Nematicidal activities of diamides with diphenylacetylene scaffold against Meloidogyne Incognita

Article abstract of DOI:10.1071/CH15065

With the goal of searching for new potential nematicides with high activity and low toxicity, new molecules are needed as potential prototypes for the synthesis of new nematicidal compounds. A series of novel diamides based on diphenylacetylene scaffold were designed and synthesised. The conformation of the amide was restricted through the ten-membered H-bonded ring. Their structures were characterised by ¹H NMR, ¹³C NMR, ¹⁹F NMR, and high-resolution mass spectrometry. The preliminary bioassays evaluated against Meloidogyne Incognita indicated that most of the title compounds were endowed with moderate-to-good activities at the concentration of 25mgL^-1. In particular, compounds 9a, 9c, 9g, 9h, 9k, and 9l displayed >50% nematicidal activity at 5mgL^-1. It is possible that the novel diamides with diphenylacetylene scaffold, which possess good nematicidal activities, provide distinct nematicidal chemotypes that can be used as leads for further optimisation.

Full text of DOI:10.1071/CH15065

CSIRO PUBLISHING
Aust. J. Chem.
Full Paper
http://dx.doi.org/10.1071/CH15065
Nematicidal Activities of Diamides with Diphenylacetylene
Scaffold Against Meloidogyne Incognita
A
A
A
A B
,
Jiling Li, Zhicheng Zhang, Xiaoyong Xu, Xusheng Shao,
A B
,
and Zhong Li
A
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China
University of Science and Technology, Shanghai 200237, China.
B
Corresponding authors. Email: shaoxusheng@ecust.edu.cn; lizhong@ecust.edu.cn
With the goal of searching for new potential nematicides with high activity and low toxicity, new molecules are needed as
potential prototypes for the synthesis of new nematicidal compounds. A series of novel diamides based on diphenyla-
cetylene scaffold were designed and synthesised. The conformation of the amide was restricted through the ten-membered
H-bonded ring. Their structures were characterised by 1H NMR, 13C NMR, 19F NMR, and high-resolution mass
spectrometry. The preliminary bioassays evaluated against Meloidogyne Incognita indicated that most of the title
compounds were endowed with moderate-to-good activities at the concentration of 25 mg Lꢀ1. In particular, compounds
9a, 9c, 9g, 9h, 9k, and 9l displayed .50 % nematicidal activity at 5 mg Lꢀ1. It is possible that the novel diamides with
diphenylacetylene scaffold, which possess good nematicidal activities, provide distinct nematicidal chemotypes that can
be used as leads for further optimisation.
Manuscript received: 6 February 2015.
Manuscript accepted: 16 April 2015.
Published online: 8 May 2015.
Introduction
functional group through pseudo-rings formed via intramolecu-
lar hydrogen bonds is a common method for conformational
lock.[21,22] Our research group has been devoted to the molecular
design using the conformational restriction strategy.[23,24] The
compounds containing amide groups exist as a mixture of
atropisomers in solution due to the restricted rotations at the
amide (CO–N) and aryl–carbonyl (Ar–CO) bonds.[25] The
conformational differences may result in certain distinctive
features.[26,27] Thus, locking the amide groups of the diamides
unit arouses our interest. Also, it is well documented that
the benzamido-diphenylacetylene scaffold provides a feasible
method for locking the amide group into a pseudo ten-
membered ring, which is constructed by the formation of intra-
molecular hydrogen bonds.[28,29]
Towards this goal, we utilised benzamido-diphenylacetylene
scaffold as a key prototype structure unit with dual effects of
locking the amide group, and incorporated pyridylpyrazolyl into
the framework (Fig. 1). Herein, we described the molecular
design, synthesis, and initial bioassays on nematicidal activities
against Meloidogyne Incognita.
Diseases and damages caused by plant parasitic nematodes are
one of the major stresses affecting crop production world-
wide.[1,2] The latest statistics in 2012 showed that plant parasitic
nematodes caused an estimated annual loss to world crop yields
of $118 billion.[3] Root-knot nematodes (RKNs), Meloidogyne
spp., being the most widespread plant parasitic nematodes, are
soil-borne root parasites that importantly affect the host plant
physiology. Some nematodes can even transmit plant viruses
and deteriorate the product quality.[4,5] However, there are only
a few commercial nematicides left in use at present due to the
drawbacks, such as toxic, volatile, and resistance, of conven-
tional nematicides.[5–7] Thus, new molecules with high nema-
ticidal activity are needed as potential prototypes for the
synthesis of new nematicidal compounds.
Diamides are one of the most important classes of modern
agricultural insecticides, and also serve as versatile building
blocks for the construction of lead compounds, which are
documented to exhibit a wide range of biological activities.
Some derivatives of amide can serve not only as pharmaceu-
ticals such as anti-tumour agents,[8–12] but also as agrochemicals
such as fungicide, insecticide, and plant virucide.[13–15] For
example, piperamides, as emerging botanical biocides, are
characterised by nematicidal properties.[16,17] Meanwhile, the
amide groups are known to improve stability and provide the
ability to establish intermolecular hydrogen bonds with biologi-
cal targets. However, the introduction of diamides into the
molecular design of nematicides is relatively seldom reported.
Conformational restriction has been considered as an effec-
tive drug design approach.[18–20] Simultaneously, fixing one
Results and Discussion
Synthesis
The synthesis of target compounds 9 is illustrated in Scheme 1.
The title compounds 9 were obtained through a six-step proce-
dure using 2-iodine benzoic acids 1 and carboxylic acids 7 as
starting materials. The treatment of 2-iodine benzoic acid with
appropriately substituted amines in the presence of 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide hydrochloride (EDCl) and
Journal compilation Ó CSIRO 2015
www.publish.csiro.au/journals/ajc

B
J. Li et al.
Stereogenic
Ar–CO axis
Stereogenic
N–CO bond
O
Scaffold
Diamide
O
R
N
Hydrogen-bonded
diphenylacetylene
R1
O
H
N
RЈ
H
N
Atropisomerism
R2
CN
Br
NK1 antagonist lead structure
Hydrogen-bonded
diphenylacetylene
H
N
O
N
N
S
CF3
NC
Br
H
N
Conformational restriction
CI
O
O
R3
N
H
N
N
N
N
N
CI
CI
CI
O
CI
N
Substituted pyrazolyl
CF3
Fipronil
Chlorantraniliprole
Fig. 1. Molecular design of compounds 9.
R1
R1
O
R1
O
C
NHR2
TMS
NHR2
C
R2NH2
COOH
I
PdCI2(PPh3)2, CuI
TMS
HOBt, EDCI
DCM, rt
Et3N, 60ЊC
I
1
2
3
K2CO3
MeOH
R1
R1
H
O
I
N
H
R2
C
NHR2
R
N
PdCI2(PPh3)2, CuI
O
H
O
Et3N, DMF, 60ЊC
R3
N
R
8
4
O
R3
DlPEA
DCM
0ЊC-rt
9p: R ϭ
R1
N
CF3
CI
O
I
Br
SOCI2
NH2
R2
N
RCOOH
RCOCI
Reflux
N
9a–9o: R ϭ
R3
N
7
6
5
4Ј
N
Scheme 1. General synthetic procedure for target compounds 9a–9p.
N-hydroxybenzotriazole (HOBt) afforded the benzamide deri-
vatives 2 in 65–72 % yields. Phenylacetylenes 3 were obtained
via Sonogashira cross-coupling reactions of 2 with tri-
methylsilylacetylene. The TMS groups of 3 were subsequently
removed with potassium carbonate at room temperature in
methanol (MeOH) to yield the key intermediates 4 in moderate
yields. It was noteworthy that the cyclisation by-products of
alkynylamines 4 were readily obtained in the step as showed in
Scheme 1 when the system was heated.[30] Meanwhile, car-
boxylic acids 7 were converted into the corresponding acid
chloride and then coupled with anilines 5 using N,N-diisopro-
pylethylamine (DIPEA) as acid acceptor to obtain the important
intermediate amides 8 in 57–65 % yields. The last step for
preparation of target compounds 9 was similar to that of 3. CuI
and PdCl2(PPh3)2 were each added in one portion to the mixture
of 4 and 8 in triethylamine (Et3N) and anhydrous THF under
nitrogen atmosphere. The system was heated at 608C with stir-
ring for 18 h to get the title compounds 9 in 71–80 % yields.
Activity
The larvicidal activities of compounds 9a–9p and Avermectin
against Meloidogyne Incognita are shown in Table 1. The results
indicated that most compounds exhibited good activity at the
concentration of 25 mg Lꢀ1. Compounds 9a, 9c, 9g, 9h, 9k, and
9l displayed .50 % nematicidal activities at 5 mg Lꢀ1 which
was higher than other title compounds relatively. Furthermore,
substituted pyrazolyl appears as a functional group in some
commercial insecticidal molecules such as chlorantraniliprole
and fipronil. We intended to investigate whether they would
present some new beneficial properties such as better patent-
ability or different physico-chemical properties if pyridylpyr-
azolyl hybridised benzamido-diphenylacetylene core structure.

Novel Diamides as Potent Nematicides
C
Table 1. Nematicidal activities of compounds 9a–9p against Meloidogyne Incognita
n.t.: not tested
Compound
R1
R2
R3
Meloidogyne Incognita (% inhibition)
20 mg Lꢀ1
25 mg Lꢀ1
10 mg Lꢀ1
5 mg Lꢀ1
9a
H
H
H
H
H
H
H
F
Methyl
H
H
H
H
H
H
H
H
Cl
Cl
H
H
H
H
Cl
H
100
100
100
100
79.2
81.5
100
66.4
n.t.
63.9
45.5
69.4
5.2
63.5
18.2
55.4
2.5
9b
Ethyl
9c
Isopropyl
9d
Cyclopropyl
Isobutyl
9e
85.6
n.t.
n.t.
9f
tert-Butyl
100
100
100
100
100
100
100
90.5
100
100
90
70
50
9g
Cyclopentyl
Methyl
70.4
93.9
71.9
39.4
76.2
55.6
15.94
n.t.
64.2
66.7
43.2
13.3
61.3
52.8
4.5
9h
9i
H
H
H
H
H
H
F
Ethyl
9j
Cyclopropyl
3-Chloro-4-methylbenzyl
4-Methoxybenzyl
2,6-Difluorobenzyl
2,3,6-Trifluorobenzyl
Methyl
73.3
100
100
62.3
n.t.
9k
9l
9m
94.2
17.9
100
9n
n.t.
9o
66.7
66.4
100
55.6
46.4
100
30.6
35.1
100
9p
H
Methyl
100
100
Avermectin
As the results showed, the substituted pyrazolyl subunits
appended to the scaffold lead to increase in potency to some
extent (9a and 9p). There were no obvious differences in
activities between analogues with benzyl groups (9k–9n) and
counterparts with aliphatic chains (9a–9g). When R2 was ben-
zyl, compounds with electro-donating substituents displayed
higher activities than analogues with electron-withdrawing
substituents, as seen in the comparison of the compounds 9k, 9l,
9m, and 9n. These observations revealed that the substitution
patterns of R2 have an important influence on the activity.
Meanwhile, it is worth noting that the introduction of either a
chlorine atom or a fluorine atom in the aromatic ring (R1 or R3)
was beneficial to nematicidal activities (9i and 9b, 9j and 9d,
and 9h and 9a). Fluoro-substituted analogue 9h exhibited high
activity at both concentrations of 25 mg Lꢀ1 and 5 mg Lꢀ1, with
inhibitions of 100 % and 66.7 %, respectively, becoming one of
the most potent compound of this series. However, the potency
decreased when R1 and R3 were replaced by fluorine atom and
chlorine atom simultaneously (9o and 9h). These assays sug-
gested that the differences in nematicidal activity might be due
to variations in combination of benzamides and aromatic ring
substitute moieties.
Experimental
Instrumentation and Chemicals
Melting points (mp) were recorded on a Bu¨chi B540 apparatus
(Bu¨chi Labortechnik, Flawil, Switzerland) and are uncorrected.
1H NMR and 13C NMR spectra were recorded on a Bruker AM-
400 spectrometer with [D6]DMSO as solvent and TMS as
internal standard. Chemical shifts are reported in d (parts per
million). High-resolution electrospray ionisation time-of-flight
(ESI-TOF) spectrometry was performed on a Micromass LC-
TOF spectrometer. Analytical thin layer chromatography (TLC)
was performed on pre-coated plates (silica gel 60 F254), and
spots were visualised with ultraviolet (UV) light. Unless oth-
erwise noted, reagents and solvents were used as received from
commercial suppliers. All reactions were conducted under a
protective atmosphere of dry nitrogen or using a calcium chlo-
ride tube.
General Procedure for Compounds
The intermediate 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-
5-carboxylic acid (7a) was synthesised according to the methods
reported in the literature.[31,32] dH ([D6]DMSO, 400 MHz) 13.95
(1H, s), 8.57 (1H, dd, J 4.4, 1.2), 8.26 (1H, dd, J 8.0, 1.6), 7.70
(1H, dd, J 8.0, 4.8), 7.25 (1H, s).
Conclusion
In conclusion, a series of novel diamides with hydrogen-bonded
diphenylacetylene scaffold were designed and synthesised
based on conformational restriction principle. The preliminary
bioassays indicated that most of the title compounds were
endowed with moderate-to-good activities against Meloidogyne
Incognita at a concentration of 25 mg Lꢀ1. In particular, com-
pound 9a, 9c, 9g, 9h, 9k, and 9l displayed .50 % nematicidal
activity at 5 mg Lꢀ1. The results indicated that the differences in
nematicidal activity might be due to variations in combination of
benzamides and aromatic ring substitute moieties. The rela-
tionships between structure and activity obtained in this study
could be beneficial for discovering new nematicides, and further
optimisation on benzamido-diphenylacetylene derivatives is
well ongoing in our laboratory.
General Procedure for Synthesis of Intermediate
Compounds 8
Intermediate carboxylic acids 7 (1.2 mmol) were heated at
reflux in SOCl2 for 2.5 h. Then, excess thionyl chloride was
removed under vacuum, and crude carbonyl chloride was
obtained as yellow oil (100 % yield), which was used directly in
the next step without further purification. To a mixture of
2-iodoaniline
5 (1 mmol) and N,N-diisopropylethylamine
(1.2 mmol) in dichloromethane (DCM; 15 mL) was added the
solution of pyrazole carbonyl chloride in dichloromethane
(1.0 mL) at 0–58C dropwise. The reaction mixture was then
stirred at room temperature for 3–4 h and washed with water
successively. The organic layer was dried over anhydrous

D
J. Li et al.
sodium sulfate. Then, the solvent was removed under vacuum,
and the residue was subjected to column chromatography on
silica gel with petroleum ether and ethyl acetate as solvents to
give products 8.
in one portion each. The system was heated at 608C with stirring
for 18 h. The solution was allowed to cool, poured into H2O,
extracted with ethyl acetate, dried over anhydrous sodium sul-
fate, and concentrated under vacuum. This crude product was
then purified by column chromatography on silica gel with
petroleum ether and ethyl acetate as solvents yielding target
compounds 9.
N-(2-Iodophenyl)-6-(trifluoromethyl)nicotinamide (8p)
Yellow solid (68 % yield). dH (CDCl3, 400 MHz) 9.34
(1H, s), 8.50 (1H, d, J 9.6), 8.44 (1H, d, J 8.0), 8.31 (1H, s),
7.91 (1H, d, J 8.8), 7.88 (1H, dd, J 8.0, 1.6), 7.47 (1H, t, J 8.4),
6.98 (1H, m).
3-Bromo-1-(3-chloropyridin-2-yl)-N-(2-((2-
(methylcarbamoyl)phenyl)ethynyl)phenyl)-
1H-pyrazole-5-carboxamide (9a)
Yellow solid (71 % yield), mp 211.3–212.58C. nmax (KBr)/
PhЈ), 1679 (–CONH–),
3-Bromo-1-(3-chloropyridin-2-yl)-N-(2-iodophenyl)-
1H-pyrazole-5-carboxamides Precursor to Compounds
8a–8h and 8k–8n
cmꢀ1 3408 (–CONH–), 3241 (Ph
1634 (–CONH–), 1409 (–CONH–). dH ([D6]DMSO, 400 MHz)
10.21 (1H, s), 8.48 (1H, dd, J 4.4, 1.2), 8.45 (1H, d, J 4.4), 8.21
(1H, dd, J 8.0, 1.6), 7.74 (1H, d, J 8.0), 7.68–7.60 (3H, m), 7.58–
7.48 (3H, m), 7.41 (1H, t, J 7.2), 7.27 (1H, t, J 7.2). 2.73 (3H, d,
J 4.4). dC ([D6]DMSO, 100 MHz) 167.7, 156.4, 148.8, 147.6,
140.0, 139.7, 138.4, 138.4, 133.3, 132.8, 130.6, 130.0, 129.3,
128.4, 128.2, 127.3, 127.1, 126.1, 124.3, 120.7, 116.6, 112.0,
94.4, 89.6, 26.7. m/z (HRMS ESþ) 556.0157; [M þ Na]þ
requires 556.0152.
Yellow solid (71 % yield). dH ([D6]DMSO, 400 MHz) 10.40
(1H, s), 8.53 (1H, dd, J 4.8, 1.6), 8.20 (1H, dd, J 8.0, 1.2), 7.92
(1H, dd, J 8.0, 0.8), 7.64 (1H, dd, J 8.4, 4.8), 7.44 (1H, d, J
6.0 Hz), 7.41 (1H, d, J 7.2), 7.31 (1H, dd, J 7.6, 1.2), 7.15–6.98
(1H, m).
3-Bromo-N-(4-chloro-2-iodophenyl)-1-(3-
chloropyridin-2-yl)-1H-pyrazole-5-carboxamides
Precursor to Compounds 8i, 8j, and 8o
3-Bromo-1-(3-chloropyridin-2-yl)-N-(2-((2-
(ethylcarbamoyl)phenyl)ethynyl)phenyl)-
1H-pyrazole-5-carboxamide (9b)
Yellow solid (61 % yield). dH ([D6]DMSO, 400 MHz) 10.45
(1H, s), 8.58 (1H, dd, J 4.8, 1.6), 8.23 (1H, dd, J 8.0, 1.2), 7.95
(1H, dd, J 8.0, 0.8), 7.75 (1H, s), 7.39 (1H, d, J 7.2), 7.36 (1H, d,
J 7.2), 6.98 (1H, s).
Yellow solid (74 % yield), mp 212.0–213.18C. nmax (KBr)/
PhЈ), 1676 (–CONH–),
cmꢀ1 3451 (–CONH–), 3239 (Ph
1638 (–CONH–). dH ([D6]DMSO, 400 MHz) 10.21 (1H, s), 8.49
(2H, dd, J 4.8, 1.2), 8.20 (1H, dd, J 8.0, 1.2), 7.74 (1H, d, J 8.0),
7.69–7.58 (4H, m), 7.57–7.48 (3H, m), 7.41 (1H, t, J 7.2), 7.27
(1H, t, J 7.6), 3.32–3.11 (2H, m), 1.08 (3H, t, J 7.2). dC ([D6]
DMSO, 100 MHz) 167.1, 156.4, 148.8, 147.6, 140.0, 139.7,
138.7, 138.5, 133.2, 132.6, 130.5, 129.9, 129.3, 128.4, 128.2,
127.3, 127.1, 126.1, 124.3, 120.6, 116.6, 111.9, 94.3, 89.5, 34.6,
15.1. m/z (HRMS ESþ) 570.0309; [M þ Na]þ requires
570.0308.
Preparation of Intermediates 4
To a mixture of 2-iodine benzoic acids 1 (4 mmol), 1-ethyl-3-(3-
dimethyllaminopropyl)carbodiimide hydrochloride (4.8 mmol)
and N-hydroxybenzotrizole (0.48 mmol) were added amines
(4.8 mmol) at room temperature. The reaction mixture was
stirred overnight and washed with water successively. The
organic layer was dried over anhydrous sodium sulfate. Then,
the solvent was removed under vacuum to afford crude com-
pounds 2. 2-Iodine benzamides 2 (3.00 mmol) were added to
30 mL triethylamine in a round-bottom flask, then the solution
was degassed with nitrogen for 10 min. CuI (0.306 mmol) and
PdCl2(PPh3)2 (0.1044 mmol) were added and the system was
placed under nitrogen atmosphere. Trimethylsilylacetylene
(6 mmol) was added dropwise over 3 min. And the mixture was
heated with stirring at 608C overnight. The reaction was allowed
to cool to room temperature and then filtered over Celite. The
filtrate was concentrated and purified by column chromatogra-
phy on silica gel with petroleum ether and ethyl acetate as sol-
vents to give the intermediates 3. Then, compounds 3
(1.73 mmol) were added to 15 mL MeOH in a flask and mixed
with K2CO3 (1.73 mmol). The flask was placed under nitrogen
atmosphere and the system was stirred for 15 min, after which
H2O was added to the flask. The organic layer was extracted
with ethyl acetate, dried over Na2SO4, and concentrated under
vacuum. The crude oil was then purified by column chroma-
tography on silica gel to get structures 4.
3-Bromo-1-(3-chloropyridin-2-yl)-N-(2-((2-
(isopropylcarbamoyl)phenyl)ethynyl)phenyl)-
1H-pyrazole-5-carboxamide (9c)
Yellow solid (65 % yield), mp 184.0–185.48C. nmax
(KBr)/cmꢀ1 3394 (–CONH–), 3306 (Ph
PhЈ), 1642
(–CONH–), 1605(–CONH–). dH ([D6]DMSO, 400 MHz)
10.19 (1H, s), 8.48 (1H, d, J 4.4 Hz), 8.29 (1H, d, J 7.6), 8.19
(1H, d, J 8.0), 7.74 (1H, d, J 8.0), 7.64–7.58 (4H, m), 7.57–7.46
(4H, m), 7.41 (1H, t, J 7.6), 7.26 (1H, t, J 7.2), 4.07–3.98 (1H,
m), 1.11 (6H, d, J 6.8). dC ([D6]DMSO, 100 MHz) 166.6, 156.4,
148.8, 147.6, 139.9, 139.7, 138.9, 138.5, 133.0, 132.5, 130.4,
129.9, 129.2, 128.4, 128.2, 127.3, 127.1, 126.0, 124.3, 120.6,
116.6, 111.9, 94.3, 89.5, 41.6, 22.7. m/z (HRMS ESþ)
562.0620; [M þ H]þ requires 562.0625.
3-Bromo-1-(3-chloropyridin-2-yl)-N-(2-((2-
(cyclopropylcarbamoyl)phenyl)ethynyl)phenyl)-
1H-pyrazole-5-carboxamide (9d)
General Procedure for Synthesis of Target Compounds 9
Yellow solid (68 % yield), mp 216.7–217.98C. nmax (KBr)/
PhЈ), 1654 (–CONH–),
1605 (–CONH–). dH ([D6]DMSO, 400 MHz) 10.20 (1H, s), 8.49
(2H, dd, J 7.6, 4.4), 8.19 (1H, d, J 8.0), 7.73 (1H, d, J 8.4), 7.65
(1H, s), 7.60 (2H, d, J 7.6), 7.57–7.46 (3H, m), 7.42 (1H, t, J 7.6),
7.27 (1H, t, J 7.6), 2.93–2.72 (1H, m), 0.74–0.63 (2H, m),
The last step for synthesis of target compounds 9 was similar to
that of 3. The key intermediates 4 (1.34 mmol) and 8
(1.12 mmol) were mixed in triethylamine (10 mL) and anhy-
drous THF (10 mL) under nitrogen atmosphere. Then, CuI
(0.022 mmol) and PdCl2(PPh3)2 (0.022 mmol) were each added
cmꢀ1 3404 (–CONH–), 3318 (Ph

Novel Diamides as Potent Nematicides
E
0.54–0.50 (2H, m). dC ([D6]DMSO, 100 MHz) 168.6, 156.4,
148.9, 147.6, 139.9, 139.6, 138.5, 138.5, 133.0, 132.6, 130.5,
129.9, 129.2, 128.4, 128.2, 127.3, 127.1, 126.1, 124.4, 120.6,
116.7, 111.9, 94.3, 89.5, 23.5, 14.6, 6.2. m/z (HRMS ESþ)
560.0488; [M þ H]þ requires 560.0489.
3-Bromo-N-(4-chloro-2-((2-(ethylcarbamoyl)phenyl)
ethynyl)phenyl)-1-(3-chloropyridin-2-yl)-1H-
pyrazole-5-carboxamide (9i)
Yellow solid (64 % yield), mp 198.4–199.68C. nmax (KBr)/
cmꢀ1 3371 (–CONH–), 3236 (Ph
PhЈ), 1674 (–CONH–),
1637 (–CONH–). dH ([D6]DMSO, 400 MHz) 10.25 (1H, s), 8.52
(1H, s), 8.49 (1H, d, J 4.8), 8.20 (1H, d, J 8.0), 7.78 (1H, d, J 8.8),
7.72–7.59 (5H, m), 7.59–7.49 (2H, m), 7.47 (1H, d, J 8.8), 3.27–
3.15 (2H, m), 1.08 (3H, t, J 7.2). dC ([D6]DMSO, 100 MHz)
167.0, 156.5, 148.7, 147.6, 140.0, 139.4, 138.6, 137.5, 133.4,
131.8, 130.6, 129.9, 129.7, 128.4, 128.2, 127.3, 127.1, 125.8,
120.3, 118.2, 112.1, 95.6, 88.2, 34.6, 15.1. m/z (HRMS ESþ)
582.0098; [M þ H]þ requires 582.0099.
3-Bromo-1-(3-chloropyridin-2-yl)-N-(2-((2-
(isobutylcarbamoyl)phenyl)ethynyl)phenyl)-
1H-pyrazole-5-carboxamide (9e)
Yellow solid (66 % yield), mp 148.4–150.68C. nmax (KBr)/
PhЈ), 1669 (–CONH–),
cmꢀ1 3394 (–CONH–), 3288 (Ph
1646 (–CONH–). dH ([D6]DMSO, 400 MHz) 10.17 (1H, s),
8.57–8.42 (2H, m), 8.20 (1H, d, J 8.0), 7.77 (1H, d, J 8.4), 7.63
(3H, t, J 5.6), 7.59 (1H, s), 7.54 (3H, d, J 6.8), 7.40 (1H, t, J 7.6),
7.25 (1H, t, J 7.6), 3.02 (2H, t, J 5.6), 1.86–1.71 (1H, m), 0.85
(7H, d, J 6.4). dC ([D6]DMSO, 100 MHz) 167.6, 156.4, 148.9,
147.6, 140.0, 139.7, 139.0, 138.6, 133.1, 132.6, 130.5, 130.0,
129.3, 128.3, 128.2, 127.3, 127.1, 125.9, 124.1, 120.6, 116.3,
111.9, 94.4, 89.4, 47.09, 28.5, 20.6. m/z (HRMS ESþ)
576.0797; [M þ H]þ requires 576.0802.
3-Bromo-N-(4-chloro-2-((2-(cyclopropylcarbamoyl)
phenyl)ethynyl)phenyl)-1-(3-chloropyridin-2-yl)-
1H-pyrazole-5-carboxamide (9j)
Yellow solid (63 % yield), mp 194.1–196.28C. nmax (KBr)/
PhЈ), 1644 (–CONH–),
cmꢀ1 3444 (–CONH–), 2065 (Ph
1401 (–CONH–). dH ([D6]DMSO, 400 MHz) 10.28 (1H, s), 8.55
(1H, d, J 2.4), 8.49 (1H, d, J 4.4), 8.20 (1H, d, J 8.0), 7.76 (1H, d,
J 8.8), 7.68–7.58 (5H, m), 7.54 (2H, dd, J 10.8, 7.2), 7.48 (1H, d,
J 8.8), 2.83 (1H, s), 0.67 (2H, d, J 6.8), 0.54 (2H, s). dC ([D6]
DMSO, 100 MHz) 168.5, 156.5, 148.8, 147.6, 140.0, 140.0,
138.5, 137.4, 133.2, 131.7, 130.7, 129.9, 129.7, 129.6, 128.4,
128.2, 127.3, 127.1, 126.0, 120.2, 118.4, 112.1, 95.5, 88.6, 23.5,
6.2. m/z (HRMS ESþ) 594.0088; [M þ H]þ requires 594.0099.
3-Bromo-N-(2-((2-(tert-butylcarbamoyl)phenyl)ethynyl)
phenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-
carboxamide (9f)
Yellow solid (57 % yield), mp 221.5–224.08C. nmax (KBr)/
PhЈ), 1644 (–CONH–),
cmꢀ1 3487 (–CONH–), 3225 (Ph
1678 (–CONH–). dH ([D6]DMSO, 400 MHz) 10.23 (1H, s), 8.49
(1H, d, J 4.8), 8.19 (1H, d, J 9.2), 8.00 (1H, s), 7.70 (1H, d, J 8.0),
7.64 (1H, dd, J 8.4, 4.8), 7.60–7.46 (6H, m), 7.42 (1H, t, J 7.6),
7.29 (1H, t, J 7.6), 1.33 (9H, s). dC ([D6]DMSO, 100 MHz)
167.4, 156.2, 148.9, 147.6, 140.4, 139.9, 139.6, 138.3, 132.7,
132.3, 129.9, 129.9, 129.2, 128.3, 128.3, 127.3, 127.1, 126.3,
124.9, 120.2, 117.2, 111.6, 94.0, 89.2, 60.2, 28.9. m/z (HRMS
ESþ) 576.0801; [M þ H]þ requires 576.0802.
3-Bromo-N-(2-((2-((3-chloro-4-methylbenzyl)
carbamoyl)phenyl)ethynyl)phenyl)-1-(3-chloropyridin-
2-yl)-1H-pyrazole-5-carboxamide (9k)
Yellow solid (56 % yield), mp 166.0–167.18C. nmax (KBr)/
PhЈ), 3119 (–CONH–), 1647 (–CONH–),
cmꢀ1 3343 (Ph
1606 (–CONH–). dH ([D6]DMSO, 400 MHz) 10.12 (1H, s), 9.04
(1H, s), 8.48 (1H, d, J 4.0), 8.19 (1H, d, J 8.4), 7.71–7.59 (4H,
m), 7.59–7.49 (3H, m), 7.43–7.34 (3H, m), 7.24–7.13 (3H, m),
4.37 (2H, d, J 5.6), 2.24 (1H, s). dC ([D6]DMSO, 100 MHz)
167.7, 166.0, 156.3, 147.6, 146.8, 139.9, 139.6, 139.4, 138.6,
138.3, 136.6, 134.9, 134.6, 134.2, 133.2, 132.7, 131.5, 131.1,
130.6, 129.9, 128.2, 128.1, 127.1, 126.6, 126.0, 119.2, 116.8,
111.7, 97.9, 95.6, 67.5, 25.6. m/z (HRMS ESþ) 658.0389;
[M þ H]þ requires 658.0412.
3-Bromo-1-(3-chloropyridin-2-yl)-N-(2-((2-
(cyclopentylcarbamoyl)phenyl)ethynyl)phenyl)-
1H-pyrazole-5-carboxamide (9g)
Yellow solid (82 % yield), mp 200.7–202.88C. nmax (KBr)/
PhЈ), 1667 (–CONH–),
cmꢀ1 3414 (–CONH–), 3283 (Ph
1640 (–CONH–). dH ([D6]DMSO, 400 MHz) 10.26 (1H, s), 8.49
(1H, dd, J 4.4, 1.2), 8.42 (1H, d, J 7.2), 8.20 (1H, dd, J 8.0, 1.2),
7.76 (1H, d, J 8.4), 7.65–7.58 (4H, m), 7.56–7.48 (3H, m), 7.40
(1H, t, J 7.2), 7.26 (1H, t, J 7.6), 4.14 (1H, m), 1.89–1.75 (2H,
m), 1.60–1.58 (2H, m), 1.53–1.40 (4H, m). dC ([D6]DMSO,
100 MHz) 167.0, 156.5, 148.8, 147.6, 134.0, 139.7, 138.9,
138.6, 133.0, 132.5, 130.4, 130.0, 129.2, 128.5, 128.2, 127.3,
127.1, 126.0, 124.2, 120.6, 116.4, 112.0, 94.4, 89.4, 51.4, 32.5,
24.0. m/z (HRMS ESþ) 588.0740; [M þ H]þ requires 588.0734.
3-Bromo-1-(3-chloropyridin-2-yl)-N-(2-((2-((4-
methoxybenzyl)carbamoyl)phenyl)ethynyl)phenyl)-
1H-pyrazole-5-carboxamide (9l)
Yellow solid (67 % yield), mp 113.6–114.78C. nmax (KBr)/
PhЈ), 1653 (–CONH–),
cmꢀ1 3448 (–CONH–), 3323 (Ph
1609 (–CONH–). dH ([D6]DMSO, 400 MHz) 10.16 (1H, s), 8.96
(1H, s), 8.48 (1H, s), 8.19 (1H, d, J 8.0), 7.71 (1H, d, J 8.0), 7.67–
7.59 (3H, m), 7.57 (1H, s), 7.52 (2H, t, J 7.2), 7.40 (2H, m), 7.23
(3H, d, J 7.6), 6.76 (2H, d, J 7.6), 4.35 (2H, d, J 5.0), 3.68 (3H, s).
dC ([D6]DMSO, 100 MHz) 167.5, 158.6, 156.3, 148.9, 147.6,
139.9, 139.7, 138.9, 138.4, 133.1, 132.7, 131.6, 130.5, 129.9,
129.3, 129.1, 128.3, 128.2, 127.3, 127.1, 126.0, 124.4, 120.5,
116.8, 114.1, 111.8, 100.0, 94.1, 55.4, 42.6. m/z (HRMS ESþ)
640.0748; [M þ H]þ requires 640.0751.
3-Bromo-1-(3-chloropyridin-2-yl)-N-(2-((3-fluoro-2-
(methylcarbamoyl)phenyl)ethynyl)phenyl)-
1H-pyrazole-5-carboxamide (9h)
Yellow solid (68 % yield), mp 211.4–213.48C. nmax (KBr)/
PhЈ), 1649 (–CONH–),
cmꢀ1 3315 (–CONH–), 3305 (Ph
1600 (–CONH–). dH ([D6]DMSO, 400 MHz) 10.30 (1H, s), 8.56
(1H, q, J 4.4), 8.48 (1H, dd, J 4.4, 1.2), 8.20 (1H, dd, J 8.0, 1.2),
7.63 (1H, dd, J 8.0, 4.8), 7.56 (1H, s), 7.54 (1H, d, J 8.0), 7.48–
7.53 (2H, m), 7.43 (1H, t, J 7.6), 7.39–7.27 (3H, m), 2.75 (3H, d,
J 4.8). dF ([D6]DMSO, 376 MHz) ꢀ115.53 (dd, J 5.64, 6.02).
m/z (HRMS ESþ) 552.0168; [M þ H]þ requires 552.0160.
3-Bromo-1-(3-chloropyridin-2-yl)-N-(2-((2-((2,6-
difluorobenzyl)carbamoyl)phenyl)ethynyl)phenyl)-
1H-pyrazole-5-carboxamide (9m)
Yellow solid (67 % yield), mp 115.7–117.98C. nmax (KBr)/
PhЈ), 1657 (–CONH–),
cmꢀ1 3384 (–CONH–), 3280 (Ph

F
J. Li et al.
1626 (–CONH–). dH ([D6]DMSO, 400 MHz) 10.12 (1H, s),
8.94 (1H, s), 8.48 (1H, d, J 4.4), 8.20 (1H, d, J 8.0), 7.70 (1H, d,
J 8.0), 7.58 (4H, s), 7.54–7.47 (3H, m), 7.40 (4H, dd, J 12.0, 8.4),
7.24 (1H, t, J 7.6), 7.14 (1H, d, J 6.0), 7.02 (2H, t, J 8.0), 4.49
(2H, d, J 4.0). dF ([D6]DMSO, 376 MHz) ꢀ114.43 (t, J 6.7),
ꢀ115.56 (t, J 6.4). m/z (HRMS ESþ) 646.0447; [M þ H]þ
requires 646.0457.
water served as the negative control, whereas the cucumber
roots treated with Phenamiphos or Avermectins were used as
the positive control. Three replicates in each trial were made
with quadruplicate samples. Inhibition ratio ¼ (score of
negative control ꢀ score of compound)/score of negative
control ꢁ 100 %.
Supplementary Material
3-Bromo-1-(3-chloropyridin-2-yl)-N-(2-((2-((2,3,6-
trifluorobenzyl)carbamoyl)phenyl)ethynyl)phenyl)-
1H-pyrazole-5-carboxamide (9n)
The NMR spectra of compounds 9a–p are available on the
Journal’s website.
Yellow solid (64 % yield), mp 150.7–153.78C. nmax (KBr)/
PhЈ), 1674 (–CONH–),
cmꢀ1 3356 (–CONH–), 3313 (Ph
Acknowledgements
This work was financially supported by the National High Technology
Research Development Program of China (863 Program, 2011AA10A207),
National Natural Science Foundation of China (21372079, 21472046),
Shanghai Pujiang Program (14PJD012), and Fundamental Research Funds
for the Central Universities (222201414015). This work was also partly
supported by Australia DC Foundation.
1653 (–CONH–). dH ([D6]DMSO, 400 MHz) 10.10 (1H, s), 9.02
(1H, s), 8.48 (1H, d, J 3.6), 8.19 (1H, d, J 8.0), 7.70 (1H, d, J 8.0),
7.66–7.56 (4H, m), 7.57–7.46 (2H, m), 7.46–7.32 (3H, m), 7.24
(1H, t, J 7.5), 7.05 (1H, t, J 8.4), 4.51 (2H, d, J 4.4). dF ([D6]
DMSO, 376 MHz) ꢀ118.96, ꢀ137.86, ꢀ143.12. m/z (HRMS
ESþ) 664.0355; [M þ H]þ requires 664.0363.
References
3-Bromo-N-(4-chloro-2-((3-fluoro-2-(methylcarbamoyl)
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1H-pyrazole-5-carboxamide (9o)
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Yellow solid (63 % yield), mp 200.5–202.68C. nmax (KBr)/
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Yellow solid (53 % yield), mp 210.6–211.88C. nmax (KBr)/
PhЈ), 1656 (–CONH–),
cmꢀ1 3384 (–CONH–), 3286 (Ph
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