Novel nitenpyram analogues with tetrahydropyridone-fixed cis-configuration: Synthesis, insecticidal activities, and molecular docking studies

Article abstract of DOI:10.3987/COM-13-12766

To make further researches on the diversity of nitenpyram analogues with a cis-nitromethylene configuration, a series of cis-nitenpyram analogues (3a-q) with tetrahydropyridone-fixed cis-configuration were designed and synthesized. Preliminary bioassays showed that most of the designed nitenpyram analogues exhibited good insecticidal activity at 100 mg/L against Nilaparvata lugens and Myzus persicae, while analogues 3n afforded the best in vitro activity. Modeling the ligand-receptor complexes by molecular docking study revealed the analogues 3 with various substituents on phenyl show their different binding affinities to the insect nAChR, which also explained the structure-activity relationships observed in vitro. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-13-12766

HETEROCYCLES, Vol. 87, No. 9, 2013
1865
HETEROCYCLES, Vol. 87, No. 9, 2013, pp. 1865 - 1880. © The Japan Institute of Heterocyclic Chemistry
Received, 2nd July, 2013, Accepted, 25th July, 2013, Published online, 5th August, 2013
DOI: 10.3987/COM-13-12766
NOVEL
NITENPYRAM
ANALOGUES
WITH
TETRAHYDROPYRIDONE-FIXED CIS-CONFIGURATION: SYNTHESIS,
INSECTICIDAL ACTIVITIES, AND MOLECULAR DOCKING STUDIES
*
a,b
a
a
a
Chuan-Wen Sun, Jing Wang, Ying Wu, Shi-Bin Nan, and Wang-Geng
b
Zhang
a
College of Life and Environment Sciences, Shanghai Normal University,
Shanghai 200234, China (Email: willin112@163.com)
b
Jiangsu Institute of Ecomones Co., Ltd. Jingsu, Jintan 213200, China
Abstract – To make further researches on the diversity of nitenpyram analogues
with a cis-nitromethylene configuration, a series of cis-nitenpyram analogues
(
3a-q) with tetrahydropyridone-fixed cis-configuration were designed and
synthesized. Preliminary bioassays showed that most of the designed nitenpyram
analogues exhibited good insecticidal activity at 100 mg/L against Nilaparvata
lugens and Myzus persicae, while analogues 3n afforded the best in vitro activity.
Modeling the ligand-receptor complexes by molecular docking study revealed the
analogues 3 with various substituents on phenyl show their different binding
affinities to the insect nAChR, which also explained the structure-activity
relationships observed in vitro.
INTRODUCTION
Nowadays, neonicotinoids insecticides(NNSs) are the most important chemical class of insecticides
1
introduced to the global market since the synthetic pyrethroids. Interacting with the insect nicotinic
2
-4
acetylcholine receptors (nAChRs), NNSs have a higher affinity for the insect receptor than for the
5
-8
mammalian and are relatively safe toward mammals and aquatic life. Although NNSs are fruitful in
modern agricultural pest management and environmental protection, it is still essential to explore novel

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HETEROCYCLES, Vol. 87, No. 9, 2013
neonicotinoid candidates, because insecticide resistance and cross-resistance have been observed in a
9-16
range of species after frequent field applications.
According to the chemical structures of neonicotinoids developed in the past several decades, the nitro
group play an important role in the activities of neonicotinoids and nitromethylene segments are in
1
7
trans-configuration in commercialized neonicotinoids. In the recent years, a number of neonicotinoid
analogues with cis-configuration have been reported and shown high insecticidal activities and gained
1
7-19
valuable results in resistance management.
But most of these cis-configuration neonicotinoid
analogues are designed on cyclic neonicotinoid insecticides, such as imidacloprid, few studies have been
focused on the structural modification of acyclic NNSs, such as nitenpyram and acctamiprid. Encouraged
by this, we have designed and synthesized cis-nitenpyram analogues 2 by using a tetrahydropyrimidine
20-23
ring to fix the the direction of nitro group of nitenpyram (Figure 1) in previous studies.
Preliminary
bioassays indicated that most of nitenpyram analogues 2 showed good insecticidal activities against
Nilaparvata lugens. However, we found that analogues 2 have similar skeleton— tetrahydropyrimidine
ring, this is not satisfactory in the research of the diversity of nitenpyram analogues. Therefore, to find the
diverse skeleton of nitenpyram analogues with a cis nitromethylene configuration, our interest is to design
novel nitenpyram analogues by introducing a new heterocycle ring into the nitenpyram.
Ar
NO2
NH
O
2
N
R
N
O N
2
N
N
N
N
N
O
Cl
N
1
Cl
N
Cl
N
Nitenpyram
Nitenpyram analogues 2
tetrahydropyrimidine ring
Nitenpyram analogues 3
tetrahydropyridone ring
Figure 1. The design of the diversity cis-Nitenpyram analogues in our group
The applications of Meldrum’s acid to the synthesis of heterocyclic compounds in recent years are
reviewed. All these heterocyclic compounds are related to pyranoid, pyridine, furan rings,
2
4-28
tetrahydropyridone rings and so on.
Motivated by this, we using nitenpyram 1, aromatic aldehyde and
Meldrum's acid as starting materials through a rapid microwave (MW)-promoted method (Scheme 1) to
obtain new cis-nitenpyram analogues 3 by introducing a tetrahydropyridone ring into the nitenpyram

HETEROCYCLES, Vol. 87, No. 9, 2013
1867
(
Figure 1). The preliminary insecticidal activities of the target compounds were tested, most of the
designed nitenpyram analogues(3a-3q) showed good insecticide activities against Myzus persicae, Aphis
medicaginis and Nilaparvata lugens. To further investigate their binding interactions, molecular docking
simulations were carried out by docking the nitenpyram analogues 3 into the active site of nAChR.
RESULTS AND DISCUSSION
1
. Chemistry
The nitenpyram analogues bearing a tetrahydropyridone ring (3a-q) were synthesized as shown in
2
9-30
Scheme 1. Nitenpyram 1 and Meldrum's acid 4 were prepared as described in the literatures,
respectively. Three-component microwave-assisted reaction of nitenpyram, aromatic aldehyde and
Meldrum's acid in ethanol gave good yields (59-89%).
Cl
CH Cl
CH NHCH Me
NO2
2
2
2
a
N
b
Cl
N
Cl
N
Cl
N
O
OH
OH
c
O
O
d
Ar
N
NO2
O N
2
O
O
e
N
NH
ArCHO
5
+
+
N
O
Cl
N
O
Cl
N
4
1
3a~3q
3
m: Ar=4-CN-C H4
6
3
3
3
3
a: Ar=Ph
b: Ar=4-MeC H
3e: Ar=4-MeOC H4
3i: Ar=2-Cl-C H4
3n: Ar=4-CF -C H
6
6
3
6
6
4
3f: Ar=2-F-C H4
3j: Ar=3-Cl-C H4
3o: Ar=4-NO
2
-C
H
4
6
4
6
6
c: Ar=4-iPrC H
3g: Ar=3-F-C H4
3k: Ar=4-CI-C H4
3p: Ar=2,4-diClC H3
6
6
4
6
6
d: Ar=2-MeOC H
3h: Ar=4-F-C H4
3l: Ar=4-BrC H4
6
4
6
6
3
q: Ar=3,4-diClC H3
6
Reagents and conditions: (a) ethanamine (42%); (b) 1,1,1-trichloro-2-nitroethane/CHCl
methanamine 3-7 C (58%); (d) acetone, H SO , Ac O, 60 C (78%); (e) piperidine, EtOH, MW, 65 C,
59-89%).
3
2-7 C (65%); (c)
2
4
2
(
Scheme 1. General Synthetic Route for the Target Compounds
Possible mechanism for the formation of the nitenpyram analogues is described in Scheme 2. The
assembly of 7 can be explained via the initial Michael addition of enamine double bond in 1 to 6, leading

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HETEROCYCLES, Vol. 87, No. 9, 2013
to the formation of an acyclic intermediate 8, which cyclized into the intermediate 9 via nucleophilic
attack of an NH group on a carbonyl carbon, then one molecule of acetone and carbon dioxide are split
27
off and finally the tetrahydropyridine ring can be closed. It is an efficient and promising method to
construct the tetrahydropyridone skeleton.
O
O
O
O
O
O
O
O
+
ArCHO
5
ArCH
4
6
O
O
NO
NH
2
O
O
ArCH
N
Cl
N
O
1
6
Ar
Ar
O
O N
O
2
O N
2
O
O
N
NH
O
O
N
N
O
Cl
N
Cl
N
8
Ar
7
Ar
O
O N
2
O N
2
O
N
N
O
N
N
9
O
O-
Cl
N
Cl
N
3
Scheme 2. Possible mechanism for the formation of the target compounds.
Figure 2. Molecular structure of compound 3g (Number CCDC 825017) with atom-labeling.

HETEROCYCLES, Vol. 87, No. 9, 2013
1869
2
. Crystal Structure Analysis
The structure of compounds 3g was unambiguously confirmed by X-ray crystallographic diffraction
analysis. As compared with the trans configuration of nitromethylene in the crystal structure of
3
1
nitenpyram, 3g is obviously in the cis configuration as anticipated. From Figure 2, the
tetrahydropyridone ring adopts a skew boat conformation and a N2/C9/C10/N4 dihedral angle of -20.2
(
5)°. In the tetrahydropyridone moiety, C(13)–C(12), C(11)–C(10) and C(12)–C(11) bond lengths
1.484(4) Å, 1.501(4) Å and 1.533(4) Å) are slightly shorter than normal (1.54 Å). The C(13)–N(3),
(
C(9)–N(3), and C(10)–N(4) bond lengths (1.390 Å(4), 1.405Å(3), and 1.412 Å(4), respectively) are
slightly shorter than normal (1.47 Å), while the C(9)=C(10) bond length (1.371(4) Å) is slightly longer
than normal (1.34 Å). Besides, the dihedral angle between the mean planes of the benzene and pryidine
rings is 80.7 (3)°.
3
. Structure activity relationship
The insecticidal activities against Nilaparvata lugens, Myzus persicae and Aphis medicaginis of the title
compounds were investigated using nitenpyram as a control, and the results are presented in Table 1.
Most of our designed analogues showed better insecticide activities against Myzus persicae , Nilaparvata
lugens and Aphis medicaginis (Table 1). Among these analogues, 3n afforded the best in vitro inhibitory
activities and had 100% mortality at 20 mg/L against Myzus persicae and Nilaparvata lugens, the LC50
values of 3n against Myzus persicae and Nilaparvata lugens are 0.191 mg/L and 0.219 mg/L, respectively,
that is very close to nitenpyram. In general, the analogues with different substituents on benzene ring
exhibited equivalent activities at high dose (500 mg/L). However, the insecticidal activities showed
significant differences when the doses were reduced to 100 and 20 mg/L.
As depicted in Table 1, against Nilaparvata lugens, compound 3a with no substitution on the phenyl
group presented moderate insecticidal activity at 100 and 20 mg/L. Introducing electron-donating
substituents on benzene ring were unfavorable to activities, most of these compounds (3b-e) exhibited
unpleasing insecticidal effectiveness. For the effect of electron-withdrawing groups, introducing halogen
atoms such as single fluro, chloro atom on benzene ring did not contribute to activity improvement of the
corresponding compounds, insecticidal activities of compounds (3f-k) were little more than those with
electron-donating substituents on benzene ring (3b-e). Interestingly, bring bromo atom in the benzene ring

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HETEROCYCLES, Vol. 87, No. 9, 2013
(
3l) resulted in greatly increased insecticidal activity, whereas double chloro atoms on benzene ring (3p,
q) also significantly increased activities. Among electron-withdrawing groups on benzene ring,
3
trifluoromethyl (3n) was most prominent group in increasing activity. For Myzus persicae and Aphis
medicaginis, all these cis-nitenpyram analogues have the similar structure activity relationship.
Considering the discussion above, we found that insecticidal potencies of our designed nitenpyam
analogues could be increased by the introduction of bromo, trifluoromethyl and dichloride substituents on
benzene rings.
Table 1．Insecticidal Activities of Nitenpyram Analogues 3 against Nilaparvata lugens, Myzus persicae
and Aphis medicaginis.
Mortality (%) at different concentrations (mg/L)
Nilaparvata lugens
Myzus persicae
Aphis medicaginis
Compd.
Ar
500
100
20
500
100
20
500
100
20
3
a
Ph
100
100
100
80
100
60
80
20
100
93
68
52
41
38
48
25
20
NT
68
38
28
55
NT
74
0
100
100
100
80
80
30
70
NT
68
NT
60
80
30
60
40
75
0
65
a
3b
4-MeC
6
H
4
NT
3
c
4-iPrC
2-MeOC
4-MeOC
6
H
4
100
NT
80
60
90
85
NT
NT
10
3d
6
6
H
4
4
NT
20
100
100
83
62
3
e
H
100
80
85
100
65
3
f
2-F-C
6
H
4
4
4
NT
80
NT
60
20
NT
NT
20
3
g
3-F-C H
100
100
100
100
80
100
85
95
80
6
3h
4-F-C
2-Cl-C
3-Cl-C H
6
H
100
80
40
52
100
80
3
i
6
H
4
4
4
50
80
58
NT
NT
10
3
j
50
NT
NT
100
10
92
76
80
6
3k
4-Cl-C
4-Br-C
4-CN-C
4-CF -C
4-NO -C
2,4-diClC
6
H
NT
100
40
82
36
80
3
l
6
H
4
100
80
100
100
100
100
100
95
100
85
100
80
10
3
m
6
H
4
NT
20
b
c
3n
3
6
H
4
100
80
100
40
100
20
100
80
100
0
100
100
100
80
70
0
3
o
p
q
2
6
H
4
NT
30
3
6
H
3
100
100
100
100
100
100
100
80
80
62
100
90
80
100
3
3,4-diClC H
80
20
6
3
d,e
d
e
Nitenpyram
100
100
100
100
100
100
a
b
c
d
e
NT,not tested. LC50 = 0.219 mg/L. LC50 = 0.191 mg/L. LC50 = 0.129 mg/L. LC50 = 0.136 mg/L.

HETEROCYCLES, Vol. 87, No. 9, 2013
1871
4
. Molecular docking study
To further explore the structural features for better activities, models of these new compounds-receptor
2
0-22
complexes were investigated by docking studies with CDOCKER.
Since the amino acids forming the
active sites are both structurally and functionally consistent in the diverse nAChRs and AchBPs, the
published crystal structure of a Lymnaea stagnalis-AChBP (Ls-AChBP) co-crystallized with imidacloprid
32
(
PDB ID: 2zju) was used as the template of receptor. The docking study was performed by using the
program CDOCK (Discovery Studio 3.1).
Figure 3. Binding site interactions of analogue 3n, 3g, 3l, 3q with the extracellular domain of nAChR
(
protein data bank code: 2zju). (a) Zoomed-in view of the interactions between compound 3n and amino
acids from the active site of the receptor. (b) Zoomed-in view of the interactions between compound 3g
and amino acids from the active site of the receptor. (c) Zoomed-in view of the interactions between
compound 3l and amino acids from the active site of the receptor. (d) Zoomed-in view of the interactions
between compound 3q and amino acids from the active site of the receptor.

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HETEROCYCLES, Vol. 87, No. 9, 2013
As a result, all active analogues exhibited significant hydrogen-bonding interactions with the nAChR
target. As illustrated in Figure (3a), chloropyridine N of 3n exhibits a hydrogen bond with NH of Trp143
backbone on loop B, while the nitro O(32) interact with OH of Tyr192 on loop C, which suggest that
chloropyridine N and nitro O play a key role in recognizing and interacting with the binding site. In
addition, its binding conformation exhibits another two important hydrogen bonds: O(24) of its carbonyl
interacts with SH of Cys187, and F(27) interacts with the side chain NH of Gln55. These observations
have also explained why the analogue 3n attained the highest score.
Furthermore, most of the other active analogues shared a quite similar binding mode with analogue 3n
and many of them exhibited more than two hydrogen-bonds with different amino acids of the active
pocket between the nAChR subunits. However, not all carbonyl O(24) of analogues 3 can form hydrogen
bond within the same hydrogen bond distance, such as the binding mode of analogue 3g (Figure 3(b)),
O(24) of its carbonyl cannot interact with amino acid residues from the Ls-AChBP.
Moreover, we found that analogues offered high experimental activities when carbonyl can exhibit
hydrogen-bond with different amino acids residues (Figure 3(a, c, d)). These observations have also
explained the structure-activity relationships observed in vitro. Thereby, the newly introduced
substituents of the designed analogues presumably played important roles in ligand recognition and
binding interactions, which may further enhance their activities and contribute to the selectivity as well.
Based on these, further target inhibitory tests and advanced insecticide design are underway.
CONCLUSION
In conclusion, a series of cis-nitenpyram analogues (3a-q) with tetrahydropyridone fixed
cis-configuration were designed and synthesized. Preliminary bioassays showed that most of the designed
nitenpyram analogues exhibited good insecticidal activity at 100 mg/L while the analogues 3n afforded
the best in vitro activity. The docking results revealed that analogues 3 with various substituents on
phenyl show their different binding affinities to the insect nAChR, which explained the SARs observed in
vitro. Moreover, carbonyl O(24) of some analogues can exhibite hydrogen-bond with amino acid residues
of receptor, which play a crucial role for their high insecticidal activities. The study herein has shed a
light on the mechanism of action of these cis-nitenpyram analogues (3a-q) containing tetrahydropyridone,

HETEROCYCLES, Vol. 87, No. 9, 2013
1873
further researches on much more test objects and structural modification of nitenpyram are underway.
EXPERIMENTAL
1
Melting points were measured using an uncorrected RK-1 microscopic melting-point apparatus. H and
1
3
1
C NMR spectra were obtained on a Bruker Avance-400 at 400 and 100 MHz, respectively. HNMR and
1
3
CNMR spectra were record with DMSO-d or CDCl as an internal standard, coupling constants (J)
6
3
-1
were recorded in Hz. The IR spectra were obtained from KBr discs in the range 4000-400cm on a
Nicolet 5DXFT-IR spectrophotometer. Mass spectra were in general recorded on an AMD 402/3 or a HP
5
989A mass selective detector. Combustion analyses for elemental composition were made with a
Perkin-Elmer 2400 instrument. All microwave experiments were performed using YL8023B1 microwave
reactor possessing a single-mode microwave cavity producing controlled irradiation at 2.45GHz. Unless
otherwise noted, reagents and solvents were of analytical reagent grade or were chemically pure and used
as received without further purification.
General Synthetic Procedures for Compounds 3a-3q
A solution of aromatic aldehyde (15 mmol), Meldrum's acid (15 mmol) and Nitenpyram 1 (10 mmol) in
EtOH (30 mL), piperidine (0.1 mmol) used as catalyst was added dropwise. The mixture solution theated
to 65 C for 30 min in a microwave reactor and cooled to room temperature. The reaction mixture was
concentrated under reduced pressure and treated with 20 mL of water. Then, the solution was extracted
2 2 4
three times with CH Cl , and the combined extracts were dried over MgSO . The organic phase was
evaporated under reduced pressure and crude product was subjected to flash chromatography on silica gel,
eluting with EtOAc /petroleum ether (1:1) to afford pure products.
6
-[N-(6-Chloro-3-pyridinylmethyl)-N-ethyl]amino-1-methyl-4-phenyl-5-nitro-1,2,3,4-tetrahydro-
-1
pyridin-2-one (3a): yield 67%; a yellow solid; mp 163-164 C; IR (KBr, cm ) 2981, 2934, 1703, 1584,
1
1
4
1
3
1
273, 1207, 1099; H NMR (400 MHz, CDCl
3
) δ 8.23 (s, 1H, Py-H), 7.40 (s, 1H, Py-H), 7.19-7.28 (m,
H, Py-H and benzene-H), 6.99 (s, 2H, benzene-H), 4.68 (t, J = 3.8 Hz, 1H, benzene-CH), 4.39 (d, J =
4.7 Hz, 1H, Py-CH ), 4.18 (d, J = 14.7 Hz, 1H, Py-CH ), 3.13-3.15 (m, 2H), 3.09 (d, J = 4.0 Hz, 2H),
.04 (s, 3H, N-CH ), 1.29 (t, J = 6.9 Hz, 3H, NCH CH ); C NMR (100 MHz, CDCl ) δ 170.3, 151.7,
2
2
1
3
3
2
3
3
49.8, 146.2, 140.3, 139.2, 131.4, 128.4, 127.9, 125.7, 123.5, 98.8, 53.5, 40.8, 35.9, 29.4, 27.1, 13.8; MS
+
(
ESI) m/z: 401 ([M+H] ). Anal. Calcd for C20
H21ClN
4
O
3
; C, 59.92; H, 5.28; N, 13.98. Found: C, 59.90; H,
5
.25; N, 13.95.

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HETEROCYCLES, Vol. 87, No. 9, 2013
6
-[N-(6-Chloro-3-pyridinylmethyl)-N-ethyl]amino-1-methyl-4-(4-methylphenyl)-5-nitro-1,2,3,4-
-1
tetrahydropyridin-2-one (3b): yield 62%; a yellow solid; mp 192-193 C; IR (KBr, cm ) 2993, 2970,
1
1
706, 1572, 1438, 1276, 1098; H NMR (400 MHz, CDCl ) δ 8.15 (s, 1H, Py-H), 7.32 (s, 1H, Py-H), 7.13
3
(
s, 1H, Py-H), 6.79-6.99 (m, 4H, benzene-H), 4.56 (s, 1H, benzene-CH), 4.32 (d, J = 14.6 Hz, 1H), 4.11
d, J = 14.6 Hz, 1H, Py-CH ), 3.06-3.15 (m, 2H), 2.97-3.00 (m, 5H), 2.24 (s, 3H), 1.22 (t, J = 6.6 Hz, 3H,
(
2
1
3
NCH
2
CH
3
); C NMR (100 MHz, CDCl
3
) δ 173.2, 155.2, 149.2, 144.3, 139.2, 135.1, 133.4, 130.2, 129.1,
+
1
27.8, 125.3, 96.8, 52.7, 40.1, 36.1, 29.1, 27.0, 20.9, 12.9; MS (ESI) m/z: 415 ([M+H] ). Anal. Calcd for
C
21
H23ClN
4
O
3
; C, 60.79; H, 5.59; N, 13.50. Found: C, 60.78; H, 5.60; N, 13.57.
6
-[N-(6-Chloro-3-pyridinylmethyl)-N-ethyl]amino-1-methyl-4-(4-isopropylphenyl)-5-nitro-1,2,3,4-
-1
tetrahydropyridin-2-one (3c): yield 72%; a yellow solid; mp 164-165 C; IR (KBr, cm ) 2992, 2980,
1
1
7
704, 1578, 1431, 1273, 1090; H NMR (400 MHz, CDCl
3
) δ 8.20 (s, 1H, Py-H), 7.35 (s, 1H, Py-H),
.12-7.15 (m, 1H, Py-H), 7.02-7.04 (m, 2H, benzene-H), 6.79 (s, 2H, benzene-H), 4.56 (t, J = 3.5 Hz, 1H,
benzene-CH), 4.33 (d, J = 14.6 Hz, 1H, Py-CH), 4.13 (d, J = 14.6 Hz, 1H, Py-CH), 3.06-3.08 (m, 2H),
2
6
1
.99 (s, 2H), 2.98 (s, 3H), 2.76-2.83 (m, 1H, CH(CH
3
)
2
), 1.23 (t, J = 7.0 Hz, 3H, NCH
2 3
CH ), 1.16 (d, J =
1
3
.9 Hz, 6H, CH (CH ) ); C NMR (100 MHz, CDCl ) δ 171.2, 151.9, 147.2, 146.1, 145.4, 140.1, 137.4,
3
2
3
31.8, 127.6, 126.2, 123.8, 97.4, 53.5, 40.1, 35.1, 31.7, 28.2, 27.0, 24.4, 13.5; MS (ESI) m/z: 443
+
(
[M+H] ). Anal. Calcd for C23
H27ClN
4
O
3
; C, 62.37; H, 6.14; N, 12.65. Found: C, 62.35; H, 6.10; N,
1
6
2.66.
-[N-(6-Chloro-3-pyridinylmethyl)-N-ethyl]amino-1-methyl-4-(2-methoxylphenyl)-5-nitro-1,2,3,4-
-1
tetrahydropyridin-2-one (3d): yield 78%; a yellow solid; mp 182-183 C; IR (KBr, cm ) 2990, 2968,
1
1
7
708, 1580, 1430, 1281, 1089; H NMR (400 MHz, CDCl
3
) δ 8.38 (s, 1H, Py-H), 7.53 (s, 1H, Py-H),
.27-7.29 (m, 1H, Py-H), 7.20-7.22 (m, 1H, benzene-H), 6.74-6.87 (m, 2H, benzene-H), 6.35 (s, 1H,
), 4.23 (d, J = 14.6 Hz, 1H,
), 2.94-3.05 (m, 2H), 1.34 (t, J = 7.2 Hz, 3H,
benzene-H), 4.84 (s, 1H, benzene-CH), 4.45 (d, J = 14.6 Hz, 1H, Py-CH
2
Py-CH
2 3
), 3.82 (s, 3H), 3.16-3.19 (m, 2H), 3.11 (s, 3H, OCH
1
3
NCH CH
2
3
); C NMR (100 MHz, CDCl
3
) δ 170.7, 159.8, 151.9, 149.1, 146.9, 138.8, 130.5, 128.9, 126.7,
+
1
25.8, 123.5, 120.7, 114.3, 98.9, 56.1, 53.9, 40.2, 35.8, 27.0, 19.5, 14.0; MS (ESI) m/z: 431 ([M+H] ).
Anal. Calcd. for C H ClN O ; C, 58.54; H, 5.38; N, 13.00. Found: C, 58.50; H, 5.36; N, 13.06.
2
1
23
4
4
6
-[N-(6-Chloro-3-pyridinylmethyl)-N-ethyl]amino-1-methyl-4-(4-methoxylphenyl)-5-nitro-1,2,3,4-
-1
tetrahydropyridin-2-one (3e): yield 69%; a yellow solid; mp 176-177 C; IR (KBr, cm ) 2971, 2931,
1
1
703, 1584, 1445, 1209, 1095; H NMR (400 MHz, CDCl
3
) δ 8.24 (s, 1H, Py-H), 7.20-7.42 (m, 2H,

HETEROCYCLES, Vol. 87, No. 9, 2013
1875
Py-H), 6.76-6.86 (m, 4H, benzene-H), 4.60 (s, 1H, benzene-CH), 4.39 (d, J = 14.6 Hz, 1H, Py-CH
2
), 4.19
(
2 3
d, J = 14.6Hz, 1H, Py-CH ), 3.79 (s, 3H, OCH ), 3.10-3.14 (m, 2H), 3.05(s, 5H), 1.29 (t, J = 6.4 Hz, 3H,
1
3
NCH
2
CH
3
); C NMR (100 MHz, CDCl
3
) δ 170.9, 161.4, 151.6, 148.1, 146.1, 138.2, 132.5, 130.8, 125.7,
+
1
20.9, 114.0, 97.9, 56.0, 53.4, 40.6, 35.2, 29.0, 26.8, 14.1; MS (EI) m/z: 431 ([M+H] ). Anal. Calcd for
C
21
H23ClN
4
O
4
; C, 58.54; H, 5.38; N, 13.00. Found: C, 58.58; H, 5.34; N, 13.02.
6
-[N-(6-Chloro-3-pyridinylmethyl)-N-ethyl]amino-1-methyl-4-(2-fluorophenyl)-5-nitro-1,2,3,4-tetra-
-
1
hydropyridin-2-one (3f): yield 81%; yellow solid; mp 136-138 C; IR (KBr, cm ) 2992, 2970, 1706,
1
1
572, 1436, 1279, 1091; H NMR (400 MHz, CDCl ) δ 8.25 (s, 1H, Py-H), 7.45 (s, 1H, Py-H), 7.18-7.26
3
(
m, 3H, Py-H and benzene-H), 7.10 (s, 1H, benzene-H), 6.84 (s, 1H, benzene-H), 4.66-4.67 (m, 1H,
benzene-CH), 4.41 (d, J = 14.7 Hz, 1H, Py-H), 4.16 (d, J = 14.7 Hz, 1H, Py-H), 3.13-3.14 (m, 2H),
1
3
3
1
1
2 3 3
.02-3.11 (m, 5H), 1.30 (t, J = 7.5 Hz, 3H, NCH CH ); C NMR (100 MHz, CDCl ) δ 169.8, 160.7,
51.8, 149.9, 148.2, 140.1, 130.8, 128.4, 127.9, 127.0, 124.0, 123.8, 115.4, 98.1, 53.1, 40.9, 35.1, 27.7,
+
8.6, 13.3; MS (ESI) m/z: 419 ([M+H] ). Anal. Calcd for C20
H
20ClFN
4
O
3
; C, 57.35; H, 4.81; N, 13.38.
Found: C, 57.33; H, 4.80; N, 13.36.
-[N-(6-Chloro-3-pyridinylmethyl)-N-ethyl]amino-1-methyl-4-(3-fluorophenyl)-5-nitro-1,2,3,4-tetra-
6
-1
hydropyridin-2-one (3g): yield 80%, a yellow solid; mp 146-148 C; IR (KBr, cm ) 2992, 2970, 1711,
1
1
534, 1436, 1256, 1091; H NMR (400 MHz, CDCl
3
) δ 8.23 (s, 1H, Py-H), 7.42 (s, 1H, Py-H), 7.22-7.24
(
m, 2H, Py-H and benzene-H), 6.92-6.97 (m, 1H, benzene-H), 6.76-6.78 (m, 2H, benzene-H), 4.68 (s, 1H,
benzene-CH), 4.40 (d, J = 14.7 Hz, 1H, Py-CH ), 4.18 (d, J = 14.7 Hz, 1H, Py-CH ), 3.08-3.14 (m, 4H),
) δ 170.7, 162.0, 151.5,
2
2
1
3
3
1
1
2 3 3
.06 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H, NCH CH ); C NMR (100 MHz, CDCl
49.9, 146.5, 141.8, 138.4, 131.8, 130.0, 124.2, 123.5, 114.9, 112.7, 98.0, 53.5, 40.5, 35.9, 28.7, 27.5,
+
3.2; MS (ESI) m/z: 419 ([M+H] ). Anal. Calcd for C20
H20ClFN
4
O
3
; C, 57.35; H, 4.81; N, 13.38. Found:
C, 57.31; H, 4.80; N, 13.35.
-[N-(6-Chloro-3-pyridinylmethyl)-N-ethyl]amino-1-methyl-4-(4-fluorophenyl)-5-nitro-1,2,3,4-tetra-
6
-
1
hydropyridin-2-one (3h): yield 84%; a yellow solid; mp 168-170 C; IR (KBr, cm ) 2994, 2973, 1702,
1
1
578, 1432, 1274, 1090; H NMR (400MHz, CDCl
3
) δ 8.15 (s, 1H, Py-H), 7.32-7.40 (s, 1H, Py-H),
7
.13-7.20 (m, 1H, Py-H), 6.80-6.88 (m, 4H, benzene-H), 4.56 (s, 1H, benzene-CH), 4.32 (d, J = 14.7 Hz,
1
H, Py-CH ), 4.12 (d, J = 14.7 Hz, 1H, Py-CH ), 3.08 (s, 2H), 2.99-3.07 (m, 5H), 1.22 (t, J = 6.9 Hz, 3H,
2
2
1
3
NCH
2
CH
3
); C NMR (100 MHz, CDCl
3
) δ 170.4, 159.3, 150.9, 148.9, 146.8, 139.2, 135.8, 131.5, 129.5,
+
1
23.5, 115.4, 98.5, 53.8, 40.9, 35.2, 29.8, 27.0, 13.4; MS (ESI) m/z: 419 ([M+H] ). Anal. Calcd for

1876
HETEROCYCLES, Vol. 87, No. 9, 2013
C
20
H
20ClFN
4
O
3
; C, 57.35; H, 4.81; N, 13.38. Found: C, 57.38; H, 4.80; N, 13.37.
6
-[N-(6-Chloro-3-pyridinylmethyl)-N-ethyl]amino-1-methyl-4-(2-chlorophenyl)-5-nitro-1,2,3,4-tetra-
-1
hydropyridin-2-one (3i): yield 71%, a yellow solid; mp 188-189 C; IR (KBr, cm ) 2993, 2971, 1706,
1
1
7
7
1
576, 1436, 1274, 1091; H NMR (400MHz, CDCl
3
) δ 8.38 (s, 1H, Py-H), 7.54 (s, 1H, Py-H), 7.39 (d, J =
.9 Hz, 1H, Py-H), 7.28 (d, J = 8.1 Hz, 1H, benzene-H), 7.19 (t, J = 7.7 Hz, 1H, benzene-H), 7.05 (t, J =
.5 Hz, 1H, benzene-H), 6.25 (s, 1H, benzene-H), 4.92-4.94 (m, 1H, benzene-CH), 4.46 (d, J = 14.6 Hz,
H, Py-CH
2
), 4.27 (d, J = 14.6 Hz, 1H, Py-CH
2
), 3.20-3.22 (m, 2H), 3.15 (s, 3H), 2.98-3.12 (m, 2H), 1.34
); C NMR (100 MHz, CDCl ) δ 172.3, 152.1, 149.9, 146.1, 140.6, 139.1,
33.1, 131.2, 129.3, 128.8, 127.1, 126.5, 123.8, 98.1, 53.9, 40.1, 35.6, 27.5, 20.4, 13.2; MS (ESI) m/z:
1
3
(
t, J = 7.1 Hz, 3H, NCH
2
CH
3
3
1
4
1
6
+
35 ([M+H] ). Anal. Calcd for C20
H20Cl
2
N
4
O
3
; C, 55.18; H, 4.63; N, 12.87. Found: C, 55.12; H, 4.64; N,
2.88.
-[N-(6-Chloro-3-pyridinylmethyl)-N-ethyl]amino-1-methyl-4-(3-chlorophenyl)-5-nitro-1,2,3,4-tetra-
-1
hydropyridin-2-one (3j): yield 59%; a yellow solid; mp 56-57 C; IR (KBr, cm ) 2991, 2971, 1706,
1
1
580, 1440, 1200, 1085; H NMR (400MHz, CDCl
3
) δ 8.25 (s, 1H, Py-H), 7.45 (s, 1H, Py-H), 7.18-7.26
(m, 3H, Py-H and benzene), 7.10 (s, 1H, benzene-H), 6.84 (s, 1H, benzene-H), 4.66-4.67 (m, 1H,
benzene-CH), 4.41 (d, J = 14.7 Hz, 1H, Py-CH ), 4.16 (d, J = 14.7 Hz, 1H, Py-CH ), 3.13-3.14 (m, 2H),
2
2
1
3
3
1
2
2 3 3
.02-3.11 (m, 5H), 1.30 (t, J = 7.5 Hz, 3H, NCH CH ); C NMR (100 MHz, CDCl ) δ 168.7, 152.3,
48.4, 145.8, 141.6, 139.2, 133.7, 131.8, 129.9, 128.4, 126.5, 126.0, 121.2, 98.2, 53.9, 40.5, 35.8, 28.9,
+
7.5, 13.0; MS (ESI) m/z: 435 ([M+H] ). Anal. Calcd for C20
H20Cl
2
N O
4 3
; C, 55.18; H, 4.63; N, 12.87.
Found: C, 55.17; H, 4.67; N, 12.88.
-[N-(6-Chloro-3-pyridinylmethyl)-N-ethyl]amino-1-methyl-4-(4-chlorophenyl)-5-nitro-1,2,3,4-tetra-
6
-
1
hydropyridin-2-one (3k): yield 75%; a yellow solid; mp 180-182 C; IR (KBr, cm ) 2991, 2970, 1708,
1
1
577, 1436, 1274, 1095; H NMR (400MHz, CDCl
3
) δ 8.15 (s, 1H, Py-H), 7.31 (s, 1H, Py-H), 7.15-7.20
(
m, 3H, Py-H and benzene-H), 6.85 (s, 2H, benzene-H), 4.57 (s, 1H, benzene-CH), 4.32 (d, J = 14.7 Hz,
H, Py-CH ), 4.12 (d, J = 14.7 Hz, 1H, Py-CH ), 3.05-3.08 (m, 2H), 2.96-3.00 (m, 5H), 1.22 (t, J = 6.2
Hz, 3H, NCH
1
2
2
1
3
2
CH
3
); C NMR (100 MHz, CDCl
3
) δ 170.2, 150.8, 148.6, 145.8, 140.2, 138.3, 130.8,
+
1
31.0, 129.4, 128.8, 123.9, 98.6, 53.2, 40.0, 35.2, 29.2, 27.8, 14.3; MS (ESI) m/z: 435 ([M+H] ).
Anal.Calcd for C20
2 4 3
H20Cl N O ; C, 55.18; H, 4.63; N, 12.87. Found: C, 55.16; H, 4.60; N, 12.87.
6
-[N-(6-Chloro-3-pyridinylmethyl)-N-ethyl]amino-1-methyl-4-(4-bromophenyl)-5-nitro-1,2,3,4-tetra-
-
1
hydropyridin-2-one (3l): yield 87%; a yellow solid; mp 205-206 C; IR (KBr, cm ) 2991, 2970, 1704,

HETEROCYCLES, Vol. 87, No. 9, 2013
1877
1
1
579, 1436, 1273, 1095; H NMR (400MHz, CDCl
m, 3H, Py-H and benzene-H), 7.10 (s, 1H, benzene-H), 6.84 (s, 1H, benzene-H), 4.66-4.67 (m, 1H,
benzene-CH), 4.41 (d, J = 14.7 Hz, 1H, Py-CH ), 4.16 (d, J = 14.7 Hz, 1H, Py-CH ), 3.13-3.14 (m, 2H),
); C NMR (100 MHz, CDCl ) δ 170.9, 152.6,
3
) δ 8.25 (s, 1H, Py-H), 7.45 (s, 1H, Py-H), 7.18-7.26
(
2
2
1
3
3
.02-3.11 (m, 5H), 1.30 (t, J = 7.5 Hz, 3H, NCH
2
CH
3
3
150.2, 149.4, 146.1, 140.3, 132.2, 131.4, 130.5, 123.8, 120.5, 98.0, 53.5, 40.1, 35.7, 29.2, 27.9, 13.0; MS
+
(
ESI) m/z: 479 ([M+H] ). Anal. Calcd for C20
H
20BrClN
4
O
3
; C, 50.07; H, 4.20; N, 11.68. Found: C, 50.06;
H, 4.20; N, 11.67.
6
-[N-(6-Chloro-3-pyridinylmethyl)-N-ethyl]amino-1-methyl-4-(4-cyanophenyl)-5-nitro-1,2,3,4-tetra-
-1
hydropyridin-2-one(3m): yield 71%; a yellow solid; mp 96-98 C; IR (KBr, cm ) 2995, 2978, 1702,
1
1
578, 1438, 1211, 1065; H NMR (400MHz, CDCl ) δ 8.18 (s, 1H, Py-H), 7.35-7.56 (m, 3H, Py-H and
3
benzene-H), 7.07-7.19 (m, 3H, benzene-H), 4.70 (s, 1H, benzene-CH), 4.37 (d, J = 14.6 Hz, 1H, Py-CH
2
),
4
.23 (d, J = 14.6 Hz, 1H, Py-CH ), 3.16-3.20 (m, 2H), 3.09-3.12 (m, 5H), 1.31 (t, J = 6.5 Hz, 3H,
2
1
3
NCH
2
CH
3
); C NMR (100 MHz, CDCl
3
) δ 170.2, 151.8, 149.8, 145.4, 144.3, 140.2, 131.4, 129.4, 128.6,
+
1
25.7, 116.5, 109.8, 99.1, 53.5, 40.8, 36.2, 28.8, 28.2, 14.3; MS (ESI) m/z: 426 ([M+H] ). Anal. Calcd for
C H ClN O ; C, 59.23; H, 4.73; N, 16.44. Found: C, 59.26; H, 4.72; N, 16.45.
2
1
20
5
3
6
1
2
7
4
3
1
2
-[N-(6-Chloro-3-pyridinylmethyl)-N-ethyl]amino-1-methyl-4-(4-trifluoromethylphenyl)-5-nitro-
-1
,2,3,4-tetrahydropyridin-2-one (3n): yield 86 %; a yellow solid; mp 152-153 C; IR (KBr, cm ) 2992,
1
970, 1706, 1572, 1436, 1279, 1091; H NMR (400MHz, CDCl
3
) δ 8.45 (s, 1H, Py-H), 7.75 (s, 1H, Py-H),
.51-7.5 4 (m, 2H, Py-H and benzene-H), 7.35-7.39 (s, 1H, benzene-H), 7.08-7.20 (m, 2H, benzene-H),
.72 (s, 1H, benzene-CH), 4.40 (d, J = 14.8 Hz, 1H, Py-CH ), 4.22 (d, J = 14.8 Hz, 1H, Py-CH ),
.11-3.12 (m, 2H), 3.06-3.07 (m, 5H), 1.26 (t, J = 7.1 Hz, 3H, NCH ) δ
2
2
1
3
2
3 3
CH ); C NMR (100 MHz, CDCl
71.5, 150.2, 148.3, 146.1, 143.5, 139.1, 131.8, 128.4, 127.9, 125.2, 122.8, 119.3, 98.1, 53.4, 40.6, 35.8,
+
9.8, 27.5, 13.9; MS (ESI) m/z: 469 ([M+H] ). Anal. Calcd for C21
H20ClF
3
N
4
O
3
; C, 53.30; H, 4.30; N,
11.95. Found: C, 53.35; H, 4.31; N, 11.98.
6
-[N-(6-Chloro-3-pyridinylmethyl)-N-ethyl]amino-1-methyl-4-(4-nitrophenyl)-5-nitro-1,2,3,4-tetra-
-
1
hydropyridin-2-one (3o): yield 89%; a yellow solid; mp 200-201 C; IR (KBr, cm ) 2990, 2975, 1702,
1
1
578, 1432, 1274, 1092; H NMR (400MHz, CDCl
3
) δ 8.19 (s, 1H, Py-H), 8.13 (s, 1H, Py-H), 8.11 (s, 1H,
Py-H), 7.39 (s, 1H, benzene-H), 7.17-7.19 (m, 3H, benzene-H), 4.75 (s, 1H, benzene-CH), 4.41 (d, J =
4.7 Hz, 1H, Py-CH ), 4.23 (d, J = 14.7 Hz, 1H, Py-CH ), 3.13-3.20 (m, 4H), 3.10 (s, 3H), 1.31 (t, J = 7.2
) δ 172.5, 151.8, 149.9, 146.8, 146.2, 145.6, 139.2,
1
2
2
1
3
2 3 3
Hz, 3H, NCH CH ); C NMR (100 MHz, CDCl

1878
HETEROCYCLES, Vol. 87, No. 9, 2013
+
1
31.2, 128.4, 123.7, 123.1, 98.2, 53.6, 40.9, 35.8, 29.2, 27.8, 13.2; MS (ESI) m/z: 446 ([M+H] ). Anal.
Calcd for C20 ; C, 53.88; H, 4.52; N, 15.71. Found: C, 53.85; H, 4.55; N, 15.77.
-[N-(6-Chloro-3-pyridinylmethyl)-N-ethyl]amino-1-methyl-4-(2,4-dichlorophenyl)-5-nitro-1,2,3,4-
5 5
H20ClN O
6
-1
tetrahydropyridin-2-one (3p): yield 76%; a yellow solid; mp 178-180 C; IR (KBr, cm ) 2998, 2973,
1
1
702, 1578, 1432, 1270, 1092; H NMR (400 MHz, CDCl ) δ 8.38 (s, 1H, Py-H), 7.51 (s, 1H, Py-H), 7.41
3
(
s, 1H, Py-H), 7.03-7.30 (m, 2H, benzene-H), 6.07-6.09 (s, 1H, benzene-H), 4.85 (s, 1H, benzene-CH),
4
3
.46 (d, J = 14.6 Hz, 1H, Py-CH
.08 (d, J = 16.7 Hz, 1H), 2.97 (d, J = 16.7 Hz, 1H), 1.35 (t, J = 7.1 Hz, 3H, NCH
) δ 171.2, 152.1, 149.2, 145.2, 139.2, 138.7, 134.6, 132.4, 131.1, 130.7, 129.2, 126.9, 121.6,
2 2
), 4.28 (d, J = 14.6 Hz, 1H, Py-CH ), 3.21-3.28 (m, 2H), 3.16 (s, 3H),
13
2
3
CH ); C NMR (100
MHz, CDCl
3
+
1
5
6
00.4, 54.8, 41.2, 35.6, 26.5, 20.3, 13.2; MS (ESI) m/z: 469 ([M+H] ). Anal. Calcd for C20
1.14; H, 4.08; N, 11.93. Found: C, 51.15; H, 4.10; N, 11.96.
-[N-(6-Chloro-3-pyridinylmethyl)-N-ethyl]amino-1-methyl-4-(3,4-dichlorophenyl)-5-nitro-1,2,3,4-
3 4 3
H19Cl N O ; C,
-1
tetrahydropyridin-2-one (3q): yield 83%; a yellow solid; mp 157-158 C; IR (KBr, cm ) 2994, 2973,
1
1
702, 1578, 1432, 1274, 1090; H NMR (400 MHz, CDCl
3
) δ 8.17 (s, 1H, Py-H), 7.36 (s, 1H, Py-H), 7.27
(
d, J = 8.3 Hz, 1H, Py-H), 7.14-7.20 (m, 2H, benzene-H), 6.73 (s, 1H, benzene-H), 4.56-4.58 (m, 1H,
benzene-CH), 4.34 (d, J = 14.7 Hz, 1H, Py-CH ), 4.09 (d, J = 14.7 Hz, 1H, Py-CH ), 3.05-3.07 (m, 2H),
2
2
1
3
2
1
1
.98-3.02 (m, 5H), 1.23 (t, J = 7.2Hz, 3H, NCH
2
CH
3
); C NMR (100 MHz, CDCl
3
) δ 171.5, 153.9, 149.2,
45.8, 139.7, 138.0, 133.5, 132.4, 131.6, 130.2, 129.7, 127.4, 122.6, 99.3, 53.5, 42.2, 35.3, 28.9, 26.4,
+
3.2; MS (ESI) m/z: 469 ([M+H] ). Anal. Calcd for C20
H19Cl
3
N
4
O
3
; C, 51.14; H, 4.08; N, 11.93. Found:
C, 51.13; H, 4.11; N, 11.96.
X-Ray Crystallography
A yellow crystal of compound 3g was recrystallized by slow evaporation from a mixed solution of
EtOAc/petroleum ether (v:v = 1:5), with dimensions of 0.16 mm x 0.12 mm x 0.10 mm was mounted on a
glass fiber for data collection which was made on a BRUKER SMART APEX 1000 CCD diffractometer
equipped with a graphite-monochromatic MoKα radiation (λ = 0.71073 Å) by using a φ-ω scan mode in
the range of 1.82≤θ≤25.50° (-10≤h≤13, -23≤k≤23, -10≤l≤10) at 298(2) K. A total of 10184 reflections
were collected with 3672 unique ones (R = 0.0565), of which 2051 with I > 2σ(I) were considered as
int
observed and used in the succeeding refinements. The intensity data were corrected for Lp factors and
2
2
2
empirical absorption. The final R = 0.0594, wR = 0.1275 (w = 1/[ (Fo ) + (0.0621P) + 0.000P], where
2
2
3
P = (Fo + 2Fc )/3), S = 1.000, (Δ/σ)max = 0.001, (Δρ)max = 0.351 and (Δρ)min = –0.266 e/Å . The

HETEROCYCLES, Vol. 87, No. 9, 2013
1879
structural graphics was drawn with SHELXTL-97 software package. Other details of the structure have
been deposited with the Cambridge CrystallographicData Centre, CCDC 825017.
ACKNOWLEDGEMENTS
We are grateful for the insecticidal activity test of the target compounds from Bioassay Department,
Branch of National Pesticide R&D South Center, Hangzhou and the support from Branch of National
Pesticide R&D South Center. This work was supported by the National Natural Science Foundation of
China (21102092), the Key Scientific "Twelfth Five-Year" National Technology Support Program
(2011BAE06B01-17), the Innovation Project of Shanghai Education Commission (12YZ078), the
Program of the Food Safety and Nutrition Innovation Team of Shanghai Normal University
(
DXL123), Shanghai Key Laboratory of Rare Earth Functional Materials, Shanghai Normal University
07dz22303).
(
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