Synthesis of novel 1,4,5-trisubstituted 3-trifluoromethylpyrazoles via microwave-assisted Stille coupling reactions

Article abstract of DOI:10.1016/j.jfluchem.2007.04.029

1,5-Disubstituted 3-trifluoromethylpyrazoles were reacted with N-bromosuccinimide in DMF at room temperature or 70-80 °C for 1-2 h to afford the corresponding 4-bromo-substituted pyrazoles 2 in 95-99% yields. The microwave-assisted Stille coupling reactio

Full text of DOI:10.1016/j.jfluchem.2007.04.029

Journal of Fluorine Chemistry 128 (2007) 1191–1197
www.elsevier.com/locate/fluor
Synthesis of novel 1,4,5-trisubstituted 3-trifluoromethylpyrazoles
via microwave-assisted Stille coupling reactions
Sung Lan Jeon a, Ji Hoon Choi a, Bum Tae Kim b, In Howa Jeong a,
*
a Department of Chemistry, Yonsei University, Wonju 220-710, South Korea
b Korea Research Institute of Chemical Technology, Daejeon 305-606, South Korea
Received 7 March 2007; received in revised form 24 April 2007; accepted 30 April 2007
Available online 3 May 2007
Abstract
1,5-Disubstituted 3-trifluoromethylpyrazoles were reacted with N-bromosuccinimide in DMF at room temperature or 70–80 8C for 1–2 h to
afford the corresponding 4-bromo-substituted pyrazoles 2 in 95–99% yields. The microwave-assisted Stille coupling reactions of 2 with
arylstannanes having a substituent on the benzene ring and allylstannane in refluxing CH3CN in the presence of Pd(PPh3)4 provided the
corresponding 1,4,5-trisubstituted 3-trifluoromethylpyrazoles 3 in 75–98% yields.
# 2007 Elsevier B.V. All rights reserved.
Keywords: Bromination; 1,5-Disubstituted 3-trifluoromethylpyrazoles; Arylstannanes; Allystannane; Microwave-assisted Stille coupling reactions; 1,4,5-
Trisubstituted 3-trifluoromethylpyrazoles
1. Introduction
1-trifluoromethyl acetylenic imines [27] and 1-pentafluoro-
ethyl-2-iodoalkenes [28,29]. 1,3-Dipolar cycloaddition reac-
tion of 2-bromo-3,3,3-trifluoropropene with diazomethane
followed by dehydration also afforded the corresponding 3-
trifluoromethylpyrazole [30]. Recently, a direct preparation
of 5-tributylstannyl-4-trifluoromethylpyrazole was accom-
plished by 1,3-dipolar cycloaddition reaction of tribu-
tyl(3,3,3-trifluoro-1-propynyl)stannane with diazomethane
[31,32]. Dipolarophiles such as phenylacetylene, vinylsulfone
and 2-bromoacrylate were also reacted with trifluoroacetyl-
triphenylsilane 2,4,6-triisopropylbenzenesulfonyl hydrazone to
give the corresponding 3-trifluoromethylpyrazoles [33]. How-
ever, the most of these methods focused on the preparation of
mono- and disubstituted trifluoromethylpyrazole derivatives. In
spite of importance of trisubstituted trifluoromethylpyrazole in
recent years, the methods for the preparation of trisubstituted
trifluoromethylpyrazoles have been quite limited in the
previous literatures [16,34–36]. Moreover, these methods have
some drawbacks such as a lack of generality and uneasy
availability of starting materials. Herein, we wish to report a
novel and general approach to 1,4,5-trisubstituted 3-trifluor-
omethylpyrazoles via the microwave-assisted Stille coupling
reactions of the corresponding 1,5-disubstituted 4-bromo-3-
trifluoromethylpyrazoles with arylstannanes or allylstannane in
the presence of palladium catalyst.
The pyrazole ring has been known as an important
framework in a large number of compounds possessing
pharmaceutical and agrochemical properties [1–6]. Numerous
methods for the synthesis of this family of compounds have
been well documented in the previous literatures [7–15], but
methods are mostly related to the synthesis of nonfluorinated
pyrazoles. However, to our knowledge, there have been limited
methodologies for the preparation of trifluoromethylated
pyrazoles. Since the introduction of a trifluoromethyl group
into the pyrazole ring system has often increased the biological
properties [16,17], many efforts have been devoted to the
development of synthetic methodologies for the preparation
of trifluoromethylated pyrazoles. General methods for the
preparation of these compounds involve the reactions of
hydrazine derivatives with trifluoromethylated precursors such
as 1-trifluoromethylated 1,3-diketones [16,18,19], trifluoro-
methylacetylenic esters [20], pentafluoroethylacetylenes [21],
trifluoroacetyl acetylenes [22], b-alkoxyvinyl trifluoromethyl
ketones [23,24], b-trifluoromethyl enaminones [25,26], N-aryl-
* Corresponding author. Tel.: +82 33 760 2240; fax: +82 33 763 4323.
E-mail address: jeongih@yonsei.ac.kr (I.H. Jeong).
0022-1139/$ – see front matter # 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2007.04.029

1192
S.L. Jeon et al. / Journal of Fluorine Chemistry 128 (2007) 1191–1197
2. Results and discussion
The starting materials, 1,5-disubstituted 3-trifluoromethyl-
pyrazoles 1a–f, were prepared in 92–98% isolated yields from
the condensation reaction of 1-trifluoromethylated 1,3-dicar-
bonyl compounds with hydrazine derivatives in 1,4-dioxane,
except for methylhydrazine, followed by dehydration reaction
in refluxing toluene. Small quantities of undesired regioisomer,
1,3-disubstituted 5-trifluoromethylpyrazoles, were separated
by column chromatographic purification. A recent study has
established that this high regioselectivity was due to electron-
withdrawing group such as CF3 on C-1 of 1,3-dicarbonyl
compounds [37]. In order to install the aryl or allyl substitutent
onto the 4-position of fully assembled pyrazoles 1, we chose to
explore a carbon–carbon bond-forming reaction in the presence
of transition-metal catalysis. Therefore, we carried out the
bromination reaction with the corresponding bromo succini-
mide to introduce a bromo substituent as a reacting site of the
coupling reaction. We found 1,5-disubstituted 4-bromo-3-
trifluoromethylpyrazoles 2a–g were prepared in 95–99%
isolated yields from the reaction of 1 with N-bromosuccinimide
in DMF at room temperature or 70–80 8C. The results of these
reactions were summarized in Table 1. The use of other solvents
such as CH2Cl2, CCl4 or CH3CN in this bromination reaction
caused not only to retard the reaction, but also to decrease the
yield of 2. The previous method using sodium acetate and
bromine did not provide a satisfied result for the formation of 2
[38].
Scheme 1.
3-trifluoromethyl-1-methylpyrazoles [39]. The resonance of
N-methyl protons of regioisomer, 4-substituted 5-trifluoro-
methyl-1-methylpyrazoles, appeared at d = 4.07–4.11 ppm.
Regiospecificity on N-methylation of 2a, 2d and 2g to give
5-substituted
4-bromo-3-trifluoromethyl-1-methylpyrazole
2h–j can be explained by the steric effect of trifluoromethyl
group in the formation of regioisomer, 3-substituted 4-bromo-
5-trifluoromethyl-1-methylpyrazole. A similar result was
established in the formation of 1-methyl-3-trimethylsilylpyr-
azole and 1-methyl-3,4-bis(trimethylsilyl)pyrazole [40].
Although several previous literature reports described the
coupling reactions, such as Suzuki, Stille, and Sonogashira
couplings, performed on nonfluorinated 5-bromopyrazoles
[10,41] and pyrazole triflates [42], there has been only one
example (Sonogashira reaction) in the coupling reactions on
trifluoromethylated halopyrazoles [38]. Among the coupling
reactions, we investigated Stille coupling reaction of 2 with
arylstannane or allylstannane. We carried out the cross-
coupling reaction of 2c with phenylstannane as a standard
reaction to find out an optimized reaction condition. When 2c
was reacted with phenylstannane in the presence of Pd(PPh3)4
(5 mol%) at refluxing CH3CN for 24 h, the cross-coupled
product 3a was obtained in 76% isolated yield based on the only
15% conversion of the starting material. The use of DMF as a
solvent under the same reaction condition caused to enhance
the conversion of the starting material up to 40%, but reaction
was still sluggish. Recently, we reported that microwave-
assisted cross-coupling reaction of trifluoromethylated chlor-
opyrimidines with arylstannanes afforded the corresponding
coupled product in high yields [43]. We applied this reaction
condition to explore the coupling reaction of 2 with
arylstannane or allylstannane. It was found that microwave-
assisted coupling reaction of 2c with phenylstannane in CH3CN
at 180 8C for 1 h afforded the coupled product 3a in 97%
isolated yield based on the 100% conversion of 2c. The
arylstannane having a substituent on the benzene ring and
allylstannane also underwent the coupling reactions with 2c to
give 3b–e in 92–98% isolated yields under the same reaction
condition. The reactions between 2b and arylstannane also
afforded the corresponding coupled products 3f–i in 91–92%
isolated yields, but the reactions were more sluggish than that of
2c with phenylstannane and a prolong reaction time (1.5 h)
was required. A small amount of reduced product was
obtained in less than 5% yield for each case. The reaction of
2b with allylstannane under the same reaction condition
afforded the corresponding coupled product 3j in 97% isolated
yield. Similarly, 2g underwent the coupling reaction with
Since 5-substituted 3-trifluoromethyl-1-methylpyrazoles
were not directly synthesized from the reaction of
1-trifluoromethylated 1,3-dicarbonyl compounds with methyl-
hydrizine, 5-substituted 4-bromo-3-trifluoromethyl-1-methyl-
pyrazoles 2h–j were prepared regiospecifically from the
methylation reaction of 2a, 2d and 2g with methyl iodide in
the presence of K2CO3 (Scheme 1). The assignment of
regioisomers 2h–j was based on 1H NMR chemical shifts. The
1H NMR spectrum of 2h–j showed that the peaks of N-methyl
protons appeared at d = 3.84–3.95 ppm which is consistent with
the range of chemical shift of a similar structure, 4-substituted
Table 1
Preparation of 1,5-disubstituted 4-bromo-3-trifluoromethylpyrazoles 2
Compound no.
R1
R2
T (8C)
t (h)
Yield (%)a
2a
2b
2c
2d
2e
2f
Ph
H
70–80
70–80
70–80
25
2
2
2
1
1
1
1
96
98
99
99
95
98
99
Ph
PhCH2
Ph
Ph
Me
Me
cy-Pr
cy-Pr
H
PhCH2
Ph
25
25
2g
H
25
a
lsolated yield.

S.L. Jeon et al. / Journal of Fluorine Chemistry 128 (2007) 1191–1197
1193
Table 2
Mattson Genesis series FT High Resolution Spectrophot-
ometer. Mass spectra were obtained by using GC/MS-Qp1000-
Shimadzu (EI, 70 eV). Microwave-assisted coupling reactions
were carried by using Biotage Microwave Organic Synthesizer.
Melting points were determined in open capillary tubes and are
uncorrected.
The coupling reactions of 1,5-disubstituted 4-bromo-3-trifluoromethylpyra-
zoles 2 with arylstannanes or allystannane
Commercially available reagents were purchased from
Aldrich, Lancaster, Tokyo Kasei and Fluorochem. All solvents
were dried by general purification method. Flash chromato-
graphy was performed on 40–60 mm silica gel (230–400 mesh).
Compound no.
R1
R2
R
t (h)
Yield (%)a
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ph
Ph
C6H5
1
97
96
98
92
97
92
92
91
92
97
81
82
84
82
90
91
93
75
80
Ph
Ph
p-MeO–C6H4
p-F–C6H4
1
4.1. General procedure for the preparation of 4-
brominated pyrazoles 2a–2g
Ph
Ph
1
Ph
Ph
p-CF3–C6H4
CH2 CH–CH2
C6H5
1
Ph
Ph
1
A 50 mL two-neck round bottom flask equipped with a
magnetic stirrer bar, a septum and reflux condenser connected
to an argon source was charged with 3-trifluoromethylated
pyrazoles 1 (2.0 mmol), NBS (4.0 mmol) and 10 mL of DMF.
After the reaction mixture was stirred at room temperature for
1 h or heated at 70–80 8C for 2 h, the reaction mixture was
quenched with water. The reaction mixture was extracted with
methylene chloride twice, dried over anhydrous MgSO4 and
chromatographed on SiO2 column. Elution with a mixture of
hexane and ethyl acetate (9:1) provided 4-brominated pyrazoles
2a–2g.
Ph
Bn
Bn
Bn
Bn
Bn
Me
Me
Me
Me
Me
Ph
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2.5
2.5
2.5
2.5
Ph
p-MeO–C6H4
p-F–C6H4
Ph
Ph
p-CF3–C6H4
CH2 CH–CH2
C6H5
3j
Ph
3k
31
3m
3n
3o
3p
3q
3r
3s
Ph
Ph
p-MeO–C6H4
p-F–C6H4
Ph
Ph
p-CF3–C6H4
CH2 CH–CH2
C6H5
Ph
cy-Pr
cy-Pr
cy-Pr
cy-Pr
Ph
CH2 CH–CH2
C6H5
Me
Me
CH2 CH–CH2
a
4.1.1. 4-Bromo-3-trifluoromethyl-5-phenylpyrazole (2a)
2a was prepared in 96% yield (0.559 g) according to the
general procedure (the reaction mixture was heated at 70–80 8C
lsolated yield.
arylstannanes or allylstannane to give the coupled products
3k–o in 81–90% isolated yields. The coupling reactions of 5-
cyclopropyl substituted pyrazole derivative 2f with phenyl-
stannane or allylstannane were much sluggish under the same
reaction condition and a prolong reaction time (2.5 h) was
required. The results of these coupling reactions were
summarized in Table 2.
1
for 2 h). 2a: mp 173–175 8C; H NMR (CDCl3) d 11.06 (bs,
1H), 7.69–7.50 (m, 5H); 19F NMR (CDCl3, internal standard
CFCl3) d À63.22 (s, 3F); MS, m/z (relative intensity) 292
(M+ + 1, 52), 290 (M+ À 1, 53), 182 (12), 163 (31), 142 (100),
133 (35), 89 (19), 77 (30). Anal. Calcd for C10H6BrF3N2: C,
41.26; H, 2.08. Found: C, 41.10; H, 2.05.
3. Conclusion
4.1.2. 1-Benzyl-4-bromo-3-trifluoromethyl-5-
phenylpyrazole (2b)
In conclusion, we synthesized 1,4,5-trisubstituted 3-trifluor-
omethylpyrazoles in excellent yields via the microwave-assisted
Stille coupling reactions of 1,5-disubstituted 4-bromo-3-trifluor-
omethylpyrazoles with arylstannane or allylstannane in the
presence of Pd(PPh3)4 catalyst. 1,5-Disubstituted 4-bromo-3-
trifluoromethylpyrazoles were easily prepared by bromination of
1,5-disubstituted 3-trifluoromethylpyrazoles with NBS. The
present methodprovided anefficientandfacile approachtonovel
1,4,5-trisubstituted 3-trifluoromethylpyrazoles.
2b was prepared in 98% yield (0.747 g) according to the
general procedure (the reaction mixture was heated at 70–80 8C
for 2 h). 2b: oil; 1H NMR (CDCl3) d 7.50–7.44 (m, 3H), 7.27–
7.23 (m, 5H), 7.00–6.97 (m, 2H), 5.28 (s, 2H); 19F NMR
(CDCl3, internal standard CFCl3) d À62.65 (s, 3F); MS, m/z
(relative intensity) 382 (M+ + 1, 10), 380 (M+ À 1, 11), 91
(100), 65 (17). Anal. Calcd for C17H12BrF3N2: C, 53.57; H,
3.17. Found: C, 53.43; H, 3.12.
4.1.3. 4-Bromo-3-trifluoromethyl-1,5-diphenylpyrazole
(2c)
4. Experimental
2c was prepared in 99% yield (0.727 g) according to the
general procedure (the reaction mixture was heated at 70–80 8C
for 2 h). 2c: mp 102–104 8C; 1H NMR (CDCl3) d 7.43–7.20 (m,
10H); 19F NMR (CDCl3, internal standard CFCl3) d À62.92 (s,
3F); MS, m/z (relative intensity) 368 (M+ + 1, 64), 366 (M+ À 1,
66), 347 (24), 286 (23), 218 (13), 120 (24), 89 (23), 77 (100).
Anal. Calcd for C16H10BrF3N2: C, 52.34; H, 2.75. Found: C,
52.11; H, 2.70.
1H NMR spectra were recorded on a 200 MHz Gemini-200
NMR spectrometer and 19F NMR spectra were recorded on a
100 MHz Bruker AC-100F NMR spectrometer with tetra-
methylsilane (TMS) and CFCl3 as an internal standard,
respectively and the upfield as negative. All chemical shifts
(d) are expressed in parts per million and coupling constant (J)
are given in Hertz. Infrared spectra were determined on a

1194
S.L. Jeon et al. / Journal of Fluorine Chemistry 128 (2007) 1191–1197
4.1.4. 4-Bromo-3-trifluoromethyl-5-methylpyrazole (2d)
2d was prepared in 99% yield (0.453 g) according to the
general procedure (the reaction mixture was stirred at room
SiO2 column. Elution with a mixture of hexane and ethyl
acetate (9:1) provided 4-brominated pyrazoles 2h–2j.
1
temperature for 1 h). 2d: mp 89–90 8C; H NMR (CDCl3) d
4.2.1. 4-Bromo-3-trifluoromethyl-1-methyl-5-
phenylpyrazole (2h)
2h was prepared in 60% yield (0.275 g) according to the
11.88 (bs, 1H), 2.33 (s, 3H); 19F NMR (CDCl3, internal
standard CFCl3) d À63.15 (s, 3F); MS, m/z (relative intensity)
230 (M+ + 1, 14), 228 (M+ À 1, 15), 211 (4), 149 (19), 101 (69),
69 (100). Anal. Calcd for C5H4BrF3N2: C, 26.22; H, 1.76.
Found: C, 26.18; H, 1.74.
1
general procedure. 2h: mp 66–67 8C; H NMR (CDCl3) d
7.56–7.51 (m, 3H), 7.49–7.36 (m, 2H), 3.84 (s, 3H); 19F
NMR (CDCl3, internal standard CFCl3) d À62.71 (s, 3F);
MS, m/z (relative intensity) 306 (M+ + 1, 28), 304 (M+ À 1,
29), 223 (47), 153 (64), 127 (95), 104 (100), 77 (42). Anal.
Calcd for C11H8BrF3N2: C, 43.30; H, 2.64. Found: C, 43.11;
H, 2.69.
4.1.5. 1-Benzyl-4-bromo-3-trifluoromethyl-5-
methylpyrazole (2e)
2e was prepared in 95% yield (0.606 g) according to the
general procedure (the reaction mixture was stirred at room
temperature for 1 h). 2e: oil; 1H NMR (CDCl3) d 7.38–7.30 (m,
3H), 7.15–7.11 (m, 2H), 5.34 (s, 2H), 2.19 (s, 3H); 19F NMR
(CDCl3, internal standard CFCl3) d À63.29 (s, 3F); MS, m/z
(relative intensity) 320 (M+ + 1, 14), 318 (M+ À 1, 13), 305
(10), 249 (7), 149 (5), 91 (100), 65 (19). Anal. Calcd for
C12H10BrF3N2: C, 45.16; H, 3.16. Found: C, 44.99; H, 3.11.
4.2.2. 4-Bromo-3-trifluoromethyl-1,5-dimethylpyrazole (2i)
2i was prepared in 79% yield (0.288 g) according to the
general procedure. 2i: mp 42–44 8C; 1H NMR (CDCl3) d 3.85
(s, 3H), 2.27 (s, 3H); 19F NMR (CDCl3, internal standard
CFCl3) d À62.55 (s, 3F); MS, m/z (relative intensity) 244
(M+ + 1, 25), 242 (M+ À 1, 27), 223 (11), 163 (48), 99 (17), 69
(72), 56 (73), 43 (100). Anal. Calcd for C6H6BrF3N2: C, 29.65;
H, 2.49. Found: C, 29.49; H, 2.51.
4.1.6. 4-Bromo-5-cyclopropyl-3-trifluoromethyl-1-
phenylpyrazole (2f)
2f was prepared in 98% yield (0.649 g) according to the
general procedure (the reaction mixture was stirred at room
temperature for 1 h). 2f: oil; 1H NMR (CDCl3) d 7.53–7.43 (m,
5H), 1.80–1.74 (m, 1H), 0.96–0.88 (m, 2H), 0.75–0.69 (m, 2H);
19F NMR (CDCl3, internal standard CFCl3) d À63.18 (s, 3F);
MS, m/z (relative intensity) 332 (M+ + 1, 8), 330 (M+ À 1, 9),
295 (10), 236 (16), 128 (13), 77 (100). Anal. Calcd for
C13H10BrF3N2: C, 47.15; H, 3.04. Found: C, 47.42; H, 2.99.
4.2.3. 4-Bromo-5-cyclopropyl-3-trifluoromethyl-1-
methylpyrazole (2j)
2j was prepared in 70% yield (0.377 g) according to the
1
general procedure. 2j: oil; H NMR (CDCl3) d 3.94 (s, 3H),
1.72–1.57 (m, 1H), 1.15–1.05 (m, 2H), 0.99–0.86 (m, 2H); 19
F
NMR (CDCl3, internal standard CFCl3) d À62.53 (s, 3F); MS,
m/z (relative intensity) 270 (M+ + 1, 92), 268 (M+ À 1, 91), 169
(95), 91 (74), 58 (93), 44 (100). Anal. Calcd for C8H8BrF3N2:
C, 35.71; H, 3.00. Found: C, 35.60; H, 2.95.
4.1.7. 4-Bromo-5-cyclopropyl-3-trifluoromethylpyrazole
(2g)
4.3. General procedure for the preparation of 1,4,5-
trisubstituted 3-trifluoromethylpyrazoles 3a–3s
2g was prepared in 99% yield (0.505 g) according to the
general procedure (the reaction mixture was stirred at room
temperature for 1 h). 2g: mp 112–114 8C; 1H NMR (CDCl3) d
11.88 (bs, 1H), 1.90–1.76 (m, 1H), 1.16–0.99 (m, 2H), 0.84–
0.76 (m, 2H); 19F NMR (CDCl3, internal standard CFCl3) d
À63.16 (s, 3F); MS, m/z (relative intensity) 256 (M+ + 1, 17),
354 (M+ À 1, 18), 155 (18), 105 (22), 69 (23), 40 (100). Anal.
Calcd for C17H6BrF3N2: C, 32.97; H, 2.37. Found: C, 32.85; H,
2.34.
A 2 mL microwave reactor was charged with 2 (0.1 mmol),
Pd(PPh3)4 (5 mol%) and 1.5 mL of dry CH3CN. After
bubbling with air gas, arylstannane or allylstannane
(0.13 mmol) was added into the reactor. The reactor was
heated at 180 8C for 1–2.5 h. After quenching with 10% KF
solution at room temperature, the reaction mixture was
extracted with CH2Cl2 twice. The CH2Cl2 solution was dried
over anhydrous MgSO4 and chromatographed on SiO2
column. Elution with a mixture of hexane and ethyl acetate
(9:1) provided 3a–3s.
4.2. General procedure for the preparation of 4-
brominated pyrazoles 2h–2j
A 50 mL two-neck round bottom flask equipped with a
magnetic stirrer bar, a septum and reflux condenser connected
to an argon source was charged with 3-trifluoromethylated 4-
bromopyrazoles 2a, 2d or 2g (1.5 mmol), K2CO3 (1.7 mmol)
and 10 mL of dry Acetone. After the reaction mixture was
stirred at room temperature for 1 h, CH3I (2.0 mmol) was added
into the reaction and then the reaction mixture was stirred at
room temperature for 1.5 h. After removal of solvent, water was
added. The reaction mixture was extracted with ethyl acetate
twice, dried over anhydrous MgSO4 and chromatographed on
4.3.1. 3-Trifluoromethyl-1,4,5-triphenylpyrazole (3a)
3a was prepared in 97% yield (0.035 g) according to the
general procedure (the reactor was heated at 180 8C for 1 h).
3a: mp 159–161 8C; 1H NMR (CDCl3) d 7.35–7.14 (m, 13H),
7.03–6.98 (m, 2H); 19F NMR (CDCl3, internal standard
CFCl3) d À59.98 (s, 3F); MS, m/z (relative intensity) 364 (M+,
22), 267 (10), 190 (12), 165 (12), 89 (11), 77 (100); IR (KBr)
3047, 2920, 1595, 1502, 1155, 1122, 755, 692 cmÀ1. Anal.
Calcd for C22H15F3N2: C, 72.52; H, 4.15. Found: C, 72.37; H,
4.09.

S.L. Jeon et al. / Journal of Fluorine Chemistry 128 (2007) 1191–1197
1195
4.3.2. 3-Trifluoromethyl-4-( p-methoxy)phenyl-1,5-
diphenylpyrazole (3b)
4.3.7. 1-Benzyl-3-trifluoromethyl-4-( p-methoxy)phenyl-5-
phenylpyrazole (3g)
3b was prepared in 96% yield (0.038 g) according to the
general procedure (the reactor was heated at 180 8C for 1 h).
3b: mp 124–125 8C; 1H NMR (CDCl3) d 7.31–7.11 (m, 10H),
7.03–6.98 (m, 2H), 6.84–6.80 (m, 2H), 3.79 (s, 3H); 19F NMR
(CDCl3, internal standard CFCl3) d À60.05 (s, 3F); MS, m/z
(relative intensity) 394 (M+, 90), 379 (16), 254 (10), 152 (13),
77 (100); IR (KBr) 3064, 2935, 1614, 1520, 1252, 1153, 1126,
825, 747, 697 cmÀ1. Anal. Calcd for C23H17F3N2O: C, 70.04;
H, 4.34. Found: C, 70.23; H, 4.27.
3g was prepared in 92% yield (0.038 g) according to the
general procedure (the reactor was heated at 180 8C for 1.5 h).
3g: mp 74–76 8C; 1H NMR (CDCl3) d 7.35–7.24 (m, 6H), 7.09–
7.02 (m, 6H), 6.78–6.74 (m, 2H), 5.30 (s, 2H), 3.75 (s, 3H); 19
F
NMR (CDCl3, internal standard CFCl3) d À59.74 (s, 3F); MS,
m/z (relative intensity) 408 (M+, 29), 339 (5), 176 (3), 151 (3),
91 (100); IR (KBr) 3032, 2920, 1520, 1250, 1178, 1134, 820,
749, 694 cmÀ1. Anal. Calcd for C24H19F3N2O: C, 70.58; H,
4.69. Found: C, 70.39; H, 4.64.
4.3.3. 3-Trifluoromethyl-4-( p-fluoro)phenyl-1,5-
diphenylpyrazole (3c)
4.3.8. 1-Benzyl-3-trifluoromethyl-4-( p-fluoro)phenyl-5-
phenylpyrazole (3h)
3c was prepared in 98% yield (0.037 g) according to the
general procedure (the reactor was heated at 180 8C for 1 h). 3c:
mp 161–162 8C; 1H NMR (CDCl3) d 7.36–7.15 (m, 10H), 7.03–
6.92 (m, 4H); 19F NMR (CDCl3, internal standard CFCl3) d
À60.06 (s, 3F), À114.90 (s, 1F); MS, m/z (relative intensity)
382 (M+, 25), 341 (11), 285 (9), 183 (9), 107 (10), 77 (100); IR
3h was prepared in 91% yield (0.036 g) according to the
general procedure (the reactor was heated at 180 8C for 1.5 h).
3h: oil; 1H NMR (CDCl3) d 7.41–6.85 (m, 14H), 5.30 (s, 2H);
19F NMR (CDCl3, internal standard CFCl3) d À59.76 (s, 3F),
À115.28 (s, 1F); MS, m/z (relative intensity) 396 (M+, 44), 377
(4), 319 (8), 207 (4), 103 (3), 91 (100); IR (neat) 3043, 2920,
1520, 1225, 1157, 1134, 825, 749, 688 cmÀ1. Anal. Calcd for
C23H16F4N2: C, 69.69; H, 4.07. Found: C, 69.48; H, 4.02.
(KBr) 3064, 2918, 1520, 1153, 1126, 817, 752, 691 cmÀ1
.
Anal. Calcd for C22H14F4N2: C, 69.11; H, 3.69. Found: C,
69.33; H, 3.74.
4.3.9. 1-Benzyl-3-trifluoromethyl-4-( p-
trifluoromethyl)phenyl-5-phenylpyrazole (3i)
4.3.4. 3-Trifluoromethyl-4-( p-trifluoromethyl)phenyl-1,5-
diphenylpyrazole (3d)
3d was prepared in 92% yield (0.040 g) according to the
3i was prepared in 92% yield (0.041 g) according to the
general procedure (the reactor was heated at 180 8C for 1.5 h).
1
general procedure (the reactor was heated at 180 8C for 1 h).
3i: oil; H NMR (CDCl3) d 7.50–7.46 (m, 2H), 7.40–7.24 (m,
1
3d: mp 121–123 8C; H NMR (CDCl3) d 7.57–7.52 (m, 2H),
8H), 7.08–7.04 (m, 4H), 5.30 (s, 2H); 19F NMR (CDCl3,
internal standard CFCl3) d À59.62 (s, 3F), À63.13 (s, 3F); MS,
m/z (relative intensity) 446 (M+, 11), 377 (7), 189 (6), 91 (100),
65 (3); IR (neat) 3039, 2922, 1454, 1325, 1126, 828, 748,
685 cmÀ1. Anal. Calcd for C24H16F6N2: C, 64.58; H, 3.61.
Found: C, 64.27; H, 3.55.
7.38–7.17 (m, 10H), 7.03–6.97 (m, 2H); 19F NMR (CDCl3,
internal standard CFCl3) d À59.90 (s, 3F), À63.11 (s, 3F); MS,
m/z (relative intensity) 432 (M+, 100), 391 (10), 363 (9), 267
(8), 146 (15), 77 (91); IR (KBr) 3060, 2924, 1600, 1487, 1327,
1169, 1128, 809, 750, 689 cmÀ1. Anal. Calcd for C23H14F6N2:
C, 63.89; H, 3.26. Found: C, 63.67; H, 3.20.
4.3.10. 4-Allyl-1-benzyl-3-trifluoromethyl-5-
phenylpyrazole (3j)
4.3.5. 4-Allyl-3-trifluoromethyl-1,5-diphenylpyrazole (3e)
3e was prepared in 97% yield (0.032 g) according to the
general procedure (the reactor was heated at 180 8C for 1 h).
3j was prepared in 97% yield (0.033 g) according to the
general procedure (the reactor was heated at 180 8C for 1.5 h).
3j: mp 62–63 8C; 1H NMR (CDCl3) d 7.45–7.34 (m, 3H), 7.27–
7.13 (m, 5H), 6.98–6.94 (m, 2H), 5.91–5.71 (m, 1H), 5.22 (s,
2H), 4.94 (d, J = 10.3 Hz, 1H), 4.83 (d, J = 16.8 Hz, 1H), 3.17
(d, J = 5.9 Hz, 2H); 19F NMR (CDCl3, internal standard CFCl3)
d À61.27 (s, 3F); MS, m/z (relative intensity) 342 (M+, 3), 251
(5), 183 (4), 91 (100), 65 (26); IR (KBr) 3081, 2922, 1641,
1495, 1454, 1275, 1149, 1126, 989, 909, 752, 690 cmÀ1. Anal.
Calcd for C20H17F3N2: C, 70.17; H, 5.00. Found: C, 69.89; H,
4.93.
1
3e: oil; H NMR (CDCl3) d 7.40–7.16 (m, 10H), 6.01–5.82
(m, 1H), 5.08–4.91 (m, 2H), 3.29 (d, J = 5.9 Hz, 2H); 19F
NMR (CDCl3, internal standard CFCl3) d À61.51 (s, 3F);
MS, m/z (relative intensity) 328 (M+, 53), 313 (42), 259 (15),
115 (22), 77 (100); IR (neat) 3064, 2922, 1641, 1599, 1493,
1277, 1165, 1128, 991, 915, 755, 694 cmÀ1. Anal. Calcd
for C19H15F3N2: C, 69.50; H, 4.60. Found: C, 69.27; H,
4.53.
4.3.6. 1-Benzyl-3-trifluoromethyl-4,5-diphenylpyrazole (3f)
3f was prepared in 92% yield (0.035 g) according to the
general procedure (the reactor was heated at 180 8C for 1.5 h).
4.3.11. 3-Trifluoromethyl-1-methyl-4,5-diphenylpyrazole
(3k)
3k was prepared in 81% yield (0.025 g) according to the
1
3f: oil; H NMR (CDCl3) d 7.43–7.01 (m, 15H), 5.30 (s, 2H);
19F NMR (CDCl3, internal standard CFCl3) d À59.65 (s, 3F);
MS, m/z (relative intensity) 378 (M+, 15), 301 (5), 189 (5), 91
(100), 77 (5); IR (neat) 3064, 2922, 1454, 1223, 1182, 1134,
753, 696 cmÀ1. Anal. Calcd for C23H17F3N2: C, 73.01; H, 4.53.
Found: C, 72.78; H, 4.59.
general procedure (the reactor was heated at 180 8C for 1.5 h).
1
3k: mp 108–110 8C; H NMR (CDCl3) d 7.40–7.34 (m, 4H),
7.27–7.12 (m, 6H), 3.87 (s, 3H); 19F NMR (CDCl3, internal
standard CFCl3) d À59.76 (s, 3F); MS, m/z (relative intensity)
302 (M+, 100), 287 (22), 233 (11), 140 (21); IR (KBr) 3072,

1196
S.L. Jeon et al. / Journal of Fluorine Chemistry 128 (2007) 1191–1197
2922, 1477, 1173, 1124, 755, 698 cmÀ1. Anal. Calcd for
C17H13F3N2: C, 67.54; H, 4.33. Found: C, 67.80; H, 4.40.
NMR (CDCl3, internal standard CFCl3) d À59.73 (s, 3F); MS,
m/z (relative intensity) 328 (M+, 59), 313 (29), 217 (13), 115
(26), 91 (23), 77 (100). Anal. Calcd for C19H15F3N2: C, 69.50;
H, 4.60. Found: C, 69.23; H, 4.55.
4.3.12. 3-Trifluoromethyl-4-( p-methoxy)phenyl-1-methyl-
5-phenylpyrazole (3l)
3l was prepared in 82% yield (0.027 g) according to the
general procedure (the reactor was heated at 180 8C for 1.5 h).
3l: mp 98–99 8C; 1H NMR (CDCl3) d 7.39–7.35 (m, 3H), 7.22–
7.17 (m, 2H), 7.09–7.03 (m, 2H), 6.81–6.75 (m, 2H), 3.85 (s,
3H), 3.76 (s, 3H); 19F NMR (CDCl3, internal standard CFCl3) d
À59.84 (s, 3F); MS, m/z (relative intensity) 332 (M+, 100), 317
(34), 269 (12), 205 (9), 148 (10), 76 (7); IR (KBr) 3064, 2927,
1522, 1250, 1171, 1124, 817, 745, 690 cmÀ1. Anal. Calcd for
C18H15F3N2O: C, 65.06; H, 4.55. Found: C, 64.88; H, 4.51.
4.3.17. 4-Allyl-5-cyclopropyl-3-trifluoromethyl-1-
phenylpyrazole (3q)
3q was prepared in 93% yield (0.027 g) according to the
general procedure (the reactor was heated at 180 8C for 2.5 h).
3q: oil; 1H NMR (CDCl3) d 7.56–7.36 (m, 5H), 6.04–5.85 (m,
1H), 5.08–4.98 (m, 2H), 3.42 (d, J = 6.0 Hz, 2H), 1.80–1.67 (m,
1H), 0.87–0.76 (m, 2H), 0.50–0.42 (m, 2H); 19F NMR (CDCl3,
internal standard CFCl3) d À61.21 (s, 3F); MS, m/z (relative
intensity) 292 (M+, 13), 127 (11), 105 (13), 77 (44), 40 (100).
Anal. Calcd for C16H15F3N2: C, 65.75; H, 5.17. Found: C,
65.48; H, 5.15.
4.3.13. 3-Trifluoromethyl-4-( p-fluoro)phenyl-1-methyl-5-
phenylpyrazole (3m)
3m was prepared in 84% yield (0.027 g) according to the
4.3.18. 5-Cyclopropyl-3-trifluoromethyl-1-methyl-4-
phenylpyrazole (3r)
general procedure (the reactor was heated at 180 8C for 1.5 h).
1
3m: oil; H NMR (CDCl3) d 7.43–6.89 (m, 9H), 3.87 (s, 3H);
3r was prepared in 75% yield (0.020 g) according to the
general procedure (the reactor was heated at 180 8C for 2.5 h).
3r: mp 65–66 8C; 1H NMR (CDCl3) d 7.43–7.28 (m, 5H), 3.99
(s, 3H), 1.79–1.65 (m, 1H), 0.88–0.78 (m, 2H), 0.37–0.29 (m,
2H); 19F NMR (CDCl3, internal standard CFCl3) d À59.78 (s,
3F); MS, m/z (relative intensity) 266 (M+, 100), 251 (40), 231
(72), 152 (24), 115 (40), 76 (33). Anal. Calcd for C14H13F3N2:
C, 63.15; H, 4.92. Found: C, 62.91; H, 4.84.
19F NMR (CDCl3, internal standard CFCl3) d À59.85 (s, 3F),
À115.31 (s, 1F); MS, m/z (relative intensity) 320 (M+, 100), 299
(17), 251 (8), 140 (11); IR (neat) 3062, 2920, 1522, 1323, 1174,
1140, 1134, 831, 747, 695 cmÀ1. Anal. Calcd for C17H12F4N2:
C, 63.75; H, 3.78. Found: C, 63.69; H, 3.75.
4.3.14. 3-Trifluoromethyl-4-( p-trifluoromethyl)phenyl-1-
methyl-5-phenylpyrazole (3n)
3n was prepared in 82% yield (0.030 g) according to the
4.3.19. 4-Allyl-5-cyclopropyl-3-trifluoromethyl-1-
methylpyrazole (3s)
3s was prepared in 80% yield (0.019 g) according to the
general procedure (the reactor was heated at 180 8C for 1.5 h).
3n: oil; 1H NMR (CDCl3) d 7.52–7.16 (m, 9H), 3.87 (s, 3H); 19
F
NMR (CDCl3, internal standard CFCl3) d À59.71 (s, 3F),
À63.12 (s, 3F); MS, m/z (relative intensity) 370 (M+, 100), 349
(14), 301 (22), 281 (24), 165 (7), 118 (8), 77 (10); IR (neat)
3064, 2922, 1491, 1327, 1173, 1126, 809, 753, 692 cmÀ1. Anal.
Calcd for C18H12F6N2: C, 58.39; H, 3.27. Found: C, 58.51; H,
3.23.
general procedure (the reactor was heated at 180 8C for 2.5 h).
3s: oil; H NMR (CDCl3) d 5.97–5.78 (m, 1H), 5.03–4.86 (m,
1
2H), 3.92 (s, 3H), 3.32 (d, J = 5.5 Hz, 2H), 1.66–1.52 (m, 1H),
1.06–0.95 (m, 2H), 0.75–0.67 (m, 2H); 19F NMR (CDCl3,
internal standard CFCl3) d À61.24 (s, 3F); MS, m/z (relative
intensity) 230 (M+, 72), 189 (100), 120 (20), 69 (8). Anal. Calcd
for C11H13F3N2: C, 57.39; H, 5.69. Found: C, 57.20; H, 5.72.
4.3.15. 4-Allyl-3-trifluoromethyl-1-methyl-5-
phenylpyrazole (3o)
Acknowledgment
3o was prepared in 90% yield (0.024 g) according to the
general procedure (the reactor was heated at 180 8C for 1.5 h).
3o: oil; 1H NMR (CDCl3) d 7.55–7.45 (m, 3H), 7.39–7.28 (m,
2H), 5.83 (ddt, J = 17.2, 9.9, 6.2 Hz, 1H), 4.97 (d, J = 9.9 Hz,
1H), 4.86 (d, J = 17.2 Hz, 1H), 3.78 (s, 3H), 3.18 (d, J = 6.2 Hz,
2H); 19F NMR (CDCl3, internal standard CFCl3) d À61.34 (s,
3F); MS, m/z (relative intensity) 266 (M+, 100), 251 (71), 231
(58), 197 (22), 115 (31), 77 (23); IR (neat) 3082, 2918, 1641,
1490, 1277, 1167, 1124, 979, 911, 755, 693 cmÀ1. Anal. Calcd
for C14H13F3N2: C, 63.15; H, 4.92. Found: C, 62.89; H, 4.86.
This work was supported by Korea Research Foundation
Grant (KRF-2003-041-C00199).
References
[1] L.V.G. Nargund, V. Hariprasad, G.R.N. Reddy, J. Pharm. Sci. 81 (1992)
892–894.
[2] G. Daidone, B. Maggio, S. Plescia, D. Raffa, C. Musiu, C. Milia, G. Perra,
M.E. Marongiu, Eur. J. Med. Chem. 33 (1998) 375–382.
[3] C. Almansa, L.A. Gomez, F.L. Cavalcanti, A.F. de Arriba, J. Garcia-
Rafanell, J. Form, J. Med. Chem. 40 (1997) 547–558.
4.3.16. 5-Cyclopropyl-3-trifluoromethyl-1,4-
diphenylpyrazole (3p)
3p was prepared in 91% yield (0.030 g) according to the
[4] S. Zhihua, J. Guan, F.P. Michael, M. Kathy, W.P. Michael, M.V. William,
S. Monica, S. Michael, R.M. Dave, C. Dennis, Bioorg. Med. Chem. Lett.
10 (2000) 601–604.
[5] J. Finn, K. Mattia, M. Morytko, S. Ram, Y. Yang, X. Wu, E. Mak, P.
Gallant, D. Keith, Bioorg. Med. Chem. Lett. 13 (2003) 2231–2234.
[6] M. Lautens, A. Roy, Org. Lett. 2 (2000) 555–558.
general procedure (the reactor was heated at 180 8C for 2.5 h).
1
3p: mp 78–80 8C; H NMR (CDCl3) d 7.65–7.36 (m, 10H),
1.88–1.77 (m, 1H), 0.69–0.60 (m, 2H), 0.25–0.16 (m, 2H); 19
F
[7] A.N. Kost, I.I. Grandberg, Adv. Heterocyclic Chem. 6 (1966) 347–429.

S.L. Jeon et al. / Journal of Fluorine Chemistry 128 (2007) 1191–1197
1197
[8] A. Padwa, 1,3-Dipolar Cycloaddition Chemistry, vol. I, John Wiley &
Sons, New York, 1984.
[26] I.H. Jeong, S.L. Jeon, Y.K. Min, B.T. Kim, Tetrahedron Lett. 43 (2002)
7171–7174.
[9] J. Bohrisch, M. Patzel, C. Mugge, J. Liebscher, Synthesis (1991) 1153–
1156.
[27] H.-B. Yu, W.-Y. Huang, J. Fluorine Chem. 87 (1998) 69–73.
[28] X.-Q. Tang, C.-M. Hu, J. Chem. Soc., Chem. Commun. (1994) 631–
632.
[10] X. Wang, J. Tan, K. Grozinger, Tetrahedron Lett. 41 (2000) 4713–4716.
[11] A.R. Katrizky, M. Wang, S. Zhang, M.V. Voronkov, J. Org. Chem. 66
(2001) 6787–6791.
[29] H.-P. Guan, X.-Q. Tang, B.-H. Luo, C.-M. Hu, Synthesis (1997) 1489–
1492.
[12] N. Haddad, J. Baron, Tetrahedron Lett. 43 (2002) 2171–2173.
[13] V.K. Aggarwal, J. de Vicente, R.V. Bonnert, J. Org. Chem. 68 (2003)
5381–5383.
[30] B. Jiang, Y.-Y. Xu, J. Yang, J. Fluorine Chem. 67 (1994) 83–85.
[31] T. Hanamoto, Y. Hakoshima, M. Egashira, Tetrahedron Lett. 45 (2004)
7573–7576.
[14] Y.R. Huang, J.A. Katzenellenbogen, Org. Lett. 2 (2000) 2833–2836.
[15] K.Y. Lee, J.M. Kim, J.N. Kim, Tetrahedron Lett. 44 (2003) 6737–6740.
[16] T.D. Penning, J.J. Talley, S.R. Bertenshaw, J.S. Carter, P.W. Collins, S.
Docter, M.J. Graneto, L.F. Lee, J.W. Malecha, J.M. Miyashiro, R.S.
Rogers, D.J. Rogier, S.S. Yu, G.D. Anderson, E.G. Burton, J.N. Cogburn,
S.A. Gregory, C.M. Koboldt, W.E. Perkins, K. Seibert, A.W. Veenhuizen,
Y.Y. Zhang, P.C. Isakson, J. Med. Chem. 40 (1997) 1347–1365.
[17] S.K.Y. Ishii, Y. Umehara, M. Kudo, T. Nawamaki, S. Watanabe, Jpn. Pat.
02,129,171 (1990).
[32] T. Hanamoto, M. Egashira, K. Ishizuka, H. Furuno, J. Inanaga, Tetra-
hedron 62 (2006) 6332–6338.
[33] F. Jin, Y. Ma, Tetrahedron Lett. 33 (1992) 6161–6164.
[34] S.M. Sakya, B. Rast, Tetrahedron Lett. 44 (2003) 7629–7632.
[35] H.G. Bonacorso, A.D. Wastowski, N. Zanatta, M.A.P. Martins, Synth.
Commun. 30 (2000) 1457–1465.
[36] E. Zouaoui, M.M. El Gaied, J. Chem. Res. [S] 4 (2003) 242–246.
[37] S.K. Singh, M.S. Reddy, S. Shivaramakrishna, D. Kavitha, R. Vasudev,
J.M. Babu, A. Sivalakshmidevi, Y.K. Rao, Tetrahedron Lett. 45 (2004)
7679–7682.
[18] L.-P. Song, S.-Z. Zhu, J. Fluorine Chem. 111 (2001) 201–205.
[19] S.P. Singh, D. Kumar, B.G. Jones, M.D. Threadgill, J. Fluorine Chem. 94
(1999) 199–203.
[38] W. Ebenbeck, F. Rampf, A. Marhold, US Pat 142,820 (2004).
[39] A. Touzot, M. Soufyane, H. Berber, L. Toupet, C. Mirand, J. Fluorine
Chem. 125 (2004) 1299–1304.
[20] B.C. Hamper, J. Fluorine Chem. 48 (1990) 123–131.
[21] X.-Q. Tang, C.-M. Hu, J. Fluorine Chem. 73 (1995) 129–131.
[22] R.J. Linderman, K.S. Kirollos, Tetrahedron Lett. 30 (1989) 2049–2052.
[23] E.F.B. Mara, C. Gunter, A.P.M. Marcos, J. Heterocyclic Chem. 30 (1993)
1159–1160.
[40] F. Effenberger, A. Krebs, J. Org. Chem. 49 (1984) 4687–4695.
[41] J. Zhang, S. Didierlaurent, M. Fortin, D. Lefrancois, E. Uridat, J.P. Vevert,
Bioorg. Med. Chem. Lett. 10 (2000) 2575–2578.
[42] C.A. Dvorak, D.A. Rudolph, S. Ma, N.I. Carruthers, J. Org. Chem. 70
(2005) 4188–4190.
[24] H.G. Bonacorso, A.D. Wastowski, N. Zanatta, M.A.P. Martins, J.A. Naue,
J. Fluorine Chem. 92 (1998) 23–26.
[43] S.L. Jeon, J.K. Kim, J.B. Son, B.T. Kim, I.H. Jeong, J. Fluorine Chem. 128
(2007) 153–157.
[25] H.-B. Yu, W.-Y. Huang, J. Fluorine Chem. 84 (1997) 65–67.