Synthesis of trifluoromethylated pyrazoles from trifluoromethylenaminones and monosubstituted hydrazines

Article abstract of DOI:10.1016/j.jfluchem.2004.03.007

Cyclocondensation of monosubstituted hydrazines 2a-c with trifluoromethylenaminones 1a-c afforded 3-CF₃ and (or) 5-CF₃ pyrazoles 3-6. Addition of N-methylhydrazine to enaminone led to 3-CF₃ pyrazole as the major product, w

Full text of DOI:10.1016/j.jfluchem.2004.03.007

Journal of Fluorine Chemistry 125 (2004) 1299–1304
Synthesis of trifluoromethylated pyrazoles from
trifluoromethylenaminones and monosubstituted hydrazines
a
Aline Touzot , Mustapha Soufyane , Hatice Berber , Loıc Toupet , Catherine Mirand
b
a
c
a,*
¨
IFR 53, FRE/CNRS 2715, Faculte de Pharmacie, Universite de Reims Champagne-Ardenne, 51 rue Cognacq-Jay, 51096 Reims Cedex, France
a
´
´
b
´ ´
Departement de Chimie, Faculte des Sciences, BP 20, 24000 El Jadida, Morocco
´ ˆ
UMR/CNRS 6626, Universite de Rennes I, Bat. 11A, Campus de Beaulieu, 35042 Rennes, France
c
Received 24 January 2004; received in revised form 13 March 2004; accepted 18 March 2004
Available online 19 June 2004
Abstract
Cyclocondensation of monosubstituted hydrazines 2a–c with trifluoromethylenaminones 1a–c afforded 3-CF3 and (or) 5-CF3 pyrazoles 3–
6. Addition of N-methylhydrazine to enaminone led to 3-CF3 pyrazole as the major product, whereas phenylhydrazine gave regiospecific
formation of 5-CF3 pyrazole.
Structural assignment of regioisomers is based on 13C NMR chemical shifts, long-range carbon–fluorine and hydrogen–fluorine coupling
1
constants and H–1H NOE.
The pyrazole 4ac was characterized by X-ray diffraction analysis.
# 2004 Elsevier B.V. All rights reserved.
Keywords: b-Enaminotrifluoromethylketones; Phenylhydrazine; Methylhydrazine; Trifluoromethyl-1H-pyrazoles
1. Introduction
the construction of pyrazole ring. In a preliminary paper
Hojo and coworkers [13a] and we [13b] mentioned the
reaction of dialkylaminomethylenehexafluoroacetylacetone
with hydrazine and phenylhydrazine giving good yields of
trifluoroacetyltrifluoromethylpyrazoles.
More recently Kawase et al. reported an elegant synthesis
of trifluoromethylpyrazoles bearing an aminoethyl side
chain from 4-trifluoroacetyl-2,3-dihydropyrroles [13c].
In this work, we describe the synthesis of phenyl and
benzoyl trifluoromethylpyrazoles from the reaction of enam-
inoketones 1a–c with methylhydrazine and some phenylhy-
drazines.
Fluorinated heterocyclic compounds play an important
role in medicinal and agrochemical fields [1]. Among them
pyrazoles containing a trifluoromethyl group have been
shown to possess high biological activities (in medicinal
field [2], in agrochemical field [3]).
Fig. 1 shows as a representative structural formula of
celecoxib, a phenyltrifluoromethylpyrazole recently mar-
keted for the treatment of rheumatoid arthritis [2b,4].
The main synthetic methods to prepare such compounds
involve [3 þ 2] atom fragments cyclization of various tri-
fluoromethyl building blocks with hydrazines: acetylenic
imines [5], acetylenic esters [6], acetylenic nitriles [7],
alkoxyalkenones [8], b-diketones [2b,9], b-ketoesters
[10], ketene dithiocetals [11].
2. Results and discussion
In recent years we have developed syntheses of fluori-
nated enaminones and their usefulness in the preparation of
various trifluoromethylpyrimidines [12]. We now wish to
report our results in the series of pyrazole.
2.1. Synthesis
In principle, the heterocyclization between enaminone
¨
and monosubstituted hydrazine proceeds by a Michael
addition/elimination on the b-carbon atom of the enamino-
ketone by the more nucleophilic function of the hydrazine,
followed by cyclodehydration to give a mixture of 3-tri-
fluoromethyl and/or 5-trifluoromethylpyrazoles [11]. The
intermediate enehydrazine-one is not isolated (Scheme 1).
Actually only a few examples have been reported in
the literature dealing with the use of such synthons for
* Corresponding author. Tel.: þ33-326-913587; fax: þ33-326-918029.
E-mail address: catherine.mirand@univ-reims.fr (C. Mirand).
0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2004.03.007

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A. Touzot et al. / Journal of Fluorine Chemistry 125 (2004) 1299–1304
Fig. 1. Structure of celecoxib
Scheme 2.
Scheme 1.
2.1.1. Preparation of phenyltrifluoromethylpyrazoles
(Scheme 2)
Enaminone 1a, prepared by a previously described pro-
cedure [12b] reacted readily with methylhydrazine 2a in
CH3CN to give a mixture of regioisomeric pyrazoles 3aa
and 4aa in which 3aa was the major product. These com-
pounds (3aa and 4aa) were previously reported by Kobaya-
shi et al. as the minor products isolated from the reaction
between diazomethane and phenyl(trifluoromethyl)acety-
lene [14].
Condensation of 1a with phenylhydrazine 2b and 4-
nitrophenylhydrazine 2c afforded higher regioselectivity.
Pyrazoles 4ab and 4ac were obtained respectively as the
major or sole product. 4ab was already prepared by reaction
of phenylhydrazine with b-chloro-b-trifluoromethylacrolein
[15].
Fig. 2. Selected 1H–1H NOE for pyrazoles 5ba, 5ca, 6ca and 7ba.
Indeed the reaction of methylhydrazine 2a with 1b led to a
mixture of the three compounds 5ba, 6ba and 7ba.
With the chlorinated enaminodiketone 1c, the formation
of 7 was not observed and the two isomeric pyrazoles 5ca
and 6ca were obtained in nearly a 3:1 ratio.
Condensation of phenylhydrazine with 1b gave the only
trifluoromethylpyrazole 6bb but an appreciable amount of
trifluoroacetylpyrazole 8bb was also isolated.
Finally the best result was observed in the reaction of 1c
and 2b that gave an excellent yield of almost exclusively
6cb.
2.1.2. Preparation of benzoyltrifluoromethylpyrazoles
(Scheme 3)
2.2. Spectral properties of pyrazoles
(Table 1, Figs. 2 and 3)
Starting materials were here enaminodiketones 1b and 1c
[12a]. In this case beside the two expected pyrazoles 5 and 6,
two other pyrazoles 7 and 8 could be formed that result from
a ring closure of the intermediate enehydrazine-one on the
benzoyl carbonyl group.
1
Structural assignment of regioisomers was based on H
and 13C NMR chemical shifts, long-range heteronuclear
coupling constants and observation of NOEs.
Scheme 3.

A. Touzot et al. / Journal of Fluorine Chemistry 125 (2004) 1299–1304
1301
Fig. 3. Molecular structure of 4ac.
Table 1
Selected 1H and 13C chemical shifts and carbon–fluorine and proton–fluorine coupling constants of pyrazoles 3, 4, 5, 6
Cpd
R
R0
CH3-N CH3-N C-3 (q)
C-5
Cpd
R
R0
CH3-N (q)
CH3-N (q)
C-3
C-5
3aa Me Ph
3ab Ph Ph
3.99
39.4
138.4, 2J ¼ 36:5 130.8 4aa Me
140.3, 2J ¼ 36:5 129.6 4ab Ph
Ph
Ph
4.07, 5J ¼ 1:1 39.0, 4J ¼ 2:0 138.8 128.2–129.2, m
140.4 128.4–129.0, m
4ac 4-NO2-Ph Ph
141.7 127.5, q, 2J ¼ 31
5ba Me COPh 4.01
39.6
39.8
141.9, 2J ¼ 38:5 135.9 6ba Me
COPh 4.11, 5J ¼ 1:3 39.4, 4J ¼ 2:5 140.1 130.2–133.0, m
6bb Ph
141.4, 2J ¼ 39:3 137.3 6ca Me
142.7, 2J ¼ 39:2 133.6 6cb Ph
COPh
COAr 4.11, 5J ¼ 1:6 40.0, 4J ¼ 4:1 141.5 130.8–132.5, m
141.1 132.1, q, 2J ¼ 39:8
5ca Me COAr 3.97
5cb Ph COAr
COAr
142.4 132.2, q, 2J ¼ 40:2
In the 13C NMR spectra the most significant data were
the chemical shifts of C-3 (at d ꢀ 141 ppm) and C-5 (at
d ꢀ 132 ppm). The carbon bearing the CF3 group was
easily identified by the two-bond carbon–fluorine cou-
pling.
For the 5-CF3 regioisomer 6ca, no NOE was detected.
Indeed, irradiation of the NMe protons at d ¼ 4:11 did not
induce NOEs on the H-3 proton.
All these findings are in full agreement with the literature
data [6,10,13c,16,17].
In addition in the case of the 5-CF3 isomers (4aa, 6ba and
6ca) we observed four-bond fluorine coupling to the N-
methyl carbon.
The 1H NMR spectra also gave information.
The resonance of the N-methyl protons of the 5-CF3
isomers (4aa, 6ba and 6ca) appeared at lower field
than that of the 3-CF3 isomers (3aa, 5ba and 5ca) and a
five-bond H–F coupling was only detected in the 5-CF3
series.
To have supplementary arguments, we examined the
homonuclear NOEs between the NMe protons and H-3 or
H-5 for N-methylpyrazoles (5ba, 5ca and 6ca) (Fig. 2)
[13c,16].
To confirm the regiochemistry of the 5-CF3 N-phenylpyr-
azoles, the X-ray structure analysis of 4ac (R ¼ p-NO2-Ph)
was performed and the molecular structure of this crystal is
shown in Fig. 3.1 The structures of the other compounds (4
and 6) follow from this result (Table 1).
In the case of the trifluoroacetylpyrazole 7ba, an NOE was
observed on proton H-5 by irradiation of the NMe protons
(Fig. 2).
One structure (8bb) was problematical to assign by NMR
experiments because of the presence of the two phenyl
groups. So we supposed, in accordance with the literature
[11], that the formation of this regioisomer could be explained
by the primary attack of the more nucleophilic amino
group of phenylhydrazine on the b-carbon of the enaminone,
followed by cyclodehydration on the benzoyl group.
For 3-CF3 isomers (5ba, 5ca), it was possible to observe
an NOE between NMe protons and H-5. Thus irradiation of
1
the proton H-5 of 5ba and 5ca at d ¼ 7:79 and 7.60 (in H
1 CCDC 229174 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge via www.ccdc.ca-
m.ac.uk/conts/retrieving.html or from the CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: þ44 1223 336033, e-mail: deposit@ccdc.-
cam.ac.uk.
NMR), respectively, induce NOEs on the NMe protons at
d ¼ 4:01 and 3.97. Moreover, irradiation of the MeN pro-
tons of 5ba at d ¼ 4:01 mutually induces NOEs on the H-5
proton at d ¼ 7:79.

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A. Touzot et al. / Journal of Fluorine Chemistry 125 (2004) 1299–1304
3. Conclusion
130.9 (Cq-ar), 138.8 (C-3). EIMS m/z: 226 [M]þ (100), 191
(23), 179 (14), 165 (16), 130 (18), 115 (35), 105 (58). Anal.
Calc. for C11H9F3N2: C, 58.39; H, 4.01; N, 12.39. Found: C,
58.27; H, 3.97; N, 12.04.
In summary trifluoromethylenaminones are efficient
building blocks for the synthesis of fluorinated 4-phenyl
or 4-benzoylpyrazoles. The cyclocondensation with phenyl
hydrazine is more regioselective than with methylhydrazine.
4.4. 1,4-Diphenyl-3-trifluoromethyl-1H-pyrazole (3ab) and
1,4-diphenyl-5-trifluoromethyl-1H-pyrazole (4ab): elutant
CH2Cl2:cyclohexane (90:10)
4. Experimental
3ab: solid, 7%, 1H NMR (CDCl3): d 7.30–7.55 (8H, m, H-
ar), 7.75 (2H, dq, J ¼ 1:1 Hz, J ¼ 8:6 Hz, H-ar), 8.01 (1H,
q, J ¼ 0:9 Hz, H-5). 13C NMR (CDCl3): d 119.7 (CH-ar),
119.6 (CH-ar), 121.5 (q, 1JC;F ¼ 269:3 Hz, CF3), 123.3 (C-
4), 127.5–128.7 (CH-ar), 129.6 (C-5), 130.2 (Cq-ar), 139.2
4.1. General techniques
Melting points were taken on a Reichert melting point
apparatus and were uncorrected. 1H (300 MHz) and 13C
(75 MHz) NMR spectra were recorded on a Bruker AC 300
spectrometer. 19F NMR spectra (235 MHz) were recorded
on a Bruker AC 250 spectrometer. Chemical shifts are
expressed in parts per million from TMS (1H and 13C) or
CFCl3 (19F) as internal reference. IR spectra were recorded
on a BOMEM MB Series apparatus. Mass spectra were
recorded on a Fison VG Autospec spectrometer at 70 eV in
electron impact mode. Elemental analyses were performed
with a Perkin-Elmer CHN 2400 apparatus. The X-ray
structure analysis was performed with a CAD4 ENRAF-
NONIUS automatic diffractometer.
2
(Cq-ar), 140.3 (q, JC;F ¼ 36:5 Hz, C-3); EIMS m/z: 288
[M]þ (100), 269 [MꢁF]þ (13), 219 [MꢁCF3]þ (47), 191
(24), 165 (46), 116 (32).
4ab: solid, 76%, 1H NMR (CDCl3): d 7.44 (5H, m, H-ar),
7.51 (5H, m, H-ar), 7.76 (1H, m, H-3). 13C NMR (CDCl3): d
120.3 (q, 1JC;F ¼ 270:5 Hz, CF3), 125.8 (CH-ar), 126.1 (C-
4), 128.0 (CH-ar), 128.4 (CH-ar), 128.4–129.0 (m, C-5),
129.0 (CH-ar), 129.1 (CH-ar), 129.2 (CH-ar), 130.7 (Cq-ar),
139.8 (Cq-ar), 140.4 (C-3); EIMS: 288 [M]þ (100), 240 (8),
219 [MꢁCF3]þ (27), 191 (16), 165 (34), 116 (17). Anal.
Calc. for C16H11F3N2: C, 66.65; H, 3.85; N, 9.72. Found: C,
66.15; H, 3.94; N, 9.71.
4.2. General experimental procedure for the synthesis
of pyrazoles
4.5. 1-(4-Nitrophenyl)-4-phenyl-5-trifluoromethyl-1H-
pyrazole (4ac): elutant CH2Cl2:cyclohexane
(80:20)
To a solution of enaminoketone (1a–c) in CH3CN was
added hydrazine (2a–c) (1.2 equiv.). The reaction mixture
was stirred at reflux or at r.t. in CH3CN for 14 h, the solvent
was evaporated in vacuo. The residue was then purified and
the regioisomers were separated and isolated by column
chromatography.
1
Crystals, 54%, mp: 145–146 8C; H NMR (CDCl3): d
7.44 (5H, m, H-ar), 7.76 (2H, d, J ¼ 9 Hz, H-ar), 7.84 (1H, s,
H-3), 8.39 (2H, d, J ¼ 9 Hz, H-ar); 13C NMR (CDCl3): d
1
120.1 (q, JC;F ¼ 270:6 Hz, CF3), 124.6 (CH-ar), 126.1
2
(CH-ar), 127.5 (q, JC;F ¼ 31 Hz, C-5), 127.7 (C-4),
4.3. 1-Methyl-4-phenyl-3-trifluoromethyl-1H-pyrazole
(3aa) and 1-methyl-4-phenyl-5-trifluoromethyl-1H-
pyrazole (4aa): elutant CH2Cl2:cyclohexane (90:10)
128.4 (CH-ar), 128.6 (CH-ar), 129.0 (CH-ar), 129.9 (Cq-
ar), 141.7 (C-3), 144.5 (Cq-ar), 147.6 (Cq-ar); EIMS: 333
[M]þ (100), 303 [MꢁNO]þ (12), 218 (10), 151 (9). Anal.
Calc. for C16H10F3N3O2: C, 57.64; H, 3.03; N, 12.61. Found:
C, 57.42; H, 2.97; N, 12.57.
3aa: solid, 58%, IR (KBr): n 2367, 1481, 1289, 1173,
1115, 984, 766, 698 cmꢁ1; 1H NMR (CDCl3): d 3.99 (3H, s,
N CH3), 7.28–7.44 (5H, m, H-ar), 7.48 (1H, s, H-5). 13C
NMR (CDCl3): d 39.4 (N-CH3), 121.6 (q, 1JC;F ¼ 269:4 Hz,
CF3), 122.4 (C-4), 127.6 (CH-ar), 128.4 (CH-ar), 128.5 (CH-
4.6. (1-Methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-
phenylmethanone (5ba), (1-methyl-5-trifluoromethyl-1H-
pyrazol-4-yl)-phenylmethanone (6ba) and 2,2,2-trifluoro-1-
(1-methyl-3-phenyl-1H-pyrazol-4-yl)-ethanone (7ba):
elutant cyclohexane:AcOEt (70:30)
2
ar), 130.5 (Cq-ar), 130.8 (C-5), 138.4 (q, JC;F ¼ 36:5 Hz,
C-3). EIMS m/z: 226 [M]þ (100), 207 [MꢁF]þ (38), 187
(14), 157 [MꢁCF3]þ (42), 142 (36), 130 (24), 116 (47).
Anal. Calc. for C11H9F3N2: C, 58.39; H, 4.01; N, 12.39.
Found: C, 58.64; H, 4.11; N, 12.28.
5ba: solid, 45%, mp: 97 8C; UV (MeOH): l 203, 251 nm;
IR (KBr): n 1658, 1305 cmꢁ1; H NMR (CDCl3): d 4.01
1
4aa: solid, 23%, IR (KBr): n 2363, 1269, 1182, 1121,
(3H, s, N-CH3), 7.46 (2H, t, J ¼ 8 Hz, H-ar), 7.58 (1H, t,
J ¼ 8 Hz, H-ar), 7.77 (2H, d, J ¼ 8 Hz, H-ar), 7.79 (1H, s,
H-5); 13C NMR (CDCl3): d 39.6 (N-CH3), 119.8 (C-4),
1080, 698 cmꢁ1 1H NMR (CDCl3): d 4.07 (3H, q,
;
J ¼ 1:1 Hz, N-CH3), 7.30–7.46 (5H, m, H-ar), 7.51 (1H,
s, H-3). 13C NMR (CDCl3): d 39.0 (q, J ¼ 2:0 Hz, N-CH3),
120.4 (q, JC;F ¼ 269:6 Hz, CF3), 128.5 (CH-ar), 128.7
1
1
120.6 (q, JC;F ¼ 270:2 Hz, CF3), 125.1 (C-4), 127.7 (CH-
(CH-ar), 132.9 (CH-ar), 135.9 (C-5), 138.2 (Cq-ar), 141.9
(q, 2JC;F ¼ 38:5 Hz, C-3), 186.9 (C¼O); 19F NMR (CDCl3):
ar), 128.2 (CH-ar), 128.2–129.2 (m, C-5), 129.2 (CH-ar),

A. Touzot et al. / Journal of Fluorine Chemistry 125 (2004) 1299–1304
1303
d ꢁ61.9 (q, 3F, J ¼ 0:5 Hz, CF3); EIMS m/z: 254 [M]þ (50),
235 [MꢁF]þ (9), 177 [MꢁPh]þ (100), 105 [PhCO]þ (30).
Anal. Calc. for C12H9F3N2O1: C, 56.70; H, 3.57; N, 11.02.
Found: C, 56.44; H, 2.92; N, 10.89.
(100), 145 [Ar]þ (22), 109 (23); HRMS Calc. for
C12H7F3N2O1Cl2: 321.9894. Found: 321.9888.
4.8. Phenyl-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-
methanone (6bb) and 1-(1,5-diphenyl-1H-pyrazol-4-yl)-
2,2,2-trifluoroethanone (8bb): elutant CH2Cl2:cyclohexane
(80:20)
6ba: solid, 17%, UV (MeOH): l 203, 254 nm; IR (KBr): n
1693, 1359, 900 cmꢁ1; H NMR (CDCl3): d 4.11 (3H, q,
1
J ¼ 1:3 Hz, N-CH3), 7.50 (2H, t, J ¼ 8 Hz, H-ar), 7.62 (1H,
t, J ¼ 8 Hz, H-ar), 7.67 (1H, s, H-3), 7.86 (2H, d, J ¼ 8 Hz,
H-ar); 13C NMR (CDCl3): d 39.4 (q, J ¼ 2:5 Hz, N-CH3),
6bb: solid, 54%, UV (MeOH): l 205, 257 nm; IR (KBr): n
119.6 (q, JC;F ¼ 270:6 Hz, CF3), 122.7 (C-4), 128.6 (CH-
1665, 1501, 1292, 1244, 1182, 1140, 899, 696 cmꢁ1; H
1
1
ar), 129.6 (CH-ar), 130.2–133.0 (m, C-5), 133.4 (CH-ar),
137.6 (Cq-ar), 140.1 (C-3), 188.0 (C¼O); 19F NMR
(CDCl3): d ꢁ58.3 (dq, 3F, J1 ¼ 1:4 Hz, J2 ¼ 0:5 Hz,
CF3); EIMS m/z: 254 [M]þ (53), 235 [MꢁF]þ (8), 177
[MꢁPh]þ (100), 105 [PhCO]þ (40). Anal. Calc. for
C12H9F3N2O1: C, 56.70; H, 3.57; N, 11.02. Found: C,
56.85; H, 3.03; N, 10.84.
NMR (CDCl3): d 7.53 (7H, m, H-ar), 7.64 (1H, t, J ¼ 7 Hz,
H-ar), 7.89 (1H, s, H-3), 7.95 (2H, d, J ¼ 7 Hz, H-ar); 13C
1
NMR (CDCl3): d 119.2 (q, JC;F ¼ 271:3 Hz, CF3), 123.5
(C-4), 125.6 (CH-ar), 128.6 (CH-ar), 129.1 (CH-ar), 129.6
2
(CH-ar), 129.8 (CH-ar), 132.1 (q, JC;F ¼ 39:8 Hz, C-5),
133.6 (CH-ar), 137.3 (Cq-ar), 138.7 (Cq-ar), 141.1 (C-3),
188.0 (C¼O); EIMS m/z: 316 [M]þ (88), 297 [MꢁF]þ (15),
247 [MꢁCF3]þ (39), 239 [MꢁPh]þ (100), 219
[MꢁCOCF3]þ (31), 144 (23), 105 [PhCO]þ (75); HRMS
for C17H11F3N2O1: 316.08235. Found: 316.08234.
7ba: solid, 19%, UV (MeOH): l 205, 217, 259 nm; IR
(KBr); n 1709, 1498, 902 cmꢁ1; H NMR (CDCl3): d 3.78
1
(3H, s, N-CH3), 7.37 (2H, m, H-ar), 7.52 (3H, m, H-ar), 8.08
(1H, q, J ¼ 2 Hz, H-5); 13C NMR (CDCl3): d 37.4 (N-CH3),
8bb: solid, 28%, mp 88 8C; UV (MeOH): l 203, 216,
263 nm; IR (KBr): n 1711, 1499, 1265, 1194, 1142, 903,
1
113.5 (C-4), 116.4 (q, JC;F ¼ 291:1 Hz, CF3), 127.6 (Cq-
766, 694 cmꢁ1; H NMR (CDCl3): d 7.32 (10H, m, H-ar),
1
ar), 128.7 (CH-ar), 129.5 (CH-ar), 130.2 (CH-ar), 141.5 (q,
2
J ¼ 4:3 Hz, C-5), 148.6 (C-3), 174.2 (q, JC;F ¼ 36:5 Hz,
8.27 (1H, s, H-3); 13C NMR (CDCl3): d 114.3 (C-4), 116.5
C¼O); EIMS m/z: 254 [M]þ (25), 217 (24), 185 [MꢁCF3]þ
(100); HRMS Calc. for C12H9F3N2O1: 254.0674. Found:
254.0667.
(q, JC;F ¼ 291:4 Hz, CF3), 125.3 (CH-ar), 127.5 (Cq),
1
128.3–130.1 (CH-ar), 138.3 (Cq-ar), 142.4 (q, J ¼ 4:4 Hz,
2
C-3), 148.1 (Cq), 174.4 (q, JC;F ¼ 36:2 Hz, C¼O); EIMS
m/z: 316 [M]þ (35), 247 [MꢁCF3]þ (100), 219
[MꢁCOCF3]þ (6), 190 (7). Anal. Calc. for C17H11F3N2O1:
C, 64.54; H, 3.50; N, 8.86. Found: C, 64.13; H, 2.65; N, 8.66.
4.7. (2,4-Dichlorophenyl)-(1-methyl-3-trifluoromethyl-1H-
pyrazol-4-yl)-methanone (5ca) and (2,4-dichlorophenyl)-
(1-methyl-5-trifluoromethyl-1H-pyrazol-4-yl)-methanone
(6ca): elutant cyclohexane:AcOEt (70:30)
4.9. (2,4-Dichlorophenyl)-(1-phenyl-3-trifluoromethyl-1H-
pyrazol-4-yl)-methanone (5cb) and (2,4-dichlorophenyl)-
(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-methanone
(6cb): elutant CH2Cl2:cyclohexane (80:20)
5ca: solid, 66%, mp 105 8C; UV (MeOH): l 203, 213,
249 nm; IR (KBr): n 1668, 1310, 1157, 1142, 910 cmꢁ1; 1H
NMR (CDCl3): d 3.97 (3H, s, N-CH3), 7.35 (2H, d,
J ¼ 1:2 Hz, H-ar), 7.46 (1H, d, J ¼ 1:2 Hz, H-ar), 7.60
(1H, s, H-5); 13C NMR (CDCl3): d 39.8 (N-CH3), 120.2
(q, 1JC;F ¼ 270 Hz, CF3), 120.5 (C-4), 127.2 (CH-ar), 129.4
(CH-ar), 130.2 (CH-ar), 132.0 (Cq-ar), 137.1 (Cq-ar), 137.2
(Cq-ar), 137.3 (C-5), 141.4 (q, 2JC;F ¼ 39:3 Hz, C-3), 184.5
(C¼O); 19F NMR (CDCl3): d ꢁ62.7 (s, 3F, CF3); EIMS m/z:
322 [M]þ (38), 177 [MꢁAr]þ (100), 145 [Ar]þ (22), 109
(23). Anal. Calc. for C12H7F3N2O1Cl2: C, 44.72; H, 2.19; N,
8.70. Found: C, 45.08; H, 1.81; N, 8.77.
6ca: solid, 24%, mp 93 8C; UV (MeOH): l 203, 213,
255 nm; IR (KBr): n 1678, 1294, 1144, 905 cmꢁ1; 1H NMR
(CDCl3): d 4.11 (3H, q, J ¼ 1:6 Hz, N-CH3), 7.35 (1H, dd,
J1 ¼ 8 Hz, J2 ¼ 2 Hz, H-ar), 7.42 (1H, d, J ¼ 8 Hz, H-ar),
7.48 (1H, d, J ¼ 2 Hz, H-ar), 7.54 (1H, s, H-3); 13C NMR
(CDCl3): d 40.0 (q, J ¼ 4:1 Hz, N-CH3), 119.4 (q,
1JC;F ¼ 271 Hz, CF3), 123.1 (C-4), 127.2 (CH-ar), 130.4
(CH-ar), 130.7 (CH-ar), 130.8–132.5 (m, C-5), 132.7 (Cq-
ar), 136.7 (Cq-ar), 137.7 (Cq-ar), 141.5 (C-3), 185.6 (C¼O);
19F NMR (CDCl3): d ꢁ58.2 (dq, 3F, J1 ¼ 1:5 Hz,
J2 ¼ 0:5 Hz, CF3); EIMS m/z: 322 [M]þ (38), 177 [MꢁAr]þ
5cb: solid, 4%, mp 105 8C; UV (MeOH): l 203, 215,
260 nm; IR (KBr): n 1674, 1499, 1308, 1223, 1146,
907 cmꢁ1 1H NMR (CDCl3): d 7.3–7.6 (6H, m, H-ar),
;
7.68 (2H, d, J ¼ 7:5 Hz, H-ar), 8.06 (1H, m, J ¼ 1 Hz,
H-5); 13C NMR (CDCl3): d 120.1 (CH-ar), 120.2 (q,
1JC;F ¼ 270:2 Hz, CF3), 121.8 (C-4), 128.3–130.4 (CH-
ar), 132.3 (Cq-ar), 133.6 (C-5), 137.1 (Cq-ar), 137.4 (Cq-
2
ar), 138.7 (Cq-ar), 142.7 (q, JC;F ¼ 39:2 Hz, C-3), 184.7
(C¼O); EIMS m/z: 384 [M]þ (34), 239 [MꢁAr]þ (100), 173
(24); HRMS Calc. for C17H9F3N2O1Cl2: 384.0049. Found:
384.0044.
6cb: solid, 85%, mp 88 8C; UV (MeOH): l 203, 211,
261 nm; IR (KBr): n 1676, 1499, 1294, 1231, 1144 cmꢁ1; 1H
NMR (CDCl3): d 7.38 (1H, dd, J1 ¼ 8:3 Hz, J2 ¼ 1:9 Hz,
H-ar), 7.51 (7H, m, H-ar), 7.77 (1H, s, H-3); 13C NMR
1
(CDCl3): d 118.9 (q, JC;F ¼ 271:9 Hz, CF3), 123.6 (C-4),
125.7–131.0 (CH-ar), 132.2 (q, 2JC;F ¼ 40:2 Hz, C-5), 133.0
(Cq-ar), 136.6 (Cq-ar), 138.0 (Cq-ar), 138.9 (Cq-ar), 142.4
(C-3), 185.9 (C¼O); EIMS m/z: 384 [M]þ (25), 287
[MꢁCOCF3]þ (23), 239 [MꢁAr]þ (100), 177 (63), 149

1304
A. Touzot et al. / Journal of Fluorine Chemistry 125 (2004) 1299–1304
[4] R. Garg, A. Kurup, S.B. Mekapati, C. Hansch, Chem. Rev. 103
(2003) 703–731.
(30), 111 (40). Anal. Calc. for C17H9F3N2O1Cl2: C, 53.12;
H, 2.34; N, 7.29. Found: C, 52.73; H, 1.95; N, 7.06.
[5] H.-B. Yu, W.-Y. Huang, J. Fluorine Chem. 87 (1998) 69–73.
[6] B.C. Hamper, M.L. Kurtzweil, J.P. Beck, J. Org. Chem. 57 (1992)
5680–5686.
Acknowledgements
[7] J. Fabron, R. Pastor, A. Cambon, J. Fluorine Chem. 37 (1987)
371–386.
[8] (a) L.-P. Song, Q.-L. Chu, S.-Z. Zhu, J. Fluorine Chem. 107 (2001)
107–112;
We thank C. Petermann (NMR and NOEs) and P. Sigaut
(MS) for spectroscopic recordings and S. Lanthony for
microanalysis and S. Gobert for English correction.
(b) H.G. Bonacorso, A.D. Wastowski, N. Zanatta, M.A.P. Martins,
J.A. Naue, J. Fluorine Chem. 92 (1998) 23–26;
(c) M.E.F. Braibante, G. Clar, M.A.P. Martins, J. Heterocyclic
Chem. 30 (1993) 1159–1160.
References
[9] (a) L.-P. Song, S.-Z. Zhu, J. Fluorine Chem. 111 (2001) 201–
205;
[1] (a) R. Filler, Y. Kobayashi, L.M. Yagupolskii, Organofluorine
Compounds in Medicinal Chemistry and Biomedical Application,
Elsevier, Amsterdam, 1993;
(b) S.P. Singh, D. Kumar, B.G. Jones, M.D. Threadgill, J. Fluorine
Chem. 94 (1999) 199–203;
(c) J.W. Lyga, R.M. Patera, J. Heterocyclic Chem. 27 (1990)
919–921.
(b) J.T. Welch, Tetrahedron 43 (1987) 3123–3197.
[2] (a) J. Elguero, Pyrazoles and their benzoderivatives, in: K.T. Potts
(Ed.), Comprehensive Heterocyclic Chemistry, vol. 1, Pergamon
Press, Oxford, 1984, pp. 167–343;
[10] L.F. Lee, F.M. Schleppnik, R.W. Schneider, D.H. Campbell, J.
Heterocyclic Chem. 27 (1990) 243–245.
[11] J.M. Mellor, S.R. Schofield, S.R. Korn, Tetrahedron 53 (1997)
17163–17170.
(b) 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;
[12] (a) M. Soufyane, S. van den Broek, L. Khamliche, C. Mirand,
Heterocycles 51 (1999) 2445–2451;
(b) H. Berber, M. Soufyane, C. Mirand, S. Schmidt, A.-M. Aubertin,
Tetrahedron 57 (2001) 7369–7375;
(c) H. Berber, M. Soufyane, M. Santillana-Hayat, C. Mirand,
Tetrahedron Lett. 43 (2002) 9233–9235.
(c) S.W. Djuric, N.Y. BaMaung, A. Basha, H. Liu, J.R. Luly, D.J.
Madar, R.J. Sciotti, N.P. Tu, F.L. Wagenaar, P.E. Wiedeman, X. Zhou,
S. Ballaron, J. Bauch, Y.-W. Chen, X.G. Chiou, T. Fey, D. Gauvin, E.
Gubbins, G.C. Hsieh, K.C. Marsh, K.W. Mollison, M. Pong, T.K.
Shaughnessy, M.P. Sheets, M. Smith, J.M. Trevillyan, U. Warrior,
C.D. Wegner, G.W. Carter, J. Med. Chem. 43 (2000) 2975–2981;
(d) Can. CA 1 130 808, Chem. Abstr. 98 (1983) 72087e.
[3] (a) Eur. Pat. Appl. EP 819 690, Chem. Abstr. 128 (1998) 140726;
(b) US Patent 5 698 708, Chem. Abstr. 128 (1998) 75398;
(c) J. Elguero, Pyrazoles, in: K.T. Potts (Ed.), Comprehensive Hetero-
cyclic Chemistry, vol. 2, Pergamon Press, Oxford, 1996, pp. 1–75;
(d) Ger. Offen. DE 19 629 826, Chem. Abstr. 128 (1998) 140699w;
(e) Jpn. Kokai Tokkyo JP 09 169 736, Chem. Abstr. 127 (1997)
81448;
[13] (a) E. Okada, R. Masuda, M. Hojo, Heterocycles 34 (1992)
791–798;
´
(b) M. Soufyane, C. Mirand, J. Levy, Tetrahedron Lett. 34 (1993)
7737–7740;
(c) M. Kawase, M. Hirabayashi, S. Saito, K. Yamamoto, Tetrahe-
dron Lett. 40 (1999) 2541–2544.
[14] Y. Kobayashi, T. Yamashita, K. Takahashi, H. Kuroda, I. Kumadaki,
Chem. Pharm. Bull. 32 (1984) 4402–4409.
´
[15] (a) J. Diab, A. Laurent, I. Le Drean, J. Fluorine Chem. 84 (1997)
145–147;
(b) D. Greif, U. Eilitz, M. Pulst, D. Riedel, M. Wecks, J. Fluorine
Chem. 94 (1999) 91–103.
[16] W. Holzer, Tetrahedron Lett. 47 (1991) 1393–1398.
¨
[17] P. Sohar, O. Feher, E. Tihanyi, Org. Magn. Res. 12 (1979)
(f) Jpn. Kokai Tokkyo Koho JP 02 129 171, Chem. Abstr. 113
(1990) 172014a.
´
´
205–208.