Urea-Zinc Chloride Eutectic Mixture-Mediated One-Pot Synthesis of Imidazoles: Efficient and Ecofriendly Access to Trifenagrel

Article abstract of DOI:10.1055/s-0037-1610679

The low-melting mixture urea-ZnCl ₂ was evaluated as a novel reaction medium for the synthesis of imidazoles. The reaction between a dicarbonyl compound, ammonium acetate, and an aromatic aldehyde is efficiently catalyzed by the eutectic solvent, yielding a wide variety of triaryl-1 H -imidazoles or 2-aryl-1 H -phenanthro[9,10- d ]imidazoles in good to excellent yields. In addition, the eutectic solvent was reused in five cycles without loss of its catalytic activity. This protocol was further explored for the synthesis of the drug trifenagrel, giving an excellent yield.

Full text of DOI:10.1055/s-0037-1610679

SYNLETT
0
9
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6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
letter
A
en
N. L. Higuera et al.
Letter
Synlett
Urea–Zinc Chloride Eutectic Mixture-Mediated One-Pot Synthesis
of Imidazoles: Efficient and Ecofriendly Access to Trifenagrel
Natalia López Higuera
Diana Peña-Solórzano
N
Cristian Ochoa-Puentes*
ArCHO
O
O
N
urea/ZnCl2
Ar
N
+
Laboratorio de Síntesis Orgánica Sostenible, Departamento de
Química, Universidad Nacional de Colombia–Sede Bogotá, Car-
rera 45 # 26-85, A.A 5997, Bogotá, Colombia
cochoapu@unal.edu.co
H
N
H
110 °C, 30 min
O
NMe2
NH4OAc
Trifenagrel
92% yield
25 examples
75–100% yield
Low cost and easy preparation of the
deep eutectic solvent (DES)
Reusabilty of DES up to 4 cycles
Easy reaction setup and workup
Received: 26.09.2018
Accepted after revision: 19.11.2018
Published online: 19.12.2018
or N-propargylamines20 with several substrates; the cata-
lytic derivatization of imidazole rings, for example by C–H
activation,21 metal-catalyzed N-arylation,22 or cross-cou-
pling reactions;23 and the catalytic formation of imidazole
cores24 have been reported as methods for obtaining this
heterocycle. However, the cyclocondensation of 1,2-dike-
tones with amines and aldehydes (the Debus–Radziszewski
reaction) in a one-pot multicomponent process remains a
versatile, efficient, and economical method that permits the
synthesis of a diverse range of substituted derivatives.
Therefore, many efforts have been devoted to attaining high
yields of pure products by this method in short reaction
times by employing various homogeneous and heteroge-
neous catalysts,25 solvents,26 ultrasound,27 or microwave ir-
radiation.28
DOI: 10.1055/s-0037-1610679; Art ID: st-2018-k0618-l
Abstract The low-melting mixture urea–ZnCl2 was evaluated as a nov-
el reaction medium for the synthesis of imidazoles. The reaction be-
tween a dicarbonyl compound, ammonium acetate, and an aromatic
aldehyde is efficiently catalyzed by the eutectic solvent, yielding a wide
variety of triaryl-1H-imidazoles or 2-aryl-1H-phenanthro[9,10-d]imidaz-
oles in good to excellent yields. In addition, the eutectic solvent was re-
used in five cycles without loss of its catalytic activity. This protocol was
further explored for the synthesis of the drug trifenagrel, giving an ex-
cellent yield.
Key words imidazoles, deep eutectic solvent, multicomponent reac-
tion, trifenagrel, phenanthroimidazoles
In recent decades, naturally occurring imidazoles and
their synthetic derivatives have drawn much interest due to
their chemical, physicochemical, and pharmaceutical prop-
erties. Several derivatives possess such biological activities
as antiallergic,1 antiinflammatory,2 antinociceptive,2 antitu-
mor,3 antibacterial,4 antiviral,5 or analgesic properties,6
whereas others act as inhibitors of p38 MAP kinase,7 as glu-
cagon receptors,8 and as multidrug-resistant modulators.9
Furthermore, imidazole derivatives have been also used in
the preparation of ionic liquids,10 and their carbenes have
found practical use as ligands in coordination chemistry
and are versatile catalysts.11 In addition, the optoelectronic
properties of some compounds have prompted their use in
materials chemistry for the development of blue-light-
emitting materials, fluorescence labeling agents,12 and che-
mosensors.13
The introduction of eutectic mixtures in various chemi-
cal processes has intensified interest in finding new appli-
cations for these versatile solvents. A deep eutectic solvent
(DES) is defined as a mixture of two or more components
that are capable of self-association through hydrogen-bond
interactions, which result a large melting-point depression
at a particular composition (the eutectic composition).29
Depending on its composition, a DES can be classified as
one of four types. The first type is formed by combining a
metal salt and an organic salt (e.g., ZnCl2 and choline chlo-
ride). The second is obtained from a metal salt hydrate and
an organic salt (e.g., CoCl2·6H2O and choline chloride). The
third is prepared from a hydrogen-bond donor and an or-
ganic salt (e.g., urea and choline chloride). Finally, the
fourth type is obtained from a metal chloride and a hydro-
gen-bond donor (e.g., ZnCl2 and acetamide).30,31 The eutec-
tic mixture urea–ZnCl2, first reported by Abbott et al.,31 is a
DES of the fourth type, and its lowest freezing temperature
(Tf = 9 °C) occurs at a urea–ZnCl2 molar ratio of 3.5:1 (the
eutectic composition). Although its physical properties are
similar to those of an ionic liquid, only scarce information is
Due to the wide range of applications of substituted im-
idazoles, numerous and well-established methods for their
synthesis can be found in the literature, including the reac-
tions of Van Leusen,14 Debus,15 Marckwald,16 Wallach,17 and
Radziszewski.18 More recently, the reactions of amidines19
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

B
N. L. Higuera et al.
Letter
Synlett
found in the literature regarding its uses, which include the
electrodeposition of Zn–Ti alloys,32 lignin modification,33
the preparation of bis(indolyl)methanes,34 and the electro-
chemical fabrication of nanoporous gold electrodes.35
The remarkable importance of imidazoles together with
the growing use of DESs in organic synthesis prompted us
to develop a sustainable methodology for the synthesis of
valuable organic compounds, and here we report the syn-
thesis of imidazole derivatives by employing the urea–ZnCl2
DES as an efficient, ecofriendly, and recyclable reaction me-
dium.
Recently, we reported that the DES formed from sodium
acetate trihydrate and urea is an effective source of ammo-
nia for the synthesis of hexahydroacridine-1,8-diones when
the reaction is performed at temperatures above 90 °C.36
With this in mind, we decided to study the Debus–
Radziszewski reaction for the preparation of 2,4,5-triaryl-
1H-imidazoles and, for our initial test reaction, we chose
the synthesis of lophine (3a; 2,4,5-triphenyl-1H-imidazole)
from a mixture of benzil (1) and benzaldehyde (2) in an eu-
tectic mixture of sodium acetate trihydrate and urea (Table
1, entry 1). Under the reaction conditions employed, 3a was
obtained in 91% yield after 90 minutes. Although this result
was promising, we decided to evaluate this multicompo-
nent reaction in other eutectic solvents based in choline
chloride (ChCl) (entries 2–6). Solvents composed of ChCl
and carboxylic acids afforded the product in 78–83% yield,
whereas ChCl–glycerol and ChCl–urea mixtures gave poor
yields (entries 5 and 6). Interestingly, when the reaction
was performed at the same temperature in the urea–ZnCl2
DES, 3a was obtained in an excellent yield of 99% after 30
minutes (entry 7). A decrease in temperature or the use of
ZnCl2 as a catalyst gave lower yields (entries 8–10), and in
the absence of the DES, only a 20% yield of the product was
obtained (entry 11). Note that other DESs have also been
used for the synthesis of lophine (entries 12–15);37 howev-
er, the our method is superior in terms of the reaction time
and the yield.
Table 1 Optimization of Reaction Conditions for the Synthesis of Lo-
phine (3a) in Deep Eutectic Solvents
Ph
Ph
O
O
N
AcONa⋅3H2O/urea
PhCHO
+
N
H
1
2
3a
DES
PhCHO
Ph
Ph
O
2
+
O
NH4OAc
1
Entry DES
Temp (°C)
Time (min)
Yield (%)
1
NaOAc·3H2O–ureaa
ChCl–malonic acidb
ChCl–succinic acidb
ChCl–citric acidb
ChCl–glycerolb
100
110
110
110
110
110
110
60
90
90
90
90
90
90
30
30
30
30
30
60
25
60
120
91d
83d
78d
80d
45d
27d
99d
70d
85d
55d
20d
90e
90e
80e
95e
2
3
4
5
6
ChCl–ureab
b
7
urea–ZnCl2
b
8
urea–ZnCl2
b
9
urea–ZnCl2
80
c
10
11
12
13
14
15
ZnCl2
110
110
110
100
100
78
–
ChCl–oxalic acid
DMU–citric acid
ChCl–ZnCl2
ChCl–TsOH in EtOH
a Reaction conditions: 1 (1 mmol), 2 (1 mmol), DES (1.2 g).
b Reaction conditions: 1 (1 mmol), 2 (1 mmol), NH4OAc (2 mmol), DES (0.8 g).
c The same amount of ZnCl2 as in entry 7 was used.
d Isolated yield.
e Reported yield.
Having optimized the reaction conditions, we evaluated
the versatility of the DES in the synthesis of trisubstituted
imidazoles from various aromatic aldehydes (Scheme 1).
As can be seen in Scheme 1, compounds 3a–p were ob-
tained in yields of 75–100%, with ortho-substituted alde-
hydes affording slightly lower yields of compounds 3f, 3g,
and 3k, presumably due to steric hindrance. This protocol
showed good substrate compatibility for aromatic alde-
hydes: aldehydes bearing electron-withdrawing groups
(chloro, bromo, or nitro) or electron-donating groups (me-
thoxy, hydroxy, dimethylamino, methylenedioxy, and iso-
propyl) gave the corresponding products in high yields.
Inspired by these results, we then applied this protocol
to the synthesis of 2-aryl-1H-phenanthro[9,10-d]imidaz-
oles from phenanthrene-9,10-dione (Scheme 1). The fused
imidazoles 3q–y were obtained in yields of 91–99%, indicat-
ing that this method is equally effective for both acyclic and
cyclic ketones.
A plausible mechanism for the synthesis of imidazole
derivatives is presented in Scheme 2. In the first step, the
diamine intermediate A is formed by nucleophilic attack of
the nitrogen atoms of ammonia, formed from NH4OAc, on
the carbonyl group of the aldehyde,39 which is activated by
the DES. Subsequent condensation of diamine A with the
1,2-diketone followed by dehydration and rearrangement of
the imino intermediate B gives the desired product. The ac-
tion of ZnCl2 (or Zn clusters) presented in the DES31 as a
Lewis acid activates the carbonyl groups, thereby increasing
the rate of production of intermediates A and B.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

C
N. L. Higuera et al.
Letter
Synlett
ArCHO
ArCHO
O
O
Ph
Ph
O
O
N
urea/ZnCl2
urea/ZnCl2
Ar
+
+
N
H
110 °C, 30 min
110 °C, 30 min
NH4OAc
NH4OAc
OMe
OMe
OMe
N
N
N
NO2
N
H
N
H
N
H
3a, 99%
3b, 100%
3c, 96%
Cl
N
N
N
Br
Cl
N
H
N
H
N
H
3d, 99%
3e, 82%
3f, 76%
O2N
OEt
OH
N
N
N
N(Me)2
N
H
N
H
N
H
3g, 75%
3h, 99%
3i, 98%
Cl
N
N
N
OH
N
H
N
N
H
H
Cl
3j, 89%
3k, 81%
3l, 91%
OMe
OH
N
N
N
N
O
N
H
N
H
N
H
N
H
O
OMe
3m, 98%
3n, 81%
3o, 91%
OMe
OMe
OMe
N
N
N
N
H
N
H
N
H
3p, 94%
3q, 98%
3r, 98%
N
N
N
NO2
Br
Cl
N
H
N
H
N
H
3s, 94%
3t, 98%
3u, 98%
OEt
N
N
N
N
OH
N(Me)2
OH
O
N
H
N
H
N
H
N
H
O
3y, 93%
3v, 99%
3w, 93%
3x, 91%
Scheme 1 Multicomponent syntheses of 2,4,5-triaryl-1H-Imidazoles 3a–p and 2-aryl-1H-phenanthro[9,10-d]imidazoles 3q–y in the urea–ZnCl2 DES38
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

D
N. L. Higuera et al.
Letter
Synlett
er imidazoles. Moreover, its operationally simple proce-
dures, combined with its use of a reusable DES as a solvent
and catalyst, together with its high yields, short reaction
times, and simple and convenient separation and purifica-
tion processes, make this method economically efficient
and environmentally benign.
In summary, we have developed an efficient and mild
procedure for the synthesis of 2,4,5-triaryl-1H-imidazoles
and 2-aryl-1H-phenanthro[9,10-d]imidazoles in the pres-
ence of the urea–ZnCl2 DES as an inexpensive, efficient,
ecofriendly, and reusable reaction medium. All compounds
were obtained in good to excellent yields in short reaction
times under mild reaction conditions. In addition, the DES
could be easily recycled and reused in at least five consecu-
tive runs without significant loss of its catalytic activity.
Further, this methodology was applied in a rapid and high-
yielding efficient synthesis of the drug trifenagrel.
Urea/ZnCl2
2 NH3
2 NH4OAc
O
Ar
H
– H2O
Ar
(A)
Urea/ZnCl2
H2N
NH2
Urea/ZnCl2
Ph
Ph
O
– 2H2O
Ph
Ph
N
Ar
Ph
Ph
H
O
N
N
N
H
Ar
Urea/ZnCl2
(B)
Scheme 2 Proposed mechanism for the synthesis of substituted imid-
azoles by using the urea–ZnCl2 DES
The reusability and recovery of reaction media are im-
portant issues, especially when their environmental impact
is considered. Therefore, in our next step, we investigated
the reusability of the DES in the model reaction and, for this
purpose, after completion of the reaction, the mixture was
washed with distilled water, and the crude product was
separated by filtration. The DES was recovered from the fil-
trate by lyophilization then recharged with fresh reactants
for a subsequent run. This process was repeated four times,
giving the target compound in yields of 94, 93, 89, and 84%,
respectively. These results show that the DES can be reused
in up to five consecutive runs without a significant detri-
mental effect on its catalytic activity.
Funding Information
The authors wish to thank COLCIENCIAS (grant no. FP44842-155-
2018) and Dirección Nacional de Investigaciones-Universidad Nacion-
al de Colombia for funding this research.()
Acknowledgment
We thank the Universidad Nacional de Colombia and Professor Hum-
berto Zamora for providing instrumental and infrastructure facilities.
Supporting Information
To further expand our method toward the synthesis of
biologically active compounds, we turned our attention to
the synthesis of the drug trifenagrel under our optimized
reaction conditions (Scheme 3). Trifenagrel is a potent ara-
chidonate cyclooxygenase inhibitor that reduces platelet ag-
gregation in several animal species, including humans.40
We began our synthesis by alkylating the phenolic hydroxy
group of salicylaldehyde with 1,2-dibromoethane, and then
aminating the terminal bromo group with dimethylamine
to obtain the desired starting aldehyde; this reacted with
benzil and ammonium acetate to give the required drug in
92% yield. These results clearly show that our synthetic
method is comparable to or more effective than other re-
ported methods for the synthesis of trifenagrel28,41 and oth-
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610679.
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References and Notes
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O
O
Br
Br
1.
O
H
Ph
Ph
O
H
K2CO3, ACN
reflux, 12 h
N
urea/ZnCl2
+
O
OH
2. NHMe2, MeOH
rt, 48 h
110 °C, 30 min
92%
N
H
NH4OAc
NMe2
O
NMe2
Trifenagrel
Scheme 3 Synthesis of trifenagrel in the urea–ZnCl2 DES
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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N. L. Higuera et al.
Letter
Synlett
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(38) Imidazoles 3a–y; General Procedure
Urea–ZnCl2 DES (3.5:1; 0.8 g) was heated to 70 °C to form a clear
melt. To this melt was added a mixture of the appropriate dicar-
bonyl compound (1 mmol), aryl aldehyde (1 mmol), and
NH4OAc (2 mmol), and the mixture was stirred at 110 °C for 30
min. When the reaction was complete (TLC), the reaction was
quenched by adding H2O to the hot mixture, which was then
cooled to r.t. The crude solid was collected by filtration then
washed with H2O and EtOH (3 × 2 mL) to afford the pure prod-
uct.
2-(4-Nitrophenyl)-4,5-diphenyl-1H-imidazole (3c)
Yellow solid; yield: 327 mg (96%); mp 235–237 °C (Lit.42 237–
239 °C). IR (KBr): 3250, 1681, 856 cm–1 1H NMR (400 MHz,
.
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CDCl3):  = 8.29 (d, J = 8.9 Hz, 2 H, ArH), 8.10 (d, J = 8.7 Hz, 2 H,
ArH), 7.58–7.52 (m, 4 H, ArH), 7.40–7.32 (m, 6 H, ArH). 13C NMR
(100 MHz, CDCl3):  = 147.4, 143.4, 135.5, 134.9, 129.9, 129.0,
128.7, 127.8, 125.5, 124.3. MS: m/z = 341 [M+].
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N,N-Dimethyl-4-(1H-phenanthro[9,10-d]imidazol-2-yl)ani-
line (3w)
Green solid; yield: 313 mg (93%); mp 258–260 °C (Lit.43 257 °C).
IR (KBr): 3381, 1689, 821 cm–1 1H NMR (400 MHz, DMSO):
.
 = 8.91 (d, J = 8.1 Hz, 3 H, ArH), 8.66 (d, J = 8.1 Hz, 2 H, ArH),
8.21 (d, J = 9.0 Hz, 2 H, ArH), 7.82–7.79 (m, 3 H, ArH), 6.95 (d, J =
9.2 Hz, 2 H), 3.06 (s, 6 H, NMe2). 13C NMR (100 MHz, DMSO):
 = 154.8, 149.6, 149.0, 146.4, 142.1, 139.5, 133.5, 130.9, 129.6,
128.9, 128.3, 128.0, 127.2, 126.6, 124.8, 124.5, 123.6, 123.0,
122.5, 112.2, 109.2, 108.7, 40.5. MS: m/z = 337 [M+].
{2-[2-(4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)phenoxy]-
ethyl}dimethylamine (Trifenagrel)
Light-yellow solid; yield: 352 mg (92%); mp 133–135 °C. FTIR
(KBr): 3429, 2922, 1734, 1219, 1039 cm–1 1H NMR (400 MHz,
.
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48675.
DMSO):  = 8.20 (dd, J = 7.8, 1.7 Hz, 1 H, ArH), 7.74 (s, 1 H, ArH),
7.49 (d, J = 7.3 Hz, 4 H, ArH), 7.37 (t, J = 8.9 Hz, 3 H, ArH), 7.24 (d,
J = 8.2 Hz, 1 H, ArH), 7.12 (t, J = 7.5 Hz, 1 H, ArH), 7.06 (dd, J = 9.0,
3.4 Hz, 3 H, ArH), 4.28 (t, J = 5.2 Hz, 2 H, –OCH2), 2.64 (t, J = 4.8
Hz, 2 H, –CH2–N–), 1.90 (s, 6 H, NMe2). 13C NMR (100 MHz,
DMSO):  = 161.2, 155.4, 143.4, 138.6, 130.0, 128.9, 128.4,
127.8, 127.4, 122.2, 120.0, 115.0, 65.9, 57.8, 44.4. MS: m/z = 383
[M+].
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