Formation and dehydration of a series of 5-hydroxy-5-trifluoromethyl-4,5-dihydropyrazoles

Article abstract of DOI:10.1016/S0022-1139(99)00011-1

Reaction of five (3-oxo-4,4,4-trifluorobutanoyl)heterocycles with hydrazine hydrate under mild conditions gave the corresponding 3-heterocyclyl-5-hydroxy-5-trifluoromethyl-4,5-dihydropyrazoles. Thermal elimination of water from the 3-(thien-2-yl), 3-(pyridin-2-yl) and 3-(pyridin-4-yl) compounds readily gave the corresponding pyrazoles but acid catalysis was required to form 3-(benzothiazol-2-yl)-5-trifluoromethylpyrazole and 3-(1-methylbenzimidazol-2-yl)-5-trifluoromethylpyrazole. More forcing conditions were required for the analogous dehydration/aromatisations giving 3,5-bis(trifluoromethyl)-1-(4-nitrophenyl)pyrazole and 3,5-bis(trifluoromethyl)-1-pentafluorophenylpyrazole.

Full text of DOI:10.1016/S0022-1139(99)00011-1

Journal of Fluorine Chemistry 94 (1999) 199±203
Formation and dehydration of a series of 5-hydroxy-5-tri¯uoromethyl-
4,5-dihydropyrazoles
Shiv P. Singha,*, Dalip Kumar1,a, Brian G. Jonesb, Michael D. Threadgill2,b
aDepartment of Chemistry, Kurukshetra University, Kurukshetra 136119, India
bDepartment of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK
Received 29 September 1998; accepted 21 December 1998
Abstract
Reaction of ®ve (3-oxo-4,4,4-tri¯uorobutanoyl)heterocycles with hydrazine hydrate under mild conditions gave the corresponding 3-
heterocyclyl-5-hydroxy-5-tri¯uoromethyl-4,5-dihydropyrazoles. Thermal elimination of water from the 3-(thien-2-yl), 3-(pyridin-2-yl) and
3-(pyridin-4-yl) compounds readily gave the corresponding pyrazoles but acid catalysis was required to form 3-(benzothiazol-2-yl)-5-
tri¯uoromethylpyrazole and 3-(1-methylbenzimidazol-2-yl)-5-tri¯uoromethylpyrazole. More forcing conditions were required for the
analogous dehydration/aromatisations giving 3,5-bis(tri¯uoromethyl)-1-(4-nitrophenyl)pyrazole and 3,5-bis(tri¯uoromethyl)-1-penta¯uor-
ophenylpyrazole. # 1999 Elsevier Science S.A. All rights reserved.
Keywords: 5-Hydroxy-5-tri¯uoromethyl-4,5-dihydropyrazole; 5-Tri¯uoromethylpyrazole; Dehydration
1. Introduction
boiling acetic acid was necessary for conversion to the 3-
substituted 1-(4-methylquinolin-2-yl)-5-tri¯uoromethylpyr-
azoles. These [1] and other observations [2±5] concerning
the reaction of (substituted)hydrazines with tri¯uoromethyl
b-diketones suggest that the ®nal elimination of water from
5-hydroxy-4,5-dihydropyrazoles to form pyrazoles is depen-
dent on the electronic nature of the 5-substituent and of any
1-substituent present. We now report the results of our
studies on the conditions required to effect this elimination
in seven additional 5-hydroxy-5-tri¯uoromethyl-4,5-dihy-
dropyrazoles.
We recently reported [1] our studies on the mechanism
and regioselectivity of the reaction of hydrazinoquinolines
with a range of tri¯uoromethyl b-diketones, speci®cally
1,1,1-tri¯uoropentane-2,4-dione, 1,1,1-tri¯uoro-4-phenyl-
butane-2,4-dione and 1,1,1-tri¯uoro-4-(thien-2-yl)butane-
2,4-dione (2e). Regioselectivity, but not regiospeci®city,
was noted in that 2-hydrazino-4-methylquinoline was pre-
dominantly added initially at the carbonyl carbon (or the
corresponding enol carbon) remote from the CF3 group,
although minor amount of products derived from attack at
the tri¯uoromethyl ketone carbonyl were isolated. Interest-
ingly, the intermediate 5-substituted 3-hydroxy-1-
(4-methylquinolin-2-yl)-3-tri¯uoromethyl-4,5-dihydropyra-
zoles could not be isolated as water was eliminated rapidly
under the reaction conditions (boiling ethanol) to give the
minor products, the 5-substituted 1-(4-methylquinolin-2-
yl)-3-tri¯uoromethylpyrazoles. In contrast, the 3-substituted
5-hydroxy-1-(4-methylquinolin-2-yl)-5-tri¯uoromethyl-
4,5-dihydropyrazoles were resistant to elimination of water
under these conditions and treatment with sulphuric acid in
2. Results and discussion
We sought to prepare a range of 5-hydroxy-5-tri¯uoro-
methyl-4,5-dihydropyrazoles as substrates for investigations
of methods and ease of dehydration to the corresponding
tri¯uoromethylpyrazoles. Whereas most of the starting tri-
¯uoromethyl b-diketones 2c±2f were commercially avail-
able, the benzothiazol-2-yl analogue 2a and the 1-
methylbenzimidazol-2-yl analogue 2b were prepared by
Claisen condensation of ethyl tri¯uoroacetate with 2-acet-
ylbenzothiazole 1a and 2-acetyl-1-methylbenzimidazole 1b,
respectively. Treatment of 2a with hydrazine hydrate in
ethanol at ambient temperature gave exclusively the 3-
aryl-5-hydroxy-5-tri¯uoromethyl-4,5-dihydropyrazole 3a
*Corresponding author. Fax: +1225-826114; e-mail: prsmdt@bath.ac.uk
1Present address: Department of Chemistry, Sam Houston State
University, Huntsville, TX 77341-2117, USA.
2Co-corresponding author.
0022-1139/99/$ ± see front matter # 1999 Elsevier Science S.A. All rights reserved.
P I I : S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 0 1 1 - 1

200
S.P. Singh et al. / Journal of Fluorine Chemistry 94 (1999) 199±203
in high yield with no evidence for formation of the other
regioisomer formally derived from initial attack at the
tri¯uoromethyl ketone. A similar reaction of 2b with etha-
nolic hydrazine hydrate gave exclusively the analogous 3-
aryl-5-hydroxy-5-tri¯uoromethyl-4,5-dihydropyrazole 3b.
Modi®cation of the reaction conditions was necessary to
achieve high yields of the 3-aryl-5-hydroxy-5-tri¯uoro-
methyl-4,5-dihydropyrazoles 3c±3e from the tri¯uoro-
methyl b-diketones 2c±2e bearing pyridine or thiophene
as substituent. In these cases, small quantities of the corre-
sponding aromatic pyrazoles 4c±4e were formed when the
condensations were conducted in ethanol but replacement of
the solvent with diethyl ether allowed clean conversion of
2c±2e with hydrazine hydrate to the 3-aryl-5-hydroxy-5-
tri¯uoromethyl-4,5-dihydropyrazoles 3c±3e. In contrast, as
we reported previously [5], prolonged treatment of hexa-
¯uoropentane-2,4-dione 2f at elevated temperature was
necessary to effect condensation with hydrazines bearing
deactivating nitrophenyl and penta¯uorophenyl groups giv-
ing the 1-aryl-5-hydroxy-3,5-bis(tri¯uoromethyl)-4,5-dihy-
dropyrazoles 3f and 3g. No dehydration to the 1-aryl-3,5-
bis(tri¯uoromethyl)pyrazoles 4f and 4g was observed even
in boiling ethanol (Scheme 1).
5-C, respectively, with the latter showing 2-bond coupling to
¯uorine (2JC F ˆ 30:9 Hz). Finally, the 19F spectrum showed
a signal at ꢀ 76.03, which is typical for CF3 attached to an
sp3 carbon [1,5,6].
The hydroxydihydropyrazoles 3a±3g were dehydrated to
the corresponding pyrazoles 4a±4g under a variety of con-
ditions. Water was easily eliminated from 3c±3e by heating
in ethanol as previously reported for 3c [7]. In contrast, the
dehydration of 3a and 3b required the presence of acetic
acid in the solvent mixture. The 5-hydroxy-3,5-bis(tri¯uor-
omethyl)-4,5-dihydropyrazoles 3f and 3g, which also carry
electron-de®cient aryl substituents at nitrogen, required
much more vigorous conditions. Prolonged treatment of
the N-mononitrophenyl compound 3f with hydrochloric
acid in boiling ethanol afforded the pyrazole 4f in good
yield but even these conditions failed to effect elimination of
water from the N-penta¯uorophenyl compound 3g. In this
case, it was necessary the acetylate the OH with acetic
anhydride and carry out the one-pot elimination in boiling
acetic acid to form 4g. The 1H NMR spectrum of 4a exhibits
a singlet at ꢀ 7.71 for the aromatic pyrazole 4-H. The
aromatic pyrazole is also con®rmed by the observation of
13C NMR signals at ꢀ 140.30, ꢀ 104.73 and ꢀ 141.61 for 3-C,
4-C and 5-C, respectively. Assignment of 5-C was possible,
since it resonates as a quartet, with 2JC Fˆ38.1 Hz. Further-
more, the 19F NMR spectrum showed a singlet at ꢀ 57.35
for the tri¯uoromethyl group, a chemical shift consistent
with those reported for other 5-tri¯uoromethylpyrazoles
[1,5].
The dihydropyrazoles were identi®ed by 1H and 13C
NMR spectroscopy and by other techniques as appropriate.
1
For example, the H NMR spectrum of 3a displayed the
dihydropyrazole 4-CH2 protons as an AB system (doublets
at ꢀA 3.34 and ꢀB 3.51, with the geminal coupling constant
2J ˆ 18:3 Hz), which corresponds with our previous obser-
vations for 1-aryl-5-hydroxy-3,5-bis(tri¯uoromethyl)-4,5-
dihydropyrazoles [5]. Further support for the structure of
3a was provided by the 13C NMR spectrum which contained
signals at ꢀ 40.73 and ꢀ 91.53 for dihydropyrazole 4-C and
It is evident, when ranking the ease of elimination of
water from 3a±3g to form the pyrazoles 4a±4g (3c±3e>
3a,3b>3f>3g), that the presence of electron-withdrawing
groups at the dihydropyrazole 5-C, the 3-C or the 1-N
Scheme 1. Formation of 3-substituted 5-hydroxy-5-trifluoromethyl-4,5-dihydropyrazoles and different methods for dehydration to 3-substituted 5-
trifluoromethylpyrazoles. Reagents: i, EtO2CCF3, NaOMe, Et2O; ii, N2H4, EtOH; iii, N2H4, Et2O; iv, R2NHNH2, EtOH, ~; v, AcOH, EtOH, ~; vi, conc.
H2SO4, EtOH, ~; vii, HCl, aq. EtOH, ~; viii, Ac2O, AcOH, ~.

S.P. Singh et al. / Journal of Fluorine Chemistry 94 (1999) 199±203
201
inhibits this process. The electron-withdrawing CF3 group
at position 5 would destabilise any carbocation character in
an E1-like mechanism as shown by the much greater ease of
elimination from 3-hydroxy-1-(4-methylquinolin-2-yl)-3-
tri¯uoromethyl-4,5-dihydropyrazoles than from 3-substi-
3-(Benzothiazol-2-yl)-5-hydroxy-5-tri¯uoromethyl-4,5-
dihydropyrazole (3a). Compound 2a (819 mg, 3 mmol) was
added dropwise to hydrazine hydrate (170 ml, 3.5 mmol) in
ethanol (10 ml) and the mixture was stirred for 2 h. The
solvent was evaporated and the solid was washed with water
and dried to give 3a (650 mg, 76%) as a white solid, m.p.
tuted
5-hydroxy-1-(4-methylquinolin-2-yl)-5-tri¯uoro-
1
methyl-4,5-dihydropyrazoles [1]. Inhibition of elimination
by the lowering of the electron density at 1-N can be
rationalised similarly, comparing the formation of 4g with
that of 4f and that of 3,5-bis(tri¯uoromethyl)pyrazole [5].
The origin of the observed inhibition of elimination by the
bicyclic benzothiazol-2-yl (3a!4a) and 1-methylbenzimi-
dazol-2-yl (3b!4b) substituents at position 3 is less clear
but may involve the in¯uence of this substituent on the
acidity of the pyrazole 4-CH2 protons.
1888C. H NMR ((CD3)2SO) ꢀ: 3.34 (d, 1H, Jˆ18.3 Hz,
pyrazole 4-H), 3.51 (d, 1H, Jˆ18.3 Hz, pyrazole 4-H), 7.43
(t, 1H, Jˆ8.3 Hz, benzothiazole 6-H), 7.49 (t, 1H,
Jˆ8.3 Hz, benzothiazole 5-H), 7.64 (s, 1H, NH), 8.00 (d,
1H, Jˆ7.6 Hz, benzothiazole 7-H), 8.08 (d, 1H, Jˆ7.6 Hz,
benzothiazole 7-H), 8.99 (s, 1H, OH) ppm. 13C NMR
((CD3)2SO) ꢀ: 40.73 (pyrazole 4-C), 91.53 (q, JC±F
ˆ30.9 Hz, pyrazole 5-C), 122.25 (benzothiazole 7-C),
122.80 (benzothiazole 4-C), 123.76 (q, JC±Fˆ283.4 Hz,
CF3), 125.95 (benzothiazole 6-C), 126.51 (benzothiazole
5-C), 133.95 (benzothiazole 7a-C), 143.27 (pyrazole 3-C),
152.99 (benzothiazole 3a-C), 161.03 (benzothiazole 2-C)
ppm. 19F NMR ((CD3)2SO) ꢀ: 76.03 (CF3) ppm. Analysis:
Found: N, 14.40%. C11H8F3N3OS requires: N, 14.63%.
5-Hydroxy-3-(1-methylbenzimidazol-2-yl)-5-tri¯uorome-
thyl-4,5-dihydropyrazole (3b). Compound 2b was treated
with hydrazine, as for the synthesis of 3a, to give 3b (74%)
as a white solid, m.p. 1948C. 1H NMR (CDCl3‡(CD3)2SO)
ꢀ: 3.36 (d, 1H, Jˆ18.2 Hz, pyrazole 4-H), 3.54 (d, 1H,
Jˆ18.0 Hz, pyrazole 4-H), 4.09 (s, 3H, Me), 7.21±7.28 (m,
2H, benzimidazole 5,6-H2), 7.41 (dd, 1H, Jˆ7.2 and 2.3 Hz,
benzimidazole 4-H), 7.61 (dd, 1H, Jˆ7.4 and 2.3 Hz,
benzimidazole 7-H), 8.05 (s, 1H, NH) ppm. 13C NMR
(CDCl3‡(CD3)2SO) ꢀ: 31.73 (Me), 42.42 (pyrazole 4-C),
91.05 (q, JC±Fˆ31.1 Hz, pyrazole 5-C), 109.34 (benzimi-
dazole 7-C), 119.04 (benzimidazole 4-C), 121.91 (benzi-
midazole 5-C), 123.07 (benzimidazole 6-C), 125.37 (q, JC±F
ˆ272.5 Hz, CF3), 136.23 (benzimidazole 7a-C), 141.83
(pyrazole 3-C), 144.93 (benzimidazole 3a-C), 149.313 (ben-
zimidazole 2-C) ppm. 19F NMR ((CD3)2SO) ꢀ: 78.20
(CF3) ppm. Analysis: Found: N, 19.42%. C12H11F3N4O
requires: N, 19.71%.
3. Experimental details
Melting points were measured on samples in open capil-
1
laries in a Mel-Temp apparatus and are uncorrected. H
NMR spectra were obtained at 270, 300 and 400 MHz, 13C
spectra at 67.5, 75 and 100 MHz and 19F spectra at 376 MHz
using Jeol GX270, Bruker 300 and Jeol EX400 instruments,
respectively, using CDCl3 as solvent, unless otherwise
noted. The internal standard for the 19F spectra was CFCl3,
setting the CF35Cl3 signal as ꢀ 0.00. Solvents were evapo-
rated under reduced pressure. The stationary phase for
chromatography was silica gel. High resolution mass spec-
tra were measured on VG 7070 and Kratos MS-50 spectro-
meters. Elemental analyses were performed at RSIC,
Chandigarh, India. 3,5-Bis(tri¯uoromethyl)-5-hydroxy-1-
(4-nitrophenyl)-4,5-dihydropyrazole 3f and 3,5-bis(tri¯uor-
omethyl)-5-hydroxy-1-(penta¯uorophenyl)-4,5-dihydro-
pyrazole 3g were prepared as previously described by
us [5].
2-(3-Oxo-4,4,4-tri¯uorobutanoyl)benzothiazole
(2a).
Ethyl tri¯uoroacetate (3.22 ml, 27 mmol) was added drop-
wise to a stirred suspension of sodium methoxide (1.60 g,
30 mmol) in dry diethyl ether. 2-Acetylbenzothiazole 1a
(4.80 g, 27 mmol) was added and the mixture was stirred for
16 h. The solvent was evaporated and the residue in water
(30 ml) was acidi®ed with sulphuric acid (10% aq.). The
mixture was extracted thrice with chloroform. The com-
bined extracts were dried (Na2SO4) and the solvent was
evaporated to give 2a (3.7 g, 50%) as a white solid, m.p. 86±
888C. MS (EI) m/z: 273.0072 (M) (C11H6F3NO2S requires
273.0072), 204 (M ± CF3), 162 (M ± CH2COCF3), 134 (M ±
COCH2COCF3).
2-(3-Oxo-4,4,4-tri¯uorobutanoyl)-1-methylbenzimida-
zole (2b). 1-Methylbenzimidazole 1b was treated with ethyl
tri¯uoroacetate and sodium methoxide, as for the synthesis
of 2a, to give 2b (34%) as a white solid, m.p. 118±1208C.
MS (EI) m/z: 270.0611 (M) (C12H9F3N2O2 requires
270.0617), 201 (M ± CF3), 159 (M ± CH2COCF3), 132
(M ± COCH2COCF3).
5-Hydroxy-3-(pyridin-2-yl)-5-tri¯uoromethyl-4,5-dihy-
dropyrazole (3c). Hydrazine hydrate (130 mg, 2.7 mmol)
was added dropwise to 2c [6] (500 mg, 2.3 mmol) in diethyl
ether (40 ml) and the mixture was stirred at ambient tem-
perature for 3.5 h. The solvent was evaporated and the
residue was treated with water. Filtration and drying gave
1
3c (415 mg, 78%) as a white solid, m.p. 1528C. H NMR
(CDCl3‡(CD3)2SO) ꢀ: 3.40 (br s, 2H, pyrazole 4-H2), 7.25
(m, 1H, pyridine 5-H), 7.70 (m, 1H, pyridine 3-H), 7.94 (d,
1H, Jˆ8.0 Hz, pyridine 4-H), 8.55 (d, 1H, Jˆ7.2 Hz, pyr-
idine 6-H) ppm. 13C NMR (CDCl3‡(CD3)2SO) ꢀ: 40.86
(pyrazole 4-C), 91.22 (q, JC±Fˆ31.2 Hz, pyrazole 5-C),
119.77 (pyridine 3-C), 120.80 (q, JC±Fˆ269.7 Hz, CF3),
122.86 (pyridine 5-C), 135.73 (pyridine 4-C), 148.56 (pyr-
idine 6-C), 149.92 (pyridine 2-C), 150.85 (pyrazole 3-C)
ppm. 19F NMR (CDCl3‡(CD3)2SO) ꢀ: 76.7 (s) ppm.
Analysis: Found: N, 18.32%. C9H8F3N3O requires: N,
18.18%.

202
S.P. Singh et al. / Journal of Fluorine Chemistry 94 (1999) 199±203
5-Hydroxy-3-(pyridin-4-yl)-5-tri¯uoromethyl-4,5-dihy-
ethanol (30 ml) in the presence of conc. sulphuric acid
(100 ml) for 30 min. Evaporation and chromatography
(ethyl acetate/hexane 1:5) gave 4c (200 mg, 72%) as a
white solid, m.p. 1328C (lit. [6] m.p. 137±1388C).
3-(Pyridin-2-yl)-5-tri¯uoromethylpyrazole (4d). Com-
pound 3d was boiled with conc. sulphuric acid in ethanol,
as for the synthesis of 4c, to give 4d (72%) as a white solid,
m.p. 1908C (lit. [6] m.p. 1908C).
3-(Thien-2-yl)-5-tri¯uoromethylpyrazole (4e). Com-
pound 3e was boiled with conc. sulphuric acid in ethanol,
as for the synthesis of 4c, to give 4e (88%) as a white solid,
m.p. 116±1178C (lit. [8] m.p. 118±1208C).
3,5-Bis(tri¯uoromethyl)-1-(4-nitrophenyl)pyrazole (4f).
3,5-Bis(tri¯uoromethyl)-4,5-dihydro-5-hydroxy-1-(4-nitro-
phenyl)pyrazole (3f) [5] (100 mg, 290 mmol) was boiled
under re¯ux with conc. aq. hydrochloric acid (0.5 ml) in
ethanol (10 ml) for 3 d. The solvent was evaporated. The
dropyrazole (3d). Compound 2d [6] was treated with
hydrazine, as for the synthesis of 3c, to give 3d (72%) as
a white solid, m.p. 1728C. 1H NMR (CDCl3‡(CD3)2SO) ꢀ:
3.24 (d, 1H, Jˆ17.8 Hz, pyrazole 4-H), 3.28 (d, 1H,
Jˆ18.0 Hz, pyrazole 4-H), 7.51 (d, 2H, Jˆ8.2 Hz, pyridine
3,5-H2), 8.56 (d, 2H, Jˆ8.1 Hz, pyridine 2,6-H2) ppm. 19F
NMR (CDCl3‡(CD3)2SO) ꢀ: 76.9 (s) ppm. Analysis:
Found: N, 17.92%. C9H8F3N3O requires: N, 18.18%.
5-Hydroxy-3-(thien-2-yl)-5-tri¯uoromethyl-4,5-dihydro-
pyrazole (3e). 2-(3-Oxo-4,4,4-tri¯uorobutanoyl)thiophene
(2e) was treated with hydrazine, as for the synthesis of
3c, to give 3e (84%) as a white solid, m.p. 1488C. 1H NMR
(CDCl3‡(CD3)2SO) ꢀ: 3.19 (d, 1H, Jˆ17.3 Hz, pyrazole 4-
H), 3.40 (d, 1H, Jˆ17.3 Hz, pyrazole 4-H), 7.02 (dd, 1H,
Jˆ3.2 and 1.2 Hz, thiophene 3-H), 7.15 (dd, 1H, Jˆ5.0 and
3.6 Hz, thiophene 4-H), 7.31 (dd, 1H, Jˆ5.0 and 1.0 Hz,
thiophene 5-H). 13C NMR (CDCl3‡(CD3)2SO) ꢀ: 42.18
(pyrazole 4-C), 91.51 (q, JC±Fˆ31.2 Hz, pyrazole 5-C),
122.50 (q, JC±Fˆ268.2 Hz, CF3), 126.87 (thiophene 4,5-
C2), 127.30 (thiophene 3-C), 135.43 (thiophene 2-C),
145.68 (pyrazole 3-C). 19F NMR (CDCl3‡(CD3)2SO) ꢀ:
77.5 (s) ppm. Analysis: Found: N, 11.43%. C8H7F3N2OS
requires: N, 11.86%.
residue,
in
dichloromethane,
was
dried
(MgSO4‡NaHCO3). Evaporation of the solvent gave 4f
1
(90 mg, 96%) as a yellow oil. H NMR (CDCl3) ꢀ: 7.18
(s, 1H, pyrazole-H), 7.77 (d, 2H, Jˆ8.9 Hz, Ar 2,6-H2), 8.42
(d, 2H, Jˆ8.9 Hz, Ar 3,5-H2) ppm. 13C NMR (CDCl3) ꢀ:
108.40 (pyrazole 4-C), 118.74 (q, JC±Fˆ270 Hz, CF3),
120.04 (q, JC±Fˆ270 Hz, CF3), 124.84 (Ar 2,6-C2),
126.32 (Ar 3,5-C2), 134.50 (q, JC±Fˆ40 Hz, C-CF3),
142.73 (Ar 4-C), 144.04 (q, JC±Fˆ40 Hz, C-CF3), 148.36
(Ar 1-C) ppm. 19F NMR (CDCl3) ꢀ: 63.18 (s, 3F, CF3),
58.07 (s, 3F, CF3) ppm. MS (EI) m/z: 325.0288 (M) (100)
(C11H5N3F6O2 requires 325.0286).
3-(Benzothiazol-2-yl)-5-tri¯uoromethylpyrazole
(4a).
Compound 3a (500 mg, 1.7 mmol) was boiled under re¯ux
in ethanol (40 ml) and acetic acid (10 ml) for 5 h. The
ethanol was evaporated. The residue was neutralised with
sodium hydrogen carbonate and was extracted with chloro-
form (3Â20 ml). Evaporation and chromatography (ethyl
acetate/hexane 1:4) gave 4a (350 mg, 74%) as a white solid,
3,5-Bis(tri¯uoromethyl)-1-(penta¯uorophenyl)pyrazole
3,5-Bis(tri¯uoromethyl)-4,5-dihydro-5-hydroxy-1-
(4g).
1
m.p. 1888C. H NMR (CDCl3‡(CD3)2SO‡CF3CO2H) ꢀ:
(penta¯uorophenyl)pyrazole (3g) [5] (850 mg, 2.2 mmol)
was boiled under re¯ux in acetic anhydride (20 ml) and
acetic acid (15 ml) for 16 h. The solvents were evaporated.
The residue in dichloromethane (50 ml) was stirred with
saturated aqueous sodium hydrogen carbonate (50 ml) for
1 h. The organic phase was separated and dried (MgSO4).
Evaporation of the solvent gave 4g (230 mg, 28%) as a
7.17 (s, 1H, pyrazole 4-H), 7.40 (t, 1H, Jˆ7.3 Hz, ben-
zothiazole 6-H), 7.48 (t, 1H, Jˆ7.1 Hz, benzothiazole 5-H),
7.98 (d, 1H, Jˆ7.8 Hz, benzothiazole 7-H), 7.99 (d, 1H,
Jˆ7.6 Hz, benzothiazole 4-H), 14.66 (s, 1H, NH) ppm.
13C NMR (CDCl3‡(CD3)2SO‡CF3CO2H) ꢀ: 104.73 (pyr-
azole 4-C), 121.50 (q, JC±Fˆ267.7 Hz, CF3), 122.51 (ben-
zothiazole 7-C), 123.48 (benzothiazole 4-C), 126.39
(benzothiazole 6-C), 127.19 (benzothiazole 5-C), 139.09
(benzothiazole 7a-C), 140.30 (pyrazole 3-C), 141.61 (q,
JC±Fˆ38.1 Hz, pyrazole 5-C), 153.73 (benzothiazole
3a-C), 157.04 (benzothiazole 2-C) ppm. 19F NMR
(CDCl3‡(CD3)2SO‡CF3CO2H) ꢀ: 57.35 (s, CF3) ppm.
Analysis: Found: N, 15.10%. C11H6F3N3S requires: N,
15.61%.
1
yellow oil. H NMR (CDCl3) ꢀ: 7.17 (s) ppm. 19F NMR
(CDCl3) ꢀ: 159.84 (m, 2F, Ar 3,5-F2), 147.30 (m, 1F, Ar
4-F), 144.45 (m, 2F, Ar 2,6-F2), 63.49 (s, 3F, CF3),
61.71 (s, 3F, CF3) ppm. MS (EI) m/z: 369.9957 (M) (100)
(C11HF11N2 requires 369.9964).
Acknowledgements
3-(1-Methylbenzimidazol-2-yl)-5-tri¯uoromethylpyra-
zole (4b). Compound 3b was boiled under re¯ux in ethanol
and acetic acid, as for the synthesis of 4b, to give 4b (80%)
as a white solid, m.p. 2158C. 1H NMR ((CD3)2SO) ꢀ: 4.02
(s, 3H, Me), 7.34 (m, 2H, benzimidazole 5,6-H2), 7.47 (s,
1H, pyrazole-H), 7.72 (m, 2H, benzimidazole 4,7-H2) ppm.
19F NMR ((CD3)2SO) ꢀ: 60.33 (s, CF3) ppm. Analysis:
Found: N, 20.62%. C12H9F3N4 requires: N, 20.03%.
3-(Pyridin-2-yl)-5-tri¯uoromethylpyrazole (4c). Com-
pound 3c (300 mg, 1.3 mmol) was boiled under re¯ux in
The authors are grateful to Professor J. Elguero (CSIC,
Madrid, Spain) for helpful discussions and suggestions to
CSIR (New Delhi, India) for providing ®nancial assistance
and to the Mass Spectrometry Facility, University of Cali-
fornia (San Francisco, USA) (supported by the Biomedical
Research Technology Programme (NIH NCCR BRTP PRO
1614)), for mass spectra. We thank Mr. D.J. Wood (Uni-
versity of Bath) for some of the NMR spectra and Mr. C.
Cryer (University of Bath) for the high resolution mass
spectra.

S.P. Singh et al. / Journal of Fluorine Chemistry 94 (1999) 199±203
203
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