Synthesis and antivirus activity of 1,3,5-triazine derivatives

Article abstract of DOI:10.1002/hc.10189

Reaction of 6-phenyl-4-thioxo-1,3,5-triazine-2-one with alkyl halide in the presence of 1 equiv. of sodium hydroxide resulted in 4-alkylthio-6-phenyl-1,3,5-triazine-2-one in good yield, whereas the above reaction provided 2-alkoxyl-4-alkylthio-6-phenyl-1,3,5-triazine in the presence of 2 equiv. of sodium hydroxide. 6-Phenyl-4-thioxo-1,3,5-triazine-2-one was oxidized with hydrogen peroxide to give 6-phenyl-1,3,5-triazine-2,4-dione. Further treatment with ethyl bromoacetate or (substituted) benzyl bromides yielded 2,4-dialkoxy-6-phenyl-1,3,5-triazines. At the same time, a small amount of 2-dimethylamino-4-alkoxy-6-phenyl-1,3,5-triazine were isolated. Preliminary bioassays indicate that the title compounds possess good activities against tobacco mosaic virus.

Full text of DOI:10.1002/hc.10189

Heteroatom Chemistry
Volume 14, Number 6, 2003
S
ynthesis and Antivirus Activity
of 1,3,5-Triazine Derivatives
Qingmin Wang, Gang Liu, Ruilian Shao, and Runqiu Huang
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic
Chemistry, Nankai University, Tianjin 300071, People’s Republic of China
Received 27 March 2003; revised 4 April 2003
these plant virucides. They have very low solu-
ABSTRACT: Reaction of 6-phenyl-4-thioxo-1,3,5-
bility in water and limited solubility in common
solvents, and so application of such triazines in
water and as emulsible concentrates is not ordi-
narily feasible. Therefore, the discovery of new
derivatives of 1,3,5-triazine, which might show
similar or enhanced biological activity and possess
favorable characteristics, could be significant.
We designed and synthesized novel 1,3,5-triazine
derivatives.
triazine-2-one with alkyl halide in the presence of 1
equiv. of sodium hydroxide resulted in 4-alkylthio-
6-phenyl-1,3,5-triazine-2-one in good yield, whereas
the above reaction provided 2-alkoxyl-4-alkylthio-6-
phenyl-1,3,5-triazine in the presence of 2 equiv. of
sodium hydroxide. 6-Phenyl-4-thioxo-1,3,5-triazine-2-
one was oxidized with hydrogen peroxide to give
6-phenyl-1,3,5-triazine-2,4-dione. Further treatment
with ethyl bromoacetate or (substituted) benzyl bro-
mides yielded 2,4-dialkoxy-6-phenyl-1,3,5-triazines. At
the same time, a small amount of 2-dimethylamino-
RESULTS AND DISCUSSION
4-alkoxy-6-phenyl-1,3,5-triazines were isolated. Pre-
liminary bioassays indicate that the title compounds
possess good activities against tobacco mosaic virus.
1-Benzoyl-2-thiobiuret (1) was treated with sodium
hydroxide to obtain 6-phenyl-4-thioxo-1,3,5-
triazine-2-one (2) in 75.2% yield. Then 2 was
oxidized with hydrogen peroxide to give 6-phenyl-
1,3,5-triazine-2,4-dione (3) in 98.8% yield, as shown
in Scheme 1.
ꢀ
C
2003 Wiley Periodicals, Inc. Heteroatom Chem 14:542–
45, 2003; Published online in Wiley InterScience
5
(
www.interscience.wiley.com). DOI 10.1002/hc.10189
Reaction of 2 with alkyl halides resulted in 4-
alkylthio-6-phenyl-1,3,5-triazine-2-ones (4) in good
yields as shown in Scheme 2 and Tables 1 and
2. Products 4a–i were all white solids, and their
INTRODUCTION
,3,5-Triazines have attracted attention because
of their marked antivirus activities [1–4]. 2,4-
Dioxohexahydro-1,3,5-triazine (DHT) and 1,5-
diacetyl-2,4-dioxohexahydro-1,3,5-triazine (DADHT)
have been commercialized as plant virucides
1
1
structures were confirmed by H NMR, IR spec-
troscopy, mass spectroscopy, and elemental analysis.
1
The physical constants and H NMR data of 4a–i are
listed in Tables 1 and 2. All absorption bands in IR
[
5–8]. However, there is a major difficulty in using
of 4h appear as expected. 1691.0, 1682.2, and 1663.9
−
1
cm (s) correspond to C O and C N stretching ab-
sorption bands. The EI-MS of 4h gives the molecu-
lar ion peak (353.20, M) and those of the main frag-
ments.
However, in the presence of 2 equiv. of sodium
hydroxide, the reaction with ethyl bromoacetate
Correspondence to: Runqiu Huang; e-mail: wang98h@263.net.
Contract grant sponsor: National Natural Science Foundation
of China.
Contract grant number: 20002003.
ꢀ
c 2003 Wiley Periodicals, Inc.
5
42

Synthesis and Antivirus Activity of 1,3,5-Triazine Derivatives 543
Ph
N
O
S
H
2
Ph
N
O
O
Ph
N
SCH CO C H
2 2 2 5
O
S
O
H2O2
PhCNHCNHCNH2
+
NaOH
2
NaOH
H N
N
H N
N
H
2
BrCH CO C H
2 2 2 5
+
5
N
N
1
3
OCH CO C H
2 2 5
2
SCHEME 1
SCHEME 3
yielded the 2-alkoxyl-4-alkylthio-6-phenyl-1,3,5-
triazine 5 as shown in Scheme 3.
compounds possess good antivirus activities. For
example, at 500 ppm, inhibition rate of compounds
Compound 3 underwent reaction with ethyl
bromoacetate or (substituted) benzyl bromides to
yield 2,4-dialkoxy-6-phenyl-1,3,5-triazines 6. At the
same time, a small amount of 2-dimethylamino-4-
alkoxy-6-phenyl-1,3,5-triazines 7 were isolated as by-
2, 4b, and DHT to TMV is 40, 45, and 45%, respec-
tively. Further studies are under way and will be re-
ported in due course.
products (Scheme 4 and Tables 3 and 4). Compounds
1
6
a–d and 7a–c were identified by IR and H NMR
spectroscopy and EI-MS and elemental analyses. All
EXPERIMENTAL
absorption bands in IR of 6d and 7a appear as ex-
All the melting points were determined with a
Thomas–Hoover melting point apparatus and are
uncorrected. IR spectra were recorded with a
−1
pected. For 6d, 1116.8 and 1064.9 cm (s) corre-
−
1
spond to C O stretching. For 7a, 1065.4 cm (s) cor-
responds to C O stretching. The EI-MS of 6d gives
the molecular ion peaks (459, M) and those of the
main fragments; the EI-MS of the product 7a gives
the molecular ion peak (302.15, M) and those of the
main fragments.
1
Shimadzu-435 spectrometer. H NMR spectra were
recorded with a Bruker AC-P200 instrument, tetram-
ethylsilane being used as internal standards. Ele-
mental analyses were carried out with a Yanaco CHN
Corder MT-3 elemental analyzer. Mass spectra were
recorded with an HP5988A spectrometer using the
EI method.
Molecular structure of compound 7a was
analyzed by X-ray diffraction (Fig. 1). Data
were acquired with a Bruker SMART 1000 CCD
6
-Phenyl-4-thioxo-1,3,5-triazine-2-one (2) was
˚
diffractometer Mo Kα radiation (λ = 0.71073 A),
prepared according to the reported procedure [11].
triclinic, C15
H
18
N
4
˚
O
3
(MW 302.33), space group
˚
˚
P-1, a = 7.977(2) A, b= 10.394(3) A, c= 10.837(3) A,
◦
◦
◦
α = 111.774(5) , β = 104.050(5) , γ = 99.446(5) , µ =
6-Phenyl-1,3,5-triazine-2,4-dione (3)
−
1
˚
3
0
.093 mm , V = 776.6(4) A , z = 2, Dx = 1.293
3
◦
To a stirred mixture of 2 (0.05 mol) and 1 mol/l aque-
ous sodium hydroxide (400 ml) was added drop-
wise a solution of 30% aqueous hydrogen perox-
Mg/m , F (000) = 320, T = 293(2) K, 2.14 ≤ θ ≤
◦
2
5.03 , reflections collected 3225, observed 2718
(
0
I ≥2σ(I)), final
R
factor
R
1
= 0.0582, wR =
2
◦
ide (100 ml) at 0 C. Then the resulting mixture
.1399.
◦
was stirred at 0 C for 15 min and then at room
temperature for 15 min. After completion of the re-
action, 1 mol/l aqueous sulfuric acid was added to
adjust the pH to 7. Finally, a white solid (9.43 g) was
ANTIVIRUS ACTIVITY
◦
Activity against tobacco mosaic virus (TMV) was
tested by the conventional half-leaf method [9,
obtained in 98.8% yield. mp 284–285 C. (Ref. [12],
◦
mp 286–288 C). Anal. Calcd for C
9
H
7
N
3
2
O : C, 57.14;
10]. Preliminary bioassays indicate that these title
H, 3.78; N, 22.22. Found: C, 57.32; H, 3.70; N, 22.19.
Ph
N
OR
Ph
N
N
OR
K CO
2
3
Ph
N
O
SCH R
3
+ BrR
2
DMF
N
N
+
N
N
NaOH
2
XCH R
2
+
7a-c
H N
N
4
a-i
OR
Me
Me
6a-d
SCHEME 2
SCHEME 4

5
44 Wang et al.
TABLE 1 Physical Constants of 4a–i
Found (Calcd)
H
◦
X
R
mp ( C)
Yield (%)
C
N
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
g
h
i
Cl
Br
Br
Cl
Cl
Cl
Cl
Cl
Br
CH CH2
157–158
200–201
190–192
200–202
226–228
228–230
223–224
226–227
193–195
74.2
72.7
59.2
83.2
77.5
76.8
74.7
81.3
69.2
58.75 (58.78)
56.40 (56.47)
58.53 (58.27)
52.21 (52.04)
56.90 (57.06)
59.84 (59.82)
50.75 (49.32)
60.76 (61.19)
53.43 (53.61)
4.30 (4.39)
3.39 (3.53)
3.85 (3.64)
3.00 (2.81)
3.50 (3.36)
3.09 (3.52)
3.24 (2.99)
4.28 (4.25)
4.47 (4.47)
17.20 (17.14)
16.20 (16.47)
12.56 (12.75)
10.78 (10.71)
11.50 (11.75)
11.97 (12.32)
10.25 (10.45)
11.65 (11.84)
14.39 (14.43)
C H -NO -p
6
4
2
C H -Cl-p
6
4
2,4-Cl -C H -CO
2
6 3
4-Cl-C H -CO
6
4
4-F-C H -CO
6
4
4-Br-C H -CO
6 4
4-OCH -C H -CO
3
6 4
CO C H5
2
2
◦
4
-Alkylthio-6-phenyl-1,3,5-triazine-2-ones (4):
in ethanol was added dropwise at 50 C. Following
the addition, the reaction mixture was stirred for 8
General Procedure
◦
h at 50 C, then cooled to room temperature, and fil-
tered to obtain a white solid. The product 5 was chro-
matographed on a silica gel column using a mixture
of petroleum ether (60–90 C) and ethyl acetate as the
eluent to give a while solid (0.86 g) in 45.6% yield. mp
O S: C, 54.11; H,
.04; N, 11.14. Found: C, 54.11; H, 5.00; N, 11.41. H
, J HH = 4.1 Hz), 1.31
, J HH = 4.1 Hz), 4.06 (s, 2H, SCH ), 4.20–
.28 (m, 4H, CO CH ), 4.83 (s, 2H, OCH ), 7.45–8.45
m, 5H, Ph).
To a stirred mixture of 0.5 mol/l aqueous sodium hy-
droxide (30 ml) and ethanol (70 ml) was added 2.
Then a solution of alkyl halide (12 mmol) in ethanol
was added dropwise at 50 C. Following the addition,
the reaction mixture was stirred for 1 h at 50 C, then
cooled to room temperature, and filtered to obtain a
white solid. The product 4 was purified by recrys-
tallization or column chromatography on a silica
gel.
◦
◦
◦
◦
1
47–149 C. Anal. Calcd for C17
H
19
N
3
5
1
5
3
NMR (DMSO) δ 1.25 (t, 3H, CH
3
3
(t, 3H, CH
3
2
4
2
2
2
(
2
-Ethoxycarbonylmethoxy-4-
ethoxycarbonylmethylthio-6-phenyl-1,3,5-
triazine (5)
2,4-Dialkoxy-6-phenyl-1,3,5-triazines (6) and
2-Dimethylamino-4-alkoxy-6-phenyl-1,3,5-
triazines (7): General Procedure
To a stirred mixture of 1 mol/l aqueous sodium hy-
droxide (30 ml) and ethanol (70 ml) was added 2.
Then a solution of ethyl bromoacetate (12 mmol)
Under a nitrogen atmosphere, to a stirred solu-
tion of 3 (5 mmol) and ethyl bromoacetate or
TABLE 2 1H NMR Data of 4a–i
4a
2.90 (d, 2H, CH2 , 3J HH = 8.6 Hz), 5.16–5.40
(
m, 2H, CH ), 5.92–6.12 (m, 1H, CH), 7.56–8.36
2
(
m, 5H, Ph)
4
4
4
4
4
b
c
d
e
f
4.48 (s, 2H, CH2 ), 7.44–8.36 (m, 9H, Ph)
4.44 (s, 2H, CH2 ), 7.34–8.33 (m, 9H, Ph)
4.52 (s, 2H, CH2 ), 7.48–8.24 (m, 8H, Ph)
4.81 (s, 2H, CH2 ), 7.48–8.28 (m, 9H, Ph)
4.82 (s, 2H, CH2 ), 7.36–8.20 (m, 9H, Ph), 12.97
(
br, 1H, NH)
4.88 (s, 2H, CH2 ), 7.45–8.10 (m, 9H, Ph), 12.97
br, 1H, NH)
4
4
g
h
(
3.87 (s, 3H, OCH ), 4.79 (s, 2H, CH ), 7.08–8.08
3
2
(m, 9H, Ph), 13.05 (br, 1H, NH)
3
4i
1.16 (t, 3H, CH , J
= 7.8 Hz), 4.04 (s, 2H, SCH ),
3
HH
2
3
4
.12 (q, 2H, OCH , J
= 7.8 Hz), 7.57–8.21
2
HH
(m, 5H, Ph)
FIGURE 1 Molecular structure of compound 7a.

Synthesis and Antivirus Activity of 1,3,5-Triazine Derivatives 545
TABLE 3 Physical Constants of 6a–d and 7a–c
Found (Calcd)
◦
No
R
mp ( C)
Yield (%)
C
H
N
6a
6b
6c
6d
7a
7b
7c
CH CO C H5
73–74
61.5
56.2
53.7
65.3
5.0
6.2
4.5
56.66 (56.51)
74.62 (74.80)
52.20 (52.37)
60.08 (60.13)
59.26 (59.60)
61.06 (61.54)
65.75 (65.62)
5.11(5.26)
5.40 (5.15)
3.41 (3.22)
4.01 (3.70)
5.44 (5.96)
5.00 (4.84)
6.13 (6.25)
11.75 (11.63)
11.36 (11.38)
7.68 (7.97)
15.31 (15.25)
18.41 (18.54)
19.00 (19.94)
20.81 (21.87)
2
2 2
CH C H5
144–146
110–111
136–138
107–108
116–118
110–111
2
6
CH C H Br-p
2
6 4
CH C H NO -p
2
6
4
2
CH CO C H5
2
2 2
CH C H NO -p
2
6
4
2
CH CH CH2
2
(
substituted) benzyl bromide (12 mmol) in N,N-
obtained free of charge via www.ccdc.cam.ac.uk/
conts/retrieving.html (or from the Cambridge Crys-
tallographic Data Centre, 12, Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44 1223 336033; or
deposit@ccdc.cam.ac.uk).
dimethylformamide (70 ml) was added potassium
carbonate at 50 C. Then the resulting mixture was
stirred at 50 C for 2 h and cooled to room tempera-
◦
◦
ture. Water and toluene were then added. The wa-
ter phase was extracted three times with toluene.
The organic phase was washed with water, and
then dried with anhydrous magnesium sulfate and
filtered. The filtrate was concentrated and chro-
matographed on a silica gel column using a mixture
of petroleum ether (60–90 C) and ethyl acetate as the
eluent. Finally, a white solid 6 and by-product 7 were
obtained.
REFERENCES
[
1] Qu, F. Q.; Xiao, C. H.; Xu, X. J. J Wuhan Univ (Natur
◦
Sci Ed) 1999, 45(2), 143.
[
[
2] Li, Z. G.; Huang, R. Q. Zhiwu Baohu 1999, 3, 37.
3] Schuster, G.; Heinisch, L.; Schulze, W.; Ulbricht, H.;
Willitzer, H. Phytopathol Z 1984, 111(2), 97.
CCDC 208080 contains the supplementary crys-
tallographic data for this paper. These data can be
[4] Esser, G.; Thust, U.; Winter, H.; Kiessling, W.;
Kochmann, W.; Kramer, W.; Schmidt, H.; Steinke,
U.; Steinke, W.; Voigt, D.; Schuster, G. Ger (East) DD
1
986, 233, 482.
TABLE 4 1H NMR Data of 6a–d and 7a–c
[
5] Schuster, G.; Horingklee, W.; Winter, H.; Esser, G.;
Steinke, U.; Kodimann, W.; Kramer, W. Acta Virol
1979, 23, 412.
[6] Schuster, G. J Phytopathol 1991, 132(2), 168.
[7] Kompiak, G. Acta Phytopathol Entomol Hung 1991,
26(1/2), 219.
[8] Schuster, G.; Huber, S. Biochem Physiol Pflanzen
1991, 187, 429.
[9] Chen, N. C. Pesticide’s Bioassay Technique; Press of
Beijing Agriculture University: Beijing, The People’s
Republic of China, 1990; p. 194.
3
6a
1.26 (t, 3H, CH , J
= 7.3 Hz), 4.24 (q, 2H,
3
HH
3
COOCH2 , J
= 7.3 Hz), 4.99 (s, 2H,
HH
OCH COO ), 7.28–8.44 (m, 5H, Ph)
2
6
6
6
b
c
d
5.54 (s, 4H, CH ), 7.34–8.49 (m, 15H, Ph)
2
5.57 (s, 4H, CH ), 7.32–8.62 (m, 13H, Ph)
2
5.14 (s, 4H, CH ), 7.10–8.19 (m, 13H, Ph)
2
3
7a
1.22 (t, 3H, CH , J
= 7.3 Hz), 3.15 (s, 3H, NCH ),
3
HH
3
=
3
3
7
.29 (s, 3H, NCH ), 4.21 (q, 2H, CO CH , J
HH
3
2
2
.3 Hz), 4.88 (s, 2H, OCH ), 7.41–8.42 (m, 5H, Ph)
2
[
10] An, T. Y.; Huang, R. Q.; Yang, Z.; Zhang, D. K.; Li,
7
b
c
3.19 (s, 3H, NCH ), 3.33 (s, 3H, NCH ), 5.38
3 3
G. R.; Yao, Y. C.; Gao, J. Phytochemistry 2001, 58,
(
s, 2H, CH ), 7.44–8.43 (m, 9H, Ph)
2
1
267.
7
3.20 (s, 3H, NCH ), 3.32 (s, 3H, NCH ), 5.23–5.46
3
3
3
[11] Basyoumi, M. N.; El-Khamry, A.-M. Bull Chem Soc
Jpn 1979, 50(1/2), 3728.
12] Joachim, G.; Jorg, N. Chem Ber 1971, 104, 1606.
(
6
m, 2H, CH ), 5.90 (d, 2H, CH , J
.02–6.24 (m, 1H, CH), 7.43–8.45 (m, 5H, Ph)
= 5.3 Hz),
2
2
HH
[