Design and synthesis of acrylate and acrylamide substituted pyrimidinediones as potential PPO herbicides

Article abstract of DOI:10.1016/j.bmc.2020.115959

PPO herbicides emerge to be widely use in the agricultural field and a focus of research to many scientists due to its environmentally-friendly properties. In lieu with this, this study presents acrylate and acrylamide substituted pyrimidinediones as PPO herbicide candidates. Most synthesized compounds exhibits herbicidal activities against both monocot and dicot weeds, especially, compound 5a which showed non-selective superior activity against the commercialized, Saflufenacil. Compound 5a was further tested for residual effect and showed promising results as shorter period is needed to cultivate the next crops. The synthesized acrylate and acrylamide substituted pyrimidinediones, especially, 5a could potentially be utilized in the development of commercial protoporphyrinogen oxidase inhibitors with further tests and studies.

Full text of DOI:10.1016/j.bmc.2020.115959

Journal Pre-proofs
Design and synthesis of acrylate and acrylamide substituted pyrimidinediones
as potential PPO herbicides
Won Hyung Lee, Young Bin Kwon, Jung Hee Kim, Kye Hwan Lee, Shizuka
Mei Bautista Maezono, Jong-Soo Choi, Young-Bae Seu
PII:
S0968-0896(20)30789-6
https://doi.org/10.1016/j.bmc.2020.115959
BMC 115959
DOI:
Reference:
To appear in:
Bioorganic & Medicinal Chemistry
Received Date:
Revised Date:
Accepted Date:
3 November 2020
10 December 2020
10 December 2020
Please cite this article as: W. Hyung Lee, Y. Bin Kwon, J. Hee Kim, K. Hwan Lee, S. Mei Bautista Maezono, J-
S. Choi, Y-B. Seu, Design and synthesis of acrylate and acrylamide substituted pyrimidinediones as potential
PPO herbicides, Bioorganic & Medicinal Chemistry (2020), doi: https://doi.org/10.1016/j.bmc.2020.115959
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Design and synthesis of acrylate and acrylamide substituted pyrimidinediones as
potential PPO herbicides
Authors
Won Hyung Leea,b, Young Bin Kwona, Jung Hee Kima, Kye Hwan Leea, Shizuka Mei Bautista
Maezonoa, Jong-Soo Choib and Young-Bae Seub*
a Central Research Institute, Kyung Nong Co. Ltd., 34-14 Summeori-gil, Gyeongju-si 38175,
Gyeongsangbuk-do, Republic of Korea
b School of Life Sciences and Biotechnology, Kyungpook National University, Daegu 41566,
Republic of Korea. *E-mail: ybseu@knu.ac.kr

Abstract
PPO herbicides emerge to be widely use in the agricultural field and a focus of research to
many scientists due to its environmentally-friendly properties. In lieu with this, this study
presents acrylate and acrylamide substituted pyrimidinediones as PPO herbicide candidates.
Most synthesized compounds exhibits herbicidal activities against both monocot and dicot
weeds, especially, compound 5a which showed non-selective superior activity against the
commercialized, Saflufenacil. Compound 5a was further tested for residual effect and showed
promising results as shorter period is needed to cultivate the next crops. The synthesized
acrylate and acrylamide substituted pyrimidinediones, especially, 5a could potentially be
utilized in the development of commercial protoporphyrinogen oxidase inhibitors with further
tests and studies.
Keywords: Pyrimidinediones, herbicidal activity, residual effect, PPO herbicides

1. Introduction
Utility of many herbicides around the world are being restricted due to its potential toxicity
and environmental issues.1-3 This problem usually arises due to the usage of huge amounts of
herbicides. To solve this problem, the development of environmentally-friendly herbicides
with safe properties without shrinkage, less toxicity, and high efficiency even at low doses are
continuously being pursued.
Peroxidising herbicides are substances that inhibit protoporphyrinogen oxidase (PPO), it
accumulates a large amount of photosensitizers such as Protoporphyrin IX and inhibits the
biosynthesis of chlorophyll due to the resulting active oxygen.4 Since PPO herbicides are fast-
acting at low concentrations with effective herbicidal activity against many weeds, they have
been evaluated as a class of herbicides that are safe for the environment and have been an
important research subject.5-7 The long-term use of any herbicides has been reported to develop
resistance over time, and the PPO class of herbicides is no exemption.8 To overcome such
dilemma, there are active researches on computational modeling and scanning techniques to
understand the mechanisms of the resistance of PPO herbicides due to mutations, etc.9, 10
Utilizing the information from the mentioned techniques, various new molecular designs are
continuously being attempted to increase activity and give advantages to existing PPO
herbicides through the introduction and modification of new structures.11-15
To date, many PPO herbicides have been commercialized. This system is largely divided
into two types of classes: diphenyl ethers and non-diphenyl ethers.16 The DPE herbicide was
first proposed by Rohm&Hass in 1963 and was initially the most widely used PPO herbicide.17
However, the initially developed class of DPE herbicides needed very high dosage of 200-
1,000 g ai/ha, and had problems such as poor activity in the gramineous weeds. After
flumiclorac-pentyl,18 from the study of cyclic imide class PPO inhibitor, a new moiety

Figure 1. Chemical structures of commercialized PPO herbicides.
20
flumioxazin19,
and many commercially available substances such as sulfentrazone,
carfentrazone, butafenacil, which have various core structures such as oxadiazole, triazolinone,
and pyrimidinedione, respectively have been developed(Fig. 1).21, 22
Among the PPO herbicides, the most recently developed pyrimidinediones such as
butafenacil23 and saflufenacil24 have broad spectrum of herbicidal activity on gramineous
weeds and broad-leaf weeds and the time to show herbicidal activity after treatment with these
herbicides is fast-acting. In addition, it can be effectively used to control weeds before
germination for a certain period, along with a strong burn-down effect on weeds in the early
germination period.23-25 Due to these advantages, many studies from both academe and
industries have had been conducted on the structure of pyrimidinediones among PPO
herbicides in crop protection. Previously, the initial commercialized pyrimidinedione PPO
inhibitors derived from the existing study have terminal structures connected by a carboxylic
acid group at the meta location of the benzene ring linked to a pyrimidinedione ring. However,

recent developments and study of compounds show that an ether or amine linkage have
improved the herbicidal activity.26-29
On the other hand, many existing herbicides have a problem of having to wait for a certain
period of time to cultivate a crop after treatment of a herbicide due to the residual period in the
30-33
soil, which acts as a hindrance for effective crop cultivation.
This problem occurs when
the treated herbicide remains in the soil without being completely degraded or remains as a
metabolite exhibiting herbicidal activity and is later absorbed by the planted crops; affecting
germination and growth.34-36
Acrylate/acrylamide has not been reported to be introduced in a PPO herbicide before.
However, it has been widely used in different industries from medicinal, industrial, and even
agricultural.37-39 It is an interesting moiety given that it has two functional groups which we
hypothesize to be possibly targeted for decomposition: the olefin and the ester/amide group.
Having the focus on the broad spectrum pyrimidinedione class, we attempted to develop novel
compounds that have effective herbicidal activity and disappears from the soil in a short time
to overcome the drawbacks of the existing herbicides. New compounds were designed and
synthesized by introducing an acrylate/acrylamide group into the terminal structure bonded to
the pyrimidinedione backbone linked with S or NH (Fig. 2), and the herbicidal activity were
evaluated. In addition, further activity evaluations of the most active substance among the
F3C
N
O
O
R2
N
F
X
Y
n
A
R3
(X, Y, A = S, O, NH)
O
R1
O
Cl
Figure 2. General structure of synthesized acrylate and
acrylamide pyrimidinediones (compound 5 and 6). The residue
of each structure descried in the Table 1.

synthesized compounds were done. Furthermore, the residual effect period on the growth of
crops were also studied.
2. Results & Discussion
2.1 Chemistry
The procedure for synthesizing the derivatives of acrylate and acrylamide tail substrates 4a-
4p is shown in Scheme 1. For the synthesis of R1 methyl substituted tail substrates 4a-4h,
commercially available starting materials S4a–S4p are reacted with 2-chloropropanoic acid
under 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl) condition
for coupling. For the synthesis of substrates with unsubstituted R1 4i-4p, S4a–S4p are reacted
with 2-chloroacetyl chloride under pyridine base condition. For monitoring each reaction, TLC
and GC were used as reference. Given the high purity of the the crude mixture 4a-4p, it was
OH
Cl
a
O
R1
O
n
A
R3
S4a S4p
-
Cl
Y
O
R2
Cl
b
Cl
4a - 4p
O
4a
4b
4c
4d
4e
4f
4i
A=Y=O, R1=Me, R2=H, R3=Me, n=1
A=O, Y=NH, R1=R2=R3=Me, n=1
A=Y=NH, R1=R3=Me, R2=H, n=1
A=NH, Y=O, R1=R3=Me, R2=H, n=1
A=O, Y=NH, R1=Me, R2=R3=H, n=1
A=Y=O, R1=Me, R2=R3=H, n=1
A=Y=O, R1=Me, R2=R3=H, n=3
A=O, Y=NH, R1=Me, R2=R3=H, n=0
A=NH, Y=O, R1=R2=H, R3=Me, n=1
A=O, Y=NH, R1=R2=R3=H, n=0
A=Y=O, R1=R2=R3=H, n=3
4j
4k
4l
A=Y=O, R1=R2=R3=H, n=1
4m
4n
4o
4p
A=Y=O, R1=R3=H, R2=Me, n=1
A=O, Y=NH, R1=R2=R3=H, n=1
A=Y=NH, R1=R2H, R3=Me, n=1
A=Y=O, R1=R2=H, R3=Me, n=1
4g
4h
Scheme 1. Synthesis of acrylate and acrylamide substrates: (a) Acrylate or acrylamide,
EDC.HCl, 4-DMAP, CH2Cl2; (b) Acrylate or acrylamide, pyridine, CH2Cl2, 0℃ to
room temperature

used on the next step with no further purification. It is good to note that the impurities did not
significantly affect the next reaction.
The routes for synthesizing target compounds 5a-5p and 6a-6b are shown in scheme 2.
Through a known 3-step methodology, pyrimidinedione substrate 1 is synthesized.40, 41 Using
a 4-chloro-2-fluoroaniline, carbamate was constructed. It was followed by a condensation
reaction with (E)-4,4,4-trifluoro-3-methylbut-2-enoate. Finally, methylation was done to
synthesize the desired pyrimidinedione 1 with an over-all yield of 64
Compound 2 with an -SH group substituted on the meta position of the aromatic ring of
compound 1 is synthesized via an in-situ addition of the chlorosulfonic acid followed by a
reduction reaction using Tin(II) chloride. Compounds 5a-5p are synthesized by performing an
SN2 coupling reaction with 4a-4p under basic conditions. Compound 3 with a -NH group
instead of -SH is synthesized via an addition of NO2 using H2SO4 and HNO3 followed by a
reduction with Fe. Compounds 6a and 6b were synthesized using the coupling reaction of 3
with 4a or 4p, respectively. All synthesized compounds are listed in Table 1.
F3C
N
O
O
F3C
N
O
O
4a - 4p
O
R2
N
F
SH
Cl
N
F
S
Y
n
e
A
R3
R1
O
a, b
Cl
F3C
N
O
O
2
5a- 5p*
N
F
Cl
F3C
N
O
O
F3C
N
O
O
1
4a, 4p
c, d
O
H
N
N
F
NH2
Cl
N
F
O
f
O
R1
O
Cl
3
6a
6b
R1=Me
R1=H
Scheme 2. Synthesis of pyrimidinedione compounds: (a) ClSO3H; (b) SnCl2,
AcOH, HCl; (c) H2SO4, HNO3, CH2Cl2, 0℃; (d) Fe. EtOH, AcOH, reflux; (e)
K2CO3, Acetonitrile, 70℃; (f) K2CO3, KI, DMF, 70℃. *To elucidate the
structures of 5a-5p, please refer to Scheme 1.

Table 1. List of compounds 5a-5p and 6a-6b
R1
R2
R3
Compound
X
A
Y
n
5a
5b
5c
5d
5e
5f
S
S
O
O
O
NH
NH
O
1
1
1
1
1
1
3
0
1
0
3
1
1
1
1
1
1
1
Me
Me
Me
Me
Me
Me
Me
Me
H
H
Me
H
Me
Me
Me
Me
H
S
NH
NH
O
S
H
S
NH
O
H
S
O
H
H
5g
5h
5i
S
O
O
H
H
S
O
NH
O
H
H
S
NH
O
H
Me
H
5j
S
NH
O
H
H
5k
5l
S
O
H
H
H
S
O
O
H
H
H
5m
5n
5o
5p
6a
6b
S
O
O
H
Me
H
H
S
O
NH
NH
O
H
H
S
NH
O
H
H
Me
Me
Me
Me
S
H
H
NH
NH
O
O
H
H
O
O
Me
H
2.2 Biological assay
2.2.1 Herbicidal activities for foliar application
After germination of the synthesized compounds against plant weeds and broadleaf weeds, the
herbicidal activity was tested by foliar treatment in a greenhouse at dose levels of 25g ai/ha
and 50g ai/ha, Saflufenacil was selected as the control in this experiment.

Table 2. Herbicidal activity of synthesized compounds
Monocot weeds a
Dosage
Dicot weeds b, c
Compound
(g ai/ha)
EC
DS
LC
CA
GC
9.8 ± 0.3ns
9.8 ± 0.3 ns
9.8 ± 0.3 ns
9.8 ± 0.3 ns
9.8 ± 0.3 ns
10 ± 0.0 ns
9.7 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
5a
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
10 ± 0.0ns
1.7 ± 0.3
7.8 ± 0.6
9.8 ± 0.3 ns
10 ± 0.0 ns
1.7 ± 1.3
8.8 ± 0.3
10 ± 0.0 ns
9.7 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
3.0 ± 1.8
5b
5c
5d
5e
5f
9.0±0.9 ns
9.7 ± 0.3 ns
9.2 ± 0.3 ns
9.7 ± 0.3 ns
9.7 ± 0.3 ns
2.2 ± 0.3
7.3 ± 0.6
9.8 ± 0.3 ns
7.7 ± 0.8
8.8 ± 0.6
10.0±0.0 ns
2.8 ± 0.3
7.2 ± 0.3
9.8 ± 0.3
9.7 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.7 ± 0.3
9.8 ± 0.3
9.7 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.7 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.7 ± 0.6 ns
9.7 ± 0.6 ns
9.3 ± 0.3 ns
9.2 ± 0.8 ns
9.8 ± 0.3 ns
8.3 ± 0.3
9.8 ± 0.3 ns
9.8 ± 0.3 ns
7.8 ± 0.3
9.8 ± 0.3 ns
8.8 ± 0.6
9.8 ± 0.3 ns
5.8 ± 0.3
9.8 ± 0.3 ns
8.7 ± 0.3
5g
5h
5i
9.7 ± 0.6 ns
9.8 ± 0.3 ns
9.8 ± 0.3 ns
2.7 ± 1.8
8.7 ± 0.3
0.0 ± 0.0
0.8 ± 0.3
1.7 ± 0.3
9.8 ± 0.3 ns
8.7 ± 0.3
9.8 ± 0.3 ns
0.3 ± 0.3
1.2 ± 0.3
0.8 ± 0.3
7.2 ± 1.3
9.2 ± 0.3 ns
0.0 ± 0.0
0.8 ± 0.3
1.7 ± 0.3
7.2 ± 0.3
5j
9.0 ± 0.9 ns
9.7 ± 0.3 ns
9.0 ± 0.9 ns
9.2 ± 0.3 ns
5k

9.8 ± 0.3 ns
9.8 ± 0.3 ns
9.8 ± 0.3 ns
9.0 ± 0.9 ns
9.8 ± 0.3 ns
9.7 ± 0.3 ns
9.7 ± 0.3 ns
9.2 ± 0.3 ns
9.7 ± 0.3 ns
8.7 ± 0.3
9.2 ± 0.3 ns
8.7 ± 0.8
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
5l
9.7 ± 0.3 ns
8.2 ± 0.3
9.8 ± 0.3 ns
7.8 ± 0.3
5m
9.8 ± 0.3 ns
8.2 ± 0.8
9.2 ± 0.3 ns
8.8 ± 0.3
5n
9.2 ± 0.3 ns
9.7 ± 0.3 ns
9.8 ± 0.3 ns
8.8 ± 0.3
5o
9.3 ± 0.6 ns
0.7 ± 0.3
9.7 ± 0.3 ns
7.7 ± 1.3
9.2 ± 0.3 ns
8.8 ± 0.8
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.7 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
10 ± 0.0
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.7 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
9.8 ± 0.3
10 ± 0.0
5p
9.7 ± 0.3 ns
0.7 ± 0.3
9.8 ± 0.3 ns
0.8 ± 0.3
7.7 ± 0.3
0.7 ± 0.3
7.3 ± 0.6
0.7 ± 0.3
7.2 ± 0.3
10 ± 0.0
10 ± 0.0
6a
6b
9.3 ± 0.3 ns
6.7 ± 0.8
8.8 ± 0.3
8.8 ± 0.3
9.2 ± 0.3 ns
10 ± 0.0
9.8 ± 0.3 ns
10 ± 0.0
Saflufenacil
10 ± 0.0
10 ± 0.0
10 ± 0.0
10 ± 0.0
All experiments were carried out in triplicate, and the activity was expressed as 1 to 10.
The ‘ns’ indicated not statistically difficult versus salufenacil.
a EC for Echinochloa crusgalli, DS for Digitaria sanguinalis, LC for Leptochloa chinensis
b CA for Chenopodium album, GC for Galinsoga ciliata.
c All data of Dicot weeds were not different statistically versus salufenacil.
As shown in Table 2, all of the synthesized compounds showed excellent herbicidal activity

against dicot weeds not only at the concentration of 50g ai/ha, but also at a lower concentration
of 25g ai/ha. The herbicidal activity for monocot weeds varied for each compound. Compounds
5a-5p, with structures in which the aromatic ring of the pyrimidinedione moiety has an
aliphatic side chain of an acrylate substrate linked by a sulfide bond, showed excellent activity
in monocot weeds. Compounds 5c, 5e, 5f, and 5g showed excellent activity at 50g ai/ha, but
the activity against monocot weeds was partially reduced at the dose of 25g ai/ha. However, in
the case of compound 5a, excellent activity in all tested monocot weeds were observed, and
the activity did not decrease even at a lower concentration of 25g ai/ha. Looking at the
structure-activity relationship, the compounds (5a-5h and 6a) that has a CH3 group introduced
in C1 next to the S showed higher herbicidal activity compared with compounds (5i-5p and
6b) that are substituted with H instead of CH3. In addition, in the terminal functional group
substitution, methacrylate showed better overall activity than acrylate, and acrylate showed
better activity than acrylamide. In the propanoyl or acetyl linkage that connects the sulfide
bridge and the acrylate end, when the amide bonds are present like compound 5d and 5i, the
activity decreases profoundly, while the activity is higher when the ester bonds are present, like
most compounds. However, even when the amide linkage is present like in compounds 5c and
5o, if the acrylamide is specifically bonded to the terminal, the herbicidal activity is greatly
improved. The carbon chain located between the first and second carbonyl of the compound
exhibited activity in the order of Et > n-Bu = i-Pr >> Me. Compounds 6a and 6b exhibited
lower activity in comparison with compounds 5a and 5p of the same terminal structure,
respectively. Therefore, the herbicidal activity was superior when the sulfide bond was
introduced compared when the pyrimidinedione moiety is connected with an amine bond. At
low doses, the herbicidal activity against monocot and dicot weeds were tested on the most
active compound (5a).

The effect on crops was additionally examined as well, and the results are shown in Table 3
and Figure S1. Among the monocot weeds, the herbicidal activity was most effective against
Echinochloa crusgalli, which showed 100% at a dose of 12.5g ai/ha, and maintained 60%
activity at the level of 6.25g ai/ha. For Digitaria sanguinalis, more than 50% activity was
maintained at a dose of 12.5 g ai/ha and for Alopecurus myosuroides and Lolium perenne,
which are a problem in wheat fields, at 12.5 g ai/ha, showed about 20% activity. Compound
5a showed excellent activity in all dicot weeds tested even at a low dosage of 6.25g ai/ha, and
the activities of Ipomoea quamoclit and Aeschynomene indica were decreased at concentrations
below that. The standard, Saflufenacil, completely lost the herbicidal activity against monocot
weeds at the dose of 3.13 g ai/ha, whereas 5a showed some activity against Echinochloa
crusgalli and Digitaria sanguinalis. Phytotoxicity to dicot crops such as soybeans (Glycine
max) and cotton (Gossypium hirsutum) is similar to that of dicots weeds. It showed very high
levels of phytotoxicity in dosages up to 3.13g ai/ha in dicot crops but low and dose-dependent
in monocot crops. It is observed that 5a has higher phytotoxicity in comparison with the
standard at the same dose. Therefore, 5a shows general superiority, compared to the experiment
control, in activity against monocot weeds. It does not just have slightly higher or similar
activity against dicot weeds, but also does not appear to have selectivity on crops. The results
of 5a shows a lot of similarity with that of pyrimidinedione PPO, a non-selective herbicide.
2.2.2 Further evaluation of the most promising compound 5a
Additional tests were carried out to determine the herbicidal properties of 5a, which is the
most promising among the synthesized acrylate compounds. Based on the observation made
from the greenhouse test results; the herbicidal activity is lower against monocots than in dicots
which led us to test the growth stage of the monocot weeds as shown in Table 4. In the 2.5 leaf

stage, compound 5a maintained excellent activity up to the dose of 10g ai/ha, whereas the
control sample showed a tendency to decrease the efficiency against some weeds from 20g
ai/ha. For weeds in the 4 leaf stage, some of the activity was decreased compared to the early
2.5 leaf stage, but in case of 5a, most of them maintained excellent activity even at low dosage.
For the compound 5a, a test was conducted to confirm the herbicidal activity against weeds
before germination and the damage to crops during soil treatment. The results are shown in
Table 5. Both compound 5a and Saflufenacil showed promising herbicidal activity in the
emerging new leaves on soil treatment, so both were tested at 12.5g ai/ha. Only compound 5a
showed activity in monocot weeds, while the standard showed higher activity in dicot weeds.
As observed, based on the data, the monocot crops were unaffected by both compound 5a and
Saflufenacil while dicot crops were only slightly affected.

2.2.3 The residual effect on soil of compound 5a
It is known from previous studies that the residue from herbicides used to treat crops and
soil affect the growth of post-harvest crops.30-36 The same is evident in the results of the
evaluation of compound 5a and Saflufenacil which both affected the growth of crops by
remaining in the soil after treatment. In this case, the remaining compound 5a in the soil was
tested for how long it affects the growth of Brassica napus, which is generally known to be
vulnerable to herbicides,42 and the results are as shown in Table 6. In case of compound 5a, a
high degree of phytotoxicity was exhibited for crops sown at more than 50g ai/ha, but from
seven days later, the effect was drastically reduced to a level that did not have a significant
impact on growth. In addition, at doses below 25g ai/ha, crops sown on the day of sample
treatment had a slight effect, but not a significant impact on growth.

On the other hand, Saflufenacil had a serious effect on the soil at levels above 25g ai/ha,
which completely inhibited and withered the growth of seeded crops for about 35 days after
sample treatment, and at levels of 6.25g ai/ha, the lowest dosage, showed signs of enough
phytotoxicity to significantly affect the growth of seeded crops on the day of treatment. The
period to which compound 5a residue remains in the soil barely affects the growth of post-
harvest crop. Since the acrylate/acrylamide structure used in many industries is decomposed
by various environmental factors such as heat, microorganisms, etc.43-45 Based on these
previous reports, the acrylate structure of 5a is possibly decomposed rapidly due to these
factors. Therefore, if compound 5a could be commercialized, it could be hypothesized that the
efficiency of utilization and crop cultivation could be greatly improved since the residue period
between the sample treatment and crop cultivation is much shorter than the commercialized
Saflufenacil.
3. Conclusion
In this paper, we have designed and synthesized novel derivatives of the acrylate and
acrylamide substituted pyrimidinedione moiety. In addition, we have evaluated and analyzed
the structural activity correlation of the synthesized compounds. Among the synthesized
compounds, a number of compounds showed excellent herbicidal activity for both monocots
and dicots, especially compound 5a which showed the most promising result. Unprecedentedly,
compound 5a exhibits superior activity compared with the non-selective herbicide standard,
Saflufenacil, to monocot weeds. Furthermore, it was found that the time compound 5a remains
in the soil is relatively short which lessens the risk of it affecting the crops. In conclusion,
compound 5a could potentially be utilized in the development of commercial herbicides due to
its excellent herbicidal activity. However, further studies such as environmental toxicity and
additional test analysis are necessary.

4. Experimental section
4.1 Chemistry
The reagents used in the synthesis of derivatives were purchased from Sigma-aldrich (USA),
TCI (Japan), and Alfa Aesar (UK), while the utilized organic solvents used were from Daejung
chemicals (Korea) and Duksan chemicals (Korea) which were dried or re-distilled as deemed.
Merck silica gel 60 F-254 glass plates were used for the analysis of Thin Layer
Chromatography (TLC). For the flash column chromatography, Merck silica gel 60 (60-230
mesh) was used for product purification and isolation and were identified using a UV lamp
(254 nm) from Vilber Lourmat. Both 1H NMR and 13C NMR spectra were taken from Bruker,
AVANCE III 500 (500 MHz) using CDCl3 or DMSO-d6 as the NMR solvent and were
expressed in ppm(δ) and TMS as an internal standard. All chemical shifts (δ) are expressed in
units of ppm and J values are given in Hz. Mass spectra were analyzed using JEOL JMS-700
High Resolution Mass Spectroscopy (HRMS) and Agilent Technologies 6410 Triple Quad
LC/MS. The nmr spectrum of all compounds was displayed on supplementary file.
4.1.1 Synthesis of compound 1
The method used was based on the works of Gary et al. and Li et. al..40, 41 Using 4-Chloro-2-
fluoroaniline as a starting material, ethyl chloroformate was added to synthesize carbamate
under
pyridine
base
conditions,
and
then
3-(4-chloro-2-fluorophenyl)-6-
(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione was synthesized by the reaction with ethyl (E)-
4,4,4-trifluoro-3-methylbut-2-enoate under NaOCH3/DMF condition. Compound 1 was
synthesized by alkylation reaction of 3-(4-chloro-2-fluorophenyl)-6-(trifluoromethyl)
pyrimidine-2,4(1H,3H)-dione under potassium carbonate (K2CO3)/DMF condition using
methyl iodide as an alkylating agent. Over-all yield is 64%.

1H-NMR (500 MHz, CDCl3): δ 7.32 – 7.24 (m, 2H), 7.20 (dd, J = 8.8, 7.7 Hz, 1H), 6.36 (s,
1H), 3.56 (q, J = 1.4 Hz, 3H); LC-ESI-MS m/z calcd for C12H7ClF4N2O2, 323.1 (M+H)+.
4.1.2 Synthesis of compound 2
14.79g (126.92mmol) of chlorosulfonic acid was placed in a round bottom flask and the
internal temperature was adjusted within the range of –10°C to 5°C. It was followed by the
addition
of
4.10g
(12.69mmol)
3-(4-chloro-2-fluorophenyl)-1-methyl-6-
(trifloromethyl)pyrimidine-2,4 (1H,3H)-dione (1). The reaction was kept for 3 hours at 130-
135°C. When the reaction is completed, ice-cold water was added to terminate the reaction.
Extracted twice with ethyl acetate (EtOAc), dried with anhydrous Magnesium(IV) sulfate
(MgSO4), filtered, and concentrated under reduced pressure. Dilute the crude mixture obtained
in 38mL acetic acid (AcOH). It was followed by the addition of 14.37 mL conc. HCl and 14.32g
(63.46mmol) tin(II) chloride dihydrate (SnCl2•2H2O). After 5 hours of reaction at 80°C, H2O
was added and the reaction mixture was extracted twice with methylene chloride (CH2Cl2).
The organic layer was dried with anhydrous MgSO4 and concentrated under reduced pressure.
The crude mixture was purified using flash column chromatography which obtained 2.61g
(7.36mmol, 58% yield) of compound 2 as a white solid.
1H-NMR (500 MHz, CDCl3): δ 7.33 (d, J = 9.0 Hz, 1H), 7.27 (d, J = 7.1 Hz, 1H), 6.36 (s, 1H),
3.86 (s, 1H), 3.55 (q, J = 1.3 Hz, 4H); LC-ESI-MS m/z calcd for C12H7ClF4N2O2S, 355.1
(M+H)+.
4.1.3 Synthesis of compound 3
A mass of 18.27g (186.30mmol) H2SO4 was stirred at 0°C then followed by the slow addition
of 5.80 g (93.12mmol) HNO3. In a separate flask, 1.50 g (15.50mmol) 3-(4-chloro-2-
fluorophenyl)-1-methyl-6-(trifloromethyl)pyrimidine-2,4,(1H,3H)-dione was diluted in 50mL

CH2Cl2, which was slowly added to the acid mixture. The reaction was kept for 3 hours at room
temperature, then water was added, extracted with ethyl acetate, dried with anhydrous MgSO4,
filtered and concentrated under reduced pressure to obtain 6.00g of -NO2 intermediate crude
mixture. The crude mixture obtained was diluted with EtOH:AcOH (7:1), then 6.38g
(114.24mmol) Fe was added. The reaction mixture was refluxed for 20 minutes then gradually
lowered down to room temperature. The reaction mixture goes through a celite filter then
concentrated under reduced pressure. Water was then added, extracted with EtOAc, dried over
anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude mixture was
purified by flash column chromatography to obtain 4.00 g (11.85 mmol, 76% yield) of
compound 3 as a white solid.
1H-NMR (500 MHz, CDCl3): δ 7.21 (d, J = 9.0 Hz, 1H), 6.64 (s, 1H), 6.37 (s, 1H), 3.56 (s,
3H); LC-ESI-MS m/z calcd for C12H8ClF4N3O2, 338.2 (M+H)+.
4.1.4 Synthesis of compounds 4a-4h
15.0 mmol of 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 2.0 mmol
of 4-(dimethylamino)pyridine (4-DMAP) were added to 10.0 mmol of 2-chloropropionic acid
in 50 mL of CH2Cl2. Then, a solution obtained by diluting 1 equiv. of acrylate (S4a, S4d, S4f,
or S4g) or acrylamide (S4b, S4c, S4e, or S4h) in 10 mL of CH2Cl2 was added to the mixture.
The reaction was kept at room temperature for 12 hours. After reaction completion, water was
added to the reaction mixture, extracted twice with CH2Cl2, dried over anhydrous MgSO4, and
concentrated under reduced pressure to obtain the target compound 4a-4h and was used for the
next step without further purification.
4.1.5 Synthesis of compounds 4i-4p
To a solution of 4.4 mmol of chloroacetyl chloride in 10 mL CH2Cl2, 2.5 mmol of pyridine and

1 equiv. of acrylate (S4i, S4k, S4l, S4m, or S4p) or acrylamide (S4j, S4n, or S4o) were added
at 0° C. After all reagents has been added, the reaction was kept at room temperature for 30
minutes. After reaction completion, water was added to the reaction mixture, extracted twice
with CH2Cl2, dried over anhydrous MgSO4, and concentrated under reduced pressure to obtain
the target compound 4i-4p and was used for the next step without further purification.
4.1.6 Synthesis of compounds 5a-5p
To a solution of 0.85 mmol of 3-(4-chloro-2-fluoro-5-mercaptophenyl)-1-methyl-6-
(trifluoromethyl)pyrimidine–2,4-(1H,3H)-dione (2) in 10 mL acetonitrile, 1.30 mmol of
potassium carbonate (K2CO3) was added. The reaction was stirred at room temperature for 10
minutes before 0.85 mmol of 4a-4p was added, and reaction was kept at 70°C for 2 hours.
After reaction completion, water was added to the reaction mixture, extracted twice with
EtOAc, dried over anhydrous MgSO4, and concentrated under reduced pressure. The resulting
concentrate was purified by flash column chromatography to obtain 5a-5p.
4.1.7 Synthesis of compounds 6a-6b
To
a
solution of 1.18 mmol 3-(5-Amino-4-chloro-2-fluoro-phenyl)-1-methyl-6-
trifluoromethyl-1H-pyrimidine-2,4-dione (3) in 20 mL Dimethylformamide (DMF), 1.52
mmol of K2CO3, 0.30 mmol of potassium iodide (KI), 1.27 mmol of 4a and 4p were added,
respectively, and was allowed to react at 70° C for 2 hours. After reaction completion, water
was added to the reaction mixture, extracted twice with EtOAc, dried over anhydrous MgSO4
and concentrated under reduced pressure. The resulting concentrate was purified by flash
column chromatography to obtain 6a-6b.

4.2 Characterization data of compounds 5a-5p
4.2.1 2-((2-((2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-
dihydropyrimidin-1(2H)-yl)phenyl)thio)propanoyl)oxy)ethyl methacrylate (5a)
White solid, Yield 81%; 1H-NMR (500 MHz, CDCl3): δ 7.45 (dd, J = 7.5, 4.2 Hz, 1H), 7.34
(dd, J = 9.1, 2.0 Hz, 1H), 6.32 (d, J = 3.5 Hz, 1H), 6.07 (dq, J = 3.6, 1.1 Hz, 1H), 5.55 (dq, J =
3.2, 1.6 Hz, 1H), 4.35 – 4.15 (m, 4H), 3.88 (qd, J = 7.1, 1.0 Hz, 1H), 3.52 (dt, J = 2.5, 1.3 Hz,
13
3H), 1.89 (t, J = 1.3 Hz, 3H), 1.50 (dd, J = 7.2, 1.6 Hz, 3H); C-NMR(125 MHz, CDCl3):
172.05, 167.22, 159.99, 158.49, 156.56, 150.78, 140.03, 136.04, 129.48, 126.37, 126.30,
121.36, 120.69, 118.87, 103.29, 63.24, 62.42, 44.26, 32.92, 18.41, 16.97; HRMS (ESI) m/z
calcd for C21H19ClF4N2O6S, 538.0588 [M + H]+; found 538.0588.
4.2.2 1-methacrylamidopropan-2-yl 2-((2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-
(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)phenyl)thio)propanoate (5b)
Colorless sticky liquid, Yield 46%; 1H-NMR (500 MHz, CDCl3): δ 7.51 – 7.42 (m, 1H), 7.40
– 7.30 (m, 1H), 6.39 – 6.26 (m, 1H), 5.63 – 5.53 (m, 1H), 5.32 – 5.20 (m, 1H), 5.02 – 4.83 (m,
1H), 3.91 – 3.73 (m, 1H), 3.57 – 3.52 (m, 3H), 3.47 – 3.25 (m, 2H), 1.88 (s, 3H), 1.52 – 1.47
(m, 3H), 1.20 – 1.12 (m, 3H); 13C-NMR(125 MHz, CDCl3): δ 172.30, 171.83, 168.45, 159.90,
150.53, 139.73, 138.72, 135.63, 135.22, 134.76, 134.68, 129.83, 119.60, 118.42, 103.06, 71.34,
44.44, 44.02, 32.77, 18.52, 17.58, 16.67; LC-ESI-MS m/z calcd for C22H22ClF4N3O5S,
552.2(M+H)+.
4.2.3 N-(2-(2-((2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-
dihydropyrimidin-1(2H)-yl)phenyl)thio)propanamido)ethyl)methacrylamide (5c)
Ivory solid, Yield 48%; 1H-NMR (500 MHz, CDCl3): δ 7.38 (d, J = 8.9 Hz, 1H), 7.27 – 7.20
(m, 1H), 6.81 (d, J = 14.2 Hz, 1H), 6.52 (s, 1H), 6.37 (d, J = 8.7 Hz, 1H), 6.05 (s, 1H), 3.83 (q,

J = 7.2 Hz, 1H), 3.56 (dt, J = 6.4, 1.3 Hz, 3H), 3.36 – 3.29 (m, 2H), 3.19 – 3.10 (m, 2H), 2.04
(s, 3H), 1.63 (s, 3H); 13C-NMR(125 MHz, CDCl3): δ 176.78, 171.47, 168.85, 160.00, 157.35,
150.74, 140.73, 136.17, 133.34, 131.57, 131.33, 118.81, 118.63, 104.98, 103.06, 45.99, 40.03,
30.39, 28.35, 18.56, 18.11; LC-ESI-MS m/z calcd for C21H21ClF4N4O4S, 537.20(M+H)+.
4.2.4 2-(2-((2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-
dihydropyrimidin-1(2H)-yl)phenyl)thio)propanamido)ethyl methacrylate (5d)
Colorless sticky liquid, Yield 60%; 1H-NMR (500 MHz, CDCl3): δ 7.29 – 7.24 (m, 1H), 7.13
(dd, J = 7.2, 5.9 Hz, 1H), 6.69 (d, J = 4.5 Hz, 1H), 6.27 (d, J = 5.7 Hz, 1H), 5.99 (dt, J = 2.3,
1.4 Hz, 1H), 5.50 (q, J = 1.5 Hz, 1H), 4.19 – 3.97 (m, 2H), 3.80 – 3.65 (m, 1H), 3.49 – 3.46
(m, 3H), 3.44 (t, J = 5.8 Hz, 2H), 1.84 (s, 3H), 1.52 (bs, 3H); 13C-NMR(125 MHz, CDCl3): δ
171.27, 168.21, 167.46, 159.97, 155.74, 150.72, 136.07, 132.18, 131.99, 130.40, 126.36,
121.67, 120.68, 118.94, 103.26, 63.49, 46.52, 39.31, 29.92, 18.44, 18.07; LC-ESI-MS m/z
calcd for C21H20ClF4N3O5S, 538.2(M+H)+.
4.2.5 2-acrylamidoethyl 2-((2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-
3,6-dihydropyrimidin-1(2H)-yl)phenyl)thio)propanoate (5e)
Colorless sticky liquid, Yield 79%; 1H-NMR (500 MHz, CDCl3): δ 7.47 (dd, J = 7.5, 5.3 Hz,
1H), 7.34 (dd, J = 9.0, 0.9 Hz, 1H), 6.35 (d, J = 1.8 Hz, 1H), 6.12 (d, J = 19.5 Hz, 1H), 5.96
(ddd, J = 17.0, 10.3, 4.4 Hz, 1H), 5.58 (d, J = 10.3 Hz, 1H), 4.19 – 3.99 (m, 2H), 3.86 (q, J =
7.1 Hz, 1H), 3.54 (s, 3H), 3.51 – 3.26 (m, 2H), 1.50 (dd, J = 7.1, 2.3 Hz, 3H); 13C-NMR(125
MHz, CDCl3): δ 172.21, 165.68, 160.03, 158.31, 156.26, 150.67, 141.98, 140.25, 135.62,
130.54, 129.62, 126.46, 121.01, 118.56, 102.98, 64.07, 44.06, 38.53, 32.85, 16.33; LC-ESI-
MS m/z calcd for C20H18ClF4N3O5S, 524.20 (M+H)+.

4.2.6 2-((2-((2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-
dihydropyrimidin-1(2H)-yl)phenyl)thio)propanoyl)oxy)ethyl acrylate (5f)
Colorless sticky liquid, Yield 88%; 1H-NMR (500 MHz, CDCl3): δ 7.47 (dd, J = 7.5, 1.3 Hz,
1H), 7.35 (dd, J = 9.1, 1.9 Hz, 1H), 6.45 – 6.24 (m, 2H), 6.07 (dd, J = 17.3, 10.5 Hz, 1H), 5.82
(dt, J = 10.5, 1.5 Hz, 1H), 4.24 (qdd, J = 9.2, 5.3, 1.8 Hz, 4H), 3.88 (qd, J = 7.1, 0.9 Hz, 1H),
13
3.52 (s, 3H), 1.51 (dd, J = 7.1, 1.7 Hz, 3H); C-NMR(125 MHz, CDCl3): δ 171.91, 165.77,
159.79, 158.30, 156.25, 150.58, 141.99, 139.61, 135.97, 131.44, 129.32, 127.93, 121.07,
118.69, 102.98, 63.08, 61.98, 44.08, 32.72, 16.75; LC-ESI-MS m/z calcd for C20H17ClF4N2O6S,
547.2 (M+Na)+.
4.2.7 4-((2-((2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-
dihydropyrimidin-1(2H)-yl)phenyl)thio)propanoyl)oxy)butyl acrylate (5g)
Colorless sticky liquid, Yield 84%; 1H-NMR (500 MHz, CDCl3): δ 7.51 – 7.38 (m, 1H), 7.35
– 7.25 (m, 1H), 6.41 – 6.18 (m, 2H), 6.13 – 5.95 (m, 1H), 5.75 (dd, J = 10.4, 1.2 Hz, 1H), 4.11
– 3.94 (m, 4H), 3.90 – 3.76 (m, 1H), 3.48 (s, 3H), 1.56 (dd, J = 6.2, 2.7 Hz, 4H), 1.48 – 1.39
13
(m, 3H); C-NMR(125 MHz, CDCl3): δ 171.99, 166.17, 159.72, 158.26, 156.22, 150.54,
141.70, 139.61, 135.73, 130.69, 129.44, 128.45, 121.17, 118.61, 103.04, 64.98, 63.97, 44.31,
32.71, 25.11, 25.05, 16.84; LC-ESI-MS m/z calcd for C22H21ClF4N2O6S, 553.2 (M+H)+.
4.2.8 acrylamidomethyl 2-((2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-
3,6-dihydropyrimidin-1(2H)-yl)phenyl)thio)propanoate (5h)
Colorless sticky liquid, Yield 61%; 1H-NMR (500 MHz, CDCl3): δ 7.58 – 7.45 (m, 1H), 7.43
– 7.30 (m, 1H), 6.43 – 6.28 (m, 2H), 6.22 – 6.06 (m, 1H), 5.78 – 5.66 (m, 1H), 5.32 (s, 1H),
4.85 (dd, J = 6.8, 4.4 Hz, 1H), 3.89 (qd, J = 7.1, 0.9 Hz, 1H), 3.61 – 3.55 (m, 3H), 1.60 (d, J =
13
3.8 Hz, 1H), 1.58 – 1.51 (m, 3H); C-NMR(125 MHz, CDCl3): δ 172.13, 166.96, 159.79,

156.39, 154.37, 150.54, 141.92, 134.09, 130.84, 130.67, 127.53, 127.07, 121.31, 118.27,
103.02, 67.05, 41.08, 32.69, 21.82; LC-ESI-MS m/z calcd for C19H16ClF4N3O5S, 510.20
(M+H)+.
4.2.9 2-(2-((2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-
dihydropyrimidin-1(2H)-yl)phenyl)thio)acetamido)ethyl methacrylate (5i)
Colorless sticky liquid, Yield 70%; 1H-NMR (500 MHz, CDCl3): δ 7.31 (d, J = 8.9 Hz, 1H),
7.08 (d, J = 7.1 Hz, 1H), 6.94 (s, 1H), 6.32 (s, 1H), 6.11 – 5.96 (m, 1H), 5.54 (p, J = 1.5 Hz,
1H), 4.20 – 4.09 (m, 2H), 3.62 (s, 2H), 3.53 (d, J = 5.8 Hz, 2H), 3.51 (d, J = 5.9 Hz, 3H), 1.91
– 1.81 (m, 3H); 13C-NMR(125 MHz, CDCl3): δ 167.22, 166.94, 159.76, 157.17, 155.14, 150.53,
135.87, 135.20, 130.59, 129.31, 126.13, 121.83, 118.76, 118.58, 103.03, 63.17, 39.18, 36.52,
32.75, 18.23; LC-ESI-MS m/z calcd for C20H18ClF4N3O5S, 524.1 (M+H)+.
4.2.10 acrylamidomethyl 2-((2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-
3,6-dihydropyrimidin-1(2H)-yl)phenyl)thio)acetate (5j)
Colorless sticky liquid, Yield 53%; 1H-NMR (500 MHz, CDCl3): δ 7.46 (dd, J = 9.2, 7.4 Hz,
1H), 7.36 (dd, J = 19.7, 9.0 Hz, 1H), 6.46 – 6.28 (m, 2H), 6.24 – 5.89 (m, 1H), 5.86 – 5.64 (m,
1H), 5.31-4.84 (m, 2H), 3.70 – 3.64 (m, 2H), 3.59 (dq, J = 14.0, 1.2 Hz, 3H); 13C-NMR(125
MHz, CDCl3): δ 171.37, 169.27, 159.92, 155.71, 150.60, 137.72, 134.79, 133.00, 130.33,
129.85, 128.37, 128.19, 121.26, 118.50, 103.09, 67.05, 35.41, 29.70; LC-ESI-MS m/z calcd
for C18H14ClF4N3O5S, 518.1 (M+Na)+.
4.2.11 4-(2-((2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-
dihydropyrimidin-1(2H)-yl)phenyl)thio)acetoxy)butyl acrylate (5k)
Colorless sticky liquid, Yield 89%; 1H-NMR (500 MHz, CDCl3): δ 7.44 (d, J = 7.3 Hz, 1H),

7.37 (d, J = 9.0 Hz, 1H), 6.47 – 6.32 (m, 2H), 6.12 (dd, J = 17.3, 10.4 Hz, 1H), 5.84 (dd, J =
10.4, 1.4 Hz, 1H), 4.15 (dtt, J = 8.4, 6.1, 2.3 Hz, 4H), 3.67 (s, 2H), 3.57 (d, J = 1.1 Hz, 3H),
1.70 (dd, J = 9.3, 3.1 Hz, 4H); 13C-NMR(125 MHz, CDCl3): δ 168.86, 166.16, 159.75, 157.66,
155.63, 150.55, 141.69, 137.48, 132.71, 130.73, 130.52, 128.42, 121.37, 118.28, 103.06, 65.31,
63.90, 35.74, 32.68, 25.12, 25.09; LC-ESI-MS m/z calcd for C21H19ClF4N2O6S, 561.2 (M+Na)
+
.
4.2.12 2-(2-((2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-
dihydropyrimidin-1(2H)-yl)phenyl)thio)acetoxy)ethyl acrylate (5l)
Colorless sticky liquid, Yield 75%; 1H-NMR (500 MHz, CDCl3): δ 7.48 – 7.37 (m, 1H), 7.33
(d, J = 9.0 Hz, 1H), 6.45 – 6.28 (m, 2H), 6.08 (dd, J = 17.3, 10.5 Hz, 1H), 5.83 (dd, J = 10.5,
13
1.3 Hz, 1H), 4.38 – 4.22 (m, 4H), 3.64 (s, 2H), 3.56 – 3.50 (m, 3H); C-NMR(125 MHz,
CDCl3): δ 168.93, 166.00, 160.03, 157.97, 155.93, 150.79, 141.89, 137.83, 133.19, 131.72,
130.47, 128.06, 121.56, 118.67, 103.27, 103.22, 103.18, 63.62, 62.14, 35.72, 32.88; LC-ESI-
MS m/z calcd for C19H15ClF4N2O6S, 533.1 (M+Na) +.
4.2.13 2-(2-((2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-
dihydropyrimidin-1(2H)-yl)phenyl)thio)acetoxy)propyl methacrylate (5m)
Colorless sticky liquid, Yield 53%; 1H-NMR (500 MHz, CDCl3): δ 7.38 (dd, J = 34.9, 8.1 Hz,
2H), 6.35 (d, J = 1.8 Hz, 1H), 6.08 (q, J = 1.2 Hz, 1H), 5.57 (q, J = 1.6 Hz, 1H), 5.19 (tdd, J =
6.5, 3.5, 1.3 Hz, 1H), 4.28 – 3.97 (m, 2H), 3.67 – 3.61 (m, 2H), 3.57 – 3.52 (m, 3H), 1.91 (q, J
13
= 1.2 Hz, 3H), 1.27 – 1.18 (m, 3H); C-NMR(125 MHz, CDCl3): δ 168.57, 167.15, 163.89,
160.04, 157.83, 150.80, 137.42, 136.00, 134.17, 132.67, 130.79, 126.42, 121.59, 118.81,
103.27, 70.18, 66.18, 35.92, 32.91, 18.42, 16.46; LC-ESI-MS m/z calcd for C21H19ClF4N2O6S,
539.10 (M+H)+.

4.2.14 2-acrylamidoethyl 2-((2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-
3,6-dihydropyrimidin-1(2H)-yl)phenyl)thio)acetate (5n)
Colorless sticky liquid, Yield 54%; 1H-NMR (500 MHz, CDCl3): δ 7.43 (d, J = 7.3 Hz, 1H),
7.36 (d, J = 9.0 Hz, 1H), 6.37 (s, 1H), 6.29 – 6.17 (m, 2H), 6.00 (dd, J = 17.0, 10.3 Hz, 1H),
5.61 (dd, J = 10.3, 1.4 Hz, 1H), 4.23 – 4.16 (m, 2H), 3.64 (s, 2H), 3.60 – 3.54 (m, 3H), 3.49 (h,
13
J = 4.0 Hz, 2H); C-NMR(125 MHz, CDCl3): δ 168.96, 165.76, 159.99, 157.71, 155.67,
150.65, 142.18, 137.85, 132.98, 130.53, 130.34, 126.48, 121.34, 118.52, 103.01, 64.84, 38.57,
35.57, 32.75; LC-ESI-MS m/z calcd for C19H16ClF4N3O5S, 510.2(M+H)+.i
4.2.15 N-(2-(2-((2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-
dihydropyrimidin-1(2H)-yl)phenyl)thio)acetamido)ethyl)methacrylamide (5o)
Ivory solid, Yield 54%; 1H-NMR (500 MHz, CDCl3): δ 7.37 (d, J = 8.9 Hz, 1H), 7.15 (d, J =
7.1 Hz, 1H), 7.04 (s, 1H), 6.52 (s, 1H), 6.37 (s, 1H), 6.06 (s, 1H), 6.05 (s, 1H), 3.66 (s, 2H),
3.57 (q, J = 1.3 Hz, 3H), 3.42 – 3.32 (m, 2H), 3.17 (dd, J = 6.5, 4.3 Hz, 2H), 2.04 (s, 3H); 13C-
NMR(125 MHz, CDCl3): δ 176.78, 168.86, 167.31, 159.93, 157.00, 156.55, 154.97, 150.68,
141.78, 140.73, 136.17, 135.14, 133.34, 130.90, 128.93, 121.73, 121.62, 118.83, 118.64,
104.99, 103.13, 103.08, 40.16, 36.24, 28.34, 25.01, 18.56; LC-ESI-MS m/z calcd for
C20H19ClF4N4O4S, 523.2 (M+H)+.
4.2.16 2-(2-((2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-
dihydropyrimidin-1(2H)-yl)phenyl)thio)acetoxy)ethyl methacrylate (5p)
Colorless sticky liquid, Yield 76%; 1H-NMR (500 MHz, CDCl3): δ 7.51 – 7.33 (m, 2H), 6.36
(s, 1H), 6.11 (dq, J = 1.9, 0.9 Hz, 1H), 5.60 (p, J = 1.5 Hz, 1H), 4.37 – 4.29 (m, 4H), 3.68 (d, J
= 0.8 Hz, 2H), 3.57 (d, J = 1.1 Hz, 3H), 2.02 – 1.85 (m, 3H); 13C-NMR(125 MHz, CDCl3): δ

168.70, 167.03, 159.81, 157.77, 155.74, 150.59, 141.95, 137.53, 135.83, 133.00, 130.28,
126.17, 121.38, 118.64, 103.02, 63.40, 62.10, 35.51, 32.69, 18.19; LC-ESI-MS m/z calcd for
C20H17ClF4N2O6S, 525.1 (M+H)+.
4.2.17 2-(((2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-
dihydropyrimidin-1(2H)-yl)phenyl)alanyl)oxy)ethyl methacrylate (6a)
Brown solid, Yield 43%; 1H-NMR (500 MHz, CDCl3): δ 7.20 (d, J = 9.0 Hz, 1H), 6.63 (d, J =
5.8 Hz, 1H), 6.36 (s, 1H), 6.14 (s, 1H), 5.61 (bs, 1H), 4.43 – 4.38 (m, 4H), 4.33 – 3.85 (m, 1H),
13
3.56 (s, 3H), 1.96 (s, 3H), 1.71 (d, J = 6.9 Hz, 3H); C-NMR(125 MHz, CDCl3): δ 169.92,
167.72, 167.03, 160.05, 150.82, 148.87, 141.78, 140.29, 135.83, 126.22, 121.02, 120.35,
117.58, 115.66, 103.10, 63.50, 61.99, 52.25, 32.66, 21.40, 18.21; LC-ESI-MS m/z calcd for
C21H20ClF4N3O6, 522.2 (M+H)+
4.2.18 2-(((2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-
dihydropyrimidin-1(2H)-yl)phenyl)glycyl)oxy)ethyl methacrylate (6b)
Brown solid, Yield 42%; 1H-NMR (500 MHz, CDCl3): δ 7.27 (d, J = 8.9 Hz, 1H), 6.40 (d, J =
6.4 Hz, 1H), 6.37 (s, 1H), 6.12 (bs, 1H), 5.62 (dp, J = 4.7, 1.5 Hz, 1H), 4.52 – 4.42 (m, 2H),
13
4.42 – 4.35 (m, 2H), 3.95 (s, 2H), 3.62 – 3.49 (m, 3H), 1.96 (dt, J = 5.3, 1.0 Hz, 3H) ; C-
NMR(125 MHz, CDCl3): δ 169.78, 167.04, 160.03, 150.76, 150.48, 148.54, 141.77, 140.34,
135.80, 126.23, 121.18, 120.71, 117.92, 111.12, 103.13, 63.26, 62.09, 45.70, 32.67, 18.23; LC-
ESI-MS m/z calcd for C20H18ClF4N3O6, 508.2 (M+H)+.
4.3 Biological assay
4.3.1 Preparation of the samples for analysis
The analyzed samples were prepared by diluting 0.001% by weight of each synthesized

compound with water in which 50% by weight of acetone and 0.1% by weight of emulsifier
were dissolved and sprayed to a ratio of 1,000 L per hectare (ha).
4.3.2 Greenhouse herbicidal activity evaluation
Monocot seeds such as barnyard grass (Echinochloa crusgalli), crabgrass (Digitaria
sanguinalis), Asian sprangletop (Leptochloa chinensis) and dicot seeds such as goosefoot
(Chenopodium album), and hair star flower (Galinsoga ciliata) were sown in a 600cm2 square
pot filled with soil. Foliage treatment was carried out by spraying the test sample (5a-5p, 6a-
6b) or standard (Saflufenacil) 15 days after sowing. The efficiency of the samples and standard
were evaluated as a grade 0 (no effect) to grade 10 (most effective) by visually comparing the
degree of damage to the plant 10 days after treatment with the negative control group
(untreated). In addition, 5a and Saflufenacil were further tested with other monocots such as
black-grass (Alopecurus myosuroides), English ryegrass (Lolium perenne), and dicots such as
cypress vine (Ipomoea quamoclit), velvetleaf (Abutilon theophrasti), Indian jointvetch
(Aeschynomene indica), and rough cocklebur (Xanthium strumarium) to broaden the spectrum
and effectiveness.
4.3.3 Growth stage herbicidal evaluation of compound 5a on various weeds
Using the same method used on the evaluation of greenhouse herbicidal activity of weeds,
the following weeds: sorghum (Sorghum bicolor), barnyard grass (Echinochloa crus-galli),
crabgrass (Digitaria ciliaris), fall panicgrass (Panicum dichotomiflorum), and Asian
sprangletop (Leptochloa chinensis) were tested according to leaf stage. The leaf stage is a unit
of the growth rate of a plant, which indicates how many plant leaves have grown. The prepared
2.5 and 4 leaf stages weeds were treated with the 5a or standard via foliar application.
Efficiency is rated grade 0 (no effect) to grade 10 (most effective) after sample treatment which