Design, synthesis, crystal structures, and insecticidal activities of eight-membered azabridge neonicotinoid analogues

Article abstract of DOI:10.1021/jf4046683

Three series of novel azabridge neonicotinoid analogues were designed and synthesized, which were constructed by starting material A, glutaraldehyde, and primary amine hydrochlorides (aliphatic amines, phenylhydrazines, and anilines). Most of the eight-membered azabridge compounds presented higher insecticidal activities than oxabridged compound B against cowpea aphid (Aphis craccivora) and brown planthopper (Nilaparvata lugens). Compared with imidacloprid, some azabridged compounds exhibited excellent insecticidal activity against brown planthopper. The crystal structures and bioassay indicated that changing bridge atoms from O to N could lead to entirely different conformations, which might be the important influential factor of the bioactivities.

Full text of DOI:10.1021/jf4046683

Article
pubs.acs.org/JAFC
Design, Synthesis, Crystal Structures, and Insecticidal Activities of
Eight-Membered Azabridge Neonicotinoid Analogues
Renbo Xu, Rui Xia, Ming Luo, Xiaoyong Xu,* Jiagao Cheng, Xusheng Shao, and Zhong Li*
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai
200237, China
S
* Supporting Information
ABSTRACT: Three series of novel azabridge neonicotinoid analogues were designed and synthesized, which were constructed
by starting material A, glutaraldehyde, and primary amine hydrochlorides (aliphatic amines, phenylhydrazines, and anilines).
Most of the eight-membered azabridge compounds presented higher insecticidal activities than oxabridged compound B against
cowpea aphid (Aphis craccivora) and brown planthopper (Nilaparvata lugens). Compared with imidacloprid, some azabridged
compounds exhibited excellent insecticidal activity against brown planthopper. The crystal structures and bioassay indicated that
changing bridge atoms from O to N could lead to entirely different conformations, which might be the important influential
factor of the bioactivities.
KEYWORDS: oxabridge, azabridge, neonicotinoids, insecticide
cycloxaprid (Figure 2), were synthesized. Interestingly,
according to the crystallographic diffraction analysis and
INTRODUCTION
■
Based on the natural alkaloid nicotine, imidacloprid, discovered
by Kagabu et al.,1 was the forerunner of neonicotinoid
insecticides. Moreover, following the organophosphates,
carbamates, and pyrethroids, neonicotinoids were regarded as
fourth-generation insecticides in modern crop protection.2
Experimental research indicated that the neonicotinoids act
selectively as agonist of the insect nicotinic acetylcholine
receptors (nAChRs), one of the most important insect targets
in mediating rapid excitatory neurotransmission in the central
nervous system (CNS) of piercing−sucking insects.3−7
The neonicotinoid compounds have the characteristics of
high efficiency, low mammalian toxicity, no cross-resistance,
and unique mode of action (MoA), which had showed great
development in agriculture and animal health markets in the
past 20 years.8 Recently, Dow AgroSciences launched a
neonicotinoid insecticide, Sulfoxaflor9 (Figure 1), which is a
new member of the neonicotinoids.10
Figure 2. Comparison of biological activities between compound B
and cycloxaprid.
In our previous work,11 by introducing succinaldehyde and
glutaraldehyde, two unexpected oxabridged compounds, B and
biological tests, the two oxabridged compounds exhibited
large differences in overall conformation and insecticidal
activities (Figure 2), which implied that the molecular structure
could significantly influence the bioactivities. Therefore, an
effort to modify the structure was carried out, in which the
oxabridge was converted to an azabridge, by replacing O with
N, to increase the insecticidal activities of bridged compounds.
Owing to the difficulties of obtaining succinaldehyde, in this
paper, the synthesis and insecticidal activities of three series of
eight-membered azabridged neonicotinoids are first reported;
these compounds were constructed by starting material A,
Received: October 16, 2013
Revised: December 12, 2013
Accepted: December 23, 2013
Figure 1. Nicotine and neonicotinoids.
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jf4046683 | J. Agric. Food Chem. XXXX, XXX, XXX−XXX

Journal of Agricultural and Food Chemistry
Article
reaction mixture was stirred at 0 °C to room temperature and
monitored by TLC. After completion, the pH value of the reaction
mixture was adjusted to 7−8 by saturated aqueous NaHCO3, and the
solvent was removed under reduced pressure. The resulting mixture
was extracted with dichloromethane (3 × 50 mL), and the organic
layer was washed with brine, dried over anhydrous sodium sulfate,
filtered, and concentrated. The residue was purified by silica gel
column chromatography to afford the corresponding product.
glutaraldehyde, and three kinds of primary amine hydro-
chlorides (Scheme 1).
Scheme 1. Reaction Route To Synthesize Three Series of
Compounds
Series 1: Compounds 1a−1d. 1-((6-Chloropyridin-3-yl)methyl)-
11-methyl-10-nitro-1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo-
[1,2-a]azocine (1a): yield, 51.5%; mp, 165.6−166.2 °C; 1H NMR
(400 MHz, DMSO-d6) δ 8.37 (d, J = 1.6 Hz, 1H), 7.84 (dd, J = 8.0, 2.0
Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 4.88 (d, J = 15.2 Hz, 1H), 4.74 (d, J
= 15.2 Hz, 1H), 4.20 (s, 1H), 3.96 (s, 1H), 3.77−3.49 (m, 4H), 2.11
(s, 3H), 1.84−1.68 (m, 2H), 1.66−1.51 (m, 2H), 1.48−1.35 (m, 1H),
1.17−0.98 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 156.66,
149.78, 149.74, 139.91, 133.33, 124.48, 104.10, 72.83, 56.33, 51.63,
49.76, 49.06, 47.15, 29.41, 28.20, 15.45; HRMS (ES+) calcd for
C16H2035ClN5O2Na (M + Na)+ 372.1203; found, 372.1185; calcd for
C16H2037ClN5O2Na (M + Na)+ 374.1174; found, 374.1168.
1-((6-Chloropyridin-3-yl)methyl)-11-ethyl-10-nitro-1,2,3,5,6,7,8,9-
octahydro-5,9-epiminoimidazo[1,2-a]azocine (1b): yield, 20%; mp,
1
130.4−131.1 °C; H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 2.4
Hz, 1H), 7.83 (dd, J = 8.4, 2.4 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 4.86
(d, J = 15.6 Hz, 1H), 4.75 (d, J = 15.6 Hz, 1H), 4.32 (s, 1H), 4.10 (s,
1H), 3.76−3.50 (m, 4H), 2.37−2.20 (m, 1H), 2.19−2.06 (m, 1H),
1.84−1.72 (m, 2H), 1.66−1.50 (m, 2H), 1.50−1.40 (m, 1H), 1.20−
1.04 (m, 1H), 0.95 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, DMSO-
d6) δ 157.34, 149.78, 149.73, 139.90, 133.01, 124.45, 104.84, 71.35,
53.86, 51.58, 49.82, 49.06, 47.17, 29.48, 28.41, 16.13, 13.18; HRMS
(ES+) calcd for C17H2335ClN5O2 (M + H)+ 364.1540; found,
364.1535; calcd for C17H2337ClN5O2 (M + H)+ 366.1511; found,
366.1517.
MATERIALS AND METHODS
Instruments and Chemicals. All melting points were obtained
■
with a Buchi Melting Point B540 and are uncorrected. Nuclear
̈
magnetic resonance spectra were recorded on a Bruker AM-400
spectrometer with CDCl3 or DMSO-d6 as the solvent (1H at 400 MHz
and 13C at 100 MHz) and TMS as the internal standard. Chemical
shifts are reported in parts per million (δ). Coupling constants (J) are
reported in hertz (Hz). High-resolution electron mass spectra (ESI-
TOF) were performed on a Micromass LC-TOF spectrometer.
Analytical thin-layer chromatography (TLC) was carried out on
precoated plates (silica gel 60 F254), and spots were visualized with
ultraviolet (UV) light. All other solvents and reagents were obtained
from commercial sources without further purification.
1-((6-Chloropyridin-3-yl)methyl)-11-isopropyl-10-nitro-
1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocine (1c):
1
yield, 3%; mp, 149.8−150.5 °C; H NMR (400 MHz, DMSO-d6) δ
8.36 (d, J = 1.6 Hz, 1H), 7.82 (dd, J = 8.4, 2.4 Hz, 1H), 7.51 (d, J = 8.0
Hz, 1H), 4.84 (d, J = 15.2 Hz, 1H), 4.78 (d, J = 15.2 Hz, 1H), 4.53 (s,
1H), 4.35 (s, 1H), 3.80−3.53 (m, 4H), 2.37−2.27 (m, 1H), 1.86−1.68
(m, 2H), 1.62−1.40 (m, 3H), 1.20−1.05 (m, 1H), 0.98 (d, J = 6.0 Hz,
3H), 0.89 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) δ
157.87, 149.76, 149.74, 139.87, 133.02, 124.45, 105.39, 68.44, 51.72,
51.47, 49.98, 49.41, 46.79, 29.61, 29.01, 21.57, 21.42, 16.27; HRMS
(ES+) calcd for C18H2535ClN5O2 (M + H)+ 378.1697; found,
378.1699; calcd for C18H2537ClN5O2 (M + H)+ 380.1667; found,
380.1674.
General Procedure for the Preparation of Aliphatic Amine
Hydrochlorides. The corresponding aliphatic amine (20 mmol) was
dissolved in diethyl ether (20 mL). With cooling and vigorous stirring,
HCl gas was introduced into the mixture to yield an off-white
precipitate. This was collected by filtration, washed with plenty of
Et2O, and used immediately.
General Procedure for the Preparation of Substituted
Aniline Hydrochlorides. The corresponding aniline (20 mmol) in
ethyl acetate (20 mL) was cooled to 0 °C. A solution of concentrated
HCl was dropwise added and adjusted the pH value of the reaction
mixture to 1−2. After the addition was completed, precipitate was
filtered and washed with less concentrated HCl and ethyl acetate. After
drying under vacuum, the obtained corresponding aniline hydro-
chloride could be used without further purification.
General Procedure for the Preparation of Substituted
Phenylhydrazine Hydrochlorides. A suspension of the correspond-
ing aniline (20 mmol) in concentrated HCl (40 mL) was cooled to
−10 °C. A solution of NaNO2 (20.2 mmol) in water (2 mL) was
dropwise added, keeping the reaction temperature below 0 °C. After
30 min of stirring, a solution of SnCl2·2H2O (40.4 mmol) in
concentrated HCl (15 mL) was slowly added. Amounts of precipitate
were immediately formed. After the addition was completed, the
mixture was stirred overnight and filtered. The precipitate was washed
with less concentrated HCl and dichloromethane. After drying under
vacuum, the obtained corresponding phenylhydrazine hydrochloride
could be used without further purification.
General Procedure for the Preparation of Three Series. A
mixture of starting material A (2 mmol), corresponding primary amine
hydrochloride (2.5 mmol), and 50% mol NaH2PO4 (1 mmol) in
acetonitrile (20 mL) was stirred at 0 °C. After 5 min of stirring, 25%
glutaraldehyde aqueous solution (1 mL) was added slowly. Then the
1-((6-Chloropyridin-3-yl)methyl)-10-nitro-11-propyl-
1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocine (1d):
yield, 5%; mp, 152.3−153.2 °C; 1H NMR (400 MHz, CDCl3) δ
8.37 (d, J = 1.6 Hz, 1H), 7.86 (dd, J = 8.4, 2.4 Hz, 1H), 7.35 (d, J = 8.4
Hz, 1H), 5.00 (d, J = 15.2 Hz, 1H), 4.81 (d, J = 15.2 Hz, 1H), 4.39 (s,
1H), 4.17 (s, 1H), 3.80−3.45 (m, 4H), 2.38−2.01 (m, 3H), 1.85−1.75
(m, 2H), 1.69−1.61 (m, 2H), 1.55−1.41 (m, 2H), 1.38−1.17 (m, 1H),
0.90 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 157.20,
151.29, 149.12, 139.56, 131.24, 124.58, 105.82, 72.97, 55.32, 54.38,
52.18, 49.23, 46.93, 29.73, 28.05, 20.90, 16.03, 11.71; HRMS (ES+)
calcd for C18H2435ClN5O2Na (M + Na)+ 400.1520; found, 400.1511;
calcd for C18H2437ClN5O2Na (M + Na)+ 402.1487; found, 402.1493.
Series 2: Compounds 2a−2n. 1-((6-Chloropyridin-3-yl)methyl)-
10-nitro-11-phenyl-1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo-
[1,2-a]azocine (2a): yield, 16.5%; mp, 186.8−187.6 °C; 1H NMR
(400 MHz, DMSO-d6) δ 8.26 (d, J = 1.6 Hz, 1H), 7.59 (dd, J = 8.4, 2.4
Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.27−7.18 (m, 2H), 6.96−6.85 (m,
3H), 5.37 (s, 1H), 5.01 (s, 1H), 4.77 (d, J = 15.6 Hz, 1H), 4.72 (d, J =
15.6 Hz, 1H), 3.78−3.48 (m, 4H), 2.06−1.95 (m, 1H), 1.95−1.84 (m,
1H), 1.84−1.71 (m, 2H), 1.65−1.51 (m, 1H), 1.33−1.22 (m, 1H); 13C
NMR (100 MHz, DMSO-d6) δ 157.59, 149.70, 149.67, 148.74, 139.50,
132.65, 129.68, 124.42, 121.27, 117.49, 105.51, 68.88, 52.77, 51.25,
49.71, 46.77, 28.94, 28.53, 15.95; HRMS (EI+) calcd for
B
dx.doi.org/10.1021/jf4046683 | J. Agric. Food Chem. XXXX, XXX, XXX−XXX

Journal of Agricultural and Food Chemistry
Article
C21H2235ClN5O2 (M)+ 411.1462; found, 411.1458; calcd for
C21H2237ClN5O2 (M)+ 413.1433; found, 413.1433.
1-((6-Chloropyridin-3-yl)methyl)-11-(2-fluorophenyl)-10-nitro-
1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocine (2g):
yield, 22.4%; mp, 148.7−149.3 °C; H NMR (400 MHz, CDCl3) δ
1
1-((6-Chloropyridin-3-yl)methyl)-10-nitro-11-(p-tolyl)-
8.29 (d, J = 2.0 Hz, 1H), 7.74 (dd, J = 8.0, 2.4 Hz, 1H), 7.29 (d, J = 8.0
Hz, 1H), 7.09−6.99 (m, 3H), 6.87−6.80 (m, 1H), 5.01−4.91 (m, 3H),
4.77 (d, J = 15.2 Hz, 1H), 3.74−3.56 (m, 2H), 3.55−3.39 (m, 2H),
2.32−2.22 (m, 1H), 2.15−2.04 (m, 1H), 2.00−1.86 (m, 2H), 1.80−
1.67 (m, 1H), 1.58−1.43 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
157.31, 155.14 (d, J = 243.4 Hz, 1C), 151.30, 149.09, 139.18, 130.95,
124.87 (d, J = 3.6 Hz, 1C), 124.58, 123.61 (d, J = 7.9 Hz, 1C), 119.70,
116.46 (d, J = 20.6 Hz, 1C), 106.27, 71.54 (d, J = 7.9 Hz, 1C), 53.16,
52.07, 49.21, 46.68, 29.62, 27.82, 16.20; HRMS (ES+) calcd for
C21H2135ClFN5O2Na (M + Na)+ 452.1266; found, 452.1250; calcd for
C21H2137ClFN5O2Na (M + Na)+ 454.1236; found, 454.1235.
1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocine (2b):
1
yield, 34.2%; mp, 200.8−201.7 °C; H NMR (400 MHz, DMSO-d6)
δ 8.25 (d, J = 2.0 Hz, 1H), 7.59 (dd, J = 8.4, 2.4 Hz, 1H), 7.37 (d, J =
8.0 Hz, 1H), 7.02 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H), 5.31 (s,
1H), 4.94 (s, 1H), 4.79 (d, J = 15.2 Hz, 1H), 4.70 (d, J = 15.2 Hz, 1H),
3.75−3.50 (m, 5H), 2.23 (s, 3H), 2.04−1.94 (m, 1H), 1.94−1.85 (m,
1H), 1.85−1.70 (m, 2H), 1.65−1.53 (m, 1H), 1.33−1.17 (m, 1H); 13C
NMR (100 MHz, DMSO-d6) δ 157.50, 149.69, 149.67, 146.41, 139.54,
132.65, 130.11, 130.07, 124.41, 117.51, 105.61, 69.18, 52.90, 51.15,
49.73, 46.86, 29.03, 28.41, 20.56, 16.00; HRMS (ES+) calcd for
C22H2435ClN5O2Na (M + Na)+ 448.1516; found, 448.1510; calcd for
C22H2437ClN5O2Na (M + Na)+ 450.1487; found, 450.1487.
11-(2-Chlorophenyl)-1-((6-chloropyridin-3-yl)methyl)-10-nitro-
1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocine (2h):
1-((6-Chloropyridin-3-yl)methyl)-10-nitro-11-(o-tolyl)-
1
yield, 22.9%; mp, 199.8−200.6 °C; H NMR (400 MHz, DMSO-d6)
1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocine (2c):
1
δ 8.35 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 8.4, 2.4 Hz, 1H), 7.50 (d, J =
8.4 Hz, 1H), 7.45 (dd, J = 8.0, 1.6 Hz, 1H), 7.27−7.20 (m, 1H), 7.13−
7.06 (m, 1H), 6.91−6.84 (m, 1H), 4.89 (s, 1H), 4.85 (d, J = 15.6 Hz,
1H), 4.79 (d, J = 15.6 Hz, 1H), 4.75 (s, 1H), 3.86−3.74 (m, 2H),
3.74−3.64 (m, 2H), 2.04−1.86 (m, 2H), 1.87−1.74 (m, 2H), 1.67−
1.56 (m, 1H), 1.34−1.19 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ
157.40, 149.81, 149.78, 146.31, 139.87, 132.74, 131.02, 128.68, 128.14,
125.20, 124.53, 121.72, 105.00, 69.94, 54.82, 51.40, 50.00, 46.13,
28.81, 28.67, 15.75; HRMS (ES+) calcd for C21H2135Cl2N5O2Na (M +
Na)+ 468.0970; found, 468.0982; calcd for C21H2137Cl2N5O2Na (M +
Na)+ 472.0911; found, 472.0932.
yield, 41.7%; mp, 164.4−165.2 °C; H NMR (400 MHz, DMSO-d6)
δ 8.35 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 8.0, 2.0 Hz, 1H), 7.50 (d, J =
8.0 Hz, 1H), 7.17 (d, J = 6.8 Hz, 1H), 7.11−7.01 (m, 1H), 7.02−6.93
(m, 1H), 6.71 (d, J = 8.0 Hz, 1H), 4.86 (d, J = 15.2 Hz, 1H), 4.80 (d, J
= 15.2 Hz, 1H), 4.72 (s, 1H), 4.47 (s, 1H), 3.85−3.72 (m, 2H), 3.72−
3.58 (m, 2H), 2.28 (s, 3H), 2.00−1.91 (m, 1H), 1.91−1.77 (m, 3H),
1.69−1.53 (m, 1H), 1.36−1.19 (m, 2H); 13C NMR (100 MHz,
DMSO-d6) δ 157.60, 149.81, 148.63, 139.90, 132.80, 132.10, 131.66,
127.13, 124.53, 123.94, 119.73, 105.51, 70.36, 55.39, 51.36, 49.92,
46.20, 29.08, 28.86, 18.50, 16.03; HRMS (ES+) calcd for
C22H2435ClN5O2Na (M + Na)+ 448.1516; found, 448.1514; calcd for
C22H2437ClN5O2Na (M + Na)+ 450.1487; found, 450.1500.
11-(2-Bromophenyl)-1-((6-chloropyridin-3-yl)methyl)-10-nitro-
1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocine (2i):
1-((6-Chloropyridin-3-yl)methyl)-10-nitro-11-(m-tolyl)-
1
yield, 12.7%; mp, 193.0−193.7 °C; H NMR (400 MHz, DMSO-d6)
1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocine (2d):
δ 8.35 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 8.0, 2.4 Hz, 1H), 7.66−7.58
(m, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.34−7.23 (m, 1H), 7.08−6.98 (m,
1H), 6.95−6.85 (m, 1H), 4.86 (s, 1H), 4.84 (d, J = 15.6 Hz, 1H), 4.79
(d, J = 15.6 Hz, 1H), 4.74 (s, 1H), 3.85−3.74 (m, 2H), 3.75−3.64 (m,
2H), 2.05−1.89 (m, 2H), 1.89−1.75 (m, 2H), 1.69−1.55 (m, 1H),
1.35−1.18 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 157.43,
149.82, 149.79, 147.65, 139.88, 134.22, 132.76, 129.28, 125.81, 124.53,
122.20, 119.39, 104.90, 70.22, 55.21, 51.40, 50.00, 46.10, 28.81, 28.64,
15.70; HRMS (ES+) calcd for C21H2135Cl79BrN5O2Na (M + Na)+
512.0465; found, 512.0463; calcd for C21H2137Cl81BrN5O2Na (M +
Na)+ 516.0415; found, 516.0424.
1
yield, 39.0%; mp, 150.4−151.2 °C; H NMR (400 MHz, DMSO-d6)
δ 8.27 (d, J = 2.4 Hz, 1H), 7.59 (dd, J = 8.0, 2.4 Hz, 1H), 7.36 (d, J =
8.0 Hz, 1H), 7.11 (t, J = 8.0 Hz, 1H), 6.77 (s, 1H), 6.72 (d, J = 7.2 Hz,
1H), 6.69−6.63 (m, 1H), 5.35 (s, 1H), 5.00 (s, 1H), 4.78 (d, J = 15.6
Hz, 1H), 4.72 (d, J = 15.6 Hz, 1H), 3.75−3.65 (m, 2H), 3.62−3.57
(m, 2H), 2.24 (s, 3H), 1.94−1.86 (m, 1H), 1.84−1.71 (m, 2H), 1.63−
1.55 (m, 1H), 1.33−1.20 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ
157.65, 149.69, 149.67, 148.76, 139.50, 138.84, 132.66, 129.50, 124.39,
122.11, 118.36, 114.36, 105.59, 68.84, 52.84, 51.25, 49.67, 46.77,
28.95, 28.50, 21.87, 15.99; HRMS (ES+) calcd for C22H2435ClN5O2Na
(M + Na)+ 448.1516; found, 448.1504; calcd for C22H2437ClN5O2Na
(M + Na)+ 450.1487; found, 450.1494.
1-((6-Chloropyridin-3-yl)methyl)-10-nitro-11-(3-nitrophenyl)-
1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocine (2j):
11-(4-Bromophenyl)-1-((6-chloropyridin-3-yl)methyl)-10-nitro-
1
yield, 4.4%; mp, 215.3-216.3 °C; H NMR (400 MHz, DMSO-d6) δ
1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocine (2e):
8.21 (d, J = 2.0 Hz, 1H), 7.78−7.70 (m, 2H), 7.61 (dd, J = 8.0, 2.4 Hz,
1H), 7.52 (t, J = 8.0 Hz, 1H), 7.41−7.32 (m, 2H), 5.57 (s, 1H), 5.14
(s, 1H), 4.80 (d, J = 15.6 Hz, 1H), 4.71 (d, J = 15.6 Hz, 1H), 3.84−
3.55 (m, 4H), 2.09−1.98 (m, 1H), 1.99−1.88 (m, 1H), 1.88−1.75 (m,
2H), 1.68−1.56 (m, 1H), 1.37−1.21 (m, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 157.40, 149.76, 149.72, 149.55, 149.29, 139.55, 132.47,
131.04, 124.34, 123.76, 115.84, 111.73, 104.93, 68.40, 52.80, 51.24,
49.98, 46.71, 28.73, 28.35, 15.68; HRMS (ES+) calcd for
C21H2135ClN6O4Na (M + Na)+ 479.1211; found, 479.1206; calcd for
C21H2137ClN6O4Na (M + Na)+ 481.1181; found, 481.1188.
1
yield, 29.2%; mp, 192.0−192.9 °C; H NMR (400 MHz, CDCl3) δ
8.25 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 8.0, 2.0 Hz, 1H), 7.37 (d, J = 8.8
Hz, 2H), 7.23 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 8.8 Hz, 2H), 5.15 (s,
1H), 5.07 (s, 1H), 4.87 (d, J = 15.6 Hz, 1H), 4.74 (d, J = 15.6 Hz, 1H),
3.74−3.60 (m, 2H), 3.52−3.38 (m, 2H), 2.33−2.24 (m, 1H), 2.04 −
1.96 (m, 2H), 1.94−1.81 (m, 1H), 1.78−1.70 (m, 1H), 1.56−1.40 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 157.32, 151.32, 149.07, 147.34,
138.83, 132.42, 130.85, 124.57, 119.23, 114.15, 106.04, 71.09, 52.52,
51.96, 49.04, 46.94, 29.86, 27.54, 16.07; HRMS (ES+) calcd for
C21H2135Cl79BrN5O2Na (M + Na)+ 512.0465; found, 512.0456; calcd
for C21H2137Cl81BrN5O2Na (M + Na)+ 516.0415; found, 516.0428.
1-((6-Chloropyridin-3-yl)methyl)-10-nitro-11-(2-nitrophenyl)-
1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocine (2f):
1-((6-Chloropyridin-3-yl)methyl)-10-nitro-11-(4-nitrophenyl)-
1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocine (2k):
1
yield, 5.2%; mp, 209.9−210.7 °C; H NMR (400 MHz, DMSO-d6)
δ 8.22 (d, J = 2.4 Hz, 1H), 8.11 (d, J = 9.6 Hz, 2H), 7.63 (dd, J = 8.0,
2.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 9.2 Hz, 2H), 5.67 (s,
1H), 5.27 (s, 1H), 4.80 (d, J = 15.6 Hz, 1H), 4.71 (d, J = 15.6 Hz, 1H),
3.82−3.60 (m, 4H), 2.09−1.99 (m, 1H), 2.00−1.89 (m, 1H), 1.86−
1.72 (m, 2H), 1.67−1.57 (m, 1H), 1.40−1.21 (m, 1H); 13C NMR
(100 MHz, DMSO-d6) δ 157.34, 153.88, 149.71, 149.54, 140.32,
139.57, 132.45, 125.99, 124.35, 116.44, 105.27, 67.56, 52.31, 51.27,
50.18, 46.82, 28.63, 28.07, 15.67; HRMS (ES+) calcd for
C21H2135ClN6O4Na (M + Na)+ 479.1211; found, 479.1196; calcd for
C21H2137ClN6O4Na (M + Na)+ 481.1181; found, 481.1175.
1
yield, 7.2%; mp, 193.1−193.6 °C; H NMR (400 MHz, DMSO-d6)
δ 8.33 (d, J = 2.0 Hz, 1H), 7.92−7.85 (m, 1H), 7.76 (dd, J = 8.0, 2.4
Hz, 1H), 7.57 (t, J = 7.2 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.26 (t, J =
7.6 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 4.87 (s, 1H), 4.84−4.75 (m,
2H), 4.58 (s, 1H), 3.83−3.62 (m, 4H), 2.03−1.93 (m, 1H), 1.80−1.74
(m, 2H), 1.66−1.54 (m, 1H), 1.32−1.18 (m, 2H); 13C NMR (100
MHz, DMSO-d6) δ 157.30, 149.82, 149.74, 144.09, 142.72, 139.80,
134.56, 132.66, 126.09, 124.49, 124.28, 122.25, 104.63, 70.21, 56.22,
51.46, 50.01, 46.10, 28.81, 28.65, 15.52; HRMS (ES+) calcd for
C21H2135ClN6O4Na (M + Na)+ 479.1211; found, 479.1219; calcd for
C21H2137ClN6O4Na (M + Na)+ 481.1181; found, 481.1175.
11-(4-Bromo-2,6-dimethylphenyl)-1-((6-chloropyridin-3-yl)-
methyl)-10-nitro-1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-
C
dx.doi.org/10.1021/jf4046683 | J. Agric. Food Chem. XXXX, XXX, XXX−XXX

Journal of Agricultural and Food Chemistry
Article
1
a]azocine (2l): yield, 32.8%; mp, 174.4−175.1 °C; H NMR (400
258.2 Hz, 1C), 154.89, 149.77, 149.61, 144.66, 139.95, 133.31, 129.64,
124.41, 115.68 (d, J = 22.0 Hz, 1C), 114.53 (d, J = 7.4 Hz, 1C),
104.01, 73.52, 57.24, 52.52, 49.98, 46.58, 29.76, 29.14, 15.14; HRMS
(ES+) calcd for C21H2235ClFN6O2Na (M + Na)+ 467.1374; found,
467.1371; calcd for C21H2237ClFN6O2Na (M + Na)+ 469.1345; found,
469.1367.
1-((6-Chloropyridin-3-yl)methyl)-N-(2-methoxyphenyl)-10-nitro-
1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocin-11-
amine (3d): yield, 28.8%; mp, 169.6−170.5 °C; 1H NMR (400 MHz,
DMSO-d6) δ 8.42 (d, J = 1.6 Hz, 1H), 7.87 (dd, J = 8.4, 2.4 Hz, 1H),
7.55 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.91−6.84 (m, 2H),
6.79−6.73 (m, 1H), 4.93 (d, J = 15.6 Hz, 1H), 4.83 (d, J = 15.6 Hz,
1H), 4.46 (s, 1H), 4.19 (s, 1H), 3.87−3.78 (m, 2H), 3.76 (s, 3H),
3.72−3.53 (m, 2H), 2.21−1.71 (m, 4H), 1.53−1.39 (m, 1H), 1.13−
0.96 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 157.31, 149.80,
149.72, 147.01, 139.88, 136.29, 132.83, 124.54, 121.52, 119.70, 113.99,
111.05, 102.96, 73.78, 57.32, 56.05, 51.62, 49.80, 46.52, 29.40, 29.25,
14.90; HRMS (ES+) calcd for C22H2535ClN6O3Na (M + Na)+
479.1574; found, 479.1574; calcd for C22H2537ClN6O3Na (M + Na)+
481.1545; found, 481.1544.
MHz, DMSO-d6) δ 8.40 (d, J = 2.4 Hz, 1H), 7.85 (dd, J = 8.0, 2.4 Hz,
1H), 7.54 (d, J = 8.4 Hz, 1H), 7.27 (s, 1H), 7.19 (s, 1H), 4.92 (d, J =
15.2 Hz, 1H), 4.79−4.64 (m, 2H), 4.32 (s, 1H), 3.82−3.59 (m, 4H),
2.31 (s, 3H), 2.15 (s, 3H), 2.10−1.96 (m, 1H), 1.96−1.85 (m, 1H),
1.86−1.72 (m, 1H), 1.72−1.53 (m, 2H), 1.46−1.27 (m, 1H); 13C
NMR (100 MHz, DMSO-d6) δ 158.59, 149.80, 149.73, 146.75, 139.91,
136.21, 132.87, 131.76, 124.51, 117.09, 108.21, 69.60, 55.15, 51.45,
49.57, 46.24, 29.11, 28.66, 20.77, 19.70, 16.15; HRMS (ES+) calcd for
C23H2635Cl79BrN5O2 (M + H)+ 518.0958; found, 518.0958; calcd for
C23H2637Cl81BrN5O2 (M + H)+ 522.0908; found, 522.0917.
11-(4-Chlorophenyl)-1-((6-chloropyridin-3-yl)methyl)-10-nitro-
1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocine (2m):
yield, 32.3%; mp, 186.4−187.3 °C; H NMR (400 MHz, DMSO-d6)
1
δ 8.26 (d, J = 1.6 Hz, 1H), 7.60 (dd, J = 8.0, 2.4 Hz, 1H), 7.37 (d, J =
8.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 5.37 (s,
1H), 4.99 (s, 1H), 4.79 (d, J = 15.2 Hz, 1H), 4.72 (d, J = 15.2 Hz, 1H),
3.77−3.52 (m, 4H), 2.05−1.96 (m, 1H), 1.96−1.85 (m, 1H), 1.85−
1.70 (m, 2H), 1.65−1.52 (m, 1H), 1.35−1.18 (m, 1H); 13C NMR
(100 MHz, DMSO-d6) δ 157.42, 149.74, 149.67, 147.66, 139.50,
132.59, 129.42, 125.03, 124.38, 119.22, 105.25, 68.82, 52.82, 51.22,
49.84, 46.80, 28.89, 28.34, 15.81; HRMS (ES+) calcd for
C21H2235Cl2N5O2 (M + H)+ 446.1151; found, 446.1150; calcd for
C21H2237Cl2N5O2 (M + H)+ 450.1092; found, 450.1094.
N-(2-Chlorophenyl)-1-((6-chloropyridin-3-yl)methyl)-10-nitro-
1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocin-11-
1
amine (3e): yield, 66.5%; mp, 165.9−166.6 °C; H NMR (400 MHz,
DMSO-d6) δ 8.42 (d, J = 1.6 Hz, 1H), 7.88 (dd, J = 8.0, 2.0 Hz, 1H),
7.54 (d, J = 8.0 Hz, 1H), 7.33−7.23 (m, 3H), 6.84−6.78 (m, 1H), 4.94
(d, J = 15.6 Hz, 1H), 4.84 (d, J = 15.6 Hz, 1H), 4.50 (s, 1H), 4.22 (s,
1H), 3.86−3.74 (m, 2H), 3.73−3.55 (m, 2H), 2.04−1.76 (m, 4H),
1.54−1.41 (m, 1H), 1.15−0.99 (m, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 156.66, 149.84, 149.80, 143.09, 139.92, 132.83, 129.63,
128.62, 124.59, 120.76, 118.39, 115.89, 102.75, 73.63, 57.73, 51.60,
49.95, 46.53, 29.39, 29.29, 14.80; HRMS (ES+) calcd for
C21H2235Cl2N6O2Na (M + Na)+ 483.1079; found, 483.1064; calcd
for C21H2237Cl2N6O2Na (M + Na)+ 487.1020; found, 487.1024.
N-(4-Bromophenyl)-1-((6-chloropyridin-3-yl)methyl)-10-nitro-
1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocin-11-
1-((6-Chloropyridin-3-yl)methyl)-11-(2,5-dimethoxyphenyl)-10-
nitro-1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocine
1
(2n): yield, 17.2%; mp, 71.2−72.1 °C; H NMR (400 MHz, DMSO-
d6) δ 8.34 (d, J = 1.6 Hz, 1H), 7.74 (dd, J = 8.4, 2.4 Hz, 1H), 7.44 (d, J
= 8.4 Hz, 1H), 6.88 (d, J = 7.2 Hz, 1H), 6.55 (d, J = 8.8 Hz, 1H), 6.21
(s, 1H), 5.02 (s, 1H), 4.87−4.72 (m, 3H), 3.76 (s, 3H), 3.73−3.67 (m,
2H), 3.65 (s, 3H), 3.64−3.54 (m, 2H), 2.00−1.90 (m, 1H), 1.89−1.75
(m, 3H), 1.63−1.54 (m, 1H), 1.34−1.19 (m, 1H); 13C NMR (100
MHz, DMSO-d6) δ 157.61, 153.99, 149.74, 149.69, 146.31, 139.66,
139.22, 132.78, 124.45, 113.67, 106.53, 106.48, 105.44, 69.47, 56.73,
55.50, 53.59, 51.43, 49.58, 46.39, 28.82, 28.69, 15.95; HRMS (ES+)
calcd for C23H2735ClN5O4 (M + H)+ 472.1753; found, 472.1746; calcd
for C23H2737ClN5O4 (M + H)+ 474.1722; found, 474.1726.
1
amine (3f): yield,75.0%; mp, 195.0−195.8 °C; H NMR (400 MHz,
DMSO-d6) δ 8.46 (d, J = 1.6 Hz, 1H), 7.93 (dd, J = 8.0, 2.0 Hz, 1H),
7.54 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.0 Hz,
2H), 5.06 (d, J = 15.6 Hz, 1H), 4.64 (d, J = 15.6 Hz, 1H), 4.39 (s, 1H),
4.20 (s, 1H), 3.77−3.56 (m, 4H), 1.97−1.73 (m, 4H), 1.53−1.40 (m,
1H), 1.31−1.00 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 157.46,
149.77, 149.65, 147.53, 139.95, 133.30, 131.86, 124.40, 115.28, 109.20,
103.99, 73.46, 57.35, 52.55, 50.00, 46.54, 29.74, 29.14, 15.11; HRMS
(ES+) calcd for C21H2235Cl79BrN6O2Na (M + Na)+ 527.0574; found,
527.0577; calcd for C21H2237Cl81BrN6O2Na (M + Na)+ 531.0524;
found, 531.0526.
Series 3: Compounds 3a−3u. 1-((6-Chloropyridin-3-yl)methyl)-
10-nitro-N-phenyl-1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo-
1
[1,2-a]azocin-11-amine (3a): yield, 42%; mp, 181.6−182.2 °C; H
NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 1.6 Hz, 1H), 7.93 (dd, J =
8.0, 2.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.14 (t, J = 7.6 Hz, 2H),
6.90 (d, J = 8.0 Hz, 2H), 6.67 (m, 1H), 5.06 (d, J = 15.6 Hz, 1H), 4.64
(d, J = 15.6 Hz, 1H), 4.39 (s, 1H), 4.21 (s, 1H), 3.78−3.52 (m, 4H),
2.01−1.73 (m, 4H), 1.51−1.42 (m, 1H), 1.30−0.98 (m, 1H); 13C
NMR (100 MHz, DMSO-d6) δ 157.47, 150.98, 149.75, 149.62, 147.98,
139.93, 133.31, 129.29, 124.41, 113.50, 104.07, 73.58, 57.25, 52.51,
50.02, 46.57, 29.76, 29.08, 15.16; HRMS (ES+) calcd for
C21H2435ClN6O2 (M + H)+ 427.1649; found, 427.1647; calcd for
C21H2437ClN6O2 (M + H)+ 429.1620; found, 429.1633.
N-(4-Chlorophenyl)-1-((6-chloropyridin-3-yl)methyl)-10-nitro-
1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocin-11-
amine (3g): yield, 66.5%; mp, 199.7−200.6 °C; 1H NMR (400 MHz,
DMSO-d6) δ 8.46 (d, J = 1.6 Hz, 1H), 7.93 (dd, J = 8.0, 2.0 Hz, 1H),
7.54 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.0 Hz,
2H), 5.06 (d, J = 15.6 Hz, 1H), 4.64 (d, J = 15.6 Hz, 1H), 4.39 (s, 1H),
4.20 (s, 1H), 3.77−3.56 (m, 4H), 1.97−1.73 (m, 4H), 1.53−1.40 (m,
1H), 1.31−1.00 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 157.48,
149.77, 149.62, 147.15, 139.95, 133.30, 129.02, 124.40, 121.69, 114.74,
104.00, 73.46, 57.34, 52.55, 49.99, 46.56, 29.73, 29.12, 15.09; HRMS
(ES+) calcd for C21H2235Cl2N6O2Na (M + Na)+ 483.1079; found,
483.1076; calcd for C21H2237Cl2N6O2Na (M + Na)+ 487.1020; found,
487.1040.
1-((6-Chloropyridin-3-yl)methyl)-10-nitro-N-(p-tolyl)-
1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocin-11-
1
amine (3b): yield, 45.5%; mp, 179.0−179.6 °C; H NMR (400 MHz,
DMSO-d6) δ 8.45 (d, J = 1.6 Hz, 1H), 7.92 (dd, J = 8.0, 2.0 Hz, 1H),
7.54 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 7.8 Hz, 2H), 6.81 (d, J = 8.0 Hz,
2H), 5.05 (d, J = 15.6 Hz, 1H), 4.63 (d, J = 15.6 Hz, 1H), 4.38 (s, 1H),
4.20 (s, 1H), 3.76−3.51 (m, 4H), 2.18 (s, 3H), 1.95−1.70 (m, 4H),
1.55−1.39 (m, 1H), 1.28−1.00 (m, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 157.39, 149.76, 149.62, 145.64, 139.93, 133.32, 129.72,
127.43, 124.40, 113.87, 103.99, 73.56, 57.13, 52.47, 50.01, 46.59,
29.89, 29.22, 20.63, 15.12; HRMS (ES+) calcd for C22H2635ClN6O2
(M + H)+ 441.1806; found, 441.1801; calcd for C22H2637ClN6O2 (M +
H)+ 443.1776; found, 443.1770.
1-((6-Chloropyridin-3-yl)methyl)-10-nitro-N-(4-nitrophenyl)-
1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocin-11-
1
amine (3h): yield, 65%; mp, 186.5−187.2 °C; H NMR (400 MHz,
DMSO-d6) δ 8.47 (d, J = 1.6 Hz, 1H), 8.07 (d, J = 8.8 Hz, 2H), 7.93
(dd, J = 8.0, 2.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 8.8 Hz,
2H), 5.06 (d, J = 15.6 Hz, 1H), 4.66 (d, J = 15.6 Hz, 1H), 4.47 (s, 1H),
4.22 (s, 1H), 3.77−3.59 (m, 4H), 1.99−1.79 (m, 4H), 1.53−1.42 (m,
1H), 1.21−1.01 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 157.46,
153.83, 149.79, 149.64, 139.95, 137.77, 133.22, 126.56, 124.41, 111.30,
103.67, 73.07, 57.71, 52.57, 50.02, 46.40, 29.51, 29.18, 14.87; HRMS
(ES+) calcd for C21H2235ClN7O4Na (M + Na)+ 494.1319; found,
1-((6-Chloropyridin-3-yl)methyl)-N-(4-fluorophenyl)-10-nitro-
1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocin-11-
1
amine (3c): yield, 43%; mp, 191.6−192.4 °C; H NMR (400 MHz,
DMSO-d6) δ 8.46 (d, J = 1.6 Hz, 1H), 7.93 (dd, J = 8.4, 2.4 Hz, 1H),
7.55 (d, J = 8.0 Hz, 1H), 6.99 (t, J = 8.8 Hz, 2H), 6.94−6.86 (m, 2H),
5.06 (d, J = 15.6 Hz, 1H), 4.64 (d, J = 15.6 Hz, 1H), 4.39 (s, 1H), 4.21
(s, 2H), 3.71−3.55 (m, 4H), 1.98−1.71 (m, 4H), 1.52−1.38 (m, 1H),
1.27−0.99 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 156.18 (d, J =
D
dx.doi.org/10.1021/jf4046683 | J. Agric. Food Chem. XXXX, XXX, XXX−XXX

Journal of Agricultural and Food Chemistry
Article
494.1318; calcd for C21H2237ClN7O4Na (M + Na)+ 496.1290; found,
496.1280.
1-((6-Chloropyridin-3-yl)methyl)-10-nitro-N-(3-nitrophenyl)-
1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocin-11-
amine (3n): yield, 49.3%; mp, 190.7−191.4 °C; 1H NMR (400 MHz,
DMSO-d6) δ 8.47 (d, J = 1.6 Hz, 1H), 7.95 (dd, J = 8.0, 2.0 Hz, 1H),
7.71 (s, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 6.0 Hz, 1H), 7.47−
7.38 (m, 1H), 7.34 (d, J = 6.8 Hz, 1H), 5.07 (d, J = 15.2 Hz, 1H), 4.66
(d, J = 15.2 Hz, 1H), 4.45 (s, 1H), 4.24 (s, 1H), 3.78−3.58 (m, 4H),
1.99−1.80 (m, 4H), 1.56−1.41 (m, 1H), 1.31−1.03 (m, 1H); 13C
NMR (100 MHz, DMSO-d6) δ 157.48, 149.78, 149.64, 149.48, 149.16,
139.96, 133.27, 130.63, 124.42, 119.17, 112.57, 106.69, 103.89, 73.37,
57.53, 52.61, 50.01, 46.54, 29.72, 29.22, 14.98; HRMS (ES+) calcd for
C21H2235ClN7O4Na (M + Na)+ 494.1319; found, 494.1320; calcd for
C21H2237ClN7O4Na (M + Na)+ 496.1290; found, 496.1311.
1-((6-Chloropyridin-3-yl)methyl)-N-(2,4-dinitrophenyl)-10-nitro-
1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocin-11-
amine (3o): yield, 37.1%; mp, 206.4−207.4 °C; 1H NMR (400 MHz,
DMSO-d6) δ 9.20 (s, 1H), 8.83 (s, 1H), 8.46 (d, J = 1.6 Hz, 1H), 8.39
(d, J = 8.8 Hz, 1H), 7.91 (dd, J = 8.0, 2.0 Hz, 1H), 7.76 (d, J = 8.8 Hz,
1H), 7.55 (d, J = 8.0 Hz, 1H), 5.01 (d, J = 15.2 Hz, 1H), 4.77 (d, J =
15.2 Hz, 1H), 4.63 (s, 1H), 4.39 (s, 1H), 3.87−3.57 (m, 4H), 2.07−
1.82 (m, 4H), 1.59−1.45 (m, 1H), 1.24−1.05 (m, 1H); 13C NMR
(100 MHz, DMSO-d6) δ 156.54, 149.85, 149.80, 147.63, 139.83,
137.16, 132.71, 130.80, 130.19, 124.55, 123.49, 116.80, 102.37, 73.10,
58.37, 52.01, 49.95, 46.45, 29.20, 28.91, 14.56; HRMS (ES+) calcd for
C21H2135ClN8O6Na (M + Na)+ 539.1163; found, 539.1165; calcd for
C21H2137ClN8O6Na (M + Na)+ 541.1141; found, 541.1150.
4-((1-((6-Chloropyridin-3-yl)methyl)-10-nitro-1,2,3,5,6,7,8,9-octa-
hydro-5,9-epiminoimidazo[1,2-a]azocin-11-yl)amino)benzonitrile
(3p): yield, 40.8%; mp, 218.9−219.7 °C; 1H NMR (400 MHz, DMSO-
d6) δ 8.47 (d, J = 1.6 Hz, 1H), 8.03 (s, 1H), 7.93 (dd, J = 8.0, 2.0 Hz,
1H), 7.55 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.0 Hz, 2H), 5.06 (d, J =
15.6 Hz, 1H), 4.64 (d, J = 15.6 Hz, 1H), 4.42 (s, 1H), 4.20 (s, 1H),
3.77−3.54 (m, 4H), 2.00−1.73 (m, 4H), 1.53−1.39 (m, 1H), 1.19−
1.01 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 157.43, 151.73,
149.80, 149.66, 139.93, 133.96, 133.20, 124.41, 120.74, 112.50, 103.72,
98.55, 73.22, 57.59, 52.48, 49.96, 46.39, 29.49, 29.28, 14.89; HRMS
(ES+) calcd for C22H2235ClN7O2Na (M + Na)+ 474.1421; found,
474.1426; calcd for C22H2237ClN7O2Na (M + Na)+ 476.1392; found,
476.1401.
N-(4-Bromo-2,6-dimethylphenyl)-1-((6-chloropyridin-3-yl)-
methyl)-10-nitro-1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-
a]azocin-11-amine (3q): yield, 32.8%; mp, 173.7−174.5 °C; 1H NMR
(400 MHz, DMSO-d6) δ 8.45 (d, J = 1.6 Hz, 1H), 7.92 (dd, J = 8.4, 2.4
Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.17 (s, 2H), 5.01 (d, J = 15.6 Hz,
1H), 4.72 (d, J = 15.6 Hz, 1H), 4.58 (s, 1H), 4.08 (s, 1H), 3.80−3.62
(m, 4H), 2.17 (s, 6H), 1.97−1.85 (m, 1H), 1.76−1.60 (m, 2H), 1.60−
1.45 (m, 1H), 1.46−1.34 (m, 1H), 1.13−1.07 (m, 1H); 13C NMR
(100 MHz, DMSO-d6) δ 157.16, 149.71, 149.70, 142.62, 139.89,
133.14, 132.88, 131.17, 124.48, 114.81, 102.94, 73.97, 65.39, 57.22,
52.16, 50.11, 46.47, 29.53, 29.13, 15.64, 15.15; HRMS (ES+) calcd for
C23H2735Cl79BrN6O2 (M + H)+ 533.1067; found, 533.1070; calcd for
C23H2737Cl81BrN6O2 (M + H)+ 537.1017; found, 537.1039.
1-((6-Chloropyridin-3-yl)methyl)-N-(2-ethyl-6-methylphenyl)-10-
nitro-1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocin-
1
11-amine (3i): yield, 22.5%; mp, 100.0−100.6 °C; H NMR (400
MHz, DMSO-d6) δ 8.45 (d, J = 1.6 Hz, 1H), 7.92 (dd, J = 8.4, 2.4 Hz,
1H), 7.55 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 7.2 Hz, 1H), 6.95 (d, J = 7.2
Hz, 1H), 6.90−6.83 (m, 1H), 5.03 (d, J = 15.6 Hz, 1H), 4.73 (d, J =
15.6 Hz, 1H), 4.60 (s, 1H), 4.12 (s, 1H), 3.81−3.65 (m, 4H), 2.57 (q,
J = 7.2 Hz, 2H), 2.16 (s, 3H), 1.97−1.88 (m, 1H), 1.79−1.59 (m, 3H),
1.58−1.46 (m, 1H), 1.45−1.34 (m, 1H), 1.17 (t, J = 7.2 Hz, 3H); 13C
NMR (100 MHz, DMSO-d6) δ 157.10, 149.86, 149.72, 142.39, 139.89,
136.35, 133.11, 129.84, 128.77, 127.27, 124.52, 123.33, 103.05, 74.08,
57.03, 52.07, 50.11, 46.54, 29.64, 29.05, 24.29, 18.46, 15.41, 15.20;
HRMS (ES+) calcd for C24H2935ClN6O2Na (M + Na)+ 491.1938;
found, 491.1938; calcd for C24H2937ClN6O2Na (M + Na)+ 493.1909;
found, 493.1901.
1-((6-Chloropyridin-3-yl)methyl)-10-nitro-N-(m-tolyl)-
1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocin-11-
1
amine (3j): yield, 76.3%; mp, 175.9−176.6 °C; H NMR (400 MHz,
DMSO-d6) δ 8.46 (d, J = 1.6 Hz, 1H), 7.94 (dd, J = 8.0, 2.0 Hz, 1H),
7.55 (d, J = 8.0 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.78−6.66 (m, 2H),
6.50 (d, J = 6.8 Hz, 1H), 5.06 (d, J = 15.2 Hz, 1H), 4.64 (d, J = 15.2
Hz, 1H), 4.38 (s, 1H), 4.20 (s, 1H), 3.82−3.54 (m, 4H), 2.22 (s, 3H),
1.96−1.72 (m, 4H), 1.52−1.40 (m, 1H), 1.25−1.01 (m, 1H); 13C
NMR (100 MHz, DMSO-d6) δ 157.46, 149.77, 149.60, 148.01, 139.96,
138.31, 133.35, 129.17, 124.41, 119.55, 113.99, 110.76, 104.05, 73.60,
57.24, 52.56, 50.07, 46.63, 29.80, 28.97, 21.83, 15.19; HRMS (ES+)
calcd for C22H2535ClN6O2Na (M + Na)+ 463.1625; found, 463.1627;
calcd for C22H2537ClN6O2Na (M + Na)+ 465.1620; found, 465.1609.
1-((6-Chloropyridin-3-yl)methyl)-N-(2,6-diethylphenyl)-10-nitro-
1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocin-11-
1
amine (3k): yield, 12.2%; mp, 169.6−170.1 °C; H NMR (400 MHz,
DMSO-d6) δ 8.45 (d, J = 1.6 Hz, 1H), 7.92 (dd, J = 8.0, 2.0 Hz, 1H),
7.56 (d, J = 8.0 Hz, 1H), 7.02−6.89 (m, 3H), 5.04 (d, J = 14.8 Hz,
1H), 4.72 (d, J = 14.8 Hz, 1H), 4.61 (s, 1H), 4.14 (s, 1H), 3.83−3.64
(m, 4H), 2.01−1.85 (m, 1H), 1.81−1.59 (m, 3H), 1.58−1.45 (m, 1H),
1.45−1.33 (m, 1H), 1.30−0.95 (m, 10H); 13C NMR (100 MHz,
DMSO-d6) δ 157.03, 149.87, 149.72, 141.64, 139.90, 136.07, 133.06,
126.94, 124.52, 123.60, 102.99, 74.01, 56.93, 52.03, 50.08, 46.60,
29.69, 28.98, 24.26, 15.43, 15.20; HRMS (ES+) calcd for
C25H3135ClN6O2Na (M + Na)+ 505.2095; found, 505.2093; calcd for
C25H3137ClN6O2Na (M + Na)+ 507.2065; found, 507.2059.
1-((6-Chloropyridin-3-yl)methyl)-10-nitro-N-(o-tolyl)-
1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocin-11-
1
amine (3l): yield, 41.9%; mp, 180.0−180.4 °C; H NMR (400 MHz,
DMSO-d6) δ 8.44 (d, J = 1.6 Hz, 1H), 7.90 (dd, J = 8.0, 2.0 Hz, 1H),
7.55 (d, J = 8.4 Hz, 1H), 7.12−7.08 (m, 2H), 7.03 (d, J = 7.2 Hz, 1H),
6.81−6.69 (m, 1H), 4.98 (d, J = 14.8 Hz, 1H), 4.77 (d, J = 14.8 Hz,
1H), 4.47 (s, 1H), 4.23 (s, 1H), 3.84−3.72 (m, 2H), 3.72−3.58 (m,
2H), 2.04 (s, 3H), 1.94−1.86 (m, 1H), 1.85−1.70 (m, 3H), 1.50−1.40
(m, 1H), 1.15−1.00 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ
157.03, 149.79, 149.76, 145.09, 139.96, 133.04, 130.76, 127.06, 124.53,
124.01, 120.18, 114.97, 103.24, 73.64, 57.31, 51.83, 49.92, 46.65,
29.54, 29.15, 17.69, 15.08; HRMS (ES+) calcd for C22H2535ClN6O2Na
(M + Na)+ 463.1625; found, 463.1610; calcd for C22H2537ClN6O2Na
(M + Na)+ 465.1596; found, 465.1597.
1-((6-Chloropyridin-3-yl)methyl)-10-nitro-N-(4-(trifluoromethyl)-
phenyl)-1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]-
1
azocin-11-amine (3r): yield, 32.1%; mp, 212.2−212.9 °C; H NMR
(400 MHz, DMSO-d6) δ 8.47 (d, J = 1.6 Hz, 1H), 7.94 (dd, J = 8.0, 2.0
Hz, 1H), 7.71 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.4 Hz,
2H), 7.02 (d, J = 8.4 Hz, 2H), 5.07 (d, J = 15.6 Hz, 1H), 4.64 (d, J =
15.6 Hz, 1H), 4.43 (s, 1H), 4.22 (s, 1H), 3.77−3.58 (m, 4H), 1.98−
1.89 (m, 1H), 1.88−1.75 (m, 3H), 1.52−1.42 (m, 1H), 1.20−1.03 (m,
1H); 13C NMR (100 MHz, DMSO-d6) δ 157.45, 151.29, 149.77,
149.64, 139.91, 133.24, 126.71 (d, J = 3.7 Hz, 1C), 125.85 (d, J =
213.6 Hz, 1C), 124.51 (d, J = 56.6 Hz, 1C), 124.38, 118.03 (q, J = 31.8
Hz, 1C), 112.34, 103.83, 73.34, 57.51, 52.52, 49.96, 46.45, 29.60,
29.24, 14.97; HRMS (ES+) calcd for C22H2235ClF3N6O2Na (M + Na)+
517.1353; found, 517.1337; calcd for C22H2237ClF3N6O2Na (M + Na)+
519.1313; found, 519.1307.
1-((6-Chloropyridin-3-yl)methyl)-10-nitro-N-(2-nitrophenyl)-
1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocin-11-
amine (3m): yield, 11.8%; mp, 139.6−140.2 °C; 1H NMR (400 MHz,
DMSO-d6) δ 8.70 (s, 1H), 8.44 (d, J = 1.6 Hz, 1H), 8.07 (d, J = 8.4
Hz, 1H), 7.91 (dd, J = 8.0, 2.0 Hz, 1H), 7.71−7.60 (m, 1H), 7.55 (d, J
= 8.0 Hz, 1H), 6.92−6.83 (m, 1H), 5.00 (d, J = 15.6 Hz, 1H), 4.74 (d,
J = 15.6 Hz, 1H), 4.59 (s, 1H), 4.31 (s, 1H), 3.87−3.54 (m, 4H),
2.07−1.77 (m, 4H), 1.56−1.42 (m, 1H), 1.20−1.00 (m, 1H); 13C
NMR (100 MHz, DMSO-d6) δ 156.76, 149.80, 149.75, 144.34, 139.85,
137.31, 132.74, 131.67, 126.33, 124.56, 118.23, 116.34, 102.72, 73.50,
58.35, 51.94, 49.88, 46.61, 29.26, 28.98, 14.66; HRMS (ES+) calcd for
C21H2235ClN7O4Na (M + Na)+ 494.1319; found, 494.1311; calcd for
C21H2237ClN7O4Na (M + Na)+ 496.1290; found, 496.1287.
1-((6-Chloropyridin-3-yl)methyl)-N-(3-methoxyphenyl)-10-nitro-
1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocin-11-
1
amine (3s): yield, 9%; mp, 113.1−114.1 °C; H NMR (400 MHz,
DMSO-d6) δ 8.47 (d, J = 1.6 Hz, 1H), 7.94 (dd, J = 8.0, 2.0 Hz, 1H),
E
dx.doi.org/10.1021/jf4046683 | J. Agric. Food Chem. XXXX, XXX, XXX−XXX

Journal of Agricultural and Food Chemistry
Article
7.55 (d, J = 8.0 Hz, 1H), 7.10−6.99 (m, 1H), 6.88 (s, 1H), 6.48 (s,
1H), 6.27 (d, J = 8.0 Hz, 1H), 5.07 (d, J = 15.6 Hz, 1H), 4.63 (d, J =
15.6 Hz, 1H), 4.39 (s, 1H), 4.22 (s, 1H), 3.70 (s, 3H), 3.69−3.55 (m,
4H), 1.97−1.88 (m, 1H), 1.88−1.70 (m, 3H), 1.53−1.40 (m, 1H),
1.13−1.06 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 160.70,
157.45, 149.77, 149.63, 149.54, 139.93, 133.32, 130.12, 124.40, 106.04,
104.20, 104.00, 99.03, 73.55, 57.33, 55.17, 52.52, 49.99, 46.55, 29.75,
29.15, 15.14; HRMS (ES+) calcd for C22H2535ClN6O3Na (M + Na)+
479.1573; found, 479.1569; calcd for C22H2537ClN6O3Na (M + Na)+
481.1545; found, 481.1538.
(0.0613P) 2 + 0.0371P] gave final values of R = 0.0378, ωR = 0.1077,
and GOF (F) = 1.033 for 325 variables and 7970 contributing
reflections. Maximum shift/error = 0.000(3) and max/min residual
electron density = 0.521/−0.639 e Å−3. Hydrogen atoms were
observed and refined with a fixed value of their isotropic displacement
parameter.
Biological Assay. All bioassays were performed on representative
test organisms reared in the laboratory. The bioassay was repeated at
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 X-100 (0.1 mg L−1) to obtain series concentrations
of 500, 100, and 4 mg L−1 and others for bioassays. For comparative
purposes, imidacloprid, cycloxaprid and oxabridged compound B were
tested under the same conditions.
1-((6-Chloropyridin-3-yl)methyl)-N-(2,6-difluorophenyl)-10-nitro-
1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocin-11-
1
amine (3t): yield, 15.6%; mp, 159.9−160.5 °C; H NMR (400 MHz,
DMSO-d6) δ 8.45 (d, J = 1.6 Hz, 1H), 7.92 (dd, J = 8.0, 2.0 Hz, 1H),
7.53 (d, J = 8.0 Hz, 1H), 7.11− 6.98 (m, 3H), 5.02 (d, J = 15.6 Hz,
1H), 4.70 (d, J = 15.6 Hz, 1H), 4.55 (s, 1H), 4.34 (s, 1H), 3.82−3.60
(m, 4H), 1.94−1.85 (m, 1H), 1.85−1.75 (m, 1H), 1.72−1.54 (m, 2H),
1.44−1.33 (m, 1H), 1.15−1.00 (m, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 157.07, δ 155.65 (dd, J = 244.9, 5.9 Hz, 1C), 139.79,
133.20, 124.60 (d, J = 14.1 Hz, 1C), 124.53, 124.41, 123.58 (t, J = 9.5
Hz, 1C), 112.26 (dd, J = 17.0, 6.8 Hz, 1C), 103.19, 74.24, 58.26, 52.32,
50.11, 46.76, 29.85, 29.10, 14.98; HRMS (ES+) calcd for
C21H2135ClF2N6O2Na (M + Na)+ 485.1289; found, 485.1275; calcd
for C21H2137ClF2N6O2Na (M + Na)+ 487.1251; found, 487.1245.
N-(2-Bromophenyl)-1-((6-chloropyridin-3-yl)methyl)-10-nitro-
1,2,3,5,6,7,8,9-octahydro-5,9-epiminoimidazo[1,2-a]azocin-11-
Insecticidal Test. The insecticidal activities of the synthetic
compounds against cowpea aphid (Aphis craccivora) and brown
planthopper (Nilaparvata lugens) were tested according to our
previously reported procedure.11,14
RESULTS AND DISCUSSION
Synthesis. Generally, the eight-membered nitrogen-con-
■
taining rings (azocines) were constructed by intra- or
intermolecular reactions.15,16 Among these, Robinson−Schopf
̈
reaction was regarded as a classical and efficient intermolecular
methodology to synthesize azabridged bicyclic systems, which
involved 1,3-dicarbonyl compounds, methylamine hydrochlor-
ide, and dialdehydes via double-Mannich condensation.17 Thus,
by comparing the 1,3-dicarbonyl derivatives and cyclic β-
nitroenamines (starting material A), it was discovered that
these two structures have very similar nucleophilic centers
(Figure 3), which indicated the possibility of synthesizing eight-
1
amine (3u): yield, 35.8%; mp, 182.4−183.3 °C; H NMR (400 MHz,
DMSO-d6) δ 8.43 (d, J = 1.6 Hz, 1H), 7.88 (dd, J = 8.0, 2.0 Hz, 1H),
7.55 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.34−7.22 (m, 2H),
6.76 (t, J = 6.8 Hz, 1H), 4.95 (d, J = 15.6 Hz, 1H), 4.83 (d, J = 15.6
Hz, 1H), 4.51 (s, 1H), 4.22 (s, 1H), 3.86−3.76 (m, 2H), 3.74−3.64
(m, 2H), 2.01−1.90 (m, 1H), 1.88−1.75 (m, 3H), 1.51−1.42 (m, 1H),
1.14−0.98 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 156.66,
149.85, 149.80, 143.89, 139.95, 132.78, 132.71, 129.24, 124.61, 121.52,
116.25, 108.75, 102.62, 73.70, 57.78, 51.64, 49.95, 46.62, 29.38, 29.23,
14.78; HRMS (ES+) calcd for C21H2235Cl79BrN6O2Na (M + Na)+
527.0574; found, 527.0568; calcd for C21H2237Cl81BrN6O2Na (M +
Na)+ 531.0524; found, 531.0517.
X-ray Diffraction Analysis. Compound 2a was recrystallized by
slow evaporation from a mixture of acetone, dichloromethane, and
cyclohexane to afford a suitable single crystal. Green blocks of 2a (0.23
mm × 0.18 mm × 0.13 mm) 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 Kα radiation (λ = 0.71073 Å); θmax = 25.99°; 11673
measured reflections; 3763 independent reflections (Rint = 0.0277).
Data were corrected for Lorentz and polarization effects and for
absorption (tmin = 0.4568 and tmax = 1.0000). The structure was solved
by direct methods using SHELXS-97;12 all other calculations were
performed with a Bruker SAINT System and Bruker SMART
programs.13 Full-matrix least-squares refinement based on F2 using
Figure 3. Structural comparison of the 1,3-dicarbonyl derivatives and
cyclic β-nitroenamines.
membered azabridge neonicotinoid analogues by reacting with
various primary amine hydrochlorides and glutaraldehyde
(Scheme 2).
2
the weight of 1/[σ2 (Fo ) + (0.0613P)2 + 0.0371P] gave final values of
R = 0.0331, ωR = 0.0844, and GOF (F) = 1.035 for 263 variables and
3763 contributing reflections. Maximum shift/error = 0.000(3) and
max/min residual electron density = 0.178/−0.156 e Å−3. Hydrogen
atoms were observed and refined with a fixed value of their isotropic
displacement parameter.
When compound 1a was synthesized, oxabridged compound
B and a lot of unreacted starting material A were observed,
which resulted in low yield (Table 1, entry 1). To optimize this
reaction, several buffer salts and Lewis acids, such as MgCl2,
NiCl2, BF3·Et2O, ZnCl2, CoCl2, NH4OAc, NaH2PO4, and
Na2HPO4, were investigated (Table 1, entries 2−9). According
to the screening of catalysts, NaH2PO4 presented higher yield.
Furthermore, through adjusting the amounts of NaH2PO4, it
was observed that 50 mol % was more appropriate to the
reaction (Table 1, entry 10). Then, the influence of reaction
temperature was studied. The results showed that increasing
the reaction temperature led to decreasing yields. However,
when the temperature was below 0 °C, the yield of 1a was no
longer improved (Table 1, entries 10 and 12−14). The effect of
the solvent in the reaction was also investigated; various
solvents such as acetonitrile, tetrahydrofuran (THF), H2O,
Compound 3o was recrystallized by slow evaporation from a
mixture of acetone, dichloromethane, and cyclohexane to afford a
suitable single crystal. Yellow blocks of 3o (0.36 mm × 0.30 mm ×
0.20 mm) 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 Kα
radiation (λ = 0.71073 Å); θmax = 32.64°; 24369 measured reflections;
7970 independent reflections (Rint = 0.0222). Data were corrected for
Lorentz and polarization effects and for absorption (tmin = 0.9203 and
tmax = 0.9546). The structure was solved by direct methods using
SHELXS-97; all other calculations were performed with a Bruker
SAINT System and Bruker SMART programs. Full-matrix least-
2
squares refinement based on F2 using the weight of 1/[σ2 (Fo ) +
F
dx.doi.org/10.1021/jf4046683 | J. Agric. Food Chem. XXXX, XXX, XXX−XXX

Journal of Agricultural and Food Chemistry
Article
Scheme 2. Retrosynthetic Strategy for Eight-Membered Azabridge Neonicotinoids
a
very close to those of the unreacted starting material A or
oxabridged compound B, which resulted in the difficulties of
isolation. For studying the effects of substituents on the bridged
nitrogen atom, other primary amine hydrochlorides such as
aniline hydrochlorides (series 2) and phenylhydrazine hydro-
chlorides (series 3) were employed. Consequently, another two
series of azabridged analogues were synthesized. Compared to
series 1, the compounds of series 2 and 3 could be obtained
with higher yields and the reaction could finish in shorter
reaction time because of the different reaction activities among
the three primary amine hydrochlorides (Scheme 1). However,
the oxabridged compound B was still observed in the mixtures,
which led to the low yields.
Table 1. Optimization of Compound 1a
catalyst
amount
b
c
temperature
yield
(%)
entry
solvent
catalyst
none
(mol %)
(°C)
1
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
MeOH
25
25
25
25
25
25
25
25
25
25
25
40
0
19
20
20
18
16
18
16
2
MgCl2
10
10
10
10
10
10
10
10
50
100
50
50
50
50
50
50
50
50
50
50
50
3
NiCl2
4
BF3·Et2O
ZnCl2
5
6
CoCl2
7
NH4OAc
Na2HPO4
NaH2PO4
NaH2PO4
NaH2PO4
NaH2PO4
NaH2PO4
NaH2PO4
NaH2PO4
NaH2PO4
NaH2PO4
NaH2PO4
NaH2PO4
NaH2PO4
NaH2PO4
NaH2PO4
d
8
NR
30
47
45
11
60
51
10
16
18
24
14
tr
9
Crystal Structure Analysis. Azabridged compounds 2a
and 3o were recrystallized by slow evaporation from mixed
solvent of dichloromethane and acetone (v/v = 1:1), and their
single-crystal structures were determined by X-ray crystallog-
raphy as illustrated in Figures 4 and 5.
10
11
12
13
14
15
16
17
18
19
20
21
22
−5
0
In these two crystal structures, the pharmacophore nitro
groups lay approximately in the same plane with the imidazole
ring. Under the delocalization role of the lone pair electron on
the amine and the electron-withdrawing effect of the nitro
group, a coplanar olefin-amine extended π electron network
was formed in these two compounds. It resulted in the
corresponding bond lengths of CN (Table 2, entries 3 and
4) being shorter than the typical CN single bond (1.47 Å)
but close to the length of CN (1.33 Å).18,19 The bond
lengths of CC in 2a and 3o were 1.408 and 1.401 Å,
respecitvely, which were longer than the normal CC (1.34
Å), and the CNO2 was shorter than the typical CNO2
(1.49 Å) (Table 2, entry 1). Whereas the pyridine ring and the
bridged oxygen atom of oxabridged compound B were directed
in same orientation,11 the pyridine and benzene rings of 2a
pointed in opposite directions. For 3o, the directions of the
nitrogen atom in the pyridine plane and the bridged nitrogen
atom were contrary. Obviously, from the crystal structures, it
was exhibited that the changing of bridge atoms or the
substituents of the bridged nitrogen atom could lead to entirely
different conformations, which might be important influential
factors of the bioactivities.
acetone
0
dioxane
0
THF
0
CH2Cl2
0
e
H2O
0
EtOH
0
4.7
2.2
1,2-
0
dichloroethane
a
All reactions were performed with glutaraldehyde (1.2 equiv mol),
methylamine hydrochloride (1.2 equiv mol), and starting material A (1
equiv mol). All reaction time were 12 h. Yields were determined by
b
c
d
e
HPLC. No reaction. Trace.
acetone, EtOH, CH2Cl2, 1,2-dichloroethane, and dioxane were
employed. According to the yields of HPLC, acetonitrile was
more suitable to carry out the reaction (Table 1, entries 13 and
15−22).
On the basis of the optimizations above, various aliphatic
amine hydrochlorides were introduced to obtain series 1
(compounds 1a−1d). With the extension of the alkyl chains, it
was found the Rf values of the corresponding compounds were
Figure 4. Crystal structure of compound 2a.
G
dx.doi.org/10.1021/jf4046683 | J. Agric. Food Chem. XXXX, XXX, XXX−XXX

Journal of Agricultural and Food Chemistry
Article
Figure 5. Crystal structure of compound 3o.
exhibited excellent insecticidal activity against brown planthop-
per (Table 6).
Table 2. Compared Bond Lengths of Compounds 2a and 3o
bond lengths (Å)
The insecticidal activities of series 2 are listed in Table 4.
Most of the azabridged compounds showed 100% mortality at
500 mg L−1, which were higher than the oxabridged compound
B against cowpea aphid. Compared to the unsubstituted
compound 2a, introducing electron-withdrawing groups,
electron-donating groups, or halogen atoms did not contribute
to great improvement of the bioactivities of the corresponding
compounds. Moreover, when a bromine atom was introduced
into the phenyl ring, related compounds 2e, 2i, and 2l showed
lower insecticidal activity than oxabridged compound B against
cowpea aphid, which indicated that a bromine atom on position
2 or 4 of the phenyl ring would decrease the insecticidal
activity. Meanwhile, compounds 2c, 2g, 2h, and 2n with
electron-donating groups or halogen atoms (except Br) on
position 2 of the phenyl group showed relatively high mortality
at 4 mg L−1 against cowpea aphid, which confirmed that
position 2 was the key substitution site for structural derivation
to obtain high-activity molecules.
The bioactivities of series 3 are shown in Table 5. At the
concentration of 100 mg L−1, the mortality of most tested
compounds reached 100% against cowpea aphid and brown
planthopper, which was much higher than that of oxabridged
compound B. Introducing halogen atoms into position 2 (3e,
3t, and 3u) and position 4 (3c, 3f, and 3g) of the phenyl ring
could increase the activity against brown planthopper.
Furthermore, the compounds with electron-donating groups
entry
2a
N(5)−C(6)
C(6)−C(7)
N(2)−C(7)
N(3)−C(7)
3o
N(4)−C(10)
C(9)−C(10)
N(2)−C(9)
N(3)−C(9)
1
2
3
4
1.361
1.408
1.347
1.344
1.380
1.401
1.373
1.350
Insecticidal Activities. The insecticidal activities of series 1
are shown in Table 3. At the concentration of 100 mg L−1, the
Table 3. Insecticidal Activities of Series 1
mortality (%)
Aphis craccivora
Nilaparvata lugens
compd
R
100 mg L−1 4 mg L−1 100 mg L−1 4 mg L−1
1a
1b
1c
1d
B
Me
Et
100
100
100
100
0
20
0
100
100
100
100
100
100
100
10
100
90
i-Pr
n-Pr
0
50
0
20
0
cycloxaprid
100
100
100
100
100
100
imidacloprid
mortality of all tested compounds reached 100% against
cowpea aphid (A. craccivora) and brown planthopper (N.
lugens). Compared with imidacloprid, compounds 1b and 1c
Table 4. Insecticidal Activities of Series 2
mortality (%)
Aphis craccivora
500 mg L−1
Nilaparvata lugens
500 mg L−1
compd
R
4 mg L−1
4 mg L−1
2a
2b
2c
2d
2e
2f
H
100
100
100
100
0
20
5
100
100
100
100
0
0
50
0
4-Me
2-Me
3-Me
4-Br
2-NO2
2-F
30
10
0
0
0
100
100
100
34
5
100
100
100
100
100
100
100
100
100
100
100
100
0
2g
2h
2i
20
30
5
0
2-Cl
2-Br
0
0
2j
3- NO2
80
15
0
0
2k
2l
4-NO2
100
40
0
2,6-(Me)2-4-Br
4-Cl
0
0
2m
14
0
0
2n
2,5-(OMe)2
100
87
20
0
20
0
B
cycloxaprid
imidacloprid
100
100
100
100
100
100
H
dx.doi.org/10.1021/jf4046683 | J. Agric. Food Chem. XXXX, XXX, XXX−XXX

Journal of Agricultural and Food Chemistry
Article
Table 5. Insecticidal Activities of Series 3
mortality (%)
Aphis craccivora
Nilaparvata lugens
100 mg L−1 4 mg L−1
)
compd
R
100 mg L−1
)
4 mg L−1
)
)
3a
3b
3c
3d
3e
3f
H
100
40
45
0
100
100
100
100
100
100
100
100
100
100
100
100
100
85
0
0
4-Me
4-F
100
100
100
100
100
100
100
100
100
100
100
100
60
40
5
80
50
60
60
90
50
50
80
0
2-OMe
2-Cl
4
4-Br
40
30
15
45
30
15
20
5
3g
3h
3i
4-Cl
4-NO2
2-Me-6-Et
3-Me
3j
3k
3l
2,6-(Et)2
2-Me
0
3m
2-NO2
3- NO2
2,4- (NO2)2
4-CN
0
3n
20
20
20
20
45
30
30
30
0
0
3o
50
0
3p
100
100
100
100
100
100
0
100
100
100
100
100
100
100
100
100
0
3q
2,6-(Me)2-4-Br
4-CF3
100
100
90
100
50
0
3r
3s
3-OCH3
2,6-(F)2
2-Br
3t
3u
B
cycloxaprid
imidacloprid
100
100
100
100
100
100
on position 3 (3j and 3s) also had higher insecticidal activity
against brown planthopper compared with unsubstituted
compound 3a.
bioactivities than eight-membered oxabridged compound B
against cowpea aphid and brown planthopper, which indicated
that the modification on the bridge atom was an effective
strategy to discover new candidates as pesticides. However, the
insecticidal activities against cowpea aphid and brown
planthopper were lower than that of seven-membered
oxabridged compound cycloxaprid. Therefore, the obtaining
of seven-membered azabridges and study of their biological
behavior are underway.
In conclusion, three series of eight-membered azabridged
neonicotinoid analogues were designed and synthesized. All of
the target compounds were obtained in optimized reaction
conditions. The azabridged compounds constructed by
aliphatic amine and phenylhydrazine hydrochlorides exhibited
excellent insecticidal activities against cowpea aphid and brown
planthopper among three series. On the basis of the LC50
values (Table 6), compounds 1b, 1c, 3c, 3g, 3j, and 3r showed
higher bioactivity than imidacloprid against brown planthopper
(Table 6). Most of the azabridged compounds presented higher
ASSOCIATED CONTENT
* Supporting Information
■
S
Crystallographic information files (CIFs) of compounds 2a and
3o. This material is available free of charge via the Internet at
http://pubs.acs.org.
Table 6. LC50 Values of Some Azabridged Compounds
against Brown Planthoppper
AUTHOR INFORMATION
Corresponding Authors
*(Z.L.) Phone: +86-21-64253540. Fax: +86-21-64252603. E-
mail: lizhong@ecust.edu.cn.
■
LC50
compd
Y=a + bx
(mg L−1
)
95% limits
1b
1c
3c
3e
3f
Y = 5.419 + 1.445x
Y = 5.195 + 1.486x
Y = 4.981 + 1.439x
Y = 4.875 + 1.049x
Y = 4.896 + 1.082x
Y = 5.130 + 1.302x
Y = 5.211 + 1.118x
Y = −0.739 + 1.867x
Y = 0.526 + 1.705x
Y = −0.771 + 1.768x
Y = −0.624 + 1.850x
Y = 5.743 + 1.786x
Y = 4.908 + 2.477x
0.584
0.739
1.032
1.315
1.248
0.794
0.647
2.489
0.491
2.730
2.175
0.383
1.089
0.427−0.784
0.533−0.983
0.794−1.338
0.967−1.817
0.895−1.786
0.599−1.038
0.453−0.882
1.672−4.554
0.403−0.593
2.204−3.581
1.797−2.732
0.197−0.593
0.973−1.218
*(X.X.) E-mail: xyxu@ecust.edu.cn
Funding
This work was financially supported by the National Basic
Research Program of China (973 Program, 2010CB126100),
the National High Technology Research and Development
Program of China (863 Program, 2011AA10A207), and the
National Natural Science Foundation of China (21272071).
This work was also partly supported by the National Key
Technology R&D Program of China (2011BAE06B01) and the
Fundamental Research Funds for the Central Universities.
3g
3j
3q
3r
3s
3t
cycloxaprid
Notes
imidacloprid
The authors declare no competing financial interest.
I
dx.doi.org/10.1021/jf4046683 | J. Agric. Food Chem. XXXX, XXX, XXX−XXX

Journal of Agricultural and Food Chemistry
Article
REFERENCES
■
(1) Zapol’skii, V. A; Fischer, R.; Namyslo, J. C.; Kaufmann, D. E.
Chemistry of polyhalogenated nitrobutadienes, 8: nitropolychlorobu-
tadienes − precursors for insecticidal neonicotinoids. Bioorg. Med.
Chem. 2009, 17, 4206−4215.
(2) Tomizawa, M.; Casida, J. E. Neonicotinoid insecticides: highlights
of a symposium on strategic molecular designs. J. Agric. Food Chem.
2011, 59, 2883−2886.
(3) Jepson, J. E. C.; Brown, L. A.; Sattelle, D. B. The actions of the
neonicotinoid imidacloprid on cholinergic neurons of Drosophila
melanogaster. Invert. Neurosci. 2006, 6, 33−40.
(4) Kagabu, S.; Ishihara, R.; Hieda, Y.; Nishimura, K.; Naruse, Y.
Insecticidal and neuroblocking potencies of variants of the
imidazolidine moiety of imidacloprid-related neonicotinoids and the
relationship to partition coefficient and charge density on the
pharmacophore. J. Agric. Food Chem. 2007, 55, 812−818.
(5) Tomizawa, M.; Casida, J. E. Molecular recognition of
neonicotinoid insecticides: the determinants of life or death. Acc.
Chem. Res. 2009, 42, 260−269.
(6) Tomizawa, M.; Casida, J. E. Unique neonicotinoid binding
conformations conferring selective receptor interactions. J. Agric. Food
Chem. 2011, 59, 2825−2828.
(7) Kagabu, S. Discovery of imidacloprid and further developments
from strategic molecular designs. J. Agric. Food Chem. 2010, 59, 2887−
2896.
(8) Jeschke, P.; Nauen, R.; Schindler, M.; Elbert, A. Overview of the
status and global strategy for neonicotinoids. J. Agric. Food Chem.
2011, 59, 2897−2908.
(9) Zhu, Y. M.; Lose, M. R.; Watson, G. B.; Sparks, T. C.; Rogers, R.
B.; Huang, J. X.; Gerwick, B. C.; Babcock, J. M.; Kelley, D.; Hegde, V.
B.; Nugent, B. M.; Renga, J. M.; Denholm, I.; Gorman, K.; DeBoer, G.
J.; Hasler, J.; Meade, T.; Thomas, J. D. Discovery and characterization
of sulfoxaflor, a novel insecticide targeting sap-feeding pests. J. Agric.
Food Chem. 2011, 59, 2950−2957.
(10) Qian, W. J.; Shi, X. L. Sulfoxaflor: a novel pesticide developed by
Dow AgroSciences. Pestic. Market News 2010, 23, 35−35.
(11) Shao, X. S.; Fu, H.; Xu, X. Y.; Xu, X. L.; Liu, Z. W.; Li, Z.; Qian,
X. H. Divalent and oxabridged neonicotinoids constructed by
dialdehydes and nitromethylene analogues of imidacloprid: design,
synthesis, crystal structure, and insecticidal activities. J. Agric. Food
Chem. 2010, 58, 2696−2702.
(12) Sheldrick, G. M. SHELXTL (version 5.0); University of
Gottingen: Gottingen, Germany, 2001.
̈
̈
(13) Bruker. SMART (version 5.628), SAINT (version 6.45), and
SADABS; Brucker AXS: Madison, WI. USA, 2001.
(14) Tian, Z. Z.; Shao, X. S.; Li, Z.; Qian, X. H.; Huang, Q. C.
Synthesis, insecticidal activity, and QSAR of novel nitromethylene
neonicotinoids with tetrahydropyridine fixed cis configuration and exo-
ring ether modification. J. Agric. Food Chem. 2007, 55, 2288−2292.
(15) Ohno, H.; Tanaka, T. Palladium(0)-catalyzed synthesis of
medium-sized heterocycles by using bromoallenes as an allyl dication
equivalent. J. Am. Chem. Soc. 2004, 126, 8744−8754.
(16) Majumdar, K. C.; Chattopadhyay, B. Synthesis of highly
substituted dibenzoazocine derivatives by the aza-Claisen rearrange-
ment and intramolecular Heck reaction via 8-exo-trig mode of
cyclization. Tetrahedron Lett. 2009, 50, 3178−3181.
(17) Simon, S.; Constantieux, T.; Rodriguez, J. Utilisation of 1,3-
dicarbonyl derivatives in multicomponent reactions. Eur. J. Org. Chem.
2004, 4957−4980.
(18) Sasada, Y. Molecular and crystal structure. In Chemistry
Handbook, 3rd ed.; Springer: Berlin, Germany, 1984.
(19) Kagabu, S.; Matsuno, H. Chloronicotinyl insecticides. 8. Crystal
and molecular structures of imidacloprid and analogous compounds. J.
Agric. Food Chem. 1997, 45, 276−281.
J
dx.doi.org/10.1021/jf4046683 | J. Agric. Food Chem. XXXX, XXX, XXX−XXX