Microwave-Assisted, One-Pot Multicomponent Synthesis of Some New Cyanopyridines

Article abstract of DOI:10.1002/jhet.2926

An efficient and facile synthesis of cyanopyridines via a one-pot four-component reaction of aromatic aldehydes, acetophenones, malononitrile, or 2-aminoprop-1-ene-1,1,3-tricarbonitrile in presence of sodium alkoxide or ammonium acetate under both microwave and thermal reaction conditions was introduced.

Full text of DOI:10.1002/jhet.2926

Month 2017
Microwave-Assisted, One-Pot Multicomponent Synthesis of Some New
Cyanopyridines
*
Amer A. Amer and Antar A. Abdelhamid
Chemistry Department, Faculty of Science, Sohag University, Sohag 82524, Egypt
*
E-mail: drantar25@yahoo.com
Received February 7, 2017
DOI 10.1002/jhet.2926
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
An efficient and facile synthesis of cyanopyridines via a one-pot four-component reaction of aromatic
aldehydes, acetophenones, malononitrile, or 2-aminoprop-1-ene-1,1,3-tricarbonitrile in presence of sodium
alkoxide or ammonium acetate under both microwave and thermal reaction conditions was introduced.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
reaction times from hours to minutes but it can also reduce
side reactions, increase yields, and enhance reproducibility
compared with conventional heating conditions [20].
According to the current synthetic requirements,
environmentally benign multicomponent procedures
employing MW methodology are particularly welcome.
In view of the aforementioned facts, we have developed
and designed a strategy to perform and achieve highly
substituted pyridines in high yields applying the MW
irradiation technique and using multicomponent coupling
reaction.
The improvement of synthetic methods for
functionalized pyridines is a significant research matter in
organic chemistry due to their importance in the topics of
chemistry and biology. Pyridines are openly dispersed
and found in natural products, pharmaceuticals, vitamins,
and other functional as well as important materials [1–5].
In fact, the pyridine moiety system emerged integral
backbone of more than thousands existing drugs [6–8].
Among a broad range of pyridines, cyanopyridine
achieved a special attention due to it great therapeutic
importance as antihypertensive [9], anticonvulsant [10],
antihypertensive [11], antibacterial [12], anti-inflamatory
[13], antifungal [14], cardiovascular [15], anti-Alzheimer’s
disease [16], antitumor [17], and antiallergic [18]
properties. Therefore, the synthesis of cyanopyridinesis of
current benefit owes to their massive occurrence in
biologically active derivatives.
From an environmental and economic perspective, it is
becoming obvious that the traditional methods of
proceeding chemical synthesis are unsustainable and have
to be changed. Multicomponent coupling reactions
provide a solution because they are more cost effective,
efficient, and less wasteful than traditional methods [19].
Microwave (MW) produces a powerful way to do
synthetic chemistry in the light of the current paradigm
shift to “green chemistry.” Not only can it reduce chemical
RESULTS AND DISCUSSION
In this work, a simple one-pot and efficient method has
been described for the synthesis of substituted
cyanopyridines through a four-component reaction of
aromatic aldehydes, acetophenones, malononitrile, and
sodium alkoxide (molar ratio 1:1:1:1.3) in ethanol or
methanol under MW (method A). Products of 4,6-diaryl-
2-alkoxypyridine-3-carbonitriles 2a–m were procured
(Scheme 1) within a few minutes (1–5 min) of irradiation.
The optimized results are summarized in Table 1. Good
yields were obtained (72–84%), and problems associated
with toxic solvent use were avoided. The same products
2a–m were also produced in good yields under reflux
conditions (68–82%) (method B). The reactions proceeded
© 2017 Wiley Periodicals, Inc.

A. A. Amer and A. A. Abdelhamid
Vol 000
Scheme 1
to completion almost in 3–9 h. And highly pure components
were obtained in good-to-excellent yields, without using
any chromatographic techniques, simply by filtration after
pouring on ice-cold water and acidification by diluted
HCl, washing with water several times, and
recrystallization from ethanol. Also, product 2 was
obtained by a three-component reaction of malononitrile,
sodium alkoxide, and the corresponding chalcone under
MW. From Table 1, it is clear that application of the MW
technique is an efficient and clean method that is superior
to the traditional thermal heating and affords products in
excellent yields and high purity after shorter reaction
times. On the other hand, we found that the reaction time
and the yield vary depending upon the anion catalyst and
that methoxypyridines can be produced in less time and
more yield than ethoxypyridines.
The chemical structure of these components is
determined on the basis of IR, NMR spectral data, and
elemental analyses. The IR spectra of 2a–m did not
contain any absorption band corresponding to a carbonyl
group function. On the other hand, bands assignable for
the nitrile stretching vibration absorption appeared at
2215–2225 cmꢀ1. In the 1H-NMR spectra of the 2-
methoxypyridines 2a–f,
a
singlet at 4.12 ppm
characteristic for the methoxyl group was afforded and
the aromatic protons appeared at 7.08–8.03 ppm, while in
the 2-ethoxypyridines 2g–m, the ethyl group gave rise to
a quartet around 4.59 ppm and a triplet at 1.43 ppm. The
Table 1
Comparison of the yields and reaction times for synthesis of products 2a–m under MW and conventional conditions.
MW irradiation
Method A
Conventional protocol
Method B
Product
2a
2b
2c
2d
2e
2f
X
Y
R
Yield (%)
Time (min)
Yield (%)
Time (h)
Cl
Cl
Cl
Cl
H
Cl
Me
84
81
83
79
80
78
79
80
77
76
81
77
72
2
1
1
2
2
3
2
4
2
5
5
3
5
80
79
82
77
74
78
72
74
69
70
79
71
68
4
5
3
4
4
4
7
6
8
9
7
7
8
Me
Me
Me
Me
Me
Et
MeO
(Me)2N
H
MeO
H
MeO
MeO
Cl
2 g
2 h
2i
Cl
Cl
Cl
Cl
Et
Et
Et
Et
Et
Et
MeO
(Me)2N
H
2j
2 k
2 l
2 m
MeO
MeO
MeO
Cl
MeO
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis of Some New Cyanopyridines
Scheme 2
aromatic protons show as a multiplet at 7.04–8.21 ppm.
13C-NMR spectra substantiated the results of the IR and
1H-NMR analyses. For example, the 13C-NMR spectrum
of 2a shows that the peak at δ 55.04 could be attributed
and characteristic for methoxide carbon in addition to the
aromatic carbons at δ 164.83, 157.06, 156.54, 136.25,
136.06, 130.55, 129.72, 129.39, 129.28, 129.05, 115.60,
114.35, and 93.24.
the conventional methods. Due to the availability of the
starting materials, the simplicity of the procedures, and
the high yields of the products, this synthetic approach
might be valuable for the synthesis of such heterocyclic
systems.
EXPERIMENTAL
The credible mechanism for the formation of products
2a–m was presupposed to proceed through production of
chalcone 1 by reaction between acetophenones and
aromatic aldehydes, then a Michael addition of the
malononitrile anion at α, β-unsaturated ketones to
generated adduct A reacts with alkoxide anion to form
intermediate B, which undergoes intramolecular
cyclization through loss of water to produce C, and
subsequent dehydrogenation of the cyclized product C
procures to the 2-alkoxy cyanopyridines 2a–m (Scheme 1).
Under the same reaction conditions, a one-pot reaction
of aromatic aldehydes, 3-acetylpyridine, malononitrile,
and sodium alkoxide was performing to give a new series
Melting points were measured with a Kofler melting
point apparatus and uncorrected. Infrared spectra (IR)
were recorded with an FT-IR ALPHBROKER-Platinum-
1
ATR (Bruker, Germany). H-NMR and 13C-NMR spectra
were recorded in DMSO-d6 on a Bruker Bio Spin AG
spectrometer (Bruker, Switzerland) at 400 MHz and
100 MHz, respectively. Elemental analyses were obtained
on a Perkin-Elmer CHN analyzer (USA) model. MW
irradiations were carried out in a Kenstar OM9925E MW
oven (2450 MHz, 800 W; India).
General procedure for the synthesis of compounds 2a–m.
Method A: General procedure (MW irradiation). A mixture
of
4-heteroaryl-6-aryl-2-alkoxypyridine-3-carbonitriles
of 0.02 mol of aromatic aldehydes and 0.02 mol of
acetophenone derivatives was added to sodium alkoxide
solution (0.022 mol of sodium in 10 mL of each of
absolute methanol and ethanol, respectively) and was
stirred for 5 min at room temperature, then malononitrile
(0.02 mol) was added and the reaction mixture was
irradiated in an MW oven for 1–4 min (Table 1). After
cooling to room temperature, the precipitated products
were filtered and recrystallized from suitable solvent.
3a–d with high yields (Scheme 2).
The same methodologies were prolonged for the
synthesis
phenylpyridin-3-yl]methylidene}propanedinitrile 4 under
the similar reaction conditions, using 4-
of
{amino[6-(4-chlorophenyl)-2-ethoxy-4-
chlorpacetophenone, benzaldehyde, tricyanoaminopropene,
and sodium ethoxide. We have then looked into possible
replacing sodium alkoxide by ammonium acetate, hoping
to achieve 2-amino-6-(4-chlorophenyl)-4-arylpyridine-3-
carbonitrile 5a,b the goal was supposed to implement, and
product 5a,b was separated in about 71% yield
(Scheme 3). The chemical structure of produces 4 and 5a,
b was approved by IR, NMR, and elemental analysis.
Method B: General procedure (conventional heating).
A
mixture of 0.02 mol of aromatic aldehydes and 0.02 mol
of acetophenone derivatives was added to sodium
alkoxide solution (0.022 mol of sodium in 60 mL of each
of absolute methanol and ethanol, respectively) and was
stirred for 5 min at room temperature, then malononitrile
(0.02 mol) was added and the reaction mixture was
refluxed for 3–9 h (Table 1). On completion of the
reaction (TLC monitoring), the reaction mixture was
allowed to cool to room temperature. The solid
precipitates were collected by filtration, dried, and
recrystallized from suitable solvent.
CONCLUSION
Microwave irradiation technique can be used as a
facile and fast method for synthesis of some new
substituted cyanopyridines in high yields compared with
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. A. Amer and A. A. Abdelhamid
Vol 000
Scheme 3
6-(4-Chlorophenyl)-2-methoxy-4-phenylpyridine-3-carbonitrile
C21H18ClN3O (363): C, 69.32; H, 4.99; N, 11.55. Found:
(2a). mp 180°C; IR: 2987, 2946 (CH-aliph), 2225 (CN);
C, 69.42; H, 4.80; N, 11.45.
2-Methoxy-6-(4-methoxyphenyl)-4-phenylpyridine-3-carbonitrile
(2e). mp 180°C; IR: 2950, 2844 (CH-aliph), 2217 (CN);
1H-NMR: δ 8.30 (t, J = 4, 8 Hz, 2H, arom), 7.86 (s,1H,
pyridine nucleus), 7.76 (s, 2H, arom), 7.60 (s, 5H, arom),
4.15 (s, 3H, OCH3); 13C-NMR: δ 164.83, 157.06, 156.54,
136.25, 136.06, 130.55, 129.72, 129.39, 129.28, 129.05,
115.60, 114.35, 93.24, 55.04. Anal. Calcd. for
C19H13ClN2O: C, 71.14; H, 4.08; N, 8.73. Found: C,
1H-NMR: δ 8.24 (s, 2H, arom), 7.73 (s, 3H, 2H,
arom + 1H, pyridine nucleus), 7.59 (s, 3H, arom), 7.08 (s,
2H, arom), 4.13 (s, 1H, OCH3), 3.84 (s, 3H, OCH3); 13C-
NMR: δ 164.79, 162.01, 157.68, 156.66, 136.53, 130.37,
129.62, 129.24, 128.98, 114.82, 113.24, 91.73, 55.89, 54.82.
Anal. Calcd. for C20H16N2O2 (316): C, 75.93; H, 5.10; N,
71.08; H, 4.20; N, 8.69.
4,6-Bis(4-chlorophenyl)-2-methoxypyridine-3-carbonitrile
(2b). mp >300°C; IR: 2990, 2942 (CH-aliph), 2224
8.86. Found: C, 76.02; H, 5.19; N, 8.85.
1
(CN); H-NMR: δ 8.27 (d, J = 8 Hz, 2H, arom), 7.95
2-Methoxy-4,6-bis(4-methoxyphenyl)pyridine-3-carbonitrile
(2f). mp 196°C; IR: 2951, 2931, 2838 (CH-aliph), 2215
(d, J = 8 Hz, 2H, arom), 7.87 (s,1H, pyridine nucleus),
7.58 (t, J = 4, 12 Hz, 3H, arom), 7.12 (s, 1H, arom),
4.01 (s, 3H, OCH3). Anal. Calcd. for C19H12Cl2N2O:
C, 64.24; H, 3.40; N, 7.89. Found: C, 64.25; H, 3.43;
1
(CN); H-NMR: δ 8.24 (s, 2H, arom), 7.72 (s, 3H, 2H,
arom + 1H, pyridine nucleus), 7.14 (s, 2H, arom), 7.08
(s, 2H, arom), 4.13 (s, 3H, OCH3), 3.85 (s, 6H, 2OCH3).
Anal. Calcd. for C21H18N2O3 (346): C, 72.82; H, 5.24;
N, 7.75.
6-(4-Chlorophenyl)-2-methoxy-4-(4-methoxyphenyl)pyridine-
3-carbonitrile (2c). mp 236°C; IR: 2981, 2945 (CH-aliph),
N, 8.09. Found: C, 72.79; H, 5.32; N, 8.17.
6-(4-Chlorophenyl)-2-ethoxy-4-phenylpyridine-3-carbonitrile
(2g). mp 148°C; IR: 2984, 2973 (CH-aliph), 2220 (CN);
2221 (CN); 1H-NMR: δ 8. 30 (d, J = 8 Hz, 2H, arom), 7.82
(s, 1H, pyridine nucleus), 7. 75 (d, J = 8 Hz, 2H, arom),
7.60 (d, J = 4 Hz, 2H, arom), 7.15 (d, J = 8 Hz, 2H,
arom), 4.14 (s, 3H, OCH3), 3.87 (s, 3H, OCH3); 13C-
NMR: δ 161.44, 156.62, 156.31, 136.15, 135.96, 130.69,
129.69, 129.36, 114.84, 114.09, 92.73, 55.95, 54.97.
Anal. Calcd. for C20H15ClN2O2: C, 68.48; H, 4.31; N,
1H-NMR: δ 8.26 (t, J = 4 Hz, 2H, arom), 7.79 (s, 1H,
pyridine nucleus), 7.74 (s, 2H, arom), 7.9 (m, 5H, arom),
4.64 (q, J = 4, 2H, CH2), 1.46 (t, J = 4 Hz, 3H, CH3); 13C-
NMR: δ 164.47, 157.04, 156.52, 136.31, 136.03, 130.49,
129.65, 129.37, 129.25, 129.03, 115.59, 114.15, 93.28,
63.67, 15.00. Anal. Calcd. for C20H15ClN2O (334.5): C,
71.75; H, 4.52; N, 8.37. Found: C, 71.43; H, 4.28; N, 8.18.
4,6-Bis(4-chlorophenyl)-2-ethoxypyridine-3-carbonitrile
(2h). mp 240°C; IR: 2995, 2961 (CH-aliph), 2218 (CN);
7.99. Found: C, 68.50; H, 4.20; N, 8.01.
6-(4-Chlorophenyl)-4-[4-(dimethylamino)phenyl]-2-
methoxypyridine-3-carbonitrile (2d). mp 287°C; IR: 2994,
1H-NMR: δ 8.30 (d, J = 8 Hz, 2H, arom), 7.87 (s, 1H,
pyridine nucleus), 7.80 (d, J = 8 Hz, 2H, arom), 7.68 (d,
J = 8 Hz, 2H, arom), 7.62 (d, J = 8 Hz, 2H, arom), 4.65
(q, J = 7 Hz, 2H, CH2), 1.45 (t, J = 7 Hz, 3H, CH3).
1
2946 (CH-aliph), 2215 (CN); H-NMR: δ 8.28 (s, 2H,
arom), 7.77 (s, 1H, pyridine nucleus), 7.68 (s, 2H, arom),
7.60 (s, 2H, arom), 6.86 (s, 2H, arom), 4.12 (s, 3H,
OCH3), 3.02 (s, 6H, N(CH3)2). Anal. Calcd. for
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis of Some New Cyanopyridines
Anal. Calcd. for C20H14Cl2N2O (369): C, 65.06; H, 3.82;
N, 7.59. Found: C, 65.21; H, 3.68; N, 7.58.
General procedure for the synthesis of compounds 3a–d.
Method A: General procedure (MW irradiation). A mixture
6-(4-Chlorophenyl)-2-ethoxy-4-(4-methoxyphenyl)pyridine-3-
carbonitrile (2i). mp 162°C; IR: 2993, 2955, 2848 (CH-
aliph), 2217 (CN); H-NMR: δ 8.29 (d, J = 9 Hz, 2H,
of 0.02 mol of aromatic aldehydes and 0.02 mol of 3-
acetylpyridine was added to sodium alkoxide solution
(0.022 mol of sodium in 10 mL of each of absolute
methanol and ethanol, respectively) and was stirred for
5 min at room temperature, then malononitrile (0.02 mol)
was added and the reaction mixture was irradiated in a
MW oven for 1–4 min. (Table 1). After cooling to room
temperature, the precipitated products were filtered and
recrystallized from suitable solvent.
1
arom), 7.82 (s, 1H, pyridine nucleus), 7.76 (d, 2H,
J = 9 Hz, arom), 7.72 (d, 2H, J = 9 Hz, arom), 7.16 (d,
J = 9 Hz, 2H, arom), 4.63 (q, J = 7 Hz, 2H, CH2), 3.86 (s,
3H, OCH3), 1.44 (t, J = 7 Hz, 3H, CH3); 13C-NMR: δ
164.61, 161.40, 156.62, 156.31, 136.20, 135.92, 130.66,
129.62, 129.35, 128.41, 115.89, 114.82, 113.90, 92.79,
63.57, 55.93, 14.78. Anal. Calcd. for C21H17ClN2O2
(364.5): C, 69.14; H, 4.70; N, 7.68. Found: C, 69.19; H,
Method B: General procedure (conventional heating).
A
mixture of 0.02 mol of aromatic aldehydes and 0.02 mol
of 3-acetylpyridine was added to sodium alkoxide
solution (0.022 mol of sodium in 60 mL of each of
absolute methanol and ethanol, respectively) and was
stirred for 5 min at room temperature, then malononitrile
(0.02 mol) was added and the reaction mixture was
refluxed for the time indicated in Table 1. On completion
of the reaction (TLC monitoring), the reaction mixture
was allowed to cool to room temperature. The solid
precipitate was collected by filtration, dried, and
4.99; N, 7.61.
6-(4-Chlorophenyl)-4-[4-(dimethylamino)phenyl]-2-ethoxypyridine-
3-carbonitrile (2j). mp 209°C; IR: 2971, 2917, 2848 (CH-
1
aliph), 2216 (CN); H-NMR: δ 8.24 (s, 2H, arom), 7.72
(m, 3H, 2H, arom + 1H, pyridine nucleus), 7.66–758 (m,
2H, arom), 6.85 (s, 2H, arom), 4.59 (q, J = 5 Hz, 2H,
CH2), 3.86 (s, 3H, OCH3), 3.01 (s, 6H, N(CH3)2), 1.42 (t,
J = 5 Hz, 3H, CH3); 13C-NMR: δ 164.84, 156.87, 155.88,
152.07, 136.40, 135.71, 130.11, 129.51, 129.29, 122.76,
116.39, 113.24, 112.25, 91.68, 63.38, 40.14, 14.80. Anal.
Calcd. for C22H20ClN3O (377.5): C, 69.93; H, 5.33; N,
recrystallized from suitable solvent.
6-Methoxy-4-(4-methoxyphenyl)-2,30-bipyridine-5-carbonitrile
(3a). Yield (method A 83%, method B 80); mp 241°C; IR:
2953, 2845 (CH-aliph), 2219 (CN); 1H-NMR: δ 9.43 (s, 1H,
11.12. Found: C, 69.87; H, 5.22; N, 11.10.
2-Ethoxy-6-(4-methoxyphenyl)-4-phenylpyridine-3-carbonitrile
(2k). mp 181°C; IR: 2984, 2947, 2898 (CH-aliph), 2216
pyridine nucleus), 8.71 (s, 1H, pyridine nucleus), 8.60 (d,
J = 7 Hz, 1H, pyridine nucleus), 7.66 (s, 1H, pyridine
nucleus), 7.77 (d, J = 9 Hz, 2H, arom), 7.57 (s, 1H,
pyridine nucleus), 7.16 (d, J = 8 Hz, 2H, arom), 4.18 (s,
3H, OCH3), 3.88 (s, 3H, OCH3); 13C-NMR: δ 165.09,
161.49, 156.69, 155.44., 151.55, 149.10, 135.26, 132.91,
130.75, 128.24, 124.24, 115.82, 114.87, 114.47, 93.15,
55.96, 55.10. Anal. Calcd. for C19H15N3O2 (317): C,
1
(CN); H-NMR: δ 8.21 (s, 2H, arom), 7.72 (m, 3H, 2H,
arom + 1H, pyridine nucleus), 7.58 (m, 3H, arom), 7.07 (s,
2H, arom), 4.61 (q, J = 7 Hz, 2H, CH2), 3.84 (s, 3H,
OCH3), 1.44 (t, J = 7 Hz, 3H, CH3); 13C-NMR: δ 164.45,
161.98, 157.67, 156.68, 136.60, 130.33, 129.69, 129.55,
129.22, 128.96, 115.86, 114.82, 113.08, 91.79, 63.42,
55.89, 14.80. Anal. Calcd. for C21H11N2O2 (330): C,
76.34; H, 5.49; N, 8.48. Found: C, 76.57; H, 5.35; N, 8.31.
4-(4-Chlorophenyl)-2-ethoxy-6-(4-methoxyphenyl)pyridine-3-
carbonitrile (2l). mp 231°C; IR: 2973, 2939, 2840 (CH-
71.91; H, 4.76; N, 13.24, Found: C, 72.00; H, 4.62; N, 13.19.
4-[4-(Dimethylamino)phenyl]-6-methoxy-2,30-bipyridine-5-
carbonitrile (3b). Yield (method A 85%, method B 83);
aliph), 2217 (CN); 1H-NMR: δ 8.16 (s, 2H, arom), 7.71 (m,
2H, arom), 7.64 (m, 3H, 2H, arom + 1H, pyridine nucleus),
7.04 (s, 2H, arom) 4.56 (q, J = 4 Hz, 2H, CH2), 3.82 (s,
3H, OCH3), 1.42 (t, J = 4 Hz, 3H, CH3); 13C-NMR: δ
164.38, 162.01, 157.77, 155.24, 135.41, 135.31, 130.84,
129.54, 129.24, 115.70, 114.77, 112.91, 91.65, 63.45,
55.85, 14.76. Anal. Calcd. for C21H17ClN2O2 (364.5): C,
mp 264°C; IR: 2995, 2946, 2856 (CH-aliph), 2215 (CN);
1H-NMR: δ 9.40 (s, 1H, pyridine nucleus), 8.69 (s, 1H,
pyridine nucleus), 8.56 (d, J = 7 Hz, 1H, pyridine
nucleus), 7.81 (s, 1H, pyridine nucleus) 7.69 (d,
J = 8 Hz, 2H, arom), 7.55 (s, 1H, pyridine nucleus), 6.86
(d, J = 8 Hz, 2H,arom), 4.14 (s, 3H, OCH3), 3.02 (s, 6H,
N(CH3)2). Anal. Calcd. for C20H18N4O (330): C, 72.71;
H, 5.49; N, 16.96. Found: C, 72.83; H, 5.50; N, 17.00.
6-Ethoxy-4-phenyl-2,30-bipyridine-5-carbonitrile (3c). Yield
(method A 79%, method B 78); mp 232°C; IR: 2974, 2918,
2848 (CH-aliph), 2223 (CN); 1H-NMR: δ 9.37 (s, 1H,
pyridine nucleus), 8.64 (s, 1H, pyridine nucleus), 8.30 (m,
1H, pyridine nucleus), 7.93 (t, 3H, J = 8 Hz, 2H,
arom + 1H, pyridine nucleus), 7.57–7.09 (m, 2H, arom),
7.09 (s, 1H, pyridine nucleus), 4.50 (q, J = 8 Hz, 2H, CH2),
1.41 (t, J = 8 Hz, 3H, CH3); 13C-NMR: δ 164.52, 155.78,
152.79, 150.70, 150.33, 148.50, 136.51, 134.75, 134.45,
69.14; H, 4.70; N, 7.68. Found: C, 79.31; H, 4.71; N, 7.70.
2-Ethoxy-4,6-bis(4-methoxyphenyl)pyridine-3-carbonitrile
(2m). mp 184°C; IR: 2984, 2950, 2835 (CH-aliph), 2218
1
(CN); H-NMR: δ 8.20 (s, 2H, arom), 7.71–7.66 (m, 3H,
2H, arom + 1H, pyridine nucleus), 7.13–7.07 (m, 2H,
arom) 4.59 (q, J = 4 Hz, 2H, CH2), 3.85 (s, 6H, 2OCH3),
1.43 (t, J = 4 Hz, 3H, CH3); 13C-NMR: δ 164.57, 161.90,
161.26, 157.45, 156.23, 130.4, 129.80, 129.49, 128.70,
116.15, 114.78, 112.80, 91.36, 63.32, 55.89, 14.81. Anal.
Calcd. for C22H20N2O3 (360): C, 73.32; H, 5.59; N, 7.77.
Found: C, 73.31; H, 5.42; N, 7.64.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. A. Amer and A. A. Abdelhamid
Vol 000
134.27, 129.41, 124.04, 107.62, 93.67, 61.96, 14.97. Anal.
Calcd. for C19H15N3O (301): C, 75.73; H, 5.02; N, 13.94.
for 15 min at room temperature, then malononitrile
(0.02 mol) in 10 mL of ethanol was added and the
reaction mixture was irradiated in an MW oven for
6 min. On cooling at room temperature, the precipitated
products were filtered and recrystallized from ethanol.
Found: C, 75.80; H, 5.00; N, 13.69.
4-[4-(Dimethylamino)phenyl]-6-ethoxy-2,30-bipyridine-5-
carbonitrile (3d). Yield (method A 82%, method B 80);
mp 261°C; IR: 2984, 2900, 2812 (CH-aliph), 2216 (CN);
1H-NMR: δ 9.37 (s, 1H, pyridine nucleus), 8.68 (d,
J = 4 Hz, 1H, pyridine nucleus), 8.54 (d, J = 8 Hz, 1H,
pyridine nucleus), 7.78 (s, 1H, pyridine nucleus), 7.78 (d,
J = 9 Hz, 2H, arom), 7.54 (t, J = 8 Hz, 1H, pyridine
nucleus), 6.85 (d, J = 8 Hz, 2H, arom), 4.62 (q, J = 7 Hz,
2H, CH2), 3.02 (s, 6H, N(CH3)2), 1.44 (t, J = 7 Hz, 3H,
CH3); 13C-NMR: δ 169.26, 167.42, 166.90, 151.31,
148.94, 135.07, 139.13, 130.17, 129.76, 129.46, 124.17,
113.60, 112.23, 107.62, 92.17, 63.50, 40.17, 14.79. Anal.
Calcd. for C21H20N4O (344): C, 73.23; H, 5.85; N,
16.27. Found: C, 73.30; H, 5.78; N, 16.20.
Method B: General procedure (conventional heating).
A
mixture of aromatic aldehydes (0.02 mol), 4-
chloroacetophenone (0.02 mol), and ammonium acetate
(0.03 mol) was stirred for 15 min at room temperature,
then malononitrile (0.02 mol) in 60 mL of ethanol was
added and the reaction mixture was allowed to reflux for
9 h. On completion of the reaction (TLC monitoring), the
reaction mixture was allowed to cool to room
temperature. The solid precipitate was collected by
filtration, dried, and recrystallized from ethanol.
2-Amino-6-(4-chlorophenyl)-4-phenylpyridine-3-carbonitrile
(5a). Yield (method A 78%, method B 76); mp 228°C;
1
IR: 3500, 3395 (NH2), 2209 (CN); H-NMR: δ 8.18 (d,
Synthesis of {[6-(4-chlorophenyl)-2-ethoxy-4-phenylpyridin-3-yl]
J = 8 Hz, 2H, arom), 7.68 (d, 2H, J = 8 Hz, 2H, arom),
7.55 (d, J = 4 Hz, 5H, arom), 7.32 (s, 1H, pyridine
nucleus), 7.06 (br, s, 2H, NH2); 13C-NMR: δ 161.27,
157.80, 155.57, 137.40, 136.91, 135.44, 130.06, 129.49,
129.15, 128.77, 117.28, 114.37, 109.81, 87.69. Anal.
Calcd. for C18H12ClN3 (305.5): C, 70.71; H, 3.96; N,
methylidene}-propanedinitrile 4. Method A: General procedure
(MW irradiation).
A
mixture of benzaldehyde
(0.02 mol), 4-chloroacetophenone (0.02 mol), and sodium
ethoxide solution (0.022 mol of sodium in 15 mL of each
of absolute methanol and ethanol, respectively) was
stirred for 10 min at room temperature, then 2-aminoprop-
1-ene-1,1,3-tricarbonitrile (0.02 mol) was added and the
reaction mixture was irradiated in an MW oven for 3 min.
On cooling at room temperature, the precipitated products
were filtered and recrystallized from ethanol.
13.74. Found: C, 70.70; H, 4.00; N, 13.69.
2-Amino-6-(4-chlorophenyl)-4-(4-methoxyphenyl)pyridine-
3-carbonitrile (5b).
Yield (method A 75%, method B
1
76); mp 243°C; IR: 3455, 3363 (NH2), 2205(CN); H-
NMR: δ 8.16 (d, J = 12 Hz, 2H, arom), 7.67 (d, 2H,
J = 8 Hz, 2H,arom), 7.56 (d, J = 8 Hz, 2H, arom), 7.28
(s, 1H, pyridine nucleus), 7.12 (d, J = 12 Hz, 2H,
arom), 7.00 (br, s, 2H, NH2), 3.85(s, 3H, OCH3); 13C-
Method B: General procedure (conventional heating).
A
mixture
of
benzaldehyde
(0.02
mol),
4-
chloroacetophenone (0.02 mol), and sodium ethoxide
solution (0.022 mol of sodium in 60 mL of each of
absolute methanol and ethanol, respectively) was stirred
for 10 min at room temperature, then 2-aminoprop-1-ene-
1,1,3-tricarbonitrile (0.015 mol) was added and the
reaction mixture was refluxed for the time indicated in
Table 1. On completion of the reaction (TLC
monitoring), the reaction mixture was allowed to cool to
room temperature. The solid precipitate was collected by
filtration, dried, and recrystallized from ethanol.
NMR:
δ 161.36, 161.09, 157.68, 155.12, 137.06,
135.37, 130.26, 129.54, 129.44, 129.07, 117.51, 114.75,
109.69, 87.54, 55.90. Anal. Calcd. for C19H14ClN3O
(335.5): C, 67.96; H, 4.20; N, 12.51. Found: C, 67.64; H,
4.13; N, 12.20.
REFERENCES AND NOTES
Yield (method A 89%, method B 87); mp > 300°C; IR:
3455, 3363 (NH2), 2954, 2928, 2833 (CH-aliph), 2190,
2139 (2CN); H-NMR: δ 8.09 (d, J = 8 Hz, 2H, arom),
7.71 (d, J = 8 Hz, 2H, arom), 7.53–7.46 (m, 5H, 3H,
arom + 2H, NH2), 7.27 (s, 1H, pyridine nucleus), 6.81 (s,
12H, arom); 13C-NMR: δ 162.10, 154.35, 146.56,
138.77, 138.17, 133.82, 133.66, 128.91, 128.75, 128.68,
125.20, 109.68, 107.06, 56.50, 19.00. Anal. Calcd. for
C23H17ClN4O (400.5): C, 68.91; H, 4.27; N, 13.98.
Found: C, 68.89; H, 4.21; N, 13.41.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet