Synthesis and insecticidal activities of 1,3,5-trisubstituted-1,3,5- hexahydrotriazine-2-N-nitroimines

Article abstract of DOI:10.1002/cjoc.201180373

A new series of 1,3,5-trisubstituted-1,3,5-hexahydrotriazine-2-N- nitroimines (3a-3j) were designed and synthesized as novel neonicotinoid analogues, and their structures were characterized by ¹H NMR, IR, elemental analysis and MS. The preliminary bioassay tests showed that most of the target compounds had good insecticidal activities against Nilaparvata lugens as well as Aphis medicaginis at 500 mg/L, while compound 3i had 100% mortality against Nilaparvata lugens at 20 mg/L.

Full text of DOI:10.1002/cjoc.201180373

FULL PAPER
Synthesis and Insecticidal Activities of 1,3,5-Trisubstituted-
1,3,5-hexahydrotriazine-2-N-nitroimines
Xue, Sijia*(薛思佳)
Ma, Xubo(马旭波)
Bu, Hongfei(步洪飞)
Liu, Li(刘丽)
Xu, Xiao(许效)
Department of Chemistry, Shanghai Normal University, Shanghai 200234, China
A new series of 1,3,5-trisubstituted-1,3,5-hexahydrotriazine-2-N-nitroimines (3a— 3j) were designed and syn-
thesized as novel neonicotinoid analogues, and their structures were characterized by 1H NMR, IR, elemental analy-
sis and MS. The preliminary bioassay tests showed that most of the target compounds had good insecticidal activi-
ties against Nilaparvata lugens as well as Aphis medicaginis at 500 mg/L, while compound 3i had 100% mortality
against Nilaparvata lugens at 20 mg/L.
Keywords neonicotinoid analogues, hexahydrotriazine, insecticidal activities
Introduction
the most effective resistance-management tactics. Until
recently, most of the researches about structure optimi-
zation of NNs are based on cyclic neonicotinoid insecti-
cides, such as imidacloprid.20,21 Previous studies show
that compounds containing the structure segment of
hexahydrotriazine have high insecticidal activities.22
Hence we developed a new structure developing
strategy, using acyclic clothianidin as the lead com-
pound (Figure 1), and a series of novel 1,3,5-trisub-
stituted-1,3,5-hexahydrotriazine-2-N-nitroimines were
designed by introducing a new substituted amide into
clothianidin and forming a hexahydrotriazine ring. The
structures of all new compounds have been confirmed
Neonicotinoid insecticides (NNs), which act agonis-
tically on the insect nicotinic acetylcholine receptors
(nAChRs), have recently received considerable interests
from both agricultural chemistry and medicinal fields,
due to their broad spectrum of biological activities and
high selectivity for crop protection and public health.1,2
The first successful member of this family was imida-
cloprid (1a) in 1991.3 Six other neonicotinoids insecti-
cides (NNs): acetamiprid,4 nitenpyram,5 thiameth-
oxam,6,7 thiacloprid,8 clothianidin9 and dinotefuran10
were successively commercialized, which are all
nAChR agonists that act on the ligandgated ion channels
responsible for rapid neurotransmission of insects.11
However, a recent potential problem of the resis-
tance facing NNs is more and more serious, due to the
frequent field applications of NNs during the past dec-
ades.12-17 Especially, recently collected strains of the
whitefly exhibited much stronger resistance to imida-
cloprid and clothianidin.18,19 Hence, development of
noval neonicotinoids with good insecticidal activities
and less resistance is highly desirable.
1
by H NMR, IR and elemental analysis. And most of
these compounds exhibited good insecticidal activities
against Nilaparvata lugens and Aphis medicaginis, and
some of them had ≥85% mortality against Nilaparvata
lugens at 20 mg/L.
Experimental
Materials and physical measurements
All chemical reagents and solvents were purchased
Structure modification of the existing NNs is one of
Figure 1 Chemical structures of the target compounds.
*
E-mail: sjxue@sohu.com
Received January 13, 2011; revised May 26, 2011; accepted June 17, 2011.
Project supported by the Key Laboratory of Rare Earth Functional Materials of Shanghai (No. 07dz22303) and the Key Scientific and Technological
Project of Shanghai Science and Technology Commission (No. 09391212100).
Chin. J. Chem. 2011, 29, 2153— 2156
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Xue et al.
FULL PAPER
1
and used as received without further purification. H
NMR spectra (CDCl3) were recorded on a Bruker
AVANCE 400 MHz with TMS as an internal standard.
Elemental analyses were performed with a Perkin-Elmer
2400 instrument and melting points were determined by
an RK1 microscopic melting apparatus. IR spectra were
for C16H18ClN7O3S: C 39.05, H 3.53, N 24.52; found C
41.11, H 3.45, N 23.91.
1-(2-Chloro-5-thiazolylmethyl)-3-methyl-5-(-3-
methylbenzamido)-1,3,5-hexahydrotriazine-2-N-
nitroimines (3c) Yield 55%, white solid, m.p. 166—
1
167 ℃; H NMR (CDCl3, 400 MHz) δ: 8.23 (s, 1H,
obtained from KBr discs in the range 4000— 400 cm－
1
N-H), 7.54 (s, 1H, thiazole-H), 7.47 (s, 1H, Ph-H), 7.33
— 7.44 (m, 3H, Ph-H), 4.85 (s, 2H, thiazole-CH2 ), 4.66
(s, 4H, triazine-H), 3.19 (s, 3H, NCH3), 2.43 (s, 3H,
on a Nicolet 5DXFT-IR spectrophotometer. MS spectra
were recorded on a Trace DSQ mass spectrograph.
－
1
Ph-CH3); IR (KBr) ν: 3206, 1671, 1135 cm ; MS (ESI)
m/z: 422 ([M－ H]－ ). Anal. calcd for C16H18ClN7O3S: C
43.34, H 4.28, N 23.13; found C 44.13, H 3.71, N 24.09.
1-(2-Chloro-5-thiazolylmethyl)-3-methyl-5-(-4-
tert-butyl benzamido)-1,3,5-hexahydrotriazine-2-N-
nitroimines (3d) Yield 52%, white solid, m.p. 162—
163 ℃; 1H NMR (CDCl3, 400 MHz) δ: 8.22 (s, 1H, NH),
7.48— 7.63 (m, 5H, thiazole-H, Ph-H), 4.86 (s, 2H, thi-
azole-CH2 ), 4.66 (d, J＝ 6 Hz, 4H, triazine-H), 3.15 (s,
3H, NCH3), 1.34 (s, 9H, CCH3); IR (KBr) ν: 3128, 1645,
Synthesis of 1-(2-chloro-5-thiazolylmethyl)-3-methyl-
5-amido-1,3,5-hexahydrotriazine-2-N-nitroimines 3a
— 3j
Preparation of the target compound (3a): Benzoyl
hydrazine (2.72 g, 0.02 mol), clothianidin (4.98 g, 0.02
mol) and paraformaldehyde (1.80 g, 0.06 mol) were dis-
solved under heating in anhydrous ethanol (50 mL). The
reaction mixture was heated at reflux for 8 h and then
concentrated under vacuum. The residue was purified by
chromatography on silica gel using ethyl acetate∶
ethanol (2∶ 1, V∶ V) as eluent to yield 3a as a white
solid.
－
－
1
1093 cm ; MS (ESI) m/z: 464 ([M－ H] ). Anal. calcd
for C19H24ClN7O3S: C 48.98, H 5.19, N 21.04; found C
46.76, H 6.11, N 22.15.
The syntheses of 3b— 3j were carried out by the
similar method. The analytical data for the compounds
3a— 3j were summarized as follows:
1-(2-Chloro-5-thiazolylmethyl)-3-methyl-5-(-3-
N,N-dimethylaminobenzamido)-1,3,5-hexahydro-
triazine-2-N-nitroimines (3e) Yield 41.3%, white
solid, m.p. 141— 142 ℃; 1H NMR (CDCl3, 400 MHz) δ:
8.322 (s, 1H, NH), 7.544 (s, 1H, thiazole-H), 7.313 (d,
J＝ 8 Hz, 1H, Ph-H), 7.107 (s, 1H, Ph-H ), 6.920— 6.936
(m, 2H, Ph-H), 4.826 (s, 2H, thiazole-CH2 ), 4.654 (s,
4H, triazine-H), 3.167 (s, 3H, triazine-CH3), 3.025 (s,
6H); MS (ESI) m/z: 452 ([M－ H]－ ); IR (KBr) ν: 3122,
1-(2-Chloro-5-thiazolylmethyl)-3-methyl-5-benz-
amido-1,3,5-hexahydrotriazine-2-N-nitroimines (3a)
1
Yield 56%, m.p. 232— 233 ℃; H NMR (CDCl3, 400
MHz) δ: 7.81 (s, 1H, NH), 7.45— 7.61 (m, 5H, Ph-H),
7.42 (s, 1H, thiazole-H), 4.59 (s, 2H, thiazole-CH2),
4.47 (d, J＝ 22 Hz, 4H, triazine-H), 2.95 (s, 3H, NCH3);
－
1
IR (KBr) ν: 3182 (NH), 1645 (C＝ N), 1109 (CN) cm ;
MS (ESI) m/z: 408 ([M － H] － ). Anal. calcd for
C15H16ClN7O3S: C 43.96, H 3.93, N 23.92; found C
44.13, H 3.93, N 23.92.
－
1
1637, 1098 cm . Anal. calcd for C17H21ClN8O3S: C
45.08, H 4.67, N 24.74; found C 46.38, H 4.19, N 24.31.
1-(2-Chloro-5-thiazolylmethyl)-3-methyl-5-(-4-
chlorobenzamido)-1,3,5-hexahydrotriazine-2-N-
nitroimines (3f) Yield 40%, white solid, m.p. 145—
1-(2-Chloro-5-thiazolylmethyl)-3-methyl-5-phenyl-
acetamido-1,3,5-hexahydrotriazine-2-N-nitroimines
1
1
146 ℃; H NMR (CDCl3, 400 MHz) δ: 8.41 (s, 1H,
(3b) Yield 39%, white solid, m.p. 232— 233 ℃; H
N-H), 7.43— 7.67 (m, 5H, thiazole-H, Ph-H), 4.84 (s,
NMR (CDCl3, 400 MHz) δ: 8.06 (s, 1H, NH), 7.34—
7.35 (m, 6H, Ph-H, thiazole-H), 4.65 (s, 2H, thiazole-
CH2), 4.44 (d, J＝ 12.4 Hz, 4H, triazine-H), 3.47 (s, 2H,
Ph-CH2), 3.03 (s, 3H, NCH3); IR (KBr) ν: 3206, 1671,
2H, thiazole-CH2 ), 4.67 (s, 4H, triazine-H), 3.19 (s, 3H,
－
1
N-CH3); IR (KBr) ν: 3127, 1619, 1114 cm ; MS (ESI)
m/z: 443 ([M－ H]－ ). Anal. calcd for C15H15Cl2N7O3S: C
40.55, H 3.40, N 22.07; found C 41.76, H 3.40, N 22.07.
－
－
1
1135 cm ; MS (ESI) m/z: 422 ([M－ H] ). Anal. calcd
Scheme 1
3a: R = C6H5, 3b: R = C6H5CH2, 3c: R = 3-MeC6H4, 3d: R = 4-t-BuC6H4, 3e: R = 3-N(CH3)2C6H4, 3f: R = 4-ClC6H4, 3g: R = 2-thienyl, 3h: R =
2-furfuryl, 3i: R = CH3, 3j: R = C8H17
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Chin. J. Chem. 2011, 29, 2153— 2156

Synthesis and Insecticidal Activities of 1,3,5-Ttrisubstituted-1,3,5-hexahydrotriazine-2-N-nitroimines
1-(2-Chloro-5-thiazolylmethyl)-3-methyl-5-(2-the-
namido)-1,3,5-hexahydrotriazine-2-N-nitroimines
(3g) Yield 39%, pale yellowish solid, m.p. 84—85 ℃;
1H NMR (CDCl3, 400 MHz) δ: 9.19 (s, 1H, NH), 7.46 (s,
1H, thiazole-H), 6.90—6.95 (m, 3H, thiophene-H), 4.70
(s, 2H, thiazole-CH2 ), 4.48 (d, J＝4 Hz, 4H, triazine-H),
centage scale of 0—100, in which 100 total kill and 0 no
activity. The mortality rates were subjected to probit
analysis.24
The reference compound was clothianidin, and water
containing Triton X-80 (0.1 mg/L) was used as a nega-
tive control.
－
1
2.99 (s, 3H, NCH3); IR (KBr) ν: 3210, 1619, 1122 cm ;
MS (ESI) m/z: 414 ([M － H] － ). Anal. calcd for
C13H14ClN7O3S2: C 37.57, H 3.39, N 23.58; found C
40.03, H 3.48, N 22,19.
Results and discussion
Synthesis
A three-step synthetic strategy was adopted for the
synthesis of 1,3,5-trisubstituted-1,3,5-hexahydrotri-
azine-2-N-nitroimines (3a—3j). The general schematic
representation describing the routes of syntheses is fur-
nished in Scheme 1. The intermediates of hydrazides
(2a—2l) were synthesized with carboxylic acids as raw
materials via esterification and nucleophilic substitution.
The target products (3a—3j) were obtained, using in-
termediate 2, clothianidin and paraformaldehyde by
Mannich reaction. In addition, the products were puri-
fied by chromatography on silica gel using ethyl ace-
tate∶ethanol (2∶1, V∶V) as eluent.
1-(2-Chloro-5-thiazolylmethyl)-3-methyl-5-(2-
furancarboxamido)-1,3,5-hexahydrotriazine-2-N-
nitroimines (3h) Yield 42%, white solid, m.p. 97—98
1
℃; H NMR (CDCl3, 400 MHz) δ: 8.99 (s, 1H, NH),
7.52 (s, 1H, thiazole-H), 7.34—7.35 (m, 1H, furan-H),
6.41—6.42 (m, 2H, furan-H), 4.69 (s, 2H, thiazole-CH2),
4.47 (d, J＝4 Hz, 4H, triazine-H), 3.01 (s, 3H, NCH3);
－
1
IR (KBr) ν: 3158, 1624, 1108 cm ; MS (ESI) m/z: 398
([M－H]－ ). Anal. calcd for C13H14ClN7O4S: C 39.05, H
3.53, N 24.52; found C 41.11, H 3.45, N 23.91.
1-(2-Chloro-5-thiazolylmethyl)-3-methyl-5-
acetamido-1,3,5-hexahydrotriazine-2-N-nitroimines
1
(3i) Yield 39%, white solid, m.p. 117—118 ℃; H
Biological activity
NMR (CDCl3, 400 MHz) δ: 9.72 (s, 1H, NH), 7.65 (s,
1H, thiazole-H), 4.72 (s, 2H, thiazole-CH2 ), 4.53 (d, J＝
8.4 Hz, 4H, triazine-H), 2.89 (s, 3H, NCH3), 2.50 (s, 3H,
The compounds 3a—3j were tested for insecticidal
activities against Nilaparvata lugens as well as Aphis
medicaginis at the different concentration. The proce-
dure of operation is presented in the experimental part.
As indicated in Table 1, most of our designed com-
pounds exhibited good insecticidal activities against
Nilaparvata lugens as well as Aphis medicaginis and
had ≥90% mortality at 500 mg/L. Among all the ana-
logues, 3i afforded the best in vitro activity against
Nilaparvata lugens, and had 100% mortality at 20 mg/L,
which is comparable to that of clothianidin. Other com-
pounds' potential varied drastically, depending upon the
size and types of the R substitutions of the title com-
pounds. When the R substitutions are the substituted
phenyl substitutions, the substituent groups holding big
size group have lower activity than small size group;
meanwhile, compounds with electron donating group
have better activity than those with electron withdraw-
ing group: 3a＞3c＞3e＞3f.
－
1
CCH3); IR (KBr) ν: 3134, 1630, 1100 cm ; MS (ESI)
m/z: 347 ([M－H]－ ). Anal. calcd for C10H14ClN7O3S: C
34.54, H 3.53, N 28.19; found C 35.63, H 3.77, N 27.45.
1-(2-Chloro-5-thiazolylmethyl)-3-methyl-5-
pelargonamido-1,3,5-hexahydrotriazine-2-N-
nitroimines (3j) Yield 41%, white solid, m.p. 81—82
1
℃; H NMR (CDCl3, 400 MHz) δ: 8.05 (s, 1H, NH),
7.56 (s, 1H, thiazole-H), 4.85 (s, 2H, thiazole-CH2 ),
4.54—4.55 (d, J＝4.4 Hz, 4H, triazine-H), 3.13 (s, 3H,
NCH3), 2.07 (t, J＝4.4 Hz, 2H, COCH2), 1.57 (s, 2H,
C6H13CH2), 1.28—1.32 (s, 2H); IR (KBr) ν: 3129, 1615,
－
－
1
1112 cm ; MS (ESI) m/z: 445 ([M－H] ). Anal. calcd
for C17H28ClN7O3S: C 45.78, H 6.33, N 21.99; found C
43.93, H 6.75, N 22.68.
Biology assay
The bioassay was measured according to the stan-
dard test23 with a slight modification. Insecticidal activi-
ties of the compounds (3a—3j) were tested against
Nilaparvata lugens as well as Aphis medicaginis. All
compounds were dissolved in DMF and serially diluted
with water containing Triton X-80 (0.1 mg/L) to get the
required test concentrations. All experiments were car-
ried out in three replicates according to statistical
requirements. The insects were reared at 25(±1) ℃,
and groups of 10 were transferred to glass Petri dishes
and sprayed with the aforementioned solutions using a
Potter sprayer. Assessments were made after 72 h by the
number and size of live insects relative to that in the
negative control, and evaluations are based on a per-
Conclusions
In summary, a series of novel neonicotinoid ana-
logues (3a—3j), which were designed based on the
acyclic NNs (clothianidin), were synthesized. These
1
compounds were characterized by IR, H NMR, ele-
mentary analysis and MS. Preliminary bioassay show
that all the target compounds had ≥90% mortality
against Nilaparvata lugens and Aphis medicaginis at
500 mg/L, especially the two compounds, 3g and 3i af-
forded the best in vitro activity, and had ≥85% mortal-
ity against Nilaparvata lugens at 20 mg/L.
Chin. J. Chem. 2010, 28, 2153— 2156
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2155

Xue et al.
FULL PAPER
Table 1 Insecticidal activities of the target compounds (3a— 3j) against Nilaparvata lugens as well as Aphis medicaginis
mortality (%) at different concentrations (mg/L)
Nilaparvata lugens Aphis medicaginis
100 20
Compd. 3
R
500
100
100
100
90
500
90
100
30
75
50
35
90
10
80
20
30
50
100
20
nt
3a
3b
3c
3d
3e
3f
C6H5
100
75
30
10
10
nt
C6H5CH2
100
100
90
10
10
nt
3-MeC6H4
4-t-BuC6H4
N,N-dimethylamino phenyl
4-ClC6H4
2-thienyl
80
40
100
100
100
100
100
90
75
10
20
85
10
100
10
100
100
100
100
90
10
nt
65
3g
3h
3i
100
80
40
nt
2-furfuryl
CH3
100
55
100
90
nt
3j
C8H17
10
100
clothianidin
100
100
100
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