A one-pot approach to ethyl 1,4,5-triaryl-1H-pyrazole-3-carboxylates via an improved claisen condensation-knorr reaction sequence

Article abstract of DOI:10.1002/cjoc.201300776

A one-pot approach to ethyl 1,4,5-triaryl-1H-pyrazole-3-carboxylates has been developed in moderate to high yields. The tert-BuOLi-mediated Claisen condensation of 1,2-diarylethanones and ethyl oxalyl chloride efficiently provided the enolized lithium salts of ethyl 2,4-dioxo-3,4-diarylbutanoates, which in situ reacted with arylhydrazine hydrochlorides via a hydrochloric acid-promoted Knorr reaction to produce the exquisite triarylpyrazole-3- carboxylates. The procedure promises a convenient access to this highly crowded framework for drug discovery. Copyright

Full text of DOI:10.1002/cjoc.201300776

FULL PAPER
DOI: 10.1002/cjoc.201300776
A One-pot Approach to Ethyl 1,4,5-Triaryl-1H-pyrazole-3-
carboxylates via an Improved Claisen Condensation-
Knorr Reaction Sequence
Jiaojiao Zhai,a Chunhui Gu,a Jianan Jiang,a Shunli Zhang,a Daohua Liao,a
Lei Wang,b Dunru Zhu,*,b and Yafei Ji*,a
a School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
b State Key Laboratory of Materials-oriented Chemical Engineering, College of Chemistry and Chemical
Engineering, Nanjing University of Technology, Nanjing, Jiangsu 210009, China
A one-pot approach to ethyl 1,4,5-triaryl-1H-pyrazole-3-carboxylates has been developed in moderate to high
yields. The tert-BuOLi-mediated Claisen condensation of 1,2-diarylethanones and ethyl oxalyl chloride efficiently
provided the enolized lithium salts of ethyl 2,4-dioxo-3,4-diarylbutanoates, which in situ reacted with arylhydrazine
hydrochlorides via a hydrochloric acid-promoted Knorr reaction to produce the exquisite triarylpyrazole-3-
carboxylates. The procedure promises a convenient access to this highly crowded framework for drug discovery.
Keywords one-pot approach, 2,4-dioxo-3,4-diarylbutanoates, Claisen condensation, Knorr reaction, triarylpyra-
zole-3-carboxylates
Introduction
for the synthesis of the overcrowded triarylpyra-
zole-3-carboxylates (Scheme 1b). A main reason is that
the labile intermediates 2,4-dioxo-3,4-diaryl-butanoates
are difficult to access via the previously developed
Claisen condensation from diethyl oxalate and
1,2-diphenylethanones, due to larger steric effect of
bulky phenyl groups.[5] Therefore, further improving the
highly sterically hindered Claisen condensation reaction
was needed for overcoming this encountered problem.
The preliminary screening on counterparts of diethyl
oxalate uncovered that ethyl oxalyl chloride was the
most competent electrophile for preparing the desired
2,4-dioxo-3,4-diarylbutanoates (2), comparing with di-
ethyl oxalate, dimethyl oxalate, di-tert-butyl oxalate and
tert-butyl ethyl oxalate. Herein, we reported a one-pot
approach to ethyl 1,4,5-triaryl-1H-pyrazole-3-carboxy-
lates (4) via a modified Claisen condensation-Knorr
reaction sequence from readily available ethyl oxalyl
chloride, 1,2-diarylethanones (1) and arylhydrazine hy-
drochlorides (3, Scheme 1c).
Pyrazoles and their derivatives have been frequently
found in large numbers of biologically active mole-
cules.[1] Among these compounds, monoaryl-1H-
pyrazole-3-carboxylate[2] and diaryl-1H-pyrazole-3-
carboxylate derivatives[3] generally possess widespread
pharmacological activities acting as anti-inflammatory
agents,[2a] antifungal agents,[2b] antimicrobials,[2c] L-2-
hydroxy acid oxidase inhibitors,[2d] acrosin inhibitors,[2e]
cannabinoid-1 (CB1) receptor antagonists,[3a-3e,3g] Iκβ
kinase β (IKKβ or IKK-2) inhibitors[3f] and analge-
sics.[3h] Recently, it has been revealed that 1,4,5-triaryl-
1H-pyrazole-3-carboxylic acids hold good anti-inflam-
matory and analgesic activities.[3h] In general, Knorr
reaction and 1,3-dipolar cycloaddition as two prevalent
strategies can be employed to prepare pyrazoles.[4]
However, the synthesis of the highly crowded
1,4,5-triaryl-1H-pyrazole-3-carboxylates is still scarce,
and only two examples have been documented to
date.[3h] In fact, the reported synthesis of triarylpyra-
zole-3-carboxylates was difficult to be reproduced
(Scheme 1a).[3h] Hence, we realized that the develop-
ment of an efficient approach to the special framework
is imperative for drug discovery.
Results and Discussion
Further optimization for the model reaction of
1,2-diphenylethanone (1a) with ethyl oxalyl chloride
was implemented as shown in Table 1. Initially, the
condensation was highly effective to deliver ethyl
2,4-dioxo-3,4-diphenylbutanoate (2a) in 94% yield with
More recently, we reported the synthesis of 4-sub-
stituted 1,5-diaryl-1H-pyrazole-3-carboxylates,[5] how-
ever, the method generally presented a low efficiency
*
E-mail: jyf@ecust.edu.cn, zhudr@njut.edu.cn; Tel./Fax: 0086-021-64253314
Received October 16, 2013; accepted November 18, 2013; published online December 11, 2013.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201300776 or from the author.
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Chin. J. Chem. 2013, 31, 1526—1538

A One-pot Approach to Ethyl 1,4,5-Triaryl-1H-pyrazole-3-carboxylates
Scheme 1 Synthesis of triaryl-1H-pyrazole-3-carboxylates
Ph
OMe
CO2Et
(a) Georgey's work
OMe O
N
.
diethyl oxalate
RC6H4NH2NH2 HCl
Et3N/EtOH, reflux
Ph
N
R
MeO
NaH/toluene
reflux
MeO
R = H, 53%
R = Cl, 63%
only two examples
low reproducibility
(b) Our previous work
CO2Et
Ph
O
.
PhNHNH2 HCl
diethyl oxalate
N
Ph
N
t-BuOLi, THF, r.t.
AcOH, AcCl
Ph
47%
only one example
(c) This work
O
Li
O
O-
R2
ethyl oxalyl chloride
t-BuOLi, THF, reflux
CO2Et
R1
R1
1
R2
lithium salt of 2
R2
.
NHNH2 HCl
CO2Et
R3
3
R1
N
N
conc. HCl, EtOH,
reflux
R3
4 (60% - 90%)
highly crowded motif
1.5 equiv. of ethyl oxalyl chloride and 3.0 equiv. of
tert-BuOLi under reflux for 6 h (Entry 1). Tentatively,
the yield remarkably reduced to 74% under a lowered
reaction temperature of 50 ℃ (Entry 2). Pleasingly, the
reactions still worked well to afford an excellent yield
of 94% in the presence of 1.4, 1.3 or 1.2 equiv. of ethyl
oxalyl chloride with 3.0 equiv. of tert-BuOLi (Entries 3
－5). When utilizing 1.1 equiv. of ethyl oxalyl chloride,
the yield sharply dropped to 80% (Entry 6). On the
other hand, it was observed that the use of 2.5 or 2.4
equiv. of tert-BuOLi proved to be equally effective for
the condensation with 1.2 equiv. of ethyl oxalyl chloride
(Entries 7 and 8). Besides, a lower yield of 87% was
incurred with 2.3 equiv. of tert-BuOLi (Entry 9). Thus,
the optimized conditions were established for the steri-
cally hindered Claisen condensation (Entry 8).
The combination of the Claisen condensation and
subsequent Knorr reaction into a one-pot procedure be-
came a practical choice to avoid isolating unstable 2a[6]
(Table 2). Mechanistically, acid-mediated cyclization of
the intermediate (E/Z)-5aa, produced from the initial
reaction of 2a and phenlhydrazine hydrochloride (3a),
was crucial for the Knorr reaction.[1c,5,7] However, when
using 4.0 equiv. of para-toluenesulfonic acid (p-TSA),
AcOH, TFA or ethanolic HCl, the desired ethyl
1,4,5-triphenyl-1H-pyrazole-3-carboxylate (4aa) was
afforded in low yields of 29%－56%, along with 37%－
64% yields of uncyclized N-phenylhydrazones (E/Z)-
5aa (Entries 1－4). In these cases, the concomitant gen-
eration of unknown precipitates possibly made negative
impact on the cyclization of (E/Z)-5aa as well. To our
surprise, switching to the use of 4.0 equiv. of concen-
trated hydrochloric acid, the procedure smoothly pro-
vided 4aa in a high yield of 90% with trace of (E/Z)-5aa
(Entry 5). In the case, the above detrimental precipitates
were completely eliminated. It was reasonably inferred
that the advantages of concentrated hydrochloric acid
are based on: (i) neutralizing the residual tert-BuOLi,
releasing free 2a in situ from the enolized lithium salt,
and avoiding the resulting precipitates; (ii) preferably
promoting the cyclization of (E/Z)-5aa via isomerizing
non-cyclizable (Z)-5aa into cyclizable (E)-5aa
(Scheme2).[5] Considering the cheapness of concen-
trated hydrochloric acid, its dosage was not further op-
timized.
Chin. J. Chem. 2013, 31, 1526—1538
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Zhai et al.
Table 2 Optimization of the one-pot procedurea
FULL PAPER
Table 1 Optimization of the Claisen condensation of 1a with
ethyl oxalyl chloridea
O
Li
O
O
O-
OEt
Cl
Li
O
OEt
Cl
O
CO2Et
O
O
O
O
t-BuOLi, THF, reflux, 6
h
CO2Et
t-BuOLi, THF
reflux, 6 h
1a
1a
lithium salt of 2a
O
O
lithium salt of 2a
.
aq. HCl
NHNH2 HCl
CO2Et
CO2Et
N
NH
3a
O
N
2a
+
EtOH, acid, reflux, 6 h
N
CO2Et
Ethyl oxalyl
chloride (n1 equiv.)
Entry
t-BuOLi (n2 equiv.) Yieldb/%
4aa
1
2
3
4
5
6
7
8
9
1.5
1.5
1.4
1.3
1.2
1.1
1.2
1.2
1.2
3.0
3.0
3.0
3.0
3.0
3.0
2.5
2.4
2.3
94
76c
94
94
94
80
94
94
87
(E/Z)-5aa
Entry Acid
Yieldb/% (4aa)
Yieldb/% (5aa)
1
2
3
4
5
p-TSA
29
36
41
56
90
64
AcOH
55
TFA
51
Ethanolic HCl
Conc. HCl
37
trace
a A mixture of 1a (5.0 mmol), ethyl oxalyl chloride (6.0 mmol)
and tert-BuOLi (12.0 mmol) in anhydrous THF (20 mL) was
refluxed for 6 h. After removal of THF, EtOH (20 mL), acid (4.0
equiv) and 3a (5.0 mmol) were successively added to the residue
and refluxed for another 6 h.
chromatography.
a Performed with 1a (5.0 mmol), ethyl oxalyl chloride (n1 equiv.)
and tert-BuOLi (n2 equiv.) in anhydrous THF (20 mL) for 6 h.
The product 2a was found to be extremely unstable on column
chromatography, only purified via recrystallization. Isolated
yield via recrystallization from petroleum ether (25 mL). c Per-
b
Isolated yield via column
b
formed at 50 ℃.
11). By varying substituent(s) R1 at the benzoyl moiety,
we found that, as for compound 1b (R1＝para-methyl
group), the procedure afforded the product 4ba in a
slightly low yield of 88% (Entry 2) in comparison with
the unsubstituted 1a (Entry 1). When the substrates 1c
(R1＝ortho, para-dimethyl groups) and 1d (R1＝ortho,
ortho, para-trimethyl groups) were used, the yields of
the corresponding products 4ca and 4da dropped to
With the improved Claisen condensation-Knorr re-
action sequence in hand, we investigated the scope of
substrates 1 and 3 for the synthesis of various
1,4,5-triaryl-1H-pyrazole-3-carboxylates via the one-pot
procedure (Table 3). Firstly, different 1,2-diaryl-
ethanones 1a－1k were evaluated with 3a (Entries 1－
Scheme 2 Hydrochloric acid-promoted cyclization of 5aa
CO2Et
NH
HN
N
O
N
O
N
N
OEt
OEt
O
O
4aa
(E)-5aa
(Z)-5aa
conc. HCl
reflux
conc. HCl
reflux
NH
HN
O
OEt
O
(E/Z)-enamine intermediates
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Chin. J. Chem. 2013, 31, 1526—1538

A One-pot Approach to Ethyl 1,4,5-Triaryl-1H-pyrazole-3-carboxylates
80% and 71%, respectively (Entries 3 and 4). The two
results showed that the ortho-steric hindrance of the
benzoyl moiety significantly affected the outcomes of
the procedure. In addition, the influence of R2 at the
benzyl moiety was also examined (Entries 5－9). Re-
gardless of electronic nature of R2, for the substrates 1e
and 1f (R2＝para-substitutent), the procedure delivered
the products 4ea and 4fa in slightly low yields of 85%
and 86%, respectively (Entries 5 and 6). With regard to
the substrates 1g－1i containing ortho-substituted ben-
zyl moiety, the product yields distinctly decreased to
78%－81% (Entries 7－9). These results indicated an
obvious ortho-steric hindrance in the benzyl moiety.
Moreover, the one-pot approach smoothly proceeded to
give more sterically crowded products 4ja and 4ka in
the yields of 79% and 74%, respectively (Entries 10 and
11), clearly demonstrating the feasibility of the current
procedure.
Next, arylhydrazine hydrochlorides 3 were also
evaluated with 1a (Entries 12－20). With respect to the
substrates whether 3b－3d bearing electron-donating
groups or 3f－3h bearing electron-withdrawing groups,
the procedure gave their respective products 4ab－4ad
and 4af－4ah in good yields of 81%－87% (Entries 12
－14 and 16－18). In contrast, for the sterically
crowded di-ortho-substituted substrates 3e and 3i, the
procedure provided the products 4ae and 4ai in rela-
tively low yields of 74% and 77%, respectively (Entries
15 and 19), irrespective of electronic nature of substitu-
ents. It was noteworthy that, for the substrate 4-phenyl-
Table 3 Synthesis of ethyl 1,4,5-triaryl-1H-pyrazole-3-carboxylates 4 from 1 and 3a
.
R2
O
Li
NHNH2 HCl
OEt
O-
R3
conc. HCl
O
O
Cl
R2
CO2Et
3
O
CO2Et
R1
R1
R1
N
t-BuOLi, THF
N
reflux, 6 h
EtOH, reflux, 6 h
1
4
R2
lithium salt of 2
R3
Entry
Yieldb/%
1
3
4
CO2Et
N
.
O
NHNH2 HCl
1
90
N
3a
1a
4aa
CO2Et
O
N
2
3
4
N
88
80
71
3a
3a
3a
1b
4ba
CO2Et
O
N
N
1c
4ca
CO2Et
O
N
N
1d
4da
Chin. J. Chem. 2013, 31, 1526—1538
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Zhai et al.
FULL PAPER
Continued
Yieldb/%
Entry
1
3
4
CO2Et
O
5
85
86
78
81
80
3a
N
N
1e
4ea
Cl
Cl
CO2Et
O
6
3a
3a
3a
3a
N
N
1f
4fa
CO2Et
O
N
7
N
1g
4ga
Cl
CO2Et
O
N
8
N
Cl
1h
4ha
Cl
Cl
Cl
O
CO2Et
9
N
N
Cl
1i
4ia
Cl
Cl
CO2Et
O
10
79
3a
N
N
1j
4ja
Cl
CO2Et
O
N
11
74
3a
N
Cl
1k
4ka
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Chin. J. Chem. 2013, 31, 1526—1538

A One-pot Approach to Ethyl 1,4,5-Triaryl-1H-pyrazole-3-carboxylates
Continued
Yieldb/%
Entry
1
3
4
CO2Et
.
O
NHNH2 HCl
N
N
12
85
3b
1a
4ab
CO2Et
.
NHNH2 HCl
N
N
13
83
1a
3c
4ac
CO2Et
.
NHNH2 HCl
N
14
15
16
17
84
74
86
87
1a
1a
1a
1a
N
3d
4ad
CO2Et
.
NHNH2 HCl
N
N
3e
4ae
.
CO2Et
NHNH2 HCl
N
N
Cl
3f
Cl
4af
.
CO2Et
NHNH2 HCl
N
N
NO2
3g
NO2
4ag
Chin. J. Chem. 2013, 31, 1526—1538
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Zhai et al.
FULL PAPER
Continued
Yieldb/%
Entry
1
3
4
CO2Et
.
NHNH2 HCl
N
N
18
82
1a
Cl
Cl
Cl
3h
4ah
Cl
CO2Et
Cl
.
NHNH2 HCl
N
N
19
77
1a
Cl
Cl
Cl
Cl
3i
4ai
Cl
.
NHNH2 HCl
S
CO2Et
N
N
N
N
20
21
22
81
73
66
1a
S
3j
4aj
CO2Et
O
N
N
3h
Cl
1c
4ch
Cl
N
CO2Et
N
1c
3i
Cl
Cl
4ci
Cl
Cl
CO2Et
O
N
N
23
75
3h
Cl
Cl
1h
4hh
Cl
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Chin. J. Chem. 2013, 31, 1526—1538

A One-pot Approach to Ethyl 1,4,5-Triaryl-1H-pyrazole-3-carboxylates
Continued
Yieldb/%
Entry
1
3
4
Cl
Cl
CO2Et
Cl
O
N
24
67
66
60
3i
N
Cl
Cl
Cl
1i
Cl
4ii
Cl
CO2Et
O
N
N
25
3h
Cl
Cl
1k
Cl
4kh
Cl
CO2Et
N
N
26
1k
3i
Cl
Cl
4ki
Cl
CO2Et
O
N
S
N
27
82
3h
S
Cl
1l
4lh Cl
CO2Et
S
O
S
N
N
28
83
3h
O
Cl
O
1m
Cl
4mh
a
Performed with 1 (5.0 mmol), ethyl oxalyl chloride (6.0 mmol), tert-BuOLi (12.0 mmol), anhydrous THF (20 mL), EtOH (20 mL),
concentrated hydrochloric acid (1.71 mL, 20.0 mmol) and 3 (5.0 mmol) following the general procedure. b Isolated yield via column
chromatography.
thiazol-2-ylhydrazine hydrochloride (3j), the procedure
favourably provided thiazolyl-substituted triarylpyra-
zoles 4aj in 81% yield (Entry 20).
Afterwards, the substrates 1 and 3 were changed
synchronously to further evaluate the viability of the
procedure (Entries 21－28). The results showed that the
sterically crowded triarylpyrazoles 4ch, 4ci, 4hh and 4ii
were smoothly obtained in moderate yields of 66%－
75% (Entries 21－24). Notably, the more sterically
crowded triarylpyrazoles 4kh and 4ki were also accom-
plished in moderate yields of 66% and 60%, respec-
tively (Entries 25 and 26). Impressively, as for thio-
phen-2-yl substituted ethanones 1l and 1m, the one-pot
procedure efficiently delivered elegant heteroaryl-con-
taining products 4lh and 4mh in high yields of 82% and
83%, respectively (Entries 27 and 28). The results
meant that heteroaryl group can be flexibly installed at
1-, 4- or 5-position of the framework (Entries 20, 27 and
Chin. J. Chem. 2013, 31, 1526—1538
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Zhai et al.
FULL PAPER
28). Besides, no isomers of 1,3,4-triaryl-1H-pyrazole-5-
carboxylates were detected in the procedure.
tained from commercial sources and used as received
without further purification. All reactions were carried
out in oven-dried glassware and monitored by thin layer
chromatography (TLC, precoated silica gel plates con-
taining 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 TMS as
internal standard for 1H NMR (400 MHz) and 13C NMR
(100 MHz), respectively. HRMS were carried out on a
QSTAR Pulsar I LC/TOF MS mass spectrometer. Crys-
tal data of 4ka were collected on a Brüker Smart APEX
II CCD diffractometer with monochromated Mo Kα
radiation (λ＝0.71073 Å) at 293 K, and operating in the
Ø-ω scan mode. The structure was solved by direct
methods and refined on F2 by full matrix least-squares
methods using SHELXTL.
Finally, the geometrical configuration of a represen-
tative product 4ka was determined by single crystal
X-ray crystallography (Figure 1, and see supporting
information for details).[8] The crystal structural analysis
exhibits that 4ka molecule consists of three aryl rings
and one central pyrazole ring, and these rings do not
share a common plane. The phenyl and substituted
phenyl rings lie in a propeller arrangement around the
central pyrazole ring. The pyrazole ring makes dihedral
angles of 45.4(3)°, 81.0(2)° and 76.3(3)° with the
phenyl, the ortho,para-dimethylphenyl and ortho-
chlorophenyl ring, respectively. There is an intermo-
lecular C25－H25B…O1i hydrogen bond involving the
ethyl and carboxylate groups. The crystal structure is
further stabilized by two kinds of intermolecular
edge-to-face C－H…π interactions involving the ortho-
chlorophenyl group and pyrazole ring as well as ortho,
para-dimethylphenyl ring (Table S6 and Figure S1).
Optimization of the Claisen condensation of 1a with
ethyl oxalyl chloride (Table 1)
Ethyl oxalyl chloride (n1 equiv.) was added to a so-
lution of t-BuOLi (n2 equiv.), 1a (0.98 g, 5.0 mmol) in
anhydrous THF (20 mL). The resulting mixture was
stirred under reflux for 6 h unless otherwise indicated.
Then, the mixture was concentrated in vacuo to remove
THF giving a residual, to which were added water (10
mL), CH2Cl2 (15 mL) and 5% hydrochloric acid (ca. 5
mL) until pH 3－4 to make the solution partitioned into
organic and aqueous layers. The aqueous layer was ex-
tracted with CH2Cl2 (10 mL×2). The combined organic
phase was washed with water (20 mL×2), dried over
anhydrous sodium sulfate, and concentrated to give a
crude oil, which was recrystallized from petroleum ether
(25 mL) to offer the desired 2a.
Ethyl 2,4-dioxo-3,4-diphenylbutanoate (2a) Pale
yellow solid, 1.39 g (94%, Entry 8), m.p. 74－75 ℃;
1H NMR (400 MHz, CDCl3) δ: 1.32 (t, J＝7.2 Hz, 3H),
4.32 (q, J＝7.2 Hz, 2H), 6.35 (s, 1H), 7.28－7.38 (m,
5H), 7.43 (t, J＝7.6 Hz, 2H), 7.55 (t, J＝7.6 Hz, 1H),
7.97 (d, J＝7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ:
13.9, 63.0, 63.1, 128.4, 128.8 (2C), 129.12 (2C), 129.15
(2C), 129.9 (2C), 131.2, 133.8, 135.3, 160.8, 188.4,
194.9; HRMS (ESI) m/z: [M＋H＋] calcd for C18H17O4:
297.1127, found 297.1122.
Figure 1 Single crystal structure of compound 4ka (Table 3,
Entry 11).
Conclusions
In summary, we have developed a one-pot approach
to a variety of sterically crowded ethyl 1,4,5-triaryl-1H-
pyrazole-3-carboxylates in moderate to high yields from
easily available ethyl oxalyl chloride, 1,2-diaryl-
ethanones and arylhydrazine hydrochlorides. The de-
veloped procedure involved an improved tert-BuOLi-
mediated sterically hindered Claisen condensation and
hydrochloric acid-promoted Knorr reaction, wherein
ethyl oxalyl chloride and concentrated hydrochloric acid
were identified as two key factors in the respective step
to guarantee higher yields. Due to pharmaceutically po-
tential importance of the triarylpyrazole-3-carboxylates,
this methodology is of significant value in synthetic and
medicinal chemistry.
Optimization of the one-pot procedure (Table 2)
Ethyl oxalyl chloride (0.82 g, 6.0 mmol) was added
to a solution of t-BuOLi (0.96 g, 12.0 mmol), 1a (0.98 g,
5.0 mmol) in anhydrous THF (20 mL). The resulting
mixture was stirred under reflux for 6 h. Then, the mix-
ture was concentrated in vacuo to remove THF giving a
residual. Afterwards, EtOH (20 mL), acid (4.0 equiv.)
and phenylhydrazine hydrochloride (3a, 0.72 g, 5.0
mmol) were added to the residual at room temperature,
and then the mixtures were refluxed for another 6 h. The
reaction solution was concentrated in vacuo to remove
EtOH affording a new residue, to which were added
H2O (15 mL) and CH2Cl2 (15 mL). The organic layer
Experimental
General information
Unless otherwise indicated, all reagents were ob-
1534
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© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 1526—1538

A One-pot Approach to Ethyl 1,4,5-Triaryl-1H-pyrazole-3-carboxylates
1
was separated and the aqueous layer was extracted with
CH2Cl2 (10 mL×2). Finally, the combined organic
phase was washed with brine (35 mL×2), dried over
anhydrous sodium sulfate, and concentrated to provide a
crude product, which was purified by column chroma-
tography [V(petroleum ether)∶V(EtOAc)＝1∶20] to
give (E/Z)-5aa and 4aa.
Ethyl 4-oxo-3,4-diphenyl-2-(2-phenylhydrazono)-
butanoate (5aa) Pale yellow solid, 1.24 g (64%, En-
try 1), m.p. 124－126 ℃; 1H NMR (400 MHz, CDCl3)
δ: 1.18 (t, J＝7.2 Hz, 3H), 4.14－4.29 (m, 2H), 5.97 (s,
1H), 6.89－6.92 (m, 3H), 7.19 (t, J＝8.0 Hz, 2H), 7.24
－7.36 (m, 5H), 7.41 (t, J＝8.0 Hz, 2H), 7.49 (t, J＝7.2
Hz, 1H), 7.99 (d, J＝7.2 Hz, 2H), 12.12 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ: 14.0, 56.6, 61.0, 113.8 (2C),
122.2, 126.3, 127.3, 128.3 (2C), 128.57 (2C), 128.64
(2C), 129.2 (2C), 130.2 (2C), 132.7, 135.8, 136.8, 143.2,
162.7, 196.9; HRMS (ESI) m/z: [M＋H＋] calcd for
C24H23N2O3: 387.1709, found 387.1706.
128－132 ℃; H NMR (400 MHz, CDCl3) δ: 1.26 (t,
J＝7.2 Hz, 3H), 2.26 (s, 3H), 4.33 (q, J＝7.2 Hz, 2H),
6.86 (d, J＝8.0 Hz, 2H), 6.96 (d, J＝8.0 Hz, 2H), 7.21
－7.31 (m, 10H); C NMR (100 MHz, CDCl3) δ: 14.2,
21.3, 60.9, 124.7, 125.7 (2C), 126.0, 127.1, 127.7 (2C),
128.1, 128.8 (2C), 129.1 (2C), 130.2 (2C), 130.7 (2C),
132.0, 138.4, 139.6, 141.6, 142.4, 162.6; HRMS (ESI)
m/z: [M＋H＋] calcd for C25H23N2O2: 383.1760, found
383.1737.
13
Ethyl 5-(2,4-dimethylphenyl)-1,4-diphenyl-1H-
pyrazole-3-carboxylate (4ca) Pale yellow solid, 1.59
g (80%), m.p. 126－128 ℃; H NMR (400 MHz,
1
CDCl3) δ: 1.29 (t, J＝7.2 Hz, 3H), 1.78 (s, 3H), 2.24 (s,
3H), 4.35 (q, J＝7.2 Hz, 2H), 6.85－6.99 (m, 4H), 7.16
－7.26 (m, 7H), 7.30－7.36 (m, 1H), 7.40－7.49 (m,
1H); 13C NMR (100 MHz, CDCl3) δ: 14.2, 19.6, 21.3,
60.9, 124.6 (2C), 125.3, 125.8, 126.7, 127.0, 127.6 (2C),
127.8, 128.7 (2C), 130.2 (2C), 131.1, 131.3, 131.9,
137.4, 139.1, 139.6, 141.3, 142.2, 162.7; HRMS (ESI)
m/z: [M＋H＋] calcd for C26H25N2O2: 397.1916, found
397.1921.
Ethyl 5-mesityl-1,4-diphenyl-1H-pyrazole-3-car-
boxylate (4da) Brown solid, 1.46 g (71%), m.p. 142
－144 ℃; H NMR (400 MHz, CDCl3) δ: 1.26 (t, J＝
7.2 Hz, 3H), 1.82 (s, 6H), 2.17 (s, 3H), 4.33 (q, J＝7.2
Hz, 2H), 6.69 (s, 2H), 7.08－7.11 (m, 2H), 7.15－7.17
(m, 3H), 7.21 (s, 5H); 13C NMR (100 MHz, CDCl3) δ:
14.2, 20.1 (2C), 21.2, 61.0, 123.8 (2C), 125.2, 125.5,
127.0, 127.6 (2C), 127.7, 128.5 (2C), 128.7 (2C), 129.6
Ethyl 1,4,5-triphenyl-1H-pyrazole-3-carboxylate
(4aa) Pale yellow solid, 1.66 g (90%, Entry 5), m.p.
1
146－148 ℃; H NMR (400 MHz, CDCl3) δ: 1.27 (t,
J＝7.2 Hz, 3H), 4.34 (q, J＝7.2 Hz, 2 H), 6.98 (d, J＝
7.2 Hz, 2H), 7.16 (t, J＝7.2 Hz, 2H), 7.21－7.24 (m,
3H), 7.26－7.31 (m, 6H), 7.37－7.80 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ: 14.2, 60.9, 124.9, 125.7
(2C), 127.1, 127.7 (2C), 128.1, 128.3 (2C), 128.5, 128.8
(2C), 129.0, 130.4 (2C), 130.7 (2C), 131.8, 139.5, 141.6,
142.2, 162.5; HRMS (ESI) m/z: [M＋H＋] calcd for
C24H21N2O2: 369.1603, found 369.1594.
1
(2C), 131.9, 137.8 (2C), 139.1, 139.6, 141.1, 141.4,
＋
162.8; HRMS (ESI) m/z: [M ＋ H ] calcd for
C27H27N2O2: 411.2073, found 411.2074.
Synthesis of ethyl 1,4,5-triaryl-1H-pyrazole-3-car-
boxylates 4 from 1 and 3 (Table 3)
Ethyl 1,5-diphenyl-4-p-tolyl-1H-pyrazole-3-car-
boxylate (4ea) White solid, 1.63 g (85%), m.p. 186－
Ethyl oxalyl chloride (0.82 g, 6.0 mmol) was added
to a solution of t-BuOLi (0.96 g, 12.0 mmol),
1,2-diarylethanones 1 (5.0 mmol) in anhydrous THF (20
mL). The resulting mixture was stirred under reflux for
6 h. Then, the mixture was concentrated in vacuo to
remove THF giving a residual. Afterwards, EtOH (20
mL), concentrated hydrochloric acid (1.71 mL, 20.0
mmol) and arylhydrazine hydrochlorides 3 (5.0 mmol)
were added to the residual at room temperature, and
then the mixtures were refluxed for another 6 h. The
reaction solution was concentrated in vacuo to remove
EtOH affording a new 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 (10 mL×2). Finally, the combined organic
phase was washed with brine (35 mL×2), dried over
anhydrous sodium sulfate, and concentrated to provide a
crude product, which was purified by column chroma-
tography [V(petroleum ether)∶V(EtOAc)＝1∶20] to
give the corresponding 4.
1
188 ℃; H NMR (400 MHz, CDCl3) δ: 1.30 (t, J＝7.2
Hz, 3H), 2.32 (s, 3H), 4.35 (q, J＝7.2 Hz, 2H), 6.99 (d,
J＝8.4 Hz, 2H), 7.07 (d, J＝8.4 Hz, 2H), 7.12 (d, J＝
8.4 Hz, 2H), 7.17 (t, J＝7.2 Hz, 2H), 7.22 (d, J＝7.2 Hz,
1H), 7.30－7.35 (m, 5H); 13C NMR (100 MHz, CDCl3)
δ: 14.2, 21.3, 60.9, 123.4, 124.9, 125.7 (2C), 128.1,
128.3, 128.41, 128.44 (2C), 128.6, 128.8 (2C), 129.1,
130.4 (2C), 130.5 (2C), 136.7, 139.5, 142.1, 144.9,
＋
162.5; HRMS (ESI) m/z: [M ＋ H ] calcd for
C25H23N2O2: 383.1760, found 383.1768.
Ethyl 4-(4-chlorophenyl)-1,5-diphenyl-1H-pyra-
zole-3-carboxylate (4fa) White solid, 1.73 g (86%),
m.p. 160－162 ℃; 1H NMR (400 MHz, CDCl3) δ: 1.30
(t, J＝7.2 Hz, 3H), 4.35 (q, J＝7.2 Hz, 2H), 6.97 (d, J＝
7.6 Hz, 2H), 7.15－7.22 (m, 4H), 7.23－7.35 (m, 8H);
13C NMR (100 MHz, CDCl3) δ: 14.2, 61.1, 123.7, 125.7
(2C), 128.0 (2C), 128.3, 128.5 (2C), 128.7 (2C), 128.9
(2C), 130.3 (3C), 132.1 (2C), 133.2, 139.3, 141.4, 142.4,
＋
162.4; HRMS (ESI) m/z: [M ＋ H ] calcd for
Ethyl 1,4,5-triphenyl-1H-pyrazole-3-carboxylate
(4aa) Pale yellow solid, 1.66 g (90%), m.p. 146－148
℃. The spectral data were shown above.
Ethyl 1,4-diphenyl-5-p-tolyl-1H-pyrazole-3-car-
boxylate (4ba) Pale yellow solid, 1.68 g (88%), m.p.
C24H20N2O2Cl: 403.1213, found 403.1209.
Ethyl 1,5-diphenyl-4-o-tolyl-1H-pyrazole-3-car-
boxylate (4ga) Pale yellow solid, 1.49 g (78%), m.p.
1
106－108 ℃; H NMR (400 MHz, CDCl3) δ: 1.19 (t,
J＝7.2 Hz, 3H), 2.06 (s, 3H), 4.27 (q, J＝7.2 Hz, 2H),
Chin. J. Chem. 2013, 31, 1526—1538
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1535

Zhai et al.
FULL PAPER
6.94 (d, J＝7.2 Hz, 2H), 7.09－7.22 (m, 7H), 7.31－
7.37 (m, 5H); 13C NMR (100 MHz, CDCl3) δ: 14.1,
20.3, 60.8, 124.3, 125.2, 125.6 (2C), 127.7, 128.1, 128.3
(2C), 128.4, 128.9 (2C), 129.2, 129.5, 129.7 (2C), 131.0,
131.9, 137.4, 139.6, 142.06, 142.09, 162.3; HRMS (ESI)
m/z: [M＋H＋] calcd for C25H23N2O2: 383.1760, found
383.1736.
Ethyl 4-(2-chlorophenyl)-1,5-diphenyl-1H-pyra-
zole-3-carboxylate (4ha) Brown oil, 1.63 g (81%); 1H
NMR (400 MHz, CDCl3) δ: 1.93 (t, J＝7.2 Hz, 3H),
4.30 (q, J＝7.2 Hz, 2H), 7.00 (d, J＝8.0 Hz, 2H), 7.14
－7.25 (m, 6H), 7.30－7.36 (m, 5H), 7.41 (d, J＝8.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ: 14.0, 60.9, 122.1,
125.6 (2C), 126.2, 128.1, 128.3 (2C), 128.6, 128.79,
128.85 (2C), 128.9, 129.1, 129.8 (2C), 131.8, 132.2,
135.1, 139.4, 142.2, 142.6, 162.1; HRMS (ESI) m/z: [M
＋ H ＋ ] calcd for C24H20N2O2Cl: 403.1213, found
403.1217.
Ethyl 4-(2,4-dichlorophenyl)-1,5-diphenyl-1H-py-
razole-3-carboxylate (4ia) Pale yellow solid, 1.75 g
(80%), m.p. 144－146 ℃; 1H NMR (400 MHz, CDCl3)
δ: 1.24 (t, J＝7.2 Hz, 3H), 4.31 (q, J＝7.2 Hz, 2H), 6.98
(d, J＝7.2 Hz, 2H), 7.08 (d, J＝8.4 Hz, 1H), 7.14－7.25
(m, 4H), 7.30－7.35 (m, 5H), 7.43 (d, J＝2.0 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ: 14.1, 61.0, 121.0, 125.6
(2C), 126.7, 128.3, 128.47 (2C), 128.53, 128.8, 128.9
(2C), 129.0, 129.8 (2C), 130.5, 133.0, 134.1, 135.8,
139.2, 142.1, 142.8, 161.9; HRMS (ESI) m/z: [M＋H＋]
calcd for C24H19N2O2Cl2: 437.0824, found 437.0828.
Ethyl 4-(4-chlorophenyl)-5-(2,4-dimethylphenyl)-
10H); 13C NMR (100 MHz, CDCl3) δ: 14.2, 21.1, 60.9,
124.7, 125.5 (2C), 127.1, 127.7 (2C), 128.3 (2C), 128.4,
129.1, 129.4 (2C), 130.4 (2C), 130.7 (2C), 132.0, 137.0,
138.1, 141.4, 142.2, 162.6; HRMS (ESI) m/z: [M＋H＋]
calcd for C25H23N2O2: 383.1760, found 383.1786.
Ethyl 1-(2,4-dimethylphenyl)-4,5-diphenyl-1H-
pyrazole-3-carboxylate (4ac) Pale yellow solid, 1.65
1
g (83%), m.p. 104－106 ℃; H NMR (400 MHz,
CDCl3) δ: 1.26 (t, J＝7.2 Hz, 3H), 1.94 (s, 3H), 2.30 (s,
3H), 4.33 (q, J＝7.2 Hz, 2H), 6.92 (d, J＝8.0 Hz, 2H),
6.97 (d, J＝8.0 Hz, 2H), 7.09 (t, J＝7.6 Hz, 2H), 7.15 (t,
J＝7.6 Hz, 2H), 7.22－7.30 (m, 5H); 13C NMR (100
MHz, CDCl3) δ: 14.2, 17.6, 21.2, 60.8, 123.6, 127.0,
127.1, 127.7 (2C), 128.0, 128.1 (2C), 128.2, 128.8,
129.9 (2C), 130.7 (2C), 131.4, 132.1, 135.0, 136.2,
139.2, 141.1, 143.4, 162.6; HRMS (ESI) m/z: [M＋H＋]
calcd for C26H25N2O2: 397.1916, found 397.1931.
Ethyl 1-(2,5-dimethylphenyl)-4,5-diphenyl-1H-
pyrazole-3-carboxylate (4ad) White solid, 1.67 g
(84%), m.p. 94－96 ℃; 1H NMR (400 MHz, CDCl3) δ:
1.27 (t, J＝7.2 Hz, 3H), 1.88 (s, 3H), 2.30 (s, 3H), 4.33
(q, J＝7.2 Hz, 2H), 6.93 (d, J＝7.6 Hz, 2H), 7.02 (d,
J＝7.6 Hz, 1H), 7.10 (t, J＝7.6 Hz, 3H), 7.14－7.19 (m,
2H), 7.23－7.29 (m, 5H); 13C NMR (100 MHz, CDCl3)
δ: 14.2, 17.2, 20.8, 60.8, 123.6, 127.1, 127.8 (2C), 128.1
(2C), 128.3, 128.8 (2C), 129.9 (2C), 130.2, 130.6, 130.8
(2C), 132.0, 132.1, 136.3, 138.5, 141.2, 143.3, 162.6;
HRMS (ESI) m/z: [M＋H＋ ] calcd for C26H25N2O2:
397.1916, found 397.1927.
Ethyl 1-(2,6-dimethylphenyl)-4,5-diphenyl-1H-
pyrazole-3-carboxylate (4ae) Pale yellow solid, 1.47
1-phenyl-1H-pyrazole-3-carboxylate (4ja)
Brown
1
1
solid, 1.70 g (79%), m.p. 158－160 ℃; H NMR (400
MHz, CDCl3) δ: 1.32 (t, J＝7.2 Hz, 3H), 1.79 (s, 3H),
2.26 (s, 3H), 4.37 (q, J＝7.2 Hz, 2H), 6.87－6.93 (m,
3H), 7.10 (d, J＝8.4 Hz, 2H), 7.19 (d, J＝8.4 Hz, 2H),
7.26－7.32 (m, 5H); 13C NMR (100 MHz, CDCl3) δ:
14.2, 19.6, 21.3, 61.1, 124.2, 124.6 (2C), 125.5, 126.8,
127.85 (2C), 127.90, 128.8 (2C), 130.4, 131.2 (2C),
g (74%), m.p. 170－171 ℃; H NMR (400 MHz,
CDCl3) δ: 1.27 (t, J＝7.2 Hz, 3H), 2.01 (s, 6H), 4.34 (q,
J＝7.2 Hz, 2H), 6.90 (d, J＝8.0 Hz, 2H), 7.03 (d, J＝
8.0 Hz, 2H), 7.08 (t, J＝8.0 Hz, 2H), 7.17 (q, J＝8.0 Hz,
2H), 7.26－7.29 (m, 5H); 13C NMR (100 MHz, CDCl3)
δ: 14.2, 17.9 (2C), 60.9, 123.6, 127.1, 127.8 (2C), 128.1
(2C), 128.2 (2C), 128.4, 128.6, 129.4 (4C), 130.8, 132.1,
136.2 (2C), 137.9, 141.4, 143.2, 162.6; HRMS (ESI)
m/z: [M＋H＋] calcd for C26H25N2O2: 397.1916, found
397.1927.
131.5 (2C), 133.0, 137.3, 139.4, 139.5, 141.1, 142.3,
＋
162.6; HRMS (ESI) m/z: [M ＋ H ] calcd for
C26H24N2O2Cl: 431.1526, found 431.1521.
Ethyl 4-(2-chlorophenyl)-5-(2,4-dimethylphenyl)-
1-phenyl-1H-pyrazole-3-carboxylate (4ka) Pale yel-
low solid, 1.59 g (74%), m.p. 110－112 ℃; H NMR
(400 MHz, CDCl3) δ: 1.20 (t, J＝7.2 Hz, 3H), 1.83 (s,
3H), 2.23 (s, 3H), 4.31 (q, J＝7.2 Hz, 2H), 6.86 (t, J＝
7.6 Hz, 2H), 6.96－7.11 (m, 2H), 7.12－7.21 (m, 2H),
7.22－7.40 (m, 6H); 13C NMR (100 MHz, CDCl3) δ:
14.3, 19.7, 21.2, 61.1, 124.6, 124.8, 126.4, 127.1, 127.4,
127.7 (2C), 130.05 (2C), 130.14, 130.6, 131.08, 131.12,
Ethyl 1-(3-chlorophenyl)-4,5-diphenyl-1H-pyra-
zole-3-carboxylate (4af) Pale yellow solid, 1.73 g
(86%), m.p. 86－88 ℃; 1H NMR (400 MHz, CDCl3) δ:
1.26 (t, J＝7.2 Hz, 3H), 4.34 (q, J＝7.2 Hz, 2H), 6.99 (d,
J＝7.6 Hz, 2H), 7.06 (d, J＝8.0 Hz, 1H), 7.16－7.25 (m,
5H), 7.26－7.29 (m, 2H), 7.33－7.58 (m, 4H); 13C
NMR (100 MHz, CDCl3) δ: 14.2, 61.0, 123.6, 125.1,
125.9, 127.3, 127.7 (2C), 128.3, 128.5 (2C), 128.6,
128.8, 129.7, 130.3 (2C), 130.6 (2C), 131.5, 134.6,
140.4, 142.1, 142.3, 162.3; HRMS (ESI) m/z: [M＋H＋]
calcd for C24H20N2O2Cl: 403.1213, found 403.1230.
Ethyl 1-(3-nitrophenyl)-4,5-diphenyl-1H-pyra-
zole-3-carboxylate (4ag) Pale yellow solid, 1.80 g
(87%), m.p. 130－132 ℃; 1H NMR (400 MHz, CDCl3)
δ: 1.27 (t, J＝7.2 Hz, 3H), 4.35 (q, J＝7.2 Hz, 2H), 7.03
(d, J＝8.0 Hz, 2H), 7.21－7.32 (m, 8H), 7.48 (t, J＝8.0
Hz, 1H), 7.61 (d, J＝8.0 Hz, 1H), 8.17 (d, J＝8.0 Hz,
1
131.6, 133.3, 135.8, 135.9, 137.5, 139.3, 141.7, 144.0,
＋
162.5; HRMS (ESI) m/z: [M ＋ H ] calcd for
C26H24N2O2Cl: 431.1526, found 431.1530.
Ethyl 4,5-diphenyl-1-p-tolyl-1H-pyrazole-3-car-
boxylate (4ab) Gray solid, 1.63 g (85%), m.p. 138－
1
140 ℃; H NMR (400 MHz, CDCl3) δ: 1.26 (t, J＝7.2
Hz, 3H), 2.34 (s, 3H), 4.33 (q, J＝7.2 Hz, 2H), 6.98 (d,
J＝7.6 Hz, 2H), 7.10 (d, J＝8.0 Hz, 2H), 7.14－7.26 (m,
1536
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Chin. J. Chem. 2013, 31, 1526—1538

A One-pot Approach to Ethyl 1,4,5-Triaryl-1H-pyrazole-3-carboxylates
1H), 8.25 (d, J＝1.2 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ: 14.1, 61.2, 120.5, 122.6, 125.5, 127.4, 127.8
(2C), 128.3, 128.8 (2C), 129.2, 129.8, 130.3 (2C), 130.6
(2C), 130.9, 131.2, 140.3, 142.5, 142.7, 148.3, 162.1;
HRMS (ESI) m/z: [M＋Na＋] calcd for C24H19N3O4Na:
436.1273, found 436.1285.
(m, 6H), 7.45 (s, 1H); 13C NMR (100 MHz, CDCl3) δ:
14.2, 19.5, 21.2, 61.2, 124.0, 124.8, 126.4, 127.1, 127.7
(2C), 128.5, 128.6, 128.7, 129.8, 130.1 (2C), 131.4,
131.6, 135.3, 136.2, 136.4, 137.7, 139.4, 142.2, 144.1,
＋
162.4; HRMS (ESI) m/z: [M ＋ H ] calcd for
C26H22N2O2Cl3: 499.0747, found 499.0747.
Ethyl 1-(2,4-dichlorophenyl)-4,5-diphenyl-1H-
pyrazole-3-carboxylate (4ah) Pale yellow solid, 1.79
g (82%), m.p. 124－126 ℃;1H NMR (400 MHz,
CDCl3) δ: 1.27 (t, J＝7.2 Hz, 3H), 4.34 (q, J＝7.2 Hz,
2H), 6.97 (d, J＝7.6 Hz, 2H), 7.15 (t, J＝7.6 Hz, 2H),
7.20 (d, J＝7.2 Hz, 1H), 7.26－7.29 (m, 5H), 7.30 (d,
J＝2.0 Hz, 1H), 7.39－7.42 (m, 2H); 13C NMR (100
MHz, CDCl3) δ: 14.2, 61.1, 124.0, 127.3, 127.7, 127.8
(2C), 128.2, 128.3 (2C), 128.7, 129.9 (2C), 130.1, 130.7
Ethyl 4-(2-chlorophenyl)-1-(2,4-dichlorophenyl)-
5-phenyl-1H-pyrazole-3-carboxylate (4hh)
Pale
1
yellow solid, 1.77 g (75%), m.p. 72－74 ℃; H NMR
(400 MHz, CDCl3) δ: 1.11 (t, J＝7.2 Hz, 3H), 4.20 (q,
J＝7.2 Hz, 2H), 6.91 (d, J＝8.0 Hz, 2H), 7.05 (t, J＝7.2
Hz, 2H), 7.10－7.24 (m, 6H), 7.34 (d, J＝7.2 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ: 14.0, 61.0, 121.2, 126.3,
127.7, 128.0, 128.3 (2C), 128.5, 128.8, 129.07, 129.13,
129.3, (2C), 130.1, 130.8, 131.5, 132.2, 133.4, 136.0,
136.1, 142.9, 144.6, 161.8; HRMS (ESI) m/z: [M＋H＋]
calcd for C24H18N2O2Cl3: 471.0434, found 471.0432.
Ethyl 4-(2,4-dichlorophenyl)-5-phenyl-1-(2,4,6-
trichlorophenyl)-1H-pyrazole-3-carboxylate (4ii)
(2C), 130.9, 131.5, 133.3, 136.0 (2C), 142.2, 144.1,
＋
162.2; HRMS (ESI) m/z: [M ＋ H ] calcd for
C24H19N2O2Cl2: 437.0824, found 437.0818.
Ethyl 4,5-diphenyl-1-(2,4,6-trichlorophenyl)-1H-
pyrazole-3-carboxylate (4ai) Yellow solid, 1.82 g
(77%), m.p. 130－132 ℃; 1H NMR (400 MHz, CDCl3)
δ: 1.27 (t, J＝7.2 Hz, 3H), 4.34 (q, J＝7.2 Hz, 2H), 7.07
(d, J＝8.0 Hz, 2H), 7.16 (t, J＝7.6 Hz, 2H), 7.20－7.23
(m, 1H), 7.26－7.32 (m, 3H), 7.35 (s, 2H), 7.38－7.50
(m, 2H); 13C NMR (100 MHz, CDCl3) δ: 14.2, 61.1,
124.1, 127.3, 127.7 (2C), 128.0, 128.4 (2C), 128.6 (2C),
129.1, 129.5 (2C), 130.7 (2C), 131.3, 134.3, 135.8 (2C),
136.4, 142.9, 144.6, 162.1; HRMS (ESI) m/z: [M＋H＋]
calcd for C24H18N2O2Cl3: 471.0434, found 471.0435.
Ethyl 4,5-diphenyl-1-(4-phenylthiazol-2-yl)-1H-
pyrazole-3-carboxylate (4aj) Pale yellow solid, 1.83
1
Yellow solid, 1.81 g (67%), m.p. 60－62 ℃; H NMR
(400 MHz, CDCl3) δ: 1.25 (t, J＝7.2 Hz, 3H), 4.33 (q,
J＝7.2 Hz, 2H), 7.07－7.10 (m, 2H), 7.13－7.28 (m,
5H), 7.33－7.37 (m, 1H), 7.42 (d, J＝2.0 Hz, 1H), 7.45
(d, J＝2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ:
14.1, 61.2, 120.2, 126.8, 127.4, 128.50 (2C), 128.55,
128.6, 128.9 (2C), 129.1, 129.4, 130.0, 132.9, 134.1,
134.3, 135.7, 135.86, 135.93, 136.6, 143.5, 145.3, 161.6;
HRMS (ESI) m/z: [M＋Na＋] calcd for C24H15N2OCl52-
Na: 560.9474, found 560.9475.
Ethyl 4-(2-chlorophenyl)-1-(2,4-dichlorophenyl)-
5-(2,4-dimethylphenyl)-1H-pyrazole-3-carboxylate
1
1
g (81%), m.p. 181－183 ℃; H NMR (400 MHz,
(4kh) Orange oil, 1.65 g (66%); H NMR (400 MHz,
CDCl3) δ: 1.27 (t, J＝7.2 Hz, 3H), 4.34 (q, J＝7.2 Hz,
2H), 7.24－7.38 (m, 14H), 7.47 (d, J＝6.8 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ: 14.1, 61.3, 111.1, 125.9
(2C), 126.2, 127.4, 127.7 (2C), 128.0 (2C), 128.3, 128.6
(2C), 128.8, 128.9, 130.5 (2C), 130.8, 130.9 (2C), 133.6,
143.1, 143.2, 152.4, 159.6, 161.9; HRMS (ESI) m/z: [M
＋ H ＋ ] calcd for C27H22N3O2S: 452.1433, found
452.1430.
CDCl3) δ: 1.22 (t, J＝7.2 Hz, 3H), 1.90 (s, 3H), 2.20 (s,
3H), 4.31 (q, J＝7.2 Hz, 2H), 6.78－6.83 (m, 2H), 6.97
－7.41 (m, 8H); 13C NMR (100 MHz, CDCl3) δ: 14.0,
19.4, 21.2, 61.1, 124.0, 126.2, 126.3, 127.4, 128.8,
129.2, 130.1, 130.5, 131.0, 131.1, 131.3, 131.8, 133.2,
134.7, 135.76, 135.85, 137.7, 139.30, 139.35, 144.3,
148.7, 162.1; HRMS (ESI) m/z: [M＋Na＋] calcd for
C26H21N2O2Cl3Na: 521.0566, found 521.0554.
Ethyl 1-(2,4-dichlorophenyl)-5-(2,4-dimethyl-
phenyl)-4-phenyl-1H-pyrazole-3-carboxylate (4ch)
Pale yellow solid, 1.70 g (73%), m.p. 62－64 ℃; H
Ethyl 4-(2-chlorophenyl)-5-(2,4-dimethylphenyl)-
1-(2,4,6-trichlorophenyl)-1H-pyrazole-3-carboxylate
(4ki) Pale yellow solid, 1.60 g (60%), m.p. 162－164
1
1
NMR (400 MHz, CDCl3) δ: 1.31 (t, J＝7.2 Hz, 3H),
1.82 (s, 3H), 2.22 (s, 3H), 4.38 (q, J＝6.4 Hz, 2H), 6.83
(d, J＝7.6 Hz, 2H), 6.95 (d, J＝7.6 Hz, 1H), 7.21－7.23
(m, 6H), 7.31 (s, 1H), 7.40 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ: 14.2, 19.6, 21.2, 61.1, 124.5, 124.7, 126.4,
127.1, 127.4, 127.7 (2C), 130.0 (2C), 130.1, 130.6,
131.05, 131.09, 131.6, 133.3, 135.8, 135.9, 137.5, 139.2,
141.7, 144.0, 162.4; HRMS (ESI) m/z: [M＋Na＋] calcd
for C26H22N2O2NaCl2: 487.0956, found 487.0956.
℃; H NMR (400 MHz, CDCl3) δ: 1.24 (t, J＝7.2 Hz,
3H), 1.87 (s, 2H), 2.05 (s, 1H), 2.20 (s, 1H), 2.21 (s, 2H),
4.32 (t, J＝7.2 Hz, 2H), 6.78－6.91 (m, 3H), 7.03－
7.29 (m, 4H), 7.39－7.45 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ: 14.0, 19.2, 21.2, 61.2, 121.7, 123.4, 126.3,
126.4, 128.5 (2C), 128.7, 129.3, 129.8, 130.3, 131.3,
131.4, 131.6, 134.2, 134.7, 135.4, 136.2, 136.3, 139.4,
143.7, 144.4, 162.1; HRMS (ESI) m/z: [M＋Na＋] calcd
for C26H20N2O2NaCl4: 555.0177, found 555.0173.
Ethyl 5-(2,4-dimethylphenyl)-4-phenyl-1-(2,4,6-
Ethyl 1-(2,4-dichlorophenyl)-4-phenyl-5-(thio-
phen-2-yl)-1H-pyrazole-3-carboxylate (4lh) Pale
brown solid, 1.82 g (82%), m.p. 191－192 ℃; 1H NMR
(400 MHz, CDCl3) δ: 1.24 (t, J＝7.2 Hz, 3H), 4.29 (q,
J＝7.2 Hz, 2H), 6.62 (d, J＝2.8 Hz, 1H), 6.81 (t, J＝4.0
Hz, 1H), 7.20 (d, J＝5.2 Hz, 1H), 7.32－7.39 (m, 6H),
trichlorophenyl)-1H-pyrazole-3-carboxylate
(4ci)
1
Yellow solid, 1.65 g (66%), m.p. 134－136 ℃; H
NMR (400 MHz, CDCl3) δ: 1.32 (t, J＝7.2 Hz, 3H),
1.75 (s, 3H), 2.23 (s, 3H), 4.38 (q, J＝7.2 Hz, 2H), 6.84
(t, J＝8.0 Hz, 2H), 7.10 (d, J＝8.0 Hz, 1H), 7.22－7.25
Chin. J. Chem. 2013, 31, 1526—1538
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1537

Zhai et al.
FULL PAPER
7.48－7.50 (m, 2H); 13C NMR (100 MHz, CDCl3) δ:
14.1, 61.1, 124.5, 126.9, 127.7, 127.88, 127.90, 127.95
(2C), 128.3, 129.0, 130.2, 130.7 (2C), 131.1, 131.5,
134.1, 135.9, 136.6, 138.1, 142.4, 161.9; HRMS (ESI)
m/z: [M＋Na＋] calcd for C22H16N2O2NaSCl2: 465.0207,
found 465.0214.
Lv, J. Bioorg. Med. Chem. Lett. 2013, 23, 4177.
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Ethyl 1-(2,4-dichlorophenyl)-5-(4-methoxyphe-
nyl)-4-(thiophen-2-yl)-1H-pyrazole-3-carboxylate
(4mh) Pale brown solid, 1.96 g (83%), m.p. 118－120
1
℃; H NMR (400 MHz, CDCl3) δ: 1.32 (t, J＝7.1 Hz,
3H), 3.74 (s, 3H), 4.38 (q, J＝7.2 Hz, 2H), 6.72 (d, J＝
8.4 Hz, 2H), 6.98－7.00 (m, 3H), 7.06 (d, J＝3.2 Hz,
1H), 7.29 (d, J＝8.4 Hz, 2H), 7.39 (d, J＝12.4 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ: 14.2, 55.1, 61.2, 113.9
(2C), 116.4, 120.0, 126.1, 126.6, 127.7, 128.9, 130.1,
130.9, 131.3 (2C), 131.9, 133.3, 135.9, 136.1, 142.5,
144.9, 160.0, 162.0; HRMS (ESI) m/z: [M＋H＋] calcd
for C23H19N2O3SCl2: 473.0493, found 473.0490.
Acknowledgement
The authors are grateful to the National Natural Sci-
ence Foundation of China (Nos. 21176074 and
21171093) for financial support.
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data for this paper. There data can be obtained free of charge from
The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
(Lu, Y.)
1538
www.cjc.wiley-vch.de
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 1526—1538