Efficient and divergent synthesis of polyfunctionalized 2-pyridones from β-keto amides

Article abstract of DOI:10.1039/c8ra05709e

Efficient and divergent one-pot synthesis of polyfunctionalized 2-pyridones from β-keto amides based on reaction condition selection was developed. The methodology offers several significant advantages including mild conditions, ease of handling, high yie

Full text of DOI:10.1039/c8ra05709e

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Efficient and divergent synthesis of
polyfunctionalized 2-pyridones from b-keto
amides†
Cite this: RSC Adv., 2018, 8, 33625
ab
Yufeng Sun,b Jun Wang,a Zhigang Yuan,b Liwu Zu,a Xu Zhangb
*
Baochang Gao,
and Wenbin Liu
a
*
Efficient and divergent one-pot synthesis of polyfunctionalized 2-pyridones from b-keto amides based on
reaction condition selection was developed. The methodology offers several significant advantages
including mild conditions, ease of handling, high yields, and a relatively broad range of substrates. Based
on various experiments and observations, a plausible mechanism for the selective synthesis of 2-
pyridones was proposed.
Received 4th July 2018
Accepted 24th September 2018
DOI: 10.1039/c8ra05709e
rsc.li/rsc-advances
desirable for synthesis of the valuable heterocycles. The devel-
opment of an efficient and facile methodology for the
Introduction
construction of diverse 2-pyridone derivatives still remains
a great challenge.
Molecularly diverse and complex heterocycles make a vital
contribution to the organic synthesis and discovery of new
pharmaceutical reagents.1 2-Pyridone is one of the most
signicant heteroaromatic rings in natural products, bioactive
molecules, and pharmaceutical agents.2–5 Such well-known
molecules possess a wide spectrum of biological properties
such as antimalarial,6 anti-hepatitis B,7 vasorelaxant,8 anti-
fungal,9 anti-epilepsy,10 anti-brosis,11 anti-HIV,12 MEK-1
inhibitor,13 antitumor,14 anti-ulcer,15 antioxidant, and antitu-
berculosis activities.16 Moreover, molecules bearing 2-pyridone
derivatives are also used as important structural units in the
synthesis of nitrogen-containing heterocycles, such as pyri-
dines,17 piperidines,18 b-lactams,19 indolizidines, and quinoli-
zidines.20 Thus, the synthesis of 2-pyridone derivatives has
attracted considerable attention in recent years. Owing to their
biologically and structurally interesting properties, a number of
approaches for their construction have been reported. The
classical methods for synthesis of 2-pyridones include pyr-
idinium salt chemistry and N-alkylation,21,22 Guareschi–Thorpe
reaction,23 Dieckmann-type condensation,24 Diels–Alder reac-
tion,25 and halogenated 2-pyridones under Vilsmeier condi-
tions,26 and other methods from the synthesis of 2-pyridones
under metal catalyst.27 Each of these approaches represents an
important progress for the synthesis of 2-pyridones, however,
the development of an efficient and facile strategies are
b-Keto amide and their derivatives have been proven to be
the important starting materials and reagents in the construc-
tion of heterocyclic systems since they possess six reactive sites
in the same molecule.28–35 They have also been used as building
blocks for the construction of biologically interesting hetero-
cycles.36 So far, a number of natural product-like heterocyclic
compounds have been successfully synthesized based on b-keto
amide and their derivatives. Their synthetic methodology and
associated medicinal activity should be engaged in the chem-
istry community.37 As part of our efforts to discover novel and
practical synthesis methods for the construction of heterocyclic
compounds, we recently developed an efficient synthesis of
substituted thieno[2,3-b]pyridines from b-keto amides.38 We are
interested in the elds of cleavage or construction of C–C and
C–N bonds because of its varied applications.39 The develop-
ment of a catalytic process for simultaneous cleavage and
building of C–N and C–C bonds is a signicant challenge in
synthetic chemistry.40 Liang et al. reported a new series of
compounds via three-component one-pot reactions of 1-acetyl-
1-carbamoyl cyclopropanes, malononitrile and cyclic
secondary amines.41 Given that the approach of Liang involved
the tandem reaction of b-keto amide reactants to the corre-
sponding fully substituted 2-pyridones, we supposed that the
direct reaction of b-keto amides with malononitrile through
control reaction conditions would afford 2-pyridones with
diverse structures through the control of reaction conditions.
When piperidine was replaced with other bases, the poly-
substituted 2-pyridones with different substituted patterns
could be obtained by using b-keto amides as raw material.
Inspired by these ndings, we envisioned the construction of
the 2-pyridone core from b-keto amides through intramolecular
aInstitute of Composite Materials, Key Laboratory of Superlight Material and Surface
Technology of Ministry of Education, College of Materials Science and Chemical
Engineering, Harbin Engineering University, Harbin 150001, P. R. China. E-mail:
chemgbc@hrbeu.edu.cn; liuwenbin@hrbeu.edu.cn
bDaqing Branch of Heilongjiang Academy of Sciences, Daqing 163319, P. R. China
† Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
of all products. See DOI: 10.1039/c8ra05709e
This journal is © The Royal Society of Chemistry 2018
RSC Adv., 2018, 8, 33625–33630 | 33625

View Article Online
RSC Advances
Paper
was characterized as 2-amino-4-methyl-6-oxo-1-phenyl-1,6-
dihydro-pyridine-3-carbonitrile 3a on the basis of its NMR
spectra and analytical data (Table 1, entry 2).
To optimize the reaction conditions, the reaction of b-keto
amide derivative 1a with 2 was investigated using various bases
and solvent (Table 1). Initially, different organic bases, such as
DBU and Et3N, were employed as in EtOH. When EtONa was
replaced by DBU or Et3N, the conversion of (2-amino-4-methyl-
6-oxo-1-phenyl-1,6-dihydro-pyridine-3-carbonitrile) 3a was
increased, affording compound 3a in yields of 50% and 55%,
respectively (Table 1, entries 3–4). The reaction conditions were
then optimized by screening several solvents. Hence, treatment
of 1a with 2 in the presence of Cs2CO3 or DBU in CH2Cl2 at
reux, product 3a was formed in 63 and 72% yield, respectively
(Table 1, entries 5–6). The best yield was achieved with Et3N in
reuxing CH2Cl2, the yield of desired product 3a reached 88%
yield (Table 1, entry 7). When the reaction was performed in the
presence of piperidine in DMF at room temperature, a new
compound 4a was successfully isolated in 10% yield (Table 1,
entry 8). In order to efficiently obtain a single nal product 4a,
additional attempts were made. The introduction of carbonate
such as Cs2CO3 or K2CO3 did not improve the selectivity and the
conversion (Table 1, entries 9–10). However, product 4a was
obtained in 85% yield by using tBuOK in DMF at room
temperature (Table 1, entry 11). Thus, dichloromethane was the
best medium for selectively obtaining product 3a. Conversely,
the best conditions for the preparation of 4a were conducted in
DMF at room temperature.
Under the optimal reaction conditions (Table 1, entry 7), the
2-pyridone 3 was tested by using a range of readily available b-
keto amides and malononitrile. In the following work, the scope
of the substrate was investigated (Table 2). Under the condi-
tions, a series of reactions of b-keto amides with different
substitution groups on the phenyl ring were examined, and the
results are listed in Table 2. As shown in Table 2, it was observed
that the substrate with various electron-donating and -with-
drawing groups 1b–1h could easily be converted into the cor-
responding 2-pyridones 3b–3h in high yields (85–95%) in 6–7.5
hours (Table 2, entries 2–8). Furthermore, the positions of the
Scheme 1 Proposed mechanism for the construction of 2-pyridones
3 and 4.
nucleophilic cyclization. As the result of our continued interest
in this area, we have provided an efficient and selective
synthesis methodology for the construction of two libraries of 2-
pyridones 3 and 4 via a tandem annulation of b-keto amides 1
and malononitrile 2 in CH2Cl2 and DMF, respectively (Scheme
1). Herein, we wish to report our results and the possible
mechanism involved was discussed.
Results and discussion
To reduce this idea to practice, we examined the reactivity of
the b-keto amides 1 and 2. We then selected 3-oxo-N-phenyl-
butyramide 1a as the model substrate to screen its reaction
conditions. The reaction was executed with EtONa in anhy-
drous ethanol at room temperature. Unfortunately the reac-
tions was unsuccessful, no reaction occurred even till 2 h as
indicated by TLC (Table 1, entry 1). When 1a was heated with 2
(1.1 equiv.) in EtOH at reux for 6 h, we were delighted to have
the desired 2-pyridone 3a, although the yield was very low
(38%, Table 1, entry 2). Surprisingly the transformation was
observed using EtONa to generate the reaction. The product
Table
1
Optimization of the reaction conditions for the model
reactiona
Table 2 Substrate scope of 1 and synthesis of target molecules 3a
Yieldc (%)
Entry
Solvent
Mediatedb
Temp. (ꢀC)
3a
4a
1
2
3
4
5
6
7
8
EtOH
EtOH
EtOH
EtOH
CH2Cl2
CH2Cl2
CH2Cl2
DMF
DMF
DMF
DMF
DMF
EtONa
EtONa
DBU
Et3N
Cs2CO3
DBU
rt
n.d.
38
50
55
63
72
88
32
45
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
10
Reux
Reux
Reux
Reux
Reux
Reux
rt
70
70
rt
70
Entry
1
Ar
3
Temp. (ꢀC)
Yieldb (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
Ph
3a
3b
3c
3d
3e
3f
Reux
Reux
Reux
Reux
Reux
Reux
Reux
Reux
88
95
85
88
91
85
87
85
4-ClC6H4
4-MeOC6H4
2-ClC6H4
2,4-Me2C6H3
4-MeC6H4
2-MeOC6H4
2-MeC6H4
Et3N
Piperidine
Cs2CO3
K2CO3
tBuOK
tBuOK
9
n.d.
n.d.
85
10
11
12
41
n.d.
n.d.
1g
1h
3g
4h
87
a
The reaction was performed with 1a (1.0 mmol), 2 (1.1 mmol), and the
b
a
solvent (10 mL). Mediated (1.0 mmol) was added to the reaction.
All reactions were carried out with 1 (1.0 mmol), 2 (1.1 mmol), Et3N
(1.0 equiv.), in CH2Cl2 (5.0 mL) at reux for 6 hours. b Isolated yield.
c
Isolated yields were based on b-keto amide 1a.
33626 | RSC Adv., 2018, 8, 33625–33630
This journal is © The Royal Society of Chemistry 2018

View Article Online
Paper
RSC Advances
substituents on the phenyl ring did not show any effects on the nucleophilic process. Likewise, the isomerization of I0 in the
t
reaction. It is noteworthy that all the crude products 3 could be presence of the BuOK affords nal product 4.
puried simply by recrystallization from ethanol.
Next, with the aim to make product 4 to be the main product
(Scheme 1), the selective synthesis of 2-pyridone 4a under
Conclusions
appropriate conditions may be realized. Basic conditions play
an important role in the transformation process. The use of
Et3N selectively afforded compound 3 in high conversion. Aer
several trials, we found that when Et3N was replaced by
a stronger base such as tBuOK, product 4a could be obtained in
a yield of 85% (Table 1, entry 11). Effect of temperature showed
no improvement in the yield of product 4a at room temperature
and 70 ꢀC (Table 1, entry 12). Under the optimal reaction
conditions, a series of reactions of b-keto amides with different
substitution groups on the phenyl ring were examined, afford-
ing 2-pyridones 4b–4h in good-to-high yields (85–95%). Notably,
all the crude products 4 could be puried simply by recrystal-
lization from DMF (Table 3).
A simple and efficient one-pot methodology for the divergent
synthesis of polysubstituted 2-pyridones 3 and 4 in high yield
has been developed. This method illustrates a practical protocol
using simple and inexpensive starting materials. Furthermore,
the methodology offers several signicant advantages, such as
economic availability, metal catalyst-free, ease of handling,
a relative broad range of substrates, and environmental benig-
nity under mild reaction condition. Further expanding the
scope of this reaction and application the products are currently
on-going in our laboratory.
Experimental
On the basis of the obtained results and previously reported
work,41,42 a plausible mechanism for the syntheses of 2-pyr-
idones 3 and 4 are presented, as depicted in Scheme 2. First, the
b-keto amide 1 reacts with malononitrile 2 accompanying the
loss of one molecule of H2O to generate intermediate 5, and
affords intermediate 6. Then, the isomerization of I in the
presence of Et3N forms nal product 3 under the control
experiments conditions, which is cyclized by intramolecular
General
All reagents were purchased from commercial sources and used
without treatment, unless otherwise indicated. The products
were puried by recrystallization. 1H and 13C NMR spectra were
recorded on a Bruker AVANCE-300 spectrometer at 25 ꢀC using
TMS as an internal standard and deuterated DMSO (DMSO-d6)
as the solvent. Petroleum ether (PE) used was the fraction
boiling in the range 30–60 ꢀC. Elemental analyses were obtained
on a Vario EL analyzer.
Table 3 Substrate scope of 1 and synthesis of target molecules 4a
General procedure for the synthesis of compounds 3a–h
To a solution of b-keto amides 1 (1.0 mmol) and malononitrile
(1.1 mmol) in CH2Cl2 (10 mL) was added Et3N (1.0 mmol) in one
portion. The mixture was well stirred for 6 h at reux. When
consumption of 1 was complete (TLC), the mixture was washed
with saturated sodium chloride solution (10 mL ꢁ 3) and dried
over anhydrous MgSO4. The organic solvent CH2Cl2 was then
removed under reduced pressure and the residue was puried
by recrystallization from ethanol to give product 3a–h.
Entry
1
Ar
4
Temp. (ꢀC)
Yieldb (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
Ph
4a
4b
4c
4d
4e
4f
rt
rt
rt
rt
rt
rt
rt
rt
88
95
85
88
91
85
87
85
4-ClC6H4
4-MeOC6H4
2-ClC6H4
2,4-Me2C6H3
4-MeC6H4
2-MeOC6H4
2-MeC6H4
2-Amino-4-methyl-6-oxo-1-phenyl-1,6-dihydro-pyridine-3-
carbonitrile (3a). White solid; mp 281–282 ꢀC; 1H NMR (300
MHz, DMSO-d6): d ¼ 7.57–7.47 (m, 3H), 7.24 (t, J ¼ 7.0 Hz, 2H),
6.68 (s, 2H), 5.67 (s, 1H), 2.17 (s, 3H); 13C NMR (75 MHz, DMSO-
d6): d ¼ 161.1, 156.3, 152.1, 135.2, 130.6, 129.9, 129.3, 129.1,
118.0, 117.7, 105.5, 71.8, 20.9; anal. calcd for C13H11N3O: C,
76.98; H, 7.00; N, 7.48; found: C, 76.96; H, 7.01; N, 7.49.
2-Amino-4-methyl-6-oxo-1-phenyl-1,6-dihydro-pyridine-3-
1g
1h
4g
4h
a
All reactions were carried out with 1 (1.0 mmol), 2 (1.1 mmol), tBuOK
b
(1.0 equiv.), in CH2Cl2 (5.0 mL) at room temperature. Isolated yield.
1
carbonitrile (3b). White solid; mp 328–329 ꢀC; H NMR (300
MHz, DMSO-d6): d ¼ 7.62–7.57 (m, 2H), 7.31–7.26 (m, 2H), 6.91
(s, 2H), 5.66 (d, J ¼ 1.1 Hz, 1H), 2.18 (s, 3H); 13C NMR (75 MHz,
DMSO-d6): d ¼ 161.0, 156.4, 152.4, 134.5, 134.3, 131.4, 130.6,
117.6, 105.2, 71.8, 20.9; anal. calcd for C13H10ClN3O: C, 60.12;
H, 3.88; N, 16.18; found: C, 60.11; H, 3.90; N, 16.17; MS: m/z
calcd for C13H10ClN3O, 259.05; found, 260.1 [M + 1].
2-Amino-1-(4-methoxy-phenyl)-4-methyl-6-oxo-1,6-dihydro-
pyridine-3-carbonitrile (3c). White solid; mp 273–274 ꢀC; 1H
NMR (300 MHz, DMSO-d6): d ¼ 7.16–7.12 (m, 2H), 7.09–7.05 (m,
2H), 6.68 (s, 2H), 5.65–5.64 (d, J ¼ 3 Hz, 1H), 3.81 (s, 3H), 2.16 (s,
Scheme 2 Plausible mechanism for the construction of 2-pyridones 3
and 4.
This journal is © The Royal Society of Chemistry 2018
RSC Adv., 2018, 8, 33625–33630 | 33627

View Article Online
RSC Advances
Paper
3H); 13C NMR (75 MHz, DMSO-d6): d ¼ 161.3, 160.1, 156.7, (t, J ¼ 7.8 Hz, 2H), 7.09 (t, J ¼ 7.3 Hz, 1H), 3.77 (s, 2H), 2.36 (s,
152.0, 130.4, 127.5, 117.7, 115.8, 105.4, 71.6, 55.8, 20.9; anal. 3H); 13C NMR (75 MHz, DMSO-d6): d ¼ 178.3, 164.7, 138.9,
calcd for C14H13N3O2: C, 65.87; H, 5.13; N, 16.46; found: C, 129.3, 124.3, 119.8, 112.6, 112.6, 87.2, 45.1, 24.1; anal. calcd for
65.88; H, 5.11; N, 16.47.
3- Amino-1-(2-chloro-phenyl)-4-methyl-6-oxo-1,6-dihydro- 4.94; N, 18.65; MS: m/z calcd for C13H11N3O, 225.09; found,
pyridine-3-carbonitrile (3d). White solid; mp 265–266 ꢀC; 1H 226.0 [M + 1].
C13H11N3O: C, 69.32; H, 4.92; N, 18.66; found: C, 69.31; H,
NMR (300 MHz, DMSO-d6): d ¼ 7.65 (dd, J1¼ 7.3 Hz, J2¼ 1.9 Hz,
1-(4-Chloro-phenyl)-2-imino-4-methyl-6-oxo-1,2,5,6-tetrahydro-
1H), 7.54–7.48 (m, 2H), 7.40 (dd, J1 ¼ 7.2 Hz, J2 ¼ 2.2 Hz, 1H), pyridine-3-carbonitrile (4b). White solid; mp 125–126 ꢀC; 1H
7.00 (s, 2H), 5.66 (s, 1H), 2.18 (s, 3H); 13C NMR (75 MHz, DMSO- NMR (300 MHz, DMSO-d6): d ¼ 10.50 (s, 1H), 7.60 (d, J ¼ 8.8 Hz,
d6): d ¼ 160.3, 156.1, 152.8, 132.9, 132.5, 131.8, 131.6, 131.1, 2H), 7.39 (d, J ¼ 8.8 Hz, 2H), 3.78 (s, 2H), 2.36 (s, 3H); 13C NMR
129.5, 117.6, 105.1, 71.6, 21.0; anal. calcd for C13H10ClN3O: C, (75 MHz, DMSO-d6): d ¼ 178.1, 164.9, 137.9, 129.2, 127.9, 121.4,
60.12; H, 3.88; N, 16.18; found: C, 60.11; H, 3.90; N, 16.17.
2-Amino-1-(2,4-dimethyl-phenyl)-4-methyl-6-oxo-1,6-dihydro-
pyridine-3-carbonitrile (3e). White solid; mp 296–297 ꢀC; 1H
112.6, 112.5, 87.3, 45.0, 24.1; anal. calcd for C13H10ClN3O: C,
60.12; H, 3.88; N, 16.18; found: C, 60.13; H, 3.88; N, 16.17.
2-Imino-1-(4-methoxy-phenyl)-4-methyl-6-oxo-1,2,5,6-tetrahydro-
NMR (400 MHz, DMSO-d6): d ¼ 7.21 (s, 1H), 7.14 (d, J ¼ 7.9 Hz, pyridine-3-carbonitrile (4c). White solid; mp 138–139 ꢀC; 1H NMR
1H), 6.99 (d, J ¼ 8.0 Hz, 1H), 6.67 (s, 2H), 5.65 (s, 1H), 2.16 (s, (300 MHz, DMSO-d6): d ¼ 10.21 (s, 1H), 7.48 (d, J ¼ 9.0 Hz, 2H),
3H), 1.91 (s, 3H); 13C NMR (100 MHz, DMSO-d6): d ¼ 160.6, 6.90 (d, J ¼ 9.0 Hz, 2H), 3.73 (s, 2H), 3.72 (s, 3H), 2.35 (s, 3H); 13
C
156.1, 152.2, 139.4, 135.8, 132.5, 131.6, 128.9, 128.8, 117.7, NMR (75 MHz, DMSO-d6): d ¼ 178.4, 164.2, 156.0, 132.0, 121.4,
105.4, 71.6, 21.2, 20.9, 17.1; anal. calcd for C15H15N3O: C, 71.13; 114.4, 112.6, 112.6, 87.0, 55.6, 45.0, 24.1; anal. calcd for
H, 5.97; N, 16.59; found: C, 71.15; H, 5.96; N, 16.60.
C14H13N3O2: C, 65.87; H, 5.13; N, 16.46; found: C, 65.86; H,
2-Amino-4-methyl-6-oxo-1-p-tolyl-1,6-dihydro-pyridine-3-
carbonitrile (3f). White solid; mp 264–265 ꢀC; 1H NMR (300
5.15; N, 16.45.
1-(2-Chloro-phenyl)-2-imino-4-methyl-6-oxo-1,2,5,6-tetrahydro-
MHz, DMSO-d6): d ¼ 7.35 (d, J ¼ 8.0 Hz, 2H), 7.13–7.09 (m, 2H), pyridine-3-carbonitrile (4d). White solid; mp 145–146 ꢀC; 1H
6.66 (s, 2H), 5.66 (d, J ¼ 1.1 Hz, 1H), 2.38 (s, 3H), 2.16 (d, J ¼ NMR (300 MHz, DMSO-d6): d ¼ 10.04 (s, 1H), 7.65 (dd, J1 ¼ 8.0,
0.9 Hz, 3H); 13C NMR (75 MHz, DMSO-d6): d ¼ 161.1, 156.4, J2 ¼ 1.7 Hz, 1H), 7.51 (dd, J1 ¼ 7.9, J2 ¼ 1.5 Hz, 1H), 7.36–7.28
152.0, 139.2, 132.5, 131.1, 128.9, 117.7, 105.5, 71.7, 21.3, 20.9. (m, 1H), 7.27–7.19 (m, 1H), 3.83 (s, 2H), 2.36 (s, 3H); 13C NMR
anal. calcd for C14H13N3O: C, 70.28; H, 5.48; N, 17.56; found: C, (75 MHz, DMSO-d6): d ¼ 178.0, 165.3, 134.7, 130.0, 128.0, 127.6,
70.26; H, 5.49; N, 17.57.
127.5, 127.2, 112.6, 112.5, 87.2, 44.6, 24.0; anal. calcd for
C13H10ClN3O: C, 60.12; H, 3.88; N, 16.18; found: C, 60.13; H,
2-Amino-1-(2-methoxy-phenyl)-4-methyl-6-oxo-1,6-dihydro-
pyridine-3-carbonitrile (3g). White solid; mp 281–282 ꢀC; 1H 3.88; N, 16.17.
NMR (300 MHz, DMSO-d6): d ¼ 7.52–7.47 (m, 1H), 7.24–7.19 (m,
1-(2,4-Dimethyl-phenyl)-2-imino-4-methyl-6-oxo-1,2,5,6-
1H), 7.18–7.16 (m, 1H), 7.12–7.06 (m, 1H), 6.72 (s, 2H), 5.64 (s, tetrahydro-pyridine-3-carbonitrile (4e). White solid; mp 137–
1H), 3.75 (s, 3H), 2.18 (s, 3H); 13C NMR (75 MHz, DMSO-d6): d ¼ 138 ꢀC; 1H NMR (300 MHz, DMSO-d6): d ¼ 9.67 (s, 1H), 7.22 (d, J
160.7, 156.4, 155.4, 152.1, 131.5, 130.5, 123.2, 121.8, 117.8, ¼ 8.0 Hz, 1H), 7.04 (s, 1H), 6.97 (d, J ¼ 8.1 Hz, 1H), 3.77 (s, 2H),
113.6, 105.4, 71.5, 56.2, 20.9; anal. calcd for C14H13N3O2: C, 2.37 (s, 3H), 2.25 (s, 3H), 2.16 (s, 3H); 13C NMR (75 MHz, DMSO-
65.87; H, 5.13; N, 16.46; found: C, 65.88; H, 5.11; N, 16.47.
d6): d ¼ 178.6, 164.8, 135.4, 133.5, 132.5, 131.4, 127.0, 125.8,
2-Amino-4-methyl-6-oxo-1-o-tolyl-1,6-dihydro-pyridine-3-
112.7, 112.6, 87.0, 44.6, 24.1, 21.0, 18.2; anal. calcd for
1
ꢀ
carbonitrile (3h). White solid; mp 284–285 C; H NMR (300
C15H15N3O: C, 71.13; H, 5.97; N, 16.59; found: C, 71.12; H,
MHz, DMSO-d6): d ¼ 7.43 (d, J ¼ 4.6 Hz, 2H), 7.40–7.38 (m, 1H), 5.99; N, 16.58.
7.16 (d, J ¼ 7.4 Hz, 1H), 6.72 (s, 2H), 5.71 (s, 1H), 2.21 (s, 3H),
2-Imino-4-methyl-6-oxo-1-p-tolyl-1,2,5,6-tetrahydro-pyridine-
1
2.00 (s, 3H); 13C NMR (75 MHz, DMSO-d6): d ¼ 160.5, 156.0, 3-carbonitrile (4f). White solid; mp 100–101 C; H NMR (300
152.4, 136.2, 134.2, 131.9, 130.1, 129.2, 128.2, 117.6, 105.5, MHz, DMSO-d6): d ¼ 10.25 (s, 1H), 7.45–7.41 (m, 2H), 7.13–7.10
71.7, 20.9, 17.2; anal. calcd for C14H13N3O: C, 70.28; H, 5.48; N, (m, 2H), 3.73 (s, 2H), 2.34 (s, 3H), 2.24 (s, 3H); 13C NMR (75
ꢀ
17.56; found: C, 70.26; H, 5.49; N, 17.57.
MHz, DMSO-d6): d ¼ 178.4, 164.5, 136.4, 133.3, 129.7, 119.8,
112.6, 112.6, 87.1, 45.1, 24.1, 20.9; anal. calcd for C14H13N3O: C,
70.28; H, 5.48; N, 17.56; found: C, 70.30; H, 5.47; N,17.55.
2-Imino-1-(2-methoxy-phenyl)-4-methyl-6-oxo-1,2,5,6-tetrahydro-
General procedure for the synthesis of compounds 4a–h
To a solution of b-keto amides 1 (1.0 mmol) and malononitrile pyridine-3-carbonitrile (4g). White solid; mp 101–102 ꢀC; 1H NMR
(1.1 mmol) in DMF (10 mL) was added tBuOK (1.0 mmol) in one (300 MHz, DMSO-d6): d ¼ 9.70 (s, 1H), 7.89 (d, J ¼ 7.2 Hz, 1H),
portion. The mixture was well stirred for 4 hours at room 7.16–7.06 (m, 2H), 6.96–6.91 (m, 1H), 3.88 (s, 2H), 3.86 (s, 3H),
temperature. When consumption of 1 was complete (TLC), the 2.36 (s, 3H); 13C NMR (75 MHz, DMSO-d6): d ¼ 178.5, 165.1,
mixture was poured into sat. aq. NaCl (50 mL) under stirring. 150.5, 127.0, 125.7, 123.0, 120.7, 112.7, 112.6, 111.8, 87.1, 56.2,
The precipitated solid was collected by ltration, washed with 45.0, 23.9; anal. calcd for C14H13N3O2: C, 65.87; H, 5.13; N,
water (3 ꢁ 20 mL) and dried in vacuo to afford the product 4a–h. 16.46; found: C, 65.86; H, 5.15; N, 16.45.
2-Imino-4-methyl-6-oxo-1-phenyl-1,2,5,6-tetrahydro-pyridine-3-
2-Imino-4-methyl-6-oxo-1-o-tolyl-1,2,5,6-tetrahydro-pyridine-
carbonitrile (4a). White solid; mp 130–131 ꢀC; 1H NMR (300 3-carbonitrile (4h). White solid; mp 154–155 ꢀC;1H NMR (300
MHz, DMSO-d6): d ¼ 10.36 (s, 1H), 7.57 (d, J ¼ 7.8 Hz, 2H), 7.33 MHz, DMSO-d6): d ¼ 9.75 (s, 1H), 7.37 (d, J ¼ 7.4 Hz, 1H), 7.23 (d,
33628 | RSC Adv., 2018, 8, 33625–33630
This journal is © The Royal Society of Chemistry 2018

View Article Online
Paper
RSC Advances
J ¼ 7.2 Hz, 1H), 7.13 (dd, J1 ¼ 12 Hz, J2 ¼ 6 Hz, 2H), 3.80 (s, 2H),
2.37 (s, 3H), 2.22 (s, 3H); 13C NMR (75 MHz, DMSO-d6): d ¼
M. G. Livingston, J. G. Otten, G. Hingorani, R. Woessner,
P. Lee, J. Winkler and K. Koch, J. Med. Chem., 2006, 49, 441.
178.5, 164.9, 136.1, 132.5, 130.9, 126.5, 126.2, 125.7, 112.7, 14 (a) Z. Lv, Y. Zhang, M. Zhang, H. Chen, Z. Sun, D. Geng,
112.6, 87.0, 44.6, 24.1, 18.3; anal. calcd for C14H13N3O: C, 70.28;
H, 5.48; N, 17.56; found: C, 70.30; H, 5.47; N, 17.55.
C. Niu and K. Li, Eur. J. Med. Chem., 2013, 67, 447; (b)
M. T. Cocco, K. C. Congiu and V. Onnis, Eur. J. Med.
Chem., 2000, 35, 545.
15 K. Otsubo, S. Morita, M. Uchida, K. Yamasaki, T. Kanbe and
T. Shimizu, Chem. Pharm. Bull., 1991, 39, 2906.
Conflicts of interest
There are no conicts to declare.
16 (a) P. S. Ng, U. H. Manjunatha, S. P. Rao, L. R. Camacho and
N. L. Ma, Eur. J. Med. Chem., 2015, 106, 144; (b) H. Tomioka,
Curr. Pharm. Des., 2006, 12, 4047.
17 H. Zhang, B. C. Chen, B. Wang, S. T. Chao, R. Zhao, N. Lim
and B. Balasubramanian, Synthesis, 2008, 1523.
Acknowledgements
The authors greatly appreciated the nancial supports from the
National Natural Science Foundation of China (Project No. 18 E. Klegraf, M. Follmann, D. Schollmeyer and H. Kunz, Eur. J.
0973022), International Science & Technology Cooperation
Program of China (No. 2015DFR50260).
Org. Chem., 2004, 3346.
19 K. Tanaka, T. Fujiwara and Z. Urbanczyk-Lipkowska, Org.
Lett., 2002, 4, 3255.
20 (a) S. M. Sheehan and A. Padwa, J. Org. Chem., 1997, 62, 438;
(b) S. S. P. Chou, C. L. Lu and Y. H. Hu, J. Chin. Chem. Soc.,
2012, 59, 365.
Notes and references
1 (a) J. D. Sunderhaus, C. Dockendorff and S. F. Martin, Org.
´
Lett., 2007, 9, 4223; (b) F. Lieby-Muller, T. Constantieux 21 (a) H. Decker, Chem. Ber., 1982, 25, 443; (b) D. L. Comins and
and J. Rodriguez, J. Am. Chem. Soc., 2005, 127, 17176; (c)
C. Hulme and V. Gore, Curr. Med. Chem., 2003, 10, 51; (d)
J. K. Saha, J. Org. Chem., 1996, 61, 9623; (c) W. Du,
Tetrahedron, 2003, 59, 8649.
T. Liu, Y. Sun, C. Yang, C. Huang and X. Chen, RSC Adv., 22 (a) D. L. Comins and J. L. Gao, Tetrahedron Lett., 1994, 35,
2018, 8, 12635.
2819; (b) T. Hu and C. Li, Org. Lett., 2005, 7, 2035; (c)
H. J. Cristau, P. P. Cellier, J. F. Spindler and M. Taillefer,
Chem. - Eur. J., 2004, 10, 5607.
2 (a) Q. Li, L. A. Mitscher and L. L. Shen, Med. Res. Rev., 2000,
20, 231; (b) M. Nagarajan, X. S. Xiao, S. Antony,
G. Kohlhagen, Y. Pommier and M. Cushman, J. Med. 23 (a) H. Baron, H. Renfry and J. Thorpe, J. Chem. Soc., 1904, 85,
Chem., 2003, 46, 5712.
1726; (b) T. Aggarwal, G. Sing, H. Ila and H. Junjappa,
Synthesis, 1982, 214; (c) L. R. Gibson, L. Hitzel,
R. J. Mortishire-Smith, U. Gerhard, R. A. Jelley, A. J. Reeve,
M. Rowley, A. Nadin and A. P. Owens, J. Org. Chem., 2002,
67, 9354.
3 (a) R. E. Dolle and K. C. Nicolaou, J. Am. Chem. Soc., 1985,
107, 1691; (b) R. J. Cox and D. J. Hagan, J. Chem. Soc.,
Perkin Trans. 1, 1991, 1, 2537.
4 (a) G. Jones and S. P. Stanforth, in Organic Reactions, Wiley,
New York, 1997, vol. 49, pp. 1–330; (b) E. F. V. Scriven, in 24 (a) A. Robin, K. Julienne, J. C. Meslin and D. Deniaud,
Comprehensive Heterocyclic Chemistry, Pergamon Press,
Oxford, 1984, vol. 2; (c) G. Jones, Org. React., 1967, 15, 204.
5 S. M. B. Maezono, T. N. Poudel, L. k. Xia and Y. R. Lee, RSC
Adv., 2016, 6, 82321.
6 M. J. Capper, O. Neil, P. M. S. A. Moss and N. G. Ward, Proc.
Natl. Acad. Sci. U. S. A., 2015, 112, 755.
7 Z. Lv, C. Sheng, T. Wang, Y. Zhang, J. Liu, J. Feng, H. Sun and
H. Zhong, J. Med. Chem., 2010, 53, 660.
8 T. Przygodzki, B. Grobelski, P. Kazmierczak and C. Watala, J.
Physiol. Biochem., 2012, 68, 329.
Tetrahedron Lett., 2004, 45, 9557; (b) F. Sainta, B. Serckx-
Poncin, A. M. Hesbain-Frisque and L. Ghosez, J. Am. Chem.
Soc., 1982, 104, 1428.
25 (a) J. A. Varela and C. Saa, Chem. Rev., 2003, 103, 3787; (b)
Y. Yamamoto, G. Takagishi and K. Itoh, Org. Lett., 2001, 3,
2117; (c) A. Padwa, S. M. Sheehan and C. S. Straub, J. Org.
Chem., 1999, 64, 8648.
26 D. Xiang, Y. Yang, R. Zhang, Y. Liang, W. Pan, J. Huang and
D. Dong, J. Org. Chem., 2007, 72(22), 8593; W. Pan, D. Dong,
J. Wang, R. Zhang, E. Wu, D. Xiang and Q. Liu, Org. Lett.,
2007, 9, 2421.
9 (a) J. Breinholt, S. Ludvigesen, B. R. Rassing and
C. N. Rosendahl, J. Nat. Prod., 1997, 60, 33; (b) K. Otsubo, 27 (a) B. Stanovnik and J. Svete, Chem. Rev., 2004, 104, 2433; (b)
S. Morita, M. Uchida, K. Yamasaki, T. Kanbe and
T. Shimizu, Chem. Pharm. Bull., 1991, 39, 2906.
P. Wan and Y. Gao, Chem. Rec., 2016, 16, 1164.
28 (a) T. Sengupta, K. S. Gayen, P. Pandit and D. K. Maiti,
Chem.–Eur. J., 2012, 18, 1905; (b) J. B. Pierce, Z. S. Ariyan
and G. S. Ovenden, J. Med. Chem., 1982, 25, 131; (c)
H. L. Wang, Z. Li, G. W. Wang and S. D. Yang, Chem.
Commun., 2011, 47, 11336; (d) B. Lu and D. Ma, Org. Lett.,
2006, 8, 6115; (e) L. Tan, P. Zhou, C. Chen and W. Liu,
Beilstein J. Org. Chem., 2013, 9, 2681.
10 L. Ceolin, Z. A. Bortolotto, N. Bannister, G. L. Collingridge,
D. Lodge and A. Volianskis, RSC Adv., 2014, 4, 44141.
11 S. Mirkovic, A. M. L. Seymour, A. Fenning, S. B. Strachan,
S. M. Margolin, S. M. Taylor and L. Br. Brown, J.
Pharmacol., 2002, 135, 961.
12 J. L. Medina-Franco, K. Mayorga, C. Gordiano and
R. Castillo, ChemMedChem, 2007, 2, 1141.
´
29 (a) I. Couto, I. Tellitu and E. Domınguez, J. Org. Chem., 2010,
13 E. M. Wallace, J. Lyssikatos, J. Blake, F. J. Seo, H. W. Yang,
C. Perrier, M. Jarski, H. V. Marsh, G. Poch,
75, 7954; (b) A. M. Farag, N. A. Kheder and Y. N. Mabkhot,
This journal is © The Royal Society of Chemistry 2018
RSC Adv., 2018, 8, 33625–33630 | 33629

View Article Online
RSC Advances
Paper
Heterocycles, 2009, 78, 1787; (c) L. Xia and Y. R. Lee, Org.
Biomol. Chem., 2013, 11, 5254.
Tetrahedron Lett., 2008, 49, 5217; (e) B. Zaleska and S. Lis,
Synth. Commun., 2001, 31, 189.
30 R. J. Clemens, Chem. Rev., 1986, 86, 241.
31 N. Nishiwaki, Y. Nakaike and M. J. Ariga, J. Oleo Sci., 2008,
57, 53.
37 F. Liu, T. Sun, Y. Yang, C. Huang and X. Chen, RSC Adv.,
2018, 8, 12635.
38 B. Gao, D. Dong, J. Zhang, C. Ding, C. m. Dong, Y. Liang and
R. Zhang, Synthesis, 2012, 44, 201.
32 R. Jayalakshmi, P. Neelakatan, S. N. Rao, D. S. Iyengar and
U. T. Bhalerao, Indian J. Chem., Sect. B: Org. Chem. Incl. 39 (a) T. Koreeda, T. Kochi and F. Kakiuchi, J. Am. Chem. Soc.,
Med. Chem., 1979, 18B, 366.
2009, 131, 7238; (b) X. Zhao, D. Liu, H. D. Guo, Y. Liu and
W. Zhang, J. Am. Chem. Soc., 2011, 133, 19354; (c)
W. L. Man, J. Xie, Y. Pan and W. W. Y. Lam, J. Am. Chem.
Soc., 2013, 135, 5533; (d) S. Khamarui, R. Maiti and
D. K. Maiti, Chem. Commun., 2015, 51, 384.
33 W. Ehm and J. Liebigs, Ann. Chem., 1977, 1642.
34 Y. Wang, X. Xin, Y. Liang, Y. Lin, H. Duan and D. Dong, Adv.
Synth. Catal., 2009, 351, 2217.
35 M. Han, K. D. Nam, H. G. Hahn and D. Shin, Tetrahedron
Lett., 2008, 49, 5217.
40 K. Hirano and M. Miura, Chem. Sci., 2018, 9, 22.
36 (a) S. M. Hussain, A. M. El-Reedy and S. A. El-Sherabasy, J. 41 F. Liang, X. Cheng, J. Liu and Q. Liu, Chem. Commun., 2009,
Heterocycl. Chem., 1988, 25, 9; (b) T. Kato, Acc. Chem. Res., 3636.
1974, 7, 265; (c) R. J. Clemens, Chem. Rev., 1986, 86, 241; 42 For similar spiroannulated structures, see: P. Langer and
(d) M. Han, K. D. Nam, H. G. Hahn and D. Shin, G. Bose, Angew. Chem., Int. Ed., 2003, 42, 4033.
33630 | RSC Adv., 2018, 8, 33625–33630
This journal is © The Royal Society of Chemistry 2018