Synthesis and herbicidal activities of 2-cyano-3-benzylaminoacrylates containing thiazole moiety

Article abstract of DOI:10.1016/j.bmcl.2010.04.027

Two series of novel 2-cyano-3-benzylaminoacrylates containing long-chain thiazole ring moiety were synthesized as herbicidal inhibitors of photosystem II (PS II) electron transportation. Their structures were confirmed by ¹H NMR and elemental a

Full text of DOI:10.1016/j.bmcl.2010.04.027

Bioorganic & Medicinal Chemistry Letters 20 (2010) 3348–3351
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and herbicidal activities of 2-cyano-3-benzylaminoacrylates
containing thiazole moiety
Tingting Wang, Guifang Bing, Xin Zhang, Zhenfang Qin, Haibo Yu, Xue Qin, Hong Dai, Wenke Miao,
*
Shanshan Wu, Jianxin Fang
State Key Laboratory of Elemento-Organic Chemistry and Tianjin Key Laboratory of Pesticide Science, Nankai University, Tianjin 300071, 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:
Two series of novel 2-cyano-3-benzylaminoacrylates containing long-chain thiazole ring moiety were
synthesized as herbicidal inhibitors of photosystem II (PS II) electron transportation. Their structures
were confirmed by 1H NMR and elemental analysis. The bioassay showed that these compounds retain
high herbicidal activities and especially compounds 13a and 13h have excellent herbicidal activities.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 11 January 2010
Revised 4 March 2010
Accepted 9 April 2010
Available online 14 April 2010
Keywords:
2-Cyanoacrylates
Thiazole
Inhibitors of photosystem II electron
transportation
Herbicidal activities
Synthesis
Cyanoacrylates have been the subject of intense interest for the
past decades as one kind of herbicides. A detailed study of
compounds with general structure A (Fig. 1) revealed that cyanoac-
rylates are inhibitors of photosystem II (PS II) electron transporta-
tion, which inhibits the growth of weeds by disrupting
photosynthetic electron transportation at a common binding do-
main on the 32 kDa polypeptide (D1 protein) of the PS II reaction
center.1–3 Among these cyanoacrylates, the compound B (Fig. 1)
has been a representative compound because of its excellent herbi-
cidal activity and high Hill reaction inhibitory activity.4–6 Bayer AG
reported compound C (Fig. 1), but little information was given on
its herbicidal activity.7 Wang et al. reported that some compounds
D (Fig. 1) modified by replacing phenyl with heterocycles (pyri-
dine, thiazole, furan, and tetrahydrofuran) showed higher herbi-
cidal activity than parent compounds B and C.8–10 Then they
reported that compound E (Fig. 1) containing arylhydrazino groups
did not show herbicide activities but showed some anti-tumor
activities.11 Recently, Song et al. first reported that cyanoacrylates
derivatives F (Fig. 1) also exhibited moderate to excellent antiviral
activity against tobacco mosaic virus (TMV).12,13 According to the
bioisosterism principles, compounds D, E, and F were all analogues
of structures A, B, and C. It has been reported that the D1 protein of
PS II is the herbicide binding site, and the benzyl group of cyanoac-
rylate fits into the hydrophobic domain of the site maximizing van
der Waals ring-stacking interactions with aromatic amino acids
(Phe 211, Phe 255, and Tyr 262) flanking this part of the binding
domain.4,14,15 However, the complete nature and topography of
this hydrophobic domain of the D1 protein are unknown. Based
on the above considerations, we attempted to introduce longer-
chain benzyl groups into cyanoacrylates B and C to fit into the
hydrophobic domain better. Various N- or S-containing heterocy-
clic derivatives always display broad-spectrum biological activi-
ties,16–18 all which encouraged us to introduce 2-chlorothiazole
ring into benzylamino group of 2-cyanoacrylates and further study
the relationship of structure–herbicidal activity. Herein, we are
reporting the synthesis of new 2-cyano-3-benzylaminoacrylates
containing thiazole moiety and evaluation of their herbicidal activ-
ities in detail.
The key intermediate 4-((2-chlorothiazol-5-yl)methoxy)ben-
zylamine (10) was successfully prepared from readily available
2-chloro-5-chloromethylthiazole and 4-hydroxybenzaldehyde (1)
as shown in Scheme 1. 4-Hydroxybenzaldehyde (1) was reacted
with 2-chloro-5-chloromethylthiazole in the presence of potas-
sium carbonate to obtain 4-((2-chlorothiazol-5-yl)methoxy)benz-
aldehyde (3) in 95.7% yield. Borohydride reduction of substituted
benzaldehyde 3 in ethanol gave 4-((2-chlorothiazol-5-yl)methox-
y)benzyl alcohol (5) in 91.0% yield, which was chlorinated by using
thionyl chloride to obtain 4-((2-chlorothiazol-5-yl)methoxy)ben-
zyl chloride (7) in 95.8% yield. The reaction of benzyl chloride 7
with potassium phthalimide (9) gave intermediate N-substituted
phthalimide which was subsequently refluxed with hydrazine to
* Corresponding author.
E-mail address: fjx@nankai.edu.cn (J. Fang).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.04.027

T. Wang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3348–3351
3349
O
O
C
R1NH
R2
R3
Cl
CH2NH
C
OC2H4OC2H5
Cl
CH2NH
CH3S
OC2H4OC2H5
CN
(CH3)2CH
CN
CN
A
B
C
O
O
C
O
C
O
ArNHNH
R6
O2N
NH
NH
OCH2CH3
Het CH2NH
R4
OR5
O
CN
CN
CN
H
D
E
F
Figure 1. Structures of cyanoacrylates A–F.
R1
R1
N
N
Cl
Cl
CH2O
CHO
+
HO
CHO
a
Cl
Cl
S
b
S
1 R1 = H
3 R1 = H
2 R1 = OCH3
4 R1 = OCH3
O
R1
R1
1.
NK
N
N
9d
O
CH2O
CH2OH
Cl
CH2O
CH2Cl
c
S
2.e
S
5 R1 = H
7 R1 = H
6 R1 = OCH3
8 R1 = OCH3
R4
R3
COOR2
R1
R1
12a-h
N
N
CN
f
COOR2
CN
Cl
S
CH2O
CH2NH
R3
Cl
CH2O
CH2NH2
S
10 R1 = H
13a-h R1 = H
11 R1 = OCH3
14a-h R1 = OCH3
13a, 14a R2 = C2H4OC2H5, R3 = MeS, R4=MeS; 13b, 14b R2 = C2H4OCH3, R3 = MeS, R4=MeS;
13c, 14c R2 = C2H4OC2H5, R3 = Me, R4=MeO; 13d, 14d R2 = C2H4OCH3, R3 = Me, R4=MeO;
13e, 14e R2 = C2H4OC2H5, R3 = Et, R4=MeO; 13f, 14f R2 = C2H4OCH3, R3 = Et, R4=MeO;
13g, 14g R2 = C2H4OC2H5, R3 = i-Pr, R4=MeO; 13h, 14h R2 = C2H4OCH3, R3 = i-Pr, R4=MeO;
Scheme 1. Reagents and conditions: (a) K2CO3, EtOH, reflux 6 h; (b) NaBH4, EtOH, 0 °C to rt, 1 h; (c) SOCl2, CH2Cl2, 0 °C to rt, 10 h; (d) potassium pathalimide, DMF, rt, 10 h; (e)
hydrazine hydrate (85%), EtOH, reflux, 4 h; (f) EtOH, reflux, 3 h.
afford the corresponding benzylamine 10 in one step. We got ben-
zylamine 11 in good overall yield by using the above synthetic pro-
cedure (Scheme 1). The target compounds (13a–h and 14a–h)
were synthesized by the nucleophilic addition and elimination
reaction of substituted benzylamine 10 or 11 and 12a–h.
The abilities of all the target compounds 13a–h and 14a–h were
evaluated as inhibitors of the photosynthetic electron transport by
detecting their inhibiting effects on the Hill reaction at 1.0 lg/mL.
Photosynthetically active thylakoid membranes were used and
isolated from spinach (S. oleracea L.) leaves. Observed inhibitory
activity data are listed in Table 1. (Z)-Ethoxyethyl 2-cyano-
3-methylthio-3-(2-chloro-5-pyridyl)methaneaminoacrylate (16)
was reported to display excellent herbicidal activity8 and was used
for comparison in the present Hill inhibitory and herbicidal activity
study. This comparison (Table 1) clearly showed a significant en-
hanced activity, with compounds 13b, 13h, 14a, 14g, and 14h having
higher level of Hill inhibitory activities than compound 16. From Ta-
ble 1, the Hill inhibitory activities of most compounds bearing iso-
propyl group are a little higher than those of compounds bearing
methyl or ethyl at R3 position. All of these experimental results
encouraged us to further evaluate their in vivo herbicidal activities
in detail.
5-one showed relatively lower herbicidal activities than the parent
compound.19 This possibly due to the relatively high polarity and
the decrease in the overall lipophilicity of the molecule.
To further strengthen the interaction of these cyanoacrylates
with the lipophilic binding domain of the PS II reaction center
and explore the influence of aromatic ring and their substitutions
on the activity, we introduced benzylamino group containing low
polarity thiazole moiety into the cyanoacrylates (Schemes 1 and
2). Their herbicidal activities were evaluated as shown in Table 1.
From the biological assay results in Table 1, most of the com-
pounds synthesized showed a greater herbicidal activity in post-
emergence treatment than in preemergence treatment. So, we
herein analyzed the structure–activity relationship mainly
according to the data of biological assay in the postemergence
treatment.
In postemergence treatment, most of the compounds showed
greater herbicidal activities against dicotyledonous weeds (ama-
ranth pigweed and rape) than monocotyledon weeds (alfalfa),
especially rape. Compounds 13a, 13e, and 13g containing methyl-
thio, ethyl, isopropyl at the 3-position of 2-cyanocrylate (R1 = H,
R2 = CH2CH2OCH2CH3), respectively, had better inhibitory effect
on weed (amaranth pigweed) development as compared with
compound 13c containing methyl at the 3-position, indicating that
methyl at the 3-position of 2-cyanocrylate is not a suitable group
In our previous work, the cyanoacrylate structure modified by
the replacement of phenyl with 4,5-dihydro-1,3,4-thiadiazol-

3350
T. Wang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3348–3351
Table 1
Hill inhibitory activity (1.0
l
g/mL) and herbicidal activities of products 13a–h and 14a–hb,c (1500 g/ha,a percent inhibition (%))
R1
N
O
C
Cl
CH2O
CH2NH
R3
COOR2
CN
Cl
CH2NH
MeS
OC2H4OC2H5
S
N
C C
CN
16
Compd
R1
R2
R3
Hill activity (%)
Postemergence treatment
Amaranth pigweed
Preemergence treatment
Alfalfa
Rape
Alfalfa
Amaranth pigweed
Rape
13a
13b
13c
13d
13e
13f
13g
13h
14a
14b
14c
14d
14e
14f
H
H
H
H
H
H
H
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
C2H4OEt
C2H4OMe
C2H4OEt
C2H4OMe
C2H4OEt
C2H4OMe
C2H4OEt
C2H4OMe
C2H4OEt
C2H4OMe
C2H4OEt
C2H4OMe
C2H4OEt
C2H4OMe
C2H4OEt
C2H4OMe
MeS
MeS
Me
Me
Et
72.5
80.9
56.5
65.2
70.2
59.6
72.5
82.0
87.1
61.2
68.5
42.7
71.3
70.2
93.8
80.4
75.8
0
30.0
0
0
10.0
0
15.0
30.0
49.2
66.1
30.0
56.5
41.9
46.8
68.5
71.1
85.0
100.0
71.3
32.6
0
96.3
0
91.6
91.6
97.4
89.6
89.6
92.2
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
98.5
100.0
100.0
100.0
100.0
86.3
83.6
94.2
84.6
98.3
0
0
0
0
0
0
0
0
10.0
50.6
30.6
0
0
2.0
0
0
0
0
0
0
0
0
0
0
2.7
5.0
0
10.0
0
0
0
35.1
10.0
0
0
0
0
0
0
0
10.0
0
Et
i-Pr
i-Pr
MeS
MeS
Me
Me
Et
Et
i-Pr
i-Pr
0
15.0
5.0
0
0
41.7
90.7
96.6
14g
14h
16d
100.0
100.0
100.0
42.9
0
a
b
c
g/ha means gram per hectare.
Assay method and procedure were described in Supplementary data.
Triplicate each treatment. Activity numbers represent percent displaying herbicidal damage as compared to control. 0 mean no activity. Error of these numbers is 2%.
d
Compound 16 and its activity were reported in Ref. 8, while all of the data here of it came from our own work.
O
OR2
O
CH3S
CH3S
C
12a R2 = C2H4OC2H5;
12b R2 = C2H4OCH3;
NCCH2C OR2
+
+
CS2
R3
+
(CH3)2SO4
a
CN
15
O
C
OR2
O
O
C
CH3O
R3
c
NCCH2C OR2
Cl
b
CN
15
12c R2 = C2H4OC2H5, R3 = CH3; 12d R2 = C2H4OCH3, R3 = CH3;
12e R2 = C2H4OC2H5, R3 = Et; 12f R2 = C2H4OCH3, R3 = Et;
12g R2 = C2H4OC2H5, R3 = i-Pr; 12h R2 = C2H4OCH3, R3 = i-Pr;
Scheme 2. Reagents and conditions: (a) KOH (2.0 equiv), CH3CN, rt, 4 h; (b) Et3N, MgCl2, CH3CN, À15 °C, 5 h; (c) CH2N2, Et2O, rt, 12 h.
for high herbicidal activity. Compounds 13b and 13h containing
methylthio, isopropyl at the 3-position of 2-cyanocrylate (R1 = H,
R2 = CH2CH2OCH3), respectively, had better inhibitory effect on
weed (amaranth pigweed) development as compared with com-
pounds 13d and 13f containing methyl, ethyl at the 3-position,
respectively, indicating that methyl and ethyl at the 3-position of
2-cyanocrylate are not suitable groups for high herbicidal activity.
So, methylthio and isopropyl are suitable groups at the 3-position
for high herbicidal activity when R1 position of benzene ring is H-
atom.
The replacement of H-atom by an alkoxy (methoxy) group
(14a–h) at the R1 position of benzene ring affected the herbicidal
activity obviously (Table 1). In general, an introduction of a meth-
oxy into the R1 position of benzene ring not only modified the elec-
tronic structure, greatly increased herbicidal activity both in
postemergence treatment and in preemergence treatment, but also
the range of substitutent groups at the 3-position of 2-cyanoacry-
late was widened compared with the above compounds 13a–h.
Not only compounds 14a, 14b, 14g, and 14h with methylthio, iso-
propyl at the 3-position but also compounds 14c, 14d, 14e, and 14f
with methyl, ethyl at the 3-position exhibited excellent herbicidal
activities, indicating that introduction of an electron-donating
methoxy group into benzene ring was very essential for whole her-
bicidal activity.
At the rate of 750 g/ha, compounds 13a, 13e, 13g, 13h, 14g, and
14h still exhibited excellent herbicidal activities against amaranth
pigweed and rape (Table 2). Their herbicidal activities decreased
when the dose was further reduced. At the rate of 375 g/ha, com-
pound 13a still exhibited excellent herbicidal activity to rape and
compound 13h still exhibited excellent herbicidal activities to both
amaranth pigweed and rape (Table 2). The herbicidal activity assay
of high active compounds 13a, 13e–h, 14a, and 14e–h (Table 1)
was continued in lower concentrations. The concentrations causing
50% and 90% inhibition (LD50 and LD90) of in vivo activity against
rape were estimated utilizing the linear regression equation as
shown in Table 3. From the LD50 and LD90 values in Table 3, com-
pounds 13a and 13h showed greater herbicidal activity than other
compounds except 16, which is well coincident with the results
judged from Table 2.
In conclusion, we have demonstrated that 2-cyano-3-benzyla-
minoacrylates containing thiazole moiety presented excellent her-
bicidal activity, and their structure–activity relationships were

T. Wang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3348–3351
3351
Table 2
activities even at a dose of 375 g/ha. It was found that suitable
groups such as methylthio, isopropyl at the 3-position of 2-cyano-
acrylates were essential for high herbicidal activities. Introduction
of an electron-donating methoxy group into benzene ring of ben-
zylamine was beneficial for the whole herbicidal activity. 2-Cya-
no-3-benzylaminoacrylates containing thiazole moiety have the
research potency, further study is underway.
Herbicidal activities of products 13a, 13e, 13g, 13h and 14e–ha,b
Compd
Rate (g/ha)
Postemergence treatment
Amaranth pigweed
Rape
13a
13e
13g
13h
14e
14f
750
375
750
375
750
375
750
375
750
375
750
375
750
375
750
375
750
375
91.6
55.6
84.4
24.5
100.0
47.2
100.0
98.1
30.9
21.0
32.9
0
87.8
59.3
89.8
73.6
100.0
100.0
100.0
95.1
100.0
40
100.0
51.2
100.0
92.8
74.6
41.2
46.4
42.9
100.0
73.5
94.1
62.4
100.0
100.0
Acknowledgements
We gratefully acknowledge the National Natural Science Foun-
dation of China (NNSFC) (NO. 20772068) and the National Key Pro-
ject of Scientific and Technical Supporting Programs Funded by
Ministry of Science & Technology of China (NO. 2006BAE01A01-
5) for financial support.
14g
14h
16c
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.04.027.
a
Assay method and procedure were described in Supplementary data.
Triplicate each treatment. Activity numbers represent percent displaying her-
b
References and notes
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c
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Table 3
Herbicidal activities (LD50 and LD90 values) of high active compounds against rapea
Compd
Correlation
y = a + bx
LD50 (g/ha)
LD90 (g/ha)
coefficient (r)
13a
13e
13f
13g
13h
14a
14e
14f
14g
14h
16
0.97
0.99
0.99
0.99
0.98
0.97
0.98
0.97
0.98
0.99
0.99
y = 3.91 + 2.12x
y = 3.17 + 2.36x
y = 2.06 + 2.59x
y = 2.82 + 3.17x
y = 3.38 + 2.94x
y = 2.20 + 1.83x
y = 2.77 + 1.99x
y = 2.14 + 2.38x
y = 2.87 + 2.26x
y = 2.29 + 3.26x
y = 5.25 + 1.09x
49.14
83.96
205.19
73.01
197.66
311.43
640.88
185.40
146.04
2548.33
862.13
817.35
484.40
251.01
133.77
53.48
507.90
196.53
237.10
131.42
101.62
8.84
a
Assay method and procedure were described in Supplementary data.
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studied. In particular, (E)-ethoxyethyl 2-cyano-3-methylthio-3-
(4-(2-chlorothiazol-5-yl)methoxy)benzylaminoacrylate (13a) and
(Z)-ethoxymethyl 2-cyano-3-isopropyl-3-(4-(2-chlorothiazol-5-yl)-
methoxy)benzylaminoacrylate (13h) showed excellent herbicidal