Efficient Domino Strategy for the Synthesis of Substituted Bipyrazole Derivatives

Article abstract of DOI:10.1002/jhet.3096

An efficient domino strategy for the synthesis of bipyrazole derivatives has been established successfully using Y(OTf)₃ as catalyst. This new reaction allows direct formation of highly functionalized bipyrazole derivatives with a wide diversity in substituents in a one-pot manner. The present synthesis shows attractive characteristics, such as the use of water as reaction media, simple one-pot operation, highly efficient catalyst, and mild reaction conditions.

Full text of DOI:10.1002/jhet.3096

Month 2018
Efficient Domino Strategy for the Synthesis of Substituted
Bipyrazole Derivatives
*
*
and Chunmei Li
Xi Zhang, Kai Long, Jiayi He, Jialian Fu, Furen Zhang,
School of Chemistry and Chemical Engineering, Zhejiang Key Laboratory of Alternative Technologies for Fine Chemicals
Process, Shaoxing University, Shaoxing, Zhejiang Province 312000, China
*
E-mail: frzhang@usx.edu.cn; lchm@usx.edu.cn
Received August 29, 2017
DOI 10.1002/jhet.3096
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
An efficient domino strategy for the synthesis of bipyrazole derivatives has been established successfully
using Y(OTf)3 as catalyst. This new reaction allows direct formation of highly functionalized bipyrazole de-
rivatives with a wide diversity in substituents in a one-pot manner. The present synthesis shows attractive
characteristics, such as the use of water as reaction media, simple one-pot operation, highly efficient catalyst,
and mild reaction conditions.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
attention. A diversity of pyrazole and bipyrazole
derivatives has been synthesized using different starting
materials by various methods [19–23].
In recent years, assembly of molecular diversity from
easily available starting materials with regard to
environmental and economic aspects constitutes a great
challenge in modern organic synthesis chemistry. Then,
the multicomponent domino reaction for the synthesis of
biologically and pharmacologically important active
molecules has become useful tools because of their
efficiency and green chemistry characteristic [1–4]. These
reactions avoid time-consuming and costly processes for
separation and purification of precursors and tedious steps
of protection procedures [5–8]. Therefore, the
development of new domino reactions for diversity of
active molecules is a continuing challenge for modern
organic synthesis.
Heterocycles containing pyrazole rings belong to
important building blocks because of their diversity of
biological and pharmacological activities [9]. These
compounds show anxiolytic [10], cholesterol formation-
inhibiting compounds [11], treatment of Alzheimer’s
disease, anorexia nervosa, drug and alcohol withdrawal
symptoms, drug addiction, and infertility activities [12].
In addition, they have also been reported as potent and
selective inhibitors of A1 adenosine receptor [13],
inhibitors in immune and inflammatory cells [14], and
kinase inhibitors as anti-inflammatory drugs [15].
Because of the important biological activities of them,
these compounds have distinguished themselves as
heterocycles of profound chemical and biological
significance [16–18]. Thus, the development of new
strategy for these compounds has attracted considerable
In recent years, our group has developed a series of
multicomponent domino reaction that can provide a lot of
multi-functionalized heterocyclic structures with chemical
and pharmaceutical interest [24]. Recently, Puchala and
co-workers have reported a microwave-assisted reaction
between 1H-pyrazol-5-amines and aldehydes affording
structurally diverse pyrazole and dipyrazole derivatives
(Scheme 1, eq 1) [25]. However, a new compound was
obtained when the 1H-pyrazol-5-amines, aldehydes, and
cyclohexanone were submitted to reaction system [24b].
As a continuation of our research, in this manuscript, we
would like to report a new chemistry approach for
bipyrazole derivatives that may be of potential chemical
and biomedical activities (Scheme 1, eq 2). This reaction
was carried out by mixing 1H-pyrazol-5-amines and
aldehydes in aqueous phase using Lewis acid Y(OTf)3 as
catalyst at 80°C.
RESULTS AND DISCUSSION
An appropriate catalyst is of crucial importance in
successful organic transformations. First of all, we started
this methodology by mixing 3-methyl-1-phenyl-1H-
pyrazol-5-amine and benzaldehyde for goal product 3a as
model reaction with different catalysts (Scheme 2). The
results were summarized in Table 1. As shown in Table 1,
none of the product 3a was given without any catalysts.
Good yields (77–85%) of goal product 3a was obtained,
© 2018 Wiley Periodicals, Inc.

X. Zhang, K. Long, J. He, J. Fu, F. Zhang, and C. Li
Vol 000
Scheme 1. The reaction of 1H-pyrazol-5-amine and aldehydes.
when Lewis acids, such as Sc(OTf)3, Y(OTf)3, and
Yb(OTf)3 were chosen to catalyze the model reaction,
respectively. However, Brønsted acids, such as TsOH,
TFA, HOAc, and H2SO4 only exhibited poor activities
and gave 18–31% of goal product. The alkali catalysts
Et3N and pyridine did not show any activities.
Considering the cost and catalytic activity, the Y(OTf)3
was chosen to catalyze the following reactions.
Subsequently, the model reaction was repeated many
times with different amount of catalyst loading. The
results indicated Y(OTf)3 (5 mol%) was enough to push
the reaction forward successfully.
The use of water as reaction media allowed the direct
conversion of model substrates into the corresponding
product 3a in a chemical yield of 80% (Table 1, entry
12). Other organic solvents, such as ethanol,
chloroform, acetonitrile, tetrahydrofuran, and toluene
gave much lower yields of 19–76% (Table 1 entries
14–18). Then, the examination of the reaction
temperature led to a regulation that the model reaction
proceeded more smoothly at an elevated temperature
because the model reaction became much faster when
the temperature was increased from 20°C to 80°C
(Table 1, entries 12, 19–21). However, no significant
improvement in yield was obtained, when further
increased the temperature to 100°C. Therefore, 80°C
was chosen as the reaction temperature for all the
further studies.
Scheme 2. The model reaction for the synthesis of compound 3a.
With the optimized reaction condition in hand, we
next set out to explore its scope using various readily
available starting materials (Scheme 3). The reaction of
Table 1
Reaction conditions for the synthesis of model goal product 3a.a
various
aromatic
aldehydes
bearing
different
substituents were submitted to water with 3-methyl-1-
phenyl-1H-pyrazol-5-amine for a given time under the
conditions described above, respectively. The results
are summarized in Table 2. Obviously, not only
aromatic aldehydes 1b–1c (Table 2, entries 2–3), which
possess electron-donating substituents, such as methyl
and methoxy groups at the para position of the
benzene ring but also 1d–1j (Table 2, entries 4–10)
having electron-withdrawing substituents, such as
fluoro, chloro, bromo, trifluoromethyl, and nitro groups
produced the corresponding bipyrazole derivatives in
Entry
Catalyst (mg)
Solvent
T (°C)
Yield (%)b
1
2
3
4
5
6
7
8
–
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
EtOH
CHCl3
CH3CN
THF
Toluene
H2O
80
80
80
80
80
80
80
80
80
80
80
80
80
reflux
reflux
80
reflux
80
0
85
82
77
25
18
31
21
0
Sc(OTf)3 (10)
Y(OTf)3 (10)
Yb(OTf)3 (10)
TsOH (10)
TFA (10)
HOAc (10)
H2SO4 (10)
Et3N (10)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Pyridine (10)
Y(OTf)3 (20)
Y(OTf)3 (5)
Y(OTf)3 (3)
Y(OTf)3 (5)
Y(OTf)3 (5)
Y(OTf)3 (5)
Y(OTf)3 (5)
Y(OTf)3 (5)
Y(OTf)3 (5)
Y(OTf)3 (5)
Y(OTf)3 (5)
Y(OTf)3 (5)
0
83
80
67
76
25
35
30
19
0
Scheme 3. Synthesis of bipyrazole derivatives 3.
20
40
60
100
H2O
H2O
H2O
<10
41
82
aReaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), Y(OTf)3 (X mol%),
and solvent (3.0 mL) in the sealed tube in 4 h.
bIsolated yields.
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The Synthesis of Substituted Bipyrazole Derivatives
Table 2
Domino synthesis of multi-substituted bipyrazole derivatives 3.a
fact, all cases can be finished within 6 h. The results
exhibit the scope and generality of the novel
multicomponent domino reaction with respect to a
range of aromatic aldehyde substrates.
On the basis of literature reports [21e, 22a, d] and our
experimental results, a possible mechanism for the
formation of compound 3 was proposed and is depicted
in Scheme 4. The competing reaction between 3-methyl-
1-phenyl-1H-pyrazol-5-amine 1 and aldehyde occurs to
generate intermediate A, which favors the following
coordination and reaction in the presence of Y(OTf)3.
Intermediate A then smoothly reacted with another
Entry
3
Ar
Time
Yield (%)b
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
C6H5
4
4
4
4
4
4
6
6
6
6
6
6
80
77
81
76
79
72
69
67
69
61
67
76
4-MeC6H4
4-OMeC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-CF3C6H4
4-NO2C6H4
2,4-Cl2C6H3
2,6-Cl2C6H3
1-Naphthyl
2-Thienyl
9
10
11
12
3j
3k
3l
3-methyl-1-phenyl-1H-pyrazol-5-amine
1
to yield
intermediate B. Subsequently, the intermediate
B
aReaction conditions: 1a (1.0 mmol), 2 (1.0 mmol), Y(OTf)3 (5 mol%),
and water (3.0 mL) in the sealed tube in 4–6 h.
bIsolated yields.
condensed with redundant aldehyde and gave desired
product 3.
In view of these results, we then turned our attention
to investigate other substrates. To study the scope of
this methodology, isatin (4) was submitted to react with
3-methyl-1-phenyl-1H-pyrazol-5-amine (1) under the
same conditions. Unfortunately, the corresponding goal
product (5) was not obtained under similar reaction
conditions, probably because of the low reactivity or
large steric hindrance of isatin [21e]. Then, to further
explore the possibility of the multicomponent domino
reaction, we used 1,3-dimethyl-1H-pyrazol-5-amine to
good to high yields. We also noted that the aromatic
aldehydes
bearing
electron-donating
substituents
showed higher activities and gave higher yields than
those bearing electron-withdrawing groups. The
substituents on the ortho-position of the ring of the
aromatic aldehydes hampered the reaction process and
gave slightly low yields of goal products. The 2,6-
dichlorobenzaldehyde only gave 61% yields of goal
product (Table 2, entry 10). Particularly noteworthy
was the fact that the bulky aromatic aldehyde, such as
1-naphthaldehyde and less reactive heterocyclic
aldehyde, such as thiophene-2-carbaldehyde, also
exhibited good reactivity and gave corresponding
products with 67% and 76% yields, respectively. In all
cases, the reaction occurred at a very fast speed; in
replace
3-methyl-1-phenyl-1H-pyrazol-5-amine
to
investigate the possibility of the domino reaction. As
anticipated, 3-(5-amino-1,3-dimethyl-1H-pyrazol-4-yl)-3-
hydroxyindolin-2-one was obtained instead of domino
product. Then, 3-(5-amino-1,3-dimethyl-1H-pyrazol-4-
yl)-3-hydroxyindolin-2-one derivatives bearing different
substituents were obtained with different yields
(Scheme 5).
Scheme 4. Proposed mechanism for the synthesis of products 3.
Journal of Heterocyclic Chemistry
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X. Zhang, K. Long, J. He, J. Fu, F. Zhang, and C. Li
Vol 000
Scheme 5. The synthesis of 3-(5-amino-3-methyl-1H-pyrazol-4-yl)-3-hydroxyindolin-2-one 6.
CONCLUSIONS
relative to TMS as the internal reference, with coupling
constants (J) in Hz. 13C–NMR spectra were recorded at
100 MHz. Chemical shift were reported in ppm with the
internal chloroform signal at 77.0 ppm at as a standard.
Elemental analysis was carried out on EuroEA elemental
analyzer.
In conclusion, we have discovered a novel domino
reaction for the synthesis of bipyrazole derivatives by
varying the substituents on the ring of aromatic
aldehydes. The mild conditions, the maximum efficiency
of a process, and short reaction periods as well as
operational simplicity are clearly represented in this one-
pot transformation that provides an elegant methodology
for the synthesis of highly functionalized bipyrazole
derivatives. The reactions were conducted in water using
readily available and inexpensive substrates. Further
investigations are in progress in our laboratory to
evaluate the process with a broader range of substrates
and to synthesize closely related natural-like products and
test their biological activity.
General procedure for the synthesis of bipyrazole
derivatives 3a–3l.
3-methyl-1-phenyl-1H-pyrazol-5-
amine (1, 1.0 mmol), aromatic aldehyde (2, 1.0 mmol),
Y(OTf)3 (0.05 mmol), and water (3.0 mL) were mixed
and heated at 80°C for 4–6 h. When the reaction was
finished indicated by TLC monitoring, the reaction
mixture was cooled to room temperature and exacted
with ethyl acetate (5 mL × 3). The resulting residue was
purified by column chromatography on silica gel with the
eluent (ethyl acetate/petroleum ether = 1:10–1:4) to
afford the pure product. 3a-3l. The compounds were
characterized using spectroscopic techniques (1H–NMR,
13C NMR, and elemental analyzer).
EXPERIMENTAL
(E)-4-((5-(benzylideneamino)-3-methyl-1-phenyl-1H-
pyrazol-4-yl)(phenyl)methyl)-3-methyl-1-phenyl-1H-pyrazol-5-
amine (3a). Yellow plates. Mp 123–124°C. IR (KBr) ν:
General. Analytical thin layer chromatography (TLC)
was performed using Merck silica gel GF254 plates. Flash
column chromatography was performed on silica gel
(300–400 mesh). Melting points were measured on an
X-4 melting point apparatus. 1H–NMR spectra were
recorded on a 400 MHz instrument (Bruker Avance 400
Spectrometer). Chemical shifts (δ) are given in ppm
3446, 3360, 2961, 2921, 1716, 1617, 1594, 1490, 1341,
1017, 758, 693 cmÀ1 1H–NMR (400 MHz, CDCl3, δ
.
ppm): 8.02 (s, 1H, NH), 7.65 (d, 2H, J = 7.2 Hz, ArH),
7.53 (d, 2H, J = 7.2 Hz, ArH), 7.36–7.40 (m, 11H, ArH),
7.30–7.35 (m, 5H, ArH), 5.21 (s, 1H, CH), 3.35 (br, s,
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Month 2018
The Synthesis of Substituted Bipyrazole Derivatives
2H, NH2), 2.05 (s, 3H, CH3), 1.98 (s, 3H, CH3). 13C–NMR
(100 MHz, CDCl3, δ ppm): 162.5, 148.4, 147.5, 146.4,
142.7, 139.5, 138.4, 131.1, 131.0, 129.9, 130.1, 129.4,
128.6, 127.3, 126.1, 123.9, 123.6, 116.2, 116.1, 115.6,
115.4, 108.7, 101.5, 13.6, 12.5. Anal. Calcd for
C34H30N6 (522.66): C 78.13, H 5.79, N 16.08; Found: C
(E)-4-((5-((4-chlorobenzylidene)amino)-3-methyl-1-phenyl-
1H-pyrazol-4-yl)(4-chlorophenyl)methyl)-3-methyl-1-phenyl-
1H-pyrazol-5-amine (3e). Yellow needles. Mp 94–95°C.
IR (KBr) ν: 3442, 3367, 3135, 2961, 2922, 1716, 1619,
1595, 1491, 1399, 1088, 1015, 816, 757, 693 cmÀ1
.
1H–NMR (400 MHz, CDCl3, δ ppm): 7.96 (s, 1H, NH),
7.61 (d, 2H, J = 8.0 Hz, ArH), 7.52 (d, 2H, J = 8.4 Hz,
ArH), 7.37–7.45 (m, 8H, ArH), 7.25–7.30 (m, 6H, ArH),
5.23 (s, 1H, CH), 3.50 (br, s, 2H, NH2), 2.06 (s, 3H,
CH3), 2.02 (s, 3H, CH3). 13C–NMR (100 MHz, CDCl3, δ
ppm): 162.2, 148.5, 147.9, 146.8, 142.8, 139.4, 138.3,
131.1, 131.2, 130.1, 130.1, 129.4, 128.8, 127.3, 126.2,
123.9, 123.5, 116.2, 116.1, 115.5, 115.4, 108.8, 101.5,
13.5, 12.6. Anal. Calcd for C34H28Cl2N6 (591.54): C
77.89, H 5.47, N 15.87.
(E)-3-methyl-4-((3-methyl-5-((4-methylbenzylidene)amino)-
1-phenyl-1H-pyrazol-4-yl)(p-tolyl)methyl)-1-phenyl-1H-
pyrazol-5-amine (3b). Yellow powder. Mp 95–96°C. IR
(KBr) ν: 3448, 3365, 2962, 2921, 1717, 1619, 1594,
1
1491, 1341, 1089, 1015, 816, 759, 693 cmÀ1. H–NMR
(400 MHz, CDCl3, δ ppm): 8.01 (s, 1H, NH), 7.67
(d, 2H, J = 8.4 Hz, ArH), 7.52 (d, 2H, J = 8.0 Hz, ArH),
7.37–7.40 (m, 5H, ArH), 7.13–7.24 (m, 6H, ArH), 5.22
(s, 1H, CH), 3.33 (br, s, 2H, NH2), 2.39 (s, 3H, CH3),
2.32 (s, 3H, CH3), 2.07 (s, 3H, CH3), 1.99 (s, 3H, CH3).
13C–NMR (100 MHz, CDCl3, δ ppm): 162.8, 148.5,
147.6, 146.8, 142.8, 139.5, 138.3, 131.1, 131.0, 130.1,
130.1, 129.5, 128.8, 127.4, 126.2, 123.9, 123.6, 116.2,
116.1, 115.5, 115.4, 108.8, 101.6, 15.3, 14.9, 13.5, 12.6.
Anal. Calcd for C36H34N6 (550.71): C 78.52, H 6.22, N
69.04, H 4.77, N 14.21; Found: C 68.78, H 4.59, N 13.95.
(E)-4-((5-((4-bromobenzylidene)amino)-3-methyl-1-phenyl-
1H-pyrazol-4-yl)(4-bromophenyl)methyl)-3-methyl-1-phenyl-
1H-pyrazol-5-amine (3f). Yellow needles. Mp 110–112°C.
IR (KBr) ν: 3444, 3366, 3135, 2961, 2920, 1716, 1619,
1594, 1492, 1341, 1085, 1015, 818, 758, 693 cmÀ1
.
1H–NMR (400 MHz, CDCl3, δ ppm): 7.94 (s, 1H, NH),
7.60 (d, 2H, 8.0 Hz, ArH), 7.52 (d, 2H,
J
=
J = 8.4 Hz, ArH), 7.32–7.46 (m, 11H, ArH), 7.25–7.30
(m, 1H, ArH), 7.19 (d, 2H, J = 8.4 Hz, ArH), 5.21
(s, 1H, CH), 3.50 (br, s, 2H, NH2), 2.06 (s, 3H, CH3),
2.02 (s, 3H, CH3). 13C–NMR (100 MHz, CDCl3, δ ppm):
162.7, 148.8, 147.9, 146.9, 142.6, 139.4, 138.4, 131.0,
130.9, 130.1, 130.1, 129.3, 128.7, 127.1, 126.5, 123.9,
123.3, 116.3, 116.1, 115.7, 115.4, 108.7, 101.6, 13.6,
12.7. Anal. Calcd for C34H28Br2N6 (680.45): C 60.02,
15.26; Found: C 78.86, H 5.99, N 15.50.
(E)-4-((5-((4-methoxybenzylidene)amino)-3-methyl-1-
phenyl-1H-pyrazol-4-yl)(4-methoxyphenyl)methyl)-3-methyl-1-
phenyl-1H-pyrazol-5-amine (3c).
Yellow powder. Mp
92–94°C. IR (KBr) ν: 3445, 3363, 3132, 2961, 2923,
1716, 1619, 1595, 1492, 1087, 1016, 812, 756,
1
693 cmÀ1. H–NMR (400 MHz, CDCl3, δ ppm): 7.97
(s, 1H, NH), 7.67 (d, 2H, J = 8.0 Hz, ArH), 7.57 (d, 2H,
J = 8.4 Hz, ArH), 7.36–7.40 (m, 6H, ArH), 7.23–7.28
(m, 2H, ArH), 6.86–6.90 (m, 4H, ArH), 5.20 (s, 1H,
CH), 3.84 (s, 3H, OMe), 3.79 (s, 3H, OMe), 3.39 (br, s,
2H, NH2), 2.06 (s, 3H, CH3), 1.99 (s, 3H, CH3).
13C–NMR (100 MHz, CDCl3, δ ppm): 163.2, 148.8,
147.7, 146.9, 142.8, 139.4, 138.5, 131.0, 130.7, 130.3,
130.0, 129.4, 128.8, 127.1, 126.4, 123.9, 123.5, 116.2,
116.1, 115.7, 109.1, 101.5, 53.4, 52.8, 13.5, 12.7. Anal.
Calcd for C36H34N6O2 (582.71): C 74.20, H 5.88, N
H 4.15, N 12.35; Found: C 59.85, H 3.97, N 12.55.
(E)-3-methyl-4-((3-methyl-1-phenyl-5-((4-(trifluoromethyl)
benzylidene)amino)-1H-pyrazol-4-yl)(4-(trifluoromethyl)
phenyl)methyl)-1-phenyl-1H-pyrazol-5-amine (3g).
Yellow
powder. Mp 107–108°C. IR (KBr) ν: 3447, 3367, 3133,
2962, 2920, 1716, 1619, 1595, 1493, 1341, 1086, 1015,
1
755, 692 cmÀ1. H–NMR (400 MHz, CDCl3, δ ppm):
8.02 (s, 1H, NH), 7.56–7.66 (m, 8H, ArH), 7.28–7.46
(m, 10H, ArH), 5.36 (s, 1H, CH), 3.60 (br, s, 2H, NH2),
2.10 (s, 3H, CH3), 2.07 (s, 3H, CH3). 13C–NMR
(100 MHz, CDCl3, δ ppm): 162.8, 148.8, 147.8, 146.9,
142.7, 139.4, 138.4, 131.0, 130.8, 130.1, 139.9, 129.4,
128.7, 127.1, 126.5, 123.9, 123.4, 116.1, 116.0, 115.6,
115.4, 109.1, 101.5, 13.6, 12.7. Anal. Calcd for
C36H28F6N6 (658.65): C 65.65, H 4.29, N 12.76; Found:
C 65.81, H 4.00, N 12.93.
14.42; Found: C 73.88, H 6.01, N 14.23.
(E)-4-((5-((4-fluorobenzylidene)amino)-3-methyl-1-phenyl-
1H-pyrazol-4-yl)(4-fluorophenyl)methyl)-3-methyl-1-phenyl-
1H-pyrazol-5-amine (3d). Yellow needles. Mp 126–127°C.
IR (KBr) ν: 3446, 3365, 3135, 2962, 2921, 1719, 1618,
1595, 1492, 1399, 1087, 1013, 818, 750, 693 cmÀ1
.
1H–NMR (400 MHz, CDCl3, δ ppm): 7.99 (s, 1H, NH),
7.59–7.64 (m, 4H, ArH), 7.38–7.42 (m, 4H, ArH),
7.00–7.09 (m, 4H, ArH), 5.24 (s, 1H, CH), 3.50 (br, s,
2H, NH2), 2.05 (s, 3H, CH3), 2.02 (s, 3H, CH3).
13C–NMR (100 MHz, CDCl3, δ ppm): 162.8, 148.7,
147.9, 146.9, 142.8, 139.4, 138.4, 131.0, 130.9, 130.1,
130.0, 129.4, 128.8, 127.1, 126.4, 123.9, 123.4, 116.2,
116.0, 115.6, 115.4, 108.9, 101.6, 13.5, 12.7. Anal. Calcd
for C34H28F2N6 (558.64): C 73.10, H 5.05, N 15.04;
Found: C 72.87, H 4.87, N 15.30.
(E)-3-methyl-4-((3-methyl-5-((4-nitrobenzylidene)amino)-1-
phenyl-1H-pyrazol-4-yl)(4-nitrophenyl)methyl)-1-phenyl-1H-
pyrazol-5-amine (3h). Yellow powder. Mp 150–152°C.
IR (KBr) ν: 3447, 3364, 3135, 2961, 1716, 1621,
1594, 1494, 1086, 1011, 820, 758, 692 cmÀ1
.
1H–NMR (400 MHz, CDCl3, δ ppm): 8.17–8.22 (m, 4H,
ArH), 8.10 (s, 1H, NH), 7.71 (d, 2H, J = 8.4 Hz,
ArH), 7.56 (d, 2H, J = 8.0 Hz, ArH), 7.49 (d, 2H,
J = 8.4 Hz, ArH), 7.41–7.46 (m, 6H, ArH), 7.33–7.36
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X. Zhang, K. Long, J. He, J. Fu, F. Zhang, and C. Li
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(m, 2H, ArH), 5.38 (s, 1H, CH), 3.68 (br, s, 2H, NH2), 2.07
(s, 3H, CH3), 2.04 (s, 3H, CH3). 13C–NMR (100 MHz,
CDCl3, δ ppm): 174.7, 161.2, 160.3, 150.2, 150.0, 149.4,
146.7, 142.9, 139.0, 129.6, 129.4, 129.1, 127.5, 127.2,
124.1, 123.9, 101.6, 13.6, 12.8. Anal. Calcd for
C34H28N8O4 (612.65): C 66.66, H 4.61, N 18.29; Found:
C 66.83, H 4.80, N 17.96.
(E)-4-((5-((2,4-dichlorobenzylidene)amino)-3-methyl-1-
phenyl-1H-pyrazol-4-yl)(2,4-dichlorophenyl)methyl)-3-methyl-
(E)-3-methyl-4-((3-methyl-1-phenyl-5-((thiophen-2-
ylmethylene)amino)-1H-pyrazol-4-yl)(thiophen-2-yl)methyl)-1-
phenyl-1H-pyrazol-5-amine (3l).
Brown powder. Mp
140–142°C. IR (KBr) ν: 3449, 3364, 3135, 2961, 2922,
1598, 1498, 1403, 1259, 1074, 1044, 809, 760, 692 cmÀ1
.
1H–NMR (400 MHz, CDCl3, δ ppm): 8.16 (s, 1H, NH),
7.60 (d, 2H, J = 8.0 Hz, ArH), 7.52 (d, 2H, J = 4.8 Hz,
ArH), 7.38–7.43 (m, 6H, ArH), 7.25–7.31 (m, 2H, ArH),
7.22 (d, 2H, J = 6.0 Hz, ArH), 7.06 (t, 1H, J = 4.4 Hz,
ArH), 6.93–6.96 (m, 2H, ArH), 5.46 (s, 1H, CH), 3.65
(br, s, 2H, NH2), 2.18 (s, 3H, CH3), 2.08 (s, 3H, CH3).
13C–NMR (100 MHz, CDCl3, δ ppm): 156.8, 149.3,
149.0, 146.8, 145.3, 144.2, 133.6, 131.8, 129.4, 128.8,
128.1, 127.0, 126.3, 124.8, 124.0, 123.4, 106.7, 105.2,
103.2, 13.3, 12.6. Anal. Calcd for C30H26N6S2 (534.70):
C 67.39, H 4.90, N 15.72; Found: C 67.66, H 5.21, N 15.98.
General procedure for the synthesis of compound 6a–6d.
3-Methyl-1H-pyrazol-5-amine (1, 1.0 mmol), isatin (4,
1.0 mmol), Y(OTf)3 (0.05 mmol), and water (3.0 mL)
were mixed and heated at 80°C for 4 h. When the
reaction was finished indicated by TLC monitoring,
the reaction mixture was cooled to room temperature.
The solid product was collected by Büchner filtration and
subsequently recrystallized from hot EtOH (95%) to give
1-phenyl-1H-pyrazol-5-amine (3i).
Yellow needles. Mp
126–128°C. IR (KBr) ν: 3445, 3364, 3135, 2961, 1716,
1617, 1593, 1492, 1085, 1018, 814, 761, 693 cmÀ1
.
1H–NMR (400 MHz, CDCl3, δ ppm): 8.44 (s, 1H, NH),
7.86 (d, 1H, J = 8.8 Hz, ArH), 7.56 (d, 2H, J = 8.0 Hz,
ArH), 7.43–7.50 (m, 4H, ArH), 7.44–7.50 (m, 4H, ArH),
7.15 (d, 1H, J = 9.6 Hz, ArH), 5.36 (s, 1H, CH), 3.62
(br, s, 2H, NH2), 2.04 (s, 3H, CH3), 1.99 (s, 3H, CH3).
13C–NMR (100 MHz, CDCl3, δ ppm): 162.9, 148.9,
148.1, 146.8, 142.5, 139.4, 139.2, 138.4, 131.1, 130.9,
130.7, 130.3, 130.1, 129.3, 128.7, 127.2, 126.5, 123.9,
123.5, 116.2, 116.1, 115.8, 115.4, 108.5, 101.4, 13.6,
12.8. Anal. Calcd for C34H26Cl4N6 (660.42): C 61.84, H
3.97, N 12.73; Found: C 61.66, H 4.24, N 12.94.
(E)-4-((5-((2,6-dichlorobenzylidene)amino)-3-methyl-1-
phenyl-1H-pyrazol-4-yl)(2,6-dichlorophenyl)methyl)-3-methyl-
the pure product 6.
3-(5-Amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)-3-
hydroxyindolin-2-one (6a). Yellow powder. Mp 234–236°C.
1-phenyl-1H-pyrazol-5-amine (3j).
Yellow powder. Mp
104–105°C. IR (KBr) ν: 3446, 3365, 3135, 2923, 1716,
1619, 1597, 1492, 1086, 1013, 818, 755, 692 cmÀ1
.
IR (KBr) ν: 3440, 3364, 3138, 2832, 1714, 1619, 1515,
1H–NMR (400 MHz, CDCl3, δ ppm): 8.53 (s, 1H, NH),
7.69–7.71 (m, 2H, ArH), 7.38–7.63 (m, 6H, ArH),
7.14–7.33 (m, 10H, ArH), 6.05 (s, 1H, CH), 3.60 (br, s,
2H, NH2), 2.03 (s, 3H, CH3), 1.93 (s, 3H, CH3).
13C–NMR (100 MHz, CDCl3, δ ppm): 164.0, 149.3,
148.5, 146.8, 142.5, 141.2, 139.5, 139.2, 138.6, 131.2,
130.9, 130.6, 130.4, 130.1, 129.3, 128.7, 127.2, 126.5,
123.9, 123.2, 116.0, 116.1, 115.9, 115.2, 108.1, 101.6,
13.6, 12.6. Anal. Calcd for C34H26Cl4N6 (660.42): C
1
1385, 1188, 1115, 1051, 934, 745, 693 cmÀ1. H–NMR
(400 MHz, DMSO-d6, δ ppm): 10.42 (s, 1H, NH), 7.56
(d, 2H, J = 8.0 Hz, ArH), 7.46 (t, 2H, J = 7.6 Hz, ArH),
7.23–7.31 (m, 3H, ArH), 6.98 (t, 1H, J = 7.2 Hz, ArH),
7.46 (d, 1H, J = 7.6 Hz, ArH), 5.30 (br, s, 1H, NH2),
1.44 (s, 3H, CH3). Anal. Calcd for C18H16N4O2 (320.35):
C 67.49, H 5.03, N 17.49; Found: C 67.24, H 4.79,
N 17.23.
3-(5-Amino-1,3-dimethyl-1H-pyrazol-4-yl)-3-hydroxyindolin-
2-one (6b).
Light yellow powder. Mp 196–197°C. IR
61.84, H 3.97, N 12.73; Found: C 61.57, H 3.87, N 12.48.
(E)-3-methyl-4-((3-methyl-5-((naphthalen-1-ylmethylene)
amino)-1-phenyl-1H-pyrazol-4-yl)(naphthalen-1-yl)methyl)-1-
(KBr) ν: 3440, 3364, 3138, 2832, 1714, 1619, 1515,
1
1385, 1188, 1115, 1051, 934, 745, 693 cmÀ1. H–NMR
phenyl-1H-pyrazol-5-amine (3k).
Yellow powder. Mp
127–128°C. IR (KBr) ν: 3444, 3364, 3135, 2961, 1716,
1617, 1595, 1492, 1342, 1087, 1012, 755, 693 cmÀ1
(400 MHz, DMSO-d6, δ ppm): 10.31 (s, 1H, NH), 7.20
(d, 2H, J = 8.0 Hz, ArH), 6.95 (t, 1H, J = 7.6 Hz, ArH),
6.80 (t, 1H, J = 7.2 Hz, ArH), 6.37 (s, 1H, OH), 5.03 (br,
s, 1H, NH2), 3.41 (s, 3H, NCH3), 1.33 (s, 3H, CH3).
Anal. Calcd for C13H14N4O2 (258.28): C 60.45, H 5.46,
.
1H–NMR (400 MHz, CDCl3, δ ppm): 1H–NMR (400 MHz,
CDCl3, δ ppm): 8.68 (s, 1H, NH), 7.97 (t, 2H, J = 7.6 Hz,
ArH), 7.87 (d, 2H, J = 8.4 Hz, ArH), 7.81 (d, 2H,
J = 8.0 Hz, ArH), 7.38–7.62 (m, 15H, ArH), 7.25–7.37
(m, 1H, ArH), 7.06 (m, 1H, J = 7.6 Hz, ArH), 5.90 (s, 1H,
CH), 3.18 (br, s, 2H, NH2), 2.08 (s, 3H, CH3), 1.97 (s, 3H,
CH3). 13C–NMR (100 MHz, CDCl3, δ ppm): 162.5, 149.0,
148.2, 146.8, 142.6, 139.4, 139.1, 138.5, 131.1, 130.9,
130.6, 130.7, 130.0, 129.3, 128.7, 127.3, 126.6, 123.9,
123.4, 116.2, 116.2, 115.7, 115.4, 108.6, 101.8, 13.6, 12.7.
Anal. Calcd for C42H34N6 (622.78): C 81.00, H 5.50, N
13.49; Found: C 81.35, H 5.25, N 13.72.
N 21.69; Found: C 60.61, H 5.11, N 21.98.
3-(5-Amino-1,3-dimethyl-1H-pyrazol-4-yl)-5-fluoro-3-
hydroxyindolin-2-one (6c).
Light yellow crystal. Mp
195–196°C. IR (KBr) ν: 3445, 3365, 3135, 2830, 1714,
1617, 1515, 1382, 1189, 1116, 1051, 932, 745, 692 cmÀ1
.
1H–NMR (400 MHz, DMSO-d6, δ ppm): 10.32 (s, 1H,
NH), 7.03–7.08 (m, 2H, ArH), 6.81–6.84 (m, 1H, ArH),
6.59 (s, 1H, OH), 5.10 (br, s, 1H, NH2), 3.44 (s, 3H, NCH3),
1.37 (s, 3H, CH3). Anal. Calcd for C13H13FN4O2 (276.27):
C 56.52, H 4.74, N 20.28; Found: C 56.22, H 5.01, N 19.87.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
The Synthesis of Substituted Bipyrazole Derivatives
3-(5-Amino-1,3-dimethyl-1H-pyrazol-4-yl)-5-bromo-3-
hydroxyindolin-2-one (6d).
M.; Lucas, F. S.; Mitchell, C. J.; Neu, M. Y.; Ranshaw, L. E.; Solanke,
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Light yellow powder. Mp
200–202°C. IR (KBr) ν: 3445, 3364, 3138, 2830, 1714,
1619, 1516, 1385, 1184, 1115, 1052, 934, 746, 693 cmÀ1
.
1H–NMR (400 MHz, DMSO-d6, δ ppm): 10.05 (s, 1H,
NH), 7.31 (d, 1H, J = 3.2 Hz, ArH), 7.23 (dd, 1H, J = 2.0,
8.4 Hz, ArH), 6.70 (d, 1H, J = 8.4 Hz, ArH), 6.37 (s, 1H,
OH), 4.76 (br, s, 2H, NH2), 3.45 (s, 3H, NCH3), 1.44
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46.31, H 3.89, N 16.62; Found: C 46.71, H 4.11, N 16.51.
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Acknowledgment. We are grateful for the financial support from
the science and technology innovation program for college
students in Zhejiang province (grant no. 2017R428016). We are
also grateful to Shaoxing University for spiritual support.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet