Divalent and oxabridged neonicotinoids constructed by dialdehydes and nitromethylene analogues of imidacloprid: Design, synthesis, crystal structure, and insecticidal activities

Article abstract of DOI:10.1021/jf902531y

A series of divalent and oxabridged neonicotinoids were synthesized by reactions of nitromethylene analogues of imidacloprid and dialdehydes, and their structures were confirmed by ¹H NMR, ¹³C NMR, high-resolution mass spectroscopy, and X-ray diffraction analysis. The bioassays indicated that some of them were endowed with excellent insecticidal activities against cowpea aphid (Aphis craccivora), armyworm (Pseudaletia separata Walker), and brown planthopper (Nllaparvata lugens). Divalent neonicotinoid 6 and oxabridged 8a had higher activities than imidacloprid against cowpea aphids and armyworm; furthermore, the activity of 8a was 40.4-fold higher than that of imidacloprid against imidacloprid-resistant brown planthopper.

Full text of DOI:10.1021/jf902531y

2696 J. Agric. Food Chem. 2010, 58, 2696–2702
DOI:10.1021/jf902531y
Divalent and Oxabridged Neonicotinoids Constructed by
Dialdehydes and Nitromethylene Analogues of Imidacloprid:
Design, Synthesis, Crystal Structure, and Insecticidal
†
Activities
§
^
,§
§
#
,§
X
USHENG
S
HAO, HUA
F
U
, XIAOYONG
AND
X
X
U
,* XINGLEI
X
U
, ZEWEN
L
IU, ZHONG
LI,*
§
UHONG
Q
IAN
§
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science
and Technology, Shanghai 200237, China, Key Laboratory of Monitoring and Management of Plant
#
Disease and Insect, Ministry of Agriculture, Nanjing Agricultural University, Tongwei Road 6, Nanjing
^
2
10095, China, and Department of Applied Chemistry, Chemical Engineering College, Qinghai
University, Xining 810016, China
A series of divalent and oxabridged neonicotinoids were synthesized by reactions of nitromethylene
13
1
analogues of imidacloprid and dialdehydes, and their structures were confirmed by H NMR,
C
NMR, high-resolution mass spectroscopy, and X-ray diffraction analysis. The bioassays indicated
that some of them were endowed with excellent insecticidal activities against cowpea aphid (Aphis
craccivora), armyworm (Pseudaletia separata Walker), and brown planthopper (Nilaparvata lugens).
Divalent neonicotinoid 6 and oxabridged 8a had higher activities than imidacloprid against cowpea
aphids and armyworm; furthermore, the activity of 8a was 40.4-fold higher than that of imidacloprid
against imidacloprid-resistant brown planthopper.
KEYWORDS: Neonicotinoids; dialdehydes; imidacloprid; insecticide; oxabridge
INTRODUCTION
observed in a range of species after frequent field applica-
tions (16-23).
The past decades have witnessed the great power and versatile
ability of neonicotinoids as a novel class of insecticides (1, 2),
which account for 18% of world insecticide sales with a turnover
of $1.7 billion in 2006 (3). By virtue of novel modes of action
The rationale for our molecular design involved the use of
fused heterocycles or bulky groups to fix the direction of the nitro
group, which was one of the most important groups in neonico-
tinoids. Fortunately, our foray into this arena met with encoura-
ging insecticidal activities, and some novel neonicotinoids with
high activities happened to be discovered (24-28). In our pre-
vious studies, it was found that 6-Cl-PMNI (1) could react with
various R,β-unsaturated aldehydes to give high-insecticidal com-
(targeting insect nicotinic acetylcholine receptors (nAChRs))
(4-6), low mammalian toxicity, broad insecticidal spectra, and
good systemic properties (7, 8), neonicotinoids are increasingly
used in crop protection and animal health care against a broad
spectrum of sucking and biting insects. Since their inception
about 30 years ago, the development of neonicotinoids with
novel structures and higher insecticidal activities has provoked
continuing interest; for example, divalent neonicotinoids (9, 10),
proinsecticides of imidacloprid (11), neonicotinoids with exten-
ded N-substituted-imine (12), neonicotinoid substituents forming
a water bridge (13), and crown-capped imidacloprid (14) have
consecutively appeared in the literature in recent years. Further-
more, the discoveries of high-resolution crystal structures of
AChBP-neonicotinoid complexes have promoted the receptor
structure guided neonicotinoid design (4, 12, 13, 15). Despite the
tremendous amount of effort invested in the development of
neonicotinoids, it is still essential to explore novel neonicotinoid
candidates, because significant increases in resistance have been
pounds
2 with tetrahydropyridine fixed cis-configuration
(26, 27), and it could also react with five-membered aromatic
aldehydes to give compounds 3 with bulky groups fixed in
the direction of the nitro group, which showed higher insecti-
cidal activities than imidacloprid (28). It is noteworthy that
toward R,β-unsaturated aldehydes and five-membered aromatic
aldehydes, C1 or N1 in 6-Cl-PMNI acted as nucleophilic
centers.
Inspired by the promising results described above, we next
turned our attentions to reactions of dialdehydes with 6-Cl-
PMNI with a view to incorporate dialdehydes to 6-Cl-PMNI
and search for high insecticidal neonicotinoids. Fortunately,
different fates of dialdehydes upon reacting with 6-Cl-PMNI
were observed due to the two electrophilic aldehyde groups in
dialdehydes. Herein, for the sake of comparison and extending
our studies, we report the synthesis and insecticidal activities of
divalent and oxabridged neonicotinoids constructed by dialde-
hydes and nitromethylene analogues of imidacloprid.
†
Part of the ECUST-Qian Pesticide Cluster.
Corresponding authors [telephone þ 86 21 64253540; fax þ86 21
*
6
4252603; e-mail (Z.L.) lizhong@ecust.edu.cn or (X.X.) xyxu@ecust.
edu.cn].
pubs.acs.org/JAFC
Published on Web 12/11/2009
© 2009 American Chemical Society

Article
J. Agric. Food Chem., Vol. 58, No. 5, 2010 2697
1
MATERIALS AND METHODS
product as a brown solid: yield, 39%; mp, 136.5-137.8 ꢀC; H NMR
(
6 1
400 Mz, DMSO-d ) δ 8.34 (d, J= 2.4 Hz, 2H), 7.82 (dd, J = 2.4 Hz,
= 8.4 Hz, 2H), 7.47 (d, J= 8.4 Hz, 2H), 4.96 (t, J= 2.8 Hz, 2H), 4.81 (d,
J= 15.8 Hz, 2H), 4.44 (d, J= 15.8 Hz, 2H), 3.92-3.97 (m, 4H), 3.65-3.72
m, 2H), 3.49-3.56 (m, 2H), 1.92-1.93 (m, 2H); C NMR (100 Mz,
Instruments. Melting points (mp) were recorded on B u€ chi B540
apparatus (B u€ chi Labortechnik AG, Flawil, Switzerland) and are un-
J
2
1
13
corrected. H NMR and C NMR spectra were recorded on a Bruker
AM-400 (400 MHz) spectrometer with CDCl or DMSO-d as the solvent
13
(
3
6
DMSO-d
8.5, 28.1. HRMS (ESþ) calcd for C23
found, 545.1201; calcd for C23
found, 547.1178; calcd for C23
49.1181.
General Synthetic Procedure for 8a-d. Succinaldehyde was pre-
pared according to the previously reported procedure (30). A mixture of
,5-diethoxytetrahydrofuran (2 g, 12.5 mmol) and HCl aqueous solution
0.1 M, 10 mL) was heated to 90 ꢀC for 1 h and then cooled to room
temperature. Acetonitrile (40 mL), compound 1 or 7a-c (10 mmol), and
anhydrous Na SO (3 g) were successively added, and the obtained
6
) δ 155.3, 147.9, 147.8, 138.0, 130.9, 122.7, 104.8, 502, 48.9, 48.5,
and TMS as the internal standard. Chemical shifts are reported in δ (parts
per million) values. High-resolution mass spectra were recorded under
electron impact (70 eV) condition using a MicroMass GCT CA 055
instrument. Analytical thin-layer chromatography (TLC) was carried out
on precoated plates (silica gel 60 F254), and spots were visualized with
ultraviolet (UV) light. X-ray diffraction was performed with a Bruker
Smart 1000.
35
þ
þ
4
H
23
N
8
O
4
Cl
2
(M þ H) , 545.1219;
35 37
H
23
N
8
O
4
Cl Cl (M þ H) , 547.1190;
37
þ
H
23
N
8
O
4
Cl
2
(M þ H) , 549.1160; found,
5
2
(
Synthesis. The general synthetic methods for compounds 4, 5, 6, 8a-d,
and 9a-d are depicted in Schemes 2-5. Unless otherwise noted, reagents
and solvents were used as received from commercial suppliers. Yields were
not optimized. All reactions were carried out under a protective atmo-
sphere of drying nitrogen or utilizing a calcium chloride tube.
2
4
mixture was stirred at room temperature. The progress of the reaction
was monitored by TLC. After completion, the mixture was filtered to
remove Na SO , and then the pH value of the filtrate was adjusted to 7-8
2 4
by triethylamine and the solvent was removed under reduced pressure. The
residue was purified by flash chromatography eluting with dichloro-
methane/acetone (v/v 3:1) to afford the desired products 8a-d.
Data for 8a: yield, 53%; mp, 149.0-150.0 ꢀC; H NMR (400 Mz,
6 1 2
DMSO-d ): δ 8.35 (d, J= 2.4 Hz, 1H), 7.81 (dd, J = 2.4 Hz, J = 8.4 Hz,
H), 7.51 (d, J= 8.4 Hz, 1H), 5.36-5.39 (s, 2H), 5.00 (d, J= 15.6 Hz, 1H),
.68 (d, J= 15.6 Hz, 1H), 3.57-3.73 (m, 4H), 1.94-2.04 (m, 4H);
4
-(1-((6-Chloropyridin-3-yl)methyl)-4,5-dihydro-1H-imidazol-2-
yl)-1-(1-((6-chloropyridin-3-yl)methyl)imidazolidin-2-ylidene)-1,4-
dinitrobut-3-en-2-ol (4). A mixture of compound 1 (2.54 g, 10 mmol),
40% oxalaldehyde aqueous solution (4 mL, 30 mmol), and acetonitrile
1
(50 mL) was stirred at room temperature. After it was stirred for about 1 h,
concentrated hydrochloric acid (0.20 mL) was added to the reaction
mixture. The progress of the reaction was monitored by TLC. After
completion, the solvent was removed under reduced pressure. The
obtained residue was added to methanol (20 mL), and then the product
was precipitated. The precipitate was filtered, washed with dichloro-
1
4
13
C
NMR (100 Mz, DMSO-d
6
) δ 155.6, 149.7, 149.6, 139.7, 132.6, 124.5,
1
C
H
C
C
09.6, 87.0, 75.1, 51.2, 50.3, 46.6, 31.9, 31.7; HRMS (ESþ) calcd for
3
5
þ
þ
methane, and dried to give the corresponding product as a white solid:
14
H
16
N
4
O
3
Cl (M þ H) , 323.0911; found, 323.0912; calcd for C14
-
1
3
7
yield, 58%; mp, 164.6-165.3 ꢀC; H NMR (400 Mz, DMSO-d
6
) δ 9.01 (s,
16
N
4
O
3
Cl (M
þ
H) , 325.0811; found, 325.0895.; calcd for
3
5
þ
þ
1
7
H), 8.41 (d, J= 2.0 Hz, 1H), 8.38 (d, J= 2.0 Hz, 1H), 7.80-7.86 (m, 2H),
.51-7.54 (m, 2H), 6.50 (d, J= 7.2 Hz, 1H), 5.34 (d, J= 15.2 Hz, 1H), 5.18
= 2.4 Hz, J = 7.2 Hz, 1H), 4.77 (d, J=
6.8 Hz, 1H), 4.67 (d, J= 16.8 Hz, 1H), 3.98 (d, J= 2.4 Hz, 1H), 3.86-3.95
14
H
H
15
N
N
4
O
O
3
ClNa (M þ Na) , 345.0730; found, 345.0722; calcd for
37
3
14
15
4
ClNa (M þ Na) , 347.0701; found, 347.0692.
1
(d, J= 15.2 Hz, 1H), 4.84 (dd, J
1
2
Data for 8b: yield, 56%; mp, 136.5-138.0 ꢀC; H NMR (400 Mz,
1
DMSO-d
6
) δ 7.47 (s, 1H), 5.61 (d, J= 5.2 Hz, 1H), 5.28 (d, J= 15.4 Hz,
H), 5.16 (d, J= 5.00 Hz, 1H), 4.70 (d, J= 15.4 Hz, 1H), 3.66-3.82 (m,
H), 3.54-3.61 (m, 1H), 2.22-2.29 (m, 1H), 2.12-2.21 (m, 2H),
1
3
(
m, 2H), 3.61-3.80 (m, 5H), 3.40-3.47 (m, 1H); C NMR (100 Mz,
DMSO-d ) δ 162.7, 158.7, 148.3, 148.2, 148.0, 147.7, 138.1, 137.7, 130.9,
30.2, 123.1, 123.0, 102.5, 101.4, 81.4, 53.8, 52.6, 49.4, 48.8, 46.4, 41.2, 41.0.
1
6
3
1
13
1
6
.99-2.07 (m, 1H); C NMR (100 Mz, DMSO-d ) δ 154.6, 154.3,
3
5
þ
HRMS (ESþ) calcd for C22
H
23
N
8
O
5
Cl
2
(M þ H) , 549.1168; found,
1
40.6, 135.1, 110.4, 87.4, 75.4, 49.6, 47.9, 46.5, 31.8, 31.8. HRMS (ESþ)
3
5
37
þ
þ
3
5
þ
5
5
5
49.1178; calcd for C22
H
23
N
8
O
5
Cl Cl (M þ H) , 551.1139; found,
calcd for C12
for C12
H
14
N
4
O
3
S Cl (M þ H) , 329.0475; found, 329.0475; calcd
3
7
3
7
þ
51.1152; calcd for C22
H
23
N
8
O
5
Cl
2
(M þ H) , 553.1109; found,
H
14
N
4
O
3
S Cl (M þ H) , 331.0446; found, 331.0461.
53.1108.
1
Data for 8c: yield, 58%; mp, 149.0-149.8 ꢀC; H NMR (400 Mz,
2
-Chloro-5-((2-(4-(1-((6-chloropyridin-3-yl)methyl)-4,5-dihydro-
DMSO-d
6
) δ 7.28-7.39 (m, 5H), 5.66 (d, J= 4.3 Hz, 1H), 5.14 (d, J= 4.5
1
H-imidazol-2-yl)-2-methoxy-1,4-dinitrobut-3-enylidene)imidazolidin-
-yl)methyl)pyridine (5). To a mixture of compound 4 (1.1 g, 2 mmol),
Hz, 1H), 4.92-5.01 (m, 2H), 3.57-3.74 (m, 3H), 3.47-3.53 (m, 1H),
2.30-2.34 (m, 1H), 2.13-2.22 (m, 2H), 2.00-2.07 (m, 1H); C NMR (100
Mz, DMSO-d ): δ 155.5, 135.9, 128.9, 128.2, 128.1, 87.7, 75.6, 54.4, 48.9,
47.2, 31.8, 31.6. HRMS (ESþ) calcd for C H N O (M þ H) , 287.1270;
13
1
methanol (10 mL), and dichloromethane (30mL) was added three drops of
concentrated hydrochloric acid. The resulting mixture was refluxed for 10
h, cooled to room temperature, and then concentrated under reduced
pressure. The residue was purified by flash chromatography eluting
with dichloromethane/acetone (v/v 3:1) to afford the desired products as
6
þ
15
17
3 3
found, 287.1272.
1
Data for 8d: yield, 38%; mp, 140.0-140.9 ꢀC; H NMR (400 Mz,
DMSO-d ) δ 7.27-7.34 (m, 4H), 5.63 (d, J= 5.4 Hz, 1H), 5.14 (d, J= 5.2
Hz, 1H), 5.04 (d, J= 15.1 Hz, 1H), 4.78 (d, J= 15.1 Hz, 1H), 3.62-3.73(m,
H), 3.45-3.51 (m, 1H), 2.26-2.31 (m, 1H), 2.11-2.21 (m, 2H),
6
.98-2.07 (m, 1H); C NMR (100 Mz, DMSO-d ) δ 155.3, 134.4,
33.9, 129.6, 129.0, 110.2, 87.6, 75.5, 53.9, 49.2, 47.0, 31.8, 31.7. HRMS
6
1
a brown solid: yield, 20%; mp, 170.2-170.6 ꢀC; H NMR (400 Mz,
DMSO-d ) δ 8.84 (s, 1H), 8.38-8.39 (m, 2H), 7.81-7.86 (m, 2H),
6
3
1
1
13
7
1
.50-7.55 (m, 2H), 5.37 (d, J = 15.4 Hz, 1H), 5.14 (d, J = 15.4 Hz,
H), 4.69 (s, 2H), 4.62 (d, J= 2.2 Hz, 1H), 3.83-4.01 (m, 3H), 3.67-3.82
13
35
þ
(
1
m, 5H), 3.50-3.58 (m, 1H), 3.20 (s, 3H); C NMR (100 Mz, DMSO-d
6
) δ
(
ESþ) calcd for C15
H
17
N O
3 3
Cl (M þ H) , 322.0958; found, 322.0972;
3
7
þ
64.0, 161.1, 150.0, 149.9, 149.6, 149.3, 139.7, 139.3, 132.4, 132.0, 124.7,
calcd for C15
H
17
N
3
O
3
Cl (M þ H) , 324.0929; found, 324.0938.
124.6, 104.0, 102.3, 90.8, 55.4, 55.1, 54.4, 52.9, 50.8, 48.1, 45.5, 42.7.
General Synthetic Procedure for 9a-d. A mixture of compound 1
or 7a-c (10 mmol), 25% glutaraldehyde aqueous solution (4 mL), and
acetonitrile (50 mL) was stirred at room temperature. After it had been
stirred for about 30 min, concentrated hydrochloric acid (0.20 mL) was
added to the reaction mixture. The progress of the reaction was monitored
by TLC. After completion, the pH value of the filtrate was adjusted to 7-8
by triethylamine, and the solvent was removed under reduced pressure.
The residue was purified by flash chromatography eluting with dichlor-
omethane/acetone (v/v 3:1) to afford the desired products 9a-d.
3
5
Cl
þ
HRMS (ESþ) calcd for C23
H
C
24
N
8
O
5
2
Na (M þ Na) , 585.1144;
35
5
37
þ
þ
found, 585.1113; calcd for
23
H
24
N
8
O
Cl ClNa (M
þ
Na) ,
3
7
5
5
87.1115; found, 587.1104; calcd for C23
89.1085; found, 589.1110.
-Chloro-5-((2-(5-(1-((6-chloropyridin-3-yl)methyl)-4,5-dihydro-
H
24
N
8
O
5
Cl
2
Na (M þ Na) ,
2
1
H-imidazol-2-yl)-1,5-dinitropenta-1,4-dienyl)-4,5-dihydroimidazol-
-yl)methyl)pyridine (6). Malonaldehyde was prepared according to the
1
previously reported procedure (29). 1,1,3,3-Tetramethoxypropane (2.2 g,
1
13 mmol) was stirred with 5.0 mL of 2.0 M HCl for 1.5 h. Then compound
Data for 9a: yield, 76%; mp, 174.7-175.4 ꢀC; H NMR (400 Mz,
1
(2.54 g, 10 mmol) was added followed by 30 mL of acetonitrile, and the
DMSO-d
6
) δ 8.38 (dd, J
1
= 0.6 Hz, J
= 0.6 Hz, J
2
2
= 2.4 Hz, 1H), 7.84 (dd, J
1
= 2.4 Hz,
= 8.4 Hz, 1H), 5.12 (s, 1H),
reaction mixture was stirred at room temperature. The progress of the
reaction was monitored by TLC. After completion, the pH value of the
filtrate was adjusted to 7-8 by triethylamine, and the solvent was removed
under reduced pressure. The residue was purified by flash chromatography
eluting with dichloromethane/acetone (v/v 2:1) to afford the desired
J
2
= 8.4 Hz, 1H), 7.52 (dd, J
1
5.04-5.05 (m, 1H), 4.97 (d, J= 15.6 Hz, 1H), 4.71 (d, J= 15.6 Hz, 1H),
3.62-3.74 (m, 4H), 1.66-1.81 (m, 4H), 1.51-1.55 (m, 1H), 1.32-1.44 (m,
6
) δ 156.6, 149.7, 149.6, 139.7, 132.9,
124.5, 105.8, 81.7, 68.9, 51.7, 50.0, 46.3, 28.8, 27.2, 14.8. HRMS (EIþ)
13
1H); C NMR (100 Mz, DMSO-d

2698 J. Agric. Food Chem., Vol. 58, No. 5, 2010
Shao et al.
3
5
þ
-1
calcd for C15
H
17
N
4
O
3
Cl (M ), 336.0989; found, 336.0988; calcd for
solutions of the chemicals containing Triton X-100 (0.1 mg L ) for 5 s,
3
7
þ
C H N O
15 17 4 3
Cl (M ), 338.0960; found, 338.0968.
and the excess dilution was sucked out with filter paper; burgeons were
placed in a conditioned room (25 ( 1 ꢀC, 50% RH). Water containing
Triton X-100 (0.1 mg L ) was used as control. The mortality rates
were evaluated 24 h after treatment. Each treatment had three repeti-
tions, and the data were adjusted and subjected to probit analysis as
before.
1
Data for 9b: yield, 62%; mp, 159.1-160.5 ꢀC; H NMR (400 Mz,
DMSO-d ) δ 7.48 (s, 1H), 5.30 (d, J= 3.2 Hz, 1H), 5.24 (d, J= 15.4 Hz,
H), 4.98 (s, 1H), 4.78 (d, J= 15.4 Hz, 1H), 3.76-3.87 (m, 1H), 3.60-3.71
m, 3H), 2.12 (d, J= 14.0 Hz, 1H), 1.82-1.96 (m, 2H), 1.64-1.77 (m, 2H),
-1
6
1
(
1
1
13
6
.48-1.60 (m, 1H); C NMR (100 Mz, DMSO-d ) δ 155.7, 154.1, 140.5,
35.6, 107.0, 82.7, 69.4, 49.4, 48.3, 46.2, 29.4, 26.5, 14.9. HRMS (EIþ)
Insecticidal Test for Armyworm (Pseudaletia separata Walker).
The activities of insecticidal compounds against armyworm were tested
using previously reported procedures (33, 34). The insecticidal activity
against armyworm was tested by foliar application. Individual corn (Zea
mays) leaves were placed on moistened pieces of filter paper in Petri dishes.
The leaves were then sprayed with the compound solution and exposed to
dry. The dishes were infested with 10 second-instar larvae and placed in the
conditioned room. The mortality rates were evaluated 48 h after treatment.
Each treatment had three repetitions, and the data were adjusted and
subjected to probit analysis as before.
3
5
þ
calcd for C13
H
15
N
4
O
3
S Cl (M ), 342.0553; found, 342.0548; calcd for
3
7
þ
13 15 4 3
C H N O S Cl (M ), 344.0524; found, 344.0564.
1
Data for 9c: yield, 77%; mp, 180.5-181.2 ꢀC; H NMR (400 Mz,
DMSO-d ) δ 7.29-7.37 (m, 5H), 5.33 (d, J= 3.1 Hz, 1H), 5.02 (d, J= 15.0
Hz, 1H), 4.95 (s, 1H), 4.85 (d, J= 15.0 Hz, 1H), 3.68-3.75 (m, 1H),
6
3
1
1
.48-3.64 (m, 3H), 2.14 (d, J = 13.1 Hz, 1H), 1.81-1.93 (m, 2H),
13
6
.51-1.70 (m, 3H); C NMR (100 Mz, DMSO-d ) δ 156.6, 136.4,
28.8, 128.3, 128.0, 106.7, 83.0, 69.7, 54.8, 48.6, 46.7, 29.5, 26.5, 15.0.
þ
HRMS (EIþ) calcd for C16
H
19
N
O
3 3
(M ), 301.1426; found, 301.1429.
1
Data for 9d: yield, 70%; mp, 156.9-158.3 ꢀC; H NMR (400 Mz,
DMSO-d ) δ 7.29-7.34 (m, 4H), 5.33 (d, J= 4.0 Hz, 1H), 5.05 (d, J= 15.1
Insecticidal Test for Brown Planthopper (Nilaparvata lugens).
The bioassay against brown planthopper followed the microtopical
application technique reported by Nagata (35). Macropterous adult
females (2-3 days old, unmated) were used as test animals. Insecticidal
compounds were diluted to a series of concentrations with acetone. Under
carbon dioxide anesthesia, a droplet (0.08 μL) of insecticide solution was
applied topically to the prothorax notum of test hoppers with a hand
microapplicator (Burkard Manufacturing Co. Ltd., Rickmansworth,
U.K.). About 30 insects were treated at each concentration, and every
treatment was repeated three times. The controls used acetone instead of
insecticide solution. The treated insects were reared on seedlings cultured
soilless in the rearing box (20 ꢀ 20 ꢀ 10 cm) at 25 ( 1 ꢀC and 16/8 h light/
dark. The results were checked after 48 h. LD50 values were determined on
the basis of standard probit analysis.
6
Hz, 1H), 4.96 (s, 1H), 4.75 (d, J= 15.1 Hz, 1H), 3.66-3.73 (m, 1H),
3
1
1
.55-3.60 (m, 3H), 2.14 (d, J = 13.6 Hz, 1H), 1.82-1.95 (m, 2H),
13
.51-1.71 (m, 3H); C NMR (100 Mz, DMSO-d
6
) δ 156.5, 134.9,
33.8, 129.7, 129.0, 106.8, 83.0, 69.6, 54.4, 48.9, 46.6, 29.6, 26.5, 15.0.
3
5
þ
HRMS (EIþ) calcd for
C
16
H
18
N
O
3 3
Cl (M ), 335.1037; found,
3
7
þ
3
35.1044; calcd for C16
H
18
N
3
O
3
Cl (M ), 337.1007; found, 337.1036.
X-ray Diffraction. Compound 8a was recrystallized by slow evapora-
tion from dichloromethane to afford a suitable single crystal. Colorless
blocks of 8a (0.421 mm ꢀ 0.369 mm ꢀ 0.327) were mounted on a quartz
fiber. Cell dimensions and intensities were measured at 293 K on a Bruker
SMART CCD area detector diffractometer with graphite monochro-
mated Mo KR radiation (λ= 0.71073 A); θmax= 25.50; 7954 measured
reflections; 2958 independent reflections (Rint = 0.0985). Data were
˚
corrected for Lorentz and polarization effects and for absorption
(Tmin= 0.7954 and Tmax= 1.0000). The structure was solved by direct
RESULTS AND DISCUSSION
Synthesis. Compounds 1 and 7a-c were prepared according to
the literature (36). 1 and 7a-c were cyclic β-nitroenamines, which
consist of push-pull ethylene systems with a donor (amine) at
one end and an acceptor (nitro) at the other end of the ethylene.
These nitroenamines manifest themselves as common enamines
in electrophilic reactions and could react with a variety of
electrophiles, with electrophilic attack proceeding at either or
both of two nucleophilic centers (C1 and N1 in Scheme 1)
methods with SHELXS-97 (31). All other calculations were performed
with Bruker SAINT System and Bruker SMART programs (32). Full-
2
2
2
o
matrix least-squares refinement based on F using the weight of 1/[σ (F )
2
þ (0.0903P) þ 0.0000P] gave final values of R= 0.0744, ωR= 0.1670, and
GOF (F) = 0.977 for 213 variables and 2958 contributing reflections.
Maximum shift/error= 0.000(3) and max/min residual electron density=
-
3
˚
0
.510/-0.522 e A . Hydrogen atoms were observed and refined with a
fixed value of their isotropic displacement parameter.
Compound 9a was recrystallized by slow evaporation from dichloro-
methane to afford a suitable single crystal. Colorless blocks of 9a (0.468
mm ꢀ 0.391 mm ꢀ 0.229) were mounted on a quartz fiber. Cell dimensions
and intensities were measured at 293 K on a Bruker SMART CCD area
detector diffractometer with graphite monochromated Mo KR radiation
(36-40). Shiokawa et al. made tremendous efforts on the
chemical derivatizations of cyclic nitroenamine units by attack
of the electrophile (such as sulfurizocyanatidic chloride, thiocya-
nogen, phenyl isocyanate, benzoyl isothiocyanate, and acrylate),
and some neonicotinoid derivatives with desirable activities
were found (40). Dialdehydes bearing two electrophilic centers
are good electrophiles, which could readily react with cyclic
β-nitroenamine. The synthetic proceduresfor the title compounds
are depicted in Schemes 2-5.
˚
(
λ= 0.71073 A); θmax= 27.00; 8730 measured reflections; 3254 indepen-
dent reflections (Rint = 0.0649). Data were corrected for Lorentz and
polarization effects and for absorption (Tmin = 0.84981 and Tmax
.0000). The structure was solved by direct methods with SHELXS-97.
=
1
All other calculations were performed with Bruker SAINT System and
Bruker SMART programs. Full-matrix least-squares refinement based on
Initially, the reaction of compound 1 with oxalaldehyde in
acetonitrile catalyzed by concentrated hydrochloric acid at room
temperature was investigated; the reaction proceeded smoothly,
and a white powder was precipitated from the reaction mixture
2
2
2
2
F using the weight of 1/[σ (F
o
) þ (0.0585P) þ 0.1852P] gave final values
of R= 0.0482, ωR= 0.1193, and GOF (F)= 1.032 for 208 variables and
3
254 contributing reflections. Maximum shift/error= 0.000(3) and max/
-3
˚
min residual electron density= 0.280/-0.215 e A . Hydrogen atoms were
observed and refined with a fixed value of their isotropic displacement
parameter.
(
Scheme 2). Analysis of the isolated precipitate by NMR showed
the formation of 1:2 condensation compound 4. HRMS lent
1
Biological Assay. All bioassays were performed on representative test
organisms reared in the laboratory. The bioassay was repeatedat 25( 1 ꢀC
according to statistical requirements. All compounds were dissolved in N,
N-dimethylformamide (AP, Shanghai Chemical Reagent Co., Ltd.,
Shanghai, China) and diluted with distilled water containing Triton
further support for formation of divalent compound 4. H NMR
spectra of compound 4 showed the signal of NH at 9.01 ppm,
which agreed with the one in compound 1 (8.90 ppm). Complete
disappearance of the OH signal at 3.98 ppm on deuteration
showed the existence of a hydroxyl group in 4. To further confirm
the structure of 4, the etherization of 4 by methanol was carried
out in refluxing dichloromethane catalyzed by concentrated HCl,
and compound 5 was formed as expected. When malonaldehyde
was subjected to reaction with 1 according to the aforementioned
reaction conditions, a novel type of divalent neonicotinoid 6 was
generated. Different from compound 4, no hydroxyl group was
-1
X-100 (0.1 mg L ) to obtain series concentrations of 500.0, 250.0, and
-1
1
25.0 mg L and others for bioassays. For comparative purposes,
imidacloprid was tested under the same conditions.
Insecticidal Test for Cowpea Aphid (Aphis craccivora). The
activities of insecticidal compounds against cowpea aphid were tested by
leaf-dip method according to our previously reported procedure (25, 26).
Horsebean plant leaves with 40-60 apterous adults were dipped in diluted

Article
J. Agric. Food Chem., Vol. 58, No. 5, 2010 2699
Scheme 1. Reactions of 6-Cl-PMNI (1) with R,β-Unsaturated Aldehydes and Five-Membered Aromatic Aldehydes
Scheme 2. Reactions of 6-Cl-PMNI (1) with Oxalaldehyde
Scheme 3. Reactions of 6-Cl-PMNI (1) with Malonaldehyde
Scheme 5. Reactions of 6-Cl-PMNI (1) with Glutaraldehyde
could also proceed to afford 6 (Scheme 3), which provided one-
pot operation for the procurement of compound 6. Previously,
Kagabu also reported some divalent neonicotinoids, in which two
imidacloprid molecules were coupled between two nitrogen
atoms on the imidazoline (9), whereas linking two carbon atoms
as described here could be another way to construct novel
divalent neonicotinoids.
Scheme 4. Reactions of 6-Cl-PMNI (1) with Succinaldehyde
Subsequently, we embarked on reaction of 1 with succinalde-
hyde. Commercially available 2,5-diethoxytetrahydrofuran was
stirred in 0.1 M HCl at 90 ꢀC, affording succinaldehyde, and this
mixture was used immediately without further purification. Upon
treatment of 1 with succinaldehyde in the presence of hydro-
chloric acid in acetonitrile at room temprature, a white powder
was obtained after column chromatography. The product was
found to be a peculiar oxabridged compound 8a rather than a
divalent compound on the basis of its spectral and analytical data.
Reaction of glutaraldehyde with 1 was accomplished under iden-
tical conditions, affording the oxabridged compound 9a in 76%
yield. Oxabridged compounds 8b-d and 9b-d, analogues of 8a
and 9a, respectively, were easily obtained under similar condi-
tions.
retained in compound 6. The latter observation revealed that
reaction of 1 with 1,1,3,3-tetramethoxypropane in acetonitrile
catalyzed by concentrated hydrochloric acid at room temperature
Crystal Structure Analysis. The oxabridged structure of com-
pounds 8a and 9a was unambiguously confirmed by X-ray
crystallographic diffraction analysis (Figures 1 and 2), which

2700 J. Agric. Food Chem., Vol. 58, No. 5, 2010
Shao et al.
Table 1. Insecticidal Activities of Compounds 4, 5, 6, 8a-d, and 9a-d and
Imidacloprid against Cowpea Aphid (Aphis craccivora) and Armyworm
(
Pseudaletia separata Walker)
Aphis
craccivora
Pseudaletia
separata Walker
mortality
(%, 500 mg L-
LC50
(mmol L
mortality
(%, 500 mg L
LC50
(mmol L )
1
)
-1
-1
-1
compd
)
)
a
4
5
6
8
8
8
8
9
9
9
9
78.1
97.7
100
nt
100
100
100
100
100
0
0.19471
nt
nt
0.00951
0.00471
0.00883
0.02798
0.03873
0.04956
a
b
c
d
a
b
c
d
100
100
13.6
95.7
87.3
98.2
55.6
38.9
100
nt
nt
nt
nt
nt
nt
nt
0
nt
nt
nt
nt
nt
0
0
0
0
imidacloprid
6-Cl-PMNI
0.03502
0.00512
100
100
0.12549
0.07087
Figure 1. ORTEP drawing of 8a with the atom-labeling scheme. Ellipsoids
are drawn at the 30% probability level.
100
a
Not tested.
Table 2. Insecticidal Activities of Compounds 8a and 9a and Imidacloprid
against Imidacloprid-Resistant Brown Planthoppper (Nilaparvata lugens)
LC50
(ng/pest)
toxic
a
strain
compd
y = a þ bx
ratio
sensitive 8a
9
y = 7.3127 þ 2.0474x
y = 3.9543 þ 1.6936x
0.0742 ( 0.0106
4.1440 ( 0.6136
0.1316 ( 0.0154
1.77
0.32
1.00
a
imidacloprid y = 7.1823 þ 2.4778x
resistant 8a
y = 5.4068 þ 1.3225x
y = 3.1320 þ 1.4613x 18.9795 ( 2.3501
imidacloprid y = 2.5873 þ 1.7930x 22.1614 ( 3.7522
0.4925 ( 0.0811 50.00
9
a
1.17
1.00
a
Toxic ratio is defined as the ratio of the imidacloprid’s LC50 value for baseline
toxicity and the compounds’ LC50 value.
activity than imidacloprid against cowpea aphid, but also had
excellent activity against armyworm, which indicated that linkage
of the two molecules in this way could maintain the insecticidal
activities.
Oxabridged compound 8a constructed by succinaldehyde
demonstrated remarkable activities, which were higher than that
of imidacloprid, against cowpea aphid (LC = 0.00471 mmol
5
0
-1
-1
L
) and armyworm (LC = 0.03873 mmol L ). Intriguingly,
50
the insecticidal activity of compound 8a against imidacloprid-
resistant brown planthopper was 50-fold higher than that of
Figure 2. ORTEP drawing of 9a with the atom-labeling scheme. Ellipsoids
are drawn at the 30% probability level.
imidacloprid based on the value of LC , and 9a also exhibited
50
higher activity than imidacloprid (Table 2). The higher insecti-
cidal activity of 8a than imidacloprid might be attributed to the
improved hydrophobicity. Replacement of 2-chloro-5-pyridine in
8a with 2-chloro-5-thiazole to generate analogue 8b maintained
high insecticidal activity, which was consistent with the fact that
the 2-chloro-5-thiazole unit has been proved to be an effective
bioisosteric replacement for the 2-chloro-5-pyridine. Benzyl ana-
logue 8c and 4-chlorobenzyl counterpart 8d showed low insecti-
cidal activities as anticipated. Unexpectedly, compound 9a con-
structed by glutaraldehyde had moderate activity against cowpea
aphid but was inactive against armyworm. Analogues 9c and 9d
also exhibited weak activities against cowpea aphid but no
activity against armyworm. The volume or conformation of
substitutent at the N3-atom on the imidazoline had an influence
on activities (1, 7, 10, 41), and the difference of ring size and
conformation between 8a and 9a could possibly account in part
for the higher potency of 8a than of 9a.
successfully provided the most convincing evidence for their
proposed molecular structures. Although most key bond angles
and distances are comparable for compounds 8a and 9a, rather
surprisingly, the torsion angles of the chains containing oxygen
are considerably different. When the torsion angle of 8a was
positive, the corresponding one of 9a was negative and vice versa.
For 8a, the nitrogen atom in the pyridine ring and the oxygen
atom pointed in opposite directions, whereas these two atoms in
9a were oriented in the same direction.
Insecticidal Activities. Table 1 shows the insecticidal activities
of the title compounds against cowpea aphid and armyworm.
Divalent compound 4 showed moderate insecticidal activity
-1
against cowpea aphid at 500 mg L and high activity against
-
1
armyworm with an LC50 value of 0.19271 mmol L . The
etherified product 5 also had high insecticidal activity against
cowpea aphid. Divalent compound 6 not only exhibited higher

Article
In conclusion, a series of divalent and oxabridged neonicoti-
noids were designed and synthesized by incorporating dialde-
hydes to nitromethylene analogues of imidacloprid. The bio-
assays showed that some of the compounds exhibited excellent
insecticidal activities against cowpea aphid and armyworm.
Further bioassay demonstrated that compound 8a displayed a
J. Agric. Food Chem., Vol. 58, No. 5, 2010 2701
Kuroda, S.; Mega, R.; Kuramitsu, S.; Sattelle, D. B.; Matsuda, K.
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006AA10A201), the National Science Foundation China Program
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(
(
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(