One-pot synthesis of 5-sulfonamidopyrazole from terminal alkynes, sulfonyl azides and hydrozones

Article abstract of DOI:10.1016/j.tet.2011.08.067

5-Sulfonamidopyrazoles were efficiently synthesized from terminal alkynes, sulfonyl azides and hydrozones. The sequential reaction involves a copper-catalyzed three-component reaction, a Lewis acid-catalyzed electrocyclic reaction and a dehydrogenation.

Full text of DOI:10.1016/j.tet.2011.08.067

Tetrahedron 67 (2011) 8086e8091
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-pot synthesis of 5-sulfonamidopyrazole from terminal alkynes, sulfonyl
azides and hydrozones
*
*
Yao Li, Deng Hong, Yuanxun Zhu, Ping Lu , Yanguang Wang
Department of Chemistry, Zhejiang University, Hangzhou 310027, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 July 2011
Received in revised form 13 August 2011
Accepted 23 August 2011
Available online 27 August 2011
5-Sulfonamidopyrazoles were efficiently synthesized from terminal alkynes, sulfonyl azides and hy-
drozones. The sequential reaction involves a copper-catalyzed three-component reaction, a Lewis acid-
catalyzed electrocyclic reaction and a dehydrogenation.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent reactions
Alkynes
Sulfonyl azides
Hydrozones
Pyrazoles
Electrocyclic reactions
1. Introduction
cascade reaction (Scheme 1). In this way, skeletons of coumar-
ins,10a,b quinolines,10c pyrrolines,10d pyrimidines,10e azetidines10f
5-Aminopyrazoles are useful intermediates for the synthesis of
pyrazolo[3,4-b]pyridines,1 which are an important class of hetero-
cyclic compounds due to their structural analogy to purine bases2
and their broad range of bioactivities.3 These compounds have
been extensively investigated over the past 100 years.4a Conven-
and oxetanes10g were successfully synthesized. Applying this
strategy, we used hydrazones, which could be easily prepared from
phenylhydrazines and benzaldehydes, to trap the in situ generated
ketenimines and obtained cyclization products in a cascade pro-
cess. Unfortunately, instead of obtaining the expected 5-
sulfonimido-tetrahydropyrazole, we only observed the linear ad-
dition product, which could be extended to 5-sulfonamidopyrazole
in the presence of a Lewis acid and an oxidant (Scheme 1). Herein,
we would like to report the details of this work.
tional methods, such as condensation of b-ketonitriles, malononi-
trile and their derivatives with hydrazines in addition to modern
methods of resin supported solid-phase synthesis, multi-
component synthesis and ring transformations provide useful
synthetic routes to 5-aminopyrazoles.4 However, efficient synthesis
of 5-aminopyrazoles with a broad range of substituents is still
necessary.5
Previous Work:
Ketenimine was firstly described and prepared by Staudinger
and Hauser in 1921.6 Due to the fact that the central carbon of
ketenimine is highly electron deficient and active towards various
nucleophiles,7 it has been explored and applied in the construction
of various heterocycles. Among several methods leading to the
generation of ketenimines, the copper-catalyzed azideealkyne cy-
cloaddition reaction (CuAAC) attracted much attention because of
its reliable mechanism and its mild formation conditions.8 The in
situ generated ketenimine intermediates via this reaction could be
trapped by various nucleophiles.9 Previous works in building het-
erocycles starting from ketenimines were largely focused on the
R1
C
N
R2
R1
R1
E
N
R2
C
Nu
N
R2
E
Nu
Nu
E
This Work:
R1
R1
R1 R3
R2HN
R4
C
N
R2
R3
LA
R3
R2
N
N
N
N
H
N
N
R4
R4
N
5-sulfonamidopyrazole
* Corresponding authors. Tel./fax: þ86 571 87951512; e-mail addresses: pinglu@
Scheme 1. Heterocycle syntheses via ketenimine intermediate.
zju.edu.cn (P. Lu), orgwyg@zju.edu.cn (Y. Wang).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.08.067

Y. Li et al. / Tetrahedron 67 (2011) 8086e8091
8087
Table 2
2. Results and discussion
Optimization of the reaction condition for the cyclization of 4aa
Ph
Primarily, when we stirred the mixture of phenylacetylene (1a),
p-toluenesulfonyl azide (2a), (E)-1-benzylidene-2-phenyl hydra-
zine (3a), CuI and Et3N at 25 ꢀC for 12 h, we obtained a three-
component product 4a in 88% yield. Its structure was established
by single crystal analysis.11
Ph
H
N
catalyst/oxidant
solvent
Ts
Ts
N
Ph
Ph
N
N
N
N
Ph
Ph
4a
5a
Optimization of reaction conditions for the formation of 4a was
then conducted (Table 1). Dichloroethane (DCE) and dichloro-
methane (DCM) were found to be the suitable solvent for this
transformation in comparison with others, such as toluene, aceto-
nitrile and tetrahydrofuran (Table 1, entries 1e6). Triethylamine was
the best base in comparison with pyridine and potassium carbonate
(Table 1, entries 6e8). Altering the copper source to CuBr, the yield
actually decreased (Table 1, entries 6 and 9). Thus, the best reaction
condition for the formation of 4a was established (Table 1, entry 6).
Entry
Catalyst
Solvent
Oxidant
Temp (ꢀC)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
Cu(OTf)2
AgOTf
Zn(OTf)2
Zn(OAc)2
ZnCl2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
PhMe
PhMe
PhMe
PhMe
PhMe
CH3CN
DCE
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DCP
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
80
Reflux
80
80
Reflux
80
50
48
48
48
48
48
48
48
48
72
120
48
48
120
72
72
36
72
56
62
66
n.r.
n.r.
15
32
13
THF
9
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
36
31
10
11
12
13
14
15
16
17
O2
Table 1
TBHP
Oxone
Air
DTBP
DTBP
DTBP
DTBP
Trace
Trace
Trace
39
n.r.
61
Optimization of the reaction condition of the formation of 4aa
Ph
H
Cat./base
N
+
Ph
TsN3
+
Ts
N
Ph
Ph
N
Ph
N
N
Ph
solvent, N2
Reflux
Reflux
25 o
C
1a
2a
3a
67
4a
a
Reaction conditions: 4a (0.5 mmol), catalyst (0.05 mmol), oxidant (2 mmol),
Yieldb (%)
solvent (12 mL).
Entry
Solvent
Base
Catalyst
Time (h)
b
Isolated yield.
1
2
3
4
DCE
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Py
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
12
12
12
12
12
12
12
14
12
88
42
49
21
89
89
21
86
66
PhMe
CH3CN
THF
substrate diversity for the synthesis of 5-aminopyrazoles 5. Sub-
strates 1, 2 and 3 with versatile substituents could tolerate this one-
pot procedure (Table 3). Hydrazones 3aef, derived from phenyl hy-
drazine and substituted benzaldehydes, performed the reaction
smoothly (Table 3, entries 1e6), no matter the substituent on the
benzaldehydes was a strong electron donating group (3b) or a strong
electron withdrawing group (3f). Hydrazone 3g, derived from 2-
formyl pyridine, did not form any product even in the first step
(Table 3, entry 7). For hydrazones 3h and 3i, we also did not obtained
the desired products (Table 3, entries 8 and 9), but the first step
products 4b and 4c (Scheme 2) were isolated in 87% and 49% yields,
respectively. Refluxing 4b or 4c in the presence of Zn(OTf)2, no iso-
lable pyrazole was obtained although 4b or 4c was completely dis-
appeared. Hydrazones 3j and 3k, derived from p-methylphenyl
hydrazine or p-chlorophenyl hydrazine, worked for the reaction
(Table 3, entries 10 and 11). Aromatic sulfonyl azides 2aed were
suitable for the reaction, while aliphatic sulfonyl azide 2e gave a de-
creased yield (Table 3, entries 1 and 12e15). Substituent effect on the
phenylacetylenes 1aef was apparent, typically in case of 4-
methoxybenzeneacetylene 1c, which gave a decreased yield (Table
3, entries 1 and 16e22). 2-Ethynylthiophene (1g) furnished 5t in
yield of 41% (Table 3, entry 23). However, aliphatic alkyne, such as 1-
hexyne (1h), onlyafforded the linear product 4d in 73% yield (Table 3,
entry 24; Scheme 2). Further efforts to cyclize 4d in the presence of
Lewis acid failed.
Based on these results, we postulated a possible mechanism for
this sequential reaction (Scheme 3). In the first step, ketenimine A is
generated in situ from 1a and 2a via a CuAAC mechanism.9,10 Then,
amino nitrogen of hydrazone 3a nucleophilically attacks the central
carbon of ketenimine A to generate B, which tautomerizes to more
stable 4a. Bothiminesin4aareinEconfigurationsthatcouldbeseenin
its crystal structure. Its isomer Z,E-4a was not found, which might be
because of the steric hindrance raised from phenyl and tosyl as in-
dicated in Scheme 3. In the second step, the imine in B is activated by
Lewis acid,13 and then a Lewis acid-catalyzed electrocyclic reaction
occurs. Electron flows from enamine to iminium to form D.14 Sub-
5c
6c
7c
8c
9c
DCE
DCM
DCM
DCM
DCM
K2CO3
Et3N
a
Reaction conditions: 1a (1 mmol), 2a (1 mmol), 3a (0.5 mmol), solvent (8 mL),
Et3N (1.5 mmol), CuI (0.1 mmol).
b
Isolated yield.
c
Reaction conditions: 1a (0.75 mmol), 2a (0.75 mmol), 3a (0.5 mmol), solvent
(8 mL), Et3N (1 mmol), CuI (0. 075 mmol).
We then investigated the possibility for the cyclization of 4a using
a Lewisacid(LA) as catalyst. Initially, wetried Cu(OTf)2 to catalyzethe
cyclization of 4a in the presence of di-tert-butyl peroxide (DTBP). As
we expected, 5a was isolated in 56% yield. Skeleton of 5a was
established by the comparative crystal analysis of 5h.12 We then
screened the reaction conditions for the cyclization of 4a (Table 2).
Altering the catalyst from Cu(OTf)2 to AgOTf, and finally to Zn(OTf)2,
yield was steadily increased (Table 2, entries 1e3). However, both
Zn(OAc)2 and ZnCl2 did not catalyze the cyclization and the starting
material (4a) was recovered, individually (Table 2, entries 4 and 5).
Toluene was found to be the most suitable solvent for this cyclization
in comparison with others, such as acetonitrile, dichloroethane and
tetrahydrofuran (Table 2, entries 3 and 6e8). Other oxidants, such as
dicumyl peroxide (DCP) and oxygen, worked for the reaction, but
gave relatively lower yields (Table 2, entries 9 and 10). When tert-
butyl hydroperoxide (TBHP) or oxone (potassium perox-
ymonosulfate sulfate) was used as oxidant, only trace amount of 5a
was detected by TLC. Most of starting material was recovered in these
cases (Table 2, entries 11 and 12), similar to the case when the reactor
was opened to aircondition(Table 2, entry 13). Refluxingthereaction
mixture for 48 h was essential in order to complete the cyclization
(Table 2, entries 3,14e17). Thus, entry 3 inTable 2 was selected as the
most suitable reaction conditions for the formation of 5a.
With the optimized conditions for these two separated reactions,
we tried to efficiently obtain 5a in a one-pot, sequential procedure.
Using DCM for the first step and toluene for the second step, we
obtained 5a in 64% yield (Table 3, entry 1). We then tested the
sequently, D encounters a stepwise
b-H elimination and metal-
ehydrogen exchange to form dihydropyrazole F. Assisted by the
oxidant, dehydrogenation occurs spontaneously and leads to the final

8088
Y. Li et al. / Tetrahedron 67 (2011) 8086e8091
Table 3
Substrate diversity of synthesis of pyrazoles 5a
1, CuI/Et3N, N2
H
R1
O
S
O
H
N
R2
DCM, 25 oC, 12 h
N
R1
+ R2
N3
S
R3
N
R4
+
R3
O2
2, Zn(OTf)2/DTBP
PhMe, reflux, 48 h
N
N
R4
3
2
1
5
Entry
1 (R1)
2 (R2)
3 (R3/R4)
3a (Ph/Ph)
3b (4-MeOC6H4/Ph)
3c (4-MeC6H4/Ph)
3d (4-BrC6H4/Ph)
3e (2-ClC6H4/Ph)
3f (4-NO2C6H4/Ph)
3g (2-Py/Ph)
3h (2-Furyl/Ph)
3i (n-C5H11/Ph)
3j (Ph/4-MeC6H4)
3k (Ph/4-ClC6H4)
3a
3a
3a
3a
3a
3a
3a
3c
3k
3a
3a
3a
3a
5
Yieldb (%)
1
2
3
4
5
6
7
8
1a (Ph)
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
2a (4-MeC6H4)
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b (Ph)
2c (4-BrC6H4)
2d (4-MeOC6H4)
2e (Me)
2a
2a
2a
2a
2a
2a
2a
2a
2a
5a
5b
5c
5d
5e
5f
d
d
d
5g
5h
5i
64
73
63
58
60
77
0
0
0
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
52
61
57
57
67
36
52
42
51
52
54
53
52
41
0
5j
5k
5l
1b (4-MeC6H4)
1c (4-MeOC6H4)
1d (2-BrC6H4)
1d
5m
5n
5o
5p
5q
5r
5s
5t
1d
1e (3-BrC6H4)
1f (4-BrC6H4)
1g (2-thienyl)
1h (n-C4H9)
d
a
Reaction conditions: (1) 1a (0.75 mmol), 2a (0.75 mmol), 3a (0.5 mmol), DCM (8 mL), Et3N (1 mmol), CuI (0. 075 mmol), 25 ꢀC, 12 h, then DCM and Et3N was removed under
reduced pressure. (2) Zn(OTf)2 (0.05 mmol), DTBP (2 mmol) and toluene (12 mL), reflux, 48 h.
b
Isolated yield.
promoted the electron flow possible,13,15 while DTBP could assist the
dehydrogenation to occur and push the reaction forward.
Ph
Ph
O
Ts
N
Ph
Ts
N
Ts
N
N
N
Ph
N
N
N
N
Ph
Ph
3. Conclusions
4d (73%)
4c (49%)
4b (87%)
In conclusion, we developed an efficient, one-pot synthesis of 5-
sulfonamidopyrazoles from terminal alkynes, sulfonyl azides and
hydrazones. This sequential reaction includes a copper-catalyzed
three-component reaction, a Lewis acid-catalyzed electrocyclic
reaction and a dehydrogenation. Further investigations on keteni-
mine chemistry and the synthetic applications of this method are
ongoing in our laboratory.
Scheme 2. Structures of compounds 4bed.
product5a. In thisreaction, the activation of imine and the existenceof
oxidant are essential. Zn(OTf)2 could lower the activation energy and
Ph
Ph
Ph
Ph
4. Experimental section
4.1. General
DTBP
Ts
Ts
N
NH
N
N
−
N
Ph
5a
t-BuOH
N
Ph
H
H
Ts N3
Ph
+
F
1a
2a
Ph
Ph
Melting points were measured with micro melting point appa-
ratus. Infrared spectra were obtained on an FTIR spectrometer. 1H
NMR spectra were recorded on 500 or 400 MHz spectrometer in
CDCl3 solution and the chemical shifts were reported relative to
internal standard TMS (0 ppm). The following abbreviations are
used to describe peak patterns where appropriate: s¼singlet,
d¼doublet, t¼triplet, q¼quartet, m¼multiplet. Coupling constants
are reported in Hertz (Hz). 13C NMR were recorded on 125 or
100 MHz and referenced to the internal solvent signals (central
peak is 77.27 ppm). HRMS were obtained using EI ionization.
CH2Cl2 was distilled over CaH2 and toluene was distilled over Na.
Et3N
CuI
H+
Ts
Zn(OTf)2
N
Zn(OTf)2
N
N
Ph
H
Ph
Ph
Ph
Ph
D
N
C
E
Ts
H+
A
Ts
N
N
H
N
Ph
B
H
N
N
Ph
Ph
Ph
Ph
Ph
N
3a
H
Ts
N
Ts
N
H
N
Ph
C
Zn(OTf)2
N
Zn(OTf)2
N
Ph
H
Ph
Ph
N
Ph
Ph
N
N
Ts
N
N
N
Ph
Ts Ph
4.2. General procedure for the synthesis of 4
E,E-4a
4a
Z, E-
NOT FOUND
To a mixture of CuI (0.075 mmol), sulfonyl azide 2 (0.75 mmol),
hydrazone 3 (0.5 mmol) and alkyne 1 (0.75 mmol) in CH2Cl2 (8 mL)
was added Et3N (1 mmol) under an N2 atmosphere. The mixture
Scheme 3. Proposed mechanism for the formation of 4a and 5a.

Y. Li et al. / Tetrahedron 67 (2011) 8086e8091
8089
was stirred at 25 ꢀC for 12 h and then evaporated on vacuum. The
residue was subjected to silica gel column chromatography with
petroleum ether/ethyl acetate as eluent. The products were
recrystallized from ethyl acetate/hexane.
(s, 3H); 13C NMR (125 MHz, CDCl3):
132.9, 131.5, 131.3, 129.9, 129.6, 129.2, 128.7, 128.4, 128.2, 128.1,
128.0, 127.3, 127.2, 125.1, 118.8, 21.7; HRMS (EI) calcd for
C28H23N3O2S, 465.1511; found, 465.1513.
d
149.5, 143.9, 139.2, 136.2,
4.2.1. (E)-N-(1-((E)-2-Benzylidene-1-phenylhydrazinyl)-2-
phenylethylidene)-4-methylbenzenesulfonamide (4a). White solid,
mp 170e171 ꢀC; IR (film): v 3060, 3021, 1599, 1552, 1489, 1424,
1278, 1144, 1084, 942, 814, 724, 692, 555 cmꢁ1; 1H NMR (400 MHz,
4.3.2. 3-(4-Methoxyphenyl)-1,4-diphenyl-N-tosyl-1H-pyrazol-5-
amine (5b). White solid, mp 193e194 ꢀC; IR (film): v 3253, 3066,
1596, 1498, 1435, 1250, 1166, 732, 666, 568 cmꢁ1 1H NMR
;
(400 MHz, CDCl3):
d
7.61 (d, J¼8.0 Hz, 2H), 7.40e7.31 (m, 5H),
CDCl3):
7.09e7.06 (m, 4H), 4.97 (s, 2H), 2.31 (s, 3H); 13C NMR (100 MHz,
CDCl3): 168.3, 145.5, 142.2, 140.7, 136.4, 135.9, 133.7, 130.7, 130.4,
d
7.52e7.43 (m, 9H), 7.32e7.27 (m, 5H), 7.24e7.17 (m, 2H),
7.18e7.08 (m, 6H), 6.96 (d, J¼7.2 Hz, 2H), 6.82 (d, J¼8.4 Hz, 2H),
6.76 (d, J¼8.8 Hz, 2H), 3.74 (s, 3H), 2.27 (s, 3H); 13C NMR
d
(100 MHz, CDCl3): d 159.5, 149.3, 143.7, 139.2, 136.2, 131.4, 131.3,
129.7, 129.1, 129.0, 128.92, 128.87, 128.8, 127.8, 126.8, 126.2, 37.2,
21.6; HRMS (EI) calcd for C28H25N3O2S, 467.1667; found, 467.1662.
129.9, 129.5, 129.4, 129.1, 128.5, 127.8, 127.1, 125.4, 125.0, 118.6,
113.8, 55.4, 21.7; HRMS (EI) calcd for C29H25N3O3S, 495.1617;
found, 495.1631.
4.2.2. (E)-N-(1-((E)-2-(Furan-2-ylmethylene)-1-phenylhydrazinyl)-
2-phenylethylidene)-4-methylbenzenesulfonamide
solid, mp 135e136 ꢀC; IR (film): v 3060, 3027, 1599, 1549, 1495,
1427, 1281, 1141, 1084, 817, 680 cmꢁ1 1H NMR (500 MHz, CDCl3):
7.63 (d, J¼7.0 Hz, 2H), 7.51e7.44 (m, 6H), 7.29 (t, J¼7.5 Hz, 2H), 7.20
(t, J¼7.0 Hz, 1H), 7.09e7.03 (m, 5H), 6.57 (d, J¼3.0 Hz, 1H), 6.43 (m,
1H), 4.91 (s, 2H), 2.32 (s, 3H); 13C NMR (125 MHz, CDCl3):
168.3,
149.7, 144.9, 142.2, 140.8, 136.1, 135.8, 134.7, 130.4, 129.8, 129.1,
128.8, 128.6, 126.8, 126.3, 113.5, 112.3, 37.1, 21.6; HRMS (EI) calcd for
C26H23N3O3S, 457.1460; found, 457.1461.
(4b). Yellow
4.3.3. 1,4-Diphenyl-3-p-tolyl-N-tosyl-1H-pyrazol-5-amine
(5c). White solid, mp 217e218 ꢀC; IR (film): v 3253, 3063, 3030,
;
1596, 1498, 1156, 906, 727, 662, 567 cmꢁ1 1H NMR (400 MHz,
;
d
CDCl3):
d
7.62 (d, J¼8.0 Hz, 2H), 7.38 (t, J¼7.2 Hz, 2H), 7.33e7.30
(m, 3H), 7.18e7.10 (m, 5H), 7.04e7.02 (m, 3H), 6.98e6.94 (m, 2H),
6.82 (d, J¼8.4 Hz, 2H), 2.28 (s, 3H), 2.27 (s, 3H); 13C NMR
d
(100 MHz, CDCl3): d 149.6, 143.7, 139.2, 137.8, 136.2, 131.4, 131.3,
130.0, 129.9, 129.5, 129.1, 128.5, 128.0, 127.8, 127.1, 125.0, 118.9,
21.7, 21.5; HRMS (EI) calcd for C29H25N3O2S, 479.1667; found,
479.1668.
4.2.3. (E)-N-(1-((E)-2-Hexylidene-1-phenylhydrazinyl)-2-
phenylethylidene)-4-methylbenzenesulfonamide (4c). Yellow liquid,
IR(film):v3060, 3030, 2953, 2923, 2852,1554,1489,1424,1278,1150,
4.3.4. 3-(4-Bromophenyl)-1,4-diphenyl-N-tosyl-1H-pyrazol-5-amine
(5d). White solid, mp 221e222 ꢀC; IR (film): v 3254, 3063, 1596,
1084, 924, 811, 698, 552cmꢁ1;1HNMR (500MHz, CDCl3):
d
7.47e7.44
1497, 1441, 1361, 1328, 1165, 662, 573 cmꢁ1 1H NMR (500 MHz,
;
(m, 6H), 7.40 (t, J¼7.5 Hz, 1H), 7.28 (t, J¼7.5 Hz, 2H), 7.20 (t, J¼7.0 Hz,
1H), 7.05(d, J¼8.0 Hz, 2H), 6.98 (d, J¼7.5 Hz, 2H), 6.61 (t, J¼5.5 Hz,1H),
4.83 (s, 2H), 2.31 (s, 3H), 2.17e2.13 (m, 2H), 1.36e1.30 (m, 2H),
1.25e1.21 (m, 2H), 1.16e1.10 (m, 2H), 0.84 (t, J¼7.5 Hz, 3H); 13C NMR
CDCl3):
d
7.62 (d, J¼7.5 Hz, 2H), 7.41 (t, J¼7.5 Hz, 2H), 7.36e7.35 (m,
3H), 7.29 (d, J¼8.5 Hz, 2H), 7.23e7.14 (m, 5H), 6.95 (d, J¼7.0 Hz,
2H), 6.90 (s, 1H), 6.85 (d, J¼8.0 Hz, 2H), 2.30 (s, 3H); 13C NMR
(125 MHz, CDCl3):
d 148.4, 143.9, 139.1, 136.2, 131.8, 131.7, 131.6,
(125 MHz, CDCl3):
d
168.1,150.0,142.0,141.0,136.7,136.0,130.2,129.4,
131.0, 129.9, 129.7, 129.6, 129.2, 128.8, 128.1, 127.5, 127.2, 125.1,
122.3, 119.0, 21.7; HRMS (EI) calcd for C28H22BrN3O2S, 543.0616;
found, 543.0610.
129.3,129.0,128.8,128.5,126.6,126.2, 37.1, 32.7, 31.3, 25.8, 22.5, 21.6,
14.1; HRMS (EI) calcd for C27H31N3O2S, 461.2137; found, 461.2121.
4.2.4. (E)-N-(1-((E)-2-Benzylidene-1-phenylhydrazinyl)hexylidene)-
4-methylbenzenesulfonamide (4d). White solid, mp 88e89 ꢀC; IR
(film): v 3057, 3024, 2952, 2926, 2864, 1557, 1421, 1284, 1153, 1081,
4.3.5. 3-(2-Chlorophenyl)-1,4-diphenyl-N-tosyl-1H-pyrazol-5-amine
(5e). White solid, mp 238e239 ꢀC; IR (film): v 3241, 3063, 1599,
1495, 1435, 1358, 1328, 1162, 903, 751, 727, 662 cmꢁ1 1H NMR
;
695 cmꢁ1
;
1H NMR (500 MHz, CDCl3):
d
7.57e7.52 (m, 4H),
(500 MHz, CDCl3):
d
7.66 (d, J¼8.0 Hz, 2H), 7.43e7.32 (m, 5H),
7.50e7.46 (m, 3H), 7.39e7.37 (m, 3H), 7.31 (s, 1H), 7.13e7.08 (m,
4H), 3.52 (d, J¼7.5 Hz, 2H), 2.32 (s, 3H), 1.97e1.91 (m, 2H), 1.60e1.54
(m, 2H), 1.48e1.41 (m, 2H), 0.95 (t, J¼7.0 Hz, 3H); 13C NMR
7.26e7.18 (m, 5H), 7.09 (t, J¼7.5 Hz, 1H), 7.03 (t, J¼7.5 Hz, 2H),
6.84e6.80 (m, 4H), 2.26 (s, 3H); 13C NMR (125 MHz, CDCl3):
d
148.6, 143.9, 139.0, 135.7, 134.3, 132.4, 131.1, 130.4, 129.91, 129.89,
(125 MHz, CDCl3):
d
171.7, 145.0, 142.0, 141.0, 136.5, 133.9, 130.7,
129.5, 129.2, 128.7, 128.4, 128.0, 127.2, 126.80, 126.77, 124.9, 120.4,
21.7; HRMS (EI) calcd for C28H22ClN3O2S, 499.1121; found,
499.1105.
130.4, 129.6, 129.0, 127.7, 126.1, 32.4, 31.9, 27.3, 22.5, 21.6, 14.2;
HRMS (EI) calcd for C26H29N3O2S, 445.1824; found, 445.1810.
4.3. General procedure for the synthesis of 5
4.3.6. 3-(4-Nitrophenyl)-1,4-diphenyl-N-tosyl-1H-pyrazol-5-amine
(5f). Yellow solid, mp 192e193 ꢀC; IR (film): v 3256, 3063, 1596,
To a mixture of CuI (0.075 mmol), sulfonyl azide 2 (0.75 mmol),
hydrazone 3 (0.5 mmol) and alkyne 1 (0.75 mmol) in CH2Cl2 (8 mL)
was added Et3N (1 mmol) under an N2 atmosphere. The mixture
was stirred at 25 ꢀC for 12 h and then evaporated on vacuum. The
residue was dissolved in toluene (12 mL) and Zn(OTf)2 (0.05 mmol)
and DTBP (2 mmol) were added. The mixture was stirred at reflux
temperature for 48 h and then evaporated on vacuum. The residue
was subjected to silica gel column chromatography with petroleum
ether/ethyl acetate as eluent.
1516, 1495, 1346, 1165, 858, 724, 570 cmꢁ1 1H NMR (400 MHz,
;
CDCl3):
d
8.07 (d, J¼8.8 Hz, 2H), 7.64e7.59 (m, 4H), 7.44e7.36 (m,
3H), 7.26 (t, J¼7.2 Hz, 1H), 7.20e7.14 (m, 5H), 6.98 (d, J¼7.2 Hz, 2H),
6.86 (d, J¼8.0 Hz, 2H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
147.3, 147.1, 144.0, 139.4, 138.8, 136.1, 132.2, 130.5, 129.9, 129.6,
129.3, 128.9, 128.5, 128.4, 127.8, 127.1, 125.1, 123.7, 120.0, 21.7; HRMS
(EI) calcd for C28H22N4O4S, 510.1362; found, 510.1357.
4.3.7. 3,4-Diphenyl-1-p-tolyl-N-tosyl-1H-pyrazol-5-amine
(5g). White solid, mp 187e188 ꢀC; IR (film): v 3254, 3060, 1514,
4.3.1. 1,3,4-Triphenyl-N-tosyl-1H-pyrazol-5-amine
solid, mp 203e204 ꢀC; IR (film): v 3244, 3063, 1599, 1492, 1360,
1162, 760, 724, 698, 671 cmꢁ1; 1H NMR (500 MHz, CDCl3):
7.65 (d,
(5a). White
1366, 1333, 1166, 910, 733, 700 cmꢁ1 1H NMR (500 MHz, CDCl3):
;
d
7.49 (d, J¼8.0 Hz, 2H), 7.43e7.41 (m, 2H), 7.25e7.17 (m, 8H), 7.14 (t,
J¼7.0 Hz, 2H), 6.97 (d, J¼7.0 Hz, 2H), 6.88 (s, 1H), 6.84 (d, J¼8.0 Hz,
2H), 2.39 (s, 3H), 2.29 (s, 3H); 13C NMR (125 MHz, CDCl3):
149.3,
143.7, 137.9, 136.7, 136.4, 132.9, 131.4, 129.9, 129.7, 129.5, 128.6,
d
J¼7.5 Hz, 2H), 7.44e7.41 (m, 4H), 7.36 (t, J¼7.5 Hz,1H), 7.24e7.14 (m,
d
8H), 6.96 (d, J¼7.0 Hz, 2H), 6.87 (d, J¼8.0 Hz, 2H), 6.74 (s, 1H), 2.30

8090
Y. Li et al. / Tetrahedron 67 (2011) 8086e8091
128.4, 128.2, 128.0, 127.2, 125.0, 118.7, 21.7, 21.4; HRMS (EI) calcd for
C29H25N3O2S, 479.1667; found, 479.1674.
(400 MHz, CDCl3):
6.89e6.83 (m, 4H), 6.65 (d, J¼8.4 Hz, 2H), 3.77 (s, 3H), 2.28 (s, 3H);
13C NMR (100 MHz, CDCl3):
158.9, 149.5, 143.7, 139.2, 136.5, 133.0,
d
7.61 (d, J¼7.2 Hz, 2H), 7.45e7.10 (m, 11H),
d
4.3.8. 1-(4-Chlorophenyl)-3,4-diphenyl-N-tosyl-1H-pyrazol-5-amine
(5h). White solid, mp 202e203 ꢀC; IR (film): v 3244, 3057, 1492,
1361, 1325, 1159, 1090, 909, 730, 698, 659 cmꢁ1; 1H NMR (500 MHz,
131.4, 131.0, 129.4, 129.1, 128.4, 128.1, 128.0, 127.8, 127.1, 125.0, 123.5,
118.8, 114.0, 55.3, 21.7; HRMS (EI) calcd for C29H25N3O3S, 495.1617;
found, 495.1615.
CDCl3):
d
7.56 (d, J¼8.5 Hz, 2H), 7.41e7.40 (m, 2H), 7.32 (d, J¼8.5 Hz,
2H), 7.25e7.14 (m, 8H), 7.11(s, 1H), 6.97 (d, J¼7.0 Hz, 2H), 6.87 (d,
4.3.15. 4-(2-Bromophenyl)-1,3-diphenyl-N-tosyl-1H-pyrazol-5-
J¼8.0 Hz, 2H), 2.32 (s, 3H); 13C NMR (125 MHz, CDCl3):
d
149.9,
amine (5o). White solid, mp 214e215 ꢀC; IR (film): v 3256, 3063,
144.1, 137.7, 136.1, 133.7, 132.6, 131.5, 131.0, 129.9, 129.6, 129.2, 128.7,
128.5, 128.3, 128.1, 127.4, 127.1, 126.1, 119.4, 21.8; HRMS (EI) calcd for
C28H22ClN3O2S, 499.1121; found, 499.1119.
1593, 1498, 1168, 909, 727, 668, 570 cmꢁ1 1H NMR (500 MHz,
;
CDCl3):
d
7.70e7.68 (m, 2H), 7.52e7.50 (m, 1H), 7.45 (t, J¼8.0 Hz,
2H), 7.39e7.33 (m, 3H), 7.26e7.21 (m, 5H), 7.11e7.07 (m, 1H),
7.00e6.97 (m, 1H), 6.87 (d, J¼8.0 Hz, 2H), 6.74e6.72 (m, 1H), 6.64 (s,
4.3.9. N-(1,3,4-Triphenyl-1H-pyrazol-5-yl)benzenesulfonamide
(5i). White solid, mp 201e202 ꢀC; IR (film): v 3250, 3063, 1495,
1358, 1328, 1162, 1087, 912, 751, 683, 587 cmꢁ1; 1H NMR (500 MHz,
1H), 2.28 (s, 3H); 13C NMR (125 MHz, CDCl3):
d 149.6, 143.8, 139.0,
136.3, 133.4, 132.9, 132.6, 132.4, 131.7, 129.6, 129.24, 129.19, 128.5,
128.2, 128.1, 127.7, 127.6, 127.0, 125.2, 123.8, 117.7, 21.7; HRMS (EI)
calcd for C28H22BrN3O2S, 543.0616; found, 543.0618.
CDCl3):
2H), 7.34e7.12 (m, 10H), 7.07 (t, J¼8.0 Hz, 2H), 7.01e6.97 (m, 3H);
13C NMR (125 MHz, CDCl3):
149.6, 139.3, 139.1, 133.0, 132.8, 131.4,
d
7.61 (d, J¼7.5 Hz, 2H), 7.44e7.42 (m, 2H), 7.39 (d, J¼8.0 Hz,
d
4.3.16. N-(4-(2-Bromophenyl)-1-phenyl-3-(p-tolyl)-1H-pyrazol-5-
131.2, 129.9, 129.2, 128.9, 128.8, 128.4, 128.13, 128.08, 127.5, 127.1,
125.1, 119.1; HRMS (EI) calcd for C27H21N3O2S, 451.1354; found,
451.1353.
yl)-4-methylbenzenesulfonamide
245e246 ꢀC; IR (film): v 3253, 3062, 2915, 1597, 1496, 1362, 1330,
1166, 1090, 907, 824, 753, 730, 671 cmꢁ1 1H NMR (500 MHz,
CDCl3):
(5p). White
solid,
mp
;
d
7.69e7.67 (m, 2H), 7.52e7.50 (m, 1H), 7.44 (t, J¼7.5 Hz,
4.3.10. 4-Bromo-N-(1,3,4-triphenyl-1H-pyrazol-5-yl)benzenesulfo-
2H), 7.36 (t, J¼7.5 Hz, 1H), 7.26e7.22 (m, 4H), 7.10e7.07 (m, 1H),
7.02e6.97 (m, 3H), 6.86 (d, J¼8.0 Hz, 2H), 6.75e6.73 (m,1H), 6.59 (s,
namide (5j). White solid, mp 201e202 ꢀC; IR (film): v 3250, 3063,
1575, 1495, 1337, 1165, 1067, 903, 736, 698, 608 cmꢁ1
;
1H NMR
1H), 2.28 (s, 6H); 13C NMR (125 MHz, CDCl3):
d 149.6, 143.8, 139.1,
(500 MHz, CDCl3):
d
7.62 (d, J¼8.0 Hz, 2H), 7.44e7.41 (m, 4H), 7.37
138.0, 136.4, 133.5, 132.8, 132.6, 131.7, 129.8, 129.6, 129.2, 128.0,
127.6, 127.5, 127.1, 125.2, 123.8, 117.6, 21.7, 21.5; HRMS (EI) calcd for
C29H24BrN3O2S, 557.0773; found, 557.0787.
(t, J¼7.5 Hz, 1H), 7.25e7.23 (m, 4H), 7.18 (t, J¼7.5 Hz, 2H), 7.16e7.10
(m, 4H), 7.01 (s, 1H), 6.96 (d, J¼7.0 Hz, 2H); 13C NMR (125 MHz,
CDCl3):
d 149.7, 139.0, 138.1, 132.7, 132.2, 131.1, 130.9, 129.8, 129.3,
128.8, 128.54, 128.48, 128.24, 128.17, 127.5, 125.1, 119.2; HRMS (EI)
calcd for C27H20BrN3O2S, 529.0460; found, 529.0458.
4.3.17. N-(4-(2-Bromophenyl)-1-(4-chlorophenyl)-3-phenyl-1H-pyr-
azol-5-yl)-4-methylbenzenesulfonamide (5q). White solid, mp
221e222 ꢀC; IR (film): v 3258, 3056, 1496, 1362, 1333, 1166, 1090,
4.3.11. 4-Methoxy-N-(1,3,4-triphenyl-1H-pyrazol-5-yl)benzenesulfo-
namide (5k). White solid, mp 205e206 ꢀC; IR (film): v 3250, 3057,
1596, 1495, 1260, 1156, 754, 730, 699, 665 cmꢁ1; 1H NMR (500 MHz,
965, 906, 830, 733, 665 cmꢁ1 1H NMR (500 MHz, CDCl3):
;
d
7.66e7.63 (m, 2H), 7.54e7.52 (m, 1H), 7.39e7.37 (m, 2H),
7.34e7.32 (m, 2H), 7.26e7.21 (m, 5H), 7.13e7.09 (m, 1H), 7.01e6.98
(m, 1H), 6.90 (d, J¼8.0 Hz, 2H), 6.75e6.73 (m, 1H), 6.66 (s, 1H), 2.31
CDCl3):
d
7.65 (d, J¼7.5 Hz, 2H), 7.43e7.40 (m, 4H), 7.34 (t, J¼7.5 Hz,
1H), 7.25e7.14 (m, 8H), 6.98 (d, J¼6.5 Hz, 2H), 6.94 (s, 1H), 6.50 (d,
(s, 3H); 13C NMR (125 MHz, CDCl3):
d 149.9,144.1,137.6,136.3,133.9,
J¼8.0 Hz, 2H), 3.77 (s, 3H); 13C NMR (125 MHz, CDCl3):
d
163.1,
133.4, 132.9, 132.4, 132.2, 131.9, 129.7, 129.4, 129.3, 128.5, 128.3,
127.7, 127.6, 127.0, 126.2, 123.7, 118.1, 21.7; HRMS (EI) calcd for
C28H21BrClN3O2S, 577.0226; found, 577.0217.
149.5, 139.3, 132.9, 131.6, 131.4, 130.6, 129.9, 129.3, 129.2, 128.7,
128.4, 128.2, 128.1, 128.0, 127.3, 125.0, 118.9, 114.1, 55.7; HRMS (EI)
calcd for C28H23N3O3S, 481.1460; found, 481.1454.
4.3.18. 4-(3-Bromophenyl)-1,3-diphenyl-N-tosyl-1H-pyrazol-5-
4.3.12. N-(1,3,4-Triphenyl-1H-pyrazol-5-yl)methanesulfonamide
amine (5r). White solid, mp 200e201 ꢀC; IR (film): v 3250, 3060,
(5l). White solid, mp 94e95 ꢀC; IR (film): v 3238, 3060, 1596, 1498,
1590, 1498, 1361, 1328, 1162, 1090, 909, 763, 686 cmꢁ1 1H NMR
;
1361, 1328, 1150, 968, 903, 730, 698 cmꢁ1
;
1H NMR (500 MHz,
(500 MHz, CDCl3):
d
7.66 (d, J¼7.5 Hz, 2H), 7.46e7.36 (m, 5H),
CDCl3):
6H), 7.27e7.26 (m, 3H), 6.85 (s, 1H), 2.16 (s, 3H); 13C NMR (125 MHz,
CDCl3): 149.6, 138.6, 132.7, 131.8, 131.7, 130.3, 129.4, 129.2, 128.6,
d
7.65 (d, J¼7.5 Hz, 2H), 7.50e7.44 (m, 4H), 7.39e7.33 (m,
7.29e7.25 (m, 4H), 7.21 (d, J¼8.0 Hz, 2H), 7.06e7.05 (m, 2H) 6.99 (t,
J¼7.5 Hz, 1H), 6.94e6.89 (m, 3H), 2.32 (s, 3H); 13C NMR (125 MHz,
d
CDCl3): d 149.6, 144.1, 138.9, 136.2, 133.5, 132.5, 132.4, 131.6, 130.2,
128.5, 128.3, 128.2, 128.1, 125.6, 119.0, 41.9; HRMS (EI) calcd for
C22H19N3O2S, 389.1198; found, 389.1197.
130.1, 129.6, 129.3, 128.7, 128.5, 128.4, 128.23, 128.20, 127.0, 125.2,
122.6, 117.4, 21.9; HRMS (EI) calcd for C28H22BrN3O2S, 543.0616;
found, 543.0609.
4.3.13. 1,3-Diphenyl-4-p-tolyl-N-tosyl-1H-pyrazol-5-amine
(5m). White solid, mp 202e203 ꢀC; IR (film): v 3247, 3063, 1593,
4.3.19. 4-(4-Bromophenyl)-1,3-diphenyl-N-tosyl-1H-pyrazol-5-
1498, 1447, 1361, 1165, 1090, 909, 730, 665 cmꢁ1
;
1H NMR
amine (5s). White solid, mp 214e215 ꢀC; IR (film): v 3253, 3063,
(500 MHz, CDCl3):
d
7.64 (d, J¼7.5 Hz, 2H), 7.46e7.44 (m, 2H), 7.40
1495, 1364, 1328, 1165, 906, 730, 695, 665, 573 cmꢁ1 1H NMR
;
(t, J¼7.5 Hz, 2H), 7.34 (t, J¼7.5 Hz, 1H), 7.25e7.23 (m, 3H), 7.18 (d,
J¼8.0 Hz, 2H), 6.94e6.92 (m, 3H), 6.85e6.84 (m, 4H), 2.33 (s, 3H),
(400 MHz, CDCl3):
7.24e7.16 (m, 7H), 6.87 (d, J¼10.0 Hz, 2H), 6.81 (d, J¼10.5 Hz, 2H),
2.34 (s, 3H); 13C NMR (100 MHz, CDCl3):
149.5, 144.2, 136.4, 132.5,
d
7.63 (d, J¼9.5 Hz, 2H), 7.44e7.36 (m, 6H),
2.30 (s, 3H); 13C NMR (125 MHz, CDCl3):
d
149.5, 143.7, 139.2, 136.9,
d
136.4, 133.0, 131.4, 129.7, 129.4, 129.3, 129.2, 128.4, 128.2, 128.1,
128.0, 127.9, 127.2, 125.0, 118.9, 21.7, 21.5; HRMS (EI) calcd for
C29H25N3O2S, 479.1667; found, 479.1663.
131.6, 131.4, 131.3, 130.2, 129.5, 129.2, 128.5, 128.3, 128.2, 127.0,
125.2, 121.5, 118.0, 21.8; HRMS (EI) calcd for C28H22BrN3O2S,
543.0616; found, 543.0621.
4.3.14. 4-(4-Methoxyphenyl)-1,3-diphenyl-N-tosyl-1H-pyrazol-5-
4.3.20. 1,3-Diphenyl-4-(thiophen-2-yl)-N-tosyl-1H-pyrazol-5-amine
(5t). Yellow solid, mp 92e93 ꢀC; IR (film): v 3250, 3066, 1593, 1492,
1447, 1367, 1328, 1156, 906, 730, 698, 668 cmꢁ1; 1H NMR (500 MHz,
amine (5n). White solid, mp 204e205 ꢀC; IR (film): v 3250, 3063,
1593, 1498, 1358, 1248, 1165, 733, 683, 668 cmꢁ1
;
1H NMR

Y. Li et al. / Tetrahedron 67 (2011) 8086e8091
8091
K.; Kishikawa, K.; Yamamoto, S.; Takeda, H.; Obata, T.; Nakai, H.; Toda, M. Bioorg.
Med. Chem. 2004, 12, 4089; (c) Bare, T. M.; McLaren, C. D.; Campbell, J. B.; Firor,
J. W.; Resch, J. F.; Walters, C. P.; Salama, A. I.; Meiners, B. A.; Patel, J. B. J. Med.
Chem. 1989, 32, 2561; (d) Hohn, H.; Polacek, I.; Schulze, E. J. Med. Chem. 1973, 16,
1340; (e) Chu, I.; Lynch, B. M. J. Med. Chem. 1975, 18, 161; (f) Shutske, G. M.;
Roehr, J. E. J. Heterocycl. Chem. 1997, 34, 789.
4. (a) Aggarwal, R.; Kumar, V.; Kumar, R.; Singh, S. P. Beilstein J. Org. Chem. 2011, 7,
179; (b) Pierce, L. T.; Cahill, M. M.; McCarthy, F. O. Tetrahedron 2011, 67, 4601; (c)
Dodd, D. S.; Martinez, R. L.; Kamau, M.; Ruan, Z. M.; Kirk, K. V.; Cooper, C. B.;
Hermsmeier, M. A.; Traeger, S. C.; Poss, M. A. J. Comb. Chem. 2005, 7, 584.
5. Atlan, V.; ElKaim, L.; Grimaud, L.; Jana, N. K.; Majee, A. Synlett 2002, 352.
6. Staudinger, H.; Hauser, E. Helv. Chim. Acta 1921, 4, 887.
CDCl3):
d
7.55 (d, J¼7.5 Hz, 2H), 7.53e7.51 (m, 2H), 7.36 (d, J¼7.5 Hz,
2H), 7.32e7.25 (m, 6H), 7.20 (d, J¼5.0 Hz, 1H), 6.92 (d, J¼8.0 Hz, 2H),
6.89 (s, 1H), 6.86e6.85 (m, 1H), 6.64 (d, J¼3.5 Hz, 1H), 2.30 (s, 3H);
13C NMR (125 MHz, CDCl3):
d 150.1, 143.9, 139.0, 136.4, 132.5, 132.1,
131.7, 129.6, 129.2, 128.5, 128.3, 128.1, 128.0, 127.5, 127.2, 126.5,
125.0, 112.3, 21.7; HRMS (EI) calcd for C26H21N3O2S2, 471.1075;
found, 471.1070.
Acknowledgements
7. (a) Krow, G. R. Angew. Chem., Int. Ed. Engl. 1971, 10, 435; (b) Lu, P.; Wang, Y. G.
Synlett 2010, 165; (c) Yoo, E. J.; Chang, S. Curr. Org. Chem. 2009, 13, 1766.
8. (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2002, 41, 2596; (b) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem.
2002, 67, 3057.
We thank the National Nature Science Foundation of China (Nos.
21032005 and 20872128) for financial support.
9. (a) Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005, 127, 2038; (b) Yoo, E. J.; Bae,
I.; Cho, S. H.; Han, H.; Chang, S. Org. Lett. 2006, 8, 1347; (c) Cho, S. H.; Chang, S.
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5743; (e) Wang, J.; Wang, J. J.; Zhu, Y. X.; Lu, P.; Wang, Y. G. Chem. Commun.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.08.067.
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