An effective, one-pot synthesis of fully substituted pyridines under microwave irradiation in the absence of solvent

Article abstract of DOI:10.1002/jhet.1035

A convenient, rapid, and environmentally benign protocol is described for the preparation of fully substituted pyridine derivatives via four-component reactions between 2-substituted acetophenones, aromatic aldehydes, malononitrile, and ammonium acetate under microwave irradiation with good yield and without solvent.

Full text of DOI:10.1002/jhet.1035

1346
An Effective, One‐Pot Synthesis of Fully Substituted Pyridines
Vol 50
under Microwave Irradiation in the Absence of Solvent
a
a
b
a
*
Xiao‐Hui Yang, Yong‐Hong Zhou, Ping‐Hu Zhang, and Li‐Yun Zhang
aInstitute of Chemical Industry of Forestry Products, CAF; National Engineering Lab. for Biomass
Chemical Utilization; Key Lab. of Forest Chemical Engineering, SFA; Key Lab. of Biomass
Energy and Material, Nanjing 210042, People’s Republic of China
bJiangsu Center for New Drug Screening and National Drug Screening Laboratory, China
Pharmaceutical University, Nanjing 210009, People’s Republic of China
*
E-mail: yhzhou777@sina.com
Received February 28, 2011
DOI 10.1002/jhet.1035
Published online 12 September 2013 in Wiley Online Library (wileyonlinelibrary.com).
A convenient, rapid, and environmentally benign protocol is described for the preparation of fully
substituted pyridine derivatives via four‐component reactions between 2‐substituted acetophenones,
aromatic aldehydes, malononitrile, and ammonium acetate under microwave irradiation with good yield
and without solvent.
J. Heterocyclic Chem., 50, 1346 (2013).
INTRODUCTION
butylimidazolium hydroxide [12], piperidine/microwave
[13], a Lewis acid, ZnCl2 [14], and mesoporous silica
[15] have been exploited as catalysts to improve the
yields. These three components MCRs provided the fully
substituted pyridines with two identical substitutions.
As part of our current ongoing medicinal chemistry
project aiming to identify novel schistosome treatment, it is
necessary to synthesize the substituted 2‐amino‐3‐
cyanopyridine compounds with five different substituents,
using the aromatic aldehydes from lignin, one of the most
abundant renewable natural resources richly found in wood
pulp and papermaking waste. In that case, it will be easy to
construct diversified pyridines and research their structure‐
activity relationships. The synthesis of such fully substituted
pyridines was not reported, requiring the four‐component
MCRs, when we commenced our research programme.
However, at around the same time as we prepared our
manuscript, Kobayashi et al. reported the first synthesis of
the substituted 2‐amino‐3‐cyanopyridines with five differ-
ent substituents but in rather low yields (11–37%) [7].
Although conductive heating is still the primary way
for chemical transformations, the microwave technology
as an alternative method accelerates reaction rate, shortens
reaction time, and improves product yields. Because of
transferring energy directly to the reactive species, the
microwave synthesis attracts the interests of chemists to
exploit new chemical reactions [16]. A synthesis of
The synthesis of 2‐amino‐3‐cyanopyridine deriva-
tives, a group of compounds containing the pyridine
scaffold [1], has captured much attention of synthetic
chemists due to their biological activities of antimicro-
bial [2], antihypertensive [3], cardiovascular [4], anti‐
inflammatory, analgesic, and antipyretic properties [5]
as well as IKK‐β inhibitory activity [6]. Additionally, a
variety of heterocyclic compounds have been prepared
with them as the important intermediates [7]. Although
the highly substitute pyridines could be obtained widely
in stepwise methods, for example, the preparation of 2‐
amino‐6‐aryl‐4‐methylsulfanylnicotinonitriles was carried
out on ring transformation of 6‐aryl‐3‐cyano‐4‐
methylsulfanyl‐2H‐pyran‐2‐ones by using cyanamide as
a nucleophilic source [8], the multicomponent reactions
(MCRs), a valuable approach widely applied to synthesis
of pyridines [9], attracted our interest due to its excep-
tional synthetic efficiency, usually providing a robust
protocol for constructing a chemically diverse range of
molecules by the introduction of several functional
groups in a single chemical event [10]. The preparation
of fully substituted pyridines via a three‐component
reaction was first reported using triethylamine or 1,4‐
diazabicyclo[2.2.2]octane as a catalyst with unsatisfactory
yields (20–48%) [11]. A basic ionic liquid 1‐methyl‐3‐
© 2013 HeteroCorporation

November 2013 An Effective, One‐Pot Synthesis of Fully Substituted Pyridines under Microwave
1347
Irradiation in the Absence of Solvent
Scheme 1
possible generation of ethoxide ion in the presence of
NH4OAc that might facilitate the intermediate forma-
tion. Such expectation was not realized as trace of the
desired product was observed and no product could be
isolated (Table 1, entry 1). Once the solvent was changed
to 1,4‐dioxane, more product was obtained but the yield
was still poor (20%, Table 1, entry 2). Interestingly, when
the reaction was carried out without any solvent, we isolated
the desired fully substituted pyridine 5a in a yield of 49%
(Table 1, entry 3). Next, the microwave technology was
applied for the reaction either with or without solvent. Not
surprisingly, the yield was improved under microwave irra-
diation (Table 1, entries 4–6). Again, it was also noticed that
more product was formed in neat instead of in the solvents.
The microwave technology application not only increased
the yield but also shorten the reaction time—even after
2‐min reaction time, 67% of the product was afforded
(Table 1, entry 6) and longer irradiation could increase the
yield from 67–71% to 75% (Table 1, entries 7 and 8).
After establishment of a general experimental protocol,
we applied the optimized conditions for the four compo-
nents MCRs with different 4‐hydroxy‐benzyladehydes
and ethylphenylketones (Table 2). The different substitu-
ents on 4‐hydroxy‐benzyladehydes showed no impact on
the yield (Table 2, entries 1–3). A Cl‐substituent on the
ethylphenylketone gave the corresponding pyridine
derivates in similar yields as well (Table 2, entries 4–6),
while the reaction with benzylphenylketone provided the
products in slightly lower yield (Table 2, entries 7–9)
as expected because of the steric hindrance of the
phenyl group.
2,3,4,6‐substituted pyridines with the microwave technol-
ogy [7] was reported. This encourages us to continue our
effort toward the synthesis of the fully substituted 2‐
amino‐3‐cyanopyridines under microwave irradiation.
Herein, we report the synthesis of fully substituted pyri-
dines by the one‐pot, four‐component reaction of aromatic
aldehydes obtained from lignin, 2‐substituted acetophenones,
malononitrile, and ammonium acetate under microwave
irradiation (Scheme 1). The study on antischistosome activity
of the synthesized compounds is currently under the way, and
the results will be reported separately.
RESULTS AND DISCUSSION
Our study started with exploration and optimization
for the synthesis of fully substituted pyridine derivatives
under different reaction parameters and conditions using
propiophenone (1 mmol), syringaldehyde (1 mmol),
ammonium acetate (2 mmol), and malononitrile
(1 mmol) (Table 1) as a model reaction. The transfor-
mation was first performed in EtOH considering the
Table 1
Optimization of reaction conditions for the synthesis of highly substituted
pyridines.a
Table 2
One‐pot synthesis of highly substituted pyridine derivatives 5a–i.
Yield
Entries
Solvents Temperature MW
Time
(%)b
c
Entries
Products
R1
R2
R3
R4
Yield (%)a
1
2
3
4
5
6
7
8
Ethanol
1,4‐Dioxane
No solvent
Ethanol
1,4‐Dioxane
No solvent
No solvent
No solvent
Reflux
Reflux
110°C
110°C
110°C
110°C
110°C
110°C
No Overnight
No Overnight
No Overnight
Yes 10 min
Yes 10 min
–
20
49
13
37
67
71
75
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
OMe
OMe
H
OMe
OMe
H
OMe
OMe
H
OMe
H
H
OMe
H
H
OMe
H
H
Me
Me
Me
Me
Me
Me
Ph
H
H
H
Cl
Cl
Cl
H
75
72
73
76
71
72
64
66
63
Yes
Yes
Yes
2 min
5 min
10 min
aPropiophenone (1 mmol), syringaldehyde (1 mmol), malononitrile (1 mmol)
and ammonium acetate (2 mmol).
bIsolated yield.
Ph
Ph
H
H
cNo product isolated.
aIsolated yield.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1348
X.‐H. Yang, Y.‐H. Zhou, P.‐H. Zhang, and L.‐Y. Zhang
Vol 50
ionization (ESI). 1H‐NMR and 13C‐NMR spectra were recorded with
a Bruker DRX‐300 Avance spectrometer at 300 and 75 MHz,
respectively. Elemental analyses (C, H, N, and S) were conducted
using a PE‐2400(II) elemental analyser, and results were found to
be in good agreement ( 0.2%) with the calculated values.
Typical procedure for the preparation of highly substituted
pyridines. A grinded mixture of the 2‐substituted acetophenone
(1 mmol), aromatic aldehyde (1 mmol), malononitrile (1 mmol),
and ammonium acetate (2 mmol) was put in a 20‐mL reactor
without removal of air and irradiated in a microwave oven at 110°
C for 10 min. The reaction mixture was cooled to room
temperature. The crude product was purified by recrystallization or
column chromatography.
4‐(4‐Hydroxy‐3,5‐dimethoxyphenyl)‐5‐methyl‐6‐phenyl‐2‐
Figure 1. Structure of 5i-ethanol.
amino‐3‐cyanopyridine 5a (0.27 g, 75%). IR (KBr)
ν
(cm−1): 3483, 3366, 3222, 2970, 2938, 1626, 1604, 1556,
1518, 1448, 1245, 1114, 723, 706; 1H‐NMR (300 MHz,
DMSO‐d6) δ (ppm): 7.40–7.54 (m, 5H, ArH), 6.67 (s, 2H,
ArH), 3.80 (s, 6H, 2×OCH3), 1.92 (s, 3H, CH3); 13C‐NMR
1
All the products were characterized with IR, H‐NMR,
13C‐NMR, mass spectrometry (MS), and elemental
analysis (EA). Furthermore, the structure of 5i·ethanol
was established by the X‐ray crystallographic analysis
(Fig. 1, CCDC 804795) [17].
The mechanism of the formation of fully substituted
pyridines was discussed by Magedov et al. [11], Beining
Chen [13], and Banerjee et al. [15]. According to our
results, we believe that the oxidation with atmospheric
oxygen contributed to some more content than the
Knoevenagel adduct hydrogen‐transfer as the yields in
our hands were much higher (up to 75%) under microwave
irradiation in a sealed system but without removal of air.
(75.5 MHz, DMSO‐d6)
δ (ppm): 161.7, 158.4, 156.1,
148.3, 140.5, 136.2, 129.2, 128.8, 128.4, 127.3, 117.7,
117.4, 106.7, 90.0, 56.7, 17.4; MS (ESI) m/z: 362.1 [M
+H]+, 384.1 [M+Na]+; Anal. Calcd. for C21H19N3O3: C,
69.79; H, 5.30; N, 11.63; found: C, 69.71; H, 5.35; N,
11.74.
4‐(4‐Hydroxy‐3‐methoxyphenyl)‐5‐methyl‐6‐phenyl‐2‐amino‐
3‐cyanopyridine 5b (0.24 g, 72%). IR (KBr) ν (cm−1): 3477,
3349, 3226, 2222, 1631, 1558, 1515, 1448, 1271, 1244, 1216,
1
1121, 776; H‐NMR (300 MHz, DMSO‐d6) δ (ppm): 7.42–7.52
(m, 5H, ArH), 6.96 (d, 1H, ArH, J = 1.8 Hz), 6.91 (d, 1H,
ArH, J = 7.8 Hz), 6.91 (dd, 1H, ArH, J = 1.8, 7.8 Hz), 3.80
(s, 3H, OCH3), 1.89 (s, 3H, CH3); 13C‐NMR (75.5 MHz,
DMSO‐d6) δ (ppm): 161.7, 158.4, 155.9, 147.9, 147.3, 140.5,
129.2, 128.8, 128.4, 128.3, 121.7, 117.7, 117.4, 115.8, 113.2,
90.0, 56.3, 17.3; MS (ESI) m/z: 332.0 [M+H]+, 354.0 [M
+Na]+, 370.0 [M+K]+; Anal. Calcd. for C20H17N3O2: C,
72.49; H, 5.17; N, 12.68; found: C, 72.41; H, 5.29; N, 12.60.
4‐(4‐Hydroxyphenyl)‐5‐methyl‐6‐phenyl‐2‐amino‐3‐cyanopyridine
5c (0.22 g, 73%). IR (KBr) ν (cm−1): 3447, 3330, 3224, 2212, 1644,
1557, 1486, 1408, 1301, 770, 712; 1H‐NMR (300 MHz, DMSO‐
d6) δ (ppm): 7.67–7.71 (m, 2H, ArH), 7.42–7.58 (m, 3H, ArH),
7.38 (d, 2H, ArH, J = 8.1 Hz), 7.16 (d, 2H, ArH, J = 8.1 Hz),
1.90 (s, 3H, CH3); 13C‐NMR (75.5 MHz, DMSO‐d6) δ (ppm):
165.4, 161.9, 159.4, 151.0, 138.2, 130.5, 129.0, 128.9, 128.6,
128.5, 117.2, 115.5, 115.4, 81.5, 16.9; MS (ESI) m/z: 302.1
[M+H]+, 324.0 [M+Na]+, 340.0 [M+K]+; Anal. Calcd. for
C19H15N3O: C, 75.73; H, 5.02; N, 13.94; found: C, 75.79; H,
5.21; N, 14.00.
4‐(4‐Hydroxy‐3,5‐dimethoxyphenyl)‐5‐methyl‐6‐(4‐chlorophenyl)‐
2‐amino‐3‐cyanopyridine 5d (0.30 g, 76%). IR (KBr) ν (cm−1): 3463,
3364, 3239, 2203, 1642, 1611, 1551, 1520, 1415, 1332, 1125, 831;
1H‐NMR (300 MHz, DMSO‐d6) δ (ppm): 8.69 (s, 1H, OH),
7.51–7.59 (m, 4H, ArH), 6.66–6.70 (m, 4H, ArH, NH2), 3.80
(s, 6H, 2×OCH3), 1.91 (s, 3H, CH3); 13C‐NMR (75.5 MHz,
DMSO‐d6) δ (ppm): 159.8, 158.0, 155.8, 147.9, 138.9, 136.0,
133.1, 130.7, 128.0, 126.7, 117.1, 116.8, 106.3, 89.8, 56.2,
16.9; MS (ESI) m/z: 396.1 [M+H]+, 418.1 [M+Na]+; Anal.
Calcd. for C21H18ClN3O3: C, 63.72; H, 4.58; N, 10.62; found:
C, 63.83; H, 4.50; N, 10.51.
CONCLUSIONS
A microwave irradiated four‐component MCR was
described for the rapid solvent‐free synthesis of fully
substituted pyridine derivatives with five different substitu-
ents in good yields. The HO‐group and/or MeO‐group on
the aromatic aldehydes at 3, 4, and 5 positions showed
no impact for the pyridine derivates formation, while the
steric hindrance of the phenyl group of the ketones was
observed providing lower yield. Such transformation
provided additional information for the mechanism study.
The preliminary bioactivity test against schistosome of
the synthesized compounds showed some promising
results and more systematical studies are underway, and
the results will be published separately.
EXPERIMENTAL
Vanillin, syringaldehyde, and p‐hydroxybenzaldehyde were
synthesized according to previously reported methods [18]. Other
reagents were obtained from Sinopharm Chemical Reagent. All
reactions were conducted in CEM Discover. All synthesized
compounds were characterized by infrared (IR), 1H‐NMR,
13C‐NMR, MS, and EA. IR spectra were recorded with a Nicolet
Magna‐IR 550 spectrometer. Mass spectra were recorded on
WATERS Q‐TOF Premier mass spectrometer using electrospray
4‐(4‐Hydroxy‐3‐methoxyphenyl)‐5‐methyl‐6‐(4‐chlorophenyl)‐
2‐amino‐3‐cyanopyridine 5e (0.26 g, 71%). IR (KBr) ν (cm−1):
3462, 3338, 3211, 2228, 1634, 1556, 1516, 1276, 1242, 1092,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2013 An Effective, One‐Pot Synthesis of Fully Substituted Pyridines under Microwave
1349
Irradiation in the Absence of Solvent
1032, 824; 1H‐NMR (300 MHz, DMSO‐d6) δ (ppm): 9.32 (s, 1H,
≤ 12, –10 ≤ l ≤ 56), of which 2312 reflections were observed with
I > 2σ(I). The final R and wR values were 0.0665 and 0.1504,
s = 1.005, (δ/σ) max = 0.044. The maximum peak and minimum
peak in the final difference map is 0.418 and −0.202 e Å−3,
respectively. CCDC number for compound 5i is CCDC 804795.
OH), 7.50–7.58 (m, 4H, ArH), 6.95 (d, 1H, ArH, J = 1.8 Hz),
6.90 (d, 1H, ArH, J = 8.1 Hz), 6.78 (dd, 1H, ArH, J = 1.8, 8.1
Hz), 6.67 (s, 2H, NH2), 3.79 (s, 3H, OCH3), 1.88 (s, 3H, CH3);
13C‐NMR (75.5 MHz, DMSO‐d6) δ (ppm): 160.3, 158.5, 156.2,
147.9, 147.5, 139.4, 133.6, 131.2, 128.4, 128.2, 121.7, 117.6,
117.3, 116.0, 113.3. 90.3, 56.3, 17.3; MS (ESI) m/z: 366.0 [M
+H]+; Anal. Calcd. for C20H16ClN3O2: C, 65.67; H, 4.41; N,
11.49; found: C, 65.76; H, 4.55; N, 11.40.
4‐(4‐Hydroxyphenyl)‐5‐methyl‐6‐(4‐chlorophenyl)‐2‐amino‐
3‐cyanopyridine 5f (0.24 g, 72%). IR (KBr) ν (cm−1): 3457,
3360, 3241, 2217, 1634, 1550, 1516, 1249, 1167, 1092, 842;
1H‐NMR (300 MHz, DMSO‐d6) δ (ppm): 9.75 (s, 1H, OH),
7.48–7.55 (m, 4H, ArH), 7.19 (d, 2H, ArH, J = 7.5 Hz), 6.89
(d, 2H, ArH, J = 7.5 Hz), 6.67 (s, 2H, NH2), 1.85 (s, 3H, CH3);
13C‐NMR (75.5 MHz, DMSO‐d6) δ (ppm): 159.8, 158.0, 157.8,
155.4, 133.1, 130.9, 130.7, 129.8, 127.9, 127.2, 117.1, 116.8,
115.3, 89.9, 16.7; MS (ESI) m/z: 336.1 [M+H]+, 358.1 [M
+Na]+; Anal. Calcd. for C19H14ClN3O: C, 67.96; H, 4.20; N,
12.51; found: C, 67.85; H, 4.29; N, 12.44.
4‐(4‐Hydroxy‐3,5‐dimethoxyphenyl)‐5,6‐diphenyl‐2‐amino‐
3‐cyanopyridine 5g (0.27 g, 64%). IR (KBr) ν (cm−1): 3480,
3406, 3282, 3136, 2211, 1627, 1548, 1516, 1453, 1414, 1227,
1118, 717, 705; 1H‐NMR (300 MHz, DMSO‐d6) δ (ppm):
8.53 (s, 1H, OH), 6.36–7.17 (m, 14H, ArH, NH2), 3.53 (s, 6H,
2×OCH3); 13C‐NMR (75.5 MHz, DMSO‐d6) δ (ppm): 160.0,
159.0, 154.8, 147.2, 140.0, 137.4, 135.4, 131.4, 129.3, 127.7,
127.4, 127.3, 126.1, 124.1, 116.8, 107.4, 84.8, 55.8; MS (ESI)
m/z: 424.1 [M+H]+, 446.2 [M+Na]+; Anal. Calcd. for
C26H21N3O3: C, 73.74; H, 5.00; N, 9.92; found: C, 73.86; H,
5.15; N, 9.80.
4‐(4‐Hydroxy‐3‐methoxyphenyl)‐5,6‐diphenyl‐2‐amino‐3‐
cyanopyridine 5h (0.26 g, 66%). IR (KBr) ν (cm−1): 3471,
3382, 3290, 3124, 2216, 1633, 1547, 1518, 1460, 1279,
1234, 1028, 707; 1H‐NMR (300 MHz, DMSO‐d6) δ (ppm):
9.12 (s, 1H, OH), 6.54–7.17 (m, 15H, ArH, NH2), 3.56 (s, 3H,
OCH3), 1.89 (s, 3H, CH3); 13C‐NMR (75.5 MHz, DMSO‐d6) δ
(ppm): 160.5, 159.5, 155.3, 147.1, 146.9, 140.5, 137.8, 132.0,
129.8, 128.2, 127.9, 127.8, 126.6, 124.7, 122.5, 117.2, 115.4,
114.2, 89.9, 55.8; MS (ESI) m/z: 394.1 [M+H]+, 416.1 [M
+Na]+; Anal. Calcd. for C25H19N3O2: C, 76.32; H, 4.87; N,
10.68; found: C, 76.41; H, 4.80; N, 10.63.
Acknowledgments. This work was supported by Key Projects
in the National Science and Technology Pillar Program in the
11th Five‐year Plan Period (2006BAD18B10) and the
President Foundation of the Chinese Academy of Forestry
(CAFYBB2008009).
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4‐(4‐Hydroxyphenyl)‐5,6‐diphenyl‐2‐amino‐3‐cyanopyridine
5i (0.23 g, 63%). IR (KBr) ν (cm−1): 3475, 3360, 3206, 2212,
1
1611, 1550, 1513, 1450, 1273, 1230, 1110, 865, 703; H‐NMR
(300 MHz, DMSO‐d6) δ (ppm): 9.51 (s, 1H, OH), 6.80–7.22
(m, 14H, ArH, NH2), 6.60 (d, 2H, ArH, J = 8.4 Hz); 13C‐NMR
(75.5 MHz, DMSO‐d6) δ (ppm): 160.0, 158.9, 157.1, 155.0,
140.0, 137.2, 131.5, 130.3, 129.3, 127.7, 127.3, 127.2, 127.1,
126.1, 124.4, 116.6, 114.6, 89.5; MS (ESI) m/z: 364.3 [M+H]+;
Anal. Calcd. for C24H17N3O: C, 79.32; H, 4.72; N, 11.56;
found: C, 79.21; H, 4.79; N, 11.50.
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X‐Ray structure determination of 5i. Colorless blocks,
C26H23N3O2, Mr = 409.47, Orthorhombic, space group Pcab
,
a = 9.3681(12) Å, b = 9.9916(14) Å, c = 46.994(10) Å, β = 90.00°,
V = 4398.8(12) Å3, Z = 8, Dcalc = 1.237 g cm−3, F(000) = 1728, μ
(MoKα) = 0.080 mm−1, crystal dimensions 0.30 × 0.20 × 0.20 mm3.
Intensity data were collected using a Bruker Smart APEX CCD‐
based diffractometer at 293(2) K, graphite monochromator Mo Kα
radiation (λ = 0.071073 nm) using a φ‐ω can mode. Four thousand
nine hundred ninety‐two reflections [3946 unique (Rint = 0.0237)]
were collected in the range of 1.73 < θ < 25.37 (0 ≤ h ≤ 11, 0 ≤ k
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1350
X.‐H. Yang, Y.‐H. Zhou, P.‐H. Zhang, and L.‐Y. Zhang
Vol 50
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The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
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[17] CCDC 804795 contains the supplementary crystallographic
data recorded for the 2‐amino‐3‐cyano‐4,5,6‐triarylpyridine 5i·ethanol
reported in this Letter. These data can be obtained free of charge from
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet