Synthesis and insecticidal activities of tetrahydroimidazo[1,2-a] pyridinones: Further exploration on cis-neonicotinoids

Article abstract of DOI:10.1080/00397911.2013.837487

cis-Neonicotinoid, in which the nitro and cyano pharmacophore point to the same position relative to the heteroaromatic moiety, is a further extension of the neonicotinoid library. While seeking new cis-neonicotinoid candidates, a series of tetrahydroimidazo[1,2-a]pyridinone derivatives were synthesized by reactions of nitromethylene analogs with itaconic anhydride. All the compounds were confirmed by ¹H NMR, ¹³C NMR, and high-resolution mass spectroscopy. The target compounds had excellent insecticidal activities against cowpea aphids (Aphis craccivora) and brown planthopper (Nilaparvata lugens). Against armyworm, most of the compounds showed moderate activities. Interestingly, compound 12p was active against Tetranychus cinnabarinus. The synthesized compounds displayed good insecticidal activities against different insect species, which might provide useful guidance for further design of cis-neonicotinoid candidates. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]

Full text of DOI:10.1080/00397911.2013.837487

Synthetic Communications1, 44: 858–867, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.837487
SYNTHESIS AND INSECTICIDAL ACTIVITIES
OF TETRAHYDROIMIDAZO[1,2-a]PYRIDINONES:
FURTHER EXPLORATION ON CIS-NEONICOTINOIDS
Liping Ren, Yanpeng Lou, Nanyang Chen, Shanshan Xia,
Xusheng Shao, Xiaoyong Xu, and Zhong Li
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy,
East China University of Science and Technology, Shanghai, China
GRAPHICAL ABSTRACT
Abstract cis-Neonicotinoid, in which the nitro and cyano pharmacophore point to the
same position relative to the heteroaromatic moiety, is a further extension of the neoni-
cotinoid library. While seeking new cis-neonicotinoid candidates, a series of tetrahydroi-
midazo[1,2-a]pyridinone derivatives were synthesized by reactions of nitromethylene
analogs with itaconic anhydride. All the compounds were confirmed by 1H NMR, 13C
NMR, and high-resolution mass spectroscopy. The target compounds had excellent
insecticidal activities against cowpea aphids (Aphis craccivora) and brown planthopper
(Nilaparvata lugens). Against armyworm, most of the compounds showed moderate
activities. Interestingly, compound 12p was active against Tetranychus cinnabarinus.
The synthesized compounds displayed good insecticidal activities against different insect
species, which might provide useful guidance for further design of cis-neonicotinoid
candidates.
[Supplementary materials are available for this article. Go to the publisher’s online edi-
tion of Synthetic Communications1 for the following free supplemental resource(s): Full
experimental and spectral details.]
Keywords Activities; insecticide; neonicotinoids
Received April 29, 2013.
Address correspondence to Xusheng Shao or Xiaoyong Xu, Shangai Key Laboratory of Chemical
Biology, School of Pharmacy, East China University of Science and Technology, Shangai 200237, China.
E-mail: shaoxusheng@ecust.edu.cn; xyxu@ecust.edu.cn
858

TETRAHYDROIMIDAZO[1,2-a]PYRIDINONES
859
INTRODUCTION
The largest group of insecticides used worldwide today is the neonicotinoids.[1,2]
They act selectively on insect central nervous system as agonists of the postsynaptic
nicotinic acetylcholine receptors (nAChRs).[3] Although many years have passed
since their invention, research relating to neonicotinoids is still an active area. These
studies focus mainly on discovery of novel neonicotinoid molecules to conquer resist-
ance and high bee toxicity,[4] elucidation of modes of action,[5,3a,6] resistance monitor-
ing and management,[7] metabolism[8], and receptor structure-guided neonicotinoid
design.[4b,4c,9] Sulfoxaflor, developed by Dow AgroSciences as a new chemotype of
neonicotinoid, is a good representative.[10] Sulfoxaflor exhibits high potency and lacks
cross-resistance, which could be used as an alternative tool in controlling sap-feeding
insect pests.[11 12]
,
Nitromethylene neonicotinoid 2-chloro-5-((2-(nitromethylene)imidazolidin-1-
yl)methyl)pyridine (6-Cl-PMNI) is not only an insecticidal compound but also an attract-
ive scaffold for further transformations.[13] Lots of chemical derivatizations focusing on
6-Cl-PMNI have been performed in our group to construct cis-neonicotinoids, and two
of them, paichongding and cycloxaprid (Fig. 1), have been commercialized in China.[14]
In the effort to develop neonicotinoids with cis-configuration, reactions of
6-Cl-PMNI with various aldehydes were investigated systematically. Different types of
aldehydes exhibited different reaction behaviors toward 6-Cl-PMNI. Reaction of
6-Cl-PMNI with formaldehyde, a,b-unsaturated aldehydes, five-membered aromatic
aldehydes, and succinaldehyde afforded 1:2 condensation product,[13] hexahydroimidazo
[1,2-a]pyridine derivatives,[15] 2-alkenyl-4,5-dihydro-imidazole derivatives,[16] and oxab-
ridged compound,[17] respectively (Fig. 2). The encouraging results inspired us to further
explore reaction diversity of 6-Cl-PMNI for constructing novel cis-neonicotinoids.
Itaconic anhydride 5 is an important chemical intermediate with multiple
reactive sites and could react with heterocyclic ketene animals 6 (Fig. 3).[18]
Enlightened by this observation, we examined the reaction behavior of 6-Cl-PMNI
with itaconic anhydride with a view to search for novel cis-neonicotinoid derivatives
(Fig. 2). Herein, we present the results of our findings on insecticidal tetrahydroimi-
dazo[1,2-a]pyridinone derivatives.
RESULTS AND DISCUSSION
Synthesis
The synthetic route of the target compounds is depicted in Scheme 1. From
precursor 2-chloro-5-chloromethylpridine, the desired b-nitroenamines 6-Cl-PMNI
Figure 1. Commercialized neonicotinoids imidacloprid, sulfoxaflor, paichongding, and cycloxaprid.

860
L. REN ET AL.
Figure 2. Reaction diversity of 6-Cl-PMNI towards various aldehydes. (Figure is provided in color
online.)
was readily synthesized according to the conventional method.[19] It can be
categorized as a cyclic b-nitroenamine with two reactive nucleophilic sites (the C
=
in C C and the N in imidazolidine), which were proven to be efficient partners in
aza-annulation reactions. 6-Cl-PMNI manifests itself as a common enamine in elec-
trophilic reactions in spite of the presence of the strongly electron-withdrawing nitro
group, and reactions of nitroenamines with a variety of electrophiles (such as such as
sulfurisocyanatidic chloride, thiocyanogen, phenyl isocyanate, benzoyl isothiocya-
nate, and acrylate) have been well studied.[20]
6-Cl-PMNI could react smoothly with itaconic anhydride in acetonitrile at
refluxing temperature, and compound 10 precipitated from the reaction mixture with
good purity as expected. After filtration, compound 10 was obtained as a pale yellow
powder and was used directly for further reaction without purification. Reactions of
Figure 3. Design of novel tetrahydroimidazo[1,2-a]pyridinones. (Figure is provided in color online.)

TETRAHYDROIMIDAZO[1,2-a]PYRIDINONES
861
Scheme 1. Synthetic route of tetrahydroimidazo[1,2-a]pyridinones.
10 with various alcohols could proceed readily catalyzed by thionyl chloride furnish-
ing the corresponding esters 11a–d in moderate yields. Amination of 10 with various
amines in acetonitrile catalyzed by ethylene dichloride (EDC), dimethylaminopyride
(DMAP), and pyridine afforded amides 12a–y in good yields. The solubility of
acid 10 is very poor, which makes it take a long time for the reaction to complete.
Various solvent (such as dichloromethane, THF, acetonitrile, and acetone) had been
screened. No reactions were detected in dichloromethane, THF, acetonitrile, or
acetone, due to the poor solubility of 10 in these solvents, while the pyridine and
acetonitrile mixture had good solubility to 10 and was selected as the reaction
solvent. The reaction temperature must be controlled below 40 ꢀC, for many by-
products would form and the yield was rather poor (<10%) at higher temperature.
The electron-withdrawing substituents and bulky groups of benzene in amine would
decrease the yield of amination; for example, the 2-iodoaniline could not react with
10 at room temperature, and the reaction temperature should be raised to 80 ꢀC.
Activity
To evaluate the overall insecticidal activities of tetrahydroimidazo[1,2–a]
pyridinones, four representative insects from three different orders (Lepidoptera,
Hemiptera, and Acarina) were selected as the test pests. Table 1 lists the results
against these four insects. Cycloxaprid, a cis-neonicotinoids with the greatest activi-
ties discovered in our group, was selected as a comparison. Meanwhile, nitenpyram
and emamectin were also tested under the same conditions.
Insecticidal Activities Against Cowpea Aphids (Aphis craccivora)
Acid 10 and the esters 11a–d were initially tested, but all these compounds
demonstrated poor activity. Subsequently, amides 12a–y were obtained with
improvement of activity. All the amide analogs showed moderate insecticidal activity
with the exception of 12o. Compound 12o gave the best activity with 40% mortality

862
L. REN ET AL.
Table 1. Insecticidal activities of compounds 10, 11a–d, and 18a–y against cowpea aphids (Aphis
craccivora), Tetranychus cinnabarinus, armyworm (Pseudaletia separate Walker), and brown planthopper
(Nilaparvata lugens)
Mortality (%)
Pseudaletia
separate
Walker
Yield
Concentration Aphis
(mg LÀ1
)
Tetranychus
Nilaparvata
lugens
Compound (%)
R2
R3
craccivora cinnabarinus
10
79
47
32
44
52
63
–
–
500
500
500
500
500
500
100
20
20
28
17
47
18
100
0
–
–
–
–
–
0
–
–
–
0
–
–
–
0
–
–
–
0
–
–
–
0
–
–
–
0
–
–
–
0
–
–
–
0
–
–
–
0
–
–
–
0
0
0
–
–
11a
11b
11c
11d
12a
–
–
–
–
–
–
0
–
0
–
–
Ethyl
–
Ethyl
0
–
30
0
100
100
0
0
0
4
0
0
0
12b
12c
12d
12e
12f
12g
12h
12i
47
68
88
80
36
28
25
37
21
R2 and R3 taken together
formed -CH2 CH2 CH2
CH2-
500
100
20
0
50
0
100
60
0
–
–
0
4
–
0
0
H
H
H
H
H
H
H
H
n-Butyl
500
100
20
0
50
0
100
70
0
–
–
0
4
–
0
0
Phenyl
500
100
20
0
90
0
100
100
80
0
0
0
0
4
0
0
4-Fluorophenyl
500
100
20
0
90
0
100
100
0
0
0
0
4
0
0
0
2-Methyl-4-
(perfluoropropa-
n-2-yl)phenyl
500
100
20
0
100
0
100
40
0
0
0
0
4
0
0
0
2,3-Difluorophenyl
500
100
20
100
0
100
0
100
85
0
0
0
4
0
0
0
2,4,5-Trifluorophenyl
500
100
20
0
90
0
100
100
0
0
0
0
4
0
0
0
3-Chloro-4-
fluorophenyl
500
100
20
100
0
100
0
100
0
0
0
0
4
0
0
0
12j
4-Nitrophenyl
500
0
90
100
(Continued )

TETRAHYDROIMIDAZO[1,2-a]PYRIDINONES
863
Table 1. Continued
Mortality (%)
Pseudaletia
separate
Walker
Yield
Compound (%)
Concentration Aphis Tetranychus
(mg LÀ1
) craccivora cinnabarinus
Nilaparvata
lugens
R2
R3
100
20
0
0
–
–
–
0
–
–
–
0
–
–
–
0
–
–
–
0
–
–
–
0
–
–
–
95
0
0
0
0
–
–
–
0
0
0
0
0
–
–
–
0
–
–
–
0
–
–
–
0
–
–
–
0
0
0
0
0
4
0
0
0
12k
12l
55
58
51
60
70
77
51
90
35
66
56
56
54
H
H
H
H
H
H
H
H
H
H
H
H
H
p-Tolyl
500
100
20
100
0
20
0
100
100
95
0
0
0
4
0
0
2,6-Dimethylphenyl
Thiazol-2-yl
500
100
20
0
0
100
100
0
0
0
0
0
4
0
0
0
12m
12n
12o
12p
12q
12r
12s
12t
500
100
20
0
100
0
0
0
0
0
0
0
4
0
0
0
Pyridin-2-yl
500
100
20
100
30
0
0
95
0
0
0
0
4
0
0
0
4-Methylpyridin-2-yl
Pyridin-3-yl
500
100
20
100
100
70
40
0
100
30
0
95
0
0
4
0
0
500
100
20
95
0
100
20
0
0
0
0
4
0
0
0
6-Chloropyridin-3-yl
Benzyl
500
100
20
0
100
0
0
0
0
0
0
0
4
0
0
0
500
100
20
100
80
0
0
100
70
0
0
0
4
0
0
0
4-Trifluoromethyl-
benzyl
500
100
20
100
0
100
0
100
100
0
0
0
4
0
0
0
3,4-Difluorobenzyl
2,5-Difluorobenzyl
500
100
20
100
60
0
100
0
100
95
30
0
0
4
0
0
12u
12v
12w
500
100
20
100
0
30
0
100
100
70
0
0
0
4
0
0
3-Chloro-4-
fluorobenzyl
500
100
20
100
0
0
100
100
85
0
0
0
0
4
0
0
2,3,6-Trifluorobenzyl
500
100
100
100
(Continued )

864
L. REN ET AL.
Table 1. Continued
Mortality (%)
Pseudaletia
Yield
Compound (%)
Concentration Aphis
(mg LÀ1
Tetranychus
craccivora cinnabarinus
separate
Walker
Nilaparvata
lugens
R2
R3
)
100
20
4
0
0
–
–
0
0
100
0
0
–
0
0
12x
12y
90
60
H
H
3-Trifluoromethyl-
benzyl
500
100
20
4
100
0
0
70
0
100
100
30
0
–
0
–
0
0
–
0
4-Methoxybenzyl
500
100
20
4
100
0
0
50
0
100
100
95
0
–
0
–
0
0
–
0
Cycloxaprid
Nitenpyram
Emamectin benzoate
4
100
100
100
–
–
30
10
–
100
90
100
–
1
–
4
100
–
4
100
at the dosage of 4 mg LÀ1. From the existing results, it had some difficulties in
acquiring precise structure–activity relationship. The influence of substituent’s elec-
tronic property, position, or number was also not easy to determine. Monofluori-
nated 12e showed no activities, all difluorinated substituted compounds 12g, 12t,
and 12u exhibited certain activity irrespective of fluorine’s positions, and trifluori-
nated compounds manifested poor (12w) or no (12h) activity. Compound 12n with
pyridine-2-yl had good activity, whereas 12p with pyridine-3-yl was totally devoid
of activity. All the compounds showed less activity than cycloxaprid and niten-
pyram, which could not meet the requirements for commercialized development.
Insecticidal Activities Against Tetranychus cinnabarinus and
Armyworm (Pseudaletia separate Walker)
As anticipated, no activities were found in synthesized compounds against Tet-
ranychus cinnabarinus except compound 12p with 95% mortality at 500 mg LÀ1
,
which was consistent with the fact that all the commercialized neonicotinoids showed
no or poor activity against Tetranychus cinnabarinus. Against armyworm, most of
the target compounds exhibited 20% to 100% mortality at 500 mg LÀ1, whereas
the ester compounds 11a–d and amide analogs 12 l and 12v were completely inactive.
When tested at the dosage lower than 100 mg LÀ1, all the candidates lose the activity,
which made it difficult to find the influence factor on bioactivity tendency.
Insecticidal Activities Against Brown Planthopper (Nilaparvata
lugens)
Although 12m and 12q were ineffective, the rest of the amide analogs were
endowed with high activity against brown planthopper. At the dosage of 20 mg LÀ1
,

TETRAHYDROIMIDAZO[1,2-a]PYRIDINONES
865
compounds 12d, 12k, 12t, 12u, 12v, 12x, and 12y still exhibited good activity.
Interestingly, compound 12o had excellent activity against cowpea aphids but very
poor activity against brown planthopper. In comparison with cycloxaprid, nitenpyram
and imidacloprid, the activities of the target compounds were not high enough, and
they need further structural modification to improve activity.
CONCLUSION
Tetrahydroimidazo[1,2–a]pyridinones expanded the molecular libraries of cis-
neonicotinoid. These tetrahydroimidazo[1,2–a]pyridinone derivatives could easily
be synthesized by nitromethylene analogs of imidacloprid and itaconic anhydride.
Against hemiptera insects, brown planthopper, and cowpea aphids, the synthesized
compounds exhibited excellent insecticidal activity, whereas the activities against
Tetranychus cinnabarinus and armyworm were not desirable enough. This type of
compounds could be used as the lead compounds for further structural optimization.
EXPERIMENTAL
Chemical Synthesis
Unless otherwise noted, reagents and solvents were used as received from com-
mercial suppliers. Yields were not optimized. All reactions were carried out under a
protective atmosphere of drying nitrogen or utilizing a calcium chloride tube.
Melting points (mp) were recorded on Buchi B540 apparatus (Buchi Labortechnik
¨
¨
AG, Flawil, Switzerland) and are uncorrected. 1H NMR and 13C NMR spectra were
recorded on Bruker AM-400 (400-MHz) spectrometer with dimethylsulfoxide
(DMSO-d6) as the solvent and tetramethylsilane (TMS) as the internal standard.
Chemical shifts are reported in d (parts per million) values. High-resolution mass
spectra (HRMS) were recorded under 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 with ultraviolet (UV) light.
General synthetic procedure for compound 10. A mixture of compound
6-Cl-PMNI (10 mmol), itaconic anhydride (10 mmol), and acetonitrile was refluxed
until the reaction was completed and the product was precipitated. The precipitate
was filtered, washed with acetonitrile, and dried to give the corresponding product.
General synthetic procedure for compounds 11a–d. A mixture of
compound 10 (1.5 mmol) and corresponding alcohol (12 ml) was stirred at room
temperature for 10 min, then SOCl2 was dropped into it, and the reaction liquid
was stirred at room temperature. The progress of the reaction was monitored by
TLC. After completion of the reaction, the organic solvent was extracted thoroughly
with CH2Cl2, washed with water, and dried with anhydrous Na2SO4. The solvent was
removed under reduced pressure. The residue was purified by flash chromatography
eluting with dichloromethane=acetone (v=v 4:1) to afford target products 11a–d.
General synthetic procedure for compounds 12a–y. A mixture of
compound 10 (1.5 mmol), corresponding anime (2.25 mmol), EDC Á HCl (1.8 mmol),

866
L. REN ET AL.
DMAP (0.15 mmol), and pyridine (10 ml) was stirred at room temperature for 10
min. Then, acetonitrile (20 ml) was added and the mixture was stirred at room tem-
perature. The progress of the reaction was monitored by TLC. After completion of
the reaction, the solvent was removed under reduced pressure. The residue was
purified by flash chromatography eluting with dichloromethane=acetone (v=v 10:1)
to afford target products 12a–y.
Biological Assay
All bioassays were performed on representative test organisms reared in the
laboratory. The bioassay was repeated at 25 Æ 1 ꢀC according to statistical require-
ments. All compounds with a purity of more than 98% were dissolved in N,N-
dimethylformamide (AP, Shanghai Chemical Reagent Co., Ltd., Shanghai, China)
and diluted with distilled water containing Triton X-100 (0.1 mg LÀ1) to obtain series
concentrations of 500.0, 250.0, 125.0 mg LÀ1 and others for bioassays.
Experimental details, characterization of the target compounds, and bioassay
methods are available online as the Supplemental Information.
ACKNOWLEDGMENTS
This work was financial supported by National Basic Research Program of
China (973 Program, 2010CB126100), National High Technology Research Devel-
opment Program of China (863 Program, 2011AA10A207), Key Projects in the
National Science and Technology Pillar Program (2011BAE06B05), National Natu-
ral Science Foundation of China (21372079), Shanghai Education Committee
(12ZZ057), and the Fundamental Research Funds for the Central Universities. This
work was also partly supported by the Australia DC Foundation. We thank
Amanda Ly from the University of California at Berkeley for assistance.
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