Synthesis of 5-arylamino-1-arylpyrazoles from 5-aminopyrazoles with arylhalides via CuI catalyzed Ullman coupling reaction

Article abstract of DOI:10.1016/j.tet.2012.11.022

An efficient method for synthesis of 5-arylamino-1-arylpyrazoles was developed by Ullman coupling reaction of 5-aminopyrazoles and arylhalides in the presence of cuprous iodide (CuI) as the catalyst. The corresponding 5-N-arylaminopyrazole products were o

Full text of DOI:10.1016/j.tet.2012.11.022

Tetrahedron 69 (2013) 570e576
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Tetrahedron
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Synthesis of 5-arylamino-1-arylpyrazoles from 5-aminopyrazoles
with arylhalides via CuI catalyzed Ullman coupling reaction
,
,
*
En-Chiuan Chang b, Chun-Yen Chen b 1, Li-Ya Wang c, Yu-Ying Huang a, Mou-Yung Yeh b
,
,
Fung Fuh Wong a
*
a Graduate Institute of Pharmaceutical Chemistry, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan, ROC
b Department of Chemistry, National Cheng Kung University, No. 1, Ta Hsueh Rd., Tainan 70101, Taiwan, ROC
c The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method for synthesis of 5-arylamino-1-arylpyrazoles was developed by Ullman coupling
reaction of 5-aminopyrazoles and arylhalides in the presence of cuprous iodide (CuI) as the catalyst. The
corresponding 5-N-arylaminopyrazole products were obtained in good yields (ꢀ65%).
Ó 2012 Elsevier Ltd. All rights reserved.
Received 6 September 2012
Received in revised form 30 October 2012
Accepted 6 November 2012
Available online 14 November 2012
Keywords:
Cross-coupling reaction
5-Amino-pyrazoles
5-Mono-N-substituted aminopyrazoles
Amination
Copper iodide
1. Introduction
containing aromatic C(sp2)eN bonds possess various important
pharmacologically activities.11 Many metal-catalyzed aryl amina-
Numerous compounds containing 1-N-arylpyrazole moiety
have been shown to exhibit antihyperglycemic, analgesic, anti-
inflammatory sedative, and hypnotic activities.1e3 5-Alkyl/aryla-
mino substituted pyrazoles have been exploited in the design of
pharmaceuticals and agrochemical agents exhibiting a range of
biological activities.2,4e6 Several previous literature were reported
for the synthesis of 1-aryl-5-N,N-disubstituted aminopyrazoles by
tion methods were reported by using palladium catalyst and
phosphine ligand11e13 or copper iodide and salicylic amide de-
rivatives or proline.14e16 However, most of methods were per-
formed in the amination of aryl compounds. That we provided the
new development of a novel 5-amino-pyrazoles amination cata-
lyzed by CuI, K2CO3, and 1,10-phenanthroline for efficient synthesis
of 5-arylamino-1-arylpyrazole derivatives in this study was due to
the copper-mediated reactions are significantly superior to the
conventional palladium-mediated reactions.17
means of the cyclization of hydrazines with b
-ketoamides,5d,6,7 the
defined starting precursors containing the hydrazones with an
electron withdrawing group,5b,8 or the pre-generated 2-oxocarbo-
thioamides (b
-ketothioamides).9 However, a few methods could
2. Result and discussion
provide the satisfactory reaction conditions for the preparation of
the 5-arylamino-1-arylpyrazoles. Herein, we reported an efficient
method for the synthesis of 5-arylamino-1-arylpyrazoles de-
rivatives, of which analogues are known selective COX-2 in-
hibitors,2,10 via CuI-catalyzed Ullman coupling reaction.
The 5-aminopyrazoles 1e13 were prepared as the starting
substrates by following our previous published procedure via
cyclodehydration and dehydrogenation in the neat condition.18 In
this newly developed method, we chose 3-phenyl-1-(pyridin-2-yl)-
1H-pyrazol-5-amine (1)18 as the model for the selection of best
condition for the CuI-catalyzed Ullman coupling reaction (see
Scheme 1). To search for the optimum conditions and establish
a reproducible procedure, we firstly investigated the ligand effect.
Compound 1 was allowed to react with phenyl iodide (PhI), K2CO3,
Introduction of nitrogen functionalities on aromatic rings has
been one of the main topics in organic synthesis due to compounds
* Corresponding authors. E-mail address: wongfungfuh@yahoo.com.tw (F.F.
and the various ligands including
L-proline, DMEDA, pyrozole-2-
Wong).
1
The contribution equal to first author.
COOH, N-methylglycine, and 1,10-phenanthroline in the presence
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.022

E.-C. Chang et al. / Tetrahedron 69 (2013) 570e576
571
Ph
NH2
HN
CuI, ligand
N
+
PhI
N
N
Base, solvent
N
N
N
Ph
Ph
14
1
Scheme 1.
of the catalytic amount of CuI (0.10 equiv) at 70 ꢁC for 1.0 h in DMF.
Following the experimental results, we found that the use of
0.10 equiv of 1,10-phenanthroline as the ligand in DMF provided the
best result to give the corresponding product 14 in 84% yield (see
entries 1e5 of Table 1). Consequently, we explored the cross-
coupling reaction by modifying the polarity of aprotic polar sol-
vents, such as DMF, DMSO, and DMAC. Based on the result, the
0.10 equiv of 1,10-phenanthroline in DMF solution can be consid-
ered as the best suitable ligand and solvent system (see entry 5e7
of Table 1).
with column chromatography on silica gel, the desired 5-N-mono-
arylamino substituted pyrazole 14 was isolated as solids (entries 5
and 8e12 of Table 1). Among of bases, we found that the use of
potassium phosphate (K3PO4) and potassium carbonate (K2CO3)
gave the better results in 72% and 84% yields, respectively (see
entries 5 and 14 of Table 1). Yields of the desired 5-arylamino-1-
arylpyrazole 14 after 1.0 h were substantially decreased when us-
ing potassium, sodium, and lithium carbonate salts (entries 5 and
8e9 of Table 1). However, low yield was also observed with Cs2CO3
(entry 10 of Table 1). Conditions using other bases, such as sodium
bicarbonate (NaHCO3), potassium tert-butoxide (t-BuOK), or with-
out bases resulted in only poor result (entries 11 and 13e15 of Table
1). Based on these optimizations, we finally decided to choose the
combination of CuI, 1,10-phenanthroline, and K2CO3 in DMF as the
standard conditions for the metal catalyzed cross-coupling reaction
of 5-arylamino-1-arylpyrazoles in the following studies.
In this reaction, the reliable procedure involved the treatment of
5-amino-pyrazole substrates, aryl halide, and K2CO3 using 0.10 equiv
of catalytic amount CuI and 1,10-phenanthroline ligand in anhydride
DMF at 70 or 140 ꢁC for more than 1.0 h (see Scheme 2). For in-
vestigation of the reactivity of different phenyl halide substrates, the
amination reaction was performed with phenyl chloride, bromide,
and iodide, and tolyl iodide. After comparing the results, we found
that the use of phenyl and tolyl iodides were obviously better than
the use of phenyl bromide and chloride (entries 1e4 of Table 2). For
phenyl chloride, reaction was incomplete even after 7.0 h at 140 ꢁC
(entry 1 of Table 2). These results were consistent with the literature
amination order.18 Application of same cross-coupling reaction
conditions to 3-p-methylphenyl-1-(pyridin-2-yl)-1H-pyrazol-5-
amine 2, 3-p-methoxylphenyl -1-(pyridin-2-yl)-1H-pyrazol-5-
amine 3, and 3-tert-butyl-1-(pyridin-2-yl)-1H-pyrazol-5-amine 4
with various of aryl iodine, including PhI, tolyl iodine, and p-
methoxylphenyl iodine also gave the corresponding products 16e18
in good yields (80e93%, entries 5e7 of Table 2).
Table 1
The result of optimization studies
Entry
Ligand
-Proline
DMEDA
Pyrozole-2-COOH
N-Methylglycine
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
Solvent
Base
Yieldsa,b (%) of
compound 14
1
2
3
4
5
6
7
8
L
DMF
DMF
DMF
DMF
DMF
DMSO
DMAC
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Li2CO3
Na2CO3
Cs2CO3
t-BuOK
NaOMe
NaHCO3
K3PO4
d
62
77
74
16
84
52
34
34
39
43
60
55
54
72
9
10
11
12
13
14
15
Non-detectable
a
Compound 1 (1.0 mmol, 1.0 equiv), PhI (1.0 mmol, 1.0 equiv), and various bases
(1.2 mmol, 1.2 equiv) and ligands (0.10 mmol, 0.10 equiv) with catalytic amount CuI
(0.10 mmol, 0.10 equiv) in aprotic polar solvents at 70 ꢁC for 1.0 h under nitrogen
gas.
b
The isolated yields were determined by column chromatography on silica gel.
Ar
NH2
HN
CuI,
N
N
+
ArI
X N
X N
K2CO3, DMF, 70-140 oC
X = aryl, pyridyl, quinolinyl
Y = t-Bu, Ph, p-Cl-Ph, p-Me-Ph,
p-OMe-Ph
N
N
Y
Y
1-13
14-27
Ar = Ph, tolyl
Scheme 2.
We knew that the appropriate choice of base might be impor-
tant for the cross-coupling reaction. Thus, we treated an anhydrous
DMF solution of 3-phenyl-1-(pyridin-2-yl)-1H-pyrazol-5-amine (1)
and PhI with catalytic amount of CuI and 1,10-phenanthroline in the
presence of 1.2 equiv of different bases, including lithium, sodium,
cesium and potassium carbonate (Li2CO3, Na2CO3, Cs2CO3 and
K2CO3), potassium tert-butoxide (t-BuOK), sodium methoxide
(NaOMe), sodium bicarbonate (NaHCO3) and potassium phosphate
(K3PO4) at 70 ꢁC for 1.0 h. After normal work-up and purification
The synthetic strategy was applicable to 3-p-totyl-1-(quinolin-
2-yl)-1H-pyrazol-5-amine 5 with phenyl chloride, bromide, and
iodide to afford the desired amination products 18 in 23%, 77%, and
96% yields, respectively (see entries 8e10 of Table 2). Although
phenyl bromide and chloride were also successfully coupled by
using the CuI/L catalyst system, higher temperatures (>100 ꢁC) and
long reaction times were required. For further demonstration of the
reactivity of phenyl halides, 3-(4-methoxyphenyl)-1-(quinolin-2-
yl)-1H-pyrazol-5-amine
6,
3-tert-butyl-1-(quinolin-2-yl)-1H-

572
E.-C. Chang et al. / Tetrahedron 69 (2013) 570e576
Table 2
The result of CuI catalyzed Ullman coupling reaction of 5-aminopyrazoles with arylhalides
Entry
5-Aminopyrazoles
ArX
Reaction time & temperature
Products
Yieldsa,b (%)
h
ꢁC
Ph
NH2
N
HN
1
1
1
1
1
PhCl
48
140
14
14
14
15
d
N
N
N
N
N
N
N
N
N
N
Ph
Ph
Ph
Ph
Ph
Ph
NH2
HN
N
N
2
3
4
PhBr
PhI
7
4
3
70
70
70
75
91
84
N
N
Ph
Ph
NH2
HN
N
N
N
N
Ph
p-Me-Ph
NH2
HN
N
N
TolyleI
N
N
N
N
Ph
p-Me-Ph
NH2
HN
N
5
6
2
3
TolyleI
2
1
70
70
16
17
93
80
N
N
N
N
N
p-Me-Ph
p-Me-Ph
p-OMe-Ph
NH2
HN
N
p-OMeePheI
N
N
N
N
p-OMe-Ph
p-OMe-Ph
p-OMe-Ph
NH2
7
8
9
3
3
4
p-NO2ePheI
p-NO2ePheBr
PhI
>3
>7
3
70
70
70
dc
d
d
18
dc
dc
86
N
N
N
N
NH2
dc
N
N
p-OMe-Ph
Ph
NH2
HN
N
N
N
N
N
N
t-Bu
NH2
t-Bu
Ph
HN
N
N
10
11
12
13
5
5
5
6
PhCl
PhBr
PhI
12
140
70
19
19
19
20
23
77
96
21
N
N
N
N
p-Me-Ph
p-Me-Ph
Ph
NH2
HN
N
N
5
N
N
N
N
N
p-Me-Ph
p-Me-Ph
Ph
NH2
HN
N
N
3
70
N
N
N
N
p-Me-Ph
p-Me-Ph
Ph
NH2
HN
N
N
PhCl
22
140
N
N
N
p-OMe-Ph
p-OMe-Ph

E.-C. Chang et al. / Tetrahedron 69 (2013) 570e576
573
Table 2 (continued )
Entry
5-Aminopyrazoles
ArX
Reaction time & temperature
ꢁC
Products
Yieldsa,b (%)
h
Ph
NH2
N
HN
14
15
16
6
6
7
PhBr
PhI
3
3
70
20
20
21
68
94
17
N
N
N
N
N
N
N
p-OMe-Ph
p-OMe-Ph
Ph
NH2
N
HN
70
N
N
N
p-OMe-Ph
p-OMe-Ph
NH2
Ph
HN
N
PhCl
48
140
N
N
N
N
N
t-Bu
Ph
t-Bu
NH2
HN
N
17
18
7
7
PhBr
PhI
24
22
70
70
21
21
73
95
N
N
N
N
N
N
t-Bu
t-Bu
Ph
NH2
HN
N
N
N
N
N
t-Bu
t-Bu
p-Me-Ph
NH2
HN
N
19
20
8
9
TolyleI
TolyleI
3
3
70
70
22
23
90
86
N
N
N
N
N
Ph
Ph
p-Me-Ph
NH2
N
HN
N
N
N
N
N
p-Cl-Ph
p-Cl-Ph
Ph
NH2
HN
N
N
21
10
11
PhI
PhI
30
36
70
70
24
25
78
72
N
N
Ph
Ph
Ph
Cl
NH2
Cl
HN
22
23
N
N
N
N
Ph
Ph
Ph
NH2
HN
MeO
N
12
13
PhI
2
70
70
26
27
88
65
MeO
N
N
N
Ph
Ph
O2N
Ph
24
TolyleI
36
NH2
O2N
HN
N
N
N
N
Ph
Ph
a
5-Amino-pyrazole substrates 1e13 (1.0 mmol, 1.0 equiv), arylhalides (PhCl, PhBr, PhI, p-MeO-PhI, or tolyl iodide, 1.0 mmol, 1.0 equiv), and K2CO3 (1.2 mmol, 1.2 equiv)
with catalytic amount CuI (0.10 mmol, 0.10 equiv) and 1,10-phenanthroline (0.10 mmol, 0.10 equiv) in DMF at 70 or 140 ꢁC within 1e48 h under nitrogen gas.
b
The isolated yields were performed by column chromatography on silica gel.
Non-detectable.
c

574
E.-C. Chang et al. / Tetrahedron 69 (2013) 570e576
pyrazol-5-amine 7 were allowed to react with phenyl halides (PhCl,
PhBr, and PhI) under the same reaction conditions. Following the
experimental results, the similar reactive tendency of phenyl ha-
lides (PhI>PhBr>>PhCl) were detected in the newly developed
Ullman coupling amination (see the entries 11e16 of Table 2).
When employing 3-phenyl-1-(quinolin-2-yl)-1H-pyrazol-5-amine
8 and 3-p-chlorophenyl-1-(quinolin-2-yl)-1H-pyrazol-5-amine 9
as the reactant to treat with tolyl iodine, a good to excellent yields
were also achieved (90% and 86%, entry 17e18 of Table 2).
J¼8.3 Hz, ArH), 8.37 (d, 1H, J¼4.5 Hz, ArH), 10.43 (br, 1H, NH); 13C
NMR (CDCl3, 75 MHz)
d 20.72, 86.75, 114.15, 117.65, 118.77, 119.59,
125.89, 128.25, 128.49, 129.87, 131.50, 133.18, 138.76, 146.03, 147.47,
152.27,154.99; IR (diffuse reflectance) 3282 (m), 3056 (w), 2924 (m),
2855 (m), 1683 (m), 1651 (s), 1557 (m), 1505 (s), 1455 (s), 1361 (m),
1262 (m), 1044 (m), 955 (m) cmꢂ1; MS (ESI) m/z: 327 (MþH)þ.
HRMS (ESI) calcd for C21H19N4 (MþH)þ 327.1610, found 327.1609.
4.1.3. 1-(2-Pyridyl)-5-p-toluidine-3-p-tolyl-1H-pyrazole (16). Yellow
On the other hand, we extended the new developed coupling
amination to 1-aryl-3-phenyl-5-amino-1H-pyrazoles 10e13, bear-
ing various N-1 substituents including Ph, m-ClePh, m-NO2Ph, and
p-OMePh. The corresponding 5-arylamino-1-aryl-3-phenyl-pyr-
azole products 24e27 were obtained in good yields (65e88%, en-
tries 19e22 in Table 2). All 5-mono-N-substituted aminopyrazole
Products 14e27 were fully characterized by spectroscopic methods
and consistent with the literature data. Served as an example,
powder; mp 86e87 ꢁC; 1H NMR (CDCl3, 300 MHz)
d 2.33 (s, 3H,
CH3), 2.38 (s, 3H, CH3), 6.29 (s, 1H, Py), 7.09e7.23 (m, 7H, ArH),
7.76e7.85 (m, 3H, ArH), 8.16 (d, 1H, J¼8.3 Hz, ArH), 8.36 (dd, 1H,
J¼4.8, 1.1 Hz, ArH), 10.42 (br, 1H, NH); 13C NMR (CDCl3, 75 MHz)
d
20.72, 21.32, 86.64, 114.12, 118.73, 119.48, 125.79, 129.19, 129.86,
130.37, 131.41, 138.09, 138.72, 138.80, 146.01, 147.38, 152.34, 155.01;
IR (diffuse reflectance) 3253 (m), 2923 (m), 2852 (m), 1594 (s), 1557
(s), 1539 (m), 1468 (m), 1442 (m), 1362 (m), 1248 (m), 948 (m) cmꢂ1
;
compound 14 presented a peak at
position of pyrazole ring in 1H NMR. In 13C NMR spectrum, com-
pound 14 possessed characterization absorptions at 87.30 ppm for
d
6.41 ppm for 1HeC] in C-4
MS (ESI) m/z: 341 (MþH)þ. HRMS (ESI) calcd for C22H21N4 (MþH)þ
341.1766, found 341.1764.
d
sp2 carbon 13CeH and at
d
146.80 ppm for imine carbon N]13C in
4.1.4. 5-Anisidino-3-(4-methoxyphenyl)-1-(2-pyridyl)-1H-pyrazole
pyrazole ring. The IR absorptions of 14 showed peaks at 3215 cmꢂ1
for the stretching of the eNH group.
(17). Yellow powder; mp 110e111 ꢁC; 1H NMR (CDCl3, 300 MHz)
d
3.81 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 6.12 (s, 1H, Py), 6.89e7.26
(m, 7H, ArH), 7.79e7.81 (m, 3H, ArH), 8.14 (d, 1H, J¼8.3 Hz, ArH),
3. Conclusion
8.34 (d, 1H, J¼3.4 Hz, ArH), 10.22 (br, 1H, NH); 13C NMR (CDCl3,
75 MHz)
d 55.27, 55.57, 85.64, 113.86, 113.91, 114.63, 119.34, 121.30,
In conclusion, we have successfully developed a new cross-
coupling method for the synthesis of 5-arylamino-1-arylpyrazoles
using 1,10-phenanthroline as the ligand and CuI as catalyst. This
methodology can applicable to the wide range of N-1 substituted
aryl, pyridin-2-yl, isoquinolinyl or C-3 substituted aryl and tert-
butyl of 5-amino-pyrazole substrates to give the corresponding 5-
arylamino-1-arylpyrazole products in good yields.
125.95, 127.15, 134.65, 138.69, 146.03, 148.43, 152.10, 154.99, 155.28,
159.77; IR (diffuse reflectance) 3243 (m), 2923 (m), 2852 (m), 1593
(s), 1556 (s), 1531 (s), 1470 (s), 1441 (s), 1361 (m), 1295 (m), 1246 (s),
1173 (m), 1033 (m), 948 (m) cmꢂ1; MS (ESI) m/z: 373 (MþH)þ.
HRMS (ESI) calcd for C22H21N4O2 (MþH)þ 373.1665, found
373.1667.
4.1.5. 5-Anilino-3-tert-butyl-1-(2-pyridyl)-1H-pyrazole
NMR (CDCl3, 300 MHz)
(t, 1H, J¼7.3 Hz, ArH), 7.06 (t, 1H, J¼6.2 Hz, ArH), 7.21 (d, 2H,
J¼8.2 Hz, ArH), 7.29e7.34 (m, 2H, ArH), 7.77 (td, 1H, J¼8.1, 1.4 Hz,
ArH), 8.04 (d, 1H, J¼8.4 Hz, ArH), 8.32 (d, 1H, J¼4.9 Hz, ArH), 10.50
(18). 1H
4. Experimental section
d
1.34 (s, 9H, 3ꢃ CH3), 5.95 (s, 1H, Py), 6.96
4.1. General procedure for the CuI catalyzed cross-coupling
reaction of primary 5-amino-pyrazoles
(br, 1H, NH); 13C NMR (CDCl3, 75 MHz)
d 30.04, 32.51, 86.89,
A 5-amino-pyrazole substrates (1.0 mmol, 1.0 equiv), arylhalides
(PhCl, PhBr, PhI, p-MeOePhI, or tolyl iodide, 1.0 mmol, 1.0 equiv),
and K2CO3 (1.2 mmol, 1.2 equiv) with catalytic amount CuI
(0.1 mmol, 0.1 equiv) and 1,10-phenanthroline (0.1 mmol, 0.1 equiv)
in DMF at 70 or 140 ꢁC within 1e48 h under nitrogen gas. After 5-
amino-pyrazoles were completely consumed, the reaction mixture
was work-up, extracted with CH2Cl2 (20 mLꢃ2), and concentrated
under reduced pressure. The residue was purified by column
chromatography on silica gel to give the corresponding 5-
arylamino-1-arylpyrazole products in 17e96%.
114.13, 117.81, 119.12, 121.28, 129.27, 138.62, 141.51, 145.81, 145.93,
155.10, 163.42; IR (diffuse reflectance) 3247 (m), 2949 (m), 2923
(m), 2854 (m), 1592 (s), 1556 (s), 1470 (s), 1441 (s), 1365 (m), 1255
(m), 1132 (m), 1086 (m), 981 (m) cmꢂ1; MS (ESI) m/z: 293
(MþH)þ. HRMS (ESI) calcd for C18H21N4 (MþH)þ 293.1766, found
293.1767.
4.1.6. 5-Anilino-1-(2-quinolinyl)-3-p-tolyl-1H-pyrazole (19). Yellow
powder; mp 160e161 ꢁC; 1H NMR (CDCl3, 300 MHz)
d 2.40 (s,
3H, CH3), 6.44 (s, 1H, Py), 7.03e7.06 (m, 1H, ArH), 7.27e7.51 (m,
7H, ArH), 7.69e7.85 (m, 4H, ArH), 7.95 (d, 1H, J¼8.5 Hz, ArH),
8.24 (d, 1H, J¼9.0 Hz, ArH), 8.40 (d, 1H, J¼8.9 Hz, ArH); 13C NMR
4.1.1. 5-Anilino-3-phenyl-1-(2-pyridyl)-1H-pyrazole
powder; mp 98e99 ꢁC; 1H NMR (CDCl3, 300 MHz)
(14). Yellow
6.41 (s, 1H, Py),
d
(CDCl3, 75 MHz) d 21.35, 87.21, 114.08, 117.84, 121.66, 125.65,
7.01 (t, 1H, J¼7.1 Hz, ArH), 7.13 (t, 1H, J¼6.4 Hz, ArH), 7.28e7.45 (m,
7H, ArH), 7.81e7.92 (m, 3H, ArH), 8.19 (d,1H, J¼8.4 Hz, ArH), 8.38 (d,
1H, J¼4.3 Hz, ArH), 10.59 (br, 1H, NH); 13C NMR (CDCl3, 75 MHz)
125.73, 125.88, 127.34, 127.74, 129.25, 129.47, 130.20, 130.26,
138.30, 138.80, 141.24, 145.00, 147.09, 152.57, 154.00; IR (diffuse
reflectance) 3210 (m), 3057 (m), 2922 (m), 2855 (m), 1602 (s),
1589 (s), 1556 (s), 1504 (s), 1455 (m), 1430 (s), 1371 (s), 1252
(m), 1119 (m), 1042 (m), 947 (m) cmꢂ1; MS (ESI) m/z: 377
(MþH)þ. HRMS (ESI) calcd for C25H21N4 (MþH)þ 377.1766, found
377.1763.
d
87.30, 114.24, 118.20, 119.71, 121.76, 125.91, 128.31, 128.52, 129.38,
133.11, 138.83, 141.27, 146.03, 146.80, 152.25, 154.96; IR (diffuse
reflectance) 3215 (m), 2927 (m), 2862 (w), 1682 (m), 1651 (s), 1557
(s), 1538 (m), 1505 (m), 1455 (m), 1252 (m), 1140 (m), 1075
(m) cmꢂ1; MS (ESI) m/z: 313 (MþH)þ. HRMS (ESI) calcd for
C20H17N4 (MþH)þ 313.1453, found 313.1454.
4.1.7. 5-Anilino-3-(4-methoxyphenyl)-1-(2-quinolinyl)-1H-pyrazole
(20). Yellow powder; mp 183e184 ꢁC; 1H NMR (CDCl3, 300 MHz)
4.1.2. 3-Phenyl-1-(2-pyridyl)-5-p-toluidine-1H-pyrazole (15). Yellow
d 3.86 (s, 3H, OCH3), 6.40 (s, 1H, Py), 6.96e7.05 (m, 3H, ArH),
powder; mp 77e78 ꢁC; 1H NMR (CDCl3, 300 MHz)
d
2.34 (s, 3H,
7.33e7.51 (m, 5H, ArH), 7.69e7.96 (m, 5H, ArH), 8.24 (d, 1H,
CH3), 6.32 (s,1H, Py), 7.10e7.22 (m, 5H, ArH), 7.34e7.44 (m, 3H, ArH),
7.80e7.86 (m, 1H, ArH), 7.90 (d, 2H, J¼7.4 Hz, ArH), 8.18 (d, 1H,
J¼9.0 Hz, ArH), 8.38 (d, 1H, J¼9.2 Hz, ArH), 11.40 (br, 1H, NH); 13C
NMR (CDCl3, 75 MHz)
d 55.30, 87.00, 113.95, 114.04, 117.86, 121.66,

E.-C. Chang et al. / Tetrahedron 69 (2013) 570e576
575
125.62, 125.70, 125.77, 127.28, 127.32, 127.74, 129.47, 130.26, 138.79,
1557 (s), 1538 (m), 1362 (m), 1250 (m), 1076 (m), 952 (m) cmꢂ1
;
MS (ESI) m/z: 348 (Mþ3)þ, 346 (MþH)þ. HRMS (ESI) calcd for
C21H17ClN3 (MþH)þ 346.1111, found 346.1109.
141.24, 145.01, 147.11, 152.34, 153.99, 159.93; IR (diffuse reflectance)
3195 (w), 3072 (m), 2920 (m), 2847 (m), 1591 (s), 1556 (s), 1504 (s),
1455 (m), 1428 (s), 1366 (m), 1245 (s), 1174 (m), 1025 (m), 944
(m) cmꢂ1; MS (ESI) m/z: 393 (MþH)þ. HRMS (ESI) calcd for
C25H21N4O (MþH)þ 393.1715, found 393.1716.
4.1.13. 5-Anilino-1-(4-methoxyphenyl)-3-phenyl-1H-pyrazole (26).
Yellow powder; mp 147e148 ꢁC; 1H NMR (CDCl3, 300 MHz)
d 3.78
(s, 3H, OCH3), 6.77 (s, 1H, Py), 7.04 (d, 2H, J¼8.8 Hz, ArH), 7.32e7.45
(m, 6H, ArH), 7.63 (d, 2H, J¼8.8 Hz, ArH), 7.70 (d, 2H, J¼7.6 Hz, ArH),
7.90 (d, 2H, J¼7.1 Hz, ArH), 8.76 (br,1H, NH); IR (diffuse reflectance)
3434 (m), 2922 (s), 2852 (m), 1651 (m), 1613 (m), 1557 (s), 1539 (s),
4.1.8. 5-Anilino-3-tert-butyl-1-(2-quinolinyl)-1H-pyrazole (21). Yellow
powder; mp 119e120 ꢁC; 1H NMR (CDCl3, 300 MHz)
d
1.39 (s, 9H, 3ꢃ
CH3), 6.03 (s, 1H, Py), 7.00 (t, 1H, J¼7.0 Hz, ArH), 7.27e7.49 (m, 5H,
ArH), 7.67e7.72 (m, 1H, ArH), 7.78 (d, 1H, J¼8.0 Hz, ArH), 7.92 (d, 1H,
J¼8.4 Hz, ArH), 8.19 (d, 1H, J¼9.1 Hz, ArH), 8.29 (d, 1H, J¼9.1 Hz, ArH),
1505 (s), 1455 (m), 1273 (m), 1252 (m), 1161 (m), 1024 (m) cmꢂ1
;
MS (ESI) m/z: 342 (MþH)þ. HRMS (ESI) calcd for C22H20N3O
11.32 (br, 1H, NH); 13C NMR (CDCl3, 75 MHz)
d 30.04, 32.62, 86.98,
(MþH)þ 342.1606, found 342.1605.
114.18, 117.56, 121.29, 125.39, 125.54, 127.29, 127.70, 129.40, 130.11,
138.58, 141.47, 145.07, 146.28, 154.16, 163.69; IR (diffuse reflectance)
3456 (m), 3223 (m), 3063 (w), 2959 (m), 2862 (m), 1586 (s), 1556 (s),
1504 (s), 1430 (s), 1371 (s), 1225 (m), 1134 (m), 1044 (m), 981
(m) cmꢂ1; MS (ESI) m/z: 343 (MþH)þ. HRMS (ESI) calcd for C22H23N4
(MþH)þ 343.1923, found 343.1922.
4.1.14. 1-(3-Nitrophenyl)-3-phenyl-5-p-toluidine-1H-pyrazole (27).
Yellow powder; mp 148e149 ꢁC; 1H NMR (CDCl3, 300 MHz)
d 2.28
(s, 3H, CH3), 5.43 (br, 1H, NH), 6.48 (s, 1H, Py), 6.83 (d, 2H, J¼8.3 Hz,
ArH), 7.07 (d, 2H, J¼8.3 Hz, ArH), 7.34e7.45 (m, 3H, ArH), 7.58 (t, 1H,
J¼8.1 Hz, ArH), 7.84 (d, 2H, J¼7.5 Hz, ArH), 8.08e8.14 (m, 2H, ArH),
8.63e8.65 (m, 1H, ArH); 13C NMR (CDCl3, 75 MHz)
d 20.55, 96.02,
4.1.9. 3-Phenyl-1-(2-quinolinyl)-5-p-toluidine-1H-pyrazole
(22).
d 2.36
116.51, 118.33, 121.41, 125.63, 128.44, 128.65, 128.77, 130.03, 130.09,
131.20, 132.61, 139.87, 140.43, 143.36, 148.70, 152.45; IR (diffuse
reflectance) 3376 (m), 3036 (w), 2923 (m), 2855 (m), 1593 (m),
1556 (s), 1532 (s), 1455 (m), 1350 (s), 1247 (m), 1078 (m), 951
(m) cmꢂ1; MS (ESI) m/z: 371 (MþH)þ. HRMS (ESI) calcd for
C22H19N4O2 (MþH)þ 371.1508, found 371.1510.
Yellow powder; mp 174e175 ꢁC; 1H NMR (CDCl3, 300 MHz)
(s, 3H, CH3), 6.39 (s, 1H, Py), 7.18e7.52 (m, 8H, ArH), 7.72 (td, 1H,
J¼7.5, 1.0 Hz, ArH), 7.81 (d, 1H, J¼7.9 Hz, ArH), 7.93e7.95 (m, 3H,
ArH), 8.25 (d, 1H, J¼9.0 Hz, ArH), 8.40 (d, 1H, J¼9.0 Hz, ArH), 11.22
(br, 1H, NH); 13C NMR (CDCl3, 75 MHz)
d 20.74, 86.78, 114.04, 118.41,
125.65, 125.75, 125.98, 127.38, 127.73, 128.39, 128.53, 129.97, 130.25,
131.45, 133.09, 138.69, 138.79, 145.04, 147.81, 152.53, 154.01; IR
(diffuse reflectance) 3210 (m), 3057 (m), 2922 (m), 2855 (w), 1621
(m), 1592 (s), 1556 (s), 1504 (s), 1430 (m), 1367 (m), 1249 (m), 1042
(m), 946 (m) cmꢂ1; MS (ESI) m/z: 377 (MþH)þ. HRMS (ESI) calcd for
C25H21N4 (MþH)þ 377.1766, found 377.1768.
Acknowledgements
We are grateful to the China Medical University (CMU100-
ASIAe17 and CMU101-Se23), and the National Science Council of
Republic of China (NSC-99-2320-B-039-014-MY3) for financial
support. This study is also supported in part by Taiwan Department
of Health Clinical Trial and Research Center of Excellence (DOH100-
TD-B-111-004).
4.1.10. 3-(4-Chlorophenyl)-1-(2-quinolinyl)-5-p-toluidine-1H-pyr-
azole (23). Yellow powder; mp 180e181 ꢁC; 1H NMR (CDCl3,
300 MHz) d 2.36 (s, 3H, CH3), 6.31 (s,1H, Py), 7.18e7.22 (m, 4H, ArH),
7.38 (d, 2H, J¼8.3 Hz, ArH), 7.48 (t, 1H, J¼7.5 Hz, ArH), 7.70 (t, 1H,
J¼7.8 Hz, ArH), 7.77e7.93 (m, 4H, ArH), 8.22 (d, 1H, J¼9.0 Hz, ArH),
8.34 (d, 1H, J¼9.0 Hz, ArH), 11.21 (br, 1H, NH); 13C NMR (CDCl3,
Supplementary data
Supplementary data related to this article can be found online at
http://dx.doi.org/10.1016/j.tet.2012.11.022.
75 MHz) d 20.75, 86.50,113.88,118.46,125.72,125.75,127.20,127.37,
127.72, 128.67, 129.98, 130.28, 131.58, 131.62, 134.08, 138.55, 138.81,
144.97,147.94,151.31,153.87; IR (diffuse reflectance) 3217 (m), 3065
(m), 2921 (m), 2855 (w), 1602 (s), 1591 (s), 1556 (s), 1504 (s), 1465
(m), 1431 (s), 1367 (s), 1249 (m), 1090 (m), 1043 (m), 1013 (m), 946
(m) cmꢂ1; MS (ESI) m/z: 413 (Mþ3)þ, 411 (MþH)þ. HRMS (ESI)
calcd for C25H20ClN4 (MþH)þ 411.1376, found 411.1380.
References and notes
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mp 152e153 ꢁC; 1H NMR (CDCl3, 300 MHz)
d 5.55 (br, 1H, NH), 6.52
(s, 1H, Py), 6.99 (d, 2H, J¼7.8 Hz, ArH), 7.18e7.50 (m, 9H, ArH), 7.63
(d, 2H, J¼7.7 Hz, ArH), 7.86 (d, 2H, J¼7.2 Hz, ArH); 13C NMR (CDCl3,
75 MHz)
d 93.72, 115.91, 120.94, 124.38, 125.61, 127.67, 127.93,
128.50, 129.34, 129.44, 133.18, 138.33, 142.17, 142.98, 151.47; IR
(diffuse reflectance) 3233 (m), 3004 (m), 2935 (m), 1596 (s), 1494
(m), 1452 (m), 1361 (m), 1301 (m), 1255 (w), 1165 (m) cmꢂ1; MS
(ESI) m/z: 312 (MþH)þ. HRMS (ESI) calcd for C21H18N3 (MþH)þ
312.1501, found 312.1503.
~
4.1.12. 5-Anilino-1-(3-chlorophenyl)-3-phenyl-1H-pyrazole (25).
Yellow powder; mp 128e129 ꢁC; 1H NMR (CDCl3, 300 MHz)
d 5.49
~
ꢀ
(br, 1H, NH), 6.51 (s, 1H, Py), 6.97 (d, 2H, J¼8.4 Hz, ArH), 7.28e7.43
(m, 7H, ArH), 7.56 (d, 1H, J¼7.7 Hz, ArH), 7.73 (s, 1H, ArH), 7.85 (d,
2H, J¼7.4 Hz, ArH); 13C NMR (CDCl3, 75 MHz)
d 94.54, 116.10,
121.32, 121.86, 124.39, 125.60, 127.54, 128.18, 128.59, 129.55,
130.28, 132.92, 135.09, 139.60, 142.37, 142.79, 151.92; IR (diffuse
reflectance) 3390 (m), 3065 (w), 2923 (m), 2855 (m), 1593 (s),

576
E.-C. Chang et al. / Tetrahedron 69 (2013) 570e576
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