Synthesis and insecticidal activities: Cis-nitenpyram analogs with 1,4-dihydropyridine scaffold

Article abstract of DOI:10.1002/jhet.1021

By means of multicomponent reactions, via Michael addition, nucleophilic addition, using nitenpyram, substituted aromatic aldehydes, and cyanoacetate compounds or propanedinitrile, a new series of cis-configuration nitenpyram analogs (1a-1k) were synthesized by introducing the 1,4-dihydropyridine scaffold pharmacophore, as shown in Scheme 1. The structures of all compounds were confirmed by IR, ¹HNMR, ¹³C NMR, and elemental analysis. The preliminary bioassay showed that most of the target compounds exhibited good mortality against Aphis craccivora at 500 mg/L.

Full text of DOI:10.1002/jhet.1021

1376
Synthesis and Insecticidal Activities: cis-Nitenpyram Analogs
Vol 49
with 1,4-Dihydropyridine Scaffold
*
Tian-Yan Liu, Si-Jia Xue, Yan-Xia Chen, Ting Fang, Ying Wu, and Jing Wang
College of Life and Environment Sciences, Shanghai Normal University, Shanghai 200234, China
*
E-mail: liutianyan19870@yeah.net
Received March 25, 2011
DOI 10.1002/jhet.1021
View this article online at wileyonlinelibrary.com.
By means of multicomponent reactions, via Michael addition, nucleophilic addition, using nitenpyram, substi-
tuted aromatic aldehydes, and cyanoacetate compounds or propanedinitrile, a new series of cis-configuration
nitenpyram analogs (1a-1k) were synthesized by introducing the 1,4-dihydropyridine scaffold pharmacophore,
as shown in Scheme 1. The structures of all compounds were confirmed by IR, 1HNMR, 13C NMR, and elemental
analysis. The preliminary bioassay showed that most of the target compounds exhibited good mortality against
Aphis craccivora at 500 mg/L.
J. Heterocyclic Chem., 49, 1376 (2012).
INTRODUCTION
insectidal activities [13,14]. It is well established that
trans/cis isomers may differ significantly in biological
activity, toxicity, and metabolic properties and medicinal
chemistry. Fixing the nitro group in the cis-configuration
provided a new approach for neonicotinoid molecular design.
This cis/trans isomeric selectivity has been an ongoing
research interest for our laboratory over the past years.
To discover novel neonicotinoid leading compounds, based
on these reports, by means of Michael addition, nucleophilic
addition, using nitenpyram, substituted aromatic aldehydes,
and cyanoacetate compounds or propanedinitrile, fixing
the nitro group in the cis-configuration, a new series of
cis-configuration nitenpyram analogues (1a-1k) were
designed and synthesized. The structures of all title compounds
Neonicotinoid insecticides (NNs), which act agonistically
on the insect nicotinic acetylcholine receptors (nAChRs), are
gaining widespread use as a way to control pests, because of
their high potency, low mammalian toxicity, and broad
insecticidal spectra [1,2].
The NNs exhibit a novel mode of action because they are
agonists of the nicotinic acetylcholinereceptor (nAChR),
leading to paralysis and death of pest organisms [3]. This
selectivity of neonicotinoids to insect nAChR is attributed
to the pharmacophore group, such as nitromethylene
( C NO2) in nitenpyram because they have a much higher
affinity for insects as compared to vertebrate nAChRs,
and the loss of the nitro group can completely reverse
the selective toxicity of neonicotinoids for insects over
vertebrates [4]. The nitro groups in all commercialized
neonicotinoids have a trans configuration, on which three
proposals formodes of action are based [5]. However,
there is very little information on the biological properties
and binding model of the cis-neonicotinoids.
1
were confirmed by IR, H NMR, and elemental analysis.
The result of preliminary biological activity test showed
that a majority of compounds exhibited good insecticidal
activity against Aphis craccivora.
RESULTS AND DISCUSSION
Nowadays, a well-recognized potential problem facing all
insecticides is the insects’ acquisition of resistance [6,7],
during the past decade, significant increases in resistance
and cross-resistance were observed in a range of species after
frequent applications of NNSs [8], such as nitenpyram [9].
Hence, research in the design and screening for novel
neonicotinoid leading compounds with less resistance is a
high priority [10]. In the late 1980s, Bayer and Nihon
Tokushu Noyaku Seizo. reported that several cis-configuration
neonicotinoids [11,12], showed high insecticidal activity.
Li and coworkers introductions of the heterocycle or
a bulky group are two synthesis concepts to fix the cis-
configuration of the nitro group, which show excellent
Synthesis of compounds. The title compounds 1a–1k
were synthesized by the method outlined in Scheme 1.
By means of MCRs (multicomponent reactions), the
nitenpyram, substituted aromatic aldehydes and cyanoacetate
compounds or propanedinitrile via Knoevenagel
reaction, Michael addition, nucleophilic addition form
1,4-dihydropyridine scaffold, fixing the nitro group in
the cis-configuration.
Insecticidal activity. The insecticidal activities of the
title compounds 1a–1k were screened against Aphis
craccivora using the standard testing method [15] with a
slight modification. Results of the in vitro insecticidal
© 2012 HeteroCorporation

November 2012
Synthesis and Insecticidal Activities: cis-Nitenpyram Analogs with
1377
1,4-Dihydropyridine Scaffold
Scheme 1
their relatively strong affinities with their target. And in
conclusion, the substituent Z show more influence than
substituent phenyl groups in insecticidal activity, such as
compound (1a,1b) > (1g,1h).
Table 1
The insectcidal activities of target compounds in 500(mg/L).
Mortality (%) at
500 (mg/L)
Compound
Ar
Z
500
CONCLUSION
1a
1b
1c
1d
1e
1f
1g
1h
2 F C6H4
2 F C6H4
4 CN C6H4
3 F C6H4
3 Cl C6H4
4 OCH3 C6H4 COOCH2CH3
2 OCH3 C6H4 CN
2 Cl C6H4
2,4 diCl C6H4
2 F C6H4
COOCH3
90
85
85
80
70
75
65
80
80
70
80
100
In summary, we have been synthesized 11 unreported
cis-Nitenpyram analogs with 1,4-dihydropyridine scaffold
(1a-1k), and their structures were characterized by 1H
NMR, IR, and elemental analysis. Bioassay against Aphis
craccivora shows that the compounds (1a-1k) exhibit a
certain insecticide activities at 500 mg/L.
COOCH2CH3
COOCH2CH3
COOCH2CH3
COOCH2CH3
CN
CN
CN
CN
1i
1j
1k
EXPERIMENTAL
3 F C6H4
Nitenpyram
Thin-layer chromatography was carried out on silica gel 60
1
F254 plates Merck KGaA. H NMR spectra were recorded on a
Bruker Avance 400 (400 MHz) spectrometer, using CDCl3 as
solvents and tetramethylsilane as internal standard. Melting
points were determined by an RK1 microscopic melting apparatus
uncorrected. Elemental analysis was performed with a Perkin-Elmer
2400 instrument. IR spectra were obtained on a Nicolet 5DX FTIR
spectrophotometer in the region 4000–400 cm−1 using KBr discs.
Reagents and solvents were of analytical reagent grade or were
chemically pure and used as received without further purification
activities of compounds 1a-1k were summarized in Table 1.
As indicated in Table 1, most of our synthesized
compounds showed good insecticidal activities against
Aphis craccivora at 500 mg/L. Among these analogs, 1a
afforded the best in vitro activity, and had 90% mortality
at 500 mg/L. When Z are different subsitutents in the 1,4-
dihydropyridine scaffold, their insecticidal activities vary
wildly, their insecticidal activities increased in the order
cyano group(1c,1d) < ethyl ester group (1b,1e) <
methyl ester group (1a), respectively. As for the effect of
substituents at the benzene, it was observed that
compounds demonstrated better activities with electron-
withdrawing than electron-donating groups, not only in
compound (1a-1f), but also in compound (1f-1k). In
addition, the substituent positions on the benzene also
causes changes in different insecticidal activities, 2-
position(1d) > 3-position(1b), which may be related to
General synthetic procedure for synthesis of 1a-1k.
A
mixture of methyl cyanoacetate (12 mmol), benzaldehyde (12
mmol), piperidine (0.1 mmol), and nitenpyram (10 mmol) in
anhydrous alcohol (20 mL) was heated to 60–75°C for 5 min in
a microwave reactor and stirred for 30 min at the room
temperature. The reaction mixture was concentrated under
reduced pressure and treated with 20 mL of water. Then, the
solution was extracted three times with ethyl acetate, and the
combined extracts were dried over MgSO4. The organic phase
was evaporated under reduced pressure, and crude product was
subjected to flash chromatography on silica gel, eluting with
ethyl acetate/petroleum ether to afford pure products 1a.
Compounds 1b-1k were synthesized with the same method.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1378
T.-Y. Liu, S.-J. Xue, Y.-X. Chen, T. Fang, Y. Wu, and J. Wang
Vol 49
cis-2-Amino-6-[N-(6-chloro-3-pyridinylmethyl)-N-ethyl]
(t, J = 7.2 Hz, 3H, NCH2CH3) 13C NMR (400 MHz, CDCl3)
13.9, 24.6, 29.1, 44.5, 51.9, 52.3, 62.8, 84.5, 92.3, 117.7, 115.4,
123.1, 125.3, 132.7, 133.5, 136.3, 145.3, 146.3, 148.3, 151.7,
163.1, 167.5, 167.9. Anal. Calcd for C23H25ClFN5O4: C, 56.39;
H, 5.14; N, 14.29. Found: C, 56.37; H, 5.17; N, 14.33.
amino-4-(2-fluorophenyl)-1-methyl-3-methoxycarbonyl -5-
nitro-1,4-dihydropyridine (1a). Yield: 51.1%; yellow solid.
m.p.: 159–161°C; IR (KBr cm−1): vmax 2923 (CH3), 3335, 3202
(NH2), 1502–1416(NO2),1646,1615,1592(benzene); 1H NMR
(400MHz, CDCl3): δ 8.12 (s, 1H, Py H), 7.83 (d,1H, J = 7.5 Hz,
Py H), 7.35(s, 1H, Py H), 7.19–7.15 (m, 2H, Ph H), 7.07–6.99
(m, 2H, Ph H), 6.21 (br, 2H, NH2), 5.29 (s, 1H, CH), 4.32
(d, J = 4 Hz,1H), 4.02 (d, J = 16 Hz, 1H), 3.8 (s, 3H, OCH3),
3.21 (s, 3H, NCH2CH3), 3.19–3.13 (m, 1H), 3.11–3.04
(m, 1H), 1.22–1.20 (t, J = 8 Hz, 3H, NCH2CH3). 13C NMR
(400 MHz, CDCl3) 13.9, 25.5, 29.9, 42.4, 50.8, 51.1, 82.2,
91.1, 114.5, 115.5, 122.2, 123.5, 131.3, 132.1, 138.7, 144.2,
145.3, 148.8, 151.3, 163.1, 166.8, 169.4. Anal. Calcd for
C22H23ClFN5O4:C,55.52; H, 4.87; N, 14.72. Found: C, 55.54;
H, 4.92; N, 14.73.
cis-2-Amino-6-[N-(6-chloro-3-pyridinylmethyl-N-ethyl]
amino-3-ethoxycarbonyl-4-(2-fluorophenyl)-1-methyl -5-nitro-
1,4-dihydropyridine (1b). Yield: 57.3%; yellow solid. m.p.:
169–171°C; IR (KBr cm−1): vmax 2956 (CH3), 3322, 3196(NH2),
1501–1415(NO2), 1647, 1615, 1590(benzene); 1H NMR (400
MHz, CDCl3): δ 8.24 (s, 1H, Py H), 7.84 (s, 1H, Py H), 7.33 (d,
J = 7.8 Hz, 1H, Py H), 7.19–7.12 (m, 1H, Ph H), 7.04–6.98 (dd,
J = 15.6, 7.8 Hz, 2H, Ph H), 6.88 (dd, J = 11.5, 8.4 Hz, 1H,
Ph H), 6.18 (br, 2H, NH2), 5.36 (s, 1H, CH), 4.35 (d, J = 14.5
Hz, 1H), 4.10–4.05 (m, J = 7.1 Hz, 2H, COOCH2CH3), 4.02
(d, J = 14.5 Hz, 1H), 3.27 (s, 3H, NCH2CH3), 3.23–3.21
(m, 1H), 3.14–3.05 (m, 1H), 1.33–1.29 (t, J = 7.1 Hz, 3H,
COOCH2CH3), 1.23–1.20 (t, J = 7.2 Hz, 3H, NCH2CH3). 13C
NMR (400 MHz, CDCl3) 13.7, 25.1, 29.4, 42.4, 50.9, 51.5, 61.9,
83.1, 91.6, 115.1, 114.9, 122.3, 122.9, 131.3, 132.1, 138.7, 144.3,
145.7, 148.2, 151.7, 163.4, 167.2, 168.5. Anal. Calcd for
C23H25ClFN5O4:C, 56.39; H, 5.14; N, 14.29. Found: C, 56.41; H,
5.16; N, 14.32.
cis-2-Amino-6-[N-(6-chloro-3-pyridinylmethyl)-N-ethyl]
amino-4-(4-cyanophenyl)-3-ethoxycarbonyl-1-methyl-5-nitro-
1,4-dihydropyridine (1c). Yield: 56.7 %; yellow solid. m.p:
205-207 °C; IR (KBr cm−1): vmax 2954(CH3), 3325, 3194 (NH2),
1501–1415(NO2), 1649, 1613, 1585(benzene) 1H NMR(400 MHz,
CDCl3) δ 8.31 (s, 1H, Py H), 8.07 (s, 1H, Py H), 7.36 (s, 1H,
Py H), 7.47 (d, J = 8.0 Hz, 2H, Ph H), 7.09 (d, J =8.0 Hz, 2H,
Ph H), 6.26 (br, 2H, NH2), 5.42 (s, 1H, CH), 4.32 (d, J = 14.6
Hz, 1H), 4.15–4.11 (m, 2H, COOCH2CH3), 4.08–4.05 (m, 1H),
3.32–3.28 (dd, J = 14.0, 7.2 Hz, 1H), 3.25 (s, 3H, NCH2CH3),
3.18–3.13 (dd, J = 14.0, 7.2 Hz, 1H), 1.32 (t, J = 7.0 Hz, 3H,
COOCH2CH3), 1.16 (t, J = 7.1 Hz, 3H, NCH2CH3). 13C NMR
(400 MHz, CDCl3) 25.9, 27.9, 30.3, 45.7, 51.5, 53.6, 85.4, 91.6,
114.6, 116.3, 117.1, 119.2, 124.7, 126.2, 132.5, 134.5, 139.2,
145.4, 146.4, 149.1, 152.5, 164.4, 167.2, 169.4. Anal. Calcd for
C24H25ClN6O4: C, 58.01; H, 5.07; N, 16.91. Found: C, 58.03; H,
5.09; N, 16.89.
cis-2-Amino-4-(3-chlorophenyl)-6-[N-(6-chloro-3-
pyridinylmethyl)-N-ethyl]amino-3-ethoxycarbonyl-1-methyl-
5-nitro-1,4-dihydropyridine (1e). Yield: 66.2%; yellow solid.
m.p.: 147–149°C; IR (KBr cm−1): vmax 2919(CH3), 3329, 3195
(NH2), 1465, 1413(NO2), 1652, 1612, 1562(benzene) 1H NMR
(CDCl3, 400MHz) δ 8.10 (s, 1H, Py H), 7.82 (d, 1H, J = 8.0 Hz,
Py H), 7.31(s, 1H, Py H), 7.19–7.18 (m, 3H, Ph H), 6.98
(d, J = 8.0 Hz, 1H, Py H), 6.19–6.02 (2H, br, NH2), 5.49
(s, 1H, CH), 4.32 (d, J = 14.6 Hz, 1H), 4.16–4.09 (m, 2H,
COOCH2CH3), 4.06 (d, J = 14.8 Hz, 1H), 3.27–3.20 (m,1H),
3.16 (s, 3H, NCH3), 3.09 (m, 1H), 1.31 (t, J = 7.0 Hz, 3H,
OCH2CH3), 1.23 (t, J = 7.0 Hz, 3H, NCH2CH3). 13C NMR
(400 MHz, CDCl3)14.9, 25.2, 28.7, 43.9, 51.6, 52.7, 61.1,
81.3, 91.6, 118.7, 114.1, 125.6, 126.1, 132.7, 133.5, 136.5,
145.1, 145.5, 146.1, 151.6, 163.1, 167.5, 167.6. Anal. Calcd
for C23H25Cl2N5O4: C, 54.55; H, 4.98; N, 13.83. Found: C,
54.57; H, 5.02; N, 13.85.
cis-2-Amino-6-[N-(6-chloro-3-pyridinylmethyl)-N-ethyl]
amino-3-ethoxycarbonyl-4-(4-methoxylphenyl)-1-methyl-
5-nitro-1,4-dihydropyridine (1f). Yield: 71.6%; yellow solid.
m.p.: 166–168°C. IR (KBr cm−1): vmax 2963(CH3), 3323, 3211
(NH2), 1477, 1413(NO2), 1652, 1612, 1577 (benzene) 1H
NMR (CDCl3, 400 MHz) δ 8.19 (s, 1H, Py H), 7.81 (s, 1H,
Py H), 7.27 (s, 1H, Py H), 7.22 (d, J = 8.0 Hz, 2H, Ph H),
7.03 (d, J = 8.0 Hz, 2H, Ph H), 6.24 (s, 2H, NH2), 5.68
(s, 1H, CH), 4.36 (d, J = 14.5 Hz, 1H), 4.14–4.09 (m, 2H,
COOCH2CH3), 4.07–4.033 (m, 1H), 3.80 (s, 3H, OCH3),
3.23 (s, 3H, NCH3), 3.19 (d, J = 7.3 Hz, 1H), 3.11 (dd, J = 13.7,
6.9 Hz, 1H), 1.32 (dd, J = 13.3, 6.2 Hz, 3H, COOCH2CH3),
1.21 (t, J = 7.1 Hz, 3H, NCH2CH3). 13C NMR (400 MHz,
CDCl3)15.9, 24.7, 27.3, 44.9, 52.6, 53.3, 53.6, 62.1, 85.2,
92.6, 117.8, 114.4, 125.6, 125.1, 132.7, 132.5, 136.1, 142.9,
144.6, 147.1, 151.6, 163.8, 167.9, 167.4. Anal. Calcd for
C24H28ClN5O5: C, 57.43; H, 5.62; N, 13.95. Found: C, 57.46;
H, 5.65; N, 13.91.
cis-2-Amino-6-[N-(6-chloro-3-pyridinylmethyl)-N-ethyl]
amino-3-cyano-1-methyl -4-(2-methoxylphenyl)-5-nitro-
1,4-dihydropyridine (1g). Yield: 58.3%; yellow solid. m.p:
175–177°C; IR (KBr, cm−1): vmax 2934(CH3), 3332, 3201
(NH2), 2185(CN), 1460, 1410(NO2), 1648, 1610, 1556
1
(benzene) H NMR (CDCl3, 400 MHz) δ 8.33 (d, 1H, Py H),
7.84 (s, 1H, Py H), 7.37(s, 1H, Py H), 7.20–7.17 (m, 2H,
Ph H), 6.93–6.77 (m, 2H, Ph H), 5.30 (s, 1H, CH), 4.44
(s, 1H), 4.32 (s, 2H, NH2), 4.14 (dd, J = 14.3, 7.2 Hz, 1H),
3.91 (s, 3H, OCH3), 3.31–3.18 (m, 4H), 3.10–3.05 (m, 1H),
1.28 (dd, J = 13.5, 6.4 Hz, 3H, NCH2CH3) 13C NMR
(400 MHz, CDCl3) 18.7, 24.6, 29.6, 44.6, 53.7, 53.9, 54.6,
87.8, 94.7, 117.3, 115.8, 123.2, 126.6, 133.8, 133.4, 135.7,
142.9, 144.6, 147.1, 151.6, 167.9, 167.2. Anal. Calcd
for C22H23ClN6O3: C, 58.09; H, 5.10; N, 18.47. Found: C,
58.12; H, 5.12; N, 18.51.
cis-2-Amino-6-[N-(6-chloro-3-pyridinylmethyl)-N-ethyl]
amino-3-ethoxycarbonyl-4-(3-fluorophenyl)-1-methyl-5-nitro-
1,4-dihydropyridine (1d). Yield: 82.1%; yellow solid. m.p:
184–186°C; IR (KBr cm−1): vmax 2967(CH3), 3322, 3201 (NH2),
1
1485–1421(NO2), 1644, 1621, 1577(benzene) H NMR (CDCl3,
400 MHz) 8.24 (d, 1H, J = 7.8 Hz, Py H), 7.83 (s, 1H, Py H),
7.36 (d, 1H, J = 8.1 Hz, Py H), 7.23–6.96 (m, 4H, Ph H), 6.18
(br, 2H, NH2), 5.36 (s, 1H, CH), 4.35 (d, J = 14.5 Hz, 1H),
4.10–4.05 (m, J = 7.1 Hz, 2H, COOCH2CH3), 4.02 (d, J = 14.5
Hz, 1H), 3.27 (s, 3H, NCH2CH3), 3.23–3.21 (m, 1H), 3.14–3.05
(m, 1H), 1.33–1.29 (t, J = 7.1 Hz, 3H, COOCH2CH3), 1.21–1.20
cis-2-Amino-4-(2-chlorophenyl)-6-[N-(6-chloro-3-
pyridinylmethyl)-N-ethyl]amino-3-cyano-1-methyl-5-nitro-
1,4-dihydropyridine (1h). Yield: 44.6%; yellow solid. m.p:
144–146°C. IR (KBr cm−1): vmax 2989 (CH3), 3333, 3224
(NH2), 2188(CN), 1489, 1423(NO2), 1658, 1625, 1588
1
(benzene) H NMR (CDCl3, 400 MHz) δ 8.32 (d, J = 7.9, 1H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2012
Synthesis and Insecticidal Activities: cis-Nitenpyram Analogs with
1379
1,4-Dihydropyridine Scaffold
Py H), 7.84 (dd, J = 14.1, 6.9, 1H, Py H), 7.37 (d, J = 7.5, 1H,
Py H), 7.23–7.18 (m, 2H, Ph H), 6.91–6.81 (m, 2H, Ph H),
5.29 (s, 1H, CH), 4.42 (s, 1H), 4.32 (s, 2H, NH2), 4.12 (dd, J
= 14.1, 7.3 Hz, 1H), 3.30–3.19 (m, 1H), 3.12 (s, 3H, NCH3),
3.11–3.04 (m,1H), 1.29 (t, J = 8.5 Hz, 3H, NCH2CH3). 13C
NMR (400 MHz, CDCl3) 19.4, 25.2, 28.1, 45.7, 54.9, 55.6,
88.8, 92.1, 113.6, 118.6, 123.2, 126.6, 133.2, 133.7, 135.1,
142.6, 144.2, 147.3, 151.5, 167.7, 167.9. Anal. Calcd for
C21H20Cl2N6O2: C, 54.91; H, 4.39; N, 18.30. Found: C,
54.95; H, 4.36; N, 18.32.
(s, 1H, Pyridine), 7.36 (s, 1H, Pyridine), 7.23–6.99 (m, 5H,
Ph H), 5.06 (s, 1H, CH), 4.69 (br, 2H, NH2), 4.35 (d, J = 14.3
Hz, 1H), 4.09 (d, J = 14.8 Hz, 1H), 3.36–3.24 (m, 1H), 3.21
(s, 3H, NCH3), 3.16 (d, J = 6.5 Hz, 1H), 1.36–1.27 (m, 3H,
NCH2CH3). 13C NMR (400 MHz, CDCl3) 21.7, 24.2, 26.4,
48.4, 54.8, 59.8, 88.9, 91.6, 112.4, 112.5, 125.2, 126.8, 135.3,
136.8, 136.6, 144.8, 145.5, 149.9, 151.2, 169.6, 172.1. Anal.
Calcd for C21H20ClFN6O2: C, 56.95; H, 4.55; N, 18.98.
Found: C, 56.97; H, 4.56; N, 18.93.
cis-2-Amino-6-[N-(6-chloro-3-pyridinylmethyl)-N-ethyl]
amino-4-(2,4-dichlorophenyl)-3-ethoxycarbonyl-1-methyl-5-
nitro-1,4-dihydropyridine (1i). Yield: 77.2%; yellow solid.
m.p: 136–138°C. IR (KBr cm−1): vmax 2975(CH3), 3328, 3199
(NH2), 1410 (NO2), 1656, 1614, 1557 (benzene). 1H NMR
(CDCl3, 400 MHz) δ 8.27 (s, 1H, Py H), 7.78 (s, 1H, Py H),
7.35 (s, 1H, Py H), 7.14 (d, J = 14.2 Hz, 2H, Ph H), 6.63
(s, 1H, Ph H), 5.32 (d, J =13.2 Hz, 1H, CH), 4.57 (s, 2H, NH2),
4.42 (d, J = 13.2 Hz, 1H), 4.13 (m, 2H, COOCH2CH3)
4.12–4.04 (m, 1H), 3.30–3.25 (m, 4H), 3.14 (d, J = 2Hz,
1H), 1.32–1.27 (m, 3H, COOCH2CH3), 1.14–1.12 (t, J = 7.2
Hz, 3H, NCH2CH3). 13C NMR (400 MHz, CDCl3) 19.4,
25.2, 28.1, 45.7, 54.9, 55.2, 88.9, 91.6, 112.4, 116.2, 124.8,
125.1, 134.6, 135.2, 137.5, 143.6, 145.4, 147.6, 151.2,
168.9, 171.2. Anal. Calcd for C21H19Cl3N6O2: C, 51.08; H,
3.88; N, 17.02. Found: C, 51.11; H, 3.87; N, 17.03.
cis-2-Amino-6-[N-(6-chloro-3-pyridinylmethyl)-N-ethyl]
amino-3-cyano-4-(2-fluorophenyl) 1-methyl-5-nitro-1,4-
dihydropyridine (1j). Yield: 72.4%; yellow solid. m.p:
184–186°C; IR (KBr cm−1): vmax 2973(CH3), 3331, 3199
(NH2), 2186(CN), 1507–1411 (NO2), 1648, 1613, 1608
(benzene); 1H NMR (CDCl3, 400 MHz) δ 8.27 (d, J = 19.0
Hz, 1H, Py H), 7.80 (s, 1H, Py H), 7.31 (d, J = 7.2 Hz, 1H, Py H),
7.12–6.87 (m, 5H, Ph H), 4.97 (s, 1H, CH), 4.37(d, J =15.8
Hz, 1H), 4.01 (d, J = 14.7 Hz, 2H, NH2), 3.45–3.28 (m, 1H),
3.25(s, 3H, NCH3), 3.11 (dd, J = 13.6, 6.6 Hz, 1H), 1.29
(dd, J = 20.1, 7.0 Hz, 3H, NCH2CH3). 13C NMR (400 MHz,
CDCl3) 19.5, 25.7, 27.5, 45.2, 53.6, 56.1, 88.9, 91.6, 112.4,
116.2, 124.8, 125.1, 134.6, 135.2, 137.4, 143.7, 144.5, 148.2,
152.7, 169.1, 174.5. Anal. Calcd for C21H20ClFN6O2: C,
56.95; H, 4.55; N, 18.98. Found: C, 56.92; H, 4.51; N, 18.99.
cis-2-Amino-6-[N-(6-chloro-3-pyridinylmethyl)-N-ethyl]
amino-3-cyano-4-(3-fluorophenyl) 1-methyl -5-nitro-1,4-
dihydropyridine (1k). Yield: 79.7%; yellow solid. m.p.:
173–175°C; IR (KBr cm−1): vmax 2981(CH3), 3322, 3203
(NH2), 2186(CN), 1486, 1412(NO2), 1653, 1607, 1589(benzene)
1H NMR (CDCl3, 400 MHz) δ 8.31 (s, 1H, Pyridine), 8.07
Acknowledgments. This work was supported by the Nature Science
Foundation of China (21042010), the Key Laboratory of Rare Earth
Functional Materials of Shanghai (07dz22303), and the Key
Scientific and Technological Project of Shanghai (09391912100).
The authors are also grateful for the support from Bioassay
department, Branch of National Pesticide R&D South Center.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet