An Efficient Synthesis of Substituted Imidazoles Catalyzed by 3-N-Morpholinopropanesulfonic Acid (MOPS) under Ultrasound Irradiation

Full text of DOI:10.1080/00304948.2020.1804773

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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An Efficient Synthesis of Substituted Imidazoles
Catalyzed by 3-N-Morpholinopropanesulfonic Acid
(MOPS) under Ultrasound Irradiation
Amol U. Khandebharad , Swapnil R. Sarda , Charansingh Gill & Brijmohan R.
Agrawal
To cite this article: Amol U. Khandebharad , Swapnil R. Sarda , Charansingh Gill & Brijmohan
R. Agrawal (2020): An Efficient Synthesis of Substituted Imidazoles Catalyzed by 3-N-
Morpholinopropanesulfonic Acid (MOPS) under Ultrasound Irradiation, Organic Preparations and
Procedures International, DOI: 10.1080/00304948.2020.1804773
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Published online: 26 Oct 2020.
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ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
https://doi.org/10.1080/00304948.2020.1804773
EXPERIMENTAL PAPER
An Efficient Synthesis of Substituted Imidazoles Catalyzed
by 3-N-Morpholinopropanesulfonic Acid (MOPS) under
Ultrasound Irradiation
Amol U. Khandebharada, Swapnil R. Sardaa, Charansingh Gillb, and
Brijmohan R. Agrawala
b
aDepartment of Chemistry, J. E. S. College, Jalna, India; Department of Chemistry, Dr. Babasaheb
Ambedkar Marathwada University, Aurangabad, India
ARTICLE HISTORY Received 19 July 2019; Accepted 20 April 2020
Imidazoles are a major class of five-membered, nitrogen-containing heterocyclic com-
pounds possessing a wide spectrum of biological and physical activities.1–5 Because of
its importance, numerous methods have been reported in the literature for the synthesis
of the imidazole moiety. For example, the synthesis of 1,2,4,5-tetraarylimidazoles is gen-
erally carried out by using 1,2-diphenylethanedione, an aromatic aldehyde and an amine
in the presence of ammonium acetate and a number of catalysts, reagents and sol-
vents.6–21 Following a recent trend in organic synthesis, considerable research activity
has centered on using catalysts with the sulfonic acid functionality.22–26 In view of this,
we sought to develop a new, mild, simple and nontoxic method for the preparation of
substituted imidazoles. We also tried to find a method that would replace lengthy heat-
ing with ultrasound and would be greener.27–30 In continuation of our research on
developing green methods and catalysts,31–32 we examined the activity of the readily
available and environmentally benign 3-(N-morpholino)propane sulfonic acid (MOPS)
as a catalyst for the one-pot four-component synthesis of 2,4,5-trisubstituted and
1,2,4,5-tetrasubstituted imidazole derivatives in aqueous ethanol under ultrasound
(Schemes 1 and 2).
In search of suitable reaction conditions, we chose the model reaction of 1,2-dipheny-
lethanedione, 4-hydroxy benzaldehyde and ammonium acetate in ethanol in the pres-
ence of a number of additives, as shown in Table 1. In the presence of MOPS it was
found that the desired product was formed in 85% yield in just 30 min.
To probe the role of the solvent, the model reaction was carried out with MOPS
under different solvent conditions. The studies in Table 2 showed that ethanol-water
(1:1 v/v) was the best choice of solvent for this transformation.
The model reaction was tested at different temperatures. The reaction at reflux tem-
perature gave a high yield of 90% in 20 min (Table 2). The reaction was also carried out
using different amounts of the catalyst and the results showed that 10 mol % of catalyst
was the best choice for completing the reaction in the ethanol-water (1:1) system. See
the Experimental section for details on catalyst recovery and re-cycling. After optimizing
the reaction conditions, the model reaction was also performed using ultrasonic
CONTACT Swapnil R. Sarda
srsarda1@rediff.com
Department of Chemistry, J. E. S. College, Jalna (MS), India
ß 2020 Taylor & Francis Group, LLC

2
A. U. KHANDEBHARAD ET AL.
Scheme 1. Synthesis of 2,4,5-tetrasubstituted imidazoles catalyzed by MOPS.
Scheme 2. Synthesis of 1,2,4,5-tetrasubstituted imidazoles catalyzed by MOPS.
irradiation. The reaction was found to proceed smoothly within a very short reaction
time and delivered the desired product in excellent yield (Tables 3 and 4).
In summary, we found that MOPS serves as an effective catalyst for the preparation
of imidazoles in high yields. Our method avoids the use of harsh reagents, and the use
of ultrasonic irradiation greatly shortens the over-all reaction time.
Experimental section
All reagents were obtained from Sigma Aldrich. The reaction was monitored on TLC
using pre-coated plates (silica gel on aluminum, Merck). Ethyl acetate and n-hexane
were used as eluting solvents. Chemicals used were SD Fine or Sigma Aldrich and used
without further purification. Melting points were measured in open glass capillaries and
1
are uncorrected. H NMR was recorded on a Varian 200 MHz instrument in CDCl3
using TMS as internal standard. All of the products were known compounds, character-
ized by comparison of their melting points with literature values in the references cited.
An Equitron ultrasonic cleaner (50 KHz and 170 W) was used for ultrasonication.
Synthesis of 2,4,5-Trisubstituted Imidazoles
General Procedure: 1,2-Diphenylethanedione (0.210 g, 1.00 mmol), aromatic aldehyde
(1.00 mmol), and ammonium acetate (0.308 g, 4.00 mmol) were dissolved in 10 mL of etha-
nol-water (1:1). Then 10 mol % of the MOPS was added to the reaction mixture and
heated at reflux with constant stirring for the appropriate time, as monitored by TLC. The
reaction mixture was cooled to room temperature and poured onto crushed ice to get the
solid product. This crude product was filtered and washed several times with water and
dried. Further purification was carried out by recrystallization from ethanol.
Procedure using ultrasound irradiation: The same reaction was carried out using
ultrasound irradiation. We used the Equitron ultrasonic cleaner with 50 KHz and 170
W power. The same stoichiometry of reactants was taken in a round bottom flask and

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
3
Table 1. Influence of different catalysts and solvents on the model reaction.
Entry
Catalyst
Solvent
Isolated yield (%)
Time (min)
1.
2.
3.
4.
5.
6.
7.
8.
–
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Methanol
Water
DMSO
DMF
Acetonitrile
20
55
50
65
68
80
85
78
65
48
40
42
60
90
80
75
300
120
120
90
60
60
30
60
90
120
120
100
120
20
30
45
Ferric sulfate
CuSO4
Sulfamic acid
Sulfinilic acid
Methane sulfonic acid
MOPS
MOPS
MOPS
MOPS
MOPS
MOPS
MOPS
MOPS
MOPS
9.
10.
11.
12.
13.
14.
15.
16.
PEG 400
Ethanol -Water (1:1)
Ethanol -Water (2:1)
Ethanol -Water (1:2)
MOPS
Reaction Conditions: 1,2-diphenylethanedione (1 mmol), 4-hydroxy benzaldehyde (1 mmol), NH4OAc (3 mmol), catalyst
(20 mol%), in solvent (10 mL) at reflux.
Table 2. The effect of temperature and catalyst concentration.a
Entry
Catalyst
Temperature (ꢀC)
Time(min)
Isolated yield (%)
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
MOPS (20%)
MOPS (20%)
MOPS (20%)
MOPS (20%)
MOPS (20%)
MOPS (15%)
MOPS (10%)
MOPS (5%)
Reflux
80
60
40
RT
Reflux
Reflux
Reflux
Reflux
Reflux
20
20
45
80
120
20
20
80
120
20
90
80
78
60
32
90
90
88
MOPS (3%)
70
MOPS (10%)b
90, 90, 88
aReaction Conditions: 1,2-diphenyl ethanedione (1 mmol), 4-hydroxy benzaldehyde (1 mmol), NH4OAc (3 mmol) and cata-
lyst in 10 mL of ethanol-water (1:1 v/v) at specified temperature.
bThe reaction was carried out on 50 mmol scale and catalyst was reused three times.
kept in the ultrasonic bath containing water at 40 ꢀC. The surface of the reaction mix-
ture was adjusted vertically to achieve the optimum position at the point at which the
maximum surface disturbance occurred. The reaction mixture was continuously soni-
cated (20 to 60 min.) for the appropriate time, as monitored by TLC. After completion
of the reaction, work-up and purification followed as above.
The catalyst was recovered from the aqueous filtrate by evaporating the water; the cata-
lyst was washed with acetone and then air dried and could be reused in subsequent cycles.
A similar method was applied for the synthesis of 1,2,4,5-tetrasubstituted-1H-imidazole
derivatives by the condensation of 1,2-diphenylethanedione, aromatic aldehydes, aromatic
amines and ammonium acetate. Representative spectrometric data are shown below.
2,4,5-Triphenyl-1H-imidazole (4b)
1H NMR (200 MHz, DMSO-d6): d 7.56–7.22 (m, 13H), 8.09 (d, J ¼ 7.8 Hz, 2H), 12.69
(s, 1H); 13C NMR (75 MHz, DMSO-d6): d 145.6, 137.2, 135.2, 131.2, 130.4, 128.7, 128.5,
128.3, 128.2, 127.8, 127.2, 126.6, 125.3; ESI MS (m/z): 297.3 (Mþþ1).

4
A. U. KHANDEBHARAD ET AL.
Table 3. Synthesis of 2-Aryl-4,5-Diphenyl-1H-Imidazoles.
With USa
Without USb
Mp
Entry
R1
4-OH
H
4-CH3
4-OCH3
4-N(CH3)2
4-NO2
4-Cl
Time (min)
Yieldc (%)
Time (min)
Yieldc(%)
Obs (lit)ref
4a
4b
4c
4d
4e
4f
15
20
30
20
15
30
20
90
84
84
90
92
85
90
20
40
50
30
25
40
30
90
80
86
86
88
82
85
264-266 (260-262)13
270-272 (274-276)13
228-230 (227-228)13
230-232 (228-230)12
260-262 (258-260)12
230-232 (229-231)12
258-260 (260-262)12
4g
aReaction conditions: 1,2-diphenyl ethanedione (1 mmol), aromatic aldehyde (1 mmol), NH4OAc (3 mmol), catalyst
(10 mol %), in 10 mL of ethanol-water (1:1) under ultrasonic waves.
bReaction conditions: 1,2-diphenyl ethanedione (1 mmol), aromatic aldehyde (1 mmol), ammonium acetate (3 mmol),
catalyst (10 mol %), in 10 mL of aqueous ethanol (1:1) at reflux.
cIsolated yield.
Table 4. Synthesis of 1,2,4,5-tetrasubstituted imidazole derivatives.
With USa
Without USb
mp
Entry
R1
R2
Time (min)
Yield (%)c
Time (min)
Yield (%)c
Obs (lit)ref
5a
5b
5c
5d
5e
5f
5g
5h
5i
4-CH3
4-Cl
4-Cl
4-OCH3
H
4-OH
4-N(CH3)2
4-CH3
H
4-Cl C6H4
4-Cl C6H4
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5 CH2
C6H5 CH2
C6H5 CH2
C6H5 CH2
20
25
20
25
30
10
25
20
25
20
30
20
88
94
90
92
92
90
90
90
92
94
90
90
50
30
40
45
40
20
40
60
55
45
40
40
80
82
85
76
84
90
88
85
88
80
90
80
170-172 (168-170)11
186-188 (188-190)11
162-164 (162-164)7
180-182 (179-181)7
216-218 (213-215)11
280-282 (283-285)7
256-258 (261-264)7
184-186 (183-184)11
162-164 (161-163)11
165-166 (162-163)21
132-134 (134-136)21
190-192 (190-192)12
5j
5k
5l
4-Cl
4-OH
4-CH3
aReaction conditions: 1,2-diphenylethanedione (1 mmol), aromatic aldehyde (1 mmol), aromatic amine (1 mmol), NH4OAc
(3 mmol), catalyst (10 mol %), in 10 mL of ethanol-water (1:1) under ultrasonic irradiation.
bReaction conditions: Reflux temperature.
cIsolated yield.
2-(4-Methoxyphenyl)-4,5-diphenyl-1H-imidazole (4d)
1H NMR (200 MHz, DMSO-d6): d 3.82 (s, 3H), 7.05 (d, J ¼ 8.4 Hz, 2H), 7.50–7.33 (m,
10H), 8.03 (d, J ¼ 8.1 Hz, 2H), 12.50 (s, 1H), 13C NMR (75 MHz, DMSO-d6): d
55.2,114.1,123.1,126.58,127.7, 128.4, 145.7, 159.5; ESI MS (m/z): 327.2 (Mþþ1).
1,2-bis(4-Chlorophenyl)-4,5-diphenyl-1H-imidazole (5b)
1H NMR (200MHz,CDCl3) d 6.93 (d,1H), 6.98(d,1H), 7.07 (d,1H), 7.11 (d,1H), 7.18-
7.37 (m,12H),7.51 (d,1H), 7.55(d,1H) ppm; 13C NMR (100MHz,CDCl3) d96.16, 126.94,
127.94, 128.27, 128.38, 128.55, 128.62, 129.51, 129.53, 130.10, 130.17, 130.79, 131.06,
133.71, 134.53, 134.59, 140.71, 145.61 ppm; ESI MS M/Z 441.2 (Mþ)
1,4,5-Triphenyl-2-p-tolyl-1H-imidazole (5h)
1H NMR (200 MHz, CDCl3): d 2.30 (s, 3H) 7.31–7.02 (m, 17H), 7.60 (d, J ¼ 7.2 Hz,
2H); 13C NMR (75 MHz, CDCl3): d 147.1, 138.1, 137.2, 134.5, 131.1, 130.7, 130.6, 128.9,
128.8, 128.4, 128.2, 128.1, 127.8, 127.6, 127.4, 126.5, 21.3; ESI MS (m/z): 387.3 (Mþþ1).

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
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Acknowledgment
We are thankful to Dr. J. D. Kabra, Principal, J. E. S. College Jalna, for providing laboratory
facilities and for his kind support in the completion of this work.
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