Synthesis and fungicidal activities of novel benzothiophene-substituted oxime ether strobilurins

Article abstract of DOI:10.1016/j.bmcl.2014.03.024

Twenty-one novel benzothiophene-substituted oxime ether strobilurins, which employed a benzothiophene group to stabilise the E-styryl group in Enoxastrobin (an unsaturated oxime strobilurin fungicide developed by Shenyang Research Institute of Chemical Industry, China) were designed and synthesised. The biological assay indicated that most compounds exhibited good or excellent fungicidal activities, especially against Colletotrichum lagenarium and Puccinia sorghi Schw. In addition, methyl 3-methoxypropenoate oxime ethers and N-methoxy-carbamic acid methyl esters exhibited good in vivo fungicidal activities against Erysiphe graminis, Colletotrichum lagenarium and Puccinia sorghi Schw. under the tested concentrations. Notably, (E,E)-methyl 3-methoxy-2-(2-((((6-chloro-1-(1H-benzo[b]thien-2-yl)ethylidene)amino)oxy) methyl)phenyl)propenoate (5E) exhibited more potent in vivo fungicidal activities against nearly all of the tested fungi at a concentration of 0.39 mg/L compared to Enoxastrobin.

Full text of DOI:10.1016/j.bmcl.2014.03.024

Bioorganic & Medicinal Chemistry Letters 24 (2014) 2173–2176
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and fungicidal activities of novel
benzothiophene-substituted oxime ether strobilurins
⇑
Song Tu , Ya-Qiang Xie, Si-Zhe Gui, Li-Yi Ye, Zi-Long Huang, Yi-Bing Huang, Li-Ming Che
Department of Chemical and Biochemical Engineering, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Twenty-one novel benzothiophene-substituted oxime ether strobilurins, which employed a benzothio-
phene group to stabilise the E-styryl group in Enoxastrobin (an unsaturated oxime strobilurin fungicide
developed by Shenyang Research Institute of Chemical Industry, China) were designed and synthesised.
The biological assay indicated that most compounds exhibited good or excellent fungicidal activities,
especially against Colletotrichum lagenarium and Puccinia sorghi Schw. In addition, methyl 3-methoxy-
propenoate oxime ethers and N-methoxy-carbamic acid methyl esters exhibited good in vivo fungicidal
activities against Erysiphe graminis, Colletotrichum lagenarium and Puccinia sorghi Schw. under the tested
concentrations. Notably, (E,E)-methyl 3-methoxy-2-(2-((((6-chloro-1-(1H-benzo[b]thien-2-yl)ethyli-
dene)amino)oxy)methyl)phenyl)propenoate (5E) exhibited more potent in vivo fungicidal activities
against nearly all of the tested fungi at a concentration of 0.39 mg/L compared to Enoxastrobin.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 28 January 2014
Revised 6 March 2014
Accepted 8 March 2014
Available online 26 March 2014
Keywords:
Benzothiophene
Oxime ether
Strobilurins
Fungicide
Fungicidal activities
Strobilurins are naturally occurring derivatives of b-methoxyac-
rylic acid that comprise an important class of agricultural fungi-
cides.1–4 However, these compounds are natural, and they could
not be used directly due to insufficient photochemical stability
and volatility.2,5 To date, several chemists have published synthetic
analogues of strobilurin A (Fig. 1) to stabilise the triene structure of
the compound.6–14
Compounds I (Fig. 1), which were discovered by the Rohm and
Haas Company [the 4-Cl-substituted derivatives of compounds I
were developed by Shenyang Research Institute of Chemical Indus-
try and named Enoxastrobin (Fig. 1)10], contain an unsaturated
oxime ether group and exhibit effective fungicidal activities.7 In
addition, novel arylcyclopropyl oxime ether compounds II
(Fig. 1), which replace the E-styryl group in compounds I with a
trans-arylcyclopropyl group, have been reported. These com-
pounds exhibit excellent fungicidal activities.8 In our previous
study, we synthesised a series of novel indene–substituted oxime
ethers III (Fig. 1) to study the structure–activity relationships of
this type of compound.12,15 A benzopentatomic ring structure
was used to stabilise the E-styryl group in Enoxastrobin. Most of
the indene–substituted oxime ethers (III) exhibited effective fungi-
cidal activity. In addition, the fungicidal activities of some com-
pounds (III) were better than those of Enoxastrobin.
discovery.16–21 The heterocyclic scaffold of a crop protection agent
often has a positive effect on its synthetic accessibility and its
physicochemical properties, driving values, such as lipophilicity
and solubility toward the optimal balanced range for uptake and
bioavailability.16 Heterocycles are deemed to be perfect bioisoster-
es of other carba- or heterocyclic rings as well as of several differ-
ent functional groups which deliver equal or even better biological
efficacy through their similarity in structural shape and electronic
distribution.16,20 In addition, the substitution of a heteroaryl group
(i.e., pyridine or furane) with one of the aryl residues of the com-
pound results in increased biological activity.21 More importantly,
environmental compatibility of the synthesised organic com-
pounds is enhanced when heteroatoms are introduced into the car-
ba-rings.16,19,20
Based on these facts, a series of novel benzothiophene-substi-
tuted oxime ethers 5 (Fig. 1) utilising a benzothiophene group as
a bioisostere to replace the E-styryl group in Enoxastrobin was syn-
thesised in this Letter. The target compounds (5) were predicted to
retain or further enhance their biological activity and simulta-
neously improve their environmental compatibility. The struc-
ture–activity relationship of this type of compound was also
studied. The biological assay indicated that most compounds (5)
maintained or enhanced their fungicidal activities compared to
Enoxastrobin.
Many heterocyclic compounds have shown good insecticidal or
fungicidal activities, increasing their importance in pesticide
The synthetic route for the target compounds is outlined in
Scheme 1, and the reaction yields were not optimised.
The 2-(ethylthio)-benzaldehyde intermediates (2) were
⇑
Corresponding author. Tel./fax: +86 592 2183751.
E-mail address: tusong@xmu.edu.cn (S. Tu).
prepared according to a previously published protocol.22 the
http://dx.doi.org/10.1016/j.bmcl.2014.03.024
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

2174
S. Tu et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2173–2176
Figure 1. Structure of strobilurin A and its analogues.
2-chlorobenzaldehydes (1) were reacted with 1.4 equiv of etha-
nethiol in the presence of 1.4 equiv of sodium hydroxide and
0.03 equiv of tetrabutylammonium bromide at 82 °C for 4.0–6.0 h
to afford 2-(ethylthio)-benzaldehydes (2A, 2B, 2C and 2E).
2,4-Dichlorobenzaldehyde was reacted with 2.8 equiv of ethaneth-
iol in the presence of 2.8 equiv of sodium hydroxide and 0.06 equiv
of tetrabutylammonium bromide at 82 °C for 2.5 h to yield
2,4-bis(ethylthio)benzaldehyde (2D). When 2,4-dichlorobenzalde-
hyde (R1 = 4-Cl) was used to synthesis 2E, significant byproduct,
presumably from the reaction of 4-Cl in 2,4-dichlorobenzaldehyde
with ethanethiol, made isolation of the product difficult. Due to
the low yielding nature of this reaction and difficulties with purifi-
cation, only one derivative where R1 = 6-Cl (5E) were synthesized.
Second, according to the literature,22 the 2-(ethylthio)-benzal-
dehydes (2) were reacted with 1.25 equiv of 1-chloropropan-2-
one in the presence of 1.25 equiv of potassium carbonate at 59 °C
to afford 1-(benzo[b]thiophen-2-yl)ethanones (3) in good yields.
Then, according to
a
previously described method,23 the
1-(benzo[b]thiophen-2-yl)ethanones (3) were reacted with
1.5 equiv of hydroxylamine hydrochloride and 1.5 equiv of sodium
acetate trihydrate in the presence of a 2:1 (v/v) mixture of ethanol
and water under reflux to produce (E)-1-(1H-benzo[b]thien-
2-yl)ethanoneoximes (4) in high yields.
Next, the target compounds (5A–M) were obtained by reaction of
ethanone oximes (4) with (E)-methyl 2-(2-(chloromethyl)phenyl)-
3-methoxypropenoate (A), (E)-methyl 2-(2-(bromomethyl)
Scheme 1. General synthetic route for the target compounds 5. Reagents and conditions: (a) NaOH, H2O, tetrabutylammonium bromide, ethanethiol, 82 °C, 4.0–6.0 h; (b)
1-chloropropan-2-one, CaO, acetone, 59 °C, 10.0–14.0 h; (c) hydroxylamine hydrochloride, sodium acetate, 2:1 (v/v) mixture of ethanol and H2O, reflux, 0.5–9.5 h; (d–f)
K2CO3, anhydrous acetonitrile, reflux, 5.0–14.5 h; (g and h) CH3NH2, methanol, reflux, 0.5–18.0 h.

S. Tu et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2173–2176
2175
phenyl)-2-methoxyiminoacetate (B) or methyl (2-(bromomethyl)-
phenyl)methoxycarbamate (C) in the presence of a base and solvent
according to a literature protocol.15,21 The target compounds (5N–Q
and 5R–U) were produced by ammonolysisofthe correspondingtar-
Schw. at 100 mg/L (Table 1). Most of the compounds exhibited
effective fungicidal activities. Some compounds exhibited better
fungicidal activities against E. graminis, C. lagenarium and P. sorghi
Schw. but lower activities against P. cubensis compared to Enox-
astrobin. In addition, all of the synthesised methyl 3-methoxy-
propenoate oxime ethers (5A–E) and N-methoxy-carbamic acid
methyl esters (5J–M) exhibited substantial fungicidal activities
against E. graminis, C. lagenarium and P. sorghi Schw.
Compounds 5A–E and 5J–M were tested in vivo against
E. graminis, C. lagenarium and P. sorghi Schw. at lower concentra-
tions (Table 2). The results indicate that 5A–E and 5J–M exhibited
good fungicidal activities against E. graminis, C. lagenarium and
P. sorghi Schw. at a concentration of 1.56 mg/L. Especially, the
6-chlorobenzothiophene-substituted compound (5E) was the
most promising candidate for further study because it exhibited
more potent fungicidal activities against nearly all of the tested
fungi at 0.39 mg/L compared to Enoxastrobin and it owned a
broader spectrum of fungicidal activities.
get compounds methyl
a-(methoxy-imino)benzeneacetate oxime
ethers (5F–I) and N-methoxy-carbamic acid methyl esters (5J–M)
according to a literature protocol.24 The structures of the desired
compounds were confirmed by 1H NMR, 13C NMR and HRMS.
Evaluation of the biological activities of compounds 5 was per-
formed according to previously published protocols.12,25–31
The results of fungicidal activity are listed in Tables 1 and 2,
where the inhibition percentage was expressed as the mean of
the values obtained in three independent experiments. The biolog-
ical data were reported as a range from 0% (indicates no control) to
100% (complete control). To determine the fungicidal potency of
the target compounds, a commercial oxime ether fungicide (i.e.,
Enoxastrobin) was used as the standard.
The in vitro fungicidal activity results for compounds 5 against
Pyricularia oryzae and Botrytis cinerea at
a
concentration of
In summary, a series of new benzothiophene-substituted oxime
ether strobilurins (5) were designed and synthesised by modifying
the side chain of an unsaturated oxime ether strobilurin fungicide
(i.e., Enoxastrobin). The biological assay results indicated that most
compounds maintained or enhanced their fungicidal activities,
especially against C. lagenarium and P. sorghi Schw. In addition,
methyl 3-methoxypropenoate oxime ethers (5A–E) and N-meth-
oxy-carbamic acid methyl esters (5J–M) exhibited good in vivo
fungicidal activities against E. graminis, C. lagenarium and P. sorghi
Schw. Notably, 5E exhibited more potent fungicidal activities
6.25 mg/L are listed in Table 1. The results of the preliminary bio-
assays were compared to those of Enoxastrobin. Compounds 5
exhibited potent fungicidal activities against the tested fungi. All
of the compounds were more potent or exhibited a similar potency
for in vitro fungicidal activities against P. oryzae and B. cinerea com-
pared to Enoxastrobin. Compounds 5 exhibited 100% growth inhi-
bition against B. cinerea.
Compounds 5 were tested in vivo against Erysiphe graminis,
Colletotrichum lagenarium, Psilocybe cubensis and Puccinia sorghi
Table 1
Chemical structures and fungicidal activity of target compounds 5 (inhibition %)
R3
R2
R1
Q
S
N
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=
No.
Substituents
R2
Testing concentration (mg/L)
100 mg/L
R1
R3
Q
6.25 mg/L
P. oryzae
B. cinerea
E. graminis
C. lagenarium
P. cubensis
P. sorghi Schw.
5A
5B
5C
5D
5E
5F
5G
5H
5I
5J
5K
5L
5M
5N
5O
5P
H
H
H
H
H
CF3
H
H
H
H
CF3
H
H
H
CF3
H
H
H
CF3
H
H
H
CF3
H
H
Cl
H
H
H
H
Cl
H
H
H
Cl
H
H
H
Cl
H
H
H
Cl
H
H
Q1
Q1
Q1
Q1
Q1
Q2
Q2
Q2
Q2
Q3
Q3
Q3
Q3
Q4
Q4
Q4
Q4
Q5
Q5
Q5
Q5
50
50
50
50
50
50
50
50
50
80
50
50
50
50
50
50
50
80
50
50
50
50
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
90
100
100
90
100
0
100*
100
95
95
90
0
100*
100
80
80
100
90
0
70
80
90
100*
80
100
0
SCH2CH3
Cl
H
H
100*
100
100*
0
0
95
95
0
0
0
0
0
0
0
0
0
0
0
0
50
0
0
20
H
90
0
70
50
100
100
80
95
0
0
0
SCH2CH3
H
H
H
SCH2CH3
H
H
H
SCH2CH3
H
H
H
100
100
100
100
0
0
0
0
98
90
0
0
100
0
0
0
5Q
5R
5S
5T
0
98
100*
80
80
70
90
100*
50
5U
SCH2CH3
60
98
Enoxastrobin
*
The compound appeared to be phytotoxic.

2176
S. Tu et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2173–2176
Table 2
The in vivo fungicidal activity of target compounds 5A–E and 5J–M (inhibition %)
R3
R2
R1
Q
S
N
O
H
O
O
O
O
O
O
N
Q1=
ꢀ Q3=
No.
Substituents
R2
Testing concentration (mg/L)
R1
R3
Q
E. graminis
C. lagenarium
P. sorghi Schw.
6.25
1.56
0.39
6.25
1.56
0.39
6.25
1.56
0.39
5A
5B
5C
5D
5E
5J
5K
5L
H
H
H
H
H
CF3
H
H
H
H
CF3
H
H
Cl
H
H
H
H
Cl
H
H
Q1
Q1
Q1
Q1
Q1
Q3
Q3
Q3
Q3
100
98
30
20
50
50
95
30
40
100
30
50
0
0
30
0
40
20
20
50
0
0
0
0
20
0
20
0
0
20
100
100
70
85
100
80
95
0
60
85
80
0
60
90
65
85
0
60
40
0
10
80
30
50
0
100
100
80
100
70
65
95
50
20
80
80
60
80
50
20
50
30
0
50
70
20
50
30
0
0
0
0
20
SCH2CH3
Cl
H
H
H
5M
Enoxastrobin
SCH2CH3
10
80
5
20
90
98
70
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