Regioselective synthesis of trifluoromethyl group substituted pyrazole derivatives from 1-aryl-3,4,4,4-tetrafluoro-2-buten-1-ones

Article abstract of DOI:10.3987/COM-09-S(S)26

Trifluoromethyl group substituted pyrazole derivatives were prepared from hydrazines and 1-aryl-3,4,4,4-tetrafluoro-2-buten-1-ones obtained by the deoxyfluorination of β-diketones. The reaction proceeded regioselectively and 5-aryl-3-trifluoromethyl-1-phe

Full text of DOI:10.3987/COM-09-S(S)26

HETEROCYCLES, Vol. 80, No. 1, 2010
349
HETEROCYCLES, Vol. 80, No. 1, 2010, pp. 349 - 357. © The Japan Institute of Heterocyclic Chemistry
Received, 14th May, 2009, Accepted, 15th June, 2009, Published online, 15th June, 2009
DOI: 10.3987/COM-09-S(S)26
REGIOSELECTIVE SYNTHESIS OF TRIFLUOROMETHYL GROUP
SUBSTITUTED
PYRAZOLE
DERIVATIVES
FROM
1-ARYL-3,4,4,4-TETRAFLUORO-2-BUTEN-1-ONES
Keisuke Sano and Shoji Hara*
Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
E-mail: shara@eng.hokudai.ac.jp
Abstract – Trifluoromethyl group substituted pyrazole derivatives were prepared
from hydrazines and 1-aryl-3,4,4,4-tetrafluoro-2-buten-1-ones obtained by the
deoxyfluorination of -diketones. The reaction proceeded regioselectively and
5-aryl-3-trifluoromethyl-1-phenyl-1H-pyrazole
was
obtained
from
phenylhydrazine. On the other hand, when methylhydrazine was used,
3-aryl-5-trifluoromethyl-1-methyl-1H-pyrazole was selectively formed.
INTRODUCTION
Pyrazoles with a trifluoromethyl substituent are of considerable interest because they are present in
pharmacologically and agrochemically important compounds.1 A pyrazole ring was generally prepared
from -diketones with hydrazines.2 However, when unsymmetrical -diketones such as
1-aryl-4,4,4-trifluoro-1,3-butanones were used, a mixture of regioisomers were formed and it was
difficult to obtain the desired regioisomer selectively.3 Recently, we reported the regioselective synthesis
of
1-aryl-3,4,4,4-tetrafluoro-2-buten-1-ones
(1)
by
the
deoxyfluorination
reaction
of
1-aryl-4,4,4-trifluoro-1,3-butanones with N,N-diethyl--difluoro-(m-methylbenzylamine) (DFMBA).4
Dedicated to Professor Akira Suzuki on the occasion of his 80th birthday.

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HETEROCYCLES, Vol. 80, No. 1, 2010
In this paper, we report the regioselective synthesis of a trifluoromethyl group substituted pyrazole
derivative (2 or 3) by the reaction of 1-aryl-3,4,4,4-tetrafluoro-2-buten-1-ones (1) with mono-substituted
hydrazines (Scheme 1).5
Me
Ph
N N
N
N
O
F
R-NHNH2
or
CF3
Ar
Ar
CF3
Ar
CF3
1
R = Ph or Me
2
3
Scheme 1
RESULTS AND DISCUSSION
The reaction of 3,4,4,4-tetrafluoro-1-phenyl-2-buten-1-one (1a) with phenylhydrazine was performed in
ether under reflux for 24 h and 3-trifluoromethyl-1,5-diphenyl-1H-pyrazole (2a) was obtained in 88%
yield (Entry 1 in Table 1). Interestingly, its regioisomer, 5-trifluoromethyl-1,3-diphenyl-1H-pyrazole, was
not
formed
at
all.
On
the
other
hand,
when
methylhydrazine
was
used,
5-trifluoromethyl-1-methyl-3-phenyl-1H-pyrazole (3a) was obtained in 95% yield and its regioisomer,
3-trifluoromethyl-1-methyl-5-phenyl-1H-pyrazole, was not formed (Entry 2). The selectivity is not
dependent on the type of aryl group in 1, and 5-aryl-3-trifluoromethyl-1-phenyl-1H-pyrazole (2a-d) was
formed selectively from phenylhydrazine (Entries 1, 3, 4, and 6). On the other hand, from
methylhydrazine, 3-aryl-5-trifluoromethyl-1-methyl-1H-pyrazole (3a,c) was selectively obtained (Entries
2 and 5). Recently, the regioselective synthesis of 1-aryl-3-trifluoromethyl-1H-pyrazoles 2 by the reaction
of 1-aryl-4,4,4-trifluoro-1,3-butanones with phenylhydrazines was reported.6 However, the selective
synthesis of 3-aryl-5-trifluoromethyl-1-methyl-1H-pyrazole 3 from 1-aryl-4,4,4-trifluoro-1,3-butanones
and methylhydrazine has not yet been performed. Therefore, our method is useful for the selective
synthesis of various pyrazole derivatives with trifluoromethyl substituent.

HETEROCYCLES, Vol. 80, No. 1, 2010
351
Table 1. Synthesis of trifluoromethylpyrazolesa
Yield(%)c
88
Substrateb
Time (h)
24
Entry
Hydrazine, R
Product
Ph
O
F
N N
1
Ph
Ph
CF3
Ph
CF3
Ph
1a
1a
2a
Me
N
N
2
3
Me
12
24
95
94
CF3
3a
Ph
O
F
N N
Ph
CF3
CF3
1b
2b
O
F
Ph
O
O
O
N N
4
5
Ph
24
12
89
86
CF3
CF3
1c
2c
Me
N N
1c
Me
CF3
CF3
3c
Ph
O
F
S
S
N
6
Ph
24
N
90
CF3
1d
2d
a. The reaction was carried out in ether under reflux. b. A mixture of stereoisomers was used.
c. Isolation yield based on 1.
This high selectivity can be explained by the difference between the reactivity of phenylhydrazine and
that of methylhydrazine. In phenylhydrazine, -NH2 is more nucleophilic than –NHPh due to the
electron-withdrawing effect of the Ph group6c and –NH2 attacks the C3 carbon of 1 to yield the
intermediate 4.7 The subsequent addition of –NHPh to the carbonyl group yields a cyclic imminium salt 5
that changes to the pyrazole 2. On the other hand, in the reaction with methylhydrazine, –NHMe is more
reactive than –NH2 due to the electron-donating effect of the methyl group and –NHMe attacks the C3
carbon of 1 to yield an intermediate 6.6c The subsequent cyclization proceeds by the attack of –NH2 on
the carbonyl group to give the pyrazole 3, selectively. As the formation of 4 or 6 by the 1,4-addition
reaction of the hydrazines to 1 is irreversible, the regioselectivity of the reaction is determined at the

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HETEROCYCLES, Vol. 80, No. 1, 2010
initial step, attack of nitrogen to C3, and largely influenced by the nucleophilicity of the nitrogen on the
hydrazines. On the other hand, in the reaction with -diketones, the initial addition of the nitrogen to the
carbonyl group is reversible and the regioselectivity is determined at the dehydration step.2,3,6c Therefore,
the regioselectivity in the reaction with -diketones is not so influenced by the nucleophilicity of the
nitrogen on the hydrazines as in the reaction with 1 and a similar selectivity was not observed (Scheme 2).
Ph
H
Ph
Ph
HN
Ar NH
N N
-H2O
N
N
-H
CF3
Ar
CF3
Ar
O
CF3
R = Ph
2
5
4
R = Ph
R = Me
O
F
R-NHNH2
Ar
CF3
1
R = Me
Me
H2N
Ar
Me
-H2O
N
N
N
CF3
Ar
O
CF3
3
6
Scheme 2
For the synthesis of 3-trifluoromethyl-5-methyl-1-phenyl-1H-pyrazole (2e),
a
volatile
4,5,5,5-tetrafluoro-3-penten-2-one (1e) is required. Therefore, we synthesized 2e from -diketone without
isolating 1e. The reaction of 1,1,1-trifluoropentane-2,4-dione with DFMBA was carried out at room
19
temperature for 24 h. From the F NMR analysis of the crude mixture, deoxyfluorination was found to
occur at the C2 position selectively and 4,5,5,5-tetrafluoro-3-penten-2-one (1e) was formed in 70% yield.
Crude 1e was used for the reaction with phenylhydrazine, and 2e was selectively formed in 54% yield
from the diketone (Scheme 3).
Ph
O
F
O
O
Ph-NHNH2
DFMBA
N N
Me
CF3
Et2O
Me
CF3
CH2Cl2
rt 24 h
Me
CF3
reflux 24 h
2e
1e
54% from diketone
Scheme 3

HETEROCYCLES, Vol. 80, No. 1, 2010
353
Celecoxib, 4-[5-(4-methylphenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulphonamide, is widely
used as an anti-inflammatory drug for the treatment of osteoarthritis, rheumatoid arthritis, and acute pain.8
Using our method, we prepared Celecoxib from 4,4,4-trifluorobutane-1-(p-tolyl)-1,3-dione.9 The
deoxyfluorination of the diketone with DFMBA was performed in CH2Cl2 at 20 °C for 24 h to produce
3,4,4,4-tetrafluoro-1-(p-tolyl)-2-buten-1-one (1f) in 91% yield as a mixture of stereoisomers. The reaction
of 1f with p-aminosulfonylphenylhydrazine hydrochloride was performed in a mixture of DMF and H2O
(4:1) at 40 °C for 12 h to give Celecoxib in 80% yield and the formation of its regioisomer was not
observed (Scheme 4).
O
F
O
O
DFMBA
CF3
CF3
CH2Cl2 20 °C, 24 h
Me
1f
Me
91% (E:Z = 17:83)
SO2NH2
HCl
SO2NH2
NH2NH
N
N
DMF/H2O (4:1)
40 °C, 12 h
CF3
80%
Me
Celecoxib
Scheme 4
EXPERIMENTAL
4.1. General
The melting points were measured with a Yanagimoto micro melting-point apparatus. The IR spectra
were recorded using a JASCO FT/IR-410. The 1H NMR (400 MHz) spectra, 19F NMR (376 MHz) spectra,
13
and C NMR (100 MHz) were recorded in CDCl3 on a JEOL JNM-A400II FT NMR and the chemical
13
shift, δ, is referred to TMS (1H, C) and CFCl3 (19F), respectively. The EI-high-resolution mass spectra
were
measured
on
a
JEOL
JMS-700TZ.
Methylhydrazine,
phenylhydrazine,
4-hydrazinobenzenesulfonamide hydrochloride, and diketones were purchased from Tokyo Kasei Kogyo
Co., Ltd. 4,4,4-Trifluoro-1-(p-tolyl)-butane-1,3-dione was prepared according to a literature.9
1-Aryl-3,4,4,4-tetrafluoro-2-buten-1-ones 1a, 1b, 1c, and 1d were prepared from the corresponding
diketones by the reported method.4 DFMBA was donated from Mitubishi Gas Chemical Company Inc.
Preparation of 1-Aryl-3,4,4,4-tetrafluoro-2-buten-1-one4 (1)
A mixture of 1-aryl-4,4,4-trifluorobutane-1,3-dione (1 mmol), DFMBA (426 mg, 2 mmol), and CH2Cl2 (1

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HETEROCYCLES, Vol. 80, No. 1, 2010
mL) in a reaction vessel made of Teflon FEP with a tight screw cap was stirred at 20 °C for 24 h. The
mixture was poured into water, neutralized with sat. aq. NaHCO3, and extracted with Et2O (20 mL x 3).
The combined organic layer was dried over MgSO4 and concentrated under reduced pressure. Purification
by column chromatography (silica gel/hexane-Et2O) gave 1.
Preparation of 5-Aryl-3-trifluoromethyl-1-phenyl-1H-pyrazole (2)
To 1 (0.48 mmol) in Et2O (8 mL) was added at rt phenylhydrazine (64 mg, 0.59 mmol) and the mixture
was stirred under reflux for 24 h. Solid material was removed by filtration and the filtrate was
concentrated under reduced pressure. Purification by column chromatography (silica gel/hexane-Et2O)
gave 2.
Preparation of 3-aryl-5-trifluoromethyl-1-methyl-1H-pyrazole (3)
To 1 (0.48 mmol) in Et2O (8 mL) was added at rt methylhydrazine (50 mg, 1.08 mmol) and the mixture
was stirred under reflux for 12 h. Solid material was removed by filtration and the filtrate was
concentrated under reduced pressure. Purification by column chromatography (silica gel/hexane-Et2O)
gave 3.
3-Trifluoromethyl-1,5-diphenyl-1H-pyrazole (2a)
1
a pale yellow solid; mp 87–88 °C (lit.,10 87–88 °C): IR (KBr): 1496, 1236, 1122 cm-1. H NMR 
13
7.37–7.21 (m, 10H), 6.76 (s, 1H). C NMR  144.6, 143.1 (q, J = 38.1 Hz), 139.1, 129.1, 129.0 (2C),
19
129.0, 128.8 (2C), 128.7 (2C), 128.4, 125.4 (2C), 121.3 (q, J = 268.9 Hz), 105.5 (q, J = 1.9 Hz). F
NMR –62.82 (s, 3F) {lit.,11 –62.6 (s)}.
5-Trifluoromethyl-1-methyl-3-phenyl-1H-pyrazole (3a)
clear oil: IR (neat): 1441, 1275, 1204, 1126 cm-1. 1H NMR  7.78–7.76 (m, 2H), 7.43–7.32 (m, 3H), 6.89
13
(s, 1H), 4.04 (s, 3H). C NMR  150.3, 133.1 (q, J = 39.1 Hz), 132.0, 128.8 (2C), 128.3, 125.5 (2C),
19
120.0 (q, J = 268.3 Hz), 104.5 (q, J = 2.7 Hz), 38.1 (q, J = 1.9 Hz). F NMR  –61.10 (s, 3F) {lit.,6c
–60.9 (s)}.
3-Trifluoromethyl-5-(2-naphtyl)-1-phenyl-1H-pyrazole (2b)
highly viscous liquid: IR (neat): 1599, 1486, 1124 cm-1. 1H NMR  7.84–7.74 (m, 4H), 7.55–7.49 (m, 2H),
13
7.43–7.35 (m, 5H), 7.22–7.20 (m, 1H), 6.87 (s, 1H). C NMR  144.6, 143.2 (q, J = 38.6 Hz), 139.2,
132.9, 132.9, 129.1 (2C), 128.4, 128.3 (2C), 128.1, 127.7, 127.0, 126.7, 126.4, 125.7, 125.3 (2C), 121.3
(q, J = 268.9 Hz), 105.8 (q, J = 1.9 Hz). 19F NMR –62.79 (s, 3F) {lit.,10 –62.3 (s)}.
3-Trifluoromethyl-5-(fur-2-yl)-1-phenyl-1H-pyrazole (2c)
clear liquid; IR (neat): 1496, 1247, 1134 cm-1. 1H NMR  7.51–7.42 (m, 6H), 6.91 (s, 1H), 6.35–6.34 (m,
13
1H), 5.96 (d, J = 2.5 Hz, 1H). C NMR  143.2, 143.2 (q, J = 38.2 Hz), 143.0, 139.3, 136.1, 129.5,
129.3 (2C), 126.0 (2C), 121.1 (q, J = 268.9 Hz), 111.4, 109.8, 103.7 (q, J = 2.4 Hz). 19F NMR  –62.95

HETEROCYCLES, Vol. 80, No. 1, 2010
355
(s, 3F) {lit.,10 –62.5 (s)}.
5-Trifluoromethyl-3-(fur-2-yl)-1-methyl-1H-pyrazole (3c)
1
clear liquid; IR (neat): 1274, 1126 cm-1. H NMR  7.46 (s, 1H), 6.82 (s, 1H), 6.68 (d, J = 3.6 Hz, 1H),
13
6.47 (dd, J = 3.2, 1.8 Hz, 1H), 4.02 (s, 3H). C NMR  147.3, 142.8, 142.2, 132.8 (q, J = 39.1 Hz),
19
119.7 (q, J = 269.0 Hz), 111.3, 106.4, 104.2 (q, J = 1.9 Hz), 38.0 (q, J = 1.9 Hz). F NMR  –61.26 (s,
3F) {lit.,6c –61.1 (s, 3F)}.
3-Trifluoromethyl-1-phenyl-5-(thien-2-yl)-1H-pyrazole (2d)
yellow solid; mp 65-66 °C (lit.,10 82–83 °C): IR (KBr): 1469, 1251, 1129 cm-1. 1H NMR  7.46–7.39 (m,
13
5H), 7.33–7.32 (m, 1H), 6.96 (dd, J = 5.0, 3.7 Hz, 1H), 6.87–6.86 (m, 1H), 6.81 (s, 1H). C NMR 
143.0 (q, J = 38.1 Hz), 138.8, 138.7, 129.5, 129.2, 129.2 (2C), 128.0, 127.5, 127.4, 126.3 (2C), 121.1 (q,
J = 269.0 Hz), 105.2 (q, J = 1.9 Hz). 19F NMR  –62.94 (s, 3F)
3-Trifluoromethyl-5-methyl-1-phenyl-1H-pyrazole (2e)
A mixture of 1,1,1-trifluoropentane-2,4-dione (74 mg, 0.48 mmol), DFMBA (212 mg, 1 mmol) and
CH2Cl2 (2 mL) in a reaction vessel made of Teflon FEP with a tight screw cap was stirred at rt for 24 h.
Then, the mixture was poured into sat. aq. NaHCO3 (20 mL) and extracted with Et2O (10 mL). The
ethereal solution of 4,5,5,5-tetrafluoro-3-penten-2-one was transferred into a reaction vessel and
phenylhydrazine (45.5 mg, 0.42 mmol) was added. The mixture was stirred under reflux for 24 h. The
solid material was removed by filtration and filtrate was concentrated under reduced pressure.
Purification by column chromatography (silica gel/hexane-Et2O) gave 2e (59 mg) in 54% overall yield
1
from 1,1,1-trifluoropentane-2,4-dione. clear oil: IR (neat): 1489, 1384, 1240, 1140 cm-1. H NMR 
7.53–7.43 (m, 5H), 6.46 (s, 1H), 2.35 (s, 3H). 13C NMR  142.6 (q, J = 37.6 Hz), 140.7, 138.8, 129.2 (2C),
128.7, 125.2 (2C), 121.4 (q, J = 268.9 Hz), 104.8 (q, J = 1.9 Hz), 12.2. 19F NMR –62.85 (s, 3F) {lit.,10
–62.5 (s)}.
Synthesis of Celecoxib
3,4,4,4-Tetrafluoro-1-(p-tolyl)-2-buten-1-one (1f)
A mixture of 1,1,1-trifluoro-4-(p-tolyl)pentane-2,4-dione (232 mg, 1.01 mmol), DFMBA (425 mg, 1.99
mmol) and CH2Cl2 (2 mL) in a reaction vessel made of Teflon FEP with a tight screw cap was stirred at
30 °C for 24 h. Then, the mixture was poured into sat. aq. NaHCO3 (20 mL) and extracted with Et2O (20
mL x 3). The combined organic layer was dried over MgSO4 and the volatile part was removed under
reduced pressure. Purification by column chromatography (silica gel/hexane-Et2O) gave 1f (196 mg) in
84% yield as a mixture of stereoisomers (E:Z = 13:77, only Z isomer is isolable as a pure form). clear oil:
(Z)-isomer: IR (neat): 2929, 1707, 1608, 1208 cm-1. 1H NMR  7.82 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 7.9
Hz, 2H), 6.90 (d, J = 31.6 Hz, 1H, =CH), 2.45 (s, 3H). 13C NMR  185.9, 150.7 (dq, J = 282.0, 39.4 Hz),

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HETEROCYCLES, Vol. 80, No. 1, 2010
19
145.6, 133.7, 129.6 (2C), 128.8 (2C), 117.8 (dq, J = 40.3, 273.1 Hz), 107.9-107.8 (m), 21.6. F NMR 
–73.75 (d, J = 9.8, 3F), –118.28 (dq, J = 31.4, 9.8 Hz, 1F). HRMS(EI): calcd for C11H8OF4; 232.0511.
Found; 232.0514.
Celecoxib
To 1f (a mixture of the stereoisomers was used, 114 mg, 0.49 mmol) in a 4:1 mixture of DMF and H2O (5
mL) was added 4-hydrazinobenzenesulfonamide hydrochloride (133 mg, 0.60 mmol) and the mixture was
stirred at 40 °C for 12 h. After cooling to rt, H2O (40 mL) was added to the mixture. The mixture was
extracted with Et2O (40 mL x 3), and the organic layer was washed with H2O (40 mL x 3), and brine (40
mL). The organic layer was dried over MgSO4, concentrated under reduced pressure. Purification by
column chromatography (silica gel/hexane-Et2O) gave Celecoxib (150 mg) in 80% yield; a white crystal;
mp 154–156 °C (lit.,8a 157–159 °C): IR (KBr): 3267, 1164 cm-1. 1H NMR  7.91 (d, J = 8.4 Hz, 2H), 7.48
(d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 6.75 (s, 1H), 4.85 (s, 2H), 2.39 (s,
13
3H). C NMR  145.2, 144.1 (q, J = 38.7 Hz), 142.5, 141.2, 139.8, 129.7 (2C), 128.7 (2C), 127.5 (2C),
125.6, 125.5 (2C), 121.0 (q, J = 269.0 Hz), 106.3 (q, J = 1.9 Hz), 21.3. 19F NMR  –63.03 (s, 3F).
ACKNOWLEDGEMENTS
We are grateful to Mitsubishi Gas Chemical Company Inc. for their donation of DFMBA.
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