Synthesis of 2,4-Disubstituted Imidazoles via Nucleophilic Catalysis

Article abstract of DOI:10.1055/s-0039-1690832

A convergent, microwave-assisted protocol for the synthesis of disubstituted NH-imidazoles via nucleophilic catalysis is described. The substituted imidazoles are accessed via the intramolecular addition of a variety of amidoxime substrates to activated a

Full text of DOI:10.1055/s-0039-1690832

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–D
letter
A
en
D. A. Shabalin et al.
Letter
Synlett
Synthesis of 2,4-Disubstituted Imidazoles via Nucleophilic Catalysis
Dmitrii A. Shabalina
Jay J. Dunsfordb
Simbarashe Ngwerumeb
Alexandra R. Saundersb
Duncan M. Gillc
MeO C
DABCO, DMF, MW
80 °C, 15 min
i.
2
NH2OH·HCl
Na2CO3
CO2Me
OH
N
N
N
R
ii. MW, 240 °C, 2 min
9 examples
6–25%
N
R
EtOH/H2O
reflux, 1–3 h
11 examples
81–95%
NH2
R
H
Jason E. Camp*b,c,d
0
0
0
0-
0
0
0
1-7
3
9
4-2
1
0
1
a A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch
of the Russian Academy of Sciences, 1 Favorsky St, Irkutsk
664033, Russian Federation
b School of Chemistry, University of Nottingham, Nottingham,
NG7 2RD, UK
c Department of Chemical Sciences, University of Huddersfield,
Queensgate Huddersfield, HD1 3DH, UK
d Department of Chemistry, University of Bath, Claverton
Down, Bath, BA2 7AY, UK
j.e.camp@hud.ac.uk
Received: 07.01.2020
Accepted after revision: 31.01.2020
Published online: 18.02.2020
nally, Zhong and co-workers reacted arylamidoximes with
the electron-deficient alkyne dimethylacetylene dicarbox-
ylate (DMAD) under microwave irradiation to afford pyrim-
idones.10,11 Due to our interest in the development of novel
heterocyclic dyes for solar cells, an expedient synthesis to
2-aryl-4-ester-substituted 1H-imidazoles was sought.12
Building upon our work on the synthesis of highly substi-
tuted pyrroles from the reactions of ketoximes and activat-
ed alkynes catalyzed by both noble metals and via nucleo-
philic catalysis methods,13,14 we felt that a similar approach
could be taken for the synthesis of imidazoles. Herein we
report the findings from our study, including the develop-
ment of a rapid, one-pot, nucleophilic catalysis approach to
2,4-disubstituted imidazoles from the reaction of a variety
of amidoximes and electron-deficient alkynes (Scheme 1).
DOI: 10.1055/s-0039-1690832; Art ID: st-2020-d0012-l
Abstract A convergent, microwave-assisted protocol for the synthesis
of disubstituted NH-imidazoles via nucleophilic catalysis is described.
The substituted imidazoles are accessed via the intramolecular addition
of a variety of amidoxime substrates to activated alkynes followed by a
thermally induced rearrangement of the in situ generated O-vinylamid-
oxime species. The unprotected imidazoles contain an aryl group at the
2-position as well as an ester moiety at the 4-position.
Key words nucleophilic catalysis, imidazole, heterocycles, microwave,
19F NMR, rearrangement
Imidazoles are a very common structural motif in
chemistry and are utilized in a diverse range of applications
from drug-like compounds1 and natural product synthesis2
to dyes for solar cells,3 functional materials4 and catalysts.5
It is due to their versatility and utility in a number of these
areas that expedient methods for the synthesis of imidaz-
oles is both highly topical and necessary.6 One underuti-
lized method for their synthesis is from the reaction of am-
idoximes with electron-deficient alkynes.7 Heindel and
Chun showed that arylamidoximes could be reacted with
activated alkynes to form O-vinylamidoximes, which could
subsequently be thermally rearranged into NH-imidazoles
with an aryl group at the 2-position and an ester moiety at
the 4-position (Scheme 1).8a These functional handles
would be useful for further synthetic manipulations and
this disconnection provided a convergent route to form two
C–N bonds. Unfortunately, only imidazoles containing ei-
ther a phenyl or 4-chlorophenyl moiety at the two position
have been synthesized using this protocol.8 More recently,
Lobanov and co-workers examined the reaction of alkylam-
idoximes and electron-deficient alkynes. In contrast to the
previous work, only the 4-acylpyrroles were isolated.9 Fi-
Heindel 1971
CO2R
CO2R
diphenyl ether
250 °C, 30 min
OH
RO2C
N
N
O
MeOH, reflux
3 h
N
N
NH2
Ar
Ar = Ph, 4-ClC6H4 Ar
30–36% (2 steps)
H
Ar
NH2
Lobanov 2012
O
NR2
OH
R1O2C
R1
O
N
NH
Et3N, 40 °C, 10 d
3 examples
12–56%
NH2
R2N
N
R1
O
H
R1
Zhong 2006
O
CO2Me
O
OH
N
OH
DMAD
o-xylene
N
HN
Ar
MeOH
–10 °C to rt
6 h
CO2Me MW, 180 °C
1–5 min
NH2
NH2
Ar
Ar
N
CO2Me
11 examples
39–68% (over 2 steps)
CO2Me
This work
i.
(1.0 equiv)
MeO2C
DABCO (10 mol%)
DMF, MW, 80 °C, 15 min
OH
N
N
N
H
R
NH2
R
ii. MW, 240 °C, 2 min
Scheme 1 Reactions of amidoximes with electron-deficient alkynes
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
D. A. Shabalin et al.
Letter
Synlett
To begin, the formation of O-vinylamidoximes 3 from
amidoximes 2 was investigated. It was anticipated that a
solvent capable of reaching high temperatures in a micro-
wave would be needed to ultimately synthesize the imidaz-
oles, so the initial focus was on the use of dimethylforma-
mide (DMF).15 A variety of nucleophilic catalysts and bases
were screened for their ability to promote the formation of
the desired O-vinylamidoxime 3. The reaction of phenylam-
idoxime (2a) with methyl propiolate in the presence of a
nucleophilic catalyst, 1,4-diazabicyclo[2.2.2]octane (DAB-
CO), triphenylphosphine (PPh3) or 4-dimethylaminopyri-
dine (DMAP), at 80 °C for 10 minutes in DMF under micro-
wave heating afforded the desired O-vinylamidoxime 3a in
good to excellent yield (Table 1, entries 1–3). In contrast,
the use of bases such as 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) and pyridine only afforded O-vinylamidoxime 3a in
moderate yield (Table 1, entries 4–6). It was found that add-
ing 50 to 100 mol% of triethylamine (Et3N) to the reaction
mixture also resulted in the formation of O-vinylamidoxime
3a in good yields (Table 1, entries 7 and 8). Unfortunately,
due to potential thermal degradation of triethylamine, it
was unsuitable for the second step of the process. Only
starting material was recovered in the absence of a nucleo-
philic catalyst or base (Table 1, entry 9).
Table 2 Optimization of Imidazole Formation
MeO2C
(1.0 equiv)
CO2Me
DABCO
(10 mol%)
O
OH
N
CO2Me
N
N
Ar
NH2
3b
MW, DMF
N
Ar
Stage 2
NH2
Ar
H
Stage 1
2b
4b
Ar = 4-fluorophenyl
Entry
Stage 1a
Stage 2a
–
Yield of 4b (%)b
1
80 °C, 10 min
80 °C, 15 min
80 °C, 10 min
80 °C, 10 min
80 °C, 10 min
80 °C, 10 min
80 °C, 10 min
80 °C, 10 min
80 °C, 10 min
80 °C, 10 min
80 °C, 15 min
80 °C, 15 min
80 °C, 15 min
(82)c
14
2
200 °C, 45 min
200 °C, 30 min
200 °C, 5 min
220 °C, 5 min
240 °C, 5 min
260 °C, 5 min
240 °C, 0.5 min
240 °C, 1 min
240 °C, 10 min
240 °C, 1 min
240 °C, 2 min
240 °C, 5 min
3
17
4
15
5
20
6
21
7
12
8
22
9
(17)
18
10
11
12
13
(10)
(19)
(15)
a Reactions were conducted under microwave irradiation.
b Determined by 19F NMR with yields of isolated products in brackets.
c Yield of O-vinylamidoxime 3b.
Table 1 Optimization of O-Vinylamidoxime Formation
(1.0 equiv)
MeO2C
OH
O
N
N
CO2Me
catalyst/base
NH2
NH2
DMF, MW, 80 °C, 10 min
zimidamide (2b) was converted into methyl 3-({[amino(4-
fluorophenyl)methylene]amino}oxy)acrylate (3b) using the
conditions identified previously (cf. Table 1). Having shown
the amenability of this substrate to the O-vinylation proto-
col, the one-pot conversion of amidoxime 2b into imidazole
4b was undertaken. Subjection of amidoxime 2b to a two-
stage microwave protocol led to its initial conversion into
O-vinylamidoxime 3b, which was subsequently rearranged
at high temperature to give imidazole 4b (Table 2). Running
the second stage of the reaction at 200 °C for between 5 and
45 minutes gave moderate yields of the desired imidazole
4b (Table 2, entries 2–4). In order to minimize degradation
due to exposure of the substrate to high temperatures, the
second stage of the reaction was run for five minutes over
the temperature range of 200 °C to 260 °C in 20 °C incre-
ments (Table 2, entries 4–7). It was found that a tempera-
ture of 240 °C gave the highest NMR yield of imidazole 4b.
Experiments investigating the timings of the two stages of
the reaction showed that the best isolated yield of imidaz-
ole 4b could be obtained when stage 1 was run for 15 min-
utes and stage 2 for 2 minutes, at 80 °C and 240 °C, respec-
tively (Table 2, entries 8–13).
2a
3a
Entry
Catalyst/base
mol%
Yield (%)a
1
2
3
4
5
6
7
8
9
DABCO
PPh3
10
10
10
10
10
50
50
100
–
90
81
61
17
37
15
71
80
0b
DMAP
DBU
pyridine
pyridine
Et3N
Et3N
–
a Yield of isolated product.
b Only starting material was recovered.
With a better understanding of the conditions required
to convert amidoximes into O-vinylamidoximes and then
onto imidazoles (see Table S1), investigations on the feasi-
bility of a convergent, one-pot method were undertaken
(Table 2). The optimization process was conducted using 19
F
Next, the synthesis of a range of amidoximes from dif-
ferent nitriles was investigated. After screening a variety of
conditions, it was found that the method that worked best
for the substrates of interest was to reflux aryl nitriles 1 in
NMR analysis of the crude reaction mixture to determine
the conversion of the starting material and distribution of
the products. To begin the study, 4-fluoro-N′-hydroxyben-
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

C
D. A. Shabalin et al.
Letter
Synlett
an ethanol/water (3:2 v/v) mixture containing hydroxyl-
amine hydrogen chloride and sodium carbonate for 1–3
hours. Using these conditions, a small library of amidoxime
substrates was generated that included substituted aromat-
ics 2b–h, heteroaromatics 2i–k as well as a benzylic amid-
oxime 2l (Scheme 2).
CO2Me
i. MeO2C
DABCO (10 mol%)
DMF, MW, 80 °C, 15 min
(1.0 equiv)
OH
N
N
NH2
R
N
H
R
ii. MW, 240 °C, 2 min
2
4
CO2Me
CO2Me
R =
H, 23%, 4a
F, 19%, 4b
Cl, 24%, 4c
I, 19% (20%a), 4d
NMe2, 0%
N
N
NH2OH·HCl (4.0 equiv)
OH
N
N
H
N
H
N
Na2CO3 (2.0 equiv)
O
R
R
R
R
NH2
NO2, 9%, 4f
18%, 4i
CO2Me
EtOH/H2O (3:2, v/v)
reflux, 1–3 h
1
2
CO2Me
CO2Me
R = Me, 25%, 4g
OMe, 21%, 4h
N
N
N
H
N
R =
F, 87%, 2b
Cl, 85%, 2c
I, 95%, 2d
OH
H
N
NH
NH2
NMe2, 81%, 2e
NO2, 94%, 2f
6%, 4j
CO2Me
N
N
R
R
N
Ph
H
N
H
R =
Me, 95%, 2g
OMe, 90%, 2h
OH
N
N
H
0%
0%
NH2
Scheme 3 One-pot synthesis of imidazoles 4 from amidoximes 2. a The
reaction was carried out on a 4.3 mmol scale.
OH
OH
N
N
NH2
NH2
NH
isolation/purification of the imidazoles, a tert-butylcarbon-
yl protecting group was installed on fluoro derivative 4b
leading to Boc-imidazole 5b in good yield (see the Support-
ing Information for details). Thus, upon completion of the
two-stage imidazole formation protocol, di-tert-butyl di-
carbonate was added to the crude reaction mixture. Unlike
our previous experience with NH-pyrrole, in which the in
situ protection of the basic nitrogen facilitated isolation,13c
no improvement in the isolated yield was observed for the
imidazole compounds.
O
90%, 2i
83%, 2j
OH
OH
N
N
Ph
NH2
NH2
N
H
90%, 2k
95%, 2l
Scheme 2 Synthesis of substituted amidoximes 2
With optimal conditions in hand for the one-pot gener-
ation of substituted imidazoles from an amidoxime and an
activated alkyne (Table 2, entry 12), the substrate scope and
functional group tolerance of the protocol was investigated
(Scheme 3).16 Thus, subjection of both neutral 2a and elec-
tron-deficient aromatic amidoximes 2b–d and 2f to the
two-stage microwave protocol afforded the desired imidaz-
oles 4a–d and 4f in moderate yields. Importantly, the reac-
tion could be run on a 4.3 mmol scale without a decrease in
the isolated yield of the desired imidazole 4d. Interestingly,
subjection of the dimethylaniline compound 2e to the stan-
dard reaction conditions resulted in tar formation (vide in-
fra). In addition, electron-rich phenyl derivatives 2g and 2h
also afforded the desired imidazoles 4g17 and 4h in moder-
ate yields. Thus, the electronics of the system do not appear
to play a significant role on the isolated yield. Furan-ami-
doxime 2i and pyrrole-amidoxime 2j were converted into
imidazoles 4i and 4j, respectively, under the standard reac-
tion conditions.
In summary, we have disclosed a convergent protocol
for the synthesis of substituted imidazoles via a microwave-
assisted one-pot nucleophilic catalysis approach. Of note is
the amenability of this method to the regioselective syn-
thesis of 2,4-disubstituted NH-imidazoles. The functional
group handles at the C2 and C4 positions should be amena-
ble for further manipulations. The substrate scope of this
disconnection was probed and expanded significantly from
the two known aryl derivatives that have been reported in
the literature (aryl group = phenyl and 4-chlorophenyl). In
addition, the isolated yields compare favorably to the relat-
ed two-step process. To the best of our knowledge, this is
the first example of a catalytic one-pot method for the di-
rect synthesis of imidazoles from amidoximes and activated
alkynes and we anticipate that it will find wide application
due to its simple operating procedure.
Funding Information
Unfortunately, no imidazoles were isolated from the re-
actions of indole-amidoxime 2k and benzylic amidoxime 2l
with methyl propiolate. This was due to the formation of in-
tractable tar-like mixtures. In an attempt to improve the
We gratefully acknowledge the financial support received from the
Engineering and Physical Sciences Research Council (EPSRC, postdoc-
toral associateship for J.J.D. through First-Grant EP/J003298/1), a
Pfizer Summer Research Fellowship (A.R.S.), the University of Nottingham
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

D
D. A. Shabalin et al.
Letter
Synlett
(S.N.) and the Royal Society of Chemistry for a Researcher Mobility
(8) (a) Heindel, N. D.; Chun, M. C. Tetrahedron Lett. 1971, 18, 1439.
(b) Kudo, N.; Furuta, S.; Taniguchi, M.; Endo, T.; Sato, K. Chem.
Pharm. Bull. 1999, 47, 857.
Grant (D.A.S.).
n
g
i
n
e
eri
n
g
a
n
d
P
h
ysi
c
a
lS
c
i
e
n
c
es
R
esearc
h
C
o
u
n
c
i
l(EP/J
0
0
3
2
9
8/1)Pfi
z
er(U)n
i
v
ersityof
N
oti
n
g
h
a
m
(R)
o
y
a
lS
o
c
i
etyof
C
h
e
m
i
stry()
(9) Pivneva, E. E.; Galenko, A. V.; Dar’in, D. V.; Lobanov, P. S. Chem.
Heterocycl. Compd. 2012, 48, 942.
Supporting Information
(10) Zhong, Y.-L.; Zhou, H.; Gauthier, D. R. Jr.; Askin, D. Tetrahedron
Lett. 2006, 47, 1315.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690832.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
(11) For related work on the synthesis of pyrimidones via amidox-
imes, see: Culbertson, T. P. J. Heterocycl. Chem. 1979, 16, 1423.
(12) (a) Black, F. A.; Wood, C. J.; Ngwerume, S.; Summers, G. H.;
Clark, I. P.; Towrie, M.; Camp, J. E.; Gibson, E. A. Faraday Discuss.
2017, 198, 449. (b) Summers, G. H.; Lowe, G.; Lefebvre, J.-F.;
Ngwerume, S.; Bräutigam, M.; Dietzek, B.; Camp, J. E.; Gibson, E.
A. ChemPhysChem 2017, 18, 406.
(13) (a) Ngwerume, S.; Lewis, W.; Camp, J. E. J. Org. Chem. 2013, 78,
920. (b) Ngwerume, S.; Camp, J. E. Chem. Commun. 2011, 47,
1857. (c) Ngwerume, S.; Camp, J. E. J. Org. Chem. 2010, 75, 6271.
(d) Britton, J.; Camp, J. E. Chem. Today 2012, 30, 6.
(14) For recent examples of nucleophilic catalysis, see: (a) Chung,
W.; Lindovská, P.; Camp, J. E. Tetrahedron Lett. 2011, 52, 6785.
(b) Toda, Y.; Sakamoto, T.; Komiyama, Y.; Kikuchi, A.; Suga, H.
ACS Catal. 2017, 7, 6150. (c) Tamaki, A.; Kojima, S.; Yamamoto,
Y. J. Org. Chem. 2016, 81, 8710. (d) Fu, G. C. Acc. Chem. Res. 2000,
33, 412. (e) Lester, R. P.; Camp, J. E. ACS Sustainable Chem. Eng.
2013, 1, 545.
References and Notes
(1) For recent examples, see: (a) Jeanmart, S.; Gagnepain, J.; Maity,
P.; Lamberth, C.; Cederbaum, F.; Rajan, R.; Jacob, O.; Blum, M.;
Biere, S. Bioorg. Med. Chem. 2018, 26, 2009. (b) Naureen, S.;
Chaudhry, F.; Munawar, M. A.; Ashraf, M.; Hamid, S.; Khan, M.
A. Bioorg. Chem. 2018, 76, 365. (c) Hu, Y.; Shen, Y.; Wu, X.; Tu,
X.; Wang, G.-X. Eur. J. Med. Chem. 2018, 143, 958. (d) Kuzu, B.;
Tan, M.; Taslimi, P.; Gülçin, İ.; Taşpınar, M.; Menges, N. Bioorg.
Chem. 2019, 86, 187.
(2) For recent examples, see: (a) Roy, M. S.; Meg, X.; Koda, K.;
Rasapalli, S.; Gout, D.; Lovely, C. J. Tetrahedron Lett. 2019, 60,
979. (b) Jin, Z. Nat. Prod. Rep. 2011, 28, 1143. (c) O’Malley, D. P.;
Li, K.; Maue, M.; Zografos, A. L.; Baran, P. S. J. Am. Chem. Soc.
2007, 129, 4762.
(3) For recent examples, see: (a) Dhanunjayarao, K.; Mukundam, V.;
Chinta, R. V. R. N.; Venkatasubbaiah, K. J. Organomet. Chem.
2018, 865, 234. (b) Khan, S. A.; Asiri, A. M.; Al-Dies, A.-A. M.;
Osman, O. I.; Asad, M.; Zayed, M. E. M. J. Photochem. Photobiol. A
2018, 364, 390. (c) Hariharan, A.; Kumar, S.; Alagar, M.;
Dinakaran, K.; Subramanian, K. Polym. Bull. 2018, 75, 93.
(4) For recent examples, see: (a) Wang, C.; Zhou, Y.; Xu, C.; Zhao, X.;
Li, J.; Ren, Q. Int. J. Hydrogen Energy 2018, 43, 20739. (b) Yang, S.;
Zhang, Q.; Hu, Y.; Ding, G.; Wang, J.; Huo, S.; Zhang, B.; Cheng, J.
Mater. Lett. 2018, 216, 127. (c) Elanthamilan, E.; Rajkumar, S.;
Rajavalli, R.; Merlin, J. P. New J. Chem. 2018, 42, 10300.
(5) For recent examples, see: (a) Castro-Osma, J. A.; Martínez, J.; de
la Cruz-Martínez, F.; Caballero, M. P.; Fernández-Baeza, J.;
Rodríguez-López, J.; Otero, A.; Lara-Sánchez, A.; Tejeda, J. Catal.
Sci. Technol. 2018, 8, 1981. (b) Gholinejad, M.; Bonyasi, R.;
Najera, C.; Saadati, F.; Bahrami, M.; Dasvarz, N. ChemPlusChem
2018, 83, 431.
(6) For recent examples of imidazole syntheses, see: (a) Sundar, S.;
Rengan, R. Org. Biomol. Chem. 2019, 17, 1402. (b) Beuvin, M.;
Manneveau, M.; Diab, S.; Picard, B.; Sanselme, M.; Piettre, S. R.;
Legros, J.; Chataigner, I. Tetrahedron Lett. 2018, 59, 4487. (c) Cai,
J.; Bai, H.; Wang, Y.; Xu, X.; Xie, H.; Liu, J. Chem. Commun. 2019,
55, 3821. (d) Strelnikova, J. O.; Rostovskii, N. V.; Starova, G. L.;
Khlebnikov, A. F.; Novikov, M. S. J. Org. Chem. 2018, 83, 11232.
(7) For the synthesis and reactivity of electron-rich O-vinylamidox-
imes, see: (a) Trofimov, B. A.; Schmidt, E. Y.; Mikhaleva, A. I.;
Vasil’tsov, A. M.; Afonin, A. V. Mendeleev Commun. 2000, 10, 29.
(b) Trofimov, B. A.; Schmidt, E. Y.; Vasil’tsov, A. M.; Mikhaleva,
A. I.; Zaitsev, A. B.; Morozova, L. V.; Gorshkov, A. G.;
Henkelmann, J.; Arndt, J.-D. Synthesis 2001, 2427.
(15) Unfortunately, the commercially available bioalternative
solvent Cyrene™ could not be used at the requisite elevated
temperatures due to its thermal instability, see: (a) Bousfield, T.
W.; Pearce, K. P. R.; Nyamini, S. B.; Angelis-Dimakis, A.; Camp, J.
E. Green Chem. 2019, 21, 3675. (b) Camp, J. E. ChemSusChem
2018, 11, 3048. (c) Mistry, L.; Mapesa, K.; Bousfield, T. W.;
Camp, J. E. Green Chem. 2017, 19, 2123. (d) Camp, J. E.; Nyamini,
S. B.; Scott, F. J. RSC Med. Chem. 2020, 11, 111.
(16) 2,4-Disubstituted Imidazoles 4; General Procedure An oven-
dried microwave vial was loaded with the desired amidoxime 2
(0.66 mmol) and DABCO (7.4 mg, 0.066 mmol), then methyl
propiolate (55 mg, 0.66 mmol) in dry DMF (3 mL) was added
under a nitrogen atmosphere. The reaction mixture was sub-
jected to a two-stage microwave irradiation sequence (Stage 1:
80 °C, 15 min; Stage 2: 240 °C, 2 min). The mixture was concen-
trated under reduced pressure and the obtained residue dis-
solved in EtOAc (20 mL), washed with H2O (2 × 10 mL) and dried
over anhydrous Na2SO4. The residue after solvent evaporation
was purified by flash column chromatography on silica gel
(PE/EtOAc) to afford the desired imidazole 4.
(17) Methyl 2-(m-Tolyl)-1H-imidazole-4-carboxylate(4g) Yield:35
mg (25%); yellow solid; mp 168–170 °C. 1H NMR (DMSO-d6):
 = 13.22 (br s, 1 H, NH), 7.92 (s, 1 H, CH), 7.87 (s, 1 H, Ar), 7.81
(d, J = 7.6 Hz, 1 H, Ar), 7.35 (t, J = 7.7 Hz, 1 H, Ar), 7.21 (d, J = 7.6
Hz, 1 H, Ar), 3.78 (s, 3 H, Me), 2.36 (s, 3 H, Me). 13C{1H} NMR
(DMSO-d6):  = 162.8, 147.2, 138.0, 129.68, 129.66, 128.7,
126.1, 122.7, 51.1, 21.0 (2 С missed). HRMS (ESI/Q-TOF): m/z [M
+ H]+ calcd for C12H13N2O2: 217.0977; found: 217.0970.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D