Novel synthesis of 1-substituted-4-imidazolecarboxylates via solvent-free cycloaddition reaction between formamidines and isocyanides

Article abstract of DOI:10.1016/j.tet.2020.131205

A simple and efficient protocol for cyclization between formamidines and ethyl isocyanoacetate has been described in the absence of metal catalyst and solvent. A series of 1-substituted-4-imidazolecarboxylates were synthesized in moderate to good yields with DABCO as base additive.

Full text of DOI:10.1016/j.tet.2020.131205

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Novel synthesis of 1-substituted-4-imidazolecarboxylates via solvent-free
cycloaddition reaction between formamidines and isocyanides
Han Cao, Fu-sheng Bie, Xue-jing Liu, Ying Han, Jie Ma, Yi-jun Shi, Peng Yan, Chao-
yue Sun, Hai-meng Wang
PII:
S0040-4020(20)30340-9
https://doi.org/10.1016/j.tet.2020.131205
TET 131205
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 2 January 2020
Revised Date: 26 March 2020
Accepted Date: 13 April 2020
Please cite this article as: Cao H, Bie F-s, Liu X-j, Han Y, Ma J, Shi Y-j, Yan P, Sun C-y, Wang H-m,
Novel synthesis of 1-substituted-4-imidazolecarboxylates via solvent-free cycloaddition reaction between
formamidines and isocyanides, Tetrahedron (2020), doi: https://doi.org/10.1016/j.tet.2020.131205.
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Novel synthesis of 1-substituted-4-
imidazolecarboxylates via solvent-free
cycloaddition reaction between
formamidines and isocyanides
Leave this area blank for abstract info.
Han Cao,* Fu-sheng Bie,* Xue-jing Liu, Ying Han, Jie Ma, Yi-jun Shi, Peng Yan, Chao-yue Sun, Hai-meng
Wang
Engineering and Technology Research Institute of Lunan Coal Chemical, College of Chemistry, Chemical
Engineering and Materials Science, Zaozhuang University, 1 Beian Road, Zaozhuang 277160, Shandong
Province, P. R. China

1
Tetrahedron
journal homepage: www.elsevier.com
Novel synthesis of 1-substituted-4-imidazolecarboxylates via solvent-free
cycloaddition reaction between formamidines and isocyanides
Han Cao,* Fu-sheng Bie,* Xue-jing Liu, Ying Han, Jie Ma, Yi-jun Shi, Peng Yan, Chao-yue Sun, Hai-
meng Wang
Engineering and Technology Research Institute of Lunan Coal Chemical, College of Chemistry, Chemical Engineering and Materials Science, Zaozhuang
University, 1 Beian Road, Zaozhuang 277160, Shandong Province, P. R. China
*E-mail: hcao@uzz.edu.cn; fsbie@uzz.edu.cn
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple and efficient protocol for cyclization between formamidines and ethyl isocyanoacetate
has been described in the absence of metal catalyst and solvent. A series of 1-substituted-4-
imidazolecarboxylates were synthesized in moderate to good yields with DABCO as base
additive.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
4-Imidazolecarboxylates
Ethyl isocyanoacetate,
Formamidines
Microwave synthesis
Solvent free
Cycloaddition
1. Introduction
organic synthesis have been proved to perform well in
solvent-free conditions.[4]
Figure
1
.
Examples of biologically active 4-
imidazolecarboxylates
4-imidazolecarboxylate, as the precursor of 4-
imidazolecarboxamide, is a structural motif in numerous
biologically active pharmacophores, as reported in the
literature studies.[5] A particular example is 1-substituted-4-
imidazolecarboxylates which get coupled with various
amines to 1-substituted-4-imidazolecarboxamide, such as
ADA Inhibitor (FR221647)[6], SCD-1 inhibitors (Ⅰ)[7], CB2
receptor antagonists (Ⅱ)[8], mGlu2 receptors (THIIC)[9], etc.
Although several synthetic routes using isocyanoacetates
have been known[10-13]
,
however, two representative
approaches have been highlighted for the synthesis of the
imidazole rings. Hela et al. described 1-alkyl-4-
imidazolecarboxylates resulting from the reaction of anilines
with ethyl 3-N, N-(dimethylamino)-2-isocyanoacrylate
obtained by ethyl isocyanoacetate reacting with Bredereck’s
reagent.[11] However, the preparation of ethyl 3-N, N-
(dimethylamino)-2-isocyanoacrylate is complex, and the
yield is not excellent. Especially, on using aniline to prepare
ethyl 1-phenyl-4-imidazolecarboxylate, a long reaction time
is required, and the yield is modest (Scheme 1a). Yamamoto
and co-workers have described an efficient synthetic
procedure via cross-cycloaddition using copper (I) oxide as
catalyst and 1,10-phenanthroline as ligand between two
different isocyanides (Scheme 1b).[12] Roy et al. developed
this approach a step further.[13] Moreover, isocyanides
Formamidines are the important intermediates for the
synthesis of heterocycles.[1] As a result, three categories of
methods have been developed to prepare variously
，Besson and co-workers have
reported a method for the rapid preparation of N-(2-cyano-4-
nitrophenyl)-N, N-dimethylimidoformamide by microwave
formamidines.[2] Interestingly
irradiation,
yet
only
5-nitroanthranilonitrile
and
anthranilonitrile have been reported as amine source.[3]
Solvent-free reaction strategies have evolved as a green and
sustainable approach in recent decades. Formamidines in

2
Tetrahedron
1a
1b
1c
resulted from dehydration of formamides, and proline was
1
2
3
2-Br, n=0
H,n=0
85
94
96
used as ligand to decrease the reaction temperature without
reduced yields. However, the solvent-free reaction between
formamidines and isocyanides has not yet been reported.
4-NO2,n=0
1d
4
4-F, n=0
99
97
96
99
96
91
95
94
87
85
91
92
Scheme
imidazolecarboxylates
1
.
The synthesis of 1-substituted-4-
1e
1f
5
4-Cl, n=0
4-I, n=0
6
1g
1h
1i
7
4-CH3, n=0
4-OCH3, n=0
2-OCH3, n=0
3-OCH3, n=0
H, n=1
8
9
1j
10
11
12
13
14
15
1k
1l
4-Cl, n=1
4-CH3, n=1
4-CN, n=1
H, n=2
1m
1n
1o
a
The mixture of amine (1.0 mmol), DMF-DMA (1.1 mmol) was
stirred at 80 using 10-25min of irradiation(150 W). b Isolated yield.
In this communication, we report the first ever synthesis
of 1-substituted-4-imidazolecarboxylates using ethyl
isocyanoacetate and corresponding formamidines, which, in
turn, are prepared by the microwave synthesis of a variety of
substituted aromatic and benzylic amines or phenethylamine
with DMF-dimethylacetal (Scheme 1c).
N, N-dimethyl-N'-phenylformimidamide (1b) and ethyl
isocyanoacetate were chosen as the model reaction to find
the optimal reaction conditions. Twelve reactions were run
and the results are summarized in Table 2.
Table 2. Optimization of the reaction conditions
2.Results and discussion
As part of our ongoing efforts towards the application of
formamidines for the synthesis of 1-substituted-4-
imidazolecarboxylates, we carried out the reaction of amines
with DMF-DMA in solvent-free conditions by microwave
irradiation. After optimization of the reaction conditions by
varying the reaction time and temperature, we were able to
obtain formamidines 1 at 80 and 150W in 10-25 minutes,
with 85-99% yield (Table 1).
Yield (%)
Entry
Base (equiv.)
Solvent
3
a,b,c,d
1
2
-
-
-
3b
3b
23a,c
ethanol
N.Rb,c
Table 1. Microwave-assisted synthesis of formamidines 1a
3
-
butyl alcohol
DMF
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
traceb,c
N.Rb,c
69a,c
4
-
5
Et3N (1.0)
DBU (1.0)
TEMED (1.0)
DMAP (1.0)
DABCO (1.0)
DABCO (1.0)
DABCO (0.5)
DABCO (1.5)
-
-
yield (%)b
6
12b,c
Entry
R, n
1
-
-
-
-
7
59a,c
8
10b,c
9
87a,c
10
11
12
59a,d
51a,c
87 a,c
a Isolated yield. bBased on HPLC analysis. c Oil bath heating process. d
Microwave heating process.
The product 3b was obtained in 23% yield without base
and solvent at 110 for 24 h (Table 2, entry 1). No or trace
desired product 3b was observed with ethanol or N, N-
dimethylformamide (DMF) or butyl alcohol as solvent at
reflux temperature for 24 h (entry 2, 4, 3). These results led

3
a Reaction condition: formamidines (1.0 mmol), ethyl isocyanoacetate
to the choice of the solvent-free strategy due to the
environmental benefits of solvent-free reactions. Et3N (1.0
equiv.) has been examined as base which significantly
improved the yield of 3b (Table 2, entries 5). Different
bases, such as DBU, TEMED, DMAP and DABCO (Table
2, entries 6−9) were screened, and the results show that
DABCO was the best choice with the yield of 3b reaching
87%. It was found that decreasing the amount of DABCO to
0.5 equiv. could reduce the yield of 3b to 51% (entry 11);
while increasing the amount of DABCO to 1.5 equiv. did
not further improve the yield of 3b (entry 12). (The structure
has been confirmed by X-ray crystallographic analysis; see
the Supporting Information (ESI).)
(0.113 g, 1.0 mmol) under oil bath at 110 with DABCO (0.112 g, 1.0 mmol)
for 14h-24h. b Isolated yields.
To improve the utility of this protocol, a one-pot process
was performed using aniline as the starting material; it was
found that the reactions provided 3b in 10-12% yield, which
were not good whether adding DABCO or not (Scheme 2a).
In addition, the two-component reaction by adding DMF-
DMA (1.0 eq.) or aniline (1.0 eq.) or additive free was used
as a control experiment under the same conditions,
producing 3b in 7-23% yield (Scheme 2b; table 2, entry 1).
The results suggest that DMF-DMA has an inhibitory effect
on the reaction, and the two-component reaction of
formamidine and ethyl isocyanoacetate is noted to be better.
In order to improve the reaction efficiency, we compared
the conventional heating process with the microwave
heating process. The microwave heating failed to reduce the
reaction time, the yield declined to 59% (Table 2, entry 10).
With the established optimal conditions, we explored the
substrate scope by testing various formamidines (1a-o) for
the synthesis of 1-substituted-4-imidazolecarboxylates
(Table 3).
Scheme 2. One-pot experiments a, b
Table 3. Scope of 1-substituted-4-imidazolecarboxylatesa,b
aStandard conditions: 1b (1.0 mmol), 2 (1.0 mmol), DABCO (1.0 mmol),
solvent-free, 110 . bIsolated yield.
Conclusions
In conclusion, we have developed a new strategy for
synthesizing 1-substituted-4-imidazolecarboxylates from
formamidines and ethyl isocyanoacetate under solvent-free
conditions. The process consists of two steps, the step one
contains the rapid microwave-assisted preparation of
formamidines and the step two results in cyclization to 1-
substituted-4-imidazolecarboxylates in the absence of any
metal catalyst. The new methodology is applied for the first
time towards the preparation of 1-substituted-4-
imidazolecarboxylates using formamidines, thus, confirming
formamidines as useful building blocks for organic
synthesis.
3.Experimental
General Information
All reagents and solvents were obtained from commercial
suppliers and used without further purification. All reagents
were weighed and handled in air at room temperature.
Experimental microwave irradiation was carried out in a
microwave single-mode reactor (Biotage, Initiator+).
Melting points were recorded on a INESA (SGWX-4B)
1
microscopic melting apparatus and uncorrected. H NMR
spectra were recorded on 400 MHz and 13C NMR spectra
were recorded on 125 MHz by using a Bruker Avance 400
spectrometer. Chemical shifts were reported in parts per
million (δ) relative to tetramethylsilane (TMS). HRMS data
were recorded on Agilent 6530 Accurate-Mass Q-TOF
LCMS spectrometer by ESI in positive mode. The X-ray
single-crystal diffraction was performed on an Agilent
Supernova CCD diffractometer instrument.

4
Tetrahedron
General procedure for the preparation of formamidines
1a-o
d) δ 153.36, 149.62, 131.73, 129.62, 120.98, 40.15, 34.54,
：
20.79; ESI-MS (m/z): Calcd for C10H15N2 [(M + H)+]
163.1235, Found 163.1236.
Amine (10.0mmol) and DMF-dimethylaceta (11.0mmol)
was transferred into the microwave vessels, these vessels
were capped inside the synthesizer and transferred to the
autosampler of the Biotage Initiator Sixty and heated to 80℃
at 150W for 10-25 minutes. These products were dried by
vacuum and identified by NMR and HRMS, being in good
agreement with the assigned structures.
N'-(4-methoxyphenyl)-N,N-dimethylformimidamide (1h)
Light brown oil; yield: 96%; 1H NMR (400 MHz,
Chloroform-d) δ 7.43 (s, 1H), 6.86 (dd, J = 8.8, 2.2 Hz, 2H),
6.81 – 6.75 (m, 2H), 3.72 (s, 3H), 2.93 (s, 6H); 13C NMR
(101 MHz, Chloroform-d) δ 155.43, 153.14, 145.60, 121.74,
114.29, 55.46, 40.01, 34.53; ESI-MS (m/z): Calcd for
C10H15N2O [(M + H)+] 179.1184, Found 179.1195.
Data for the formamidines 1a-o products:
N'-(2-bromophenyl)-N,N-dimethylformimidamide (1a)
N'-(2-methoxyphenyl)-N,N-dimethylformimidamide (1i)
1
Light brown oil; yield: 85%; 1H NMR (400 MHz,
Chloroform-d) δ 7.52 (dd, J = 7.8, 1.5 Hz, 1H), 7.42 (s, 1H),
7.17 (td, J = 7.6, 1.5 Hz, 1H), 6.89 – 6.80 (m, 2H), 3.04 (d, J
= 15.4 Hz, 6H).; 13C NMR (101 MHz, Chloroform-d) δ
153.46, 150.08, 132.82, 128.17, 123.57, 121.06, 118.78,
40.29, 34.60; ESI-MS (m/z): Calcd for C9H12BrN2 [(M +
H)+] 227.0184, Found 227.0195.
Brown oil; yield: 91%; H NMR (400 MHz, Chloroform-d)
δ 7.48 (s, 1H), 6.96 (ddd, J = 9.6, 4.8, 1.9 Hz, 1H), 6.84 (td,
J = 7.5, 1.5 Hz, 2H), 6.78 (dd, J = 7.5, 1.9 Hz, 1H), 3.81 (s,
3H), 2.99 (s, 6H); 13C NMR (101 MHz, Chloroform-d) δ
153.80, 152.45, 141.66, 123.06, 121.14, 120.97, 110.93,
55.71, 40.20, 34.51; ESI-MS (m/z): Calcd for C10H15N2O
[(M + H)+] 179.1184, Found 179.1194.
N,N-dimethyl-N'-phenylformimidamide (1b)
N'-(3-methoxyphenyl)-N,N-dimethylformimidamide (1j)
1
Light brown oil; yield: 94%; 1H NMR (400 MHz,
Chloroform-d) δ 7.40 (s, 1H), 7.20 – 7.12 (m, 2H), 6.91 (td,
J = 7.3, 1.2 Hz, 1H), 6.87 (dd, J = 8.4, 1.3 Hz, 2H), 2.89 (s,
6H); 13C NMR (101 MHz, Chloroform-d) δ 153.48, 152.15,
129.02, 122.44, 121.24, 40.03, 34.67; ESI-MS (m/z): Calcd
for C9H13N2 [(M + H)+] 149.1079, Found 149.1086.
Brown oil; yield: 95%; H NMR (400 MHz, Chloroform-d)
δ 7.52 (d, J = 1.9 Hz, 1H), 7.18 – 7.10 (m, 1H), 6.61 – 6.50
(m, 3H), 3.81 – 3.75 (m, 3H), 3.00 (d, J = 2.5 Hz, 6H); 13C
NMR (101 MHz, Chloroform-d) δ 160.38, 153.61, 153.53,
129.63, 113.37, 108.47, 106.89, 55.19, 40.22, 34.51; ESI-
MS (m/z): Calcd for C10H15N2O [(M + H)+] 179.1184,
Found 179.1194.
N,N-dimethyl-N'-(4-nitrophenyl)formimidamide (1c)
N'-benzyl-N,N-dimethylformimidamide (1k)
1
Yellow solid; yield: 96%; mp 73-74 °C; H NMR (400
Pale yellow oil; yield: 94%; 1H NMR (400 MHz,
Chloroform-d) δ 7.30 (s, 1H), 7.24 – 7.17 (m, 4H), 7.11
(ddd, J = 8.6, 5.6, 2.5 Hz, 1H), 4.37 (s, 2H), 2.79 (s, 6H); 13C
NMR (101 MHz, Chloroform-d) δ 155.91, 142.35, 128.24,
127.43, 126.34, 59.56, 37.22; ESI-MS (m/z): Calcd for
C10H15N2 [(M + H)+] 163.1235, Found 163.1244.
MHz, Chloroform-d) δ 8.12 (dd, J = 9.1, 2.4 Hz, 2H), 7.60
(s, 1H), 6.98 (dd, J = 9.0, 1.9 Hz, 2H), 3.08 (d, J = 8.7 Hz,
6H); 13C NMR (101 MHz, Chloroform-d) δ 158.43, 153.93,
142.68, 125.26, 121.06, 40.59, 34.72; ESI-MS (m/z): Calcd
for C9H12N3O2 [(M + H)+] 194.0930, Found 194.0940.
N'-(4-fluorophenyl)-N,N-dimethylformimidamide (1d)
N'-(4-chlorobenzyl)-N,N-dimethylformimidamide (1l)
1
Pale brown solid; yield: 99%; mp 68-69 °C; H NMR (400
1
Pale yellow solid; yield: 87%; mp 96-97 °C; H NMR (400
MHz, Chloroform-d) δ 7.45 (s, 1H), 7.09 – 6.71 (m, 4H),
2.99 (d, J = 2.2 Hz, 6H); 13C NMR (101 MHz, Chloroform-
d) δ 160.25, 157.87, 153.49, 148.33, 121.99 (d, J = 8.0 Hz),
115.43 (d, J = 21.9 Hz), 40.16, 34.46; ESI-MS (m/z): Calcd
for C9H12FN2 [(M + H)+] 167.0985, Found 167.0987.
MHz, Chloroform-d) δ 7.35 (s, 1H), 7.26 – 7.17 (m, 4H),
4.39 (s, 2H), 2.86 (d, J = 3.7 Hz, 6H); 13C NMR (101 MHz,
Chloroform-d) δ 155.99, 140.93, 131.89, 128.72, 128.27,
58.83, 37.24; ESI-MS (m/z): Calcd for C10H14ClN2 [(M +
H)+] 197.0846, Found 197.0852.
N'-(4-chlorophenyl)-N,N-dimethylformimidamide (1e)
N,N-dimethyl-N'-(4-methylbenzyl)formimidamide (1m)
Pale yellow oil; yield: 97%; 1H NMR (400 MHz,
Chloroform-d) δ 7.41 (s, 1H), 7.15 (dt, J = 6.5, 2.3 Hz, 2H),
6.87 – 6.78 (m, 2H), 2.94 (s, 6H); 13C NMR (101 MHz,
Chloroform-d) δ 153.48, 150.79, 128.89, 127.29, 122.37,
40.19, 34.46; ESI-MS (m/z): Calcd for C9H12ClN2 [(M +
H)+] 183.0689, Found 183.0697.
1
White solid; yield: 85%; mp 79-80 °C; H NMR (400 MHz,
Chloroform-d) δ 7.38 (s, 1H), 7.19 (d, J = 7.8 Hz, 2H), 7.12
(d, J = 7.9 Hz, 2H), 4.43 (s, 2H), 2.87 (s, 6H), 2.33 (s, 3H);
13C NMR (101 MHz, Chloroform-d) δ 155.76, 139.36,
135.78, 128.96, 127.43, 59.35, 37.20, 21.13; ESI-MS (m/z):
Calcd for C11H17N2 [(M + H)+] 177.1392, Found 177.1390.
N'-(4-iodophenyl)-N,N-dimethylformimidamide (1f)
N'-(4-cyanobenzyl)-N,N-dimethylformimidamide (1n)
Pale brown oil; yield: 96%; 1H NMR (400 MHz,
Chloroform-d) δ 7.56 – 7.46 (m, 2H), 7.48 – 7.41 (m, 1H),
6.72 – 6.68 (m, 2H), 3.72 – 2.20 (m, 6H); 13C NMR (101
MHz, Chloroform-d) δ 153.47, 151.88, 137.84, 123.48,
85.45, 40.32, 34.55; ESI-MS (m/z): Calcd for C9H12IN2 [(M
+ H)+] 275.0045, Found 275.0053.
Pale brown oil; yield: 91%; 1H NMR (400 MHz,
Chloroform-d) δ 7.59 – 7.52 (m, 2H), 7.37 (d, J = 7.7 Hz,
3H), 4.47 (s, 2H), 2.88 (d, J = 1.9 Hz, 6H); 13C NMR (101
MHz, Chloroform-d) δ 156.33, 148.25, 132.03, 127.93,
119.32, 109.90, 59.08, 41.68, 35.54; ESI-MS (m/z): Calcd
for C11H14N3 [(M + H)+] 188.1188, Found 188.1193.
N,N-dimethyl-N'-(p-tolyl)formimidamide (1g)
N,N-dimethyl-N'-phenethylformimidamide (1o)
Pale yellow oil; yield: 92%; 1H NMR (400 MHz,
1
Yellow oil; yield: 99%; H NMR (400 MHz, Chloroform-d)
δ 7.49 (s, 1H), 7.07 (d, J = 8.2 Hz, 2H), 6.96 – 6.69 (m, 2H),
3.00 (s, 6H), 2.30 (s, 3H); 13C NMR (101 MHz, Chloroform-
Chloroform-d) δ 7.28 – 7.24 (m, 2H), 7.22 – 7.16 (m, 3H),

5
7.15 (s, 1H), 3.51 – 3.42 (m, 2H), 2.83 – 2.76 (m, 8H); 13C
NMR (101 MHz, Chloroform-d) δ 155.34, 140.75, 129.07,
128.19, 125.82, 58.21, 39.66, 37.14; ESI-MS (m/z): Calcd
for C11H17N2 [(M + H)+] 177.1392, Found 177.1393.
1.58 – 1.16 (m, 3H); 13C NMR (101 MHz, Chloroform-d) δ
162.59, 139.26, 136.06, 135.48, 123.67, 123.34, 93.18,
60.88, 14.44; ESI-MS (m/z): Calcd for C12H11IN2O2Na [(M
+ Na)+] 364.9763, Found 364.9771.
General procedure for the preparation of formamidines 3b
Ethyl 1-(p-tolyl)-1H-imidazole-4-carboxylate (3g)
1
To a mixture of N,N-dimethyl-N'-phenylformimidamide
1b (0.148g, 1 mmol), ethyl isocyanoacetate (0.113g, 1
mmol) and DABCO (0.112g, 1 mmol) at 110 with stirring
for 14h. The reaction mixture was passed through short
column to give pure ethyl 1-phenyl-1H-imidazole-4-
White solid; yield: 53%; mp 60-61 °C; H NMR (400 MHz,
Chloroform-d) δ 7.92 (d, J = 1.4 Hz, 1H), 7.81 (d, J = 1.4
Hz, 1H), 7.29 (s, 4H), 4.40 (q, J = 7.1 Hz, 2H), 2.41 (s, 3H),
1.41 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, Chloroform-
d) δ 162.86, 138.58, 136.36, 134.96, 134.12, 130.62, 124.15,
121.63, 60.75, 21.06, 14.46; ESI-MS (m/z): Calcd for
C13H14N2O2Na [(M + Na)+] 253.0953, Found 253.0962.
carboxylate
(3b).
Ethyl
1-phenyl-1H-imidazole-4-
1
carboxylate (3b) Brown solid; yield: 87%; mp 82–83 °C; H
NMR (400 MHz, Chloroform-d) δ 7.96 (s, 2H), 7.60 – 7.50
(m, 2H), 7.49 – 7.37 (m, 3H), 4.41 (q, J = 7.1 Hz, 2H), 1.41
(t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, Chloroform-d) δ
161.00, 135.33, 133.02, 129.22, 127.77, 120.78, 60.07,
13.37; ESI-MS (m/z): Calcd for C12H12N2O2Na [(M + Na)+]
239.0796, Found 239.0800.
Ethyl
(3h)
1-(4-methoxyphenyl)-1H-imidazole-4-carboxylate
1
Pale yellow solid; yield: 57%; mp 65-66 °C; H NMR (400
MHz, Chloroform-d) δ 7.91 (dd, J = 23.8, 1.3 Hz, 2H), 7.37
– 7.30 (m, 2H), 7.07 – 6.94 (m, 2H), 4.40 (q, J = 7.1 Hz,
2H), 3.86 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H); 13C NMR (101
MHz, Chloroform-d) δ 161.23, 158.74, 135.60, 132.88,
128.40, 123.46, 122.45, 114.16, 59.94, 54.67, 13.39; ESI-
MS (m/z): Calcd for C13H14N2O3Na [(M + Na)+] 269.0902,
Found 269.0916.
Ethyl 1-(2-bromophenyl)-1H-imidazole-4-carboxylate (3a)
Pale yellow oil; yield: 73%; 1H NMR (400 MHz,
Chloroform-d) δ 7.76 (d, J = 1.4 Hz, 1H), 7.71 (dd, J = 7.9,
1.2 Hz, 1H), 7.64 (d, J = 1.4 Hz, 1H), 7.43 (td, J = 7.6, 1.5
Hz, 1H), 7.37 – 7.29 (m, 2H), 4.36 (q, J = 7.1 Hz, 2H), 1.36
(t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, Chloroform-d) δ
162.70, 138.28, 135.74, 134.28, 134.11, 130.91, 128.71,
127.97, 126.33, 119.77, 60.75, 14.41; ESI-MS (m/z): Calcd
for C12H11BrN2O2Na [(M + Na)+] 316.9902, Found
316.9903.
Ethyl
(3i)
1-(2-methoxyphenyl)-1H-imidazole-4-carboxylate
1
Pale yellow solid; yield: 72%; mp 83-84 °C; H NMR (400
MHz, Chloroform-d) δ 7.87 (d, J = 1.3 Hz, 1H), 7.75 (d, J =
1.4 Hz, 1H), 7.39 (ddd, J = 8.4, 7.5, 1.7 Hz, 1H), 7.28 (dd, J
= 7.8, 1.7 Hz, 1H), 7.10 – 6.99 (m, 2H), 4.39 (q, J = 7.1 Hz,
2H), 3.84 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H); 13C NMR (101
MHz, Chloroform-d) δ 163.04, 152.56, 138.48, 133.76,
129.88, 126.42, 125.51, 121.12, 112.41, 60.60, 55.89, 14.47;
ESI-MS (m/z): Calcd for C13H14N2O3Na [(M + Na)+]
269.0902, Found 269.0915.
Ethyl 1-(4-nitrophenyl)-1H-imidazole-4-carboxylate (3c)
1
Grey solid; yield: 56%; mp 189–190 °C; H NMR (400
MHz, DMSO-d6) δ 8.64 (d, J = 22.8 Hz, 2H), 8.37 (d, J =
8.6 Hz, 2H), 8.10 (d, J = 8.7 Hz, 2H), 4.29 (q, J = 7.1 Hz,
2H), 1.32 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, DMSO-
d6) δ 162.38, 146.43, 141.33, 137.72, 134.94, 125.86,
124.54, 121.73, 60.46, 14.77; ESI-MS (m/z): Calcd for
C12H11N3O4Na [(M + Na)+] 284.0647, Found 284.0662.
Ethyl
(3j)
1-(3-methoxyphenyl)-1H-imidazole-4-carboxylate
1
Brown solid; yield: 68%; mp 90-91 °C; H NMR (400 MHz,
Chloroform-d) δ 7.93 (d, J = 1.5 Hz, 1H), 7.83 (d, J = 1.5
Hz, 1H), 7.39 (t, J = 8.1 Hz, 1H), 6.97 (ddd, J = 7.9, 2.1, 0.9
Hz, 1H), 6.95 – 6.89 (m, 2H), 4.38 (q, J = 7.1 Hz, 2H), 3.84
(s, 3H), 1.39 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,
Chloroform-d) δ 162.76, 160.81, 137.51, 136.30, 135.02,
130.98, 124.00, 113.74, 113.66, 107.82, 60.76, 55.64, 14.43;
ESI-MS (m/z): Calcd for C13H14N2O3Na [(M + Na)+]
269.0902, Found 269.0917.
Ethyl 1-(4-fluorophenyl)-1H-imidazole-4-carboxylate (3d)
1
White solid; yield: 44%; mp 109-110 °C; H NMR (400
MHz, Chloroform-d) δ 7.89 (d, J = 1.5 Hz, 1H), 7.79 (d, J =
1.4 Hz, 1H), 7.47 – 7.34 (m, 2H), 7.25 – 7.15 (m, 2H), 4.39
13
(q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H); C NMR (101
MHz, Chloroform-d) δ 163.45, 162.69, 160.98, 136.48,
135.25, 132.74 (d, J = 3.3 Hz), 124.29, 123.85 (d, J = 8.7
Hz), 117.12 (d, J = 23.2 Hz), 60.83, 14.43; ESI-MS (m/z):
Calcd for C12H11FN2O2Na [(M + Na)+] 257.0702, Found
257.0705.
Ethyl 1-benzyl-1H-imidazole-4-carboxylate (3k)
1
Yellowish brown oil; yield: 62%; H NMR (400 MHz,
Ethyl 1-(4-chlorophenyl)-1H-imidazole-4-carboxylate (3e)
Chloroform-d) δ 7.56 (dd, J = 12.5, 1.4 Hz, 2H), 7.39 – 7.32
(m, 3H), 7.16 (dd, J = 7.5, 2.0 Hz, 2H), 5.12 (s, 2H), 4.33 (q,
J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR (101
MHz, Chloroform-d) δ 162.86, 138.08, 135.02, 134.46,
129.23, 128.75, 127.56, 125.33, 60.58, 51.36, 14.41; ESI-
MS (m/z): Calcd for C13H14N2O2 Na[(M + Na)+] 253.0953,
Found 253.0961.
1
Grey solid; yield: 62%; mp 128-130 °C; H NMR (400
MHz, Chloroform-d) δ 7.94 (dd, J = 15.2, 1.4 Hz, 2H), 7.53
– 7.45 (m, 2H), 7.42 – 7.33 (m, 2H), 4.41 (q, J = 7.1 Hz,
2H), 1.41 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,
Chloroform-d) δ 160.83, 135.36, 133.71, 133.67, 133.27,
129.40, 122.82, 122.09, 60.15, 13.36; ESI-MS (m/z): Calcd
for C12H11ClN2O2Na [(M + Na)+] 273.0407, Found
273.0417.
Ethyl 1-(4-chlorobenzyl)-1H-imidazole-4-carboxylate (3l)
1
Brown solid; yield: 67%; mp 74-75 °C; H NMR (400 MHz,
Ethyl 1-(4-iodophenyl)-1H-imidazole-4-carboxylate (3f)
Chloroform-d) δ 7.57 – 7.52 (m, 2H), 7.37 – 7.31 (m, 2H),
7.13 – 7.07 (m, 2H), 5.11 (s, 2H), 4.34 (q, J = 7.1 Hz, 2H),
1.36 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, Chloroform-
d) δ 161.71, 136.98, 133.78, 133.68, 132.46, 128.44, 127.83,
1
White solid; yield: 55%; mp 113-114 °C; H NMR (400
MHz, Chloroform-d) δ 7.91 (q, J = 1.4 Hz, 1H), 7.83 (dq, J
= 4.7, 2.7 Hz, 3H), 7.21 – 7.14 (m, 2H), 4.61 – 4.19 (m, 2H),

6
Tetrahedron
Armand, Cancer Chemother Pharmacol 2011, 68, 53. (c) E.
Serrao, Z. L. Xu, B. Debnath, F. Christ, Z. Debyser, Y. Q. Long,
N. Neamati, Bioorg. Med. Chem. 2013, 21, 5963. (d) S. M. A.
Islam, R. Patel, M. Acevedo-Duncan, BBA - Molecular Cell
Research 2018, 1865, 650.
(a) T. Terasaka, K. Tsuji, T. Kato, I. Nakanishi, T. Kinoshita, Y.
Kato, M. Kuno, T. Inoue, K. Tanaka, K. Nakamura, J. Med.
Chem. 2005, 48, 4750. (b) T. Terasaka, T. Kinoshita, M. Kuno, N.
Seki, K. Tanaka, I. Nakanishi, J. Med. Chem. 2004, 47, 3730.
K. A. Atkinson, E. E. Beretta, J. A. Brown, M. Castrodad, Y.
Chen, J. M. Cosgrove, P. Du, J. Litchfield, M. Makowski, K.
Martin, T. J. McLellan, C. Neagu, D. A. Perry, D. W. Piotrowski,
C. M. Steppan, R. Trilles, Bioorganic & Medicinal Chemistry
Letters 2011, 21, 1621.
124.10, 59.63, 49.62, 13.38; ESI-MS (m/z): Calcd for
C13H13ClN2O2Na [(M + Na)+] 287.0563, Found 287.0577.
Ethyl 1-(4-methylbenzyl)-1H-imidazole-4-carboxylate (3m)
1
6
7
Brown oil; yield: 60 %; H NMR (400 MHz, Chloroform-d)
δ 7.54 (d, J = 13.1 Hz, 2H), 7.16 (d, J = 7.8 Hz, 2H), 7.06 (d,
J = 7.8 Hz, 2H), 5.06 (s, 2H), 4.32 (q, J = 7.2 Hz, 2H), 2.33
(s, 3H), 1.34 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,
Chloroform-d) δ 161.84, 137.64, 136.98, 133.29, 130.93,
128.83, 126.60, 124.26, 59.51, 50.14, 20.11, 13.38; ESI-MS
(m/z): Calcd for C14H16N2O2Na [(M + Na)+] 267.1109,
Found 267.1101.
8
9
R. P. Moldovan, K. Hausmann, W. Deuther-Conrad, P. Brust,
ACS Med. Chem. Lett. 2017, 8, 566.
M. J. Fell, et al, The Journal of pharmacology and experimental
therapeutics 2011, 336, 165.
Ethyl 1-(4-cyanobenzyl)-1H-imidazole-4-carboxylate (3n)
1
Grey white solid; yield: 38%; mp 104-105 °C; H NMR
10 (a) B. Henkel, Tetrahedron Letters 2004, 45, 2219. (b) L. D. Luca,
G. Giacomelli, A. Porcheddu, J. Comb. Chem. 2005, 7, 905.
11 C. J. Helal, J. C. Lucas, Org. Lett. 2002, 4 (23), 4133.
12 C. Kanazawa, S. Kamijo, Y. Yamamoto, J. Am. Chem. Soc. 2006,
128, 10662.
(400 MHz, Chloroform-d) δ 7.70 (d, J = 8.4 Hz, 2H), 7.60
(d, J = 1.3 Hz, 2H), 7.28 (s, 2H), 5.24 (s, 2H), 4.38 (q, J =
7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,
Chloroform-d) δ 161.56, 139.22, 137.10, 134.10, 132.03,
126.80, 124.08, 117.01, 111.85, 59.77, 49.64; ESI-MS
(m/z): Calcd for C14H13N3O2Na [(M + Na)+] 278.0905,
Found 278.0906.
13 M. A. Bonin, D. Giguère, R. Roy, Tetrahedron 2007, 63, 4912.
Ethyl 1-phenethyl-1H-imidazole-4-carboxylate (3o)
1
Brown solid; yield: 49%; mp 51-52 °C; H NMR (400 MHz,
Chloroform-d) δ 7.52 (d, J = 1.4 Hz, 1H), 7.34 – 7.20 (m,
4H), 7.07 – 7.01 (m, 2H), 4.35 (q, J = 7.1 Hz, 2H), 4.20 (t, J
= 7.0 Hz, 2H), 3.06 (t, J = 7.0 Hz, 2H), 1.37 (t, J = 7.1 Hz,
3H); 13C NMR (101 MHz, Chloroform-d) δ 161.84, 136.87,
135.70, 133.03, 127.94, 127.54, 126.24, 123.92, 59.54,
48.05, 36.57, 13.38; ESI-MS (m/z): Calcd for C14H16N2O2Na
[(M + Na)+] 267.1109, Found 267.1106.
Conflicts of interest
“There are no conflicts to declare”.
Acknowledgements
This work was financially supported by the Program of
Independent and Achievement Transformation Plan for
Zaozhuang, China (Grant Nos. 2017GH10); Zaozhuang
University and Lunan Institute of Coal Chemical-
engineering Technology Research.
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Highlights
A
novel
and
green
protocol
for
synthesis
of
1-substituted-4-imidazolecarboxylates .
This cycloaddition reaction in the presence of DABCO under
metal-free and solvent-free conditions.
Novel applications of formamidine for synthesis of heterocyclic
compounds.

Declaration of interests
☐ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:
None