Effect of substituents at the 5-position of the pyridine ring of imidacloprid on insecticidal activity against Periplaneta americana

Article abstract of DOI:10.1002/ps.1326

The insecticidal activities of imidacloprid derivatives with a wide range of substituents at the 5-position on the pyridine ring against American cockroaches, Periplaneta americana (L.), were measured by injection with and without synergists propyl 2-prop

Full text of DOI:10.1002/ps.1326

Pest Management Science
Pest Manag Sci 63:75–83 (2007)
Effect of substituents at the 5-position
of the pyridine ring of imidacloprid on
insecticidal activity against Periplaneta
americana
Shinzo Kagabu,1∗ Yuko Murase,1 Rie Imai,1 Nakako Ito1 and Keiichiro Nishimura2
1Department of Chemistry, Faculty of Education, Gifu University, Gifu 501-1193, Japan
2Research Institute for Advanced Science and Technology, Osaka Prefecture University, Osaka 599-8570, Japan
Abstract: The insecticidal activities of imidacloprid derivatives with a wide range of substituents at the 5-position
on the pyridine ring against American cockroaches, Periplaneta americana (L.), were measured by injection
with and without synergists propyl 2-propynyl phenylphosphonate and piperonyl butoxide. The log(1/MLD) value
(MLD = minimal lethal dose in mol) without synergists was 7.96 for the methyl derivative, and the values were
lower for other derivatives. Synergists enhanced the potencies of all the compounds tested. Considering these
compounds and those with other substituents at this position, the region for maximum activity was predicted to
be in the conjunction of the pyridyl 6-chlorine atom with a lipophilic small group in the 5-position.
 2007 Society of Chemical Industry
Keywords: neonicotinoid insecticide; imidacloprid; American cockroach; Periplaneta americana; insecticidal
activity; synergist; substituted pyridine
co-workers10–13 found that the introduction of an
azido group at the 5-position of the pyridine ring (1b)
retains or even improves the affinity to Myzus and
Drosophila nAChRs. This new result has prompted an
examination of the overall effect of added substituents
at the 5-position on insecticidal activity as assessed
by the authors’ estimation method.14 Firstly, the
effect of halogen and pseudohalogen substituents
such as azido and cyano on insecticidal activity was
examined by injection into American cockroaches,
Periplaneta americana (L.). Although the activity of
azido compounds did not stand out against the insect
tested, potency was observed to be strongly dependent
on the substituents, and the fluoro derivative (1c)
showed a high insecticidal potency comparable with
that of imidacloprid.14 The following experiments
with 5-substituted alkoxy derivatives showed that all
of the added substituents significantly lowered the
potency of the parent compound.15 In the present
work, the effect of alkyl, trifluoromethyl, phenyl and
ester derivatives of imidacloprid was examined, and
the effect of substituents at this position was evaluated.
1
INTRODUCTION
Manifold structural variations of imidacloprid (1a;
Fig. 1), the first neonicotinoid insecticide, have been
contrived to find a new product with its own
biological prominence.1 Addition of a substituent
to a site of the original structure or replacement
with other groups is one of the most widely applied
methodologies for drug design.2 In the neonicotinoid
field, introduction of a new substituent to the
pyridine ring of imidacloprid or replacement of
the chlorine atom at the 6-position with other
groups has been studied.3 However, structure–activity
relationship studies showed that no variation of the
original structure elevated the insecticidal potency
of the original compound, regardless of the nature
of the substituent and the site or the substituent
number, except that the 6-fluoro derivative afforded
comparable activity.3,4 Similar insecticidal tendencies
of single and double substitutions were reported in
the case of the benzene derivative,5,6 and the best
fitness of the 6-chloro-3-pyridin-3-ylmethyl moiety
for monosubstituted pyridin-3-ylmethyl molecules
was verified by stereoelectronic considerations.6,7
Against such a background, significant factors such
as the relevant activities of 1-(5,6-dichloropyridin-
3-ylmethyl)-2-nitromethylene or N-cyanoguanidine-
imidazolidine8,9 and the prediction of permissible
steric regions in the vicinity of a chlorine atom at
the 6-position on the pyridine ring of imidacloprid6
may have gone unnoticed. Recently, Casida and
2
MATERIALS AND METHODS
2.1 Chemicals
All melting points (MP) are uncorrected. IR spec-
tra were measured with a Perkin Elmer FTIR
1600 spectrometer. NMR spectra were obtained
by a Varian Gemini 2000 C/H (400 MHz). The
∗ Correspondence to: Shinzo Kagabu, Department of Chemistry, Faculty of Education, Gifu University, Gifu 501-1193, Japan
E-mail: kagabus@gifu-u.ac.jp.
(Received 5 December 2005; revised version received 4 August 2006; accepted 4 August 2006)
DOI: 10.1002/ps.1326
 2007 Society of Chemical Industry. Pest Manag Sci 1526–498X/2007/$30.00

S Kagabu et al.
solution of diisopropylamine (10 mg, 0.1 mmol) and
3 (416 mg, 2 mmol) in THF (0.5 mL) was added
dropwise. The mixture was stirred at a temperature
ranging from −10 to 0 ◦C for 3 h and then cooled
again to −70 ◦C before dropwise introduction of a
solution of iodoethane (1.56 g, 10 mmol) in THF
(0.5 mL). The mixture was allowed to stand in a
cooling bath overnight (the temperature rose to about
0 ◦C in this time). During ice cooling, a few drops of
a mixture of concentrated hydrochloric acid and THF
(2 mL) was added, and, after 5 min, aqueous sodium
hydroxide (40 g L−1, 2 mL) was added. After 30 min of
stirring, the reaction mixture was poured onto water
and extracted with IPE (3 × 10 mL). The solution
was dried, the solvent was evaporated and the residue
(280 mg), composed of products 4p and 3 in a ratio
of about 3:2 (NMR), was used in the next step. The
following 1H NMR shifts were assigned for compound
4
X
3 CH2
N
NH
5
6
2
NNO2
Cl
N
1a: imidacloprid (X=H)
1b: 5-azidoimidacloprid (X=N3)
1c: 5-fluoroimidacloprid (X=F)
Figure 1. Imidacloprid and 5-substituted compounds.
chemical shifts
δ were recorded in ppm and
the coupling constants J in Hz. Mass spectra
were recorded by a Jeol JMS-700. The following
products were prepared according to procedures
described previously:16 1-(6-chloro-5-methylpyridin-
3-ylmethyl)-2-nitroiminoimidazolidine (1o), 1-(6-
chloro-5-trifluoromethylpyridin-3-ylmethyl)-2-nitro-
iminoimidazolidine (1t) and 1-(6-chloro-5-methoxy-
carbonylpyridin-3-ylmethyl)-2-nitroiminoimidazoli-
dine (1u). Propyl 2-propynyl phenylphosphonate
(NIA16388 or NIA) for insecticidal testing was
obtained from the stock sample used in previous
studies.17–21 Piperonyl butoxide (PB), an inhibitor of
mixed-function oxidases, was purchased from Nakalai
Tesque (Kyoto, Japan).
1
4p. H NMR (δ, CDCl3): 1.21 (t, 3H, CH3CH2Py,
J = 7.3), 2.42 (m, 2 × 2H, NCH2CH2O), 2.58 (q,
2H, CH3CH2Py, J = 7.3), 3.40 (s, 2H, CH2), 3.69
(m, 2 × 2H, NCH2CH2O), 3.94 (s, 3H, CH3), 7.39
(d, 1H, 4-Py-H, J = 2.4 Hz), 7.87 (d, 1H, 6-Py-H,
J = 2.4 Hz).
2.2.3 5-Ethyl-6-methoxypyridin-3-ylmethyl chloride
(5p)
2.2 Synthesis
The mixture of Section 2.2.2 in 20 mL of THF
was treated with 280 mg of ethyl chloroformate
and stirred at 60 ◦C for 2 h, and the volatile
materials were evaporated. The residue was purified by
chromatography on SiO2, using IPE + hexane (1 + 4
by volume) as the eluate, to yield 135 mg of product.
IR (liquid) (cm−1): 2880 (m), 1610 (m), 1560 (m),
1510 (s), 1475 (vs), 1405 (m), 1250 (s), 1205 (s),
1025 (m), 835 (m), 760 (s), 690 (s). 1H NMR (δ,
CDCl3): 1.20 (t, 3H, CH2CH3, J = 7.4 Hz), 2.58 (q,
2H, CH2CH3, J = 7.4 Hz), 3.95 (s, 3H, OCH3), 4.53
(s, 2H, CH2Cl), 7.43 (d, 1H, 4-Py-H, J = 2.6 Hz),
7.97 (d, 1H, 6-Py-H, J = 2.6 Hz); 13C NMR: 13.0,
22.8, 43.7, 53.5, 126.1, 137.1, 138.9, 143.6, 162.2.
MS m/z (%): 187 (12), 185 (M+, 37), 171 (11),
170 (26), 151 (11), 150 (100), 136 (28), 107 (14).
HRMS (EI) m/z (M+): calculated for C9H12ClNO,
185.0608; found, 185.0621.
2.2.1 N-(6-Methoxypyridin-3-ylmethyl)morpholine
(3; Fig. 2)
Powdered potassium hydroxide (5.60 g, 100 mmol)
was added rapidly to a stirred mixture of dibenzo-
18-crown-6 (420 mg) in dry toluene (20 mL), with
subsequent dropwise addition of a solution of N-
(6-chloropyridin-3-ylmethyl)morpholine10 (2; 4.42 g,
20.1 mmol) in dry methanol (4.2 mL). The mixture
was warmed at 65 ◦C for 5 h. The toluene was
evaporated, the residue was diluted 3 times with
isopropyl ether (IPE; 3 × 15 mL) and the combined
IPE-soluble fraction was dried. After evaporation of
IPE, column chromatography of the residue on SiO2,
with IPE + hexane (1 + 1 by volume) as the eluate,
afforded a colourless liquid. Yield: 2.73 g (62%). IR
(liquid) (cm−1): 1595 (m), 1510 (vs), 1455 (m), 1255
(vs), 1230 (m), 1130 (s), 740 (m), 670 (m). 1H NMR
(δ, CDCl3): 2.42 (m, 2 × 2H, NCH2CH2O), 3.42 (s,
2H, CH2), 3.69 (s, 2 × 2H, NCH2CH2O), 3.92 (s,
3H, CH3), 6.71 (d, 1H, 3-Py-H, J = 8.6 Hz), 7.56
(dd, 1H, 4-Py-H, J = 8.6/2.3 Hz), 8.04 (d, 1H, 6-
Py-H, J = 2.3 Hz); 13C NMR: 53.4, 53.5, 60.0, 67.0,
110.7, 125.8, 139.8, 147.1, 163.7. MS m/z (%): 208
(M+, 97), 207 (23), 177 (35), 137 (11), 136 (15), 135
(11), 123 (22), 122 (100), 86 (40). HRMS (EI) m/z
(M+): calculated for C11H16N2O2, 208.1211; found,
208.1236.
2.2.4 6-Chloro-5-ethylpyridin-3-ylmethyl chloride (6p)
POCl3 (0.5 mL) was added to a solution of 5p
(130 mg) in N,N-dimethylformamide (DMF; 0.5 mL)
with external ice cooling. The mixture was allowed
to warm to room temperature and was then heated
at 140 ◦C for 2 h. The cooled reaction mixture
was poured onto cold water. IPE extracts were
washed with water, dried and evaporated. Preparative
chromatography of the residue on SiO2 with hexane +
IPE (4 + 1 by volume) afforded 100 mg (79%) of
product. IR (liquid) (cm−1): 2930 (m), 1595 (m),
1565 (m), 1430 (m), 1405 (vs), 1175 (m), 1080 (s),
925 (m), 740 (m), 690 (m). 1H NMR (δ, CDCl3): 1.28
(t, 3H, CH2CH3, J = 7.5), 2.76 (q, 2H, CH2CH3,
2.2.2 N-(5-Ethyl-6-methoxypyridin-3-
ylmethyl)morpholine (4p)
A solution of methyllithium (1.6 M in diethyl ether,
6.3 mL, 10 mmol) was added to tetrahydrofuran
(THF; 8 mL) under an argon atmosphere at −45 ◦C. A
76
Pest Manag Sci 63:75–83 (2007)
DOI: 10.1002/ps

Insecticidal activity of substituted imidacloprid derivatives
R
CH2 N
CH2 N
CH2 N
O
O
O
b
a
(1)
MeO
MeO
Cl
N
N
N
4p (R=Et), 4q(R=n-Pr)
4r (R=n-Bu)
3
2
c
R
R
CH2Cl
CH2Cl
d
MeO
Cl
N
N
6p (R=Et), 6q(R=n-Pr)
6r (R=n-Bu)
5p (R=Et), 5q (R=n-Pr)
5r (R=n-Bu)
C6H5
Cl
I
C6H5
Cl
CH3
CH3
CH2Br
(2)
(3)
e
f
Cl
N
N
N
7
9
8
X
X
CH2
N
NH
NNO2
CH2Y
g
HN
NH
+
Cl
Cl
6 (Y=Cl), 9 (Y=Br)
N
N
NNO2
10
1p-1s
Reagents and conditions.
(a) KOH, MeOH, toluene, dibenzo-18-crown-6, 65°C, 5 h.
(b) (i) MeLi, diisopropylamine, THF, -45°C to 0°C, 3 h; (ii) RI, -70°C to 0°C, overnight.
(c) ClCO2Et, THF, 60°C, 2 h.
(d) POCl3 / DMF, room temp gradually to 140°C, 2 h.
(e) C6H5B(OH)2, [P(C6H5)3]4Pd(0), dimethoxyethane / H2O, 85°C, 10 h.
(f) NBS, (C6H5CO2)2, CCl4, reflux, 10 h.
(g) NaH / DMF, 0°C to room temperature, 2 h.
Figure 2. Route to 5-alkyl and phenyl substituted imidacloprid.
1080 (s), 1050 (s), 950 (s), 750 (m), 660 (m). 1H
NMR (δ, CDCl3): 1.25 (t, 3H, CH2CH3, J = 8.0 Hz),
2.75 (q, 2H, CH2CH3, J = 8.0 Hz), 3.50 (m, 2H,
NCH2CH2N), 3.80 (m, 2H, NCH2CH2N), 4.52 (s,
2H, Py-CH2), 7.57 (d, 1H, 4-Py-H, J = 2.3 Hz), 8.15
J = 7.5 Hz), 4.56 (s, 2H, CH2Cl), 7.60 (d, 1H, 4-Ph-
H, J = 2.3 Hz), 8.23 (d, 1H, 6-Py-H, J = 2.3 Hz); 13C
NMR: 13.2, 26.2, 42.3, 123.5, 138.1, 139.5, 146.5,
151.2. MS m/z (%): 191 (26), 189 (M+, 41), 176 (10),
175 (11), 174 (15), 156 (52), 155 (15), 154 (100), 142
(14), 140 (44), 118 (16), 117 (11), 91 (21). HRMS
(EI) m/z (M+): calculated for C8H9Cl2N, 189.0112;
found, 189.0123.
(d, 1H, 6-Py-H, J = 2.3 Hz), 8.19 (bs, 1H, NH); 13
C
NMR: 13.3, 26.3, 41.5, 45.2, 45.4, 130.0, 138.2,
138.5, 146.5, 151.4, 161.3. MS m/z (%): 283 (M+,
3), 240 (41), 239 (100), 238 (100), 237 (100), 235
(54), 224 (27), 223 (54), 223 (36), 222 (73), 221
(42), 210 (31), 209 (77), 208 (61), 207 (56), 202
(100), 195 (33), 187 (72), 182 (40), 174 (23), 168
(30), 154 (90), 140 (24). Analysis. Found: C, 46.56;
H, 4.82; N, 24.80. Calculated for C11H14ClN5O2: C,
46.57; H, 4.97; N, 24.69.
2.2.5 1-(6-Chloro-5-ethylpyridin-3-ylmethyl)-
2-nitroiminoimidazolidine (1p)
A solution of 2-nitroimino-4-imidazoline (10; 130 mg,
1.00 mmol) in DMF (15 mL) was treated with sodium
hydride (60% oil dispersion, 60 mg, 1.50 mmol) at
5 ◦C. The mixture was stirred at room temperature
until no hydrogen was produced and then cooled
again to 0 ◦C. A solution of 6p (189 mg, 1.0 mmol)
in DMF (5 mL) was added dropwise. The cooling
bath was set aside and the solution was stirred at
room temperature for 2 h. The reaction was quenched
with one drop of acetic acid, and the DMF was
evaporated under vacuum. Chromatography on SiO2
with hexane + ethyl acetate (1 + 10 by volume) gave
122 mg (43% yield) of product, which was purified
by recrystallization from methanol. MP: 146–147 ◦C.
IR (KBr) (cm−1): 3300 (m), 1600–1575 (s–vs), 1550
(vs), 1480 (s), 1450 (vs), 1405 (vs), 1280–1220 (s),
Compounds 1q and 1r were prepared according to
the procedures above.
Pure
6-methoxy-5-n-propylpyridine-3-ylmethyl-
morpholine (4q) could not be isolated. A mixture
(the ratio of 4q to 3 was 2:5, based on 1H NMR)
1
was used to the next step. The following H NMR
1
shifts were assigned for compound 4q. H NMR (δ,
CDCl3): 0.94 (t, 3H, J = 7.4 Hz), 1.62 (m, 2H), 2.42
(m, 4H), 2.53 (t, 2H, J = 7.4 Hz), 3.69 (m, 4H),
3.93 (s, 3H), 7.37 (d, 1H, J = 2.3 Hz), 7.87 (d, 1H,
J = 2.3 Hz).
Pest Manag Sci 63:75–83 (2007)
77
DOI: 10.1002/ps

S Kagabu et al.
2.2.6 6-Methoxy-5-n-propylpyridin-3-ylmethyl chloride
(5q)
(m), 1475 (s), 1405 (s), 1350 (m), 1250 (m), 1120
(vs), 1025 (s), 865 (m), 760 (m), 670 (m). 1H
NMR (δ, CDCl3): 0.93 (t, 3H, (CH2)2CH2CH3,
J = 7.3 Hz), 1.36 (m, 2H, (CH2)2CH2CH3), 1.55 (m,
2H, CH2CH2C2H5), 2.42 (t, 2 × 2H, NCH CH2O,
IR (liquid) (cm−1): 2960 (m), 1610 (s), 1580 (m),
1475 (vs), 1405 (vs), 1315 (s), 1255 (vs), 1145 (m),
1
1025 (s), 765 (m), 695 (m). H NMR (δ, CDCl3):
0.95 (t, 3H, CH2CH2CH3, J = 7.5 Hz), 1.62 (m,
2H, CH2CH2CH3), 2.54 (t, 2H, CH2CH2CH3,
J = 7.4 Hz), 3.95 (s, 3H, OCH3), 4.52 (s, 2H,
CH2Cl), 7.43 (d, 1H, 4-Py-H, J = 2.3 Hz), 7.98 (d,
1H, 6-Py-H, J = 2.3 Hz); 13C NMR: 13.90, 22.0,
31.8, 43.7, 53.5, 125.5, 126.0, 138.1, 143.7, 162.3.
MS m/z (%): 201 (17), 199 (M+, 51), 184 (58),
164 (100), 136 (38), 107 (22). HRMS (EI) m/z
(M+): calculated for C10H14ClNO, 199.0765; found,
199.0790.
J = 4.4 Hz), 2.54 (t, 2H, CH CH2C2H5, J = 27.7 Hz),
2
3.40 (s, 2H, Py-CH2), 3.69 (t, 2 × 2H, NCH2CH2O,
J = 4.4 Hz), 3.93 (s, 3H, OCH3), 7.38 (d, 1H, 4-Py-
H, J = 2.6 Hz), 7.87 (d, 1H, 6-Py-H, J = 2.6 Hz); 13
C
NMR: 14.0, 22.6, 29.5, 31.2, 53.4, 53.5, 60.2, 67.0,
125.1, 125.5, 138.9, 144.2, 161.8. MS m/z (%): 264
(M+, 46), 233 (11), 192 (25), 178 (100), 149 (54),
136 (14), 113 (12), 97 (14), 86 (25). HRMS (EI) m/z
(M+): calculated for C15H24N2O2, 264.1837; found,
264.1856.
2.2.7 6-Chloro-5-n-propylpyridin-3-ylmethyl chloride
(6q)
2.2.10 5-n-Butyl-6-methoxypyridin-3-ylmethyl chloride
(5r)
IR (liquid) (cm−1): 2950 (m), 1595 (m), 1565 (m),
1435 (m), 1405 (vs), 1350 (m), 1180 (m), 1080
(s), 730 (m), 690 (m). 1H NMR (δ, CDCl3):
0.99 (t, 3H, CH2CH2CH3, J = 7.3), 1.67 (m,
2H, CH2CH2CH3), 2.70 (t, 2H, CH2CH2CH3,
J = 7.3 Hz), 4.56 (s, 2H, CH2Cl), 7.60 (d, 1H, 4-
Py-H, J = 2.6 Hz), 8.23 (d, 1H, 6-Py-H, J = 2.6 Hz);
13C NMR: 13.7, 22.2, 34.9, 42.2, 132.3, 136.6, 138.8,
146.4, 151.2. MS m/z (%): 205 (38), 203 (M+, 60),
176 (52), 175 (131), 174 (80), 170 (43), 168 (100),
140 (20), 104 (15). HRMS (EI) m/z (M+): calculated
for C9H11Cl2N, 203.0269; found, 203.0298.
IR (liquid) (cm−1): 2960 (m), 1560 (m), 1430
(s), 1405 (vs), 1265 (m), 1175 (m), 1095 (s),
1065 (vs), 930 (m), 735 (vs). 1H NMR (δ,
CDCl3): 0.94 (t, 3H, (CH2)2CH2CH3, J = 7.3 Hz),
1.36 (m, 2H, CH2CH2CH2CH3), 1.62 (m, 2H,
CH2CH2CH2CH3), 2.54 (t, 2H, CH2CH2C2H5,
J = 7.7 Hz), 3.95 (s, 3H, OCH3), 4.54 (s, 2H,
Py-CH2), 7.43 (d, 1H, 4-Py-H, J = 2.5 Hz), 7.98
(d, 1H, 6-Py-H, J = 2.5 Hz); 13C NMR: 14.0, 22.6,
29.5, 31.1, 43.8, 53.6, 125.8, 126.1, 138.1, 143.7,
162.4. MS m/z (%): 215 (10), 213 (M+, 30), 196
(40), 178 (100), 150 (20), 120 (15). HRMS (EI) m/z
(M+): calculated for C11H16ClNO, 213.0921; found,
213.0955.
2.2.8 1-(6-Chloro-5-n-propyl-pyridin-3-ylmethyl)-2-
nitroiminoimidazolidine
2.2.11 5-n-Butyl-6-chloropyridin-3-ylmethyl chloride
(6r)
(1q)
MP: 125–127 ◦C. IR (KBr) (cm−1): 3400 (m),
2960 (m), 1600–1550 (s–vs), 1480 (m), 1450–1405
(s–vs), 1295 (vs), 1220 (vs), 1140 (s), 1090 (m), 1045
(s), 945 (s), 760 (m), 710 (m). 1H NMR (δ, CDCl3):
0.97 (t, 3H, CH2CH2CH3, J = 7.3 Hz), 1.66 (m,
2H, CH2CH2CH3), 2.69 (t, 2H, CH2CH2CH3,
J = 7.4 Hz), 3.54 (m, 2H, NCH2CH2N), 3.83 (m,
2H, NCH2CH2N), 4.53 (s, 2H, CH2Cl), 7.54 (d,
1H, 4-Py-H, J = 2.5 Hz), 8.16 (d, 1H, 6-Py-H,
J = 2.5 Hz), 8.26 (bs, 1H, NH); 13C NMR: 14.0,
22.6, 35.2, 41.8, 45.4, 45.5, 130.2, 137.2, 139.1,
146.7, 151.4, 161.4. MS m/z (%): 297 (M+, 1), 253
(81), 251 (100), 223 (13), 222 (22), 221 (21), 213
(61), 209 (44), 187 (34), 168 (20), 118 (10), 104
(14). Analysis. Found: C, 48.52; H, 5.55; N, 23.59.
Calculated for C12H16ClN5O2: C, 48.40; H, 5.42; N,
23.52.
IR (liquid) (cm−1): 2560 (m), 1610 (m), 1580 (m),
1475 (vs), 1405 (vs), 1320 (s), 1255 (vs), 1145
(m), 1025 (vs), 780 (m), 695 (m). 1H NMR (δ,
CDCl3): 0.97 (t, 3H, CH2CH2CH2CH3, J = 7.3 Hz),
1.40 (m, 2H, CH2CH2CH2CH3), 1.65 (m, 2H,
CH2CH2CH2CH3), 2.73 (t, 2H, CH2CH2C2H5,
J = 7.6 Hz), 4.55 (s, 2H, CH2Cl), 7.58 (d, 1H, 4-
Py-H, J = 2.2 Hz), 8.23 (d, 1H, 6-Py-H, J = 2.2 Hz);
13C NMR: 14.1, 22.8, 31.5, 33.1, 42.6, 132.6, 137.2,
139.1, 146.8, 151.2. MS m/z (%): 217 (M+, 65),
184 (36), 182 (100), 175 (81), 174 (71), 140 (60),
104 (36). HRMS (EI) m/z (M+): calculated for
C10H13Cl2N, 217.0425; found, 217.0426.
2.2.12 1-(5-n-Butyl-6-chloropyridin-3-ylmethyl)-
2-nitroiminoimidazolidine (1r)
MP: 115–118 ◦C. IR (KBr) (cm−1): 3430 (m), 1575
(vs), 1480 (m), 1440 (vs), 1400 (s), 1325 (s),
1295 (vs), 1230 (s), 1140 (m), 1090 (m), 1045
(s), 940 (s), 780 (m), 710 (m). 1H NMR (δ,
CDCl3): 0.96 (t, 3H, (CH2)2CH2CH3, J = 7.3 Hz),
1.41 (m, 2H, CH2CH2CH2CH3), 1.60 (m, 2H,
CH2CH2CH2CH3), 2.71 (t, 2H, CH2CH2C2H5,
J = 7.7 Hz), 3.50 (m, 2H, NCH2CH2N), 3.79 (m,
2H, NCH2CH2N), 4.52 (s, 2H, CH2Cl), 7.54 (d,
2.2.9 N-(5-n-Butyl-6-methoxypyridin-3-ylmethyl)
morpholine (4r)
A portion of a 1:1 mixture of the product and
3 obtained according to the above procedures was
subjected to repeated separation by preparative thin-
layer chromatography with IPE + hexane (1 + 4 by
volume), and the purified product was obtained as
colourless liquid. IR (liquid) (cm−1): 2955 (m), 1610
78
Pest Manag Sci 63:75–83 (2007)
DOI: 10.1002/ps

Insecticidal activity of substituted imidacloprid derivatives
Table 1. Insecticidal activities of substituted imidacloprid derivatives and (S)-nicotinea
Compound log(1/MLD) (mol) Compound
log(1/MLD) (mol)
No.
X
Alone
+NIA
10.15
8.18
9.91
9.05
9.11
8.64
<7.24
<7.22
8.74
+(PB + NIA)
No.
X
Alone
+NIA
+(PB + NIA)
b
b
c
1a
1b
H
N3
F
Cl
Br
8.96
7.37
8.82
8.35
8.02
10.15
8.18
9.91
9.05
9.11
8.64
6.30
5.77
8.74
8.08
6.89
1l
OPr(i)
OBu(n)
OPent(n)
Me
Et
Pr(n)
Bu(n)
Ph
CF3
6.99
7.12
5.86
7.89
8.12
6.46
9.26
7.58
7.51
6.17
7.52
7.99
<6.50
5.51
8.10
8.12
6.46
9.26
7.88
7.62
6.27
7.92
8.20
<6.50
c
1m
1n
b
c
1c
1d
b
1o
1p
1q
1r
1s
1t
7.96
b
1e
<6.97
<7.02
<6.08
<7.22
6.69
b
1f
I
7.54
b
1g
1h
CN
NO2
OMe
OEt
OPr(n)
<7.24
<7.22
7.43
7.07
<6.89
b
c
c
1i
1j
7.87
6.89
1u
COOMe
<6.50
c
1k
(S)-nicotined
a See Fig. 1 for the general structure.
b Ref. 14.
c Ref. 15.
d Ref. 21.
1H, 4-Py-H, J = 2.5 Hz), 8.14 (d, 1H, 6-Py-H,
J = 2.5 Hz), 8.17 (bs, 1H, NH); 13C NMR: 13.9,
22.5, 31.3, 32.9, 41.5, 45.2, 45.5, 129.9, 137.5, 139.0,
146.6, 151.6, 161.4. MS m/z (%): 313 (2), 311 (M+,
5), 268 (43), 266 (100), 221 (55), 211 (45), 209
(99), 187 (81), 167 (10). Analysis. Found: C, 50.31;
H, 5.65; N, 22.80. Calculated for C13H18ClN5O2: C,
50.08; H, 5.82; N, 22.47.
amount of benzoyl peroxide at reflux temperature
for 10 h. The solids precipitated on cooling were
filtered off, and the filtrate, after evaporation of the
solvent, was subjected to column chromatography of
the residual liquid on SiO2 with hexane + IPE (10 + 1
by volume). Yield: 158 mg (50%). MP: 56–57 ◦C. IR
(KBr) (cm−1): 1440 (m), 1400 (vs), 1210 (s), 1105
(s), 1080 (m), 1045 (m), 1030 (m), 895 (m), 760
(s), 700 (vs). 1H NMR (δ, CDCl3): 4.49 (s, 2H,
CH2), 7.41–7.50 (m, 5H, Ph), 7.72 (d, 1H, 4-Py-
H, J = 2.2 Hz), 8.40 (d, 1H, 6-Py-H, J = 2.2 Hz);
13C NMR: 28.3, 128.4, 128.6, 129.2, 132.9, 136.8,
137.1, 140.2, 148.0, 149.5. MS m/z (%): 283 (18),
281 (M+, 13), 204 (33), 202 (100), 167 (20), 166
(13), 140 (14), 139 (36). Analysis. Found: C, 49.98;
H, 3.45; N, 4.79. Calculated for C12H9BrClN: C,
51.01; H, 3.21; N, 4.96.
2.2.13 2-Chloro-5-methyl-3-phenylpyridine (8)
A mixture of 714 (253 mg, 1 mmol), phenylboronic
acid (195 mg, 1.5 mmol), tetrakis(triphenylphosphine)
palladium(0) (20 mg) and potassium carbonate
(202 mg, 1.5 mmol) in dimethoxyethane (4 mL) and
water (1 mL) was stirred at 85 ◦C for 3.5 h. The
mixture was diluted with IPE (20 mL) and insoluble
materials were discarded. The separated organic phase
was washed with brine and dried over magnesium
sulfate. After evaporating the solvents, the residue
was chromatographed on SiO2 with hexane + IPE
(4 + 1 by volume) as the eluate, and a colourless
liquid product was obtained. Yield: 102 mg (50%).
IR (liquid) (cm−1): 3150 (m), 1565 (m), 1510 (vs),
1320 (m), 1220 (s), 1155 (m), 1140 (m), 1000 (s),
2.2.15 1-(6-Chloro-5-phenylpyridin-3-ylmethyl)-
2-nitroiminoimidazolidine (1s)
The compound was prepared analogously to com-
pound 1p. Yield: 36%. MP: 194–196 ◦C. IR (KBr)
(cm−1): 3400 (s), 2870 (m), 1580–1540 (s), 1440
(s), 1400 (vs), 1320 (s), 1290 (vs), 1220 (vs), 1100
(m), 1040 (m), 940 (m), 700 (m). 1H NMR (δ,
CDCl3): 3.56 (m, 2H, NCH2CH2N), 3.80 (m, 2H,
NCH2CH2N), 4.59 (s, 2H, CH2), 7.40–7.49 (m, 5H,
Ph), 7.66 (d, 1H, 4-Py-H, J = 2.2 Hz), 8.22 (bs, 1H,
NH), 8.32 (d, 1H, 6-Py-H, J = 2.2 Hz); 13C NMR:
41.5, 45.2, 45.3, 128.5, 128.6, 129.2, 130.1, 136.7,
137.3, 139.7, 147.7, 149.7, 161.2. MS m/z (%): 331
(M+, 2), 287 (39), 286 (100), 249 (37), 202 (8), 167
(9), 139 (19). Analysis. Found: C, 54.63; H, 4.56; N,
20.86. Calculated for C15H14ClN5O2: C, 54.30; H,
4.25; N, 21.11.
1
820 (s), 810 (s). H NMR (δ, CDCl3): 2.35 (s, 3H,
CH3), 7.38–7.48 (m, 5H, Ph), 7.48 (d, 1H, 4-Py-
H, J = 1.8 Hz), 8.21 (d, 1H, 6-Py-H, J = 1.8 Hz);
13C NMR: 17.6, 128.1, 128.2, 129.2, 132.3, 136.1,
137.5, 140.4, 146.7, 148.5. MS m/z (%): 205 (77),
204 (68), 203 (M+, 100), 168 (71), 167 (61), 166
(46), 165 (18), 153 (19), 152 (18), 141 (36), 140
(32), 139 (25), 138 (21), 115 (32), 114 (31). Analy-
sis. Found: C, 70.56; H, 4.79; N, 6.56. Calculated for
C12H10ClN: C, 70.77; H, 4.95; N, 6.88.
2.2.14 6-Chloro-5-phenylpyridin-3-ylmethyl bromide
(9)
2.3 Insecticidal tests
A mixture of compound 8 (228 mg, 1.12 mmol) and
N-bromosuccinimide (300 mg, 1.68 mmol) in carbon
tetrachloride (15 mL) was stirred with a catalytic
The insecticidal test against male adult P. americana
was carried out as described previously.17,21,22 Various
volumes (1–10 µL) of solutions of each compound
Pest Manag Sci 63:75–83 (2007)
79
DOI: 10.1002/ps

S Kagabu et al.
in dimethyl sulfoxide (DMSO) containing some
methanol were injected into the abdomen of a
cockroach. Organic solvents alone in this range did
not have any toxic effect. Details of the dosage were
fundamentally the same as described previously.22
The doses were varied by 0.1 in log units. In some
experiments, a methanol solution (1 µL) containing
NIA (50 µg) or a mixture of PB (50 µg) and NIA
(50 µg) was injected 1 h before injection of the test
compound. The metabolic inhibitors at these amounts
did not have any toxic effect. Three insects were used
to test each dose of each compound, and were kept
at 24–26 ◦C for 24 h after injection. The minimum
lethal doses (MLD; mol) for the test compounds
were determined. The activity values of compounds
1o–1u were expressed by log(1/MLD) and are listed
in Table 1 together with previously reported data for
1a–1n and (S)-nicotine. Each value is the mean of at
least two experimental runs, with a deviation of 0.2.
A2B2 coupling pattern for the imidazolidine ring
protons, and and AX pattern for 2,3,5-trisubstituted
pyridine ring protons. The acidic imidazolidine NH
appeared as a broad signal. The 13C signal around
160 ppm is informative for confirming the existence
of a guanidinyl central carbon. The molecular ion
peaks of the present compounds appeared with very
weak intensity or were often lacking in the electron
impact mass method, like other imidacloprid-type
compounds, because of the fragile N–NO2 bond,
while the ion with a relatively strong intensity due
to the ‘benzylic’ fragment was a good mark for the
structure.25
3.2 Insecticidal activity
The potencies of alkyl derivatives were considerably
less than that of imidacloprid (1a). Of the set of alkyl
compounds, the potency of the methyl compound (1o)
was the highest, with log(1/MLD) of 7.96, which is 10
times weaker than imidacloprid (1a), and comparable
with the bromo derivative (1e) at the molar level.
Introduction of higher alkyl or phenyl substitutions
in the 5-position drastically decreased the activity,
so that the MLD values could not be determined.
The methoxycarbonyl derivative (1u) afforded no
determinable lethal value at 310 nmol dose.
3
RESULTS AND DISCUSSION
3.1 Synthesis
The scheme in Fig. 2 represents the route to deriva-
tives substituted in the 5-position of the pyri-
dine ring of imidacloprid. The known 2-chloro-5-
morpholinomethylpyridine (2)10 was selected as the
precursor for 5-alkyl-6-chloronicotinyl chloride. The
first step of the electrophilic alkylation of position α to
the 6-chlorine, using, as the base, the well-documented
lithium diisopropyl amide (LDA), prepared in situ
from diisopropylamine and butyllithium, failed under
various conditions. Therefore, the precursor for the
alkylation was changed to the 2-methoxy derivative (3)
in expectation of its more powerful effect on chelating
the lithium ion.23 The chlorine atom was rather inert to
nucleophilic attack by the methoxide ion in a conven-
tional way. The substitution reaction proceeded at last
with the aid of crown ether catalysis. However, alkyla-
tion using an equimolar amount of LDA again failed to
give this methoxy derivative. Fortunately, a modifying
procedure using methyllithium with a catalytic amount
of diisopropylamine24 afforded the alkylated products
in 20–40% yields. The morpholinomethyl group could
be converted to the chloromethyl group by an estab-
lished procedure using ethyl chloroformate without
isolating the alkylated products.10 Another precur-
sor, 6-chloro-5-phenyl-3-picoline (8), was accessible
by the Suzuki coupling reaction of 6-chloro-5-iodo-
3-picoline (7)15 with phenylboronic acid using a
palladium phosphine complex. The final imidaclo-
prid derivatives substituted in the 5-position of the
pyridine ring were obtained by the coupling reaction
of 5-substituted 6-chloro-3-pyridylmethyl bromide or
chloride with 2-nitroiminoimidazolidine (10) in DMF
using sodium hydride as an acid acceptor.
NIA16388, which was originally reported as
an inhibitor of the hydrolytic metabolism of
tetramethrin,26 a pyrethroid, has also been used to
improve the activity of neonicotinoids. The previ-
ous experiments suggested that the synergistic effect
of NIA could be due to the inhibition of oxida-
tive metabolism at the carbon(s) in the α-position
to the imidazolidine nitrogen atom(s).17,21,27 Also,
Liu et al.28 observed a similar enhancement effect
of NIA on insecticidal activity against houseflies.
Recent experiments with houseflies have evidenced the
retarded degradation of [3H]imidacloprid in the pres-
ence of NIA.29 The present results reflected well the
synergistic effect of NIA, which increased the poten-
cies by more than 1 log unit for compounds 1o and
1t, so that the potency of 1o was raised to nanomolar
level, and the log(1/MLD) values for the higher alkyl
derivatives were elevated enough to allow their deter-
mination. The present authors have reported that the
activity of neonicotinoid compounds could be further
enhanced by adding PB, another oxidative metabolism
inhibitor.17,20 This showed a slight synergistic effect
with the compounds tested here, except for the methyl
derivative (1o), which was not affected. The MLD
value of ester (1u) could not yet be determined even
under these synergist-pretreated conditions. All of the
newly prepared compounds except 1u showed higher
activity than nicotine.
The insecticidal potency under synergistic condi-
tions should reflect the intrinsic activity more closely
than that without the synergist. In order to compare
their activities in the presence of combined synergists,
the tested compounds were divided into four classes
(1–4 below), and compounds were selected from each
The analytical data supported the structures of
the new products (1p–1s). Substituted imidacloprid
derivatives shared characteristic spectral features with
imidacloprid.25 Proton NMR spectra showed a typical
80
Pest Manag Sci 63:75–83 (2007)
DOI: 10.1002/ps

Insecticidal activity of substituted imidacloprid derivatives
class to compare the potencies among the classes (5
below).
(amidinyl) nitrogen atom (N1) to the electron-negative
tip (O1 or O2) on one side and to the pyridyl nitrogen
atom on the other side is also crucial for activity. As
for the chloropyridyl part, it has been considered in
the present model as a contributor to activity enhance-
ment by participation in a certain bonding with the
hydrophobic residues near the essential binding sites
in the receptor peptide segment, instead of the pri-
mary role of the hydrogen bond of the pyridyl nitrogen
that was advocated in the preceding model.34 The
prominent insecticidal activity of the later developed
dinotefuran bearing a 3-tetrahydrofuranylmethyl moi-
ety in place of the 3-pyridylmethyl group is in accord
with the present model in that the ether oxygen in
the former is apparently a weaker hydrogen bonding
donator than the pyridyl nitrogen.35
The present study with an additional substituent at
the neighbouring position to the 6-chlorine atom on
the pyridine ring added another aspect to the binding
model. The high activity of the fluoro derivative
(1c), comparable with that of imidacloprid, means
that there is a permissible region to accommodate
a lipophilic group in proximity to the 6-chlorine,
although it is limited in space from accepting larger
groups, as seen in the significant activity decrease
with increasing atom size or alkyl chain length of the
substituent. Another activity tendency independent of
the σm constant of the group suggests that the hydrogen
bond strength related to the negative charge density of
the pyridyl nitrogen does not primarily determine the
level of activity, although its hydrogen bond accepting
property seems necessary for neonicotinoids to exert
activity.
1. H > F ꢀ Br ∼ Cl > I ꢀ N3.
2. Me ꢀ CF3 > Ph ∼ Et > Pr (n) ꢀ Bu (n).
3. OMe ꢀ OBu(n) ∼ OPr(i) ∼ OEt
ꢀ OPr(n) > OPentyl(n).
4. CN, NO2, CO2Me.
5 (F ꢀ Me > Cl > OMe > I ꢀ CF3 ∼ N3 ꢀ CN).
It can be seen that (1) the activity is largely inversely
proportional to the size of the atom or group in
the same class; (2) the activity is not parallel to
the electronic inductive effect of the group with the
Hammet σm constants;30 (3) the activity seems not to
be determined primarily by lipophilicity; (4) CN, NO2
and CO2Me groups deactivate to an extraordinary
degree.
Neonicotinoids act on the insect nicotinic acetyl-
choline receptors agonistically in the same way as
nicotine.31,32 The present authors proposed a binding
model by emphasizing the important role of a nitro
or cyano group conjugated to the amidine or guani-
dine part for the hydrogen bonding to the receptor
(Fig. 3).33 The distance (∼4.5 A) from the guanidinyl
˚
N
+
H
N
The enormous degeneration of activity caused by
NO2, CN and CO2Me is puzzling at first glance. It is
suspected that this phenomenon arises as follows. The
electronegative tips of the 5-substituents (nitro oxygen,
carbonyl oxygen and cyano nitrogen) are separated
from the pyridyl nitrogen by a similar distance to that
between the nitro oxygen and the guanidinyl nitrogen
atom in imidacloprid, so that these compounds
possibly approach the imidacloprid-binding site on
the receptor in a similar fashion to imidacloprid.
However, there are two essential differences between
the ‘false’ compounds and imidacloprid. Firstly, the
pyridyl and guanidinyl nitrogen atoms are indeed of
sp2 configuration, but the former nitrogen possesses
a lone electron pair extending in the horizontal
direction, while the latter is inherently electron
deficient and the lone pair is incorporated into the
conjugation cascade. Secondly, as argued above,
the substantial effect of the chloropyridyl moiety
N
X
N1
N
δ+
O2
N2
N
δ-
H
H
O1
O
N1
N
δ+
O2
δ-
N2
Me
N
H
O1
H
-
˚
appending 4.5 A from the nitroguanidinyl part (the
main part hereafter) is needed for imidacloprid to
exert its high activity. In molecules 1g, 1h and
1u, the guanidinyl part is located in turn at a
similar distance from the pyridine part substituted
with a nitro, cyano or methoxycarbonyl group at
the 5-position (the main part in these molecules).
However, the two main parts differ considerably
5.9 Å
nAChR
Figure 3. Binding model of agonists to nAChR: nicotine (upper),
6-substituted imidacloprid (middle) and dinotefuran (lower).
Pest Manag Sci 63:75–83 (2007)
81
DOI: 10.1002/ps

S Kagabu et al.
W
Z
A or B : at least one of them is N
R1, R2: H, Alkyl including R1-R2-bonding
Y=CH or N
A
δ+
Y
R1
O
δ-
B
R2
N
Z: lone-pair possessing atom
O
W: permissible space for small lipophilic substituent
N
C
N
Figure 4. Hypothetical pharmacophore model for neonicotinoids.
6 Okazawa A, Akamatsu M, Ohoka A, Nishiwaki H, Cho W,
Nakagawa Y, et al Prediction of the binding mode of imidaclo-
prid and related compounds to house-fly head acetylcholine
receptors using three-dimensional QSAR analysis. Pestic Sci
54:134–144 (1998).
7 Okazawa A, Akamatsu M, Nishiwaki H, Nakagawa Y, Miya-
gawa H, Nishimura K, et al Three dimensional quantitative
structure–activity relationship analysis of acyclic and cyclic
chloronicotinyl insecticides. Pest Manag Sci 56:509–515
(2000).
8 Gsell L, Preparation and testing of [(pyridylmethyl)amino]-
nitroethylenes as insecticides, acaricides and ectoparasitcides.
European Patent Application EP 302833 A2 19890208; Chem
Abst 111:39194 (1989).
9 Gsell L, Preparation and testing of pyridylmethylcyanoguani-
dines as insecticides and acaricides. European Patent Applica-
tion EP 306696 A1 19890315; Chem Abst 111:97093 (1989).
10 Kagabu S, Maienfisch P, Zhang A, Granda-Minones J, Haet-
tenschweiler J, Kayser H, et al, 5-Azidoimidacloprid and an
acyclic analogue as candidate photoaffinity probes for mam-
malian and insect nicotinic acetylcholine receptors. J Med
Chem 43:5003–5009 (2000).
from each other in their physicochemical properties
such as hydrogen bond facility and lipophilicity.
Such inadequate molecular frameworks combined
would reduce the effective action at the receptor
site.
Based on the present results, a schematic phar-
macophore of neonicotinoid molecules is shown in
Fig. 4. The pharmacophore is constructed with two
parts lying at a certain distance; one is an amidine or
guanidine conjugated to a powerful electronegative tip
such as NO2 or CN, and the other is an atom possess-
ing a lone-pair electron in conjunction with a small
round lipophilic moiety. A picture is being gained of
the structural features around the nicotinoid-binding
site on the putative insect nAChR.36,37 The nitro or
cyano group of neonicotinoids is predicted to interact
electrostatically with a basic residue in the ligand-
binding pocket, the amidine part would interact with
the vicinal tryptophan residue and the heteroaromatic
part such as chloropyridine will be oriented towards
one of the tyrosine residues.36,37 The positional aber-
ration of each pharmacophore part or the deviation of
the electronic nature causes the activity to degenerate
significantly.
11 Tomizawa M, Wen Z, Chin H-L, Morimoto H, Kayser H
and Casida JE, Photoaffinity labeling of insect nicotinic
acetylcholine receptors with a novel [3H]azidoneonicotinoid.
J Neurochem 78:1359–1366 (2001).
12 Zhang N, Tomizawa M and Casida JE, Structural features of
azidopyridinyl neonicotinoid probes conferring high affinity
and selectivity for mammalian α4β2 and Drosophila nicotinic
receptors. J Med Chem 45:2832–2840 (2002).
13 Zhang N, Tomizawa M and Casida JE, 5-Azidoepibatidine: an
exceptionally potent photoaffinity ligand for neuronal α4β2
and α7 nicotinic acetylcholine receptors. Bioorg Med Chem
Lett 13:525–527 (2003).
14 Kagabu S, Ito N, Imai R, Hieta Y and Nishimura K, Effects of
halogen introduction at the C5 position of the imidacloprid
pyridine upon insecticidal activity. J Pestic Sci 30:409–413
(2005).
15 Kagabu S, Fujii Y and Nishimura K, Alkoxy-introduction to
the 5th position on pyridine ring of imidacloprid and their
insecticidal activity. J Pestic Sci 31:150–155 (2006).
16 Kagabu S, Methyl, trifluoromethyl, and methoxycarbonyl-
introduction to the 5th position on pyridine ring of
chloronicotinyl insecticide imidacloprid. Synth Commun
36:1235–1245 (2006).
17 Nishimura K, Kanda Y, Okazawa A and Ueno T, Relationship
between insecticidal and neurophysiological activities of
imidacloprid and related compounds. Pestic Biochem Physiol
50:51–59 (1994).
ACKNOWLEDGEMENTS
This work was partly supported by a Grant-in-Aid
for Scientific Research to SK (No. 17580094) from
the Japan Society for the Promotion of Science.
The authors thank Earth Chemical Co., Ltd for the
donation of American cockroaches.
REFERENCES
1 Kagabu S, Molecular design of neonicotinoids: past, present and
future, in Chemistry of Crop Protection, Progress and Prospects in
Science and Regulation, ed. by Voss G and Ramos G. Wiley-
VCH, Weiheim, pp. 193–212 (2003).
2 Patani GA and LaVoie EJ, Bioisosterism: a rational approach in
drug design. Chem Rev 96:3147–3176 (1996).
3 Kagabu S, Chloronicotinyl insecticides – discovery, application
and future perspective. Rev Toxicol 1:75–129 (1997).
4 Jeschke P, The unique role of fluorine in the design of
active ingredients for modern crop protection. ChemBioChem
5:570–589 (2004).
5 Nishiwaki H, Nakagawa Y, Takeda D, Okazawa A, Aka-
matsu M, Miyagawa H, et al Binding activity of substituted
benzyl derivatives of chloronicotinyl insecticides to housefly-
head membranes and its relationship to insecticidal activ-
ity against the housefly Musca domestica. Pest Manag Sci
56:875–881 (2000).
18 Kiriyama K, Iwaya K, Kagabu S and Nishimura K, Relationship
between insecticidal and nerve activities of an imidacloprid-
related nitromethylene compound and its N-alkyl congeners.
J Pestic Sci 26:55–59 (2001).
19 Kiriyama K and Nishimura K, Structural effects of dinotefuran
and analogues in insecticidal and neural activities. Pest Manag
Sci 58:669–676 (2002).
20 Kagabu S, Azuma A and Nishimura K, Insecticidal and neu-
roblocking activities of thiacloprid and its acyclic analogues
and their related cyanoguanidine derivatives. J Pestic Sci
27:267–271 (2002).
82
Pest Manag Sci 63:75–83 (2007)
DOI: 10.1002/ps

Insecticidal activity of substituted imidacloprid derivatives
21 Kiriyama K, Kagabu S and Nishimura K, Insecticidal activ-
ities of the enantiomers of asymmetric 1-[1-(6-chloro-
3-pyridyl)ethyl]-2-nitroiminoimidazolidine against American
cockroach, cucurbit leaf beetle, green rice leafhopper and
green peach aphid following injection, dipping and spraying.
J Pestic Sci 29:43–45 (2004).
29 Nishiwaki H, Sato K, Nakagawa Y, Miyashita M and Miya-
gawa H, Metabolism of imidacloprid in houseflies. J Pestic
Sci 29:110–116 (2004).
30 Hansch C, Leo A, Unger SH, Kim K-H, Nikaitani D and Lien
EJ, ‘Aromatic’ substituent constants for structure–activity
correlations. J Med Chem 16:1207–1216 (1973).
22 Nakagawa S, Okajima N, Kitahaba T, Nishimura K, Fujita T
and Nakajima M, Quantitative structure–activity studies
of substituted benzyl crysanthemates. 2. Physicochemical
substituent effects and neurophysiological and symptomatic
activities against American cockroaches. Pestic Biochem Physiol
17:243–258 (1982).
23 Sclosser M, Organometallics in Synthesis. Wiley, Chichester, UK,
Ch. 1 (1994).
24 Trecourt F, Mallet M, Marsais F and Queguiner G, Catalyzed
31 Schroeder ME and Flattum RF, The mode of action and
neurotoxic properties of the nitromethylene heterocyclic
insecticides. Pestic Biochem Physiol 22:148–160 (1991).
32 Bai D, Lummis SCR, Leicht W, Breer H and Sattelle DB,
Actions of imidacloprid and a related nitromethylene on
cholinergic receptors of an identified insect motor neurone.
Pestic Sci 33:197–204 (1991).
33 Kagabu S and Matsuno H, Chloronicotinyl insecticides. 8.
Crystal and molecular structures of imidacloprid and
metalation applied to 2-methoxypyridine.
53:1367–1371 (1988).
J
Org Chem
analogous compounds.
(1997).
J Agric Food Chem 45:276–281
25 Kagabu S, Yokoyama K, Iwaya K and Tanaka M, Imidacloprid
and related compounds: structure and water solubility of
N-alkyl derivatives of imidacloprid. Biosci Biotechnol Biochem
62:1216–1224 (1998).
34 Yamamoto I, Tomizawa M, Saito T, Miyamoto T and Kagabu
S, Molecular mechanism for selective toxicity of nicotinoids
and neonicotinoids. J Pestic Sci 20:33–40 (1995).
35 Wakita T, Kinoshita K, Yamada E, Yasui N, Kawahara N,
26 Suzuki T and Miyamoto J, Metabolism of tetramethrin in
houseflies and rats in vitro. Pestic Biochem Physiol 4:86–97
(1974).
27 Nishimura K, Tanaka M, Iwaya K and Kagabu S, Relationship
between insecticidal and nerve-excitatory activities of imi-
dacloprid and its alkylated congeners at the imidazolidine
NH-site. Pestic Biochem Physiol 62:172–178 (1998).
Naoi A, et al, The discovery of dinotefuran:
neonicotinoid. Pest Manag Sci 59:1016–1022 (2003).
a novel
36 Tomizawa M, Zhang N, Durkin A, Olmstead MM and Casida
JE, The neonicotinoid electronegative pharmacophore plays a
crucial role in the high affinity and selectivity for the Drosophila
nicotinic receptor: an anomaly for the nicotinoid cation-π
interaction model. Biochemistry 42:7819–7827 (2003).
37 Matsuda K, Shimomura M, Ihara M, Akamatsu M and Sat-
telle DB, Neonicotinoids show selective and diverse actions
on their nicotinic receptor targets: electrophysiology, molec-
ular biology, and receptor modeling studies. Biosci Biotechnol
Biochem 69:1442–1452 (2005).
28 Liu M-Y, Lanford
J
and Casida JE, Relevance of
[3H]imidacloprid binding site in house fly head acetylcholine
receptor to insecticidal activity of 2-nitromethylene- and 2-
nitroimino-imidazolidines. Pestic Biochem Physiol 46:200–206
(1993).
Pest Manag Sci 63:75–83 (2007)
83
DOI: 10.1002/ps