Synthesis and insecticidal bioactivities of 2,3-dihydroimidazo[1,2-a]pyridin-5(1H)-one derivatives

Article abstract of DOI:10.1016/j.cclet.2018.09.012

A novel synthesis of 2,3-dihydroimidazo[1,2-a]pyridin-5(1H)-one 4 and its derivatives were described. Preliminary bioassays showed that some of the target compounds exhibited excellent insecticidal activities against brown planthopper (Nilaparvata lugens), cowpea aphids (Aphis craccivora) (4, 5a, 5c, 5g, 5h, 5j, 5r, 6b, 6e) and carmine spider mite (Tetranychus cinnabarinus (5f, 5s, 6a) at 500 mg/L. Among them, compound 4 was still active against brown planthopper and cowpea aphids at 4 mg/L. The insecticidal activities were influenced by the types and position of the substituents, which provided guidance for the structure modifications.

Full text of DOI:10.1016/j.cclet.2018.09.012

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CCLET 4654 No. of Pages 5
Chinese Chemical Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Synthesis and insecticidal bioactivities of 2,3-dihydroimidazo[1,2-a]
pyridin-5(1H)-one derivatives
Letian Zhanga, Kun Liua, Xusheng Shaoa, Zhong Lia,b, Xiaoyong Xua,b,
*
a
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
b
Shanghai Collaborative Innovation Center for Biomanufacturing Technology, Shanghai 200237, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Received 26 July 2018
Received in revised form 13 September 2018
Accepted 14 September 2018
Available online xxx
A novel synthesis of 2,3-dihydroimidazo[1,2-a]pyridin-5(1H)-one 4 and its derivatives were described.
Preliminary bioassays showed that some of the target compounds exhibited excellent insecticidal
activities against brown planthopper (Nilaparvata lugens), cowpea aphids (Aphis craccivora) (4, 5a, 5c, 5g,
5h, 5j, 5r, 6b, 6e) and carmine spider mite (Tetranychus cinnabarinus (5f, 5s, 6a) at 500 mg/L. Among them,
compound 4 was still active against brown planthopper and cowpea aphids at 4 mg/L. The insecticidal
activities were influenced by the types and position of the substituents, which provided guidance for the
structure modifications.
Keywords:
Reaction selectivity
2,3-Dihydroimidazo[1,2-a]pyridin-5(1H)-
one
© 2018 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Bicyclic pyridone
Insecticidal activities
Acaricidal activitiy
Bicyclic pyridones are a mainstay in chemistry of medicine,
agrochemicals and fluorescent development, which are found in
biologically active natural products [1] {Perreault, 2010 #2}
{Perreault, 2010 #2}. As reported, A series of substituted bicyclic
pyridones have become a basis for anti-inflammatory [2,3]
(Fig. 1, I), anti-cancer agents [4] and acetylcholinesterase
inhibitors [5] (Fig. 1, II). For example, imidacloprid derivatives
containing bicyclic pyridone fragment were reported [6] (Fig. 1, III)
as insecticide by Bayer. Besides, bicyclic pyridone have recently
been considered as fluorescent derivatives [7,8], and also serve as
the main building blocks to self-assemble into supramolecular
nanodots [9] (Fig. 1, IV).
The reported synthesis methods of bicyclic pyridones I are
noteworthy and mainly based on follow approaches: (1) the
cyclocondensation of ketenaminals [10–12], (2) the addition of
diamines to cyanobutenoic esters [13], and (3) the addition of
diamines to halo- or thiomethylpyridones [14]. Moreover, the
survey of literatures reveals a few early examples on the synthesis
of bicyclic pyridines. David team developed a practical two-step
procedure in which N-(prop-2-yn-1-yl)pyridin-2-amines under-
goes Sandmeyer reaction [15] (Scheme 1a). Besides, other two
approaches which used polarized N,N-acetals to synthesize
bicyclic pyridones [11,12] were described in Scheme 1b. Our
previous work reported that the synthesis of tetrahydroimidazo
[1,2-a]pyridin-5(1H)-one derivatives were synthesized through
Aza-ene annulation [16] (Scheme 1c). Recent methods included
halocyclization of allylamino pyridines [17], intramolecular
Mitsunobu reaction, hydrolysis of a bicyclic pyridinium salt
intermediate [18] and cyclic condensation of heterocyclic ketene
aminals with b-keto ester enol tosylates [19,20].
Considering the importance of imidazole pyridones groups in
pharmaceuticals and agrochemicals, it was necessary to develop a
novel and simple methodology. 2-(1-((6-Chloropyridin-3-yl)meth-
yl)imidazolidin-2-ylidene)-2-nitroacetaldehyde (1) is a high active
and common intermediate in many fields. Under the motivation,
we synthesized (Z)-2-(1-((6-chloropyridin-3-yl)methyl)imidazoli-
din-2-ylidene)-2-nitroacetaldehyde (2) using 1 as the starting
material and developed a new synthesis method of imidazole
pyridone 4 starting from 2 and 2-aminoacetic acid methyl ester
hydrochloride and characterized it well by spectroscopic techni-
ques. Amide structure is common and focused scaffold in various
pesticides [21–24] and natural product [25]. In order to increase
the biological activity, the generated bicyclic pyridone intermedi-
ate (4) was considered to be amidated further.
The general synthesis procedures are shown in Scheme 2. Our
route to synthesize the target compounds began with 1 and DMF-
DMA which underwent condensation to provide 10. Hydrolysis of 10
gave 2 as the substrate of the key intermediate 4 and then
* Corresponding author at: Shanghai Key Laboratory of Chemical Biology, School
of Pharmacy, East China University of Science and Technology, Shanghai 200237,
China
E-mail address: xyxu@ecust.edu.cn (X. Xu).
https://doi.org/10.1016/j.cclet.2018.09.012
1001-8417/© 2018 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: L. Zhang, et al., Synthesis and insecticidal bioactivities of 2,3-dihydroimidazo[1,2-a]pyridin-5(1H)-one
derivatives, Chin. Chem. Lett. (2018), https://doi.org/10.1016/j.cclet.2018.09.012

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CCLET 4654 No. of Pages 5
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L. Zhang et al. / Chinese Chemical Letters xxx (2018) xxx–xxx
Fig. 1. Active compounds that possess bicyclic pyridone framework.
Scheme 1. Approaches to synthesis of imidazole pyridone derivatives.
Scheme 2. General procedure for the synthesis of 5aꢀs,6aꢀe.
amidation derivatives were obtained. The details are given in the
Supporting information.
inorganic bases showed lower catalytic efficiency (entries 13–17)
which could probably be explained by the poor solubility in MeCN.
It can be observed that product 3 was obtained easily in good yields
and high selectivity with Et3N or DIPEA as base (entries 3 and 4),
whereas low yields and selectivity for 4. Among them, 20.7% yield
with DBU was better and selected for further optimization, which
was investigated under a different equivalent/time/temperature
combination (entries 18–27). The ratio of A and DBU was
investigated first, and the conversion of 4 was better when 4.0
equiv. A and 2.5 equiv. DBU were selected (entries 18–22). Basing
on this results, we conjectured that the instability of 2 resulted
high conversion rate together with low yield in the relatively
fastidious reflux conditions. Keeping this in mind, we hypothesized
At first, the reaction of key intermediate 4 was optimized.
Compound 2 was selected as the model substrate to optimize the
reaction conditions. The solubility of 2-aminoacetic acid methyl
ester hydrochloride A in MeCN is moderate, while the replacement
of MeCN by other solvents brought inferior yields (the data were
not shown). Therefore, a variety of bases were explored using
MeCN as the solvent (Table 1, entries 1–17). Initially, the screening
of the bases revealed that base played a unique role in this
transformation. As shown in Table 1, the conversion rates of
substrates were over 90% by the treatment of 3.0 equiv. of organic
bases with 2.5 equiv. of A in refluxing MeCN (entries 1–12), while
Please cite this article in press as: L. Zhang, et al., Synthesis and insecticidal bioactivities of 2,3-dihydroimidazo[1,2-a]pyridin-5(1H)-one
derivatives, Chin. Chem. Lett. (2018), https://doi.org/10.1016/j.cclet.2018.09.012

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3
Table 1
Optimization for reaction conditions of intermediate 4.
Entry
Base
2:Aa:Bb(mol)
Temp. (ꢁC)
Time (h)
Conversion rate (%)
Yield (%)c
3
4
C
1
2
3
4
5
6
7
8
Piperidine
DABCO
Et3N
DIPEA
Diethylamine
Pyrrole
Piperazine
Morpholine
NMM
1.0:3.0:2.5
1.0:3.0:2.5
1.0:3.0:2.5
1.0:3.0:2.5
1.0:3.0:2.5
1.0:3.0:2.5
1.0:3.0:2.5
1.0:3.0:2.5
1.0:3.0:2.5
1.0:3.0:2.5
1.0:3.0:2.5
1.0:3.0:2.5
1.0:3.0:2.5
1.0:3.0:2.5
1.0:3.0:2.5
1.0:3.0:2.5
1.0:3.0:2.5
1.0:2.5:2.5
1.0:4.0:2.5
1.0:5.0:2.5
1.0:6.0:2.5
1.0:4.0:2.5
1.0:4.0:2.5
1.0:4.0:2.5
1.0:4.0:2.5
1.0:4.0:2.5
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
25
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
96
41
64
41
41
>99.9
98.4
98.8
96.2
99.8
>99.9
99.5
>99.9
93.3
>99.9
98.3
98.0
87.4
62.5
62.8
82.0
80.7
73.1
55.0
58.9
52.2
trace
22.3
23.2
16.0
64.5
69.4
36.4
3.2
12.3
78.4
20.0
15.4
9.7
trace
3.6
4.4
0
0
0
0
0
0
0
0
21.2
8.3
6.2
6.0
9.5
20.4
24.2
13.2
52.3
19.0
24.2
24.4
6.5
9
0
10
11
12
13
14
15
16
17
18
20
21
22
23
24
25
26
27
DBU
DBN
20.7
11.3
7.4
0
Imidazole
Na2CO3
KHCO3
K2CO3
Cs2CO3
NaHCO3
DBU
DBU
DBU
DBU
DBU
83.1
77.1
18.1
0
11.4
13.0
4.5
14.3
8.2
6.1
0
22.5
21.7
18.3
52.0
50.3
34.1
36.1
25.7
74.3
>99.9
96.7
96.4
92.4
66.2
83.2
93.3
87.3
11.8
12.4
20.2
20.9
20.0
trace
11.6
11.5
16.2
20.0
DBU
DBU
DBU
DBU
50
50
60
70
4.1
12.3
96.9
a
2-Aminoacetic acid methyl ester hydrochloride.
Base.
Yield was determined by the analysis of HPLC.
b
c
that it was important to choose mild room temperature while
extended the reaction time to improve the selectivity (entries 23–
27). After the optimization, 4 could be given with high selectivity
despite of the decreased conversion rate. In summary, when
compound 2 was treated with A (4.0 equiv.) and DBU (2.5 equiv.)
(entry 23) in MeCN at room temperature for 96 h, the reaction
proceeded effectively, affording 4 in 52%.
Target products 5aꢀs, 6aꢀe were synthesized from compound 4
and acyl chloride (Scheme 2). For substituted phenyl amide,
different substituents were introduced into phenyl ring including
halogen, methyl, methoxyl, cyano, trifluoromethoxyl and so on. The
spectrum data of representative compound 4 and 6a were given as
follows.
DMSO-d6): d 168.5, 156.1, 151.7, 149.0, 146.6, 138.7, 129.7, 124.8,
120.5, 119.3, 115.0, 52.5, 50.2, 43.1, 24.5; HRMS (EI+) calcd. for
C
C
15H1435ClN5O4 (M)+: 363.0734; Found: 363.0730; Calcd. for
15H1437ClN5O4 (M)+: 365.0705; Found: 365.0729.
Bioassays were performed on representative test organisms
grown in the laboratory. The insecticidal activities of the synthetic
compounds against Tetranychus cinnabarinus, Aphis craccivora,
Prodenia litura and Nilaparvata lugens were tested according to our
previous reported procedure [26–28], and detailed procedures are
given in the Supporting information.
TheresultsofbioassayaredepictedinTable 2, precursorcompound4
showed100% mortalityagainstA.craccivoraandN.lugensat500 mg/
L. Compounds 5aꢀs, 6aꢀe were the derivatives of compound 4. No
substituent (5a), moderate electron-donating and electron-with-
drawing (5c, 5g, 5h) had good activity against A. craccivora and N.
lugens. However, electron-withdrawing Cl group (5b) and strong
electron-donating (5d, 5e), showed low activity. Meanwhile, when
introducing disubstituted and polysubstituted groups into benzene
ringexcept5i, 5l, 5m, 5n, 5o, 5p, 5q, the othercompounds exhibited
the insecticidal activity. For aliphatic amide, derived alkyl groups
(6a, 6b, 6e) exhibited 90%–100% mortality against A. craccivora and
N. lugens. Compounds 5f, 5s and 6a showed 95% mortality against T.
cinnabarinus. Among them, only 6a still kept the activity against A.
craccivora and N. lugens, besides T. cinnabarinus.
6-Amino-1-((6-chloropyridin-3-yl)methyl)-8-nitro-2,3-dihy-
droimidazo[1,2-a]pyridin-5(1H)-one (4). Red powder, yield 49.3%;
IR (KBr, cmꢀ1): 3436, 3337, 1671, 1630, 1574, 1449, 1396, 1332,1274,
1236, 1203; Mp 181.9–182.4 ꢁC; 1H NMR (400 MHz, DMSO-d6):
d
8.40 (d, 1H, J = 2.4 Hz), 7.86 (dd, 1H, J1 = 2.4 Hz, J2 = 8.4 Hz), 7.52 (d,
1H, J = 8.4 Hz), 7.03 (s, 1 H), 4.91 (s, 2H), 4.70 (s, 2H), 4.13–3.83 (m,
4H); 13C NMR (100 MHz, DMSO-d6):
d 157.0, 149.6, 149.4, 146.6,
139.4, 132.6, 129.9, 124.5, 114.7, 106.7, 52.6, 51.2, 43.7; HRMS (ESI+)
calcd. for C13H12ClN5O3 (M + Na)+: 344.0526; Found: 344.0521.
N-(1-((6-Chloropyridin-3-yl)methyl)-8-nitro-5-oxo-1,2,3,5-
tetrahydroimidazo[1,2-a]pyridin-6-yl)acetamide (6a). Yellow
powder, yield 93.0%; IR (KBr, cmꢀ1): 3481, 1651, 1619, 1526,
1466, 1400, 1320, 1284; Mp 220.7–222.0 ꢁC; 1H NMR (400 MHz,
Furthermore, the compounds with 100% mortality at 500 mg/L
compounds4,5a,5c,5g,5h,5j,5r,6b,6ewereselectedtoinvestigate
their activity at lower concentration. As shown in Table 3, the result
was undesirable, most compounds almost completely lost the
DMSO-d6):
d 8.97 (s, 1H), 8.38 (s, 1H), 7.81-7.77 (m, 2H), 7.37 (d, 1H,
J = 8.0 Hz), 4.74 (s, 2H), 4.27–3.82 (m, 4H); 13C NMR (100 MHz,
Please cite this article in press as: L. Zhang, et al., Synthesis and insecticidal bioactivities of 2,3-dihydroimidazo[1,2-a]pyridin-5(1H)-one
derivatives, Chin. Chem. Lett. (2018), https://doi.org/10.1016/j.cclet.2018.09.012

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L. Zhang et al. / Chinese Chemical Letters xxx (2018) xxx–xxx
Table 2
Insecticidal activity test result of targeted compounds (500 mg/L).
Compounds
R1/R2
Mortality (%) (500 mg/L)
T. cinnabarinus
A. craccivora
P. litura
N. lugens
4
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
5s
6a
6b
6c
6d
/
H
2-Cl
2-Me
0
0
0
0
0
0
95
0
0
0
0
0
0
0
0
0
0
0
0
95
95
0
0
0
0
/
100
100
0
80
0
0
0
80
80
0
0
80
0
0
0
0
0
0
0
0
0
0
0
0
0
/
0
80
0
0
0
/
/
/
/
0
/
0
/
/
0
0
0
0
/
100
100
0
100
0
2-OEt
2-OMe
3-OMe
4-Me
0
0
100
100
0
100
0
/
/
/
/
4-CF3
3,4-OMe2
3,5-OMe2
3,6-OMe2
3-OCF3-5-Br
2-NO2-3-Me
2-I-6-F
3-F-4-CN
2,4,6-Cl3
2-Br-4,5-F2
2,4,5-F3-3-OMe
2,3,4,5,6-F5
Me
Et
CH2Cl
t-Bu
Benzyl
/
0
/
100
0
90
100
0
0
90
100
0
0
0
6e
100
100
/
100
100
/
Imidacloprid
Avermectins
/
100
100
Table 3
Insecticidal activity of some targeted compounds against A. craccivora and N. lugens.
methyl ester hydrochloride, which can be used to synthesize
various bicyclic pyridones by the replacement of chloropyridine
ring. And then a series of amidation derivatives of 4 were
Compounds
Mortality (%) (mg/L)
synthesized. Their structures were characterized by 1H NMR, 13
C
A. craccivora
N. lugens
NMR, 19F NMR and HRMS. The bioassays showed that some of the
target compounds exhibited excellent insecticidal activities
against brown planthopper (N. lugens) (4, 5a, 6b, 6e), cowpea
aphids (A. craccivora) (4, 5a, 5c, 5g, 5h, 5j, 5r, 6b, 6e) and T.
cinnabarinus (5f, 5s, 6a) at 500 mg/L. Despite the activities of most
derivatives were undesirable at low concentration, precursor
compound 4 kept high activity and broad insecticidal spectra on N.
lugens and A. craccivora and could be used as the lead for further
derivation. The further structural optimizations are in progress.
100
20
4
100
20
4
4
5a
5c
5g
5h
5j
5r
6b
100
0
0
0
0
0
0
0
0
100
0
0
0
0
0
0
0
0
70
0
0
0
0
0
0
0
0
100
0
100
0
80
0
0
100
0
0
0
0
0
0
0
0
100
0
0
0
0
0
0
0
0
100
0
6e
Imidacloprid
100
100
100
100
100
100
Acknowledgments
This work was financial supported by the National Key Research
Program of China (No. 2017YFD0200500), National Natural Science
Foundation of China (No. 21672061). This work was also supported
by the Fundamental Research Funds for the Central Universities (No.
222201718004).
activity except 5c and 6b which exhibited 100% mortality against N.
lugens at 100 mg/L. But when the concentration further decreased,
the bioactivity of 5c and 6b sharply decreased and disappeared
completely. To our surprise, precursor compound 4 kept its activity
at 4 mg/L and the bioactivity still reached 70% and 100% mortality
againstA.craccivoraandN.lugens,respectively.Itmeantthatitcould
be used as a lead for further derivation.
Appendix A. Supplementary data
In summary, we have developed an efficient synthetic approach
of bicyclic pyridone 4 starting from 2 and 2-aminoacetic acid
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.cclet.2018.09.012.
Please cite this article in press as: L. Zhang, et al., Synthesis and insecticidal bioactivities of 2,3-dihydroimidazo[1,2-a]pyridin-5(1H)-one
derivatives, Chin. Chem. Lett. (2018), https://doi.org/10.1016/j.cclet.2018.09.012

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5
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Please cite this article in press as: L. Zhang, et al., Synthesis and insecticidal bioactivities of 2,3-dihydroimidazo[1,2-a]pyridin-5(1H)-one
derivatives, Chin. Chem. Lett. (2018), https://doi.org/10.1016/j.cclet.2018.09.012