Synthesis and herbicidal evaluation of aryloxyphenoxypropiona te derivatives containing purine moiety

Article abstract of DOI:10.2174/1570180814666170505123102

series of purinoxyphenoxypropionates were designed and synthesized by introducing 8-(trifluoromethyl)-9H-purine into the aryloxyphenoxypropionate backbone. Methods: The products were characterized by 1H NMR and HRMS. Results and Conclusion: Preliminary bioassays indicated that most of the compounds exhibited good herbicidal activity at 200 mg/L.

Full text of DOI:10.2174/1570180814666170505123102

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15
Letters in Drug Design & Discovery, 2018, 15, 15-20
RESEARCH ARTICLE
eISSN: 1 58 7 05 - 16 82 08 8X
FI m
a
c
p. 1t
a
o7
c
r
t:
1
Synthesis and Herbicidal Evaluation of Aryloxyphenoxypropionate
Derivatives Containing Purine Moiety
SB EC N
I
ET NH AC ME
a,b
a
a
c
a
c
Jianjun Shi , Guihua Ren , Zhimeng Dai , Ningjie Wu , Jianquan Weng , Tianming Xu ,
a,*
a,*
Xinghai Liu and Chengxia Tan
a
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, Zhejiang, P.R. China;
School of Chemistry and Chemical Engineering, Huangshan University, Huangshan 245041, Anhui, P.R. China;
b
c
Zhejiang Base of National Southern Pesticide Research Centre, Zhejiang Research Institute of Chemical Industry,
Hangzhou 310023, Zhejiang, P.R. China
Abstract: Background: A series of purinoxyphenoxypropionates were designed and synthesized
A R T I C L E H I S T O R Yꢀ
by introducing 8-(trifluoromethyl)-9H-purine into the aryloxyphenoxypropionate backbone.
Received: January 25, 2017
Revised: March 20, 2017
Accepted: March 27, 2017
1
Methods: The products were characterized by H NMR and HRMS.
Results and Conclusion: Preliminary bioassays indicated that most of the compounds exhibited
DOI:
1
0.2174/1570180814666170505123102
good herbicidal activity at 200 mg/L.
Keywords: Purinoxyphenoxypropionates, herbicidal activity, ACCase, synthesis, antimycobacterial, antiviral.
1
. INTRODUCTION
activity against monocotyledonous and dicotyledonous
plants.
Acetyl-coenzyme A carboxylase (ACCase) is a key en-
zyme in fatty acid biosynthesis in both eukaryotes and pro-
karyotes [1, 2]. Aryloxyphenoxypropionate (APP) deriva-
tives [3], such as diclofop-methyl, fenoxaprop-p-methyl,
quizalofop-p-ethyl and haloxyfop-methyl (Fig. 1), are strong
inhibitors of ACCase and are a very important class of post-
emergence herbicides used for the control of annual and per-
ennial grasses in broadleaf crops.
2. EXPERIMENTAL
The melting points were determined on an X-4 binocular
microscope melting point apparatus（Beijing Tech Instru-
1
ment Co., China) and were uncorrected. H NMR spectra
were recorded at 600 MHz using a Bruker AVANCE III HD
3
spectrometer (Bruker Co., Switzerland) in CDCl solution
with TMS as the internal standard, and chemical shift values
(δ) were given in parts per million (ppm). HRMS were re-
corded on an UPLC/Xevo G2-XS Q-TOF Waters mass spec-
trometer (Waters Corp., USA). Unless otherwise noted, all
chemicals and reagents were commercially available and
were used directly without further purification. All solvents
were dried and redistilled before use.
From Fig. (1), recently discovered APP herbicides al-
ways contain different heterocycles motifs, such as pyridine,
quizaline, benzoxazole and so on. In order to discover new
bioactive compounds [4-14], especially new APP herbicides,
the natural product purine was applied in this structure, be-
cause the purine possessed diverse activities including insec-
ticidal [15], antimycobacterial [16], antiviral [17], anticancer
[
18]. Following our drug design strategies, the main structure
2.1. Synthesis of 4,6-dichloropyrimidin-5-amine (1)
phenoxypropionate was maintained, the heterocycle was
replaced by purine. Here we described the synthesis and
structural characterization of APP derivatives containing
purine moiety, as well as the evaluation of their herbicidal
Iron powder (57.59 g, 1031.2 mmol) and saturated am-
monium chloride solution (260.0 mL) were added to a solu-
tion of 4,6-dichloro-5-nitropyrimidine (100.02 g, 515.6
mmol) in 1200 mL of ethanol-water mixed solvent (5:1, v/v).
The mixture was stirred and refluxed for 4 h. The insoluble
materials were filtered off and washed with tetrahydrofuran.
The filtrate was concentrated to 1/5 of its original volume
under reduced pressure and extracted with ethyl acetate. The
*
Address correspondence to these authors at the College of Chemical Engi-
neering, Zhejiang University of Technology, Hangzhou 310014, Zhejiang,
P.R. China; Tel: +86 571 88320238; E-mails: xhliu@zjut.edu.cn and
tanchengxia@zjut.edu.cn
1
875-628X/18 $58.00+.00
©2018 Bentham Science Publishers

1
6
Letters in Drug Design & Discovery, 2018, Vol. 15, No. 1
Shi et al.
organic solution was washed with saturated salt water
with anhydrous magnesium sulfate, and evaporated under
(
3×300 mL), dried over anhydrous magnesium sulfate and
vacuum to afford the compound 3a-3h.
evaporated under vacuum to get 4,6-dichloropyrimidin-5-
amine (1) as pale yellow solid which was used without fur-
2.1.2.1. 6-chloro-9-(m-tolyl)-8-(trifluoromethyl)-9H-purine
(3a)
o
1
ther purification. Yield 73.8%, m.p. 144-148 C; H NMR
(
600 MHz, CDCl
3 2
) δ: 4.53 (s, 2H, NH ), 8.23 (s, 1H, pyrimi-
o
1
Yellow solid, yield 74.1%, m.p. 78-79 C; H NMR
600MHz, CDCl ) δ: 2.48 (s, 3H, CH ), 7.22-7.23 (m, 2H,
Ar-H), 7.45 (d, J = 7.7 Hz, 1H, Ar-H), 7.51 (t, J = 8.1 Hz,
H), 8.85 (s, 1H, pyrimidine-H).
dine-H).
(
3
3
.1.1. General Synthetic Procedure for 6-chloro-N4-
2
1
(
substituted phenyl) pyrimidine-4, 5-diamine (2)
Compound 1 (11.48 g, 70.0 mmol) was added to a solu-
2.1.2.2. 6-chloro-9-(4-ethoxyphenyl)-8-(trifluoromethyl)-
9H-purine (3b)
tion containing 190 mL of water, 30 mL of ethanol, 3 mL of
concentrated hydrochloric acid and substituted phenyl amine
1
Yellow viscous liquid, yield 74.1%, H NMR (600MHz,
(
91.0 mmol). The solution was stirred and refluxed till the
CDCl
H, CH
Hz, 2H, Ar-H), 8.84 (s, 1H, pyrimidine-H).
3
) δ: 1.48 (t, J = 7.0 Hz, 3H, CH ), 4.13 (q, J = 7.0 Hz,
3
reaction finished (monitored by thin layer chromatography).
The reaction mixture was cooled, neutralized with potassium
carbonate and filtered. The residue was washed and recrys-
tallized from a 1:2 water-methanol mixture to give the com-
pounds 2a-2h.
2
2
), 7.08 (d, J = 8.9 Hz, 2H, Ar-H), 7.32 (d, J = 8.9
2
.1.2.3. 6-chloro-9-(p-tolyl)-8-(trifluoromethyl)-9H-purine (3d)
o
1
Yellow solid, yield 74.1%, m.p. 78-80 C; H NMR (600
4
2
.1.1.1. 6-chloro-N -(m-tolyl)pyrimidine-4,5-diamine (2a)
3 3
MHz, CDCl ) δ: 2.50 (s, 3H, CH ), 7.31 (d, J = 8.1 Hz, 2H,
o
1
Ar-H), 7.42 (d, J = 8.0 Hz, 2H, Ar-H), 8.84 (s, 1H, pyrimidi-
Brown solid, yield 69.3%, m.p. 155-157 C; H NMR
600 MHz, CDCl ) δ: 2.37 (s, 3H, CH ), 3.53 (s, 2H, NH ),
.79 (s, 1H, NH), 6.95 (d, J = 7.5 Hz, 1H, Ar-H), 7.24-7.25
ne-H).
(
3
3
2
6
Other compounds 3 were synthesized using a similar
experimental procedure and were used directly without fur-
ther structure characterization in the next reaction.
(
m, 1H, Ar-H), 7.32-7.33 (m, 2H, Ar-H), 8.18 (s, 1H, pyri-
midine-H).
4
2
.1.1.2.
6-chloro-N -(4-ethoxyphenyl)pyrimidine-4,5-
2
.1.3. General Procedure for the Synthesis of Target
diamine (2b)
Compounds (4)
o
1
Brown solid, yield 77.5%, m.p. 173-174 C; H NMR
600MHz, CDCl ) δ: 1.42 (t, J = 7.0 Hz, 3H, CH ), 3.49 (s,
), 4.03 (q, J = 7.0 Hz, 2H, CH ), 6.68 (s, 1H, NH),
To a mixture of compound 3 (0.95 mmol) and potassium
carbonate (0.26 g, 1.9 mmol) in dimethyl formamide (10
mL), appropriate alkyl 2-(4-hydroxyphenoxy)propanoate
(1.14 mmol)was added while stirring. The reaction mixture
(
2
6
3
3
H, NH
2
2
.91 (d, 2H, J = 8.9 Hz, Ar-H), 7.38 (d, J = 8.8 Hz, 2H, Ar-
o
H), 8.14 (s, 1H, pyrimidine-H).
was heated with stirring at 100 C for 7 h. After cooling the
solution was poured into saturated brines (60 mL) and ex-
tracted with ethyl acetate (3×30mL). The combined extracts
4
2
.1.1.3.
6-chloro-N -(3-isopropylphenyl)pyrimidine-4,5-
diamine (2c)
were dried over MgSO , filtered, and evaporated. The resi-
4
due was separated by flash chromatography (silica gel, 20:80
o
1
Brown solid, yield 74.1%, m.p. 126-128 C; H NMR
600MHz, CDCl ) δ: 1.26 (d, J = 6.9 Hz, 6H, CH(CH ),
.88-2.95 (m, 1H, CH(CH ), 3.58 (s, 2H, NH ), 6.87 (s,
ethyl acetate/hexane) to afford the corresponding pure title
(
2
1
3
3 2
)
compounds 4a-4o.
3
)
2
2
H, NH), 7.00 (d, J=7.6 Hz, 1H, Ar-H), 7.20-7.31 (m, 2H,
2
.1.3.1. (S)-methyl 2-(4-((9-(m-tolyl)-8-(trifluoromethyl)-9H-
Ar-H), 7.41-7.43 (m, 1H, Ar-H), 8.17 (s, 1H, pyrimidine-H).
purin-6-yl)oxy)phenoxy) Propanoate (4a)
Other compounds 2 can be synthesized according to the
similar procedure and can be used in the next reaction di-
rectly without further structure characterization.
1
Yellow viscous liquid, yield 74%, H NMR (600MHz,
CDCl
CH
.97 (d, J = 9.0 Hz, 2H, Ar-H), 7.21 (d, J = 9.1 Hz, 2H, Ar-
H), 7.24-7.25 (m, 2H, Ar-H), 7.42 (d, J = 7.7 Hz, 1H, Ar-H),
.49 (t, J = 8.1 Hz, 1H, Ar-H), 8.58 (s, 1H, pyrimidine-H);
3
) δ: 1.64 (d, J = 6.8 Hz, 3H, CHCH
3
), 2.47 (s, 3H, Ar-
3
), 3.79 (s, 3H, OCH
3
3
), 4.77 (q, J = 6.8 Hz, 1H, CHCH ),
6
2
(
.1.2. General Synthetic Procedure for 6-chloro-9-
substituted phenyl)-8-(trifluoro-methyl) -9H-purine (3)
7
+
HRMS calcd for C23
H
20
N
4
O
4
F
3
([M + H] ) 473.1437, found
To a solution of compound 2 (15.0 mmol) in dry toluene
40.0 mL) was added trifluoroacetic acid (2.28 g, 30.0
4
73.1426.
(
mmol) and phosphorus oxychloride (4.2 mL, 45.0 mmol).
The resulting mixture was stirred at room temperature for 0.5
h and then heated to reflux. After the reaction was com-
pletely finished, the reaction mixture was slowly and cau-
tiously poured into 100 mL of ice/water, and the resulting
2
.1.3.2. (S)-ethyl 2-(4-((9-(m-tolyl)-8-(trifluoromethyl)-9H-
purin-6-yl)oxy)phenoxy)propanoate (4b)
1
Yellow viscous liquid, yield 77%, H NMR (600MHz,
CDCl
CHCH
CH CH
3
) δ: 1.28 (t, 3H, CH
2
CH
3
), 1.64 (d, J = 6.8 Hz, 3H,
mixture was basified with solid NaOH and NaHCO
3
. The
3
), 2.47 (s, 3H, Ar-CH
3
), 4.25 (q, 2H, J = 7.1 Hz,
), 6.97 (d, J = 9.1
organic layer was then separated, washed with water, dried
2
3
), 4.75 (q, J = 6.8 Hz, 1H, CHCH
3

Synthesis and Herbicidal Evaluation of Aryloxyphenoxypropionate Derivatives
Letters in Drug Design & Discovery, 2018, Vol. 15, No. 1 17
Hz, 2H, Ar-H), 7.21 (d, J = 9.1 Hz, 2H, Ar-H), 7.24-7.25 (m,
J = 6.8 Hz, CHCH
Hz, 2H, CH CH
3
), 2.48 (s, 3H, Ar-CH
3
), 4.25 (q, J = 7.1
), 6.97 (d,
2
H, Ar-H), 7.42 (d, J = 7.9 Hz, 1H, Ar-H), 7.49 (t, J = 8.1
2
3
), 4.75 (q, J = 6.8 Hz, 1H, CHCH
3
Hz, 1H, Ar-H), 8.58 (s, 1H, pyrimidine-H); HRMS calcd for
J = 9.0 Hz, 2H, Ar-H), 7.20 (d, J = 9.0 Hz, 2H, Ar-H), 7.33
+
24 22 4 4 3
C H N O F ([M + H] ) 487.1593, found 487.1574.
(d, J = 8.2 Hz, 2H, Ar-H), 7.41 (d, J = 8.1 Hz, 2H, Ar-H),
8
22 4 4 3
.56 (s, 1H, pyrimidine-H); HRMS calcd for C24H N O F
+
2
.1.3.3. (S)-methyl 2-(4-((9-(4-ethoxyphenyl)-8-(trifluoromethyl)-
([M + H] ) 487.1593, found 487.1619.
9
H-purin-6-yl)oxy)phenoxy)propanoate (4c)
1
2.1.3.8. (S)-butyl 2-(4-((9-(p-tolyl)-8-(trifluoromethyl)-9H-
purin-6-yl)oxy)phenoxy)propanoate (4h)
Yellow viscous liquid, yield 70%, H NMR (600MHz,
CDCl
3
2 3
) δ: 1.47 (t, J = 7.0 Hz, 3H, CH CH ), 1.64 (d, J = 6.8
1
Hz, 3H, CHCH
3
), 3.79 (s, 3H, OCH
), 4.77 (q, J = 6.8 Hz, 1H, CHCH
.0 Hz, 2H, Ar-H), 7.07 (d, J = 8.9 Hz, 2H, Ar-H), 7.21 (d, J
9.0 Hz, 2H, Ar-H), 7.35 (d, J = 8.9 Hz, 2H, Ar-H), 8.57 (s,
H, pyrimidine-H); HRMS calcd for C24 ([M +
3
), 4.12 (q, J = 6.9 Hz,
Yellow viscous liquid, yield 74%, H NMR (600MHz,
2
9
H, CH
2
CH
3
3
), 6.96 (d, J =
CDCl
3
) δ: 0.91 (t, J =7.4Hz, 3H, O(CH
2
)
3
CH
3
), 1.32-1.36
CH
), 2.48 (s, 3H, Ar-
), 4.76 (q, J = 6.8
), 6.96 (d, J = 9.1 Hz, 2H, Ar-H), 7.20 (d, J
9.0 Hz, 2H, Ar-H), 7.33 (d, J = 8.3 Hz, 2H, Ar-H), 7.41 (d,
J = 8.1 Hz, 2H, Ar-H), 8.56 (s, 1H, pyrimidine-H); HRMS calcd
(m, 2H, O(CH
2
)
2
CH
), 1.64 (d, J = 6.8 Hz, 3H, CHCH
), 4.13-4.21 (m, 2H, OCH (CH CH
3
2
CH
3
), 1.58-1.62 (m, 2H, OCH
2
2
=
CH
CH
2
CH
3
3
1
H
22
N
4
O
5
F
3
3
2
2
)
2
+
H] ) 503.1542, found 503.1553.
Hz, 1H, CHCH
3
=
2
.1.3.4. (S)-ethyl 2-(4-((9-(4-ethoxyphenyl)-8-(trifluoromethyl)-
H-purin-6-yl)oxy)phenoxy)propanoate (4d)
+
9
26 4 4 3
for C26H N O F ([M + H] ) 515.1906, found 515.1922.
1
Yellow viscous liquid, yield 65%, H NMR (600MHz,
2
.1.3.9. (S)-methyl 2-(4-((9-(4-fluorophenyl)-8-(trifluoromethyl)-
CDCl
3
) δ: 1.28 (t, J = 7.1 Hz, 3H, CH
2
CH
3
), 1.47 (t, J = 7.0
),
), 4.25 (q, J = 7.1Hz,
), 4.75 (q, J = 6.8 Hz, 1H, CHCH ), 6.97 (d, J =
.1 Hz, 2H, Ar-H), 7.07 (d, J = 8.9 Hz, 2H, Ar-H), 7.20 (d, J
9.1 Hz, 2H, Ar-H), 7.34 (d, J = 8.9 Hz, 2H, Ar-H), 8.57 (s,
H, pyrimidine-H); HRMS calcd for C25 ([M +
9
H-purin-6-yl)oxy)phenoxy)propanoate (4i)
Hz, 3H, Ar-OCH
2
CH
.12 (q, J = 7.0 Hz, 2H, Ar-OCH
H, CH CH
3
), 1.64 (d, J = 6.8 Hz, 3H, CHCH
3
1
4
2
9
2
CH
3
Yellow viscous liquid, yield 80%, H NMR (600MHz,
2
3
3
CDCl
OCH
3
3
) δ: 1.65 (d, J = 6.8 Hz, 3H, CHCH ), 3.79 (s, 3H,
3
), 4.77 (q, J = 6.8 Hz, 1H, CHCH ), 6.97 (d, J = 9.1
3
=
Hz, 2H, Ar-H), 7.21 (d, J = 9.1 Hz, 2H, Ar-H), 7.29-7.33 (m,
1
H
24
N
4
O
5
F
3
2H, Ar-H), 7.44-7.47 (m, 2H, Ar-H), 8.57 (s, 1H, pyrimidi-
ne-H); HRMS calcd for C22
found 477.1196.
+
+
H] ) 517.1699, found 517.1719.
H
17
N
4
O
4
F
4
([M + H] ) 477.1186,
2
.1.3.5. (S)-butyl 2-(4-((9-(4-ethoxyphenyl)-8-(trifluoromethyl)-
H-purin-6-yl)oxy)phenoxy)propanoate (4e)
9
2
.1.3.10. (S)-ethyl 2-(4-((9-(2-fluorophenyl)-8-(trifluoromethyl)-
1
9H-purin-6-yl)oxy)phenoxy)propanoate (4j)
Yellow viscous liquid, yield 68%, H NMR (600MHz,
1
CDCl
m, 2H, O(CH
OCH CH ), 1.58-1.60 (m, 2H, OCH
J = 6.8 Hz, 3H, CHCH ), 4.12 (q, J = 7.0 Hz, 2H,
OCH CH ), 4.17-4.21 (m, 2H, OCH (CH CH ), 4.76 (q, J
6.8 Hz, 1H, CHCH ), 6.96 (d, J = 9.1 Hz, 2H, Ar-H), 7.07
d, J = 8.9 Hz, 2H, Ar-H), 7.20 (d, J = 9.1 Hz, 2H, Ar-H),
.35 (d, J = 8.9 Hz, 2H, Ar-H), 8.56 (s, 1H, pyrimidine-H);
3
) δ: 0.90 (t, J = 7.4 Hz, 3H, O(CH
2 3 3
) CH ), 1.31-1.37
Yellow viscous liquid, yield 82%, H NMR (600MHz,
(
2
)
2
CH
2
CH
3
), 1.47 (t, J = 7.0 Hz, 3H,
CDCl
3
) δ: 1.27 (t, 3H, J = 7.1 Hz, CH
2
CH
3
), 1.64 (d, J = 6.8
CH ), 4.75 (q,
), 6.97 (d, J = 9.1 Hz, 2H, Ar-H),
.22 (d, J = 9.1 Hz, 2H, Ar-H), 7.36-7.41 (m, 2H, Ar-H),
.48 (t, J = 7.4 Hz, 1H, Ar-H), 7.62-7.66 (m, 1H, Ar-H), 8.57
([M +
2
3
2
CH CH CH ), 1.65 (d,
2
2
3
Hz, 3H, CHCH
), 4.25 (q, J = 7.1 Hz, 2H, CH
3
2
3
3
J = 6.8 Hz, 1H, CHCH
3
2
3
2
2
)
2
3
7
7
=
3
(
(
s, 1H, pyrimidine-H); HRMS calcd for C23
H
19
N
4
O
4
F
4
+
7
H] ) 491.1342, found 491.1338.
+
HRMS calcd for C27
45.1998.
28 4 5 3
H N O F ([M + H] ) 545.2012, found
5
2
.1.3.11.
(S)-methyl
2-(4-((9-(3,4-difluorophenyl)-8-
(
(
trifluoromethyl)-9H-purin-6-yl)oxy)phenoxy)propanoate
2
.1.3.6. (S)-butyl 2-(4-((9-(3-isopropylphenyl)-8-(trifluoromethyl)-
4k)
9
H-purin-6-yl)oxy)phenoxy)propanoate (4f)
Yellow solid, yield 83%, m.p. 98-100 C; 1H NMR
o
1
Yellow viscous liquid, yield 73%, H NMR (600MHz,
(
600MHz, CDCl
s, 3H, OCH
.0 Hz, 2H, Ar-H), 7.20 (d, J = 9.0 Hz, 2H, Ar-H), 7.24-7.25
m, 1H, Ar-H), 7.33-7.37 (m, 1H, Ar-H), 7.40-7.45 (m, 1H,
Ar-H), 8.58 (s, 1H, pyrimidine-H); HRMS calcd for
3
) δ: 1.65 (d, J = 6.8 Hz, 3H, CHCH
3
), 3.79
CDCl
m, 8H, CH(CH
CH CH CH
3
2 3 3
) δ: 0.89 (t, J = 7.1 Hz, 3H, O(CH ) CH ), 1.27-1.31
(
3
), 4.77 (q, J = 6.8 Hz, 1H, CHCH
3
), 6.97 (d, J =
(
3
)
2
, O(CH
, CHCH
(CH
3
), 6.94-6.98 (m, 2H, Ar-H), 7.17-7.26 (m, 4H,
2
)
2
CH
), 2.99-3.03 (m, 1H, CH(CH
CH ), 4.74 (q, 1H, J = 6.8
2
CH
3
), 1.60-1.64 (m, 5H,
9
(
OCH
2
2
2
3
3
3 2
)
),
4
.14-4.20 (m, 2H, OCH
2
2
)
2
3
+
Hz, CHCH
22 16 4 4 5
C H N O F ([M + H] ) 495.1092, found 495.1081.
Ar-H), 7.44-7.51 (m, 2H, Ar-H), 8.58 (s, 1H, pyrimidine-H);
+
HRMS calcd for C28
H
30
N
4
O
4
F
3
([M + H] ) 543.2219, found
2
.1.3.12.
(S)-ethyl
2-(4-((9-(3,4-difluorophenyl)-8-
5
43.2244.
(
(
trifluoromethyl)-9H-purin-6-yl)oxy)phenoxy)propanoate
4l)
2
.1.3.7. (S)-ethyl 2-(4-((9-(p-tolyl)-8-(trifluoromethyl)-9H-
Yellow solid, yield 81%, m.p. 97-98 C; 1H NMR
o
purin-6-yl)oxy)phenoxy)propanoate (4g)
(
(
600MHz, CDCl
3
2 3
), δ: 1.28 (t, J = 7.1 Hz, 3H, CH CH ), 1.64
1
Yellow viscous liquid, yield 76%, H NMR (600MHz,
d, J = 6.8 Hz, 3H, CHCH
3
), 4.25 (q, J = 7.1 Hz, 2H,
), 6.97 (d, J = 9.1
CDCl
3
2 3
) δ: 1.28 (t, J = 7.1Hz, 3H, CH CH ), 1.64 (d, 3H,
CH
2
CH ), 4.75 (q, J = 6.8 Hz, 1H, CHCH
3
3

1
8
Letters in Drug Design & Discovery, 2018, Vol. 15, No. 1
Shi et al.
Hz, 2H, Ar-H), 7.20 (d, J = 9.1 Hz, 2H, Ar-H), 7.24-7.25 (m,
H, Ar-H), 7.34-7.37 (m, 1H, Ar-H), 7.41-7.45 (m, 1H, Ar-
H), 8.57 (s, 1H, pyrimidine-H); HRMS calcd for
2.1.3.14.
(S)-methyl
2-(4-((9-(2,4-difluorophenyl)-8-
1
(trifluoromethyl)-9H-purin-6-yl)oxy)phenoxy)propanoate
(4n)
+
C
23
H
18
N
4
O
4
F
5
([M + H] ) 509.1248, found 509.1237.
1
Yellow viscous liquid, yield 81%, H NMR (600MHz,
CDCl
OCH
H, Ar-H), 7.12-7.16 (m, 2H, Ar-H), 7.21 (d, J = 9.1 Hz, 2H,
3
) δ: 1.65 (d, J = 6.8Hz, 3H, CHCH
3
), 3.79 (s, 3H,
2
.1.3.13.
(S)-butyl
2-(4-((9-(3,4-difluorophenyl)-8-
3
), 4.78 (q, J = 6.8Hz, 1H, CHCH ), 6.97 (d, J = 9.1Hz,
3
(
(
trifluoromethyl)-9H-purin-6-yl)oxy)phenoxy)propanoate
2
4m)
Ar-H), 7.47-7.50 (m, 1H, Ar-H), 8.57(s, 1H, pyrimidine-H);
1
+
Yellow viscous liquid, yield 86%, H NMR (600MHz,
HRMS calcd for C22
495.1081.
16 4 4 5
H N O F ([M + H] ) 495.1092, found
CDCl
m, 2H, O(CH
CH ), 1.64 (d, J = 6.8 Hz, 3H, CHCH
H, OCH (CH CH ), 4.76 (q, J = 6.8 Hz, 1H, CHCH
.97 (d, J = 9.1 Hz, 2H, Ar-H), 7.19 (d, J = 9.1 Hz, 2H,
3
) δ: 0.91 (t, J = 7.4 Hz, 3H, O(CH
2
)
3
CH
3
), 1.30-1.36
CH
), 4.15-4.22 (m,
),
(
2
)
2
CH
2
CH
3
), 1.62-1.63 (m, 2H, OCH
2
2
CH
2
3
3
2.1.3.15.
(S)-ethyl
2-(4-((9-(2,4-difluorophenyl)-8-
2
6
2
2
)
2
3
3
(trifluoromethyl)-9H-purin-6-yl)oxy)phenoxy)propanoate
(4o)
Ar-H), 7.24-7.25 (m, 1H, Ar-H), 7.34-7.37(m, 1H, Ar-H),
1
Yellow viscous liquid, yield 84%, H NMR (600MHz,
7
.40-7.45 (m, 1H, Ar-H), 8.57 (s, 1H, pyrimidine-H);
CDCl
3
2 3
) δ: 1.28 (t, J = 7.1 Hz, 3H, CH CH ), 1.65 (d, J = 6.8
+
HRMS calcd for C25
37.1536.
H
22
N
4
O
4
F
5
([M + H] ) 537.1561, found
Hz, 3H, CHCH
3
2 3
), 4.25 (q, J = 7.1 Hz, 2H, CH CH ), 4.75 (q,
5
J = 6.8 Hz, 1H, CHCH
3
), 6.97 (d, J = 9.1 Hz, 2H, Ar-H),
O
O
Cl
Cl
O
O
O
Cl
O
N
O
O
O
diclofop-methyl
fenoxaprop-p-methyl
F
O
O
F
F
Cl
O
Cl
N
O
O
O
N
O
N
O
haloxyfop-methyl
quizalofop-p-ethyl
Fig. (1). The representative aryloxphenoxypionate herbicides.
1
2
2
a: R =3-CH ;
3
1
b: R =4-OCH CH ;
H N
NH2
2
3
2
NO2
NH
2
2c: R
1
=3-CH(CH3)2;
R1
H
N
R1
Cl
1
2
2
2
2
d: R =4-CH ;
Cl
Cl
Cl
Cl
3
4
Fe/NH Cl
1
1
e: R =4-F; 2f: R =2-F;
N
N
1
N
N
N
N
g: R =3,4-di-F;
ethanol/water
reflux
R1
1
h: R =2,4-di-F.
2
1
F3C
HO
N
F3C
R1
N
O
O
N
R2
O
CF
3
COOH
N
Cl
O
N
N
O
O
R2
N
N
K CO , DMF
2 3
POCl3
O
3a-3h
4a-4o
1
2
1
2
1
2
4
4
4
4
4
a: R =3-CH , R =CH ;
4f: R =3-CH(CH ) , R =(CH ) CH ; 4k: R =3,4-di-F, R =CH ;
3
3
3 2
2
2 3
3
3
1
2
1
1
2
b: R =3-CH , R =CH CH ;
4g: R =4-CH , R =CH CH ;
4l: R =3,4-di-F, R =CH CH ;
3
2
2
3
3
2
3
2 3
1
1
2
1
2
c: R =4-OCH CH , R =CH ;
4h: R =4-CH , R =(CH ) CH ;
4m: R =3,4-di-F, R =(CH ) CH ;
2 3 3
2
3
3
3
2 3
3
1
2
1
2
1
2
d: R =4-OCH CH , R =CH CH ; 4i: R =4-F, R =CH ;
4n: R =2,4-di-F, R =CH ;
2
3
2
3
3
3
1
2
1
2
1
2
e: R =4-OCH CH , R =(CH ) CH ; 4j: R =2-F, R =CH CH ;
4o: R =2,4-di-F, R =CH CH .
2 3
2
3
2 3
3
2
3
Scheme 1. The synthetic route of title compounds.

Synthesis and Herbicidal Evaluation of Aryloxyphenoxypropionate Derivatives
Letters in Drug Design & Discovery, 2018, Vol. 15, No. 1 19
Table 1. Herbicidal activity (growth inhibition, %) of title compounds at 200mg/L concentration.
Triticum aestivum
Sorghum bicolor
Echinochloa crus-galli
Cucumis sativus
Brassica campestris
Raphanus sativus
Compound
Root/Stalk
Root/Stalk
Root/Stalk
Root/Stalk
Root/Stalk
Root/Stalk
4
4
4
4
4
a
b
c
20/30
0/0
30/40
50/0
30/0
30/45
20/0
0/55
50/40
0/45
25/0
45/0
100/85
100/95
100/100
70/60
100/95
100/90
100/85
55/65
100/100
100/100
100/100
70/80
100/90
100/100
100/100
85/65
100/100
100/85
100/100
75/70
100/100
100/100
95/100
80/60
d
e
4
f
4
4
g
100/100
100/95
100/100
70/50
100/100
100/95
100/100
65/45
100/100
100/100
100/100
70/65
85/100
100/100
100/100
70/50
100/100
100/100
100/100
0/65
100/95
100/100
100/100
0/0
h
4
4
i
j
4
k
100/100
100/100
100/100
0/0
100/100
100/100
100/95
0/0
100/100
100/100
100/100
0/0
100/100
100/100
100/100
0/0
100/100
100/100
100/100
0/0
100/100
100/100
100/100
0/0
4
l
4
m
4
n
o
4
0/0
0/0
0/0
0/0
0/0
0/0
Pyribambenz
propyl
9
5/95
100/90
100/95
95/90
100/100
100/90
7
7
.12-7.16 (m, 2H, Ar-H), 7.21 (d, J = 9.1 Hz, 2H, Ar-H),
1.65 ppm corresponded to the methyl protons, and the pro-
tons in the purine appeared as characteristic singlet signal at
δ 8.56-8.58 ppm.
.47-7.50 (m, 1H, Ar-H), 8.57 (s, 1H, pyrimidine-H);
+
HRMS calcd for C23
H
18
N
4
O
4
F
5
([M + H] ) 509.1248, found
5
09.1283.
4
. HERBICIDAL ACTIVITY
3
3
. RESULTS AND DISCUSSION
Preliminary herbicidal activity of compounds 4a-4o was
.1. Synthesis
evaluated against monocotyledonous (Triticum aestivum,
Sorghum bicolor, Echinochloa crus-galli) and dicotyledon-
ous (Cucumis sativus, Brassica campestris, Raphanus sati-
vus) plants, respectively according to the reported procedure
The synthetic route of the title compounds is outlined in
Scheme 1. The intermediate 4,6-dichloropyrimidin-5-amine
(
1) was prepared from 4,6-dichloro-5-nitropyrimidine by
[
22, 23]. Pyribambenz propyl was used as positive control.
reduction using iron powder. Compound 1, in an aqueous
ethanol solution containing a small amount of hydrochloric
acid, was coupled with a diverse set of anilines giving rise to
diaminopyrimidine intermediates (2) which were cyclized
with trifluoroacetic acid to give the corresponding substi-
tuted purines (3) according to the literatures [19, 20]. The
series 4 compounds were synthesized by condensation reac-
tion of the series 3 compounds with the appropriate 2-(4-
hydroxyphenoxy)propanoate according to the reported method
All test compounds were dissolved in DMF with the Tween-
8
2
0 as emulsifying reagent, then diluted with water to
00mg/L and applied to the plants which were cultivated in
culture dish. The inhibition of root and stem growth was
evaluated 7 days after treatment. As listed in Table 1, most
of the compounds displayed excellent herbicidal activity
against all test plants. Particularly. Nine compounds (4c-4e,
4
g-4i, 4k-4m) in particular exhibited 85%-100% herbicidal
activity at 200 mg/L. The structure-activity relationship is as
follows: Compounds 4a, 4b, 4f, 4j exhibited much lower
herbicidal activity than compounds 4c-4e and 4g-4i, which
indicated that substitution at the ortho-position or meta-
position instead of para-position of the phenyl ring will lead
to a decrease in herbicidal activity. Compounds 4k-4m
showed similar herbicidal activity, which indicated that dif-
ferent alkyl groups will not affect the activity. Meanwhile,
[
21].
3
.2. Spectra
1
The title compounds were identified by H NMR and
HRMS. The HRMS showed an ion of M+H, which was con-
sistent with the calculated masses of the compounds. In the
1
H NMR spectra of 4a-4o, quartet at δ 4.74-4.78 ppm was
assignable to the methyne protons, and doublet at δ 1.64-
3
comparing our previous work, when the CH of purine was

2
0
Letters in Drug Design & Discovery, 2018, Vol. 15, No. 1
Shi et al.
replaced to CF
3
, the herbicidal activity was increased. The
[8]
Liu, X.H.; Zhao, W.; Shen, Z.H.; Xing, J.H.; Xu, T.M.; Peng, W.L.
Synthesis, nematocidal activity and sar study of novel difluoro-
methylpyrazole carboxamide derivatives containing flexible alkyl
chain moieties. Eur. J. Med. Chem., 2017, 125, 881-889.
halo Cl on the benzene ring decrease the herbicidal activity.
In this paper, we applied the halo F to the benzene ring, the
herbicidal activity is higher than that of Cl.
[9]
Zhao, W.; Shen, Z.H.; Xu, T.M.; Peng, W.L.; Liu, X.-H. Synthesis,
nematocidal activity and docking study of novel chiral 1-(3-
chloropyridin-2-yl)-3-(difluoromethyl)-1H-pyrazole-4-carboxamide
derivatives. J. Heterocycl. Chem., 2017, 54, 1751-1756.
CONCLUSION
In summary, a series of APP derivatives containing
purine were synthesized, and their structures were confirmed
[10]
Zhao, W.; Shen, Z.H.; Xu, T.M.; Peng, W.L.; Liu, X.H. Synthesis
and nematocidal activity of novel pyrazole carboxamide derivatives
against Meloidogyne incognita. Lett. Drug Des. Discov., 2017, 14,
1
by H NMR and HRMS. Bioassays indicated that some of
3
23-329.
the title compounds exhibited better herbicidal activity
against monocotyledonous and dicotyledonous plants.
[11]
[12]
[13]
Liu, X.-H.; Wang, Q.; Sun, Z.H.; Wedge, D.E.; Becnel, J.J.; Estep,
A.S.; Tan, C.X.; Weng, J.Q. synthesis and insecticidal activity of
novel pyrimidine derivatives containing urea pharmacophore
against Aedes aegypti. Pest Manag. Sci., 2017, 73, 953-959.
Yan, S.L.; Yang, M.Y.; Sun, Z.H.; Min, L.J.; Tan, C.X.; Weng, J.
Q.; Wu, H.K.; Liu X.H. Synthesis and antifungal activity of 1,2,3-
thiadiazole derivatives containing 1,3,4-thiadiazole moiety. Lett.
Drug Des. Discov., 2014, 11, 940-943.
CONSENT FOR PUBLICATION
Not applicable.
Zhai, Z.W.; Shi, Y.X.; Yang, M.Y.; Zhao, W.; Sun, Z.H.; Weng,
J.Q.; Tan, C.X.; Liu, X.H.; Li, B.J.; Zhang, Y.G. microwave as-
sisted synthesis and antifungal activity of some novel thioethers
containing 1,2,4-triazolo[4,3-a]pyridine moiety. Lett. Drug Des.
Discov., 2016, 13, 521-525.
Liu, X.H.; Fang, Y.M.; Xie, F.; Zhang, R.R.; Shen, Z.H.; Tan,
C.X.; Weng, J.Q.; Xu, T.M.; Huang, H.Y. Synthesis and in vivo
fungicidal activity of some new quinoline derivatives against rice
blast. Pest Manag. Sci., 2017, 73, 1900-1907.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
[
14]
15]
ACKNOWLEDGEMENTS
This work was supported by Key Projects of the National
Science and Technology Pillar Program of China (No.
[
Carmo, A.M.L.; Braga, F.G.; De Paula, M.L.; Ferreira, A.P.;
Teixeira, H.C.; da Silva, A.D.; Coimbra, E.S. Synthesis and bio-
logical activity of new tricyclic purine derivatives obtained by in-
tramolecular N-7 alkylation. Lett. Drug Des. Discov., 2008, 5, 122-
2
011BAE06B03-01).
1
26.
REFERENCES
[
[
16]
17]
Braendvang, M.; Gundersen, L.L. Synthesis, biological activity,
and SAR of antimycobacterial 2- and 8-substituted 6-(2-furyl)-9-(p-
methoxybenzyl)purines. Bioorg. Med. Chem., 2007, 15, 7144-7165.
Zhou, L.H.; Zhang, H.W.; Tao, S.J.; Bassit, L.; Whitaker, T.;
McBrayer, T.R.; Ehteshami, M.; Amiralaei, S.; Pradere, U.; Cho,
J.H.; Amblard, F.; Bobeck, D.; Detorio, M.; Coats, S.J.; Schinazi,
R.F. β-D-2’-C-methyl-2,6-diaminopurine ribonucleoside phos-
phoramidates are potent and selective inhibitors of hepatitis C Vi-
rus (HCV) and are bioconverted intracellularly to bioactive 2,6-
diaminopurine and guanosine 5’-triphosphate forms. J. Med.
Chem., 2015, 58, 3445-3458.
[
[
1]
2]
Harwood, J.L. Recent advances in the biosynthesis of plant
fatty acids. Biochim. Biophys. Acta, Lipids Lipid Metab., 1996, 1301,
7
-56.
Jursik, M.; Soukup, J.; Holec, J.; Venclova, V. Herbicide mode of
actions and symptoms of plant injury by herbicides: inhibitors of
lipids biosynthesis-ACCase inhibitor. Listy Cukrov. Reparske,
2
010, 126, 445-448.
[
[
[
3]
4]
5]
Yang, X.Y.; Guschina, I.A.; Hurst, S.; Wood, S.; Langford, M.;
Hawkes, T.; Harwood, J.L. The action of herbicides on fatty acid
biosynthesis and elongation in barley and cucumber. Pest Manag.
Sci., 2010, 66, 794-800.
Zhang, L.J.; Yang, M.Y.; Sun, Z.H.; Tan, C.X.; Weng, J.Q.; Wu,
H.K.; Liu, X.H. Synthesis and antifungal activity of 1,3,4-
thiadiazole derivatives containing pyridine group. Lett. Drug Des.
Discov., 2014, 11, 1107-1111.
Liu, X.H.; Zhao, W.; Shen, Z.H.; Xing, J.H.; Yuan, J.; Yang, G.;
Xu, T.M.; Peng, W.L. Synthesis, nematocidal activity and docking
study of novel chiral 1-(3-chloropyridin-2-yl)-3-(trifluoromethyl)-
[
[
[
[
[
18]
19]
20]
21]
22]
Kowalska, A.; Latocha, M.; Pluta, K. Synthesis and anticancer
activity of thiosubstituted purines. Med. Chem. Res., 2015, 24,
3
107-3116.
Greenberg, S.M.; Ross, L.O.; Robins, R.K. Potential purine an-
tagonists XXI: Preparation of some 9-phenyl-6-substituted purines.
J. Org. Chem., 1959, 24, 1314-1317.
Dai, Z.M.; He, H.Q.; Shi, J.J.; Liu, X.H.; Tan, C.X. Synthesis and
biological activities of purinoxy-phenoxy-propionate derivatives.
Chin. J. Pestic. Sci., 2015, 17, 610-615.
1
H-pyrazole-4-carboxamide derivatives. Bioorg. Med. Chem. Lett.,
016, 26, 3626-3628.
Jiang, L.; Wang, H.; Wang, M.R.; Teng, X.H. Synthesis and bio-
logical activity of 4-(4, 6-disubstituted-pyrimidin-2-yloxy) phenoxy
acetates. Molecules, 2010, 15, 1074-1081.
2
[
6]
7]
Liu, X.H.; Zhai, Z.W.; Xu, X.Y.; Yang, M.Y.; Sun, Z.H.;Weng,
J.Q.;Tan, C.X.; Chen, J. Facile and efficient synthesis and herbi-
cidal activity determination of novel 1,2,4-triazolo[4,3-a]pyridin-
Zhong, L.K.; Ni, Y.; Kong, X.Y.; Huang H.Y.; Li, J.; Tang, W.;
Zhang, R.R.; Kong, X.L.; Ji, W.J.; Xu, T.M. Synthesis and biologi-
cal activity of novel carbamates containing methoxyimino-
isoxazoline. Chin. J. Pestic. Sci., 2015, 17, 512-519.
3
(2H)-one derivatives via microwave irradiation. Bioorg. Med.
Chem. Lett., 2015, 25, 5524-5528.
[
Zhao, W.; Xing, J.H.; Xu, T.M.; Peng, W.L.; Liu, X.H. Synthesis
and in vivo nematocidal evaluation of novel n-substituted 3-
[
23]
Liu, X.H.; Xu, X.Y.; Tang, C.X.; Weng, J.Q.; Xin, J.H.; Chen, J.
Synthesis, crystal structure, herbicidal activities and 3D-QSAR
study of some novel 1,2,4-triazolo [4,3-a] pyridine derivatives. Pest
Manag. Sci., 2015, 71, 292-301.
(
Trifluoromethyl)-1H-pyrazole-4-carboxamide derivatives. Front.
Chem. Sci. Eng., 2017, 11, 363-368.