Efficient Copper-Catalyzed Synthesis of Substituted Pyrazoles at Room Temperature

Article abstract of DOI:10.1055/s-0037-1610330

An efficient method for the synthesis of pyrazoles through a copper-catalyzed condensation reaction has been developed. The new catalytic system not only maintained a broad substrate scope but was also active under acid-free reaction conditions, overcoming the conventional requirement for an acid-catalyzed system. Furthermore, the copper catalyst enabled this reaction to be performed at room temperature and in a short reaction time.

Full text of DOI:10.1055/s-0037-1610330

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
letter
A
en
H. Wang et al.
Letter
Synlett
Efficient Copper-Catalyzed Synthesis of Substituted Pyrazoles at
Room Temperature
Haifeng Wang*
Xiangli Sun
Shuangling Zhang
Guanglu Liu
Chunjie Wang
Lili Zhu
Hui Zhang
School of Chemistry & Chemical Engineering, Zhoukou Normal
University, Zhoukou, 466001, Henan, P. R. of China
skytacle@139.com
Received: 15.09.2018
Accepted after revision: 22.10.2018
Published online: 15.11.2018
Despite remarkable advances in the last few decades,
this method has the following limitations in terms of its
practical applications.9 First, substituted pyrazoles are only
accessible in the presence of strongly acidic conditions, for
example in the presence of corrosive and environmentally
unfriendly hydrochloric or sulfuric acid. Secondly, the con-
ventional process is often performed under harsh condi-
tions by heating at elevated temperature for long reaction
times. Thirdly, complex and expensive transition-metal cat-
alysts are used. Therefore, the development of an efficient
and convenient method for the synthesis of pyrazole and its
derivatives is of great significance and is highly desirable.
Copper salts, especially copper nitrate, are abundant in na-
ture and have a vast range of practical uses. Here, we de-
scribe an unprecedented process employing low-cost cop-
per nitrate as an acid-free catalyst to afford pyrazole and its
derivatives in good yields at room temperature in short re-
action times.
First, we determined the optimal conditions for the con-
densation reaction between phenylhydrazine (1a) and pen-
tane-2,4-dione (2) in the presence of various copper salts as
a model reaction (Table 1). No reaction occurred when cop-
per (II) tartrate hydrate was used as a catalyst in acetonitrile
at room temperature (Table 1, entry 1). However, various
levels of reactivity were observed when other copper salts
were used, and the reaction proceeded smoothly to furnish
the pyrazole 3a (entries 2–6). Importantly, the use of
Cu(NO3)2·3H2O resulted in a significant increase in yield to
87% (entry 7). Without the addition of any catalyst, none of
the desired product was observed (entry 8). We also inves-
tigated the effects of various other solvents: ethanol, 1,4-di-
oxane, dichloromethane, dimethyl sulfoxide, and tetrahy-
drofuran. Compared with the favorable results obtained
with acetonitrile (87% yield; entry 7), ethanol was similarly
effective, giving 3a in 79% yield (entry 9). Tetrahydrofuran
and dimethyl sulfoxide were less effective, yielding 3a in
DOI: 10.1055/s-0037-1610330; Art ID: st-2018-k0523-l
Abstract An efficient method for the synthesis of pyrazoles through a
copper-catalyzed condensation reaction has been developed. The new
catalytic system not only maintained a broad substrate scope but was
also active under acid-free reaction conditions, overcoming the conven-
tional requirement for an acid-catalyzed system. Furthermore, the cop-
per catalyst enabled this reaction to be performed at room tempera-
ture and in a short reaction time.
Key words pyrazoles, condensation reaction, copper catalysis, arylhy-
drazines, sulfonyl hydrazides
Pyrazole and its derivatives represent an important
class of fused nitrogen-containing heterocycles. They dis-
play a wide spectrum of biological activities and they have
long attracted extensive pharmacological, chemical, and
synthetic interest.1 For instance, structural cores containing
pyrazole rings offer valuable building blocks for the synthe-
sis of biologically active compounds and are found in many
biologically active molecules, such as pharmaceuticals.2
Consequently, considerable attention has been given to the
development of an efficient approach for the construction
of substituted pyrazole derivatives, including the condensa-
tion of 1,3-dicarbonyl compounds with substituted hydra-
zines,3 1,3-dipolar cycloaddition employing alkenes or
alkynes,4 the reaction of unsaturated aldehydes or ketones
with hydrazines,5 metal-catalyzed oxidative carbonylations
of arylhydrazines and alkynes,6 or functionalizations of un-
substituted pyrazoles,7 among others.8 Among the many
advantages of these reported methods, the condensation
reaction between 1,3-dicarbonyl compounds and substitut-
ed hydrazines provides one of the most-efficient and sim-
plest routes for the construction of pyrazoles.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
H. Wang et al.
Letter
Synlett
electron-withdrawing functional groups on the phenyl ring,
including Br, Cl, NO2, CH3, OCH3 and 4-benzyloxy groups,
were also tolerated (3f–m).
Table 1 Optimization of the Reaction Conditions.
O
O
N
H
N
R3
catalyst
N
R2
N
NH2
solvent
r.t.
H
N
O
O
R2
Cu(NO3)2⋅3H2O
NH2
R1
R2
R2
N
CH3CN
r.t.
1a
2a
3a
R3
R1
1
2
3
Entry
1
Catalyst
Solvent
Time
(h)
Yieldb
(%)
tBu
Et
tBu
Et
N
Copper(II) tartrate hydrate
CH3CN
8
trac
e
N
N
N
N
N
2
CuSO4
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
EtOH
1
2
1
1
1
1
1
1
1
1
1
1
2
1
39
36
64
80
70
87
0
3a, 87%
Ph
3b, 82%
3c, 68%
3
CuCl2
4
CuCl
N
Ph
N
N
N
N
N
5
Cu(OAc)2
O2N
6
CuI
3d, 70%
3f, 82%
3e, 67%
7
Cu(NO3)2·3H2O
–
8
N
N
N
N
N
N
9
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
79
68
66
23
20
55
80
Br
10
11
12
13
14c
15d
1,4-dioxane
CH2Cl2
THF
BnO
OMe
Cl
3g, 87%
3h, 71%
3i,72%
N
N
N
N
DMSO
CH3CN
CH3CN
N
N
O2N
NO2
3j, 83%
Cl
Cl
3k, 80%
3l, 69%
a Unless otherwise noted, all reactions were performed with phenylhydra-
zine (1a; 0.5 mmol), catalyst (0.05 mmol) and pentane-2,4-dione (2a; 0.6
mmol) in CH3CN (2 mL) at r.t.
Et
N
b Yield of the isolated product.
N
N
c The catalyst loading was 5 mol%.
N
d The catalyst loading was 20 mol%.
3m, 74%
3n, 81%
Scheme 1 The substrate scope of Cu-catalyzed synthesis of pyrazoles
from various arylhydrazines and diones. Reaction conditions: arylhydra-
zine 1 (0.5 mmol), Cu(NO3)2·3H2O (0.05 mmol), dione 2 (0.6 mmol),
CH3CN (2 mL), r.t., 1 h.
yields of 23% and 20%, respectively (entries 12 and 13). The
yield also clearly dropped on decreasing the catalyst loading
(entry 14). In contrast, a higher catalyst loading did not re-
sult in an improvement in the yield (entry 15). Thus, the
optimal conditions were established to be as follows:
phenylhydrazine (0.5 mmol), Cu(NO3)2·3H2O (10 mol%), di-
one 2 (0.6 mmol) in CH3CN for one hour at room tempera-
ture.
With optimal conditions established, we focused on the
scope and generality of this copper-catalyzed condensation
reaction by examining the reactions of a variety of substi-
tuted 2,4-diones and substituted phenylhydrazines in the
presence of 10 mol% Cu(NO3)2·3H2O in CH3CN (2 mL) at
room temperature.10 The results are outlined in Scheme 1.
To investigate the factors that control the reaction, the ef-
fects of dione substituents R2 and R3 with various electronic
and steric properties were examined. A range of diones
2a−e and 2n gave the expected pyrazoles 3a−e and 3n, re-
spectively, in moderate to excellent yields under the stan-
dard reaction conditions. Various electron-donating and
Inspired by the success of the formation of substituted
pyrazoles from substituted phenylhydrazines, the scope of
this Cu-catalyzed synthesis of substituted pyrazoles was
further explored by examining the reactions of sulfonyl hy-
drazides 4 with various diones (Scheme 2).11 The transfor-
mations proceeded smoothly to afford the corresponding
N-substituted pyrazoles 5a, 5b, and 5d in good to excellent
yields. Good yields of 5e, 5f, and 5k were also obtained
when the R3 substituent in the diketone was replaced by a
methyl, ethyl, or Cl group, respectively. Similarly, sulfonyl
hydrazide containing an ortho-nitro or a para-bromo sub-
stituent on the aromatic ring gave the corresponding pyra-
zoles 5i and 5j in excellent yields. The enhanced reactivity
of sulfonyl hydrazides was proven by comparison with the
copper-catalyzed condensation reaction of arylhydrazines.
The reaction was completed within 15 minutes when a
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
H. Wang et al.
Letter
Synlett
copper catalyst was used. Remarkably, the sterically hin-
dered tert-butyl-substituted dione 2c and the isopropyl-
substituted sulfonyl hydrazide 2g were also well tolerated
in this reaction, providing the desired products 5c and 5g in
73% and 80% yield, respectively. This result showed that ste-
ric effects in the dione or sulfonyl hydrazide had little influ-
ence on this reaction. Notably, product 5h containing a
naphthyl group was also successfully prepared in 95% yield.
yields of 57% and 24% and a ratio of 70:30 [Scheme 3, equa-
tion (4)]. Furthermore, 4a failed to react with dione 6c to
provide the corresponding product, mainly as a result of the
presence of a strongly electron-withdrawing substituent
(CF3).
Ph
O
O
Cu(NO3)2⋅3H2O
NH
N
(1)
Ph
N
1a
N
Ph
CH3CN
r.t.
Ph
R3
Ph
7a2
R2
6a
7a1
90%
2%
O
R2
O
O
O
NHNH2
N
S
(7a1/7a2 = 98:2)
N
S
Cu(NO3)2⋅3H2O
R2
R2
R1
O
O
CH3CN
r.t.
R3
2
O
O
N
R1
tBu
Ph
N
4
5
Cu(NO3)2⋅3H2O
1a
N
(2)
Et
CH3CN
r.t.
N
tBu
O
O
O
Et
N
Ph
N
N
N
O
N
S
S
N
6b
7b1
7b2
5%
S
O
80%
O
(7b1/7b2 = 94:6)
5a, 81%
5b, 83%
5c, 73%
CF3
Ph
CF3
Cl
N
Ph
O
O
Cu(NO3)2⋅3H2O
(3)
N
N
1a
O
N
Ph
Ph
CF3
Ph
O
N
O
N
CH3CN
r.t.
N
N
S
N
N
S
S
Ph
Ph
6c
O
O
O
7c1
7c2
78%
9%
5d, 68%
5e, 71%
5f, 84%
(7c1/7c2 = 90:10)
Ts
N
Ts
O
O
O
N
Cu(NO3)2⋅3H2O
O
N
O
Ph
N
N
N
N
N
S
(4)
N
N
S
TsNHNH2
S
Ph
O
CH3CN
r.t.
O
O
Ph
4a
6a
7d1
7d2
NO2
N
24%
57%
5g, 80%
5h, 95%
5i, 87%
(7d1/7d2 = 70:30)
Et
Scheme 3 Substrate scope of Cu-catalyzed synthesis of pyrazoles from
unsymmetrical diones. Reaction conditions: phenylhydrazine (0.5 mmol)
or TsNHNH2 (0.5 mmol), Cu(NO3)2·3H2O (0.05 mmol), unsymmetrical
dione 6 (0.6 mmol), CH3CN (2 mL), r.t.
O
N
O
N
N
S
N
S
O
O
Br
5j, 89%
5k, 82%
In conclusion, we have developed a copper-catalyzed
procedure for the synthesis of substituted pyrazoles under
acid-free conditions at room temperature. The reaction is
general with good functional-group compatibility, giving
the corresponding substituted pyrazoles in good to excel-
lent yields in short reaction times. This synthetic method
offers a convenient, practical, and economical approach to
the synthesis of the structurally important pyrazole skele-
ton for biological research and drug discovery. Further de-
velopment of this approach and application of the reaction
system to other reaction manifolds is currently underway
in our laboratory.
Scheme 2 Substrate scope of Cu-catalyzed synthesis of pyrazoles from
various sulfonyl hydrazides and diones. Reaction conditions: sulfonyl hy-
drazide 4 (0.5 mmol), Cu(NO3)2·3H2O (0.05 mmol), dione 2 (0.6
mmol), CH3CN (2 mL), 15 min, r.t.
Compared with symmetrical diones, unsymmetrical di-
ones are much more challenging substrates due to the diffi-
culty in controlling the regioselectivity of the reaction
(Scheme 3). Pleasingly, unsymmetrical diones also per-
formed well with our catalyst system, and were successfully
converted into the corresponding substituted pyrazoles
with excellent yields and regioselectivities [Scheme 3,
equations (1) and (2)]. A fluorinated dione was also suc-
cessfully employed in the condensation reaction, with satis-
factory results [Scheme 3, equation (3)]. However, p-tolue-
nesulfonyl hydrazide (4a) gave two isomers 7d1 and 7d2 in
Funding Information
The work is supported by a high-level personal fund of Zhoukou Nor-
mal University (No. ZKNUC2017040).()
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

D
H. Wang et al.
Letter
Synlett
Supporting Information
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Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610330.
S
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(9) (a) Stoit, A. R.; Lange, J. H. M.; den Hartog, A. P.; Ronken, E.;
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(10) 3,5-Dimethyl-1-phenyl-1H-pyrazole (3a); Typical Procedure
Cu(NO3)2·3 H2O (10 mol%) was added to a stirred solution of
PhNHNH2 (1a; 0.5 mmol) and pentane-2,4-dione (2; 0.6 mmol)
in CH3CN (2 mL) at r.t., and the resulting solution was stirred at
r.t. for 1 h. When the reaction was complete, the mixture was
concentrated to remove MeCN, and the residue was dissolved in
CH2Cl2 (30 mL). The organic layer was washed with H2O (3 × 10
mL), dried (Na2SO4), filtered, concentrated, and purified by
column chromatography [silica gel, PE–EtOAc (20:1)] to give a
colorless oil; yield: 75 mg (87%). 1H NMR (400 MHz, CDCl3):
 = 7.46–7.40 (m, 4 H), 7.36–7.32 (m, 1 H), 6.01 (s, 1 H), 2.32 (s,
3 H), 2.31 (s, 3 H). 13C NMR (100 MHz, CDCl3):  = 148.94,
139.99, 139.35, 128.98, 127.21, 124.75, 106.94, 13.53, 12.37.
HRMS (ESI): m/z [M + H]+ calcd for C11H13N2: 173.1073; found:
173.1074.
(11) 3,5-Dimethyl-1-tosyl-1H-pyrazole (5a); Typical Procedure
Pentane-2,4-dione (2; 0.6 mmol) and Cu(NO3)2·3H2O (10 mol%)
were added to a round-bottomed flask containing a solution of
TsNHNH2 (4a, 0.5 mmol) in CH3CN (2 mL), and the mixture was
stirred for 15 min. The mixture was then concentrated to
remove MeCN, and the residue was dissolved in CH2Cl2 (30 mL).
The organic layer was washed with H2O (3 × 10 mL), dried
(Na2SO4), filtered, concentrated, and purified by column chro-
matography [silica gel, PE–EtOAc (20:1)] to give a white solid;
yield 101 mg (81%); mp 97–98 °C. 1H NMR (400 MHz, CDCl3):
 = 7.83 (d, J = 8.3 Hz, 2 H), 7.31 (d, J = 8.1 Hz, 2 H), 5.90 (s, 1 H),
2.49 (s, 3 H), 2.41 (s, 3 H), 2.20 (s, 3 H). 13C NMR (100 MHz,
CDCl3):  = 153.46, 145.22, 144.15, 135.48, 129.96, 127.63,
110.81, 21.71, 13.90, 13.16. HRMS (ESI): m/z [M + H]+ calcd for
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D