An efficient solvent-free synthesis of NH-pyrazoles from β-dimethylaminovinylketones and hydrazine on grinding

Article abstract of DOI:10.1016/j.tetlet.2010.04.038

A series of NH-pyrazoles was efficiently synthesized from the reaction of β-dimethylaminovinylketones ([R¹C(O)C(R²){double bond, long}CHN(Me₂)], where R¹ = Me, Ph, 3-MeO-Ph, 4-Me-Ph, 4-MeO-Ph, 4-F-Ph, 4-Cl-Ph, 4

Full text of DOI:10.1016/j.tetlet.2010.04.038

Tetrahedron Letters 51 (2010) 3193–3196
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient solvent-free synthesis of NH-pyrazoles from
b-dimethylaminovinylketones and hydrazine on grinding
Kelvis Longhi, Dayse N. Moreira, Mara R. B. Marzari, Vagner M. Floss, Helio G. Bonacorso,
*
Nilo Zanatta, Marcos A. P. Martins
Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, CEP.: 97105-900 Santa Maria, RS, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of NH-pyrazoles was efficiently synthesized from the reaction of b-dimethylaminovinylketones
([R1C(O)C(R2)@CHN(Me2)], where R1 = Me, Ph, 3-MeO-Ph, 4-Me-Ph, 4-MeO-Ph, 4-F-Ph, 4-Cl-Ph, 4-Br-Ph,
4-O2N-Ph, fur-2-yl, thien-2-yl; R2 = H, 2-MeO-Ph; R1, R2 = –(CH2)3C(O)–) and hydrazine sulfate in solid
state on grinding in the presence of p-toluenesulfonic acid (PTSA). Most of the reactions proceeded
smoothly at room temperature under solvent-free conditions. In comparison with the classical reaction
conditions, which employ molecular solvent (ethanol), this new synthetic method has the advantages
of shorter times, higher yields, mild reaction conditions as well as being environmentally friendly.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 5 March 2010
Revised 7 April 2010
Accepted 9 April 2010
Available online 14 April 2010
Keywords:
Enaminones
Pyrazoles
Grinding
Solvent-free conditions
At the beginning of the new century, interest in the develop-
ment of economically simple and environmentally safe methods
in synthetic organic chemistry is greater than ever. This interest
is mostly apparent in the growth of ‘Green Chemistry’. Green
chemistry approaches not only offer significant potential to reduce
by-products, waste produced, and energy costs but also in the
development of new methodologies for previously unobtainable
materials.1 The perfectly ‘green’ reaction might be described as
one which proceeds at room temperature, requires no organic sol-
vent, is highly selective, and exhibits high atom efficiency, and yet
produces no waste products.2
be conducted by grinding the reactants together for a few minutes
without using any organic solvent, nevertheless this method does
not seem to be effective for endothermic reactions.11d,e
Synthesis of nitrogen-containing heterocyclic systems occupies
an important place in the realm of natural and synthetic organic
chemistry, due to their therapeutic and pharmacological proper-
ties.12a In particular, pyrazoles and their derivatives have attracted
considerable attention due to their wide variety of biological
activities, including anti-inflammatory, antipyretic, and analgesic
activities,12b,c bactericides, fungicides,12d–f as well as promising
inhibitory activity against monoamine oxidase for the treatment
of diseases such as Parkinson’s and Alzheimer’s.12g The synthesis
of pyrazoles has been well explored using the so-called [3+2] atom
fragments, where 1,3-dielectrophilic compounds are used as
3-atom building blocks and hydrazines as the 2-atom fragment.13
Our research group has developed new synthetic methodologies
for the synthesis of both building blocks and heterocyclic
compounds based on the use of ultrasound irradiation,14 microwave
In recent years, solvent-free organic reactions3 have captured
great interest because of their many advantages such as high effi-
ciency and selectivity, easy separation and purification, mild reac-
tion conditions, reduction in waste, and benefit to the industry as
well as the environment. Solvent-free organic reactions based on
grinding two macroscopic particles together mostly involve the
formation of a liquid phase prior to the reaction, that is, formation
of a eutectic melt of uniform distribution where the reacting com-
ponents being in proximity are poised to react in a controlled way.4
The grinding mode for solid-state reactions has been reported
for Grignard reactions,5 Reformatsky reactions,6 Aldol condensa-
tions,7 Dieckmann condensations,8 Knoevenagel condensations,9
reductions,10 and others.11 Most of these reactions are carried
out at room temperature in an absolutely solvent-free environ-
ment using only a mortar and pestle. Exothermic reactions can
irradiation,15 ionic liquids16
,
and solvent-free conditions.17,3a
Recently, we reported an efficient method to obtain a series of
b-dimethylaminovinylketones (b-enaminones) from condensation
of methyl ketones with dimethylformamide dimethylacetal
(DMFDMA) in the presence of imidazolium-based ionic liquid
[BMIM][BF4].16b Thus, in continuation of our interest in the develop-
ment of new methodologies, we describe herein the synthesis of a
series of NH-pyrazoles from the reaction of b-dimethylaminovinylk-
etones and hydrazine sulfate in solid state on grinding, using
p-toluenesulfonic acid (PTSA) as a catalyst and solvent-free condi-
tions. The b-dimethylaminovinylketones 1 used in this study were
* Corresponding author. Tel./fax: +55 55 3220 8756.
E-mail address: mmartins@base.ufsm.br (M.A.P. Martins).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.038

3194
K. Longhi et al. / Tetrahedron Letters 51 (2010) 3193–3196
Table 1
densation reaction. The reaction failed in the presence of SiO2 and
Optimization for the synthesis of 3a
1a was recovered (Table 1, entries 2 and 3). We found PTSA, an
inexpensive and common organic chemical, to be an efficient
catalyst for this reaction. PTSA was used in 20 mol %, which led
to a yield improvement and completion of the reaction in 6 min
(Table 1, entry 4). In order to evaluate the amount of catalyst,
PTSA was employed in 50 mol % for 3 and 6 min, however in the
first case compound 1a was partially recovered together with
product 3a, while the second attempt led to a yield decrease
(Table 1, entries 5 and 6). A mixture of the pyrazole and the
starting material was obtained in a molar ratio of 20:1, respec-
tively, when KHSO4 was used and 1:1 when NaHSO4 was used
(Table 1, entries 7 and 8). The efficiency of solid-acid catalysts
on the solid support SiO2 was also investigated, and the results re-
vealed the conversion of only half of the starting material to the
desired product (Table 1, entries 9–11). Another parameter evalu-
ated was the amount of hydrazine used. It was observed that the
molar ratio of 1:1.2 (b-enaminone/hydrazine) was enough for the
total conversion of the starting material. These data demonstrate
that the cyclocondensation reaction between 1a and hydrazine 2
can be performed under mild conditions. During the optimization
reactions using PTSA, it was observed that the reaction mixture,
which was initially in a solid state, melted during the grinding
process leading to a light yellow solid mass. The product was ex-
tracted from the solid mass furnishing 5-phenyl-1H-pyrazole 3a
in excellent yield (90%).
O
i
N
Me
+ NH2NH2 H2SO4
N
N
H
Me
2
1a
3a
i: grinding, r.t.
Entry
Catalyst
Catalyst amount (mol %)
Time (min)
Yielda (%)
b
1
2
3
4
5
6
7
8
9
Neat
SiO2
SiO2
PTSA
PTSA
PTSA
KHSO4
NaHSO4
KHSO4/SiO2
NaHSO4/SiO2
PTSA/SiO2
—
20
100
20
50
50
20
20
20
20
20
6
6
6
6
3
6
6
6
6
6
6
—
—
—
b
b
90
c
—
64
d
—
—
—
—
c
c
c
10
11
c
—
a
b
c
Yield of isolated product.
The starting material was recovered.
A mixture of the starting material and pyrazole was obtained in a molar ratio of
1:1, respectively. This ratio was determined by 1H NMR from the integration signal
area of vinylic proton, and based on the consumption of compound 1.
A mixture of the pyrazole and the starting material was obtained in a molar
ratio of 20:1, respectively (determined as in the item c).
d
In order to evaluate the scope and limitations of this solvent-
free reaction, we extended it to b-enaminones 1b–l, using the same
reaction conditions that were established for 1a. The mixture was
ground with a pestle, and the reaction was completed within 6–
12 min in good yields (Table 2).19 From Table 2, it is possible to af-
firm that the grinding allowed the reaction to proceed in a shorter
reaction time, furnishing better yields when compared to conven-
tional thermal heating, with ethanol reflux and a Brønsted catalyst
(PTSA). A possible explanation for the shorter reaction time and
better yield under solvent-free conditions is that the formation of
a liquid phase prior to the reaction, that is, formation of a eutectic
mixture with uniform distribution of the reactants, brings the
prepared according to the experimental procedures described previ-
ously in our laboratory.16b,18
We began our study by evaluating the efficiency of grinding in
the reaction between b-dimethylaminovinylketone 1a and hydra-
zine sulfate 2 in solid phase to obtain the pyrazole 3a under the
reaction conditions described in Table 1.
Initially, the mixture was ground in a mortar with a pestle at
room temperature under neat conditions. However the results
demonstrated the need of a catalyst, since the starting material
was recovered (Table 1, entry 1). Thus, we chose four catalysts
(SiO2, PTSA, KHSO4, and NaHSO4) to be analyzed in this cyclocon-
Table 2
Solvent-free reactions of solid b-enaminones 1a–l with hydrazine 2
R2
O
R1
i or ii
Me
R2 Me
+ NH2NH2 H2SO4
N
R1
N
N
H
2
1a-l
3a-l
i: PTSA, grinding, r.t.
ii: PTSA, ethanol, reflux
Product
R1
R2
Grinding
Ethanol reflux
Yieldb (%)
Time (min)
Conv.a (%)
Yieldb (%)
Time (h)
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ph
H
H
H
H
H
H
H
H
H
H
6
6
6
6
6
9
6
12
6
6
>99
>99
>99
>99
>99
95
>99
91
>99
>99
>99
97
90
84
75
91
72
84
85
75
65
75
92
60
2
3
3
3
3
4
3
6
3
3
3
3
79
81
66
74
72
83
80
69
51
67
75
50
3-MeO-Ph
4-Me-Ph
4-MeO-Ph
4-F-Ph
4-Cl-Ph
4-Br-Ph
4-O2N-Ph
Fur-2-yl
Thien-2-yl
Me
3j
3k
3l
2-MeO-Ph
–(CH2)3C(O)–
6
6
a
Determined by 1H NMR from the integration signal area of vinylic proton, and based on the consumption of compound 1.
Yield of isolated products.
b

K. Longhi et al. / Tetrahedron Letters 51 (2010) 3193–3196
3195
Table 3
25 and 50 mmol scale (Table 3, entries 1 and 2). The reaction mix-
ture was ground for just few minutes and the desired product was
obtained in 90% and 92% yield, respectively. Similar results were
attained for b-enaminones 1c and 1e (Table 3, entries 3 and 4).
In summary, this Letter describes an efficient and practical sol-
vent-free process for the synthesis of NH-pyrazoles in both small
and large scale. Furthermore, the procedure described herein offers
several advantages including high yields, clean product, and mini-
mal environmental impact. The short reaction time coupled with
the simplicity of the reaction procedure makes this method one
of the most efficient methods for the synthesis of this class of
compounds.
Results obtained using large-scale synthesis (Grindstone Chemistry)
Entry
Product
R1
b-Enaminone
amount (mmol)
Time
(min)
Yielda
(%)
1
2
3
4
3a
3a
3c
3e
Ph
Ph
4-Me-Ph
4-F-Ph
25
50
25
25
6
6
6
6
90
92
89
84
a
Yield of isolated products.
reacting species into proximity than does a solvent.20 In addition,
this implies that some heat is released upon the grinding of the
two components which leads to complete melting of the mixture.
Such heat may be generated by the occurrence of ‘hot spots’ during
initial grinding of the solids.1,2,4
Acknowledgments
The authors thank the Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento
de Pessoal de Nível Superior (CAPES), and Fundação de Apoio à
Pesquisa do Estado do Rio Grande do Sul (FAPERGS) for finan-
cial support. The fellowships from CNPq and CAPES are also
acknowledged.
All the reactions proceeded smoothly until completion at room
temperature. The conversion of starting material into the respec-
tive products was determined by 1H NMR from the integration
signal area of vinylic proton, and based on the consumption of b-
enaminones 1, as demonstrated in Table 2. It is important to men-
tion that the conversion was 100% for most compounds, except for
compounds 3f, 3h, and 3l, where small amounts of the starting
material were observed. The substituent effect on the aromatic
ring in 1b–h was also evaluated. As shown in Table 2, compounds
1b–g containing electron-donating groups (such as alkyl group) or
weak electron-withdrawing groups (such as halides) reacted well
to give the corresponding 3b–g in high yields. This finding demon-
strated no influence of the electronic nature of the substituent on
the reaction time, except for the 4-Cl-Ph group, which required a
longer reaction time (9 min). On the other hand, when a strong
electron-withdrawing group (4-O2N-Ph) was used, a longer time
(12 min) was necessary to obtain product 3h. The smaller reactiv-
ity of 1h in relation to 1a can be explained in terms of substituent
(R1) effect on the electrophilicity of C-1 (C@O) and/or C-3 (carbon-
b). From the semi-empirical AM1 calculation data,21 it was ob-
served that the charge density and the LUMO coefficient values
of C-1 and C-3 for 1h (R1 = 4-O2N-Ph) are close to half of those ob-
served for the b-enaminone 1a (R1 = Ph). Also, the charge density of
Supplementary data
Supplementary data (general procedures and characterization
data (1H NMR, 13C NMR, GC/MS and melting points) of compounds
3a–l) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2010.04.038.
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this new synthetic approach for obtaining NH-pyrazoles, the reac-
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average yield presented a standard deviation of 2%.
The spectroscopic data of the compounds synthesized herein
are in accordance with the literature.22
Recently, the technique ‘Grindstone Chemistry’ has been
reported as an efficient way for the synthesis of organic com-
pounds in large scale.23,11d,e This method was developed especially
for solvent-free reactions activated by grinding solid reactants
together. To support this process, we investigated the efficiency
of our procedure using the b-enaminones 1a,c,e and hydrazine 2
(Table 3). For this purpose we chose three representative b-enami-
nones containing in their structure hydrogen, electron-donating
groups and weak electron-withdrawing groups. The reactions were
performed in a mortar and pestle at room temperature and the
reactants were used in the same ratio as previously determined.
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and the product was extracted with CHCl3 (2 Â 3 mL). The combined organic
layers were dried over Na2SO4 and concentrated under reduced pressure to
give the product 3a with high purity. Typical spectral data are as follows: 5(3)-
Phenyl-1H-pyrazole (3a): mp 69–71 °C; 1H NMR (200 MHz, CDCl3) dH (ppm)
6.58 (d, 3J = 2 Hz, 1H, H4), 7.26–7.42 (m, 3H, Ar), 7.58 (d, 3J = 2 Hz, 1H, H3),
7.73–7.72 (m, 2H, Ar), 10.12 (br s, 1H, NH); 13C NMR (50 MHz, CDCl3) dC (ppm)
102.5 (C4), 125.8, 127.9, 128.7, 132.1 (C-Ar), 134.4 (C5), 149.0 (C3); GC/MS (m/
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grinding:
A mixture of the appropriate solid b-enaminone 1a (1 mmol),
hydrazine sulfate 2 (1.2 mmol), and p-toluenesulfonic acid (20 mol %) was
ground in a mortar and pestle at room temperature for the appropriate time.
After completion of the reaction, water was added and the product was
extracted with CHCl3 (2 Â 3 mL). The combined organic layers were dried over
Na2SO4 and concentrated under reduced pressure to give a product 3a with
high purity.
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Mandadi, A. Tetrahedron Lett. 2005, 46, 3011.
(b) Reactions in ethanol: Powdered reactants 1a and
2 were dissolved in
ethanol, and p-toluenesulfonic acid (20 mol %) was added. The reaction
mixture was stirred in ethanol under reflux during 2 h. After completion of