Design, synthesis, and insecticidal activity of novel 1-Alkoxy-2-nitroguanidines

Article abstract of DOI:10.1039/c7ra11454k

In searching for new insecticidal lead compounds, a series of novel 1-Alkoxy-2-nitroguanidine, guadipyr analogues bearing alkoxy groups were designed, synthesized and confirmed by ¹H NMR, ¹³C NMR, high-resolution mass spectrometry and X-ray diffraction. The primary bioassays showed that most of these compounds exhibited moderate to good insecticidal activity against Myzus persicae and Aphis gossypii. Especially, the precise insecticidal assay showed that compounds 4-02, 4-07 and 4-08 displayed excellent in vitro activity with IC₅₀ values lower than 10 μg mL^-1 to M. persicae which is comparable to guadipyr. On the other hand, the toxicity of compound 4-07 and guadipyr against honey bees was much lower than imidacloprid. The results indicated that the flexible chain on the nitrogen atom was the most crucial factor on honey bee toxicity, which existed in both neonicotinoids and guadipyr series.

Full text of DOI:10.1039/c7ra11454k

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Design, synthesis, and insecticidal activity of novel
1-alkoxy-2-nitroguanidines†
Cite this: RSC Adv., 2018, 8, 1838
a
Dongyan Yang,
and Zhaohai Qin
Chuan Wan,a Yumei Xiao,a Chuanliang Che,a Changhui Ruib
a
*
In searching for new insecticidal lead compounds, a series of novel 1-alkoxy-2-nitroguanidine, guadipyr
1
analogues bearing alkoxy groups were designed, synthesized and confirmed by H NMR, 13C NMR, high-
resolution mass spectrometry and X-ray diffraction. The primary bioassays showed that most of these
compounds exhibited moderate to good insecticidal activity against Myzus persicae and Aphis gossypii.
Especially, the precise insecticidal assay showed that compounds 4-02, 4-07 and 4-08 displayed
excellent in vitro activity with IC50 values lower than 10 mg mLꢀ1 to M. persicae which is comparable to
guadipyr. On the other hand, the toxicity of compound 4-07 and guadipyr against honey bees was much
lower than imidacloprid. The results indicated that the flexible chain on the nitrogen atom was the most
crucial factor on honey bee toxicity, which existed in both neonicotinoids and guadipyr series.
Received 17th October 2017
Accepted 20th December 2017
DOI: 10.1039/c7ra11454k
rsc.li/rsc-advances
possessing a pyridopyrimidinedione core.12–14 It is belonging to
the novel class of mesoionic insecticides, and targets at nAChR
1 Introduction
but binds to the orthosteric site of the nAChR. These products
provide outstanding control of insects, including the aphids,
whiteies, leaoppers, and are also effective against some
insects which even display strong resistance to imidacloprid
(IMI).
As a part of continual efforts for developing novel, effective
and bee-safety insecticides, guadipyr was designed by the
combination of the pharmacophores of neonicotinoid and
semicarbazone.15 It has a ve-carbon alkyl chain containing
imine substituent, which is distinct from the short alkyl chain
of neonicotinoids, and targets the nicotinic acetylcholine
receptor. The insecticidal activity of guadipyr was measured
against aphids in laboratory (Myzus persicae) and eld trials
(Myzus persicae and Brevicoryne brassicae Linnaeus). The inu-
ence of length and exibility of the straight alkyl chain on the
bioactivity was investigated. Interestingly, the long carbon-
In the last three decades, neonicotinoids have made a signi-
cant contribution to the protection of crops from insect pests.1–3
Neonicotinoids, which target nicotinic acetylcholine receptors
(nAChRs), almost have no cross-resistance to conventional
insecticides,4 such as organophosphates, carbamates, and
synthetic pyrethroids. However, with the wide and long term
use of neonicotinoid insecticides, problems for resistant
development and bee safety have thrown neonicotinoids on the
cusp.5,6 The development of new varieties of high-activity and
multi-site action insecticides is essential in solving these
problems. New insecticides, such as sulfoxaor, upyradifur-
one (FPF) and triumezopyrim (TFM) (see Fig. 1), with novel
modes of action and favorable environmental proles emerge
continually. Sulfoxaor, which belongs to sulfoximine-class
insecticide, targets sap-feeding insect pests probably via
acting on the insect nicotinic acetylcholine receptor (nAChR) in
a distinct manner relative to neonicotinoids.7–9 Flupyradifurone
is a novel butenolide-class insecticide possessing a butenolide
ring which has been developed and commercialized by Bayer
CropScience.10,11 It shows unique properties, highly effective
insecticidal activities and favorable ecotoxicological proles.
Triumezopyrim was invented by DuPont Crop Protection,
aCollege of Science, China Agricultural University, Beijing 100193, China. E-mail:
qinzhaohai@263.net; Fax: +86-10-62732958; Tel: +86-10-62732958
bInstitute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing
100193, China
† Electronic supplementary information (ESI) available: The synthetic procedures
and NMR spectrum of intermediates, the NMR and HRMS spectrum of title
compounds. CCDC 1518112. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c7ra11454k
Fig. 1 Chemical structure of imidacloprid, sulfoxaflor, flupyradifurone
and triflumezopyrim.
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Scheme 3 Side reactions in the amination.
Scheme 1 Design of the target compounds.
chain associated analogues showed better peach aphid activity
than the short carbon-chain contained analogues.15,16 Guadipyr
is also effective against sap-feeding insects that are resistant to
imidacloprid.
In our investigation process, an interesting question has
always attracted us, and that is whether the compounds would
also show the same excellent biological characteristics when the
hydrazinecarboximidamide system was destroyed. So in this
work, an oxygen contained side-chain was introduced instead of
nitrogen contained side-chain, and a series of alkoxyni-
troguanidine compounds were designed and synthesized by
replacing the imine moiety with more exible alkoxyl group (see
Scheme 1).
Fig. 2 X-ray crystal structure of compound 4-02 (CCDC number:
1518112).
1
All of the title compounds were identied by H NMR, 13C
compounds 3 were only between 34% and 44%, the reason is
that compound 2 was underwent addition–elimination reaction
(Scheme 3), resulting in byproduct (5). For instance, compound
2 reacted with O-allylhydroxylamine, not only giving compound
3 but also byproduct 5-01.
Compound 3 was reacted with halides in DMF in the pres-
ence of NaH to afford target compound 4. Most of compounds 4
were obtained in moderate to good yields. In addition, the
structure of 4-02 was further identied by X-ray diffraction
studies (see Fig. 2). To further verify the structure of the title
compound, the compound 4-02 was recrystallized by a slow
evaporation from a dichloromethane/n-hexane (v/v ¼ 1 : 5)
solution. The molecular structure of compound 4-02 is shown in
Fig. 2. The double C]NNO2 bond in compound 4-02 (as well as
in other nitroimines for which X-ray diffraction data are avail-
able17) appears to be a double bond which consists with
NMR and HRMS. The insecticidal activities of these compounds
were evaluated against Aphis gossypii, Myzus persicae and Plu-
tella xylostella. Furthermore, the toxicity and safety evaluation
of compound 4-07 to honey bees (Apis melliferal) were also
investigated.
2 Results and discussion
Synthesis
The synthetic procedures for the title compounds are depicted
in Scheme 2. The nitration of S-methyl-isothiourea was con-
ducted under concentrated nitric acid and sulfuric acid at
ꢀ15 ꢁC to produce the key intermediate 2. R1ONH2 was then
reacted with intermediate 2 via a directly amination under room
temperature gave the compound 3. The synthetic yields of
Scheme 2 Preparation of title compounds.
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precursor 1–3 but differs from guadipyr. In addition, there is Secondly, R1 is another key factor affecting the activity. Inter-
intramolecular hydrogen bond present in compound 4-02. The estingly, a short chain, for example, ethyl is the best one in the
intramolecular hydrogen bond between the hydrogen atom in series. This is quite different from guadipyr and its structural
NH2 and the oxygen atoms of the nitro group forms a six- isomer series, in which a long linear chain is benecial to
numbered ring. The hydrogen bond makes an important insecticidal activities.15,16 The two structure requirements made
contribution to enhancing the robustness of the compound.
4-07 as the best candidate for further development. Thirdly,
these compounds were nearly ineffective against Plutella xylos-
tella at 100 mg Lꢀ1 (Table 3), and this is agreed with the selec-
tivity of neonicotinoids.
Structure–activity relationship (SAR)
Honey bee toxicity. The honey bee toxicity of compound 4-02,
4-03, 4-07 and 4-08 was tested on Apis melliferal and compared
to imidacloprid and guadipyr (Table 5). Surprisingly, compound
4-02, 4-03 and 4-08 showed no activity against honey bee at the
concentration 1000 mg mLꢀ1, and the LD50 of compound 4-07
(5.56 mg beeꢀ1) and Guadipyr (5.19 mg beeꢀ1) were signicantly
higher than those of commercial insecticides (3.25 ꢂ 10ꢀ2 mg
beeꢀ1 of imidacloprid, 1.2 mg beeꢀ1 of FPF and 0.51 mg beeꢀ1 of
TFM, respectively), suggesting the lower toxicity to honey bee for
these two compounds. Therefore, compound 4-07 and guadipyr
showed selectivity in their effects against the honey bee and
aphid. Contrast to traditional acyclic neonicotinoid insecti-
cides, the high effect and low toxicity of guadipyr and 4-07 may
attribute to their exible side-chain.
Insecticidal Activity. The insecticidal activities of these
compounds were evaluated against A. gossypii, M. persicae and
P. xylostella. The initial insecticidal activities were calculated for
each compound and the results were summarized in Tables 1–3.
The LC50s were calculated for elected compounds and the
results were summarized in Table 4. The preliminary bioassay
showed that most of the designed compounds exhibited good
insecticidal activities against M. persicae and A. gossypii (see
Tables 1 and 2). The results also provide us important struc-
ture–activity relationship informations for this class of
compounds. At rst, the structure of R2 might be the most
crucial factor for their aphid toxicities, an electron-decient
group, especially a heterocyclic ring might be appreciated.
Table 1 The insecticidal activity of title compounds against A. gossypii
(Glover)a
3 Experimental
Instruments and materials
100 mg Lꢀ1
Total
25 mg Lꢀ1
Total
Melting points (mp) were recorded on a Cole-Parmer micro-
scope melting point apparatus and are uncorrected. 1H NMR
and 13C NMR spectra were recorded on a Bruker Avance DPX300
spectrometer with CDCl3 or DMSO-d6 as the solvent and TMS as
the internal standard. Chemical shis are reported in d (parts
per million) values. High resolution mass spectrometry data
were obtained with an Accurate-Mass-Q-TOF MS 6520 system
equipped with an electrospray ionization (ESI) source. The
single crystal structure analysis was performed using X-ray
diffraction on Thermo Fisher ESCALAB 250 diffractometer.
Analytical thin-layer chromatography (TLC) was carried out on
precoated plates (silica gel 60 F254), and spots were visualized
with ultraviolet (UV) light.
worm
Death
Mortality worm
Death
Mortality
Compd
number number (%)
number number (%)
4-01
4-02
4-03
4-04
4-05
4-06
4-07
4-08
4-09
4-10
4-11
4-12
4-13
4-14
4-15
4-16
4-17
4-18
4-19
4-20
4-21
4-22
4-23
4-24
4-25
184
214
180
186
139
191
109
140
202
112
91
116
152
118
186
104
80
102
109
130
102
74
196
112
85
138
199
116
118
84
182
104
86
98
64
70
14
34
10
126
28
73
93
31
76
87
75.00
92.99
64.44
63.44
60.43
95.29
95.41
61.43
48.51
57.14
76.92
12.07
22.37
8.47
67.74
26.92
91.25
91.18
28.44
58.46
85.29
86.49
62.24
71.43
77.65
97.47
98.04
200
252
165
120
102
122
113
94
160
82
108
96
104
108
54
57
133
74
142
227
94
47
41
84
106
48
82
29
54
4
71.00
90.08
56.97
39.17
40.20
68.85
93.81
51.06
51.25
35.37
50.00
4.17
Unless otherwise noted, reagents and solvents were used as
received from commercial suppliers. Precursor 2 and R1ONH2
were synthesized as literature report.18–20 All of the yields were
not optimized.
6
2
5.77
1.85
24
11
109
55
13
37
70
41
43
57
92
74
87
44.44
19.30
81.95
74.32
14.94
57.81
70.00
56.94
39.81
30.16
66.67
93.67
94.57
General procedure for the preparation of compound (3-01).
To the solution of R1ONH2 (10 mmol) in methanol (10 mL) was
added methyl (E)-N0-nitrocarbamimidothioate 8 mmol (inter-
mediate 2). The mixture was stirred at room temperature for 4 h.
Aer completion, concentrated the mixture to oil under reduced
pressure, and puried by column chromatography with ethyl
acetate and petroleum ether, yield compound 3-01 and
byproduct 5-01 38% and 37%, respectively.
87
64
100
72
108
189
138
79
64
122
80
66
77
Guadipyr 79
Data for 3-01. Yield 38%; light yellow solid; mp 52–53 ꢁC; 1H
NMR (300 MHz, DMSO) d 11.27 (s, 1H), 8.31 (s, 2H), 6.01 (ddt, J
¼ 16.7, 10.3, 6.3 Hz, 1H), 5.55–5.17 (m, 2H), 4.34 (d, J ¼ 6.3 Hz,
2H).
IMI
102
100
92
The lethal rate of CK was 3.98%. When IMI was used at 6.25 mg mLꢀ1
the lethal rate of IMI was 93.75%.
,
a
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Table 2 The insecticidal activity of title compounds against M. persicae at the concentration of 50 mg mLꢀ1
Total worm
number
Corrected
mortality (%)
Total worm
number
Corrected
mortality (%)
Compd
Death number
Compd
Death number
4-01
4-02
4-03
4-04
4-05
4-06
4-07
4-08
4-09
4-10
4-11
4-12
IMIa
Guadipyr
87
94
86
95
113
50
88
82
67
73
78
55
84
78
51
68
65
57
63
38
78
63
48
51
45
38
82
73
55.8
70.4
73.9
57.2
52.7
74.3
87.9
76.8
69.7
67.8
54.8
66.9
97.5
93.2
4-13
4-14
4-15
4-16
4-17
4-18
4-19
4-20
4-21
4-22
4-23
4-24
4-25
78
88
70
106
49
63
77
98
71
49
65
47
170
36
46
48
61
14
15
20
79
37
14
50
27
120
42.4
49.0
66.4
54.6
23.6
18.6
22.8
79.3
48.8
23.6
75.3
54.5
68.6
a
Imidacloprid was used at 20 mg mLꢀ1. The lethal rate of CK was 6.5%.
Table 3 The insecticidal activity of title compounds against Plutella xylostella (Linnaeus) at the concentration of 100 mg mLꢀ1
Total worm
number
Death
number
Corrected
mortality (%)
Total worm
number
Death
number
Corrected
mortality (%)
Compd
Compd
CK
56
34
36
32
32
32
30
43
36
30
36
34
30
30
34
1
4
2
2
9
7
0
14
8
0
5
1
0
2
23
1.79
11.76
5.56
4-13
4-14
4-15
4-16
4-17
4-18
4-19
4-20
4-21
4-22
4-23
4-24
33
30
35
35
30
30
30
32
30
35
30
30
30
30
30
1
0
3
3
1
4
0
1
0
1
0
2
0
2
27
3.03
0.00
8.57
8.57
3.33
13.33
0.00
3.13
0.00
2.86
0.00
6.67
0.00
6.67
90.00
4-01
4-02
4-03
4-04
4-05
4-06
4-07
4-08
4-09
4-10
4-11
4-12
IMI
6.25
28.13
21.88
0.00
32.56
22.22
0.00
13.89
2.94
0.00
4-25
6.67
67.65
Guadipyr
Spinosada
Indoxacarba
a
Spinosad and indoxacarb were used at 25 mg mLꢀ1
.
1
Data for 5-01. Yield 37%; yellow oil; 1H NMR (300 MHz,
Data for 3-02. Yield 34%; white solid; mp 66–67 C; H NMR
ꢁ
CDCl3) d 5.89 (ddd, J ¼ 16.2, 11.0, 5.8 Hz, 1H), 5.29–5.01 (m, 2H), (300 MHz, DMSO) d 11.29 (s, 1H), 8.31 (s, 2H), 3.88 (q, J ¼ 7.0 Hz,
4.89 (s, 2H), 4.37 (d, J ¼ 5.8 Hz, 2H), 2.26 (s, 3H). 13C NMR (75 2H), 1.22 (t, J ¼ 7.0 Hz, 3H).
1
ꢁ
MHz, CDCl3) d 151.55, 134.19, 116.87, 73.92, 13.34. HRMS (ESI)
m/z calcd for C5H11N2OS (M + H)+ 147.0587, found 147.0586.
Data for 3-03. Yield 44%; white solid; mp 64–65 C; H NMR
(300 MHz, DMSO) d 11.29 (s, 1H), 8.26 (s, 2H), 3.77 (t, J ¼ 6.8 Hz,
2H), 1.82–1.55 (m, 2H), 1.01–0.83 (m, 3H).
1
ꢁ
Data for 3-04. Yield 41%; white solid; mp 73–74 C; H NMR
(300 MHz, CDCl3) d 11.25–10.58 (m, 1H), 9.16–8.06 (m, 1H),
Table 4 The precise insecticidal assay of six compounds against M.
persicae
Compd
LC50 (mg mLꢀ1
)
95% FL
Table 5 The toxicities of commercial insecticides and compound 4-
07 against honey bee
Imidacloprid
Guadipyr
4-02
4-03
4-06
4-07
4-08
4-20
0.16
0.70
1.80
12.16
13.13
0.38
0.12–0.22
0.45–1.01
0.73–3.78
8.29–19.33
6.57–29.14
0.05–2.01
2.28–9.47
7.89–33.62
Compd
IMI
FPFa
TFMb
Guadipyr
5.19
4-07
LD50 (mg beeꢀ1
)
3.25 ꢂ 10ꢀ2
1.20
0.51
5.56
a
The data was calculated in 72 h and cited from ref. 10. b The data was
4.84
17.21
cited from ref. 14.
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6.84–5.96 (m, 1H), 4.02 (t, J ¼ 6.7 Hz, 2H), 1.79–1.57 (m, 2H), d 160.60, 150.69, 149.37, 139.11, 129.41, 123.92, 74.93, 49.02,
1.42 (dd, J ¼ 15.1, 7.4 Hz, 2H), 0.96 (t, J ¼ 7.3 Hz, 3H).
27.39, 26.93, 21.85, 13.37. HRMS (ESI) m/z calcd for
1
12H19ClN5O3 (M + H)+ 316.1171, found 316.1173.
ꢁ
Data for 3-05. Yield 40%; white solid; mp 62–63 C; H NMR
C
(300 MHz, DMSO) d 11.26 (s, 1H), 8.25 (s, 2H), 3.81 (t, J ¼ 6.9 Hz,
Data for (4-06). Yield 64%; yellow solid; mp 78–79 ꢁC; 1H NMR
2H), 1.75–1.49 (m, 2H), 1.44–1.20 (m, 4H), 0.87 (dd, J ¼ 8.3, (300 MHz,CDCl3) d 9.09 (s, 1H), 7.50 (s, 1H), 7.11 (s, 1H), 5.98
5.5 Hz, 3H).
(ddt, J ¼ 16.9, 10.2, 6.6 Hz, 1H), 5.61–5.27 (m, 2H), 4.90 (s, 2H),
General procedure for the preparation of title compounds 4.45 (d, J ¼ 6.6 Hz, 2H). 13C NMR (75 MHz, CDCl3) d 161.15,
(4). To an ice-cooled solution of 3 (4.8 mmol) in DMF (10 mL) 152.84, 141.34, 132.16, 129.78, 122.70, 76.00, 45.81. HRMS (ESI)
was added sodium hydride (60% oil dispersion; 0.288 g (7.2 m/z calcd for C8H11ClN5O3S (M + H)+ 292.0266, found 292.0271.
mmol)) in portions. The mixture was stirred below 10 ꢁC for 1 h
Data for (4-07). Yield 53%; white solid; mp 67–68 ꢁC; 1H NMR
in an ice-water bath followed by adding a solution of halide (300 MHz, CDCl3) d 9.10 (s, 1H), 7.51 (s, 1H), 7.01 (s, 1H), 4.91 (s,
(5.2 mmol in 10 mL DMF) slowly. Subsequently, the ice-water 2H), 4.06 (q, J ¼ 7.1 Hz, 2H), 1.34 (t, J ¼ 7.1 Hz, 3H). 13C NMR (75
bath was removed, and the mixture was stirred at room MHz, CDCl3) d 161.08, 152.86, 141.29, 132.20, 70.74, 45.44,
temperature for 22 h. Aer completion, 30 mL of water was 13.06. HRMS (ESI) m/z calcd for C7H11ClN5O3S (M + H)+
added slowly to the solution and then the product was precip- 280.0266, found 280.0265.
itated. The precipitates were ltered, dried and recrystallized
Data for (4-08). Yield 61%; white solid; mp 47–48 ꢁC; 1H NMR
from ethyl acetate. If it did not precipitate, extracted the solu- (300 MHz, CDCl3) d 9.11 (s, 1H), 7.51 (s, 1H), 6.85 (s, 1H), 4.91 (s,
tion with ethyl acetate (3 ꢂ 30 mL) and concentrated the 2H), 3.96 (t, J ¼ 6.7 Hz, 2H), 1.89–1.57 (m, 2H), 1.02 (t, J ¼ 7.4 Hz,
organic layer to oil under reduced pressure, and puried by 3H). 13C NMR (75 MHz, CDCl3) d 160.98, 152.89, 141.33, 132.14,
column chromatography with ethyl acetate and petroleum 76.69, 45.32, 20.92, 10.04. HRMS (ESI) m/z calcd for C8H13-
ether.
Data for (4-01). Yield 72%; white solid; mp 83–84 ꢁC; 1H NMR
ClN5O3S (M + H)+ 294.0422, found 294.0424.
Data for (4-09). Yield 62%; yellow oil; 1H NMR (300 MHz,
(300 MHz, CDCl3) d 9.11 (s, 1H), 8.35 (d, J ¼ 2.1 Hz, 1H), 7.71 CDCl3) d 9.36–8.60 (m, 1H), 7.42 (s, 1H), 7.19–6.78 (m, 1H), 4.82
(dd, J ¼ 8.2, 2.5 Hz, 1H), 7.46–7.27 (m, 1H), 7.09 (s, 1H), 5.93 (s, 2H), 3.91 (t, J ¼ 6.7 Hz, 2H), 1.69–1.47 (m, 2H), 1.33 (dd, J ¼
(ddt, J ¼ 16.6, 10.0, 6.6 Hz, 1H), 5.53–5.21 (m, 2H), 4.84 (s, 2H), 15.1, 7.4 Hz, 2H), 0.86 (t, J ¼ 7.3 Hz, 3H). 13C NMR (75 MHz,
4.39 (d, J ¼ 6.6 Hz, 2H). 13C NMR (75 MHz, CDCl3) d 161.12, CDCl3) d 160.88, 152.78, 141.25, 132.26, 74.98, 45.24, 29.45,
151.02, 149.59, 139.25, 129.68, 129.15, 124.04, 122.56, 75.86, 18.77, 13.39. HRMS (ESI) m/z calcd for C9H15ClN5O3S (M + H)+
49.78. HRMS (ESI) m/z calcd for C10H13ClN5O3 (M + H)+ 308.0579, found 308.0581.
286.0701, found 286.0704.
Data for (4-10). Yield 43%; yellow oil; 1H NMR (300 MHz,
Data for (4-02). Yield 78%; white solid; mp 71–72 ꢁC; 1H NMR CDCl3) d 9.02 (s, 1H), 7.43 (s, 1H), 7.11 (s, 1H), 4.83 (s, 2H), 3.91
(300 MHz, CDCl3) d 9.12 (s, 1H), 8.36 (d, J ¼ 2.3 Hz, 1H), 7.72 (t, J ¼ 6.8 Hz, 2H), 1.61 (dd, J ¼ 13.9, 6.9 Hz, 2H), 1.40–1.16 (m,
(dd, J ¼ 8.2, 2.5 Hz, 1H), 7.32 (d, J ¼ 7.8 Hz, 1H), 7.01 (s, 1H), 4H), 0.82 (t, J ¼ 7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 160.75,
4.84 (s, 2H), 3.99 (q, J ¼ 7.1 Hz, 2H), 1.29 (t, J ¼ 7.1 Hz, 3H). 13
C
152.63, 141.16, 132.41, 75.17, 45.13, 27.48, 27.04, 21.93, 13.45.
NMR (75 MHz, CDCl3) d 160.98, 151.05, 149.56, 139.19, 129.18, HRMS (ESI) m/z calcd for C10H17ClN5O3S (M + H)+ 322.0735,
124.05, 70.59, 49.40, 12.97. HRMS (ESI) m/z calcd for found 322.0740.
C9H13ClN5O3 (M + H)+ 274.0701, found 274.0704.
Data for (4-11). Yield 64%; white solid; mp 80–81 ꢁC; 1H NMR
1
Data for (4-03). Yield 59%; white solid; mp 101–102 ꢁC; H (300 MHz, CDCl3) d 9.09 (s, 1H), 7.50 (s, 1H), 7.11 (s, 1H), 5.98
NMR (300 MHz, CDCl3) d 9.50–8.79 (m, 1H), 8.40 (d, J ¼ 2.4 Hz, (ddt, J ¼ 16.9, 10.2, 6.6 Hz, 1H), 5.61–5.27 (m, 2H), 4.90 (s, 2H),
1H), 7.76 (dd, J ¼ 8.2, 2.5 Hz, 1H), 7.35 (d, J ¼ 8.2 Hz, 1H), 7.00– 4.45 (d, J ¼ 6.6 Hz, 2H). 13C NMR (75 MHz, CDCl3) d 161.09,
6.23 (m, 1H), 4.87 (s, 2H), 3.90 (t, J ¼ 6.7 Hz, 2H), 1.73 (dd, J ¼ 133.82, 132.92, 129.92, 129.86, 128.46, 122.26, 75.79, 52.29.
14.3, 7.0 Hz, 2H), 1.01 (t, J ¼ 7.4 Hz, 3H). 13C NMR (75 MHz, HRMS (ESI) m/z calcd for C11H13ClN4NaO3 (M + Na)+ 307.0568,
CDCl3) d 160.94, 151.26, 149.67, 139.19, 129.02, 124.08, 76.54, found 307.0571.
49.41, 20.92, 10.04. HRMS (ESI) m/z calcd for C10H15ClN5O3 (M +
Data for (4-12). Yield 63%; white solid; mp 73–74 ꢁC; 1H NMR
(300 MHz, CDCl3) d 9.14 (s, 1H), 7.39–7.20 (m, 4H), 6.87 (s, 1H),
H)+ 288.0858, found 288.0858.
Data for (4-04). Yield 60%; white solid; mp 68–69 ꢁC; 1H NMR 4.82 (s, 2H), 3.93 (q, J ¼ 7.1 Hz, 2H), 1.27 (t, J ¼ 7.1 Hz, 3H). 13
C
(300 MHz, CDCl3) d 9.38–8.80 (m, 1H), 8.37 (s, 1H), 7.73 (d, J ¼ NMR (75 MHz, CDCl3) d 160.94, 133.82, 132.98, 129.85, 128.47,
8.2 Hz, 1H), 7.32 (d, J ¼ 8.2 Hz, 1H), 6.87–6.24 (m, 1H), 4.84 (s, 70.47, 51.94, 12.96. HRMS (ESI) m/z calcd for C10H13ClN4NaO3
2H), 3.91 (t, J ¼ 6.6 Hz, 2H), 1.63 (d, J ¼ 8.0 Hz, 2H), 1.39 (d, J ¼ (M + Na)+ 295.0568, found 295.0572.
7.6 Hz, 2H), 0.94 (t, J ¼ 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3)
Data for (4-13). Yield 45%; white solid; mp 106–107 ꢁC; H
1
d 161.09, 151.45, 149.84, 139.34, 129.14, 124.24, 75.03, 49.56, NMR (300 MHz, CDCl3) d 9.48–8.69 (brs, 1H), 7.41–7.23 (m, 4H),
29.70, 19.01. HRMS (ESI) m/z calcd for C11H17ClN5O3 (M + H)+ 6.92–6.38 (brs, 1H), 4.84 (s, 2H), 3.84 (t, J ¼ 6.7 Hz, 2H), 1.76–
302.1014, found 302.1018.
1.59 (m, 2H), 0.98 (t, J ¼ 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3)
Data for (4-05). Yield 57%; white solid; mp 67–68 ꢁC; 1H NMR d 160.87, 133.90, 132.92, 129.91, 128.49, 76.31, 51.90, 20.89,
(300 MHz, CDCl3) d 9.01 (s, 1H), 8.25 (d, J ¼ 2.4 Hz, 1H), 7.62 10.04. HRMS (ESI) m/z calcd for C11H15ClN4NaO3 (M + Na)+
(dd, J ¼ 8.2, 2.4 Hz, 1H), 7.23 (t, J ¼ 17.1 Hz, 2H), 4.74 (s, 2H), 309.0725, found 309.0729.
3.82 (t, J ¼ 6.8 Hz, 2H), 1.67–1.38 (m, 2H), 1.17 (dd, J ¼ 8.8,
Data for (4-14). Yield 65%; white solid; mp 92–93 ꢁC; 1H NMR
5.3 Hz, 4H), 0.73 (t, J ¼ 6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3) (300 MHz, CDCl3) d 9.15 (s, 1H), 7.33–7.27 (m, 4H), 6.68 (s, 1H),
1842 | RSC Adv., 2018, 8, 1838–1845
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4.82 (s, 2H), 3.87 (d, J ¼ 6.7 Hz, 2H), 1.62 (dt, J ¼ 14.7, 6.8 Hz, CDCl3) d 160.95, 139.85, 132.12, 128.92, 118.09, 111.83, 70.62,
2H), 1.38 (dt, J ¼ 14.9, 7.4 Hz, 2H), 1.02–0.85 (m, 3H). 13C NMR 52.19, 13.01. HRMS (ESI) m/z calcd for C11H13N5NaO3 (M + Na)+
(75 MHz, CDCl3) d 160.78, 133.82, 132.99, 129.86, 128.45, 74.66, 286.0911, found 286.0915.
51.81, 29.47, 18.77, 13.38. HRMS (ESI) m/z calcd for
Data for (4-23). Yield 59%; white solid; mp 64–65 ꢁC; 1H NMR
(300 MHz, CDCl3) d 9.16 (s, 1H), 7.65 (d, J ¼ 8.2 Hz, 2H), 7.48 (d, J
C
12H18ClN4O3 (M + H)+ 301.1062, found 301.1064.
Data for (4-15). Yield 58%; white solid; mp 78–79 ꢁC; 1H NMR ¼ 8.3 Hz, 2H), 7.14–6.32 (m, 1H), 4.94 (s, 2H), 3.87 (t, J ¼ 6.7 Hz,
(300 MHz, CDCl3) d 9.14 (s, 1H), 7.41–7.22 (m, 4H), 6.74 (s, 1H), 2H), 1.78–1.60 (m, 2H), 0.97 (t, J ¼ 7.4 Hz, 3H). 13C NMR (75
4.82 (s, 2H), 3.85 (t, J ¼ 6.7 Hz, 2H), 1.62 (dd, J ¼ 14.0, 6.9 Hz, MHz, CDCl3) d 160.79, 139.87, 132.10, 128.92, 118.10, 111.80,
2H), 1.31 (dd, J ¼ 9.2, 5.3 Hz, 4H), 0.90 (t, J ¼ 6.9 Hz, 3H). 13C 76.49, 52.03, 20.86, 9.99. HRMS (ESI) m/z calcd for C12H16N5O3
NMR (75 MHz, CDCl3) d 160.81, 133.83, 132.98, 129.87, 128.45, (M + H)+ 278.1248, found 278.1250.
74.94, 51.85, 27.60, 27.15, 21.96, 13.47. HRMS (ESI) m/z calcd for
Data for (4-24). Yield 52%; white crystal; mp 88–89 ꢁC; 1H
NMR (300 MHz, CDCl3) d 9.14 (s, 1H), 7.75–7.58 (m, 2H), 7.46 (d,
C
13H20ClN4O3 (M + H)+ 315.1218, found 315.1220.
Data for (4-16). Yield 56%; white solid; mp 76–77 ꢁC; 1H NMR J ¼ 8.4 Hz, 2H), 6.79 (s, 1H), 4.92 (s, 2H), 3.90 (t, J ¼ 6.7 Hz, 2H),
(300 MHz, CDCl3) d 9.12 (s, 1H), 8.13 (t, J ¼ 5.5 Hz, 2H), 7.50 (d, J 1.64 (dt, J ¼ 14.7, 6.9 Hz, 2H), 1.38 (dt, J ¼ 14.9, 7.3 Hz, 2H), 0.94
¼ 8.7 Hz, 2H), 7.09 (s, 1H), 6.04–5.80 (m, 1H), 5.38 (dd, J ¼ 12.3, (dt, J ¼ 14.7, 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 160.73,
5.7 Hz, 2H), 4.97 (s, 2H), 4.39 (d, J ¼ 6.6 Hz, 2H). 13C NMR (75 139.95, 132.09, 128.87, 118.12, 111.70, 74.81, 51.97, 29.44,
MHz, CDCl3) d 160.99, 147.30, 141.98, 129.74, 129.03, 123.43, 18.75, 13.35. HRMS (ESI) m/z calcd for C13H18N5O3 (M + H)+
122.52, 75.90, 52.10. HRMS (ESI) m/z calcd for C11H13N5NaO5 (M 292.1404, found 292.1406.
+ Na)+ 318.0809, found 318.0813.
Data for (4-25). Yield 62%; white solid; mp 70–71 ꢁC; 1H NMR
Data for (4-17). Yield 64%; white solid; mp 76–77 ꢁC; 1H NMR (300 MHz, CDCl3) d 9.62–8.61 (m, 1H), 7.79–7.59 (m, 2H), 7.48
(300 MHz, CDCl3) d 9.16 (s, 1H), 8.20 (d, J ¼ 8.7 Hz, 2H), 7.54 (d, J (d, J ¼ 8.2 Hz, 2H), 7.08–6.41 (m, 1H), 4.94 (s, 2H), 3.90 (t, J ¼
¼ 8.6 Hz, 2H), 6.86 (s, 1H), 4.98 (s, 2H), 4.00 (q, J ¼ 7.1 Hz, 2H), 6.7 Hz, 2H), 1.73–1.58 (m, 2H), 1.32 (dd, J ¼ 9.2, 5.3 Hz, 4H), 0.91
1.32 (t, J ¼ 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 160.92, (t, J ¼ 6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 160.78, 139.87,
147.42, 141.88, 129.05, 123.50, 70.67, 51.89, 12.99. HRMS (ESI) 132.11, 128.92, 118.09, 111.82, 75.11, 52.05, 27.59, 27.16, 21.95,
m/z calcd for C10H13N5NaO5 (M + H)+ 306.0809, found 306.0812. 13.47. HRMS (ESI) m/z calcd for C14H20N5O3 (M + H)+ 306.1561,
Data for (4-18). Yield 48%; yellow solid; mp 74–75 ꢁC; 1H NMR found 306.1565.
(300 MHz, CDCl3) d 9.17 (s, 1H), 8.34–8.12 (m, 2H), 7.54 (d, J ¼
8.8 Hz, 2H), 6.77 (s, 1H), 4.99 (s, 2H), 3.90 (t, J ¼ 6.7 Hz, 2H),
X-ray diffraction
1.80–1.62 (m, 2H), 0.98 (t, J ¼ 7.4 Hz, 3H). 13C NMR (75 MHz,
Compound 4-02 was recrystallized by a slow evaporation from
CDCl3) d 160.79, 147.44, 141.85, 129.06, 123.50, 76.55, 51.77,
a dichloromethane/n-hexane (v/v ¼ 1 : 5) solution to afford
a single crystal suitable for X-ray crystallography and mounted
in inert oil and transferred to the cold gas stream of the
diffractometer. Cell dimensions and intensities were measured
using a Thermo Fisher ESCALAB 250 diffractometer with
graphite monochromated Mo Ka radiation. A total of 4458
20.87, 9.99. HRMS (ESI) m/z calcd for C11H15N5NaO5 (M + Na)+
320.0965, found 320.0971.
Data for (4-19). Yield 69%; white solid; mp 93–94 ꢁC; 1H NMR
(300 MHz, CDCl3) d 9.16 (s, 1H), 8.19 (d, J ¼ 8.7 Hz, 2H), 7.53 (d, J
¼ 8.7 Hz, 2H), 6.79 (s, 1H), 4.98 (s, 2H), 3.93 (t, J ¼ 6.7 Hz, 2H),
1.79–1.53 (m, 2H), 1.38 (dq, J ¼ 14.5, 7.3 Hz, 2H), 0.92 (t, J ¼
7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 160.74, 147.40, 141.92,
129.02, 123.48, 74.88, 51.71, 29.45, 18.76, 13.35. HRMS (ESI) m/z
calcd for C12H18N5O5 (M + H)+ 312.1302, found 312.1306.
Data for (4-20). Yield 57%; white solid; mp 88–89 ꢁC; 1H NMR
(300 MHz, CDCl3) d 9.15 (s, 1H), 8.19 (d, J ¼ 8.7 Hz, 2H), 7.53 (d, J
¼ 8.7 Hz, 2H), 6.80 (s, 1H), 4.98 (s, 2H), 3.92 (t, J ¼ 6.7 Hz, 2H),
reections were measured, of which 2357 were unique (Rint
¼
0.0201) in the range of 6.32 < 2q < 51.98ꢁ (ꢀ14 # h # 14, ꢀ11 # k
# 6, ꢀ7 # l # 14), and 2357 observed reections with I > 2s(I)
were used in the renement on F2. The structure was solved by
direct method with the SHELXTL-97 program. All of the non-H
atoms were rened anisotropically by fullmatrix least-squares to
give the nal wR(F2) ¼ 0.1039. The atomic coordinates for 4-02
have been deposited at the Cambridge Crystallographic Data
Centre.† CCDC-1518112 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
CCDC CIF Depository Request Crystallographic data in CIF
format are in the ESI.†
1.83–1.49 (m, 2H), 1.49–1.12 (m, 4H), 0.89 (t, J ¼ 7.0 Hz, 3H). 13
C
NMR (75 MHz, CDCl3) d 160.74, 147.39, 141.93, 129.02, 123.48,
75.15, 51.72, 27.57, 27.13, 21.95, 13.45. HRMS (ESI) m/z calcd for
C
13H20N5O5 (M + H)+ 326.1459, found 326.1463.
Data for (4-21). Yield 52%; white solid; mp 91–92 ꢁC; 1H NMR
(300 MHz, CDCl3) d 9.10 (s, 1H), 7.60 (d, J ¼ 8.2 Hz, 2H), 7.44 (d, J
¼ 8.3 Hz, 2H), 7.07 (s, 1H), 5.93 (ddt, J ¼ 16.7, 10.1, 6.6 Hz, 1H),
5.56–5.18 (m, 2H), 4.91 (s, 2H), 4.36 (d, J ¼ 6.6 Hz, 2H). 13C NMR
(75 MHz, CDCl3) d 160.98, 139.97, 132.07, 129.76, 128.90,
122.49, 118.17, 111.55, 75.85, 52.36. HRMS (ESI) m/z calcd for
Biological assays
Insecticidal activity. Insecticidal bioassays were performed
C
12H13N5NaO3 (M + H)+ 298.0911, found 298.0915.
on representative test organisms prepared in the laboratory.
1
ꢁ
Data for (4-22). Yield 45%; white solid; mp 111–113 ꢁC; H The bioassay was repeated at 25 ꢃ 1 C. All compounds were
NMR (300 MHz, CDCl3) d 9.57–8.76 (m, 1H), 7.66 (d, J ¼ 8.1 Hz, dissolved in N,N-dimethylformamide and diluted with 0.05%
2H), 7.48 (d, J ¼ 8.1 Hz, 2H), 7.15–6.36 (m, 1H), 4.94 (s, 2H), 3.98 Triton X-100 to obtain a series of concentrations for bioassays.
(q, J ¼ 7.0 Hz, 2H), 1.31 (t, J ¼ 7.0 Hz, 3H). 13C NMR (75 MHz, For comparative purposes, imidacloprid was tested under the
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same conditions. The preliminary bioassay of compounds
against A. gossypii (Glover) was tested by leaf-dipping method
and M. persicae (Sulzer) was tested by spray-method and
according to previously reported procedures and the results
were summarized in Tables 1 and 2.21–23 The precise insecticidal
assay was also tested by spray-method. Imidacloprid (95%)
purchased from Jiangsu Changlong Chemicals Co. was used as
control treating in the same way. Plutella xylostella was tested by
leaf-dipping method which was recommended by Insecticide
Resistance Action Committee (IRAC).24 A. mellifera was provided
by Institute of Apicultural Research, Chinese Academy of Agri-
cultural Sciences in July 2016, and a bioassay was performed
following the Organisation for Economic Cooperation and
Development (OECD) method for the acute oral toxicity test on
honey bees.25,26 The mortality was recorded in 48 h. The data
obtained were analyzed using IBM SPSS Statistics 20 to deter-
mine LD50 or LC50 values based on the bioassay methods.
J. E. Casida and T. C. Sparks, Insect Biochem. Mol. Biol.,
2011, 41, 432–439.
´
5 F. Sanchezbayo, Science, 2014, 346, 806–807.
6 Y. C. Zhu, J. Adamczyk, T. Rinderer, J. X. Yao, R. Danka,
R. Luttrell and J. Gore, J. Econ. Entomol., 2015, 108, 2640–
2647.
7 Y. M. Zhu, M. R. Loso, G. B. Watson, T. C. Sparks,
R. B. Rogers, J. X. Huang, B. C. Gerwick, J. M. Babcock,
D. Kelley, V. B. Hegde, B. M. Nugent, J. M. Renga,
I. Denholm, K. Gorman, G. J. DeBoer, J. Hasler, T. Meade
and J. D. Thomas, J. Agric. Food Chem., 2011, 59, 2950–2957.
8 G. B. Watson, M. R. Loso, J. M. Babcock, J. M. Hasler,
T. J. Letherer, C. D. Young, Y. M. Zhu, J. E. Casida and
T. C. Sparks, Insect Biochem. Mol. Biol., 2011, 41, 432–439.
9 T. C. Sparks, G. B. Watson, M. R. Loso, C. X. Geng,
J. M. Babcock and J. D. Thomas, Pestic. Biochem. Physiol.,
2013, 107, 1–7.
10 R. Nauen, P. Jeschke, R. Velten, M. E. Beck, U. Ebbinghaus-
¨
Kintscher, W. Thielert, K. Wolfel, M. Haas, K. Kunz and
4 Conclusions
G. Raupach, Pest Manage. Sci., 2015, 71, 850–862.
11 P. Jeschke, R. Nauen, O. Gutbrod, M. E. Beck, S. Matthiesen,
M. Haas and R. Velten, Pestic. Biochem. Physiol., 2015, 121,
31–38; R. Nauen, P. Jeschke, R. Velten, M. E. Beck,
In summary, by replacing the iconic imine chain with alkoxyl
group, the hydrazine-carboximidamide system which assigned
to the sodium ion channel inhibiting activity in guadipyr and its
structural isomers was destroyed, and a novel series of standard
neonicotinoid compounds, alkoxynitroguanidine compounds
were designed and synthesized. Most of these compounds
exhibited good insecticidal activity against M. persicae and A.
gossypii (Glover), and compound 4-07 was the best. Its high
insecticidal activity and low toxicity to honey bees made it
a good candidate for further development. The structure–
activity relationship (SAR) analysis also points us the optimal
path for further development of this kind of neonicotinoids,
and this is undergoing in our lab.
¨
U. Ebbinghaus-Kintscher, W. Thielert, K. Wolfel, M. Haas,
K. Kunz and G. Raupach, Pest Manage. Sci., 2015, 71, 850–
862.
12 D. Cordova, E. A. Benner, M. E. Schroeder, C. W. Holyoke,
W. Zhang, T. F. Pahutski, R. M. Leighty, D. R. Vincent and
J. C. Hamm, Insect Biochem. Mol. Biol., 2016, 74, 32–41;
P. Jeschke, R. Nauen, O. Gutbrod, M. E. Beck,
S. Matthiesen, M. Haas and R. Velten, Pestic. Biochem.
Physiol., 2015, 121, 31–38.
13 D. Cordova, E. A. Benner, M. E. Schroeder, C. W. Holyoke,
W. M. Zhang, G. P. Lahm, M. H. T. Tong, T. F. Pahutski,
D. R. Vincent and R. M. Leighty, Abstr. Pap. Am. Chem.
Soc., 2014, 248.
Conflicts of interest
14 C. W. Holyoke, W. M. Zhang, T. F. Pahutski, G. P. Lahm,
M. H. T. Tong, D. Cordova, M. E. Schroeder, E. A. Benner,
J. J. Rauh, R. F. Dietrich, R. M. Leighty, R. F. Daly,
R. M. Smith and D. R. Vincent, Abstr. Pap. Am. Chem. Soc.,
2014, 248.
15 W. Su, Y. Zhou, Y. Ma, L. Wang, Z. Zhang, C. Rui, H. Duan
and Z. Qin, J. Agric. Food Chem., 2012, 60, 5028–5034.
16 X. Yong, D. Y. Yang, X. G. Zou, C. H. Rui, Z. Y. Zhou, Y. Q. Ma
and Z. H. Qin, Pest Manage. Sci., 2017, 73, 1927–1934.
17 A. M. Astakhov, A. D. Vasil'Ev and M. S. Molokeev, Russ. J.
Org. Chem., 2005, 41, 910–915.
The authors declare no competing nancial interest.
Acknowledgements
This work was supported by the National Technology R&D
Program in the 13th Five year plan of China (grant No.
2017YFD0200504).
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This journal is © The Royal Society of Chemistry 2018
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