One-Pot Synthesis of Highly Substituted 1H-Pyrazole-5-carboxylates from 4-Aryl-2,4-diketoesters and Arylhydrazines

Article abstract of DOI:10.1002/jhet.2354

A one-pot synthesis of highly substituted 1H-pyrazole-5-carboxylates 1 has been developed starting from easily available 4-aryl-2,4-diketoesters 2 and arylhydrazine hydrochlorides 3. More active 2-carbonyl group of 2 was blocked with methoxyamine hydrochloride to give 2-methoxy imine intermediates, which were then subjected to condensation cyclization with 3 in situ to provide the desired products 1. In addition, the geometrical configuration of 1aa was unambiguously confirmed by single crystal X-ray crystallography.

Full text of DOI:10.1002/jhet.2354

840
One-Pot Synthesis of Highly Substituted 1H-Pyrazole-5-carboxylates from
Vol 53
4-Aryl-2,4-diketoesters and Arylhydrazines
Jiao-Jiao Zhai, Chun-Hui Gu, Ying Guo, Dao-Hua Liao, Dun-Ru Zhu, and Ya-Fei Ji
a
a
a
a
b
a
*
*
aSchool of Pharmacy, East China University of Science and Technology, Campus P. O. Box 363, 130 Meilong Road,
Shanghai, 200237, China
bState Key Laboratory of Materials-Oriented Chemical Engineering, College of Chemistry and Chemical Engineering,
Nanjing Tech University, Nanjing, 210009, China
*
E-mail: zhudr@njtech.edu.cn; jyf@ecust.edu.cn
Received June 12, 2014
DOI 10.1002/jhet.2354
Published online 17 June 2015 in Wiley Online Library (wileyonlinelibrary.com).
A one-pot synthesis of highly substituted 1H-pyrazole-5-carboxylates 1 has been developed starting from
easily available 4-aryl-2,4-diketoesters 2 and arylhydrazine hydrochlorides 3. More active 2-carbonyl group
of 2 was blocked with methoxyamine hydrochloride to give 2-methoxy imine intermediates, which were
then subjected to condensation cyclization with 3 in situ to provide the desired products 1. In addition, the
geometrical configuration of 1aa was unambiguously confirmed by single crystal X-ray crystallography.
J. Heterocyclic Chem., 53, 840 (2016).
INTRODUCTION
diketoesters was first blocked with methoxyamine hydrochlo-
ride to give the 2-methoxy imine derivatives, and a compelling
in situ attack of arylhydrazines on the 4-carbonyl group,
followed by a cyclization with the elimination of methoxylamine
led to the desired 1H-pyrazole-5-carboxylates.
Pyrazoles are of significant synthetic targets in organic
and pharmaceutical chemistry because of pyrazole motif
generally acting as a core framework in numerous
biologically active compounds [1–3]. In particular,
substituted 1H-pyrazole-3-amidate derivatives have been
well developed as cannabinoid (designated CB1) receptor
antagonists such as Rimonabant [4], SR147778 [5],
CP-272,871 [6], and OMAR [7] (Fig. 1). Structurally,
these CB1 receptor antagonists are characterized by
the ornament of 1H-pyrazole-3-carboxylate framework,
which is usually constructed by regioselective Knorr
reaction of 2,4-diketoesters and hydrazines via a direct
route [1–3]. On the other hand, the isomeric framework-based
1H-pyrazole-5-amidate derivatives have also displayed
important biological activities [8–10] and owned identical
significance as 1H-pyrazole-3-carboxylates in the drug
discovery (Fig. 1). Traditionally, the 1,3-dipolar cycloaddition
method, often suffering from commercially unavailable feed-
stocks and tedious procedures, has undertaken a synthetic
priority to selectively access the 1H-pyrazole-5-carboxylate
framework [8–10]. Therefore, it is still greatly desirable to
develop a concise and facile approach to highly substituted
1H-pyrazole-5-carboxylates.
RESULTS AND DISCUSSION
Inspired by Ashton’s synthesis of a sole 1H-pyrazole-5-
carboxylate compound starting from 2,4-diketoesters [13]
and the related report about amine exchange reaction of en-
amine with another amine resulting in a new enamine [14],
we firstly investigated various amines as 2-carbonyl-
protection reagent to access 1H-pyrazole-5-carboxylates
with freshly prepared ethyl 2,4-dioxo-4-phenylbutanoate
(2a) as a model substrate. As shown in Scheme 1, the
control experiments showed that the carbonyl-protection
reactions of more active 2-carbonyl group with various
amine hydrochlorides (one equivalent) all performed well
giving the 2-imine intermediates. However, only the
methoxy imine intermediate was observed to conduct a
4-carbonyl condensation with phenylhydrazine hydro-
chloride (3a) and a subsequent cyclization with the elim-
ination of methoxyamine, successfully affording the
desired 1H-pyrazole-5-carboxylates 1aa in 72% yield
via this one-pot procedure (feasible route). In contrast,
the 2-imine intermediates derived from methylamine,
ethylamine, aniline and benzylamine hydrochlorides
failed to give 1aa, without the cyclization reaction of their
respective hydrazone-imine intermediate being detected
Continuing our recent work involving the synthesis of
highly substituted 1H-pyrazole-3-carboxylates [11,12],
herein, we reported a viable one-pot approach to highly
substituted 1H-pyrazole-5-carboxylates from easily available
4-aryl-2,4-diketoesters and arylhydrazine hydrochlorides. In
the methodology, more active 2-carbonyl group of 4-aryl-2,4-
© 2015 HeteroCorporation

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One-Pot Synthesis of 1H-Pyrazole-5-carboxylates
841
Figure 1. Structures of biologically active 1H-pyrazole-3-amidate and 1H-pyrazole-5-amidate derivatives.
(infeasible route). In the case of the hydrazone-methoxy
imine intermediate (feasible route), we speculated that
the cyclized intermediate greatly tended to release more
stable salt methoxyamine hydrochloride with an aromati-
zation to drive powerfully the formation of 1aa. Notably,
the geometrical configuration of 1aa was further deter-
mined by single crystal X-ray crystallography. The struc-
tural analysis indicates that 1aa consists of two phenyl rings
and one pyrazole ring (Fig. 2a). These rings do not share a
common plane. The phenyl ring linked with N1 atom and
the phenyl ring attached on C9 atom make dihedral angles
of 55.3(1) and 4.8(1)°, respectively, with the pyrazole ring.
The bond lengths and bond angles in the structure of 1aa
are in the usual ranges and can be comparable with the
related compounds [12,15,16].
As shown in Figure 2b, there are three kinds of face-
to-face π · ·· π interactions in the crystal structure of 1aa.
The first one is formed between two parallel pyrazole rings,
Scheme 1. A carboxyl-protection, compelling condensation and cyclization sequence for one-pot synthesis of 1aa.
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J.-J. Zhai, C.-H. Gu, Y. Guo, D.-H. Liao, D.-R. Zhu, and Y.-F. Ji
Vol 53
Figure 2. (a) Crystal structure of 1aa. (b) View of the crystal packing showing π · · · π interactions in 1aa. [Color figure can be viewed in the online issue,
which is available at wileyonlinelibrary.com.]
the second one between the two parallel phenyl rings linked
with N1 atom and the third one between the two parallel phe-
nyl rings attached on C9 atom. These π ···π interactions link
the molecules of 1aa to form an infinite chain along a axis.
With the one-pot synthesis of 1aa established, we then
tried to prepare a series of fully substituted 1H-pyrazole-
5-carboxylates starting from diverse 4-aryl-2,4-diketoesters
2 and arylhydrazine hydrochlorides 3, using methoxyamine
hydrochloride as a 2-carbonyl-protection reagent (Table 1).
Firstly, 4-aryl-2,4-diketoesters 2b–2g containing different R1
and R2 groups were assessed on the basis of arylhydrazine
hydrochlorides 3a (entries 1–6). Compared with 1aa, the pro-
cedure delivered the products 1ba–1da in slightly low yields
of 65–68% from the 3-methyl-2,4-diketoesters 2b–2d with a
slight steric effect of the methyl group (entries 1–3). By
comparison, 4-bulky group substituted compounds 1ea–1ga
were obtained in lower yields of 47–52% (entries 4–6),
showing an obvious detrimental impact of R2 groups on the
efficiency of the procedure.
Next, arylhydrazine hydrochlorides 3b–3g containing dif-
ferent substituents were evaluated with freshly prepared ethyl
3-methyl-2,4-dioxo-4-phenylbutanoate (2b, entries 7–12).
Varying the number of substituents, the yields of the products
1bb–1bg could change from 47 to 63% (entries 7–12).
Therein, it should be noted that, regardless of the electronic na-
ture of substituents, the ortho,ortho-disubstituted arylhydrazine
hydrochlorides 3d and 3g gave rise to lower yields of 50 and
47%, respectively (entries 9 and 12), indicating a visible steric
influence of R3 groups on the outcomes. Finally, more diverse
1H-pyrazole-5-carboxylates were generally accomplished in
moderate yields of 57–62% from different 2,4-diketoesters
and arylhydrazine hydrochlorides (entries 13–18), further
verifying the feasibility of the one-pot procedure.
in situ attack of arylhydrazine hydrochlorides on less active
4-carbonyl group was steadily implemented. In the end of the
reaction, methoxyamine acts as a responsible leaving group
with aromatization to achieve the desired 1. We believe that
the procedure may promise a potential value in synthetic
chemistry and drug discovery.
EXPERIMENTAL
Unless otherwise indicated, all reagents were obtained from
commercial sources and used as received without further purifica-
tion. 4-Aryl-2,4-diketoesters 2 were freshly prepared from
alkylphenones and diethyl oxalate [11]. All reactions were carried
out in oven-dried glassware and monitored by thin layer chroma-
tography (precoated silica gel plates containing HF254). All
solvents were only dried over 4 Å molecular sieves. Melting
points were determined using an open capillaries and uncorrected.
NMR spectra were determined on Bruker AV400 in CDCl3 with
1
TMS as the internal standard for H NMR (400 MHz) and 13C
NMR (100 MHz), respectively. HRMS were carried out on a
QSTAR Pulsar I LC/TOF MS mass spectrometer and Micromass
GCTTM gas chromatograph-mass spectrometer.
General procedure for the synthesis of highly substituted
1H-pyrazole-5-carboxylates.
Freshly prepared 4-aryl-2,4-
diketoesters (5.0 mmol) was added to
2
a
solution of
methoxyamine hydrochloride (5.0 mmol) in EtOH (15 mL) and
stirred at room temperature for 3 h. To the resulting mixture
were added arylhydrazine hydrochlorides (5.0 mmol) in situ and
stirred at room temperature for 3 h and then refluxed for
additional 10 h. The reaction solution was concentrated in vacuo
to remove EtOH affording a residue, to which were added H2O
(15 mL) and CH2Cl2 (15 mL). The organic layer was separated,
and the aqueous layer was extracted with CH2Cl2 (15 mL × 2).
The combined organic phase was washed with brine (30 mL),
dried over anhydrous sodium sulfate. The crude product was
purified by column chromatography (200–300 mesh silica gel,
petroleum ether/ethyl acetate = 20/1) to give the desired products 1.
In summary, we have developed a one-pot procedure for the
rapid synthesis of highly substituted 1H-pyrazole-5-carboxyl-
ates 1 from easily available 4-aryl-2,4-diketoesters 2 and
arylhydrazine hydrochlorides 3, avoiding the troublesome 1,3-
dipolar cycloaddition method. Using methoxyamine hydro-
chloride as a 2-carbonyl-protection reagent, the compelling
Ethyl 1,3-diphenyl-1H-pyrazole-5-carboxylate (1aa). Pale yellow
solid, 1.05 g (72%), mp 66–68°C. 1H NMR (400 MHz, CDCl3, ppm) δ:
7.89 (d, J= 7.2 Hz, 2H, ArH), 7.50–7.41 (m, 7H, ArH), 7.36 (d,
J= 7.2 Hz, 1H, ArH), 7.33 (s, 1H, ArH), 4.27 (q, J=7.2Hz, 2H, CH2),
1.27 (t, J= 7.2 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3, ppm) δ:
159.14, 151.48, 140.41, 134.71, 132.17, 128.74 (2C), 128.69, 128.59
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Table 1
One-pot synthesis of highly substituted 1H-pyrazole-5-carboxylatesa.
Entry
1
2
3
1
Yieldb
68%
2
67%
3a
3a
3a
3
4
65%
52%
5
48%
3a
6
47%
3a
(Continued)
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Table 1
(Continued)
Entry
2
3
1
Yieldb
7
2b
63%
8
2b
61%
9
2b
50%
10
11
12
2b
2b
2b
60%
57%
47%
(Continued)
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Table 1
(Continued)
Entry
2
3
1
Yieldb
13
14
2c
2c
3b
61%
62%
3e
15
2c
60%
16
2d
3h
61%
17
2d
60%
(Continued)
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Table 1
(Continued)
Entry
2
3
1
Yieldb
18
2d
57%
aThe reaction performed with freshly prepared 4-aryl-2,4-diketoesters 2 (5.0 mmol), methoxyamine hydrochloride (5.0 mmol), arylhydrazine hydrochlo-
rides 3 (5.0 mmol) in EtOH (15 mL).
bIsolated yield.
(2C), 128.39, 126.14 (2C), 125.81 (2C), 109.45, 61.23, 14.06. HRMS
(ESI, m/z): [M + H+] calcd. for C18H17N2O2 293.1290, found 293.1290.
Ethyl 4-methyl-1,3-diphenyl-1H-pyrazole-5-carboxylate (1ba). Pale
7.43 (br s, 5H, ArH), 7.25–7.21 (m, 1H, ArH), 7.20–7.12
(m, 1H, ArH), 4.23 (q, J = 7.2 Hz, 2H, CH2), 2.46 (s, 3H, CH3),
2.40 (s, 3H, CH3), 1.16 (t, J = 6.8 Hz, 3H, CH3).13C NMR
(100 MHz, CDCl3, ppm) δ: 160.28, 151.59, 141.08, 137.79,
131.99, 129.85, 129.19 (2C), 128.57 (2C), 128.19 (3C), 125.83
(2C), 120.79, 60.94, 21.31, 13.89, 10.57. HRMS (ESI, m/z):
[M + H+] calcd. for C20H21N2O2 321.1603, found 321.1607.
Ethyl 4-ethyl-1,3-diphenyl-1H-pyrazole-5-carboxylate (1ea). Pale
yellow solid, 0.83 g (52%), mp 65–67°C. 1H NMR (400 MHz, CDCl3,
ppm) δ: 7.67 (d, J= 7.2 Hz, 2H, ArH), 7.47–7.35 (m, 8H, ArH), 4.24 (q,
J= 7.2 Hz, 2H, CH2), 2.89 (q, J= 7.2 Hz, 2H, CH2), 1.28 (t, J=7.2Hz,
3H, CH3), 1.18 (t, J= 7.2 Hz, 3H, CH2). 13C NMR (100 MHz, CDCl3,
ppm) δ: 160.17, 151.30, 141.08, 132.93, 131.58, 128.59 (2C), 128.52
(2C), 128.33 (2C), 128.23, 128.04, 127.43, 125.76 (2C), 61.00, 17.64,
15.68, 13.82. HRMS (ESI, m/z): [M + H+] calcd. for C20H21N2O2
321.1603, found 321.1604.
Ethyl 1,3-diphenyl-4-propyl-1H-pyrazole-5-carboxylate (1fa). Pale
yellow solid, 0.80 g (48%), mp 85–86°C. 1H NMR (400 MHz,
CDCl3, ppm) δ: 7.65 (d, J= 7.6 Hz, 2H, ArH), 7.49–7.34 (m, 8H,
ArH), 4.23 (q, J= 7.2 Hz, 2H, CH2), 2.83 (t, J= 7.2 Hz, 2H, CH2),
1.70–1.60 (m, 2H, CH2), 1.18 (t, J= 7.2 Hz, 3H, CH3), 0.97 (t,
J=7.2Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3, ppm) δ:
160.24, 151.47, 141.02, 132.98, 131.76, 128.59 (2C), 128.51 (2C),
128.35 (2C), 128.23, 128.02, 125.92, 125.73 (2C), 61.00, 26.30,
1
yellow solid, 1.04 g (68%), mp 68–70°C. H NMR (400 MHz, CDCl3,
ppm) δ: 7.69 (d, J= 7.2 Hz, 2H, ArH), 7.48–7.35 (m, 8H, ArH), 4.24 (q,
J= 7.2 Hz, 2H, CH2), 2.48 (s, 3H, CH3), 1.17 (t, J=7.2Hz, 3H, CH3).13C
NMR (100 MHz, CDCl3, ppm) δ: 160.25, 151.60, 141.08, 132.80, 132.06,
128.58 (2C), 128.49 (2C), 128.31 (2C), 128.24, 127.98, 125.81 (2C),
120.90, 60.97, 13.89, 10.55. HRMS (ESI, m/z): [M + H+] calcd. for
C19H19N2O2 307.1447, found 307.1448.
Ethyl 3-(4-chlorophenyl)-4-methyl-1-phenyl-1H-pyrazole-
5-carboxylate (1ca).
Pale yellow solid, 1.16 g (67%), mp
62–63°C. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.65–7.63 (m,
1H, ArH), 7.62–7.61 (m, 1H, ArH), 7.46–7.44 (m, 1H, ArH),
7.44–7.42 (m, 4H, ArH), 7.42–7.40 (m, 2H, ArH), 4.23 (q,
J = 7.2 Hz, 2H, CH2), 2.46 (s, 3H, CH3), 1.16 (t, J = 7.2 Hz, 3H,
CH3). 13C NMR (100 MHz, CDCl3, ppm) δ: 160.11, 150.43,
140.97, 133.98, 132.25, 131.31, 129.51 (2C), 128.71 (2C),
128.63 (2C), 128.39, 125.77 (2C), 120.80, 61.04, 13.87, 10.52.
HRMS (ESI, m/z): [M + H+] calcd. for C19H18ClN2O2 341.1057,
found 341.1056.
Ethyl 4-methyl-1-phenyl-3-(p-tolyl)-1H-pyrazole-5-carboxylate
(1da).
NMR (400 MHz, CDCl3, ppm) δ: 7.58 (d, J = 7.4 Hz, 2H, ArH),
Pale yellow solid, 1.04 g (65%), mp 92–93°C. 1H
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24.53, 14.26, 13.82. HRMS (ESI, m/z): [M + H+] calcd. for
C21H23N2O2 335.1760, found 335.1760.
Ethyl 1-(2,6-dimethylphenyl)-4-methyl-3-phenyl-1H-pyrazole-
5-carboxylate (1bg). Pale yellow solid, 0.79 g (47%), mp 89–91°C.
1H NMR (400 MHz, CDCl3, ppm) δ: 7.71 (d, J= 7.2 Hz, 2H, ArH),
7.45 (t, J = 7.2 Hz, 2H, ArH), 7.38 (t, J = 7.2 Hz, 1H, ArH),
7.25–7.21 (m, 1H, ArH), 7.12 (d, J = 7.6 Hz, 2H, ArH), 4.15
(q, J = 7.2 Hz, 2H, CH2), 2.54 (s, 3H, CH3), 2.00 (s, 6H, CH3),
1.07 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3,
ppm) δ: 159.74, 151.49, 140.15, 135.82, 133.00, 132.45,
128.82, 128.46 (2C), 128.26 (2C), 127.87 (2C), 127.81 (2C),
119.85, 60.65, 17.38 (2C), 13.74, 10.72. HRMS (ESI, m/z):
[M + H+] calcd. for C21H23N2O2 335.1760, found 335.1760.
Ethyl 1-(3-chlorophenyl)-3-(4-chlorophenyl)-4-methyl-1H-
Ethyl 1,3,4-triphenyl-1H-pyrazole-5-carboxylate (1ga).
Pale
1
yellow solid, 0.87 g (47%), mp 120–122°C. H NMR (400 MHz,
CDCl3, ppm) δ: 7.55 (d, J= 7.6 Hz, 2H, ArH), 7.52–7.44 (m, 5H,
ArH), 7.36 (br s, 5H, ArH), 7.26 (br s, 3H, ArH), 4.06 (q, J=7.2Hz,
2H, CH2), 0.91 (t, J= 7.2 Hz, 3H, CH3). 13C NMR (100MHz,
CDCl3, ppm) δ: 160.01, 150.06, 140.41, 132.49, 132.2, 132.17,
130.38 (2C), 128.71 (2C), 128.33, 128.11 (2C), 128.07 (2C), 127.96
(2C), 127.82, 127.45, 125.27 (2C), 124.97, 61.13, 13.33. HRMS
(ESI, m/z): [M + H+] calcd. for C24H21N2O2 369.1603, found
369.1601.
Ethyl 1-(3-chlorophenyl)-4-methyl-3-phenyl-1H-pyrazole-
pyrazole-5-carboxylate (1cb).
Pale yellow solid, 1.14 g
1
5-carboxylate (1bb).
Pale yellow solid, 1.07 g (63%), mp
(61%), mp 80–82°C. H NMR (400 MHz, CDCl3, ppm) δ: 7.61
(d, J = 7.6 Hz, 2H, ArH), 7.48–7.36 (m, 5H, ArH), 7.34–7.32
(m, 1H, ArH), 4.26 (q, J = 6.8 Hz, 2H, CH2), 2.45 (s, 3H, CH3),
1.21 (t, J = 6.8 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3,
ppm) δ: 159.85, 150.91, 141.82, 134.19, 132.21, 131.03,
129.53, 129.50 (2C), 128.99, 128.78 (2C), 128.47, 126.17,
124.03, 121.42, 61.23, 13.92, 10.53. HRMS (ESI, m/z): [M
+ H+] calcd. for C19H17Cl2N2O2 375.0667, found 375.0667.
Ethyl 3-(4-chlorophenyl)-4-methyl-1-(p-tolyl)-1H-pyrazole-
1
89–91°C. H NMR (400 MHz, CDCl3, ppm) δ: 7.67 (dd, J=8.4,
J= 1.6 Hz, 2H, ArH), 7.49–7.40 (m, 3H, ArH), 7.40–7.38 (m, 3H,
ArH), 7.34–7.31 (m, 1H, ArH), 4.27 (q, J= 7.2 Hz, 2H, CH2), 2.47
(s, 3H, CH3), 1.21 (t, J= 7.2 Hz, 3H, CH3). 13C NMR (100 MHz,
CDCl3, ppm) δ: 160.01, 152.20, 141.95, 134.14, 132.53, 132.03,
129.49, 128.56 (2C), 128.33, 128.30 (2C), 128.19, 126.21, 124.07,
121.55, 61.16, 13.94, 10.56. HRMS (ESI, m/z): [M + H+] calcd. for
C19H18ClN2O2 341.1057, found 341.1057.
Ethyl 1-(2,4-dichlorophenyl)-4-methyl-3-phenyl-1H-pyrazole-5-
carboxylate (1bc). Pale yellow solid, 1.14 g (61%), mp 90–92°C.
1H NMR (400 MHz, CDCl3, ppm) δ: 7.68 (d, J= 7.2 Hz, 2H, ArH),
7.52 (d, J= 2.0 Hz, 1H, ArH), 7.48–7.35 (m, 5H, ArH), 4.24 (q,
J= 7.2 Hz, 2H, CH2), 2.51 (s, 3H, CH3), 1.19 (t, J= 7.2 Hz, 3H,
CH3). 13C NMR (100 MHz, CDCl3, ppm) δ: 159.62, 152.44, 138.11,
135.25, 132.92, 132.90, 132.46, 129.82, 129.53, 128.54 (2C), 128.33
(2C), 128.20, 127.56, 120.84, 61.06, 13.90, 10.64. HRMS (ESI, m/z):
[M + H+] calcd. for C19H17Cl2N2O2 375.0667, found 375.0672.
Ethyl 4-methyl-3-phenyl-1-(2,4,6-trichlorophenyl)-1H-pyrazole-
5-carboxylate (1bd). Pale yellow solid, 1.02 g (50%), mp 80–81°C.
1H NMR (400 MHz, CDCl3, ppm) δ: 7.69 (d, J= 8.4 Hz, 2H, ArH),
7.49–7.43 (m, 4H, ArH), 7.42–7.37 (m, 1H, ArH), 4.25 (q,
J= 7.2 Hz, 2H, CH2), 2.54 (s, 3H, CH3), 1.21 (t, J= 7.2 Hz, 3H,
CH3). 13C NMR (100 MHz, CDCl3, ppm) δ: 159.18, 153.15, 136.33,
135.44, 135.12, 132.46, 132.30, 128.42 (2C), 128.28 (2C), 128.17
(2C), 128.14 (2C), 120.87, 60.97, 13.79, 10.60. HRMS (ESI, m/z):
[M + H+] calcd. for C19H16Cl3N2O2 409.0277, found 409.0276.
Ethyl 4-methyl-3-phenyl-1-(p-tolyl)-1H-pyrazole-5-carboxylate
5-carboxylate (1ce).
Pale yellow solid, 1.10 g (62%), mp
94–96°C. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.62 (dd,
J = 8.4, 2.0 Hz, 2H, ArH), 7.41 (d, J = 8.4 Hz, 2H, ArH), 7.30
(d, J = 8.4 Hz, 2H, ArH), 7.24 (d, J = 8.4 Hz, 2H, ArH), 4.24 (q,
J = 7.2 Hz, 2H, CH2), 2.45 (s, 3H, CH3), 2.41 (s, 3H, CH3),
1.20 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3,
ppm) δ: 160.07, 150.09, 138.39, 138.26, 133.80, 132.11,
131.28, 129.42 (2C), 129.09 (2C), 128.58 (2C), 125.46 (2C),
120.37, 60.90, 21.11, 13.84, 10.45. HRMS (ESI, m/z): [M + H+]
calcd. for C20H20ClN2O2 355.1213, found 355.1216.
Ethyl 3-(4-chlorophenyl)-4-methyl-1-(4-nitrophenyl)-1H-
pyrazole-5-carboxylate (1ch).
Pale yellow solid, 1.16 g
1
(60%), mp 130–132°C. H NMR (400 MHz, CDCl3, ppm) δ: 8.35
(d, J= 7.6 Hz, 2H, ArH), 7.62 (t, J= 7.6 Hz, 4H, ArH), 7.45 (d,
J= 7.6 Hz, 2H, ArH), 4.32 (q, J= 7.2 Hz, 2H, CH2), 2.46 (s, 3H,
CH3), 1.27 (t, J=7.2Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3,
ppm) δ: 160.05, 153.21, 146.73, 145.65, 138.42, 131.94, 129.36
(2C), 129.18, 128.16 (2C), 125.96 (2C), 124.09 (2C), 122.67, 61.49,
14.06, 10.67. HRMS (ESI, m/z): [M + H+] calcd. for C19H17ClN3O4
386.0908, found 386.0909.
1
(1be). Pale yellow solid, 0.96 g (60%), mp 128–130°C. H NMR
(400 MHz, CDCl3, ppm) δ: 7.71 (d, J= 7.6 Hz, 2H, ArH), 7.47 (t,
J= 7.6 Hz, 2H, ArH), 7.41 (d, J= 7.6 Hz, 1H, ArH), 7.34 (d,
J= 7.6 Hz, 2H, ArH), 7.28 (br s, 2H, ArH), 4.27 (q, J= 7.2 Hz, 2H,
CH2), 2.49 (s, 3H, CH3), 2.44 (s, 3H, CH3), 1.23 (t, J= 7.2 Hz, 3H,
CH3). 13C NMR (100 MHz, CDCl3, ppm) δ: 160.32, 151.37, 138.61,
138.20, 132.88, 132.02, 129.16 (2C), 128.47 (2C), 128.33 (2C),
127.92, 125.61 (2C), 120.57, 60.94, 21.22, 13.98, 10.60. HRMS (ESI,
m/z): [M + H+] calcd. for C20H21N2O2 321.1603, found 321.1606.
Ethyl 1-(2,4-dimethylphenyl)-4-methyl-3-phenyl-1H-pyrazole-
Ethyl 4-methyl-1-(4-nitrophenyl)-3-(p-tolyl)-1H-pyrazole-
5-carboxylate (1dh).
Pale yellow solid,1.11 g (61%), mp
100–102°C. 1H NMR (400 MHz, CDCl3, ppm) δ: 8.33 (d,
J = 8.4 Hz, 2H, ArH), 7.65 (d, J = 8.4 Hz, 2H, ArH), 7.56 (d,
J = 8.0 Hz, 2H, ArH), 7.28 (d, J = 8.0 Hz, 2H, ArH), 4.34 (q,
J = 7.2 Hz, 2H, CH2), 2.49 (s, 3H, CH3), 2.44 (s, 3H, CH3),
1.30 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3,
ppm) δ: 159.93, 153.11, 146.63, 145.55, 138.30, 131.84, 129.24
(2C), 129.10, 128.05 (2C), 125.84 (2C), 123.96 (2C), 122.55,
61.36, 21.22, 13.94, 10.54. HRMS (ESI, m/z): [M + H+] calcd.
for C20H20N3O4 366.1454, found 366.1456.
5-carboxylate (1bf).
Pale yellow solid, 0.95 g (57%), mp 141–
142°C. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.70 (d, J= 8.4 Hz, 2H,
ArH), 7.44 (t, J= 7.6 Hz, 2H, ArH), 7.37 (t, J= 7.6 Hz, 1H, ArH),
7.13 (t, J= 7.6 Hz, 2H, ArH), 7.08 (t, J= 7.6 Hz, 1H, ArH), 4.19 (q,
J= 7.2 Hz, 2H, CH2), 2.51 (s, 3H, CH3), 2.37 (s, 3H, CH3), 2.05 (s,
3H, CH3), 1.14 (t, J=7.2Hz, 3H, CH3). 13C NMR (100 MHz,
CDCl3, ppm) δ: 159.97, 151.16, 138.81, 138.26, 135.04, 133.03,
132.63, 131.05, 128.43 (2C), 128.30 (2C), 127.83, 127.12, 126.77,
119.80, 60.71, 21.23, 17.25, 13.86, 10.72. HRMS (ESI, m/z): [M
+H+] calcd. for C21H23N2O2 335.1760, found 335.1758.
Ethyl 4-methyl-1-(3-nitrophenyl)-3-(p-tolyl)-1H-pyrazole-5-carboxylate
(1di).
Pale yellow solid, 1.10 g (60%), mp 124–126°C. 1H NMR
(400 MHz, CDCl3, ppm) δ: 8.28 (s, 1H, ArH), 8.20 (d, J=8.0Hz, 1H,
ArH), 7.75 (d, J= 8.0 Hz, 1H, ArH), 7.56 (t, J= 8.0 Hz, 1H, ArH), 7.49 (d,
J= 7.2 Hz, 2H, ArH), 7.21 (d, J= 8.0 Hz, 2H, ArH), 4.22 (q, J= 6.8 Hz, 2H,
CH2), 2.41 (s, 3H, CH3), 2.34 (s, 3H, CH3), 1.18 (t, J= 6.8 Hz, 3H, CH3).
13C NMR (100 MHz, CDCl3, ppm) δ: 159.93, 152.88, 148.08, 141.80,
138.30, 131.85, 131.75, 129.33 (2C), 129.29 (2C), 128.18 (2C), 122.74,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

848
J.-J. Zhai, C.-H. Gu, Y. Guo, D.-H. Liao, D.-R. Zhu, and Y.-F. Ji
Vol 53
Table 2
5 cm and frame exposure time of 10s using a graphite-
monochromated Mo Kα (λ = 0.71073Å) radiation. The structures
were all solved by direct methods and refined on F2 by full-matrix
least squares procedures using SHELXTL software [17]. All
non-hydrogen atoms were anisotropically refined. All H atoms
were located from a difference map and refined isotropically.
Details on crystal data of 1aa are summarized in Table 2, and the
selected bond lengths and angles are listed in Table 3.
CCDC 1018793 (1aa) contains the supplementary crystallo-
graphic data for this article. The data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Crystallographic data for 1aa.
Empirical formula
C18H16N2O2
Formula weight
Temperature (K)
Crystal size (mm3)
Crystal system
Space group
a (Å)
292.33
296 (2)
0.20 × 0.15 × 0.10
Triclinic
P-1
4.1383 (9)
10.306 (2)
17.804 (4)
86.384 (3)
88.893(3)
88.680 (3)
757.5 (3)
2
b (Å)
c (Å)
α (°)
β (°)
γ (°)
V (Å3)
Z
Dc (g cmÀ3
)
1.282
0.085
308
Acknowledgments. The authors are grateful to the National
Natural Science Foundation of China (Project Nos. 21176074,
21476074, 21476115 and 21171093) and Research Fund for
the Doctoral Program of Higher Education of China (Project
No. 20130074110009) for financial support.
μ (mmÀ1
F (000)
)
θ Range
1.15 to 25.04
5387
2630 [Rint = 0.0230]
2630/6/201
1.056
0.0479, 0.1215
0.0663, 0.1312
0.139, À0.113
Reflections collected
Independent reflections
Data/restraints/parameters
Goodness-of-fit on F2
R/wR [I > 2σ(I)]
REFERENCES AND NOTES
R/wR (all data)
Max., Min. Δρ (e ÅÀ3
)
[1] Fustero, S.; Sanchez-Rosello, M.; Barrio, P.; Simon-Fuentes, A.
Chem Rev 2011, 111, 6984.
[2] Yoon, J. Y.; Lee, S.; Shin, H. Curr Org Chem 2011, 15, 657.
[3] Fustero, S.; Simon-Fuentes, A.; Sanz-Cervera, J. F. Org Prep
Proced Int 2009, 41, 253.
[4] Rinaldi-Carmona, M.; Barth, F.; Heaulme, M.; Shire, D.;
Calandra, B.; Congy, C.; Martinez, S.; Maruani, J.; Neliat, G.; Caput, D.;
Ferrara, T.; Soubrie, P.; Breliere, J. C.; Le Fur, G. FEBS Lett 1994,
350, 240.
Table 3
Selected bond lengths (Å) and angles (°) for 1aa.
Bond distances (Å)
[5] Rinaldi-Carmona, M.; Barth, F.; Congy, C.; Martinez, S.;
Oustric, D.; Perio, A.; Poncelet, M.; Maruani, J.; Arnone, M.;
Finance, O.; Soubrie, P.; Fur, G. L. J Pharmacol Exp Ther 2004,
310, 905.
[6] Meschler, J. P.; Kraichely, D. M.; Wilken, G. H.; Howlett, A. C.
Biochem Pharacol 2000, 60, 1315.
[7] Wong, D. F.; Kuwabara, H.; Horti, A. G.; Raymont, V.;
Brasic, J.; Guevara, M.; Ye, W.; Dannals, R. F.; Ravert, H. T.; Nandi, A.;
Rahmim, A.; Ming, J. E.; Grachev, I.; Roy, C.; Cascella, N. Neuro Image
2010, 52, 1505.
N1–N2
N1–C6
N1–C7
N2–C9
1.349 (2)
1.439 (2)
1.366 (2)
1.341 (2)
C7–C16
C16–O1
C16–O2
C17–O2
1.471 (3)
1.200 (2)
1.335 (2)
1.455 (3)
Bond angles (°)
C7-N1-N2
C7-N1-C6
N1-N2-C9
111.51 (15)
131.05 (17)
105.69 (15)
C7-C16-O1
O1-C16-O1
C16-O2-C17
126.6 (2)
123.7 (2)
115.88 (17)
[8] Abdel-Aziz, H. A.; El-Zahabi, H. S. A.; Dawood, K. M. Eur J
Med Chem 2010, 45, 2427.
[9] Strocchi, E.; Fornari, F.; Minguzzi, M.; Gramantieri, L.;
Milazzo, M.; Rebuttini, V.; Breviglieri, S.; Camaggi, C. M.; Locatelli, E.;
Bolondi, L.; Comes-Franchini, M. Eur J Med Chem 2012, 48, 391.
[10] Qiao, J. X.; Cheng, X.; Smallheer, J. M.; Galemmo, R. A.;
Drummond, S.; Pinto, D. J. P.; Cheney, D. L.; He, K.; Wong, P. C.;
Luettgen, J. M.; Knabb, R. M.; Wexler, R. R.; Lam, P. Y. S. Bioorg
Med Chem Lett 2007, 17, 1432.
[11] Jiang, J.-A.; Huang, W.-B.; Zhai, J.-J.; Liu, H.-W.; Cai, Q.;
Xu, L.-X.; Wang, W.; Ji, Y.-F. Tetrahedron 2013, 69, 627.
[12] Zhai, J.-J.; Gu, C.-H.; Zhang, S.-L.; Liao, D.-H.; Wang, L.;
Zhu, D.-R.; Ji, Y.-F. Chin J Chem 2013, 31, 1526.
[13] Ashton, W. T.; Doss, G. A. J Heterocycl Chem 1993, 30, 307.
[14] Ji, Y.-F.; Jiang, J.-A.; Liu, H.-W.; Liao, D.-H.; Wei, X.-Y..
Syn Commun 2013, 43, 1517.
122.21, 121.21, 61.37, 21.34, 14.02, 10.72. HRMS (ESI, m/z): [M + H+] calcd.
for C20H20N3O4 366.1454, found 366.1455.
Ethyl 1-(2,4-dinitrophenyl)-4-methyl-3-(p-tolyl)-1H-pyrazole-5-
carboxylate (1dj).
Pale yellow solid, 1.17 g (57%), mp 117–
1
118°C. H NMR (400MHz, CDCl3, ppm) δ: 8.97 (s, 1H, ArH),
8.55 (d, J = 8.4 Hz, 1H, ArH), 7.83 (d, J= 8.4 Hz, 1H, ArH), 7.53
(d, J = 8.0Hz, 2H, ArH), 7.28 (d, J = 8.0 Hz, 2H, ArH), 4.27 (q,
J =7.2Hz, 2H, CH2), 2.50 (s, 3H, CH3), 2.41 (s, 3H, CH3), 1.29
(t, J = 6.8 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3, ppm) δ:
159.78, 154.42, 146.85, 145.08, 139.78, 138.67, 132.47, 131.50,
129.37 (2C), 128.81, 128.24 (2C), 127.53, 122.75, 120.51, 61.73,
21.35, 14.03, 10.93. HRMS (ESI, m/z): [M + H+] calcd. for
C20H19N4O6 411.1305, found 411.1799.
[15] Gu, C.-H.; Zhai, J.-J.; Jiang, J.-A.; Liu, H.-W.; Wang, L.; Zhu,
D.-R.; Ji, Y.-F. Chin J Chem 2014, 32, 179.
[16] Jiang, J.-J.; Shen, G.-P.; He, X.; Shen, X.; Zhu, D.-R.
J Heterocycl Chem 2014. DOI: 10.1002/jhet.1894
Single-crystal X-ray diffraction analysis of 1aa. The well-
shaped single crystals of 1aa were selected for lattice parameter
determination and collection of intensity data at 296 K on a
Bruker SMART CCD diffractometer with a detector distance of
[17] Sheldrick, G. M. Acta Crystallogr 2008, A64, 112.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet