Synthesis and acaricidal activity of strobilurin-pyrimidine derivatives

Article abstract of DOI:10.1016/j.cclet.2013.10.006

Pyriminostrobin, a new acaricide, was discovered in our previous studies. Because introducing fluorine into organic compounds can increase bioactivity, pyriminostrobin was modified as a series of strobilurin-pyrimidine derivatives for biological screening. The compounds were characterized by ¹H NMR, MS and elemental analysis. Preliminary bioassays demonstrated that compounds 7e and 7i exhibited significant control against Tetranychus cinnabarinus (Boisd.) at 0.625 mg L^-1, and their acaricidal potencies were higher than pyriminostrobin in a greenhouse. The relationship between structure and acaricidal activity was also studied.

Full text of DOI:10.1016/j.cclet.2013.10.006

Chinese Chemical Letters 25 (2014) 137–140
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Synthesis and acaricidal activity of strobilurin-pyrimidine derivatives
b
b
b
Bao-Shan Chai a,b, Chang-Ling Liu b, , Hui-Chao Li , Shao-Wu Liu , Ying Xu ,
*
Yu-Quan Song b, Jun-Biao Chang a,
*
a College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, China
b State Key Laboratory of the Discovery and Development of Novel Pesticide, Shenyang Research Institute of Chemical Industry Co., Ltd., Shenyang 110021,
China
A R T I C L E I N F O
A B S T R A C T
Article history:
Pyriminostrobin, a new acaricide, was discovered in our previous studies. Because introducing fluorine
into organic compounds can increase bioactivity, pyriminostrobin was modified as a series of
strobilurin-pyrimidine derivatives for biological screening. The compounds were characterized by 1H
NMR, MS and elemental analysis. Preliminary bioassays demonstrated that compounds 7e and 7i
exhibited significant control against Tetranychus cinnabarinus (Boisd.) at 0.625 mg Lꢀ1, and their
acaricidal potencies were higher than pyriminostrobin in a greenhouse. The relationship between
structure and acaricidal activity was also studied.
Received 15 May 2013
Received in revised form 10 September 2013
Accepted 13 September 2013
Available online 12 November 2013
Keywords:
Strobilurin-pyrimidine
Acaricidal activity
ß 2013 Chang-Ling Liu and Jun-Biao Chang. Published by Elsevier B.V. on behalf of Chinese Chemical
Society. All rights reserved.
Intermediate derivatization method
Pyriminostrobin
1. Introduction
2. Experimental
Pyriminostrobin (SYP-11277), a novel acaricide, was reported
in our previous work [1,2]. The discovery of pyriminostrobin was
outlined in Fig. 1, in which the lead compound was altered by the
intermediate derivatization method [3–5], and then optimized to
synthesize pyriminostrobin. There has been increasing interest in
the introduction of fluorine or appropriate fluorinated functional
groups into organic compounds in recent years [6–12]. Incorpo-
ration of one or several fluorine atoms into organic molecules can
enhance their biological potency due to the intrinsic properties of
the fluorine atom. These include having the highest electronega-
tivity, a small atomic radius, high thermal stability and lipophi-
licity, which could provide easier absorption and transportation of
organic molecules within biological systems [12]. Thus, substitu-
tion of fluorine into a potential drug molecule is an important
strategy in drug and agrochemical development [10].
The general synthetic scheme for representative compounds
7a–k is shown in Scheme 1. Reaction yields were not optimized,
and each new compound was identified and verified by 1H NMR,
MS and elemental analyses. The strobilurin derivatives containing
pyrimidine moieties have been reported in previous works [1,14].
Compounds 7a–k were synthesized by the same synthetic
methods. Substituted phenyl guanidines (2) were prepared from
substituted anilines (1) and cyanamide under acidic conditions.
Ethyl 4,4,4-trifluoro-2-methyl-3-oxobutanoate was obtained from
ethyl 4,4,4-trifluoro-3-oxobutanoate following procedures in the
literature [15].
General procedure for the synthesis of intermediate substituted
phenyl guanidines (2): Substituted anilines (1, 0.02 mol) was added
to concentrated hydrochloric acid (0.02 mol). The mixture was
heated to 85 8C and cyanamide (0.024 mol) was added portion-
wise. Heating continued for 5 h before the reaction solution was
cooled to 60 8C, and then sodium carbonate (0.01 mol) water
solution was added. After continued cooling, the mixture was
filtered to obtain the crude substituted phenyl guanidine
carbonates 2.
The above-mentioned biological and synthetic significance
prompted us to carry out the synthesis of some new strobilurin-
pyrimidine derivatives
7 with fluorine substitution, which
showed promising acaricidal activity in addition to its fungicidal
activity [13].
General procedure for the synthesis of intermediate pyrimidin-
4(3H)-one (5): Substituted phenyl guanidine carbonates (2,
0.01 mol) and
b-keto esters (3 or 4, 0.02 mol) were added to
*
Corresponding authors.
toluene (30 mL), and the mixture was heated to reflux with a Dean
Stark trap until all water was azeotropically removed. The reaction
E-mail addresses: liuchangling@sinochem.com (C.-L. Liu),
changjunbiao@zzu.edu.cn (J.-B. Chang).
1001-8417/$ – see front matter ß 2013 Chang-Ling Liu and Jun-Biao Chang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.10.006

138
B.-S. Chai et al. / Chinese Chemical Letters 25 (2014) 137–140
intermediate derivatisation method
Cl
Cl
NH
O
NH
O
NH
O
N
N
O
O
optimisation
N
N
O
O
N
N
O
O
O
F3C
O
F3C
O
Lead compound
Secondary lead compound
Fig. 1. The discovery of pyriminostrobin.
pyriminostrobin
solution was cooled and then filtered. The solid was washed with
toluene and dried as intermediate 5.
7c: White solid. 1H NMR (300 MHz, CDCl3): 8.40 (s, 1H, Ph0-
d
NH-Py), 7.58 (s, 1H, C55CH), 7.55 (m, 2H, Ph0-2,6-2H), 7.50 (m,
1H, Ph-6-H), 7.37 (m, 2H, Ph-3,5-2H), 7.31 (m, 2H, Ph0-3,5-2H),
7.20 (m, H, Ph-4-H), 7.00 (s, 1H, Py-5-H), 5.40 (s, 2H, PhCH2O),
3.80 (s, 3H, COOCH3), 3.68 (s, 3H, 55C–OCH3); Mol. wt: 477.41.
LC–MS: m/z 476.5 [MꢀH]ꢀ, 478.4 [M+H]+, Anal. calcd. (%) for
Synthesis of (E)-methyl 2-(2-(((2-((2,4-difluorophenyl)amino)-6-
(trifluoromethyl)pyrimidin-4-yl)oxy)methyl)phenyl)-3-methoxya-
crylate (7e): A mixture of 2-((2,4-difluorophenyl)amino)-6-(tri-
fluoromethyl)pyrimidin-4(3H)-one (5e) (0.35 g, 1.2 mmol), (E)-
methyl 2-(2-(chloromethyl)phenyl)-3-methoxyacrylate (6) (0.30 g,
1.25 mmol) and K2CO3 (0.33 g, 2.4 mmol) in DMF (15 mL) was stirred
and heated at 80 8C for 8 h. The reaction mixture was then cooled,
diluted with water (100 mL), and extracted with ethyl acetate
(3 ꢁ 25 mL). The organic layer was separated, washed with saturated
brine, dried over MgSO4, and filtered. The filtrate was evaporated, and
the crude product was purified via silica gel column chromatography
using a 1:10 (v/v) mixture of ethyl acetate and petroleum ether
(boiling point range: 60–90 8C) as the eluent to obtain 0.44 g of white
C
23H19F4N3O4: C, 57.86; H, 4.01; N, 8.80; Found: C, 57.79; H,
4.00; N, 8.82.
7d: White solid. 1H NMR (300 MHz, CDCl3):
d
7.82 (s, 1H, Ph0-
NH-Py), 7.61 (s, 1H, C55CH), 7.48–7.06 (m, 7H, Ph0-3H + Ph-4H),
6.53 (s, 1H, Py-5-H), 5.34 (s, 2H, PhCH2O), 3.82 (s, 3H, COOCH3),
3.73 (s, 3H, 55C–OCH3); Mol. wt: 477.41. LC–MS: m/z 476.5
[MꢀH]ꢀ, 478.4 [M+H]+, Anal. calcd. (%) for C23H19F4N3O4: C, 57.86;
H, 4.01; N, 8.80; Found: C, 57.80; H, 4.02; N, 8.82.
7f: White solid. 1H NMR (300 MHz, CDCl3):
d
8.37 (s, 1H, Ph0-
crystals. 1H NMR (300 MHz, CDCl3):
d
8.28 (s, 1H, Ph0-NH-Py), 7.59 (s,
NH-Py), 7.59 (s, 1H, C55CH), 7.50–7.12 (m, 7H, Ph0-3H + Ph-4H),
6.56 (s, 1H, Py-5-H), 5.33 (s, 2H, PhCH2O), 3.80 (s, 3H, COOCH3),
3.70 (s, 3H, 55C–OCH3); Mol. wt: 511.85. LC–MS: m/z 510.7
[MꢀH]ꢀ, 512.8 [M+H]+, Anal. calcd. (%) for C23H18ClF4N3O4: C,
53.97; H, 3.54; N, 8.21; Found: C, 53.91; H, 3.55; N, 8.21.
1H, C55CH), 7.48–6.90 (m, 7H, Ph0-3H + Ph-4H), 6.54 (s, 1H, Py-5-H),
5.31 (s, 2H, PhCH2O), 3.80 (s, 3H, COOCH3), 3.70 (s, 3H, 55C–OCH3);
Mol. wt: 495.40. LC–MS: m/z 494.2 [MꢀH]ꢀ, 496.3 [M+H]+, Anal.
calcd. (%) for C23H18F5N3O4: C, 55.76; H, 3.66; N, 8.48; Found: C, 55.78;
H, 3.66; N, 8.52.
7g: White solid. 1H NMR (300 MHz, CDCl3):
d
8.06 (s, 1H, Ph0-
7a: White solid. 1H NMR (300 MHz, CDCl3):
d
7.86 (s, 1H, Ph0-
NH-Py), 7.81–7.18 (m, 9H, Ph0-4H + Ph-4H + C55CH), 6.53 (s, 1H,
Py-5-H), 5.30 (s, 2H, PhCH2O), 3.80 (s, 3H, COOCH3), 3.73 (s, 3H,
55C–OCH3); Mol. wt: 511.85. LC–MS: m/z 510.7 [MꢀH]ꢀ, 512.8
[M+H]+, Anal. calcd. (%) for C23H18–ClF4N3O4: C, 53.97; H, 3.54; N,
8.21; Found: C, 53.92; H, 3.50; N, 8.18.
NH-Py), 7.78 (d, 2H, Ph0-2,6-2H, J = 9.0 Hz), 7.62 (s, 1H, C55CH), 7.57
(d, 2H, Ph0-3,5-2H, J = 9.0 Hz), 7.48 (m, 1H, Ph-6-H), 7.35 (m, 2H,
Ph-3,5-2H), 7.20 (m, 1H, Ph-4-H), 6.57 (s, 1H, Py-5-H), 5.35 (s, 2H,
PhCH2O), 3.81 (s, 3H, COOCH3), 3.74 (s, 3H, 55C–OCH3); Mol. wt:
527.42. LC–MS: m/z 526.5 [MꢀH]ꢀ, 528.3 [M+H]+, Anal. calcd. (%)
for C24H19F6N3O4: C, 54.65; H, 3.63; N, 7.97; Found: C, 54.69; H,
3.66; N, 7.98.
7h: White solid. 1H NMR (300 MHz, CDCl3):
d 7.54 (s, 1H,
C55CH), 7.00–7.33 (m, 7H, Ph0-3H + Ph-4H), 6.71 (br s, 1H, Ph0-NH-
Py), 6.48 (s, 1H, Py-5-H), 5.16 (s, 2H, PhCH2O), 3.75 (s, 3H, COOCH3),
3.67 (s, 3H, 55C–OCH3); Mol. wt: 495.40. LC–MS: m/z 494.2
[MꢀH]ꢀ, 496.3 [M+H]+, Anal. calcd. (%) for C23H18F5N3O4: C, 55.76;
H, 3.66; N, 8.48; Found: C, 55.78; H, 3.68; N, 8.50.
7b: White solid. 1H NMR (300 MHz, CDCl3): 8.06 (br s, 1H, Ph0-
d
NH-Py), 7.81–7.18 (m, 9H, Ph0-4H + Ph-4H + C55CH), 6.53 (s, 1H,
Py-5-H), 5.30 (s, 2H, PhCH2O), 3.80 (s, 3H, COOCH3), 3.73 (s, 3H,
55C–OCH3); Mol. wt: 527.42. LC–MS: m/z 526.5 [MꢀH]ꢀ, 528.3
[M+H]+, Anal. calcd. (%) for C24H19F6N3O4: C, 54.65; H, 3.63; N,
7.97; Found: C, 54.66; H, 3.65; N, 7.98.
7i: White solid. 1H NMR (300 MHz, CDCl3): 8.06 (br s, 1H, Ph0-
d
NH-Py), 7.59 (s, 1H, C55CH), 7.48–6.98 (m, 6H, Ph0-2H + Ph-4H),
6.57 (s, 1H, Py-5-H), 5.31 (s, 2H, PhCH2O), 3.81 (s, 3H, COOCH3),
O
H
NH
N
2
NH
2
a
O
O
1
1
R
R
NH
Cl
1/2 H CO
2
1
3
CF
R
3
1
2
2
R
NH
O
c
6
N
1
R
O
O
N
N
O
d
O
N
H
N
H
O
F C
O
3
F C
O
3
3
5
2
b
R
O
O
7
F C
3
O
CH
3
4
Scheme 1. Synthetic route of title compounds 7: (a) NH2CN, HCl, 85 8C; (b) CH3Br, NaH, DMF; (c) toluene, reflux; and (d) K2CO3, DMF, 80 8C.

B.-S. Chai et al. / Chinese Chemical Letters 25 (2014) 137–140
139
Table 1
Physical properties and acaricidal activity of strobilurin-pyrimidine analogs 7.
Compd.
R1
R2
Mp (8C)
Yield (%)
T. cinnabarinus (% mortality at given concentration mg Lꢀ1
)
40 10 2.5 1.25
5
0.625
7a
4-CF3
H
149–151
138–140
136–138
142–144
105–107
118–120
135–137
146–149
129–130
129–131
156–158
74.3
68.8
75.1
59.9
75.0
65.9
69.8
70.1
68.9
58.0
48.6
0
0
/
/
/
/
/
/
/
/
/
/
/
7b
3-CF3
H
100
0
30
0
/
/
7c
4-F
H
7d
2-F
H
100
100
100
95
100
100
100
90
90
40
20
98
86
0
7e
2,4-F2
2-F-4-Cl
3-Cl-4-F
2,6-F2
2,3,4-F3
2,4-F2
2,3,4-F3
H
100
98
100
92
90
62
7f
H
7g
H
40
10
/
/
7h
H
0
0
/
/
/
7i
H
100
100
100
100
100
100
100
99
100
40
100
0
100
0
95
7j
CH3
CH3
/
/
7k
20
11
98
65
0
Pyriminostrobin
Fluacrypyrim
100
95
100
94
90
30
62
/
/, not tested.
Cl
Cl
F
F
R1
NH
O
NH
O
NH
O
introduction of fluorine
N
N
O
O
N
N
O
O
N
N
O
O
F3C
O
F3C
O
F3C
O
R2
pyriminostrobin
7
7e
(1) Sequence of the substitution patterns R1: 2,3,4-3F, 2,4-2F > 2-F-4-Cl > 2-F > 3-Cl-4-F > 3-CF3 >> 4-CF3, 4-F, 2,6-2F
(2) Sequence of the substitution patterns R2: H > CH3
Fig. 2. Optimizations of compound 7e.
3.71 (s, 3H, 55C–OCH3); Mol. wt: 513.39. LC–MS: m/z 512.4
[MꢀH]ꢀ, 514.7 [M+H]+, Anal. calcd. (%) for C23H17F6N3O4: C, 53.81;
H, 3.34; N, 8.18; Found: C, 53.78; H, 3.40; N, 8.12.
40 mg Lꢀ1. A number of disubstituted and trisubstituted com-
pounds exhibited potent acaricidal activity, though, with two
compounds (7e and 7i) proving much more active than the
reference compound fluacrypyrim [16] at 0.625 mg Lꢀ1. However,
5-methylation of the pyrimidine ring (7j and 7k) greatly reduced
the compound’s potency against T. cinnabarinus (vs 7e and 7i). This
result demonstrated that the 5-hydrogen of the pyrimidine ring is
both necessary and an optimal substituent for maintaining the
compounds’ activity. Two highly active acaricidal compounds were
identified in this study. As shown in Table 1, they exhibited greater
mortality rates than 90% at doses of 0.625 mg Lꢀ1 against T.
cinnabarinus. Anticipating agricultural utilization, two compounds,
7e and 7i, were chosen as candidates for extensive greenhouse
bioassays on larvae and eggs of T. cinnabarinus. Both of them
showed potency consistent with pyriminostrobin against larvae,
and weaker potency than pyriminostrobin against eggs, as shown
in (Table 2).
7j: White solid. 1H NMR (300 MHz, CDCl3): 8.40 (br s, 1H, Ph0-
d
NH-Ph), 7.44–6.82 (m, 7H, Ph0-3H + Ph-4H), 6.03 (br s, 1H, NH),
5.51 (s, 2H, PhCH2O), 3.67 (s, 3H,55N–OCH3), 2.93 (d, J = 4.8 Hz, 3H,
NHCH3), 2.24 (s, 3H, CH3); Mol. wt: 509.43. LC–MS: m/z 509.2
[MꢀH]ꢀ, 511.4 [M+H]+, Anal. calcd. (%) for C24H20F5N3O4: C, 56.58;
H, 3.96; N, 8.25; Found: C, 56.60; H, 3.99; N, 8.21.
7k: White solid. 1H NMR (300 MHz, CDCl3): 8.20 (br s, 1H, Ph0-
d
NH-Py), 7.40–6.91 (m, 6H, Ph0-2H + Ph-4H), 6.05 (br s, H, NH), 5.49
(s, 2H, PhCH2O), 3.68 (s, 3H, 55N–OCH3), 2.94 (d, J = 4.8 Hz, 3H,
NHCH3), 2.25 (s, 3H, CH3); Mol. wt: 527.42. LC–MS: m/z 526.3
[MꢀH]ꢀ, 528.5 [M+H]+, Anal. calcd. (%) for C24H19F6N3O4: C, 54.65;
H, 3.63; N, 7.97; Found: C, 54.66; H, 3.65; N, 7.94.
3. Results and discussion
As shown in Scheme 1, the target compounds were readily
synthesized. Table 1 summarized the physical characteristics,
yields, and acaricidal activities of all strobilurin-pyrimidine
analogs. Two fluorines were introduced into pyriminostrobin to
replace the chlorines to produce 7e, a more potent acaricidal
compound with 90% mortality against Tetranychus cinnabarinus at
4. Conclusion
In order to introduce fluorine into pyriminostrobin to improve
its bio-activity, a series of strobilurin-pyrimidine derivatives
0.625 mg Lꢀ1
.
Table 2
Acaricidal activity of 7e and 7i against T. cinnabarinus.
The current investigation studied the effects of incorporating
various fluorine substitution patterns in compound 7e. Also, the
effects of replacement of the hydrogen by a methyl group in the 5-
position of the pyrimidine scaffold were investigated. The
acaricidal biological activities were evaluated, and the results
furthered understanding of the structure–activity profile (Fig. 2).
The 2-phenylamino motif was modified with various fluorine
substituent phenyl amines, including mono-substituted,
disubstituted, and trisubstituted phenyl rings. Some substitution
patterns, such as 4-CF3, 4-F, 2,6-2F, were not active at all at
Compd.
T. Cinnabarinus
(% mortality at given
concentration mg Lꢀ1
)
10
2.5
0.625
7e
Larvae
Eggs
100
100
100
75
98
77
25
70
100
20
7i
Larvae
Eggs
100
10
Pyriminostrobin
Larvae
Eggs
100
100
100
100
96
20

140
B.-S. Chai et al. / Chinese Chemical Letters 25 (2014) 137–140
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discovered by using fluorine to replace chlorine of pyriminos-
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into various fluorine substitution patterns (7a–d, 7f–k). Com-
pounds 7e and 7i were shown to be more potent than
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.
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We are grateful to the Outstanding Young Scholarship from the
National Natural Science Foundation of China (No. 30825043),
NSFC (No. 21172202), and the Outstanding Scholar Foundation of
Henan Province (No. 094100510019) for financial support. This
project was also supported by the National Key Basic Research
Program of China (973 Program) (Nos. 2010CB126105 and
2012CB724501) and the National Key Technology Support
Program during the 12th Five-Year Plan Period (Nos.
2011BAE06B00, 2011BAE06B01, 2011BAE06B02, 2011BAE06B03
and 2011BAE06B05).
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