A simple and efficient synthesis of pyrazoles in water

Article abstract of DOI:10.1016/j.tet.2011.09.074

A simple, highly efficient, and environmentally friendly method for the synthesis of substituted 1H-pyrazoles by one-pot condensation reaction of α,β-unsaturated carbonyl compounds with tosyl hydrazide in water was developed. The reaction system exhibited tolerance with various functional groups, Aromatic moiety with both electron-rich and electron-deficient substituents could give desired products in good to excellent yields.

Full text of DOI:10.1016/j.tet.2011.09.074

Tetrahedron 67 (2011) 9618e9621
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A simple and efficient synthesis of pyrazoles in water
*
*
Jun Wen, Yun Fu, Ruo-Yi Zhang, Ji Zhang , Shan-Yong Chen, Xiao-Qi Yu
Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu, 610064, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 July 2011
Received in revised form 6 September 2011
Accepted 16 September 2011
Available online 1 October 2011
A simple, highly efficient, and environmentally friendly method for the synthesis of substituted 1H-
pyrazoles by one-pot condensation reaction of a,b-unsaturated carbonyl compounds with tosyl hydra-
zide in water was developed. The reaction system exhibited tolerance with various functional groups,
Aromatic moiety with both electron-rich and electron-deficient substituents could give desired products
in good to excellent yields.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
1H-pyrazoles
In water
Condensation reaction
One-pot
1. Introduction
Pyrazoles are well known five-membered nitrogen-containing
heterocyclic compounds possessing diverse bioactivities, such as
analgesic agent, platelet aggregation inhibitors, and nonsteroidal
anti-inflammatory agents, thus these compounds are widely used
in the development of drug research1 and agriculture.2 Conse-
quently, pyrazoles have attracted much attention, and various
procedures for their syntheses have been developed.3
As reported in the literature, the synthesis methods toward
substituted pyrazoles include: (a) Condensation of a,b-unsaturated
carbonyl compounds with hydrazines, which is used as a major
strategy.4 However, these reactions often result in a mixture of
regioisomeric 4,5-dihydro-1H-pyrazoles that need to be further ox-
idized to corresponding pyrazoles (Scheme 1). (b) 1,3-Dipolar cy-
cloadditions of diazo compounds onto triple bonds,5 whereas diazo
compounds were known to be toxic and potentially explosive. (c)
Pyrazoles could be formed through the nucleophilic attack of hy-
drazines to chromones, flavones, or isoxazoles.6 However, these
special substrate sources have limited application of this method. Of
these approaches, hydrazine hydrate is a major nitrogen source for
the synthesis of 1H-pyrazoles, and a large excess of hydrazine hy-
drate was required for most of these reactions. In 2003, Aggarwal and
co-workers have reported a convenient one-pot procedure for the
preparation of pyrazoles by 1,3-dipolar cycloaddition (Scheme 1).7 In
their studies, only 1 equiv of tosyl hydrazide with substrate aldehyde
was used as nitrogen source. Nevertheless, only aldehyde substrates
were reported, and moderate yields were obtained in this reaction.
Scheme 1. Methods toward the preparation of substituted pyrazoles.
Considering the requirement of green chemistry, the use of
water as solvent in place of organic solvent led to remarkable
progress in the development of organic synthesis due to the low
cost, safety, and environmental benignity.8 Herein, we report a one-
pot condensation reaction of a,b-unsaturated carbonyl compounds
with tosyl hydrazide by using water as the sole reaction medium
(Scheme 1), and a wide variety of substituted pyrazoles were ob-
tained in good to excellent yields.
2. Results and discussion
For initial optimization of the reaction conditions, the conden-
sation between benzylidenacetone (1a) and tosyl hydrazide (2) was
selected as the model reaction system, and the results are sum-
marized in Table 1. Initially, we found that the desired product
* Corresponding authors. Tel./fax: þ86 28 85415886; e-mail address: xqyu@
scu.edu.cn (X.-Q. Yu).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.074

J. Wen et al. / Tetrahedron 67 (2011) 9618e9621
9619
Table 2
could be obtained in 47% yield with NaOH as base, and no product
was detected in the absence of base (entries 1 and 2). Addition of
(n-Bu)4NBr as phase transfer catalyst (PTC) to the reaction system
led to dramatically increased yields (entries 3e5). After the
screening of PTC amounts on a small scale, 1.5 equiv of (n-Bu)4NBr
was found to be the best amount for the reaction, in which 94%
yield was obtained (entry 4). Comparison among PTCs with dif-
ferent anions indicated that (n-Bu)4NBr is superior to others (en-
tries 4, 6e7). A range of bases including NaOH, KOH, K3PO4, t-BuOK,
and K2CO3 were then screened, and NaOH was found to be most
suitable (entries 4, 8e11). The reaction was also carried out under
nitrogen atmosphere, and same yield was found, indicating that
oxygen is not necessary for this reaction (entry 12).
The substrate scope was subsequently investigated under the
optimized conditions. Table 2 summarizes the results of conden-
sation reactions between a variety of substituted benzylidenace-
tone and tosyl hydrazide mediated by NaOH in water. Substituted
benzylidenacetone with both electron-rich and electron-deficient
substituents could afford the corresponding pyrazoles in good to
excellent yields, and most of them were higher than those from
literature in different methods.4-7 It is worth mentioning that o-
hydroxyphenylpyrazole, which is usually be prepared by treatment
of chromone with hydrazines6 and widely used as ultraviolet sta-
bilizers, analytical reagents, and analgesic agents,9 could also be
formed smoothly in moderate yield (entry 6), indicating good
substituent tolerance of the synthetic method.
Condensation reactions between a variety of substituted benzylidenacetone and
tosyl hydrazidea
H
O
N
N
NaOH
(n-Bu)4NBr / H2O
NH2NHTs
+
R1
R1
1
2
3
Entry
R1
Product
Yieldb (%)
H
O
N
N
1
2
94
87
(1a)
(3a)
H
N
O
N
MeO
Me
MeO
(1b)
(3b)
H
N
O
N
3
88
(1c)
Me
(3c)
Table 1
H
N
Optomization of the reaction conditionsa
O
N
Cl
H
4
5
82
82
O
N
N
Base
PTC / H2O
Cl
(1d)
+ NH2NHTs
(3d)
H
N
O
1a
2
3a
N
Entry
Base
PTC
Yieldb (%)
O2N
1
d
d
NR
47
74
94
79
83
76
60
75
39
35
92
O2N
HO
(1e)
2
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
KOH
d
(3e)
3c
4
(n-Bu)4NBr
(n-Bu)4NBr
(n-Bu)4NBr
(n-Bu)4NCl
(n-Bu)4NI
(n-Bu)4NBr
(n-Bu)4NBr
(n-Bu)4NBr
(n-Bu)4NBr
(n-Bu)4NBr
5d
6
H
N
O
N
7
8
9
10
11
12e
6
7
8
69
93
96
K3PO4
OH
(1f)
(3f)
t-BuOK
K2CO3
NaOH
H
N
O
a
N
Reaction conditions: 1a (0.2 mmol),
2 (0.24 mmol), base (1.5 equiv), PTC
(1.5 equiv), H2O (2 mL), 80 ꢀC, 10 h, under air.
b
Isolated yields.
c
(n-Bu)4NBr (1 equiv).
(n-Bu)4NBr (2 equiv).
F3C
d
F3C
(1g)
(1h)
e
(3g)
Under N2.
H
a,b-un-
O
O
Subsequently, reactions of some others substituted
N
N
saturated carbonyl compounds with tosyl hydrazide were in-
vestigated. Table 3 summarizes the results. Various substituted
cinnamaldehyde could give target pyrazoles through the same re-
action with excellent yields (5aed). Chalcone was also investigated,
and product 5e was obtained in low yield. We speculated that this
result might be ascribed to the difficulty of chalcone to form tosyl
hydrazone. Tetrahydroindazole could also be synthesized in good
Br
Br
(3h)
H
N
yield by this method (5g). Several a,b-unsaturated carbonyl com-
N
pounds with both electron-rich and electron-deficient hetero-
arenes can also be successfully applied to this reaction (5hek).
To demonstrate the practicality of the present approach, a gram-
scale synthesis of the 5-methyl-3-phenyl-1H-pyrazole was per-
formed under the optimized conditions. As shown in Scheme 2,
9
94
Cl
(1i)
Cl
(3i)
(continued on next page)

9620
J. Wen et al. / Tetrahedron 67 (2011) 9618e9621
Table 2 (continued )
3. Conclusion
Entry
10
R1
Product
Yieldb (%)
In conclusion, we have developed a simple, highly efficient, and
H
N
O
environmentally friendly method for the synthesis of substituted
1H-pyrazoles in water. The reaction system exhibits tolerance with
various functional groups, and gives desired product in good to
excellent yields. Moreover, the present reaction process provides
a potential for the large-scale synthesis of substituted 1H-pyrazoles.
Further applications of this methodology are now in progress.
N
99
96
NC
(1j)
NC
Br
(3j)
H
O
N
N
4. Experimental
4.1. General
11
Br
(1k)
(3k)
1H NMR, 13C NMR spectra were measured on a Bruker AM400
NMR spectrometer (400 MHz or 100 MHz, respectively) with CDCl3
as solvent and recorded in parts per million relative to internal
tetramethylsilane standard. Mass spectroscopy data of the product
was collected on an Agilent 6890-5973N GCMS-EI instrument. ESI-
MS spectral data were recorded on a Finnigan LCQDECA mass
spectrometer. Unless otherwise noted, all reagents were obtained
from commercial suppliers and used without further purification.
Solvents were freshly distilled prior to use.
H
H
N
N
N
N
12
99
F
F
(1l)
(3l)
a
Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), NaOH (1.5 equiv), (n-Bu)4NBr
(1.5 equiv), H2O (2 mL), 80 ꢀC, 10 h, under air.
b
Isolated yields.
4.2. General procedure for the substituted benzylidenacetone
Table 3
Condensation reactions between substituted
a
,
b
-unsaturated carbonyl compounds
To a solution of aldehyde 6 (5 mmol) in acetone (12.5 mL) was
added amine salt 7 (1 mmol, 201.14 mg). The reaction mixture was
stirred at 75 ꢀC in a sealed vial. After stirring at this temperature for
10 h, the reaction mixture was cooled to room temperature, satu-
rated NaHCO3 solution and ethyl acetate was added. After phase
separation the aqueous phase was extracted three times with ethyl
acetate and the organic layer was dried over sodium sulfate and
concentrated in vacuo to give mostly analytical pure products. If
necessary the crude product was purified by column chromatog-
raphy (ethyl acetate/hexane).
and tosyl hydrazidea
H
O
N
N
R3
NaOH
R1
R3
+ NH2NHTs
(n-Bu)4NBr / H2O
R1
R2
4
R2
5
2
H
N
H
H
N
H
N
N
N
N
N
N
Br
5d
, 97 %
4.3. General procedure for the substituted benzylidenacetone
5c,92%
5b, 98%
5a,94%
H
N
H
N
H
Ph
A Schlenk tube with a magnetic stir bar charged with a,b-un-
N
N
N
N
Ph
saturated carbonyl compounds (0.5 mmol, 1 equiv), tosyl hydrazide
(0.6 mmol, 1.2 equiv), NaOH (1.5 equiv), (n-Bu)4NBr (1.5 equiv). The
reaction vessel was placed in an 80 ꢀC oil bath, and then stirring at
this temperature for 10 h. The reaction mixture was then allowed to
cool to ambient temperature, and diluted with 20 mL of ethyl ac-
etate, and washed with brine (15 mL), water (15 mL), and then the
organic layer was dried over Na2SO4. After concentrated in vacuo,
the crude product was purified by column chromatography. The
identity and purity of the known product was confirmed by 1H
NMR, 13C NMR, and GC-MS.
b
b
5f,56%
5e,35%
5g
,69%
H
N
H
H
N
H
N
N
N
N
N
N
N
N
O
N
5k
5h,93%
97%
5i, 99%
5j, 84%
Compound 3a: White solid, 1H NMR (400 MHz, CDCl3)
aReaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), NaOH (1.5 equiv), (n-Bu)4NBr
(1.5 equiv), H2O (2 mL), 80 ꢀC, 10 h, under air, all yields given are isolated yields.
bNaOH (3 equiv), 20 h.
d
¼7.71e7.68 (m, 2H), 7.36e7.33 (d, 2H), 7.33e7.38 (m, 1H), 6.31 (s,
1H), 2.23 (s, 3H). 13C NMR (100 MHz, CDCl3),
d
¼148.91, 142.14,
131.53, 127.63, 126.74, 124.72, 101.02, 10.61. MS (EI) m/z (%) 158 (Mþ,
100), 128 (8), 77 (4). HRMS (ESI): m/z¼159.0925 [MþH]þ.
upon treatment of 10 mmol of starting materials, product 3a was
provided in 91% yield.
Compound 5a: Colorless oil, 1H NMR (400 MHz, CDCl3)
d¼9.23
(s, 1H), 7.79e7.76 (m, 2H), 7.62e7.61 (d, 1H), 7.43e7.39 (m, 2H),
7.36e7.43 (d, 1H), 6.63e6.62 (d, 1H). 13C NMR (100 MHz, CDCl3),
d
¼149.10, 133.29, 132.14, 128.81, 128.05, 125.86, 102.65. MS (EI) m/z
(%) 144 (Mþ, 100), 115 (12), 90 (6), 77 (6). HRMS (ESI): m/
z¼145.0762 [MþH]þ.
Acknowledgements
Scheme 2. Gram-scale reactions of benzylidenacetone and tosyl hydrazide. Reaction
conditions: 1a (10 mmol), 2 (12 mmol), NaOH (1.5 equiv), (n-Bu)4NBr (1.5 equiv), H2O
(50 mL), 80 ꢀC, 15 h, under air, isolated yield.
This work was financially supported by the National Science
Foundation of China (Nos. 20725206, 20732004, and 21021001),

J. Wen et al. / Tetrahedron 67 (2011) 9618e9621
9621
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