Catalyst-free one-pot synthesis of 1,4,5-trisubstituted pyrazoles in 2,2,2-trifluoroethanol

Article abstract of DOI:10.1016/j.jfluchem.2011.07.014

A simple, efficient and three component one-pot synthesis of 1,4,5-trisubstituted pyrazoles by condensation of β-dicarbonyls, N,N-dimethylformamide dimethyl acetal (DMFDMA) and hydrazine derivatives in 2,2,2-trifluoroethanol without using any catalyst and activation, is described.

Full text of DOI:10.1016/j.jfluchem.2011.07.014

Journal of Fluorine Chemistry 132 (2011) 995–1000
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Short Communication
Catalyst-free one-pot synthesis of 1,4,5-trisubstituted pyrazoles
in 2,2,2-trifluoroethanol
*
Heshmatollah Alinezhad , Mahmood Tajbakhsh, Mahboobeh Zare
Faculty of Chemistry, Mazandaran University, Babolsar, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
A simple, efficient and three component one-pot synthesis of 1,4,5-trisubstituted pyrazoles by
Received 25 April 2011
Received in revised form 30 June 2011
Accepted 15 July 2011
condensation of
derivatives in 2,2,2-trifluoroethanol without using any catalyst and activation, is described.
ß 2011 Published by Elsevier B.V.
b-dicarbonyls, N,N-dimethylformamide dimethyl acetal (DMFDMA) and hydrazine
Available online 23 July 2011
Keywords:
2,2,2-Trifluoroethanol
Pyrazole
Cyclization
Enaminone
1. Introduction
N-methylpyrazoles are also synthesized from methylhydrazine
and enaminones, but, the observed regioselectivities reported, are
usually low [16a,b,c,21].
Pyrazoles have attracted much attention in the last decades as
their synthesis has become more accessible and their diverse
properties appreciated [1]. Specifically, the pyrazole moiety is
present in many pharmacologically and agrochemically important
compounds, including those used as inhibitors of HIV-1 reverse
transcriptase [2], COX-2 inhibitors [3], sodium hydrogen ion
exchanger NHE-1 [4], dipeptidyl peptidase IV (DPP-IV) [5] and in
the pesticides such as Cyanopyrafen [6] and Tebufenpyrad [7].
Numerous methods for the synthesis of pyrazole derivatives
have been reported in the literature [8–11], for example addition of
On the other hand, fluorinated alcohols have been shown to
display unique properties as solvents, cosolvents and additives in
organic synthesis due to their CF3 group. Their high hydrogen bond
donating ability, low nucleophilicity, strong ionizing power and
ability to solvate water, differentiating them from their non-
fluorinated counterparts and other protic solvents [22]. Trifluor-
oethanol (TFE) modifies the course of reactions when it is used as
solvent. Reactions in TFE are generally selective and carried out
without using any reagents or catalysts under mild conditions,
allowing thus a facile isolation of the product and a recovery of the
solvent by distillation [23].
Due to the fact that, most of the aforementioned methods
focused on the preparation of mono-and disubstituted pyrazoles
and the importance of trisubstituted pyrazoles in recent years, we
wish to report here, an efficient, one-pot, regioselective and
catalyst-free procedure to prepare 1,4,5-trisubstituted pyrazoles
via the condensation of 1,3-dicarbonyls, N,N-dimethylformamide
dimethyl acetal and hydrazines in TFE under mild reaction
conditions.
hydrazines to 1,3-dicarbonyl [12], or
compounds [13] and 1,3-cycloaddition of diazoalkanes to alkynes
[14].
a,b-unsaturated carbonyl
Enaminone derivatives, which are usually prepared from
formamide acetals and active methylene ketones [15], are highly
reactive intermediates on the synthesis of heterocyclic com-
pounds. Among the different methodologies for the synthesis of
the pyrazoles, several examples of the reaction between arylhy-
drazine derivatives and enaminones have been reported [16],
which provide better regioselectivity compared to the former ones.
Low yields, acid (HOAc) requirement, two step synthesis and
limited substitution patterns have been described in most cases
[17–20].
2. Results and discussion
In our work, we initially showed the effectiveness of TFE as a
solvent in the preparation of ethyl 5-methyl-1-phenyl-1H-
pyrazole-4-carboxylate. 3-Oxo-butyric acid ethyl ester, N,N-
dimethylformamide dimethyl acetal (DMFDMA) were treated
* Corresponding author. Fax: +98 11253 42302.
E-mail address: heshmat@umz.ac.ir (H. Alinezhad).
0022-1139/$ – see front matter ß 2011 Published by Elsevier B.V.
doi:10.1016/j.jfluchem.2011.07.014

996
H. Alinezhad et al. / Journal of Fluorine Chemistry 132 (2011) 995–1000
Table 1
Reactions of 3-oxo-butyric acid ethyl ester (1 mmol) and
DMFDMA (1.2 mmol) with various arylhydrazines (1.2 mmol) in
TFE (1 ml) at room temperature, afforded 4-carboxylate pyrazoles
Preparation of pyrazoles in different solvents.a
O
in excellent yields (Table 2, entries 1–3). Similarly other
esters reacted smoothly under reaction conditions to give high
yield of the desired pyrazoles (Table 2, entries 4–9).
b-keto
EtO
Me
O
O
MeO
MeO
Me
Me
PhNHNH2
rt
+
Me
N
N
EtO
N
1,3-Cyclohexanedione as cyclic
b-diketone required higher
temperature (refluxing in TFE) and longer reaction time to afford
excellent yield of the corresponding pyrazoles (Table 2, entries 10–
Ph
.
12). Reactions of open-chain b-diketones (Scheme 1, 1: R = Me or
Entry
Solvent
Time
Yield (%)b
Et) under optimal reaction conditions produced a mixture of 4-
acylpyrazoles (4m–4r) and 3,5-dialkyl-1-aryl pyrazoles (5).
However, using an excess amount of DMFDMA (two equivalents),
led to formation of the 4-acylpyrazoles as sole product in excellent
yields (Table 2, entries 13–18). It is believed that, compounds (4m–
4r) are produced through formation of enaminone (2) [19] and
1
2
3
4
5
6
7
THF
5 h
5 h
20
24
30
35
98
80
80
CH2Cl2
EtOH
MeOH
TFE
4 h
4 h
10 min
10 min
2 h
HFIP
trisubstituted pyrazoles (5), are obtained from
zone intermediate (3) [12].
b-ketoarylhydra-
EtOH/TFE (1:1)
a
Reactions were performed at room temperature using 1 mmol of 3-oxo-butyric
acid ethyl ester, 1.2 mmol DMFDMA and 1.2 mmol of phenylhydrazine.
In contrast with arylhydrazines, when methylhydrazine was
used as a bidentate nucleophile, a mixture of isomers was formed.
This mightbe due to the close nucleophilicity of bothnitrogen atoms
in methylhydrazine as, it was reported for similar reactions [16]. In
our effort, when 3-oxo-butyric acid ethyl ester and DMFDMA
condensed with methylhydrazine under conditions of arylhydra-
zines at room temperature, a mixture of regioisomers 6a and 7 (3:1)
was obtained in 10 min, as determined by NMR spectra (Scheme 2).
In order to improve the selectivity, different reaction conditions
were examined. A high selectivity (95:5) was achieved when
methylhydrazine (1.2 mmol) was added dropwise to a mixture of
DMFDMA (1.2 mmol) and 3-oxo-butyric acid ethyl ester (1 mmol)
at 0 8C in TFE (2 ml) and subsequently stirred at room temperature
for 10 min.
b
Yields refer to isolated products.
with phenylhydrazine at room temperature in various solvents
(Table 1). As it is clear from this table, high yield of the desired
pyrazole is obtained in fluorinated solvents (Table 1, entries 5 and
6). This has further confirmed when TFE was used as a co-solvent
with ethanol which significantly reduced the reaction time and
increased the yield of the product (Table 1, entries 3 and 7).
Reactions in aprotic solvents such as THF and CH2Cl2 (Table 1,
entries 1 and 2) occur quite slowly and a low yield of the product is
formed. The highest yield was achieved in TFE only after 10 min
(Table 1, entry 5)
In order to show the generality of this reaction we synthesized
This reaction was extended to cyclic and open-chain 1,3-
diketones and in all cases high regioselectivity in favour of 1,4,5-
trisubstituted pyrazoles were observed (Table 3, entries 1–6).
different substituted pyrazoles using a variety of
and arylhydrazines in TFE as a solvent (Table 2).
b
-dicarbonyls
Table 2
Preparation of arylpyrazole derivatives.a
O
O
O
MeO
MeO
Me
Me
rt
TFE
N
+
2
N
2
ArNHNH2
+
R
1
N
R
R
Ar
1
R
4a-4r
.
Entry
R1
R2
Ar
Time (min)
Product
Yield (%)b
1
Me
Me
Me
Me
Me
Me
i-Pr
i-Pr
i-Pr
OEt
OEt
OEt
Ph
10
15
10
10
16
10
60
80
30
60
180
30
5
4a
4b
4c
4d
4e
4f
98
95
97
93
94
98
94
94
97
91
92
90
94
95
93
92
93
95
2
p-ClC6H4
3
p-OMeC6H4
Ph
4
Ot-Bu
5
Ot-Bu
Ot-Bu
OEt
OEt
OEt
–
p-ClC6H4
p-OMeC6H4
Ph
6
7
4g
4h
4i
8
p-ClC6H4
p-OMeC6H4
Ph
9
10c
11c
12c
13d
14d
15d
16d
17d
18d
–(CH2)3–
–(CH2)3–
–(CH2)3–
Me
4j
–
p-ClC6H4
p-OMeC6H4
Ph
4k
4l
–
Me
Me
Me
Et
4m
4n
4o
4p
4q
4r
Me
p-ClC6H4
p-OMeC6H4
Ph
10
5
Me
Et
5
Et
Et
p-ClC6H4
p-OMeC6H4
5
Et
Et
5
a
Reactions were performed using
Isolated yield.
b-dicarbonyls (1 mmol), DMFDMA (1.2 mmol) and arylhydrazines (1.2 mmol) at room temperature.
b
c
Reaction was carried out under reflux conditions.
2 mmol of DMFDMA was used.
d

H. Alinezhad et al. / Journal of Fluorine Chemistry 132 (2011) 995–1000
997
O
Me
N
O
O
ArNHNH2
MeO
MeO
N
R
Me
N
R
R
O
Ar
R
O
O
4m-4r
N(Me)2
2
R
R
1
R
ArNHNH2
R= Me or Et
NNHAr
R
N
R
N
Ar
5
R
3
Scheme 1.
O
O
O
O
N
Me
N
N
MeO
MeO
Me
EtO
Me-NHNH2, TFE
+
EtO
N
N
+
Me
OEt
Me
rt,
Me
10 min
Me
Me
7 (25%)
6a
(75%)
Scheme 2.
O
O
O
O
F3CH2C
H
H
R2
CH2CF3
F3CH2C
H
H
CH2CF3
O
O
O
H
F3CH2C
H
F3CH2C
H
H
CH2CF3
O
O
O
O
H
O
O
O
O
R1
R1
R2
Me
R1
R2
Me
R1
R2
Me
MeO
MeO
-MeOH
N
MeO
N
MeO
N
Me
Me
Me
O
-MeOH
O
H
CH2CF3
O
H
CH2CF3
O
O
O
O
O
R1
R2
R1
R2
R1
R2
N
R1
R2
N
N
N
O
-Me2NH
Me2N
R3
R3
H
NHNHR3
9
NH2NHR3
CH2CF3
H
O
H
O
CH2CF3
Scheme 3.
8
Table 3
Preparation of methylpyrazole derivatives.a
O
O
O
O
MeO
MeO
Me
Me
TFE
+
N
N
Me
N
N
+
+
2
2
Me-NHNH2
R
R
2
N
1
Me
0 0
R
R
to rt
C
1
1
R
R
6a-
7
6f
.
Entry
R1
R2
Time (min)
Product
Yield (%)b
1
Me
Me
i-Pr
OEt
Ot-Bu
OEt
–
10
15
30
5
6a
6b
6c
6d
6e
6f
95:5 (98)
96:4 (96)
92:8 (96)
100:0 (90)
95:5 (97) (90e)
97:3 (98)
2
3
4c
5d
6d
–(CH2)3–
Me
Me
Et
5
Et
5
a
b
c
Reactions were performed using
Isolated yield.
b-dicarbonyls (1 mmol), DMFDMA (1.2 mmol) and methylhydrazines (1.2 mmol) at 0 8C to room temperature.
Reaction was carried out under reflux conditions.
2 mmol of DMFDMA was used.
d
e
After recrystallization from anhydrous diethyl ether.

998
H. Alinezhad et al. / Journal of Fluorine Chemistry 132 (2011) 995–1000
It is believed that, the electrophilic character of the carbonyl
6.99 (d, J = 15.6 Hz, 2H, Ph), 7.30 (d, J = 15.6 Hz, 2H, Ph), 8.00 (s, 1H,
CH). 13C NMR (100 MHz, CDCl3): 11.81, 14.43, 55.55, 59.89, 114.33,
120.99, 126.88, 131.83, 141.58, 143.59, 159.64, 163.87. Calcd. For
groups is enhanced by high hydrogen bond donating ability of the
CF3CH2OH [22a] which facilitate the in situ generation of the
enaminone 8. Subsequent Michael addition of the terminal amino
group of the substituted hydrazines to enaminone 8 forms the
acyclic species 9 which undergoes an intramolecular cyclodehy-
dration to afford the pyrazole derivative (Scheme 3) [16a,19].
C14H16N2O3: C, 64.60; H, 6.20; N, 10.76. Found: C, 64.65; H, 6.18; N,
10.70.
4.2.4. 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid tert-butyl
ester 4d (Table 1, entry 4)
3. Conclusion
Oil [21a]. 1H NMR (400 MHz, CDCl3): 1.58 (s, 9H, Me), 2.53 (s,
3H, Me), 7.39–7.51 (m, 5H, Ph), 7.97 (s, 1H, CH). 13C NMR (100 MHz,
CDCl3): 11.94, 28.40, 80.42, 114.36, 125.51, 128.52, 129.20, 138.93,
142.01, 143.02, 163.26. Calcd. For C15H18N2O2: C, 69.74; H, 7.02; N,
10.84. Found: C, 69.73; H, 7.05; N, 10.85.
In this study, we have developed
regioselective one pot approach for the preparation of 1,4,5-
trisubstituted pyrazoles starting from different -keto esters or b-
a simple, mild and
b
diketones and various hydrazines in TFE which are completed in
excellent yields without use of any catalyst or additive.
4.2.5. 1-(4-Chloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid
tert-butyl ester 4e (Table 1, entry 5)
4. Experimental
Oil. 1H NMR (400 MHz, CDCl3):
d 1.59 (s, 9H, Me), 2.54 (s, 3H, Me),
7.37 (d, J = 14.2 Hz, 2H, Ph), 7.55 (d, J = 14.4 Hz, 2H, Ph) 7.97, (s, 1H,
CH). 13C NMR (100 MHz, CDCl3): 11.94, 28.39, 80.59, 114.70, 126.70,
129.42, 134.40, 137.46, 142.29, 143.04, 163.08. Calcd. For
4.1. General
Materials were purchased from Fluka and Merck companies.
Products were characterized by comparison of their spectroscopic
data (1H NMR, 13C NMR) and elemental analysis (CHN).
C15H17ClN2O2: C, 61.54; H, 5.85; N, 9.57. Found: C, 61.50; H, 5.79;
N, 9.55.
4.2.6. 1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazole-4-carboxylic
acid tert-butyl ester 4f (Table 1, entry 6)
4.2. General procedure for preparation of the arylpyrazole derivatives
Oil. 1H NMR (400 MHz, CDCl3):
d 1.57 (s, 9H, Me), d 2.48 (s, 3H,
Arylhydrazine (1.2 mmol) in TFE (0.5 ml) was slowly added to a
solution of b-dicarbonyl (1.2 mmol) and N,N-dimethylformamide
Me), 3.84 (s, 3H, Me), 6.97 (d, J = 12.4 Hz, 2H, Ph), 7.29 (d, J = 12 Hz,
2H, Ph), 7.93 (s, 1H, CH). 13C NMR (400 MHz, CDCl3): 11.82, 28.40,
55.54, 80.34, 114.31, 120.98, 126.91, 131.91, 141.71, 143.11,
159.58, 163.31. Calcd. For C16H20N2O3: C, 66.65; H, 6.99; N, 9.72.
Found: C, 66.67; H, 6.94; N, 9.73.
dimethyl acetal (1.2 mmol) in TFE (0.5 ml) at room temperature.
The progress of reactions was monitored by TLC. After completion
of the reaction solvent was evaporated under reduced pressure,
and water (10 ml) was added to the residue and extracted with
ethylacetate (2Â 10 ml). The organic layer was successively
washed with sodium hydrogen carbonate solution and water,
and then dried with magnesium sulfate. Evaporation of the solvent
afforded 4-carboxylate pyrazole. If necessary the products were
further purified by column chromatography on silica gel.
Reactions with 1,3-cyclohexanedione were carried out at reflux
temperature (Table 2, entries 10–12). In the case of open-chain b-
diketones, under optimal reaction conditions two equivalents of
DMFDMA were used (Table 2, entries 13–18).
4.2.7. 5-Isopropyl-1-phenyl-1H-pyrazole-4-carboxylic acid ethyl
ester 4g (Table 1, entry 7)
mp 48–50 8C. 1H NMR (400 MHz, CDCl3):
d 1.36 (d, J = 6.8 Hz, 6H,
Me), 1.38(t, J = 7.2, 3H,Me), 3.24–3.31(m, 1H, CH), 2.25(q, J = 7.2, 2H
CH2) 7.35–7.52 (m, 5H, Ph), 8.04 (s, 1H, CH). 13C NMR (100 MHz,
CDCl3): 14.41, 20.07, 26.38, 60.00, 111.56, 126.63, 129.15, 129.20,
139.46, 142.99, 152.81, 163.36. Calcd. For C15H18N2O2: C, 69.74; H,
7.02; N, 10.84. Found: C, 69.72; H, 7.04; N, 10.81.
Spectral data of all products are as follows.
4.2.8. 1-(4-Chloro-phenyl)-5-isopropyl-1H-pyrazole-4-carboxylic
acid ethyl ester 4h (Table 1, entry 8)
4.2.1. 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester
4a (Table 1, entry 1)
mp 62–65 8C. 1H NMR (400 MHz, CDCl3):
d 1.37 (d, J = 6.8 Hz,
6H, Me), 1.39 (t, J = 6.8, 3H, Me), 3.21–3.28 (m, 1H, CH), 4.33 (q,
J = 6.8, 2H, CH2) 7.37 (d, J = 8.8 Hz, 2H, Ph), 7.49 (d, J = 8.8 Hz, 2H,
Ph), 8.03 (s, 1H, CH). 13C NMR (100 MHz, CDCl3): 14.40, 20.08,
26.41, 60.12, 111.87, 127.9, 129.45, 135.16, 137.90, 143.24, 152.93,
163.21. Calcd. For C15H17ClN2O2: C, 61.54; H, 5.85; N, 12.11. Found:
C, 61.53; H, 5.84; N, 12.11.
mp 49–52 8C [18]. 1H NMR (400 MHz, CDCl3):
d 1.40 (t,
J = 7.2 Hz, 3H, Me), 2.59 (s, 3H, Me), 4.35 (q, J = 7.2 Hz, 2H, CH2)
7.28–7.55 (m, 5H, Ph), 8.05 (s, 1H, CH). 13C NMR (100 MHz, CDCl3):
11.96, 14.45, 59.98, 112.97, 125.52, 128.64, 129.26, 138.86, 141.92,
143.54, 163.87. Calcd. For C13H14N2O2: C, 67.81; H, 6.13; N, 12.17.
Found: C, 67.83; H, 6.12; N, 12.17.
4.2.9. 5-isopropyl-1-(4-Methoxy-phenyl)-1H-pyrazole-4-carboxylic
acid ethyl ester 4i (Table 1, entry 9)
4.2.2. 1-(4-Chloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid
ethyl ester 4b (Table 1, entry 2)
mp 63–66 8C. 1H NMR (400 MHz, CDCl3):
d 1.34 (d, J = 6.8 Hz,
mp 60–61 8C. 1H NMR (400 MHz, CDCl3):
d
1.38 (t, J = 7.2 Hz, 3H,
6H, Me), 1.38 (t, J = 7.2, 3H, Me), 3.23–3.30 (m, 1H, CH), 3.22 (q,
J = 7.2, 2H CH2), 3.87 (s, 3H, Me), 6.99 (d, J = 8.8 Hz, 2H, Ph), 7.27 (d,
J = 8.8 Hz, 2H, Ph), 8.01 (s, 1H, CH). 13C NMR (100 MHz, CDCl3):
14.41, 20.08, 26.35, 55.57, 59.95, 111.26, 114.35, 127.87, 132.40,
124.72, 152.97, 156.00, 163.42. Calcd. For C16H20N2O3: C, 66.65; H,
6.99; N, 9.72. Found: C, 66.63; H, 6.96; N, 9.72.
Me), 2.57 (s, 3H, Me), 4.33 (q, J = 7.2 Hz, 2H, CH2) 7.37 (d,
J = 11.6 Hz, 2H, Ph), 7.46 (d, J = 11.6 Hz, 2H, Ph), 8.032 (s, 1H, CH).
13C NMR (100 MHz, CDCl3): 11.93, 14.42, 60.05, 113.29, 126.67,
129.46, 134.51, 137.35, 142.14, 143.55, 163.66. Calcd. For
C
13H13ClN2O2: C, 58.99; H, 4.95; N, 10.58. Found: C, 58.94; H,
4.97; N, 10.60.
4.2.10. 1-Phenyl-1,5,6,7-tetrahydro-4H-indazol-4-one 4j (Table 1,
entry 10)
4.2.3. 1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazole-4-carboxylic
acid ethyl ester 4c (Table 1, entry 3)
mp 77–80 8C [19]. 1H NMR (400 MHz, CDCl3):
d 2.16–2.22 (m,
mp 63–65 8C. 1H NMR (400 MHz, CDCl3):
Me),
d
1.36 (t, J = 7.2 Hz, 3H,
2H, CH2), 2.57 (t, J = 6.4, 2H, CH2), 3.00 (t, J = 6.4, 2H, CH2), 7.43–
7.53 (m, 5H, Ph), 8.09 (s, 1H, CH). 13C NMR (100 MHz, CDCl3): 23.28,
d
2.51 (s, 3H, Me), 3.85 (s, 3H, Me), 4.31 (q, J = 7.2 Hz, 2H, CH2),

H. Alinezhad et al. / Journal of Fluorine Chemistry 132 (2011) 995–1000
999
23.64, 37.91, 120.53, 123.62, 128.25, 120.41, 138.51, 138.7, 149.13,
193.30. Calcd. For C13H12N2O: C, 73.57; H, 5.70; N, 13.20. Found: C,
73.55; H, 5.73; N, 13.22.
18.91, 33.98, 119.82, 127.11, 129.54, 134.98, 137.22, 141.67,
148.97, 169.20. Calcd. For C14H15ClN2O: C, 64.00; H, 5.75; N, 10.66.
Found: C, 64.08; H, 5.73; N, 10.60.
4.2.11. 1-(4-Chloro-phenyl)-1,5,6,7-tetrahydro-4H-indazol-4-one 4k
(Table 1, entry 11)
4.2.18. 1-(5-Ethyl-1-(4-methoxy-phenyl)-1H-pyrazol-4-yl)-propan-
1-one 4r (Table 1, entry 18)
mp 94–97 8C. 1H NMR (400 MHz, CDCl3):
d
2.19–2.22 (m, 2H,
CH2), 2.57 (t, J = 6, 2H, CH2), 2.99 (t, J = 6, 2H, CH2), 7.48 (d,
J = 9.2 Hz, 2H, Ph), 7.52 (d, J = 9.2 Hz, 2H, Ph), 8.09 (s, 1H, CH). 13
mp 84–89 8C. 1H NMR (400 MHz, CDCl3): 1.14 (t, J = 7.6 Hz, 3H,
Me), 1.22 (t, J = 7.2 Hz, 3H, Me), 2.67 (q, J = 7.2 Hz, 2H, CH2), 2.91 (q,
J = 7.6 Hz, 2H, CH2), 3.88 (s, 3H, Me), 7.01 (d, J = 8.8 Hz, 2H, Ph), 7.31
(d, J = 8.8 Hz, 2H, Ph), 8.00 (s, 1H, CH). 13C NMR (100 MHz, CDCl3):
8.22, 13.24, 18.93, 33.87, 55.59, 114.39, 119.36, 127.26, 131.63,
141.21, 149.05, 159.92, 196.30. Calcd. For C15H18N2O2: C, 69.74; H,
7.02; N, 10.84. Found: C, 69.70; H, 7.09; N, 10.80.
C
NMR (100 MHz, CDCl3): 23.28, 23.59, 37.84, 120.76, 124.75,
129.61, 134.08, 137.23, 138.77, 149.09, 193.11. Calcd. For
C13H11ClN2O: C, 63.29; H, 4.49; N, 11.36. Found: C, 63.29; H,
4.46; N, 11.37.
4.2.12. 1-(4-Methoxy-phenyl)-1,5,6,7-tetrahydro-4H-indazol-4-one
4l (Table 1, entry 12)
4.3. General procedure for preparation of the methylpyrazoles
mp 142–144 8C. 1H NMR (400 MHz, CDCl3):
d
2.14–2.19 (m, 2H,
Methylhydrazine (1.2 mmol) in TFE (1 ml) was slowly added to a
CH2), 2.55 (t, J = 6, 2H, CH2), 2.92 (t, J = 6, 2H, CH2), 3.88 (s, 3H, Me),
7.02 (d, J = 9.2 Hz, 2H, Ph), 7.24 (d, J = 9.2 Hz, 2H, Ph), 8.05 (s, 1H,
CH). 13C NMR (100 MHz, CDCl3): 2.99, 23.58, 37.91, 55.62, 114.5,
120.14, 125.17, 131.73, 138.16, 149.10, 159.41, 193.39. Calcd. For
solution of b-dicarbonyl (1 mmol) and N,N-dimethylformamide
dimethylacetal(1.2 mmol)inTFE(1 ml)at0 8Candthenthemixture
was stirred at room temperature. The reaction was monitored by
TLC. Aftercompletion of the reaction, water(10 ml)was added tothe
mixture and extracted with ethylacetate (2Â 10 ml). The ethylace-
tate was washed with sodium hydrogen carbonate solution and
water, thendriedandevaporatedthesolventtogivedesiredproduct.
The percent of regioisomers 3 and 4 was identified by 1H NMR
spectroscopy (Table 3, entries 1–3, 5–6).
C14H14N2O2: C, 69.41; H, 5.82; N, 11.56. Found: C, 69.40; H, 5.79; N,
11.58.
4.2.13. 1-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)ethan-1-one 4m
(Table 1, entry 13)
mp 103–107 8C [21b]. 1H NMR (400 MHz, CDCl3): 2.48 (s, 3H,
Me), 2.57 (s, 3H, Me), 7.39–7.49 (m, 5H, Ph), 8.00 (s, 1H, CH). 13C
NMR (100 MHz, CDCl3): 12.40, 28.71, 121.09, 125.54, 128.82,
129.30, 138.54, 141.94, 142.99, 193.57. Calcd. For C12H12N2O: C,
71.98; H, 6.04; N, 13.99. Found: C, 71.94; H, 6.03; N, 13.94.
Reaction with 1,3-cyclohexanedione was carried out at reflux
temperature (Table 3, entry 4). In the case of open-chain
b-
diketones, under optimal reaction conditions required two
equivalents of DMFDMA under optimal reaction conditions
required two equivalents of DMFDMA.
Spectral data of all products are as follows.
4.2.14. 1-(1-(4-Chlorophenyl)-5-methyl-1H-pyrazol-4-yl)ethan-1-
one 4n (Table 1, entry 14)
4.3.1. 1,5-Dimethyl-1H-pyrazole-4-carboxylic acid ethyl ester 6a
(Table 2, entry 1)
mp 110–113 8C. 1H NMR (400 MHz, CDCl3): 2.51 (s, 3H, Me),
2.60 (s, 3H, Me), 7.39 (d, J = 12 Hz, 2H, Ph), 7.46 (d, J = 12 Hz, 2H,
Ph), 8.02 (s, 1H, CH). 13C NMR (100 MHz, CDCl3): 12.37, 28.73,
121.29, 126.73, 129.51, 134.74, 137.04, 142.13, 143.01, 193.45.
Calcd. For C12H11ClN2O: C, 61.41; H, 4.72; N, 11.94. Found: C,
61.47; H, 4.70; N, 11.90.
Oil [21a]. 1H NMR (400 MHz, CDCl3):
d 1.33 (t, J = 7.2 Hz, 3H,
Me), 2.51 (s, 3H, Me), 3.78 (s, 3H, Me), 4.26 (q, J = 7.2 Hz, 2H, CH2),
7.80 (s, 1H, CH). 13C NMR (100 MHz, CDCl3): 10.50, 14.37, 36.26,
59.72, 111.80, 140.54, 142.94, 163.83. Calcd. For C8H12N2O2: C,
57.13; H, 7.19; N, 16.66. Found: C, 57.10; H, 7.20; N, 16.64.
4.2.15. 1-(1-(4-Methoxyphenyl)-5-methyl-1H-pyrazol-4-yl)ethan-1-
one 4o (Table 1, entry 15)
4.3.2. 1,5-Dimethyl-1H-pyrazole-4-carboxylic acid tert-butyl ester 6b
(Table 2, entry 2)
mp 86–88 8C. 1H NMR (400 MHz, CDCl3): 2.50 (s, 3H, Me), 2.55
(s, 3H, Me), 3.88 (s, 3H, Me), 7.02 (d, J = 8.8 Hz, 2H, Ph), 7.3 (d,
J = 8.8 Hz, 2H, Ph), 8.00 (s, 1H, CH). 13C NMR (100 MHz, CDCl3):
12.30, 28.65, 55.60, 114.4, 120.83, 126.90, 131.51, 141.69, 143.06,
159.77, 193.54. Calcd. For C13H14N2O2: C, 67.81; H, 6.13; N, 12.17.
Found: C, 67.82; H, 6.15; N, 12.20.
Oil [21a]. 1H NMR (400 MHz, CDCl3):
d 1.53 (s, 9H, Me), 2.48 (s,
3H, Me), 3.78 (s, 3H, Me), 7.73 (s, 1H, CH). 13C NMR (100 MHz,
CDCl3): 10.51, 28.36, 38.81, 80.14, 113.23, 134.48, 140.65, 163.29.
Calcd. For C10H16N2O2: C, 61.20; H, 8.22; N, 14.27. Found: C, 61.25;
H, 8.24; N, 14.25.
4.3.3. 5-Isopropyl-1-methyl-1H-pyrazole-4-carboxylic acid ethyl
ester 6c (Table 2, entry 3)
4.2.16. 1-(5-Ethyl-1-phenyl-1H-pyrazol-4-yl)-propan-1-one 4p
(Table 1, entry 16)
Oil. 1H NMR (400 MHz, CDCl3):
d 1.33 (t, J = 7.2, 3H, Me), 1.37 (d,
Oil [21b]. 1H NMR (400 MHz, CDCl3):
d
1.14 (t, J = 7.6 Hz, 3H,
J = 7.2 Hz, 6H, Me), 3.68–3.72 (m, 1H, CH), 3.88 (s, 3H, Me), 4.25 (q,
J = 7.2, 2H, CH2) 7.80 (s, 1H, CH). 13C NMR (100 MHz, CDCl3): 14.35,
19.71, 25.06, 38.98, 59.68, 110.85, 141.3, 151.44, 163.54. Calcd. For
Me), 1.95 (t, J = 7.2 Hz, 3H, Me), 2.65 (q, J = 7.2 Hz, 2H, CH2), 2.94 (q,
J = 7.6 Hz, 2H, CH2), 7.28–7.51 (m, 5H, Ph), 8.00 (s, 1H, CH). 13C
NMR (100 MHz, CDCl3): 8.18, 13.23, 18.91, 33.91, 119.59, 125.89,
129.02, 129.29, 138.69, 141.44, 148.88, 196.26. Calcd. For
C10H16N2O2: C, 61.20; H, 8.22; N, 14.27. Found: C, 61.25; H, 8.23; N,
14.25.
C14H16N2O: C, 73.66; H, 7.06; N, 12.27. Found: C, 73.62; H, 7.06;
N, 12.28.
4.3.4. 1-Methyl-1,5,6,7-tetrahydro-4H-indazol-4-one 6d (Table 2,
entry 4)
4.2.17. 1-(1-(4-Chloro-phenyl)-5-ethyl-1H-pyrazol-4-yl)-propan-1-
one 4q (Table 1, entry 17)
mp 94–99 8C [21b]. 1H NMR (400 MHz, CDCl3):
d 2.17–2.24 (m,
2H, CH2), 2.48 (t, J = 6.4, 2H, CH2), 2.83 (t, J = 6.4, 2H, CH2), 3.84 (s,
3H, Me), 7.89 (s, 1H, CH). 13C NMR (100 MHz, CDCl3): 21.45, 29.70,
32.99, 38.44, 127.31, 134.66, 167.29, 196.72. Calcd. For
C8H10N2O: C, 63.98; H, 6.71; N, 18.65. Found: C, 63.96; H, 6.70;
N, 18.66.
mp 55–57 8C. 1H NMR (400 MHz, CDCl3):
d 1.17 (t, J = 7.6 Hz, 3H,
Me), 1.22 (t, J = 7.2 Hz, 3H, Me), 2.87 (q, J = 7.2 Hz, 2H, CH2), 2.96 (q,
J = 7.6 Hz, 2H, CH2), 7.36 (d, J = 8.8 Hz, 2H, Ph), 7.49 (d, J = 8.8 Hz,
2H, Ph), 8.02 (s, 1H, CH). 13C NMR (100 MHz, CDCl3): 8.15, 13.26,

1000
H. Alinezhad et al. / Journal of Fluorine Chemistry 132 (2011) 995–1000
[5] W.T. Ashton, R.M. Sisco, H. Dong, K.A. Lyons, H. He, G.A. Doss, B. Leiting, R.A. Patel,
J.K. Wu, F. Marsilio, N.A. Thornberry, A.E. Weber, Bioorg. Med. Chem. Lett. 15
(2005) 2253–2258.
[6] H. Murakami, S. Masuzawa, S. Takii, T. Ito, Jpn. Patent 2003201280 A 20030718.
[7] D. Marcic, Exp. Appl. Acarol. 36 (2005) 177–185.
[8] K.Y. Lee, J.M. Kim, J.N. Kim, Tetrahedron Lett. 44 (2003) 6737–6740.
[9] N. Haddad, J. Baron, Tetrahedron Lett. 43 (2002) 2171–2173.
[10] J. Bohrisch, M. Patzel, C. Mugge, J. Liebscher, Synthesis (1991) 1153–1156.
[11] Y.R. Huang, J.A. Katzenellenbogen, Org. Lett. 2 (2000) 2833–2836.
[12] Z.X. Wang, H.L. Qin, Green Chem. 6 (2004) 90–92.
4.3.5. 1-(1,5-Dimethyl-1H-pyrazol-4-yl)-ethan-1-one 6e (Table 2,
entry 5)
mp 54–56 8C [21b]. 1H NMR (400 MHz, CDCl3): 2.43 (s, 3H, Me),
2.57 (s, 3H, Me), 3.81 (s, 3H, Me), 7.81 (s, 1H, CH). 13C NMR
(100 MHz, CDCl3): 10.91, 28.45, 36.10, 120.32, 140.76, 142.46,
193.39. Calcd. For C7H10N2O: C, 60.85; H, 7.30; N, 20.27. Found: C,
60.83; H, 7.33; N, 20.25.
[13] K.N. Zelenin, Org. Prep. Proc. Int. 27 (1995) 521–540.
[14] K. Tkagi, M. Hubert-Habart, J. Heterocycl. Chem. 33 (1996) 1003–1008.
[15] S. Chimichi, M. Boccalini, M.M.M. Hassan, G. Viola, F. Dall’Acquab, M. Curinic,
Tetrahedron 62 (2006) 90–96.
[16] (a) R. Oliver, R. SanMartin, E. Dominguez, J. Org. Chem. 65 (2000) 7010–7019;
(b) S.L.J. Kennedy, Synlett (2008) 600–604;
4.3.6. 1-(5-Ethyl-1-methyl-1H-pyrazol-4-yl)-propan-1-one 6f (Table
2, entry 6)
Oil [21b]. 1H NMR (400 MHz, CDCl3):
d 1.13–1.18 (m, 6H, Me),
2.75 (q, J = 7.2 Hz, 2H, CH2), 2.99 (q, J = 7.6 Hz, 2H, CH2), 3.8 (s, 3H,
Me), 7.79 (s, 1H, CH). 13C NMR (100 MHz, CDCl3): 8.16, 12.56,
18.32, 33.62, 35.88, 118.94, 140.21, 147.89, 196.19. Calcd. For
C9H14N2O: C, 65.03; H, 8.49; N, 16.85. Found: C, 65.05; H, 8.49; N,
16.84.
(c) D. Kralj, M. Friedrich, U. Groselj, S. Kiraly-Potpara, A. Meden, J. Wagger, G.
Dahmann, B. Stanovnik, J. Svete, Tetrahedron 65 (2009) 7151–7162;
(d) G. Pellegrino, F. Leonetti, A. Carotti, O. Nicolotti, L. Pisani, A. Stefanachi, M.
Catto, Tetrahedron Lett. 51 (2010) 1702–1705;
(e) K. Longhi, D.N. Moreira, M.R.B. Marzari, V.M. Floss, H.G. Bonacorso, N. Zanatta,
M.A.P. Martins, Tetrahedron Lett. 51 (2010) 3193–3196;
(f) M. Barcelo, E. Ravina, C.F. Masaguer, E. Domınguez, F. Miguel Areias, J. Breab,
M.I. Loza, Bioorg. Med. Chem. Lett. 17 (2007) 4873–4877.
[17] (a) J. Barluenga, J.F. Lopez-Ortiz, M. Tomas, V. Gotor, J. Chem. Soc. Perkin Trans. 1
(1981) 1891–1893;
(b) S. Bhardwaj, V.S. Jolly, Orient. J. Chem. 12 (1996) 185–187;
(c) M.V. Kadu, V.S. Jamode, Asian J. Chem. 10 (1998) 480–483.
[18] L.D. Luca, G. Giacomelli, A. Porcheddu, M. Salaris, M. Taddei, C. R. Chim. 6 (2003)
607–611.
Acknowledgment
Financial support of this work from the Research Council of
Mazandaran University is gratefully acknowledged.
References
[19] V. Molteni, M.M. Hamilton, L. Mao, C.M. Crane, A.P. Termin, D.M. Wilson, Synthe-
sis (2002) 1669–1674.
[1] A.R. Katritzky, A.V. Vakulenko, R. Akue-Gedu, A.V. Gromova, R. Witek, J.W. Rogers,
Arkivoc (2007) i9–i21.
[20] G. Giacomelli, A. Porcheddu, M. Salaris, M. Taddei, Eur. J. Org. Chem. (2003)
537–541.
[2] M.J. Genin, C. Biles, B.J. Keiser, S.M. Poppe, S.M. Swaney, W.G. Tarpley, Y. Yagi, D.L.
Romero, J. Med. Chem. 43 (2000) 1034–1040.
[3] T.D. Penning, J.J. Talley, S.R. Bertenshaw, J.S. Carter, P.W. Collins, J. Med. Chem. 40
(1997) 1347–1365.
[4] A. Guzman-Perez, R.T. Webster, M.C. Allen, J.A. Brown, A.R. Buchholz, E.R. Cook,
W.W. Day, E.S. Hamanaka, S.P. Kennedy, D.R. Knight, P.J. Kowalcyk, R.B. Marala, C.J.
Mularski, W.A. Novomisle, R.B. Ruggeri, W.R. Tracy, R. Hill, J. Bioorg. Med. Chem.
Lett. 11 (2001) 803–807.
[21] (a) G. Menozzi, L. Mosti, P. Schenone, J. Heterocycl. Chem. 24 (1987) 1669;
(b) P. Schenone, L. Mosti, G. Menozzi, J. Heterocycl. Chem. 19 (1982) 1355.
[22] (a) S. Fustero, R. Roman, J.F. Sanz-Cervera, A. Simon-Fuentes, A.C. Cunat, S.
Villanova, M. Murguıa, J. Org. Chem. 73 (2008) 3523–3529;
(b) J.P. Begue, D. Bonnet-Delpon, B. Crousse, Synlett (2004) 18–29;
(c) I.A. Shuklov, N.V. Dubrovina, A. Bo¨rner, Synthesis (2007) 2925–2943.
[23] K. De, J. Legros, B. Crousse, D. Bonnet-Delpon, Tetrahedron 64 (2008) 10497–
10500.