Synthesis of 1,3,5-Trisubstituted Pyrazoles by the Cope-Type Hydroamination of 1,3-Dialkynes with Alkylhydrazines

Article abstract of DOI:10.1055/s-0034-1378660

An efficient method to synthesize 1,3,5-trisubstituted pyrazoles was developed. The reaction of 1,3-dialkynes with alkylhydrazines smoothly proceeded in dimethyl sulfoxide under suitable heating conditions to produce 1,3,5-trisubstituted pyrazoles in sati

Full text of DOI:10.1055/s-0034-1378660

2422▌
FEATURE ARTICLE
feature article
Synthesis of 1,3,5-Trisubstituted Pyrazoles by the Cope-Type Hydroamination
of 1,3-Dialkynes with Alkylhydrazines
1,3,5-Trisubstituted Pyrazoles
Xiaoqiang Yu,*a Nan Huang,a Xiujuan Feng,a Yoshinori Yamamoto,a,b Ming Bao*a
a
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116023, P. R. of China
Fax +86(411)84986180; E-mail: yuxiaoqiang@dlut.edu.cn; E-mail: mingbao@dlut.edu.cn
b
WPI-AIMR (WPI-Advanced Institute for Materials Research), Tohoku University, Sendai 980-8577, Japan
Received: 30.05.2014; Accepted after revision: 04.07.2014
previous work
Abstract: An efficient method to synthesize 1,3,5-trisubstituted
O
O
pyrazoles was developed. The reaction of 1,3-dialkynes with alkyl-
hydrazines smoothly proceeded in dimethyl sulfoxide under suit-
able heating conditions to produce 1,3,5-trisubstituted pyrazoles in
satisfactory to excellent yields.
R3
R1
R1
R1
R2
R2
Knorr reaction
N
N
R3 NH NH2
or
+
(1)
(2)
R2
O
Key words: 1,3,5-trisubstituted pyrazole, 1,3-dialkyne, alkylhy-
drazine, synthesis, Cope-type hydroamination
R3
[3 + 2] cycloaddition
R3
N
R2
N
N
X
+
R1
N
R2
H
R1
X = SO2Ar, NO2
1,3,5-Trisubstituted pyrazoles are important building
blocks in the pharmaceutical industry because of their an-
ticancer,1 antibacterial,2 analgesic,3 and anti-inflammato-
ry activities.4 For example, 1,3,5-trisubstituted pyrazoles
constitute the core structures of commercial drugs, such as
Acomplia, Viagra, and Celebrex. Two methods have been
developed for the synthesis of 1,3,5-trisubstituted pyra-
zoles over the past years. The first method involves the re-
action of substituted hydrazines with a three-carbon-atom
component (such as 1,3-dicarbonyl compound, α,β-unsat-
urated carbonyl compound) (Scheme 1, equation 1).5 The
second method involves the [3+2] cycloaddition of
alkenes/alkynes with 1,3-dipoles (Scheme 1, equation 2).6
The transition metal-catalyzed cross-coupling reactions
for the synthesis of 1,3,5-trisubstituted pyrazoles have
also been reported.7 However, these methods have several
drawbacks, such as harsh reaction conditions, multistep
reactions, and the use of transition-metal catalysts and
special starting materials, or poor selectivity.
this work
Cope-type
hydroamination
R3
N
N
R3 NH NH2
R1
R2
+
(3)
R2
R1
Scheme 1 Synthesis of 1,3,5-trisubstituted pyrazoles
The reaction of 1,4-diphenylbuta-1,3-diyne (1a) with
methylhydrazine sulfate was initially selected as a model
to optimize the reaction conditions. The results are sum-
marized in Table 1. The reaction of 1a with methylhydra-
zine sulfate was performed under the same reaction
conditions as for the reaction of 1a with hydrazine (in
DMSO at 60 °C for 20 h).8 The desired product, 5-benzyl-
1-methyl-3-phenyl-1H-pyrazole (2a), was obtained in
only 6% yield (entry 1). Subsequent analysis of the reac-
tion temperature indicated that 110 °C was the most suit-
able temperature to produce 2a in 65% yield (entry 6).
The intermolecular Cope-type hydroamination reaction of
1,3-dialkynes with hydrazine to produce 3,5-disubstituted
pyrazoles have been reported by our group recently.8 This
reaction proceeded smoothly in dimethyl sulfoxide
(DMSO) in the absence of strong acid, strong base, and
transition metal. From mechanistic analysis of this reac-
tion, we anticipated that the intermolecular Cope-type
hydroamination reaction of 1,3-dialkynes with alkylhy-
drazines (NH2NHR) might also occur to produce 1,3,5-
disubstituted pyrazoles. As expected, the desired 1,3,5-
disubstituted pyrazoles were obtained at a relatively high
temperature (Scheme 1, equation 3). The results are re-
ported in the current work.
An excess of methylhydrazine sulfate was tested to im-
prove the yield of 2a. The results showed that 4 equiva-
lents of methylhydrazine sulfate is necessary to afford
product 2a in a higher yield (73%; Table 1, entry 8 vs en-
tries 6 and 9). The bases, which included Et2NH, i-Pr2NEt,
Bu3N, K2CO3, K3PO4, and NaOAc (entries 10–17) were
then screened. Among the tested bases, Et2NH resulted in
the formation of 2a in relatively high yield (entry 10, 80%
yield). Therefore, the subsequent reactions of the symmet-
rical 1a–h and asymmetrical 3a–f 1,3-dialkynes with
methylhydrazine sulfate (4 equiv) were performed in
DMSO at 110 °C for 20 hours using Et2NH as the base.
The reactions of symmetrical 1,3-dialkynes 1a–h with
methylhydrazine were carried out under optimized condi-
tions, and the results are shown in Table 2. 1,3,5-Trisub-
stituted pyrazoles 2a–e were obtained from the reactions
of 1,3-dialkynes 1a–e in good yields (Table 2, entries 1–
5, 71%–89%). The formation of 1,3,5-trisubstituted pyr-
SYNTHESIS 2014, 46, 2422–2429
Advanced online publication: 29.07.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0034-1378660; Art ID: ss-2014-e0332-fa
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
1,3,5-Trisubstituted Pyrazoles
2423
Biographical Sketches█
Dr. Xiaoqiang Yu received of natural products. He was Key Laboratory of Fine
his B.Sc. degree from Fush- a postdoctoral fellow from Chemicals, Dalian Univer-
un Institute of Petroleum, 2001 to 2004 with Prof. N. sity of Technology, China.
China in 1999. He then Miyaura at Hokkaido Uni- His research interests focus
moved to Japan and in 2006 versity, Japan, where he was on the development of new
received his Ph.D. degree involved in the transition- methods for the synthesis of
from Hokkaido University, metal-catalyzed cross-cou- biologically important het-
Japan under the supervision pling reactions with boronic erocycles.
of Prof. M. Miyashita, acids. He is now an associ-
studying the total synthesis ate professor at the State
Nan Huang received his Protection Agency of Shan- (DUT) as a master course
B.Sc. degree from Qingdao dong for one year, he joined student. His research work
Agricultural
University the group of Prof. Ming Bao focuses on the development
(QAU), China in 2010. Af- at State Key Laboratory of of novel synthetic method-
ter gaining work experience Fine Chemicals, Dalian ologies for heterocyclic
at Penglai Environmental University of Technology compounds.
Dr. Xiujuan Feng received Chemistry from Dalian Uni- University of Technology
her B.Sc. degree from China versity of Technology (DUT) in China. Her re-
University of Petroleum, (DUT) in China on the de- search interests focus on the
China in 1997. She then velopment of novel method development of novel syn-
moved to Fushun and re- for the synthesis of dimethyl thetic methodologies using
ceived her M.Sc. degree carbonate under supercriti- transition-metal catalysts
from Fushun Institute of Pe- cal conditions. Currently and resource utilization of
troleum, China in 2000. In she is an associate Professor carbon dioxide.
December 2004, she re- at the State Key Laboratory
ceived her Ph.D. in Applied of Fine Chemicals, Dalian
Prof. Ming Bao studied Yoshinori Yamamoto at and Dr. Masao Shimizu
Chemistry at Northeast Nor- Tohoku University, Japan, (JSPS fellow 2002–2004).
mal University, China where he received his Ph.D. In 2005, he began his inde-
(1986) and obtained his in 2001. From 2001 to 2004, pendent career at Dalian
M.Sc. degree at the same he conducted postdoctoral University of Technology.
university in 1989. After research at the National In- His current research inter-
gaining research experience stitute of Advanced Indus- ests focus on the develop-
at Northeast Normal Uni- trial
Science
and ment of novel synthetic
versity for eight years, he Technology (AIST), Japan, methods using transition-
joined the group of Prof. with Dr. Shigeru Shimada metal catalysts.
Yoshinori Yamamoto re- (2002), Purple Ribbon Med- 2012, he is now Professor at
ceived M.S. and Ph.D. de- al from The Cabinet (2006), the State Key Laboratory of
grees
from
Osaka A. C. Cope Scholar Award Fine Chemicals, Dalian
University, and became a from ACS, USA (2007), and University of Technology
full professor at Tohoku Centenary Prize from RSC, (DUT) in China. Presently,
University in 1986. He was UK (2009). He was the Re- he is interested in the inter-
awarded the Chemical Soci- gional Editor of Tetrahe- disciplinary research be-
ety of Japan Award (1996), dron Letters (1995–2012). tween organic synthesis and
the Humboldt Research After formal retirement materials science.
Award from Germany from Tohoku University in
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2422–2429

2424
X. Yu et al.
FEATURE ARTICLE
azole in relatively higher yield from a 1,3-dialkyne bear-
ing an electron-withdrawing group on benzene ring than
those from a 1,3-dialkyne bearing an electron-donating
group on benzene ring was observed (entries 4 and 5 vs
entries 1–3). This result suggests that 1,3-dialkynes can be
activated by decreasing their electron density. The 1,3-di-
alkynes 1f and 1g that contain a halogen atom (Br or Cl)
were also employed successfully in the synthesis of 1,3,5-
trisubstituted pyrazoles. The corresponding products 2f
and 2g were obtained in 86 and 82% yield, respectively
(entries 6 and 7). The reaction of 1,4-di(thiophen-3-yl)bu-
ta-1,3-diyne (1h) was finally tested under the same condi-
tions. The corresponding product 2h was obtained in 80%
yield (entry 8).
Table 2 Synthesis of 1,3,5-Trisubstituted Pyrazoles from Symmetric
1,3-Dialkynesa
Me
NH2NHMe•H2SO4
N
N
DMSO, NHEt2
110 °C, 20 h
+
R
R
R
R
1a–h
2a–h
Entry
Diyne
R
Product
Yield (%)b
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
Ph
2a
2b
2c
2d
2e
2f
80
71
73
88
89
86
82
80
4-MeOC6H4
4-MeC6H4
4-O2NC6H4
4-F3CC6H4
4-BrC6H4
4-ClC6H4
3-thienyl
Table 1 Screening of Reaction Conditionsa
Me
N
N
NH2NHMe•H2SO4
DMSO, base
heating, 20 h
1g
1h
2g
2h
+
a Reaction conditions: symmetrical 1,3-dialkyne 1a–h (0.4 mmol),
methylhydrazine sulfate (4.0 equiv, 231 mg), Et2NH (8.0 equiv, 234
mg), and DMSO (5.0 mL) in a sealed tube at 110 °C for 20 h.
b Isolated yield.
1a
2a
Entry
Temp
(°C)
NH2NHMe·H2SO4 Base
(equiv)
Yield
(%)b
1
2
60
70
3.0
3.0
3.0
3.0
3.0
3.0
3.0
4.0
5.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
6
11
22
45
59
65
65
73
73
80
62
25
46
25
44
37
39
under the optimized reaction conditions. The results are
summarized in Table 3. The reaction of 3a–d with 1a pro-
duced 1,3,5-trisubstituted pyrazoles 4a–d in satisfactory
yields (Table 3, entries 1–4, 62–73%). The desired prod-
ucts 4e and 4f could not be obtained from the reactions of
isopropylhydrazine (3e) and tert-butylhydrazine (3f) un-
der the optimized conditions. However, a decomposition
product, 5-benzyl-3-phenyl-1H-pyrazole, was isolated in
56% and 49% yield, respectively (entries 5 and 6).9
3
80
4
90
5
100
110
120
110
110
110
110
110
110
110
110
110
110
6
7
The reactions of various unsymmetrical 1,3-dialkynes
with methylhydrazine were then examined, and the results
are summarized in Table 4. The reactions of unsymmetri-
cal 1,3-dialkynes 5a and 5b bearing the same 4-methoxy-
phenyl group with methylhydrazine proceeded smoothly
to produce a mixture of two products, which cannot be
separated by chromatography (Table 4, entries 1 and 2: 6a
and 6a′ in 77% total yield; 6b and 6b′ in 78% total yield).
However, the use of unsymmetrical 1,3-dialkynes 5c, 5d,
and 5f having the same 4-nitrophenyl group led to the se-
lective formation of 1,3,5-trisubstituted pyrazoles 6c, 6d,
and 6f in good yields (entries 3, 4, and 7; 83–87%). 1,3,5-
Trisubstituted pyrazole 6e was also obtained as a sole
product from the reaction of unsymmetrical 1,3-dialkyne
5e with methylhydrazine (entry 6, 76% yield). The use of
benzylhydrazine (3d) instead of methylhydrazine to react
with 1,3-dialkyne 5d also led to the selective formation of
1,3,5-trisubstituted pyrazole (entry 5: 6da, 66% yield).
These results obtained indicated that the reaction selectiv-
ity was controlled by the electron property of substituents
R1 and R2 in 1,3-dialkynes; the Cope-type hydroamination
of 1,3-dialkynes with alkyl hydrazine facilely took place
on the triplet bond bearing an electron-donating group to
produce 1,3,5-trisubstituted pyrazoles 6c–f and 6da. New
8
9
10
11
12
13
14
15
16
17
Et2NH
i-Pr2NEt
Bu3N
Na2CO3
K2CO3
Na3PO4
NaOH
KOH
a Reaction conditions: 1,4-diphenylbuta-1,3-diyne (1a; 0.4 mmol, 81
mg), methylhydrazine sulfate (3.0–4.0 equiv), base (8.0 equiv), and
DMSO (5.0 mL) in a sealed tube for 20 h.
b Isolated yield.
Good preliminary results prompted an examination of the
scope of this reaction with various hydrazine substrates
Synthesis 2014, 46, 2422–2429
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
1,3,5-Trisubstituted Pyrazoles
2425
Table 4 Synthesis of 1,3,5-Trisubstituted Pyrazoles from Unsym-
Table 3 Synthesis of 1,3,5-Trisubstituted Pyrazoles by the Reaction
of Various Alkylhydrazine Substrates with 1aa
metrical 1,3-Dialkynesa
Me
Me
R
NH2NHMe•H2SO4
N
N
N N
N
N
DMSO, NHEt2
110 °C, 20 h
NH2NHR 3a–f
+
+
R2
R1
DMSO
R1
R2
+
R1
R2
110 °C, 20 h
5a–f
6a–f
6a'–f'
1a
4a–f
Entry
1c
Alkyne
Yield (%)b
Entry
Hydrazine
R
Product
Yield (%)b
5a
R1 = Ph
6a and 6a′, 77
6b and 6b′, 78
6c, 83
R2 = 4-MeOC6H4
1
3a
3b
3c
3d
3e
3f
CH2CH2OH
CH2CF3
CH2CH2CN
Bn
4a
4b
4c
4d
4e
4f
73
70
67
62
0
2
5b
5c
5d
5d
5e
5f
R1 = 4-ClC6H4
R2 = 4-MeOC6H4
2
R1 = 4-O2NC6H4
R2 = 4-MeOC6H4
6c′, 0
3
3
4c
5d
6e
4
R1 = 4-O2NC6H4
R2 = Ph
6d, 87
6d′, 0
6da′, 0
6e′, 0
6f′, 0
i-Pr
t-Bu
0
5d
6
R1 = 4-O2NC6H4
R2 = Ph
6da, 66
a Reaction conditions: 1,4-diphenylbuta-1,3-diyne (1a; 0.4 mmol, 81
mg), alkylhydrazine (4.0 equiv), and DMSO (5.0 mL) in a sealed tube
at 110 °C for 20 h.
R1 = Ph
6e, 76
R2 = n-C6H13
b Isolated yield.
c Benzylhydrazine dihydrochloride (0.4 mmol, 78 mg) and Et2NH (16
equiv, 467 mg) were used.
7
R1 = 4-O2NC6H4
6f, 84
R2 = n-C6H13
d 5-Benzyl-3-phenyl-1H-pyrazole was obtained in 56% yield.
e 5-Benzyl-3-phenyl-1H-pyrazole was obtained in 49% yield.
a Reaction conditions: unsymmetrical 1,3-dialkyne 5a–f, 0.4 mmol),
methylhydrazine sulfate (1.6 mmol, 231 mg), Et2NH (3.2 mmol, 234
mg), and DMSO (5.0 mL) in a sealed tube at 110 °C for 20 h.
b Isolated yield.
products, namely, 2a–h, 4a–d, 6c–f, and 6da were identi-
fied through their NMR, IR, and HRMS data. The product
6da was further identified by determining its X-ray crystal
structure (Figure 1).10
c Compound 5a was recovered in 20% yield.
d Benzylhydrazine (3d) was used instead of methylhydrazine as the
substrate.
The one-pot synthesis of 1,3,5-trisubstituted pyrazole 2e
from the respective terminal alkyne was also examined.
After the Cu-catalyzed homocoupling reaction of 1-
ethynyl-4-(trifluoromethyl)benzene was completed,11
methylhydrazine sulfate and Et2NH were added to the re-
sultant mixture. The reaction mixture was heated at
110 °C for 20 hours to afford 2e in good yield (82%)
(Scheme 2).
A gram-scale synthesis of the 1,3,5-trisubstituted pyra-
zole 2a was performed to prove the practicality of the de-
veloped method in the synthesis of 1,3,5-trisubstituted
pyrazoles. The result is shown in Scheme 3. When 1.01
grams of 1a was utilized, 0.98 grams of product 2a was
obtained in 80% yield.
In summary, a novel and general method for the synthesis
of 1,3,5-trisubstituted pyrazoles was developed by using
simple and readily available starting materials, namely,
1,3-dialkynes and alkylhydrazines. The target reactions
proceeded smoothly in the absence of transition metal,
strong base, and strong acid to produce 1,3,5-trisubstitut-
ed pyrazoles in satisfactory to good yields. The wide
availability of the starting materials and the simplicity of
the experiment should render the developed method very
useful in organic synthesis.
Figure 1 Molecular structure of product 6da
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2422–2429

2426
X. Yu et al.
FEATURE ARTICLE
CF3
Me
N
N
NH2NHMe•H2SO4, HNEt2
CuCl2 (5 mol%)
CF3
110 °C, 20 h
DMSO, 90 °C
in air, 8 h
CF3
CF3
2e, 82%
1e
F3C
Scheme 2 One-pot synthesis of 1,3,5-trisubstituted pyrazole 2e from 1-ethynyl-4-(trifluoromethyl)benzene
Me
One-Pot Synthesis of 1-Methyl-5-[4-(trifluoromethyl)benzyl]-3-
[4-(trifluoromethyl)phenyl]-1H-pyrazole (2e)
N
N
NH2NHMe•H2SO4
A reaction flask was charged with a mixture of 1-ethynyl-4-(tri-
fluoromethyl)benzene (102 mg, 0.6 mmol), CuCl (3.0 mg, 5 mol%),
and DMSO (5.0 mL). The reaction mixture was stirred at 90 °C for
8 h under air atmosphere and then cooled to r.t. Methylhydrazine
sulfate (4.0 equiv, 231 mg) and Et2NH (3.2 mmol, 234 mg) were
added to the resultant mixture, and then the reaction flask was
sealed and the mixture stirred at 110 °C for 20 h. H2O (10 mL) was
added to the resultant mixture at r.t. The product was extracted with
EtOAc (3 × 10 mL), the combined organic layers were washed with
brine (2 × 10 mL), and dried (Na2SO4). The solvent was removed
under reduced pressure, and the residue obtained was purified via
silica gel chromatography (eluent: PE–EtOAc, 5:1) to afford 2e as
a colorless oil; yield: 189 mg (82%).
HNEt2, DMSO
110 °C, 20 h
+
1a, 1.01 g
2a, 0.98 g (80% yield)
Scheme 3 Gram-scale synthesis of the 1,3,5-trisubstituted pyrazole
2a
Solvents were dried and degassed before use by standard proce-
dures. Petroleum ether (PE) used refers to the fraction boiling in the
60–90 °C range. NMR spectra were run in CDCl3 on a 400 MHz in-
strument and recorded at the following frequencies: 1H (400 MHz),
13C (100 MHz). IR spectra were recorded on a FT-IR spectropho-
tometer. High-resolution mass spectra were recorded on either a Q-
TOF mass spectrometer or a GC-TOF mass spectrometer. Diffrac-
tion intensity data were collected with a Bruker Smart APEX CCD
area detector diffractometer (graphite monochrometer, MoKα radi-
ation, λ = 0.71073 Å) at 293(2) K. The starting materials 1a–h and
5a–f were prepared according to the literature;8,12–18 substituted hy-
drazines are commercially available.
5-Benzyl-1-methyl-3-phenyl-1H-pyrazole (2a)
Yield: 79.4 mg (80%); colorless oil.
IR (neat): 3185, 3131, 3046, 3025, 2912, 1949, 1604, 1570, 1494,
1464, 1453, 764, 721, 694 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.40–7.35 (m, 5 H), 7.33–7.27 (m,
5 H), 6.04 (s, 1 H), 4.00 (s, 2 H), 3.84 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 151.1, 144.5, 140.1, 130.8, 128.9,
128.64, 128.61, 128.5, 128.3, 126.2, 105.3, 37.2, 34.8.
1,3,5-Trisubstituted Pyrazoles 2 from Symmetrical 1,3-Di-
alkynes; General Procedure
HRMS (EI): m/z [M + H]+ calcd for C17H17N2: 249.1386; found:
249.1379.
A reaction flask was charged with a mixture of symmetrical 1,3-di-
alkyne 1 (0.4 mmol), methylhydrazine sulfate (4.0 equiv, 231 mg),
Et2NH (3.2 mmol, 234 mg), and DMSO (5.0 mL). The flask con-
taining the reaction mixture was sealed and the mixture was stirred
at 110 °C for 20 h, and then was cooled to r.t. H2O (10 mL) was add-
ed to the resultant mixture. The product was extracted with EtOAc
(3 × 10 mL), the combined organic layers were washed with brine
(2 × 10 mL), and dried (Na2SO4). The solvent was removed under
reduced pressure, and the residue obtained was purified via silica
gel chromatography (eluent: PE–EtOAc, 10:1) to afford the desired
1,3,5-trisubstituted pyrazole 2 (Table 2).
5-(4-Methoxybenzyl)-3-(4-methoxyphenyl)-1-methyl-1H-pyra-
zole (2b)
Yield: 87.5 mg (71%); colorless oil.
IR (neat): 2999, 2834, 1895, 1611, 1578, 1552, 1511, 1462, 1377,
1248, 1176, 1030, 836, 792 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.29 (d, J = 8.4 Hz, 2 H), 7.23 (d,
J = 8.4 Hz, 2 H), 6.94 (d, J = 8.8 Hz, 2 H), 6.84 (d, J = 8.4 Hz, 2 H),
5.97 (s, 1 H), 3.92 (s, 2 H), 3.83 (s, 3 H), 3.81 (s, 3 H), 3.78 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 159.8, 158.2, 151.6, 144.4, 132.5,
130.1, 129.0, 123.4, 114.2, 114.0, 104.9, 55.5, 37.3, 34.1.
HRMS (EI): m/z [M + H]+ calcd for C19H21N2O2: 309.1598; found:
1,3,5-Trisubstituted Pyrazoles 6 from Unsymmetrical 1,3-Di-
alkynes; General Procedure
A reaction flask was charged with a mixture of unsymmetrical 1,3-
dialkynes 5 (0.4 mmol), methylhydrazine sulfate (4.0 equiv, 231
mg), Et2NH (3.2 mmol, 234 mg), and DMSO (5.0 mL). The flask
containing the reaction mixture was sealed and the mixture was
stirred at 110 °C for 20 h, and then cooled to r.t. H2O (10 mL) was
added to the resultant mixture. The product was extracted with
EtOAc (3 × 10 mL), the combined organic layers were washed with
brine (2 × 10 mL), and dried (Na2SO4). The solvent was removed
under reduced pressure and the residue obtained was purified via
silica gel chromatography (eluent: PE–EtOAc, 20:1) to afford the
respective 1,3,5-trisubstituted pyrazole 6 (Table 4).
309.1592.
5-(4-Methylbenzyl)-3-(4-methylphenyl)-1-methyl-1H-pyrazole
(2c)
Yield: 80.6 mg (73%); colorless oil.
IR (neat): 3020, 2921, 2862, 1906, 1615, 1555, 1566, 1505, 1446,
1377, 999, 823, 788 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.27–7.20 (m, 6 H), 7.10 (d,
J = 7.6 Hz, 2 H), 6.00 (s, 1 H), 3.94 (s, 2 H), 3.83 (s, 3 H), 2.38 (s,
3 H), 2.31 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 151.5, 144.7, 138.4, 137.2, 135.7,
129.4, 129.3, 128.9, 128.7, 128.1, 105.1, 37.4, 34.5, 21.4, 21.4.
Synthesis 2014, 46, 2422–2429
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
1,3,5-Trisubstituted Pyrazoles
2427
HRMS (EI): m/z [M + H]+ calcd for C19H21N2: 277.1699; found:
277.1695.
HRMS (EI): m/z [M + H]+ calcd for C13H13N2S2: 261.0515; found:
261.0509.
5-(4-Nitrobenzyl)-3-(4-nitrophenyl)-1-methyl-1H-pyrazole (2d)
Yield: 119.0 mg (93%); colorless oil.
2-(5-Benzyl-3-phenyl-1H-pyrazol-1-yl)ethanol (4a)
Yield: 57.6 mg (73%); colorless oil.
IR (neat): 3113, 3072, 3002, 1625, 1602, 1509, 1349, 1107, 963,
855 cm–1.
IR (KBr): 3373, 3061, 3027, 2942, 2853, 1603, 1546, 1508, 1469,
1454, 1372, 1072, 1028, 765, 695 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.15 (d, J = 8.4 Hz, 2 H), 7.46 (d,
J = 8.4 Hz, 2 H), 7.16 (d, J = 8.8 Hz, 2 H), 6.71 (d, J = 8.4 Hz, 2 H),
5.97 (s, 1 H), 4.07 (s, 2 H), 3.82 (s, 3 H).
1H NMR (400 MHz, CDCl3): δ = 7.76 (d, J = 7.2 Hz, 2 H), 7.38–
7.26 (m, 6 H), 7.19 (d, J = 7.2 Hz, 2 H), 6.36 (s, 1 H), 4.07 (t, J = 2.4
Hz, 2 H), 4.04 (s, 2 H), 3.92 (t, J = 4.4 Hz, 2 H), 1.72 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 147.4, 146.5, 145.2, 143.6, 128.2,
128.0, 122.1, 113.3, 103.0, 35.7, 33.1.
13C NMR (100 MHz, CDCl3): δ = 150.8, 143.2, 137.4, 133.2, 130.6,
129.0, 128.6, 127.9, 126.4, 125.7, 103.5, 61.8, 50.5, 31.9.
HRMS (EI): m/z [M + H]+ calcd for C17H15N4O4: 339.1088; found:
HRMS (EI): m/z [M + H]+ calcd for C18H19N2O: 279.1492; found:
339.1090.
279.1486.
5-[4-(Trifluoromethyl)benzyl]-3-[4-(trifluoromethyl)phenyl]-1-
methyl-1H-pyrazole (2e)
5-Benzyl-3-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole (4b)
Yield: 88.5 mg (70%); colorless oil.
Yield: 136.7 mg (91%); colorless oil.
IR (neat): 3063, 3029, 2961, 2928, 1724, 1604, 1552, 1496, 1469,
1372, 1267, 1160, 767, 695 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.75 (d, J = 7.6 Hz, 2 H), 7.36–
7.29 (m, 6 H), 7.19 (d, J = 7.6 Hz, 2 H), 6.33 (s, 1 H), 4.56 (q, J = 8.4
Hz, 2 H), 4.03 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 152.2, 144.4, 136.7, 133.0, 131.1,
129.1, 128.8, 128.2, 127.3, 125.9, 105.1, 65.7, 50.6 (q, J = 160.0
Hz), 31.8.
IR (neat): 2939, 1619, 1508, 1447, 1407, 1326, 1165, 1125, 1068,
848 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.69 (d, J = 8.0 Hz, 2 H), 7.56 (d,
J = 8.0 Hz, 2 H), 7.51 (d, J = 8.0 Hz, 2 H), 7.42 (d, J = 8.0 Hz, 2 H),
6.11 (s, 1 H), 4.05 (s, 2 H), 3.87 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 150.3, 144.0, 143.2, 134.1, 130.4
1
1
(q, J = 140.0 Hz), 129.1, 128.9, 128.8, 128.5 (q, J = 140.0 Hz),
125.6 (q, 2J = 16.0 Hz), 125.4 (q, 2J = 16.0 Hz), 105.8, 37.4, 34.5.
HRMS (EI): m/z [M + H]+ calcd for C18H16F3N2: 317.1260; found:
317.1258.
HRMS (EI): m/z [M + H]+ calcd for C18H13F6N2: 385.1134; found:
385.1137.
3-(5-Benzyl-3-phenyl-1H-pyrazol-1-yl)propanenitrile (4c)
Yield: 76.9 mg (67%); colorless oil.
5-(4-Bromobenzyl)-3-(4-bromophenyl)-1-methyl-1H-pyrazole
(2f)
IR (neat): 3061, 3027, 2942, 2853, 1603, 1546, 1508, 1469, 1454,
1372, 1072, 1028, 765, 695 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.76 (d, J = 6.8 Hz, 2 H), 7.39–
7.26 (m, 6 H), 7. 21 (d, J = 6.8 Hz, 2 H), 6.37 (s, 1 H), 4.24 (t, J = 7.0
Hz, 2 H), 4.10 (s, 2 H), 2.76 (t, J = 7.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 143.0, 136.9, 133.0, 129.0, 128.8,
128.7, 128.5, 127.9, 127.1, 125.6, 117.4, 104.1, 44.5, 31.8, 18.7.
HRMS (EI): m/z [M + H]+ calcd for C19H18N3: 288.1495; found:
Yield: 139.0 mg (86%); colorless oil.
IR (neat): 3121, 3109, 3004, 2920, 2853, 1894, 1636, 1487, 1367,
1072, 1007, 826, 802 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.52 (d, J = 8.4 Hz, 2 H), 7.38 (d,
J = 8.0 Hz, 2 H), 7.21 (d, J = 8.4 Hz, 2 H), 7.16 (d, J = 8.0 Hz, 2 H),
6.01 (s, 1 H), 3.91 (s, 2 H), 3.80 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 150.7, 143.5, 132.0, 131.6, 130.7,
130.2, 127.0, 122.8, 120.2, 105.4, 37.4, 34.3.
HRMS (EI): m/z [M + H]+ calcd for C17H15Br2N2: 404.9597; found:
288.1492.
404.9592.
1,5-Dibenzyl-3-phenyl-1H-pyrazole (4d)
Yield: 80.4 mg (62%); colorless oil.
5-(4-Chlorobenzyl)-3-(4-chlorophenyl)-1-methyl-1H-pyrazole
IR (neat): 3121, 3109, 3004, 2920, 2853, 1894, 1636, 1487, 1367,
1072, 1007, 826, 802 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.81–7.79 (m, 2 H), 7.39–7.35 (m,
2 H), 7.29–7.23 (m, 7 H), 7.09–7.07 (m, 4 H), 6.34 (s, 1 H), 5.26 (s,
2 H), 3.86 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 150.5, 143.0, 137.5, 137.2, 133.7,
128.8, 128.7, 127.7, 127.6, 127.0, 126.9, 126.8, 125.7, 104.2, 53.5,
32.1.
(2g)
Yield: 103.6 mg (82%); colorless oil.
IR (neat): 3102, 2938, 1576, 1476, 1430, 1007, 854, 780, 753 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.39 (d, J = 8.4 Hz, 2 H), 7.30 (d,
J = 8.4 Hz, 2 H), 7.27–7.21 (m, 4 H), 6.01 (s, 1 H), 3.94 (s, 2 H),
3.82 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 150.8, 143.6, 138.6, 134.7, 132.1,
130.3, 130.0, 129.1, 128.7, 105.5, 37.4, 34.2.
HRMS (EI): m/z [M + H]+ calcd for C17H15Cl2N2: 317.0607; found:
317.0599.
HRMS (EI): m/z [M + H]+ calcd for C23H21N2: 325.1699; found:
325.1693.
3-(4-Methoxyphenyl)-1-methyl-5-(4-nitrobenzyl)-1H-pyrazole
3-(Thiophen-3-yl)-5-(thiophen-3-ylmethyl)-1-methyl-1H-pyra-
zole (2h)
(6c)
Yield: 107.3 mg (83%); colorless oil.
Yield: 83.2 mg (80%); colorless oil.
IR (neat): 3010, 2930, 2838, 1607, 1577, 1505, 1377, 1251, 1035,
837, 728 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.15 (d, J = 8.8 Hz, 2 H), 7.46 (d,
J = 8.8 Hz, 2 H), 7.30 (d, J = 8.8 Hz, 2 H), 6.96 (d, J = 8.8 Hz, 2 H),
6.01 (s, 1 H), 4.08 (s, 2 H), 3.84 (s, 3 H), 3.83 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 160.0, 149.2, 148.1, 146.7, 144.8,
130.1, 129.7, 123.9, 123.0, 114.3, 105.0, 55.5, 37.4, 34.8.
IR (neat): 3102, 2938, 1576, 1476, 1430, 1007, 854, 780, 753 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.35 (d, J = 3.2 Hz, 1 H), 7.30–
7.15 (m, 3 H), 7.05–7.01 (m, 2 H), 6.10 (s, 1 H), 3.98 (s, 2 H), 3.87
(s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 150.5, 140.3, 139.5, 131.1, 128.6,
127.7, 126.3, 125.6, 123.4, 121.3, 105.0, 37.6, 29.4.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2422–2429

2428
X. Yu et al.
FEATURE ARTICLE
HRMS (EI): m/z [M + H]+ calcd for C18H18N3O3: 324.1443; found:
324.1441.
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000084.SunogIpimrfiantoSuIpg
n
fonirtat
ori
1-Methyl-5-(4-nitrobenzyl)-3-phenyl-1H-pyrazole (6d)
Yield: 102.0 mg (87%); colorless oil.
References
IR (neat): 3107, 3058, 2929, 1724, 1604, 1517, 1440, 1346, 1015,
857, 720 cm–1.
(1) (a) Stauffer, S. R.; Coletta, C. J.; Tedesco, R.; Nishiguchi,
G.; Carlson, K.; Sun, J.; Katzenellenbogen, B. S.;
Katzenellenbogen, J. A. J. Med. Chem. 2000, 43, 4934.
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1H NMR (400 MHz, CDCl3): δ = 8.15 (d, J = 8.4 Hz, 2 H), 7.46 (d,
J = 8.4 Hz, 2 H), 7.43–7.37 (m, 5 H), 6.07 (s, 1 H), 4.09 (s, 2 H),
3.85 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 149.3, 148.0, 146.7, 145.0, 129.8,
128.84, 128.77, 123.9, 105.4, 37.5, 34.8.
HRMS (EI): m/z [M + H]+ calcd for C17H16N3O2: 294.123; found:
294.1237.
(3) Katoch-Rouse, R.; Pavlova, L. A.; Caulder, T.; Hoffman, A.
F.; Mukhin, A. G.; Horti, A. G. J. Med. Chem. 2003, 46, 642.
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R.; Chakraborti, A. K. Bioorg. Med. Chem. Lett. 2005, 15,
1793.
1-Benzyl-5-(4-nitrobenzyl)-3-phenyl-1H-pyrazole (6da)
Yield: 97.5 mg (66%); light yellow solid; mp 127–128 °C.
IR (KBr): 2933, 2835, 1897, 1611, 1577, 1551, 1376, 1249, 835,
792, 771 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.10 (d, J = 8.4 Hz, 2 H), 7.81 (d,
J = 7.6 Hz, 2 H), 7.42–7.38 (m, 2 H), 7.31–7.21 (m, 6 H), 7.07–7.05
(m, 2 H), 6.37 (s, 2 H), 5.29 (s, 2 H), 3.98 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 150.7, 147.0, 145.0, 141.1, 136.7,
133.3, 129.5, 128.9, 128.8, 127.9, 126.7, 125.6, 124.0, 104.4, 53.8,
31.9.
(5) For the reaction of hydrazine with a three-carbon-atom
component, see: (a) Baxendale, I. R.; Schou, S. C.;
Sedelmeier, J.; Ley, S. V. Chem. Eur. J. 2010, 16, 89.
(b) Chen, X.; She, J.; Shang, Z.-C.; Wu, J.; Zhang, P. Synth.
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(c) Guillou, S.; Bonhomme, F. J.; Janin, Y. L. Synthesis
2008, 3504. (d) Chen, X.; She, J.; Shang, Z.; Wu, J.; Wu, H.;
Zhang, P. Synthesis 2008, 3478. (e) Liu, H.-L.; Jiang, H.-F.;
Zhang, M.; Yao, W.-J.; Zhu, Q.-H.; Tang, Z. Tetrahedron
Lett. 2008, 49, 3805. (f) Bagley, M. C.; Lubinu, M. C.;
Mason, C. Synlett 2007, 704. (g) Negri, G.; Kascheres, C.
J. Heterocycl. Chem. 2001, 38, 109; and references cited
therein. (h) Sreekumar, R.; Padmakumar, R. Synth.
Commun. 1998, 28, 1661. (i) Trxier-Boullet, F.; Hamelin, B.
K. J. Synthesis 1986, 409.
(6) For the [3+2] cycloaddition of alkenes/alkynes with 1,3-
dipoles, see: (a) Dadiboyena, S.; Valente, E. J.; Hamme, A.
T. Tetrahedron Lett. 2010, 51, 1341. (b) Gao, D.; Zhai, H.;
Parvez, M.; Back, T. G. J. Org. Chem. 2008, 73, 8057.
(c) Deng, X.; Mani, N. S. J. Org. Chem. 2008, 73, 2412; and
references cited therein. (d) Aggarwal, V. K.; Vicente, J.;
Bonnert, R. V. J. Org. Chem. 2003, 68, 5381; and references
cited therein. (e) Padwa, A.; Pearson, W. H. Synthetic
Applications of 1,3-Dipolar Cycloaddition Chemistry
Toward Heterocycles and Natural Products; Wiley: New
York, 2002.
HRMS (EI): m/z [M + H]+ calcd for C23H20N3O2: 370.1550; found:
370.1547.
5-Benzyl-3-hexyl-1-methyl-1H-pyrazole (6e)
Yield: 77.9 mg (76%); colorless oil.
IR (neat): 3165, 3100, 3018, 2949, 2920, 2851, 1722, 1612, 1570,
1490, 1462, 1449, 716 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.44–7.40 (m, 5 H), 6.11 (s, 1 H),
4.08 (s, 2 H), 3.83 (s, 3 H), 2.63 (t, J = 8.0 Hz, 2 H), 1.70–1.66 (m,
2 H), 1.36–1.28 (m, 6 H), 0.88 (t, J = 6.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 152.6, 144.2, 131.0, 128.7, 128.6,
128.3, 125.4, 104.6, 37.1, 31.8, 29.9, 29.5, 29.2, 28.3, 22.7, 14.1.
HRMS (EI): m/z [M + H]+ calcd for C17H25N2: 257.2012; found:
257.2005.
3-Hexyl-1-methyl-5-(4-nitrobenzyl)-1H-pyrazole (6f)
Yield: 101.2 mg (84%); colorless oil.
IR (neat): 3185, 3100, 2915, 2842, 1922, 1600, 1572, 1512, 1342,
852, 716 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.10 (d, J = 8.8 Hz, 2 H), 7.38 (d,
J = 8.8 Hz, 2 H), 5.74 (s, 1 H), 3.98 (s, 2 H), 3.72 (s, 3 H), 2.49 (t,
J = 8.0 Hz, 2 H), 1.58–1.55 (m, 2 H), 1.35–1.23 (m, 6 H), 0.86 (t,
J = 6.6 Hz, 3 H).
(7) For the transition-metal-catalyzed cross-coupling reactions,
see: (a) Martin, R.; Rodriguez Rivero, M.; Buchwald, S. L.
Angew. Chem. Int. Ed. 2006, 45, 7079; Angew. Chem. 2006,
118, 7237. (b) Zhang, T.; Bao, W. J. Org. Chem. 2013, 78,
1317. (c) Hu, J.; Chen, S.; Sun, Y.; Yang, J.; Rao, Y. Org.
Lett. 2012, 14, 5030.
13C NMR (100 MHz, CDCl3): δ = 148.6, 148.3, 146.6, 144.6, 129.6,
123.7, 103.4, 36.0, 34.7, 31.6, 29.0, 28.4, 25.7, 22.6, 14.1.
HRMS (EI): m/z [M + H]+ calcd for C17H24N3O2: 302.1863; found:
302.1854.
(8) Wang, L.; Yu, X.; Feng, X.; Bao, M. J. Org. Chem. 2013, 78,
1693.
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2007, 44, 89.
(10) The structural assignment was based on the analysis of the
1H and 13C NMR spectra. The unsymmetrical product was
further identified by determining its X-ray crystal structure;
the crystallographic data are provided in the Supporting
Information.
Acknowledgment
We are grateful to the National Natural Science Foundation of Chi-
na (Grant No: 21173032 and 21273026) for their financial support.
This work was also supported by the Fundamental Research Funds
for the Central Universities (DUT13LK03).
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(a) Niu, X.; Li, C.; Li, J.; Jia, X. Tetrahedron Lett. 2012, 53,
5559. (b) Li, Y.-N.; Wang, J.-L.; He, L.-N. Tetrahedron
Synthesis 2014, 46, 2422–2429
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Lett. 2011, 52, 3485. (c) Yin, K.; Li, C.; Li, J.; Jia, X. Green
1,3,5-Trisubstituted Pyrazoles
2429
(15) Yu, M.; Pan, D.; Jia, W.; Chen, W.; Jiao, N. Tetrahedron
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2422–2429