cis-Nitromethylene neonicotinoids as new nicotinic family: Synthesis, structural diversity, and insecticidal evaluation of hexahydroimidazo[1,2-α]pyridine

Article abstract of DOI:10.1016/j.bmcl.2008.10.048

A series of neonicotinoids analogues of hexahydroimidazo[1,2-α]pyridine were modified at 5-, 6-, and 7-positions, and their insecticidal activities were evaluated. Introducing a methyl or ethyl at 7-position increased the insecticidal activities, while ot

Full text of DOI:10.1016/j.bmcl.2008.10.048

Bioorganic & Medicinal Chemistry Letters 18 (2008) 6513–6516
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
cis-Nitromethylene neonicotinoids as new nicotinic family: Synthesis,
structural diversity, and insecticidal evaluation of hexahydroimidazo[1,2-
a]pyridine
*
*
Xusheng Shao, Wenwen Zhang, Yanqing Peng, Zhong Li , Zhongzhen Tian, Xuhong Qian
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of neonicotinoids analogues of hexahydroimidazo[1,2-a]pyridine were modified at 5-, 6-, and 7-
Received 26 August 2008
Revised 12 September 2008
Accepted 10 October 2008
Available online 14 October 2008
positions, and their insecticidal activities were evaluated. Introducing a methyl or ethyl at 7-position
increased the insecticidal activities, while other substituents decreased activities. When alkyl substitu-
ents were introduced to 7-position, the insecticidal activities against Pea aphids decreased in the order
methyl (7a) > ethyl (7b) > n-butyl (7e) > phenyl (7f) > n-propyl (7c) > iso-propyl (7d), p-NO2-phenyl
(7g). Modifications at 5-, 6- or both at 6- and 7-positions with methyl or ethyl were unfavorable to activ-
ities. Interestingly, introducing methyl to 7-position not only increased insecticidal activities against pea
aphids, but also show higher insecticidal activities than imidacloprid against imidacloprid-resistant
brown planthopper.
Keywords:
Neonicotinoid
cis-Configuration
Insecticide
Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
Resistance
Nicotinic acetylcholine receptors (nAChRs) are major excitatory
neurotransmitter receptors in both vertebrates and invertebrates.1
Ligands for nAChRs are of considerable interest, due to their impor-
tant physiological, pharmacological, medical, and insecticidal
applications.2,3 Insect nAChRs mediate fast synaptic transmission
in the insect nervous system and are targets of a major group of
insecticides, the neonicotinoids.4 Neonicotinoids represented
by imidacloprid5 (1, Fig. 1) are the most important class of insecti-
cides over the past three decades because of their potency, low
mammalian toxicity, broad insecticidal spectra, and good systemic
properties.6,7 After imidacloprid, six insecticides of this class: ace-
tamiprid,8 nitenpyram,9 thiamethoxam,10,11 thiacloprid,12 clothi-
anidin,13 and dinotefuran14 were commercialized. The relatively
low risk combined with their suitability for a range of application
methods maintain neonicotinoids as major insecticides widely
used against a broad spectrum of sucking and biting insects.15
A potential problem facing all insecticides is the development of
resistance and its concomitant detrimental effect on agricultural
productivity.16 Although the new mode of action, frequent applica-
tions and structural similarity of neonicotinoids have led to the
Discovering insecticides with novel structures or mode of ac-
tions is one of the effective resistance-management tactics. Hence,
the development of new neonicotinoids with high insecticidal
activities against resistance strains is highly desirable. As well
known, the structural feature of –NO2 in imidacloprid act impor-
tant role in its activities. The –NO2 in all commercialized neonicot-
inoids are in trans-configuration and three proposals for modes of
action are based on trans-configuration.26 However, some dicyclic
neonicotinoids with cis-configuration also showed high insecti-
cidal activities.27,28 In previous study, we have found some poten-
tial neonicotinoids with cis-configuration, unfortunately, the
activities of these compounds had no superiority over imidaclo-
prid.29–31 Interestingly, further bioassay on sensitive and resistance
strains against imidacloprid of brown planthopper, N. lugens,
showed that compounds 2 have higher activity against resistance
strains, which implied the further structural modification might
give valuable results in resistance management. Moreover, the
previous results showed interesting effects of small alkyl substitu-
ents on final bioactivities. In order to explore the influence of alkyl
acquisition of resistance and cross-resistance in
a range of
species.17–24 Especially, the brown planthopper, Nilaparvata lugens,
a major rice pest in many parts of Asia, has developed strong
resistance to imidacloprid.17,20,25
R4
R
O
Cl
N
Cl
N
Cl
N
O
R3
R2
NH
N
N
N
N
N
5
6
N
NO2
O2N
7
O2N
R1
Imidacloprid
2
1
2a
R = H
3
* Corresponding authors. Tel.: +86 21 64253540; fax: +86 21 64252603.
E-mail addresses: lizhong@ecust.edu.cn (Z. Li), xhqian@ecust.edu.cn (X. Qian).
Figure 1. Neonicotinoids.
0960-894X/$ - see front matter Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.10.048

6514
X. Shao et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6513–6516
substituents on the bioactivities, a series of nitromethylene neon-
icotinoids 3 were designed and synthesized by introducing various
alkyl substituents at 5-, 6-, and 7-positions of hexahydroimi-
dazo[1,2-a]pyridine scaffold of lead compounds 2. Some of these
candidates show higher activities against pea aphids, while four
active compounds have higher activities against imidacloprid-
resistant brown planthopper than imidacloprid.
The novel neonicotinoid derivatives described herein were syn-
thesized as shown in Scheme 1. Starting from 2-chloro-5-chlorom-
ethylpridine 4, N0-((5-chloropyridin-2-yl)-methyl)ethane-1,2-dia-
mine 5 and intermediate 6 were obtained following the procedure
reported previously.32 Reaction of 6 with various
a
, b-unsaturated
aldehydes or
a, b-unsaturated ketones was catalyzed by concen-
trated HCl or glacial acetic acid in acetonitrile at 40–50 °C, afford-
ing desired compounds 7a–g, 9, 11a–b, 12, and 13. The further
reaction of 7a–g or 9 with various alcohols could proceed readily
in refluxing dichloromethane catalyzed by hydrochloric acid to
give ethers 8a–y or 10a–b. The structures of the compounds were
well characterized by 1H NMR, 13C NMR, HRMS, and/or EA.
Ethers 8a–y and 10a–b were obtained in excellent yields. The
yields of 7a–g, 9, 11a–b, 12, and 13 were relatively low and the
reaction temperature should be controlled bellow 50 °C in order
Figure 2. ORTEP view showing the atom-labeling scheme with thermal ellipsoids
drawn at 30% probability for compound 8a.
the electron-withdrawing group, –NO2, forming a coplanar ole-
to inhibit the formation of hydroxyl-eliminated byproducts.
unsaturated aldehydes bearing one substituent at 3-position could
react smoothly with 6 under catalysis of glacial acetic acid, while
b-unsaturated aldehydes bearing substituents at 2-positions
(including cyclohex-1-enecarbaldehyde) react with 6 only in the
presence of concentrated HCl, rather than AcOH. The reaction of
6 with a, b-unsaturated aldehydes bearing two substituents at 3-
position could not proceed, which may be due to steric hindrance
of two substituents.
a
, b-
fin-amine p-electron network. Furthermore, the bond lengths of
C(1)@C(2) and C–NO2 are 1.425 and 1.348 Å, which are longer than
that of typical C@C (1.34 Å) and shorter than that of typical C–NO2
(C–N in C–NO2; 1.49 Å), respectively. Compared with the trans-
configuration of nitro in the crystal structure of imidacloprid,34
the nitro group in 8a is obviously in cis-configuration as antici-
pated. As all the modes of action were put forward based on
trans-configuration, this unique cis-configuration may confer some
new properties onto the compounds.
a,
In order to obtain precise three-dimensional structural informa-
tion, compound 8a was recrystallized by slow evaporation from
mixed solvent of dichloromethane and acetone (V:V = 1:1) and
its single-crystal structure was determined by X-ray crystallogra-
phy as illustrated in Figure 2.33 The tetrahydropyridine adopts a
half-chair conformation. Owing to the transfer of the lone-pair
electrons on the amines to C(1)–C(2) double bond, the C(1)–N(1)
and C(1)–C(2) bond lengths, 1.332 and 1.335 Å, are remarkably
shorter than the pure C–N single bond (1.47 Å) but close to C@N
(1.33 Å).34,35 The delocalization of the electrons extends as far as
The insecticidal activities of compounds 7a–g, 8a–y, 9, 10a–b,
11a–b, 12 and 13, and imidacloprid were screened against Pea
aphids (Aphis craccivora) using the method described before.30 Re-
sults were summarized in Table 1.
As indicated in Table 1, many of the compounds exhibited sig-
nificant insecticidal activities against Pea aphids, although some-
what lower than that of imidacloprid (e.g., 7a, 8c, 8n). The
activities of the compounds in Table 1 varied drastically, depend-
ing upon the types and patterns of substitution on tetrahydropyr-
idine. Introducing methyl or ethyl substituents at the 7-position of
Cl
N
Cl
N
R4
O
R4
O
Cl
N
N
N
N
4
Cl
N
O2N
R1
O2N
90%
a
b
10
8
a-b
a-y
e
e
R4OH
R4OH
N
NH2
70-90%
N
70-90%
OH
H
Cl
N
5
Cl
N
Cl
N
OH
N
N
92%
d
N
O2N
NO2
NH
O
O2N
O
R1
R1
N
c
7
a-g
9
R1
Cl
N
6
O
R2
O
d
c
CHO
c
12%
%
0
3
-
0
2
Cl
N
Cl
N
OH
Cl
N
OH
R2
OH
N
N
N
N
N
N
O2N
11
a-b
O2N
R1
O2N
13
12
Scheme 1. Reagents and conditions: (a) ethane-1,2-diamine, CH3CN, 0–5 °C; (b) 1,1-bis(methylthio)-2-nitroethene, CH3CH2OH, refluxing; (c) CH3CN, concd HCl., 40–50 °C;
(d) CH3CN, AcOH, 40–50 °C; (e) CH2Cl2, concd HCl, refluxing.

X. Shao et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6513–6516
6515
Table 1
Insecticidal activities of compounds 7a–g, 8a–y, 9, 10a–b, 11a–b, 12, 13, and imidacloprid against Pea Aphids
Compound
R1
R2
R3
R4
Mortality (%) (500 mg/L)
LC50 (mg/L)
7a
7b
7c
7d
7e
7f
7g
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
Methyl
Ethyl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
100
100
25
0
85
30
0
100
100
100
100
100
100
58.4
0
31.51
61.01
n.t.
n.t.
n.t.
n-Propyl
iso-Propyl
n-Butyl
Phenyl
p-NO2-Phenyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Ethyl
n.t.
n.t.
Methyl
Ethyl
n-Propyl
iso-Propyl
Chloroethyl
Allyl
n-Butyl
sec-Butyl
iso-Butyl
Hydroxethyl
Cyclohexyl
Benzyl
Methyl
Ethyl
n-Propyl
iso-Propyl
Methyl
Ethyl
n-Propyl
iso-Propyl
Ethyl
Methyl
Ethyl
n-Propyl
iso-Propyl
H
Methyl
iso-Propyl
H
50.00
65.43
33.66
96.18
74.7
n.t.a
n.t.
n.t.
n.t.
0
n.t.
n.t.
n.t.
48.86
86.42
88.93
n.t.
n.t.
n.t.
n.t.
n.t.
0
0
0
94
90
100
100
100
89
95
82
79
72
50
89
45
0
Ethyl
Ethyl
Ethyl
n-Propyl
n-Propyl
n-Propyl
n-Propyl
iso-Propyl
Phenyl
Phenyl
Phenyl
Phenyl
H
8s
8t
8u
8v
8w
8x
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
8y
9
Methyl
Methyl
Methyl
Methyl
Methyl
70
73
67
50
0
10a
10b
11a
11b
12
H
H
Methyl
Ethyl
H
n.t.
n.t.
0
13
H
H
H
H
Methyl
H
H
H
90
100
100
n.t.
58.30
7.90
7ab
Imidacloprid
a
n.t., not tested.
Compounds from our previous paper.
b
2a generated analogues 7a and 7b with increased (up to 2-fold)
and similar insecticidal activities as 2a, respectively. Meanwhile,
introduction of other substituents was unfavorable to activities.
Comparing the alkyl groups attached at the 7-position, the insecti-
cidal activities of the corresponding analogues 7a–g decreased in
the order methyl (7a) > ethyl (7b) > n-butyl (7e) > phenyl (7f) > n-
propyl (7c) > iso-propyl (7d), p-NO2-phenyl (7g). For the effects of
the R4, the modification of compound 7a with a longer alkyl group
showed decreasing tendency in insecticidal activities. Compound
9, 10a–b, and 13, bearing a methyl group at the 6- or 5-position
of 2, demonstrated lower activities than 2. The compounds 11a,
11b, and 12 with two substituents or a six-member ring at both
6- and 7-position of 2a have low or no activities.
In conclusion, a series of novel analogues of 2 with alkyl substit-
uents at the 5-, 6-, and 7-positions were synthesized and their pre-
liminary insecticidal activities were evaluated. Introduction of a
methyl or ethyl substituent at the 7-position led to increased
insecticidal activities against Pea aphids and brown planthopper
(N. lugens). It was observed that alkyl substituents attached at 7-
position give the insecticidal activities against Pea aphids in the or-
der methyl (7a) > ethyl (7b) > n-butyl (7e) > phenyl (7f) > n-propyl
(7c) > iso-propyl (7d), p-NO2-phenyl (7g). Other alkyl substituents
Table 2
Insecticidal activities of compounds 7a, 8c, 8d, 8m, and imidacloprid against sensitive
and imidacloprid-resistant strains of brown planthoppper (Nilaparvata lugens)
Considering the bioassay results described above, compounds
7a, 8c, 8d and 8m, and imidacloprid were selected to further
evaluate the activities against sensitive and imidacloprid-resis-
tant brown planthopper ( N. lugens) used the similar method
employed for Pea aphids. The results were shown in Table 2.
Although compounds 7a, 8c, 8d, and 8m showed lower insecti-
cidal activities against sensitive brown planthopper than that
of imidacloprid, they had higher (up to 2- to 3-fold) activities
against imidacloprid-resistant strains. Brown planthopper exhib-
ited certain cross-resistance to 8m, but only slight cross-resis-
tance to 7a, 8c, or 8d.
Strains
Compound
LC50value (mg/L)
Index of relative toxicity
Sensitive strain
7a
8c
8d
8m
Imidacloprid
7a
8c
8d
20.72
7.35
5.57
1.07
0.14
7.36
7.20
6.33
8.87
19.73
145.2
7.5
51.5
39.1
1.0
51.6
62.1
50.5
44.4
138.3
Resistant strain
8m
Imidacloprid

6516
X. Shao et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6513–6516
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