The Synthesis of Fipronil Derivatives via Pd-Catalyzed Direct Alkynylation of Phenylpyrazole with Terminal Alkynes in Green Solvents

Article abstract of DOI:10.1002/jhet.2628

The palladium-catalyzed direct alkynylation of phenylpyrazole (5-amino-1-[2, 6-dichloro-4-trifluoromethylphenyl]-lH-pyrazole-3-carbonitrile) with terminal alkynes is being reported. The protocol utilizes EtOH/H₂O as the solvents and does not require the preactivation of phenylpyrazole with halide to form its halide substrate, which exemplifies the ideal condition of green chemistry. Various terminal alkynes such as arylacetylenes and aliphatic alkynes are used in the reaction to afford a series of fipronil derivatives of 4-alkynyl-1-phenylpyrazoles with potential bioactivity in good yields. All the compounds were characterized by¹H NMR,¹³C NMR, and HRMS spectroscopic techniques.

Full text of DOI:10.1002/jhet.2628

Month 2016
The Synthesis of Fipronil Derivatives via Pd-Catalyzed Direct
Alkynylation of Phenylpyrazole with Terminal Alkynes in Green Solvents
*
Su-Qin Chen and Xiao-Hong Zhang
College of Chemistry and Materials Science, Wenzhou University, Wenzhou 325035, China
*
E-mail: kamenzxh@wzu.edu.cn
Additional Supporting Information may be found in the online version of this article.
Received December 6, 2015
DOI 10.1002/jhet.2628
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
The palladium-catalyzed direct alkynylation of phenylpyrazole (5-amino-1-[2, 6-dichloro-4-
trifluoromethylphenyl]-lH-pyrazole-3-carbonitrile) with terminal alkynes is being reported. The protocol uti-
lizes EtOH/H2O as the solvents and does not require the preactivation of phenylpyrazole with halide to form
its halide substrate, which exemplifies the ideal condition of green chemistry. Various terminal alkynes such
as arylacetylenes and aliphatic alkynes are used in the reaction to afford a series of fipronil derivatives of 4-
alkynyl-1-phenylpyrazoles with potential bioactivity in good yields. All the compounds were characterized
by 1H NMR, 13C NMR, and HRMS spectroscopic techniques.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
phenylpyrazole to produce the 4-alkynyl-1-phenylpyrazole
derivatives was seldom reported.
Phenylpyrazoles are an important class of heterocycles
that are present in many natural products and
It is well known that palladium/copper-catalyzed
Sonogashira cross-coupling reactions of aryl hailides
with terminal alkynes are the most straightforward and pow-
erful methods for the construction of C(Sp2)–C(Sp) bonds
[18–20]. Since its inception, great developments related to
the Sonogashira cross-coupling reaction have been achieved,
including the enhancement of catalytic efficiency [21,22],
copper- [23–25] and/or solvent-free versions [26], and low
reaction temperature [27,28]. However, all these reactions
are dependent on preactivation of alkene with halide to form
the substrate of vinyl halide, which requires several
extrasynthetic steps and results in the production of waste
and the low yield. Therefore, there is still a need for develop-
ing a direct and novel method to synthesize the 4-alkynyl-1-
phenylpyrazole derivatives.
pharmaceutical
intermediates
[1–5].
Moreover,
phenylpyrazole derivatives containing fluorine groups
have been found to exhibit a broad range of biological
activities [6,7]. For example, the commercial fipronil (I,
Fig. 1) (5-amino-1-[2, 6-dichloro-4-trifluoromethylphenyl]-
4-trifluoromethylsulfinyl-lH-pyrazole-3-carbonitrile) is effec-
tive against a host of insect pests of crops including grass
hoppers, boll weevils, rice insects, termites, houseflies,
fruitflies, and thrips [8–10]. Similar insecticidal activity can
be observed in its new analogs such as ethiprole (II, Fig. 1)
[11], with 4-EtSO replacing the 4-CF3SO and
desulfinylethiprole (III, Fig. 1) [12], with 4-Et instead of 4-
CF3SO.
Recently, fipronil was greatly limited to be used as a
pesticide because of its harm to animals [13]. In view of
the biologically important fipronil, we have been devoted
to the structural modification of fipronil parent in order to
seek for its new analogs with highly biological activity
and low toxicity to animals [14–16]. For example, the
compounds of 4-aryl-1-phenylpyrazoles were successfully
synthesized via the palladium-catalyzed direct arylation
of phenylpyrazoles with boronic acids [17]. These works
provided a series of fipronil derivatives with potential
bioactivity. However, the direct alkynylation of
Encouraged by the successful synthesis of 4-aryl-1-
phenylpyrazoles, we envisioned that 4-alkynyl-1-
phenylpyrazoles can be obtained through the metal-catalyzed
direct alkynylation of phenylpyrazoles with terminal
alkynes. Fortunately, the direct alkynylation of
phenylpyrazoles could be achieved smoothly when using
PdCl2(PPh3)2 as catalyst in green solvents. Herein, we
describe the efficient synthesis of 4-alkynyl-1-
phenylpyrazoles bearing CF3 group. All the compounds
1
were characterized by H NMR, 13C NMR, and HRMS
spectroscopic techniques.
© 2016 Wiley Periodicals, Inc.

S.-Q. Chen and X.-H. Zhang
Vol 000
equiv N-iodosuccinimide (NIS) as iodine source, and
C2H5OH :H2O (2:1) as solvent at 100°C. It was found that
PdCl2(PPh3)2 gave better yield of the product than PdCl2,
Pd(OAc)2, and Pd(PPh3)4 (entries 1–4). Notably, the yield
of cross-coupling product 5-amino-1-(2,6-dichloro-4-
(trifluoromethyl)phenyl)-4-(p-tolylethynyl)-1H-pyrazole-
3-carbonitrile (3b) could be dramatically increased in the
presence of Cu source. Evaluation of addition of Cu sources
such as CuCl and Cu(OAc)2 provided conditions that gave
a much lower yield relative to CuI (entries 5–7). Next,
K2CO3 was replaced with different bases, such as Cs2CO3,
t-BuOK, Na2CO3, CH3COOK, and NaHCO3. The results
indicated that the identity of base affected the reaction
efficiency, and Cs2CO3 was proved to be the optimal base
for the direct alkynylation reaction (entries 8–12). It was
interesting that no aimed product but only the intermediate
4-iodo-1-phenylpyrazole can be obtained in high yields
when the mixture solvent of C2H5OH :H2O was replaced
Figure 1. Fipronil (I) and analogs (II, III).
RESULTS AND DISCUSSION
We chose to study the reaction of 5-amino-1-(2,6-
dichloro-4-trifluoromethylphenyl)-lH-pyrazole-3-
carbonitrile (1) with 4-ethynyltoluene (2b) as a model
system to determine the optimal reaction conditions
(Table 1). Initially, in the absence of Cu source, four com-
monly used catalyst precursors for the direct alkynylation
were surveyed when using 2 equiv K2CO3 as base, 1.5
Table 1
Optimization of the alkynylation conditionsa.
b
Entry
Pd
PdCl2
Pd(OAc)2
PdCl2(PPh3)2
Pd(PPh3)4
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
Cu source
Base
Iodide source
Solvent
Yield (%)
1
2
3
4
5
6
7
8
—
—
—
—
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
t-BuOK
Na2CO3
CH3COOK
NaHCO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
I2
C2H5OH : H2O
C2H5OH : H2O
C2H5OH : H2O
C2H5OH : H2O
C2H5OH : H2O
C2H5OH : H2O
C2H5OH : H2O
C2H5OH : H2O
C2H5OH : H2O
C2H5OH : H2O
C2H5OH : H2O
C2H5OH : H2O
DMSO
15
10
40
Trace
65
CuI
CuCl
Cu(OAc)2
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
55
45
70 (65c, 40d)
9
55
60
20
63
85e
65
40
80e
47
65
10
11
12
13
14
15
16
17
18
C2H5OH
CH3CN
DMF
C2H5OH : H2O
C2H5OH : H2O
ICl
aReaction conditions: 1 (0.2 mmol), 2b (0.4 mmol), [NIS or I2] (0.3 mmol), [Pd] and [Cu] (10 mol%), base (0.4 mmol), solvent (6 mL), 100°C for 18 h.
bIsolated yield.
cNIS (0.2 mmol).
d80°C.
eThe yield of intermediate 4-iodo-1-phenylpyrazole.
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The Synthesis of Fipronil Derivatives in Green Solvents
with DMSO and DMF (entries 13, 16), whereas the yield of
product 3b was decreased to 65 and 40% when using
C2H5OH and CH3CN as solvent (entries 14–15), respec-
tively. Subsequently, promoted by the beneficial help from
NIS, other iodide reagents, such as I2 and ICl, were investi-
gated to give lower yields than NIS (entries 17–18).
Unfortunately, the yields of the product 3b were dropped
when decreasing the amount of NIS to 1 equiv as well as
decreasing the reaction temperature to 80°C (entry 8). Thus,
the optimal condition was finally identified as follows: 5-
amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-lH-pyrazole-
3-carbonitrile (1) (0.2 mmol), terminal alkyne (0.4 mmol),
PdCl2(PPh3)2 (10 mmol%), CuI (10 mmol%), NIS
(0.3mmol), Cs2CO3 (0.4mmol), C2H5OH:H2O (2:1, 6mL),
100°C for 18h.
With the preliminary optimized reaction in hand, the
scope of terminal alkynes was next discussed. The results
were summarized in Table 2. As expected, various
arylacetylenes worked well under the reaction condition.
A series of functional groups, such as methyl, ethyl,
n-propyl, n-butyl, methoxyl, chloro, bromo, fluoro, and
the active group NH2, were tolerated well in this process.
Generally, the electron-withdrawing substituents on the
phenyl of aryacetylenes were beneficial for the transforma-
tion, whereas electron-donating groups decreased the
efficiency. For example, the arylacetylenes with fluoro,
chloro, and bromo gave the cross-coupling products in
more than 80% yields (entries 7–9), while their methyl,
ethyl, n-propyl, n-butyl, and methoxyl equivalents
generated the corresponding products in less than 75%
(entries 1–6). To our delight, the treatment of 3-
aminophenylacetylene with 5-amino-1-(2,6-dichloro-4-
trifluoromethylphenyl)-lH-pyrazole-3-carbonitrile (1) also
afforded product 3k in 50% yield (entry 11). Meanwhile,
the steric hindrance affected the efficiency slightly.
Substrates with para-methyl and para-chloro gave similar
yields as their meta-methyl and meta-chloro equivalents
(entries 2, 8, 10, 12). Fortunately, the aliphatic terminal
alkyne such as 1-hexyne was also well tolerant to the
catalytic system, providing the corresponding product in a
moderate yield (entry 13).
The possible mechanism was listed in Figure 2 on the
basis of reported mechanism [20,29]. Firstly, 5-amino-
1-(2,6-dichloro-4-trifluoromethylphenyl)-lH-pyrazole-3-
carbonitrile (1) was reacted with NIS, giving the
intermediate 4-iodo-1-phenylpyrazole. Then, the oxidative
addition of Pd(0) with 4-iodo-1-phenylpyrazole proceed to
form intermediate A. On the other hand, the copper
acetylide was generated by the reaction of terminal alkyne
with base. Subsequently, the replacement between
Table 2
Pd-catalyzed direct alkynylation of phenylpyrazole with terminal alkynesa.
Entry
R
Compounds
Yield (%)b
1
2
3
4
5
6
7
8
C6H5
4-MeC6H4
4-EtC6H4
3a
3b
3c
3d
3e
3f
3g
3h
3i
75
70
65
66
71
74
80
85
83
72
50
82
71
4-n-PrC6H4
4-n-BuC6H4
4-OCH3C6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
3-MeC6H4
3-NH2C6H4
3-ClC6H4
1-heptyne
9
10
11
12
13
3j
3k
3l
3m
aReaction conditions: 1 (0.2 mmol), terminal alkynes (0.4 mmol), NIS (0.3 mmol), PdCl2(PPh3)2 (10 mmol%), CuI (10 mmol%), Cs2CO3 (0.4 mmol),
C2H5OH : H2O (2:1, 6 mL), 100°C for 18 h.
bIsolated yield.
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S.-Q. Chen and X.-H. Zhang
Vol 000
completion of the reaction, as monitored by TLC, the
mixture was cooled and filtrated. The filtrate was
extracted with ethyl acetate and washed with brine. Then,
the combined organic extracts were dried over Na2SO4
and concentrated under vacuum, and the resulting residue
was purified by silica gel column chromatography to
afford the desired products.
5-Amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-
phenylethynyl-1H-pyrazole-3-carbonitrile (3a).
Yellow
solid, mp 187–189°C. 1H NMR (500MHz, CDCl3) δ 7.73
(s, 2H), 7.47–7.76 (m, 2H), 7.30–7.29 (m, 3H), 4.41 (s,
2H). 13C NMR (125MHz, CDCl3) δ 148.7, 136.8, 135.2,
135.0 (q, J = 34.1Hz), 131.8, 129.3, 129.0, 128.7, 126.5
(q, J = 3.6 Hz), 122.7, 122.2 (q, J = 274.1Hz), 112.6, 96.9,
92.4, 75.9. HRMS (ESI) calcd for C19H10Cl2F3N+4([M
+ H]+) 421.0229, found 421.0247.
5-Amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-
(p-tolylethynyl)-1H-pyrazole-3-carbonitrile (3b).
Yellow
1
solid, mp 229–230°C. H NMR (500 MHz, d6-acetone) δ
8.11 (s, 2H), 7.44 (d, J= 8.5 Hz, 2H), 7.24 (d, J = 8.0Hz,
2H), 6.42 (s, 2H), 2.36 (s, 3H); 13C NMR (125MHz, d6-
acetone)
δ 151.9, 139.5, 137.5, 136.6, 134.8 (q,
Figure 2. The possible mechanism.
J = 34.0Hz), 132.1, 130.1, 129.0, 127.4 (q, J= 3.75 Hz),
122.4 (q, J = 271.6Hz), 120.9, 113.7, 96.3, 89.7, 76.9,
21.4. HRMS (ESI) calcd for C20H12Cl2F3N+4([M +H]+)
435.0386, found 435.0397.
5-Amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-((4-
ethylphenyl)ethynyl)-1H-pyrazole-3-carbonitrile (3c). Yellow
intermediate A and the copper acetylide occurred to afford
intermediate B, which released the aimed product and the
active Pd(0) species via the reductive elimination reaction.
In summary, we have developed an efficient method for the
palladium-catalyzed direct alkynylation of phenylpyrazole (5-
amino-1-[2, 6-dichloro-4-trifluoromethylphenyl]-lH-pyrazole-
3-carbonitrile) with terminal alkynes. The protocol does not
require the preactivation of phenylpyrazole with halide to form
its halide substrate, and the reaction adopted EtOH/H2O as the
solvent, which exemplifies the ideal condition of green
chemistry. Various terminal alkynes, including arylacetylenes
bearing electron-donating or withdrawing groups and ali-
phatic terminal alkynes, can participate in the reaction,
affording a series of fipronil derivatives of 4-alkynyl-1-
phenylpyrazole in moderate to good yields. Undoubtedly,
this efficient method will be useful for the synthesis of
trifluoromethyl-containing 4-alkynyl-1-phenylpyrazole de-
rivatives for drug discovery.
1
solid, mp 187–189°C. H NMR (500MHz, CDCl3) δ 7.79
(s, 2H), 7.45 (d, J=8.0Hz, 2H), 7.19 (d, J=8.0Hz, 2H),
4.23 (s, 2H), 2.67 (q, J=7.5Hz, 2H), 1.25 (t, J=7.5Hz,
3H); 13C NMR (125MHz, CDCl3) δ 149.3, 146.3, 137.4,
135.9, 135.6 (q, J=34.5Hz), 132.5, 129.8, 128.9, 127.2 (q,
J=3.5Hz), 122.9 (q, J=272.2Hz), 120.4, 113.3, 97.8,
93.2, 75.8, 29.8, 16.2. HRMS (ESI) calcd for
C21H14Cl2F3N+4([M+H]+) 449.0542, found 449.0554.
5-Amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-((4-n-
propylphenyl)ethynyl)-1H-pyrazole-3-carbonitrile (3d). White
1
solid, mp 208–209°C. H NMR (500MHz, CDCl3) δ 7.78
(s, 2H), 7.43 (d, J=8.5 Hz, 2H), 7.15 (d, J=8.5Hz, 2H),
4.16 (s, 2H), 2.59 (t, J=7.5Hz, 2H), 1.63 (q, J=7.5Hz,
2H), 0.93 (t, J=7.5Hz, 3H); 13C NMR (125MHz, CDCl3)
δ 148.4, 143.9, 136.6, 135.1, 134.8 (q, J=33.75Hz),
131.5, 129.0, 128.7, 126.3 (q, J=3.63Hz), 122.0 (q,
J=272.5Hz), 119.6, 112.4, 96.9, 92.4, 74.9, 38.0, 24.3,
13.7. HRMS (ESI) calcd for C22H16Cl2F3N+4([M+H]+)
463.0699, found 463.0717.
EXPERIMENTAL
Typical experimental procedure for the palladium-
catalyzed direct alkynylation of phenylpyrazole with terminal
alkynes. 5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-
lH-pyrazole-3-carbonitrile (1) (0.2 mmol), terminal alkyne
(0.4 mmol), [NIS] (0.3 mmol), PdCl2(PPh3)2 (10 mmol%),
CuI (10 mmol%), Cs2CO3 (0.4 mmol), and C2H5OH : H2O
(2:1, 6 mL) were added to a Schlenk tube. Then, the
reaction mixture was stirred at 100°C. After the
5-Amino-4-((4-n-butylphenyl)ethynyl)-1-(2,6-dichloro-4-
(trifluoromethyl)phenyl)-1H-pyrazole-3-carbonitrile (3e).
White
1
solid, mp 171–173°C. H NMR (500MHz, CDCl3) δ 7.77
(s, 2H), 7.42 (d, J=8.0Hz, 2H), 7.15 (d, J=8.0Hz, 2H),
4.18 (s, 2H), 2.61 (t, J= 8.0 Hz, 2H), 1.60–1.57 (m, 2H),
1.36–1.32 (m, 2H), 0.92 (t, J=7.5Hz, 3H); 13C NMR
(125MHz, CDCl3) δ 148.4, 144.1, 136.6, 135.1, 134.8 (q,
Journal of Heterocyclic Chemistry
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The Synthesis of Fipronil Derivatives in Green Solvents
J=34.6Hz), 131.5, 128.9, 128.6, 126.3 (q, J= 3.60 Hz), 122.0
(q, J=272.2Hz), 119.5, 112.4, 96.9, 92.4, 74.9, 35.6, 33.4,
22.3, 13.9. HRMS (ESI) calcd for C23H18Cl2F3N+4([M + H]+)
477.0855, found 477.0873.
(s, 2H), 7.11 (t, J=7.5Hz, 1H), 6.90 (d, J=7.5Hz, 1H),
6.83 (s, 1H), 6.67–6.65 (m, 1H), 4.20 (s, 2H); 13C NMR
(125 MHz, CDCl3) δ 148.5, 146.4, 136.6, 135.0, 134.8
(q, J=36.7Hz), 129.4, 128.9, 126.3 (q, J=3.7Hz), 123.1,
121.9 (q, J=272.1Hz), 121.9, 117.7, 115.8, 112.4, 97.0,
92.2, 75.0. HRMS (ESI) calcd for C19H11Cl2F3N+5([M
+H]+) 436.0338, found 436.0359.
5-Amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-((4-
methoxyphenyl)ethynyl)-1H-pyrazole-3-carbonitrile (3f). White
1
solid, mp 138–140°C. H NMR (500MHz, CDCl3) δ 7.77
5-Amino-4-((3-chlorophenyl)ethynyl)-1-(2,6-dichloro-4-
(trifluoromethyl)phenyl)-1H-pyrazole-3-carbonitrile (3l). White
solid, mp 215–217°C. 1H NMR (500MHz, CDCl3) δ
7.78 (s, 2H), 7.50–7.49 (m, 1H), 7.41–7.39 (m, 1H),
7.33–7.26 (m, 2H), 4.21 (s, 2H); 13C NMR (125MHz,
CDCl3) δ 148.6, 136.6, 134.9 (q, J= 34.3Hz), 134.8,
134.4, 131.3, 129.7, 129.6, 129.1, 129.0, 126.4 (q,
J = 3.6 Hz), 124.1, 121.9 (q, J = 273.8Hz), 112.2, 95.3,
91.5. HRMS (ESI) calcd for C19H9Cl3F3N+4([M + H]+)
454.9839, found 454.9836.
(s, 2H), 7.45 (d, J= 9.0Hz, 2H), 6.88 (d, J= 9.0 Hz, 2H),
4.17 (s, 2H), 3.82 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
160.3, 148.3, 136.8, 135.3, 134.9 (q, J= 34.4Hz), 133.4,
129.3, 126.5 (q, J=3.6 Hz), 122.2 (q, J= 272.3Hz), 114.7,
114.4, 112.7, 96.8, 92.7, 74.4, 55.6. HRMS (ESI) calcd for
C20H12Cl2F3N4O+([M +H]+) 451.0335, found 451.0341.
5-Amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-((4-
fluorophenyl)ethynyl)-1H-pyrazole-3-carbonitrile (3g).
White
1
solid, mp 219–221°C. H NMR (500MHz, CDCl3) δ 7.78
(s, 2H), 7.52–7.48 (m, 2H), 7.06–7.03 (m, 2H), 4.17 (s,
2H); 13C NMR (125 MHz, CDCl3)
δ
162.8 (d,
5-Amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-(hept-
1-yn-1-yl)-1H-pyrazole-3-carbonitrile (3m). White solid, mp
J= 249.0 Hz), 148.5, 136.6, 135.0, 134.8 (q, J=30.3Hz),
133.6 (d, J= 8.1Hz), 129.0, 126.3 (q, J=3.6Hz), 121.9 (q,
J= 272.6 Hz), 118.5 (d, J=3.5Hz), 115.8 (d, J=22.1Hz),
112.4, 95.6, 91.9, 75.4. HRMS (ESI) calcd for
C19H9Cl2F4N+4([M +H]+) 439.0135, found 439.0134.
1
215–217°C. H NMR (500MHz, CDCl3) δ 7.76 (s, 2H),
4.01 (s, 2H), 2.44 (t, J = 7.0 Hz, 2H), 1.63–1.60 (m, 2H),
1.46–4.41 (m, 2H), 1.39–1.33 (m, 2H), 0.91 (t, J =7.5Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 148.3, 136.5,
135.2, 134.7 (q, J = 34.4Hz), 129.1, 126.3 (q, J =3.7 Hz),
121.9 (q, J = 272.3 Hz), 112.5, 98.2, 93.1, 66.9, 31.1,
28.4, 22.2, 19.7, 14.0. HRMS (ESI) calcd for
C18H16Cl2F3N+4([M+ H]+) 415.0699, found 415.0697.
5-Amino-4-((4-chlorophenyl)ethynyl)-1-(2,6-dichloro-4-
(trifluoromethyl)phenyl)-1H-pyrazole-3-carbonitrile (3h). White
1
solid, mp 221–223°C. H NMR (500MHz, CDCl3) δ 7.78
(s, 2H), 7.44 (d, J= 9.0 Hz, 2H), 7.32 (d, J=9.0Hz, 2H) 4.20
(s, 2H); 13C NMR (125MHz, CDCl3) δ 148.5, 136.6, 134.9
(q, J= 34.5 Hz), 134.9, 133.7, 132.7, 129.0, 128.9, 128.8,
126.4 (q, J=3.6Hz), 121.9 (q, J=272.2Hz), 120.9, 112.3,
95.6, 91.7. HRMS (ESI) calcd for C19H9Cl3F3N+4([M + H]+)
454.9839, found 454.9857.
Acknowledgments. The authors thank the National Natural
Science Foundation of China (21302144).
5-Amino-4-((4-bromophenyl)ethynyl)-1-(2,6-dichloro-4-
REFERENCES AND NOTES
(trifluoromethyl)phenyl)-1H-pyrazole-3-carbonitrile (3i).
White
1
[1] Akbas, E.; Berber, I.; Sener, A.; Hasanov, B. IL Farmaco
2005, 60, 23.
[2] Kasimogullari, R.; Bulbul, M.; Arslan, B. S.; Gokce, B. Eur J
Med Chem 2010, 45, 4769.
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Nogueras, M.; Sanchez, A.; Cobo, J. Bioorg Med Chem 2010, 18, 4965.
[4] Moon, M. W.; Bell, L. T.; Cutting, T. L.; Keyser, H. R.;
Tiller, R. H.; Vostral, H. J. J Agric Food Chem 1977, 25, 1039.
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Hara, T.; Yamaoka, M.; Kanzaki, N.; Hasuoka, A.; Baba, A.; Ito, M.
Bioorg Med Chem 2012, 20, 2338.
[7] Meegalla, S. K.; Doller, D.; Liu, R.; Sha, D. Y.; Lee, Y.;
Soll, R. M.; Wisnewski, N.; Silver, G. M.; Dhanoa, D. Bioorg Med Chem
Lett 2006, 16, 1702.
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1998, 57, 195.
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Lydy, M. J Chemosphere 2009, 77, 22.
solid, mp 191–193°C. H NMR (500 MHz, CD3COCD3)
δ 8.10 (s, 2H), 7.64–7.62 (m, 2H), 7.53–7.51 (m, 2H),
6.57 (s, 2H); 13C NMR (125 MHz, CD3COCD3) δ 152.3,
137.4, 136.5, 134.8 (q, J =33.8 Hz), 133.8, 132.6, 128.9,
127.4 (q, J = 3.4 Hz), 123.3 (q, J =272.1 Hz), 123.2,
122.9, 111.6, 95.2, 89.1, 79.1. HRMS (ESI) calcd for
C19H9BrCl2F3N+4([M +H]+) 498.9334, found 498.9363.
5-Amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-(m-
tolylethynyl)-1H-pyrazole-3-carbonitrile (3j).
White solid,
1
mp 219–220°C. H NMR (500 MHz, CDCl3) δ 7.78 (s,
2H), 7.35–7.31 (m, 2H), 7.23–7.22 (m, 1H), 7.16–7.15
(m, 1H), 4.18 (s, 2H), 2.34 (s, 3H); 13C NMR (125MHz,
CDCl3)
δ 148.5, 138.2, 136.6, 135.0, 134.8 (q,
J =34.4 Hz), 132.1, 129.7, 128.9, 128.6, 128.4, 126.3
(q, J =3.6 Hz), 122.2, 121.9 (q, J = 272.3Hz), 112.4,
96.9, 92.6, 75.3, 21.2. HRMS (ESI) calcd for
C20H12Cl2F3N+4([M + H]+) 435.0386, found 435.0401.
5-Amino-4-((3-aminophenyl)ethynyl)-1-(2,6-dichloro-4-
(trifluoromethyl)phenyl)-1H-pyrazole-3-carbonitrile (3k). White
[11] Wu, T. T. US Patent 5,814,652, 1998; Chem Abstr 1998,
129, 256473.
[12] Sammelson, R. E.; Caboni, P.; Durkin, K. A.; Casida, J. E.
Bioorg Med Chem 2004, 12, 3345.
1
solid, mp 119–121°C. H NMR (500MHz, CDCl3) δ 7.77
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S.-Q. Chen and X.-H. Zhang
Vol 000
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet