Synthesis and Acaricidal Activity of Some New 1,2,4-Triazine Derivatives

Article abstract of DOI:10.1002/jhet.3401

A new series of 1,2,4-triazine derivatives were designed, synthesized, and identified on the basis of IR, ¹H-NMR, ¹³C-NMR, and EI-MS spectral data. The potent acaricidal activity of 1,2,4-triazine derivatives against eggs and adult female of Tetranychus urticae (Koch) was assessed compared with pyridaben under laboratory conditions. Structure acaricidal activity relationships of the promising 1,2,4-triazine derivatives were analyzed for eggs and adult female; the nature and position of the substituents were important in demonstration of the activities.

Full text of DOI:10.1002/jhet.3401

Month 2018 Synthesis and Acaricidal Activity of Some New 1,2,4-Triazine Derivatives
a
Ghada G. El-Bana,a Mohamed El-H. Mostafa,b and Hanafi H. Zooroba
*
Wafaa S. Hamama,
aDepartment of Chemistry, Faculty of Science, Mansoura University, El-Gomhoria Street, Mansoura ET-35516, Egypt
bPlant Protection Research Institute, Agriculture Research Center, 12618, Egypt
*E-mail: wshamama53@gmail.com; wshamama@yahoo.com
Received August 6, 2018
DOI 10.1002/jhet.3401
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A new series of 1,2,4-triazine derivatives were designed, synthesized, and identified on the basis of IR,
1H-NMR, 13C-NMR, and EI-MS spectral data. The potent acaricidal activity of 1,2,4-triazine derivatives
against eggs and adult female of Tetranychus urticae (Koch) was assessed compared with pyridaben under
laboratory conditions. Structure acaricidal activity relationships of the promising 1,2,4-triazine derivatives
were analyzed for eggs and adult female; the nature and position of the substituents were important in dem-
onstration of the activities.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
biological
activities.
4-Amino-6-benzyl-3-mercapto-
1,2,4-triazin-5(4H)-one (3) acts as a building block for
the synthesis of fused heterocyclic rings incorporating
1,2,4-triazines ring junction nitrogen. Compound 3 was
prepared as previously reported in the literature from
Triazine derivatives are widely utilized in different fields
as pharmaceuticals, herbicides, pesticides, dyes, and
agriculture. So that is great concern, is paid us to the
synthesis of trains as the result of its importance as
biological agents in medical and agricultural fields [1,2].
The 1,2,4-triazin has two competing reactive sites at both
the amino and thiol groups that can be used for the
synthesis of binary and/or fused triazines [3]. Two-
spotted spider mite, Tetranychus urticae (Koch), is
considered to be highly polyphagous species of the
Tetranychidae, causing economic injuries to cotton,
vegetables, fruits, and several other agricultural crops [4].
The primary method used for controlling this pest is the
chemical control using of different synthetic acaricides to
protect the crops and reduce the crops yield losses [4,5].
The intensive use of many conventional acaricides to
control this pest population lead to very rapidly mite
pesticide resistant [6]. Therefore, there is a continuous
need for development and application of new synthetical
acaricides with new biochemical modes of action, to
prevent the development of mite resistance [6,7]. The
present study is directed to the synthesis and evaluates
the acaricidal activity of some 1,2,4-triazine derivatives
against eggs and adult females of two-spotted spider
mite, T. urticae (Koch).
4-benzylidene-2-methyloxazol-5(4H)-one
(1)
and
thiocarbohydrazide (2) [8,9]. While, in our case, when
attempting preparation of 3 following the literature
procedure, 3 was separated on hot from the reaction
mixture as a major product besides a minor product of
thiocarbohydrazide acetic acid salt 4 (Scheme 1).
Triazine 3 has two competing reactive sites at both the
thiol and amino groups, which can be used for the
synthesis of nitrogen ring junction triazines [3].
Heterocyclic fused ring systems consisting of 1,2,4-
triazolo, 1,3,4-thiadiazole, and 1,3,4-thiadiazine represent
a class of compounds that possesses a broad spectrum of
biological activities such as anti-inflammatory, antiviral,
antimicrobial,
and
antitumor
activity
[10–14].
Consequently, in view of the myriad biological activities
of these ring systems and as a part of an ongoing
investigation into biologically more active and less toxic
substances, we focused our attention on the synthesis of a
series of new 1,2,4-triazolo[5,1-c]1,2,4-triazin, 1,3,4-
thiadiazolo[2,3-c]1,2,4-triazin-4-ones, and 1,2,4-triazolo[3,4-
b]1,3,4-thiadiazines in order to investigate their acaricidal
activity. Thus, cyclocondensation reaction of triazine 3 with
phenyl isothiocyanate [15] in DMF afforded 3-benzyl-8-
phenyl-7-thioxo-7,8-dihydro-1,2,4-triazolo[5,1-c]1,2,4-
triazin-4(6H)-one (5). The structure of compound 5 was
established by its spectral analysis. Thus, the IR spectrum
of 5 showed a band at 3192 cmꢀ1 for NH, which
RESULTS AND DISCUSSION
Chemistry. A great attention has been directed to the
synthesis of fused 1,2,4-triazines with ring junction
nitrogen systems because they constitute an important
class of natural products and exhibit many useful
1
appeared at δ = 10.87 ppm in its H-NMR. Also, triazine
3 was refluxed with mono chloroacetic acid in phosphorus
oxychloride (POCl3) [16] and afforded the corresponding
© 2018 Wiley Periodicals, Inc.

W. S. Hamama, G. G. El-Bana, M. E.-H. Mostafa, and H. H. Zoorob
Vol 000
Scheme 1. Synthetic pathways of compounds 3 and 4.
3-benzyl-7-(chloromethyl)-4H-[1,3,4]thiadiazolo[2,3-c]
[1,2,4]triazin-4-one (6). The 1H-NMR showed new peaks at
δ = 4.82 ppm attributed to CH2Cl, indicating that the
carboxylic group of the acids used was reacted with SH
and NH2 groups to afford 1,3,4-thiadiazolo[2,3-c]1,2,4-
triazin-4-ones 6. Also, 13C-NMR spectra of compound 6
Scheme 2. Synthetic pathways of 1,2,4-triazines derivatives 5–15. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis and Acaricidal Activity of Some New 1,2,4-Triazine Derivatives
showed signals at δ = 58.43 ppm attributed to CH2Cl.
Additionally, refluxing 6 with benzoimidazole-2-thiol in
EtOH afforded 7-((1H-benzo[d]imidazol-2-ylthio)methyl)-
3-benzyl-4H-1,3,4-thiadiazolo[2,3-c]1,2,4-triazin-4-one
(7). The IR spectrum of compound 7 revealed the
and (C═O amide), respectively. Also, the IR spectrum of
N-alkyl triazine 11a [R═CH3] displayed bands at 3330,
3298 (NH2), 1669 (C═O amide), and 1162 cmꢀ1 for
(C═S), and its mass spectrum showed a molecular ion
peak at m/z = 248 (M+, 77.32) and a base peak at m/
z = 91 (100.0%) corresponding to the molecular formula
C11H12N4OS.
1
appearance of the NH group at 3144 cmꢀ1, and its H-
NMR spectrum showed singlet signals at δ = 4.98 and
12.81 ppm for CH2-S and NH protons, respectively
(Scheme 2).
In addition, the IR spectrum of S-alkyl triazine 10b
[R = ─CH2─COOEt] appeared bands at 3323, 3258 (NH2)
and 1739 cmꢀ1 (─OOC), and its 1H-NMR showed signals
at δ = 1.30 (t, 3H, CH3), 3.99 (s, 2H, CH2─Ph), 4.06 (s,
2H, CH2), 4.28 (q, 2H, CH2─CH3), and 4.82 ppm (s, 2H,
NH2). Also, the IR spectrum of N-alkyl triazine 11b
displayed bands at 3310, 3219 (NH2), 1742 (COO), and
Alkylation of compound 3 with chloroacetonitrile in
dioxin [17] in the presence of Et3N produced 2-((4-
amino-6-benzyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)thio)
acetonitrile (8) in 53% yield and 7-amino-3-benzyl-4H,8H-
1,2,4-triazino[3,4-b]1,3,4-thiadiazin-4-one (9) in 41%
yield. Compound 8 was obtained via direct attack of
4-amino group to the nitrile bond followed by
isomerization of the imino group to the amino group
(Scheme 2).
1
1177 cmꢀ1 for (C═S), and its H-NMR showed signals at
δ = 1.20 (t, 3H, CH3), 4.19 (q, 2H, CH2─CH3), and
5.17 ppm (s, 2H, N─CH2), while its 13C-NMR spectrum
displayed signals at δ = 13.92, 59.05, 61.33, 145.78,
166.57, and 168.65 ppm for (CH3─CH2), (─OCCH2),
(CH2─CH3), (C6), (C═O), and (COO─), respectively.
The IR spectrum of compound 8 showed bands at 3445,
3320 and 2249 cmꢀ1 for NH2 and CN groups, respectively.
1
The H-NMR spectrum of compound 8 showed singlet
Reaction
of
hydrazine
hydrate
with
10b
signals at δ = 6.48 ppm for NH2 protons and at
δ = 5.48 ppm attributed to CH2-S protons, which also
verified by appearance at δ = 17.10 ppm in its 13C-NMR
spectrum, indicating that the thiol group reacted with a
chloro atom of choloroacetonitrile beside the presence of
CN group at δ = 114.37 ppm. In addition, the IR
spectrum of compound 9 showed the disappearance of
CN group and presence of bands at 3445, 3320 cmꢀ1 for
NH2. Also, its H-NMR spectrum showed singlet signals
at δ = 4.13 and 4.78 ppm attributed to CH2-S and NH2
protons, respectively.
Once more, stirring of 3 with halo compounds such as
methyl iodide and ethyl bromoacetate [18,19] at room
temperature furnished the respective triazine derivatives
10 (major) and/or 11 (minor) (Scheme 2).
Thus, alkylation of triazine 3 with either methyl iodide
or ethyl bromoacetate afforded a higher ratio of S-alkyl
versus N-alkyl-1,2,4-triazine derivatives 4-amino-6-
benzyl-3-(methylthio)-1,2,4-triazin-5(4H)-one (10a) and
ethyl-2-(4-amino-6-benzyl-5-oxo-4,5-dihydro-1,2,4-
triazin-3-ylthio)acetate (10b) and 4-amino-6-benzyl-2-
methyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one
(11a) and ethyl-2-(4-amino-6-benzyl-5-oxo-3-thioxo-4,5-
dihydro-1,2,4-triazin-2(3H)-yl)acetate (11b). Compound
10a [R═CH3] was prepared as previously reported in the
literature (method a) [18]. But in our case, when
attempting preparation of 10a under the same condition
(method a) and/or under condition (method b) afforded
both 10a and 11a. The structures of 1,2,4-triazines 10a,b
and 11a,b were established on the basis of their spectral
analyses.
(R = CH2COOC2H5) furnished 3-benzyl-7-hydrazinyl-
4H,8H-1,2,4-triazino[3,4-b]1,3,4-thiadiazin-4-one (12) in
35% yield besides the 4-amino-6-benzyl-3-hydrazinyl-
1,2,4-triazin-5(4H)-one (13) in 57% yield (Scheme 2).
The IR spectrum of compound 12 showed bands at
3330, 3282, and 1686 cmꢀ1 related to NH2, NH, and
1
(C═O amide) groups. In addition, its H-NMR spectrum
showed singlet signals at δ = 3.81, 3.92, 5.51, and
6.06 ppm for CH2─Ph, S─CH2, NH2, and NH protons,
respectively. 13C-NMR also revealed signals at δ = 35.52
and 36.40 ppm for S─CH2 and CH2─Ph, respectively,
which indicated the formation of compound 12.
Furthermore, the assignment of the structure for
compound 13 was based on its spectroscopic analysis.
Thus, IR spectrum of 13 showed the disappearance of the
ester group and a presence of new hydrazinyl group
bands at 3330, 3283, 3226 cmꢀ1 for (2NH2) and
3184 cmꢀ1 for NH groups, respectively. Its mass
spectrum revealed a molecular ion peak at m/z = 232
(M+, 25.35) corresponding to the molecular formula
C10H12N6O and a base peak at m/z = 50 (100.0%).
1
In addition, the reaction of 3 with cyanoacetic acid in
acetic anhydride yielded N-(6-benzyl-5-oxo-3-thioxo-2,5-
dihydro-1,2,4-triazin-4(3H)-yl)acetamide (14) via
a
pathway a which confirmed by its spectral analysis
(Scheme 2). The 1H-NMR spectrum of 14 showed
signals at δ = 1.99, 10.94, and 13.79 ppm attributable to
CH3, NH─C═O, and NHtriazine protons, respectively.
The nucleophilic displacement reaction of compound 3
with 4,40-diselanediyldianiline yielded 3,30-((diselanediylbis(4,1-
phenylene))bis(azanediyl))bis(4-amino-6-benzyl-1,2,4-
triazin-5(4H)-one (15). The structure of this compound
The IR spectrum of S-alkyl triazine 10a [R═CH3]
showed bands at 3308, 3260 and 1687 cmꢀ1 for (NH2)
was established by its spectral analysis. The H-NMR
1
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W. S. Hamama, G. G. El-Bana, M. E.-H. Mostafa, and H. H. Zoorob
Vol 000
spectrum of compound 15 indicates singlet signals at
δ = 5.35 and 8.28 ppm for 2NH2 and 2NH protons,
respectively.
triazines 17 and 18 were established on the basis of their
spectral analyses. The 1H-NMR spectrum of S-alkyl
triazine 17 showed signals at δ = 2.61, 8.64, and
9.11 ppm attributed to CH3, CH─pyrazole, and ═CH
protons, respectively. Also, the IR spectrum of S-alkyl
triazine 18 demonstrated bands at 1739 cmꢀ1 for
The reaction of 4-amino-6-benzyl-3-mercapto-1,2,4-
triazin-5(4H)-one (3) with various aldehydes [20] under
reflux in ethanol in the presence either of conc. H2SO4
and/or conc. HCl resulted in the formation of the
corresponding imines 6-benzyl-4-((1,3-diphenyl-1H-
pyrazol-4-yl)methyleneamino)-3-mercapto-1,2,4-triazin-
5(4H)-one (16a) and 6-benzyl-4-((2-hydroxynaphthalen-1-
yl)methyleneamino)-3-mercapto-1,2,4-triazin-5(4H)-one
(16b). These compounds were characterized by their
1
(─OOC), and its H-NMR showed signals at δ = 1.16 (t,
3H, CH3), 4.09 (s, 2H, CH2), 4.11 (q, 2H, CH2─CH3),
9.10 (s, 1H, CHpyrazole), and 9.13 ppm (s, 1H, ═CH).
Furthermore, compound 16a was reacted with either
allyl bromide or 1,2-bis(bromomethyl)benzene only in the
presence of Et3N to yield 3-(allylthio)-6-benzyl-4-((1,3-
diphenyl-1H-pyrazol-4-yl)methyleneamino)-1,2,4-triazin-
5(4H)-one (19) and 3,30-((1,2-phenylenebis(methylene))
bis(sulfanediyl))bis(6-benzyl-4-(((1,3-diphenyl-1H-pyrazol-
1
spectroscopic data. The H-NMR of 16a,b showed the
methine (═CH) proton at δ = 8.26 and 9.54 ppm, which
supported the condensation products and not the cyclized
structure 16` (Scheme 3).
4-yl)methylene)amino)-1,2,4-triazin-5(4H)-one)
(20),
Once more, stirring of 16a with halo compounds [21]
such as methyl iodide and/or ethyl bromoacetate at room
temperature under three different solvent such as
EtOH/DMF in presence of Et3N gave solely the
corresponding 6-benzyl-4-((1,3-diphenyl-1H-pyrazol-4-yl)
methyleneamino)-3-(methylthio)-1,2,4-triazin-5(4H)-one
(17) and ethyl 2-(6-benzyl-4-((1,3-diphenyl-1H-pyrazol-4-
yl)methyleneamino)-5-oxo-4,5-dihydro-1,2,4-triazin-3-
ylthio)acetate (18) in high yield while in sodium methoxide
solution or EtOH/DMF in presence of fused sodium
acetate, afforded triazines 17 and 18 in low yield
[R = ─N═CH─Ar] (Scheme 3). The structures of 1,2,4-
respectively (Scheme 3). An assignment of the structure of
compounds 19 and 20 was based on their spectroscopic
analyses. Therefore, compound 19 showed signals at
δ = 3.89 (d, 2H, S─CH2═CH), 5.01 (dd, 2H, CH2═CH),
6.02 (m, 1H, CH), 8.63 (s, 1H, CHpyrazole), and 9.09 ppm
(s, 1H, ═CH) in its H-NMR spectrum. Also, H-NMR of
compound 20 displayed singlet signals at δ = 4.64, 8.51,
and 9.067 ppm corresponding to (CH2─S), CHpyrazole and
═CH protons. Furthermore, the mass spectrum of
compound 19 showed an ion peak at m/z =505 (M+1,
24.2) (1.00) and a base peak at m/z = 50 (100.0%)
corresponding to the molecular formula C36H27N7O4S.
1
1
Scheme 3. Synthetic pathways of 1,2,4-triazines derivatives 16–20. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
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Synthesis and Acaricidal Activity of Some New 1,2,4-Triazine Derivatives
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W. S. Hamama, G. G. El-Bana, M. E.-H. Mostafa, and H. H. Zoorob
Vol 000
Table 2
Toxicity of 1,2,4-triazines derivatives against 24 h old eggs of T. urticae.
Compound LC50 (ppm) and confidence limits at 95% LC90 (ppm) and confidence limits at 95%
Slope SE
Toxicity index
3
626.03
1899.00
1548.34
14335.87
380.64
4382.83
12465.36
16059.88
24744.8 E + 2
680094.08
346831.6 E + 3
27001.65
1.516 0.190
1.568 0.221
1.262 0.390
0.765 0.191
0.692 0.187
2.053 0.231
0.872 0.103
1.563 0.213
2.126 0.251
0.729 0.093
1.086 0.179
1.404 0.263
1.208 0.239
1.125 0.325
3.08
1.02
1.25
0.14
5.07
6.08
1.18
1.50
4.59
0.53
0.41
2.75
0.18
100.00
521.05
1478.18
1004.06
5700.43
157.82
266.18
1173.68
1020.30
352.22
2274.19
3417.17
523.72
6271.33
1.37
748.96
2826.25
6921.27
191426.74
567.47
2913.78
6704.14
4581.85
78354.19
7350.55
1006.15
19843.63
4883.21
1262.76
61213.97
28203.40
3115.06
37738.58
172.19
8415.70
5
36624.21
6
8
9
1717790.61
10 a
10 b
13
317.58
1337.19
48324.93
8489.56
1684.16
374.83
2037.54
1639.50
1285.59
420.34
2613.61
1770.99
496.90
196961.60
21533.92
2603.36
16 a
16 b
17
3635.46
4742.98
701.40
207969.41
1558421.68
71726.12
7520.87
8325.57
940.08
433781.21
20354.85
18
5741.72
19
11015.69
19.29
126830.85
36596.40
42.41
19072.10 E + 2
Pyridaben
265.58
758.46
*Pyridaben was used as reference acaricide in the tests
Acaricidal activity.
The acaricidal properties of the
The analysis of the relationships of 1,2,4-triazines
derivatives structures to its effects as miticidal properties
revealed that the nature and position of the substituents
were important. Compound 6 was superior to the
standard pyridaben; also, compounds 8 and 10b were
the most significantly toxic than the standard one against
adult females after 24 h of treatment. This may be
attributed to the fused and/or infused mercapto 1,2,4-
triazines active methylene, which appear in each active
previously mentioned compound. Moreover, the presence
of electron-withdrawing groups found to enhance the
pesticidal activity [22]. So, the active methylene
component with chlorine substitution 6 was the most
potent, followed by the cyano substitution 8 and then the
acetate substitution 10b.
The structure/ovicidal activity relationships differed
somewhat from those obtained by the adulticidal one.
The ovicidal properties were remarkably observed in
mercapto 1,2,4-triazines containing (N─NH2 group) such
as compounds 10a and 3, also compounds containing
imino group 9 and (N─NH─ group) 16a in addition to
unfused 1,2,4-triazines containing (N─NH2 and
hydrazine groups) 13 [22].
new series of 1,2,4-triazine derivatives against eggs and
adult females of T. urticae using the leaf-dip technique
are shown in Tables 1 and 2. Comparing the toxicity
indexes at LC50 values for adult females after 24 h of
exposure (Table 1), the tested compounds can be
classified according to their toxic action into two main
groups: the first group included the most toxic
compounds in the series, 6, 8, and 10b and then the
standard pyridaben and the second group included the
least active compounds 19, 17, 16a, 18, 3, 5, 13, 10a,
16b, and 9. Of the tested 13 compounds that
significantly showed adulticide activity on the basis of
toxicity index against T. urticae after 72 h of exposure,
four (6, 10b,13, 8, and then the standard pyridaben)
followed by nine less active compounds 3, 16b, 5, 16a,
10a, 19, 17, 18, and 9.
The susceptibility of 24 h old egg stage of T. urticae
(Table 2) to the same series of synthesized compounds
showed that the standard pyridaben exhibited a high
degree of efficiency followed by 10a, 9, 16a, 3, 18, 13, 6,
10b, 5, 16b, 17, 19, and 8, the lowest activity. The LC50
values of compounds were 43.36, 317.58, 380.64, 420.34,
626.03, 701.40, 1285.59, 1548.34, 1639.50, 1899.00,
3635.46, 4742.98, 11,015.69, and 14,335.87, respectively.
The results obtained from these laboratory studies have
shown the acaricidal properties of 1,2,4-triazines
Journal of Heterocyclic Chemistry
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Month 2018
Synthesis and Acaricidal Activity of Some New 1,2,4-Triazine Derivatives
derivatives compared with pyridaben against T. urticae.
Three of these compounds may be investigated practically
in the field after its toxicity application to mammalians.
added to a solution of thiocarbahydrazide 2 (1.06 g,
10 mmol) in warm water (30 mL). The reaction mixture
was refluxed on a water bath for 1 h. The solid that
precipitated on hot was filtered off, dried, and
recrystallized in ethanol to afford pure compound 3.
CONCLUSIONS
4-Amino-6-benzyl-3-mercapto-1,2,4-triazine-5(4H)-one
(3). White crystals (1.9 g, 85%); m.p 205–206°C (lit.
Design and synthesis of 1,2,4-triazine derivatives had a
great demand because of their biological interest,
especially as pesticides. The results showed significant
achievements in the synthesis of a new series of 1,2,4-
triazine derivatives and its investigations as acaricides
against T. urticae (Koch). Structure–activity relationship
of the most effective 1,2,4-triazine derivatives was
analyzed and laid pillars to structure modification of more
new 1,2,4-triazine derivatives.
yield 78%), (lit. m.p 204–205 [8], 195–198°C [9]);
Rf = 0.37 ]pet. ether/ethyl acetate (4:1)[. IR (KBr):
ν/cmꢀ1 = 3298, 3209 (NH2), 1686 (C═O amide). 1H-
NMR (DMSO-d6) δ (ppm) = 2.51 (s, 1H, SH), 3.91 (s,
2H, CH2─Ph), 6.57 (s, 2H, NH2), 7.22–7.32 (m, 5H,
H─Ar). 13C-NMR (DMSO-d6) δ (ppm) = 36.34 (1C,
CH2Ph), 127.11 (1C, CAr), 128.88 (2CH, CAr), 129.67
(2CH, CAr), 136.83 (1C, CAr), 147.44 (1C, C6), 148.94
(1C, C3), 169.00 (1C, C═O). 13C-NMR (DEPT-135,
DMSO-d6) δ = 35.54 (1C, CH2). Elemental analysis:
found: C, 51.25; H, 4.01; N, 23.94%. Calcd for
C10H10N4OS (234.06): C, 51.27; H, 4.30; N, 23.92%.
EXPERIMENTAL
Thiocarbohydrazide acetic acid (4).
White crystals
General. Gallenkamp electric melting point apparatus.
Elemental analyses were carried out at Micro Analytical
Center, Faculty of Science, Cairo University. IR spectra
were recorded (KBr), (ύ cmꢀ1) on a Mattson 5000 FTIR
Spectrophotometer at Micro Analytical Center Faculty of
Science, Mansoura University. The 1H-NMR and
(0.25 g, 15%); m.p 230–232°C. Rf = 0.45 ]pet. ether
(60:80)/ethyl acetate (4:1)[; IR (KBr): ν/cmꢀ1 = 3271,
3177 (NH2), 3098 (NH), 1715 (COOH). 1H-NMR
(DMSO-d6) δ (ppm) = 2.24 (s, 3H, CH3), 3.33 (s, 4H,
2NH2), 5.5 (s, 2H, 2NH), 8.4 (S, 1H, OH). 13C-NMR
(DMSO-d6) δ (ppm) = 10.39 (1C, CH3), 149.10 (C═O),
165.37 (C═S); MS (EI, 70 eV) m/z (%) = 166 (4.1), 165
(10.1), 150 (9.3), 149 (9.7), 135 (7.2), 133 (10.9), 121
(12.1), 106 (5.3), 90 (20.3), 89 (20.4), 78 (24.1), 62
(14.5), 46 (36.4), 45 (82.4). Elemental analysis: found: C,
21.66; H, 6.05; N, 33.73%. Calcd for C3H10N4O2S
(166.06): C, 21.68; H, 6.07; N, 33.71%.
13C-NMR spectra were measured on
a
Varian
Spectrophotometer at 300 and 75 MHz, respectively. Using
TMS as an internal reference and DMSO-d6 as solvent at
Chemistry Department, Faculty of Science, Cairo
University. The chemical shifts (δ) are reported in parts per
million and were referenced to the residual solvent peak.
Mass spectra were recorded on (Kratos, 70 eV) MS
equipment and/or a Varian MAT 311A Spectrometer, at
Micro Analytical Center, Faculty of Science, Cairo
University. Reaction mixtures were monitored by thin-
layer chromatography (TLC) using EM science silica gel
coated plates with visualization by irradiation with
ultraviolet lamp. Pyridaben 20% WP (2-tert-butyl-5-(4-tert-
3-Benzyl-8-phenyl-7-thioxo-7,8-dihydro-1,2,4-triazolo[5,1-
c]1,2,4-triazin-4(6H)-one (5).
A mixture of triazine 3
(0.5 g, 2.1 mmol) and phenyl isothiocyanate (0.37 mL,
3.15 mmol) in DMF 10 mL with K2CO3 (0.6 g) was
stirred overnight. The reaction mixture was cooled and
then poured onto crushed ice. The formed precipitate was
collected by filtration and recrystallized in ethanol/dioxan
(1:2) to afford 5.
butyl-benzylthio)-4-chloropyridazin-3(2H)-one)
was
obtained in a formulated form, and the dosages were
calculated on the basis of parts per million of active
ingredient. All melting points are in degree centigrade
(uncorrected) and were determined on.
White powder (0.67 g, 93%); m.p 260–262°C. Rf = 0.24
[pet. ether (60:80)/ethyl acetate (4:2)]. IR (KBr):
ν/cmꢀ1 = 3192 (NH), 1675 (C═O amide). 1H-NMR
(DMSO-d6) δ (ppm) = 4.12 (s, 2H, CH2-Ph), 7.10–7.61
(m, 10H, H─Ar), 10.87 (s, 1H, NH). MS (EI, 70 eV) m/z
(%) = 336 (M+ + 1, 1.6), 260 (4.3), 161 (11.1), 152 (2.5),
150 (2.44), 136 (25.0), 117 (24.7), 104 (24.1), 91 (70.3),
77 (99.4), 53 (16.8), 50 (100.0). Elemental analysis:
found: C, 60.85; H, 3.94; N, 20.90%. Calcd for
C17H13N5OS (335.08): C, 60.88; H, 3.91; N, 20.88%.
Synthesis of target compounds.
Synthesis of
4-amino-6-benzyl-3-mercapto-1,2,4-triazine-5(4H)-one (3).
Method a. A mixture of azalactone 1 (1.87 g, 10 mmol) in
warm aq. ethanol 50% (18 mL) and thiocarbohydrazide 2
(1.06 g, 10 mmol) in warm water (18 mL) was refluxed for
4 h. A binary solid mixture was separated upon cooling by
filtration and further purified by column chromatography
(petroleum ether/ethyl acetate 4:1) to afford 3 and 4.
3-Benzyl-7-(chloromethyl)-4H-[1,3,4]thiadiazolo[2,3-c]
[1,2,4]triazin-4-one (6). A mixture of triazine 1 (0.5 g,
Method b.
A solution of phenyl pyruvic acid 3c
2.14 mmol) and mono chloroacetic acid (0.2 mL,
2.14 mmol) in phosphorus oxychloride (7.5 mL) was
(1.64 g, 10 mmol) in ethanol (20 mL) was dropwise
Journal of Heterocyclic Chemistry
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W. S. Hamama, G. G. El-Bana, M. E.-H. Mostafa, and H. H. Zoorob
Vol 000
refluxed for 12 h over a water bath. The reaction mixture
was cooled and poured onto crushed ice. The resulting
solid was filtered off and washed with aqueous (2%)
sodium bicarbonate solution till neutralize at pH 7 and
then water (30 mL). It was dried and recrystallized in
ethanol to yield 6.
Yellow powder (0.5 g, 80%); m.p 225–227°C.
Rf = 0.45] pet. ether (60:80)/ethyl acetate (4:1)[. IR
(KBr): ν/cmꢀ1 = 1697 (C═O). 1H-NMR (DMSO-d6) δ
(ppm): 4.327 (s, 2H, CH2─Ph), 4.823 (s, 2H, CH2─Cl),
7.259–7.486 (m, 5H, H─Ar). 13C-NMR (DMSO-d6) δ
36.264 (1C, CH2Ph), 58.437 (1C, CH2Cl), 126.110
(1CH, CAr), 128.781 (2CH, CAr), 129.016 (2CH, CAr),
142.850 (1C, CAr), 152.810 (1C, C-3), 153.705 (1C, C-
6), 160.842 (1C, C-3), 165.467 (1C, CO); MS (EI,
70 eV) m/z (%) = 292/294 (M+, 100.0/83.7), 217 (23.8),
117 (61.5), 91 (54.3), 78 (8.5), 77 (57.1), 76 (18.5), 75
(13.4), 52 (10.9), 50 (22.4). Elemental analysis: found: C,
49.22; H, 3.08; N, 19.13%. Calcd for C12H9ClN4OS
(292.02): C, 49.24; H, 3.10; N, 19.14%.
CH2─Ph), 114.36 (CN), 126.50 (1C, CAr), 128.98
(2CH, CAr), 129.05 (2CH, CAr), 135.59 (1C, CAr),
146.68 (1C, C6), 147.38 (1C, C3), 168.13 (1C, C═O);
MS (EI, 70 eV) m/z (%) = 273 (M+, 62.2), 257 (24.3),
233 (14.2), 219 (2.7), 217 (8.7), 201 (8.9), 198 (11.1),
175 (6.0), 160 (5.3), 146 (7.5), 144 (26.4), 117 (100.0),
104 (11.9), 103 (61.5), 91 (95.9), 65 (9.8), 53 (7.9), 51
(45.0). Elemental analysis: found: C, 52.70; H, 4.09; N,
25.60%. Calcd for C12H11N5OS (273.31): C, 52.73; H,
4.06; N, 25.62%.
Compound 9. Gray powder (0.24 g, 41%); m.p 91–
92°C. Rf = 0.22 [pet. ether/ethyl acetate (4:1)]. IR (KBr):
ν/cmꢀ1 = 3445, 3320 (NH2), 1679 (C═O amide). 1H-
NMR (CDCl3) δ (ppm) = 3.93 (s, 2H, CH2─Ph), 4.13 (s,
2H, CH2─S), 4.78 (S, 2H, NH2), 7.22–7.39 (m, 5H,
H─Ar). MS (EI, 70 eV) m/z (%) = 273 (M+, 48.7), 257
(2.7), 233 (1.5), 188 (34.9), 118 (8.9), 117 (37.0), 91
(100.0), 76 (54.2), 53 (7.1), 50 (25.3). Elemental
analysis: found: C, 52.71; H, 4.03; N, 25.59%. Calcd for
C12H11N5OS (273.31): C, 52.73; H, 4.06; N, 25.62%.
Synthesis of S-alkyl and N-alkyl triazines 10a,b and 11a,b.
General procedure. Method a. Triazine 3 (10 mmol) was
7-((1H-benzo[d]imidazol-2-ylthio)methyl)-3-benzyl-4H-
1,3,4-thiadiazolo[2,3-c]1,2,4-triazin-4-one (7). A mixture of
dissolved in cold methanolic sodium methoxide solution
[prepared from sodium metal (0.23 g, 10 mmol) and 10-
mL methanol], and then, either methyl iodide (10 mmol)
or ethyl bromoacetate (10 mmol) was added. The
reaction mixture was stirred at room temperature. The
precipitate obtained was collected by filtration, washed
with water, and dried at room temperature to give 10a,b
and 11a,b.
Method b. A mixture of triazine 3 (0.5 g, 2.14 mmol),
methyl iodide (0.13 mL, 2.14 mmol), or ethyl
bromoacetate (0.24, 2.14 mmol) in EtOH/DMF mixture
(1:1) (10 mL) in the presence of either fused sodium
acetate (0.3 g, 3.21 mmol) or Et3N (0.45 mL,
3.21 mmol) was stirred at room temperature. The reaction
mixture was monitored by TLC and then poured into
cold water. The precipitate that formed was filtered off,
washed with water (10 mL), and dried at room
temperature to give 10a,b and 11a,b.
6 (0.5 g, 2.14 mmol) and 1H-benzo[d]imidazole-2-thiol
(0.1 g, 2.14 mmol) in ethanol (15 mL) was refluxed for
6 h; the precipitate that formed on hot was separated by
filtration and recrystallized in ethanol to afford 7.
Yellow powder (0.8 g, 92%); m.p 191–192°C. Rf = 0.15
[pet. ether (60:80)/ethyl acetate (4:1)]. IR (KBr):
ν/cmꢀ1 = 3144 (NH), 1714 (C═O amide). 1H-NMR
(DMSO-d6) δ (ppm) = 4.13 (s, 2H, CH2─Ph), 4.98 (s,
2H, CH2─S), 7.15–7.60 (m, 9H, H─Ar), 12.81 (s, 1H,
NH). MS (EI, 70 eV) m/z (%) = 406 (M+, 20.07), 373
(1.5), 346 (1.0), 289 (5.6), 266 (4.1), 257 (16.8), 219
(67.3), 209 (0.57), 207 (12.5), 199 (12.1), 187 (29.2), 175
(9.1), 164 (1.05), 162 (27.9), 131 (27.7), 123 (100.0), 110
(3.5), 77 (50.01), 65 (86.9), 51 (70.8). Elemental analysis:
found: C, 56.11; H, 3.49; N, 20.66%. Calcd for
C19H14N6OS2 (406.48): C, 56.14; H, 3.47; N, 20.68%.
2-((4-Amino-6-benzyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)
thio)acetonitrile (8) and 7-amino-3-benzyl-4H,8H-1,2,4-
triazino[3,4-b]1,3,4-thiadiazin-4-one (9).
A mixture of
4-Amino-6-benzyl-3-(methylthio)-1,2,4-triazin-5(4H)-one
(10a). RX═CH3I
White crystal (0.39 g, 75%); m.p 195–196°C [lit. m.p.
196–198°C [18]]. Rf = 0.24 [pet. ether/ethyl acetate
(4:1)]. IR (KBr): ν/cmꢀ1 = 3308, 3260 (NH2), 1687
(C═O).
triazine 3 (0.5 g, 2.14 mmol) and chloroacetonitrile
(0.2 mL, 3.16 mmol) in dioxan (15 mL) was refluxed for
5 h in the presence of TEA (0.6 mL, 8.30 mmol), cooled to
room temperature, and poured onto crushed ice. The
precipitate that formed the two components was separated
byPTLCsilicagel(eluent:petroleumether/ethylacetate4:1).
Compound 8. Brown powder (0.30 g, 53%); m.p 290–
293°C. Rf = 0.30 [pet. ether (60:80)/ethyl acetate (4:1)].
IR (KBr): ν/cmꢀ1 = 3445, 3320 (NH2), 2249 (CN),
4-Amino-6-benzyl-2-methyl-3-thioxo-3,4-dihydro-1,2,4-
triazin-5(2H)-one (11a). RX═CH3I
White crystal (0.06 g, 12%); m.p 110°C. Rf = 0.15 [pet.
ether/ethyl acetate (4:1)]. IR (KBr): ν/cmꢀ1 = 3305, 3258
(NH2), 1687 (C═O amide), 1162 (C═S); MS (EI, 70 eV)
m/z (%) = 248 (M+, 77.3), 231 (19.4), 230 (28.1), 221
(2.6), 204 (2.1), 188 (11.1), 173 (1.2), 160 (4.2), 149
(10.9), 145 (10.9), 131 (3.7), 117 (13.9), 116 (28.1), 103
1687 (C═O amide). 1H-NMR (DMSO-d6)
δ
(ppm) = 3.94 (s, 2H, CH2─Ph), 5.48 (s, 2H, CH2─S),
6.48 (s, 2H, NH2), 7.21–7.32 (m, 5H, H─Ar). 13C-NMR
(DMSO-d6) δ (ppm) = 17.10 (1C, CH2─S), 35.75 (1C,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis and Acaricidal Activity of Some New 1,2,4-Triazine Derivatives
1
(9.1), 102 (12.8), 91 (100.0), 77 (13.8), 53 (3.4), 50 (6.8).
Elemental analysis: found: C, 53.19; H, 4.90; N, 22.53%.
Calcd for C11H12N4OS (248.07): C, 53.21; H, 4.87; N,
22.56%.
(NH2), 3184 (NH), 1686 (C═O). H-NMR (DMSO-d6) δ
(ppm) = 3.81 (s, 2H, CH2─Ph), 3.92 (s, 2H, CH2), 5.55
(s, 2H, NH2), 6.06 (s, 1H, NH), 7.19–7.28 (m, 5H,
Ar─H); 13C-NMR (DMSO-d6) δ (ppm) = 35.52 (1C,
CH2─S), 36.40 (1C, CH2─Ph), 126.13 (1CH, CAr),
128.15 (2CH, CAr), 128.69 (2CH, CAr), 137.31 (1C, CAr),
147.48 (1C, C6), 148.55 (1C, C3), 168.142 (1C, C═O).
MS (EI, 70 eV) m/z (%) = 288 (M+, 3.1), 257 (5.6), 230
(6.4), 232 (16.5), 218 (26.8), 219 (10.9), 215 (10.9), 188
(32.7), 185 (18.6), 172 (20.1), 171 (36.7), 161 (47.5),
158 (7.0), 145 (14.6), 115 (100.0), 104 (19.0), 97 (43.6),
94 (35.7), 72 (23.3), 71 (6.3), 59 (23.8). Elemental
analysis: found: C, 49.96; H, 4.24; N, 29.18%. Calcd for
C12H12N6OS (288.08): C, 49.99; H, 4.20; N, 29.15%.
Ethyl-2-(4-amino-6-benzyl-5-oxo-4,5-dihydro-1,2,4-triazin-
3-ylthio)acetate (10b). RX═Br─CH2─COOEt
White flakes (0.65 g, 82%); m.p 130–131°C [ethanol].
Rf = 0.26 [pet. ether/ethyl acetate (4:2)]. IR (KBr):
ν/cmꢀ1 = 3323, 3258 (NH2), 1739 (COO), 1691 (C═O
1
amide). H-NMR (CDCl3) δ (ppm) = 1.30 (t, 3H, CH3),
3.99 (s, 2H, CH2─Ph), 4.06 (s, 2H, CH2), 4.28 (q, 2H,
CH2─CH3), 4.82 (s, 2H, NH2), 7.19–7.40 (m, 5H,
H─Ar). MS (EI, 70 eV) m/z (%) = 321 (M+ + 1, 26.9),
305 (2.1), 292 (1.0), 275 (16.7), 259 (2.1), 247 (33.7),
230 (13.2), 219 (14.7), 198 (1.3), 174 (3.6), 160 (2.7),
144 (18.8), 130 (49.8), 119 (13.5), 117 (45.9), 102
(32.8), 91 (100.0), 77 (40.9), 73 (27.4), 53 (10.1), 50
(41.3), 45 (77.1). Elemental analysis: found: C, 52.52; H,
5.06; N, 17.46%. Calcd for C14H16N4O3S (320.09): C,
52.49; H, 5.03; N, 17.49%.
4-Amino-6-benzyl-3-hydrazinyl-1,2,4-triazin-5(4H)-one
(13). White needles (0.84 g, 85%); m.p 265–266°C [lit. m.
p 254–255°C [23]]. [ethanol]. Rf = 0.14 [pet. ether (60:80)/
ethyl acetate (4:1)]. IR (KBr): ν/cmꢀ1 = 3330, 3283, 3226
(2NH2), 3184 (NH), 1685 (C═O amide). MS (EI, 70 eV)
m/z (%) = 232 (M+, 25.3), 216 (3.8), 185 (1.6), 186 (5.8),
117 (24.1), 91 (96.7), 76 (67.4), 53 (27.6), 50 (100.0).
Elemental analysis: found: C, 51.70; H, 5.24; N, 36.22%.
CalcdforC10H12N6O(232.11):C,51.72;H,5.21;N,36.19%.
Ethyl-2-(4-amino-6-benzyl-5-oxo-3-thioxo-4,5-dihydro-
1,2,4-triazin-2(3H)-yl)acetate
(11b).
RX═Br─CH2─COOEt
Pale yellow powder (0.1 g, 15%); m.p 152–153°C.
[Separated by pet. ether]. Rf = 0.5 [pet. ether (60:80)/
ethyl acetate (4:1.5)]. IR (KBr): ν/cmꢀ1 = 3310, 3219
(NH2), 1742 (COO), 1687 (C═O amide), 1177 (C═S).
1H-NMR (DMSO-d6) δ (ppm) = 1.20 (t, 3H, CH3), 3.97
(s, 2H, CH2─Ph), 4.19 (q, 2H, CH2─CH3), 5.17 (s, 2H,
CH2), 6.63 (s, 2H, NH2), 7.23–7.29 (m, 5H, Ar─H). 13C-
NMR (DMSO-d6) δ (ppm) = 13.92 (1C, CH3─CH2),
35.85 (1C, CH2Ph), 59.05 (1C, CH2─COO), 61.33 (1C,
CH2─CH3), 126.73 (1CH, CAr), 128.27 (2CH, CAr),
128.81 (2CH, CAr), 135.87 (1C, CAr), 145.78,147.15 (1C,
C6), 147.15 (1C, C3), 166.53 (1C, C═O), 168.68 (1C,
COO─). MS (EI, 70 eV) m/z (%) = 321 (M+ + 1, 1.0),
320 (2.7), 260 (1.0), 244 (1.0), 218 (4.6), 117 (16.1), 116
(24.3), 105 (61.8), 104 (27.2), 103 (31.4), 91 (100.0), 88
(4.4), 87 (2.1), 78 (12.3), 77 (82.7), 74 (3.3), 73 (2.3), 68
(15.5), 62 (15.6), 61 (5.7), 58 (11.3), 55 (12.4), 53 (6.5),
51 (23.3), 50 (11.7), 45 (18.7), 43 (42.9). Elemental
analysis: found: C, 52.46; H, 5.00; N, 17.51%. Calcd for
C14H16N4O3S (320.09): C, 52.49; H, 5.03; N, 17.49%.
N-(6-benzyl-3-mercapto-5-oxo-1,2,4-triazin-4(3H)-yl)
acetamide (14).
Method a.
A warm solution of
cyanoacetic acid (2 g, 2.14 mmol) in acetic anhydride
(2 mL) was left at 50°C for 5 min, followed by the
addition of triazine
3 (0.5 g, 2.14 mmol). The
temperature of the reaction mixture was raised to 85°C
and left for 2 h. The precipitate, which formed on hot,
was separated by filtration, washed with hot
ethanol (10 mL, threefold), and recrystallized in DMF to
afford 14.
Method b. A mixture of triazine 3 (0.5 g, 2.14 mmol),
acetic anhydride (2 mL), and acetic acid (2 mL) was
refluxed for 2 h over a water bath. The precipitate, which
formed on hot, was separated by filtration, washed with
hot ethanol (10 mL, threefold), and recrystallized in DMF
to afford 14.
White crystals (0.54 g, 92%); m.p 230–232°C. Rf = 0.15
[pet. ether/ethyl acetate (4:1)]. IR (KBr): ν/cmꢀ1 = 3227
1
(NH), 1717 (C═O), 1686 (C═O amide), 1174 (C═S). H-
NMR (DMSO-d6) δ (ppm) = 1.99 (s, 3H, CH3), 3.89 (s,
2H, CH2─Ph), 7.23–7.33 (m, 5H, H─Ar), 10.94 (s, 1H,
NH─C═O), 13.79 (s, 1H, NHtriazine). MS (EI, 70 eV) m/z
(%) = 277 (M+ + 1, 33.9), 260 (1.4), 242 (4.5), 235 (76.8),
218 (2.7), 217 (11.5), 188 (7.5), 175 (4.6), 160 (6.5), 145
(7.6), 130 (57.53), 117 (15.2), 102 (20.6), 91 (100.0), 76
(41.1), 59 (84.9), 52 (8.3), 50 (57.6). Elemental analysis:
found: C, 52.14; H, 4.35; N, 20.30%. Calcd for
C12H12N4O2S (276.31): C, 52.16; H, 4.38; N, 20.28%.
Formation of hydrazinyl-1,2,4-triazine derivatives 12 and
13. A solution of compound 10b (0.46 g, 1 mmol) in
ethanol (50 mL) and hydrazine hydrate 98% (0.2 mL,
4 mmol) was added. The reaction mixture was refluxed
for 1 h. The precipitate, which formed on hot, was
separated by filtration and recrystallized to afford 12, and
the filtrate was cooled to afford 13.
3-Benzyl-7-hydrazinyl-4H,8H-1,2,4-triazino[3,4-b]1,3,4-
3,30-((Diselanediylbis(4,1-phenylene))bis(azanediyl))bis(4-
thiadiazin-4-one (12).
Pale yellow (0.24 g, 35%); m.p
295–297°C. [DMF:EtOH (2:1)]. Rf 0.33 [pet.
ether/ethyl acetate (4:3)]. IR (KBr): ν/cmꢀ1 = 3330, 3282
=
amino-6-benzyl-1,2,4-triazin-5(4H)-one (15). A mixture of
triazine
3
(0.5 g, 2.14 mmol) and 4,40-
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W. S. Hamama, G. G. El-Bana, M. E.-H. Mostafa, and H. H. Zoorob
Vol 000
diselanediyldianiline (1.5 g, 4.28 mmol) in DMF was
refluxed for 30 h, cooled, and poured onto crushed ice.
The obtained solid was filtered off, washed with hot
ethanol (10 mL, threefold), and recrystallized in EtOH–
DMF (1:2) to afford 15.
Brown powder (0.37 g, 23%); m.p >300°C. Rf = 0.21
[ethyl acetate/pet. ether (60:80) (4:2.5)]. IR (KBr):
ν/cmꢀ1 = 3339, 3305 (NH2), 3212 (NH), 1669 (C═O
amide). 1H-NMR (DMSO-d6) δ (ppm) = 3.90 (s, 2H,
CH2─Ph), 5.35 (s, 4H, 2NH2), 7.11–7.53 (m, 18H,
H─Ar), 8.28 (s, 2H, 2NH). MS (EI, 70 eV) m/z
(%) = 746 (M+ + 2, 1.0), 451 (1.0), 371 (1.0), 159 (24.7),
157 (29.0), 155 (28.0), 130 (16.8), 116 (41.7), 103
(17.3), 91 (31.2). 76 (100.0), 53 (9.3), 50 (61.8).
Elemental analysis: found: C, 51.73; H, 3.83; N, 18.84%.
Calcd for C32H28N10O2Se2 (744.07): C, 51.76; H, 3.80;
N, 18.86%.
found: C, 64.95; H, 4.12; N, 14.40%. Calcd for
C21H16N4O2S (388.10): C, 64.93; H, 4.15; N, 14.42%.
Synthesis of S-alkyl triazines 17–20. General procedure for
synthesis of compounds 17 and 18. Method a.
Triazine 16a
(2.14 mmol) was dissolved in cold methanolic sodium
methoxide solution [prepared from sodium metal (0.23 g,
10 mmol) and 10-mL methanol], and then either methyl
iodide (0.13 mL, 2.14 mmol) or ethyl bromoacetate (0.24,
2.14 mmol) was added. The reaction mixture was stirred at
room temperature. The precipitate obtained was collected
by filtration, washed with water, and dried at room
temperature to give 17 and 18.
Method b.
A mixture of triazine 16a (2.14 mmol),
methyl iodide (0.13 mL, 2.14 mmol), or ethyl bromoacetate
(0.24, 2.14 mmol), in EtOH–DMF mixture (1:1) (10 mL)
in the presence of either fused sodium acetate (0.3 g,
3.21 mmol) or Et3N (0.45 mL, 3.21 mmol), was stirred at
room temperature. The reaction mixture was monitored by
TLC and then poured into cold water. The precipitate that
formed was filtered off, washed with water (10 mL), and
dried at room temperature to give 17 and 18.
Preparation
of
Schiff’s
bases
16a,b. General
procedure. A mixture of triazine 3 (0.5 g, 2.14 mmol)
and aldehyde derivatives (2.14 mmol) in either
ethanol/conc. H2SO4 (20 mL:5 drops) or ethanol/HCl
(15 mL:5 mL) was boiled under reflux for 6 or 10 h,
respectively. The precipitate, which formed on hot,
was separated by filtration and recrystallized to afford
16a,b.
6-Benzyl-4-((1,3-diphenyl-1H-pyrazol-4-yl)methyleneamino)-
3-(methylthio)-1,2,4-triazin-5(4H)-one (17). White powder
(0.88 g, 86%); m.p 228–230°C. [Ethanol]. Rf = 0.26 [pet.
ether/ethyl acetate (4:1)]. IR (KBr): ν/cmꢀ1 = 1668 (C═O
amide). 1H-NMR (DMSO-d6) δ (ppm) = 2.61 (s, 3H,
CH3), 4.17 (s, 2H, CH2─Ph), 7.27–7.85 (m, 15H,
H─Ar), 8.64 (s, 1H, CHpyrazole), 9.11 (s, 1H, ═CH). MS
(EI, 70 eV) m/z (%) = 478 (M+, 1.3), 463 (1.9), 362
(1.1), 349 (1.0), 322 (1.1), 259 (3.5), 245 (100.0), 233
(32.7), 217 (7.8), 203 (3.2), 186 (1.7), 165 (1.9), 155
(7.3), 131 (25.6), 117 (18.6), 104 (16.9), 91(14.2), 52
(12.4), 47 (6.2). Elemental analysis: found: C, 67.79; H,
4.95; N, 17.53%. Calcd for C27H22N6OS (478.16): C,
67.76; H, 4.63; N, 17.56%.
6-Benzyl-4-((1,3-diphenyl-1H-pyrazol-4-yl)methyleneamino)-
3-mercapto-1,2,4-triazin-5(4H)-one (16a).
The aldehyde
used was 1,3-diphenyl-1H-pyrazole-4-carbaldehyde.
Yellow powder (0.84 g, 85%); m.p 215–217°C.
[Toluene]. Rf = 0.4 [pet. ether (60:80)/ethyl acetate (4:1)].
1
IR (KBr): ν/cmꢀ1 = 1699 (C═O amide), 1177 (C═S). H-
NMR (DMSO-d6) δ (ppm) = 3.91 (s, 2H, CH2─Ph), 7.29–
8.05 (m, 15H, H─Ar), 8.67 (s, 1H, CHpyrazole), 8.26 (s,
1H, ═CH), 13.73 (s, 1H, NH, D2O exchangeable). MS
(EI, 70 eV) m/z (%) = 464 (M+, 2.1), 433 (2.1), 378 (2.6),
328 (2.1), 287 (2.9), 261 (2.1), 246 (71.7), 245 (18.1), 219
(21.6), 217 (8.3), 187 (7.5), 168 (3.6), 141 (11.0), 132
(3.5), 127 (2.3), 117 (19.3), 104 (18.4), 91 (20.2), 77
(100.0), 76 (18.2), 52 (17.1), 50 (23.9). Elemental
analysis: found: C, 67.20; H, 4.32; N, 18.07%. Calcd for
C26H20N6OS (464.14): C, 67.22; H, 4.34; N, 18.09%.
6-Benzyl-4-((2-hydroxynaphthalen-1-yl)methyleneamino)-
Ethyl-2-(6-benzyl-4-((1,3-diphenyl-1H-pyrazol-4-yl)
methyleneamino)-5-oxo-4,5-dihydro-1,2,4-triazin-3-ylthio)
acetate (18). White powder (1 g, 85%); m.p 183–184°C.
[Ethanol]. Rf = 0.37 [pet. ether/ethyl acetate (4:1)]. IR
1
(KBr): ν/cmꢀ1 = 1740 (OC═O), 1680 (C═O amide). H-
NMR (CDCl3) δ (ppm) = 1.20 (t, 3H, CH3), 3.78 (s, 2H,
CH2─Ph), 4.01 (s, 2H, CH2), 4.11 (q, 2H, CH2─CH3),
7.25–7.95 (m, 15H, H─Ar), 9.10 (s, 1H, CHpyrazole), 9.13
(s, 1H, ═CH). MS (EI, 70 eV) m/z (%) = 550 (M+, 2.8),
120 (2.8), 117 (7.8), 94 (2.2), 91 (11.7), 87 (2.2), 78
(13.4), 76 (6.1), 52 (12.8), 50 (8.4). Elemental analysis:
found: C, 65.41; H, 4.79; N, 15.24%. Calcd for
C30H26N6O3S (550.18): C, 65.44; H, 4.76; N, 15.26%.
3-mercapto-1,2,4-triazin-5(4H)-one (16b).
The aldehyde
used was 2-hydroxy-1-naphthaldehyde.
Yellow powder (0.69 g, 83%); m.p 250–253°C.
[Ethanol]. Rf = 0.4 [pet. ether/ethyl acetate (4:1.5)]. IR
(KBr): ν/cmꢀ1 = 3143 (OH), 1690 (C═O amide), 1176
(C═S). 1H-NMR (DMSO-d6) δ (ppm) = 3.96 (s, 2H,
CH2─Ph), 7.29–8.69 (m, 11H, H─Ar), 9.54 (s, 1H,
═CH), 11.70 (s, 1H, OH), 13.84 (s, 1H, NH). MS (EI,
70 eV) m/z (%) = 388 (M+, 17.9), 334 (1.0), 220 (17.6),
219 (59.1), 201 (1.2), 186 (2.3), 170 (21.8), 169 (100.0),
148 (2.5), 140 (28.3), 127 (13.4), 117 (14.1), 114 (42.7),
91 (72.6), 76 (6.5), 53 (1.6), 51 (4.2). Elemental analysis:
General procedure for synthesis of compounds 19 and 20.
6-Benzyl-4-((1,3-diphenyl-1H-pyrazol-4-yl)methyleneamino)-
3-(prop-1-enylthio)-1,2,4-triazin-5(4H)-one (19). A mixture
of triazine 16a (0.5 g, 2.14 mmol), allyl bromide (0.2 mL,
2.14 mmol), or 1,2-bis (bromomethyl) benzene (0.6 g,
2.14 mmol) and Et3N (0.45 mL, 3.21 mmol) in EtOH–
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis and Acaricidal Activity of Some New 1,2,4-Triazine Derivatives
DMF mixture (1:1) (10 mL) was stirred at room temperature
for 5 min for allylbromide and overnight for 1,2-
bis(bromomethyl)benzene. The reaction mixture was poured
into cold water; the precipitate that formed was filtered,
washed with water, dried, and recrystallized to afford 19 and
20, respectively, whereas, repeating the same reaction, but
using fused sodium acetate instead of Et3N or in cold
methanolic sodium methoxide solution, no reaction occurred.
White powder (1.3 g, 83%); m.p 177–178°C. [Ethanol].
Rf = 0.4 [pet. ether/ethyl acetate (4:1)]. IR (KBr):
ν/cmꢀ1 = 1674 (C═O amide). 1H-NMR (CDCl3) δ
(ppm) = 3.89 (d, 2H, S─CH2═CH), 4.21 (s, 2H,
CH2─Ph), 5.08 (dd, 2H, CH2═CH), 6.02 (m, H, CH),
7.27–7.84 (m, 15H, H─Ar), 8.63 (s, 1H, CHpyrazole), 9.09
(s, 1H, ═CH). MS (EI, 70 eV) m/z (%) = 505 (M+ + 1,
4.2), 259 (17.0), 246 (35.1), 245 (92.0), 244 (85.6), 150
(14.4), 142 (18.6), 127 (13.8), 117 (11.7), 115 (17.6),
114 (21.3), 104 (21.3), 94 (4.7), 91 (38.8), 77 (100.0), 52
(13.3), 50 (39.4). Elemental analysis: found: C, 69.06; H,
4.77; N, 16.68%. Calcd for C29H24N6OS (504.17): C,
69.03; H, 4.79; N, 16.65%.
replicated three times, in addition, to control and were
left under laboratory condition. Controls were dipped in
the solvent mixture minus the tested extract. Mortality
was taken after 24 and 72 h of exposure [24].
Ten adults females of T. urticae were transferred from the
sensitive laboratory culture to castor oil leaf discs (3 cm in
diameter), placed on moist cotton wool pads in petri-dishes.
Adult females were removed after 24 h, as it deposits their
eggs of 1 day old. The toxic effect of tested compounds
was evaluated by dipping these castor oil leaf discs in a
series of diluted concentrations for 10 s. Discs with the
same age of eggs were dipped in the emulsion mixture
minus the tested extracts as a control. Three replicates of
leaf discs for each concentration as well as control were
used. Discs with treated eggs were placed onto pads of wet
cotton in petri-dishes and kept under laboratory conditions
until hatching (25°C 2°C and 60% 5% R.H). After
complete hatching of control eggs, the number of
unhatched eggs of different concentrations was counted,
and the percentage of unhatchability was determined [26].
3,30-((1,2-Phenylenebis(methylene))bis(sulfanediyl))bis(6-
benzyl-4-(((1,3-diphenyl-1H-pyrazol-4-yl)methylene)amino)-
1,2,4-triazin-5(4H)-one) (20). White powder (2.2 g, 73%);
STATISTICAL ANALYSIS
m.p 165–167°C. [Ethyl acetate]. Rf = 0.15 [pet. ether
Mortality was recorded for adult females after 24 and 72 h
of treatment and for eggs after complete hatching of control
eggs. This mortality was corrected according to Abbott’s
formula [27] and statistically analyzed to estimate LC50,
LC90, and slope values utilizing LDP line probit analysis
program version 1.0 according to Finney [28].
(60:80)/ethyl acetate (4:1)]. IR (KBr): ν/cmꢀ1 = 1678
1
(C═O amide). H-NMR (CDCl3) δ (ppm) = 4.15 (s, 2H,
CH2─Ph), 4.64 (s, 2H, CH2─S), 7.18–7.76 (m, 15H,
H─Ar), 8.51 (s, 1H, CHpyrazole), 9.06 (s, 1H, ═CH).
Elemental analysis: found: C, 69.91; H, 4.47; N, 16.00%.
Calcd for C60H46N12O2S2 (1030.33): C, 69.88; H, 4.50; N,
16.30%.
Acaricidal activity assay. Test pest.
Two-spotted
Acknowledgments. The authors are indebted to Chemistry
Department, Faculty of Science Mansoura University for all
support and the facilities provided.
spider mite, T. urticae (Koch), colonies were laboratory
reared by the same procedure previously described by
Dittrich [24]. A pure culture of the spider mite was
maintained on castor oil leaf plants under laboratory
REFERENCES AND NOTES
conditions (25°C
Protection Research Institute branch, Dakahlia Governorate.
Laboratory
2°C and 60%
5% R.H) at Plant
[1] (a) Hamama, W. S.; El-Bana, G. G.; Shaaban, S.; Zoorob, H.
H. J Heterocyclic Chem 2018, 55, 971; (b) Hamama, W. S.; El-Bana,
G. G.; Shaaban, S.; Habib, O. M. O.; Zoorob, H. H. J Heterocyclic Chem
2017, 54, 422; (c) Hamama, W. S.; El-Bana, G. G.; Shaaban, S.; Habib,
O. M. O.; Zoorob, H. H. RSC Adv 2016, 6, 24010.
[2] Diana, P.; Barraja, P.; Lauria, A.; Montalbano, A.; Almerico, A.
M.; Dattolo, G.; Cirrincione, G. Eur J Med Chem 2002, 37, 267.
[3] Ashok, M.; Holla, B. S. Phosphorus Sulfur Silicon Relat Elem
2007, 182, 981.
[4] Kim, M.; Sim, C.; Shin, D.; Suh, E.; Cho, K. Crop Prot 2006,
25, 542.
[5] Yanar, D.; Kadiolu, I.; Gökçe, A. Afr J Biotechnol 2011, 10,
11745.
Assessment
of
acaricidal
activity.
experiments are conducted to evaluate the acaricidal
activity of tested 1,2,4-triazine derivatives against eggs and
adult females of T. urticae using the leaf-dip technique [25].
All tested compounds were formulated as an emulsion in
water containing 0.3% triton X-100 and 5% ethanol as
solvent [22]. The emulsions were used immediately after
preparation to minimize any decomposition. Serial five
concentrations of each compound were prepared for each
tested stage.
Castor oil leaf discs (2-cm diameter) were dipped in each
concentration for 10 s and left to dry. Discs were placed
onto cotton wool pads in petri-dishes (12 cm in
diameter). Ten T. urticae individuals of the same age
were transferred to treated castor oil leaf disc, which was
[6] Schmidt-Jeffris, R. A.; Beers, E. H. Crop Prot 2018, 103, 56.
[7] Seliman, L. E. M.; Hamedy, A. A. Egy J Plant Pro Res 2015,
3, 50.
[8] Hegde, J. C.; Girisha, K. S.; Dhikari, A. A.; Kalluraya, B. Eur J
Med Chem 2008, 43, 2831.
[9] Holla, B. S.; Gonsalves, R.; Sarojini, B. K. Indian J Chem B
1997, 36, 943.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

W. S. Hamama, G. G. El-Bana, M. E.-H. Mostafa, and H. H. Zoorob
Vol 000
[10] Agarwal, A.; Srivastava, K.; Puri, S. K.; Chauhan, P. M. S.
Bioorg Med Chem Lett 2005, 15, 531.
[11] Khan, I.; Zaib, S.; Ibrar, A.; Rama, N. H.; Simpson, J.; Iqbal, J.
Eur J Med Chem 2014, 78, 167.
[21] Ashour, H. M.; El-Wakil, M. H.; Khalil, M. A.; Ismail, K. A.;
Labouta, I. M. Med Chem Res 2013, 22, 1909.
[22] Ibrahim, Y. B.; Knowles, C. O. J Econ Entomol 1986,
79, 7.
[12] Kuo, G. H.; DeAngelis, A.; Emanuel, S.; Wang, A.; Zhang, Y.;
Connolly, P. J.; Chen, X.; Gruninger, R. H.; Rugg, C.; Fuentes-Pesquera,
A.; Middleton, S. A.; Jolliffe, L.; Murray, W. V. J Med Chem 2005, 48, 4535.
[13] Srinivas, K.; Srinivas, U.; Bhanuprakash, K.; Harakishore, K.;
Murthy, U. S. N.; Rao, V. J. Eur J Med Chem 2006, 41, 1240.
[14] McKay, G. A.; Reddy, R.; Arhin, F.; Belley, A.; Lehoux, D.;
Moeck, G.; Sarmiento, I.; Parr, T. R.; Gros, P.; Pelletier, J.; Far, A. R.
Bioorg Med Chem Lett 2006, 16, 1286.
[23] EL Massry, A. M.; Asal, A. M.; Khattab, S. N.; Haiba, N. S.;
Awney, H. A.; Helmy, M.; Langer, V.; Amer, A. Bioorg Med Chem
2012, 20, 2624.
[24] Dittrich, V. J Econ Entomol 1962, 55, 644.
[25] Siegler, E. H. J Econ Entomol 1947, 40, 441.
[26] Afifi, A. M.; Ibrahim, G. A.; El Safty, A. F. A. 1st, Int Conf of
Pest Control, Mansoura, Egypt 1995, 461.
[27] Abbott, W. J Econ Entomol 1925, 18, 265.
[28] Finney, D. J. Probit Analysis. A Statistical Treatment of the
Sigmoid Response Curve 7th Edition; Cambridge University Press: Cam-
bridge, 1971.
[15] Molina, P.; Alajarin, M.; Benzal, R. Synthesis 1983, 9, 759.
[16] Holla, B. S.; Shivananda, M. K.; Veerendra, B. Indian J Chem
2002, 41B, 2690.
[17] Ibrahim, Y. A.; Al-Awadi, N. A.; John, E. Tetrahedron 2008,
64, 10365.
[18] (a) Khalil, N. S. A. M.; Abdel Kader, M.; Eid, M. M. Nucleo-
sides Nucleotides Nucleic Acids 2004, 23, 1889; (b) Hamama, W. S.; Waly,
M. A.; EL-Hawary, I. I.; Zoorob, H. H. J Heterocyclic Chem 2016, 53, 953.
[19] Hamama, W. S.; Waly, M. A.; EL-Hawary, I. I.; Zoorob Syn-
thetic Communications1 2014, 44, 1.
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
[20] Al-Etaibi, A.; John, E.; Ibrahim, M. R.; Al-Awadi, N. A.;
Ibrahim, Y. A. Tetrahedron 2011, 67, 6259.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet