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

Article abstract of DOI:10.1002/jhet.745

By extracting active moieties from typical insecticides and recombining to a same molecule, a series of novel title compounds were designed and synthesized as shown in Scheme 1. The structures of all compounds were confirmed by IR, ¹H NMR, MS, and elemental analysis. The preliminary bioassay showed that the partial target compounds gave 90% mortality against Tetranychus cinnabarnus at 500 mg/L.

Full text of DOI:10.1002/jhet.745

November 2013
Synthesis and Insecticidal Activities of 1,5‐Disubstituted‐1,3,5‐
hexahydrotriazine‐2‐N‐nitroimines
1333
a
a
a
b
*
Si‐jia Xue, Li Liu, Hong‐fei Bu, and Yong‐hua Xu
aCollege of Life and Environment Sciences, Shanghai Normal University, Shanghai 200234, China
bBioassay Department, Branch of National Pesticide R&D South Center, Hangzhou 310023, China
*
E-mail: sjxue@sohu.com
Received July 22, 2010
DOI 10.1002/jhet.745
Published online 12 September 2013 in Wiley Online Library (wileyonlinelibrary.com).
By extracting active moieties from typical insecticides and recombining to a same molecule, a series of
novel title compounds were designed and synthesized as shown in Scheme 1. The structures of all com-
pounds were confirmed by IR, 1H NMR, MS, and elemental analysis. The preliminary bioassay showed that
the partial target compounds gave 90% mortality against Tetranychus cinnabarnus at 500 mg/L.
J. Heterocyclic Chem., 50, 1333 (2013).
INTRODUCTION
RESULTS AND DISCUSSION
Synthesis of compounds. The title compounds 5a–k were
synthesized by the method outlined in Scheme 1.
Nitro hydrocarbylideneamino guanidine is of consider-
able pharmacological interest as a number of derivatives
have shown outstanding insecticidal activities against
Myzus persicae and Aphis gossypii [1].
Neonicotinoid insecticides represent the fastest‐growing
class of insecticides introduced to the market since the
launch of pyrethroids. 6‐Chloro‐3‐pyridylmethyl group
and 2‐tetrahydrofurfuryl group are structural segments of
neonicotinoids [2–4].
Previous studies show that 1,5‐disubstituted‐1,3,5‐
hexahydrotriazine‐2‐N‐nitroimines have highly insecticidal
activities. For example, 100% mortality was given
against Pseudaletia separate Walker by 1‐(2‐chloro‐5‐
thiazolylmethyl)‐5‐(3‐pyridylmethyl)‐1,3,5‐hexahydrotriazine‐
2‐N‐nitroimine at 20 mg/L [5,6].
On the basis of above observations and obeying the
principle of active‐factor‐addition, we synthesized a
novel series of compounds for the purpose of obtaining
the bioactive pesticide lead compounds via extracting
active moieties from neonicotinoids and nitro hydro-
carbylideneamino guanidine and recombining to a same
molecule 1,5‐disubstituted‐1,3,5‐hexahydrotriazine‐2‐N‐
nitroimines by mannich reaction. The structures of all
title compounds were confirmed by IR,1H NMR, MS,
and elemental analysis. The result of preliminary
biological activity test showed that a majority of
compounds had preferable insecticidal activity against
Tetranychus cinnabarnus.
Insecticidal activity. The insecticidal activities of the title
compounds 5a–k were screened against Tetranychus
cinnabarnus using the standard testing method [7] with a
slight modification. Results of the in vitro insecticidal
activities of compounds 5a–k were summarized in Table
1. As indicated in Table 1, most of our synthesized
compounds exhibited good insecticidal activities against
Tetranychus cinnabarnus which had > 70% mortality at
500 mg/L. Among them, the compounds 5a and 5j had
the preferable insecticidal activity which gave > 90%
mortality against Tetranychus cinnabarnus at 500 mg/L.
Other compounds’ potential varied drastically, depending
upon the types of the 1‐position and 5‐position substitution
on 1,3,5‐hexahydrotriazine. The introduction of 6‐chloro‐
3‐pyridyl methyl and 2‐furyl methyl at the 5‐position of
1,3,5‐hexahydrotriazine showed preferable inhibitory
activities. The appending 2‐fururylamino at 1‐position of
1,3,5‐hexahydro‐triazine also had conspicuous influence
on their insecticide activities. In addition, the insecticidal
activities of the synthesized compounds decreased in the
order phenyl substituted with electron‐withdrawing group
> phenyl > phenyl substituted with electron‐donating
group introduced at 1‐position. The observations herein
corroborate our point of view that a heterocyclic methyl or
phenyl with electron‐withdrawing group introduced will
increase the insecticidal activity of the compounds.
© 2013 HeteroCorporation

1334
S.‐J. Xue, L. Liu, H.‐F. Bu, and Y.-H. Xu
Vol 50
Scheme 1. Synthesis of title compounds 5a–k.
EXPERIMENTAL
Nitroguanidine was converted to 1‐amino‐3 –nitroguanidine(1)
in 35% yield as described in the literature [9].
General synthetic procedure for synthesis of 3a–d. Compound
1 (2.00 g, 0.017 mmol), glacial acetic acid (0.2 mL) were dissolved
Thin‐layer chromatography (TLC) was carried out on silica gel
60 F254 plates Merck KGaA. 1H NMR spectra were recorded on a
Bruker Avance 400 (400 MHz) spectrometer, using DMSO‐d6 as
solvents and tetramethylsilane (TMS) as internal standard. The
chemical shift (δ) values are expressed in parts per million (ppm)
relative to tetramethylsilane as an internal standard: s = singlet,
d = doublet, dd = double doublet, m = multiplet. Melting points
were determined by an RK1 microscopic melting apparatus
uncorrected. Elemental analysis was performed with a Perkin‐
Elmer 2400 instrument. IR spectra were obtained on a Nicolet
5DX FT‐IR spectrophotometer in the region 4000–400 cm−1
using KBr discs. MS spectra were recorded on a Trace DSQ mass
spectrograph.
under heating in anhydrous ethanol (80 mL), which was added
dropwise a solution of 2a (1.79 g, 0.019 mmol) in anhydrous
ethanol (5 mL). The reaction mixture was then heated at reflux
for 2 h and cooled to room temperature. The product (3a) was
separated out from the solution and then obtained by filtration.
The product was washed three times with ethanol and dried at
50–60°C. Compound 3a was given as brown power. Compounds
3b–d were synthesized with the same method.
General synthetic procedure for synthesis of 5a–k. The
mixture of 2‐chloro‐5‐(aminomet‐hyl)pyridine (1.45 g, 0.010
mol) and 37% formaldehyde (1.97 g, 0.024 mol) was gently
stirred at room temperature for 0.5 h. A solution of 3a (2.00 g,
0.010 mol) in acetonitrile (25 mL) was gently heated at 60°C till
3a dissolved in acetonitrile, which was added previous mixture.
Stirring was continued for 1h at 60°C. The reaction was
The 2‐chloro‐5‐(aminomethyl)pyridine was prepared according
to the method from Ref.[[8]]. Unless otherwise noted, reagents
and solvents were of analytical reagent grade or were chemically
pure and used as received without further purification.
Table 1
Insecticidal activities of compounds 5a–k against Tetranychus cinnabarnus.
Concn (mg/L)a
100
Compd
R1
R2
500
20
5a
5b
5c
5d
5e
5f
5g
5h
5i
2‐furyl
2‐furyl
2‐furyl
2‐HO‐C6H4
2‐HO‐C6H4
2‐HO‐C6H4
C6H5
C6H5
C6H5
2‐Cl‐C6H4
2‐Cl‐C6H4
6‐Cl‐Py‐3‐CH2
2‐furyl‐CH2
2‐tetrahydrofuryl‐CH2
6‐Cl‐Py‐3‐CH2
2‐furyl‐CH2
2‐tetrahydrofuryl‐CH2
6‐Cl‐Py‐3‐CH2
2‐furyl‐CH2
2‐tetrahydrofuryl‐CH2
2‐furyl‐CH2
+++++
++++
++++
+++
++
++
++++
++++
+++
+++++
++++
+++
+
++
+
−
−
++
++
−
+++
++
++
−
−
n.t
n.t
n.t
+
−
n.t
+
5j
5k
2‐tetrahydrofuryl‐CH2
−
aRating system for the mortality percentage: ++++++, 100%; +++++, ≥ 90%; ++++, ≥ 80%; +++, ≥ 70%; ++, ≥ 60%; +, ≥ 50%; −, <50%;
n.t means not tested.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2013
Synthesis and Insecticidal Activities of 1,5‐Disubstituted‐1,3,5‐
hexahydrotriazine‐2‐N‐nitroimines
1335
monitored by TLC. The mixture was cooled to room temperature,
and then concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel with ethyl
acetate/petroleum ether (v/v 1:2) to afford desired product 5a.
Compounds 5b–k were synthesized with the same method.
1‐(2‐Furfurylideneamino)‐5‐(6‐chloro‐3‐pyridylmethyl)‐1,3,5‐
hexahydrotriazine‐2‐N‐nitro‐imine (5a). Yield: 63 %; m.p.: 153–
(s, 1H, N H), 7.875 (s, 1H, CH N), 7.315 (m, 1H, Ph‐H),
7.178–7.158 (d, J = 8.0 Hz, 1H, Ph‐H), 6.891–6.854 (t, J = 7.2
Hz, 1H, Ph‐H), 5.142–5.112(d, J = 12.0, 1H, triazine), 4.853–
4.824 (d, J = 12.0, 1H, triazine), 4.656–4.624(d, J = 12.8 Hz,
1H, triazine), 4.479–4.447 (d, J = 12.8 Hz, 1H, triazine),
4.147–4.078 (m, 1H, THF‐H), 3.869–3.742 (m, 2H, THF‐CH2),
2.911–2.841 (m, 2H, THF‐H), 2.065–2.006 (m, 1H, THF‐H),
1.935–1.857 (m, 2H, THF‐H), 1.598–1.527 (m, 1H, THF‐H).
[M+H]+: 349.1; Anal. Calc. for C15H20N6O4: C, 51.72; H, 5.79;
N, 24.12.; Found C, 51.68; H, 5.83; N, 24.16.
1
155 °C; IR (KBr disc): 3134, 1646, 1630, 1100 cm−1; H NMR
(400 MHz, DMSO‐d6): δH 9.718 (s, 1H, N H), 8.387–8.381 (d, J =
2.4 Hz, 1H, Pyri‐H), 8.004 (s, 1H, CH N), 7.871–7.840 (m, 2H,
Pyri‐H), 7.541–7.521 (d, J = 8.0 Hz, 1H, Furan‐H), 6.871–6.863
(d, J = 3.2 Hz, 1H, Furan‐H) 6.642–6.650 (m, 1H, Furan‐H) 4.867
(s, 2H, Py‐CH2), 4.350 (s, 2H, triazine), 3.951 (s, 2H, triazine). [M
+H]+: 364.2; Anal. Calc. for C14H14ClN7O3: C, 46.23; H, 3.88; N,
26.95.; Found C, 46.14; H, 3.97; N, 26.90.
1‐(Benzylideneamino)‐5‐(6‐chloro‐3‐pyridylmethyl)‐1,3,5‐
hexahydrotriazine‐2‐N‐nitroimine (5g). Yield: 55%; m.p.:
1
138–141°C; IR (KBr disc): 3120, 1649, 1625, 1128 cm−1; H
NMR (400 MHz, DMSO‐d6): δH 9.678 (s, 1H, N H), 8.393
(s, 1H, Pyri‐H), 8.108 (s, 1H, CH N), 7.876–7.849 (dd, J1
= 2.4 Hz, J2 = 8.0 Hz, 1H, Pyri‐H), 7.712–7.687 (m, 2H,
Ph‐H), 7.536 (d, J = 8.4 Hz, 1H, Pyri‐H), 7.467–7.449 (m,
3H, Ph‐H), 4.933 (s, 2H, Py‐CH2), 4.356 (s, 2H, triazine),
3.969 (s, 2H, triazine), 4.501 (s, 2H, triazine), 4.022 (s,
2H, Furan‐CH2), 4.818 (s, 2H, triazine). [M+H]+: 374.2;
Anal. Calc. for C16H16ClN7O2: C, 51.41; H, 4.31; N,
26.23.; Found C, 51.52; H, 4.29; N, 26.28.
1‐(2‐Furfurylideneamino)‐5‐(2‐furfuryl)‐1,3,5‐hexahydrotriazine‐
2‐N‐nitroimine (5b). Yield: 69 %; m.p.: 114–117°C; IR (KBr disc):
1
3130, 1641, 1633, 1100 cm−1; H NMR (400 MHz, DMSO‐d6): δH
9.835 (s, 1H, N H), 8.110 (s, 1H, CH N), 7.582–7.440 (m, 3H,
Pyri‐H), 6.916–6.908 (d, J = 3.2 Hz, 1H, Pyri‐H), 6.543–6.502
(m, 2H, Py‐H), 5.065–5.037 (d, J = 11.2 Hz, 2H, triazine), 4.807
(s, 2H, triazine), 4.026 (s, 2H, Furan‐CH2). [M+H]+: 319.3; Anal.
Calc. for C13H14N6O4: C, 49.06; H, 4.43; N, 26.40.; Found C,
49.14; H, 4.50; N, 26.81.
1‐(Benzylideneamino)‐5‐(2‐furfuryl)‐1,3,5‐hexahydrotriazine‐
2‐N‐nitroimine (5h). Yield: 63%; m.p.: 154–156°C; IR (KBr
disc): 3109, 1652, 1640, 1128 cm−1; 1H NMR (400 MHz,
DMSO‐d6): δH 9.859 (s, 1H, N H), 8.047 (s, 1H, CH N), 7.781–
7.757 (q, 2H, Ph‐H), 7.459–7.437 (m, 3H, Ph‐H), 7.428–4.410
(m, 1H, Furan‐H), 6.376–6.363 (q, 1H, Furan‐H), 6.339–6.331
(d, J = 3.2 Hz, 1H, Furan‐H), 4.818 (s, 2H, triazine), 4.501
(s, 2H, triazine), 4.022 (s, 2H, Furan‐CH2). Anal. Calc. for
C13H14N6O4: C, 49.06; H, 4.43; N, 26.40.; Found C, 49.14; H,
4.50; N, 22.81. [M+H]+: 330.2; Anal. Calc. for C15H16N6O3: C,
54.87; H, 4.91; N, 25.60.; Found C, 54.92; H, 4.85; N, 25.63.
1‐(Benzylideneamino)‐5‐(2‐tetrahydrofurfuryl)‐1,3,5‐
hexahydrotriazine‐2‐N‐nitroimine (5i). Yield: 65%; m.p.: 113–
1‐(2‐Furfurylideneamino)‐5‐(2‐tetrahydrofurfuryl)‐1,3,5‐
hexahydrotriazine‐2‐N‐nitro‐imine (5c). Yield: 72 %; m.p.: 142–
1
143°C; IR (KBr disc): 3129, 1649, 1629, 1115 cm−1; H NMR
(400 MHz, DMSO‐d6): δH 9.820 (s, 1H, N H), 8.101 (s, 1H,
CH N), 7.581 (s, 1H, Furan‐H), 6.902 (s, 1H, Furan‐H), 6.540–
6.521 (m, 1H, Furan‐H), 5.011–4.980 (d, J = 3.0 Hz, 1H,
triazine), 4.818–4.790 (d, J = 3.0 Hz, 1H, triazine), 4.643–4.611
(d, J = 12.8 Hz, 1H, triazine), 4.503–4.471 (d, J = 12.8 Hz, 1H,
triazine), 4.142–4.070 (m, 1H, THF‐H), 3.877–3.771 (m, 2H,
THF‐CH2), 2.958–2.848 (m, 2H, THF‐H), 2.189 (d, J = 2.0 Hz,
1H, THF‐H), 1.942–1.883 (m, 2H, THF‐H), 1.296–1.256(m, 1H,
THF‐H). [M+H]+: 324.1; Anal. Calc. for C13H18N6O4: C, 48.44;
H, 5.63; N, 26.07.; Found C, 49.55; H, 4.69; N, 26.15.
1‐(2‐Hydroxybenzylideneamino)‐5‐(6‐chloro‐3‐pyridylmethyl)‐
1,3,5‐hexahydrotriazine‐2‐N‐nitroimine (5d). Yield: 59%; m.p.:
157–159°C; IR (KBr disc): 3150, 1639, 1630, 1100 cm−1; 1H
NMR (400 MHz, DMSO‐d6): δH 11.326 (s, 1H, Ph‐OH), 9.826
(s, 1H, N H), 8.414 (d, J = 2.4 Hz, 1H, Pyri‐H), 8.266 (s, 1H,
CH N), 7.891–7.864 (dd, J1 = 2.4 Hz, J2 = 8.4 Hz, 1H, Pyri‐H),
7.460–7.436 (dd, J1 = 2.4 Hz, J2 = 8.2 Hz, 1H, Pyri‐H) 7.329–
7.286 (t, J1 = 8.0 Hz, J2 = 9.2 Hz, 1H, Ph‐H), 6.937–6.905 (m, 2H,
Ph‐H), 4.984 (s, 2H, Py‐CH2), 4.389 (s, 2H, triazine), 3.996 (s, 2H,
triazine).[M+H]+: 390.4; Anal. Calc. for C16H16ClN7O3: C, 49.30;
H, 4.14; N, 25.15.; Found C, 49.25; H, 4.17; N, 25.18.
1
114°C; IR (KBr disc): 3121, 1700, 1635, 1120 cm−1; H NMR
(400 MHz, DMSO‐d6): δH 9.945 (s, 1H, N H), 8.339 (s, 1H,
CH N), 8.162–8.160 (d, J = 8.0 Hz, 2H, Ph‐H), 7.400–7.311 (m,
3H, Ph‐H), 5.159–5.129(d, J = 12.0 Hz, 1H, triazine), 4.889–
4.859 (d, J = 12.0 Hz, 1H, triazine), 4.674–4.641(d, J = 13.2 Hz,
1H, triazine), 4.513–4.481 (d, J = 13.2 Hz, 1H, triazine), 4.116
(d, J = 3.6 Hz, 1H, THF‐H), 3.890–3.753 (m, 2H, THF‐CH2),
2.964–2.867 (m, 2H, THF‐H), 2.086–2.003 (m, 1H, THF‐H),
1.936–1.869 (m, 2H, THF‐H), 1.597–1.501 (m, 1H, THF‐H). [M
+H]+: 334.3; Anal. Calc. for C15H20N6O3: C, 54.21; H, 6.07; N,
25.29.; Found C, 54.25; H, 6.00; N, 25.23.
1‐(2‐Chloro‐benzylideneamino)‐5‐(2‐furfuryl)‐1,3,5‐
hexahydrotriazine‐2‐N‐nitroimine (5j). Yield: 52%; m.p.: 148–
1
1‐(2‐Hydroxybenzylideneamino)‐5‐(2‐furfuryl)‐1,3,5‐
hexahydrotriazine‐2‐N‐nitroimine (5e). Yield: 65%; m.p.: 163–
151°C; IR (KBr disc): 3170, 1658, 1640, 1130 cm−1; H NMR
(400 MHz, DMSO‐d6): δH 9.968 (s, 1H, N H), 8.345 (s, 1H,
CH N), 8.178–8.159 (d, J = 7.6 Hz, 1H, Ph‐H), 7.460 (s, 1H,
Furan‐H), 7.392–7.341 (m, 3H, Ph‐H), 6.382–6.374 (d, J = 3.2 Hz,
2H, Furan‐H), 4.877 (s, 2H, triazine), 4.527 (s, 2H, triazine), 4.045
(s, 2H, Funan‐CH2). [M+H]+: 363.1; Anal. Calc. for C15H15N6O3:
C, 49.66; H, 4.17; N, 23.17.; Found C, 49.65; H, 4.12; N, 23.22.
1‐(2‐Chloro‐benzylideneamino)‐5‐(2‐tetrahydrofurfuryl)‐
1,3,5‐hexahydrotriazine‐2‐N‐nitr‐oimine (5k). Yield: 57%; m.p.:
135–138°C; IR (KBr disc): 3142, 1692, 1640, 1100 cm−1; 1H
NMR (400 MHz, DMSO‐d6): c9.863 (s, 1H, N H), 8.271 (s, 1H,
CH N), 8.158–8.139 (d, J = 7.6 Hz, 1H, Ph‐H), 7.412–7.310
(m, 3H, Ph‐H), 5.159–5.129(d, J = 12.0 Hz, 1H, triazine),
4.889–4.859(d, J = 12.0 Hz, 1H, triazine),4.674–4.641(d,
1
166°C; IR (KBr disc): 3135, 1650, 1635, 1113 cm−1; H NMR
(400 MHz, DMSO‐d6): δH 11.209 (s, 1H, Ph‐OH), 9.779 (s, 1H,
N H), 7.898 (s, 1H, CH N), 7.459 (d, J = 1.2 Hz, 1H, Ph‐H),
7.355–7.311 (m, 1H, Ph‐H), 7.195–7.172 (dd, J1 = 1.6 Hz, J2
= 7.6 Hz, 1H, Furan‐H), 6.916–6.876 (q, 1H, Furan‐H), 4.841
(s, 2H, triazine), 4.530 (s, 2H, triazine), 4.039 (s, 2H, Furan‐
CH2). [M+H]+: 345.3; Anal. Calc. for C15H16N6O4: C, 52.32;
H, 4.68; N, 24.41.; Found C, 52.28; H,4.72; N, 24.38.
1‐(2‐Hydroxybenzylideneamino)‐5‐(2‐tetrahydrofurfuryl)‐
1,3,5‐hexahydrotriazine‐2‐N‐nit‐roimine (5f). Yield: 66%; m.p.:
149–152°C; IR (KBr disc): 3129, 1648, 1629, 1115 cm−1; 1H
NMR (400 MHz, DMSO‐d6): δH 11.318 (s, 1H, Ph‐OH), 9.724
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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S.‐J. Xue, L. Liu, H.‐F. Bu, and Y.-H. Xu
Vol 50
REFERENCES AND NOTES
J = 13.2 Hz, 1H, triazine), 4.513–4.481(d, J = 13.2 Hz, 1H,
triazine), 4.125–4.116 (d, J = 3.6 Hz, 1H, THF‐H), 3.873–
3.735 (m, 2H, THF‐CH2), 2.964–2.850 (m, 2H, THF‐H),
2.162–2.001 (m, 1H, THF‐H), 1.935–1.859 (m, 2H, THF‐
H), 1.588–1.521 (m, 1H, THF‐H). [M+H]+: 367.3; Anal.
Calc. for C15H19ClN6O3: C, 49.12; H, 5.22; N, 22.91.;
Found C, 49.14; H, 5.18; N, 22.86.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet