Design, synthesis, and herbicidal activity of novel substituted 3-(pyridin-2-yl)benzenesulfonamide derivatives

Article abstract of DOI:10.1021/jf504018z

A series of novel substituted 3-(pyridin-2-yl)benzenesulfonamide derivatives were designed and synthesized using 2-phenylpridines as the lead compound by intermediate derivatization methods in an attempt to obtain novel compound candidates for weed contro

Full text of DOI:10.1021/jf504018z

Article
pubs.acs.org/JAFC
Design, Synthesis, and Herbicidal Activity of Novel Substituted
3‑(Pyridin-2-yl)benzenesulfonamide Derivatives
Yong Xie, Hui-Wei Chi, Ai-Ying Guan, Chang-Ling Liu,* Hong-Juan Ma, and Dong-Liang Cui
State Key Laboratory of the Discovery and Development of Novel Pesticide, Shenyang Research Institute of Chemical Industry Co.
Ltd., Shenyang 110021, China
S
* Supporting Information
ABSTRACT: A series of novel substituted 3-(pyridin-2-yl)benzenesulfonamide derivatives were designed and synthesized using
2-phenylpridines as the lead compound by intermediate derivatization methods in an attempt to obtain novel compound
candidates for weed control. The herbicidal activity assay in glasshouse tests showed several compounds (II6, II7, II8, II9, II10,
II11, III2, III3, III4, and III5) could efficiently control velvet leaf, youth-and-old age, barnyard grass, and foxtail at the 37.5 g/ha
active substance. Especially, the activities of II6, II7, III2, and III4 were proved roughly equivalent to the saflufenacil and better
than 95% sulcotrione at the same concentration. The result of the herbicidal activity assay in field tests demonstrated that II7 at
60 g/ha active substance could give the same effect as bentazon at 1440 g/ha active substance to control dayflower and
nightshade, meanwhile II7 showed better activity than oxyfluorfen to control arrowhead and security to rice. The present work
indicates that II7 may be a novel compound candidate for potential herbicide.
KEYWORDS: substituted 3-(pyridin-2-yl)benzenesulfonamide compounds, intermediate derivatization methods, herbicide
replacement method has been proved as an effective and
practical method.37−44 As shown in Figure 1, according to the
terminal group replacement method, modification of the
sulfonamide group of 2-phenylpridines by introducing
hydrazine derivatives, fatty alcohols, and substituted amines
gave compounds I1−I5, II1−II5, II11−II12, II16, and III1.
Meanwhile, carbamic acid ester, which is the important group
of the herbicide asulam,45 was employed to replace the
sulfonamide group of 2-phenylpridines to synthesize com-
pounds II6−II10 and III2−III4. Then, other derivatives were
further derived from compounds II6−II10 or III2−III4.
Furthermore, the herbicidal effects of the substituted 3-
(pyridin-2-yl)benzenesulfonamide derivatives were investigated
in the glasshouse and the field.
INTRODUCTION
■
Pyridine has been widely used in the fields of medicine1−3 and
pesticide4−7 as an important intermediate. For instance,
neonicotinoid insecticides8−10 and sulfonylurea herbicides,11
which are important pesticides in the world, all contain a
pyridine ring. According to some statistics, there are more than
30 herbicides containing pyridine ring at present,12 and more
highly active compounds containing pyridine ring were
reported in recent years.13−24
Substituted 2-phenylpyridines which were disclosed by
Schaefer Peter et al. showed good herbicidal activity;25,26
several compounds could efficiently control velvet leaf (abutilon
thephrasti), redroot pigweed (amaranthus retroflexus), and
morningglory (ipomoea subspecies) at 250 and 125 g/ha by
the postemergence method. T. Konakahara et al.27 disclosed
that fluorinated 2-phenylpyridines could been provided as
intermediates for drugs and agrochemicals, such as substituted
thiobarbituric acids28 and 4-[(trifluoromethyl)pyridyl]-
phenols.26,29−32 Yanagi Akihiko et al.33 discovered 2,6-diary-
lpyridine derivatives could be used as herbicide and defoliating
agent. However, those known compounds which in fact have
herbicidal effect are not always completely satisfactory
Accordingly, in order to search for novel compounds which
have in particular herbicidal activity and which can be used for
the targeted control of unwanted plants, we designed and
synthesized substituted 3-(pyridin-2-yl)benzenesulfonamide
derivatives (Figure 1 and Table 1) using 2-phenylpyridines as
the lead compound by intermediate derivatization methods
(IDM)a practical approach to agrochemical discovery.
Intermediate derivatization methods use a three-pronged
approach to agrochemical discoverycommon intermediate
method (CIM), terminal group replacement method (TRM or
RM), and active compound derivatization method (ADM or
DM).34−36 Among these three approaches, the terminal group
MATERIALS AND METHODS
■
Synthesis. All starting materials and reagents were commercially
available and used without further purification except as indicated.
Melting points were determined on a Buchi melting point apparatus
̈
1
and are uncorrected. H NMR spectra were recorded with a Mercury
300 (Varian, 300 MHz) spectrometer with deuterochloroform as the
solvent and tetramethylsilane (TMS) as the internal standard.
Elemental analyses were determined on a Yanaco MT-3CHN
elemental analyzer.
An overview synthesis of substituted 3-(pyridin-2-yl)-
benzenesulfonamide analogues is shown in Scheme 1.
Synthesis of Intermediate a. Substituted 2-dichloro-5-trifluor-
omethylpyridine (0.18 mol), substituted 4-chlorobezeneboronic (0.18
mol), tetrakis(triphenylphosphine)palladim(0) (0.7 g, 0.61 mmol),
and sodium bicarbonate (45.3 g, 0.539 mol) in a mixture of 550 mL of
Received: August 26, 2014
Revised: November 24, 2014
Accepted: December 1, 2014
Published: December 1, 2014
© 2014 American Chemical Society
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Figure 1. Design of 3-(pyridin-2-yl)benzenesulfonamide derivatives. “RM” means “terminal group replacement method”.
dimethoxyethane and 550 mL of water were refluxed for 4 h. The
mixture was then acidified to pH 4−5 with dilute hydrochloric acid,
and dimethoxyethane was removed by distillation. The remaining
aqueous phase was extracted with methylene chloride. The combined
methylene chloride phased was washed with water, dried over sodium
sulfate, and evaporated. The residue was stirred with a little cold n-
hexane, filtered off with suction, and dried.
H2O at 0−5 °C, and the mixture was stirred at room temperature.
Then the mixture was concentrated under reduced pressure to obtain a
1
pale yellow solid. Yield: 85%. Melting point: 163−165 °C. H NMR
(300 MHz, CDCl3) δH (ppm) = 8.97 (s, 1H), 8.76 (d, J = 2.3 Hz, 1H),
8.28 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.93 (s, 1H), 7.70 (d, J = 8.3
Hz, 1H), 5.17 (s, 2H). Anal. Calcd (%) for C12H8ClF3N2O2S: C,
42.80; H, 2.39; N, 8.32. Found: C, 42.81; H, 2.42; N, 8.35.
2-(4-Chlorophenyl)-5-(trifluoromethyl)pyridine (a1). Yield: 60% of
2-((2-Chloro-5-(5-(trifluoromethyl)pyridin-2-yl)phenyl)sulfonyl)-
acetonitrile (I2). 2-amino acetonitrile (3 mmol), the intermediate b1
(1.5 mmol), and triethylamine in 15 mL of THF were stirred at room
temperature. Then the mixture was concentrated under reduced
pressure to get the target compound. Yield: 40% of yellow solid of
melting point 158−160 °C. 1H NMR (300 MHz, CDCl3) δH (ppm) =
8.99 (s, 1H), 8.81 (s, 1H), 8.33 (d, J = 8.3 Hz, 1H), 8.05 (s, 1H), 7.93
(d, J = 7.9 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 5.52 (s, 1H), 4.12 (d, J =
6.7 Hz, 2H). Anal. Calcd (%) for C14H9ClF3N3O2S: C, 44.75; H, 2.41;
N, 11.18. Found: C, 44.76; H, 2.43; N, 11.16.
1
colorless crystals of melting point 89−90 °C. H NMR (300 MHz,
CDCl3) δH (ppm) = 7.47 (d, J = 8.3 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H),
8.04 (d, J = 8.5 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 8.83 (s, 1H).
3-Chloro-2-(4-chlorophenyl)-5-(trifluoromethyl)pyridine (a2).
Yield: 70% of colorless crystals of melting point 72−74 °C. 1H
NMR (300 MHz, CDCl3) δH (ppm) = 7.47 (d, J = 8.4 Hz, 2H), 7.73
(d, J = 8.4 Hz, 2H), 8.04 (s, 1H), 8.83 (s, 1H).
3-Chloro-2-(4-chloro-2-fluorophenyl)-5-(trifluoromethyl)pyridine
1
(a3). Yield: 76% of colorless crystals of melting point 34−35 °C. H
NMR (300 MHz, CDCl3) δH (ppm) = 7.32 (dd, J = 8.3, 2.2 Hz, 2H),
7.43 (d, 1H), 8.05 (s, 1H), 8.86 (s, 1H).
II1-II5, II11, II12, II16, and III1 were synthesized using the
synthetic method of I2
Synthesis of Intermediate b. The intermediate a (0.033 mol)
was added dropwise to chlorosulfonic acid at 0−5 °C, and the mixture
was heated at 130 °C for 8 h.25 The reaction mixture was then cooled
to room temperature and was poured into crushed ice with ethyl
acetate (3 × 60 mL). The combined extract was washed with water
and saturated brine and dried over anhydrous magnesium sulfate, and
then filtered and concentrated under reduced pressure to give a pale
yellow liquid.
Methyl ((2-Chloro-5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-
phenyl)sulfonyl)carbamate (II6). Synthesis of 2-chloro-5-(3-chloro-
5-(trifluoromethyl)pyridin-2-yl)benzenesulfonamide. The intermedi-
ate b2 (0.01 mol) in 20 mL of THF was added dropwise to NH3·H2O
(0.02 mol) at 0−5 °C, and the mixture was stirred at room
temperature for 2 h. Then the mixture was concentrated under
reduced pressure to obtain a pale yellow solid. Yield: 81%. Melting
point: 166−168 °C. 1H NMR (300 MHz, CDCl3) δH (ppm) =
5.17(2H, s), 7.69(1H, d), 7.96(1H, d), 8.09(1H, s), 8.57(1H, s),
8.86(1H, s). Synthesis of methyl ((2-chloro-5-(3-chloro-5-
(trifluoromethyl)pyridin-2-yl)phenyl)sulfonyl)carbamate. 2-Chloro-5-
(3-chloro-5-(trifluoromethyl)pyridin-2-yl)benzenesulfonamide (0.6 g,
1.6 mmol), K2CO3 (0.31 g, 2.26 mmol), and methyl chloroformate
(0.2 g, 1.67 mmol) in 15 mL of acetone were refluxed for 6 h. The
mixture was concentrated under reduced pressure. Then the crude
product was purified by column chromatography with a mixture of
ethyl acetate and petroleum ether (1:3) to get 0.25 g of target
compound. Yield: 31% of yellow solid of melting point 144−146 °C.
1H NMR (300 MHz, CDCl3) δH (ppm) = 8.90 (s, 1H), 8.77 (d, J =
2-Chloro-5-(5-(trifluoromethyl)pyridin-2-yl)benzene-1-sulfonyl
1
Chloride (b1). Yield: 90%. H NMR (300 MHz, CDCl3) δH (ppm) =
7.73 (d, J = 8.3 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 8.3 Hz,
1H), 8.32 (d, J = 8.4 Hz, 1H), 8.80 (s, 1H), 8.99 (s, 1H).
2-Chloro-5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)benzene-1-
1
sulfonyl Chloride (b2). Yield: 90%. H NMR (300 MHz, CDCl3) δH
(ppm) = 7.68 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 8.08 (s,
1H), 8.52 (s, 1H), 8.87 (s, 1H).
2-Chloro-5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-4-fluoro-
1
benzene-1-sulfonyl Chloride (b3). Yield: 91%. H NMR (300 MHz,
CDCl3) δH (ppm) = 7.40 (d, J = 8.3 Hz, 1H), 8.05 (s, 1H), 8.25 (d,
1H), 8.86 (s, 1H).
S y n t h e s i s o f S u b s t i t u t e d 3 - ( p y r i d i n - 2 - y l ) -
benzenesulfonamide Compounds. 2-Chloro-5-(5-
(trifluoromethyl)pyridin-2-yl)benzenesulfonamide (I1). The inter-
mediate b1 (0.01 mol) in 20 mL of THF was added dropwise to NH3·
2.2 Hz, 1H), 8.12 (s, 1H), 8.07 (dd, J = 8.3, 2.2 Hz, 1H), 7.89 (s, 1H),
7.72 (d, J = 8.3 Hz, 1H), 3.75 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
156.42, 150.51, 144.57, 144.52, 144.47, 135.76, 135.71, 135.63, 134.27,
133.95, 133.44, 131.81, 127.32, 53.87. Anal. Calcd (%) for
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Table 1. Chemical Structures and Herbicidal Activity of Substituted 3-(Pyridin-2-yl)benzenesulfonamide Analogues by
b
Postemergence Treatment in Glasshouse Tests
a
b
Stands for no data. YOApost-, VELpost-, FOXpost-, and BYG post- mean youth-and-old age (Zinnia elegans Jacq.), velvet leaf (Abutilon theophrasti
Medic.), foxtail (Setaria glauca (L.) Beauv), and barnyard grass (Echinochloa crus-galli (L.) Beauv), respectively.
Scheme 1. Overview Synthetic Methods of Substituted 3-(Pyridin-2-yl)benzenesulfonamide Derivatives
C14H9Cl2F3N2O4S: C, 39.18; H, 2.11; N, 6.53; Found: C, 39.19; H,
2.15; N, 6.52.
II7−II10, II13−II15, II17, II18, and III2−III5 were synthesized
using the synthetic method of II6.
Discovery Department in Shenyang Research Institute of Chemical
Industry. Plants were grown in plastic flowerpots containing loamy
sand with about 3.0% humus as substrate. The seeds of the test plants
were sown separately according to species.
The test plants were grown to a height of 3−15 cm, depending on
the species, and only then treated with the active ingredients
Herbicidal Activity Assay. Herbicidal Activity Assay in Glass-
house Tests. All plant materials were obtained from the Agrochemical
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Table 2. Herbicidal Activity of II5, II6, II7, II10, III2, and III4 by Postemergence Treatment in Glasshouse Tests Employing a
a
Parallel Experiment
YOApost-
VELpost-
FOXpost-
BYGpost-
compd
300
150
37.5
18.75
300
150
37.5
18.75
300
150
37.5
18.75
300
150
37.5
18.75
II5
II6
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
90
100
100
100
85
100
100
100
55
70
100
100
45
55
100
100
40
100
100
100
100
100
100
100
100
100
98
100
100
100
50
75
100
100
45
II7
II10
III2
III4
100
100
100
100
65
50
100
100
60
50
80
50
50
25
a
YOApost-, VELpost-, FOXpost- and BYG post- mean youth-and-old age (Zinnia elegans Jacq.), velvet leaf (Abutilon theophrasti Medic.), foxtail
(Setaria glauca (L.) Beauv), and barnyard grass (Echinochloa crus-galli (L.) Beauv), respectively.
suspended or emulsified in water. For this purpose, the test plants
were either sown directly or grown in the same vessels or they were
germinated separately and transplanted into the test vessels a few days
before the treatment. The application rate for postemergence
treatment was 600, 150, and 37.5 g/ha active substance.
The plants were kept at 10−25 °C or 20−35 °C depending on the
species. The test lasted 2−4 weeks during which the plants were
tended and their reaction to the individual treatments was evaluated.
Evaluation was on a scale from 0 to 100, where 100 means no
emergence of the plants or complete destruction of at least the above-
ground parts and 0 means no damage or normal growth.
substance, and most compounds of series II and III could
efficiently control velvet leaf, youth-and-old age, barnyard grass,
and foxtail. Especially, II6, II7, II8, II9, II10, II11, III2, III3,
III4, and III5 showed higher activity than the lead compound
which showed detective values of 20, 15, 10, and 10 for velvet
leaf, youth-and-old age, barnyard grass, and foxtail at the 37.5
g/ha active substance, respectively. The activity of II6, II7, III2,
and III4 proved roughly equivalent to the saflufenacil and
better than 95% sulcotrione at the same concentration.
Meanwhile, the other compounds of series II and III did not
show exciting activity.
By comparison of activity of series I, series II, and series III,
it may be seen that substituent site R1 is a critical active group,
and it could clearly improve the activities once R1 is chlorine.
Hydrogen and fluorine were designed to infer the preliminary
structure−activity relationship of substituent site R2; II6 and
III3 which have the same structure except R2 showed similar
excellent activity for velvet leaf, youth-and-old age, barnyard
grass, and foxtail. However, the activities of II5 and III1 differ
significantly. II5 of which R2 is hydrogen could obviously
control target weeds, while III1 of which R2 is fluorine loses the
ability to control weeds. Therefore, more compounds should be
synthesized to get the structure−activity relationship at site R2.
Moreover, it is evident that introduction at substituent position
Q of methyl carbamate (II6), ethyl carbamate (II7), isopropyl
carbamate (II8), buty carbamate (II9) and 2-methoxyethyl
carbamate (II10) could improve the herbicidal activity, and it
seems that the ability to control barnyard grass and foxtail may
decrease with the increase in number of carbon of carbamic
acid ester.
The plants used in the glasshouse tests comprised the following
species: velvet leaf (Abutilon Theophrasti Medic.), youth-and-old age
(Zinnia Elegans Jacq.), barnyard grass (Echinochloa crus-galli(L.)
Beauv.), and foxtail (Setaria Glauca(L.) Beauv.).
Herbicidal Activity Assay in Field Tests. The experiment of the field
tests was operated on the basis of field efficacy trials of Chinese
pesticide standards (a) GB/T17980.40-2000. The test weeds in rice
field were at 2−4 leaf stage. The controlling weeds comprised the
following species: dayflower (commelina tuberosa) and nightshade
(disambiguation) in Liaoning and arrowhead (sagittarian trifolia) in
Heilongjiang. The application rate for treatment was 30 and 60 g/ha
active substance. The application rate for treatment of bentazon46-
(48%, water dispersible granule) which was used as the control in
Liaoning was 1440 g/ha active substance, while 24% oxyfluorfen EC
was used as the control in Herlongjiang.
Formulas used in these tests are as follows: Control effect (%) =
(the number of live weeds in the control area − the number of live
weeds in the treated area)/the number of live weeds in the control
area × 100%.
RESULTS AND DISCUSSION
■
Chemistry. The designed substituted 3-(pyridin-2-yl)-
benzenesulfonamide compounds were synthesized through
critical intermediates (b) as shown in Scheme 1. The reactions
of the intermediates b1, b2, and b3 via the amino compounds
and triethylamine using THF as the solvent afforded series I,
series II, and series III in considerable yield, respectively. The
28 target compounds and intermediates were characterized by
1H NMR and elemental analyses. All spectral and analytical
data were consistent with the assigned structures.
In order to compare activity of these highly reactive
compounds (II5, II6, II7, II10, III2, and III4), a parallel
experiment was executed in glasshouse. As shown in Table 2,
II6 and II7 could excellently control youth-and-old age, velvet
leaf, foxtail, and barnyard grass at 18.5 g/ha active substance.
II5, II10, III2, and III4 showed detective values of 100 for
youth-and-old age and velvet leaf at 18.5 g/ha active substance
and not good enough for foxtail and barnyard grass at low
concentration.
Herbicidal Activity. The 28 target compounds were
evaluated for their herbicidal ability to control the unwanted
plants using postemergence treatment in the glasshouse and the
field tests. For postemergence treatment in the glasshouse, the
designed substituted 3-(pyridin-2-yl)benzenesulfonamide com-
pounds were compared to the lead compounds which were
disclosed by researchers at BASF Aktiengesellschaft,26
saflufenacil47 and sulcotrione.48 As shown in Table 1, series I
compounds which were synthesized through intermediates b1
could not control unwanted plants at the 600 g/ha active
Herbicidal activity results in field test (Table 3) showed that
II7 at 60 g/ha active substance showed roughly the same
activity with bentazon (48%, water dispersible granule) at 1440
g/ha active substance. The detective value of control effect of
II7 at 60 g/ha active substance is 70% after 7 days treatment
and 60% after 15 days treatment. Especially, 10% II7 OF (oil
miscible flowable concentrate) could excellently control
arrowhead and showed better activity than 24% oxyfluorfen
EC (emulsifiable concentrate). As shown in Table 4, the
control effect of 10% II7 OF showed 95, 100, and 100 at 150
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Notes
Table 3. Herbicidal Activity of II7 in Field Tests (Liaoning,
China)
The authors declare no competing financial interest.
control effect to dayflower and
nightshade (%)
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compd
II7
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30
60
40
70
70
40
60
70
bentazon
1440
Table 4. Herbicidal Activity of II7 in Field Tests
(Heilongjiang, China)
control effect to
arrowhead (%)
control effect to rice
(%)
concn
g(a.i./ha)
15
30
45
15
30
45
compd
days days days days days days
10% II7 OF
100
150
180
95
95
31
97
100
68
95
100
69
0
0
0
0
0
0
0
0
0
24%
oxyfluorfen
EC
g(a.i./ha) after 15 days, 30 days, and 45 days treatment,
respectively, while 24% oxyfluorfen EC showed detective values
of 31, 68, and 69 for arrowhead at 180 g(a.i./ha) after 15 days,
30 days, and 45 days treatment, respectively. Meanwhile, II7
and oxyfluorfen could not control rice and showed high security
to rice.
In summary, a series of novel substituted 3-(pyridin-2-
yl)benzenesulfonamide compounds were designed and synthe-
sized by intermediate derivatization methods. The compounds
(II6, II7, II8, II9, II10, II11, III2, III3, III4, and III5) showed
higher activity than the lead compound at the 37.5 g/ha active
substance using herbicidal activity assay in glasshouse tests, and
the activity of II6, II7, III2, and III4 proved roughly equivalent
to the saflufenacil and better than 95% sulcotrione at the same
concentration. The result of the herbicidal activity assay in field
tests in Liaoning showed that II7 could effectively control
dayflower and nightshade. The activity of II7 at 60 g/ha active
substance proved roughly equivalent to bentazon at 1440 g/ha
active substance. Meanwhile, the herbicidal assay in field tests in
Heilongjiang showed 10% II7 OF could excellently control
arrowhead. Compound II7 excited better activity than
oxyfluorfen and security to rice. Our results suggest that II7
may be a novel compound candidate for potential herbicide.
This study will be useful for the design of new herbicides for
weed control.
ASSOCIATED CONTENT
■
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* Supporting Information
1H NMR, melting point data, and elemental analyses data for
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material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Telephone: 86-24-85869078. Fax: 86-24-85869137. E-mail:
liuchangling@vip.163.com.
■
Funding
The project was supported by the National Key Technology
Support Program during the 12th Five-Year Plan Period of
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