Seven-membered azabridged neonicotinoids: Synthesis, crystal structure, insecticidal assay, and molecular docking studies

Article abstract of DOI:10.1021/jf504014y

To study the influence of the ring sizes, 37 novel seven-membered azabridged neonicotinoid analogues were synthesized by reactions of nitromethylene analogues, succinaldehyde, and aniline hydrochlorides. Most of the title compounds presented higher insecticidal activities than that of imidacloprid (IMI), cycloxaprid (CYC), and eight-membered compounds against cowpea aphid (Aphis craccivora), armyworm (Pseudaletia separata Walker), and brown planthopper (Nilaparvata lugens), which indicated that introducing the structure of a seven-membered azabridge could significantly improve the insecticidal activities of neonicotinoid analogues. Docking study and binding mode analysis also revealed that introducing methyl group into position 2 of phenyl ring could increase the hydrophobic interactions with receptor, which implied that position 2 might be the key site to get high insecticidal compounds.

Full text of DOI:10.1021/jf504014y

Article
pubs.acs.org/JAFC
Seven-Membered Azabridged Neonicotinoids: Synthesis, Crystal
Structure, Insecticidal Assay, and Molecular Docking Studies
Renbo Xu,§ Ming Luo,§ Rui Xia,§ Xiaoqing Meng,§ Xiaoyong Xu,*,§,# Zhiping Xu,§ Jiagao Cheng,§
Xusheng Shao,§ Houju Li,§ and Zhong Li*,§,#
§Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai
200237, China
#Shanghai Collaborative Innovation Center for Biomanufacturing Technology, 130 Meilong Road, Shanghai 200237, China
S
* Supporting Information
ABSTRACT: To study the influence of the ring sizes, 37 novel seven-membered azabridged neonicotinoid analogues were
synthesized by reactions of nitromethylene analogues, succinaldehyde, and aniline hydrochlorides. Most of the title compounds
presented higher insecticidal activities than that of imidacloprid (IMI), cycloxaprid (CYC), and eight-membered compounds
against cowpea aphid (Aphis craccivora), armyworm (Pseudaletia separata Walker), and brown planthopper (Nilaparvata lugens),
which indicated that introducing the structure of a seven-membered azabridge could significantly improve the insecticidal
activities of neonicotinoid analogues. Docking study and binding mode analysis also revealed that introducing methyl group into
position 2 of phenyl ring could increase the hydrophobic interactions with receptor, which implied that position 2 might be the
key site to get high insecticidal compounds.
KEYWORDS: cycloxaprid, seven-membered azabridge, neonicotinoids, insecticide
INTRODUCTION
■
The nicotinic acetylcholine receptors (nAChRs) belong to the
Cys-loop superfamily of agonist-gated ion channels.1 They are
widely distributed in the central nervous systems (CNS) and
participated in regulating major physiological functions and
pathophysiological processes.2,3 The nAChRs mediate rapid
excitatory neurotransmission and are the target of many
toxicants, potential therapeutic agents,4 and insecticides.5
The natural azabridged compound epibatidine (EPI) (Figure
1) is an extremely potent but nonselective nAChRs agonist6
Figure 2. Oxabridged and neonicotinoid compounds.
analogues were designed and synthesized.10 Most of the
azabridged compounds displayed higher bioactivities than
eight-membered oxabridged compound A against cowpea
Figure 1. Ring expansion of epibatidine.
aphid (Aphis craccivora) and brown planthopper (Nilaparvata
lugens), which indicated that changing the bridge atom from O
to N could greatly affect the insecticidal activities.
To study the influence of ring sizes on insecticidal activities,
that has been subjected to numerous structure−activity
relationship (SAR) studies. With the expansion of the bridged
ring, the seven- and eight-membered compounds homoepiba-
tidine7 and UB-1658 (Figure 1) were synthesized, respectively,
in this paper, a series of seven-membered azabridged
neonicotinoids were synthesized from starting material B,
and reported to show high affinity and selectivity for the α4β2
succinaldehyde, and aniline hydrochlorides (Scheme 1),
receptor subtype, which means that the variation of bridged
followed with crystal structure, insecticidal assay, docking, and
ring sizes could significantly influence the bioactivities.
Moreover, to our best knowledge, such SAR studies were
SAR analysis.
rarely reported in the exploration of potential neonicotinoid
insecticides.
In our previous work, enlightened by two unexpected
oxabridged compounds A and cycloxaprid (CYC)9 (Figure
2), three series of eight-membered azabridged neonicotinoid
Received: August 20, 2014
Revised: October 23, 2014
Accepted: October 27, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jf504014y | J. Agric. Food Chem. XXXX, XXX, XXX−XXX

Journal of Agricultural and Food Chemistry
Article
Scheme 1. Synthetic Routes of Compounds 1−37
49.8, 47.3, 31.6, 31.4; HRMS (ES+) calcd for C20H2035Cl79BrN5O2 (M
+ H)+ 476.0489, found 476.0487; calcd for C20H2037Cl81BrN5O2 (M +
H)+ 480.0439, found 480.0447.
MATERIALS AND METHODS
■
Instruments. 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 chromatog-
raphy (TLC) was carried out on precoated plates (silica gel 60 F254),
and spots were visualized with ultraviolet (UV) light.
General Synthetic Procedure for the Substituted Aniline
Hydrochloride. The corresponding aniline (10 mmol) in ethyl
acetate (15 mL) was cooled to 0 °C. A solution of concentrated HCl
was dropwise added and the pH value of the reaction mixture adjusted
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 hydrochloride
could be used without further purification.
Preparation of the Solution of Succinaldehyde. A mixture of
2,5-dimethoxydihydrofuran (0.290 g, 2.2 mmol) and 0.4 mL of 10%
aqueous HCl was stirred at room temperature. After 12 h, the pH
value of the mixture was adjusted to 2−3 by saturated aqueous
NaHCO3. The solution could be used directly in the next step.
General Synthetic Procedure for Compounds 1−37. A
mixture of starting material B (2 mmol) and corresponding aniline
hydrochloride (2.5 mmol) in acetonitrile (20 mL) was stirred at 0 °C.
Then the solution of succinaldehyde was slowly added, and the
reaction was monitored by TLC. After 1.5 h, the pH value of the
mixture was adjusted to 7−8 by saturated aqueous NaHCO3, and the
solvent was removed under reduced pressure. Then, water was added,
the 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.
1-((6-Chloropyridin-3-yl)methyl)-9-nitro-10-phenyl-2,3,5,6,7,8-
hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine (1): yield, 44.8%;
mp, 173−174 °C;1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 2.0
Hz, 1H), 7.30−7.20 (m, 4H), 6.94 (d, J = 8.0 Hz, 2H), 6.89 (t, J = 7.2
Hz, 1H), 5.62 (s, 1H), 5.26 (s, 1H), 4.79 (d, J = 15.6 Hz, 1H), 4.60 (d,
J = 15.6 Hz, 1H), 3.82−3.71 (m, 1H), 3.70−3.50 (m, 2H), 3.46−3.36
(m, 1H), 2.28−2.12 (m, 3H), 2.00−1.85 (m, 1H); 13C NMR (100
MHz, DMSO-d6) δ 156.0, 149.6, 149.6, 145.0, 138.9, 132.4, 129.7,
124.5, 120.6, 117.7, 109.3, 71.5, 56.9, 50.7, 49.7, 47.4, 31.5, 31.4;
HRMS (ES+) calcd for C20H2035ClN5O2Na (M + Na)+ 420.1203,
found 420.1195; calcd for C20H2037ClN5O2Na (M + Na)+ 422.1174;
found 422.1186.
1-((6-Chloropyridin-3-yl)methyl)-10-(4-methoxyphenyl)-9-nitro-
2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine (3):
1
yield, 82.5%; mp, 177−178 °C; H NMR (400 MHz, DMSO-d6) δ
8.13 (d, J = 2.0 Hz, 1H), 7.28−7.20 (m, 2H), 6.88 (d, J = 8.4 Hz, 2H),
6.82 (d, J = 8.4 Hz, 2H), 5.53 (s, 1H), 5.17 (s, 1H), 4.87 (d, J = 15.6
Hz, 1H), 4.57 (d, J = 15.6 Hz, 1H), 3.84−3.75 (m, 1H), 3.74 (s, 3H),
3.71−3.58 (m, 2H), 3.58−3.48 (m, 1H), 2.26−2.05 (m, 3H), 1.95−
1.83 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 155.9, 153.6, 149.6,
138.9, 138.5, 132.5, 124.5, 124.3, 118.9, 115.0, 109.2, 72.0, 55.5, 50.5,
49.5, 47.5, 31.6, 31.5, 15.6; HRMS (ES+) calcd for C21H2235ClN5O3Na
(M + Na)+ 450.1303, found 450.1324; calcd for C21H2237ClN5O3Na
(M + Na)+ 452.1279, found 452.1290.
1-((6-Chloropyridin-3-yl)methyl)-10-(4-fluorophenyl)-9-nitro-
2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine (4):
1
yield, 35.9%; mp, 165−166 °C; H NMR (400 MHz, DMSO-d6) δ
8.15 (d, J = 1.6 Hz, 1H), 7.37 (dd, J = 8.4, 1.6 Hz, 1H), 7.28 (d, J = 8.4
Hz, 1H), 7.05 (t, J = 8.8 Hz, 2H), 6.98−6.89 (m, 2H), 5.58 (s, 1H),
5.22 (s, 1H), 4.81 (d, J = 15.6 Hz, 1H), 4.61 (d, J = 15.6 Hz, 1H),
3.82−3.71 (m, 1H), 3.70−3.61 (m, 1H), 3.61−3.51 (m, 1H), 3.50−
3.39 (m, 1H), 2.29−2.07 (m, 3H), 1.97−1.87 (m, 1H); 13C NMR
(100 MHz, DMSO-d6) δ 156.9 (d, J = 236.8 Hz), 155.8, 149.7, 149.6,
141.5 (d, J = 2.0 Hz), 139.0, 132.3, 124.3, 119.1 (d, J = 7.6 Hz), 116.1
(d, J = 22.1 Hz), 109.1, 71.9, 57.4, 50.7, 49.8, 47.3, 31.7, 31.5; HRMS
(ES+) calcd for C20H2035ClFN5O2 (M + H)+ 416.1290, found
416.1278; calcd for C20H2037ClFN5O2 (M + H)+ 418.1260, found
418.1265.
1-((6-Chloropyridin-3-yl)methyl)-9-nitro-10-(p-tolyl)-2,3,5,6,7,8-
hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine (5): yield, 72.3%;
mp, 183−184 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 1.6
Hz, 1H), 7.29 (dd, J = 8.4, 1.6 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.02
(d, J = 7.2 Hz, 2H), 6.82 (d, J = 7.2 Hz, 2H), 5.57 (s, 1H), 5.20 (s,
1H), 4.86 (d, J = 15.2 Hz, 1H), 4.56 (d, J = 15.2 Hz, 1H), 3.84−3.70
(m, 1H), 3.72−3.59 (m, 1H), 3.58−3.47 (m, 1H), 3.47−3.36 (m, 1H),
2.24 (s, 3H), 2.23−2.03 (m, 3H), 1.97−1.83 (m, 1H); 13C NMR (100
MHz, DMSO-d6) δ 155.8, 149.6, 149.6, 142.6, 139.0, 132.4, 130.1,
129.3, 124.4, 117.7, 109.3, 71.7, 57.0, 50.5, 49.7, 47.6, 31.5, 31.4, 20.6;
HRMS (ES+) calcd for C21H2335ClN5O2 (M + H)+ 412.1540, found
412.1542; calcd for C21H2337ClN5O2 (M + H)+ 414.1511, found
414.1517.
1-((6-Chloropyridin-3-yl)methyl)-9-nitro-10-(4-(trifluoromethyl)-
phenyl)-2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]-
1
azepine (6): yield, 46.2%; mp, 190−191 °C; H NMR (400 MHz,
DMSO-d6) δ 8.15 (d, J = 1.6 Hz, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.35
(dd, J = 8.4, 1.6 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 8.0 Hz,
2H), 5.75 (s, 1H), 5.35 (s, 1H), 4.87 (d, J = 15.6 Hz, 1H), 4.59 (d, J =
15.6 Hz, 1H), 3.83−3.73 (m, 1H), 3.73−3.56 (m, 2H), 3.53−3.42 (m,
1H), 2.31−2.14 (m, 3H), 2.01−1.91 (m, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 155.9, 149.7, 149.6, 148.4, 139.0, 132.3, 126.9 (d, J = 3.6
Hz), 125.2 (d, J = 270.9 Hz), 124.2, 120.6 (q, J = 32.0 Hz), 117.7,
109.0, 71.2, 57.0, 50.7, 50.0, 47.2, 31.6, 31.3; HRMS (ES+) calcd for
C21H2035ClN5O2F3 (M + H)+ 466.1258, found 466.1252; calcd for
C21H2037ClN5O2F3 (M + H)+ 468.1228, found 468.1225.
10-(4-Bromophenyl)-1-((6-chloropyridin-3-yl)methyl)-9-nitro-
2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine (2):
1
yield, 84.0%; mp, 203−204 °C; H NMR (400 MHz, DMSO-d6) δ
8.18 (d, J = 2.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.27 (s, 2H), 6.91
(d, J = 8.4 Hz, 2H), 5.62 (s, 1H), 5.23 (s, 1H), 4.86 (d, J = 15.6 Hz,
1H), 4.58 (d, J = 15.6 Hz, 1H), 3.82−3.71 (m, 1H), 3.72−3.61 (m,
1H), 3.62−3.52 (m, 1H), 3.50−3.39 (m, 1H), 2.28−2.10 (m, 3H),
1.98−1.88 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 155.8, 149.7,
149.6, 144.5, 138.8, 132.3, 124.4, 119.9, 112.2, 109.0, 71.5, 57.1, 50.6,
4-(1-((6-Chloropyridin-3-yl)methyl)-9-nitro-2,3,5,6,7,8-hexahy-
dro-1H-5,8-epiminoimidazo[1,2-a]azepin-10-yl)benzonitrile (7):
B
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1
yield, 89.4%; mp, 220−221 °C; H NMR (400 MHz, DMSO-d6) δ
3.0 Hz), 116.7 (d, J = 20.9 Hz), 108.7, 72.5 (d, J = 8.2 Hz), 58.2 (d, J =
3.5 Hz), 50.9, 49.9, 46.8, 31.5, 31.2; HRMS (ES+) calcd for
C20H2035ClFN5O2 (M + H)+ 416.1290, found 416.1293; calcd for
C20H2037ClFN5O2 (M + H)+ 418.1260, found 418.1267.
8.11 (d, J = 1.6 Hz, 1H), 7.64 (d, J = 7.6 Hz, 2H), 7.40 (dd, J = 8.0, 1.6
Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 8.0 Hz, 2H), 5.75 (s,
1H), 5.36 (s, 1H), 4.81 (d, J = 15.6 Hz, 1H), 4.59 (d, J = 15.6 Hz, 1H),
3.82−3.43 (m, 4H), 2.31−2.10 (m, 3H), 2.01−1.89 (m, 1H); 13C
NMR (100 MHz, DMSO-d6) δ 160.6, 154.5, 154.2, 153.7, 143.9,
138.8, 137.0, 129.1, 124.6, 122.8, 113.9, 106.8, 75.9, 61.7, 55.5, 54.9,
51.9, 36.4, 36.0; HRMS (ES+) calcd for C21H2035ClN6O2 (M + H)+
423.1336, found 423.1337; calcd for C21H2037ClN6O2 (M + H)+
425.1307, found 425.1313.
1-((6-Chloropyridin-3-yl)methyl)-9-nitro-10-(o-tolyl)-2,3,5,6,7,8-
hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine (13): yield, 40.8%;
mp, 155−156 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J = 1.6
Hz, 1H), 7.69 (dd, J = 8.4, 2.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.15
(d, J = 7.2 Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 6.97−6.90 (m, 1H), 6.76
(d, J = 8.0 Hz, 1H), 5.15 (s, 1H), 4.96 (s, 1H), 4.81 (d, J = 15.6 Hz,
1H), 4.73 (d, J = 15.6 Hz, 1H), 3.75−3.58 (m, 2H), 3.56−3.36 (m,
2H), 2.27 (s, 3H), 2.24−2.04 (m, 3H), 1.93−1.84 (m, 1H); 13C NMR
(100 MHz, DMSO-d6) δ 160.9, 154.6, 154.5, 147.9, 144.5, 137.2,
136.7, 135.0, 131.7, 129.3, 127.8, 124.4, 113.7, 77.5, 63.4, 55.7, 54.6,
51.4, 36.6, 36.3, 24.2; HRMS (ES+) calcd for C21H2335ClN5O2 (M +
H)+ 412.1540, found 412.1535; calcd for C21H2337ClN5O2 (M + H)+
414.1511, found 414.1513.
10-(4-Chlorophenyl)-1-((6-chloropyridin-3-yl)methyl)-9-nitro-
2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine (8):
1
yield, 68.6%; mp, 200−201 °C; H NMR (400 MHz, DMSO-d6) δ
8.13 (d, J = 1.6 Hz, 1H), 7.30−7.18 (m, 4H), 6.91 (d, J = 8.0 Hz, 2H),
5.57 (s, 1H), 5.19 (s, 1H), 4.80 (d, J = 15.6 Hz, 1H), 4.54 (d, J = 15.6
Hz, 1H), 3.79−3.67 (m, 1H), 3.67−3.57 (m, 1H), 3.57−3.47 (m, 1H),
3.47−3.34 (m, 1H), 2.25−2.06 (m, 3H), 1.95−1.83 (m, 1H); 13C
NMR (100 MHz, DMSO-d6) δ 160.6, 154.4, 154.4, 148.8, 143.7,
137.1, 134.2, 129.1, 129.1, 124.2, 113.8, 76.3, 62.0, 55.4, 54.6, 52.1,
36.4, 36.1; HRMS (ES+) calcd for C20H2035Cl2N5O2 (M + H)+
432.0994, found 432.0982; calcd for C20H2037Cl2N5O2 (M + H)+
436.0935, found 436.0940.
1-((6-Chloropyridin-3-yl)methyl)-10-(2-methoxyphenyl)-9-nitro-
2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine (14):
1
yield, 42.5%; mp, 120−121 °C; H NMR (400 MHz, DMSO-d6) δ
8.22 (d, J = 2.0 Hz, 1H), 7.52 (dd, J = 8.4, 2.4 Hz, 1H), 7.37 (d, J = 8.0
Hz, 1H), 7.01−6.92 (m, 2H), 6.82−6.75 (m, 1H), 6.66 (d, J = 7.6 Hz,
1H), 5.58 (d, J = 5.2 Hz, 1H), 5.10 (d, J = 5.2 Hz, 1H), 4.74 (d, J =
16.4 Hz, 1H), 4.68 (d, J = 16.4 Hz, 1H), 3.83 (s, 3H), 3.78−3.57 (m,
2H), 3.40−3.36 (m, 1H), 3.30−3.23 (m, 1H), 2.26−1.99 (m, 3H),
1.96−1.84 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 155.8, 151.2,
149.8, 149.7, 139.4, 133.4, 132.4, 124.5, 122.9, 121.4, 119.6, 112.6,
108.9, 71.9, 58.0, 50.8, 49.7, 47.2, 31.6, 30.9, 15.6; HRMS (ES+) calcd
for C21H2335ClN5O3 (M + H)+ 428.1489, found 428.1489; calcd for
C21H2337ClN5O3 (M + H)+ 430.1460, found 430.1468.
1-((6-Chloropyridin-3-yl)methyl)-9-nitro-10-(4-nitrophenyl)-
2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine (9):
1
yield, 65.7%; mp, 234−235 °C; H NMR (400 MHz, DMSO-d6) δ
8.10 (d, J = 9.2 Hz, 2H), 8.05 (d, J = 2.0 Hz, 1H), 7.44 (dd, J = 8.4, 2.4
Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 9.2 Hz, 2H), 5.80 (s,
1H), 5.43 (d, J = 5.6 Hz, 1H), 4.84 (d, J = 15.6 Hz, 1H), 4.58 (d, J =
15.6 Hz, 1H), 3.82−3.61 (m, 3H), 3.57−3.49 (m, 1H), 2.31−2.16 (m,
3H), 2.03−1.94 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 155.7,
151.0, 149.6, 149.3, 140.3, 139.3, 132.1, 126.0, 124.2, 117.3, 109.2,
71.2, 57.4, 50.7, 50.3, 47.1, 31.7, 31.2; HRMS (ES+) calcd for
C20H2035ClN6O4 (M + H)+ 443.1235, found 443.1252; calcd for
C20H2037ClN6O4 (M + H)+ 445.1205, found 445.1221.
2-(1-((6-Chloropyridin-3-yl)methyl)-9-nitro-2,3,5,6,7,8-hexahy-
dro-1H-5,8-epiminoimidazo[1,2-a]azepin-10-yl)benzonitrile (15):
1
yield, 52.6%; mp, 197−198 °C; H NMR (400 MHz, DMSO-d6) δ
8.23 (d, J = 2.4 Hz, 1H), 7.73 (dd, J = 7.6, 1.6 Hz, 1H), 7.60 (dd, J =
8.0, 2.4 Hz, 1H), 7.56−7.49 (m, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.13 (t,
J = 7.2 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 5.56 (s, 1H), 5.49 (d, J = 5.2
Hz, 1H), 4.78 (d, J = 15.6 Hz, 1H), 4.72 (d, J = 15.6 Hz, 1H), 3.83−
3.51 (m, 4H), 2.33−2.18 (m, 3H), 2.00−1.91 (m, 1H); 13C NMR
(100 MHz, DMSO-d6) δ 155.8, 149.8, 149.6, 147.6, 139.5, 135.2,
134.9, 132.3, 124.5, 122.8, 120.4, 118.7, 108.4, 103.2, 72.8, 59.1, 51.1,
50.1, 46.2, 31.9, 31.8; HRMS (ES+) calcd for C21H2035ClN6O2 (M +
H)+ 423.1336, found 423.1338; calcd for C21H2037ClN6O2 (M + H)+
425.1307, found 425.1299.
10-(2-Chlorophenyl)-1-((6-chloropyridin-3-yl)methyl)-9-nitro-
2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine (10):
1
yield, 75.8%; mp, 181−182 °C; H NMR (400 MHz, DMSO-d6) δ
8.28 (d, J = 2.0 Hz, 1H), 7.69 (dd, J = 8.4, 2.4 Hz, 1H), 7.48−7.40 (m,
2H), 7.19 (t, J = 7.6 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.93 (d, J = 8.0
Hz, 1H), 5.47 (s, 1H), 5.20 (s, 1H), 4.81 (d, J = 15.6 Hz, 1H), 4.74 (d,
J = 15.6 Hz, 1H), 3.80−3.61 (m, 2H), 3.59−3.40 (m, 2H), 2.26−2.06
(m, 3H), 1.98−1.85 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ
155.9, 149.8, 149.7, 141.5, 139.7, 132.4, 131.3, 128.5, 126.0, 124.5,
124.4, 121.9, 108.5, 72.4, 58.7, 51.0, 49.9, 46.5, 31.7, 31.6; HRMS (ES
+) calcd for C20H1935Cl2N5O2Na (M + Na)+ 454.0808, found
454.0819; calcd for C20H1937Cl2N5O2Na (M + Na)+ 458.0754,
found 458.0745.
1-((6-Chloropyridin-3-yl)methyl)-9-nitro-10-(m-tolyl)-2,3,5,6,7,8-
hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine (16): yield, 64.6%;
mp, 199−200 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 1.6
Hz, 1H), 7.24 (s, 2H), 7.15−7.07 (m, 1H), 6.78 (s, 1H), 6.76−6.68
(m, 2H), 5.60 (s, 1H), 5.24 (s, 1H), 4.81 (d, J = 15.6 Hz, 1H), 4.59 (d,
J = 15.6 Hz, 1H), 3.84−3.71 (m, 1H), 3.70−3.51 (m, 2H), 3.49−3.36
(m, 1H), 2.25 (s, 3H), 2.21−2.07 (m, 3H), 1.96−1.87 (m, 1H); 13C
NMR (100 MHz, DMSO-d6) δ 156.1, 149.6, 149.6, 145.0, 138.9,
138.8, 132.5, 129.5, 124.4, 121.5, 118.3, 114.9, 109.3, 71.4, 56.9, 50.7,
49.6, 47.5, 31.5, 31.4, 21.9; HRMS (ES+) calcd for C21H2335ClN5O2
(M + H)+ 412.1540, found 412.1540; calcd for C21H2337ClN5O2 (M +
H)+ 414.1511, found 414.1514.
10-(2-Bromophenyl)-1-((6-chloropyridin-3-yl)methyl)-9-nitro-
2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine (11):
1
yield, 76.0%; mp, 181−182 °C; H NMR (400 MHz, DMSO-d6) δ
8.30 (d, J = 2.0 Hz, 1H), 7.71 (dd, J = 8.0, 2.0 Hz, 1H), 7.60 (d, J = 8.0
Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.03−6.90
(m, 2H), 5.44 (s, 1H), 5.21 (s, 1H), 4.82 (d, J = 15.6 Hz, 1H), 4.75 (d,
J = 15.6 Hz, 1H), 3.81−3.62 (m, 2H), 3.62−3.51 (m, 1H), 3.52−3.42
(m, 1H), 2.26−2.05 (m, 3H), 1.97−1.85 (m, 1H); 13C NMR (100
MHz, DMSO-d6) δ 156.0, 149.8, 149.8, 142.8, 139.8, 134.5, 132.4,
129.0, 125.1, 124.5, 122.3, 116.8, 108.4, 72.8, 59.0, 51.1, 50.0, 46.5,
31.7, 31.6; HRMS (ES+) calcd for C20H1935Cl79BrN5O2Na (M + Na)+
498.0303, found 498.0321; calcd for C20H1937Cl81BrN5O2Na (M +
Na)+ 502.0258, found 502.0267.
1-((6-Chloropyridin-3-yl)methyl)-9-nitro-10-(3-(trifluoromethyl)-
phenyl)-2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]-
1
azepine (17): yield, 69.8%; mp, 222−223 °C; H NMR (400 MHz,
DMSO-d6) δ 8.14 (d, J = 1.6 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.33
(d, J = 8.4 Hz, 1H), 7.29−7.24 (m, 2H), 7.21 (d, J = 8.0 Hz, 2H), 5.77
(s, 1H), 5.36 (s, 1H), 4.77 (d, J = 15.6 Hz, 1H), 4.61 (d, J = 15.6 Hz,
1H), 3.85−3.71 (m, 1H), 3.73−3.51 (m, 2H), 3.52−3.40 (m, 1H),
2.34−2.11 (m, 3H), 2.01−1.87 (m, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 156.1, 149.7, 149.5, 145.8, 138.9, 132.3, 130.8, 130.5 (d, J
= 31.0 Hz), 126.0, 124.3, 121.5, 115.5 (dd, J = 298.6, 4.3 Hz), 108.9,
71.4, 57.2, 50.8, 49.8, 47.2, 31.6, 31.3; HRMS (ES+) calcd for
C21H2035ClF3N5O2 (M + H)+ 466.1258, found 466.1258; calcd for
C21H2037ClF3N5O2 (M + H)+ 468.1228, found 468.1232.
1-((6-Chloropyridin-3-yl)methyl)-10-(2-fluorophenyl)-9-nitro-
2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine (12):
1
yield, 42.1%; mp, 168−169 °C; H NMR (400 MHz, DMSO-d6) δ
8.21 (d, J = 1.6 Hz, 1H), 7.50 (dd, J = 8.0, 1.6 Hz, 1H), 7.35 (d, J = 8.4
Hz, 1H), 7.22−7.12 (m, 1H), 7.07−6.94 (m, 2H), 6.88−6.79 (m, 1H),
5.41 (s, 1H), 5.21 (s, 1H), 4.76 (d, J = 15.2 Hz, 1H), 4.69 (d, J = 15.2
Hz, 1H), 3.81−3.63 (m, 2H), 3.54−3.42 (m, 2H), 2.26−2.09 (m, 3H),
1.99−1.87 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 155.68,
154.09 (d, J = 243.2 Hz), 149.7, 149.6, 139.3, 132.4 (d, J = 9.0 Hz),
132.3, 125.5 (d, J = 3.1 Hz), 124.5, 122.9 (d, J = 8.0 Hz), 120.9 (d, J =
1-((6-Chloropyridin-3-yl)methyl)-10-(3-methoxyphenyl)-9-nitro-
2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine (18):
C
dx.doi.org/10.1021/jf504014y | J. Agric. Food Chem. XXXX, XXX, XXX−XXX

Journal of Agricultural and Food Chemistry
Article
1
yield, 72.2%; mp, 204−205 °C; H NMR (400 MHz, DMSO-d6) δ
6.64 (m, 1H), 5.35 (s, 1H), 5.15 (s, 1H), 4.81 (d, J = 15.2 Hz, 1H),
4.66 (d, J = 15.2 Hz, 1H), 3.81−3.59 (m, 2H), 3.57−3.38 (m, 2H),
2.26 (s, 3H), 2.23−2.03 (m, 3H), 1.97−1.84 (m, 1H); 13C NMR (100
MHz, DMSO-d6) δ 155.5, 153.8 (d, J = 243.1 Hz), 149.7, 149.6, 139.4,
132.5 (d, J = 7.7 Hz), 132.3, 129.7 (d, J = 8.9 Hz), 125.8, 124.4, 120.6,
117.2 (d, J = 20.8 Hz), 108.8, 72.5 (d, J = 8.0 Hz), 58.2, 50.7, 49.9,
46.9, 31.5, 31.2, 20.4; HRMS (ES+) calcd for C21H2235ClFN5O2 (M +
H)+ 430.1446, found 430.1444; calcd for C21H2237ClFN5O2 (M + H)+
432.1417, found 432.1416.
8.17 (d, J = 2.4 Hz, 1H), 7.31 (dd, J = 8.0, 2.4 Hz, 1H), 7.27 (d, J = 8.0
Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 6.53 (d, J = 8.4 Hz, 1H), 6.51−6.45
(m, 2H), 5.63 (s, 1H), 5.24 (s, 1H), 4.83 (d, J = 15.6 Hz, 1H), 4.60 (d,
J = 15.6 Hz, 1H), 3.86−3.72 (m, 1H), 3.71 (s, 3H), 3.69−3.51 (m,
2H), 3.50−3.39 (m, 1H), 2.29−2.10 (m, 3H), 1.96−1.85 (m, 1H); 13C
NMR (100 MHz, DMSO-d6) δ 160.7, 156.2, 149.6, 149.5, 146.4,
138.9, 132.5, 130.5, 124.4, 110.3, 109.2, 106.0, 103.9, 71.6, 57.0, 55.4,
50.8, 49.6, 47.4, 31.5; HRMS (ES+) calcd for C21H2335ClN5O3 (M +
H)+ 428.1489, found 428.1489; calcd for C21H2337ClN5O3 (M + H)+
430.1460, found 430.1465.
1-((6-Chloropyridin-3-yl)methyl)-10-(2,6-difluorophenyl)-9-nitro-
2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine (24):
1
yield, 34.2%; mp, 163−164 °C; H NMR (400 MHz, DMSO-d6) δ
10-(3-Chlorophenyl)-1-((6-chloropyridin-3-yl)methyl)-9-nitro-
8.25 (d, J = 2.4 Hz, 1H), 7.62 (dd, J = 8.0, 2.4 Hz, 1H), 7.40 (d, J = 8.0
Hz, 1H), 7.06−6.98 (m, 3H), 5.46−5.34 (m, 2H), 4.81 (d, J = 15.6
Hz, 1H), 4.73 (d, J = 15.6 Hz, 1H), 3.82−3.64 (m, 2H), 3.64−3.43
(m, 2H), 2.24−2.06 (m, 3H), 1.91−1.81 (m, 1H); 13C NMR (100
MHz, DMSO-d6) δ 155.0 (d, J = 244.6 Hz), 155.5, 154.9 (d, J = 244.7
Hz), 149.7, 149.6, 139.4, 132.5, 124.5, 122.7 (t, J = 10.5 Hz), 121.6 (t,
J = 12.5 Hz), 113.4 (d, J = 25.8 Hz), 113.4 (d, J = 11.7 Hz), 110.0, 73.2
(t, J = 5.4 Hz), 59.6 (t, J = 6.0 Hz), 51.0, 50.1, 46.4, 31.5, 31.1; HRMS
(ES+) calcd for C20H1935ClF2N5O2 (M + H)+ 434.1195, found
434.1196; calcd for C20H1937ClF2N5O2 (M + H)+ 436.1166, found
436.1173.
2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine (19):
1
yield, 59.6%; mp, 209−210 °C; H NMR (400 MHz, DMSO-d6) δ
8.18 (d, J = 2.4 Hz, 1H), 7.36 (dd, J = 8.4, 2.4 Hz, 1H), 7.29 (d, J = 8.0
Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H), 7.03 (t, J = 2.0 Hz, 1H), 6.92 (dd, J
= 8.0, 1.2 Hz, 1H), 6.88 (dd, J = 8.0, 1.6 Hz, 1H), 5.67 (s, 1H), 5.27 (s,
1H), 4.79 (d, J = 15.6 Hz, 1H), 4.62 (d, J = 15.6 Hz, 1H), 3.85−3.71
(m, 1H), 3.71−3.54 (m, 2H), 3.53−3.42 (m, 1H), 2.30−2.11 (m, 3H),
1.97−1.86 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 156.1, 149.7,
149.5, 146.7, 138.9, 134.3, 132.4, 131.3, 124.4, 120.4, 117.4, 116.3,
108.9, 71.4, 57.0, 50.9, 49.8, 47.2, 31.6, 31.3; HRMS (ES+) calcd for
C20H2035Cl2N5O2 (M + H)+ 432.0994, found 432.0990; calcd for
C20H2037Cl2N5O2 (M + H)+ 436.0935, found 436.0942.
1-((6-Chloropyridin-3-yl)methyl)-10-(3,4-dichlorophenyl)-9-nitro-
2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine (25):
1-((6-Chloropyridin-3-yl)methyl)-9-nitro-10-(3-nitrophenyl)-
1
yield, 64.7%; mp, 206−207 °C; H NMR (400 MHz, DMSO-d6) δ
2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine (20):
1
8.17 (d, J = 1.6 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.38 (dd, J = 8.0, 1.6
Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 2.0 Hz, 1H), 6.91 (dd, J
= 8.8, 2.0 Hz, 1H), 5.67 (s, 1H), 5.27 (d, J = 5.2 Hz, 1H), 4.84 (d, J =
15.6 Hz, 1H), 4.61 (d, J = 15.6 Hz, 1H), 3.81−3.71 (m, 1H), 3.72−
3.55 (m, 2H), 3.56−3.45 (m, 1H), 2.28−2.09 (m, 3H), 1.98−1.86 (m,
1H); 13C NMR (100 MHz, DMSO-d6) δ 155.9, 149.7, 149.5, 145.4,
138.9, 132.3, 132.1, 131.4, 124.2, 122.2, 119.3, 118.1, 108.8, 71.5, 57.3,
50.8, 50.0, 47.1, 31.6, 31.3; HRMS (ES+) calcd for C20H1935Cl3N5O2
(M + H)+ 466.0604, found 466.0599; calcd for C20H1937Cl3N5O2 (M +
H)+ 472.0516, found 472.0512.
yield, 73.6%; mp, 221−222 °C; H NMR (400 MHz, DMSO-d6) δ
8.06 (d, J = 2.4 Hz, 1H), 7.75−7.70 (m, 2H), 7.53−7.46 (m, 1H),
7.43−7.35 (m, 2H), 7.26 (d, J = 8.0 Hz, 1H), 5.79 (s, 1H), 5.37 (d, J =
5.6 Hz, 1H), 4.79 (d, J = 15.6 Hz, 1H), 4.59 (d, J = 15.6 Hz, 1H),
3.84−3.74 (m, 1H), 3.73−3.58 (m, 2H), 3.54−3.46 (m, 1H), 2.31−
2.14 (m, 3H), 2.01−1.92 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ
155.8, 149.6, 149.4, 146.3, 143.3, 139.1, 132.2, 131.0, 124.2, 124.2,
115.3, 111.9, 108.8, 71.5, 57.4, 50.8, 50.2, 47.1, 31.7, 31.3; HRMS (ES
+) calcd for C20H2035ClN6O4 (M + H)+ 443.1235, found 443.1237;
calcd for C20H2037ClN6O4 (M + H)+ 445.1205, found 445.1202.
1-((6-Chloropyridin-3-yl)methyl)-10-(3-fluorophenyl)-9-nitro-
2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine (21):
1-((6-Chloropyridin-3-yl)methyl)-10-(2,5-dimethoxyphenyl)-9-
nitro-2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine
(26): yield, 41.2%; mp, 125−126 °C; 1H NMR (400 MHz, DMSO-d6)
δ 8.21 (d, J = 2.4 Hz, 1H), 7.49 (dd, J = 8.0, 2.4 Hz, 1H), 7.33 (d, J =
8.0 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 6.53 (dd, J = 8.8, 2.8 Hz, 1H),
6.28 (d, J = 2.8 Hz, 1H), 5.63 (d, J = 4.8 Hz, 1H), 5.16 (d, J = 4.8 Hz,
1H), 4.78 (d, J = 15.6 Hz, 1H), 4.71 (d, J = 15.6 Hz, 1H), 3.77 (s, 3H),
3.76−3.68 (m, 1H), 3.65 (s, 3H), 3.64−3.56 (m, 1H), 3.45−3.34 (m,
2H), 2.25−2.02 (m, 3H), 1.93−1.82 (m, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 156.0, 154.0, 149.7, 149.5, 145.4, 139.2, 134.5, 132.5,
124.4, 113.8, 108.7, 107.1, 105.9, 71.9, 58.0, 56.6, 55.6, 50.8, 49.4, 47.0,
31.6, 30.9; HRMS (ES+) calcd for C22H2535ClN5O4 (M + H)+
458.1595, found 458.1597; calcd for C22H2537ClN5O4 (M + H)+
460.1566, found 460.1578.
1-((6-Chloropyridin-3-yl)methyl)-10-(2,3-dimethylphenyl)-9-
nitro-2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine
(27): yield, 41.1%; mp, 171−172 °C; 1H NMR (400 MHz, DMSO-d6)
δ 8.30 (d, J = 2.0 Hz, 1H), 7.72 (dd, J = 8.0, 2.4 Hz, 1H), 7.47 (d, J =
8.0 Hz, 1H), 6.99−6.83 (m, 2H), 6.65 (d, J = 7.6 Hz, 1H), 5.03 (d, J =
4.4 Hz, 1H), 4.88 (d, J = 4.4 Hz, 1H), 4.82 (d, J = 15.2 Hz, 1H), 4.74
(d, J = 15.2 Hz, 1H), 3.75−3.58 (m, 2H), 3.59−3.44 (m, 1H), 3.42−
3.34 (m, 1H), 2.25−2.22 (m, 1H), 2.22 (s, 3H), 2.21−2.18 (m, 1H),
2.15 (s, 3H), 2.12−2.05 (m, 1H), 1.91−1.85 (m, 1H); 13C NMR (100
MHz, DMSO-d6) δ 156.2, 149.9, 149.8, 143.2, 139.8, 138.0, 132.4,
129.2, 126.0, 125.1, 124.5, 117.6, 109.0, 73.5, 59.1, 51.0, 49.8, 46.6,
31.8, 31.7, 20.8, 15.1; HRMS (ES+) calcd for C22H2535ClN5O2 (M +
H)+ 426.1697, found 426.1692; calcd for C22H2537ClN5O2 (M + H)+
428.1667, found 428.1678.
1
yield, 47.7%; mp, 205−206 °C; H NMR (400 MHz, DMSO-d6) δ
8.16 (d, J = 2.0 Hz, 1H), 7.38 (dd, J = 8.4, 2.4 Hz, 1H), 7.29 (d, J = 8.0
Hz, 1H), 7.24 (dd, J = 15.2, 8.0 Hz, 1H), 6.83−6.77 (m, 1H), 6.77−
6.72 (m, 1H), 6.72−6.64 (m, 1H), 5.64 (s, 1H), 5.26 (d, J = 5.6 Hz,
1H), 4.79 (d, J = 15.6 Hz, 1H), 4.62 (d, J = 15.6 Hz, 1H), 3.83−3.71
(m, 1H), 3.71−3.56 (m, 2H), 3.54−3.43 (m, 1H), 2.29−2.11 (m, 3H),
1.97−1.87 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 162.3, 156.1,
149.5, 148.4 (d, J = 260.8 Hz), 147.2, 139.0, 132.4, 131.3 (d, J = 9.9
Hz), 124.4, 113.6 (d, J = 2.4 Hz), 109.1, 107.1 (d, J = 21.1 Hz), 104.7
(d, J = 25.3 Hz), 71.5, 57.1, 50.8, 49.9, 47.2, 31.6, 31.3; HRMS (ES+)
calcd for C20H2035ClFN5O2 (M + H)+ 416.1290, found 416.1279;
calcd for C20H2037ClFN5O2 (M + H)+ 418.1260, found 418.1269.
1-((6-Chloropyridin-3-yl)methyl)-10-(3-fluoro-4-methoxyphenyl)-
9-nitro-2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]-
1
azepine (22): yield, 61.0%; mp, 195−196 °C; H NMR (400 MHz,
DMSO-d6) δ 8.12 (d, J = 1.6 Hz, 1H), 7.38 (dd, J = 8.4 Hz, 2.0 Hz,
1H), 7.28 (d, J = 8.4 Hz, 1H), 7.01 (t, J = 9.2 Hz, 1H), 6.93 (d, J =
14.0 Hz, 1H), 6.61 (d, J = 8.8 Hz, 1H), 5.54 (s, 1H), 5.17 (s, 1H), 4.86
(d, J = 16.0 Hz, 1H), 4.60 (d, J = 16.0 Hz, 1H), 3.81 (s, 3H), 3.79−
3.71 (m, 1H), 3.70−3.53 (m, 2H), 3.51−3.40 (m, 1H), 2.30−2.05 (m,
3H), 1.97−1.81 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 155.9,
152.3 (d, J = 242.3 Hz), 149.6, 149.5, 141.3 (d, J = 11.0 Hz), 139.2 (d,
J = 8.7 Hz), 139.1, 132.4, 124.3, 115.3 (d, J = 2.6 Hz), 113.2 (d, J = 2.8
Hz), 109.0, 106.5 (d, J = 21.7 Hz), 71.9, 57.4, 56.7, 50.7, 49.7, 47.3,
31.6, 31.4; HRMS (ES+) calcd for C21H2235ClFN5O3 (M + H)+
446.1395, found 446.1389; calcd for C21H2237ClFN5O3 (M + H)+
448.1366, found 448.1375.
1-((6-Chloropyridin-3-yl)methyl)-10-(2,4-dimethylphenyl)-9-
nitro-2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine
(28): yield, 31.9%; mp, 157−158 °C; 1H NMR (400 MHz, DMSO-d6)
δ 8.28 (d, J = 2.0 Hz, 1H), 7.70 (dd, J = 8.0, 2.0 Hz, 1H), 7.45 (d, J =
8.0 Hz, 1H), 6.96 (s, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.63 (d, J = 8.4 Hz,
1H), 5.09 (d, J = 3.6 Hz, 1H), 4.90 (d, J = 3.6 Hz, 1H), 4.80 (d, J =
15.6 Hz, 1H), 4.75 (d, J = 15.6 Hz, 1H), 3.76−3.59 (m, 2H), 3.59−
1-((6-Chloropyridin-3-yl)methyl)-10-(2-fluoro-4-methylphenyl)-9-
nitro-2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine
(23): yield, 83.0%; mp, 174−175 °C; 1H NMR (400 MHz, DMSO-d6)
δ 8.17 (d, J = 1.6 Hz, 1H), 7.52 (dd, J = 8.0, 1.6 Hz, 1H), 7.35 (d, J =
8.0 Hz, 1H), 6.99 (d, J = 14.4 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.73−
D
dx.doi.org/10.1021/jf504014y | J. Agric. Food Chem. XXXX, XXX, XXX−XXX

Journal of Agricultural and Food Chemistry
Article
3.46 (m, 1H), 3.45−3.37 (m, 1H), 2.23 (s, 3H), 2.21 (s, 3H), 2.19−
2.00 (m, 3H), 1.93−1.83 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ
156.1, 149.8, 149.8, 140.6, 139.8, 132.5, 132.4, 131.7, 130.0, 127.2,
124.5, 119.6, 109.0, 72.9, 58.7, 50.9, 49.8, 46.7, 31.8, 31.5, 20.7, 19.3;
HRMS (ES+) calcd for C22H2535ClN5O2 (M + H)+ 426.1697, found
426.1693; calcd for C22H2537ClN5O2 (M + H)+ 428.1667, found
428.1660.
1-((6-Chloropyridin-3-yl)methyl)-10-(2,5-dimethylphenyl)-9-
nitro-2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine
(29): yield, 80.0%; mp, 157−158 °C; 1H NMR (400 MHz, DMSO-d6)
δ 8.29 (d, J = 2.0 Hz, 1H), 7.67 (dd, J = 8.0, 2.4 Hz, 1H), 7.42 (d, J =
8.4 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 7.2 Hz, 1H), 6.64 (s,
1H), 5.15 (d, J = 4.0 Hz, 1H), 4.99 (d, J = 4.0 Hz, 1H), 4.86 (d, J =
15.6 Hz, 1H), 4.68 (d, J = 15.6 Hz, 1H), 3.79−3.67 (m, 1H), 3.67−
3.56 (m, 1H), 3.52−3.35 (m, 2H), 2.23 (s, 3H), 2.22−2.20 (m, 1H),
2.20 (s, 3H), 2.19−2.15 (m, 1H), 2.13−2.03 (m, 1H), 1.93−1.86 (m,
1H); 13C NMR (100 MHz, DMSO-d6) δ 156.4, 149.7, 149.6, 143.1,
139.5, 135.8, 132.5, 131.8, 126.9, 124.4, 123.7, 120.4, 108.9, 72.8, 58.6,
51.1, 49.5, 46.7, 31.8, 31.5, 21.5, 19.1; HRMS (ES+) calcd for
C22H2535ClN5O2 (M + H)+ 426.1697, found 426.1690; calcd for
C22H2537ClN5O2 (M + H)+ 428.1667, found 428.1679.
8.0 Hz), 58.3, 51.0, 50.1, 46.5, 31.4, 31.2; 19F NMR (376 MHz,
DMSO-d6) δ −115.94 to −116.56 (m, 1F), −127.09 to −127.39 (m,
1F); HRMS (ES+) calcd for C20H1835ClF2N5O2Na (M + Na)+
456.1015, found 456.1021; calcd for C20H1837ClF2N5O2Na (M +
Na)+ 458.0985, found 458.0995.
1-((6-Chloropyridin-3-yl)methyl)-9-nitro-10-(2,3,4,5-tetrafluoro-
phenyl)-2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]-
1
azepine (34): yield, 51.3%; mp, 195−196 °C; H NMR (400 MHz,
DMSO-d6) δ 8.12 (d, J = 2.4 Hz, 1H), 7.61 (dd, J = 8.0, 2.4 Hz, 1H),
7.37 (d, J = 8.0 Hz, 1H), 6.80−6.69 (m, 1H), 5.42 (s, 1H), 5.26 (d, J =
4.8 Hz, 1H), 4.85 (d, J = 15.6 Hz, 1H), 4.66 (d, J = 15.6 Hz, 1H),
3.79−3.58 (m, 4H), 2.25−2.13 (m, 3H), 1.96−1.88 (m, 1H); 13C
NMR (100 MHz, DMSO-d6) δ 153.8, 148.2, 147.8, 137.9, 136.6,
130.6, 128.1, 125.5, 122.7, 117.0, 106.9, 101.4, 101.2, 70.7 (d, J = 6.5
Hz), 57.1 (d, J = 5.0 Hz), 49.3, 48.9, 44.7, 29.8, 29.6; 19F NMR (376
MHz, DMSO-d6) δ −138.96 to −139.37 (m, 1F), −149.38 to −149.60
(m, 1F), −156.26 (t, J = 21.3 Hz, 1F), −166.60 to −167.07 (m, 1F);
HRMS (ES+) calcd for C20H1635ClF4N5O2Na (M + Na)+ 492.0826,
found 492.0825; calcd for C20H1637ClF4N5O2Na (M + Na)+ 494.0797,
found 494.0795.
1-((6-Chloropyridin-3-yl)methyl)-10-(2,4-difluorophenyl)-9-nitro-
1-((6-Chloropyridin-3-yl)methyl)-10-(2,5-dichlorophenyl)-9-nitro-
2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine (35):
2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine (30):
1
yield, 56.4%; mp, 189−190 °C; H NMR (400 MHz, DMSO-d6) δ
1
yield, 46.8%; mp, 157−158 °C; H NMR (400 MHz, DMSO-d6) δ
8.20 (d, J = 2.0 Hz, 1H), 7.57 (dd, J = 8.0, 2.0 Hz, 1H), 7.38 (d, J = 8.0
Hz, 1H), 7.29−7.19 (m, 1H), 6.95−6.87 (m, 1H), 6.87−6.79 (m, 1H),
5.34 (d, J = 3.6 Hz, 1H), 5.16 (d, J = 3.6 Hz, 1H), 4.76 (d, J = 15.6 Hz,
1H), 4.70 (d, J = 15.6 Hz, 1H), 3.81−3.62 (m, 2H), 3.57−3.43 (m,
2H), 2.26−2.06 (m, 3H), 1.98−1.85 (m, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 156.8 (d, J = 240.8 Hz), 156.6 (d, J = 240.8 Hz), 155.1,
153.4 (d, J = 246.9 Hz), 153.2 (d, J = 246.6 Hz), 149.3, 149.1, 139.0,
131.8, 128.8 (d, J = 3.4 Hz), 128.7 (d, J = 3.3 Hz), 123.9, 120.9 (d, J =
4.5 Hz), 120.8 (d, J = 4.2 Hz), 111.4 (d, J = 3.4 Hz), 111.2 (d, J = 3.3
Hz), 108.0, 105.1, 104.9 (d, J = 51.9 Hz), 72.0 (d, J = 7.4 Hz), 57.9 (d,
J = 3.3 Hz), 50.4, 49.5, 46.2, 31.0, 30.8; 19F NMR (376 MHz, DMSO-
d6) δ −117.30 to −117.47 (m, 1F), −119.20 to −119.35 (m, 1F);
HRMS (ES+) calcd for C20H1935ClF2N5O2 (M + H)+ 434.1195, found
434.1195; calcd for C20H1937ClF2N5O2 (M + H)+ 436.1166, found
436.1156.
8.28 (d, J = 2.0 Hz, 1H), 7.67 (dd, J = 8.4, 2.8 Hz, 1H), 7.47 (d, J = 8.8
Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.13 (dd, J = 8.4, 2.4 Hz, 1H), 6.92
(d, J = 2.4 Hz, 1H), 5.54 (s, 1H), 5.32 (d, J = 4.0 Hz, 1H), 4.83 (d, J =
15.6 Hz, 1H), 4.75 (d, J = 15.6 Hz, 1H), 3.80−3.61 (m, 2H), 3.61−
3.49 (m, 2H), 2.28−2.13 (m, 3H), 1.96−1.85 (m, 1H); 13C NMR
(100 MHz, DMSO-d6) δ 156.1, 149.8, 149.6, 142.8, 139.4, 132.7,
132.6, 132.3, 124.6, 124.5, 124.0, 121.4, 107.9, 72.3, 58.7, 51.1, 49.8,
46.3, 31.6, 31.5; HRMS (ES+) calcd for C20H1935Cl3N5O2 (M + H)+
466.0604, found 466.0591; calcd for C20H1937Cl3N5O2 (M + H)+
472.0516, found 472.0529.
1-((6-Chloropyridin-3-yl)methyl)-10-(3,4-dimethylphenyl)-9-
nitro-2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine
(31): yield, 66.1%; mp, 196−197 °C; 1H NMR (400 MHz, DMSO-d6)
δ 8.08 (d, J = 2.0 Hz, 1H), 7.26 (dd, J = 8.4, 2.4 Hz, 1H), 7.18 (d, J =
8.4 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.75 (s, 1H), 6.67−6.61 (m,
1H), 5.55 (d, J = 4.0 Hz, 1H), 5.20 (d, J = 4.8 Hz, 1H), 4.87 (d, J =
16.0 Hz, 1H), 4.56 (d, J = 16.0 Hz, 1H), 3.84−3.71 (m, 1H), 3.68−
3.50 (m, 2H), 3.45−3.36 (m, 1H), 2.23−2.17 (m, 2H), 2.16 (s, 3H),
2.15 (s, 3H), 2.13−2.05 (m, 2H), 1.95−1.85 (m, 1H); 13C NMR (100
MHz, DMSO-d6) δ 155.9, 149.5, 149.5, 142.9, 138.9, 137.3, 132.4,
130.6, 128.2, 124.2, 119.0, 115.1, 109.4, 71.5, 57.0, 50.6, 49.5, 47.6,
31.5, 31.4, 20.3, 19.0; HRMS (ES-) calcd for C22H2335ClN5O2 (M −
H)+ 424.1540, found 424.1543; calcd for C22H2337ClN5O2 (M − H)+
426.1511, found 426.1516.
1-((6-Chloropyridin-3-yl)methyl)-10-(3,5-dimethylphenyl)-9-
nitro-2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine
(32): yield, 53.2%; mp, 214−215 °C; 1H NMR (400 MHz, DMSO-d6)
δ 8.15 (s, 1H), 7.26−7.18 (m, 2H), 6.57 (s, 2H), 6.54 (s, 1H), 5.57 (d,
J = 3.6 Hz, 1H), 5.22 (d, J = 4.8 Hz, 1H), 4.82 (d, J = 15.6 Hz, 1H),
4.59 (d, J = 15.6 Hz, 1H), 3.82−3.73 (m, 1H), 3.69−3.52 (m, 2H),
3.47−3.37 (m, 1H), 2.20 (s, 6H), 2.18−2.03 (m, 3H), 1.95−1.85 (m,
1H); 13C NMR (100 MHz, DMSO-d6) δ 156.1, 149.6, 149.5, 145.0,
138.8, 138.6, 132.5, 124.3, 122.5, 115.5, 109.3, 71.4, 57.0, 50.7, 49.6,
47.6, 31.5, 31.4, 21.8; HRMS (ES-) calcd for C22H2335ClN5O2 (M −
H)+ 424.1540, found 424.1543; calcd for C22H2337ClN5O2 (M − H)+
426.1511, found 426.1517.
1-((6-Chloropyridin-3-yl)methyl)-10-(2,3-difluorophenyl)-9-nitro-
2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine (36):
1
yield, 67.9%; mp, 193−194 °C; H NMR (400 MHz, DMSO-d6) δ
8.20 (d, J = 1.6 Hz, 1H), 7.53 (dd, J = 8.0, 1.6 Hz, 1H), 7.36 (d, J = 8.0
Hz, 1H), 7.09−6.94 (m, 2H), 6.75−6.59 (m, 1H), 5.44 (s, 1H), 5.25
(s, 1H), 4.78 (d, J = 15.6 Hz, 1H), 4.69 (d, J = 15.6 Hz, 1H), 3.81−
3.64 (m, 2H), 3.61−3.47 (m, 2H), 2.26−2.10 (m, 3H), 1.99−1.86 (m,
1H); 13C NMR (100 MHz, DMSO-d6) δ 155.1, 150.7 (d, J = 243.7
Hz), 150.6 (d, J = 243.6 Hz), 149.3, 149.1, 142.0 (d, J = 245.1 Hz),
141.8 (d, J = 244.9 Hz), 138.9, 133.9 (d, J = 4.1 Hz), 131.8, 124.6 (dd,
J = 8.6, 4.3 Hz), 123.9, 115.7, 109.7 (d, J = 17.3 Hz), 108.1, 72.0 (d, J =
7.5 Hz), 58.0 (d, J = 3.6 Hz), 50.4, 49.6, 46.1, 30.9, 30.8; 19F NMR
(376 MHz, DMSO-d6) δ −138.08 to −138.43 (m, 1F), −148.91 to
−149.30 (m, 1F); HRMS (ES+) calcd for C20H1935ClF2N5O2 (M +
H)+ 434.1195, found 434.1185; calcd for C20H1937ClF2N5O2 (M + H)+
436.1166, found 436.1159.
1-((6-Chloropyridin-3-yl)methyl)-9-nitro-10-(2,4,5-trifluorophen-
yl)-2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine
(37): yield, 77.9%; mp, 184−185 °C; 1H NMR (400 MHz, DMSO-d6)
δ 8.18 (d, J = 2.0 Hz, 1H), 7.60 (dd, J = 8.4, 2.0 Hz, 1H), 7.57−7.48
(m, 1H), 7.37 (d, J = 8.4 Hz, 1H), 6.90−6.80 (m, 1H), 5.38 (s, 1H),
5.24 (d, J = 4.8 Hz, 1H), 4.81 (d, J = 15.6 Hz, 1H), 4.70 (d, J = 15.6
Hz, 1H), 3.78−3.66 (m, 2H), 3.67−3.52 (m, 2H), 2.26−2.10 (m, 3H),
1.95−1.85 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 155.2, 149.3,
149.0, 138.9, 131.8, 123.8, 108.6 (d, J = 4.6 Hz), 108.4 (d, J = 4.6 Hz),
107.9, 106.9, 106.7 (d, J = 6.2 Hz), 106.4, 71.8 (d, J = 7.0 Hz), 58.0 (d,
J = 4.8 Hz), 50.4, 49.7, 45.9, 30.8, 30.7; 19F NMR (376 MHz, DMSO-
d6) δ −122.75 to −123.04 (m, 1F), −141.06 to −141.51 (m, 1F),
−144.07 to −144.38 (m, 1F); HRMS (ES+) calcd for
C20H1835ClF3N5O2 (M + H)+ 452.1101, found 452.1091; calcd for
C20H1837ClF3N5O2 (M + H)+ 454.1072, found 454.1087.
1-((6-Chloropyridin-3-yl)methyl)-10-(2,5-difluorophenyl)-9-nitro-
2,3,5,6,7,8-hexahydro-1H-5,8-epiminoimidazo[1,2-a]azepine (33):
1
yield, 74.8%; mp, 195−196 °C; H NMR (400 MHz, DMSO-d6) δ
8.20 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 8.0, 2.0 Hz, 1H), 7.35 (d, J = 8.0
Hz, 1H), 7.27−7.16 (m, 1H), 6.84−6.74 (m, 1H), 6.68−6.58 (m, 1H),
5.44 (s, 1H), 5.27 (s, 1H), 4.79 (d, J = 15.6 Hz, 1H), 4.69 (d, J = 15.6
Hz, 1H), 3.79−3.65 (m, 2H), 3.62−3.50 (m, 2H), 2.25−2.11 (m, 3H),
1.96−1.83 (m, 1H); 13C NMR (101 MHz, DMSO-d6) δ158.8 (d, J =
239.3 Hz), 155.8, 150.2 (d, J = 238.9 Hz), 149.8, 149.5, 139.2, 132.3,
124.4, 117.9 (d, J = 10.8 Hz), 117.7 (d, J = 10.4 Hz), 108.6 (d, J = 8.2
Hz), 108.5, 108.4 (d, J = 8.1 Hz), 107.8 (d, J = 27.7 Hz), 72.3 (d, J =
E
dx.doi.org/10.1021/jf504014y | J. Agric. Food Chem. XXXX, XXX, XXX−XXX

Journal of Agricultural and Food Chemistry
Article
X-ray Diffraction Analysis. Compound 1 was recrystallized by
slow evaporation from a mixture of acetone, dichloromethane, and
cyclohexane (1:1:1, v/v/v) to afford a suitable single crystal. Yellow
blocks of compound 1 (0.29 mm × 0.21 mm × 0.14 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 = 25.99°; 10716 measured reflections; 3627
independent reflections (Rint = 0.0475). Data were corrected for
Lorentz and polarization effects and for absorption (tmin = 0.7050 and
tmax = 1.0000). The structure was solved by direct methods using
SHELXS-97;11 all other calculations were performed with a Bruker
SAINT System and Bruker SMART programs.12 Full-matrix least-
membered azabridged neonicotinoid analogues. Therefore, to
obtain seven-membered azabridges, the preparation of
succinaldehyde was the main task in this work.
Hitherto, various methods of acidic17−23 and nonacidic
hydrolysis24 were reported to prepare succinaldehyde from
commercially available and synthetic equivalent 2,5-dimethox-
ydihydrofuran (DMTHF). Furthermore, according to our
previous study of eight-membered azabridges,10 it was found
that an acidic environment was conducive to the formation of
azabridged neonicotinoid compounds. Thus, compound 3 was
chosen to study the influence of the pH value, and the results
are listed in Table 1.
2
squares refinement based on F2 using the weight of 1/ [σ2 (F0 ) +
(0.0613P)2 + 0.0371P] gave final values of R = 0.0542, ωR = 0.1462,
and GOF (F) = 1.022 for 253 variables and 3627 contributing
reflections. Maximum shift/error = 0.000(3) and max/min residual
electron density = 0.530/−0.519 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 20 and 4 mg L−1 and others for bioassays. For comparative
purposes, IMI and CYC were tested under the same conditions.
Insecticidal Test for Cowpea Aphid (A. craccivora). The
insecticidal activity of synthetic compounds against cowpea aphid was
tested by using the leaf-dip method.13,14 Horsebean plant leaves with
30−40 apterous adults were dipped in diluted solutions of the
chemicals containing Triton X-100 (0.1 mg L−1) for 5 s, and the excess
dilution was sucked out with filter paper; the burgeons were placed in
Table 1. Optimization of Compound 3
a
entry
hydrolyzed succinaldehyde
time (h)
yield (%)
1
2
3
4
5
6
7
8
pH 1−2
pH 2−3
pH 6−7
pH 8−9
pH 2−3
pH 2−3
pH 2−3
1.5
1.5
66.0
82.5
44.2
1.5
b
1.5
tr
0.5
45.5
26.2
20.0
60.1
5.0
10.0
1.5
c
nonacidic
a
b
c
Isolated yields. tr, trace. See ref 24.
To begin with, the solution of succinaldehyde was used
immediately after acidic hydrolysis of DMTHF. The reaction
was monitored by TLC, and the target compound 3 was
successfully acquired in a good yield (Table 1, entry 1), which
encouraged us to optimize the pH value of succinaldehyde
solution before it was used in the next step. From the
experimental data in Table 1, it was observed that the pH value
below 2 or above 3 would display relatively low yields (Table 1,
entries 1−4). These results demonstrated that the pH value at
2−3 was more suitable to synthesize seven-membered
azabridged compounds.
On the basis of this optimal condition, the reaction time was
also investigated. The corresponding yields were increased, but
decreased with the extension of time (Table 1, entries 2 and 5−
7). Therefore, the reaction was carried out in 1.5 h, because the
decomposition rate of our target compound was more rapid
than the formation rate after a period of time. Eventually, the
nonacidic condition was also studied (Table 1, entry 8). The
succinaldehyde was prepared following literature procedures;24
however, the corresponding yield was still lower than that of
acid condition.
Crystal Structure Analysis. To provide more evidence for
the proposed molecular structure and establish the conforma-
tion of the target compounds, compound 1 was recrystallized
by slow evaporation and its single-crystal structure was
determined by X-ray crystallography as illustrated in Figure 3.
Unlikely eight-membered compounds, the pyridine ring, and
benzene ring of compound 1 pointed to the same direction.
Compared with the trans-configuration of nitro in the crystal
structure of IMI,26 the nitro groups of compound 1 was in cis-
configuration as anticipated. There are some characteristics of
the bond lengths. For example, the bond lengths of C(9)
N(2) (1.35 Å) and C(9)N(3) (1.34 Å) were obviously
shorter than the typical CN single bond (1.47 Å) but close to
that of CN (1.33 Å), owing to the transfer of the lone-pair
electrons on the amines to C(10)C(9) and the delocalization
of the electrons extended as far as the electron-withdrawing
the conditioned room (25
1 °C, 50% realtive humidity). Water
containing Triton X-100 (0.1 mg L−1) was used as control. The
mortality rates were evaluated 24 h after treatment. Each treatment
had three repetitions, and the data were adjusted and subjected to
probit analysis as before.
Insecticidal Test for Armyworm (Pseudaletia separata
Walker). The insecticidal activity against armyworm was tested by
foliar application.15−17 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 allowed to dry. The
dishes were infested with 10 third-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.
Insecticidal Test for Brown Planthopper (N. lugens). The
insecticidal activity against brown planthopper was tested by foliar
application. Rice seedlings were placed on moistened pieces of filter
paper in Petri dishes. The dishes were infested with 30−40 third-instar
larvae and then sprayed with the compound solutions (2.5 mL) using a
Potter spray tower (pressure, 5 lb/in2; settlement, 4.35 mg/cm2).
Samples were 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 subject to probit analysis as
before.
RESULTS AND DISCUSSION
■
Synthesis. To synthesize azabridged neonicotinoid com-
pounds, the major obstacle was the synthetic methodology.
Through comparison of the structures of the 1,3-dicarbonyl
derivative and our starting material B (cyclic β-nitroenamine),
similar nucleophilic centers were found in these two types of
substances, which implied that the target compounds can be
constructed in an intermolecular way involving primary amine
hydrochlorides and dialdehydes.10 Consequently, the commer-
cialized glutaraldehyde was first chosen to synthesize eight-
F
dx.doi.org/10.1021/jf504014y | J. Agric. Food Chem. XXXX, XXX, XXX−XXX

Journal of Agricultural and Food Chemistry
Article
Table 2. Insecticidal Activities of Compounds 1−37
a
mortality (%)
P. separata Walker
A. craccivora
compd
R
20 mg L−1 4 mg L−1 20 mg L−1 4 mg L−1
1
H
0
0
0
0
100
100
100
100
100
100
100
100
0
100
100
100
100
100
80
2
4-Br
3
4-OMe
4-F
80
80
90
60
50
80
0
10
10
10
0
4
5
4-Me
6
4-CF3
7
4-CN
0
80
8
4-Cl
30
0
100
0
9
4-NO2
2-Cl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
CYC
IMI
80
70
90
80
80
0
10
10
30
30
30
0
100
100
100
100
100
50
100
100
100
100
100
0
Figure 3. Crystal and chemical structures of compound 1.
2-Br
2-F
2-Me
group (−NO2), forming a coplanar olefin−amine π-electron
network.25,26 Moreover, it also made the bond lengths of
C(10)C(9) (1.41 Å) and CNO2 (C(10)N(4); 1.36 Å)
longer than that of normal CC (1.34 Å) and shorter than
that of typical CNO2 (CN; 1.49 Å), respectively.
Insecticidal Activity. Table 2 lists the insecticidal activities
of the title compounds against cowpea aphid (A. craccivora),
brown planthopper (N. lugens), and armyworm (P. separata
Walker). Most of the compounds exhibited significant
insecticidal activities against these three species of pests.
Compound 1 with no substituent on the phenyl group
presented similar insecticidal activities against cowpea aphid
and brown planthopper, but lower bioactivity against army-
worm, compared with seven-membered oxabridged compound
CYC (Table 3). Then, the substitution effect on insecticidal
activities was investigated.
2-OMe
2-CN
3-Me
40
0
0
100
0
100
0
3-CF3
0
3-OMe
3-Cl
100
100
80
50
100
70
100
0
0
100
100
100
100
100
100
100
0
40
0
30
3-NO2
3-F
0
0
0
70
3-F-4-OMe
2-F-4-Me
2,6-(F)2
3,4-(Cl)2
2,5-(OMe)2
2,3-(Me)2
2,4-(Me)2
2,5-(Me)2
2,5-(Cl)2
3,4-(Me)2
3,5-(Me)2
2,5-(F)2
2,3,4,5-(F)4
2,4-(F)2
2,3-(F)2
2,4,5-(F)3
0
0
0
0
0
50
0
0
70
80
100
90
70
0
30
20
0
100
100
100
100
100
100
100
90
100
100
100
100
90
50
0
The compounds with various types of substitutions on
position 4 of the phenyl group were first synthesized (2−9).
The bioassay showed that introducing an electron-donating
group (OMe and Me) (3 and 5) and a fluorine atom (4) could
contribute to great improvement of activity against armyworm
while presenting considerable activities against brown plan-
thopper and cowpea aphid. Meanwhile, bringing in an electron-
withdrawing group (CF3, CN, NO2) (6, 7, and 9), a bromine
atom (2), or a chlorine atom (8) on the phenyl ring would
decrease the activities against brown planthopper and cowpea
aphid but increase the bioactivity against armyworm, compared
with compound 1.
On position 2 of the phenyl group, the compound with a
cyano group (15) displayed relatively low insecticidal activities
and the others (10−14) exhibited excellent bioactivities against
the three species of pests, which confirmed that position 2 was
the key substitution site for structural derivation to obtain high-
activity molecules. Moreover, on the basis of the LC50 value in
Table 3, with the radius of the halogen atom increasing (10−
12), the insecticidal activities showed decreasing tendency
against armyworm, but still higher than that of CYC and IMI.
Notably, compounds 12 and 13 demonstrated the relatively
higher bioactivities among the structures with substitution on
position 2.
0
0
80
80
0
10
0
80
70
0
0
0
30
90
80
40
40
0
100
100
100
100
100
95
30
0
95
90
0
100
100
0
a
At 4 mg L−1, the mortality of all compounds against brown
planthopper (Nilaparvata lugens) was 100%.
conclude that introducing a methyl group and a fluorine atom
on any site of the phenyl group was favorable to increase the
insecticidal activities and that position 2 was an important site
for obtaining high-activity compounds.
Therefore, further SAR study of two substitutions on the
phenyl group was carried out. Initially, the combinations of
fluorine atom with methoxy group (22) and methyl (23) were
carried out. Unfortunately, the insecticidal activities against
cowpea aphid and armyworm were decreased dramatically,
which was not a good result for exploring a potential
neonicotinoid insecticide with superior bioactivities against
the three species of pests. Then, we turned our attention to
dimethyl substitution on the phenyl group.
The insecticidal activities of all the compounds with a
substituent on position 3 (16−21) were lower than that of
compound 1 against brown planthopper and cowpea aphid.
However, among these, compounds 16 and 21 presented
relatively high bioactivities against the three species of pests.
Combined with the discussion above, we could preliminarily
2,3-Dimethyl (27), 2,4-dimethyl (28), and 2,5-dimethyl
groups (29) were introduced into the phenyl group; owing
to the sterically hindered effect of the substituent, the
G
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Journal of Agricultural and Food Chemistry
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Table 3. LC50 Values of Some Compounds against Three Species of Pests
LC50 (95% fiducial limits) (mg L−1
)
compd
R
A. craccivora
N. lugens
P. separata Walker
a
1
H
0.342 (0.256−0.438)
0.574 (0.481−0.679)
0.172 (0.064−0.270)
0.403 (0.341−0.464)
0.196 (0.158−0.233)
2.938 (2.433−3.602)
2.718 (2.241−3.324)
2.469 (1.965−3.220)
0.412 (0.352−0.481)
0.409 (0.343−0.487)
0.184 (0.149−0.219)
0.396 (0.334−0.462)
0.419 (0.247−0.615)
0.421 (0.357−0.491)
nt
0.504 (0.427−0.597)
1.015 (0.870−1.181)
0.179 (0.140−0.221)
0.338 (0.239−0.450)
0.511 (0.439−0.591)
0.860 (0.721−1.029)
1.803 (1.544−2.111)
0.558 (0.451−0.671)
0.232 (0.193−0.277)
0.151 (0.119−0.183)
0.338 (0.239−0.450)
0.129 (0.047−0.231)
0.178 (0.134−0.222)
0.831 (0.710−0.951)
0.418 (0.351−0.489)
0.429 (0.360−0.506)
0.395 (0.327−0.469)
0.859 (0.629−1.230)
0.062 (0.041−0.082)
0.279 (0.133−0.473)
0.039 (0.006−0.077)
0.054 (0.033−0.077)
0.072 (0.045−0.099)
0.383 (0.197−0.593)
1.089 (0.973−1.218)
nt
nt
2
4-Br
3
4-OMe
4-F
10.937 (9.526−12.536)
4
nt
5
4-Me
nt
6
4-CF3
nt
7
4-CN
nt
8
4-Cl
7.550 (5.497−10.387)
10.984 (7.696−15.326)
11.019 (9.436−12.845)
6.103 (4.590−7.823)
10
11
12
13
14
16
18
19
24
25
26
27
28
29
30
CYC
IMI
2-Cl
2-Br
2-F
2-Me
6.762 (4.993−8.961)
2-OMe
3-Me
nt
nt
3-OMe
3-Cl
nt
nt
nt
2,6-(F)2
3,4-(Cl)2
2,5-(OMe)2
2,3-(Me)2
2,4-(Me)2
2,5-(Me)2
2,5-(Cl)2
nt
nt
nt
nt
0.490 (0.325−0.702)
0.864 (0.556−1.339)
0.450 (0.229−0.744)
0.426 (0.156−0.793)
1.268 (0.855−1.982)
0.435 (0.168−0.748)
0.634 (0.458−0.838)
8.421 (6.037−11.292)
9.549 (6.996−12.899)
nt
4.756 (3.510−6.374)
nt
26.692 (22.904−31.123)
34.078 (26.087−49.535)
a
Not tested.
compound with a 2,6-dimethyl group could not be synthesized.
Excitingly, compounds 28 (LC50 = 0.039 mg L−1) and 29 (LC50
= 0.054 mg L−1) displayed an improvement of about 1 order of
magnitude over CYC (LC50 = 0.383 mg L−1) in insecticidal
activity against brown planthopper and an activity similar to
that of 13 against cowpea aphid. Furthermore, the insecticidal
activity of compound 29 was 7-fold higher than that of IMI
against armyworm. Thus, we replaced the 2,5-dimethyl with
2,5-dimethoxy (26), 2,5-dichloro (30), and 2,5-difluoro (33) to
study the variations of bioactivities. Compounds 26, 30, and 33
showed comparable activity against brown planthopper, but
lower activities against armyworm and cowpea aphid,
respectively, which implied that introducing disubstitution on
positions 2 and 5 of the phenyl group could obtain a molecule
with high activity against brown planthopper.
Difluoro- and multifluoro-substituted compounds were also
studied (24, 33−37). Compared with compound 12,
introducing multiple fluorine atoms into the phenyl group
could not lead to the increase of bioactivities against three
species of pests. Therefore, the substitution of a methyl group
on the phenyl group was more favorable for the improvement
of insecticidal activities than that of fluorine atoms.
Table 4 lists the comparison of insecticidal activities between
eight-membered10 and seven-membered compounds. At low
concentration (4 and 20 mg L−1), most seven-membered
azabridged compounds showed apparently higher bioactivities
than eight-membered compounds against the three species of
pests. These results indicated that the ring size played a very
important role in increasing the insecticidal activities.
Docking Study. A docking study was performed to explore
the binding modes of our compounds. The crystal structure of
the Aplysia californica acetylcholine binding protein (Ac-
Table 4. Comparison of Insecticidal Activities between
Eight- and Seven-Membered Compounds
mortality (%)
P. separata
Walker
a
a
b
N. lugens
A. craccivora
entry
R
n = 1 n = 2 n = 1 n = 2 n = 1 n = 2
1
H
100
100
100
100
100
100
100
100
100
100
100
100
0
50
0
100
100
100
100
100
100
100
100
0
20
5
0
90
80
40
0
0
0
0
0
0
0
0
0
0
0
0
0
2
4-Me
2-Me
3-Me
4-Br
3
30
10
0
4
0
5
0
6
2-F
0
20
30
5
90
80
70
80
0
7
2-Cl
0
8
2-Br
0
9
3-NO2
4-NO2
4-Cl
0
15
0
10
11
12
0
0
0
100
100
0
80
70
2,5-(OMe)2
20
20
a
b
At 4 mg L−1. At 20 mg L−1.
AChBP) complexed with IMI (PDB code 3C79) was selected
to construct the binding models,27 which showed high affinity
with neonicotinoids and was a good prototype for investigating
the binding mode of neonicotinoids.28 For comparison,
compounds 1 and 29 were built, minimized, and docked into
H
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Journal of Agricultural and Food Chemistry
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Figure 4. Binding modes of compounds 1 (A, B) and 29 (C, D).
the ligand binding pocket of Ac-AChBP by using the Induced
Fit Docking approach, of which the IFDScore scoring function
was selected to evaluate the docking results. All atoms within 20
Å around IMI in the 3C79 structure were selected as binding
pocket and considered in the docking study. All computational
excellent yields. The bioassays showed that most of the
compounds presented superior bioactivities to IMI and seven-
membered oxabridged compound CYC against cowpea aphid,
brown planthopper, and armyworm. Compared with IMI,
compound 29 with 2,5-dimethyl group, displayed 7 fold and 20
fold higher activities against armyworm and brown planthop-
per, respectively. Moreover, seven-membered compounds
showed much higher bioactivities against three species of
pests than that of eight-membered azabridge neonicotinoids,
which implied that the framework of a seven-membered
azabridge could significantly improve the insecticidal activity of
neonicotinoid analogues and was a very good lead structure to
discover potential pesticides. Further studies on field testing of
the title compounds are in progress.
studies were performed using Maestro 9.0 (Schrodinger, LLC,
̈
2013).
The docking poses of compounds 1 and 29 were depicted in
Figure 4. It was found that water bridged hydrogen bonding
network played key roles for the ligands recognition, which has
also been reported for the binding of IMI and other
neonicotinoid compounds.27,28 Also, N−H···O hydrogen
bonds were observed between the peptide N−H of Cys190
and the nitro groups of compounds. The phenyl group inserted
into the interspace between loop C and the adjacent subunit,
and located between the Tyr188 and Tyr55. Comparing with
compound 1, the methyl group introduced into position 2 of
phenyl group in compound 29 could improve the hydrophobic
interactions with receptor (Figure 4B and 4D), which might be
one of the reasons for the improvement of insecticidal activity.
In conclusion, 37 novel seven-membered azabridged
neonicotinoid analogues were designed and synthesized. The
pH value at 2−3 of hydrolyzed succinaldehyde solution was an
optimized condition to synthesize target compounds in
ASSOCIATED CONTENT
■
S
* Supporting Information
Crystallographic information files (CIF) of compound 1. This
material is available free of charge via the Internet at http://
pubs.acs.org.
I
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Journal of Agricultural and Food Chemistry
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(16) Li, C.; Wang, Q.; Huang, R.; Mao, C.; Shang, J.; Bi, F. Synthesis
and insecticidal evalution of propesticides of benzoylphenylureas. J.
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AUTHOR INFORMATION
■
Corresponding Authors
*(Z.L.) Phone: +86-21-64253540. Fax: +86-21-64252603. E-
mail: lizhong@ecust.edu.cn.
*(X.X.) E-mail: xyxu@ecust.edu.cn.
Funding
This work was financially supported by the National High
Technology Research and Development Program of China
(863 Program, 2011AA10A207) and the National Natural
Science Foundation of China (21272071, 21172070, and
21472046). 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.
(18) Mueller, R.; Yang, J.; Duan, C.; Pop, E.; Zhang, L.; Huang, T.;
Denisenko, A.; Denisko, O. V.; Oniciu, D. C.; Bisgaier, C. L.; Pape, M.
E.; Freiman, C. D.; Goetz, B.; Cramer, C. T.; Hopson, K. L.; Dasseux,
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(20) Fournial, A.; Ranaivondrambola, T.; Mathe-Allainmat, M.;
The authors declare no competing financial interest.
Robins, R. J.; Lebreton, J. A short and efficient synthesis of bridgehead
mono- and dideuteriated tropinones. Eur. J. Org. Chem. 2010, 152−
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