120 oC, MW (300 w)
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b
c
a Isolated yield. The reaction was not proceeded more even after 24 h. For more information about
this catalyst please see Ref. 16a, b. d For more information about this catalyst please see Ref. 16c.
After extensive screening, the best yield and time profile were obtained with 10 mol% of TFA under
o
solvent-free condition at 140 C, which furnished the corresponding tetrasubstituted imidazol (4a) in
71% yield within 8h (Table 1, entry 11). Increasing the amount of TFA to more than 15 mol % showed
no substantial improvement in the yield (Table 1, entry 14), whereas the yield decreased and reaction
time increased by the decreasing the amount of the catalyst (Table 1, entries 12 and 13). The reaction
did not proceed efficiently in the absence of TFA after a long time (24 h) (Table 1, entry 1).
There are many investigations on the critical role of microwave irradiation on the rate acceleration
and yield enhancement of various chemical reactions.17 Considering this fact, we decided to examine
our methodology under microwave irradiation to improve the overall yield of the reaction. For this
purpose, the model reaction was subjected to microwave irradiation in the presence of TFA (10 mol%)
at various temperatures. Moreover, in order to enhance the microwave irradiation efficiency, glycerol
has been applied as a benign and nonvolatile microwave active reaction medium and obtained results
are summarized in Table 1. The optimum reaction conditions were found to be 120 °C for 10 min with
the maximum power of 300 W and desired product (4a) was obtained in 89% yield (Table 1, entry 23).
Increasing the temperature and microwave irradiation power did not affect the yield of product or
reaction time (Table 1, entries 26 and 27).
With the optimized conditions in hand, the scope and efficiency of the process were explored with
the one-pot condensation of a broad range of structurally diverse aromatic nitriles as well as primary
amines (aliphatic or aromatic) with benzoin under microwave irradiation (Scheme 2), and the results are
displayed in Table 2.
Table 2. The one-pot condensation of nitriles (1 mmol), primary amines (1 mmol) and benzoin (1
mmol) in the presence of TFA (10 mol%) in glycerol (5 mL) under microwave irradiation (300 w) at
120 oC.
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R1
R3
OH
CN
R2
O
TFA (10 mol%)
Glycerol
N
(1)
R3
R1
N
MW (300 W)
120 oC
(3)
R2 NH2
R3
6-18 min
83-91 %
R3
(4a-x and 4aa-af)
(2)
Scheme 2. The new more atom-efficient one-pot three-component route to tetrasubstituted imidazoles.
M.P. (oC)
Time
(min)
Yield
(%)a
Entry
R1
R2
R3
Found
ReportedRef.
4a
4b
H
H
C6H5
H
H
10
10
89
91
218-220
219-22114w
p-CH(CH3)2-C6H4
152-155
146-147
155-158
239-241
214-215
150-152
189-190
163-164
202-204
145-147
219-221
160-162
190-192
145-147
135-138
280-282
> 300
-
4c
4d
4e
4f
H
H
CH3
C6H5CH2
p-OCH3-C6H4
CH3
10
10
7
91
90
90
90
84
88
91
90
83
85
90
90
91
89
86
90
90
91
86
91
86
144-14614w
157-15914w
-
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
p-CH3
p-CH3
p-CH3
p-CH3
p-Br
10
13
13
10
15
7
210-21314w
155-15614w
191-19314w
166-16814w
200-20314w
145-14714w
215-21714w
161-16314w
194-19614w
149-15114w
136-13814w
283-28414w
-
4g
4h
4i
Iso-C4H9
C6H5
C6H5CH2
CH3
4j
4k
4l
m-NO2
p- NO2
p-Cl
p-CH3-C6H4
p-CH3-C6H4
C6H5CH2
p-CH3-C6H4
C6H5CH2
C6H5CH2
C6H5
7
4m
4n
4o
4p
4q
4r
10
10
6
p-CH3
p-Cl
p-OH
p-OH
p-OH
p-OH
p-OCH3
p-C(CH3)3
p-CH3
p-NO2
15
18
15
18
15
13
12
7
p-OCH3-C6H4
p-Cl-C6H4
C6H5CH2
C6H5CH2
p-Br- C6H4
p-CH(CH3)2-C6H4
4s
4t
290-292
167-169
177-179
217-219
195-198
-
-
-
4u
4v
4w
-
-
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p-
H
4x
(bezimiazole-
2-yl)
C6H5CH2
15
88
254-256
-
H
4y
4z
H
p-NO2-C6H4
o-NO2-C6H4
C6H5CH2
C6H5
30
30
15
17
30
30
12
18
-
-
-
-
H
H
-
-
4aa
4ab
4ac
4ad
4ae
4af
89
85
-
186-188
169-171
-
185-18614p
p-CH3
p-Cl
p-Cl
p-OCH3
H
-
p-OCH3
p-OCH3
p-CH3
p-CH3
C6H5
-
p-NO2
p-OCH3
H
C6H5CH2
C6H5CH2
C6H5
-
-
-
89
86
180-182
173-174
183-18414p
-
a Isolated yield.
As it is shown in Table 2, all reactions were proceeded in very short times (6-18 min) and in all cases
desired products were obtained in good to excellent yields (83-91%). Based on the obtained results it
can be concluded that the existence of electron withdrawing groups on the aromatic ring of nitriles was
lead to the enhancement of the reaction rate (Table 2, entries 4k, 4l and 4w) whereas the existence of
electron donating groups was lead to the decreasing of the reaction rates (Table 2, entries 4p, 4q, 4r, 4s,
4t). Moreover, it has been observed that the reaction was not proceeded with the application of aromatic
primary amines with a strong electron withdrawing groups (NO2 substituent at the para and or ortho
position of aromatic ring) even after a long time of microwave irradiation (30 min) (Table 2, entries 4y
and 4z). Besides, this method can be successfully applied for the halide or alkyl substituted benzoins
(Table 2, entries 4aa, 4ab, 4ae and 4af). Unfortunately, only a mixture of unknown products was
obtained with the application of methoxy (as an electron donating group) substituted benzoin even after
a long time of microwave irradiation (30 min) (Table2, entries 4ac and 4ad). All obtained products were
1
fully characterized by H NMR and 13C NMR spectroscopy and by comparison with the reported
spectral data.
Interestingly, this method can be easily applied for the condensation of primary amines (2) and
benzoin (3) with bis(cyanide)s such as terephthalonitrile (5) (Scheme 3). The reaction of 1 equivalent of
banzoin (3) and benzylamine (2a) with terephthalonitrile (5) proceeded rapidly to give mono-imidazole
(6a) and bis-imidazole (6b) in 91% and trace yields after 10 minutes, respectively. On the other hand,
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using 2 equivalents of benzoin (3) and benzylamine (2a) afforded compounds (6a) and (6b) in trace and
88% yields after 14 minutes, respectively, under similar reaction conditions (Scheme 3).
Ph
Ph
Ph
NC
CN
Ph
TFA (10 mol%)
Glycerol
OH
Ph
(3)
N
N
(5)
N
N
O
+
Ph
MW (300 W)
120 o
C
NH2
(2a)
CN
N
N
Ph
Ph
(6b)
(6a)
Scheme 3. The one-pot condensation of benzoin (3) and benzylamine (2a) with terephthalonitrile (5) in
the presence of TFA (10 mol%) in glycerol under microwave irradiation (300 W) at 120 oC.
The selectivity of presented method in the synthesis of tetrasubstituted imidazoles can be explained
by two different mechanistic pathways that are shown in Scheme 4.
In the first step of pathway A, an imine intermediate (7) produces from the condensation of primary
amine (2) and benzoin (3) and readily tautomerized to an α-amino carbonyl compound (8). In the next
step, desired tetrasubstituted imidazole (4) will be formed with the nucleophilic attack of α-amino
carbonyl compound (7) to the nitrile (1) that will be followed with an intramolecular nucleophilic
cyclization. In the first step of pathway B, an arylamidine (9) produces from the nucleophilic attack of
amine (2) to the nitrile (1) and in the next step desired tetrasubstituted imidazole (4) will be produced
with the condensation of aryamidine (9) with benzoin (3) (Scheme 4).
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Pathway A:
Step 1:
H2N R2
(2)
R2
R2
R2
R2
OH
NH
OH
Ph
OH
HN
Ph
O
H+
Ph
N
OH
Ph
HN
Ph
OH
Ph
Ph
H
Ph
Ph
Ph
(3)
H
O
H
Ph
-H2O Ph
O
(8)
O
(7)
Step 2:
R2
R1
R1
R1
R1
N
R2
NH
R2
R2
Ph
HN
Ph
O
N
N
N
R2
Ph
N
R1
N
H
NH
N
-H+
-H+
-H2O
-H+
Ph
Ph
Ph
(7)
Ph
H O
HO
Ph
Ph
Ph
O
H
(1)
(4)
H
Pathway B:
Step 1:
H2N R2
N R2
NH2
HN R2
NH
(2)
R1
(9)
R1
R1
N
-H+
H
(1)
H
Step 2:
Ph
Ph
H
Ph
O
H
R2
R2
N
R2
Ph
Ph
OH
O
R2
N
N
N
Ph
R1
(9)
Ph
N
H
-H+
OH
-H2O
-H+
-H2O
O
H
NH2
N
N
(4)
R1
R1
H
R1
Ph
H
(3)
Scheme 4. The plausible mechanisms for one-pot three-component condensation of nitriles, primary
amines and benzoin in the presence of TFA under microwave irradiation.
The authenticity of suggested pathways was studied with the conduction of two examinations
(Scheme 5). In the first examination, a mixture of benzoin (3) (1 mmol) and aniline (2b) (1mmol) in
o
glycerol (5 mL) was irradiated (300 W) in the presence of TFA (10 mol%) at 120 C. The progress of
the reaction was monitored by TLC. After the completion of the reaction, products were separated and
purified with plate chromatography and identified with 1H and 13C NMR. The obtained results from 1H
and 13C NMR studies established the correct structure of 1,2-diphenyl-2-(phenylamino)ethanone (8a)
(an α-aminocarbonyl compound) as it has been expected based on the pathway A. In the next step,
isolated 1,2-diphenyl-2-(phenylamino)ethanone (8a) was reacted with benzocyanide (1a) under
optimized reaction conditions and related tetrasubstituted imidazole (4a) was obtained as the only
product of the reaction as it has been expected by pathway A (Scheme 5). In order to examine the
14

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authenticity of pathway B, a mixture of benzocyanide (1a) (1 mmol) and aniline (2b) (1 mmol) in
o
glycerol (5 mL) was irradiated (300 W) in the presence of TFA (10 mol%) at 120 C. The progress of
the reaction was monitored by TLC. After completion of reaction, products were separated and purified
by plate chromatography and identified with 1H and 13C NMR. Obtained results from 1H and 13C NMR
studies established the correct structure of (Z)-N'-phenylbenzamidine (9a) as it has been expected based
on the pathway B. In the next step, isolated (Z)-N'-phenylbenzamidine (9a) was reacted with benzoin
(3) under optimized reaction conditions and related tetrasubstituted imidazole (4a) was obtained as the
only product of the reaction as it has been expected by pathway B (Scheme 5). Based on these
observations, both of pathways A and B are possible and will be occurred during the one-pot
condensation of nitriles, primary amines and benzoin in the presence of TFA in glycerol under
microwave irradiation at 120 oC.
TFA (10 mol%)
Glycerol (5 mL)
Ph
Ph
NH2
TFA (10 mol%)
Glycerol (5 mL)
O
HN
HO
O
+
Ph
MW (300 W)
120 oC
Ph
(3)
MW (300 W)
120 oC
Ph
CN
(2b)
(8a)
(1a)
Ph
Ph
N
N
Ph
(4a)
Ph
O
HO
Ph
Ph
NH2
(2b)
CN
TFA (10 mol%)
Glycerol (5 mL)
TFA (10 mol%)
Glycerol (5 mL)
(3)
Ph
N
Ph
+
NH2
MW (300 W)
120 oC
MW (300 W)
120 oC
(1a)
(9a)
Scheme 5. The study of pathways A and B authenticity.
In another study, the atom efficiency of our presented method was compared with the atom
efficiencies of previously reported four-component methods for the synthesis of tetrasubstituted
imidazoles and obtained results are summarized in Table 3. As it is obviously shown in Table 3, the
15

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atom efficiency of presented method is distinctly higher than the other reported four-component
methods.
Table 3. The comparative atom efficiency of previously reported four-component methods and
presented method for the synthesis of compound (4a).
Atom
Efficiency
Entry
Conditions
Ref.
1a
2a
Trityl chloride (10 mol%), 90 oC, Solvent-free
SiO2, Microwave irradiation, Solvent-free
60
60
14u
14j
Nanocrystalline MgAl2O4 (0.035 mol%), EtOH,
Ultrasonic Irradiation
3a
69
14n
4a
5a
6a
InCl3.3H2O (10 mol%), MeOH, Room Temperature
SiO2-BF3, 140 oC, Solvent-free
62
68
68
14a
14b
14w
[Bmim]Br, Microwave irradiation
This
work
7b
TFA (10 mol%), Microwave irradiation, Solvent-free
81
b
a Benzil (1 mmol), benzaldehyde (1 mmol), aniline (1 mmol) and NH4OAc (1 mmol). Benzoin (1
mmol), benzonitrile (1 mmol) and aniline (1 mmol).
So briefly, a new more atom-efficient approach for one-pot multi-component synthesis of
tetrasubstituted imidazoles is presented. In this method, nitriles were successfully condensed with
benzoin and primary amines in a one-pot approach in the presence of trifluoroacetic acid under
o
microwave irradiation in glycerol at 120 C. The promising points for the presented methodology are
higher atom efficiencies, generality, high yields, short reaction times, clean reaction profile, ease of
product isolation, application of microwave as a renewable energy source, and finally agreement with
some of green chemistry protocols.
Acknowledgement
We gratefully appreciate the Shiraz University Research Councils for the financial support of this work.
References
1. (a) P. P. Graczyk, A. Khan, G. S. Bhatia, V. Palmer, D. Medland, H. Numata, H. Oinuma, J. Catchick,
A. Dunne, M. Ellis, C. Smales, J. Whitfield, S. J. Neame, B. Shah, D. Wilton, L. Morgan, T. Patel, R.
Chung, H. Desmond, J. M. Staddon, N. Sato and A. Inoue, Bioorg. Med. Chem. Lett. 2005, 15, 4666;
16

Page 17 of 19
RSC Advances
View Article Online
DOI: 10.1039/C6RA11171H
(b) S. A. Laufer, W. Zimmermann and K. J. Ruff, J. Med. Chem. 2004, 47, 6311; (c) G. M. Sperandio da
Silva, C. M. R. Sant QAnna and E. J. Barreiro, Bioorg. Med. Chem. 2004, 12, 3159; (d) J. A. Murry,
Curr. Opin. Drug Discov. Dev. 2003, 6, 945; (e) J. C. Lee, J. T. Laydon, P. C. McDonnell, T. F.
Gallagher, S. Kumar, D. Green, D. McNulty, M. J. Blumenthal, J. R. Keys, S. W. L. Vatter, J. E.
Strickler, M. M. McLaughlin, I. R. Siemens, S. M. Fisher, G. P. Livi, J. R. White, J. L. Adams and P. R.
Young, Nature 2002, 372, 739; (f) K. M. Marcantonio, L. F. Frey, D. Frantz, J. Murry, A. Soheili, R.
Tillyer, E. J. J. Grabowski, P. Reider, 224th ACS National Meeting, Boston, MA, USA, August18-22,
2002; (g) S. Laufer, G. Wagner and D. Kotschenreuther, Angew. Chem. Int. Ed. 2002, 41, 2290; (h) N. J.
Liverton, J. W. Butcher, C. F. Clairborne, D. A. Claremon, B. E. Libby, K. T. Nguyen, S. M.
Pitzenberger, H. G. Selnick, G. R. Smith, A. Tebben, J. P. Vacca, S. L. Varga, L. Agarwal, K. Dancheck,
A. J. Forsyth, D. S. Fletcher, B. Frantz, W. A. Hanlon, C. F. Harper, S. J. Hofsess, M. Kostura, J. Lin, S.
Luell, E. A. Neill, C. J. Orevillo, M. Pang, J. Parsons, A. Rolando, Y. Sahly, D. M. Visco and S. J.
Keefe, J. Med.Chem. 1999, 42, 2180.
2. J. W. Black, G. J. Durant, J. C. Emmett and C. R. Ganellin, Nature 1974, 248, 65.
3. R. Uaucu, N. G. Karaburun and I. Isikdag, Farmaco 2001, 56, 285.
4. A. Mjalli, S. Sarshar, U. S. Patent 1997, US 5700826, pp 19.
5. Y. Niwano, H. Koga, H. Kodama, K. Kanai, T. Miyazaki and H. Yamaguchi, Med. Mycol. 1999, 37,
351.
6. M. Antolini, A. Bozzoli, C. Ghiron, G. Kennedy, T. Rossi and A. Ursini, Bioorg. Med. Chem. Lett.
1999, 9, 1023.
7. (a) A. Liberatore, J. Schulz, J. Pommier, M. Barthelemy, M. Huchet, P. Chabrier and D. Bigg, Bioorg.
Med. Chem. Lett. 2004, 14, 3521; (b) D. W. Cheung and E. E. Daniel, Nature 1980, 283, 485; (c) J.
Heeres, L. J. J. Backx, J. H. Mostmans and J. Van Cutsem, J. Med. Chem. 1979, 22, 1003; (d) P. R.
Conlin, W. C. Gerth, J. Fox, J. B. Roehm and S. J. Boccuzzi, Clin. Ther. 2001, 23, 1999.
8. (a) P. Wasserscheid and T. Welton, (Eds.) Ionic Liquids in Synthesis,Wiley VCH, Weinheim, 2003;
(b) T. Welton, Chem. Rev. 1999, 99, 2071.
9. (a) H. L. Lee, M. Bang and C. S. Pak, Tetrahedron Lett. 2005, 46, 7139; (b) J. M. D. Storey and C.
Williamson, Tetrahedron Lett. 2005, 46, 7337; (c) W. A. Herrmann, Angew. Chem. Int. Ed. 2002, 41,
17

RSC Advances
Page 18 of 19
View Article Online
DOI: 10.1039/C6RA11171H
1290; (d) D. Bourissou, O. Guerret, F. P. Gabba and W. G. Bertrand, Chem. Rev. 2000, 100, 39; (e) W.
A. Herrmann and C. Kçcher, Angew.Chem. Int. Ed. Eng. 1997, 36, 2162.
10. R. M. Acheson, (Ed.) An Introduction to the Chemistry of Heterocyclic Compounds, John Wiley
and Sons, New York. 1967.
11. G.W. Gribble, J. A. Joule and T. L. Gilchrist, (Eds.) Progress in Heterocyclic Chemistry, volume 13-
17, Elsevier, Oxford. 2001-2005.
12. (a) W. Li and Y. J. Lam, Comb. Chem. 2005, 7, 644; (b) Y. M. Losksha, A. A. El-Barbary, M. A. El-
Badawi, C. Nielsen and E. B. Pedersen, Bioorg. Med. Chem. 2005, 13, 4209; (c) J. A. Murry, D. Frantz,
L. Frey, A. Soheili, K. Marcantonio, R. Tillyer, E. J. J. Grabowski and P. J. Reider, ACS Sym. Ser. 2004,
870, 161; (d) O. A. Attanasi, L. DeCrescentini, G. Favi, P. Filippone, F. Mantellini and S. Santeusanio,
Synlett 2004, 549; (e) H. Zhong, S. Dubberke, S. Muller, A. Rossler, T. W. Schulz, D. J. Korey, T. Otten,
D. G. Walker and A. Abdel-Magid, PCT Int. Appl. 2002, WO02/076974, pp 55 ; (f) H. B. Lee and S.
Balasubramanian, Org.Lett. 2000, 2, 323.
13. P. Deprez, E. Mandine, A. Vermond and D. Lesuisse, Bioorg.Med. Chem. Lett. 2002, 12, 1287.
14. (a) S. D. Sharma, P. Hazarika and D. Konwar, Tetrahedron Lett. 2008, 49, 2216; (b) B. Sadeghi, B.
F. Mirjalili and M. M. Hashemi, Tetrahedron Lett. 2008, 49, 2575; (c) M. M. Heravi, F. Derikvand and
F. F. Bamoharram, J. Mol. Catal. A: Chem. 2007, 263, 112; (d) S. Kantevari, S. V. N. Vuppalapati, D. O.
Biradar and L. Nagarapu, J. Mol. Catal. A: Chem. 2007, 266, 109; (e) M. Kidwai, P. Mothsra, V. Bansal
and R. K. Somvanshi, J. Mol. Catal. A: Chem. 2007, 265, 177; (f) L. Nagarapu, S. Apuri and S.
Kantevari, J. Mol. Catal. A: Chem. 2007, 266, 104; (g) A. R. Karimi, Z. Alimohammadi and J. Azizian,
Catal. Commun. 2006, 7, 728; (h) M. M. Heravi, F. Derikvand and M. Haghighi, Monatsh. Chem. 2008,
139, 31; (i) D. R. J. Acke, R. V. A. Orru and C. V. Stevens, QSAR Comb. Sci. 2006, 25, 474; (j) S.
Balalaie, A. Arabanian, Green Chem. 2000, 2, 274; (k) G. V. M. Sharma, Y. Jyothi and P. S. Lakshmi,
Synth. Commun. 2006, 36, 2991; (l) A. R. Karimi, Z. Alimohammadi and M. M. Amini, Mol. Divers.
2010, 14, 635; (m) K. Niknam, A. Deris, F. Naeimi and F. Majleci, Tetrahedron Lett. 2011, 52, 4642; (n)
J. Safari, S. Gandomi-Ravandi and Z. Akbari, J. Adv. Res. 2013, 4, 509; (o) A. Javid, M. M. Heravi, F.
F. Bamoharram and M. Nikpour, EꢀJournal Chem. 2011, 8, 547; (p) S. Samai, G. C. Nandi, P. Singh
and M. S. Singh, Tetrahedron. 2009, 65, 10155; (q) R. A. Mekheimer, A. M. Abdel Hameed, S. A. A.
18

Page 19 of 19
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Mansour and K. U. Sadek, Chin. Chem. Lett. 2009, 20, 812; (r) X. B. Wang, L. He, T. Y. Jian and S. Ye,
Chin. Chem. Lett. 2012, 23, 13; (s) A. Teimouri and A. N. Chermahini, J. Mol. Catal. A: Chem. 2011,
346, 39; (t) A. Davoodnia, M. M. Heravi, Z. Safavi-Rad and N. Tavakoli-Hoseini, Synth. Commun.
2010, 40, 2588; (u) A. R. Moosavi-Zare, Zh. Asgari, A. Zare, M. A. Zolfigol and M. Shekouhy, RSC
Adv. 2014, 4, 60636; (v) M. R. Mohammadizadeh, A. Hasaninejad and M. Bahramzadeh, Synth.
Commun. 2009, 39, 3232; (w) A. Hasaninejad, A. Zare, M. Shekouhy and J. Ameri Rad, J. Comb.
Chem. 2010, 12, 844.
15. (a) A. Khalafi-Nezhad, M. Divar, F. Panahi, RSC Adv. 2015, 5, 2223; (b) A. Khalafi-Nezhad, M.
Nourisefat, F. Panahi, Org. Biomol. Chem. 2015, 13, 7772; (c) M. Nourisefat, F. Panahi and A. Khalafi-
Nezhad, Org. Biomol. Chem. 2014, 12, 9419; (d) M. Shekouhy, A. Masoudi Sarvestani, S. Khajeh and
A. Khalafi-Nezhad, RSC Adv. 2015, 5, 63705; (e) M. Shekouhy, A. Moaddeli and A. Khalafi-Nezhad,
Res. Chem. Intermed. 2016, 42, 3805; (f) M. Shekouhy, A. Khalafi-Nezhad, Green Chem. 2015, 17,
4815.
16. (a) A. Hasaninejad, A. Zare, M. Shekouhy and J. Ameri-Rad, Green Chem. 2011, 13, 958; (b) M.
Shekouhy, Catal. Sci. Technol. 2012, 2, 1010; (c) P. Salehi, M. A. Zolfigol, F. Shirini and M.
Baghbanzadeh, Curr. Org. Chem. 2006, 10, 2171.
17. (a) A. Zare, A. Parhami, A. R. Moosavi-Zare, A. Hasaninejad, A. Khalafi-Nezhad and M. H.
Beyzavi, Can. J. Chem. 2009, 87,416; (b) C. O. Kappe, Angew. Chem., Int. Ed. 2004, 43, 6250.
18. B. L. Korbad and S. H. Lee, Bull. Korean Chem. Soc. 2013, 34, 1266.
19