Catalyst-free three-component synthesis of 2-amino-4,6-diarylpyridine-3-carbonitriles under solvent-free conditions

Article abstract of DOI:10.1007/s10593-019-02527-0

[Figure not available: see fulltext.] A novel efficient one-pot synthesis of 2-amino-4,6-diarylpyridine-3-carbonitriles is described. Method involves heating the mixture of an acetophenone oxime, aldehyde, and malononitrile without any catalyst under solvent-free conditions to give the title compounds in good to high yields.

Full text of DOI:10.1007/s10593-019-02527-0

DOI 10.1007/s10593-019-02527-0
Chemistry of Heterocyclic Compounds 2019, 55(8), 725–728
Catalyst-free three-component synthesis
of 2-amino-4,6-diarylpyridine-3-carbonitriles
under solvent-free conditions
1
2
Mohammad Hosein Sayahi *, Seyyed Jafar Saghanezhad ,
Mohammad Mahdavi
3
1
Department of Chemistry, Payame Noor University,
P. O. Box 19395-3697, Tehran, Iran; e-mail: sayahymh@pnu.ac.ir
2
ACECR-Production Technology Research Institute,
P. O. Box 61396-84689, Ahvaz, Iran; e-mail: Saghanezhad@acecr.ac.ir
3
Endocrinology and Metabolism Research Center,
Endocrinology and Metabolism Clinical Sciences Institute,
Tehran University of Medical Sciences,
P. O. Box 14117-13137, Tehran, Iran; e-mail: Mahdavi_chem@yahoo.com
Published in Khimiya Geterotsiklicheskikh Soedinenii,
Submitted October 10, 2018
Accepted after revision May 22, 2019
2
019, 55(8), 725–728
A novel efficient one-pot synthesis of 2-amino-4,6-diarylpyridine-3-carbonitriles is described. Method involves heating the mixture of an
acetophenone oxime, aldehyde, and malononitrile without any catalyst under solvent-free conditions to give the title compounds in good
to high yields.
Keywords: acetophenone oximes, 2-amino-4,6-diarylpyridine-3-carbonitriles, solvent-free synthesis.
1
2–14
Due to their productivity, atom economy, straight-
forward reaction design, convergence and facile execution,
multicomponent reactions (MCRs) have emerged as a
highly efficient tool in modern synthetic organic chemistry
and are widely used for the preparation of chemically and
bacterial, and fungicidal activities.
They have been also
reported as novel IKK-β serine-threonine protein kinase
15
16
inhibitors,
2
A A adenosine receptor antagonists, and
17
potent inhibitors of HIV-1 integrase. Therefore, the
synthesis of these valuable N-containing heterocycles is of
great significance.
1–3
biologically important compounds.
A major challenge for synthetic chemists is to carry out
organic reactions in green solvents or without conventional
organic solvents to develop environment-friendly synthetic
procedures. One of the most promising approaches is
solvent-free organic synthesis. These reactions provide
greater selectivity, proceed with enhanced reaction rates,
So far, several synthetic methods have been reported for
the preparation of 2-amino-4,6-diarylpyridine-3-carbo-
nitrile ring systems. The most common synthetic method
involves the condensation of chalcone or carbonyl com-
pounds with malononitrile and ammonium acetate by
conventional heating in the presence of different
4–6
18–24,25a
give cleaner products, and involve simple manipulations.
catalysts.
Furthermore nitrile oxides with ylidene
25b
25c
The pyridine nucleus is an important class of nitrogen-
containing heterocyclic compounds, since it is widespread
malononitriles and oxime acetates have been used as
starting materials. However, some of these procedures have
certain limitations such as harsh reaction conditions, use of
rare earth Lewis acid catalysts with long reaction times,
high temperatures, toxic benzene as solvent, or tedious
workup with microwave assistance, and low yields.
Although a large number of reactants and functional groups
have been successfully explored in literature, to the best of
7
in natural products, and it is also broadly used in
8
medicinal chemistry and drug synthesis. Pyridines are also
9
used in coordination chemistry, supramolecular struc-
10
11
tures, and organocatalysis. Among them, 2-amino-
pyridine-3-carbonitrile derivatives are known to have
multiple biological activities, such as antiviral, anti-
0
009-3122/19/55(8)-0725©2019 Springer Science+Business Media, LLC
725

Chemistry of Heterocyclic Compounds 2019, 55(8), 725–728
our knowledge, no report has been published concerning
Scheme 2
the use of acetophenone oximes as starting materials for the
preparation of 2-amino-4,6-diarylpyridine-3-carbonitriles.
Due to the fact that acetophenone oxime is commercially
available, it is a readily accessible starting material for
performing the reaction. It should also be mentioned that
the preparation of oximes is very facile in organic
chemistry.
During the course of our studies on the development of
26–30
new routes to the synthesis of heterocyclic compounds,
herein, we disclose a novel and efficient procedure for the
synthesis of 2-amino-4,6-diarylpyridine-3-carbonitrile deri-
vatives 4a–j by condensation of acetophenone oximes 1,
aromatic aldehydes 2, and malononitrile (3) without use of
any catalyst under solvent-free conditions at 150°C in 73–
1
9
0% yields (Scheme 1). TLC and H NMR spectroscopic
analysis of the reaction mixtures clearly indicated forma-
tion of the corresponding 2-amino-4,6-diarylpyridine-
3-carbonitriles 4a–j in good to excellent yields. No product
other than compounds 4a–j could be detected by NMR
spectroscopy. The results are summarized in Table 1. In the
1
3
C NMR spectra of the products, the C–C≡N atom has the
chemical shift in the 88.3–89.0 ppm region due to the
component reaction between acetophenone oximes,
aldehydes, and malononitrile under solvent-free conditions.
The availability of the starting materials, solvent-free
conditions without need of catalyst, and short reaction
times are the main advantages of this approach. To the best
of our knowledge, there is no previous report in the
literature regarding the use of acetophenone oxime as
starting material for the synthesis of 2-aminopyridine-
1
9
anisotropic effect of the nitrile group.
Scheme 1
3-carbonitriles.
Table 1. Yields of 2-aminopyridine-3-carbonitrile derivatives 4a–j
Experimental
H and C NMR spectra were recorded on a Bruker
NMR Avance spectrometer (400 and 100 MHz, respec-
tively) in CDCl with TMS as internal standard. Elemental
analyses (CHNSO) were conducted on an ECS 4010
Costech elemental combustion system. Melting points were
determined using a Thermo Scientific Electrothermal
IA9000 Series Programmable Digital Melting Point
apparatus in a capillary tube and are not corrected. The
progress of reaction was followed with TLC using silica
gel SILG/UV 254 and 365 plates, and the crude products
were purified by column chromatography using silica gel
1
13
Com-
pound
1
2
Ar
Ar
Yield, %
Ref.
3
4
a
Ph
Ph
Ph
88
83
85
73
90
85
76
81
78
89
22
22
19
22
18
20
22
20
24
24
4
b
6 4
4-MeC H
4
c
Ph
4-MeOC
6 4
H
4
d
Ph
Thiophen-3-yl
4
e
Ph
4-ClC
Ph
6
H
4
4
f
6 4
4-MeC H
4
g
4-MeOC
6
H
4
Ph
4
h
4-ClC
6
H
4
Ph
6
0 mesh and n-hexane–EtOAc as eluent.
4
i
4-MeOC
6
6
H
4
4
4-ClC
6
H
4
All chemicals were purchased from Merck and Fluka
4
j
4-MeOC
H
4- MeOC
6
H
4
companies. All synthesized products are known com-
pounds, their physical and spectroscopic data were in
18–20,22,24
Mechanistically, it is reasonable to assume that the first
step may involve nucleophilic attack of the N-hydroxy-
enamine tautomer 5 of oxime 1 on alkylidenemalononitrile
accordance with those previously reported.
Preparation of 2-aminopyridine-3-carbonitriles 4a–j
(General method). A mixture of acetophenone oxime 1
(2.0 mmol), aldehyde 2 (2.0 mmol), and malononitrile (3)
(2.5 mmol) was stirred at 150°C for 30 min. After
completion of the reaction as indicated by TLC, the
reaction mixture was cooled to room temperature and the
residue was purified by column chromatography using
n-hexane–EtOAc, 1:4, as eluent to afford the pure products.
6
, obtained by condensation of aromatic aldehyde 2 with
malononitrile (3), to give intermediate A, followed by
cycloaddition, isomerization, and aromatization through
intermediates B and C to afford 2-aminopyridine-3-carbo-
nitrile 4 (Scheme 2).
In conclusion, we have synthesized a series of 2-amino-
3-cyanopyridine derivatives which are of potential
2-Amino-4,6-diphenylpyridine-3-carbonitrile
(4a).
synthetic and pharmacological interest by one-pot three-
Yield 0.48 g (88%), white solid, mp 178–180°C (mp 176–
7
26

Chemistry of Heterocyclic Compounds 2019, 55(8), 725–728
2
2
1
1
77°C ). H NMR spectrum, δ, ppm (J, Hz): 5.40 (2H, s,
2
161.9. Found, %: C 75.67; H 4.91; N 13.89. C19
Calculated, %: C 75.73; H 5.02; N 13.94.
15 3
H N O.
NH ); 7.23 (1H, s, H Py); 7.46–8.06 (10H, m, H Ph).
1
3
C NMR spectrum, δ, ppm: 88.6; 113.3; 116.0; 117.2;
28.6; 128.7; 129.8; 130.2; 136.7; 137.9; 151.0; 155.1;
58.8; 161.3. Found, %: C 79.67; H 4.93; N 15.42.
2-Amino-6-(4-chlorophenyl)-4-phenylpyridine-3-carbo-
1
1
C
nitrile (4h). Yield 0.49 g (81%), white solid, mp 243–244°C
20
1
(mp 238–241°C ). H NMR spectrum, δ, ppm (J, Hz):
5.35 (2H, s, NH ); 7.18 (1H, d, J = 0.8, H Ar); 7.45 (2H, d,
J = 8.1, H Ar); 7.51–7.55 (3H, m, H Ar); 7.60–7.64 (2H,
18
H
13
N
3
. Calculated, %: C 79.68; H 4.83; N 15.49.
-Amino-4-(4-methylphenyl)-6-phenylpyridine-3-carbo-
nitrile (4b). Yield 0.47 g (83%), white solid, mp 162–164°C
2
2
13
m, H Ar); 7.95 (2H, d, J = 8.1, H Ar). C NMR spectrum,
δ, ppm: 88.7; 111.9; 115.8; 117.3; 125.8; 128.5; 128.6;
129.1; 129.3; 129.5; 129.7; 130.2; 155.1; 155.2; 162.1.
22
1
(
2
mp 160–161°C ). H NMR spectrum, δ, ppm (J, Hz):
.45 (3H, s, CH ); 5.38 (2H, s, NH ); 7.23–8.02 (10H, m,
H Ar). C NMR spectrum, δ, ppm: 20.4; 88.6; 113.2;
19.9; 127.3; 128.4; 128.6; 128.8; 128.9; 129.5; 130.1; 138.2;
51.3; 154.0; 161.0. Found, %: C 79.78; H 5.21; N 14.81.
. Calculated, %: C 79.98; H 5.30; N 14.73.
-Amino-4-(4-methoxyphenyl)-6-phenylpyridinecarbo-
nitrile (4c). Yield 0.51 g (85%), white solid, mp 190–192°C
3
2
13
Found, %: C 70.69; H 3.84; N 13.61. C18
3
H12ClN .
1
1
C
Calculated, %: C 70.71; H 3.96; N 13.74.
2-Amino-4-(4-chlorophenyl)-6-(4-methoxyphenyl)-
19
H
15
N
3
pyridine-3-carbonitrile (4i). Yield 0.52 g (78%), white
24
1
2
solid, mp 195–197°C (mp 195–196°C ). H NMR spectrum,
δ, ppm (J, Hz): 3.81 (3H, s, OCH ); 6.97 (2H, s, NH ); 7.03
3
2
19
1
(
3
mp 192–195°C ). H NMR spectrum, δ, ppm (J, Hz):
.86 (3H, s, OCH ); 5.39 (2H, s, NH ); 7.06 (2H, dd,
J = 6.7, J = 2.1, H Ar); 7.17 (1H, s, H Py); 7.46–8.01 (7H,
m, H Ar). C NMR spectrum, δ, ppm: 55.5; 88.7; 110.7;
14.4; 117.5; 126.3; 128.8; 129.6; 130.7; 138.0; 150.9;
55.7; 159.7; 161.4; 162.9. Found, %: C 75.58; H 5.11;
(2H, d, J = 8.2, H Ar); 7.24 (1H, s, H Py); 7.62 (2H, d, J = 8.2,
H Ar); 7.71 (2H, d, J = 8.2, H Ar); 8.14 (2H, d, J = 8.2, H Ar).
3
2
13
C NMR spectrum, δ, ppm: 55.5; 88.6; 111.7; 115.4;
13
118.5; 127.3; 128.6; 128.8; 129.5; 129.8; 130.5; 138.5; 156.8;
159.3; 162.4; 162.9. Found, %: C 67.81; H 4.14; N 12.42.
1
1
C
19
H
14ClN
3
O. Calculated, %: C 67.96; H 4.20; N 12.51.
2-Amino-4,6-bis(4-methoxyphenyl)pyridine-3-carbo-
nitrile (4j). Yield 0.59 g (89%), white solid, mp 160–162°C
N 13.83. C19
N 13.94.
15 3
H N O. Calculated, %: C 75.73; H 5.02;
24
1
2
-Amino-6-phenyl-4-(thiophen-3-yl)pyridine-3-carbo-
nitrile (4d). Yield 0.40 g (73%), white solid, mp 208–210°C
mp 213–214°C ). H NMR spectrum, δ, ppm: 5.37 (2H, s,
NH ); 6.94 (1H, s, H Py); 7.44–7.56 (7H, m, H Ph,
(mp 159–160°C ). H NMR spectrum, δ, ppm (J, Hz):
3.70 (3H, s, OCH ); 3.86 (3H, s, OCH ); 5.38 (2H, s, NH );
3
3
2
22
1
(
6.97 (2H, d, J = 8.2, H Ar); 7.12 (1H, s, H Py); 7.31 (2H, d,
J = 8.2, H Ar); 7.53 (2H, d, J = 8.2, H Ar); 7.96 (2H, d,
2
13
13
H thiophene); 7.79 (1H, s, H thiophene). C NMR spectrum,
J = 8.2, H Ar). C NMR spectrum, δ, ppm: 54.4; 56.4;
δ, ppm: 88.9; 111.4; 118.3; 126.0; 126.5; 126.9; 127.2;
88.3; 111.3; 115.1; 118.6; 129.1; 129.8; 130.6; 131.4; 135.2;
140.9; 155.9; 160.2; 161.3; 162.4. Found, %: C 72.37;
1
27.3; 128.7; 128.9; 129.5; 131.2; 133.2; 136.3; 152.4.
Found, %: C 69.17; H 4.08; N 15.06; S 11.47. C16
Calculated, %: C 69.29; H 4.00; N 15.15; S 11.56.
H
11
N
3
S.
H 5.06; N 12.59. C20
H 5.17; N 12.68.
H
17
N
3
O
2
. Calculated, %: C 72.49;
2
-Amino-4-(4-chlorophenyl)-6-phenylpyridine-3-carbo-
1
nitrile (4e). Yield 0.55 g (90%), white solid, mp 229–231°C
mp 229–230°C ). H NMR spectrum, δ, ppm: 5.41 (2H, s,
Supplementary information file containing H and
22
1
13
(
C NMR spectra of compounds 4g,j is available from the
journal website http://link.springer.com/journal/10593.
13
NH
2
); 6.87 (1H, s, H Py); 7.45–7.57 (9H, m, H Ar). C NMR
spectrum, δ, ppm: 88.6; 111.7; 116.9; 118.8; 125.3; 128.4;
References
1
1
28.7; 129.1; 129.2; 129.6; 129.7; 129.9; 130.3; 154.8;
61.0. Found, %: C 70.62; H 3.82; N 13.78. C18
H
12ClN
3
.
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Wiley-VCH: Weinheim, 2005.
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Calculated, %: C 70.71; H 3.96; N 13.74.
-Amino-6-(4-methylphenyl)-4-phenylpyridine-3-carbo-
nitrile (4f). Yield 0.48 g (85%), white solid, mp 168–170°C
2
3
20
1
(
mp 182–183°C ). H NMR spectrum, δ, ppm (J, Hz):
2
7
7
.45 (3H, s, CH
.27 (2H, d, J = 9.2, H Ar); 7.20–7.54 (3H, m, H Ar); 7.60–
.65 (2H, m, H Ar); 7.90 (2H, d, J = 8.1, H Ar). C NMR
3 2
); 5.35 (2H, s, NH ); 7.12 (1H, s, H Py);
4
1
3
5
6
spectrum, δ, ppm: 21.5; 88.4; 110.9; 118.3; 127.5; 128.2;
1
1
28.6; 129.4; 129.8; 134.1; 136.0; 138.6; 151.4; 154.0;
58.8; 161.3. Found, %: C 79.81; H 5.26; N 14.72.
C
19
H
2
15
N
3
. Calculated, %: C 79.98; H 5.30; N 14.73.
-Amino-6-(4-methoxyphenyl)-4-phenylpyridine-3-carbo-
nitrile (4g). Yield 0.46 g (76%), white solid, mp 166–168°C
7. Allais, C.; Grassot, J.-M.; Rodriguez J.; Constantieux, T.
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8
22
1
Antipin, M. Y.; Magedov, I. V.; Kornienko, A. J. Org. Chem.
(
3
mp 166–167°C ). H NMR spectrum, δ, ppm (J, Hz):
.87 (3H, s, OCH ); 5.39 (2H, s, NH ); 7.03 (2H, dd,
J = 6.8, J = 2.0, H Ar); 7.18 (1H, s, H Py); 7.46–7.62 (5H,
2
007, 72, 3443.
3
2
9
. Bora, D.; Deb, B.; Fuller, A. L.; Slawin, A. M. Z.; Woollins, J. D.;
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3
m, H Ar); 7.97 (2H, dd, J = 6.8, J = 2.1, H Ar). C NMR
spectrum, δ, ppm: 56.4; 89.0; 112.0; 115.4; 118.5; 128.3;
1
1
29.8; 130.2; 130.6; 131.1; 139.1; 155.7; 160.7; 161.4;
7
27

Chemistry of Heterocyclic Compounds 2019, 55(8), 725–728
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