Appel reagent as novel promoter for the synthesis of polysubstituted imidazoles

Article abstract of DOI:10.24820/ark.5550190.p010.039

We present an efficient method for the synthesis of polysubstituted imidazoles in the presence of Appel reagent (Ph3P/CCl4). Tri-substituted imidazoles is synthesized via condensation of aldehydes, benzil and ammonium acetate, and tetra-substituted imidazole is prepared via condensation of aldehydes, benzil, ammonium acetate and primary amines. These protocols allow the simple preparation of the desired products using readily available reagent instead of complex, expensive and toxic reagents under mild reaction conditions in excellent yields.

Full text of DOI:10.24820/ark.5550190.p010.039

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Arkivoc 2017, part iv, 343-352
Appel reagent as novel promoter for the synthesis of polysubstituted imidazoles
Mehdi Khoshneviszadeha and Mohammad Mahdavib*
aMedicinal&Natural Products Chemistry Research Center, Shiraz University of Medicinal Sciences, Shiraz, Iran
bEndocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute,
Tehran University of Medical Sciences, Tehran
Email: mahdavi_chem@yahoo.com
Received 01-30-2017
Accepted 05-06-2017
Published on line 06-18-2017
Abstract
We present an efficient method for the synthesis of polysubstituted imidazoles in the presence of Appel
reagent (Ph3P/CCl4). Tri-substituted imidazoles is synthesized via condensation of aldehydes, benzil and
ammonium acetate, and tetra-substituted imidazole is prepared via condensation of aldehydes, benzil,
ammonium acetate and primary amines. These protocols allow the simple preparation of the desired products
using readily available reagent instead of complex, expensive and toxic reagents under mild reaction
conditions in excellent yields.
N
Ph
R
Ph3P (1.1 equiv.), CCl4 (1mL)
55 oC, 1.5 h
N
H
Ph
Ph
O
Ph
NH4OAc
+
RCHO
+
Ph
N
O
Ph
R
Ph3P (1.1 equiv.), CCl4 (1mL)
R'NH2, 60 oC, 1 h
N
R'
Keywords: Aldehydes, benzil, ammonium acetate, primary amines, Appel reagent, imidazoles
DOI: https://doi.org/10.24820/ark.5550190.p010.039
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Introduction
Imidazole and its derivatives are important class of N-heterocycles that occupies a significant place in
synthetic and medicinal chemistry. These compounds act as organic catalysts,1 precursors of ionic liquids2 and
carbene ligands,3 building blocks of complex meaningful molecules and natural products,4 and ligands in
metalloenzymes.5 The imidazole core exists in many compounds with pharmaceutical and biological activity
such as losartan, eprosartan, carnosinemia, histamine, and histidine.6 The imidazole-containing compounds
have also other useful activities such as anthelmintic,7 antifungal,8 antiviral activities,9 antitubercular,10
antitumor,11 analgesic,12 anti-inflammatory,13 and antibacterial activity.14
H
H2N
N
CO2H
CO2H
NH2
N
N
O
NH2
histidine
N
N
N
H
H
N
H
carnosinemia
histamine
CO2H
OH
S
H
N
N
Cl
N
N
N
N
N
N
CO2H
eprosartan
losartan
Figure 1. Some examples of pharmaceutical and biological active imidazoles.
Although the broad variety of synthetic routes have been reported to synthesize imidazole derivatives,15, 16
there are few protocols for preparation of polysubstituted imidazoles. The well-known route for preparation
of polysubstituted imidazoles is one-pot reaction between aldehydes, benzil, ammonium acetate and primary
amines catalyzed by various catalysts such as FeCl3·6H2O,17 silica gel/NaHSO4,18 PPA–SiO2,19 BF3·SiO2,20 silica
gel or HY zeolite,21 heteropolyacids,22 HOAc,23 L-proline,24 InCl3·3H2O,25 nanocrystalline sulfated zirconia,26 1,4-
diazabicyclo[2,2,2]octane (DABCO),27 K5CoW12O40·3H2O,28 alumina,29 ionic liquids,30 HClO4–SiO2,31 silica-
bonded propylpiperazine N-sulfamic acid,32 and Zr(acac)4.33 However, some of these methods involve the use
of toxic and expensive catalysts or media, and have notable disadvantages such as harsh reaction conditions,
long reaction times, and moderate yields. Therefore, the development of novel and efficient approaches to
generate polysubstituted imidazoles is still desirable.
Due to the chemical and pharmacological significance of imidazoles, we sought to develop a one-pot
protocol for the efficient formation of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles through the
addition reaction between aldehydes, benzil, ammonium acetate and primary amines in the presence of Ph3P
and CCl4 which known as the Appel reagent. Although, the Appel reagent converts an alcohol into the
corresponding alkyl halide, we believed that this reagent can be promoted the synthesis of the desired
imidazoles.
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Results and Discussion
To synthesize the 2,4,5-trisubstituted imidazoles, the reaction between 4-methoxybenzaldehyde 1a, benzil 2
and ammonium acetate 3, as a model reaction, was investigated in the presence of various amounts of Ph3P
and CCl4, at different temperatures. As shown in table 1, the best yield of tri-substituted imidazole 4a was
obtained in the presence of 1.1 equiv. of Ph3P at 55 °C in 1 mL of CCl4 as reactive solvent after 1.5 h (Table 1,
entry 9, 95%). In addition, we examined the reaction in various additional solvents such as CHCl3, CH2Cl2,
toluene, DMF, THF, DMSO, and it was found that although the reaction led to approximately acceptable yields
in these solvents, the addition of these solvents did not give the better yield of product (Table 1, entries 10–
15).
Table 1 Optimization of three-component synthesis of 2,4,5-trisubstituted imidazole 4a in the presence of
Appel reagenta
OMe
O
N
Ph3P, CCl4
Ph
Ph
NH4OAc
+
MeO
CHO
+
Ph
N
O
H
Ph
2
3
4a
1a
Entry
Ph3P
CCl4
Temp. °C
Solvent
Time (h)
Yield of 4a
(%)b
1
2
3
4
5
6
7
8
0.2 equiv.
0.2 equiv.
0.2 equiv.
0.2 equiv.
0.5 equiv.
1.0 equiv.
1.1 equiv.
1.1 equiv.
1.1 equiv.
1.1 equiv.
1.1 equiv.
1.1 equiv.
1.1 equiv.
1.1 equiv.
1.1 equiv.
0.2 equiv.
0.2 equiv.
0.2 equiv.
0.2 equiv.
0.5 equiv.
1.0 equiv.
1.1 equiv.
1.2 equiv.
1 mL
1 mL
1 mL
1 mL
1 mL
r.t
40
50
55
55
55
55
55
55
55
55
55
55
55
55
–
–
–
–
–
–
–
–
8
8
8
8
8
8
8
4
1.5
1.5
1.5
1.5
1.5
1.5
1.5
No reaction
12
22
25
36
60
65
67
95
70
75
73
65
62
68
9
–
10
11
12
13
14
15
CH2Cl2
CHCl3
DMSO
DMF
THF
Toluene
1 mL
1 mL
a
reaction conditions: use of 4-methoxybenzaldehyde (1 mmol), benzil (1 mmol), ammonium acetate (2.5
mmol), and appropriate amount of Ph3P and CCl4; additional solvent (3 mL); related temperature and time.
b Isolated yield.
In continuous, we examined the reaction of 4-methoxybenzaldehyde 1a, benzil 2, ammonium acetate 3,
and benzylamine 5a in the presence of various amount of Ph3P and CCl4 under several reaction conditions to
generate 1,2,4,5-tetrasubstituted imidazole 6a. As shown in table 2, the best yield of tetra-substituted
imidazole 6a was obtained in the presence of 1.1 equiv. of Ph3P at 60 °C in 1 mL of CCl4 as reactive solvent
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Khoshneviszadeh, M. et al.
after 1 h (Table 2, entry 8, 92%). Also, we found that the addition of various solvents such as CHCl3, CH2Cl2,
toluene, DMF, THF, DMSO in the reaction mixture, did not lead to better yield of product (Table 2, entries 9–
14).
Table 2 Optimization of four-component synthesis of 1,2,4,5-tetrasubstituted imidazole 6a in the presence of
Appel reagenta
OMe
O
N
Ph3P, CCl4
Ph
Ph
NH OAc
MeO
CHO +
+
+ PhCH2NH2
4
Ph
N
O
Ph
Ph
2
3
5a
6a
1a
Entry
Ph3P
CCl4
Temp. °C
Solvent
Time (h)
Yield of 6a
(%)b
1
2
3
4
5
6
7
8
0.2 equiv.
0.2 equiv.
0.2 equiv.
0.5 equiv.
1.0 equiv.
1.1 equiv.
1.1 equiv.
1.1 equiv.
1.1 equiv.
1.1 equiv.
1.1 equiv.
1.1 equiv.
1.1 equiv.
1.1 equiv.
0.2 equiv.
0.2 equiv.
0.2 equiv.
0.5 equiv.
1.0 equiv.
1.1 equiv.
1.2 equiv.
1 mL
1 mL
1 mL
1 mL
1 mL
r.t
55
60
60
60
60
60
60
60
60
60
60
60
60
–
–
–
–
–
–
–
–
8
8
8
8
8
8
6
1
1
1
1
1
1
1
No reaction
20
26
33
54
62
67
92
63
70
67
58
60
65
9
CH2Cl2
CHCl3
DMSO
DMF
THF
Toluene
10
11
12
13
14
1 mL
1 mL
a
reaction conditions: use of 4-methoxybenzaldehyde (1 mmol), benzil (1 mmol), ammonium acetate (1.2
mmol), benzylamine (1 mmol), and appropriate amount of Ph3P and CCl4; additional solvent (3 mL); related
temperature and time.
b Isolated yield.
In order to show the generality and scope of these new protocols, the reactions were performed using
various aldehydes 1 and primary amines 5 in the presence of 1.1 equiv. Ph3P in 1mL CCl4 at convenient
temperatures to produce the corresponding polysubstituted imidazoles 4 and 6 (Table 3).
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Table 3 The synthesis of polysubstituted imidazoles 4a and 6b in the presence of Appel reagenta
N
Ph
R
Ph3P (1.1 equiv.), CCl4 (1mL)
55 oC, 1.5 h
N
H
Ph
O
4
Ph
RCHO
NH4OAc
+
+
Ph
N
O
Ph
R
3
Ph3P (1.1 equiv.), CCl4 (1mL)
2
1
N
R'NH2 (5), 60 oC, 1 h
Ph
R'
6
Product
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
R
R’
–
–
–
–
–
–
–
–
–
–
–
–
Yield (%)c
95
92
90
93
91
95
94
93
94
97
92
94
92
92
94
96
95
93
93
90
91
94
91
91
94
96
90
Mp (°C)
229–230
205–207
257–259
233–234
204–206
275
233–234
255–257
260–261
234–236
308–310
231
Lit. mp (°C)
228–23026
204–20634
256–25924
234–23635
202–20524
274–27626
232–23426
254–25626
260–26226
234–23626
308–30936
230–23124
162–16437
176–17838
134–13531
214–21636
162–16439
182–18421
156–15840
188–19118
4-MeOC6H4
2-MeOC6H4
4-(Me)2NC6H4
4-OHC6H4
2-OHC6H4
Ph
4-MeC6H4
4-BrC6H4
4-ClC6H4
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-MeOC6H4
4-MeOC6H4
4-OHC6H4
Ph
Bn
4-MeC6H4
Bn
Ph
Bn
Ph
Bn
4-MeC6H4
Bn
Bn
Bn
Bn
Bn
4-MeC6H4
4-MeC6H4
163–165
177–178
135
215–216
164–165
181–183
157–158
190–192
150–151
172–173
160–161
144–145
141
Ph
4-MeC6H4
4-MeC6H4
4-MeC6H4
3-NO2C6H4
4-BrC6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-NO2C6H4
3-NO2C6H4
170–17231
160–16237
144–14618
140–14131
219–22018
149–15118
220–222
148–150
a
Reaction conditions: aldehydes (1 mmol), benzil (1 mmol), ammonium acetate (2.5 mmol), Ph3P (1.1 mmol),
CCl4 (1 mL); 55 °C; 1.5 h.
b Reaction conditions: aldehydes (1 mmol), benzil (1 mmol), ammonium acetate (1.2 mmol), primary amines (1
mmol), Ph3P (1.1 mmol), CCl4 (1 mL); 60 °C; 1 h.
c Isolated yields.
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All the reactions reached to completion within 1.5 h for 2,4,5-trisubstituted imidazoles 4 and 1 h for
1
1,2,4,5-tetrasubstituted imidazoles 6. H NMR analysis of the reaction mixtures clearly indicated formation of
the polysubstituted imidazoles 4 and 6 in excellent yields.
The structures of the polysubstituted imidazoles 4 and 6 were deduced by melting point determination and
from 1H and 13C NMR spectral data.
A proposed mechanism for the formation of the polysubstituted imidazoles 4 and 6 is depicted in Scheme
1. On the basis of the Appel reaction,41 the treatment of triphenylphosphine with carbon tetrachloride leads to
form phosphonium ion 7, that reacts with aldehydes 1 to form the oxyphosphonium intermediates 8. The
generation of the oxyphosphonium intermediates 8 promotes the nucleophilic addition of ammonium acetate
3 via removal of triphenylphosphine oxide and chloride anion to generate the iminium ions 10. The addition of
another ammonium acetate on the iminium ions 10 gives the intermediates 11. Then, the condensation of
intermediates 11 with benzil 2 produces trisubstituted imidazoles 4 by removal of 2 water molecules. In
similar pathway, the addition of primary amines 5 onto iminium ions 10 forms intermediates 14 which
produces tetrasubstituted imidazol 6 via condensation with benzil.
Cl
Ph P
+
3
Cl
Cl
Cl
+
PPh3
+
+
NH2
Cl
O
O
NH2
NH4OAc (3)
(7)
Ph3P Cl
_
R
O
R
H
R
Cl
R
H
- Ph3PO
- Cl
9
8
10
1
OH
Ph
Ph
(2)
Ph
O
Ph
+
N
Ph
Trisubstituted
imidazoles
Ph
NH2
NH2
NH2
Ph
R
NH4OAc (3)
HN
N
O
N
O
R
H
R
- H2O
- H2O
H
R
NH2
R
NH2
Ph
11
10
4
12
13
O
OH
Ph
Ph
(2)
Ph
Ph
+
N
Ph
Ph
Tetrasubstituted
imidazoles
NH2
NH2
Ph
R
HN
N
R'NH2 (5)
O
N
O
NHR'
O
NHR'
R
H
R
NHR'
- H2O
- H2O
R
R
Ph
R'
10
14
6
15
16
Scheme 1. Proposed mechanism.
Conclusions
In conclusion, we have developed a one-pot and multicomponent reaction between aldehydes, benzil,
ammonium acetate and primary amines in the presence of Ph3P and CCl4 which known as Appel reagent. The
reactions were carried out under mild reaction conditions and without the use of very high temprature, and
complex, toxic and expensive reagents to prepare the polysubstituted imidazoles which are of potential
synthetic and pharmacological interest. Use of simple materials, relatively short reaction times, and high yield
of the products are the other advantages of our protocol. We believe that the success in this process could
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Khoshneviszadeh, M. et al.
open the door to the design of diverse reactions and the generation of interesting organic compounds based
on treatment of carbonyl groups with Appel reagent.
Experimental Section
Ammonium acetate, benzil, aldehydes, primary amines, triphenylphosphine and carbon tetrachloride were
obtained from Merck (Germany) and Fluka (Switzerland) and were used without further purification. Progress
of the reactions was monitored by thin layer chromatography (TLC). Melting points were measured on an
Electrothermal 9100 apparatus. 1H and 13C NMR spectra were measured with a Bruker DRX-300 (at 300 and 75
MHz) spectrometer using CDCl3 solvent with TMS as an internal standard. Chromatography columns were
prepared from Merck silica gel 230-240 meshes.
General procedure for the preparation of 2,4,5-trisubstituted imidazoles 4, exemplified on 4a. A mixture of
4-methoxybenzaldehyde (0.136 g, 1 mmol), benzil (0.210 g, 1 mmol), ammonium acetate (0.192 g, 2.5 mmol)
and Ph3P (0.280 g, 1.1 mmol) in CCl4 (1mL) was stirred for 1.5 h at 55 ºC. After completion of the reaction, the
solvent was removed and the residue was purified by column chromatography using n-hexane–EtOAc (3:1) as
eluent. The solvent was removed to afford the product 4a as white solid.
The spectral data of some 2,4,5-trisubstituted imidazoles 4 are given next.
1
2-(4-Methoxyphenyl)-4,5-diphenyl-1H-imidazole (4a) Yield. 0.31 g, 95%; m.p = 229–230 ºC. H NMR (300
MHz, CDCl3): δ = 3.80 (3H, s, OCH3), 7.04 (2H, d, J 8.1 Hz, 2 CH), 7.15–7.53 (10H, m, 10 CH), 7.97 (2H, d, J 8.1
Hz, 2 CH), 12.61 (1H, br s, NH). 13C NMR (75 MHz, CDCl3): δ = 55.14, 114.17, 123.55, 126.83, 127.72, 128.38,
129.01, 131.64, 135.75, 137.19, 146.11, 159.80.
2-(2-Hydroxyphenyl)-4,5-diphenyl-1H-imidazole (4e). Yield 0.28 g, 91%; m.p = 204–206 ºC. 1H NMR (300 MHz,
CDCl3): δ = 6.97 (1H, d, J 7.6 Hz, CH), 7.14 (1H, d, J 7.6 Hz, CH), 7.29–7.62 (11H, m, 11 CH), 7.65 (1H, t, J 7.6 Hz,
CH), 9.40 (1H, br s, OH), 12.90 (1H, br s, NH). 13C NMR (75 MHz, CDCl3): δ = 111.42, 116.79, 118.01, 122.08,
126.43, 127.12, 127.40, 128.11, 129.46, 144.72, 156.37.
1
2-(3-Nitrophenyl)-4,5-diphenyl-1H-imidazole (4k). Yield 0.31 g, 92%; m.p = 308–310 ºC. H NMR (300 MHz,
CDCl3): δ = 7.35–7.58 (10H, m, 10 CH), 7.82 (1H, t, J 8.1 Hz, CH), 8.54 (1H, d, J 8.1 Hz, CH), 9.02 (1H, t, J 1.8 Hz,
CH), 9.46 (1H, d, J 8.1 Hz, CH), 13.13 (1H, br s, NH). 13C NMR (75 MHz, CDCl3): δ = 119.43, 122.58, 127.05,
128.41, 128.74, 130.47, 131.23, 131.90, 143.38, 148.32.
General Procedure for the Preparation of 1,2,4,5-tetrasubstituted imidazoles 6, Exemplified on 6a: A mixture
of 4-methoxybenzaldehyde (0.136 g, 1 mmol), benzil (0.210 g, 1 mmol) ammonium acetate (0.092 g, 1.2
mmol), benzylamine (0.107 g, 1 mmol) and Ph3P (0.280 g, 1.1 mmol) in CCl4 (1mL) was stirred for 1 h at 60 ºC.
After completion of the reaction, the solvent was removed and the residue was purified by column
chromatography using n-hexane–EtOAc (4:1) as eluent. The solvent was removed to afford the pure product
6a as pale yellow solid.
The spectral data of some 1,2,4,5-tetrasubstituted imidazoles 6 are given next.
1-Benzyl-2-(4-methoxyphenyl)-4,5-diphenyl-1H-imidazole (6a) Yield 0.38 g, 92%; mp = 163–165 ºC. H NMR
1
(300 MHz, CDCl3): δ = 3.80 (3H, s, OCH3), 5.09 (2H, s, CH2Ph), 6.84–7.06 (3H, m, 3 CH), 7.07 (2H, d, J 8.0 Hz, 2
13
CH), 7.08–7.56 (12H, m, 12 CH), 7.92 (2H, d, J 8.0 Hz, CH). C NMR (75 MHz, CDCl3): δ = 47.12, 54.31, 112.89,
122.38, 125.00, 125.17, 125.65, 126.25, 127.02, 127.52, 127.54, 128.00, 128.67, 129.47, 130.01, 130.16,
133.53, 136.60, 136.81, 146.92, 159.06.
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1,4,5-Triphenyl-2-p-tolyl-1H-imidazole (6f) Yield 0.36 g, 93%; mp = 181–183 ºC. 1H NMR (300 MHz, CDCl3): δ =
2.30 (3H, s, CH3), 7.11 (2H, d, J 7.9 Hz, 2 CH), 7.19 (1H, t, J 7.5 Hz, CH), 7.24–7.31 (12H, m, 12 CH), 7.35 (2H, d, J
7.5 Hz, 2 CH), 7.54 (2H, d, J 7.9 Hz, 2 CH). 13C NMR (75 MHz, CDCl3): δ = 21.56, 127.18, 128.45, 129.03, 129.06,
129.24, 129.52, 129.60, 129.66, 123.24, 131.35, 132.02, 132.17, 135.36, 137.65, 137.76, 138.58, 147.08.
1
1-Benzyl-2-(3-nitrophenyl)-4,5-diphenyl-1H-imidazole (6i) Yield 0.39 g, 91%; mp = 150–151 ºC. H NMR (300
MHz, CDCl3): δ = 5.24 (2H, s, CH2Ph), 6.84–7.12 (5H, m, 5 CH), 7.20 (2H, d, J 7.5 Hz, 2CH), 7.23–7.54 (6H, m, 6
CH), 7.59 (1H, t, J 7.9 Hz, CH), 7.70 (2H, t, J 7.5 Hz, 2CH), 8.10 (1H, d, J 7.9 Hz, CH), 8.29 (1H, d, J 7.9 Hz, CH),
13
8.59 (1H, s, CH). C NMR (75 MHz, CDCl3): δ = 47.38, 122.35, 122.62, 124.70, 125.70, 125.65, 126.73, 127.21,
127.87, 128.06, 128.58, 129.43, 129.98, 130.27, 131.63, 133.05, 133.50, 135.86, 144.33, 147.17.
1-(4-Methylphenyl)-2-(3-nitrophenyl)-4,5-diphenyl-1H-imidazole (6o) Yield 0.39 g, 90%; mp = 148–150 ºC. 1H
NMR (300 MHz, CDCl3): δ = 2.31 (3H, s, CH3), 6.87–7.39 (14H, m, 14 CH), 7.54 (1H, t, J 8.0 Hz, CH), 8.16 (1H, d, J
8.0 Hz, CH), 8.30 (1H, d, J 8.0 Hz, CH), 8.55 (1H, s, CH). 13C NMR (75 MHz, CDCl3): δ = 21.17, 122.67, 123.50,
127.00, 127.31, 127.96, 128.22, 128.85, 129.05, 131.01, 131.90, 132.27, 133.64, 134.37, 138.68, 139.12,
144.36, 147.98.
Acknowledgements
This study was supported by the Research Council of Tehran University of Medicinal Sciences (TUMS) and Iran National
Science Foundation (INSF).
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