Synthesis and biological activity of novel sulfone derivatives containing a [1,2,4]triazolo[4,3-a]pyridine moiety

Article abstract of DOI:10.1080/10426507.2017.1288626

A series of novel sulfone derivatives containing a [1,2,4]triazolo[4,3-a]pyridine moiety was synthesized and characterized via ¹H NMR, ¹³C NMR, IR, and elemental analyses. Bioassay results indicated some of the derivatives displayed good antifungal activities and insecticidal activity. The inhibition rates of 8-chloro-3-((2,6-difluorobenzyl)sulfonyl)-[1,2,4]triazolo[4,3-a]pyridine against Rhizotonia erealis and Helminthosporium maydis were 78.6% and 76.4% activities at 50?μg mL^?1, respectively. And compound 8-chloro-3-(((6-chloropyridin-3-yl)methyl)sulfonyl)-[1,2,4]triazolo[4,3-a]pyridine showed >95% mortality at 500?μg mL^?1 and >65% mortality at 200?μg mL^?1 against Plutella xylostella, respectively. As well as 8-chloro-3-(((6-chloropyridin-3-yl)methyl)sulfonyl)-[1,2,4]triazolo[4,3-a]pyridine displayed >90% mortality at 500?μg mL^?1 against Helicoverpa armigera. A preliminary structure activity relationship (SAR) is discussed.

Full text of DOI:10.1080/10426507.2017.1288626

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Synthesis and Biological Activity of Novel Sulfone
Derivatives Containing a [1,2,4]Triazolo[4,3-
a]pyridine Moiety
Fang-Zhou Xu, Yan-Yan Wang, Yun-Ying Zhu, Jia-Hui Shao, Gang Yu, Wei Xue,
Jian Wu, Hui-Bing Wu & Jun Shi
To cite this article: Fang-Zhou Xu, Yan-Yan Wang, Yun-Ying Zhu, Jia-Hui Shao, Gang Yu, Wei
Xue, Jian Wu, Hui-Bing Wu & Jun Shi (2017): Synthesis and Biological Activity of Novel Sulfone
Derivatives Containing a [1,2,4]Triazolo[4,3-a]pyridine Moiety, Phosphorus, Sulfur, and Silicon and
the Related Elements, DOI: 10.1080/10426507.2017.1288626
To link to this article: http://dx.doi.org/10.1080/10426507.2017.1288626
Accepted author version posted online: 15
Feb 2017.
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Date: 16 February 2017, At: 12:42

ACCEPTED MANUSCRIPT
Synthesis and Biological Activity of Novel Sulfone Derivatives Containing
[1,2,4]Triazolo[4,3-a]pyridine Moiety
a
Fang-Zhou Xu1, Yan-Yan Wang1,#, Yun-Ying Zhu2, Jia-Hui Shao3,Gang Yu1, Wei Xue1, Jian
Wu1,*, Hui-Bing Wu1, Jun Shi1
1State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key
Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education,
Research and Development Center for Fine Chemicals, Guizhou University, Huaxi District,
Guiyang 550025, P.R. China.
2School of Chemical Engineering, Guizhou Institute of Technology, Yunyan District, Guiyang
550001, P.R. China.
3College of Life Science, Zaozhuang University, Zaozhuang 277100, P.R. China.
#Co-first author of this work;
*Corresponding author. E-mails: jwu6@126.com, wujian2691@126.com.
ABSTRACT:
A series of novel sulfone derivatives containing a [1,2,4]triazolo[4,3-a]pyridine moiety was
1
synthesized and characterized via H NMR, 13C NMR, IR and elemental analyses. Bioassay
results indicated some of the derivatives displayed good antifungal activities and insecticidal
activity.
The
inhibition
rates
against
of
8-chloro-3-((2,6-difluorobenzyl)sulfonyl)-[1,2,4]triazolo[4,3-a]pyridine
Rhizotonia
erealis and Helminthosporium maydis were 78.6% and 76.4% activities at 50 μg mL1,
respectively. And compound
8-chloro-3-(((6-chloropyridin-3-yl)methyl)sulfonyl)-[1,2,4]triazolo[4,3-a]pyridine showed
>
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95% mortality at 500 μg mL1 and > 65% mortality at 200 μg mL1 against Plutella xylostella,
respectively.
As
well
as
8-chloro-3-(((6-chloropyridin-3-yl)methyl)sulfonyl)-[1,2,4]triazolo[4,3-a]pyridine displayed >
90% mortality at 500 μg mL1 against Helicoverpa armigera. A preliminary structure activity
relationship (SAR) is discussed.
Graphical Abstract
Keywords
Sulfone; [1,2,4]Triazolo[4,3-a]pyridine; Synthesis; Antifungal activity; Insecticidal activity
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INTRODUCTION
Food safety is one of the serious problems humans will be facing in the future, and threats from
crop diseases, weeds and insects are still considerable. In recent years, scientists dedicate in
developing active molecules with new mechanisms and eco-friendly properties, and we believe
the discovery of high efficient pesticide with low mammalian toxicity and low-residue can make
a significant contribution to the lifestyle in the future.
Sulfone derivatives are an important class of bioactive compounds with a wide spectrum of
activities. They are employed as anti-inflammatory 1, 2, anti-cancer 3-7, anti-HIV-18, 9 agents for
pharmaceutical application or insecticides 10, herbicides 11, fungicide11-14 and anti-bacterial agents
15-19
for crop protection. Especially, in the field of pesticides, several sulfone derivatives were
discovered and commercialized, such as flubendiamide (Fig. 1), the first ryanodine receptor
inhibitor, was discovered and commercialized by Japanese Pesticide Co., Ltd and Bayer Crop
Science. In recent years, Song and co-workers 14-19 reported several series of sulfone derivatives
displayed excellent anti-fungal and anti-bacteria activities, such as “jiahuangxianjunzuo (A)”,
“erlv’ezuoling (B)” and “fubian’ezuofeng (C)” (Figure 1). These three sulfone derivatives,
containing an 1,3,4-oxadiazole moiety, were developed and are under the process of
commercialization.
The [1,2,4]triazolo[4,3-a]pyridines, an important class of fused heterocycle, possess a broad
spectrum of biological and pharmaceutical activities20-25, which have proven attractive because
23,
of their good herbicidal activity
antibacterial activity 28, 29
antifungal activity 24-26, anticonvulsant activity 27, and
.
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Keeping the above aspects in the mind, a series of new sulfone derivatives containing a
[1,2,4]triazolo[4,3-a]pyridine moiety was designed and synthesized. The antifungal activity
against Rhizotonia erealis, Rhizoctonia solani, Helminthosporium maydis and Fusarium
graminearum, as well as the insecticidal insecticidal activities against Plutella xylostella and
Helicoverpa armigera. of these target compounds were evaluated and reported in this paper. To
the best of our knowledge, this is the first report on antifungal and insecticidal activities of
sulfones derivatives with scaffold of [1,2,4]triazolo[4,3-a]pyridine to date.
RESULTS AND DISCUSSION
Synthesis
The synthetic route of the sulfone derivatives containing a [1,2,4]triazolo[4,3-a]pyridine moiety
is shown in Scheme 1. Firstly, 3-chloro-2-hydrazinylpyridine (2) was prepared by treatment of
2,3-dichloropyridine (1) with hydrazine hydrate (80%) in good yield. Then,
8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (3) was synthesized via ring-closure reaction of
3-chloro-2-hydrazinylpyridine 2 with CS2 in the present of NaOH 30. Subsequently,
thioetherification of 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol were carried out by treatment
of intermediate 3 with different halogenated hydrocarbon in the presence of K2CO3 in excellent
yields. Finally, the title compounds 5a to 5s were synthesized in moderate to good yields via
oxidation reaction using H2O2 as an oxidizing agent and ammonium molybdate as the catalyst as
described in our previous work 31,32
.
The structures of the synthesized compounds (5a to 5s) were established on the basis of the
spectroscopic data. Using 5d as an example, as indicated by 1H NMR, the proton at o-position of
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“N” atom was at δ 8.34 ppm as a doublet with a coupling constant of 6.9 Hz. The proton adjacent
to the “Cl” atom was at δ 7.52 ppm, with a coupling constant of 7.2 Hz; resonance frequencies of
the proton at m-position of “Cl” atom appeared at δ 6.91 ppm as a triplet with “J = 7.1 Hz”; and
1
the protons at benzene ring were near 7.34 -- 7.27 ppm. The main characteristic of the H NMR
spectra for the compounds was the presence of a singlet at 4.99 ppm for -CH2-S(O)2- protons. In
13
the C NMR spectra of compounds containing the “F”, the carbons were split into a multiplet.
13
For instance, in C NMR spectra of compounds 4i and 5j, the resonance frequencies of the
carbons of “-CF3” near 126.5 ppm appear as a quartet with the coupling constant (1JC-F) of 114.3
Hz. In the 13C NMR spectra of compounds that contain two fluorine atoms (5k, 5l and 5m), the
carbon resonance frequencies were near δ 150-163 ppm as doublets with coupling constants
C
(1JC-F) ranging from 241 to 257 Hz.
Antifungal activity
The antifungal activities of the synthesized compounds on R. erealis, H. maydis, Rhizoctonia
solani, F. graminearum were tested and shown in Table S 1 (see Supplemental Materials). The
results indicated the synthesized compounds exhibited weak to good antifungal activities against
the tested fungus at 50 μg/mL; compounds 5c, 5d, 5j, 5k, 5l, 5m, 5n, 5o, and 5q showed > 50%
activities against both R. erealis and H. maydis. Moreover, The EC50 of 5l and 5m against R.
erealis, H. maydis, R. solani were further evaluated (Table S 2), which indicated that 5l and 5m
showed range from 39.3 to 53.6 mg/L.
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Insecticidal activity
The insecticidal activities of the synthesized compounds against P. xylostella and H. armigera
are presented in Table S 3 and Table S 4. Most of the title compounds displayed weak
insecticidal activity against the P. xylostella. However, some of the compounds displayed good
insecticidal activities. More detail can be found in Supplemental Information.
A preliminary structure activity relationship (SAR) was analyzed based on these insecticidal
activity data against both P. xylostella and H. armigera. The results indicated these compounds
containing a pyridine (5d) showed good insecticidal activities; and the introduction of a
trifluoromethyl at 2 position of benzene could offer a big increase to insecticidal activity, which
can be concluded from the t the fact that the activity of 5j was much higher than that of 5i and
5r. And interestingly, in contrast to the above antifungal activity, the insecticidal activity could
be decreased by introducing two fluorines at benzene, and the introduction of different halogens
at benzene ring (eg: 5n, 5p) was disadvantageous to enhance their insecticidal activities.
Moreover, just as with the antifungal activity, the introduction of alkyl and substituted alkene
could not improve the insecticidal activity.
CONCLUSION
In conclusion, a series of novel sulfone derivatives containing a [1,2,4]triazolo[4,3-a]pyridine
moiety was synthesized, characterized, and bio-assayed for their antifungal and insecticidal
activities. Results of bioassays indicated that the synthesized compounds showed weak to good
antifungal activity against R. erealis, H. maydis, R. solani, F. graminearum, such as compound
5m exhibited 78.6% and 76.4% activities against R. erealis and H. maydis, respectively. And
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compounds 5d and 5j displayed good insecticidal activities against both P. xylostella and H.
armigera, The preliminary SAR study indicated that antifungal activities could be enhanced by
introducing two fluorine atoms at benzene ring, and the introduction of heterocyclic rings was
favorable to the insecticidal activity. Moreover, the introduction of alkyl and substituted alkene
could not improve both the antifungal activity and insecticidal activities. This is the first study of
the synthesis, fungicidal and insecticidal activities of sulfone derivatives containing a
[1,2,4]triazolo[4,3-a]pyridine moiety, and the structural modification are underway to explore the
more potential of this kind of sulfone derivatives containing a [1,2,4]triazolo[4,3-a]pyridine
moiety.
EXPERIMENTAL
Synthesis
All solvents were purified according to standard procedures. All reactants and starting materials
were purchased from Accela ChemBio Co., Ltd (Shanghai, China). The 1H and 13C NMR spectra
(solvent CDCl3) were measured with a JEOL-ECX 500 NMR spectrometer operating at room
temperature with tetramethylsilane (TMS) as an internal standard, and chemical shifts are
expressed in δ (ppm). The melting points of the synthesized compounds were recorded on a
WRX-4 monocular microscope (Shanghai Yice Apparatus & Equipment Co., Ltd, China) and
were not corrected. Elemental analysis was carried out on an Elemental Vario-III CHN analyzer
(Elementar, Hanau, German). The progress of the reaction was monitored by TLC. The
Supplemental Materials file contains sample 1H and 13C NMR spectra of products 5 (Figures S 1
-- S 38).
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33
Preparation of intermediate 2 : To a solution of 2,3-dichloropyridine (50.0 g) in EtOH (40
mL), 25 g hydrazine hydrate (80%) was added and refluxed for 24 h. The resulting mixture was
cooled to room temperature, which was filtered and dried to get white needle crystal (41.5 g),
yield: 85.6%, m.p. 163-164 C.
30
Preparation of intermediates 3 : 3-chloro-2-hydrazinylpyridine (12.0 g, 83.58 mmol) was
reacted with carbon disulfide (7.64 g, 100 mmol) in the presence of NaOH in ethanol (100 mL)
at room temperature for 24 h, After complication of the reaction, and the residues were poured
into water (50 mL), then acidified to pH = 4-5 to obtain intermediates 3 (10.31 g), yield, 66.5%,
m.p. 298-299 C (ref. 30, 300-302 C).
Synthetic procedures for intermediates 4: To a solution of intermediates 3 (1 mmol) and
K2CO3 (0.5 mmol) in acetonitrile (20 mL), the corresponding halides (1.1 mmol) were slowly
added, and the resulting mixture was refluxed for 2 h. After filtration to remove excess K2CO3,
the residue was concentrated in vacuum and recrystallized from ether to obtain the sulfide
derivatives with [1,2,4]triazolo[4,3-a]pyridine moiety.
General synthetic procedures for compounds 5a--5s: Sulfide derivatives 4 (1 mmol) were
dissolved in ethanol (20 mL) and stirred at room temperature. Ammonium molybdate (0.20
mmol) was added as catalyst, and then 30% H2O2 (2 mmol) was added. The mixture was stirred
at room temperature and monitored by TLC, until completion of the reaction; the ethanol was
removed under reduced pressure to yield the crude products, which were purified by column
chromatography on silica gel and eluted with ethyl acetate/petroleum ether (5/1) to afford the
desired products.
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8-chloro-3-((2,4-dichlorobenzyl)sulfonyl)-[1,2,4]triazolo[4,3-a]pyridine(5a): yield 84%;
Light yellow solid; m.p. 176.8-177.9°C; 1H NMR (500 MHz, CDCl3) δ 8.34 (d, J = 6.9 Hz, 1H,
[1,2,4]triazolo[4,3-a]pyridine-H), 7.52 (d, J = 7.2 Hz, 1H, [1,2,4]triazolo[4,3-a]pyridine-H), 7.34
-- 7.27 (m, 2H, Ph-H), 7.19 (d, J = 8.3 Hz, 1H, Ph-H), 6.91 (t, J = 7.1 Hz, 1H,
13
[1,2,4]triazolo[4,3-a]pyridine-H), 4.99 (s, 3H, -CH2-). C NMR (126 MHz, CDCl3) δ 149.4,
143.9, 136.8, 136.4, 133.9, 130.1, 128.6, 127.9, 123.2, 122.9, 116.2, 59.3; IR (KBr)/cm1: 3047.7
(Ar-H), 2922.8, 2916.9, 2878.4 (-CH2-), 1560.8, 1544.5, 1428.2 (aromatic ring); Anal. Calc. for
C13H8Cl3N3O2S: C 41.46%, H 2.14%, N 11.16%. Found: C 41.42%, H 2.16%, N 11.17%.
8-chloro-3-((4-fluorobenzyl)sulfonyl)-[1,2,4]triazolo[4,3-a]pyridine (5b):yield 85%; Light
yellow solid; m.p. 166.6-167.5°C;1H NMR (500 MHz, CDCl3) δ 8.24 (d, J = 7.0 Hz, 1H,
[1,2,4]triazolo[4,3-a]pyridine-H), 7.46 (d, J = 7.3 Hz, 1H, [1,2,4]triazolo[4,3-a]pyridine-H), 7.12
(dd, J = 7.4, 5.3 Hz, 2H, Ph-H), 6.89 (t, J = 8.0 Hz, 2H, [1,2,4]triazolo[4,3-a]pyridine-H), 6.82
(dd, J = 7.2, 6.5 Hz, 1H, Ph-H), 4.78 (s, 2H -CH2-). 13C NMR (125 MHz, CDCl3) δ 164.4, 163.4
(d, 1JC-F = 250.6 Hz), 162.4, 149.1, 143.8, 133.1 (d, 2JC-F = 18.5 Hz), 128.5, 122.9, 121.9, 116.3,
116.0 (d, 2JC-F = 19.7 Hz), 62.3; IR (KBr)/cm1: 3046.9 (Ar-H), 2924.8, 2918.3, 2882.1 (-CH2-),
1566.7, 1548.5, 1428.1(aromatic ring); Anal. Calc. for C13H9ClFN3O2S: C 47.93%, H 2.78%, N
12.90%. Found: C 47.95%, H 2.74%, N 12.93%.
8-chloro-3-((4-methoxybenzyl)sulfonyl)-[1,2,4]triazolo[4,3-a]pyridine (5c)：yield 65%; white
1
solid; m.p. 157.6-159.4°C; H NMR (500 MHz, CDCl3) 8.15 (d, J = 6.6 Hz, 1H,
[1,2,4]triazolo[4,3-a]pyridine-H), 7.42 (d, J = 7.0 Hz, 1H, [1,2,4]triazolo[4,3-a]pyridine-H), 6.99
(d, J = 8.3 Hz, 2H, Ph-H), 6.77 -- 6.71 (m, 1H, [1,2,4]triazolo[4,3-a]pyridine-H), 6.67 (d, J = 8.3
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Hz, 2H,, Ph-H), 4.71 (s, 2H, -CH2-), 3.69 (s, 3H, -OCH3). 13C NMR (126 MHz, CDCl3) δ 160.6,
144.0, 132.4, 128.3, 123.1, 122.7, 117.7, 115.6, 114.5, 62.7, 55.4; IR (KBr)/cm1: 3085.3 (Ar-H),
2925.2, 2913.5, 2878.4 (-CH2-), 1547.5, 1536.5, 1456.4 (aromatic ring); Anal. Calc. for
C14H12ClN3O3S: C 49.78%, H 3.58%, N 12.44%. Found: C 49.75%, H 3.55%, N 12.47%.
8-chloro-3-(((6-chloropyridin-3-yl)methyl)sulfonyl)-[1,2,4]triazolo[4,3-a]pyridine (5d): yield
82%; White solid; m.p. 185.5-187.1°C;1H NMR (500 MHz, CDCl3) δ 8.45 (d, J = 6.9 Hz, 1H,
[1,2,4]triazolo[4,3-a]pyridine-H), 8.31 (s, 1H, [1,2,4]triazolo[4,3-a]pyridine-H), 7.60 (dd, J =
8.2, 2.2 Hz, pyridine-H)), 7.53 (d, J = 7.3 Hz, 1H, Pyridine-H), 7.24 (d, J = 6.9 Hz, 1H
[1,2,4]triazolo[4,3-a]pyridine-H)), 6.96 (t, J = 7.1 Hz, 1H, Pyridine-H), 4.89 (s, 2H, -CH2-); 13C
NMR (126 MHz, CDCl3) δ 153.0, 151.8, 143.6, 141.2, 128.8, 124.7, 122.9, 121.4, 116.5, 59.2;
IR (KBr)/cm1: 3075.2 (Ar-H), 2926.1, 2917.9, 2880.3 (-CH2-), 1547.8, 1532.1, 1452.1
(aromatic ring); Anal. Calc. for C12H8Cl2N4O2S: C 42.00%, H 2.35%, N 16.33%. Found: C
42.03%, H 2.31%, N 16.30%.
8-chloro-3-(methylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridine (5e): yield 69%; White solid; m.p.
149.1-150.0°C; 1H NMR (500 MHz, CDCl3) δ 8.74 (d, J = 6.9 Hz, 1H,
[1,2,4]triazolo[4,3-a]pyridine-H), 7.55 (d, J = 7.4 Hz, 1H, [1,2,4]triazolo[4,3-a]pyridine-H), 7.07
13
(t, J = 7.1 Hz, 1H, [1,2,4]triazolo[4,3-a]pyridine-H), 3.58 (s, 3H, -CH3); C NMR (126 MHz,
CDCl3) δ 149.2, 145.5, 128.5, 123.4, 123.2, 116.3, 44.2; IR (KBr)/cm1: 3075.2 (Ar-H), 2925.4,
2915.3, 2883.2 (--CH3); Anal. Calc. for C7H6ClN3O2S: C 36.29%, H 2.61%, N 18.14%. Found:
C 36.31%, H 2.62%, N 18.13%.
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8-chloro-3-(ethylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridine(5f): yield 74%; Light yellow solid;
1
m.p. 126.6-127.4°C; H NMR (500 MHz, CDCl3) δ 8.79 (dd, J = 6.9, 0.8 Hz, 1H,
[1,2,4]triazolo[4,3-a] pyridine-H), 7.54 (dd, J = 7.4, 0.8 Hz, 1H, [1,2,4]triazolo[4,3-a]pyridine-H),
7.06 (t, J = 7.1 Hz, 1H, [1,2,4]triazolo[4,3-a] pyridine-H), 3.67 (q, J = 7.4 Hz, 2H, -CH2-), 1.45 (t,
J = 7.4 Hz, 3H, -CH3); 13C NMR (126 MHz, CDCl3) δ 149.2, 144.4, 128.4, 123.5, 123.3, 116.2,
51.1, 6.9; IR (KBr)/cm1: 3097.2 (Ar-H), 2934.2, 2911.3, 2873.2 (-CH2CH3); Anal. Calc. for
C8H8ClN3O2S: C 39.11%, H 3.28%, N 17.10%. Found: C 39.12%, H 3.27%, N 17.14%.
8-chloro-3-((2-methylbenzyl)sulfonyl)-[1,2,4]triazolo[4,3-a]pyridine(5g): yield 80%; Light
1
yellow solid; m.p. 140.6-141.4°C; H NMR (500 MHz, CDCl3) δ 7.99 (d, J = 6.9 Hz, 1H,
[1,2,4]triazolo[4,3-a] pyridine-H), 7.42 (d, J = 7.3 Hz, 1H, [1,2,4]triazolo[4,3-a] pyridine-H),
7.12 (q, J = 7.6 Hz, 2H, [1,2,4]triazolo[4,3-a] pyridine-H), 6.87 (t, J = 7.1 Hz, 1H, Ar-H), 6.77 (d,
J = 7.6 Hz, 1H, Ar-H), 6.71 (t, J = 7.1 Hz, 1H, Ar-H), 4.84 (s, 2H, -CH2), 2.32 (s, 3H, -CH2); 13C
NMR (126 MHz, CDCl3) δ 149.1, 144.2, 139.1, 131.7, 131.3, 129.8, 128.5, 126.4, 124.3, 122.9,
122.6, 115.8, 60.6, 19.7; IR (KBr)/cm1: 3102.2 (Ar-H), 2937.5, 2913.3, 2873.2 (-CH2-), 1609.2,
1549.3, 1456.2 (aromatic ring); Anal. Calc. for C14H12ClN3O2S: C 52.26%, H 3.76%, N 13.06%.
Found: C 52.28%, H 3.74%, N 13.02%.
8-chloro-3-((4-(trifluoromethoxy)benzyl)sulfonyl)-[1,2,4]triazolo[4,3-a]pyridine (5h): yield
1
52%; Light yellow solid; m.p. 154.6-155.5°C; H NMR (500 MHz, CDCl3) δ 8.18 (dd, J = 6.9,
0.9 Hz, 1H, [1,2,4]triazolo[4,3-a] pyridine-H), 7.45 (dd, J = 7.3, 1.0 Hz, 1H, [1,2,4]triazolo[4,3-a]
pyridine-H), 7.17 (d, J = 7.9 Hz, 2H, Ar-H), 7.04 (d, J = 8.5 Hz, 2H, Ar-H), 6.79 (td, J = 7.2, 1.0
13
Hz, 1H, [1,2,4]triazolo[4,3-a] pyridine-H), 4.81 (s, 2H, -CH2); C NMR (126 MHz,, CDCl3) δ
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150.1, 149.1, 143.7, 132.8, 128.6, 124.8, 122.9, 122.8, 121.5, 116.0, 62.3; IR (KBr)/cm1: 3105.1
(Ar-H), 2923.2, 2885.3 (-CH2-), 1548.8, 1532.4, 1446.3 (aromatic ring); Anal. Calc. for
C14H9ClF3N3O3S: C 42.92%, H 2.32%, N 10.73%. Found: C 42.91%, H 2.33%, N 10.72%.
8-chloro-3-((4-(trifluoromethyl)benzyl)sulfonyl)-[1,2,4]triazolo[4,3-a]pyridine(5i):
yield
40%; Light yellow solid; m.p. 166.5-167.4°C;1H NMR (500 MHz, CDCl3) δ 8.22 (d, J = 6.8 Hz,
1H, [1,2,4]triazolo[4,3-a] pyridine-H), 7.50 -- 7.45 (m, 4H, [1,2,4]triazolo[4,3-a] pyridine-H +
Ar-H), 7.31 (d, J = 8.1 Hz, 2H, Ar-H), 6.82 (t, J = 7.2 Hz, 1H, [1,2,4]triazolo[4,3-a] pyridine-H),
13
1
4.89 (s, 2H, -CH2); C NMR (126 MHz, CDCl3) δ 143.7, 131.7, 130.0, 128.6, 126.5 (q, JC-F
=
114.3 Hz), 123.1, 122.8, 116.1, 62.5, 29.8; IR (KBr)/cm1: 3098.2 (Ar-H), 2943.2, 2895.4
(-CH2-), 1548.6, 1532.3, 1448.3 (aromatic ring); Anal. Calc. for C14H9ClF3N3O2S: C 44.75%, H
2.41%, N 11.18%. Found: C 44.72%, H 2.44%, N 11.16%..
8-chloro-3-((2-(trifluoromethyl)benzyl)sulfonyl)-[1,2,4]triazolo[4,3-a]pyridine (5j): yield
78%; Light yellow solid; m.p. 140.6-141.6°C;1H NMR (500 MHz, CDCl3) δ 8.47 (d, J = 7.0 Hz,
1H, [1,2,4]triazolo[4,3-a] pyridine-H), 7.70 -- 7.66 (m, 1H, Ar-H), 7.50 (dt, J = 11.6, 5.3 Hz, 4H,
Ar-H), 6.94 (t, J = 7.1 Hz, 1H, [1,2,4]triazolo[4,3-a] pyridine-H), 5.06 (s, 2H, -CH2); 13C NMR
1
(126 MHz, CDCl3) δ 149.3, 144.4, 133.6, 132.3, 129.9, 128.6, 127.2, 127.2, 124.2 (q, JC-F
=
114.3 Hz), 123.2, 123.2, 116.2, 59.5; IR (KBr)/cm1: 3087. (Ar-H), 2953.1, 2885.9 (-CH2-),
1549.7, 1533.7, 1449.3 (aromatic ring). Anal. Calc. for C14H9ClF3N3O2S: C 44.75%, H 2.41%, N
11.18%. Found: C 44.73%, H 2.45%, N 11.15%.
8-chloro-3-((2,4-difluorobenzyl)sulfonyl)-[1,2,4]triazolo[4,3-a]pyridine(5k). yield 83%; Light
yellow solid; m.p. 171.4-172.3°C;1H NMR (500 MHz, CDCl3) δ 8.42 (d, J = 7.0 Hz, 1H,
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[1,2,4]triazolo[4,3-a] pyridine-H), 7.52 (d, J = 7.4 Hz, 1H, Ar-H), 7.19 (dd, J = 11.5, 5.3 Hz, 1H,,
[1,2,4]triazolo[4,3-a] pyridine-H), 6.93 (t, J = 7.1 Hz, 1H, [1,2,4]triazolo[4,3-a] pyridine-H),
6.80 -- 6.71 (m, 2H, Ar-H), 4.87 (s, 2H, -CH2-); 13C NMR (126 MHz, CDCl3) δ 162.9 (d, 1JC-F
241.9 Hz), 160.9 (d, 1JC-F = 244.9 Hz),149.3, 143.8, 133.8 (dd, 2JC-F = 10.1, 3.9 Hz), 128.6, 123.1
=
2
2
(d, JC-F = 18.4 Hz), 116.2 (s), 112.3 (dd, JC-F = 21.8Hz), 109.8, 104.9, 104.7, 104.5, 55.8; IR
(KBr)/cm1: 3121.2 (Ar-H), 2943.8, 2883.2 (-CH2-), 1545.8, 1532.3, 1447.4 (aromatic ring);
Anal. Calc. for C13H8ClF2N3O2S: C 45.42%, H 2.35%, N 12.22%. Found: C 45.43%, H 2.34%,
N 12.21%.
8-chloro-3-((2,5-difluorobenzyl)sulfonyl)-[1,2,4]triazolo[4,3-a]pyridine (5l): yield 79%;
White solid; m.p. 160.0-160.7°C;1H NMR (500 MHz, CDCl3) δ 8.18 (dd, J = 6.9, 0.9 Hz, 1H,
[1,2,4]triazolo[4,3-a] pyridine-H), 7.45 (dd, J = 7.3, 1.0 Hz, 1H, [1,2,4]triazolo[4,3-a]
pyridine-H), 7.17 (d, J = 7.9 Hz, 2H, Ar-H), 7.04 (d, J = 8.5 Hz, 2H, Ar-H), 6.79 (td, J = 7.2, 1.0
13
Hz, 1H, [1,2,4]triazolo[4,3-a] pyridine-H), 4.81 (s, 2H, -CH2-); C NMR (126 MHz, CDCl3) δ
1
158.6 (d, 1JC-F = 241.9 Hz), 149.3 (d, JC-F = 244.9 Hz), 143.9, 128.6, 123.3, 123.0, 119.3 (d,
2JC-F = 17.3 Hz), 119.1 (d, 2JC-F = 17.3 Hz), 118.5 (d, 2JC-F = 23.9 Hz), 117.2 (d, 2JC-F = 24.5 Hz),
116.2, 115.1, 55.9; IR (KBr)/cm1: 3118.3 (Ar-H), 2946.7, 2889.2 (-CH2-), 1548.2, 1536.7,
1448.8 (aromatic ring); Anal. Calc. for C13H8ClF2N3O2S: C 45.42%, H 2.35%, N 12.22%. Found:
C 45.41%, H 2.33%, N 12.23%.
8-chloro-3-((2,6-difluorobenzyl)sulfonyl)-[1,2,4]triazolo[4,3-a]pyridine (5m): yield 64%;
White solid; m.p. 190.0-192.8°C;1H NMR (500 MHz, CDCl3) δ 8.42 (dd, J = 7.0, 0.6 Hz, 1H,
[1,2,4]triazolo[4,3-a] pyridine-H), 7.53 (dd, J = 12.3, 5.7 Hz, 1H, [1,2,4]triazolo[4,3-a]
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pyridine-H), 7.34 (ddd, J = 13.0, 8.4, 6.5 Hz, 1H, Ar-H), 6.92 (t, J = 7.2 Hz, 1H, Ar), 6.86 (dd, J
= 14.9, 7.0 Hz, 2H, Ar-H), 4.90 (s, 2H, -CH2-);13C NMR (126 MHz, CDCl3) δ 161.7 (d, 1J C-F
=
253.7 Hz), 160.7 (d, J = 253.2 Hz), 149.3, 144.0, 132.3, 128.5, 122.9 (t, J = 19.0 Hz), 116.2 (d,
2JC-F = 20.4 Hz), 111.9 (d, 2JC-F = 20.3 Hz), 51.2; IR (KBr)/cm1: 3082.2 (Ar-H), 2913.8, 2899.q
(-CH2-), 1565.2, 1546.3, 1447.2 (aromatic ring); Anal. Calc. for C13H8ClF2N3O2S: C 45.42%, H
2.35%, N 12.22%. Found: C 45.42%, H 2.32%, N 12.24%.
3-((2-bromo-4-fluorobenzyl)sulfonyl)-8-chloro-[1,2,4]triazolo[4,3-a]pyridine (5n):yield 63%;
Light yellow solid; m.p. 177.3-178.3°C;1H NMR (500 MHz, CDCl3) δ 8.40 (d, J = 7.0 Hz, 1H,
[1,2,4]triazolo[4,3-a] pyridine-H), 7.53 (d, J = 7.2 Hz, 1H, [1,2,4]triazolo[4,3-a] pyridine-H),),
7.22 -- 7.16 (m, 2H, Ar-H), 7.09 (t, J = 7.8 Hz, 1H, Ar-H), 6.94 (t, J = 7.1 Hz, 1H,
[1,2,4]triazolo[4,3-a] pyridine-H),), 4.86 (s, 2H);13C NMR (126 MHz, CDCl3) δ 162.3 (d, 1JC-F
=
2
253.7 Hz), 149.3, 143.8, 133.8, 128.7, 128.3, 124.8 (d, J C-F = 9.5 Hz), 123.1, 119.9, 119.7,
2
116.3, 112.9 (d, J C-F = 15.0 Hz), 55.9; IR (KBr)/cm1: 3104.1 (Ar-H), 2915.2, 2869.9 (-CH2-),
1564.7, 1566.2, 1447.3 (aromatic ring); Anal. Calc. for C13H8BrClFN3O2S: C 38.59%, H 1.99%,
N 10.38%. Found: C 38.61%, H 2.01%, N 10.34%.
8-chloro-3-((2-chloro-4-fluorobenzyl)sulfonyl)-[1,2,4]triazolo[4,3-a]pyridine (5o): yield 58%;
White solid; m.p. 180.5-181.6°C;1H NMR (500 MHz, CDCl3) δ 8.33 (dd, J = 7.0, 0.6 Hz, 1H,
[1,2,4]triazolo[4,3-a] pyridine-H), 7.51 (dd, J = 7.3, 0.6 Hz, 1H, Ar-H), 7.34 (dd, J = 8.6, 5.9 Hz,
13
1H, Ar-H), 7.06 (dd, J = 8.3, 2.6 Hz, 1H, Ar-H), 6.96 -- 6.88 (m, 2H, Ar-H), 4.98 (s, 2H); C
NMR (126 MHz, CDCl3) δ 164.2 (d, 1JC-F = 254.6 Hz), 149.4, 143.9, 136.7, 134.5 (d, 3JC-F = 9.3
Hz), 128.6, 123.2, 122.9, 120.7, 117.7 (d, 2JC-F = 24.9 Hz), 116.2, 115.1 (d, 2JC-F = 21.5 Hz), 59.2,
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29.8; IR (KBr)/cm1: 3114.4 (Ar-H), 2912.3, 2869.9 (-CH2-), 1567.1, 1564.2, 1447.3 (aromatic
ring); Anal. Calc. for C13H8Cl2FN3O2S: C 43.35%, H 2.24%, N 11.67%. Found: C 43.32%, H
2.23%, N 11.69%.
8-chloro-3-((3-chloro-2-fluorobenzyl)sulfonyl)-[1,2,4]triazolo[4,3-a]pyridine (5p): yield 82%;
White solid; m.p. 177.4-178.1°C;1H NMR (500 MHz, CDCl3) δ 8.38 (dd, J = 4.4, 3.5 Hz, 1H,
[1,2,4]triazolo[4,3-a] pyridine-H), 7.51 (dd, J = 7.4, 1.0 Hz, 1H, [1,2,4]triazolo[4,3-a]
pyridine-H), 7.37 (t, J = 7.5 Hz, 1H, Ar-H), 7.08 (t, J = 7.0 Hz, 1H, Ar-H), 6.97 (d, J = 7.9 Hz,
1H, Ar-H), 6.92 (t, J = 7.2 Hz, 1H, Ar-H), 4.92 (s, 2H, -CH2-).13C NMR (126 MHz, CDCl3) δ
156.2 (d, 1JC-F = 215.7 Hz), 152.6, 149.3, 143.9, 132.5, 131.1, 128.6, 125.1 (d, 2JC-F = 14.5 Hz),
123.2, 122.9, 116.2, 115.6, 115.4, 56.9; IR (KBr)/cm1: 3089.5 (Ar-H), 2902.3, 2879.6 (-CH2-),
1568.2, 1563.1, 1448.1 (aromatic ring);Anal. Calc. for C13H8Cl2FN3O2S: C 43.35%, H 2.24%, N
11.67%. Found: C 43.37%, H 2.26%, N 11.65%.
3-((2-bromo-4-fluorobenzyl)sulfonyl)-8-chloro-[1,2,4]triazolo[4,3-a]pyridine (5q):yield 61%;
White solid; m.p. 177.3-178.3°C;1H NMR (500 MHz, CDCl3) δ 8.29 (dd, J = 7.0, 0.8 Hz, 1H,
[1,2,4]triazolo[4,3-a] pyridine-H), 7.51 (dd, J = 7.3, 0.8 Hz, 1H, Ar-H), 7.37 (dd, J = 8.6, 5.8 Hz,
1H, Ar-H), 7.23 (dd, J = 8.0, 2.6 Hz, 1H, Ar-H), 7.00 (ddd, J = 8.6, 7.8, 2.6 Hz, 1H, Ar-H), 6.90
1
(t, J = 7.1 Hz, 1H, Ar-H), 5.01 (s, 2H, -CH2-); 13C NMR (126 MHz, CDCl3) δ 163.9 (d, JC-F
=
3
255.4 Hz), 149.4, 143.9, 134.5 (d, JC-F = 8.8 Hz), 128.6, 126.3, 123.2, 122.9, 122.5, 120.9 (d,
2JC-F = 24.6 Hz), 116.2, 115.5 (d, 2JC-F = 21.6 Hz), 61.4; IR (KBr)/cm1: 3102.4 (Ar-H), 2909.55,
2889.9 (-CH2-), 1557.1, 1547.2, 1443.2 (aromatic ring); Anal. Calc. for C13H8BrClFN3O2S: C
38.59%, H 1.99%, N 10.38%. Found: C 38.55%, H 1.97%, N 10.35%.
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8-chloro-3-((2-fluoro-5-(trifluoromethyl)benzyl)sulfonyl)-[1,2,4]triazolo[4,3-a]pyridine (5r):
yield 87%; White solid; m.p. 152.8-153.8°C;1H NMR (500 MHz, CDCl3) δ 8.39 (d, J = 7.0 Hz,
1H, [1,2,4]triazolo [4,3-a] pyridine-H), 7.62 -- 7.57 (m, 1H, Ar-H), 7.51 (d, J = 7.3 Hz, 1H,
Ar-H), 7.41 (d, J = 4.7 Hz, 1H, Ar-H), 7.17 (t, J = 8.7 Hz, 1H, [1,2,4]triazolo[4,3-a] pyridine-H),
13
6.92 (t, J = 7.1 Hz, 1H, [1,2,4]triazolo [4,3-a] pyridine-H), 4.94 (s, 2H); C NMR (126 MHz,
CDCl3) δ 164.3 (d, 1JC-F = 257.8 Hz), 149.3, 143.7, 130.1, 129.2 (q, 2JC-F = 9.1 Hz), 128.7, 124.1,
1
1
2
123.4 (q, JC-F = 94.8 Hz), 122.8, 117.0 (d, JC-F = 22.9 Hz), 116.4, 115.0 (d, JC-F = 15.9 Hz),
55.9; IR (KBr)/cm1: 3078.6 (Ar-H), 2909.1, 2879.2 (-CH2-), 1558.1, 1554.2, 1448.3 (aromatic
ring);Anal. Calc. for C14H8ClF4N3O2S: C 42.71%, H 2.05%, N 10.67%. Found: C 42.72%, H
2.04%, N 10.70%.
8-chloro-3-((3,4,4-trifluorobut-3-en-1-yl)sulfonyl)-[1,2,4]triazolo[4,3-a]pyridine (5s): yield
59%; Light yellow solid; m.p. 86.6-87.4°C;1H NMR (500 MHz, CDCl3) δ 8.76 (dd, J = 6.9, 0.8
Hz, 1H, [1,2,4]triazolo[4,3-a] pyridine-H), 7.58 (d, J = 7.6 Hz, 1H, [1,2,4]triazolo[4,3-a]
3
pyridine-H), 7.11 (t, J = 7.0 Hz, 1H, [1,2,4]triazolo[4,3-a] pyridine-H), 3.91 (t, J = 7.2 Hz, 2H,
-CH2-), 3.07 -- 2.96 (m, 2H, -CH2CF = CF2);13C NMR (126 MHz, CDCl3) δ 153.96 (ddd, 1J C-F
=
1
2
1
287.8, J C-F = 274.6, J C-F = 45.7 Hz), 149.17, 142.21, 127.81 (ddd, J C-F = 234.9 Hz, J = 53.3
2
Hz, J C-F = 16.9 Hz), 126.43, 126.09122.92 (s), 121.47, 114.12, 77.40, 77.14, 76.89, 30.22,
2
3
26.61 (dd, JC-F = 21.6, JC-F = 2.0 Hz). IR (KBr)/cm1: 3100.2 (Ar-H), 2922.3, 2888.7 (-CH2-);
Anal. Calc. for C10H7ClF3N3O2S: C 36.88%, H 2.17%, N 12.90%. Found: C 36.87%, H 2.13%,
N 12.93%.
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Bioassay
Antifungal biological assay
The antifungal activities against Rhizotonia cerealis, Helminthosporium maydis, Rhizoctonia
solani, and Fusarium graminearum were evaluated using the poison plate technique at a
34
concentration of 50 mg/L . All the synthesized compounds (5a-5s) were dissolved in DMSO
(10 mL) and then mixed with potato dextrose agar (PDA, 90 mL). All fungal species were
incubated in PDA at 27 ± 1°C for 120 h to obtain new mycelium for antifungal assay, then
mycelia dishes were cut from the culture medium in approximately 4 mm diameter. One of the
specimens was picked up with a sterilized inoculation needle and then inoculated in the center of
the PDA plate aseptically. The inoculated plates were incubated at 27 ±1°C for 120 h. DMSO in
sterile distilled water served as the control, whereas carbendazim and propiconazole acted as the
positive control. Three replicates were proformed for each treatment. The radial growth of the
fungal colonies was measured on the sixth day and the data were statistically analyzed. The in
vitro inhibiting effects of the test compounds on the fungi were calculated by the formula:
I(%) = [(C-T)/(C-0.4)] × 100
Where C represents the diameter of fungal growth on untreated PDA, T represents the
diameter of fungi on treated PDA, and I is the inhibitory rate.
Insecticidal bioassays against Plutella xylostella.
Previously reported protocol 33, 35 were employed to evluate insecticidal activities against Plutella
xylostella. Fresh cabbage discs (diameter of 2 cm) were dipped in the prepared solutions
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containing compounds 5a to 5s for 10 s, dried in air and placed in a Petri dish (diameter of 9 cm)
lined with filter paper. Twenty larvaes of secondinstar of Plutella xylostella were carefully
transferred to the Petri dishes. Chlorpyrifos was used as postive control; three replicates were
performed for each experiment. Mortalities were caculated after 72 h. Evaluations of mortality
were caculated in a percentage scale (0 = no activity and 100 = complete eradication) at 5%
intervals. The results are summarized in Table S 3 (Supplemental Materials)
Insecticidal activity against Helicoverpa armigera
The insecticidal activities of ompounds 5a to 5s against Helicoverpa armigera were tested by the
diet-incorporated method 33, 35. A quantity of 3 mL of prepared solutions containing the
compounds was added to the forage (27 g), subsequently diluted to different concentrations and
then placed in a 24-pore plate.One larva was placed in each of the wells on the plate. Mortalities
were determined after 72--96 h, Evaluations were based on a percentage scale (0 = no activity and
100 = complete eradication) at 5% intervals. The results are given in Table S 4 (Supplemental
Materials)
ACKNOWLEDGMENT
Financial assistances from the National Natural Science Foundation of China (Nos. 21562012,
21302025), the Special Funds for Training object of Outstanding Young Scientific &
Technological Talents in Guizhou Province (No. 2015-15#), and the Science & Technology
Foundation of Guizhou Province (J[2014]2056#) were appreciated.
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Figure 1. The chemical structures of pesticides containing a sulfone
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Scheme 1. Synthesis of compounds 5a to 5s
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