Design, synthesis, and biological activity of oxime ether strobilurin derivatives containing indole moiety as novel fungicide

Article abstract of DOI:10.1111/cbdd.12460

Twenty-one novel oxime ether strobilurins containing indole moiety, which employed an indole group to stabilize the E-styryl group in Enoxastrobin, were designed and synthesized. The biological assay indicated that most compounds exhibited potent fungicidal activities. The structure-activity relationship study demonstrated that the synthesized methyl 3-methoxypropenoate oxime ethers 7b-e exhibited remarkably high activities among all the synthesized oxime ether compounds 7. Moreover, the fungicidal activities of methyl α-(methoxyimino)benzeneacetate oxime ethers compounds 7f-i and N-methoxy-carbamic acid methyl esters compounds 7j-m showed significant differences compared to the corresponding products of ammonolysis.

Full text of DOI:10.1111/cbdd.12460

Chem Biol Drug Des 2014
Research Article
Design, Synthesis, and Biological Activity of Oxime
Ether Strobilurin Derivatives Containing Indole Moiety
as Novel Fungicide
E-styryl group in Enoxastrobin, some novel arylcyclopropyl
oxime ether compounds II (Figure 1), which use trans-aryl-
cyclopropyl group to replace E-styryl group in compounds
I, have been reported. These compounds show excellent
fungicidal activities (8). In our previous study, we synthe-
sized a series of novel indene-substituted oxime ethers III
(Figure 1) to study structure–activity relationship of this
type of compound (12,15). Benzopentatomic ring structure
was used to stabilize the E-styryl group in Enoxastrobin.
Fortunately, it was found most of the indene-substituted
oxime ethers III exhibited effective fungicidal activity. More-
over, the fungicidal activities of some compounds III were
better than Enoxastrobin.
Ya-Qiang Xie, Zi-Long Huang, Hui-Dong Yan, Jun
Li, Li-Yi Ye, Li-Ming Che and Song Tu*
Department of Chemical and Biochemical Engineering,
College of Chemistry and Chemical Engineering, Xiamen
University, Xiamen 361005, China
*Corresponding author: Song Tu, tusong@xmu.edu.cn
Twenty-one novel oxime ether strobilurins containing
indole moiety, which employed an indole group to sta-
bilize the E-styryl group in Enoxastrobin, were
designed and synthesized. The biological assay indi-
cated that most compounds exhibited potent fungi-
cidal activities. The structure–activity relationship
study demonstrated that the synthesized methyl
3-methoxypropenoate oxime ethers 7b–e exhibited
remarkably high activities among all the synthesized
oxime ether compounds 7. Moreover, the fungicidal
activities of methyl a-(methoxyimino)benzeneacetate
oxime ethers compounds 7f–i and N-methoxy-
carbamic acid methyl esters compounds 7j–m showed
significant differences compared to the corresponding
products of ammonolysis.
Many heterocyclic compounds have shown good insecti-
cidal or fungicidal activities, thus increasing their impor-
tance in pesticide discovery (16–23). The heterocyclic
scaffold of a crop protection agent often has a positive
effect on its synthetic accessibility and its physicochemi-
cal properties, driving values like lipophilicity and solubil-
ity toward the optimal balanced range regarding uptake
and bioavailability (21). Heterocycles are deemed to be
perfect bioisosteres of other carba- or heterocyclic rings,
as well as of several different functional groups, deliver-
ing equal or even better biological efficacy through their
similarity in structural shape and electronic distribution
Key words: fungicidal activities, fungicide, indole, oxime
ether, strobilurins
Received 30 June 2014, revised 4 September 2014 and
accepted for publication 15 October 2014
(18,21). Furthermore, the substitution of
a heteroaryl
group (i.e., pyridine or furane) with one of the aryl resi-
dues of the compound results in heightened biological
activity (19). More importantly, environmental compatibility
of the synthesized organic compounds is enhanced
when heteroatoms are introduced into the carba-rings
(17,18,21).
The synthetic strobilurins, derivatives of 3-methoxyprope-
noic acid, are one of the most important classes of
agricultural fungicide (1–4). Their discovery was inspired by
a family of natural strobilurins which, although fungicidal,
could not be used in agriculture because they are unstable
in light and volatile (2,5). To date, several chemists have
published remarkable reports on synthetic analogs of stro-
bilurin A (Figure 1) to stabilize the triene structure of the
compound (6–14).
In view of all these facts and as continuation of our
research on fungicidal important heterocycles, hereby,
a
series of novel indole-substituted oxime ethers
7
(Figure 1) utilizing indole group as bioisostere to
a
replace the E-styryl group in Enoxastrobin were synthe-
sized in this study. The title compounds (7) were envi-
sioned to retain or urther enhance their biological activity
and simultaneously improve their environmental compati-
bility. The structure–activity relationship of this type of
compound was also studied. The biological assay
showed that most title compounds (7) maintained good
fungicidal activities.
Compounds I (Figure 1), reported by Rohm and Haas
Company [the 4-Cl-substituted derivatives of compounds I
were developed by Shenyang Research Institute of
Chemical Industry and named Enoxastrobin (Figure 1)
(10)], contain an unsaturated oxime ether group and exhi-
bit effective fungicidal activities (7). To further stabilize the
ª 2014 John Wiley & Sons A/S. doi: 10.1111/cbdd.12460
1

Xie et al.
Figure 1: Structure of strobilurin A and its analogs.
38.2 °C; 1H NMR (CDCl3, 400 MHz): d 6.11 (s, 2H, NH2),
6.64 (d, J = 8.0 Hz, 1H, ArH), 6.72-6.77 (m, 1H, ArH),
7.28-7.33 (m, 1H, ArH), 7.48 (dd, J = 8.0, 1.6 Hz, 1H,
ArH), 9.87 (s, 1H, O=CH); 13C NMR (CDCl3, 100 MHz):
115.9, 116.4, 118.8, 135.2, 135.7, 149.8, 194.1.
Methods and Materials
Synthetic procedure
Oxime ether strobilurin derivatives containing indole moiety
7
were prepared by the synthetic route outlined in
Scheme 1, and the reaction yields were not optimized.
2-Aminobenzaldehyde derivatives (2b–d). A mixture
of 2-bromobenzaldehyde derivatives (1b–d, 20 mmol),
sodium ascorbate (0.59 g, 3.0 mmol), DL-proline (0.46 g,
4 mmol), sodium azide (2.42 g, 36 mmol), DMSO (45 mL)
and H2O (5 mL) was stirred. The reaction mixture was
heated to 70 °C and reacted for 4.5–12.5 h. After cooling
to room temperature, the reaction mixture was poured
into 200 mL of water and extracted with ethyl acetate.
The combined organic layers were washed with 100 mL
saturated aqueous sodium chloride solution. Then, the
combined water layers were extracted with ethyl acetate.
Finally, the combined organic layers were dried over
anhydrous Na2SO4 and concentrated under vacuum. The
residue was purified by flash chromatography using a
1:12 (v/v) mixture of ethyl acetate and petroleum ether
(boiling point range 60–90 °C) as the eluting solution to
afford 2-aminobenzaldehyde derivatives (2b–d) in moder-
ate yields.
General
All of the starting materials and reagents were commer-
cially available and used without further purification, except
as indicated. Silica gel (300–400 mesh) was used for col-
umn chromatography. The (E)-methyl 2-(2-(chloromethyl)
phenyl)-3-methoxyacrylate (A), (E)-methyl 2-(2-(bromom-
ethyl)phenyl)-2-methoxyiminoacetate (B), and methyl
(2-(bromomethyl)phenyl)methoxycarbamate (C) intermedi-
ates were provided by Shenyang Research Institute of
Chemical Industry. Melting points were determined with a
Tech X–6 micro–melting–point apparatus made in Beijing
and are uncorrected. The 1H and 13C NMR spectra were
recorded with a Bruker 400 MHz spectrometer and Bruker
500 MHz spectrometer with CDCl3 as the solvent and
TMS as the internal standard. HRMS spectra were
recorded on a 7.0T FT–MS.
Data for 2-amino-4-chlorobenzaldehyde (2b): pale yel-
low solid (1.80 g, 58.1%); M.P.: 81.8–82.2 °C; 1H NMR
2-Aminobenzaldehyde derivatives (2a–d)
(CDCl3, 400 MHz):
d 6.21 (s, 2H, NH2), 6.66 (d,
2-Aminobenzaldehyde (2a). A mixture of (2-aminophe-
nyl)methanol (1a, 3.77 g, 30 mmol), MnO2 (10.43 g,
120 mmol), and dichloromethane (50 mL) was stirred.
Keep the reaction temperature at 30 °C for 18 h. After
cooling to room temperature, the reaction mixture was
filtrated, and the combined organic layers were concen-
trated under vacuum. The residue was purified by flash
chromatography using a 1:6 (v/v) mixture of ethyl acetate
and petroleum ether (boiling point range 60–90 °C) as the
eluting solution to afford 3.42 g (94.1%) intermediate
2-aminobenzaldehyde (2a) as yellow solid: M.P.: 37.6–
J = 1.6 Hz, 1H, ArH), 6.71 (dd, J = 8.4, 1.6 Hz, 1H, ArH),
7.40 (d, J = 8.4 Hz, 1H, ArH), 9.82 (s, 1H, O=CH); 13C
NMR (CDCl3, 100 MHz): d 115.8, 117.3, 117.7, 137.3,
141.9, 150.8, 193.3.
Data for 2-amino-4-fluorobenzaldehyde (2c): yellow oil
(2.04 g, 73.4%); 1H NMR (CDCl3, 400 MHz): d 6.31 (s,
2H, NH2), 6.31 (dd, J = 10.8, 2.0 Hz, 1H, ArH), 6.42–6.47
(m, 1H, ArH), 7.46 (dd, J = 8.0, 6.4 Hz, 1H, ArH), 9.79 (s,
1H, O=CH); 13C NMR (CDCl3, 100 MHz): d 102.0 (d,
2
Chem Biol Drug Des 2014

Indole Substituted Strobilurin Derivatives
OH
NH2
O
O
N
N
1a
O
O
N
H
O
R1
R1
k
N
N
N
N
a
O
O
O
O
7n–q
7f–i
b
7n: R1=H
7f: R1=H
R1
R1
7o: R1=6-Cl
7p: R1=6-F
7q: R1=5-F
7g: R1=6-Cl
7h: R1=6-F
7i: R1=5-F
f
Br
NH2
R1
1b–d
2
2a: R1=H
2b: R1=4-Cl
2c: R1=4-F
2d: R1=5-F
N
O
O
1b: R1=4-Cl
1c: R1=4-F1
1d: R1=5-F
5
N
O
O
O
5a: R1=H
i
5b: R1=6-Cl
5c: R1=6-F
5d: R1=5-F
O
O
Br
c
Cl
O
B
O
O
g
A
O
O
R1
R1
d
e
N
R2
N
N
N
OH
R1
R1
h
O
N
H
O
R2
N
H
CF3
6
7a–e
7a: R1=H R2=H
7b: R1=H R2=CH3
7c: R1=6-Cl R2=CH3
7d: R1=6-F R2=CH3
7e: R1=5-F R2=CH3
3
4
6a: R1=H R2=H
6b: R1=H R2=CH3
6c: R1=6-Cl R2=CH3
6d: R1=6-F R2=CH3
6e: R1=5-F R2=CH3
3a: R1=H
4a: R1=H
3b: R1=4-Cl
3c: R1=4-F
3d: R1=5-F
4b: R1=6-Cl
4c: R1=6-F
4d: R1=5-F
O
O
N
O
j
Br
C
O
O
O
O
O
N
NH
N
R1
R1
l
N
N
N
N
O
O
7j–m
7j: R1=H
7r–u
7r: R1=H
7k: R1=6-Cl
7l: R1=6-F
7m: R1=5-F
7s: R1=6-Cl
7t: R1=6-F
7u: R1=5-F
Scheme 1: General synthetic route for the title compounds 7. Reagents and conditions: (a) MnO2, CH2Cl2, 30 °C; (b) sodium ascorbate,
DL-proline, sodium azide, DMSO, H2O, 70 °C; (c) trifluoroacetic anhydride, azabenzene, CH2Cl2, rt; (d) 1-chloropropan-2-one, calcium
oxide, PEG-400, 100 °C; (e, g) hydroxylamine hydrochloride, sodium acetate, H2O, ethanol, reflux; (f) iodomethane, potassium carbonate,
anhydrous acetonitrile, 70 °C; (h, i, j) potassium carbonate, anhydrous acetonitrile, reflux; (k, l) methylamine, methanol, reflux.
JCF = 24.7 Hz), 105.2 (d, JCF = 23.4 Hz), 116.4 (d,
JCF = 0.9 Hz), 139.0 (d, JCF = 12.5 Hz), 152.5 (d,
JCF = 23.5 Hz), 167.6 (d, JCF = 252.9 Hz), 192.9.
was stirred under room temperature for 1.5–12.5 h. Then,
the reaction mixture was poured into 30 mL of water and
extracted with ethyl acetate. The combined organic layers
were dried over anhydrous Na2SO4 and concentrated under
vacuum. The residue was purified by flash chromatography
using a 1:12 (v/v) mixture of ethyl acetate and petroleum
ether (boiling point range 60–90 °C) as the eluting solution
to afford 2,2,2-trifluoro-N-(2-formylphenyl)acetamide deriva-
tives (3a–d) in good yields.
Data for 2-amino-5-fluorobenzaldehyde (2d): yellow oil
(1.24 g, 44.5%); 1H NMR (CDCl3, 400 MHz): d 6.00 (s,
2H, NH2), 6.62 (dd, J = 9.2, 4.0 Hz, 1H, ArH), 7.06–7.12
(m, 1H, ArH), 7.18 (dd, J = 8.4, 3.2 Hz, 1H, ArH), 9.81 (s,
1H, O=CH); 13C NMR (CDCl3, 100 MHz): d 117.8 (d,
JCF = 6.6 Hz), 118.5 (d, JCF = 5.2 Hz), 119.8 (d, JCF
21.2 Hz), 123.8 (d, JCF = 21.2 Hz), 146.8 (d, JCF
1.2 Hz), 154.4 (d, JCF = 234.5 Hz), 193.1.
=
=
Data for 2,2,2-trifluoro-N-(2-formylphenyl)acetamide
(3a). pale yellow solid (1.67 g, 76.9%); M.P.: 68.9–
69.6 °C; 1H NMR (CDCl3, 400 MHz): d 7.38–7.43 (m, 1H,
ArH), 7.68-7.74 (m, 1H, ArH), 7.79 (dd, J = 7.6, 1.6 Hz, 1H,
ArH), 8.68 (d, J = 8.4 Hz, 1H, ArH), 9.98 (s, 1H, O=CH),
12.19 (s, 1H, NH); 13C NMR (CDCl3, 100 MHz): d 30.0,
120.8, 122.9, 125.6, 136.4, 136.7, 138.5, 156.3, 195.9.
2,2,2-Trifluoro-N-(2-formylphenyl)acetamide
derivatives (3a–d)
A
mixture of 2-aminobenzaldehyde derivatives (2a–d,
10 mmol), azabenzene (1.6 mL, 20 mmol), and dichlorome-
thane (12 mL) was stirred on ice bath. After the temperature
of the mixture was low to 4 °C, trifluoroacetic anhydride
(2.4 mL, 16 mmol) was added slowly. The reaction mixture
Data for N-(5-chloro-2-formylphen-yl)-2,2,2-trifluoro-
acetamide (3b). pale yellow solid (2.44 g, 97.2%);
M.P.: 58.5–59.0 °C; 1H NMR (CDCl3, 500 MHz): d 7.38
Chem Biol Drug Des 2014
3

Xie et al.
(dd, J = 6.4, 1.6 Hz, 1H, ArH), 7.71 (d, J = 6.4 Hz, 1H,
ArH), 8.75 (d, J = 1.2 Hz, 1H, ArH), 9.94 (s, 1H, O=C-
H), 12.24 (s, 1H, NH); 13C NMR (CDCl3, 100 MHz): d
114.2, 117.1, 121.1, 121.2, 125.9, 137.2, 139.3, 143.5,
194.8.
7.44–7.45 (m, 1H, ArH), 7.62 (d, J = 8.8 Hz, 1H, ArH), 9.49
(s, 1H, NH); 13C NMR (CDCl3, 100 MHz): d 26.2, 110.1,
112.4, 122.4, 124.3, 126.4, 132.6, 136.3, 138.0, 190.8.
Data for 1-(6-fluoro-1H-indol-2-yl)ethanone (4c).
yellow solid (0.99 g, 62.1%); M.P.: 145.2–145.4 °C; 1H
NMR (CDCl3, 400 MHz): d 2.61 (s, 3H, CH3), 7.08–7.14 (m,
1H, ArH), 7.16 (d, J = 1.2 Hz, 1H, N-C=CH), 7.34 (dd,
J = 8.8, 2.0 Hz, 1H, ArH), 7.39 (dd, J = 9.2, 4.4 Hz, 1H,
ArH), 9.49 (s, 1H, NH); 13C NMR (CDCl3, 100 MHz): d 26.2,
107.4 (d, JCF = 23.2 Hz), 109.9 (d, JCF = 5.5 Hz), 113.7 (d,
JCF = 9.5 Hz), 115.9 (d, JCF = 26.9 Hz), 128.0 (d,
JCF = 10.3 Hz), 134.4, 137.0, 158.5 (d, JCF = 235.7 Hz),
191.0.
Data for N-(5-fluoro-2-formylphen-yl)-2,2,2-trifluoro
acetamide (3c). pale yellow solid (2.15 g, 91.5%); M.P.:
47.6–48.2 °C; 1H NMR (CDCl3, 400 MHz): d 7.06–7.12
(m, 1H, ArH), 7.80 (dd, J = 8.8, 6.0 Hz, 1H, ArH), 8.46
(dd, J = 11.2, 2.4 Hz, 1H, ArH), 9.93 (s, 1H, O=C-H),
12.39 (s, 1H, NH); 13C NMR (CDCl3, 100 MHz): d 108.8
(d, JCF = 28.7 Hz), 112.9 (d, JCF = 22.7 Hz), 115.6 (d,
JCF = 286.8 Hz), 119.7, 138.8 (d, JCF = 11.6 Hz), 140.9
(d, JCF = 13.5 Hz), 156.5 (d, JCF = 76.0 Hz), 167.4 (d,
JCF = 259.6 Hz), 194.5.
Data for 1-(5-fluoro-1H-indol-2-yl)ethanone (4d). pale
yellow solid (1.38 g, 86.6%); M.P.: 187.3–187.7 °C; 1H
NMR (CDCl3, 400 MHz): d 2.61 (s, 3H, CH3), 7.08–7.14
(m, 1H, ArH), 7.16 (d, J = 1.2 Hz, 1H, N-C=CH), 7.34 (dd,
J = 8.8, 2.4 Hz, 1H, ArH), 7.39 (dd, J = 8.8, 4.4 Hz, 1H,
ArH), 9.45 (s, 1H, NH); 13C NMR (CDCl3, 100 MHz): d
26.2, 107.4 (d, JCF = 23.1 Hz), 109.9 (d, JCF = 5.6 Hz),
113.6 (d, JCF = 9.4 Hz), 115.9 (d, JCF = 26.9 Hz), 128.0
Data for N-(4-fluoro-2-formylphen-yl)-2,2,2-trifluoro-
acetamide (3d). pale yellow solid (0.23 g, 97.9%); M.P.:
96.3–97.0 °C; 1H NMR (CDCl3, 400 MHz): d 7.04–7.46
(m, 1H, ArH), 7.50 (dd, J = 7.6, 3.2 Hz, 1H, ArH), 8.72
(dd, J = 9.2, 4.8 Hz, 1H, ArH), 9.94 (s, 1H, O=C-H), 12.01
(s, 1H, NH); 13C NMR (CDCl3, 100 MHz): d 115.8 (d,
JCF = 326.9 Hz), 122.0 (d, JCF = 22.7 Hz), 122.9 (d, JCF
=
(d,
JCF = 10.2 Hz),
134.4,
137.0,
158.9
(d,
6.9 Hz), 123.7 (d, JCF = 21.9 Hz), 124.0 (d,
JCF = 235.7 Hz), 191.0.
JCF = 5.5 Hz), 134.7 (d, JCF = 2.9 Hz), 156.0 (d, JCF
37.9 Hz), 159.5 (d, JCF = 247.2 Hz), 194.6.
=
1-(1-Methyl-indol-2-yl)ethanone derivatives (5a–d)
A mixture of 1-(1H-indol-2-yl)ethanone derivatives (4a–d,
10 mmol), iodomethane (2.0 mL, 32 mmol), potassium
carbonate (1.38 g, 10 mmol), and anhydrous acetonitrile
(10 mL) was stirred. The reaction mixture was heated to
70 °C and reacted for 33–72 h. After cooling to room
temperature, the reaction mixture was poured into
30 mL of water and extracted with ethyl acetate. The
combined organic layers were dried over anhydrous
Na2SO4 and concentrated under vacuum. The residue
was purified by flash chromatography using a 1:12 (v/v)
mixture of ethyl acetate and petroleum ether (boiling
point range 60–90 °C) as the eluting solution to afford
1-(1-methyl-indol-2-yl)ethanone derivatives (5a–d) in good
yields.
1-(1H-indol-2-yl)ethanone derivatives (4a–d)
A
mixture of 2,2,2-trifluoro-N-(2-formylphenyl)acetamide
derivatives (3a–d, 9 mmol), 1-chloropropan-2-one
(1.0 mL, 11 mmol), calcium oxide (1.54 g, 27 mmol),
and PEG-400 (30 mL) was stirred. The reaction mixture
was heated to 100 °C and reacted for 3.0–11.0 h. After
cooling to room temperature, the reaction mixture was
poured into 60 mL of water and extracted with ethyl
acetate. The combined organic layers were dried over
anhydrous Na2SO4 and concentrated under vacuum.
The residue was purified by flash chromatography using
a 1:12 (v/v) mixture of ethyl acetate and petroleum ether
(boiling point range 60–90 °C) as the eluting solution to
afford 1-(1H-indol-2-yl)ethanone derivatives (4a–d) in
moderate yields.
Data for 1-(1-methyl-indol-2-yl)ethanone (5a). brown
solid (1.08 g, 62.4%); M.P.: 92.5–93.0 °C; 1H NMR
(CDCl3, 400 MHz): d 2.61 (s, 3H, C-CH3), 4.07 (s, 3H, N-
CH3), 7.13–7.17 (m, 1H, ArH), 7.28 (s, 1H, N-C=CH),
7.36–7.38 (m, 2H, ArH), 7.69 (d, J = 8.0 Hz, 1H, ArH);
13C NMR (CDCl3, 100 MHz): d 28.3, 32.5, 110.7, 112.3,
121.0, 123.2, 126.1, 126.2, 135.2, 140.4, 192.0.
Data for 1-(1H-indol-2-yl)ethanone (4a). brown solid
(1.07 g, 74.7%); M.P.: 139.7–140.6 °C; 1H NMR (CDCl3,
400 MHz): d 2.60 (s, 3H, CH3), 7.13–7.17 (m, 1H, ArH),
7.20 (dd, J = 2.4, 0.8 Hz, 1H, N-C=CH),7.32–7.37 (m,
1H, ArH), 7.43 (dd, J = 8.0, 0.8 Hz, 1H, ArH), 7.71 (dd,
J = 8.0, 0.8 Hz, 1H, ArH), 9.24 (s, 1H, NH); 13C NMR
(CDCl3, 100 MHz): d 26.2, 110.2, 112.5, 121.3, 123.4,
126.7, 127.9, 135.7, 137.7, 190.9.
Data
for
1-(6-chloro-1-methyl-indol-2-yl)ethanone
(5b). pale yellow solid (1.61 g, 86.4%); M.P.: 147.1–
147.9 °C; 1H NMR (CDCl3, 400 MHz): d 2.64 (s, 3H, C-
CH3), 3.95 (s, 3H, N-CH3), 7.25 (s, 1H, N-C=CH), 7.40
(dd, J = 8.4, 2.0 Hz, 1H, ArH), 7.62 (d, J = 7.2 Hz, 1H,
ArH), 7.96 (d, J = 2.4 Hz, 1H, ArH); 13C NMR (CDCl3,
Data for 1-(6-chloro-1H-indol-2-yl)ethanone (4b). yellow
solid (1.17 g, 67.4%); M.P.: 150.3–150.8 °C; 1H NMR
(CDCl3, 400 MHz): d 2.61 (s, 3H, CH3), 7.12 (dd, J = 8.4,
1.6 Hz, 1H, ArH), 7.17 (dd, J = 2.4, 0.8 Hz, 1H, N-C=CH),
4
Chem Biol Drug Des 2014

Indole Substituted Strobilurin Derivatives
100 MHz): d 20.5, 55.4, 110.5, 126.8, 126.9, 127.4,
127.4, 132.0, 142.9, 152.3, 154.3.
(E)-1-(1-methyl-indol-2-yl)ethanone oxime derivatives (6b–
e) in excellent yields.
Data for 1-(6-fluoro-1-methyl-indol-2-yl)ethanone (5c).
yellow solid (1.58 g, 91.9%); M.P.: 106.6–107.1 °C; 1H
NMR (CDCl3, 400 MHz): d 2.59 (s, 3H, C-CH3), 4.03 (s,
3H, N-CH3), 6.90–6.95 (m, 1H, ArH), 7.03 (dd, J = 10.0,
2.0 Hz, 1H, ArH), 7.27 (s, 1H, N-C=CH), 7.63 (dd,
J = 8.8, 5.6 Hz, 1H, ArH), 7.96 (d, J = 2.4 Hz, 1H, ArH);
13C NMR (CDCl3, 100 MHz): d 28.1, 32.7, 96.6 (d,
JCF = 28.2 Hz), 110.8 (d, JCF = 25.5 Hz), 112.5 (d,
JCF = 1.2 Hz), 122.6, 124.6 (d, JCF = 10.5 Hz), 136.0
(d, JCF = 3.6 Hz), 140.8 (d, JCF = 12.2 Hz), 162.4 (d,
JCF = 242.1 Hz), 191.4.
Data for (E)-1-(1-methyl-indol-2-yl)ethanone oxime
(6b): yellow solid (0.92 g, 98.3%); M.P.: 161.5–162.0 °C;
1H NMR (CDCl3, 400 MHz): d 2.35 (s, 3H, C-CH3), 3.94
(s, 3H, N-CH3), 6.77 (d, J = 0.8 Hz, 1H, N-C=CH), 7.08–
7.13 (m, 1H, ArH), 7.26–7.29 (m, 1H, ArH), 7.31–7.34 (m,
1H, ArH), 7.59–7.63 (m, 1H, ArH), 7.83 (s, 1H, N-OH); 13C
NMR (CDCl3, 100 MHz): d 13.8, 33.2, 105.3, 110.1,
120.2, 121.4, 123.5, 127.3, 135.6, 139.7, 151.9.
Data for (E)-1-(6-chloro-1-methyl-indol-2-yl)ethanone
oxime (6c): yellow solid (1.09 g, 98.2%); M.P.: 163.7–
164.0 °C; 1H NMR (CDCl3, 400 MHz): d 2.34 (s, 3H, C-
CH3), 3.91 (s, 3H, N-CH3), 6.73 (d, J = 0.4 Hz, 1H, N-
C=CH), 7.07 (dd, J = 8.4, 1.6 Hz, 1H, ArH), 7.32 (d,
J = 0.8 Hz, 1H, ArH), 7.50 (d, J = 8.4 Hz, 1H, ArH), 7.54
(s, 1H, N-OH); 13C NMR (CDCl3, 100 MHz): d 13.6, 33.4,
105.3, 110.1, 121.0, 122.2, 125.7, 129.4, 136.3, 140.1,
151.6.
Data for 1-(5-fluoro-1-methyl-indol-2-yl)ethanone (5d).
yellow solid (1.59 g, 92.5%); M.P.: 83.6–84.0 °C; 1H NMR
(CDCl3, 400 MHz): d 2.60 (s, 3H, C-CH3), 4.05 (s, 3H,
N-CH3), 7.10–7.16 (m, 1H, ArH), 7.22 (s, 1H, N-C=CH),
7.28–7.33 (m, 2H, ArH); 13C NMR (CDCl3, 100 MHz): d
28.3, 32.7, 107.1 (d, JCF = 23.0 Hz), 111.7, 111.8 (d,
JCF = 3.1 Hz), 115.3 (d, JCF = 26.9 Hz), 126.0 (d,
JCF = 10.3 Hz), 136.3, 136.7 (d, JCF = 71.4 Hz), 158.9 (d,
JCF = 235.6 Hz), 191.9.
Data for (E)-1-(6-fluoro-1-methyl-indol-2-yl)ethanone
oxime (6d): yellow solid (1.02 g, 99.0%); M.P.: 164.3–
164.7 °C; 1H NMR (CDCl3, 400 MHz): d 2.33 (s, 3H,
C-CH3), 3.88 (s, 3H, N-CH3), 6.74 (d, J = 0.4 Hz, 1H, N-
C=CH), 6.84–6.90 (m, 1H, ArH), 7.00 (dd, J = 10.0,
2.4 Hz, 1H, ArH), 7.51 (dd, J = 8.8, 5.6 Hz, 1H, ArH),
7.84 (s, 1H, N-OH); 13C NMR (CDCl3, 100 MHz): d 13.7,
33.5, 96.3 (d, JCF = 26.3 Hz), 105.4, 109.2 (d,
JCF = 24.7 Hz), 122.3 (d, JCF = 10.2 Hz), 123.7, 136.2(d,
JCF = 3.9 Hz), 139.9 (d, JCF = 11.9 Hz), 151.6, 161.0 (d,
JCF = 237.9 Hz).
The intermediate ethanone oximes (6a–e)
(E)-1-(1H-indol-2-yl)ethanone oxime (6a).
mixture of
1-(1H-indol-2-yl)ethanone (4a, 5 mmol), hydroxylamine
hydrochloride (0.52 g, 7.5 mmol), sodium acetate
(0.62 g, 7.5 mmol), H2O (4 mL), and ethanol (8 mL) was
stirred under reflux for 1.0 h. After cooling to room tem-
perature, the reaction mixture was poured into 25 mL of
0.5 M HCl (aq.) and extracted with ethyl acetate. The
combined organic layers were dried over anhydrous
Na2SO4 and concentrated under vacuum. The residue
was purified by recrystallization with ethyl acetate to
afford 0.21 g (24.1%) (E)-1-(1H-indol-2-yl)ethanone oxime
(6a) as white solid: M.P.: 146.9–147.8 °C; 1H NMR
(CDCl3, 400 MHz): d 2.33 (s, 3H, CH3), 6.79–6.80 (m,
1H, N-C=CH), 7.09–7.20 (m, 1H, ArH), 7.20–7.23 (m,
1H, ArH), 7.24–7.28 (m, 1H, ArH), 7.62 (d, J = 8.0 Hz,
1H, ArH), 8.20 (s, 1H, N-OH), 8.97 (s, 1H, NH); 13C
NMR (CDCl3, 100 MHz): d 11.8, 105.0, 111.3, 120.4,
121.5, 124.3, 128.3, 133.9, 137.1, 150.6.
Data for (E)-1-(5-fluoro-1-methyl-indol-2-yl)ethanone
oxime (6e): yellow solid (1.01 g, 98.0%); M.P.: 158.9–
159.4 °C; 1H NMR (CDCl3, 400 MHz): d 2.34 (s, 3H, C-
CH3), 3.92 (s, 3H, N-CH3), 6.71 (s, 1H, N-C=CH), 6.99–
7.04 (m, 1H, ArH), 7.21–7.26 (m, 2H, ArH), 7.77 (s, 1H, N-
OH); 13C NMR (CDCl3, 100 MHz): d 13.8, 33.4, 105.0 (d,
JCF = 4.9 Hz), 105.8 (d, JCF = 23.2 Hz), 110.8 (d, JCF
9.6 Hz), 112.0 (d, JCF = 26.2 Hz), 127.3 (d, JCF
=
=
10.3 Hz), 136.3, 137.0, 151.7, 158.3 (d, JCF = 233.6 Hz).
Methyl 3-methoxypropenoate oxime ethers (7a–e)
Methyl (E,E)-3-methoxy-2-(2-((((1-(1H-indol-2-yl)ethy-
(E)-1-(1-methyl-indol-2-yl)ethanone oxime (6b–e).
A
mixture of 1-(1-methyl-indol-2-yl)ethanone derivatives (5a–
d, 5 mmol), hydroxylamine hydrochloride (0.52 g,
7.5 mmol), sodium acetate (0.62 g, 7.5 mmol), H2O
(4 mL), and ethanol (8 mL) was stirred under reflux for
1.0–3.0 h. After cooling to room temperature, the reac-
tion mixture was poured into 25 mL of 0.5 M HCl (aq.)
and extracted with ethyl acetate. The combined organic
layers were dried over anhydrous Na2SO4 and
concentrated under vacuum. The residue was purified
by recrystallization with ethyl acetate to afford
lidene)amino)oxy)methyl)phenyl)propenoate (7a).
A
mixture of (E)-1-(1H-indol-2-yl)ethanone oxime (6a, 0.17 g,
1.0 mmol), (E)-methyl 2-(2-(chloromethyl)phenyl)-3-meth-
oxyacrylate (A, 0.32 g, 1.3 mmol), potassium carbonate
(0.36 g, 2.6 mmol), and anhydrous acetonitrile (6 mL) was
stirred under reflux for 7.0 h. After cooling to room tem-
perature, the reaction mixture was poured into 30 mL of
water and extracted with ethyl acetate. The combined
organic layers were dried over anhydrous Na2SO4 and
concentrated under vacuum. The residue was purified by
Chem Biol Drug Des 2014
5

Xie et al.
flash chromatography using a 1:12 (v/v) mixture of ethyl
acetate and petroleum ether (boiling point range 60–
90 °C) as the eluting solution to afford 0.35 g (91.4%) (E,
1H, O-CH=C); 13C NMR (CDCl3, 100 MHz): d 14.2, 33.4,
51.9, 62.2, 74.9, 104.9, 110.0, 110.8, 120.8, 122.1,
125.7, 127.8, 128.1, 128.8, 129.2, 131.3, 132.1, 136.4,
137.5, 140.1, 149.8, 160.1, 168.3; HRMS (ESI) calcd for
[C23H23ClN2NaO4]+ (M+Na+): 449.1239; found: 449.1229.
E)-methyl
3-methoxy-2-(2-((((1-(1H-indol-2-yl)ethylidene)
amino)oxy)methyl)phenyl)propenoate (7a) as brown solid:
M.P.: 115.7–116.2 °C; 1H NMR (CDCl3, 400 MHz): d 2.23
(s, 3H, N=C-CH3), 3.72 (s, 3H, C=C-OCH3), 3.81 (s, 3H,
O=C-OCH3), 5.12 (s, 2H, O-CH2), 6.67 (d, J = 1.2 Hz, 1H,
N-C=CH), 7.03–7.12 (m, 1H, ArH), 7.16–7.22 (m, 3H,
ArH), 7.31–7.35 (m, 2H, ArH), 7.49–7.51 (m, 1H, ArH),
7.60 (s, 1H, O-CH=C), 7.95–7.99 (m, 1H, ArH), 9.03 (s,
1H, NH); 13C NMR (CDCl3, 100 MHz): d 12.3, 52.1, 62.2,
74.4, 103.8, 110.9, 111.3, 120.0, 121.3, 123.8, 127.9,
128.3, 129.0, 131.2, 132.2, 134.4, 137.0, 137.4, 148.5,
160.3, 168.7; HRMS (ESI) calcd for [C22H22N2NaO4]+
(M+Na+): 401.1472; found: 401.1469.
Data for methyl (E,E)-3-methoxy-2-(2-((((1-(6-fluoro-1-
methy-indol-2-yl)ethylidene)amino)oxy)methyl)phe-
nyl)propenoate (7d): pale yellow solid (0.32 g, 52.0%);
M.P.: 119.0–119.5 °C; 1H NMR (CDCl3, 400 MHz): d 2.27
(s, 3H, N=C-CH3), 3.67 (s, 3H, C=C-OCH3), 3.74 (s, 3H,
N-CH3), 3.80 (s, 3H, O=C-OCH3), 5.14 (s, 2H, O-CH2),
6.68 (s, 1H, N-C=CH), 6.81-6.87 (m, 1H, ArH), 6.94 (dd,
J = 10.0, 2.0 Hz, 1H, ArH), 7.15-7.18 (m, 1H, ArH), 7.31-
7.34 (m, 2H, ArH), 7.46-7.50 (m, 2H, ArH), 7.59 (s, 1H, O-
CH=C); 13C NMR (CDCl3, 100 MHz): d 14.1, 33.5, 51.9,
62.2, 74.8, 96.3 (d, JCF = 26.3 Hz), 105.0, 108.9 (d,
JCF = 24.7 Hz), 110.8, 122.1 (d, JCF = 10.1 Hz), 123.7,
127.8, 128.1, 128.8, 131.3, 132.1, 136.3 (d,
JCF = 3.8 Hz), 137.6, 139.9 (d, JCF = 12.0 Hz), 149.9,
160.1, 160.8 (d, JCF = 237.6 Hz), 168.4; HRMS (ESI)
calcd for [C23H23FN2NaO4]+ (M+Na+): 433.1534; found:
433.1526.
Methyl 3-methoxypropenoate oxime ethers (7b–e).
A
mixture of the corresponding (E)-1-(1-methyl-indol-2-yl)eth-
anone oxime (6b–e, 1.5 mmol), (E)-methyl 2-(2-(chlorom-
ethyl)phenyl)-3-methoxyacrylate (A, 0.49 g, 2.0 mmol),
potassium carbonate (0.62 g, 4.5 mmol), and anhydrous
acetonitrile (9 mL) was stirred under reflux for 11.0–30.0 h.
After cooling to room temperature, the reaction mixture
was poured into 30 mL of water and extracted with ethyl
acetate. The combined organic layers were dried over
anhydrous Na2SO4 and concentrated under vacuum. The
residue was purified by flash chromatography using a 1:12
(v/v) mixture of ethyl acetate and petroleum ether (boiling
point range 60–90 °C) as the eluting solution to afford the
corresponding title compounds methyl 3-methoxypropeno-
ate oxime ethers (7b–e) in good yields.
Data for methyl (E,E)-3-methoxy-2-(2-((((1-(5-fluoro-1-
methy-indol-2-yl)ethylidene)amino)oxy)methyl)phe-
nyl)propenoate (7e): pale yellow solid (0.57 g, 92.6%);
M.P.: 102.8–103.4 °C; 1H NMR (CDCl3, 400 MHz): d 2.28
(s, 3H, N=C-CH3), 3.67 (s, 3H, C=C-OCH3), 3.77 (s, 3H, N-
CH3), 3.80 (s, 3H, O=C-OCH3), 5.15 (s, 2H, O-CH2), 6.65
(s, 1H, N-C=CH), 6.95–7.00 (m, 1H, ArH), 7.15–7.22 (m,
3H, ArH), 7.29–7.36 (m, 2H, ArH), 7.47–7.50 (m, 1H, ArH),
7.59 (s, 1H, O-CH=C); 13C NMR (CDCl3, 100 MHz): d 14.3,
33.4, 51.9, 62.2, 74.9, 104.6 (d, JCF = 4.9 Hz), 105.7 (d,
JCF = 23.2 Hz), 110.7(d, JCF = 9.5 Hz), 110.8, 111.7 (d,
JCF = 26.3 Hz), 127.2 (d, JCF = 10.3 Hz), 127.8, 128.1,
128.8, 131.3, 132.1, 136.3, 137.1, 137.5, 149.9, 158.1 (d,
JCF = 233.1 Hz), 160.1, 168.4; HRMS (ESI) calcd for
[C23H23FN2NaO4]+ (M+Na+): 433.1534; found: 433.1529.
Data for methyl (E,E)-3-methoxy-2-(2-((((1-(1-methy-in-
dol-2-yl)ethylidene)amino)oxy)methyl)phenyl)pro-
penoate (7b): yellow solid (0.48 g, 81.6%); M.P.: 113.4–
114.0 °C; 1H NMR (CDCl3, 400 MHz): d 2.29 (s, 3H,
N=C-CH3), 3.66 (s, 3H, C=C-OCH3), 3.78 (s, 3H, N-CH3),
3.80 (s, 3H, O=C-OCH3), 5.15 (s, 2H, O-CH2), 6.71 (d,
J = 1.2 Hz, 1H, N-C=CH), 7.05–7.09 (m, 1H, ArH), 7.15–
7.18 (m, 1H, ArH), 7.21–7.25 (m, 1H, ArH), 7.26–7.36 (m,
3H, ArH), 7.48–7.51 (m, 1H, ArH), 7.56–7.59 (m, 1H, ArH),
7.58 (s, 1H, O-CH=C); 13C NMR (CDCl3, 100 MHz): d
14.2, 33.2, 51.9, 62.2, 74.8, 105.0, 110.0, 110.8, 120.0,
121.2, 123.3, 127.2, 127.8, 128.1, 128.8, 131.3, 132.1,
135.7, 137.6, 139.7, 150.1, 160.1, 168.4; HRMS (ESI)
calcd for [C23H24N2NaO4]+ (M+Na+): 415.1628; found:
415.1620.
Methyl a-(methoxyimino)benzeneacetate oxime
ethers (7f–i)
A mixture of the corresponding (E)-1-(1-methyl-indol-2-yl)
ethanone oxime (6b–e, 1.5 mmol), (E)-methyl 2-(2-(bro-
momethyl)phenyl)-2-methoxyiminoacetate
(B,
0.57 g,
2.0 mmol), potassium carbonate (0.62 g, 4.5 mmol), and
anhydrous acetonitrile (9 mL) was stirred under reflux for
9.5–24.0 h. After cooling to room temperature, the reac-
tion mixture was poured into 30 mL of water and
extracted with ethyl acetate. The combined organic layers
were dried over anhydrous Na2SO4 and concentrated
under vacuum. The residue was purified by flash chroma-
tography with using a 1:12 (v/v) mixture of ethyl acetate
and petroleum ether (boiling point range 60–90 °C) as the
eluting solution to afford the corresponding title
Data for methyl (E,E)-3-methoxy-2-(2-((((1-(6-chloro-1-
methy-indol-2-yl)ethylidene)amino)oxy)methyl)phe-
nyl)propenoate (7c): yellow solid (0.49 g, 76.7%); M.P.:
107.8–108.3 °C; 1H NMR (CDCl3, 400 MHz): d 2.27 (s,
3H, N=C-CH3), 3.67 (s, 3H, C=C-OCH3), 3.75 (s, 3H, N-
CH3), 3.80 (s, 3H, O=C-OCH3), 5.15 (s, 2H, O-CH2), 6.67
(s, 1H, N-C=CH), 7.04 (dd, J = 8.4, 1.6 Hz, 1H, ArH),
7.15–7.19 (m, 1H, ArH), 7.27 (d, J = 0.8 Hz, 1H, ArH),
7.29–7.36 (m, 2H, ArH), 7.42–7.50 (m, 2H, ArH), 7.59 (s,
compounds
methyl
a-(methoxyimino)benzeneacetate
oxime ethers (7f–i).
6
Chem Biol Drug Des 2014

Indole Substituted Strobilurin Derivatives
Data for methyl (E,E)-2-(2-((((1-(1-methyl-indol-2-yl)
ethylidene)amino)oxy)methyl)phenyl)-2-methoxy
JCF = 9.6 Hz), 111.8 (d, JCF = 26.3 Hz), 127.2 (d,
JCF = 10.3 Hz), 128.0, 128.9, 129.1, 129.6, 130.2, 136.3,
136.8, 136.9, 150.0, 150.3, 158.2 (d, JCF = 233.4 Hz),
163.6; HRMS (ESI) calcd for [C22H22FN3NaO4]+ (M+Na+):
434.1487; found: 434.1487.
imino acetate (7f). yellow solid (0.54 g, 91.6%); M.P.:
89.0–89.6 °C; 1H NMR (CDCl3, 400 MHz): d 2.27 (s, 3H,
N=C-CH3), 3.75 (s, 3H, N-CH3), 3.79 (s, 3H, O=C-OCH3),
4.01 (s, 3H, N-OCH3), 5.13 (s, 2H, O-CH2), 6.72 (s, 1H, N-
C=CH), 7.05–7.09 (m, 1H, ArH), 7.18–7.20 (m, 1H, ArH),
7.21–7.29 (m, 2H, ArH), 7.35–7.39 (m, 1H, ArH), 7.39–7.44
(m, 1H, ArH), 7.48 (dd, J = 7.6, 0.8 Hz, 1H, ArH), 7.57 (d,
J = 8.0 Hz, 1H, ArH); 13C NMR (CDCl3, 100 MHz): d 14.2,
33.1, 53.2, 64.1, 75.1, 105.2, 110.0, 120.0, 121.3, 123.4,
127.2, 128.0, 128.9, 129.1, 129.6, 130.2, 135.4, 137.0,
139.7, 150.0, 150.6, 163.6; HRMS (ESI) calcd for
[C22H23N3NaO4]+ (M+Na+): 416.1581; found: 416.1565.
N-methoxy-carbamic acid methyl esters (7j–m)
A mixture of the corresponding (E)-1-(1-methyl-indol-2-yl)
ethanone oxime (6b–e, 1.5 mmol), methyl (2-(bromometh-
yl)phenyl)methoxycarbamate (C, 0.55 g, 2.0 mmol), potas-
sium carbonate (0.62 g, 4.5 mmol), and anhydrous
acetonitrile (9 mL) was stirred under reflux for 9.5–36.0 h.
After cooling to room temperature, the reaction mixture
was poured into 30 mL of water and extracted with ethyl
acetate. The combined organic layers were dried over
anhydrous Na2SO4 and concentrated under vacuum. The
residue was purified by flash chromatography using a 1:12
(v/v) mixture of ethyl acetate and petroleum ether (boiling
point range 60–90 °C) as the eluting solution to afford the
corresponding title compounds N-methoxy-carbamic acid
methyl esters (7j–m).
Data for methyl (E,E)-2-(2-((((1-(6-chloro-1-methyl-
indol-2-yl)ethylidene)amino)oxy)methyl)phenyl)-2-
methoxy imino acetate (7 g). pale yellow solid (0.59 g,
92.1%); M.P.: 99.0–99.7 °C; 1H NMR (CDCl3, 400 MHz):
d 2.25 (s, 3H, N=C-CH3), 3.70 (s, 3H, N-CH3), 3.80 (s,
3H, O=C-OCH3), 4.02 (s, 3H, N-OCH3), 5.12 (s, 2H, O-
CH2), 6.68 (d, J = 0.8 Hz, 1H, N-C=CH), 7.04 (dd,
J = 8.4, 1.6 Hz, 1H, ArH), 7.20 (dd, J = 7.2, 1.6 Hz, 1H,
ArH), 7.26–7.27 (m, 1H, ArH), 7.38–7.49 (m, 4H, ArH); 13C
NMR (CDCl3, 100 MHz): d 14.1, 33.4, 53.2, 64.1, 75.2,
105.1, 110.0, 120.8, 122.1, 125.7, 128.0, 128.9, 129.1,
129.3, 129.6, 130.2, 136.2, 136.9, 140.1, 149.9, 150.2,
163.6; HRMS (ESI) calcd for [C22H22ClN3NaO4]+ (M+Na+):
450.1191; found: 450.1196.
Data for (E)-N-methoxy-N-(2-((1-(1-methyl-indol-2-yl)
ethylidene)aminooxymethyl)phenyl)carbamic
acid
methyl ester (7j). brown solid (0.50 g, 87.5%); M.P.:
93.5–94.1 °C; 1H NMR (CDCl3, 400 MHz): d 2.35 (s, 3H,
N=C-CH3), 3.76 (s, 3H, N-OCH3), 3.77 (s, 3H, O=C-
OCH3), 3.82 (s, 3H, H-N-CH3), 5.30 (s, 2H, O-CH2), 6.74
(s, 1H, N-C=CH), 7.06–7.10 (m, 1H, ArH), 7.21–7.26 (m,
1H, ArH), 7.28 (d, J = 8.0 Hz, 1H, ArH), 7.35–7.40 (m,
3H, ArH), 7.54–7.57 (m, 1H, ArH), 7.58 (d, J = 8.0 Hz,
1H, ArH); 13C NMR (CDCl3, 100 MHz): d 14.4, 33.2, 53.8,
62.3, 72.4, 105.3, 110.0, 120.1, 121.3, 123.4, 127.2,
127.5, 128.5, 129.0, 129.4, 135.4, 136.5, 137.6, 139.7,
150.6, 156.1; HRMS (ESI) calcd for [C21H23N3NaO4]+
(M+Na+): 404.1586; found: 404.1581.
Data for methyl (E,E)-2-(2-((((1-(6-fluoro-1-methyl-
indol-2-yl)ethylidene)amino)oxy)methyl)phenyl)-2-
methoxy imino acetate (7h). white solid (0.55 g,
89.2%); M.P.: 123.0–124.3 °C; 1H NMR (CDCl3, 400 MHz):
d 2.24 (s, 3H, N=C-CH3), 3.69 (s, 3H, N-CH3), 3.80 (s, 3H,
O=C-OCH3), 4.01 (s, 3H, N-OCH3), 5.12 (s, 2H, O-CH2),
6.80 (d, J = 0.4 Hz, 1H, N-C=CH), 6.80–6.86 (m, 1H, ArH),
6.93 (dd, J = 10.0, 2.0 Hz, 1H, ArH), 7.20 (dd, J = 7.2,
1.2 Hz, 1H, ArH), 7.35–7.44 (m, 2H, ArH), 7.45–7.49 (m,
2H, ArH); 13C NMR (CDCl3, 100 MHz): d 14.0, 33.4, 53.2,
64.1, 75.1, 96.2 (d, JCF = 26.2 Hz), 105.2, 109.0 (d,
JCF = 24.6 Hz), 122.1 (d, JCF = 10.2 Hz), 123.6, 128.0,
128.9, 129.1, 129.6, 130.2, 136.0 (d, JCF = 3.9 Hz), 136.9,
139.9 (d, JCF = 12.1 Hz), 150.0, 150.3, 161.0 (d,
JCF = 237.8 Hz), 163.6; HRMS (ESI) calcd for
[C22H22FN3NaO4]+ (M+Na+): 434.1487; found: 434.1492.
Data for (E)-N-methoxy-N-(2-((1-(6-chloro-1-methyl-
indol-2-yl)ethylidene)aminooxymethyl)phenyl)
carbamic acid methyl ester (7k). yellow solid (0.47 g,
1
75.5%); M.P.: 98.8–99.0 °C; H NMR (CDCl3, 400 MHz): d
2.33 (s, 3H, N=C-CH3), 3.76 (s, 3H, N-OCH3), 3.77 (s, 3H,
O=C-OCH3), 3.78 (s, 3H, H-N-CH3), 5.29 (s, 2H, O-CH2),
6.70 (d, J = 0.8 Hz, 1H, N-C=CH), 7.05 (dd, J = 8.4,
1.2 Hz, 1H, ArH), 7.27–7.28 (m, 1H, ArH), 7.34–7.40 (m,
3H, ArH), 7.48 (d, J = 8.4 Hz, 1H, ArH), 7.52–7.55 (m, 1H,
ArH); 13C NMR (CDCl3, 100 MHz): d 14.4, 33.4, 53.8, 62.4,
72.5, 105.2, 110.0, 120.9, 122.1, 125.7, 127.6, 128.6,
129.0, 129.3, 129.4, 136.2, 136.3, 137.6, 140.1, 150.3,
156.1; HRMS (ESI) calcd for [C21H22FClN3NaO4]+ (M+Na+):
438.1191; found: 438.1188.
Data for methyl (E,E)-2-(2-((((1-(5-fluoro-1-methyl-
indol-2-yl)ethylidene)amino)oxy)methyl)phenyl)-2-
methoxy imino acetate (7i). pale yellow solid (0.57 g,
92.5%); M.P.: 90.5–92.1 °C; 1H NMR (CDCl3, 400 MHz):
d 2.25 (s, 3H, N=C-CH3), 3.72 (s, 3H, N-CH3), 3.80 (s,
3H, O=C-OCH3), 4.01 (s, 3H, N-OCH3), 5.12 (s, 2H, O-
CH2), 6.65 (d, J = 0.4 Hz, 1H, N-C=CH), 6.95–7.01 (m,
1H, ArH), 7.15–7.22 (m, 2H, ArH), 7.35–7.44 (m, 2H, ArH),
7.47 (dd, J = 7.6, 1.2 Hz, 1H, ArH); 13C NMR (CDCl3,
100 MHz): d 14.2, 33.4, 53.2, 64.1, 75.2, 104.8 (d,
JCF = 4.9 Hz), 105.7 (d, JCF = 23.1 Hz), 110.7 (d,
Data for (E)-N-methoxy-N-(2-((1-(6-fluoro-1-methyl-
indol-2-yl)ethylidene)aminooxymethyl)phenyl)
carbamic acid methyl ester (7 l). yellow oil (0.36 g,
60.1%); 1H NMR (CDCl3, 400 MHz): d 2.33 (s, 3H, N=C-
CH3), 3.76 (s, 3H, N-OCH3), 3.77 (s, 3H, O=C-OCH3),
Chem Biol Drug Des 2014
7

Xie et al.
3.78 (s, 3H, H-N-CH3), 5.29 (s, 2H, O-CH2), 6.71 (s, 1H,
N-C=CH), 6.81–6.87 (m, 1H, ArH), 6.94 (dd, J = 10.0,
2.0 Hz, 1H, ArH), 7.35–7.40 (m, 3H, ArH), 7.48 (dd,
J = 8.4, 5.2 Hz, 1H, ArH), 7.53–7.55 (m, 1H, ArH); 13C
NMR (CDCl3, 100 MHz): d 14.3, 33.5, 53.8, 62.4, 72.5,
96.3 (d, JCF = 26.3 Hz), 105.3, 109.0 (d, JCF = 24.7 Hz),
122.2 (d, JCF = 10.1 Hz), 123.6, 127.6, 128.6, 129.0,
129.4, 136.0 (d, JCF = 3.8 Hz), 136.4, 137.6, 140.0 (d,
JCF = 12.0 Hz), 150.3, 156.1, 161.0 (d, JCF = 237.9 Hz);
HRMS (ESI) calcd for [C21H22FN3NaO4]+ (M+Na+):
422.1487; found: 422.1486.
139.7, 150.4, 151.6, 163.2; HRMS (ESI) calcd for
[C22H24N4NaO3]+ (M+Na+): 415.1741; found: 415.1738.
Data for (E,E)-2-(2-((1-(6-chloro-1-methyl-indol-2-yl)
ethylidene)aminooxymethyl)phenyl)-2-methoxyimino-
N-methylacetamide (7o). Pale yellow solid (0.28 g,
65.7%); M.P.: 169.4–170.5 °C; 1H NMR (CDCl3,
400 MHz): d 2.24 (s, 3H, N=C-CH3), 2.88 (d, J = 5.2 Hz,
3H, H-N-CH3), 3.71 (s, 3H, C-N-CH3), 3.93 (s, 3H, N-
OCH3), 5.12 (s, 2H, O-CH2), 6.66 (d, J = 0.8 Hz, 1H, N-
C=CH), 6.74–6.76 (m, 1H, NH), 7.03 (dd, J = 8.4, 2.0 Hz,
1H, ArH), 7.19 (dd, J = 7.2, 1.6 Hz, 1H, ArH), 7.25–7.27
(m, 1H, ArH), 7.34–7.43 (m, 2H, ArH), 7.45–7.49 (m, 2H,
ArH); 13C NMR (CDCl3, 100 MHz): d 14.1, 26.5, 33.4,
63.6, 75.3, 105.0, 110.0, 120.8, 122.1, 125.7, 127.9,
129.0, 129.2, 129.3, 129.5, 129.9, 136.4, 137.0, 140.1,
Data for (E)-N-methoxy-N-(2-((1-(5-fluoro-1-methyl-
indol-2-yl)ethylidene)aminooxymethyl)phenyl)
carbamic acid methyl ester (7 m). yellow oil (0.50 g,
73.5%); 1H NMR (CDCl3, 400 MHz): d 2.33 (s, 3H, N=C-
CH3), 3.76 (s, 3H, N-OCH3), 3.78 (s, 3H, O=C-OCH3),
3.79 (s, 3H, H-N-CH3), 5.30 (s, 2H, O-CH2), 6.68 (d,
J = 0.8 Hz, 1H, N-C=CH), 6.95–7.01 (m, 1H, ArH), 7.17–
7.23 (m, 2H, ArH), 7.35–7.40 (m, 3H, ArH), 7.53–7.55 (m,
1H, ArH); 13C NMR (CDCl3, 100 MHz): d 14.4, 33.4, 53.8,
150.1,
151.6,
163.2;
HRMS
(ESI)
calcd
for
[C22H23ClN4NaO3]+ (M+Na+): 449.1351; found: 449.1353.
Data for (E,E)-2-(2-((1-(6-fluoro-1-methyl-indol-2-yl)
ethylidene)aminooxymethyl)phenyl)-2-methoxyimino-
N-methylacetamide (7p). Yellow solid (0.25 g, 60.9%);
M.P.: 167.9–168.7 °C; 1H NMR (CDCl3, 400 MHz): d 2.24
(s, 3H, N=C-CH3), 2.88 (d, J = 4.8 Hz, 3H, H-N-CH3),
3.70 (s, 3H, C-N-CH3), 3.93 (s, 3H, N-OCH3), 5.12 (s, 2H,
O-CH2), 6.67 (d, J = 0.4 Hz, 1H, N-C=CH), 6.74–6.76 (m,
1H, NH), 6.81–6.86 (m, 1H, ArH), 6.93 (dd, J = 10.0,
2.0 Hz, 1H, ArH), 7.20 (dd, J = 7.2, 1.2 Hz, 1H, ArH),
7.36–7.41 (m, 2H, ArH), 7.45–7.49 (m, 2H, ArH); 13C NMR
(CDCl3, 100 MHz): d 14.1, 26.5, 33.5, 63.6, 75.2, 96.3 (d,
JCF = 26.3 Hz), 105.1, 109.0 (d, JCF = 24.6 Hz), 122.1 (d,
JCF = 10.1 Hz), 123.7, 127.9, 129.0, 129.1, 129.5, 129.9,
136.1 (d, JCF = 3.8 Hz), 137.0, 139.9 (d, JCF = 12.0 Hz),
150.2, 151.6, 161.0 (d, JCF = 237.6 Hz), 163.2; HRMS
(ESI) calcd for [C22H23FN4NaO3]+ (M+Na+): 433.1646;
found: 433.1644.
62.4,
72.5,
104.9
(d,
JCF = 4.9 Hz),
105.6(d,
JCF = 23.2 Hz), 110.7 (d, JCF = 9.6 Hz), 111.9 (d,
JCF = 26.2 Hz), 127.2 (d, JCF = 10.3 Hz), 127.6, 128.6,
129.0, 129.4, 136.3, 136.3, 136.8, 137.6, 150.4, 156.1,
158.2 (d, JCF = 233.5 Hz). HRMS (ESI) calcd for
[C21H22FN3NaO4]+ (M+Na+): 422.1487; found: 422.1481.
a-(methoxyimino)-N-methyl-phenylacetamide
oxime ethers (7n–q)
A mixture of the corresponding methyl a-(methoxyimino)
benzeneacetate oxime ethers (7f–i, 1 mmol) and methyl-
amine (0.74 g, 6 mmol, 25% in water) was heated for 1.0–
11.0 h in 10 mL of methanol under reflux. Then, the reac-
tion mixture was cooled to room temperature and
extracted with ethyl acetate. The combined organic layers
were dried over anhydrous Na2SO4 and concentrated
under vacuum. The residue was purified by flash chroma-
tography using a 1:3 (v/v) mixture of ethyl acetate and
petroleum ether (boiling point range 60–90 °C) as the elut-
ing solution to afford the corresponding title compounds
a-(methoxyimino)-N-methyl-phenylacetamide oxime ethers
(7n–q).
Data for (E,E)-2-(2-((1-(5-fluoro-1-methyl-indol-2-yl)
ethylidene)aminooxymethyl)phenyl)-2-methoxyimino-
N-methylacetamide (7q). Yellow solid (0.35 g, 85.3%);
M.P.: 139.0–139.8 °C; 1H NMR (CDCl3, 400 MHz): d 2.25
(s, 3H, N=C-CH3), 2.88 (d, J = 5.2 Hz, 3H, H-N-CH3),
3.72 (s, 3H, C-N-CH3), 3.93 (s, 3H, N-OCH3), 5.13 (s, 2H,
O-CH2), 6.65 (d, J = 0.4 Hz, 1H, N-C=CH), 6.75–6.77 (m,
1H, NH), 6.95–6.70 (m, 1H, ArH), 7.16–7.22 (m, 3H, ArH),
7.34–7.43 (m, 2H, ArH), 7.47–7.49 (m, 2H, ArH); 13C NMR
(CDCl3, 100 MHz): d 14.2, 26.5, 33.4, 63.6, 75.3, 104.6
(d, JCF = 5.0 Hz), 105.7 (d, JCF = 23.2 Hz), 110.7 (d,
JCF = 9.5 Hz), 111.8 (d, JCF = 26.3 Hz), 127.2 (d,
JCF = 10.4 Hz), 127.9, 129.0, 129.1, 129.5, 129.9, 136.3,
137.0, 137.0, 150.2, 151.6, 158.1 (d, JCF = 233.3 Hz),
163.1; HRMS (ESI) calcd for [C22H23FN4NaO3]+ (M+Na+):
433.1646; found: 433.1645.
Data for (E,E)-2-(2-((1-(1-methyl-indol-2-yl)ethylidene)
aminooxymethyl)phenyl)-2-methoxyimino-N-
methylacetamide (7n). White solid (0.28 g, 71.6%);
M.P.: 163.6–164.2 °C; 1H NMR (CDCl3, 400 MHz): d 2.26
(s, 3H, N=C-CH3), 2.86 (d, J = 5.2 Hz, 3H, H-N-CH3),
3.76 (s, 3H, C-N-CH3), 3.93 (s, 3H, N-OCH3), 5.13 (s, 2H,
O-CH2), 6.71 (d, J = 0.4 Hz, 1H, N-C=CH), 6.73–6.74 (m,
1H, NH), 7.05–7.10 (m, 1H, ArH), 7.18–7.21 (m, 1H, ArH),
7.22–7.25 (m, 1H, ArH), 7.28 (d, J = 7.6 Hz, 1H, ArH),
7.34–7.43 (m, 2H, ArH), 7.47–7.50 (m, 2H, ArH), 7.57 (d,
J = 7.6 Hz, 1H, ArH); 13C NMR (CDCl3, 100 MHz): d 14.2,
26.5, 33.2, 63.6, 75.2, 105.1, 110.0, 120.0, 121.2, 123.4,
127.2, 127.9, 129.1, 129.1, 129.5, 129.9, 135.5, 137.0,
1-methoxy-3-methyl-1-phenyl-ureas (7r–u)
A mixture of the corresponding N-methoxy-carbamic acid
methyl esters (7j–m, 1 mmol) and methylamine (0.74 g,
8
Chem Biol Drug Des 2014

Indole Substituted Strobilurin Derivatives
6 mmol, 25% in water) was heated for 26.5–82.0 h in
10 mL of methanol under reflux. Then, the reaction mix-
ture was cooled to room temperature and extracted with
ethyl acetate. The combined organic layers were dried
over anhydrous Na2SO4 and concentrated under vacuum.
The residue was purified by flash chromatography using a
1:3 (v/v) mixture of ethyl acetate and petroleum ether (boil-
ing point range 60–90 °C) as the eluting solution to afford
the corresponding title compounds 1-methoxy-3-methyl-1-
phenyl-ureas (7r–u).
calcd for [C21H23FN4NaO3]+ (M+Na+): 421.1646; found:
421.1649.
Data for (E)-1-methoxy-3-methyl-1-(2-((((1-(5-fluoro-1-
methyl-indol-2-yl)ethylidene)amino)oxy)methyl)
phenyl)urea (7u). Brown solid (0.23 g, 57.8%); M.P.:
93.7–94.4 °C; 1H NMR (CDCl3, 500 MHz): d 2.33 (s, 3H,
N=C-CH3), 2.89 (d, J = 5.0 Hz, 3H, N-CH3), 3.68 (s, 3H,
C-N-CH3), 3.81 (s, 3H, N-OCH3), 5.36 (s, 2H, O-CH2),
5.98 (d, J = 4.5 Hz, 1H, NH), 6.67 (s, 1H, N-C=CH),
6.96–7.00 (m, 1H, ArH), 7.17–7.22 (m, 2H, ArH), 7.31–
7.38 (m, 3H, ArH), 7.51–7.53 (m, 1H, ArH); 13C NMR
(CDCl3, 125 MHz): d 14.4, 27.1, 33.5, 62.1, 72.7, 104.8
(d, JCF = 4.9 Hz), 105.7 (d, JCF = 22.9 Hz), 110.7 (d,
JCF = 9.6 Hz), 111.8 (d, JCF = 26.3 Hz), 125.8, 127.3 (d,
JCF = 10.8 Hz), 128.2, 128.5, 129.0, 136.3, 137.0, 137.1,
139.1, 150.1, 158.2 (d, JCF = 233.5 Hz), 158.5; HRMS
(ESI) calcd for [C21H23FN4NaO3]+ (M+Na+): 421.1646;
found: 421.1641.
Data for (E)-1-methoxy-3-methyl-1-(2-((((1-(1-methyl-
indol-2-yl)ethylidene)amino)oxy)methyl)phenyl)urea
(7r). Brown oil (0.16 g, 42.7%); 1H NMR (CDCl3,
400 MHz): d 2.35 (s, 3H, N=C-CH3), 2.89 (d, J = 0.4 Hz,
3H, N-CH3), 3.67 (s, 3H, C-N-CH3), 3.83 (s, 3H, N-OCH3),
5.36 (s, 2H, O-CH2), 5.97–5.98 (m, 1H, NH), 6.73 (d,
J = 0.4 Hz, 1H, N-C=CH), 7.06–7.10 (m, 1H, ArH), 7.21–
7.26 (m, 1H, ArH), 7.27–7.29 (m, 1H, ArH), 7.31–7.38 (m,
3H, ArH), 7.51–7.55 (m, 1H, ArH), 7.58 (d, J = 8.0 Hz,
1H, ArH), 7.69–7.72 (m, 1H, ArH); 13C NMR (CDCl3,
100 MHz): d 14.4, 27.1, 33.3, 62.1, 72.5, 105.1, 110.0,
120.0, 121.2, 123.3, 125.7, 127.2, 128.2, 128.4, 129.0,
135.6, 137.1, 139.0, 139.7, 150.3, 158.5; HRMS (ESI)
calcd for [C21H24N4NaO3]+ (M+Na+): 403.1741; found:
403.1738.
Biological assay (24–27)
The fungicidal activities of title compounds 7 against Py-
ricularia oryzae and Botrytis cinerea in vitro were tested
according to the following procedure: The synthesized
title compounds (0.0111 g) were dissolved in 0.5 mL of
DMF and then mixed rapidly with thawed potato glucose
agar culture medium under 50 °C to the tested concen-
trations. The mixtures were poured into Petri dishes.
After the dishes were cooled to room temperature, the
solidified plates were incubated with 4 mm mycelium
disk at 28 °C for 48 h. Water was used as the blank
control. The mycelial elongation radius (mm) of fungi set-
tlements was measured after 48 h of culture. The growth
inhibition rates were calculated with the following equa-
tion: I = [(C – T)/C] 9 100%. Here, I is the growth inhibi-
tion rate (%), C is the control settlement radius (mm),
and T is the treatment group fungi settlement radius
(mm).
Data for (E)-1-methoxy-3-methyl-1-(2-((((1-(6-chloro-1-
methyl-indol-2-yl)ethylidene)amino)oxy)methyl)
phenyl)urea (7s). Pale yellow solid (0.12 g, 29.0%);
1
M.P.: 92.9–93.6 °C; H NMR (CDCl3, 400 MHz): d 2.33 (s,
3H, N=C-CH3), 2.89 (d, J = 4.8 Hz, 3H, N-CH3), 3.68 (s,
3H, C-N-CH3), 3.79 (s, 3H, N-OCH3), 5.36 (s, 2H, O-CH2),
5.98–6.00 (m, 1H, NH), 6.69 (d, J = 0.8 Hz, 1H, N-
C=CH), 7.04 (dd, J = 8.4, 1.6 Hz, 1H, ArH), 7.26–7.28 (m,
1H, ArH), 7.31–7.38 (m, 3H, ArH), 7.47 (d, J = 8.4 Hz,
1H, ArH), 7.51–7.54 (m, 1H, ArH); 13C NMR (CDCl3,
100 MHz): d 14.4, 27.1, 33.5, 62.1, 72.7, 105.1, 110.0,
120.8, 122.1, 125.7, 125.7, 128.2, 128.5, 128.9, 129.2,
136.4, 136.9, 139.0, 140.1, 150.0, 158.5; HRMS (ESI)
calcd for [C21H23ClN4NaO3]+ (M+Na+): 437.1351; found:
437.1345.
The fungicidal activities of title compounds 7 against
Erysiphe graminis, Colletotrichum lagenarium, Pseudop-
eronospora cubensis, and Puccinia sorghi Schw. in vivo
were tested according to the following procedure: The
synthesized title compounds (0.0111 g) were dissolved in
0.5 mL of DMF, and then distilled water (containing
0.1% Tween-80) was added to the solution. The solution
was diluted to the tested concentration and sprayed
onto the plants and allowed to dry for 2 h. Twenty-four
hours later, the plants were inoculated with fungal
spores. Each test utilized control plants which were
sprayed with a 1:1:2 (by volume) mixture of acetone,
methanol, and water (containing 0.1% Tween-80) and
inoculated with fungal spores. The results are percent
disease control as compared to the untreated check,
wherein 100 is rated as complete disease control and 0
as no disease control.
Data for (E)-1-methoxy-3-methyl-1-(2-((((1-(6-fluoro-1-
methyl-indol-2-yl)ethylidene)amino)oxy)methyl)
phenyl)urea (7t). Brown solid (0.21 g, 52.7%); M.P.:
1
99.4–101.3 °C; H NMR (CDCl3, 400 MHz): d 2.33 (s, 3H,
N=C-CH3), 2.89 (d, J = 4.8 Hz, 3H, N-CH3), 3.68 (s, 3H,
C-N-CH3), 3.77 (s, 3H, N-OCH3), 5.35 (s, 2H, O-CH2),
5.98–6.00 (m, 1H, NH), 6.70 (s, 1H, N-C=CH), 6.81–6.87
(m, 1H, ArH), 6.94 (dd, J = 10.0, 2.0 Hz, 1H, ArH), 7.30–
7.38 (m, 3H, ArH), 7.46–7.54 (m, 2H, ArH); 13C NMR
(CDCl3, 100 MHz): d 14.3, 27.1, 33.6, 62.1, 72.6, 96.3 (d,
JCF = 26.2 Hz), 105.2, 109.0 (d, JCF = 24.7 Hz), 122.1 (d,
JCF = 10.1 Hz), 123.6, 125.8, 128.2, 128.5, 128.9, 136.2
(d, JCF = 3.7 Hz), 137.0, 139.0, 139.9 (d, JCF = 11.9 Hz),
150.1, 158.5, 161.0 (d, JCF = 237.7 Hz); HRMS (ESI)
Chem Biol Drug Des 2014
9

Xie et al.
The results are listed in Tables 1 and 2. To make a
judgment on the fungicidal potency of the synthesized
compounds, Enoxastrobin was used as the standard.
dichloromethane according to the precedent literature (28,
29). The intermediate 2-aminobenzaldehyde derivatives
(2b–d) were provided through the reaction of 2-bromo-
benzaldehyde derivatives (1b–d) with 1.8 equiv of sodium
azide according to the literature (30, 31).
Results and Discussion
The intermediate 2,2,2-trifluoro-N-(2-formylphenyl)acetam-
ide derivatives (3a–d) were prepared through the reaction
of 2-aminobenzaldehyde derivatives (2b–d) with 1.6 equiv
of trifluoroacetic anhydride in the presence of azabenzene
and dichloromethane. Then, 2,2,2-trifluoro-N-(2-formylphe-
nyl)acetamide derivatives (3a–d) were reacted with 1.2
equiv of 1-chloropropan-2-one in the presence of PEG-
400 and 3.0 equiv of K2CO3 to afford the intermediate 1-
(1H-indol-2-yl)ethanone derivatives (4a–d) according to
previous report (32).
Synthetic Chemistry
The synthesis of 2-aminobenzaldehyde derivatives (2a and
2b–d, respectively) necessitated a different synthetic plan
as shown in Scheme 1, as (2-aminophenyl)methanol deriv-
atives except (2-aminophenyl)methanol (1a) are too expen-
sive comparing with 2-bromobenzaldehyde derivatives
(1b–d). The intermediate 2-aminobenzaldehyde (2a) was
provided through the oxidation reaction of (2-aminophenyl)
methanol (1a) with 4.0 equiv of MnO2 in the presence of
Table 1: Chemical structures and fungicidal activity of title compounds 7 (inhibition %)
H
R2
Q
N
R3
N
R1
O
H
O
O
O
O
O
N
O
O
N
O
O
O
O
N
H
N
O
N
N
H
O
, Q4
=
, Q5 =
Q1
=
, Q2
=
, Q3 =
Substituents
Testing concentration (mg/L)
In vitro
In vivo
100
25
Pyricularia
oryzae
Botrytis
cinerea
Erysiphe
graminis
Colletotrichum
lagenarium
Pseudoperonospora
cubensis
Puccinia sorghi
Schw.
No.
R1
R2
R3
Q
7a
7b
H
H
Cl
F
H
H
Cl
F
H
H
Cl
F
H
H
Cl
F
H
H
H
H
F
H
H
H
F
H
H
H
F
H
H
H
F
H
Q1
Q1
Q1
Q1
Q1
Q2
Q2
Q2
Q2
Q3
Q3
Q3
Q3
Q4
Q4
Q4
Q4
Q5
Q5
Q5
Q5
80
100
50
50
100
80
80
80
80
100
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
0
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
100
98
100
100
100
98
100
100
90
100
100
100
100
98
98
98
100
100
98
98
98
95
0
50
98
50
75
75
0
0
0
0
0
0
0
30
45
0
0
0
0
0
98
100
95
98
100
98
98
85
98
95
95
85
98
95
98
98
98
98
95
60
95
95
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
80
80
7n
7o
100
100
100
100
80
80
80
100
50
7p
7q
50
0
H
H
Cl
F
7r
7s
H
H
H
F
80
50
80
80
100
7t
7u
H
85
100
0
40
Enoxastrobin
10
Chem Biol Drug Des 2014

Indole Substituted Strobilurin Derivatives
Table 2: The in vivo fungicidal activity of title compounds 7 (inhibition %)
H
R2
Q
N
R3
N
R1
O
H
O
O
O
O
O
N
O
O
N
O
O
O
O
N
H
N
O
N
N
H
O
, Q4 =
, Q5 =
Q1 =
, Q2 =
, Q3 =
Substituents
Testing concentration (mg/L)
6.25
No.
R1
R2
R3
Q
Erysiphe graminis
Colletotrichum lagenarium
Puccinia sorghi Schw.
7a
7b
H
H
Cl
F
H
H
Cl
F
H
H
Cl
F
H
H
Cl
F
H
H
H
H
F
H
H
H
F
H
H
H
F
H
H
H
F
H
Q1
Q1
Q1
Q1
Q1
Q2
Q2
Q2
Q2
Q3
Q3
Q3
Q3
Q4
Q4
Q4
Q4
Q5
Q5
Q5
Q5
50
95
75
90
99
15
40
45
60
85
100
95
100
88
98
95
100
40
70
///
0
80
20
65
75
30
35
25
10
10
20
30
30
0
40
70
20
30
45
0
100
90
90
90
60
0
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
7c
7d
7e
7f
7g
0
7h
7i
60
20
40
70
90
0
60
90
90
90
85
100
///
7j
7k
7l
7m
7n
7o
7p
7q
H
H
Cl
F
7r
7s
H
H
H
F
7t
7u
H
70
100
10
85
90
100
Enoxastrobin
81.6% of target intermediate (E)-1-(1H-indol-2-yl)ethanone
oxime (6a) and 18.4% of by-product (Z)-1-(1H-indol-2-yl)
ethanone oxime (6a–1, Figure 2) were produced by the
reaction of 1-(1H-indol-2-yl)ethanone (4a) with 1.5 equiv of
hydroxylamine hydrochloride and 1.5 equiv of sodium ace-
tate trihydrate in the presence of a 2:1 (v/v) mixture of eth-
anol and water under reflux according to a previously
described method (33, 34). However, it is too difficult to
purify the target intermediate (E)-1-(1H-indol-2-yl)ethanone
oxime (6a) by recrystallization from the mixture of (E)-1-
(1H-indol-2-yl)ethanone oxime (6a) and (Z)-1-(1H-indol-2-
yl)ethanone oxime (6a–1), leading the target compound 6a
was obtained only in the yield of 24.1%. From the best of
our experiences, the presence of intramolecular hydrogen
bond in the molecule of cis-by-product made the by-prod-
uct (Z)-1-(1H-indol-2-yl)ethanone oxime (6a–1) stable and
promoted the generation of (Z)-1-(1H-indol-2-yl)ethanone
oxime (6a–1), which could provide proper explain to the
above experimental result.
Considering the analysis of the above experimental results,
the active hydrogen in the molecular of 1-(1H-indol-2-yl)
ethanone derivatives (4a–d) should be protected before
their oximation reaction. So the 1-(1-methyl-indol-2-yl)etha-
none derivatives (5a–d) were produced by the reaction of
1-(1H-indol-2-yl)ethanone derivatives (4a–d) with 3.2 equiv
of iodomethane and 1.0 equiv of K2CO3 in the presence
of anhydrous acetonitrile according to the precedent litera-
ture (35).
N
N
Much to our surprise, the 1-(1-methyl-indol-2-yl)ethanone
derivatives (5a–d) were reacted with 1.5 equiv of hydroxyl-
amine hydrochloridean and 1.5 equiv of sodium acetate
HO
H
Figure 2: The structure of compound 6a–1.
Chem Biol Drug Des 2014
11

Xie et al.
trihydrate in the presence of a 2:1 (v/v) mixture of ethanol
and water under reflux to produce (E)-1-(1-methyl-indol-2-
yl)ethanone oxime derivatives (6b–e) in excellent yields
which are more than 98%.
methyl esters compounds 7j–m exhibited better fungi-
cidal activities against E. graminis but lower fungicidal
activities against P. sorghi Schw. compared to the
corresponding ammonolysis products 1-methoxy-3-
methyl-1-phenyl-ureas (7r–u).
The title compounds (7a–m) were obtained by reaction of
ethanone oximes (6a–e) with (E)-methyl 2-(2-(chloromethyl)
phenyl)-3-methoxyacrylate (A), (E)-methyl 2-(2-(bromom-
ethyl)phenyl)-2-methoxyiminoacetate (B), or methyl (2-(bro-
momethyl)phenyl)methoxycarbamate (C) in the presence of
a base and solvent according to the literature protocol
(15,18). The title compounds (7n–q and 7r–u) were pro-
duced by ammonolysis of the corresponding title com-
pounds methyl a-(methoxyimino)benzeneacetate oxime
ethers (7f–i) and N-methoxy-carbamic acid methyl esters
(7j–m) according to a literature protocol (8).
Conclusion
A series of compounds containing indole moiety were
designed and synthesized by modifying the side chain of
unsaturated oxime ether strobilurin fungicide Enoxastrobin.
Most of these synthesized compounds showed moderate
or potent fungicidal activities against the tested five fungi.
The structure–activity relationship demonstrated that the
synthesized methyl 3-methoxypropenoate oxime ethers
7b–e exhibited remarkably high activities among all the
synthesized oxime ether compounds 7. Moreover, the fun-
gicidal activities of methyl a-(methoxyimino)benzeneacetate
oxime ethers compounds 7f–i and N-methoxy-carbamic
acid methyl esters compounds 7j–m showed significant
differences compared to the corresponding products of
ammonolysis.
Biological activity and structure–activity
relationship
The in vitro fungicidal activity results for compounds 7
against P. oryzae and B. cinerea at the concentration of
25 mg/L are listed in Table 1. The results of the prelimin-
ary bioassays were compared to those of Enoxastrobin.
Compounds
7
exhibited potent fungicidal activities
against the tested fungi. All the title compounds were
more potent or exhibited a similar potency for in vitro
fungicidal activities against P. oryzae compared to
Enoxastrobin.
Acknowledgments
This work was supported by National Nature Science
Foundation of China Grant (No. 21106119) and the
Fundamental Research Funds for the Central Universities,
P. R. China (No. 2011121019). The authors also thank the
Pesticide Bioactivity Center of SYRICI (Shenyang Research
Institute of Chemical Industry) for the test of biological
activities.
The in vivo fungicidal activity results for compounds 7
against E. graminis, C. lagenarium, P. cubensis, and
P. sorghi Schw. at 100 mg/L are also listed in Table 1.
Most of the compounds showed effective fungicidal activi-
ties to some extent. Almost all compounds 7 exhibited
nearly 100% growth inhibition against E. graminis, C. la-
genarium and P. sorghi Schw. but lower activities against
P. cubensis. However, some compounds possessed bet-
ter fungicidal activities against P. cubensis than that of E-
noxastrobin.
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