Synthesis and insecticidal activities of cis-configuration nitenpyram analogues with benzoyl hydrazines

Article abstract of DOI:10.1002/jhet.1546

To research on the structure-activity relationships of our designed neonicotinoid compounds, a series of novel cis-configuration nitenpyram analogues with benzoyl hydrazines were designed and synthesized. The structures of all compounds were confirmed by IR, ¹H NMR, MS, and elemental analysis. Preliminary bioassays indicated that all the analogues exhibited good insecticidal activities against Nilaparvata legen and Aphis medicagini at 500 mg L^-1.

Full text of DOI:10.1002/jhet.1546

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Synthesis and Insecticidal Activities of cis-Configuration Nitenpyram
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Analogues with Benzoyl Hydrazines
a
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*
Xiao Xu , Chuan-wen Sun , Ding-rong Yang , Hong-fei Bu , Jing Wang and Yong-hua Xu
aCollege of Life and Environment Sciences, Shanghai Normal University, Shanghai 200234, China
bBioassay Department, Branch of National Pesticide R&D, Hangzhou 310023, China
*
E-mail: willin112@163.com
Received June 4, 2011
DOI 10.1002/jhet
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
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To research on the structure–activity relationships of our designed neonicotinoid compounds, a series of novel
cis-configuration nitenpyram analogues with benzoyl hydrazines were designed and synthesized. The structures of
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all compounds were confirmed by IR, 1H NMR, MS, and elemental analysis. Preliminary bioassays indicated that all
the analogues exhibited good insecticidal activities against Nilaparvata legen and Aphis medicagini at 500 mg LÀ1
.
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J. Heterocyclic Chem., 00, 00 (2013).
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INTRODUCTION
cis-configuration provided a new approach for neonicotinoid
molecular design.
Neonicotinoid insecticides (NNSs) act selectively on the
insect central nervous system as agonists of the postsynaptic
nicotinic acetylcholine receptors [1–3]. Because of their
unique properties such as high insecticidal potency, low
mammalian toxicity, broad insecticidal spectra, and no
cross-resistance to conventional insecticide classes [4–6],
NNSs have gained dramatic development and are fruitful in
modern agricultural pest management and environmental
protection [7]. However, during the past decades, frequent
field applications have inevitably led to insects’ resistance
to the major class of neonicotinoid insecticides [8–10].
As we have known, structure modification of the existing
commercial NNSs is one of the most effective resistance
management tactics [11–13]. It is worth pointing out that
because of the existence of the C═C or C═N double bond,
neonicotinoids can exist as an isomer in which the nitro or
cyano group is located away from the aromatic heterocycle
(trans) or as an isomer in which the nitro or cyano group is
pointed in the same direction as the aromatic heterocycle
(cis), which suggested that the double bond is indispensable
to this kind of compound and plays a crucial role in its modes
of action [14]. The nitro groups in all commercialized
Lightened by the earlier views, in our group, we had
focused our attention on introductions of the heterocycle
or a bulky group into the nitenpyram to fix the nitro group
in the cis position (Scheme 1). In this manuscript, by using
nitenpyram as the leading compound, a series of novel
nitenpyram analogues were designed by introducing the
substituent benzoyl hydrazines into nitenpyram and
forming a tetrahydropyrimidine ring fixed as cis configuration.
The new designed nitenpyram analogues (3a–3j) were
synthesized and characterized by 1H NMR, IR, and
elemental analysis. The preliminary insecticidal activity
tests indicated that the investigated compounds gave
≥90% mortality against Nilaparvata legen and Aphis
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medicagini at 500 mg LÀ1
.
RESULTS AND DISCUSSION
The target products (3a–3l)
Synthesis of compounds.
were obtained using compounds 4, formaldehyde, and the
substituent benzoyl hydrazines by Mannich reaction
(Scheme 2). The reaction of 1 with the substituent benzoyl
hydrazine could proceed readily under microwave
irradiation, which was a highly efficient way with a good
yield, as compared with those obtained under conventional
conditions by refluxing of the starting materials in
ethanol for 6 h.
neonicotinoids have
a trans-configuration [15], the
nitenpyram does. It was found that many neonicotinoid
analogues with cis-configuration also exhibited good
insecticidal activities and shown a different mechanism from
the trans-configuration neonicotinoids [11]. So, compounds
with the cis-configuration offer an opportunity for further
optimization. In other words, fixing the nitro group in the
Insecticidal activity. The insecticidal activities of these
novel nitenpyram analogues were evaluated against N.
legen and A. medicagini according to the standard test [16]
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with a slight modification. As depicted in Table 1, most
compounds exhibited good in vitro insecticidal activities
against N. legen and A. medicagini had >90% mortality at
500 mg LÀ1. In genenal, the insecticidal activities against
A. medicagini were better than N. legen. Among these
compounds, 3e and 3i showed 100% mortality against
A. medicagini at 100mg LÀ1, and 3c, 3d, and 3j also
showed good insecticidal activites.
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Scheme 1. Development of novel nitenpyram analogues in our group.
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Scheme 2. General synthetic route for the target compounds 3a–3j.
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Table 1
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Insecticidal activities of compounds 3a–j against Nilaparvata lugen and Aphis medicagini.
N. legen
A. medicagini
Mortality (%) at different concentrations (mg LÀ1
)
Compound
Ar
500
100
500
100
3a
3b
3c
3d
3e
3f
3g
3h
Ph
2-F-Ph
2-Cl-Ph
2-Br-Ph
3,5-Cl2-Ph
4-Me-Ph
4-(CH3)3C-Ph
3-(CH3)2N-Ph
C4H3O
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31a
31
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56
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100
36a
30
35a
38a
32
36
41
3i
3j
C4H3S
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Nitenpyram
100
100
aThe date from Reference [20].
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(dd, J1 = 3.2 Hz, J2 = 8.4 Hz, 1H, Py-H), 7.60–7.76 (m,3H,
Ph-H), 7.33 (d, J = 8.0 Hz, 1H, Py-H), 4.53(d, J = 16.4, 1H,
Py-CH2), 4.23 (d, J = 16.4 Hz, 1H, Py-CH2), 3.85–3.89 (m, 4H),
3.12–3.18 (m, 1H), 2.92 (s, 3H, NCH3), 2.83–2.94 (m, 1H),
1.14 (t, J = 7.0 Hz, 3H, NCH2CH3); IR (KBr, cmÀ1) 3256,
3079, 1683, 1542, 1310, 758; MS (EI + 70 eV) m/z (%): 448.8
(M+, 5.3), 126.2(67.4), 122.5 (100), 96.0 (54.2); Anal. Calcd
for C20H21Cl2FN6O3: C, 49.72; H, 4.37; N, 17.41. Found: C,
49.70; H, 4.38; N, 17.39.
When different substituents Ar were introduced to the
nitenpyram analogues, their insecticidal activities
decreased in the order C4H3O, 3,5-Cl2-Ph > 2-Cl-Ph,
C4H3S, 2-Cl-Ph > 2-F-Ph > 3-(CH3)2N-Ph, 4-(CH3)3C-Ph,
Ph, which indicated that Ar was strongly related to
their insecticidal potency. When Ar group was contained
in the electron-withdrawing group, the corresponding
nitenpyram analogues showed good insecticidal activities.
On the other hand, the nitenpyram analogues with the
electron-donating group showed the much less activity.
These observations may be related to their relatively strong
affinities with their target.
N-[(4Z)-4-[[(6-Chloro-3-pyridinyl)methyl]ethylamino]-3-methyl-
5-nitro-1,2,3,6-tetrahydropyrimidin-1-yl]-2-chlorobenzamide
(3c).
Yield, 68.9%; mp 208–210ꢀC; 1H NMR (DMSO-d6),
d 9.94(s, 1H, NNHCO), 8.32 (d, J = 2.4 Hz, 1H, Py-H), 7.75
(dd, J1 = 3.0 Hz, J2 = 8.0 Hz, 1H, Py-H), 7.50–7.80 (m, 4H, Ph-
H), 7.32 (d, J = 8.2 Hz, 1H, Py-H), 4.51(d, J= 16.0, 1H, Py-CH2),
4.21 (d, J = 16.0 Hz, 1H, Py-CH2), 3.82–3.87 (m, 4H), 3.10–
3.16 (m, 1H), 2.95 (s, 3H, NCH3), 2.80–2.92 (m, 1H), 1.12
(t, J = 7.2 Hz, 3H, NCH2CH3); IR (KBr, cmÀ1) 3253, 3080,
1679, 1541, 1309, 749; MS (EI + 70 eV) m/z (%): 465.7 (M+,
5.6), 138.0 (100), 126.2(64.7), 112.4 (50.4); Anal. Calcd for
C20H22Cl2N6O3: C, 51.62; H, 4.77; N, 18.06. Found: C, 51.69;
H, 4.71; N, 18.11.
EXPERIMENTAL
Melting points were measured using an uncorrected RK-1 micro-
scopic melting-point apparatus. 1H NMR spectra were recorded on
a Bruker AVANCE (400 MHz) spectrometer with DMSO-d6 as the
solvent and TMS as the internal standard. The IR spectra were
obtained from KBr disks in the range 4000–400 cmÀ1 on a Nicolet
5DXFT-IR spectrophotometer. Combustion analyses for elemental
composition were made with a Perkin-Elmer 2400 instrument. All
microwave experiments were performed using YL8023B1 micro-
wave reactor possessing a single-mode microwave cavity producing
controlled irradiation at 2.45GHz.
General synthetic procedure for synthesis of 1 and 4. Starting
from 2-chloro-5-chloro-methylpridine, a set of (E)-N-(6-chloro-3-
pyridylmethyl)-N-ethyl-1-chloro-2-nitroethylene-1-amine and 1 was
prepared on the basis of the procedures in the literatures [17,18].
The substituent benzoyl hydrazine was also prepared according to
the procedures given in the literatures [19].
General synthetic procedure for synthesis of 3a–3j. Ethanol
(20 mL) was added to a mixture of nitenpyram 1 (2.65 g,
9.8 mmol), substituent benzoyl hydrazine (11.95 mmol), and
formaldehyde (1.96 mL, 37%) in a microwave reactor. The
resulting mixture was heated to 70–75ꢀC for 5min with
temperature maintained for 25 min. After completion of the
reaction, the mixture was cooled to room temperature and filtered
to give the solid products 3a–3j, which were washed with
ethanol and dried in air. Tetrahydropyrimidine derivatives 3a–3j
were obtained in high purity (>98% by 1H NMR) and did not
require further purification. The analytical data for the compounds
3a–3j were summarized as follows.
N-[(4Z)-4-[[(6-Chloro-3-pyridinyl)methyl]ethylamino]-3-
methyl-5-nitro-1,2,3,6-tetrahydropyrimidin-1-yl]-2-bromobenzamide
1
(3d). Yield, 73.4%; mp 213–215ꢀC; H NMR (DMSO-d6), d
9.92(s, 1H, NNHCO), 8.30 (d, J = 2.4 Hz, 1H, Py-H), 7.73(dd,
J1 = 3.2 Hz, J2 = 8.0 Hz, 1H, Py-H), 7.53–7.76 (m, 4H, Ph-H), 7.30
(d, J = 8.0 Hz, 1H, Py-H), 4.50(d, J = 16.0, 1H, Py-CH2), 4.23
(d, J = 16.0 Hz, 1H, Py-CH2), 3.80–3.86 (m, 4H), 3.12–3.17
(m, 1H), 2.94 (s, 3H, NCH3), 2.82–2.90 (m, 1H), 1.14 (t,
J = 7.2 Hz, 3H, NCH2CH3). IR (KBr, cmÀ1) 3258, 3088,
1671, 1546, 1314, 739; MS (EI + 70 eV) m/z (%): 509.6
(M+, 7.8), 183.7 (100), 156.8 (42.3), 126.2 (65.3); Anal.
Calcd for C20H22BrClN6O3: C, 47.12; H, 4.35; N, 16.49.
Found: C, 47.18; H, 4.39; N, 16.41.
N-[(4Z)-4-[[(6-Chloro-3-pyridinyl)methyl]ethylamino]-3-methyl-
5-nitro-1,2,3,6-tetrahydropyrimidin-1-yl]-3,5-dichlorobenzamide
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(3e).
Yield, 71.3%; mp 209–211ꢀC; 1H NMR (DMSO-d6),
d 9.93 (s, 1H, NNHCO), 8.33 (d, J = 2.0 Hz, 1H, Py-H), 7.76
(dd, J1 = 3.0 Hz, J2 = 8.2 Hz, 1H, Py-H), 7.58–7.73 (m, 3H, Ph-H),
7.34 (d, J = 8.0 Hz, 1H, Py-H), 4.52 (d, J = 16.2, 1H, Py-CH2),
4.22 (d, J = 16.2Hz, 1H, Py-CH2), 3.81–3.87 (m, 4H), 3.11–3.17
(m, 1H), 2.94 (s, 3H, NCH3), 2.81–2.92 (m, 1H), 1.16
(t, J = 7.0Hz, 3H, NCH2CH3); IR (KBr, cmÀ1): 3257, 3083, 1684,
2544, 1308, 823, 703; MS (EI + 70 eV) m/z (%): 499.5 (M+, 3.5),
174.1 (100), 147.2 (69.4), 126.3 (67.5); Anal. Calcd for
C20H21Cl3N6O3: C, 48.06; H, 4.24; N, 16.82. Found: C, 48.12; H,
4.32; N, 16.88.
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N-[(4Z)-4-[[(6-Chloro-3-pyridinyl)methyl]ethylamino]-3-
methyl-5-nitro-1,2,3,6-tetrahydropyrimidin-1-yl]benzamide
1
(3a).
Yield, 72.5%; mp 235–237ꢀC; H NMR (DMSO-d6), d
N-[(4Z)-4-[[(6-Chloro-3-pyridinyl)methyl]ethylamino]-3-methyl-
5-nitro-1,2,3,6-tetrahydropyrimidin-1-yl]-4-methylbenzamide
9.97(s, 1H, NNHCO), 8.36 (d, J = 2.4 Hz, 1H, Py-H), 7.78
(dd, J1 = 3.2 Hz, J2 = 8.0 Hz, 1H, Py-H), 7.47–7.57 (m, 5H, Ph-
H), 7.36 (d, J = 8.0 Hz, 1H, Py-H), 4.54(d, J = 16.0, 1H, Py-
CH2), 4.21 (d, J = 16.0Hz, 1H, Py-CH2), 3.79–3.83 (m, 4H),
3.10–3.17 (m, 1H), 2.95 (s, 3H, NCH3), 2.84–2.92 (m, 1H),
1.13 (t, J = 7.2 Hz, 3H, NCH2CH3); IR (KBr, cmÀ1) 3252,
3077, 1682, 1541, 1311, 752; MS (EI + 70eV) m/z (%): 430.5
(M+, 7.5), 126.2(64.5), 104.1 (100),78.5 (67.4); Anal. Calcd for
C20H23ClN6O3: C, 55.75;H, 5.38; N, 19.50. Found: C, 55.67;
H, 5.31; N, 19.58.
(3f).
Yield, 72.8%; mp 219–220ꢀC; 1H NMR (DMSO-d6),
d 9.93 (s, 1H, NNHCO), 8.31 (d, J = 2.0 Hz, 1H, Py-H),
7.76 (dd, J1 = 3.2 Hz, J2 = 8.2 Hz, 1H, Py-H), 7.42–7.64
(m, J = 8.2 Hz, J = 8.2 Hz, 4H, Ph-H), 7.34 (d, J = 8.0 Hz, 1H,
Py-H), 4.53(d, J = 16.2, 1H, Py-CH2), 4.23 (d, J = 16.2 Hz, 1H,
Py-CH2), 3.82–3.85 (m, 4H), 3.13–3.17 (m, 1H), 2.97
(s, 3H, NCH3), 2.81–2.94 (m, 1H), 2.36 (s, 3H, Ph-CH3), 1.15
(t, J = 7.2 Hz, 3H, NCH2CH3); IR (KBr, cmÀ1): 3251, 3080,
1682, 1541, 1308, 805; MS (EI + 70 eV) m/z (%): 445.1
(M+, 5.3), 126.3(61.5), 119.0 (100), 92.3 (72.5); Anal. Calcd for
C21H25ClN6O3: C, 56.69; H, 5.66; N, 18.89. Found: C, 56.75;
H, 5.73; N, 18.95.
N-[(4Z)-4-[[(6-Chloro-3-pyridinyl)methyl]ethylamino]-3-methyl-
5-nitro-1,2,3,6-tetrahydropyrimidin-1-yl]-2-fluorobenzamide
(3b).
Yield, 70.5%; mp 213–215ꢀC; 1H NMR (DMSO-d6),
d 9.92(s, 1H, NNHCO), 8.35 (d, J = 2.0 Hz, 1H, Py-H), 7.78
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N-[(4Z)-4-[[(6-Chloro-3-pyridinyl)methyl]ethylamino]-3-
methyl-5-nitro-1,2,3,6-tetrahydropyrimidin-1-yl]-4-(2,2-
dimethyl)ethylbenzamide (3g). Yield, 82.2%; mp 218–221ꢀC;
1H NMR (DMSO-d6), d 9.90(s, 1H, NNHCO), 8.31 (d, J=2.0Hz,
1H, Py-H), 7.73(dd, J1 =3.0Hz, J2 = 8.2 Hz, 1H, Py-H), 7.46–7.78
(m, 4H, Ph-H), 7.30 (d, J= 8.0 Hz, 1H, Py-H), 4.50(d, J= 16.4, 1H,
Py-CH2), 4.20 (d, J= 16.4 Hz, 1H, Py-CH2), 3.80–3.85 (m, 4H),
3.12–3.17 (m, 1H), 2.93 (s, 3H, NCH3), 2.82–2.90 (m, 1H), 1.13
(t, J= 7.2 Hz, 3H, NCH2CH3); IR (KBr, cmÀ1) 3245, 3074, 1672,
1540, 1303, 701; MS (EI + 70 eV) m/z (%): 487.1 (M+, 5.1), 161.3
(100), 134.4 (62.4), 126.2 (69.4); Anal. Calcd for C24H31ClN6O3:
C, 59.19; H, 6.42; N, 17.26. Found: C, 59.12; H, 6.48; N, 17.31.
N-[(4Z)-4-[[(6-Chloro-3-pyridinyl)methyl]ethylamino]-3-methyl-
5-nitro-1,2,3,6-tetrahydropyrimidin-1-yl]-3-(N,N′-dimethyl)amino
1542, 1308, 1248; MS (EI + 70 eV) m/z (%): 436.5 (M+, 2.1),
126.3 (62.4), 111.2 (100), 84.3 (64.3); Anal. Calcd for
C18H21ClN6O3S: C, 49.48; H, 4.84; N, 19.23. Found: C, 49.46; H,
4.85; N, 19.25.
Acknowledgments. This work was supported by the National
Natural Science Foundation of China (21042010), the Key
Scientific and Technological Project of Shanghai Science and
Technology Commission (09391912100), the Leading Academic
Discipline Project of Shanghai Normal University (DZL808), the
Innovation Project of Shanghai Education Commission
(09YZ157), and the Key Laboratory of Rare Earth Functional
Materials of Shanghai (07dz22303).
benzamide (3h).
Yield, 70.5%; mp 210–213ꢀC; 1H NMR
(DMSO-d6), d 9.94(s, 1H, NNHCO), 8.33 (d, J = 2.0 Hz, 1H,
Py-H), 7.76(dd, J1 = 3.2 Hz, J2 = 8.0 Hz, 1H, Py-H), 7.67–7.75
(m, 3H, Ph-H), 7.32 (d, J = 8.4 Hz, 1H, Py-H), 4.52(d, J = 16.0,
1H, Py-CH2), 4.21 (d, J = 16.0 Hz, 1H, Py-CH2), 3.81–3.87
(m, 4H), 3.13–3.17 (m, 1H), 2.91 (s, 3H, NCH3), 2.81–2.94
REFERENCES AND NOTES
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(m, 1H), 1.12 (t, J = 7.2 Hz, 3H, NCH2CH3); IR (KBr, cmÀ1
)
3259, 3083, 1679, 1541, 1316, 758; MS (EI + 70eV) m/z (%):
474.2 (M+, 4.3), 148.3 (100), 126.2 (61.4), 121.3 (65.3); Anal.
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N-[(4Z)-4-[[(6-Chloro-3-pyridinyl)methyl]ethylamino]-3-
methyl-5-nitro-1,2,3,6-tetrahydropyrimidin-1-yl]-2-furylamide
(3i). Yield, 82.4%; mp 225–227ꢀC; 1H NMR (DMSO-d6), d 9.90
(s, 1H, NNHCO), 8.35 (d, J = 2.4 Hz, 1H, Py-H), 7.75 (dd,
J1 = 3.2 Hz, J2 = 8.2 Hz, 1H, Py-H), 7.54 (d, J = 8.0 Hz, 1H, Fr-H),
7.32 (d, J = 8.4 Hz, 1H, Py-H), 7.14 (d, J = 3.2 Hz, 1H, Fr-H), 6.65
(dd, J1 = 2.0 Hz, J2 = 2.0 Hz, 1H, Fr-H), 4.53 (d, J = 16.0, 1H,
Py-CH2), 4.25 (d, J = 16.0 Hz, 1H, Py-CH2), 3.80–3.85 (m, 4H),
3.13–3.18 (m, 1H), 2.95 (s, 3H, NCH3), 2.83–2.96 (m, 1H), 1.12
(t, J = 7.6 Hz, 3H, NCH2CH3); IR (KBr, cmÀ1) 3253, 3079, 1691,
1541, 1310, 1244; MS (EI + 70eV) m/z (%): 420.4 (M+, 1.02),
354.5 (1.25), 67.3 (69.32), 326.4 (2.34), 95.3 (100), 236.3
(43.55), 126.2 (68.31); Anal. Calcd for C18H21ClN6O4: C, 51.35;
H, 5.04; N, 19.98. Found: C, 51.37; H, 5.03; N, 19.97.
N-[(4Z)-4-[[(6-Chloro-3-pyridinyl)methyl]ethylamino]-3-
methyl-5-nitro-1,2,3,6-tetrahydropyrimidin-1-yl]-2-thienylamide
(3j). Yield, 78.1%; mp 218–219ꢀC; 1H NMR (DMSO-d6), d 9.93
(s, 1H, NNHCO), 8.33 (d, J= 2.0 Hz, 1H, Py-H), 7.72 (dd,
J1 =3.6Hz, J2 = 8.0 Hz, 1H, Py-H), 7.62 (d, J= 4.0 Hz, 1H, Tp-H),
7.58 (d, J= 3.6 Hz, 1H, Tp-H), 7.31 (d, J= 8.4 Hz, 1H, Py-H), 7.09
(dd, J1 =3.2Hz, J2 = 3.2 Hz, 1H, Tp-H), 4.51 (d, J= 16.0, 1H,
Py-CH2), 4.26 (d, J= 16.0 Hz, 1H, Py-CH2), 3.78–3.82 (m, 4H),
3.10–3.21 (m, 1H), 2.93 (s, 3H, NCH3), 2.80–2.92 (m, 1H), 1.10
(t, J= 7.6 Hz, 3H, NCH2CH3). IR (KBr, cmÀ1) 3254, 3082, 1683,
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet