Synthesis of 1,2,4,5-tetrasubstituted imidazoles and 2,4,5,6-tetrasubstituted pyrimidines: three-component, the one-pot reaction of arylamidines, malononitrile, and arylglyoxals or aryl aldehydes

Article abstract of DOI:10.1002/jhet.4053

A highly efficient one-pot synthesis of the 1,2,4,5-tetrasubstituted imidazoles and 2,4,5,6-tetrasubstituted pyrimidines through an arylamidine, malononitrile, and carbonyl compound by using Et₃N in CH₃CN at reflux conditions was dev

Full text of DOI:10.1002/jhet.4053

Received: 18 March 2020
DOI: 10.1002/jhet.4053
Revised: 15 May 2020
Accepted: 3 June 2020
A R T I C L E
Synthesis of 1,2,4,5-tetrasubstituted imidazoles and
2,4,5,6-tetrasubstituted pyrimidines: three-component,
the one-pot reaction of arylamidines, malononitrile,
and arylglyoxals or aryl aldehydes
Hossein Mehrabi
| Mina Hajipour | Fatemeh Rezazadeh-Jabalbarezi |
Farzaneh Alizadeh-Bami
Department of Chemistry, Vali-e-Asr
University of Rafsanjan, Rafsanjan, Iran
Abstract
A highly efficient one-pot synthesis of the 1,2,4,5-tetrasubstituted imidazoles
and 2,4,5,6-tetrasubstituted pyrimidines through an arylamidine, malononi-
trile, and carbonyl compound by using Et3N in CH3CN at reflux conditions
was developed. The nature of the carbonyl compounds were different; when
the carbonyl compound was arylglyoxal or aryl aldehyde, 1,2,4,5-tetrasub-
stituted imidazole and 2,4,5,6-tetrasubstituted pyrimidine were achieved
respectively.
Correspondence
Hossein Mehrabi, Department of
Chemistry, Vali-e-Asr University of
Rafsanjan, 77176 Rafsanjan, Iran.
Email: mehraby_h@yahoo.com
1 | INTRODUCTION
other methods.[37,38] However, the above-mentioned
methods for synthesis of imidazole and pyrimidine deriv-
Heterocyclic scaffolds like imidazole and pyrimidine are
atives suffer from one or more disadvantages, for example
difficult reaction conditions, low yields, complex work-up
and purification, multiple synthetic steps, and usage of
expensive catalysts and reagents. As a result, studies on
the preparation of imidazole and pyrimidine compounds
have received high importance in organic synthesis;
therefore, in continuation of our previous group works
on the development of multicomponent reactions for the
synthesis of imidazole and pyrimidine derivatives,[39–41]
we herein describe a facile and efficient strategy for the
synthesis of 1,2,4,5-tetrasubstituted imidazoles and
2,4,5,6-tetrasubstituted pyrimidine derivatives via a one-
pot, the three-component reaction of an arylamidine,
malononitrile, and arylglyoxal or aryl aldehyde in
CH3CN at reflux conditions.
an important and abundant class of five/six-membered
[1]
ring structures containing two nitrogen atom.
imidaz-
ole and pyrimidine analogs have been reported to exhibit
a wide range of unique biological activities such as anti-
[2,3]
[4,5]
[6]
HIV,
anticancer,
antihypertensive,
antiviral,
antimicrobial,
and antioxidant.[13,14] Moreover, nature utilizes the
[7,8]
[9,10]
[11]
antibacterial,
anti-tubercular,
[12]
unique type of pyrimidine ring in several biological mole-
cules such as nucleic acids, DNA, and RNA. [15] Also, the
imidazole nucleus has been found in many biological sys-
[16]
[17]
tems such as histidine,
histamine, and biotin.
Besides, many imidazole and pyrimidine-based agents
have been extensively studied as drug candidates and
[18]
some of them are used clinically such as nilotinib,
[19]
[20]
metronidazole,
voriconazole,
eprosartan, and
Due to the wide range of applications of
[21]
losartan.
imidazole and pyrimidine cores, a variety of methods
have been reported to the synthesis of them including
various multi-component methods,[22–26] cyclization
multistep
approaches,[34,35] Diels-Alder reaction,[36] and various
2 | RESULTS AND DISCUSSION
To initiate our study, the arylamidine 3 was achieved via
the reaction of aryl amine 1 and carbonitrile 2 in the
presence of AlCl3 at 120ꢀC for 1 hour under solvent-free
reaction,[22,27–29]
metal-catalyzed,[30–33]
J Heterocyclic Chem. 2020;1–8.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals LLC.
1

2
MEHRABI ET AL.
conditions (Scheme 1). The arylamidine compounds were
identified by the comparison of their physical and spec-
tral data with those of authentic samples. [42]
Then, the reaction of arylamidines 3 (1.0 mmol),
malononitrile 4 (1.0 mmol), and carbonyl compounds
such as arylglyoxals 5 (1.0 mmol) or aryl aldehydes
7 (1.0 mmol) in the presence of Et3N (1.0 mmol) as a base
for 2 hours. in 10.0 mL of CH3CN were investigated as
the model reaction. To explore the scope of transforma-
tion, different aryl aldehyde, and arylglyoxal, were
reacted with arylamidine derivatives under the same con-
ditions, and the results are summarized in Table 1.
Under the optimized reaction conditions, two series
of 1,2,4,5-tetrasubstituted imidazoles 6a-m and
2,4,5,6-tetrasubstituted pyrimidines 8a-g were synthe-
sized by the reaction of arylamidine 3, malononitrile 4,
and carbonyl compounds such as arylglyoxal 5 or aryl
aldehyde 7 to give the corresponding products. The struc-
tural type of 1,2,4,5-tetrasubstituted imidazoles 6 or
2,4,5,6-tetrasubstituted pyrimidines 8 is dependent on the
nature of the carbonyl compounds. As can be seen from
SCHEME 1 Synthesis of arylamidine
TABLE 1 Synthesis of 1,2,4,5-tetrasubstituted imidazols and 2,4,5,6-tetrasubstituted pyrimidines
Entry
1
Product
6a
R1
R2
Ar
Yield (%)a
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-ClC6H4
4-CH3C6H4
4-CH3C6H4
C6H5
C6H5
4-CH3C6H4
4-ClC6H4
C6H5
79
90
85
89
83
78
92
76
88
94
81
86
81
62
61
59
55
65
67
57
2
6b
6c
C6H5
3
C6H5
4
6d
6e
C6H5
4-ClC6H4
C6H5
5
C6H5
6
6f
C6H5
4-CH3C6H4
4-BrC6H4
4-CH3C6H4
4-ClC6H4
4-BrC6H4
4-CH3C6H4
C6H5
7
6g
C6H5
8
6h
6i
C6H5
9
C6H5
10
11
12
13
14
15
16
17
18
19
20
6j
C6H5
6 k
6l
4-FC6H4
4-FC6H4
C6H5
6 m
8a
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-OCH3C6H4
4-BrC6H4
4-BrC6H4
4-CH3C6H4
4-OCH3C6H4
4-CH3C6H4
C6H5
C6H5
8b
8c
2-ClC6H4
2-ClC6H4
2-ClC6H4
C6H11
2-ClC6H4
C6H11
8d
8e
4-CH3C6H4
CH2C6H5
4-CH3C6H4
CH2C6H5
8f
8g
aIsolated yield.

MEHRABI ET AL.
3
SCHEME 2 Proposed mechanism of the reaction
Table 1, electronic effects and the nature of substituents
on the aryl amine, the carbonitrile, and the arylglyoxal
resulted in products with different reaction yields. When
the aryl amine derivatives especially containing electron-
donating groups, the carbonitrile and the arylglyoxal
derivatives containing electron-withdrawing groups were
employed, a higher yield was obtained. Also, the steric
hindrance of substituents on substrates has no significant
effect on the rate of the reactions.
intermediate A is formed utilizing a Knoevenagel conden-
sation between the arylglyoxal 5 and malononitrile 4. Also,
the addition of arylamidine 3, the formation of intermediate
B occurred via a Michael addition reaction of the nitrogen
at the sp2 carbon atom of A, which subsequently undergoes
intramolecular nucleophilic addition the second nitrogen
to the carbonyl group and elimination of H2O affording the
intermediates C; then, by hydrolysis of the nitrile group in
CH3CN at reflux conditions. While, tetrasubstituted pyrimi-
dines 8 is formed via Dimroth rearrangement; Firstly, inter-
mediate D is formed through a Knoevenagel condensation
between the aryl aldehyde 7 and malononitrile 4. Also,
Michael addition of arylamidine 3 (as Michael donor) to α,
β-unsaturated species D (as Michael acceptor) provides
intermediate E, which subsequently undergoes intramolec-
ular nucleophilic addition of the second nitrogen to the cya-
nide carbon and oxidative dehydrogenation affording the
intermediate F; then, this compound F rearranges to
2,4,5,6-tetrasubstituted pyrimidines 8. The accepted mecha-
nism of Dimroth rearrangement involves an addition reac-
tion of water G, ring-opening H, C─C bond rotation I, and
ring closure to 8.
1
All the products' structure was characterized by H-
NMR, 13C-NMR, IR, CHN analysis, and melting points. The
IR spectrum of 2-cyano-2-(2-phenyl-1,5-di-p-tolyl-1H-imid-
azole-4-yl)acetamide 6a showed absorption bands at
3453 cm−1 for NH2, 2245 cm−1 for CN, 1682 cm−1 for C O,
and 1647 cm−1 for C N groups. For instance, the 1H NMR
spectrum of the compound 6a consisted of two singlets at
δ = 2.24 and 2.26 ppm for the methyl groups in the product.
A singlet that integrated for one hydrogen was observed at
δ = 4.92 ppm for the methine proton, the aromatic protons
and NH2 protons resonated in the region δ = 7.10-7.56 ppm.
The 13C NMR spectrum of compound 6a showed 20 distinct
signals in agreement with the proposed structure. Partial
assignments of these resonances for the other products are
given in the experimental section.
A proposed mechanism for the formation of 1,2,4,5-
tetrasubstituted imidazoles 6 and 2,4,5,6-tetrasubstituted
pyrimidines 8 is described in Scheme 2. The nature of the
carbonyl compounds were different, so that; tetrasub-
stituted imidazoles 6 is formed via four steps; at first,
3 | CONCLUSION
[39–41]
In summary, in continuation of our investigations
with some modification of starting materials and reaction
conditions; we have successfully described a facile and

4
MEHRABI ET AL.
efficient method between carbonyl compounds,
malononitrile, and arylamidines providing two different
series of products depending on the nature of the car-
bonyl compounds. The mechanism for the formation of
the resulting 1,2,4,5-tetrasubstituted imidazoles and
2,4,5,6-tetrasubstituted pyrimidines are proposed via sev-
eral processes including; Knoevenagel condensation,
Michael addition, intramolecular nucleophilic addition,
hydrolysis of nitrile or Dimroth rearrangement. The
advantages of the reaction are the mild reaction condi-
tions, readily available starting materials and the good to
high yields of products.
under reflux conditions for 2 hours. The completion of
the reaction was monitored by TLC. After completion of
the reaction, the solvent was removed under reduced
pressure. The crude product was purified by recrystalliza-
tion from ethanol to yield the highly pure compounds
6a-m (76%-94%).
4.4 | General experimental procedure for
the synthesis of compounds 8a-g
A mixture of aryl aldehyde 7 (1.0 mmol), malononitrile
4 (1.0 mmol), and arylamidine 3 (1.0 mmol) was stirred in
the presence of Et3N (1.0 mmol) in 10.0 mL of CH3CN
under reflux conditions for 2 hours. The completion of
reaction was monitored by TLC. After completion of reac-
tion, the solvent was removed under reduced pressure.
The viscous crude product was purified by plate chroma-
tography (20 × 20 cm) using n-hexane/EtOAc (2:1) as elu-
ent to yield the highly pure compounds 8a-g (55%-67%).
4 | EXPERIMENTAL
4.1 | GENERAL
All commercially available reagents and other solvents
were purchased (Merck) and used without further purifi-
cation. Melting points were obtained on a Bamslead Elec-
trothermal 9200 melting point apparatus and are
uncorrected. IR spectra were acquired on a Bruker FT-IR
Equinox-55 spectrometer. Peaks are reported in
wavenumbers (Cm−1). All of the NMR spectra were
recorded on a Varian model UNITY Inova 500 MHz (1H:
500, 13C: 125 MHz) NMR spectrometer. Chemical shifts
4.5 | 2-Cyano-2-(2-phenyl-1,5-di-p-tolyl-
1H-imidazol-4-yl)acetamide (6a)
White solid; Mp: 253-254ꢀC; IR (KBr, υ/cm−1): 3453
1
(NH2), 2245 (CN), 1682 (C O), 1647 (C N); H NMR
1
of H and 13C-NMR are reported in parts per million
(500 MHz, DMSO): δ = 2.24 (3H, s, CH3), 2.26 (3H, s,
CH3), 4.92 (1H, s, CH), 7.10-7.31 (13H, m, Ar-H), 7.42,
7.56 (2H, s, NH2) ppm. 13C NMR (125 MHz, DMSO):
δ = 21.1 (CH3), 21.2 (CH3), 38.5 (CH), 107.0 (C), 117.7
(CN), 125.5 (CH), 128.6 (C), 128.7 (CH), 128.8 (C), 129.3
(CH), 129.5 (C), 130.2 (CH), 130.5 (CH), 130.6 (CH), 133.7
(C), 134.4 (C), 138.2 (CH), 138.7 (C), 146.6 (C), 165.8
(C O) ppm. Anal. Calcd for C26H22N4O (406.49): C,
76.83; H, 5.46; N, 13.78. Found: C, 76.71; H, 5.41; N, 13.84.
(ppm) from tetramethylsilane (TMS) as an internal stan-
dard in DMSO-d6 and CDCl3 as solvents. Elemental ana-
lyses were done by Carlo Erba EA 1108 instrument.
4.2 | General procedure for the synthesis
of arylamidines 3
The mixture of arylamine 1 (1.2 mmol), carbonitrile
2 (1.0 mmol), and AlCl3 (1.0 mmol) was charged into a
round bottom flask. The mixture was stirred at 120ꢀC for
1 hour, then 20.0 mL ice water was added to the round
bottom flask, after 10% sodium hydroxide solution was
added with a mixture of reaction to obtain pH = 14, and
the precipitate was extracted with CHCl3 (3 × 7.0 mL),
dried (MgSO4), and the solvent evaporated. The crude
product was white crystallized from toluene.
4.6 | 2-(5-(4-Chlorophenyl)-2-phenyl-1-(p-
tolyl)-1H-imidazol-4-yl)-
2-cyanoacetamide (6b)
Yellow solid, Mp: 251-253ꢀC; IR (KBr, υ/cm−1): 3451
1
(NH2), 2248 (CN), 1681 (C O), 1647 (C N); H NMR
(500 MHz, DMSO): δ = 2.26 (3H, s, CH3), 5.03 (1H, s,
CH), 7.14-7.67 (15H, m, Ar-H, NH2) ppm. 13C NMR
(125 MHz, DMSO): δ = 21.1 (CH3), 38.5 (CH), 103.2 (C),
117.6 (CN), 126.7 (CH), 127.4 (C), 128.6 (CH), 128.7 (C),
128.7 (CH), 129.0 (C), 129.9 (C), 130.3 (CH), 132.5 (C),
132.6 (CH), 133.8 (CH), 134.2 (C), 138.9 (CH), 146.9 (C),
165.7 (C O) ppm. Anal. Calcd for C25H19ClN4O
(426.90): C, 70.34; H, 4.49; N, 13.12. Found: C, 70.52; H,
4.53; N, 13.06.
4.3 | General experimental procedure for
the synthesis of compounds 6a-m
A mixture of arylglyoxal 5 (1.0 mmol), malononitrile
4 (1.0 mmol), and arylamidine 3 (1.0 mmol) was stirred
in the presence of Et3N (1.0 mmol) in 10.0 mL of CH3CN

MEHRABI ET AL.
5
4.7 | 2-Cyano-2-(2,5-diphenyl-1-(p-tolyl)-
1H-imidazol-4-yl)acetamide (6c)
(500 MHz, DMSO): δ = 2.26 (3H, s, CH3), 4.94 (1H, s,
CH), 7.10-7.43 (13H, m, Ar-H), 7.66 (2H, s, NH2) ppm.
13C NMR (125 MHz, DMSO): δ = 21.2 (CH3), 38.5 (CH),
109.9 (C), 117.6 (CN), 125.2 (C), 128.7 (CH), 128.8 (C),
129.0 (CH), 129.4 (CH), 129.7 (C), 130.2 (CH), 130.6
(CH), 130.8 (C), 133.7 (CH), 133.8 (CH), 135.9 (C), 138.4
(C), 146.7 (C), 165.8 (C O) ppm.
White solid; Mp: 248-251ꢀC; IR (KBr, υ/cm−1): 3450
1
(NH2), 2250 (CN), 1681 (C O), 1645 (C N); H NMR
(500 MHz, DMSO): δ = 2.25 (3H, s, CH3), 4.94 (1H, s,
CH), 7.12-7.43 (14H, m, Ar-H), 7.65 (2H, s, NH2) ppm.
13C NMR (125 MHz, DMSO): δ = 21.1 (CH3), 38.5 (CH),
109.9 (C), 117.6 (CN), 128.4 (C), 128.6 (CH), 128.7 (C),
128.7 (CH), 128.8 (CH), 128.9 (C), 129.6 (C), 130.2 (CH),
130.4 (C), 130.8 (CH), 133.7 (CH), 134.4 (CH), 138.7
(CH), 146.7 (C), 165.8 (C O) ppm.
4.11 | 2-(1,5-Bis[4-bromophenyl]-
2-phenyl-1H-imidazol-4-yl)-
2-cyanoacetamide (6g)
Yellow solid, Mp: 253-255ꢀC; IR (KBr, υ/cm−1): 3449
(NH2), 2250 (CN),1679 (C O), 1646 (C N); 1H NMR
(500 MHz, DMSO): δ = 4.96 (1H, s, CH), 7.20-7.40 (11H,
m, Ar-H), 7.55 (2H, d, 3JHH = 10.0 Hz, Ar-H), 7.66 (2H, s,
NH2) ppm. 13C NMR (125 MHz, DMSO): δ = 38.5 (CH),
117.6 (CN), 122.4 (C), 128.1 (C), 128.7 (CH), 128.8 (CH),
128.9 (CH), 129.0 (C), 129.1 (CH), 129.8 (C), 130.2 (C),
130.8 (CH), 131.1 (CH), 132.7 (CH), 133.6 (C), 136.3 (C),
146.8 (C), 165.7 (C O) ppm. Anal. Calcd for
C24H16Br2N4O (536.23): C, 53.76; H, 3.01; N, 10.45.
Found: C, 53.90; H, 3.04; N, 10.38.
4.8 | 2-(1,5-Bis(4-chlorophenyl)-2-phenyl-
1H-imidazol-4-yl)-2-cyanoacetamide (6d)
White solid; Mp: 257-259ꢀC; IR (KBr, υ/cm−1): 3452
1
(NH2), 2251 (CN), 1681 (C O), 1646 (C N); H NMR
(500 MHz, DMSO): δ = 5.05 (1H, s, CH), 7.23 (2H, d,
3JHH = 10.0 Hz, Ar-H), 7.28-7.32 (7H, m, Ar-H), 7.40 (2H,
d, 3JHH = 5.0 Hz, Ar-H), 7.44 (2H, d, 3JHH = 10.0 Hz, Ar-
H), 7.67 (2H, s, NH2) ppm. 13C NMR (125 MHz, DMSO):
δ = 38.5 (CH), 117.5 (CN), 127.1 (C), 128.7 (CH), 128.8
(CH), 128.9 (CH), 129.2 (CH), 129.8 (C), 130.0 (C), 130.1
(CH), 130.8 (C), 132.4 (CH), 132.7 (C), 133.9 (CH), 134.0
(C), 135.6 (C), 147.0 (C), 165.7 (C O) ppm. Anal. Calcd
for C24H16Cl2N4O (447.32): C, 64.44; H, 3.61; N, 12.53.
Found: C, 64.27; H, 3.62; N, 12.47.
4.12 | 2-(1-(4-Bromophenyl)-2-phenyl-
5-(p-tolyl)-1H-imidazol-4-yl)-
2-cyanoacetamide (6h)
White solid; Mp: 249-251ꢀC; IR (KBr, υ/cm−1): 3453
(NH2), 2251 (CN),1681 (C O), 1644 (C N); 1H NMR
(500 MHz, DMSO): δ = 2.26 (3H, s, CH3), 4.94 (1H, s,
4.9 | 2-(1-(4-Chlorophenyl)-2,5-diphenyl-
1H-imidazol-4-yl)-2-cyanoacetamide (6e)
3
CH), 7.08 (2H, d, JHH = 5.0 Hz, Ar-H), 7.13 (2H, d,
3
White solid; Mp: 253-256ꢀC; IR (KBr, υ/cm−1): 3448
3JHH = 5.0 Hz, Ar-H), 7.20 (2H, d, JHH = 5.0 Hz, Ar-H),
1
3
(NH2), 2248 (CN), 1679 (C O), 1645 (C N); H NMR
7.30-7.33 (5H, m, Ar-H), 7.56 (2H, d, JHH = 10.0 Hz, Ar-
(500 MHz, DMSO): δ =4.98 (1H, s, CH), 7.21-7.32 (12H,
m, Ar-H), 7.41 (2H, d, JHH = 5.0 Hz, Ar-H), 7.69 (2H, s,
H), 7.40, 7.67 (2H, s, NH2) ppm. 13C NMR (125 MHz,
DMSO): δ = 21.2 (CH3), 38.5 (CH), 117.6 (CN), 122.4 (C),
125.2 (C), 128.7 (CH), 128.8 (CH), 129.1 (C), 129.4 (CH),
129.7 (C), 130.2 (C), 130.7 (CH), 131.1 (CH), 132.7 (CH),
133.6 (C), 136.3 (C), 138.4 (CH), 146.7 (C), 165.8 (C O)
ppm. Anal. Calcd for C25H19BrN4O (471.36): C, 63.70; H,
4.06; N, 11.89. Found: C, 63.61; H, 4.02; N, 11.92.
3
NH2) ppm. 13C NMR (125 MHz, DMSO): δ = 38.5 (CH),
111.6 (C), 117.6 (CN), 128.1 (C), 128.7 (CH), 128.8 (CH),
128.9 (C), 129.0 (C), 129.1 (CH), 129.7 (CH), 129.8 (CH),
130.2 (C), 130.8 (CH), 133.7 (C), 133.8 (CH), 135.9 (CH),
145.8 (C), 165.8 (C O) ppm. Anal. Calcd for
C24H17ClN4O (412.88): C, 69.82; H, 4.15; N, 13.57.
Found: C, 69.63; H, 4.13; N, 13.62.
4.13 | 2-(1-(4-Bromophenyl)-
5-(4-chlorophenyl)-2-phenyl-1H-imidazol-
4-yl)-2cyanoacetamide (6i)
4.10 | 2-(1-(4-Chlorophenyl)-2-phenyl-
5-(p-tolyl)-1H-imidazol-4-yl)-
2-cyanoacetamide (6f)
White solid; Mp: 252-255ꢀC; IR (KBr, υ/cm−1): 3453
1
(NH2), 2251 (CN), 1681 (C O), 1648 (C N); H NMR
White solid; Mp: 255-256ꢀC; IR (KBr, υ/cm−1): 3453
(500 MHz, DMSO): δ = 5.05 (1H, s, CH), 7.21-7.43 (11H,
m, Ar-H), 7.57 (2H, d, 3JHH = 10.0 Hz, Ar-H), 7.67 (2H, s,
1
(NH2), 2248 (CN), 1681 (C O), 1647 (C N); H NMR

6
MEHRABI ET AL.
NH2) ppm. 13C NMR (125 MHz, DMSO): δ = 38.5 (CH),
117.5 (CN), 122.5 (CH), 127.1 (C), 128.7 (CH), 128.9 (C),
129.2 (C), 130.0 (C), 130.2 (C), 131.1 (CH), 131.1 (CH),
132.4 (CH), 132.7 (CH), 132.8 (CH), 134.0 (C), 136.1 (C),
147.0 (C), 165.7 (C O) ppm. Anal. Calcd for
C24H16BrClN4O (491.77): C, 58.62; H, 3.28; N, 11.39.
Found: C, 58.75; H, 3.31; N, 11.37.
3JHF = 8.5 Hz, Ar-H), 7.41, 7.65 (2H, s, NH2) ppm. 13C
NMR (125 MHz, DMSO): δ = 21.1 (CH3), 38.5 (CH),
2
115.7 (d, JCF = 22.5 Hz, CH), 117.6 (CN), 127.0 (d,
4JCF = 3.7 Hz, C), 128.4 (C), 128.7 (CH), 128.8 (C), 129.6
(C), 130.2 (CH), 130.8 (CH), 130.9 (d, 3JCF = 7.5 Hz, CH),
133.7 (C), 134.2 (CH), 138.8 (CH), 145.9 (C), 161.4 (C),
1
163.4 (d, JCF = 247.2 Hz, C), 165.7 (C O) ppm. Anal.
Calcd for C25H19FN4O (410.45): C, 73.16; H, 4.67; N,
13.65. Found: C, 73.29; H, 4.70; N, 13.59.
4.14 | 2-(5-(4-Bromophenyl)-
1-(4-chlorophenyl)-2-phenyl-1H-imidazol-
4-yl)-2cyanoacetamide (6j)
4.17 | 2-Cyano-2-(1,2-diphenyl-5-(p-tolyl)-
1H-imidazol-4-yl)acetamide (6m)
White solid; Mp: 253-255ꢀC; IR (KBr, υ/cm−1): 3453
1
(NH2), 2252 (CN), 1682 (C O), 1648 (C N); H NMR
White solid; Mp: 247-248ꢀC; IR (KBr, υ/cm−1): 3465
1
(500 MHz, DMSO): δ = 5.05 (1H, s, CH), 7.16 (2H, d,
3JHH = 10.0 Hz, Ar-H), 7.28-7.42 (7H, m, Ar-H), 7.44 (2H,
d, 3JHH = 5.0 Hz, Ar-H), 7.54 (2H, d, 3JHH = 10.0 Hz, Ar-
H), 7.67 (2H, s, NH2) ppm. 13C NMR (125 MHz, DMSO):
δ = 38.5 (CH), 117.5 (CN), 122.7 (C), 127.5 (C), 128.7
(CH), 128.8 (CH), 129.2 (C), 129.8 (CH), 130.0 (C), 130.1
(CH), 130.8 (C), 131.8 (CH), 132.4 (C), 132.9 (CH), 134.0
(C), 135.6 (CH), 147.0 (C), 165.7 (C O) ppm.
(NH2), 2242 (CN), 1689 (C O), 1641 (C N); H NMR
(500 MHz, DMSO): δ = 2.24 (3H, s, CH3), 4.93 (1H, s,
CH), 7.09-7.42 (14H, m, Ar-H), 7.64 (2H, s, NH2) ppm.
13C NMR (125 MHz, DMSO): δ = 21.2 (CH3), 38.5 (CH),
109.9 (C), 117.7 (CN), 125.4 (C), 128.6 (CH), 128.7 (CH),
128.9 (CH), 129.0 (C), 129.3 (CH), 129.5 (CH), 129.7
(CH), 130.4 (C), 130.6 (CH), 133.7 (C), 137.0 (C), 138.2
(C), 146.5 (C), 165.8 (C O) ppm. Anal. Calcd for
C25H20N4O (392.46): C, 76.51; H, 5.14; N, 14.28.
Found: C, 76.39; H, 5.12; N, 14.24.
4.15 | 2-Cyano-2-(2-(4-fluorophenyl)-
1,5-di-p-tolyl-1H-imidazol-4-yl)
acetamide (6k)
4.18 | 4-((4-Methoxyphenyl)amino)-
2-phenyl-6-(p-tolyl)pyrimidine-
5-carbonitrile (8a)
White solid; Mp: 250-253ꢀC; IR (KBr, υ/cm−1): 3462
(NH2), 2248 (CN),1684 (C O), 1645 (C N); 1H NMR
(500 MHz, DMSO): δ = 2.25 (3H, s, CH3), 2.27 (3H, s,
CH3), 4.91 (1H, s, CH), 7.07-7.16 (10H, m, Ar-H), 7.33
IR (KBr, υ/cm−1): 3314 (NH), 2214 (CN), 1641 (C N);
1H-NMR (500 MHz, CDCl3) δ = 2.48 (s, 3H, CH3), 3.89
3
3
3
(2H, dd, JHH = 7.5 Hz, JHF = 9.0 Hz, Ar-H), 7.41, 7.65
(2H, s, NH2) ppm. 13C NMR (125 MHz, DMSO): δ = 21.1
(3H, s, OCH3), 7.01 (2H, d, JHH = 10.0 Hz, Ar-H), 7.34
(1H, s, NH), 7.38-7.53 (5H, m, Ar-H), 7.61 (2H, d,
2
3
(CH3), 21.2 (CH3), 38.5 (CH), 115.7 (d, JCF = 21.2 Hz,
3JHH = 10.0 Hz, Ar-H), 8.07 (2H, d, JHH = 10.0 Hz, Ar-
4
3
CH), 117.7 (CN), 125.4 (C), 127.1 (d, JCF = 2.5 Hz, C),
H), 8.49 (2H, d, JHH = 10.0 Hz, Ar-H) ppm. 13C-NMR
128.7 (CH), 129.3 (CH), 130.2 (CH), 130.6 (CH), 130.9 (d,
(125 MHz, CDCl3) δ = 21.5 (CH3), 55.5 (OCH3), 114.2
(CN), 116.9 (C), 123.9 (CH), 128.4 (CH), 128.7 (CH),
129.1 (CH), 129.4 (CH), 130.2 (CH), 131.7 (CH), 133.7
(C), 136.8 (C), 141.8 (C), 146.8 (C), 157.1 (C), 161.5 (C),
164.8 (C), 167.9 (C) ppm. Anal. Calcd for C25H20N4O
(392.46): C, 76.51; H, 5.14; N, 14.28. Found: C, 76.43; H,
5.11; N, 14.27.
3JCF = 8.7 Hz, CH), 133.7 (C), 134.3 (C), 138.2 (C), 138.8
1
(C), 145.8 (C), 161.4 (C), 163.4 (d, JCF = 238.7 Hz, C),
165.8 (C O) ppm. Anal. Calcd for C26H21FN4O
(424.48): C, 73.57; H, 4.99; N, 13.20. Found: C, 73.53; H,
4.94; N, 13.24.
4.16 | 2-Cyano-2-(2-(4-fluorophenyl)-
5-phenyl-1-(p-tolyl)-1H-imidazol-4-yl)
acetamide (6l)
4.19 | 2-(2-Chlorophenyl)-4-(p-tolyl)-6-(p-
tolylamino)pyrimidine-5-carbonitrile (8b)
White solid; Mp: 248-249ꢀC; IR (KBr, υ/cm−1): 3452
(NH2), 2251 (CN),1688 (C O), 1647 (C N); 1H NMR
(500 MHz, DMSO): δ = 2.26 (3H, s, CH3), 4.94 (1H, s,
CH), 7.11-7.21 (11H, m, Ar-H), 7.35 (2H, dd, 3JHH = 7.5 Hz,
IR (KBr, υ/cm−1): 3308 (NH), 2190 (CN), 1638 (C N);
1H-NMR (500 MHz, CDCl3) δ = 2.28 (3H, s, CH3), 2.43
(3H, s, CH3), 7.13-7.99 (13H, m, Ar-H, NH) ppm. 13C-
NMR (125 MHz, CDCl3) δ = 21.1 (CH3), 21.5 (CH3),

MEHRABI ET AL.
7
115.9 (CN), 121.8 (C), 126.6 (C), 126.9 (C), 127.9 (C),
128.5 (CH), 128.9 (CH), 129.3 (CH), 129.8 (CH), 130.7
(CH), 131.2 (CH), 132.3 (CH), 134.1 (C), 134.1 (C), 139.9
(C), 142.3 (C), 151.8 (C), 162.7 (C), 166.8 (C) ppm. Anal.
Calcd for C25H19ClN4 (410.91): C, 73.08; H, 4.66; N,
13.64. Found: C, 73.22; H, 4.69; N, 13.58.
(C), 161.1 (C), 168.5 (C) ppm. Anal. Calcd for C24H23BrN4
(447.38): C, 64.43; H, 5.18; N, 12.52. Found: C, 64.47; H,
5.23; N, 12.46.
4.23 | 4-(4-Bromophenyl)-
2-(2-chlorophenyl)-6-(p-tolylamino)
pyrimidine-5-carbonitrile (8f)
4.20 | 2-(2-Chlorophenyl)-
4-(phenylamino)-6-(p-tolyl)pyrimidine-
5-carbonitrile (8c)
IR (KBr, υ/cm−1): 3312 (NH), 2189 (CN), 1649 (C N);
1H-NMR (500 MHz, CDCl3) δ = 2.28 (3H, s, CH3),
7.02-7.32 (9H, m, Ar-H, NH), 7.64 (2H, d, 3JHH = 10.0 Hz,
Ar-H), 7.96 (2H, d, 3JHH = 10.0 Hz, Ar-H) ppm. 13C-NMR
(125 MHz, CDCl3) δ = 21.5 (CH3), 115.9 (CN), 126.3
(CH), 128.9 (CH), 129.3 (CH), 129.5 (CH), 129.6 (CH),
129.6 (C), 130.0 (CH), 130.8 (C), 131.5 (C), 131.5 (C),
132.3 (C), 134.0 (C), 137.1 (C), 137.3 (C), 142.3 (C), 155.2
(C), 162.7 (C), 166.9 (C) ppm. Anal. Calcd for
C24H16BrClN4 (475.77): C, 60.59; H, 3.39; N, 11.78.
Found: C, 61.12; H, 3.42; N, 11.77.
IR (KBr, υ/cm−1): 3296 (NH), 2211 (CN), 1637 (C N);
1H-NMR (500 MHz, CDCl3) δ = 2.44 (3H, s, CH3),
7.08-7.37 (12H, m, Ar-H, NH), 7.99 (2H, d, 3JHH = 10.0 Hz,
Ar-H) ppm. 13C-NMR (125 MHz, CDCl3) δ = 21.1 (CH3),
115.9 (CN), 126.3 (CH), 126.3 (CH), 128.9 (CH), 129.3
(CH), 129.5 (CH), 129.6 (C), 130.0 (CH), 130.2 (CH),
130.3 (CH), 130.7 (CH), 131.5 (C), 132.3 (C), 134.6 (C),
137.1 (C), 142.3 (C), 158.1 (C), 162.7 (C), 166.9 (C) ppm.
4.21 | 2-(2-Chlorophenyl)-
4-(4-methoxyphenyl)-6-(p-tolylamino)
pyrimidine-5-carbonitrile (8d)
4.24 | 4-(Benzylamino)-2-cyclohexyl-6-(p-
tolyl)pyrimidine-5-carbonitrile (8g)
IR (KBr, υ/cm−1): 3320 (NH), 2211 (CN), 1644 (C N);
1H-NMR (500 MHz, CDCl3) δ = 2.44 (s, 3H, CH3),
1.66-1.70 (10H, m, Cyclohexyl hydrogens), 2.71 (1H, m,
CH of cyclohexyl), 5.51 (2H, s, CH2), 7.24-7.39 (8H, m,
Ar- H, NH), 7.97 (2H, d, 3JHH = 10.0 Hz, Ar-H) ppm. 13C-
NMR (125 MHz, CDCl3) δ = 14.0 (CH2 of cyclohexyl),
21.1 (CH3), 22.6 (CH2), 29.6 (CH2 of cyclohexyl), 31.9
(CH2 of cyclohexyl), 37.0 (CH of cyclohexyl), 115.5 (CN),
121.9 (CH), 126.4 (CH), 128.8 (CH), 129.6 (C), 130.2
(CH), 131.4 (C), 133.5 (C), 136.8 (C), 137.9 (C), 156.8 (C),
161.5 (C), 167.2 (C) ppm. Anal. Calcd for C25H26N4
(382.51): C, 78.50; H, 6.85; N, 14.65. Found: C, 78.34; H,
6.82; N, 14.69.
IR (KBr, υ/cm−1): 3307 (NH), 2177 (CN), 1653 (C N);
1H-NMR (500 MHz, CDCl3) δ = 2.28 (3H, s, CH3), 3.88
(3H, s, OCH3), 6.95-7.50 (11H, m, Ar-H, NH), 8.11 (2H, d,
3JHH = 10.0 Hz, Ar-H) ppm. 13C-NMR (125 MHz, CDCl3)
δ = 21.1 (CH3), 55.4 (OCH3), 113.9 (CN), 116.3 (CH),
125.9 (CH), 126.3 (CH), 127.4 (C), 129.5 (CH), 129.6
(CH), 129.7 (C), 129.9 (C), 130.1 (C), 130.7 (CH), 130.9
(CH), 134.1 (C), 136.4 (C), 139.8 (C), 154.3 (C), 161.9 (C),
162.5 (C), 164.0 (C) ppm. Anal. Calcd for C25H19ClN4O
(426.90): C, 70.34; H, 4.49; N, 13.12. Found: C, 70.48; H,
4.52; N, 13.07.
4.22 | 4-(Benzylamino)-
6-(4-bromophenyl)-2-cyclohexylpyrimidine-
5-carbonitrile (8e)
ORCID
Hossein Mehrabi https://orcid.org/0000-0002-3264-9213
REFERENCES
IR (KBr, υ/cm−1): 3325 (NH), 2177 (CN), 1665 (C N);
1H-NMR (500 MHz, CDCl3) δ = 1.65-1.80 (10H, m,
Cyclohexyl hydrogens), 2.72 (1H, m, CH of cyclohexyl),
5.40 (2H, s, CH2), 7.24-7.40 (6H, m, Ar-H, NH), 7.63 (2H,
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How to cite this article: Mehrabi H, Hajipour M,
Rezazadeh-Jabalbarezi F, Alizadeh-Bami F.
Synthesis of 1,2,4,5-tetrasubstituted imidazoles and
2,4,5,6-tetrasubstituted pyrimidines: three-
component, the one-pot reaction of arylamidines,
malononitrile, and arylglyoxals or aryl aldehydes.
J Heterocyclic Chem. 2020;1–8. https://doi.org/10.
1002/jhet.4053
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