Synthesis of new strobilurin derivatives with modified 1,3,5-triazine moiety

Article abstract of DOI:10.14233/ajchem.2013.14895

A new procedure for the synthesis of a series of strobilurin derivatives is reported. The new compounds bear the 1,3,5-triazine ring structure and can be used as the potential fungicide. All target compounds had been identified by 1H NMR spectrum, IR spectrum and HRMS. The results of antifungal activities showed that all target compounds exhibited antifungal activities against three fungus strains at the concentration 20 μg/mL.

Full text of DOI:10.14233/ajchem.2013.14895

Asian Journal of Chemistry; Vol. 25, No. 16 (2013), 8897-8900
http://dx.doi.org/10.14233/ajchem.2013.14895
Synthesis of New Strobilurin Derivatives with Modified 1,3,5-Triazine Moiety
1
2
1
2
1,*
XIU YANG , YAO-LEI ZHANG , YU-LIANG WANG , TIAN CHEN and JUAN LUO
1College of Chemistry, Sichuan University, Chengdu 610065, P.R. China
2Department of Pathogenic Biology, School of Biomedical Science, Chengdu Medical College, Chengdu 610083, P.R. China
*Corresponding author: Tel: +86 18980715296, E-mail: loyis-luo@163.com
(Received: 3 December 2012;
Accepted: 5 September 2013)
AJC-14075
A new procedure for the synthesis of a series of strobilurin derivatives is reported. The new compounds bear the 1,3,5-triazine ring
structure and can be used as the potential fungicide. All target compounds had been identified by 1H NMR spectrum, IR spectrum and HR-
MS. The results of antifungal activities showed that all target compounds exhibited antifungal activities against three fungus strains at the
concentration 20 µg/mL.
Key Words: Synthesis, Strobilurin derivatives, 1,3,5-Triazine ring, Antifungal activities.
It could be found in the literatures7,8 that the structure of
the strobilurin derivatives was composed of the active group,
INTRODUCTION
Strobilurin A (Fig. 1, 1)1,2, a naturally occurring anti-
biotic, was first isolated from Oudemansiella mucida in 1969.
bridge and side chain. (Fig. 2) Changes in the structure of the
derivatives involved the active group and side chain, the
It was found that its application in agriculture was limited
derivatives with methyl (E)-2-(3-methoxy)acrylate had shown
because of optical instability3. Early 1980s, groups in Syngenta
good fungicidal activity9,10. The derivatives modified in the
side chain were used as high-efficiency and broad-spectrum
and BASF3,4 began to alter the structure of strobilurins. In the
fungicides11-13
.
new designed structure methyl (E)-2-(3-methoxy)acrylate
moiety was retained as active part and benzene ring was used
to replace the unstable polyene moiety, then a series of
strobilurin analogues against fungus with optimum stability
were synthe-sized2-5. Studies showed that the strobilurin
derivatives acted on the respiration process by interrupting
the electron transport6.
bridge structure
O
active group
side chain
OCH3
H3COOC
Fig. 2. Activity structure of the strobilurins
OCH3
H3COOC
Based on these structure-activity relationships, large
numbers of derivatives had been designed and synthesized. As a
result, azoxystrobin (Fig. 1, 2)14 and picoxystrobin (Fig.1, 3)6 were
developed as broad-spectrum fungicides with activity against the
four major groups of plant pathogenic fungus including Asco-
mycetes, Basidiomycetes, Deuteromycetes and Oomycetes. Up to
now, azoxystrobin has been the top sale of fungicide for agric-
ultural use in the world3. Recently Shenyang Chemical Research
Institute reported the new strobilurin analogues enestroburin
(Fig.1, 4) and pyraoxystrobin (Fig.1, 5)2, which exhibited good
fungicidal activity on a wide range of crops15.
Strobilurin A 1
N
N
F
F
N
O
O
O
F H3COOC
CN
OCH3
H3COOC
OCH3
CH3
Azoxystrobin 2
Picoxystrobin 3
O
N
O
N
N
OCH3
H3CO
Cl
H3COOC
COOCH3
Enestroburin 4
Pyraoxystrobin 5
Aiming to obtain potential drug molecules, a series of
compounds with the 1,3,5-triazine ring structure, which has
Cl
Fig. 1. Structure of strobilurins and related derivaties

8898 Yang et al.
Asian J. Chem.
Cl
N
OCH3
N
N
N
N
i
OCH3
Cl
Cl
Cl
N
Cl
1
N
N
iv
H3CO
Cl
N
O
COOH
HO
OCH3
OCH3
ii
iii
H3COOC
O
OCH3
OH
H3COOC
O
4
OCH3
2
Reaction reagents and conditons:
(i) dry CH3OH, NaHCO3, 0 °C, 5 h
3
v
(ii) (CH3CO)2O, trimethyl orthoformate, reflux, 19 h
(iii) Na, CH3OH, N2, 0-5 °C, 3 h
OCH3
N
OCH3
(iv) THF, K2CO3, 40 °C, 7 h
(v) KHSO4, reduce pressure distillation, 1.5 h
(vi) dioxane, K2CO3, 62-110 °C
N
N
N
vi
Cl
N
O
6a: R = 4-tert-butyl-C6H4; 6b: R = 4-cyano-C6H4
6c: R = isoindoline-1,3-dione-5-oxy
6d: R = 2,4-dichloro-C6H4
R
N
O
OCH3
OCH3
H3COOC
6e: R = Pyridine-2-thio; 6f: R = 1-naphthoxy
6g: R = 2-chloro-C6H4; 6h: R = 4-fluoro-C6H4
H3COOC
5
6
Scheme-I: Synthetic route of compound 6a-h
wide range of biological activity and multiple reaction sites,
were designed and synthesized. In addition, phenol with diffe-
rent kinds of substituted groups were introduced to study
whether the groups is useful to bioactivity. The synthetic route
is shown in Scheme-I.
overnight, evaporated under reduced pressure at 10 ºC to afford
a deep red oil, crude yield: 82 %. Compound 3 was used in
the next reaction without further purification.
Synthesis of compound 4: A solution of compound 1
(20 mmol, 4.76 g) in dry THF (20 mL) was added to a suspen-
sion of compound 3 (22 mmol, 3.96 g) and K2CO3 (20 mmol,
2.76 g) in dry THF (30 mL). The reaction mixture was stirred
at 40 ºC for 7 h, then cooled to room temperature and filtered.
The filtrate was evaporated under reduced pressure and the
resulting residue was taken up with dichloromethane (20 mL),
the organic layer was washed with water (10 mL × 3), dried
with anhydrous Na2SO4 and evaporated under reduced pressure
to give the crude product. The crude product was chromato-
graphed on silica gel (petroleum ether: ethyl acetate = 2:1) to
afford a pure product as a yellow solid, yield: 71 %.
EXPERIMENTAL
Melting points were determined with XRC-1 melting
point apparatus without corrected.Analytical TLC was perfor-
med on silica gel GF254 and spots were visualized with ultra-
violet light. IR spectra were recorded on a Perkin-Elemer
16PC-FT spectrometer. Mass spectra were recorded with
Agilent 6210 (DOF-MAS) spectrometer (Agilent Inc., Santa
Clara, CA, USA) using the electrospray ionization (ESI+)
1
method. H NMR spectra were run on a Varian INVOA-400
spectrometer. The reagents were all analytically or chemically
pure. All solvents were dried with anhydrous Na2SO4 and
distillated.
Synthesis of compound 5: A catalytic amount of potas-
sium bisulfate (1 mmol) and compound 4 (10 mmol, 3.63 g)
were distillated at 100 ºC under 5 mm Hg pressure whilst
determined by TLC, then cooled to room temperature, extracted
with CH2Cl2 (20 mL) and filtered. The filtrate was washed
with water (10 mL × 3), dried and concentrated to give the
crude compound 5. Recrystallization from cyclohexane gave
a pale yellow solid, yield: 62 %.
Compound 1 was synthesized according to the literature16;
Compound 2 was synthesized according to the literature17.
Synthesis of compound 3: Metallic sodium (150 mmol,
3.45 g) was added in portions to absolute methanol (100 mL)
in single-necked round bottom flask and the result mixture
was stirred at room temperature until metallic sodium was
dissolved completely, then compound 2 (50 mmol, 8.8 g) in
dry methanol (20 mL) was added dropwise to the suspension
at the atmosphere of nitrogen, the mixture was stirred at 0 ºC
for 5 h and then acidified with ice acetic acid to pH = 6 at
about -15 ºC, diluted with water (120 mL), extracted with
CH2Cl2 (30 mL × 3). The CH2Cl2 layer was combined and
washed with saturated sodium bicarbonate solution (10 mL ×
3) and water (10 mL × 3), dried with anhydrous sodium sulfate
Synthesis of target compounds 6a-h: Compound 5 (1
mmol, 0.34 g) in dry dioxane (10 mL) was added dropwise to
a suspense of substituted phenol (1.1 mmol) and K2CO3 (1.1
mmol, 0.15 g) in dry dioxane (10 mL) with stirring. The
reaction mixture was heated to reflux and maintained for 7 h,
then cooled to room temperature and filtered. The filtrate was
evaporated under reduced pressure to give the crude product.
The crude product was chromatographed using petroleum ether
and ethyl acetate as eluent to afford the target products 6a-h.

Vol. 25, No. 16 (2013)
Synthesis of New Strobilurin Derivatives with Modified 1,3,5-Triazine Moiety 8899
OMe
N
OMe
(C=O), 1635 (C=C), 1558 (Ph), 1363 (C-N), 1256, 1126 (C-
O-C), 765 (C-Cl); HR-MS (ESI+): Calcd. for C21H18N3O6Cl2
[M+H]+: 478.0572, Found: 478.0568.
NC
(H3C)3C
N
N
N
O
N
N
O
O
N
O
OMe
OMe
(E)-methyl 2-{2-[4-methoxy-6-(pyridin-2-ylthio)-1,3,5-
triazin-2-yloxy]phenyl}-3-methoxyacrylate (6e): Yellow
1
solid; yield: 76 %; m.p.: 48-50 ºC; H NMR (400 MHz; d1-
MeOOC
6b
MeOOC
OMe
6a
OMe
O
Cl
N
N
N
HN
CDCl3; TMS): δ (ppm): 8.55 (d, 1H, J = 8.0 Hz, Py-H), 7.66
(d, 1H, J = 8.0 Hz, Py-H), 7.54~7.50 (m, 1H, Py-H), 7.46 (s,
1H, C=C-H), 7.30~7.20 (m, 4H, Ar-H), 7.12-7.09 (m, 1H,
Ar-H), 3.89 (s, 3H, CH3), 3.74 (s, 3H, CH3), 3.61 (s, 3H, CH3);
IR (KBr, cm-1) 2947 (C=C-H), 1709 (C=O), 1635 (C=C), 1546
(Ph), 1352 (C-N), 1128 (C-O-C); HR-MS (ESI+): Calcd. for
C20H19N4O5S [M+H]+: 427.1076, Found: 427.1078.
O
N
O
O
N
O
O
OMe
Cl
OMe
MeOOC
OMe
6d
6c
MeOOC
OMe
N
N
N
N
N
S
N
O
O
N
O
OMe
OMe
MeOOC
MeOOC
6f
6e
(E)-methyl 2-{2-[4-methoxy-6-(naphthalen-1-yloxy)-
1,3,5-triazin-2-yloxy]phenyl}-3-methoxyacrylate (6f):
OMe
OMe
N
F
N
N
1
White solid; yield: 64 %; m.p.: 146-148 ºC; H NMR (400
N
O
N
O
O
N
O
MHz; d1-CDCl3; TMS): δ (ppm): 7.89~7.86 (m, 2H, Ar-H),
7.76 (d, 1H, J = 8.0 Hz, Ar-H), 7.52~7.43 (m, 4H, Ar-H, C=C-
H), 7.32~7.22 (m, 4H, Ar-H), 7.16 (d, 1H, J = 8.0 Hz, Ar-H),
3.83 (s, 3H, CH3), 3.67 (s, 3H, CH3), 3.62 (s, 3H, CH3); IR
(KBr, cm-1) 2953 (C=C-H), 1703 (C=O), 1629 (C=C), 1551
(Ph), 1125 (C-O-C), 787 (Ph-H); HR-MS (ESI+): Calcd. for
C25H22N3O6 [M+H]+: 460.1508, Found: 460.1510.
Cl
OMe
OMe
MeOOC
6g
6h
MeOOC
Fig. 3. Structure of the target compounds (6a-6h)
(E)-methyl 2-{2-[4-(4-tert-butylphenoxy)-6-methoxy-
1,3,5-triazin-2-yloxy]phenyl}-3-methoxyacrylate (6a):
1
Yellow solid; yield: 64 %; m.p.: 128-130 ºC; H NMR (400
MHz; d1-CDCl3; TMS): δ (ppm): 7.47 (s, 1H, C=C-H), 7.36
(d, 2H, J = 8.8 Hz, Ar-H), 7.31 (d, 2H, J = 8.0 Hz, Ar-H),
7.25~7.19 (m, 2H, Ar-H), 7.06 (d, 2H, J = 8.8 Hz, Ar-H), 3.90
(s, 3H, CH3), 3.76 (s, 3H, CH3), 3.63 (s, 3H, CH3), 1.32 (s, 9H,
C(CH3)3); IR (KBr, cm-1) 2954 (C=C-H), 1705 (C=O), 1638
(C=C), 1564 (Ph), 1377 (C-N), 1216 [C(CH3)3], 1119 (C-O-
C),817 (Ph-H); HR-MS (ESI+): Calcd. for C25H28N3O6 [M+H]+:
466.1978, Found: 466.1976.
(E)-methyl 2-{2-[4-(2-chlorophenoxy)-6-methoxy-
1,3,5-triazin-2-yloxy]phenyl}-3-methoxyacrylate (6g):
1
White solid; yield: 57 %; m.p.: 106-108 ºC; H NMR (400
MHz; d1-CDCl3; TMS): δ (ppm): 7.48~7.33 (m, 2H, Ar-H,
C=C-H), 7.39~7.29 (m, 3H, Ar-H), 7.28~7.25 (m, 2H, Ar-H),
7.23~7.14 (m, 2H,Ar-H), 3.90 (s, 3H, CH3), 3.75 (s, 3H, CH3),
3.63 (s, 3H, CH3); IR (KBr, cm-1) 2951 (C=C-H), 1711 (C=O),
1634 (C=C), 1564 (Ph), 1120 (C-O-C), 812 (Ph-H), 767 (C-
Cl); HR-MS (ESI+): Calcd. for C21H19N3O6Cl [M+H]+:
444.0962, Found: 444.0967.
(E)-methyl 2-{2-[4-(4-cyanophenoxy)-6-methoxy-
1,3,5-triazin-2-yloxy]phenyl}-3-methoxyacrylate (6b):
1
Yellow solid; yield: 50 %; m.p.: 106-108 ºC; H NMR(400
(E)-methyl 2-{2-[4-(4-fluorophenoxy)-6-methoxy-
1,3,5-triazin-2-yloxy]phenyl}-3-methoxyacrylate (6h):
1
Yellow solid; yield: 52 %; m.p.: 130-132 ºC; H NMR (400
MHz; d1-CDCl3; TMS): δ (ppm): 7.67 (d, 2H, J = 8.4 Hz,
Ar-H), 7.47 (s, 1H, C=C-H), 7.36~7.26 (m, 5H, Ar-H), 7.19
(d, 1H, J = 8.0 Hz, Ar-H), 3.92 (s, 3H, CH3), 3.77 (s, 3H,
CH3), 3.62 (s, 3H, CH3); IR (KBr, cm-1) 3053 (Ar-H), 2953
(C=C-H), 2231 (CN), 1707 (C=O), 1639 (C=C), 1577 (Ph),
1216, 1078 (C-O-C); HR-MS (ESI+): Calcd. for C22H19N4O6
[M+H]+: 435.1304, Found: 435.1305.
MHz; d1-CDCl3; TMS): δ (ppm): 7.46 (s, 1H, C=C-H),
7.35~7.27 (m, 3H, Ar-H), 7.18 (d, 1H, J = 8.0 Hz, Ar-H),
7.13~7.02 (m, 4H,Ar-H), 3.89 (s, 3H, CH3), 3.76 (s, 3H, CH3),
3.62 (s, 3H, CH3); IR (KBr, cm-1) 2950 (C=C-H), 1710 (C=O),
1633 (C=C), 1570 (Ph), 1252 (Ph-O-C), 1123 (C-O-C), 1054
(C-F), 810 (Ph-H); HR-MS (ESI+): Calcd. for C21H19N3O6F
[M+H]+: 428.1258, Found: 428.1261.
(E)-methyl 2-{2-[4-(isoin-1,3-dione5-hydroxyl)-6-
methoxy-1,3,5-triazin-2-yloxy]phenyl}-3-methoxyacrylate
(6c): Yellow solid; yield: 52 %; m.p.: 192-194 ºC; 1H NMR
(400 MHz; d1-CDCl3; TMS): δ (ppm): 7.80 (d, 1H, J = 8.0 Hz,
Ar-H), 7.70 (s, 1H, NH), 7.54~7.49 (m, 2H, Ar-H), 7.47 (s,
1H, C=C-H), 7.35~7.27 (m, 3H, Ar-H), 7.17 (d, 1H, J = 8.0
Hz, Ar-H), 3.92 (s, 3H, CH3), 3.77 (s, 3H, CH3), 3.63 (s, 3H,
CH3); IR (KBr, cm-1) 3268 (N-H), 3071 (Ar-H), 2951 (C=C-
H), 1716 (C=O), 1611 (C=C), 1555 (Ph), 1360 (C-N), 1260,
1124 (C-O-C); HR-MS (ESI+): Calcd. for C23H19N4O8 [M+H]+:
479.1203, Found: 479.1200.
Biological assay: The antifungal activities of the target
compounds in vitro were tested via an Oxford cup method.
Target compounds (1000 µg) were dissolved with DMSO (1
mL) and diluted to 20.0 µg/mL with H2O. A 150 µL solution
of each compound was injected into the corresponding cup in
the potato, dextrose and agar (PDA) culture medium which
was covered with fungus suspension in advance and the plates
were incubated at 37 ºC for 48 h. The results of average dia-
meters of the inhibition zone were listed in Table-1.
(E)-methyl 2-{2-[4-(2,4-dichlorophenoxy)-6-methoxy-
1,3,5-triazin-2-yloxy]phenyl}-3-methoxyacrylate (6d):
Yellow solid; yield: 42 %; m.p.: 74-76 ºC; 1H NMR (400 MHz;
d1-CDCl3; TMS): δ (ppm): 7.47 (s, 1H, C=C-H), 7.34~7.27
(m, 4H, Ar-H), 7.23~7.19 (m, 2H, Ar-H), 7.14 (d, 1H, J = 8.4
Hz, Ar-H), 3.93 (s, 3H, CH3), 3.76 (s, 3H, CH3), 3.63 (s, 3H,
CH3); IR (KBr, cm-1) 3068 (Ar-H), 2950 (C=C-H), 1710
RESULTS AND DISCUSSION
Synthesis: In the synthesis of intermediate 1, three chlo-
rine atoms of cyanuric chloride could be replaced at 0-5 ºC,
30-40 ºC, above 60 ºC. So the temperature was a key factor
and should be controlled below 5 ºC.

8900 Yang et al.
Asian J. Chem.
TABLE-1
in vitro THE ANTIFUNGAL ACTIVITY OF THE TARGET
COMPOUNDS AT THE CONCENTRATION OF 20 µg/mL
intermediate 5 at 60 ºC and without catalyst, but other phenols
at 90 ºC.
2) The reactivity of the phenol with electron donating
group is higher than the ones with electron withdrawing group;
For example, tert-butylphenol, naphthol reacted at 90 ºC, while
the cyano phenol and heterocyclic phenol must react with the
catalyst KI together.
Diameter of inhibition zone (mm)
Magnaporthe
Compound
Aspergillus
Aspergillus
oryzae
niger
11
12
9
10
14
8
grisea
8
6a
6b
6c
6d
6e
6f
6g
8
8
13
8
12
10
11
10
8
3) The steric effects 2,4-dichlorophenol reacted more diffi-
cult than the mono-substituted phenol, which reacted with KI
at 110 ºC.
9
12
10
8
8
8
11
8
6h
DMSOa
Biological activity: The results of antifungal activities
showed that all target compounds exhibited antifungal activities
against three fungus strains (Aspergillus niger, Magnaporthe
grisea and Aspergillus oryzae) at the concentration 20 µg/mL.
7
7
7
aNegative control: DMSO; Diameter of the cup in each plate: 6 mm
The synthesis of intermediate 3 included the transesterifi-
cation reaction and the carbon-carbon double bond addition
reaction. In order to reduce the side products, sodium
methoxide should be freshly prepared and the system should
be protected with nitrogen. In addition, post-processing was
also at low temperatures, the solvent methylene chloride was
distillated below 15 ºC under reduced pressure, or side-prod-
ucts came up.
Conclusion
In summary, a series of novel strobilurin derivatives with
modified 1,3,5-triazine moiety had been designed and synthe-
sized. All target compounds had been identified by 1H NMR
spectrum, IR spectrum and HR-MS (high resolution mass
spectrum). The results of antifungal activities showed that all
target compounds exhibited antifungal activities against three
fungus strains at the concentration 20 µg/mL.
In the synthesis of intermediate 4, compound 3 reacted
with K2CO3 to form potassium salt at room temperature. The
replacing temperature was controlled at 30-40 ºC due to the
unstability of acetal structure of intermediate 3.
ACKNOWLEDGEMENTS
The authors appreciated the financial support from the
National Science Foundation of China (No. 21072135) and
the antifungal activity test of Chengdu Medical College (cx
20100037).
For the synthesis of intermediate 5, double bond was
formed by distillation under reduced pressure with KHSO4 as
catalyst.
In the synthesis of target compounds, taking into account
the reactivity of intermediate 5 and the reaction temperature,
dioxane was the best choice as polar aprotic solvent. In order
to complete the reaction rapidly and decrease by-products,
dioxane should be dried thoroughly and distilled in advance.
The different structures of phenol have different reactivity in
the reaction process, the reaction conditions required are also
different, (Table-2) and reaction rule as follows:
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TABLE-2
REACTION CONDITION OF THE TARGET COMPOUNDS (6a-6h
)
Compound Temperature (ºC) Time (h) Catalyst Yield (%)
90
90
90
110
60
90
90
90
7
7
7
9
5
7
7
7
-
KI
KI
KI
-
64
50
52
42
76
64
57
52
6a
6b
6c
6d
6e
6f
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1) The reactivity of thiophenol was higher than reactivity
of phenol, for example, 2-mercapto pyridine reacted with