A facile approach to polysubstituted pyrazoles from hydrazonyl chlorides and vinyl azides

Article abstract of DOI:10.1016/j.tet.2011.04.103

A novel and facile approach to polysubstituted pyrazoles from readily synthesized hydrazonyl chlorides and vinyl azides was developed. The reaction was regiospecific and proceeded under mild conditions in the presence of base.

Full text of DOI:10.1016/j.tet.2011.04.103

Tetrahedron 67 (2011) 4887e4891
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A facile approach to polysubstituted pyrazoles from hydrazonyl chlorides and
vinyl azides
Hongbin Zou a, Huajian Zhu a, Jiaan Shao a, Jianwei Wu a, Wenteng Chen a, Marc A. Giulianotti b,
,b,
Yongping Yu a
*
a College of Pharmaceutical Sciences, Zhejiang University, 388 Yuhangtang Road, Hangzhou 310058, PR China
b Torrey Pines Institute for Molecular Studies, 11350 Village Parkway, Port St. Lucie, FL 34987, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 March 2011
Received in revised form 20 April 2011
Accepted 29 April 2011
Available online 6 May 2011
A novel and facile approach to polysubstituted pyrazoles from readily synthesized hydrazonyl chlorides
and vinyl azides was developed. The reaction was regiospecific and proceeded under mild conditions in
the presence of base.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Polysubstituted pyrazoles
Vinyl azides
Hydrazonyl chlorides
Regiospecific approach
X-ray structure
1. Introduction
chlorides in the presence of base with moderate to good yields.
Interestingly, we observed that the nitrogen atom of the three-
Pyrazoles are one of the most prevalent heterocyclic compounds
with wide range of biological activities, such as anti-
atom synthon in vinyl azide was not incorporated into the newly
formed molecule. The azido group herein does not act in a manner
that is usually reported.14 It serves as a leaving group and stabili-
zation of developing negative charge during the reaction in this
study.
a
hyperglycemic,1 anti-inflammatory,2 antiobesity,3 antitumor4
antimycobacterial,5 molluscicidal activity,6 and cardiac hypertro-
phy suppression.7 Considering the important biological properties
of pyrazole compounds, numerous methods toward pyrazoles
syntheses have been developed over the past decades.8,9 The 1,3-
dipolar cycloaddition is widely used for the syntheses of pyrazoles
using diverse synthons, such as nitrilimines and alkynes,10 hydra-
zones and nitroolefins,11 and azomethine imines and alkynes.12 The
most prevalent method is reacting hydrazines with 1,3-dicarbonyl
compounds.13 Despite numerous diverse approaches toward syn-
theses of pyrazoles developed so far, it is still challenging to prepare
polysubstituted pyrazoles with various substituents from readily
available building blocks.
2. Results and discussion
Initially, the reaction between N-phenylbenzohydrazonoyl
chloride 1a and vinyl azide 2a was selected as a model system to
optimize the reaction conditions (Table 1). It was found that no
reaction occurred in the absence of base. With addition of a variety
of bases at room temperature, the polysubstituted pyrazole 3a was
observed as the major product (Table 1). Screening of the solvents
showed that THF was the most efficient solvent producing the
highest yields (Table 1, entries 2e4). It is noteworthy that the se-
lection of the base plays a crucial role in the success of 3a synthesis
and Cs2CO3 was found to be the most favorable base of the ones
tested (Table 1, entries 4e9). The reaction was also tested at higher
temperature but with a slight decrease in the yield (Table 1, entry
10). Based on this initial study, the most suitable reaction condition
for the formation of 3a was established (Table 1, entry 4). The crude
product, obtained under this reaction condition, was analyzed by
LCeMS. The result showed that the 1,3-dipolar cycloaddition of 1a
Vinyl azides, precursors of 2H-azirines, have been widely uti-
lized in cycloaddition reactions yielding heterocyclic compounds in
recent years.14 Previously, we have found a domino approach to
pyrrolo[1,2-a]pyrazines from vinyl azides and 1H-2-pyrrole-
carbaldehyde.14a Herein we report a facile approach to provide
polysubstituted pyrazoles from vinyl azides and hydrazonyl
* Corresponding author. Tel.: þ86 0571 88208452; fax: þ86 0571 88205452;
e-mail address: yyu@zju.edu.cn (Y. Yu).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.103

4888
H. Zou et al. / Tetrahedron 67 (2011) 4887e4891
(Table 2, entry10,36%), compared to3a(Table 2, entry1, 81%). Itmight
Table 1
indicate that a strong electron-withdrawing group on the phenyl ring
of R1-substituent is not favorable for the reaction under the synthetic
conditions described. When the aryl R1-substituent was changed to
isopropyl group (Table 2, entry 17), the isolated yield of the reaction
decreased comparing to entry 1 (Table 2).
Optimization of reaction conditionsa
O
O
Ph
N
Cl
H
N
base
solvent
+
OEt
Ph
OEt
Ph
Ph
N
Ph
N
N3
2a
To extend the utility of this reaction, a set of vinyl azides were
also explored (Table 2, entries 11e16 and 18e20). On the basis of
these studies, we found that a range of R2- and R3-substituents can
be tolerated in this reaction. Results from entries 11e14 indicated
that the electron deficient phenyl ring of R2-substituents was fa-
vorable for the yield. The vinyl azide 2n, having a R2-substituent as
3-NO2 substituted phenyl, gave the desired product with good
isolated yield (86%, Table 2, entry 14). The electron-withdrawing
inductive effects of R3-substituent were also evaluated. In this
case the mild electron-withdrawing group (Table 2, entry 15) gave
the product in relative lower isolated yield (55%), compared to
entry 12 (Table 2, 71%). Unexpectedly, no reaction took place when
R2-substituent was just hydrogen (Table 2, entry 16).
Ph
1a
3a
Entry
Base
Solvent
T (ꢀC)
Yieldb (%)
1
2
3
4
5
6
7
8
9
d
THF
DMF
MeCN
THF
THF
THF
THF
THF
THF
THF
25
25
25
25
25
25
25
25
25
50
n.r
19
66
91
89
42
n.r.
Trace
Trace
86
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
CsF
Cs2SO4
TBAF
DBU
10
Cs2CO3
a
The polysubstituted pyrazoles were characterized by 1H and 13
C
Reaction conditions: vinyl azide (0.1 mmol, 1.0 equiv), hydrazonyl chloride
(0.11 mmol, 1.1 equiv), base (0.1 mmol, 1.0 equiv), 1.5 mL solvent, 24 h, rt.
NMR, MS, and HRMS (ESI). In the presence of base the hydrazonyl
chloride liberates the l,3-dipolar diphenyl-nitrilimine.17 It is pos-
sible that either Michael addition mode could occur, initiated by the
formed tautomeric electronegative carbon or nitrogen atom. For
this reason it is necessary to establish the reaction pathway. In
order to accomplish this, the pyrazole structures were confirmed by
single-crystal X-ray diffraction studies. Pyrazole 3f is given as an
example (Fig. 1).
b
Determined by HPLC, based on the disappearance of the starting vinyl azide. The
most successful entry is highlighted in bold.
and 2a we presented herein was regiospecific affording pyrazole
with only one isomer (3a).
With the optimized reaction conditions in hand, the scope and
limitation of the reaction were examined with a variety of hydra-
zonyl chlorides 1 and vinyl azides 2. The hydrazonyl chlorides were
readily prepared from hydrazones.15 The vinyl azides presented
herein were synthesized from benzaldehydes14bed or styrenes.16
As shown in Table 2, the reaction can tolerate a range of R1-sub-
stituents, such as alkyl, aryl, thienyl, furyl, and pyridinyl moieties. The
influence of R1-substituents in this reaction is illustrated in entries
1e10 and 17. In particular, we would like to point out entry 10 where
the 3-NO2 on the aromatic ring lead to sharp reduction in yield, 3j
Table 2
Reactions of vinyl azides and hydrazonyl chloridesa
R2
Cl
R3
R3
Ph
H
N
Cs2CO3
R2
+
R1
N
R1
Ph
THF, r.t., 24h
N
N3
N
2
1
3
Entry R1
R2
R3
Compound Yieldb (%)
1
2
3
4
5
6
7
8
Ph
4-FC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
81
91
71
68
72
74
75.
68
52
36
69
71
64
86
55
n.r
55
67
64
83
Fig. 1. Crystal structure of compound 3f.
4-BrC6H4
2-BrC6H4
4-ClC6H4
4-MeOC6H4
Furyl
2-(5-BrThiazoyl) Ph
2-Pyridinyl
3-NO2C6H4
Ph
Ph
Ph
Ph
Ph
On the basis of the above investigations, a plausible mechanism
is proposed as shown in Scheme 1. The presence of base initiates
the polarization of 1 by removal of the hydrogen. The formed active
hydrazonyl chloride is expected to have a Michael addition and
a subsequent intramolecular cyclization with vinyl azide (2) to get
the intermediate. A fast elimination of the intermediate, driven
by excellent leaving group ability of the azido group, affords the
polysubstituted pyrazole (3) in the presence of base.
9
Ph
Ph
4-FC6H4
4-BrC6H4
4-MeOC6H4 CO2Et
3-NO2C6H4 CO2Et
4-BrC6H4
H
10
11
12
13
14
15
16
17
18
19
20
4-ClC6H4eCO
1-MorpholinyleCO 3p
CO2Et
2-ThiophenyleCO 3r
CO2Et
CO2tBu
Ph
(CH3)2CH
(CH3)2CH
Ph
Ph
3q
3. Conclusions
4-FC6H4
C3H7
Ph
3s
3t
In summary, we have reported a novel, facile, and regiospecific
approach for the preparation of polysubstituted pyrazoles under
mild conditions. This reaction was realized with readily available
hydrazonyl chlorides and vinyl azides in moderate to good yields.
Ph
a
Reactions were carried out in THF (4.0 mL) with 1 (0.33 mmol), 2 (0.3 mmol),
and Cs2CO3 (0.3 mmol) at rt for 24 h under N2.
b
Isolated yield.

H. Zou et al. / Tetrahedron 67 (2011) 4887e4891
4889
m/z [MþH]þ: 369.3; HRMS (ESI): m/z calcd for C24H20N2O2 (M)þ
368.1525, found: m/z 368.1530.
l
C
l
C
H
N
base
H
N
N
R1
N
Ph
R1
N
Ph
4.2.2. 3-(4-Fluorophenyl)-1,4-diphenyl-1H-pyrazole-5-carboxylic
1
acid ethyl ester (3b). 1H NMR (500 MHz, CDCl3):
d 7.549e7.531 (2H,
l
C
m), 7.504e7.474 (2H, m), 7.458e7.412 (3H, m), 7.376e7.353 (3H, m),
7.333e7.313 (2H, m), 6.934 (2H, t, J¼9.0 Hz), 4.050 (2H, q, J¼7.5 Hz),
R3
N
Ph
R2
l
C
R1
R2
0.909 (3H, t, J¼7.5 Hz); 13C NMR (125 MHz, CDCl3):
d 162.6 (d,
N3
2
N
N3
R1
N
Ph
Ph
J¼246 Hz), 160.0, 149.3, 140.4, 132.6, 132.1, 130.4, 129.9 (d, J¼8 Hz),
128.8, 128.5, 128.3 (d, J¼3 Hz), 128.1, 127.7, 125.3, 124.9, 115.2 (d,
J¼21 Hz), 61.3, 13.4; LCeMS (ESI): m/z [MþH]þ: 387.2; HRMS (ESI):
m/z calcd for C24H19N2O2F(M)þ 386.1431, found: m/z 386.1435.
l
C
R3
R2
R1
R2
R3
N
N
N
4.2.3. 3-(4-Bromophenyl)-1,4-diphenyl-1H-pyrazole-5-carboxylic
R1
Ph
N3
N
3
acid ethyl ester (3c). 1H NMR (500 MHz, CDCl3):
d 7.548e7.529 (2H,
H
R3
m), 7.508e7.478 (2H, m), 7.465e7.431 (1H, m), 7.381e7.364 (5H, m),
7.337e7.312 (4H, m), 4.048 (2H, q, J¼7.0 Hz), 0.907 (3H, t, J¼7.0 Hz);
Scheme 1. Proposed reaction mechanism.
13C NMR (125 MHz, CDCl3):
d 160.1, 149.2, 140.6, 133.0, 132.2, 131.6,
131.4, 130.6, 129.8, 129.0, 128.8, 128.4, 127.9,125.5, 125.2, 122.4, 61.5,
13.6; LCeMS (ESI): m/z [MþH]þ: 447.2; HRMS (ESI): m/z calcd for
C24H19N2O2Br(M)þ 446.0630, found: m/z 446.0635.
Interestingly, the azido group of the vinyl azides was not in-
corporated into the newly formed molecule and served as a leaving
group in this study.
4.2.4. 3-(2-Bromophenyl)-1,4-diphenyl-1H-pyrazole-5-carboxylic
acid ethyl ester (3d). 1H NMR (500 MHz, CDCl3):
d 7.572e7.545 (3H,
4. Experimental section
4.1. General
m), 7.494e7.464 (2H, t, J¼7.5 Hz), 7.426 (1H, t, J¼7.5 Hz), 7.335 (1H,
d, J¼7.5 Hz), 7.273e7.245 (6H, m), 7.175 (1H, t, J¼7.5 Hz), 4.125 (2H,
q, J¼7.0 Hz), 0.988 (3H, t, J¼7.0 Hz); 13C NMR (125 MHz, CDCl3):
d
160.6, 150.9, 140.6, 133.9, 133.1, 132.7, 131.7, 130.3, 130.1, 129.0,
Reactions were carried out in anhydrous solvents under nitro-
gen atmosphere. THF was distilled from sodium-benzophenone.
Purifications of reaction products were carried out by chromatog-
raphy using silica gel (200e300 mesh). Melting points were
128.7, 127.9, 127.5, 127.2, 126.5, 125.5, 124.4, 61.7, 13.7; LCeMS (ESI):
m/z [MþH]þ: 447.2; HRMS (ESI): m/z calcd for C24H19N2O2Br(M)þ
446.0630, found: m/z 446.0634.
€
recorded on a BUCHI B-540 melting point apparatus. NMR spectra
were recorded for 1H NMR at 500 MHz and for 13C NMR at 125 MHz.
4.2.5. 3-(4-Chlorophenyl)-1,4-diphenyl-1H-pyrazole-5-carboxylic
acid ethyl ester (3e). 1H NMR (500 MHz, CDCl3):
d 7.547e7.528 (2H,
For 1H NMR, tetramethylsilane (TMS) served as internal standard
m), 7.506e7.476 (2H, m), 7.459e7.430 (1H, m), 7.404e7.366 (5H, m),
7.331e7.312 (2H, m), 7.211 (2H, dt, J¼9.0, 2.0 Hz), 4.050 (2H, q,
J¼7.5 Hz), 0.909 (3H, t, J¼7.5 Hz); 13C NMR (125 MHz, CDCl3):
(d) and data are reported as follows: chemical shift, integration,
multiplicity (s¼singlet, d¼doublet, t¼triplet, q¼quartet,
m¼multiplet), and coupling constant(s) in Hertz. For 13C NMR TMS
d
160.1, 149.2, 140.6, 134.1, 132.9, 132.2, 130.9, 130.6, 129.6, 129.0,
(d
¼0) or CDCl3 ( ¼77.26) was used as internal standard and spectra
d
128.8, 128.6, 128.4, 127.9, 125.6, 125.3, 61.5, 13.6; LCeMS (ESI): m/z
[MþH]þ: 403.2; HRMS (ESI): m/z calcd for C24H19N2O2Cl(M)þ
402.1135, found: m/z 402.1130.
were obtained with complete proton decoupling. MS and HRMS
were obtained using ESI ionization. A single crystal of compound 3f
was measured on a Rigaku RAXIS-RAPID single-crystal diffrac-
tometer. Crystallographic data (excluding structure factors) for 3f in
this paper have been deposited at the Cambridge Crystallographic
Data Center with a deposition number CCDC 804343. Copy of the
data can be obtained free of charge on application to CCDC by
e-mail (deposit@ccdc.cam.ac.uk).
4.2.6. 3-(4-Methoxyphenyl)-1,4-diphenyl-1H-pyrazole-5-carboxylic
acid ethyl ester (3f). 1H NMR (500 MHz, CDCl3):
d 7.550e7.531 (2H,
m), 7.490e7.460 (2H, m), 7.437e7.415 (1H, m), 7.401e7.372 (2H, m),
7.372e7.329 (5H, m), 6.776 (2H, dt, J¼8.5, 3.0 Hz), 4.043 (2H, q,
J¼7.0 Hz), 3.763 (3H, s), 0.904 (3H, t, J¼7.0 Hz); 13C NMR (125 MHz,
CDCl3):
d 160.3, 159.6, 150.2, 140.8, 132.7, 130.7, 129.6, 129.0, 128.5,
4.2. General procedure for the synthesis of 3
128.3, 127.7, 125.5, 125.0, 124.9, 113.9, 61.4, 55.4, 13.6; LCeMS (ESI):
m/z [MþH]þ: 399.3; HRMS (ESI): m/z calcd for C25H22N2O3 (M)þ
398.1630, found: m/z 398.1634.
A mixture of hydrazonyl chloride 1 (0.3 mmol, 1.0 equiv), vinyl
azide 2 (0.33 mmol, 1.1 equiv) and Cs2CO3 (0.3 mmol, 1.0 equiv) was
stirred in anhydrous THF (4 mL) at room temperature under ni-
trogen overnight. The reaction mixture was quenched with water
(5 mL), then extracted three times with EtOAc (10 mLꢁ3). The
combined organic extracts were washed with water (10 mLꢁ3),
brine (10 mL), dried over Na2SO4, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel to
afford the desired product 3.
4.2.7. 3-(Furan-2-yl)-1,4-diphenyl-1H-pyrazole-5-carboxylic
acid
ethyl ester (3g). 1H NMR (500 MHz, CDCl3):
d
7.536e7.521 (2H, d,
J¼7.5 Hz), 7.487e7.400 (9H, m), 6.288 (1H, dd, J¼3.5, 1.5 Hz), 6.025
(1H, d, J¼3.5 Hz), 4.021 (2H, q, J¼7.0 Hz), 0.873 (3H, t, J¼7.0 Hz); 13C
NMR (125 MHz, CDCl3):
d 159.8, 147.0, 142.7, 142.4, 140.5, 132.7,
132.1, 130.4, 128.9, 128.8, 128.3, 128.1, 125.8, 124.7, 111.1, 109.0, 61.4,
13.5; LCeMS (ESI): m/z [MþH]þ: 359.2; HRMS (ESI): m/z calcd for
C22H18N2O3 (M)þ 358.1317, found: m/z 358.1322.
4.2.1. 1,3,4-Triphenyl-1H-pyrazole-5-carboxylic acid ethyl ester
(3a). 1H NMR (500 MHz, CDCl3):
d
7.549 (2H, d, J¼8.0 Hz),
4.2.8. 3-(5-Bromothiophen-2-yl)-1,4-diphenyl-1H-pyrazole-5-car-
7.499e7.417 (6H, m), 7.368e7.324 (5H, m), 7.251e7.237 (2H, m),
4.052 (2H, q, J¼7.0 Hz), 0.912 (3H, t, J¼7.0 Hz); 13C NMR (125 MHz,
boxylic acid ethyl ester (3h). 1H NMR (500 MHz, CDCl3):
d
7.532e7.423 (8H, m), 7.414e7.384 (2H, m), 6.820 (1H, d, J¼3.5 Hz),
6.611 (1H, d, J¼3.5 Hz), 4.023 (2H, q, J¼7.0 Hz), 0.875 (3H, t, J¼7.0 Hz);
13C NMR (125 MHz, CDCl3):
159.7, 144.8, 140.4, 136.4, 132.9, 131.8,
CDCl3):
d 160.1, 150.2, 140.5, 132.6, 132.3, 132.2, 130.5, 128.8, 128.4,
128.2, 128.1, 128.0, 127.9, 127.5, 125.3, 125.7, 61.2, 13.4; LCeMS (ESI):
d

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H. Zou et al. / Tetrahedron 67 (2011) 4887e4891
130.6, 130.2, 129.0, 128.9, 128.5, 128.4, 126.2, 125.7, 124.6, 112.7, 61.5,
13.6; LCeMS (ESI): m/z [MþH]þ: 453.2; HRMS (ESI): m/z calcd for
C22H17N2O2BrS(M)þ 452.0194, found: m/z 452.0189.
(2H, d, J¼8.5 Hz), 7.521e7.503 (2H, m), 7.455e7.440 (2H, d,
J¼7.5 Hz), 7.358e7.270 (8H, m), 7.254e7.225 (2H, m), 7.06 (2H, d,
J¼8.5 Hz); 13C NMR (125 MHz, CDCl3):
d 187.6, 150.4, 140.8, 139.6,
138.7, 134.9, 132.0, 131.9,131.8, 131.2, 130.5, 129.5, 129.1, 128.7, 128.6,
128.5, 128.4, 124.2, 122.7, 122.1; LCeMS (ESI): m/z [MþH]þ: 513.4;
HRMS (ESI): m/z calcd for C28H18N2OBrCl (M)þ 512.0291, found: m/z
512.0295.
4.2.9. 3-(Pyridine-2-yl)-1,4-diphenyl-1H-pyrazole-5-carboxylic acid
ethyl ester (3i). 1H NMR (500 MHz, CDCl3):
d
8.610 (1H, d, J¼4.5 Hz),
7.562 (2H, d, J¼7.5 Hz), 7.529e7.414 (4H, m), 7.375e7.363 (5H, m),
7.270 (1H, d, J¼7.5 Hz), 7.153 (1H, dd, J¼7.5, 4.5 Hz), 4.050 (2H, q,
J¼7.0 Hz), 0.901 (3H, t, J¼7.0 Hz); 13C NMR (125 MHz, CDCl3):
4.2.16. 3-Isopropyl-1,4-diphenyl-1H-pyrazole-5-carboxylic acid ethyl
d
160.1, 151.5, 150.0, 149.8, 140.6, 136.2, 133.1, 132.3, 130.7, 128.9,
ester (3q). 1H NMR (500 MHz, CDCl3):
d 7.454 (4H, m), 7.396 (3H,
128.8, 128.2, 127.8, 126.2, 125.9, 123.5, 122.8, 61.5, 13.6; LCeMS
(ESI): m/z [MþH]þ: 370.4; HRMS (ESI): m/z calcd for C23H19N3O2
(M)þ 369.1477, found: m/z 369.1479.
m), 7.349 (3H, m), 4.009 (2H, q, J¼7.0 Hz), 3.012 (1H, m, J¼7.0 Hz),
1.245 (6H, d, J¼7.0 Hz), 0.876 (3H, t, J¼7.0 Hz); 13C NMR (125 MHz,
CDCl3):
d 160.3, 157.1, 140.6, 132.6, 131.2, 130.2, 128.7, 128.1, 127.9,
129.3, 125.4, 125.2, 61.0, 26.2, 22.6, 13.4; LCeMS (ESI): m/z [MþH]þ:
335.3; HRMS (ESI): m/z calcd for C28H18N2OBrCl (M)þ 334.1681,
found: m/z 334.1684.
4.2.10. 3-(3-Nitrophenyl)-1,4-diphenyl-1H-pyrazole-5-carboxylic
acid ethyl ester (3j). 1H NMR (500 MHz, CDCl3):
d 8.396 (1H, s),
8.090 (1H, dd, J¼8.0, 2.0 Hz), 7.730 (1H, d, J¼7.5 Hz), 7.561e7.461
(5H, m), 7.417e7.370 (4H, m), 7.353e7.335 (2H, m), 4.060 (2H, q,
J¼7.0 Hz), 0.912 (3H, t, J¼7.0 Hz); 13C NMR (125 MHz, CDCl3):
4.2.17. [4-(4-Fluorophenyl)-3-isopropyl-1-phenyl-1H-pyrazol-5-yl]-
(thiophen-2-yl)-methanone (3r). 1H NMR (500 MHz, CDCl3):
d 7.558
d
159.9, 148.5, 147.9, 140.5, 134.3, 133.9, 133.3, 131.7, 130.5, 129.3,
(1H, d, J¼4.5 Hz), 7.450 (2H, d, J¼8.0 Hz), 7.348 (2H, t, J¼8.0 Hz),
7.298 (1H, d, J¼4.0 Hz), 7.247 (3H, m), 6.976 (2H, t, J¼8.5 Hz), 6.864
(1H, t, J¼4.5 Hz), 3.135 (1H, m, J¼7.0 Hz), 1.319 (6H, d, J¼7.0 Hz); 13C
129.1, 129.0, 128.7, 128.4, 125.7, 125.6, 123.1, 122.8, 61.6, 13.6; LCeMS
(ESI): m/z [MþH]þ: 414.2; HRMS (ESI): m/z calcd for C24H19N3O4
(M)þ 413.1376, found: m/z 413.1372.
NMR (125 MHz, CDCl3):
d
180.7, 162.0 (d, J¼245 Hz), 156.8, 143.6,
139.8, 137.7, 135.7, 131.4 (d, J¼8 Hz), 129.2, 128.1, 127.9 (d, J¼3 Hz),
127.6, 123.8, 122.5, 115.4 (d, J¼21 Hz), 26.2, 22.6; LCeMS (ESI): m/z
[MþH]þ: 391.2; HRMS (ESI): m/z calcd for C23H19FN2OS (M)þ
390.1202, found: m/z 390.1206.
4.2.11. 4-(4-Fluorophenyl)-1,3-diphenyl-1H-pyrazole-5-carboxylic
acid ethyl ester (3k). 1H NMR (500 MHz, CDCl3):
d 7.547e7.528 (2H,
m), 7.498e7.468 (2H, m), 7.449e7.429 (3H, m), 7.339e7.302 (2H, m),
7.266e7.248 (3H, m), 7.061 (2H, t, J¼9.0 Hz), 4.061 (2H, q, J¼7.0 Hz),
0.936 (3H, t, J¼7.0 Hz); 13C NMR (125 MHz, CDCl3):
d
162.6 (d,
4.2.18. 1,3-Diphenyl-4-propyl-1H-pyrazole-5-carboxylic acid ethyl
J¼245 Hz), 160.2, 150.5, 140.7, 132.8, 132.5 (d, J¼8 Hz), 132.2, 129.1,
128.7, 128.5, 128.4 (d, J¼4 Hz), 128.4, 128.3, 125.6, 124.2, 115.3 (d,
J¼22 Hz), 61.5, 13.7; LCeMS (ESI): m/z [MþH]þ: 387.2; HRMS (ESI):
m/z calcd for C24H19N2O2F (M)þ 386.1431, found: m/z 386.1435.
ester (3s). 1H NMR (500 MHz, CDCl3):
d
7.650 (2H, d, J¼7.5 Hz),
7.453e7.358 (8H, m), 4.227 (2H, q, J¼7.0 Hz), 2.834 (2H, t, J¼8.0 Hz),
1.644 (2H, m), 1.168 (3H, t, J¼7.0 Hz), 0.964 (3H, t, J¼7.0 Hz); 13C
NMR (125 MHz, CDCl3):
d 160.3, 151.5, 141.1, 133.1, 131.8, 128.6,
128.5, 128.3, 128.1, 128.0, 125.9, 125.7, 26.3, 24.5, 14.2, 13.8; LCeMS
(ESI): m/z [MþH]þ: 335.3; HRMS (ESI): m/z calcd for C21H22N2O2
(M)þ 334.1681, found: m/z 334.1686.
4.2.12. 4-(4-Bromophenyl)-1,3-diphenyl-1H-pyrazole-5-carboxylic
acid ethyl ester (3l). 1H NMR (500 MHz, CDCl3):
d 7.529 (2H, d,
J¼8.0 Hz), 7.501e7.467 (4H, t, J¼8.5 Hz), 7.449e7.426 (3H, m),
7.275e7.248 (3H, m), 7.231e7.214 (2H, d, J¼8.5 Hz), 4.066 (2H, q,
J¼7.0 Hz), 0.944 (3H, t, J¼7.0 Hz); 13C NMR (125 MHz, CDCl3):
4.2.19. 1,3,4-Triphenyl-1H-pyrazole-5-carboxylic acid tert-butyl ester
(3t). 1H NMR (500 MHz, CDCl3):
d
7.547 (2H, d, J¼7.5 Hz),
7.494e7.405 (5H, m), 7.376e7.321 (5H, m), 7.238e7.225 (3H, m),
1.196 (9H, s); 13C NMR (125 MHz, CDCl3):
159.2, 149.9,140.6, 134.0,
d
160.1, 150.4, 140.6, 132.7, 132.4, 132.1, 131.5, 131.4, 129.0, 128.7,
128.5, 128.4, 128.3, 125.6, 124.0, 122.0, 61.6, 13.7; LCeMS (ESI): m/z
[MþH]þ: 447.2; HRMS (ESI): m/z calcd for C24H19N2O2Br (M)þ
446.0630, found: m/z 446.0633.
d
132.6, 132.4, 130.5, 128.8, 128.3, 128.2, 128.1, 127.8, 127.4, 125.4,
124.5, 82.6, 27.6; LCeMS (ESI): m/z [MþH]þ: 397.5; HRMS (ESI): m/z
calcd for C26H24N2O2 (M)þ 396.1838, found: m/z 396.1830.
4.2.13. 4-(4-Methoxyphenyl)-1,3-diphenyl-1H-pyrazole-5-carboxylic
acid ethyl ester (3m). 1H NMR (500 MHz, CDCl3):
d 7.548e7.531 (2H,
Acknowledgements
m), 7.485e7.458 (4H, m), 7.433e7.404 (1H, m), 7.272e7.245 (5H, m),
6.908e6.891 (2H, m), 4.065 (2H, q, J¼7.0 Hz), 3.835 (3H, s), 0.944
This study was supported by the National Natural Science
Foundation of China (No. 20802066), National Science & Technol-
ogy Major Project ‘Key New Drug Creation and Manufacturing
Program’ of China (No. 2009ZX09501-010) and the China Post-
doctoral Science Foundation. We would like to give our great
thanks to Mr. Jianming Gu for his help with the X-ray crystallo-
graphic analysis.
(3H, t, J¼7.0 Hz); 13C NMR (125 MHz, CDCl3):
d 160.4, 159.4, 150.5,
140.9, 132.8, 132.6, 131.8, 128.9, 128.5, 128.4, 128.0, 125.5, 125.0,
124.6, 113.8, 61.4, 55.4, 13.7; LCeMS (ESI): m/z [MþH]þ: 399.3;
HRMS (ESI): m/z calcd for C25H22N2O3 (M)þ 398.1630, found: m/z
398.1634.
4.2.14. 4-(3-Nitrophenyl)-1,3-diphenyl-1H-pyrazole-5-carboxylic
acid ethyl ester (3n). 1H NMR (500 MHz, CDCl3):
d 8.307 (1H, t,
Supplementary data
J¼2.0 Hz), 8.221 (1H, ddd, J¼8.0, 2.0, 1.0 Hz), 7.636 (1H, dt, J¼8.0,
1.5 Hz), 7.556e7.451 (6H, m), 7.404e7.385 (2H, m), 7.303e7.262
(3H, m), 4.070 (2H, q, J¼7.0 Hz), 0.925 (3H, t, J¼7.0 Hz); 13C NMR
Copies of NMR spectra for all products and single-crystal X-ray
diffraction analysis of 3f (CCDC 804343). Supplementary data re-
lated to this article can be found online at doi:10.1016/
j.tet.2011.04.103.
(125 MHz, CDCl3):
d 159.6, 150.6, 148.3, 140.6, 137.0, 134.5, 132.9,
131.6, 129.2, 129.1, 129.0, 128.7, 128.6, 128.5, 126.0, 125.8, 122.8, 61.7,
13.7; LCeMS (ESI): m/z [MþH]þ: 414.2; HRMS (ESI): m/z calcd for
C24H19N3O4 (M)þ 413.1376, found: m/z 413.1373.
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