Copper-catalyzed synthesis of 1,3,4-trisubstituted and 1,3,4,5-tetrasubstituted pyrazoles via [3+2] cycloadditions of hydrazones and nitroolefins

Article abstract of DOI:10.1016/j.tet.2016.05.034

A highly economical and efficient copper(I)-catalyzed regioselective method for the synthesis of 1,3,4-trisubstituted and 1,3,4,5-tetrasubstituted pyrazoles via [3+2] cycloaddition of hydrazones and nitroolefins has been reported. This process displays excellent applicability with a wide range of substrates under mild conditions.

Full text of DOI:10.1016/j.tet.2016.05.034

Tetrahedron 72 (2016) 4055e4058
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Copper-catalyzed synthesis of 1,3,4-trisubstituted and 1,3,4,5-
tetrasubstituted pyrazoles via [3þ2] cycloadditions of hydrazones
and nitroolefins
Chong Shi, Chaowei Ma, Haojie Ma, Xiaoqiang Zhou, Jinhui Cao, Yuxing Fan,
*
Guosheng Huang
State Key Laboratory of Applied Organic Chemistry, Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province,
Department of Chemistry, Lanzhou University, Lanzhou, 730000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly economical and efficient copper(I)-catalyzed regioselective method for the synthesis of 1,3,4-
trisubstituted and 1,3,4,5-tetrasubstituted pyrazoles via [3þ2] cycloaddition of hydrazones and nitro-
olefins has been reported. This process displays excellent applicability with a wide range of substrates
under mild conditions.
Received 29 March 2016
Received in revised form 9 May 2016
Accepted 13 May 2016
Available online 14 May 2016
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Pyrazoles
Copper-catalyzed
Regioselectivity
Cycloaddition
1. Introduction
the Knorr reaction,9 which leads to the condensation of hydrazines
with 1,3-diketones, but results in a lack of regiospecificity for the
Pyrazoles as a common type of nitrogen-containing heterocycle
play important roles in today’s organic chemistry1 and are also
recognized as ideal structural units in pharmaceutical industry.2
Numerous pyrazole-containing drugs including Celebrex, Viagra
and Acomplia have been commercialized for years.3 Substituted
pyrazole derivatives also exhibits excellent function in biological
field.4 Biologically active compounds cyclooxygenase-2 (Cox-2),5
proteinkinase,6 and HIV-1 reverse transcriptase inhibitors7 were
found using pyrazole ring as the core component. In recent years,
researchers have tried to utilize 1,3,4-trisubstituted and 1,3,4,5-
tetrasubstituted pyrazole derivates against various kinases rele-
vant in cancer.8
The importance of the pyrazoles and their derivatives has
prompted the development of routes to synthesize this kind of
heterocyclic compounds. Over the past decades, a large number of
simple and efficient methods for various functionalized pyrazoles
have been developed. Among them, the most classical procedure is
synthesis of 1,3,4-trisubstituted pyrazoles (Scheme 1-1).10 Another
important method reported in literature is the 1,3-dipolar cyclo-
addition using dipole diazoalkanes11 or nitrile imines12 with acti-
vated dipolarophiles olefins, alkynes or analogues, but the method
has been found with limited applications due to the preparation
difficulty of the reactants or potential explosion compounds used in
the reaction. Other useful synthetic strategies of pyrazole de-
rivatives is the direct oxidative CeN bond formation catalyzed by
Ru,13 Cu14 or Fe15 with substituted-hydrazones. The earliest litera-
ture of the synthesis for pyrazoles with hydrazones and nitroolefins
is reported by Arrieta’s group.16 The reaction was performed at
atmospheric pressure under microwave irradiation with little 1,3,4-
trisubstituted pyrazoles generated. Recently, Deng’s group suc-
cessfully developed novel regioselective methods for 1,3,5-
trisubstituted17 and 1,3,4-trisubstituted18 pyrazoles through the
reaction of hydrazones with nitroolefins (Scheme 1-2,3). However,
the reaction for 1,3,4-trisubstituted pyrazoles, though very efficient
for obtaining pyrazole derivatives, is associated with some draw-
backs such as usage organic strong base at ꢀ78 ꢁC, under N2 at-
mosphere and the needs of two steps. Therefore novel and efficient
pathways to the synthesis of 1,3,4-substituted pyrazoles are still
* Corresponding author. Tel.: þ86 931 8912586; fax: þ86 931 8912596; e-mail
address: hgs@lzu.edu.cn (G. Huang).
http://dx.doi.org/10.1016/j.tet.2016.05.034
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.

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C. Shi et al. / Tetrahedron 72 (2016) 4055e4058
Table 1
highly desirable for organic chemists. Herein, we report a novel and
efficient copper(I)-catalyzed synthesis of 1,3,4-trisubstituted and
1,3,4,5-tetrasubstituted pyrazoles via [3þ2] cycloaddition of nitro-
olefins with hydrazones under mild conditions.
Optimization of the reaction conditionsa
Entry
Catalyst
Solvent
Base
Yieldb(%)
1
2
3
4
5
6
7
8
d
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
DMF
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Li2CO3
35
49
40
66
34
80
83
85
Trace
46
30
79
50
35
57
40
33
27
85
75
85
75
83
75
FeCl2$4H2O
PdCl2
CuI
CuBr
CuBr2
CuCl2
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl2
CuCl2
9
10
11
12
13
14
15
16c
17d
18
19e
20f
21g
22h
23i
24j
Toluene
DMSO
Cyclohexane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
Cs2CO3
K2CO3
Na2CO3
Na2CO3
d
Scheme 1. Different methods for the pyrazoles synthesis.
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
2. Results and discussion
Initially, we optimized the reaction of ethyl (E)-2-(2-
phenylhydrazono)acetate 1a (0.2 mmol) and (E)-(2-nitrovinyl)
benzene 2a (0.24 mmol) with Na2CO3 (0.2 mmol) in 1,4-dioxane at
100 ꢁC (oil bath). To our delight, desired product 3aa was isolated
in 35% yield (Table 1, entry 1). The structure of 3aa was further
confirmed by X-ray crystallography.19 Encouraged by the initial
results, we continued to explore the optimal conditions with dif-
ferent metal catalysts and the results indicated that CuCl exhibited
an excellent ability with the desired 3aa given in 85% yield (Table
1, entries 2e8). Then other solvents, such as DMF, DMSO and cy-
clohexane, were screened to further enhance the efficiency of the
reaction, but with dissatisfactory results (Table 1, entries 9e12).
Moreover, we tested a range of other bases, including Li2CO3,
Cs2CO3 and K2CO3, but the yield didn’t improve as well (Table 1,
entries 13e15). The cyclization reaction was further conducted
under a series of temperatures and we found that 100 ꢁC was the
best of all (Table 1, entries 16, 17). After that, CuCl in the absence of
base was used in this transformation and pyrazole products were
formed in 27% yield. Subsequently, we tried to test the reaction
catalyzed by CuCl under oxygen, nitrogen or with anhydrous
condition and found that the reaction needed the participation of
oxygen (Table 1, entries 19e22). Finally, the reaction was con-
ducted under oxygen or nitrogen catalyzed by CuCl2 with product
3aa isolated in the yield of 83% and 75%, respectively (Table 1,
entries 23e24). Thus, 20 mol % CuCl in 1,4-dioxane with 1 equiv
Na2CO3 under air is chosen as the optimal conditions for this
reaction.
With the optimized reaction conditions in hand, we set out to
investigate the applicability to a series of substituted nitroolefins 2
with ethyl (E)-2-(2-phenylhydrazono)acetate 1a in this trans-
formation as shown in Table 2. Generally, various nitroolefins dis-
played good functional group tolerance and the desired pyrazole
products were furnished in moderate to good yields. In terms of the
electronic effects, we found that both electron-donating and
electron-withdrawing substituents on the aromatic rings showed
high reactivities (Table 2, 3bae3la). The electron-withdrawing
chlorine group (Cl) at meta-position showed better reactivities
and gave higher yields than other position (Table 2, 3cae3ea). As to
the electron-donating hydroxy substituent (OH), ortho-position
showed better reactivities (Table 2, 3gae3ha). It was particularly
a
Conditions: 1a (0.2 mmol), 2a (0.24 mmol), catalyst (0.04 mmol), base
(0.2 mmol), solvent (2 mL), under 100 ꢁC, monitored by TLC. DMF ¼ N,N-dime-
thylformamide, DMSO ¼ Dimethyl sulfoxide.
b
Isolated yields.
c
Under 80 ꢁC.
Under 60 ꢁC.
Under oxygen.
Under nitrogen.
Anhydrous solvent, under oxygen.
Anhydrous solvent, under nitrogen.
Under oxygen.
Under nitrogen.
d
e
f
g
h
i
j
worth noting that heterocycle furan, thiofuran group and sterically
hindered naphthalene group, also displayed well tolerance as
shown in Table 2 (3mae3oa). Finally, we successed to synthesize
1,3,4,5-tetrasubstituted pyrazoles via the reaction of hydrazones
and substituted nitroolefins. Most of reactions reflected good ap-
plicability to give ideal products in good yield (Table 2, 3pae3ua).
Encouraged by results above, we further surveyed this CuCl
catalytic system to a variety of substituted hydrazones. Substrates
with electron-withdrawing groups in the aryl ring at R1 position,
such as fluorine (F), halogen (Cl), bromine (Br) and trifluoromethyl
(CF3), were all directly converted into desired products in good
yields (Table 3, 3abe3ae). However, when we used other electron-
withdrawing nitrile (CN) and nitro (NO2) groups instead, the yields
made significant loss (Table 3, 3afe3ag). Electron-donating sub-
stituents of hydrazones can also transform efficiently except that
methoxy-substituted hydrazone furnished the product 3ai in just
57% yield (Table 3, 3ahe3aj). Moreover, pyridine heterocycle was
applied under the standard conditions with desired product in
yield of 76% (Table 3, 3ak), but other bulky benzothiazole and
naphthalene group lowered the corresponding products to 59% and
68% yield, respectively (Table 3, 3al, 3am). To our surprise, methyl
at R1 position was well tolerated as well (Table 3, 3an). Finally, ar-
omatic substitution at the R2 position was investigated. Electron-
withdrawing and electron-donating substituents on the aryl ring
all can transform successfully (Table 3, 3aoe3at).

C. Shi et al. / Tetrahedron 72 (2016) 4055e4058
4057
Table 2
Table 3
Substrate scope of nitroolefins
Substrate scope of hydrazones
Reaction conditions: 1 (0.2 mmol), 2a (0.24 mmol), catalyst (20%), base (0.2
mmol), solvent (2mL), at 100 oC, 9h, under air. Yields of isolated products
are given.
Reaction conditions: 1a (0.2 mmol), 2 (0.24 mmol), catalyst (20%), base (0.2
mmol), solvent (2mL), at 100 oC, 9h, under air. Yields of isolated products
are given.
Based on the information above and analogous mechanisms in
previous reports,18,20 a possible mechanism for this pyrazole for-
mation was proposed as shown in Scheme 2. Hydrazone 1 initially
lost one proton to give intermediate 3, which was further iso-
merized to 4. Subsequently, transition status 5 was generated via
Michael addition of deprotonated hydrazone 4 to nitroolefin 2.
After that, an intramolecular cyclization of 5 provided a five-
membered ring intermediate 6 followed by the elimination of
HNO2 to give intermediate 7. Finally, intermediate 7 was oxidized
by CuII, which derived from oxidation of CuI, to generate the in-
termediate 8 and pyrazole product 9 was furnished from the
deprotonated intermediate 8.
Scheme 2. Plausible reaction pathway.

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C. Shi et al. / Tetrahedron 72 (2016) 4055e4058
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In conclusion, an economical and efficient copper(I)-catalyzed
[3þ2] cycloaddition reaction to synthesize1,3,4-trisubstituted and
1,3,4,5-tetrasubstituted pyrazoles with hydrazones and nitroolefins
has been developed. The reaction completes under air condition
with Na2CO3 and catalyst CuCl, which are economical and eco-
friendly. The starting materials hydrazones and nitroolefins can
be easily obtained. Most of the substrates show satisfactory
substituted groups compatibility and substituted pyrazole products
could be furnished in relatively high yields in this system. A pos-
sible mechanism for this pyrazole formation was further
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