Design, synthesis, crystal structure analysis, and insecticidal evaluation of phenylazoneonicotinoids

Article abstract of DOI:10.1021/jf2029708

On the basis of research of the proposed modes of action between neonicotinoids and insect nicotinic acetylcholine receptor (nAChR), a series of phenylazoneonicotinoids were designed and synthesized to further promote the π-π interaction between molecule and amino acid residues. The target compounds have been identified on the basis of satisfactory analytical and spectral (¹H NMR, ¹³C NMR, HRMS, and X-ray) data. The preliminary results revealed that tiny differences in substitutes resulted in different configurations and great bioactivity variations. Some compounds with electron-donating groups on positions 2 and 6 of the phenyl ring presented higher insecticidal activity than imidacloprid against cowpea aphids (Aphis craccivora). The impressive crystal structure of the excellent insecticidal activity compound 9q clearly proved that the functional electronegative pharmacophore was approximately vertical to the methyleneimidazolidine plane. The differences in the mode of interaction on nAChR of typical compounds 9h and 9q remain unclear.

Full text of DOI:10.1021/jf2029708

ARTICLE
pubs.acs.org/JAFC
Design, Synthesis, Crystal Structure Analysis, and Insecticidal
Evaluation of Phenylazoneonicotinoids
Zhenjun Ye, Shuang Xia, Xusheng Shao, Jiagao Cheng, Xiaoyong Xu, Zhiping Xu, Zhong Li,* and
Xuhong Qian
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology,
Shanghai 200237, China
S Supporting Information
b
ABSTRACT: On the basis of research of the proposed modes of action between neonicotinoids and insect nicotinic acetylcholine
receptor (nAChR), a series of phenylazoneonicotinoids were designed and synthesized to further promote the πÀπ interaction
between molecule and amino acid residues. The target compounds have been identified on the basis of satisfactory analytical and
spectral (1H NMR, 13C NMR, HRMS, and X-ray) data. The preliminary results revealed that tiny differences in substitutes resulted
in different configurations and great bioactivity variations. Some compounds with electron-donating groups on positions 2 and 6 of
the phenyl ring presented higher insecticidal activity than imidacloprid against cowpea aphids (Aphis craccivora). The impressive
crystal structure of the excellent insecticidal activity compound 9q clearly proved that the functional electronegative pharmacophore
was approximately vertical to the methyleneimidazolidine plane. The differences in the mode of interaction on nAChR of typical
compounds 9h and 9q remain unclear.
KEYWORDS: phenylazo compounds, neonicotinoids, πÀπ stacking, insecticide
’ INTRODUCTION
The insect nicotinic acetylcholine receptor (nAChR) is one of
the most important targets for the insecticides1,2 represented
by neonicotinoid, which is used for crop protection and pet
hygiene.3,4 In the 1990s, imidacloprid 1 led to the booming and
prosperous development of neonicotinoids5 such as nitenpyram6
2 and dinotefuran7 3 (Figure 1). To date, it has attracted great
attention for the characteristics of high efficiency, mammalian
safety, low toxicity, no cross-resistance, and unique mode of
action. Emerging as the fourth generation of pesticide replacing
organophosphorus, carbamate, and pyrethroid compounds, neo-
nicotinoids have taken the main share of the insecticidal market
Figure 1. Some commercial neonicotinoid compounds.
(in 2009, U.S. $2.632 billion) and have been used for insect
control worldwide.8,9 The newly launched neonicotinoid insec-
ticide Sulfoxaflor10 4 potentially accounts for a market share of
the structure of the nitromethylene molecule 7 to enhance the
over U.S. $400 million.11
πÀπ stacking interaction and explore the strategy of molecular
design and synthesis to improve the bioactivity of the new
chemical entities.
According to the crystal structure and three-dimensional
arrangement of the pharmacophore, three various modes of
action of neonicotinoids against nAChR were presumed succes-
sively by Yamamoto,12 Kagabu,13 and Casida.14 Besides, Qian
proposed a new mode of action by computational modeling in
2007, which demonstrated the importance of hydrogen bonding
and cooperative πÀπ interaction between the molecule and
amino acid residues.15 Afterward, two crystal structures of acetyl-
choline receptor binding proteinÀimidacloprid (AChBPs-IMI)
complex disclosed that the πÀπ stacking effect apparently
appeared between the conjugated part of the molecule and the
amino acid residues.16,17 Meanwhile, the reported structures 5
and 6 with well-conjugated systems presented quite good
activity18,19 (Scheme 1).
’ MATERIALS AND METHODS
Instruments. All melting points were obtained with a B€uchi
Melting Point B540 (B€uchi Labortechnik AG, Flawil, Switzerland)
1
and are uncorrected. H and 13C NMR spectra were recorded on a
Bruker AM-400 (400 MHz) spectrometer with CDCl3 as the solvent
and TMS as the internal standard. Chemical shifts are reported in
δ (parts per million) values. Coupling constants nJ are reported in hertz.
High-resolution electron mass (HR-EIMS) spectra were recorded under
Received: July 24, 2011
Revised:
August 27, 2011
Aiming at increasing the electron scope and density of the
conjugated system, herein we introduce the diazene moiety into
Accepted: September 6, 2011
Published: September 06, 2011
r
2011 American Chemical Society
10615
dx.doi.org/10.1021/jf2029708 J. Agric. Food Chem. 2011, 59, 10615–10623
|

Journal of Agricultural and Food Chemistry
ARTICLE
Scheme 1. Strategy To Improve the Conjugation Effect of the Neonicotinoid Analogues
electron impact (70 eV) condition using a MicroMass GCT CA 055
instrument. Analytical thin-layer chromatography (TLC) was carried
out on precoated plates (silica gel 60 F254), and spots were visualized by
an ultraviolet (UV) ZF-C analyzer.
118.1, 116.8 (d, J = 19.0 Hz, 1C), 48.2, 47.3, 43.7. HRMS (ES+) calcd for
C16H15N6O2F35Cl (M + H)+, 377.0929, found, 377.0928; calcd for
C16H15N6O2F37Cl (M + H)+, 379.0900, found, 379.0914.
2-Chloro-5-(((E)-2-(((E)-(2,4-difluorophenyl)diazenyl)(nitro)methylene)-
imidazolidin-1-yl)methyl)pyridine (9d): yield, 63%; mp 177.8À178.2 °C;
1H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.32 (s, 1H), 7.79 (d, J =
8.0 Hz, 1H), 7.54 (dd, J = 15.6, 8.8 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.24
(t, J = 10.0 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 4.43 (s, 1H), 4.05À3.91 (m,
2H), 3.92À3.78 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 161.8, 160.5
(dd, J = 245.5, 11.5 Hz, 1C), 157.2 (dd, J = 252.7, 12.1 Hz, 1C), 150.4,
150.2, 140.1, 139.3 (dd, J = 7.2, 3.8 Hz, 1C), 130.2, 126.6, 124.5, 119.0
(d, J = 7.2 Hz, 1C), 112.1 (d, J = 18.9 Hz, 1C), 105.0, 48.2, 47.3, 43.7.
HRMS (ES+) calcd for C16H14N6O2F235Cl (M + H)+, 395.0835, found,
395.0830; calcd for C16H14N6O2F237Cl (M + H)+, 397.0805, found,
397.0814.
2-Chloro-5-(((E)-2-(((E)-(2,3-difluorophenyl)diazenyl)(nitro)methyl-
ene)imidazolidin-1-yl)methyl)pyridine (9e):yield, 66%; mp 164.2À164.8 °C;
1H NMR (400 MHz, DMSO-d6) δ8.32 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 8.0,
2.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.34À7.31 (m, 1H), 7.19À7.09 (m,
2H), 4.43 (s, 2H), 4.03À3.93 (m, 2H), 3.92À3.81 (m, 2H); 13C NMR (100
MHz, DMSO-d6) δ 161.6, 150.7 (dd, J = 242.4, 11.6 Hz, 1C), 150.4, 150.2,
145.3 (dd, J= 249.0, 14.0 Hz, 1C), 144.2, 140.1, 130.3, 127.3, 124.5, 124.3 (dd,
J=7.7, 4.8Hz, 1C), 113.7(d,J= 17.2 Hz, 1C), 113.5 (d, J= 1.8 Hz, 1C), 48.3,
47.3, 44.1. HRMS (ES+) calcd for C16H14N6O2F235Cl (M + H)+, 395.0835,
found, 395.0822; calcd for C16H14N6O2F237Cl (M + H)+, 397.0805, found,
397.0821.
General Synthetic Procedure for Compounds 9aÀy and
11aÀh . Substituted aniline (3.0 mmol) was added to a solution of
concentrated HCl (0.73 mL, 9.0 mmol) in 2 mL of water, and the
mixture was cooled to 0 °C; a 0 °C solution of NaNO2 (3.15 mmol) in
3 mL water was dropwise added over a period of 5 min, maintaining the
reaction temperature below 2 °C. After 15 min of stirring, the solution of
diazonium salt was dropped into a reaction mixture of 8 or 10 (2.5 mmol)
in 20 mL of acetone, which was immersed in a cooling bath set to 0 °C,
and the reaction progress was monitored by TLC. On completion of the
reaction, half of the solvent was evaporated under reduced pressure, and
to the resulting mixture was added 15 mL of saturated NaHCO3. The
precipitate formed was filtered, washed with dichloromethane and water,
and dried to provide the corresponding products.
2-Chloro-5-(((E)-2-(nitro((E)-phenyldiazenyl)methylene)imidazo-
1
lidin-1-yl)methyl)pyridine (9a): yield, 71%; mp 149.5À150.3 °C; H
NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.35 (d, J = 2.4 Hz, 1H),
7.81 (dd, J = 8.0, 2.4 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 7.6 Hz,
2H), 7.38 (t, J = 7.6 Hz, 2H), 7.19 (t, J = 7.2 Hz, 1H), 4.45 (s, 2H),
4.04À3.95 (m, 2H), 3.94À3.85 (m, 2H); 13C NMR (100 MHz, DMSO-
d6) δ 162.1, 154.1, 150.4, 150.2, 140.2, 130.3, 129.4, 126.8, 125.5, 124.7,
121.0, 48.1, 47.4, 43.5. HRMS (ES+) calcd for C16H16N6O235Cl
(M + H)+, 359.1023, found, 359.1031; calcd for C16H16N6O237Cl
(M + H)+, 361.0994, found, 361.0993.
2-Chloro-5-(((E)-2-(((E)-(3-chloro-4-fluorophenyl)diazenyl)(nitro)-
methylene)imidazolidin-1-yl)methyl)pyridine (9f): yield, 72%; mp
2-Chloro-5-(((E)-2-(((E)-(4-fluorophenyl)diazenyl)(nitro)methyle-
ne)imidazolidin-1-yl)methyl)pyridine (9b): yield, 74%; mp 177.0À
177.8 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.35
(s, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.60À7.45 (m, 3H), 7.21 (t, J = 8.4 Hz,
2H), 4.45 (s, 2H), 4.06À3.94 (m, 2H), 3.94À3.79 (m, 2H); 13C NMR
(100 MHz, DMSO-d6) δ 161.1 (d, J = 243.0 Hz, 1C), 162.0, 150.8 (d, J =
3.0 Hz, 1C), 150.4, 150.2, 140.2, 130.3, 125.4, 124.7, 122.5 (d, J = 8.0 Hz,
1C), 116.1 (d, J = 23.0 Hz, 1C), 48.2, 47.4, 43.6. HRMS (ES+) calcd for
C16H15N6O2F35Cl (M + H)+, 377.0929, found, 377.0918; calcd for
C16H15N6O2F37Cl (M + H)+, 379.0900, found, 379.0910.
2-Chloro-5-(((E)-2-(((E)-(2-fluorophenyl)diazenyl)(nitro)methylene)-
imidazolidin-1-yl)methyl)pyridine (9c): yield, 65%; mp 165.3À166.1 °C;
1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 2.0 Hz, 1H), 7.80 (dd, J =
8.4, 2.4 Hz, 1H), 7.55À7.48 (m, 1H), 7.26À7.10 (m, 2H), 4.43 (s, 1H),
4.03À3.92 (m, 2H), 3.91À3.82 (m, 2H); 13C NMR (100 MHz, DMSO-
d6) δ 161.9, 158.8, 156.3, 150.4, 150.2, 142.2 (d, J = 7.0 Hz, 1C), 140.2,
130.2, 127.4 (d, J = 8.0 Hz, 1C), 126.8, 124.9 (d, J = 3.0 Hz, 1C), 124.6,
1
190.8À191.7 °C; H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H),
8.33 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 8.4, 2.4 Hz, 1H), 7.54 (dd, J = 7.2,
2.0 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.46À7.37 (m, 2H), 4.45 (s, 2H),
4.05À3.96 (m, 2H), 3.95À3.84 (m, 2H); 13C NMR (100 MHz, DMSO-
d6) δ 161.6, 155.7 (d, J = 244.3 Hz, 1C), 151.46, 150.38, 150.16, 140.15,
130.19, 125.62, 124.63, 121.7 (d, J = 7.0 Hz, 1C), 121.22, 120.5 (d, J =
19.0 Hz, 1C), 117.6 (d, J = 22.0 Hz, 1C), 48.32, 47.40, 43.51. HRMS
(ES+) calcd for C16H14N6O2F35Cl2 (M + H)+, 411.0539, found, 411.0522;
calcd for C16H14N6O2F37Cl2 (M + H)+, 415.0480, found, 415.0516.
2-Chloro-5-(((E)-2-(((E)-(2-chlorophenyl)diazenyl)(nitro)methylene)-
imidazolidin-1-yl)methyl)pyridine (9g): yield, 78%; mp 163.8À164.9 °C;
1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.34 (d, J = 2.0 Hz, 1H),
7.79 (dd, J = 8.0, 2.4 Hz, 1H), 7.52 (t, J = 7.2 Hz, 1H), 7.48 (t, J = 7.6 Hz,
2H), 7.33À7.29 (m, 1H), 7.21À7.09 (m, 1H), 4.45 (s, 2H), 4.04À3.92 (m,
2H), 3.92À3.78 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ162.0, 150.4,
150.1, 150.0, 140.1, 130.5, 130.5, 130.3, 128.0, 127.4, 127.3, 124.6, 117.7,
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ARTICLE
48.5, 47.4, 44.2. HRMS (ES+) calcd for C16H15N6O235Cl2 (M + H)+,
393.0634, found, 393.0627; calcd for C16H15N6O237Cl2 (M + H)+,
397.0575, found, 397.0583.
MHz, DMSO-d6) δ 8.34 (d, J = 2.4 Hz, 1H), 7.80 (dd, J = 8.4, 2.4 Hz, 1H),
7.51 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H),
4.42 (s, 1H), 4.03À3.90 (m, 2H), 3.90À3.77 (m, 2H), 2.30 (s, 3H); 13C
NMR (100 MHz, DMSO-d6) δ 162.1, 152.1, 150.3, 150.2, 140.2, 136.2,
130.5, 129.9, 124.6, 120.9, 48.2, 47.4, 43.9, 21.2. HRMS (ES+) calcd for
C17H18N6O235Cl (M + H)+, 373.1180, found, 373.1172; calcd for
C17H18N6O237Cl (M + H)+, 375.1150, found, 375.1168.
2-Chloro-5-(((E)-2-(((E)-(3,4-dimethylphenyl)diazenyl)(nitro)methyl-
ene)imidazolidin-1-yl)methyl)pyridine (9o):yield, 75%; mp 173.9À174.8 °C;
1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 8.0 Hz, 1H), 7.79 (dd, J = 8.0,
2.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.27 (s, 1H), 7.23 (d, J = 8.0 Hz, 1H),
7.12 (d, J = 8.0 Hz, 1H), 4.40 (s, 2H), 4.01À3.91 (m, 2H), 3.86À3.80
(m, 2H), 2.23 (s, 3H), 2.20 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ
162.1, 152.3, 150.3, 150.1, 140.1, 137.0, 135.2, 130.5, 130.4, 125.7, 124.6, 122.0,
118.6, 48.2, 47.4, 44.1, 20.0, 19.6. HRMS (ES+) calcd for C18H20N6O235Cl (M
+ H)+, 387.1336, found, 387.1332; calcd for C18H20N6O237Cl (M + H)+,
389.1307, found, 389.1322.
2-Chloro-5-(((E)-2-(((E)-(2,3-dimethylphenyl)diazenyl)(nitro)methyl-
ene)imidazolidin-1-yl)methyl)pyridine (9p): yield, 72%; mp 159.3À
159.4 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J = 2.0 Hz, 1H),
7.72 (dd, J = 8.4, 2.4 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 7.6 Hz,
1H), 7.03 (t, J = 7.6 Hz, 1H), 6.98 (d, J = 7.2 Hz, 1H), 4.35 (s, 1H),
3.96À3.86 (m, 2H), 3.83À3.69 (m, 2H), 2.33 (s, 3H), 2.26 (s, 3H); 13C
NMR (100 MHz, DMSO-d6) δ 162.3, 151.8, 150.2, 150.0, 140.0, 137.6,
132.8, 131.2, 128.0, 127.7, 125.8, 124.6, 113.3, 48.5, 47.4, 45.4, 20.2, 13.2.
HRMS (ES+) calcd for C18H20N6O235Cl (M + H)+, 387.1336, found,
387.1320; calcd for C18H20N6O237Cl (M + H)+, 389.1307, found,
389.1320.
2-Chloro-5-(((E)-2-(((E)-(2,6-dimethylphenyl)diazenyl)(nitro)methyl-
ene)imidazolidin-1-yl)methyl)pyridine (9q): yield, 76%; mp 170.0À
170.9 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.35 (d, J =
2.4 Hz, 1H), 7.79 (dd, J = 8.0, 2.4 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.02
(d, J = 7.2 Hz, 2H), 6.98À6.94 (m, 1H), 4.48 (s, 2H), 4.02À3.92 (m,
2H), 3.93À3.84 (m, 2H), 2.23 (s, 6H); 13C NMR (100 MHz, DMSO-
d6) δ 162.2, 151.4, 150.4, 150.1, 140.1, 130.5, 130.4, 129.17, 125.7,
125.6, 124.7, 48.2, 47.3, 43.6, 19.6. HRMS (ES+) calcd for
C18H20N6O235Cl (M + H)+, 387.1336, found, 387.1339. calcd for
C18H20N6O237Cl (M + H)+, 389.1307, found, 389.1322.
2-Chloro-5-(((E)-2-(((E)-(2,6-dichlorophenyl)diazenyl)(nitro)methyl-
ene)imidazolidin-1-yl)methyl)pyridine (9h): yield, 71%; mp 172.3À
173.4 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.35 (d, J =
2.0 Hz, 1H), 7.77 (dd, J = 8.0, 2.4 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.44
(d, J = 8.0 Hz, 2H), 7.16 (t, J = 8.0 Hz, 1H), 4.52 (s, 2H), 4.04À3.91
(m, 2H), 3.90À3.75 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ
161.2, 150.4, 150.1, 149.0, 140.0, 130.5, 129.4, 127.7 126.9, 124.7, 55.4,
48.3, 47.5, 44.1. HRMS (ES+) calcd for C16H14N6O235Cl3 (M + H)+,
427.0244, found, 427.0229; calcd for C16H14N6O237Cl3 (M + H)+,
433.0155, found, 433.0199.
5-(((E)-2-(((E)-(4-Bromophenyl)diazenyl)(nitro)methylene)imidazo-
lidin-1-yl)methyl)-2-chloropyridine (9i): yield, 81%; mp175.4À176.2 °C;
1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 2.0 Hz, 1H), 7.78 (dd, J =
8.0, 2.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.51
(d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.4 Hz, 2H), 4.41 (s, 2H), 4.05À3.92 (m,
2H), 3.89À3.80 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 161.7,
153.4, 150.3, 150.2, 140.2, 132.2, 130.5, 126.3, 124.6, 122.8, 118.8, 48.2,
47.4, 44.3. HRMS (ES+) calcd for C16H15N6O235Cl79Br (M + H)+,
437.0128, found, 437.0113; calcd for C16H15N6O237Cl81Br (M + H)+,
441.0078, found, 441.0077.
2-Chloro-5-(((E)-2-(((E)-(2-iodophenyl)diazenyl)(nitro)methylene)-
imidazolidin-1-yl)methyl)pyridine (9j): yield, 69%; mp 173.7À174.6 °C;
1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 2.4 Hz, 1H), 7.86 (dd, J =
8.0, 1.2 Hz, 1H), 7.77 (dd, J= 8.4, 2.4 Hz, 1H), 7.48 (d, J= 8.4 Hz, 1H), 7.44
(dd, J = 8.0, 1.6 Hz, 1H), 7.39À7.32 (m, 1H), 6.97À6.90 (m, 1H), 4.45
(s, 2H), 4.02À3.93 (m, 2H), 3.90À3.80 (m, 2H); 13C NMR (100 MHz,
DMSO-d6) δ 162.1, 152.1, 150.4, 150.1, 140.1, 139.5, 130.5, 129.4, 128.4,
127.2, 124.7, 116.7, 99.9, 48.7, 47.5, 44.5. HRMS (ES+) calcd for
C16H15N6O235ClI (M + H)+, 484.9990, found, 484.9978; calcd for
C16H15N6O237ClI (M + H)+, 486.9960, found, 486.9968.
2-Chloro-5-(((E)-2-(nitro((E)-(4-nitrophenyl)diazenyl)methylene)-
imidazolidin-1-yl)methyl)pyridine (9k): yield, 76%; mp 142.1À142.7 °C;
1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.19 (d, J = 8.4 Hz, 2H),
7.79 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.0 Hz, 1H),
4.38 (s, 2H), 3.96 (t, J = 10.0 Hz, 2H), 3.77 (t, J = 10.0 Hz, 2H); 13C NMR
(100 MHz, DMSO-d6) δ 160.9, 159.9, 150.1, 150.1, 143.5, 140.1, 131.0,
129.8, 125.4, 124.5, 120.6, 48.5, 47.4, 46.1. HRMS (ES+) calcd for
C16H15N7O435Cl (M + H)+, 404.0874, found, 404.0878; calcd for
C16H15N7O437Cl (M + H)+, 406.0845, found, 406.0850.
2-Chloro-5-(((E)-2-(((E)-mesityldiazenyl)(nitro)methylene)imidazo-
1
lidin-1-yl)methyl)pyridine (9r): yield, 71%; mp =136.5À137.0 °C; H
NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.34 (d, J = 2.0 Hz, 1H),
7.78 (dd, J = 8.0, 2.4 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 16.4
Hz, 2H), 4.46 (s, 2H), 4.03À3.92 (m, 2H), 3.92À3.82 (m, 2H), 2.22
(s, 9H); 13C NMR (100 MHz, DMSO-d6) δ 162.3, 150.4, 150.1, 148.9,
140.1, 134.8, 130.5, 130.4, 129.9, 125.5, 124.7, 48.1, 47.2, 43.5, 21.0, 19.8.
HRMS (ES+) calcd for C19H22N6O235Cl (M + H)+, 401.1493, found,
401.1488; calcd for C19H22N6O237Cl (M + H)+, 403.1463, found,
403.1482.
2-Chloro-5-(((E)-2-(nitro((E)-(2-nitrophenyl)diazenyl)methylene)-
imidazolidin-1-yl)methyl)pyridine (9l): yield, 72%; mp 155.4À156.3 °C;
1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.31 (s, 1H), 7.79 (d, J =
8.0 Hz, 1H), 7.73 (dd, J = 8.0, 2.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.60
(t, J = 7.6 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 4.42
(s, 2H), 3.98À3.93 (m, 2H), 3.88À3.83 (m, 2H); 13C NMR (100 MHz,
DMSO-d6) δ 161.5, 150.4, 150.1, 146.3, 146.2, 140.0, 132.9, 130.3, 127.5,
125.9, 124.7, 124.0, 118.1, 48.5, 47.3, 43.8. HRMS (ES+) calcd for
C16H15N7O435Cl (M + H)+, 404.0847, found, 404.0879; calcd for
C16H15N7O437Cl (M + H)+, 406.0845, found, 406.0846.
2-Chloro-5-(((E)-2-(((E)-(2,6-dimethyl-4-(perfluoropropan-2-yl)-
phenyl)diazenyl)(nitro)methylene) imidazolidin-1-yl)methyl)pyridine
1
(9s): yield, 78%; mp 130.1À130.8 °C; H NMR (400 MHz, DMSO-
d6) δ 10.34 (s, 1H), 8.36 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 8.0, 2.0 Hz,
1H), 7.50 (d, J = 8.0 Hz, 1H), 7.29 (s, 2H), 4.52 (s, 2H), 4.04À3.99
(m, 2H), 3.96À3.91 (m, 2H), 2.33 (s, 6H); 13C NMR (100 MHz,
DMSO-d6) δ 161.8, 153.7, 150.5, 150.1, 140.0, 131.7, 130.3, 126.1, 125.8
(d, J = 98 Hz, 1C), 124.7, 121.0 (m, 1C), 92.5 (q, J = 32.1 Hz, 1C), 90.7
(q, J = 31.8 Hz, 1C), 48.3, 47.3, 43.4, 19.7. HRMS (ES+) calcd for
C21H19N6O2F735Cl (M + H)+, 555.1146, found, 555.1144; calcd for
C21H19N6O2F737Cl (M + H)+, 557.1117, found, 557.1133.
2-Chloro-5-(((E)-2-(nitro((E)-o-tolyldiazenyl)methylene)imidazo-
1
lidin-1-yl)methyl)pyridine (9m): yield, 68%; mp 177.0À177.8 °C; H
NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.73 (dd, J = 8.0, 2.0 Hz,
1H), 7.46 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 7.2 Hz,
1H), 7.14 (t, J = 7.6 Hz, 1H), 7.05 (t, J = 7.2 Hz, 1H), 4.33 (s, 2H), 3.89
(t, J = 10.0 Hz, 2H), 3.72 (t, J = 10.0 Hz, 2H), 2.40 (s, 3H); 13C NMR
(100 MHz, DMSO-d6) δ 162.2, 151.9, 150.1, 145.0, 134.0, 133.9, 131.5,
131.1, 128.4, 126.6, 126.4, 124.5, 115.3, 48.6, 47.5, 46.0, 17.8. HRMS
(EI+) calcd for C17H17N6O235Cl (M)+, 372.1102, found, 372.1106;
calcd for C17H17N6O237Cl (M)+, 374.1072, found, 374.1120.
2-Chloro-5-(((E)-2-(((E)-(2-ethyl-6-methylphenyl)diazenyl)(nitro)-
methylene)imidazolidin-1-yl)methyl)pyridine (9t): yield, 71%; mp 149.1À
149.8 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.36 (d, J =
2.0 Hz, 1H), 7.79 (dd, J = 8.0, 2.4 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H),
7.11À6.90 (m, 3H), 4.48 (d, J = 17.2 Hz, 2H), 4.03À3.88 (m, 2H),
2-Chloro-5-(((E)-2-(nitro((E)-p-tolyldiazenyl)methylene)imidazolidin-
1-yl)methyl)pyridine (9n): yield, 73%; mp 174.4À175.2 °C; 1HNMR(400
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ARTICLE
3.90À3.77 (m, 2H), 2.58 (q, J = 7.2 Hz, 2H), 1.09 (t, J = 7.2 Hz, 3H); 13
C
2-Chloro-5-(((E)-2-(((E)-(2,6-dichlorophenyl)diazenyl)(nitro)methyl-
ene)imidazolidin-1-yl)methyl)thiazole (11b): Yyield, 63%; mp 141.0À
NMR (100 MHz, DMSO-d6) δ 162.3, 151.3, 150.4, 150.1, 140.1, 137.2,
130.7, 129.7, 129.2, 127.6, 126.1, 125.8, 124.7, 48.2, 47.3, 44.2, 25.5, 20.0, 16.1.
HRMS (ES+) calcd for C19H22N6O235Cl (M + H)+, 401.1493, found,
401.1482; calcd for C19H22N6O237Cl (M + H)+, 403.1463, found, 403.1478.
2-Chloro-5-(((E)-2-(((E)-(2,6-diethylphenyl)diazenyl)(nitro)methyl-
ene)imidazolidin-1-yl)methyl)pyridine (9u): yield, 69%; mp 136.4À
137.5 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.37 (d, J =
2.0 Hz, 1H), 7.81 (dd, J = 8.0, 2.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.03
(s, 3H), 4.49 (s, 2H), 4.05À3.92 (m, 2H), 3.92À3.81 (m, 2H), 2.57
(q, J = 7.2 Hz, 4H), 1.09 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz,
DMSO-d6) δ 162.4, 151.1, 150.5, 150.2, 140.2, 136.5, 130.4, 127.6,
126.1, 125.6, 124.8, 48.06, 47.2, 43.5, 25.6, 16.2. HRMS (ES+) calcd for
C20H24N6O235Cl (M + H)+, 415.1649, found, 415.1649; calcd for
C20H24N6O237Cl (M + H)+, 417.1620, found, 417.1636.
1
142.0 °C; H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 7.66 (s,
1H), 7.46 (d, J = 8.0 Hz, 2H), 7.19 (t, J = 8.0 Hz, 2H), 4.72 (s, 2H),
3.98À3.93 (m, 2H), 3.89À3.83 (m, 2H); 13C NMR (100 MHz, DMSO-
d6) δ 159.6, 152.4, 148.9, 142.6, 134.7, 129.3, 127.7, 127.2, 125.9, 48.0,
43.6, 43.3. HRMS (ES+) calcd for C14H12N6O2S35Cl3 (M + H)+,
432.9808, found, 432.9810; calcd for C14H12N6O2S37Cl3 (M+H)+,
438.9720, found, 438.9730.
2-Chloro-5-(((E)-2-(((E)-(2,3-dimethylphenyl)diazenyl)(nitro)methyl-
ene)imidazolidin-1-yl)methyl)thiazole (11c): yield, 61%; mp 160.6À
161.5 °C; 1H NMR (400 MHz, DMSO-d6) δ 7.60 (s, 1H), 7.29 (d, J =
7.6 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 6.8 Hz, 1H), 4.55
(s, 2H), 3.96À3.84 (m, 2H), 3.84À3.76 (m, 2H), 2.31 (s, 3H), 2.26
(s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 161.3, 151.8, 151.6, 141.8,
137.6, 136.1, 132.8, 128.1, 127.6, 125.8, 113.3, 48.3, 45.5, 43.1, 20.2, 13.3.
HRMS (ES+) calcd for C16H18N6O2S35Cl (M + H)+, 393.0900, found,
393.0904; calcd for C16H18N6O2S37Cl (M + H)+, 395.0871, found,
495.0885.
2-Chloro-5-(((E)-2-(((E)-(2,6-dimethylphenyl)diazenyl)(nitro)methyl-
ene)imidazolidin-1-yl)methyl)thiazole (11d): yield, 68%; mp 152.4À
153.2 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 7.66
(s, 1H), 7.03 (d, J = 7.2 Hz, 1H), 6.99À6.96 (m, 1H), 4.67 (s, 2H),
3.99À3.93 (m, 2H), 3.91À3.86 (m, 2H), 2.23 (s, 6H); 13C NMR (100
MHz, DMSO-d6) δ 161.0, 152.2, 151.4, 142.5, 134.9, 130.3, 129.2,
125.8, 125.6, 47.9, 43.5, 43.2, 19.5. HRMS (ES+) calcd for
C16H18N6O2S35Cl (M + H)+, 393.0900, found, 393.0894; calcd for
C16H18N6O2S37Cl (M + H)+, 395.0871, found, 395.0857.
2-Chloro-5-(((E)-2-(((E)-mesityldiazenyl)(nitro)methylene)imidazo-
lidin-1-yl)methyl)thiazole (11e): yield, 70%; mp 127.8À129.1 °C; 1H
NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 7.65 (s, 1H), 6.84 (s, 2H),
4.63 (s, 2H), 3.98À3.89 (m, 2H), 3.87À3.78 (m, 2H), 2.22 (s, 9H); 13C
NMR (100 MHz, DMSO-d6) δ 161.0, 152.0, 149.0, 142.3, 135.4, 134.8,
130.3, 129.9, 126.0, 47.9, 44.2, 43.2, 21.0, 19.7. HRMS (ES+) calcd for
C17H20N6O2S35Cl (M + H)+, 407.1057, found, 407.1062; calcd for
C17H20N6O2S37Cl (M + H)+, 409.1027, found, 409.1032.
2-Chloro-5-(((E)-2-(((E)-(2,6-diisopropylphenyl)diazenyl)(nitro)-
methylene)imidazolidin-1-yl)methyl)pyridine (9v): yield, 66%; mp
126.3À127.1 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J =
8.0 Hz, 1H), 7.81 (dd, J = 8.0, 2.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H),
7.12À7.08 (m, 3H), 4.49 (s, 2H), 3.98À3.94 (m, 2H), 3.88À3.84
(m, 2H), 3.04À2.97 (m, 1H), 1.09 (s, 3H), 1.07 (s, 3H); 13C NMR (100
MHz, DMSO-d6) δ 162.2, 151.0, 150.5, 150.0, 140.3, 140.1, 130.3,
126.1, 125.4, 124.7, 123.3, 48.1, 47.28, 43.3, 27.7, 24.1. HRMS (ES+)
calcd for C22H28N6O235Cl (M + H)+, 443.1962, found, 443.1947; calcd
for C22H28N6O237Cl (M + H)+, 445.1933, found, 445.1921.
2-Chloro-5-(((E)-2-(((E)-(4-methoxyphenyl)diazenyl)(nitro)methyl-
ene)imidazolidin-1-yl)methyl)pyridine (9w): yield, 74%; mp 165.3À
166.3 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 8.0 Hz, 1H),
7.79 (dd, J = 8.0, 2.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.0 Hz,
1H), 6.95 (d, J = 8.8 Hz, 1H), 4.38 (s, 2H), 3.96À3.91 (m, 2H), 3.81À3.75
(m, 2H), 3.77 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 162.1, 158.6,
150.2, 150.2, 148.2, 140.2, 130.8, 125.8, 124.6, 122.3, 114.6, 55.7, 48.1, 47.4,
44.5. HRMS (ES+) calcd for C17H18N6O335Cl(M +H)+, 389.1129, found,
389.1133; calcd for C17H18N6O337Cl (M + H)+, 391.1099, found,
391.1102.
2-Chloro-5-(((E)-2-(((E)-(2-methoxyphenyl)diazenyl)(nitro)methyl-
ene)imidazolidin-1-yl)methyl)pyridine (9x): yield, 71%; mp 151.7À
152.4 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.37 (d, J =
8.4 Hz, 1H), 7.85 (dd, J = 8.4, 2.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.36
(dd, J = 8.4, 2.0 Hz, 1H), 7.19À7.15 (m, 1H), 7.05 (d, J = 8.0 Hz, 1H),
6.94À6.89 (m, 2H), 4.43 (s, 2H), 3.98À3.92 (m, 2H), 3.87 (s, 1H),
3.86À3.80 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 162.09, 154.63,
150.38, 150.35, 143.34, 140.30, 130.23, 127.99, 126.51, 124.56, 121.14,
117.01, 113.51, 56.66, 48.18, 47.49, 43.48. HRMS (ES+) calcd for
C17H18N6O335Cl (M + H)+, 389.1129, found, 389.1138; calcd for
C17H18N6O337Cl (M + H)+, 391.1099, found, 391.1105.
2-Chloro-5-(((E)-2-(((E)-(2,6-dimethoxyphenyl)diazenyl)(nitro)methyl-
ene)imidazolidin-1-yl)methyl)pyridine (9y): Yyield, 73%; mp 135.1À
135.6 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 8.0 Hz, 1H),
7.76 (dd, J = 8.4, 2.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.09 (t, J = 8.0 Hz,
1H), 6.66 (d, J = 8.0 Hz, 1H), 4.49 (s, 2H), 3.95À3.89 (m, 2H),
3.83À3.78 (m, 2H), 3.63 (s, 6H); 13C NMR (100 MHz, DMSO-d6) δ
161.54, 152.33, 150.28, 149.99, 139.93, 134.32, 130.72, 126.51, 124.59,
116.07, 105.62, 56.46, 48.34, 47.51, 43.43. HRMS (ES+) calcd for
C18H20N6O435Cl (M + H)+, 419.1235, found, 419.1229; calcd for
C18H20N6O437Cl (M + H)+, 421.1205, found, 421.1202.
2-Chloro-5-(((E)-2-(((E)-(2,6-diethylphenyl)diazenyl)(nitro)methyl-
ene)imidazolidin-1-yl)methyl)thiazole (11f): yield, 61%; mp 116.5À
1
117.4 °C; H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 7.67 (s,
1H), 7.06À7.02 (m, 3H), 4.67 (s, 2H), 3.98À3.84 (m, 4H), 2.57 (q, J =
7.2 Hz, 4H), 1.09 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, DMSO-d6) δ
161.1, 152.2, 151.0, 142.6, 136.5, 134.8, 127.5, 126.1, 125.7, 47.8, 43.5,
43.1, 25.4, 16.1. HRMS (ES+) calcd for C18H22N6O2S35Cl (M + H)+,
421.1213, found, 421.1199; calcd for C18H22N6O2S37Cl (M + H)+,
423.1184, found, 423.1177.
2-Chloro-5-(((E)-2-(((E)-(4-methoxyphenyl)diazenyl)(nitro)methyl-
ene)imidazolidin-1-yl)methyl)thiazole (11g): yield, 66%; mp 162.3À
1
163.0 °C; H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 7.65 (s,
1H), 7.49 (d, J = 9.2 Hz, 2H), 6.97 (d, J = 9.2 Hz, 2H), 4.62 (s, 2H),
4.02À3.92 (m, 2H), 3.92À3.85 (m, 2H), 3.79 (s, 3H); 13C NMR (100
MHz, DMSO-d6) δ 161.0, 158.8, 152.1, 148.0, 142.5, 134.8, 124.9,
122.4, 114.6, 55.8, 47.7, 43.4, 43.2. HRMS (ES+) calcd for
C15H16N6O3S35Cl (M + H)+, 395.1693, found, 395.0685; calcd for
C15H16N6O3S37Cl (M + H)+, 397.0664, found, 397.0683.
2-Chloro-5-(((E)-2-(((E)-(2,6-dimethoxyphenyl)diazenyl)(nitro)methyl-
ene)imidazolidin-1-yl)methyl)thiazole (11h): yield, 63%; mp 165.5À
166.3 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 7.65 (s, 1H),
7.10 (t, J = 8.4 Hz, 1H), 6.68 (d, J = 8.4 Hz, 2H), 4.69 (s, 2H), 3.91À3.86
(m, 2H), 3.81À3.73 (m, 2H), 3.63 (s, 6H); 13C NMR (100 MHz, DMSO-
d6) δ 159.5, 152.3, 152.2, 142.2, 135.4, 126.6, 126.4, 105.6, 56.4, 48.2, 43.8,
43.3. HRMS (ES+) calcd for C16H18N6O4S35Cl (M + H)+, 425.0799, found,
425.0799; calcd for C16H18N6O4S37Cl(M +H)+, 427.0769, found, 427.0760.
X-ray Diffraction Analysis. Compound 9q was recrystallized by
slow evaporation from a mixture of acetone and methanol to afford a
2-Chloro-5-(((E)-2-(nitro((E)-(4-nitrophenyl)diazenyl)methylene)-
imidazolidin-1-yl)methyl)thiazole (11a): yield, 65%; mp 157.3À157.9 °C;
1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J = 9.2 Hz, 2H), 7.66 (s, 1H),
7.63 (d, J = 8.8 Hz, 2H), 4.70 (s, 2H), 4.07À4.00 (m, 2H), 4.00À3.93 (m,
2H); 13C NMR (100 MHz, DMSO-d6) δ 159.8, 152.3, 144.4, 142.6, 134.2,
125.5, 120.6, 48.2, 43.8, 42.9. HRMS (ES+) calcd for C14H13N7O4S35Cl
(M + H)+, 410.0438, found, 410.0435; calcd for C14H13N7O4S37Cl
(M + H)+, 412.0409, found, 412.0411.
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suitable single crystal. Yellow blocks of 9q (0.400 mm  0.369 mm Â
0.227 mm) were mounted on a quartz fiber and detected by Bruker
Smart 1000 single-crystal diffraction. Cell dimensions and intensi-
ties were measured at 293 K on a Bruker SMART CCD area detec-
tor diffractometer with graphite monochromated Mo Kα radiation
(λ = 0.71073 Å); θmax = 25.99; 9673 measured reflections; 3607
independent reflections (Rint = 0.0748). Data were corrected for Lorentz
Scheme 2. Feasible Derivative Routes of the Methyleneimi-
dazolidine Intermediate
and polarization effects and for absorption (Tmin = 0.55574 and Tmax
=
1.00000). The structure was solved by direct methods using SHELXS-
97;20 all other calculations were performed with a Bruker SAINT system
and Bruker SMART programs.21 Full-matrix least-squares refinement
2
based on F2 using the weight of 1/[σ2(Fo ) + (0.0669P)2 + 0.1381P]
gave final values of R = 0.0526, ωR = 0.1343, and GOF (F) = 1.044 for
251 variables and 3607 contributing reflections. Maximum shift/error =
0.000(3), and max/min residual electron density = 0.355/À0.276 e Å À3
.
Hydrogen atoms were observed and refined with a fixed value of their
isotropic displacement parameter.
Compound 9h was recrystallized by slow evaporation from a mixture
of acetone and methanol to afford a suitable single crystal. Yellow blocks
of 9h (0.369 mm  0.317 mm  0.223 mm) were mounted on a quartz
fiber and detected by Bruker Smart 1000 single-crystal diffraction. 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 = 26.00; 9712 measured reflections;
3565 independent reflections (Rint = 0.0935). Data were corrected for
Lorentz and polarization effects and for absorption (Tmin = 0.61673 and
Tmax = 1.00000). 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-squares
prepared diazonium salt reacted with 8 or 10 to yield the
corresponding phenylazo compounds, respectively.
refinement based on F2 using the weight of 1/[σ2(Fo ) + (0.0824P)2 +
2
0.0000P] gave final values of R = 0.0510, ωR = 0.1343, and GOF (F) =
0.985 for 249 variables and 3565 contributing reflections. Maximum
shift/error = 0.000(3), and max/min residual electron density =
0.334/À0.360 e Å À3. Hydrogen atoms were observed and refined with
a fixed value of their isotropic displacement parameter.
Crystal Structure Analysis. The insecticidal activity of the
target compounds varied greatly with the substituents on the
benzene ring, which implied the requirement of specific spatial
conformation. Comprehensive structural information of phenyl-
azoneonicotinoid compounds 9h (Figure 2a) and 9q (Figure 2b)
was provided by X-ray crystallographic diffraction analysis (see
the Supporting Information). Obviously, the phenyl group with
different substituents resulted in entirely different three-dimen-
sional conformation. Selected bond lengths, bond angles, and
torsional angles are given in Table 1.
To our best knowledge, face-to-face πÀπ alignment is a rare
phenomenon, and commonly π interaction is an offset or slipped
stacking.30 In structure 9h, the plane of 2,6-dichlorophenyl and
pyridine apparently formed a face-to-face stacked arrangement,
where most of the ring-plane area overlapped. The centroidÀ
centroid distance of the rings was 3.71 Å and an angle of 6.56°
was formed between the ring normal of the pyridine plane and
the vector between the ring centroids (Figure 2a). Unexpectedly,
compound 9h presented quite poor activity against the insect
cowpea aphid (A. craccivora) compared with compound 8.
Intriguingly, compound 9q with a (2, 6-dimethylphenyl)diazene
moiety exhibited exciting insecticidal activity, and the crystal
structure revealed extraordinary characteristics. According to the
crystal structure of imidacloprid, Casida and Kagabu suggested
that the coplanarity between the electronegative pharmacophore
and the guanidineÀamidine moiety is essential to obtain a high-
activity molecule,13,14,31 and the theory gained support from the
commercial neonicotinoid compounds. Interestingly, in the
structure of compound 9q, a large torsion angle existed between
the nitro group and the imidazoline plane, which brought some
divergence with the classic theory. As shown in Figure 2b, the
torsion angles of N(3)ÀC(1)ÀC(2)ÀN(5) and N(1)ÀN(2)À
C(1)ÀN(3) were À104.5(2)° and 179.48(17)°, respectively. It
Biology Assay. All compounds were dissolved in N,N-dimethyl-
formamide (AP, Shanghai Chemical Reagent Co., Ltd., Shanghai,
China) and diluted with water containing Triton X-100 (0.1 mg LÀ1
)
to obtain series concentrations of 500.0, 250.0, and 125.0 mg LÀ1 and
others for bioassays.
Insecticidal Test for Cowpea Aphids (Aphis craccivora). The in-
secticidal activities of the synthetic compounds against pea aphids
(A. craccivora) were tested according to our previously reported
procedure.22,23
’ RESULTS AND DISCUSSION
Synthesis. The double bond on the cyclic 1,1-enediamine
bears the characteristic of high polarization resulting from the
conjugation effect of an electron-withdrawing substituent and a
strong electron-donating amino group.24 The α-carbon is the
first reaction site when the intermediate is attacked by the
electrophilic reagents owing to the delocalization effect of the
lone pair electron on the nitrogen atom.25,26 Various adducting
reactions of methyleneimidazolidine with electrophiles such as
heterocyclic aldehyde, benzyl bromide, ethyl propiolate, diphe-
nylnitrile imine, and diazonium salt proceed smoothly and have
been reported previously,18,25À29 which proved to us the possi-
bility of synthesizing the phenylazoneonicotinoids by reaction
with different substituted diazonium salts (Scheme 2).
The synthetic procedure for the title compounds is illustrated
in Scheme 3. Starting from the substituted anilines, the diazo-
nium salt solution was first prepared under 2 °C. The freshly
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Scheme 3. Synthetic Route of the Target Molecules
Figure 2. Crystal structures of compounds 9h (a) and 9q (b).
was regarded that the conjugation effect between the diazene
moiety and methyleneimidazolidine was in the form of a Mobius
strip. Evidently, no face-to-face πÀπ interaction between pyr-
idine and the 2,6-dimethylphenyl plane appeared, and these two
rings shared the same plane from a large distance, which might
due to the weaker stability of the π-deficientÀπ-rich system in
9q compared with the π-deficientÀπ-deficient one in 9h. How-
ever, the crystal configuration of 9q does not convince us that it is
the accurate configuration at the binding site, and the molecule
would regulate its spacial conformation while interacting with
nAChR. Herein, molecular binding research was also investi-
gated to present a reasonable binding model (Figure 3).
atoms did not contribute to great activity improvement of the
corresponding compounds, and most of the halides exhibited
unpleasing insecticidal effectiveness (9cÀj) with the exception of
compound 9b (LC50 = 0.03720 mmol LÀ1). Moreover, the
structures with methyl groups on various substitution positions
demonstrated entirely different insecticidal results. Positions 2
and 6 on the phenyl group were regarded as the two key sub-
stitution sites for structural derivation to obtain high-activity mole-
cules. Compound9q (LC50 = 0.00426 mmol LÀ1) displayed an im-
provement of about 1 order of magnitude over imidacloprid (LC50
= 0.03502 mmol LÀ1) in insecticidal activity. Meanwhile, compared
with 9r, compound 9s with a heptafluoroisopropyl moiety on
position 4 had no activity, which confirmed to us that the
substitution of an electron-withdrawing group on the phenyl ring
would lead to a sharp decrease in the insecticidal activity. Replacing
2,6-dimethyl with 2,6-diethyl, 2,6-diisopropyl, or 2,6-dimethoxy
Insecticidal Activities. Table 2 lists the insecticidal activities
of the title compounds against cowpea aphid (A. craccivora).
Compound 9a with no substitution on the phenyl group
presented low insecticidal activity. Introducing the halogen
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Journal of Agricultural and Food Chemistry
ARTICLE
Table 1. Selected Bond Lengths, Bond Angles, and Torsional Angles of Compounds 9h and 9q
bond lengths (Å)
bond angles (deg)
9h 9q
orsional angles (deg)
9h
9q
9h
9q
Cl(1)ÀC(8)
N(1)ÀN(2)
N(1)ÀC(11)
N(2)ÀC(1)
N(3)ÀO(1)
N(3)ÀO(2)
N(3)ÀC(1)
N(4)ÀC(2)
N(4)ÀC(5)
N(4)ÀC(4)
N(5)ÀC(2)
N(5)ÀC(3)
N(6)ÀC(8)
N(6)ÀC(7)
C(1)ÀC(2)
C(3)ÀC(4)
C(5)ÀC(6)
1.742(3)
1.266(3)
1.434(3)
1.355(3)
1.226(3)
1.250(2)
1.413(3)
1.338(3)
1.453(3)
1.467(3)
1.317(3)
1.453(3)
1.315(3)
1.340(3)
1.438(3)
1.499(4)
1.504(3)
1.756(3) N(2)ÀN(1)ÀC(11)
1.274(2) N(1)ÀN(2)ÀC(1)
1.425(2) C(2)ÀN(4)ÀC(5)
1.361(2) C(2)ÀN(4)ÀC(4)
1.241(2) C(5)ÀN(4)ÀC(4)
1.274(2) C(2)ÀN(5)ÀC(3)
1.364(2) C(8)ÀN(6)ÀC(7)
1.314(2) N(2)ÀC(1)ÀN(3)
1.453(3) N(2)ÀC(1)ÀC(2)
1.471(3) N(3)ÀC(1)ÀC(2)
1.306(2) N(5)ÀC(2)ÀN(4)
1.461(3) N(5)ÀC(2)ÀC(1)
1.348(4) N(4)ÀC(2)ÀC(1)
1.372(3) N(5)ÀC(3)ÀC(4)
1.474(3) N(4)ÀC(4)ÀC(3)
1.523(3) N(4)ÀC(5)ÀC(6)
1.510(3) C(7)ÀC(6)ÀC(5)
110.38(19) 113.16(15) C(11)ÀN(1)ÀN(2)ÀC(1) À177.4(2) À175.03(16)
122.7(2) 115.38(15) N(1)ÀN(2)ÀC(1)ÀN(3)
127.4(2) 127.18(17) N(1)ÀN(2)ÀC(1)ÀC(2)
110.3(2) 109.91(17) O(1)ÀN(3)ÀC(1)ÀC(2)
119.3(2) 121.62(17) O(2)ÀN(3)ÀC(1)ÀC(2)
112.7(2) 111.50(18) C(3)ÀN(5)ÀC(2)ÀC(1)
À4.5(3)
167.4(2)
170.2(2)
À10.3(3)
179.48(17)
8.5(3)
178.3(2)
À1.5(3)
174.5(2) À179.62(18)
116.3(2)
115.3(2) C(5)ÀN(4)ÀC(2)ÀN(5)
À162.0(2)
21.6(4)
176.4(2)
124.8(2) 116.99(16) C(5)ÀN(4)ÀC(2)ÀC(1)
115.21(19) 126.80(17) C(4)ÀN(4)ÀC(2)ÀC(1)
119.52(19) 115.65(16) N(3)ÀC(1)ÀC(2)ÀN(5)
110.1(2) 111.96(17) N(2)ÀC(1)ÀC(2)ÀN(4)
125.7(2) 123.24(18) C(2)ÀN(4)ÀC(5)ÀC(6)
124.0(2) 124.79(17) C(4)ÀN(4)ÀC(5)ÀC(6)
102.6(2) 101.95(16) N(4)ÀC(5)ÀC(6)ÀC(7)
104.1(2) 102.64(16)
À4.0(3)
À178.5(2) À171.03(18)
14.0(4) À104.5(2)
17.4(3) À112.9(2)
À102.5(3)
99.3(3)
9.8(4)
120.5(2)
À73.9(3)
117.0(2)
115.3(2) 111.36(17)
124.1(2)
136(3)
122.0(2)
156(2)
N(5)ÀH(5) O(2) 1.97(2)
3 3 3
1.95(2)
N(5)ÀH(5) O(2)
3 3 3
Figure 3. Molecular docking between AChBP and compounds 9h (a) and 9q (b).
also showed comparable activities (9u, 9v, 9y, respectively).
Similar results were also acquired when 2-chloro-5-pyridine was
modified with 2-chloro-5-thiazole, and the LC50 values of 11d,
11e, 11f, 11h were 0.00350, 0.01844, 0.01176, and 0.01464
mmol LÀ1, respectively.
the docking results. All atoms within 10 Å around the ligand
(imidacloprid) in the 3C79 structure were selected as binding
pocket and considered in the docking study. As illustrated in
Figure 3, a πÀπ stacking interaction was found between the
plane of methyleneimidazolidine and the aromatic side chain of
Tyr188. A NÀH O hydrogen bond was observed between
Docking Study. A molecular docking study was performed to
investigate the interaction between receptor and compounds.
Bearing numerous characteristics of nAChRs,32 the crystal
structure of AChBP was obtained from the Protein Data Bank
(PDB code 3C79)16 and prepared by adding hydrogen atoms,
removing water, and extracting ligand using Maestro 7.5. Com-
pounds 9h and 9q were built, minimized, and docked into the
active site pocket of AChBP by using GOLD version 3.2 (The
Cambridge Crystallographic Data Centre, Cambridge, U.K.),
and the scoring function ChemScore was selected to evaluate
3 3 3
the NÀH of the imidazole ring and the phenol oxygen atom of
Tyr55 (N O distances of 3.17 and 3.06 Å for 9h and 9q,
3 3 3
respectively). Although 9h and 9q showed quite different crystal
structures, they showed a similar binding mode with the target
from the docking results. However, the reason for their signifi-
cant insecticidal activity differences is still unclear.
In conclusion, a series of phenylazoneonicotinoid compounds
were designed and synthesized. The conjugation effect of the
nitromethylene pharmacophore was enhanced by reaction with
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Journal of Agricultural and Food Chemistry
ARTICLE
Table 2. Insecticidal Activity Results of the Synthetic Com-
’ ASSOCIATED CONTENT
pounds 9qÀy and 11aÀh
S
Supporting Information. Crystallographic information
b
Aphis craccivora
files (CIFs) of compounds 9h and 9q. This material is available
free of charge via the Internet at http://pubs.acs.org.
LC50
mortality (%)
(mmol LÀ1
)
’ AUTHOR INFORMATION
500
250
125
Corresponding Author
*Phone: +86-21-64253540. Fax: +86-21-64252603. E-mail: lizhong@
ecust.edu.cn.
compd
Ra
mg LÀ1 mg LÀ1 mg LÀ1
9a
9b
9c
9d
9e
9f
H
31.2
100
ntb
100
nt
nt
100
nt
nt
Funding Sources
4-F
0.03720
This work was financially supported by the National Basic Research
Program of China (973 Program, 2010CB126100), National
High Technology Research, the Development Program of China
(863 Program, 2011AA10A207), the National Key Technology
R&D Program of China (2011BAE06B01), and the Special Fund
for Agro-scientific Research in the Public Interest (201103007).
This work was also partly supported by the Shanghai Foundation
of Science and Technology (09391911800, 09XD1401300), the
Shanghai Leading Academic Discipline Project (Project B507),
and the Fundamental Research Funds for the Central Universities.
2-F
13.0
12.2
25.1
8.6
nt
2,4-F2
2,3-F2
nt
nt
nt
nt
nt
nt
nt
4-F-3-Cl
2-Cl
nt
nt
9g
9h
9i
7.1
nt
nt
nt
2,6-Cl2
4-Br
6.5
nt
nt
nt
58.3
0
nt
nt
nt
9j
2-I
nt
nt
nt
9k
9l
4-NO2
2-NO2
2-Me
4.7
nt
nt
nt
8.2
nt
nt
nt
9m
9n
52.5
56.6
19.7
73.3
nt
nt
nt
’ REFERENCES
4-Me
nt
nt
nt
(1) Jepson, J. E. C.; Brown, L. A.; Sattelle, D. B. The actions of the
neonicotinoid imidacloprid on cholinergic neurons of Drosophila mela-
nogaster. Invert. Neurosci. 2006, 6, 33–40.
(2) 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.
(3) Ohno, I.; Tomizawa, M.; Durkin, K. A.; Casida, J. E.; Kagabu, S.
Neonicotinoid substituents forming a water bridge at the nicotinic
acetylcholine receptor. J. Agric. Food Chem. 2009, 57, 2436–2440.
(4) Thany, S. H.; Lenaers, G.; Raymond-Delpech, V.; Sattelle, D. B.;
Lapied, B. Exploring the pharmacological properties of insect nicotinic
acetylcholine receptors. Trends Pharmacol. Sci. 2007, 28, 14–22.
(5) Tomizawa, M.; Casida, J. E. Neonicotinoid insecticide toxicol-
ogy: mechanisms of selective action. Annu. Rev. Pharmacol. Toxicol.
2005, 45, 247–268.
9o
3,4-Me2
2,3-Me2
2,6-Me2
2,4,6-Me3
nt
nt
nt
9p
nt
nt
nt
9q
100
100
100
100
nt
100
100
nt
0.00426
0.00499
nt
9r
9s
2,6-Me2-4-F7-i-Pr 12.2
9t
2-Me-6-Et
2,6-Et2
100
100
100
100
100
100
nt
100
100
100
nt
0.00374
0.00280
0.01375
nt
9u
9v
2,6-i-Pr2
4-OMe
9w
47.5
91.0
100
9x
2-OMe
76.0
100
nt
35.5
100
nt
nt
9y
2,6-OMe2
4-NO2
0.00990
nt
11a
11b
11c
11d
11e
11f
11g
11h
imidacloprid
12.1
18.2
61.7
2,6-Cl2
nt
nt
nt
2,3-Me2
2,6-Me2
2,4,6-Me3
2,6-Et2
nt
nt
nt
(6) Akayama, A.; Minamida, I. Discovery of a new systemic insecti-
cide, nitenpyram and its insecticidal properities. In Nicotinoid Insecticides
and the Nicotinic Acetylcholine Receptor; Yamamoto, I., Casida, J. E., Eds.;
Springer: Tokyo, Japan, 1999; pp 127À148.
100
100
100
100
nt
100
100
100
nt
0.00350
0.01523
0.01176
nt
100
100
(7) Kiriyama, K.; Nishimura, K. Structural effects of dinotefuran and
analogues in insecticidal and neural activities. Pest Manag. Sci. 2002,
58, 669–676.
4-OMe
11.8
2,6-OMe2
100
100
100
100
100
100
0.01464
0.03502
(8) Ohno, I.; Tomizawaa, M.; Durkin, K. A.; Casida, J. E.; Kagabu, S.
Bis-neonicotinoid insecticides: observed and predicted binding interactions
with the nicotinic receptor. Bioorg. Med. Chem. Lett. 2009, 19, 3449–3452.
(9) Jeschke, P.; Nauen, R.; Schindler, M.; Elbert, A. Overview of the
status and global strategy for noenicotinoids. J. Agric. Food Chem. 2011,
59, 2897–2908.
(10) 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.
(11) Qian, W. J.; Shi, X. L. Sulfoxaflor: a novel pesticide developed
by Dow AgroSciences. Pestic. Market News 2010, 23, 35–35.
(12) Tomizawa, M.; Yamamoto, I. Structure activity relationships of
nicotinoids and imidacloprid analogs. Nihon Noyaku Gakkaishi 1993,
18, 91–98.
a See Scheme 3 for a substituent for R. b nt, not tested.
the diazonium salts. The bioassay results implied that some
molecules displayed good insecticidal activities against cowpea
aphids. In particular, most of the compounds with electron-
donating groups on positions 2 and 6 of the phenyl ring
presented excellent bioactivity, some of which were 10-fold
higher than that of imidacloprid. The crystal structure of high-
activity compound 9q showed a large torsion angle between the
pharmacophore and the methyleneimidazolidine plane. The
preliminary computer-aided molecular docking result revealed
that 9h and 9q shared similar binding configurations despite their
great bioactivity disparity. Further studies on the mode of action
(MoA) of 9q and structural modifications are in progress.
10622
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Journal of Agricultural and Food Chemistry
ARTICLE
(13) Kagabu, S.; Matsuno, H. Chloronicotinyl insecticides. 8. Crystal
and molecular structures of imidacloprid and analogous compounds.
J. Agric. Food Chem. 1997, 45, 276–281.
subunit may confer imidacloprid selectivity between Myzus persicae and
its predatory enemy Pardosa pseudaannulata. Insect Biochem. Mol. Biol.
2009, 39, 833–841.
(14) Tomizawa, M.; Zhang, N. J.; Durkin, K. A.; Olmstead, M. M.;
Casida, J. E. The neonicotinoid electronegative pharmacophore plays
the crucial role in the high affinity and selectivity for the Drosophila
nicotinic receptor: an anomaly for the nicotinoid cationÀπ interaction
model. Biochemistry 2003, 42, 7819–7827.
(15) Wang, Y. L.; Cheng, J. G.; Qian, X. H.; Li, Z. Actions between
neonicotinoids and key residues of insect nAChR based on an ab initio
quantum chemistry study: hydrogen bonding and πÀπ interaction.
Bioorg. Med. Chem. 2007, 15, 2624–2630.
(16) Talley, T. T.; Harel, M.; Hibbs, R. E.; Radic, Z.; Tomizawa, M.;
Casida, J. E.; Taylor, P. Atomic interactions of neonicotinoids agonists
with AChBP: molecular recognition of the distinctive electronegative
pharmacophore. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 7606–7611.
(17) Ihara, M.; Okajima, T.; Yamashita, A.; Oda, T.; Hirata, K.;
Nishiwaki, H.; Morimoto, T.; Akamatsu, M.; Ashikawa, Y.; Kuroda, S.i.;
Mega, R.; Kuramitsu, S.; Sattelle, D. B.; Matsuda, K. Crystal structures of
Lymnaea stagnalis AChBP in complex with neonicotinoid insecticides
imidacloprid and clothianidin. Invert. Neurosci. 2008, 8, 71–81.
(18) Shao, X. S.; Lee, P. W.; Liu, Z. W.; Xu, X. Y.; Li, Z.; Qian, X. H.
cis-Configuration: a new tactic/rationale for neonicotinoid molecular
design. J. Agric. Food Chem. 2011, 59, 2943–2949.
(19) Samaritoni, J. G.; Demeter, D. A.; Benko, Z. L.; Gifford, J. M.;
Neese, P. A.; Dintenfass, L. P.; Schmidt, C. L. R. Compounds useful as
pesticides. PCT Int. Appl. WO058714, 2004.
(20) Sheldrick, G. M. SHELXTL, version 5.0; University of
G€ottingen: G€ottingen, Germany, 2001.
(21) SMART , version 5.628, SAINT, version 6.45, and SADABS;
Brucker AXS: Madison, WI, 2001.
(22) 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 struc-
ture, and insecticidal activities. J. Agric. Food Chem. 2010, 58, 2696–2702.
(23) 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.
(24) Huang, Z. T.; Wang, M. X. The reaction of benzoyl-substituted
heterocyclic ketene aminals with aryl azides. J. Org. Chem. 1992,
57, 184–190.
(25) Zhao, M. X.; Wang, M. X.; Huang, Z. T. The aza-ene or the
Michael addition? Examination of an unusual substitutent effect on the
reaction of heterocyclic ketene aminals with ethyl propiolate. Tetrahe-
dron 2002, 58, 1309–1316.
(26) Xu, Z. H.; Jie, Y. F.; Wang, M. X.; Huang, Z. T. The regiospecific
C-benzylation of heterocyclic ketene aminals with ethyl 2-(bromo-
methyl)benzoate: a simple route to 1H-Imidazo[1,2-b][2]benzazepin-
5-one derivatives. Synthesis 2002, 523–527.
(27) Liu, B.; Wang, M. X.; Huang, Z. T. Reaction of aroyl-substituted
heterocyclic ketene aminals with nitrile imines: an efficient synthesis of
fully substituted pyrazoles and evidence of nucleophilic addition of
enamines to 1,3-diples. Tetrahedron Lett. 1999, 40, 7399–7402.
(28) Schafer, H.; Gewald, K. Darstellung und reaktionen von
2-arylazo-2-nitro-ketenaminalen. J. Prakt. Chem. 1980, 322, 87–93.
(29) Foks, H.; Pancechowska-Ksepko, D.; Janowiec, M.; Zwolska,
Z.; Augustynowicz-Kopeꢀe, E. Synthesis and tuberculostatic activity of
some 1,1-bis-methylthio-2-nitro-ethene derivatives. Phosphorus, Sulfur
Silicon Relat. Elem. 2005, 180, 2291–2297.
(30) Janiak, C. A critical account on stacking in metal complexes
with aromatic nitrogen-containing ligands. J. Chem. Soc., Dalton Trans.
2000, 3885–3896.
(31) Tomizawa, M.; Casida, J. E. Molecular recognition of neonico-
tinoid insecticides: the determinants of life or death. Acc. Chem. Res.
2009, 42, 260–269.
(32) Song, F.; You, Z. Q.; Yao, X. M.; Cheng, J. G.; Liu, Z. W.; Lin,
K. J. Specific loops D, E and F of nicotinic acetylcholine receptor β1
10623
dx.doi.org/10.1021/jf2029708 |J. Agric. Food Chem. 2011, 59, 10615–10623