Synthesis, evaluation of insecticidal activity, and crystal analysis of cis-nitenpyram analogs bearing 1,4-dihydropyridine

Article abstract of DOI:10.1007/s00706-012-0872-8

A new series of nitenpyram analogs were designed by introducing 1,4-dihydropyridine to fix the pharmacophore (-C=C-NO₂) into the cis-configuration, as confirmed by X-ray diffraction. Crystal structure analysis showed that there was a homoconjugation effect on these cis-nitenpyram analogs, and a huge conjugated system comprising the 1,4-dihydropyridine scaffold and the ester group at the 3 position. Preliminary bioassays showed that most of the target compounds exhibit good insecticidal activities (>80 %) at 100 mg/dm³ against Aphis medicagini, while a 4-fluorophenyl cis-nitenpyram analog afforded the best activity, with >90 % mortality at 20 mg/dm³. These excellent insecticidal activities imply that this huge conjugated system results in an enhanced π-π interaction between the molecule and amino acid residues in receptors. Further studies on the mode of action of one of these cis-nitenpyram analogs and structural modifications are in progress.

Full text of DOI:10.1007/s00706-012-0872-8

Monatsh Chem (2013) 144:1003–1012
DOI 10.1007/s00706-012-0872-8
ORIGINAL PAPER
Synthesis, evaluation of insecticidal activity, and crystal analysis
of cis-nitenpyram analogs bearing 1,4-dihydropyridine
•
Chuanwen Sun Tianyan Liu Li Ding
•
•
•
Yanxia Chen Wanggeng Zhang
Received: 11 January 2012 / Accepted: 10 October 2012 / Published online: 29 May 2013
Ó Springer-Verlag Wien 2013
Abstract A new series of nitenpyram analogs were
designed by introducing 1,4-dihydropyridine to fix the
pharmacophore (–C=C–NO2) into the cis-configuration, as
confirmed by X-ray diffraction. Crystal structure analysis
showed that there was a homoconjugation effect on these
cis-nitenpyram analogs, and a huge conjugated system
comprising the 1,4-dihydropyridine scaffold and the ester
group at the 3 position. Preliminary bioassays showed
that most of the target compounds exhibit good insecticidal
activities ([80 %) at 100 mg/dm3 against Aphis medi-
cagini, while a 4-fluorophenyl cis-nitenpyram analog
afforded the best activity, with [90 % mortality at
20 mg/dm3. These excellent insecticidal activities imply
that this huge conjugated system results in an enhanced
p–p interaction between the molecule and amino acid
residues in receptors. Further studies on the mode of action
of one of these cis-nitenpyram analogs and structural
modifications are in progress.
Introduction
The discovery of neonicotinoid insecticides (NNs) can be
considered a milestone in agrochemical research over the
past three decades [1]. NNs have recently received global
interest in the fields of agricultural chemistry and medicine
due to their broad spectrum of biological activities and high
selectivity, which make them applicable to public health
applications and crop protection [2]. The first neonicotinoid
insecticide to find commercial use was imidacloprid (IMI).
Since then, new generations of NNs have entered the
market, and they account for one-fifth of the global
insecticide market [3–6].
A well-recognized potential problem facing all insecti-
cides is that insect populations gradually develop resistance
to each insecticide [7, 8]. During the past decades, signifi-
cant increases in resistance and cross-resistance have been
observed in a range of species after the widespread and
frequent use of NNs [9, 10]. In particular, some resistant
species have increased in potency, with recently collected
strains exhibiting more than 100-fold resistance to imida-
cloprid and comparable levels of resistance to thiamethoxam
and nitenpyram [6, 11]. Therefore, concerted efforts must be
made to synthesize new NNs and search for unique molec-
ular recognition and binding modes in order to overcome
this increased level of insecticide resistance [12, 13].
However, few studies have been focused on structural
modifications of acyclic NNs such as nitenpyram.
Keywords Nitenpyram analog Á 1,4-Dihydropyridine
scaffold Á Microwave-assisted synthesis Á Structure–activity
relationships Á X-ray structure determination
C. Sun (&) Á T. Liu Á L. Ding Á Y. Chen
College of Life and Environment Sciences,
Shanghai Normal University, No. 100 Guilin Road,
Xuhui district, Shanghai 200234, China
e-mail: willin112@163.com
As we all know, the electron-withdrawing nature of the
nitro group plays an important role in its activities. On the
other hand, due to the existence of the C=N double bond,
neonicotinoids can exist as two isomers [14]. However, the
nitro groups in all commercialized neonicotinoids have a
trans configuration. Encouraged by the work of Li [15–17],
who reported that many cis-imidacloprid analogs exhibited
W. Zhang
Jiangsu Institute of Ecomones Co., Ltd.,
Jintan 213200, Jiangsu, China
123

1004
C. Sun et al.
low resistance from insects, we have found a new way to
design a novel series of cis-nitenpyram analogs [18, 19]
with a fixed tetrahydropyrimidine ring that show good
insecticidal activities and a different mechanism from their
trans configuration analogs. These results encouraged us to
consider further structural derivatives of them. On the other
hand, the reported structures 2 and 3 (Fig. 1), with highly
conjugated systems, show relatively strong activities
[2, 20]. It is worth pointing out that the cis-nitenpyram
analogs that we synthesized in advance did not have any
huge conjugated system. In 2007, Qian et al. suggested a
new binding model that demonstrated the importance of
hydrogen bonding and a cooperative p–p interaction
between the molecule and amino acid residues [21]. This
prompted the question: why not replace the tetrahydropyr-
imidine ring with a 1,4-dihydropyridine scaffold to fix the
nitro group into the cis-configuration, thus producing a huge
conjugated system, enhancing the p–p interaction, and
improving the bioactivity of these new chemical entities?
In the study described in the present paper, cis-nitenpy-
ram analogs bearing 1,4-dihydropyridine were synthesized
though multicomponent reactions (MCRs), employing
nitenpyram, aryl carbonyl compounds, and malononitrile
as starting materials, and their insecticidal activity was
assessed.
assembly of 6 occurs via the initial Michael addition of 7 to
the ylidenic bond in 1b, leading to the formation of an
acyclic intermediate 8, which cyclizes into the intermediate
9 via the nucleophilic attack of an NH group on a cyano
carbon, followed by tautomerization to the final product 6.
Compound 7 is formed of through a Knoevenagel con-
densation reaction of malononitrile 4 and the appropriate
aromatic aldehyde 5. The MCRs proceed readily under
microwave irradiation (whereas the starting materials must
be refluxed in ethanol for 6 h under conventional condi-
tions; see Table 1), thus representing a highly efficient
method with good yields (63–82 %) and easy work-up.
Structure–activity relationship
As indicated in Table 2, compared with the cis-nitenpy-
ram analogs that have a fixed tetrahydropyrimidine ring,
the target compounds with a fixed 1,4-dihydropyridine
ring have a broader spectrum of insecticidal activity,
ranging from Nilaparvata legen to Aphis medicagini. Most
of our target compounds exhibited significant insecticidal
activities against Aphis medicagini, with [80 % mortality
at 100 mg/dm3. Among all of the analogs, 6b showed the
strongest ([90 %) activity at 20 mg/dm3. The activities of
the other compounds varied drastically, chiefly depending
upon the type of substituent at the 4 position on 1,4-
dihydropyridine. In general, as shown in Table 2, the
insecticidal activities varied significantly when the doses
were reduced to 100 and to 20 mg/dm3. The introduction
of a phenyl ring with electron-withdrawing groups, such
as halogen atoms (6a–6d, 6g–6l, 6m–6p), yielded analogs
with excellent inhibitory activities, even at 20 mg/dm3,
whereas appending electron-withdrawing groups such as a
Result and discussion
Preparation of compounds
The nitenpyram analogs 6a–6t bearing a 1,4-dihydropyri-
dine scaffold were synthesized as shown in Scheme 1. The
Ar
N
O
H
O2N
π−π
O2N
N
R
O2N
O
High activity
O
stack
?
N
NH
NH2
N
NH
Cl
N
Cl
N
1
Cl
N
2
cis-Nitenpyram analogues 6a-6t
ctivity
High a
H
N
O2N
X
N
HCl
Cl
N
3
Fig. 1 Our tactic for modifying cis-configuration nitenpyram analogs
123

Cis-nitenpyram analogs bearing 1,4-dihydropyridine
1005
Scheme 1
Ar
N
NO2
O2N
N
COOR
NH2
Piperidine
dry EtOH
N
NH
Ar CHO
NC
COOR
+
+
60-75 °C
Cl
N
Cl
N
4
5
6
Ar
COOR
CN
7
Ar
Ar
O2N
N
COOR
NH
O2N
N
COOR
N
N
NH
Cl
N
Cl
N
8
9
methoxy group or methyl (6e, 6f, 6r–6t) had no obvious
influence on the insecticide activities of the resulting
analogs.
position (6m) [ 2 position (6l) [ 4 position (6n). On the
other hand, the size of the R substituent does not appear to
be as strongly related to the activity. These variations in
activity may be related to differences in affinity to the
nAChR target, such as p–p stacking interactions with the
active-site residues. These results may provide useful
information for the design of new insecticides.
Moreover, the position of the substituent on the phenyl
group also influences the insecticidal activity, with inhib-
itory potency decreasing in the order 4 position (6k) [ 2
position (6i) [ 3 position (6j), and increasing in the order 3
Table 1 Yields of the title
Compound
R
Ar
Yield/%
compounds 6a–6t under
conventional conditions and
microwave irradiation
(Scheme 1)
Conventional
Microwave
6a
6b
6c
6d
6e
6f
Me
Me
Me
Me
Me
Me
Et
3-F–C6H4
55.2
57.6
55.4
64.7
62.4
67.2
61.1
65.8
64.8
63.8
64.7
67.8
65.2
64.5
64.3
65.2
77.9
51.8
53.6
70.3
71.2
74.7
67.4
73.2.
72.2
72.2
65.5
81.2
75.7
72.8
76.4
75.3
74.9
71.7
77.2
79.6
82.2
83.5
78.1
71.9
4-F–C6H4
2,4-di-Cl–C6H3
3,4-di-Cl–C6H3
4-CH3–C6H4
2-CH3O–C6H4
4-Cl–C6H4
6g
6h
6i
Pr
C6H5
Pr
2-F–C6H4
6j
Pr
3-F–C6H4
6k
6l
Pr
4-F–C6H4
Pr
2-Cl–C6H4
6m
6n
6o
6p
6q
6r
6s
Pr
3-Cl–C6H4
Pr
4-Cl–C6H4
Pr
2,4-di-Cl–C6H3
3,4-di-Cl–C6H3
4-Br–C6H4
2-CH3O–C6H4
4-CH3O–C6H4
4-CH3–C6H4
Pr
Pr
Pr
Pr
6t
Pr
123

1006
C. Sun et al.
Table 2 Insecticidal activities
of compounds 6a–6t and
nitenpyram against Aphis
medicagini
Compound
R
Ar
Concentration/mg dm-3
500
100
20
6a
6b
6c
6d
6e
6f
Me
Me
Me
Me
Me
Me
Et
3-F–C6H4
111111
111111
111111
111111
111111
111111
111111
111111
111111
111111
111111
111111
111111
111111
111111
111111
111111
111111
111111
111111
111111
1111
11111
1111
1111
11
111
4-F–C6H4
11111
2,4-di-Cl–C6H3
3,4-di-Cl–C6H3
4-CH3–C6H4
2-CH3O–C6H4
4-Cl–C6H4
11
11
nt
1
nt
6g
6h
6i
1111
111
11
Pr
C6H5
1
Pr
2-F–C6H4
1111
1111
1111
1111
1111
1111
1111
11111
11111
11
1
6j
Pr
3-F–C6H4
–
6k
6l
Pr
4-F–C6H4
11
Pr
2-Cl–C6H4
1
6m
6n
6o
6p
6q
6r
6s
6t
Pr
3-Cl–C6H4
–
Pr
4-Cl–C6H4
111
Pr
2,4-di-Cl–C6H3
3,4-di-Cl–C6H3
4-Br–C6H4
2-CH3O–C6H4
4-CH3O–C6H4
4-CH3–C6H4
–
Pr
1
Pr
nt
Rating system for the mortality
percentage: ??????, 100 %;
?????, C90 %; ????,
C80 %; ???, C70 %; ??,
C60 %; ?, C50 %; –, \50 %
Pr
–
Pr
111
–
Pr
111
–
1
111111
111111
nt not tested
Single-crystal structure of compound 6g
In addition, the 1,4-dihydropyridine ring of compound 6g
adopts a skew boat conformation. Interestingly, the C–C
bond lengths in the 1,4-dihydropyridine ring, such as
To confirm the cis configuration using precise three-
dimensional information, the single-crystal structure of
compound 6g (Figs. 2, 3) was investigated and deter-
mined by X-ray diffraction analysis (CCDC number:
824407). The dihedral angle of N2–C9–C13–N4 in the
two independent molecules is 32.0(7)°, so the nitro group
in 6g is obviously in the cis configuration, as anticipated.
˚
˚
1.507(5) A (C(12)–C(11)) and 1.507(6) A (C(12)–C(13)),
are obviously shorter than the pure C–C single bond
˚
(1.54 A) [22]. Similarly, the bond lengths of C–N on the
1,4-dihydropyridine ring, such as 1.403(5) (C(10)–N(3))
˚
and 1.382(5) A (C(9)–N(3)), are obviously shorter than
˚
that of the pure C–N single bond (1.47 A) [23]. On the
Fig. 2 Molecular structure of
compound 6g, with atom
labeling
123

Cis-nitenpyram analogs bearing 1,4-dihydropyridine
1007
Experimental
All reactions were performed in oven-dried glassware with
magnetic stirring. All of the chemical reagents purchased
were of analytical grade and used without further purifi-
cation, except for toluene, which was dried by refluxing in
the presence of sodium and distilled prior to use. Thin-
layer chromatography (TLC) was carried out on silica gel
1
60 F254 plates (Merck KGaA, Darmstadt, Germany). H
NMR spectra were recorded on a Bruker (Rheinstetten,
Germany) Avance 400 (400 MHz) spectrometer, using
CDCl3 as solvent and tetramethylsilane (TMS) as internal
standard. The chemical shift values (d) are expressed in
parts per million (ppm) relative to tetramethylsilane as an
internal standard; s = singlet, d = doublet, m = multiplet.
Melting points were determined by an RK1 microscopic
melting apparatus. IR spectra were obtained on a Nicolet
(Madison, WI, USA) 5DX FT-IR spectrophotometer in the
region 4,000–400 cm-1 using KBr discs. MS spectra were
recorded on a Finnigan (San Jose, CA, USA) Trace DSQ
mass spectrograph.
Fig. 3 Packing diagram of compound 6g
contrary, the bond lengths of C(13)=C(9) and C(11)=C(10)
˚
(1.386(6) and 1.364(6) A, respectively) are longer than that
General procedure for synthesis of 6a–6t
˚
of the pure C=C bond (1.34 A) [15]. Based on these data,
A mixture of methyl cyanoacetate (12 mmol), 3-fluo-
robenzaldehyde (12 mmol), piperidine (0.1 mmol), and
nitenpyram (10 mmol) in 20 cm3 anhydrous alcohol was
heated to 60–75 °C for 5 min in a microwave reactor and
stirred for 30 min at 65 °C. The reaction mixture was
concentrated under reduced pressure and treated with
20 cm3 of water. 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 the crude product was subjected to
flash chromatography on silica gel, eluting with ethyl
acetate/petroleum ether (3:1 v/v) to afford the pure product
6a. Compounds 6b–6t were synthesized analogously.
there is a homoconjugation effect on the 1,4-dihydropyri-
dine scaffold in 6g, and a huge conjugated system is
formed by the 1,4-dihydropyridine scaffold and the ester
group at the 3 position.
Conclusions
In summary, a new series of cis-configuration nitenpyram
analogs with a fixed 1,4-dihydropyridine scaffold were
synthesized and tested for insecticidal activity. Crystal
structure analysis showed that there is a homoconjugation
effect on the 1,4-dihydropyridine scaffold in compound 6g,
which formed a huge conjugated system with the ester
group at the 3 position. Preliminary bioassays showed that
most of the target compounds exhibited good insecticidal
activity at 100 mg/dm3 against Aphis medicagini, while 6a
exhibited the best inhibitory activity, displaying 90 %
mortality at 20 mg/dm3. These bioassay data confirm that
the huge conjugated system results in an enhanced p–p
interaction between the molecule and amino acid residues
in receptors, which plays a positive role in the promotion of
insecticidal activity. Moreover, compared with other cis-
nitenpyram analogs with a fixed tetrahydropyrimidine ring
that we designed previously, their spectrum of insecticidal
activity is broader, ranging from Nilaparvata legen to
Aphis medicagini. Further studies on the mode of action
(MoA) of 6g and structural modifications are in progress.
Methyl 2-amino-6-[(6-chloro-3-pyridinylmethyl)-
ethylamino]-4-(3-fluorophenyl)-1,4-dihydro-1-methyl-5-
nitro-3-pyridinecarboxylate (6a, C22H23ClFN5O4)
Yield 71.2 %; yellow solid; m.p.: 154–155 °C; Rf = 0.60
1
(ethyl acetate/petroleum ether 3:1); H NMR (400 MHz,
CDCl3): d = 8.20 (d, 1H, J = 16.8 Hz, Py-H), 7.82 (s, 1H,
Py-H), 7.19 (d, 1H, J = 16.8 Hz, Py-H), 7.15–7.10 (m, 3H,
Ph-H), 6.95 (d, 1H, J = 16.8 Hz, Ph-H), 6.21 (s, 2H, NH2),
5.68 (s, 1H, CH), 4.38 (d, J = 14.8 Hz, 1H, Py-CH2), 4.12
(d, 2H, J = 14.9 Hz, Py-CH2), 3.66 (s, 3H, COOCH3),
3.27–3.23 (m, 1H, NCH2CH3), 3.16 (s, 3H, NCH3), 3.10
(m, 1H, NCH2CH3), 1.32 (t, J = 6.8 Hz, 3H, NCH2CH3)
ppm; 13C NMR (100 MHz, CDCl3): d = 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,
123

1008
C. Sun et al.
166.8, 169.4 ppm; IR (KBr): vꢀ = 3,311, 3,222, 2,984,
2,935, 2,870, 1,343, 1,299, 1,235 cm-1; HRMS: m/z =
476.1423 [(M ? H)?].
NMR (100 MHz, CDCl3): d = 13.9, 24.5, 28.5, 42.1, 50.8,
51.0, 84.3, 91.1, 114.9, 116.1, 123.9, 124.5, 131.3, 133.6,
136.7, 144.2, 146.3, 149.9, 151.3, 163.1, 164.2, 167.4 ppm;
IR (KBr): vꢀ = 3,311, 3,222, 2,984, 2,935, 2,870, 1,343,
1,299, 1,235 cm-1; HRMS: m/z = 527.0737 [(M ? H)?].
Methyl 2-amino-6-[(6-chloro-3-pyridinylmethyl)-
ethylamino]-4-(4-fluorophenyl)-1,4-dihydro-1-methyl-5-
nitro-3-pyridinecarboxylate (6b, C22H23ClFN5O4)
Yield 74.7 %; yellow solid; m.p.: 161–163 °C; Rf = 0.58
Methyl 2-amino-6-[(6-chloro-3-pyridinylmethyl)-
ethylamino]-1,4-dihydro-1-methyl-4-(4-methylphenyl)-5-
nitro-3-pyridinecarboxylate (6e, C23H26ClN5O4)
Yield 72.2 %; yellow solid; m.p.: 173–175 °C; Rf = 0.62
1
(ethyl acetate/petroleum ether 3:1); H NMR (400 MHz,
CDCl3): d = 8.19 (d, 1H, J = 16.8 Hz, Py-H), 7.82 (s, 1H,
Py-H), 7.19 (d, 1H, J = 16.8 Hz, Py-H), 7.15–7.10 (m, 2H,
Ph-H), 6.95–6.93 (m, 2H, Ph-H), 6.23 (s, 2H, NH2), 5.67 (s,
1H, CH), 4.38 (d, J = 14.8 Hz, 1H, Py-CH2), 4.12 (d, 2H,
J = 14.9 Hz, Py-CH2), 3.66 (s, 3H, COOCH3), 3.27–3.23
(m, 1H, NCH2CH3), 3.16 (s, 3H, NCH3), 3.10 (m, 1H,
1
(ethyl acetate/petroleum ether 3:1); H NMR (400 MHz,
CDCl3): d = 8.10 (s, 1H, Py-H), 7.76 (s, 1H, Py-H), 7.32
(d, J = 7.6 Hz, 1H, Py-H), 7.08 (d, J = 8.2 Hz, 2H,
Ph-H), 6.93 (d, J = 8.2 Hz, 2H, Ph-H), 6.13 (s, 2H, NH2),
5.42 (s, 1H, CH), 4.21 (d, J = 14.4 Hz, 1H, Py-CH2), 3.66
(s, 3H, COOCH3), 3.31–3.22 (m, 1H, NCH2CH3), 3.17 (s,
3H, NCH3), 3.11 (m, 1H, NCH2CH3), 2.62 (s, 3H, Ph-
CH3), 1.34 (t, J = 7.1 Hz, 3H, NCH2CH3) ppm; 13C NMR
(100 MHz, CDCl3): d = 13.9, 26.5, 26.9, 42.1, 45.8, 53.8,
56.7, 82.2, 91.1, 114.9, 116.1, 119.7, 120.8, 122.5, 133.6,
136.7, 143.8, 146.3, 148.8, 151.3, 163.1, 164.8, 167.4 ppm;
IR (KBr): vꢀ = 3,327, 3,200, 2,984, 2,935, 2,870, 1,343,
1,308, 1,235 cm-1; HRMS: m/z = 472.9417 [(M ? H)?].
NCH2CH3), 1.32 (t, J = 6.8 Hz, 3H, NCH2CH3) ppm; 13
C
NMR (100 MHz, CDCl3): d = 14.9, 24.5, 28.5, 42.1, 50.8,
51.1, 82.2, 91.1, 114.9, 116.1, 122.2, 123.5, 131.3, 133.6,
136.7, 144.2, 146.3, 148.8, 151.3, 163.1, 165.2, 168.4 ppm;
IR (KBr): vꢀ = 3,311, 3,222, 2,984, 2,935, 2,870, 1,343,
1,299, 1,235 cm-1; HRMS: m/z = 476.1423 [(M ? H)?].
Methyl 2-amino-6-[(6-chloro-3-pyridinylmethyl)-
ethylamino]-4-(2,4-dichlorophenyl)-1,4-dihydro-1-methyl-
5-nitro-3-pyridinecarboxylate (6c, C22H22Cl3N5O4)
Yield 67.4 %; yellow solid; m.p.: 203–204 °C; Rf = 0.60
Methyl 2-amino-6-[(6-chloro-3-pyridinylmethyl)-
ethylamino]-1,4-dihydro-4-(2-methoxyphenyl)-1-methyl-5-
nitro-3-pyridinecarboxylate (6f, C23H26ClN5O5)
1
(ethyl acetate/petroleum ether 3:1); H NMR (400 MHz,
Yield 69.1 %; yellow solid; m.p.: 134–135 °C; Rf = 0.60
(ethyl acetate/petroleum ether 3:1); H NMR (400 MHz,
CDCl3): d = 8.18 (s, 1H, Py-H), 7.82 (s, 1H, Py-H), 7.19
(d, 1H, J = 16.8 Hz, Py-H), 7.16–7.14 (m, 1H, Ph-H), 7.07
(d, J = 8.1 Hz, 1H, Ph-H), 6.89 (m, 1H, Ph-H), 6.21 (s,
2H, NH2), 5.68 (s, 1H, CH), 4.38 (d, J = 14.8 Hz, 1H,
Py-CH2), 4.12 (d, 2H, J = 14.9 Hz, Py-CH2), 3.66 (s, 3H,
COOCH3), 3.27–3.23 (m, 1H, NCH2CH3), 3.16 (s, 3H,
NCH3), 3.10 (m, 1H, NCH2CH3), 1.32 (t, J = 6.8 Hz,
3H, NCH2CH3) ppm; 13C NMR (100 MHz, CDCl3):
d = 14.8, 24.5, 28.6, 43.2, 50.8, 52.5, 83.2, 91.1, 114.9,
116.1, 122.2, 126.3, 131.3, 134.3, 135.5, 144.2, 146.3,
148.8, 149.1, 155.2, 167.2, 169.4 ppm; IR (KBr):
vꢀ = 3,311, 3,256, 2,975, 2,921, 2,870, 1,343, 1,301,
1,247 cm-1; HRMS: m/z = 527.0737 [(M ? H)?].
1
CDCl3): d = 8.19 (s, 1H, Py-H), 7.81 (s, 1H, Py-H), 7.27
(s, 1H, Py-H), 7.17–7.10 (m, 3H, Ph-H), 6.95–6.94 (m, 1H,
Ph-H), 6.24 (s, 2H, NH2), 5.49 (s, 1H, CH), 4.36 (d,
J = 14.5 Hz, 1H, Py-CH2), 4.07–4.03 (m, 1H, Py-CH2),
3.80 (s, 3H, OCH3), 3.65 (s, 3H, COOCH3), 3.23–3.11 (m,
5H, NCH3, NCH2CH3), 3.19–3.09 (m, 2H), 3.11 (dd,
J = 13.7, 6.9 Hz, 1H), 1.21 (t, J = 7.1 Hz, 3H, NCH2
CH3) ppm; 13C NMR (100 MHz, CDCl3): d = 14.9, 24.5,
28.5, 42.1, 50.8, 51.1, 84.3, 94.5, 109.3, 116.1, 121.9,
122.7, 131.3, 133.6, 139.2, 142.5, 144.2, 146.3, 147.2,
151.3, 163.1, 165.2, 166.4 ppm; IR (KBr): vꢀ = 3,327,
3,200, 2,984, 2,935, 2,870, 1,343, 1,308, 1,235 cm-1
HRMS: m/z = 488.9325 [(M ? H)?].
;
Methyl 2-amino-6-[(6-chloro-3-pyridinylmethyl)-
ethylamino]-4-(3,4-dichlorophenyl)-1,4-dihydro-1-methyl-
5-nitro-3-pyridinecarboxylate (6d, C22H23Cl3N5O4)
Yield 73.2 %; yellow solid; m.p.: 180–182 °C; Rf = 0.61
Ethyl 2-amino-4-(4-chlorophenyl)-6-[(6-chloro-3-
pyridinylmethyl)ethylamino]-1,4-dihydro-1-methyl-5-
nitro-3-pyridinecarboxylate (6g, C23H26ClN5O5)
1
(ethyl acetate/petroleum ether 3:1); H NMR (400 MHz,
Yield 65.5 %; yellow solid; m.p.: 134–135 °C; Rf = 0.63
(ethyl acetate/petroleum ether 3:1); H NMR (400 MHz,
1
CDCl3): d = 8.19 (s, 1H, Py-H), 7.82 (s, 1H, Py-H), 7.19
(s, 1H, Py-H), 7.16–7.12 (m, 1H, Ph-H), 7.06 (d, 1H,
J = 8.1 Hz, 1H, Ph-H), 6.24 (s, 2H, NH2), 5.67 (s, 1H,
CH), 4.34 (d, J = 14.3 Hz, 1H, Py-CH2), 4.12 (d, 2H,
J = 14.9 Hz, Py-CH2), 3.66 (s, 3H, COOCH3), 3.27–3.23
(m, 1H, NCH2CH3), 3.16 (s, 3H, NCH3), 3.10 (m, 1H,
CDCl3): d = 8.19 (s, 1H, Py-H), 7.81 (s, 1H, Py-H), 7.27
(s, 1H, Py-H), 7.10 (d, J = 8.2 Hz, 2H, Ph-H), 6.93 (d,
J = 8.2 Hz, 2H, Ph-H), 6.24 (s, 2H, NH2), 5.49 (s, 1H,
CH), 4.36 (d, J = 14.5 Hz, 1H, Py-CH2), 4.14–4.08 (m,
2H, COOCH2CH3), 4.07–4.03 (m, 1H, Py-CH2), 3.23 (s,
3H, NCH3), 3.19 (d, J = 7.3 Hz, 1H, NCH2CH3), 3.07 (dd,
NCH2CH3), 1.32 (t, J = 6.8 Hz, 3H, NCH2CH3) ppm; 13
C
123

Cis-nitenpyram analogs bearing 1,4-dihydropyridine
1009
J = 13.7, 6.9 Hz, 1H), 1.30 (dd, J = 13.3, 6.2 Hz, 3H,
COOCH2CH3), 1.21 (t, J = 7.1 Hz, 3H, NCH2CH3) ppm;
13C NMR (100 MHz, CDCl3): d = 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 ppm; IR (KBr): vꢀ = 3,384, 3,298, 3,065,
2,981, 2,933, 1,337, 1,294, 1,267 cm-1; HRMS: m/z =
505.1321 [(M ? H)?].
Propyl 2-amino-6-[(6-chloro-3-pyridinylmethyl)-
ethylamino]-4-(3-fluorophenyl)-1,4-dihydro-1-methyl-5-
nitro-3-pyridinecarboxylate (6j, C24H27ClFN5O4)
Yield 82.5 %; yellow solid; m.p.: 145–147 °C; Rf = 0.60
(ethyl acetate/petroleum ether 3:1); H NMR (400 MHz,
1
CDCl3): d = 8.21 (s, 1H, Py-H), 7.76 (s, 1H, Py-H), 7.35 (d,
J = 7.8 Hz, 1H, Py-H), 7.18 (d, J = 7.2 Hz, 1H, Ph-H),
7.05–6.95 (m, 3H, Ph-H), 6.20 (s, 2H, NH2), 5.37 (s, 1H,
CH), 4.35 (d, J = 14.4 Hz, 1H, Py-CH2), 4.14–3.99 (m, 3H,
Py-CH2, COOCH2CH2CH3), 3.37–3.35 (m, 1H, NCH2CH3),
3.30 (s, 3H, NCH3), 3.19–3.08 (m, 1H, NCH2CH3), 1.64
(dd, J = 7.1, 3.1 Hz, 2H, COOCH2CH2CH3), 1.34 (t,
J = 7.1 Hz, 3H, NCH2CH3), 0.87 (t, J = 7.2 Hz, 3H,
COOCH2CH2CH3) ppm; 13C NMR (100 MHz, CDCl3):
d = 10.9, 12.1, 22.8, 28.2, 29.9, 43.5, 51.2, 68.5, 83.1, 92.9,
115.9, 115.9, 124.8, 131.5, 131.5, 132.3, 140.4, 142.7, 147.7,
148.4, 153.2, 159.1, 167.9, 170.2 ppm; IR (KBr): vꢀ = 3,371,
Propyl 2-amino-6-[(6-chloro-3-pyridinylmethyl)-
ethylamino]-1,4-dihydro-1-methyl-5-nitro-4-phenyl-3-
pyridinecarboxylate (6h, C24H28ClN5O4)
Yield 81.2 %; yellow solid; m.p.: 167–168 °C; Rf = 0.62
(ethyl acetate/petroleum ether 3:1); H NMR (400 MHz,
1
CDCl3): d = 8.08 (s, 1H, Py-H), 7.82 (s, 1H, Py-H), 7.19
(m, 3H, Ph-H), 7.05 (s, 2H, Ph-H), 6.98 (s, 1H, Py-H), 6.19
(s, 2H, NH2), 5.49 (s, 1H, CH), 4.32 (d, J = 14.6 Hz, 1H,
Py-CH2), 4.16–4.12 (m, 2H, COOCH2CH2CH3), 4.06 (d,
J = 14.8 Hz, 1H, Py-CH2), 3.27–3.23 (m, 1H, NCH2CH3),
3.16 (s, 3H, NCH3), 3.10 (dt, J = 13.9, 7.0 Hz, 1H,
NCH2CH3), 1.59 (d, J = 7.0 Hz, 2H, COOCH2CH2CH3),
1.23 (t, J = 7.0 Hz, 3H, NCH2CH3), 0.82 (t, J = 7.4 Hz,
3H, COOCH2CH2CH3) ppm; 13C NMR (100 MHz,
CDCl3): d = 10.3, 13.5, 22.1, 26.5, 29.2, 41.9, 50.6,
67.9, 80.1, 90.2, 123.4, 123.5, 125.8, 128.7, 128.7, 131.4,
137.8, 138.5, 145.9, 149.4, 150.3, 159.9, 167.2, 170.4 ppm;
IR (KBr): vꢀ = 3,327, 3,200, 2,984, 2,935, 2,870, 1,343,
1,308, 1,235 cm-1; HRMS: m/z = 486.9641 [(M ? H)?].
3,277, 2,972, 2,912, 2,855, 1,356, 1,299, 1,244 cm-1
HRMS: m/z = 504.167 [(M ? H)?].
;
Propyl 2-amino-6-[(6-chloro-3-pyridinylmethyl)-
ethylamino]-4-(4-fluorophenyl)-1,4-dihydro-1-methyl-5-
nitro-3-pyridinecarboxylate (6k, C24H27ClFN5O4)
Yield 65.0 %; yellow solid; m.p.: 126–127 °C; Rf = 0.57
(ethyl acetate/petroleum ether 3:1); 1H NMR (400 MHz,
CDCl3): d = 8.12 (s, 1H, Py-H), 7.82 (s, 1H, Py-H), 7.35 (d,
J = 7.6 Hz, 1H, Py-H), 7.17–7.15 (m, 2H, Ph-H), 6.98–6.96
(m, 2H, Ph-H), 6.21 (s, 2H, NH2), 5.43 (s, 1H, CH), 4.32 (d,
J = 14.4 Hz, 1H, Py-CH2), 4.06 (dt, J = 13.1, 5.2 Hz, 3H, Py-
CH2, COOCH2CH2CH3), 3.32–3.23 (m, 1H, NCH2CH3), 3.21
(s, 3H, NCH3), 3.14 (dt, J = 14.2, 7.2 Hz, 1H, NCH2CH3),
1.59 (dd, J = 13.9, 7.3 Hz, 2H, COOCH2CH2CH3), 1.31 (dd,
J = 12.4, 5.3 Hz, 3H, NCH2CH3), 0.83 (t, J = 7.4 Hz, 3H,
COOCH2CH2CH3) ppm; 13C NMR (100 MHz, CDCl3):
d = 11.7, 13.1, 22.9, 27.9, 28.2, 41.2, 51.6, 68.8, 81.1, 92.1,
116.3, 116.3, 124.9, 131.4, 131.4, 133.6, 137.9, 141.1, 146.2,
149.7, 151.1, 159.1, 168.1, 168.7 ppm; IR (KBr): vꢀ = 3,369,
3,273, 2,977, 2,933, 2,855, 1,356, 1,311, 1,244 cm-1; HRMS:
m/z = 504.1679 [(M ? H)?].
Propyl 2-amino-6-[(6-chloro-3-pyridinylmethyl)-
ethylamino]-4-(2-fluorophenyl)-1,4-dihydro-1-methyl-5-
nitro-3-pyridinecarboxylate (6i, C24H27ClFN5O4)
Yield 69.5 %; yellow solid; m.p.: 121–123 °C; Rf = 0.61
1
(ethyl acetate/petroleum ether 3:1); H NMR (400 MHz,
CDCl3): d = 8.26 (s, 1H, Py-H), 7.87 (s, 1H, Py-H), 7.35
(d, J = 7.8 Hz, 1H, Py-H), 7.18 (d, J = 7.2 Hz, 1H,
Ph-H), 7.05 (t, J = 7.8 Hz, 2H, Ph-H), 6.92–6.85 (m, 1H,
Ph-H), 6.20 (s, 2H, NH2), 5.38 (s, 1H, CH), 4.35 (d,
J = 14.4 Hz, 1H, Py-CH2), 4.14–3.99 (m, 3H, Py-CH2,
COOCH2CH2CH3), 3.37–3.35 (m, 1H, NCH2CH3), 3.30 (s,
3H, NCH3), 3.19–3.07 (m, 1H, NCH2CH3), 1.64 (dd,
J = 7.1, 3.1 Hz, 2H, COOCH2CH2CH3), 1.34 (t, J =
7.1 Hz, 3H, NCH2CH3), 0.88 (t, J = 7.3 Hz, 3H,
COOCH2CH2CH3) ppm; 13C NMR (100 MHz, CDCl3):
d = 11.3, 12.5, 23.5, 27.4, 29.2, 41.9, 50.6, 67.9, 81.2,
92.3, 115.4, 115.4, 125.8, 130.7, 130.7, 132.7, 138.9,
140.2, 145.9, 149.4, 150.3, 159.9, 167.2, 169.5 ppm; IR
(KBr): vꢀ = 3,371, 3,277, 2,972, 2,912, 2,855, 1,356, 1,299,
1,244 cm-1; HRMS: m/z = 504.1679 [(M ? H)?].
Propyl 2-amino-4-(2-chlorophenyl)-6-[(6-chloro-3-
pyridinylmethyl)ethylamino]-1,4-dihydro-1-methyl-5-
nitro-3-pyridinecarboxylate (6l, C24H27Cl2N5O4)
Yield 64.7 %; yellow solid; m.p.: 157–158 °C; Rf = 0.59
1
(ethyl acetate/petroleum ether 3:1); H NMR (400 MHz,
CDCl3): d = 8.20 (s, 1H, Py-H), 7.83 (s, 1H, Py-H), 7.34
(s, 1H, Py-H), 7.23 (d, J = 6.9 Hz, 1H, Ph-H), 7.13 (dd,
J = 16.4, 8.1 Hz, 2H, Ph-H), 7.04 (d, J = 8.0 Hz, 1H,
Ph-H), 6.26 (s, 2H, NH2), 5.71 (s, 1H, CH), 4.37 (d,
J = 14.3 Hz, 1H, Py-CH2), 4.17–4.11 (m, 3H, Py-CH2,
123

1010
C. Sun et al.
COOCH2 CH2 CH3), 3.33–3.31 (m, 1H, NCH2CH3), 3.25
(s, 3H, NCH3), 3.10–3.05 (m, 1H, NCH2CH3), 1.63
(dd, J = 7.0, 3.6 Hz, 2H, COOCH2CH2CH3), 1.33 (t,
J = 6.9 Hz, 3H, NCH2CH3), 0.84 (t, J = 7.4 Hz, 3H,
COOCH2CH2CH3) ppm; 13C NMR (100 MHz, CDCl3):
d = 10.7, 12.5, 23.5, 27.9, 29.4, 41.1, 51.3, 67.3, 81.5,
92.1, 114.9, 114.7, 125.2, 130.5, 130.6, 132.1, 138.1,
141.2, 145.3, 148.8, 151.2, 159.4, 166.5, 169.4 ppm; IR
(KBr): vꢀ = 3,365, 3,241, 2,966, 2,912, 2,855, 1,356, 1,303,
1,255 cm-1; HRMS: m/z = 520.4098 [(M ? H)?].
2,905, 2,877, 1,356, 1,311, 1,263 cm-1; HRMS: m/z =
520.4098 [(M ? H)?].
Propyl 2-amino-6-[(6-chloro-3-pyridinylmethyl)-
ethylamino]-4-(2,4-dichlorophenyl)-1,4-dihydro-1-methyl-
5-nitro-3-pyridinecarboxylate (6o, C24H26Cl3N5O4)
Yield: 77.2 %; yellow solid; m.p.: 136–138 °C; Rf = 0.61
1
(ethyl acetate/petroleum ether 3:1); H NMR (400 MHz,
CDCl3): d = 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), 6.83 (s,
1H, Ph-H), 6.24 (s, 2H, NH2), 5.32 (d, J = 13.2 Hz, 1H,
CH), 4.42 (d, J = 13.2 Hz, 1H), 4.13–4.02 (m, 3H, Py-
CH2, COOCH2CH2CH3), 3.30–3.25 (m, 4H, NCH3,
NCH2CH3), 3.14 (d, J = 2.0 Hz, 1H, NCH2CH3), 1.64
(dd, J = 7.1, 3.1 Hz, 2H, COOCH2CH2CH3), 1.34 (t,
J = 7.1 Hz, 3H, NCH2CH3), 0.88 (t, J = 7.3 Hz, 3H,
COOCH2CH2CH3) ppm; 13C NMR (100 MHz, CDCl3):
d = 11.4, 11.6, 23.2, 27.9, 30.1, 42.2, 49.9, 67.9, 81.2,
92.2, 115.9, 115.9, 125.8, 130.2, 130.3, 131.5, 138.5,
141.2, 145.4, 149.3, 150.3, 159.8, 167.2, 170.2 ppm; IR
(KBr): vꢀ = 3,320, 3,211, 2,951, 1,477, 1,413, 1,552, 152,
1,577 cm-1; HRMS: m/z = 555.8533 [(M ? H)?].
Propyl 2-amino-4-(3-chlorophenyl)-6-[(6-chloro-3-
pyridinylmethyl)ethylamino]-1,4-dihydro-1-methyl-5-
nitro-3-pyridinecarboxylate (6m, C24H27Cl2N5O4)
Yield 66.7 %; yellow solid; m.p.: 164–165 °C; Rf = 0.60
1
(ethyl acetate/petroleum ether 3:1); H NMR (400 MHz,
CDCl3): d = 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, Ph-H), 6.11 (s, 2H, NH2), 5.49 (s, 1H,
CH), 4.32 (d, J = 14.6 Hz, 1H, Py-CH2), 4.16–4.09 (m,
2H, COOCH2CH2CH3), 4.06 (d, J = 14.8 Hz, 1H,
Py-CH2), 3.27–3.20 (m, 1H, NCH2CH3), 3.16 (s, 3H,
NCH3), 3.09 (m, 1H, NCH2CH3), 1.63 (m, 2H, CO-
OCH2CH2CH3), 1.31 (t, J = 7.0 Hz, 3H, NCH2CH3), 0.84
(t, J = 7.4 Hz, 3H, COOCH2CH2CH3) ppm; 13C NMR
(100 MHz, CDCl3): d = 11.4, 11.9, 23.5, 27.4, 29.2, 41.5,
51.1, 67.9, 81.9, 92.8, 115.2, 115.4, 125.8, 131.2, 131.1,
133.3, 138.9, 140.2, 146.6, 149.5, 150.5, 159.9, 166.2,
169.8 ppm; IR (KBr): vꢀ = 3,370, 3,241, 2,944, 2,905,
2,855, 1,356, 1,311, 1,268 cm-1; HRMS: m/z = 520.4098
[(M ? H)?].
Propyl 2-amino-6-[(6-chloro-3-pyridinylmethyl)-
ethylamino]-4-(3,4-dichlorophenyl)-1,4-dihydro-1-methyl-
5-nitro-3-pyridinecarboxylate (6p, C24H26Cl3N5O4)
Yield 79.6 %; yellow solid; m.p.: 175–177 °C; Rf = 0.59
1
(ethyl acetate/petroleum ether 3:1); H NMR (400 MHz,
CDCl3): d = 8.33 (d, J = 8.0 Hz, 1H, Py-H), 7.84 (s, 1H),
7.37 (s, 1H), 7.20–7.17 (m, 2H, Ph-H), 6.93–6.77 (m, 1H,
Ph-H), 6.24 (s, 2H, NH2), 5.30 (s, 1H, CH), 4.44 (s, 1H, Py-
CH2), 4.09 (dt, J = 13.1, 5.2 Hz, 1H, Py-CH2), 4.05–4.03
(m, 2H, COOCH2CH2CH3), 3.31–3.18 (m, 4H, NCH3,
NCH2CH3), 3.10 (m, 1H, NCH2CH3), 1.59 (dd, J = 13.9,
7.3 Hz, 2H, COOCH2CH2CH3), 1.28 (dd, J = 13.5,
6.4 Hz, 3H, NCH2CH3), 0.83 (t, J = 7.4 Hz, 3H, CO-
OCH2CH2CH3) ppm; 13C NMR (100 MHz, CDCl3):
d = 11.3, 12.3, 23.9, 26.8, 29.2, 41.9, 51.2, 67.9, 81.1,
92.3, 116.1, 116.3, 125.7, 130.7, 130.8, 132.1, 137.9,
140.5, 145.6, 149.5, 151.1, 159.3, 167.3, 169.5 ppm; IR
(KBr): vꢀ = 3,322, 3,199, 2,963, 1,652, 1,612, 1,577, 1,457,
1,417 cm-1; HRMS: m/z = 555.8533 [(M ? H)?].
Propyl 2-amino-4-(4-chlorophenyl)-6-[(6-chloro-3-
pyridinylmethyl)ethylamino]-1,4-dihydro-1-methyl-5-
nitro-3-pyridinecarboxylate (6n, C24H27Cl2N5O4)
Yield 75.8 %; yellow solid; m.p.: 132–133 °C; Rf = 0.63
1
(ethyl acetate/petroleum ether 3:1); H NMR (400 MHz,
CDCl3): d = 8.12 (s, 1H, Py-H), 7.82 (s, 1H, Py-H), 7.35
(d, J = 7.6 Hz, 1H, Py-H), 7.12 (d, J = 8.2 Hz, 2H,
Ph-H), 6.96 (d, J = 8.2 Hz, 2H, Ph-H), 6.21 (s, 2H, NH2),
5.43 (s, 1H, CH), 4.32 (d, J = 14.4 Hz, 1H, Py-CH2),
4.06–4.01 (m, 3H, Py-CH2, COOCH2CH2CH3), 3.32–3.23
(m, 1H, NCH2CH3), 3.21 (s, 3H, NCH3), 3.14 (m, 1H,
NCH2CH3), 1.59 (dd, J = 13.9, 7.3 Hz, 2H, COOCH2
CH2CH3), 1.31 (dd, J = 12.4, 5.3 Hz, 3H, NCH2CH3),
0.83 (t, J = 7.4 Hz, 3H, COOCH2CH2CH3) ppm; 13C
NMR (100 MHz, CDCl3): d = 11.1, 12.5, 23.7, 27.5, 28.2,
41.5, 50.1, 68.2, 81.7, 92.7, 115.9, 115.7, 125.5, 130.2,
130.1, 132.7, 138.9, 141.1, 145.7, 149.9, 151.2, 159.5,
167.7, 169.8 ppm; IR (KBr): vꢀ = 3,361, 3,241, 2,944,
Propyl 2-amino-4-(4-bromophenyl)-6-[(6-chloro-3-
pyridinylmethyl)ethylamino]-1,4-dihydro-1-methyl-5-
nitro-3-pyridinecarboxylate (6q, C24H27BrClN5O4)
Yield 82.2 %; yellow solid; m.p.: 179–181 °C; Rf = 0.58
1
(ethyl acetate/petroleum ether 3:1); H NMR (400 MHz,
CDCl3): d = 8.11 (s, 1H, Py-H), 7.77 (s, 1H, Py-H), 7.34
(d, J = 7.6 Hz, 1H, Py-H), 7.10 (d, J = 8.2 Hz, 2H, Ph-
H), 6.95 (d, J = 8.2 Hz, 2H, Ph-H), 6.11 (s, 2H, NH2), 5.43
(s, 1H, CH), 4.25 (d, J = 14.4 Hz, 1H, Py-CH2), 4.01–3.95
123

Cis-nitenpyram analogs bearing 1,4-dihydropyridine
1011
(m, 3H, Py-CH2, COOCH2CH2CH3), 3.31–3.22 (m, 1H,
NCH2CH3), 3.17 (s, 3H, NCH3), 3.11 (m, 1H, NCH2CH3),
1.60 (dd, J = 13.9, 7.3 Hz, 2H, COOCH2CH2CH3), 1.25
(dd, J = 12.4, 5.3 Hz, 3H, NCH2CH3), 0.82 (t, J = 7.4 Hz,
3H, COOCH2CH2CH3) ppm; 13C NMR (100 MHz,
CDCl3): d = 11.3, 12.9, 22.8, 27.1, 29.9, 40.9, 51.2,
68.7, 81.5, 92.5, 115.9, 115.8, 126.3, 130.5, 130.4, 132.2,
138.3, 141.1, 144.9, 150.3, 150.9, 159.5, 167.5, 168.7 ppm;
IR (KBr): vꢀ = 3,355, 3,233, 2,935, 2,905, 2,877, 1,366,
1,311, 1,261 cm-1; HRMS: m/z = 564.8576 [(M ? H)?].
Propyl 2-amino-6-[(6-chloro-3-pyridinylmethyl)-
ethylamino]-1,4-dihydro-1-methyl-4-(4-methylphenyl)-5-
nitro-3-pyridinecarboxylate (6t, C25H30ClN5O4)
Yield 71.9 %; yellow solid; m.p.: 189–190 °C; Rf = 0.59
(ethyl acetate/petroleum ether 3:1); H NMR (400 MHz,
1
CDCl3): d = 8.10 (s, 1H, Py-H), 7.76 (s, 1H, Py-H), 7.32 (d,
J = 7.6 Hz, 1H, Py-H), 7.08 (d, J = 8.2 Hz, 2H, Ph-H), 6.93
(d, J = 8.2 Hz, 2H, Ph-H), 6.13 (s, 2H, NH2), 5.42 (s, 1H,
CH), 4.21 (d, J = 14.4 Hz, 1H, Py-CH2), 4.01–3.95 (m, 3H,
Py-CH2, COOCH2CH2CH3), 3.31–3.22 (m, 1H, NCH2CH3),
3.17 (s, 3H, NCH3), 3.11 (m, 1H, NCH2CH3), 2.61 (s, 3H,
Ph-CH3), 1.64 (dd, J = 7.1, 3.1 Hz, 2H, COOCH2CH2CH3),
1.34 (t, J = 7.1 Hz, 3H, NCH2CH3), 0.87 (t, J = 7.2 Hz, 3H,
COOCH2CH2CH3) ppm; 13C NMR (100 MHz, CDCl3):
d = 11.3, 12.5, 23.5, 27.4, 29.2, 44.5, 48.9, 50.6, 67.9, 82.2,
92.3, 115.3, 117.4, 125.8, 130.7, 131.4, 132.7, 139.9, 143.2,
146.9, 149.4, 153.1, 159.9, 167.2, 169.5 ppm; IR (KBr):
vꢀ = 3,327, 3,200, 2,984, 2,935, 2,870, 1,343, 1,308,
1,235 cm-1; HRMS: m/z = 500.9871 [(M ? H)?].
Propyl 2-amino-6-[(6-chloro-3-pyridinylmethyl)-
ethylamino]-1,4-dihydro-4-(2-methoxyphenyl)-1-methyl-
5-nitro-3-pyridinecarboxylate (6r, C25H30ClN5O5)
Yield 83.5 %; yellow solid; m.p.: 192–194 °C; Rf = 0.63
1
(ethyl acetate/petroleum ether 3:1); H NMR (400 MHz,
CDCl3): d = 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, Py-CH2), 4.09 (s, 1H, Py-
CH2), 4.05–4.03 (m, 2H, COOCH2CH2CH3), 3.80 (s, 3H,
OCH3), 3.27–3.25 (m, 1H, NCH2CH3), 3.23 (s, 3H, NCH3),
3.11 (dd, J = 13.7, 6.9 Hz, 1H, NCH2 CH3), 1.64 (dd,
J = 7.1, 3.1 Hz, 2H, COOCH2CH2CH3), 1.34 (t, J =
7.1 Hz, 3H, NCH2 CH3), 0.88 (t, J = 7.3 Hz, 3H,
COOCH2CH2CH3) ppm; 13C NMR (100 MHz, CDCl3):
d = 12.1, 12.5, 23.5, 27.4, 29.2, 44.5, 46.2, 50.6, 67.9,
83.2, 92.3, 114.3, 117.4, 127.6, 130.7, 133.7, 135.8, 139.9,
145.4, 146.9, 147.9, 154.1, 157.9, 168.2, 169.9 ppm; IR
(KBr): vꢀ = 3,323, 3,211, 2,963, 1,652, 1,612, 1,577, 1,477,
1,413 cm-1; HRMS: m/z = 516.9875 [(M ? H)?].
Biological assay
The insecticidal activities of compounds 6a–6t were
measured against Aphis medicagini according to the
standard test [24, 25], with a slight modification. The test
analogs were dissolved in DMF and serially diluted with
water containing Triton X-80 (0.1 mg/dm3) to get the
required concentrations. The insects were reared at
25( 1) °C, and groups of ten were transferred to glass
Petri dishes and sprayed with the aforementioned solu-
tions using a Potter sprayer. Assessments were made after
72 h based on the number and size of live insects relative
to those sprayed with the negative control, and evalua-
tions were based on a percentage scale of 0–100, in
which 100 is total kill and 0 is no activity. The mortality
rates were subjected to probit analysis. The reference
compound was nitenpyram, while water containing Triton
X-80 (0.1 mg/dm3) was used as a negative control. All
experiments were carried out in three replicates according
to statistical requirements, and the results are shown in
Table 1.
Propyl 2-amino-6-[(6-chloro-3-pyridinylmethyl)-
ethylamino]-1,4-dihydro-4-(4-methoxyphenyl)-1-methyl-
5-nitro-3-pyridinecarboxylate (6s, C25H30ClN5O5)
Yield 78.1 %; yellow solid; m.p.: 201–202 °C; Rf = 0.62
1
(ethyl acetate/petroleum ether 3:1); H NMR (400 MHz,
CDCl3): d = 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, Py-CH2), 4.09 (s, 1H, Py-
CH2), 4.05–4.03 (m, 2H, COOCH2CH2CH3), 3.80 (s, 3H,
OCH3), 3.27–3.25 (m, 1H, NCH2CH3), 3.23 (s, 3H, NCH3),
3.11 (dd, J = 13.7, 6.9 Hz, 1H, NCH2CH3), 1.64 (dd, J =
7.1, 3.1 Hz, 2H, COOCH2CH2CH3), 1.34 (t, J = 7.1 Hz,
3H, NCH2CH3), 0.88 (t, J = 7.3 Hz, 3H, COOCH2CH2
CH3) ppm; 13C NMR (100 MHz, CDCl3): d = 11.3, 12.5,
23.5, 27.4, 29.2, 44.5, 48.9, 50.6, 67.9, 83.2, 92.3, 114.3,
117.4, 125.8, 130.7, 131.4, 132.7, 139.9, 143.2, 146.9, 147.9,
154.1, 157.9, 168.2, 169.5 ppm; IR (KBr): vꢀ = 3,323, 3,211,
2,963, 1,477, 1,413, 1,652, 1,612, 1,577 cm-1; HRMS:
m/z = 516.9875 [(M ? H)?].
X-ray data for compound 6g
˚
C23H25Cl2N5O4, unit cell parameters: a = 19.8308(16) A,
˚
˚
b = 12.8128(10) A, c = 19.8844(15) A, a = 90.00°, b =
90.00°, c = 90.00°; space group Pbca. The crystallo-
graphic data for 6g reported in this paper have been
deposited with the Cambridge Crystallographic Data Cen-
ter as supplementary publication no. CCDC 824407.
Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge, CB2 1EZ,
UK (fax: ?44-1223-336033; email: deposit@ccdc.cam.ac.uk).
123

1012
C. Sun et al.
Acknowledgments The insecticidal activity test of the target
compounds was completed by the Bioassay Department, Branch of
National Pesticide R&D South Center, Hangzhou. We are grateful
for the support from Branch of National Pesticide R&D South
Center. This work was supported by the National Natural Science
Foundation of China (21042010, 21102092, and 30870560), the
Key Scientific ‘‘Twelfth Five-Year’’ National Technology Support
Program (2011BAE06B01-17), the Innovation Project of Shanghai
Education Commission (12YZ078), the Leading Academic Disci-
pline Project of Shanghai Normal University (DZL808), and
Shanghai Key Laboratory of Rare Earth Functional Materials,
Shanghai Normal University (07dz22303).
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