Synthesis of fluorinated pyrazole derivatives from β-alkoxyvinyl trifluoroketones

Article abstract of DOI:10.1016/S0022-1139(00)00348-1

1,1,1-Trifluoro-4-ethoxy-3-butene-2-one, 3-trifluoroacetyl-3, 4-dihydro-2H-pyran or furan reacted readily with pentafluorophenylhydrazine or per(poly)fluoroacectylhydrazine R_fCO-NHNH₂ (R_f: BrCF₂, C₃F₇) to give N-substituted-5-hydroxy-5-trifluoromethyl heterocycles Y-N-N=CH-CH(R)C(OH)CF₃ (Y: H, Ar_f or R_fCO), which were dehydrated by treatment with P₂O₅ or SOCl₂ to form N-substituted 5-trifluoromethyl pyrazoles Y-N-N=CH-C(R)=CCF₃ (Y: H, Ar_f or R_fCO) in good yields.

Full text of DOI:10.1016/S0022-1139(00)00348-1

Journal of Fluorine Chemistry 107 (2001) 107±112
Synthesis of ¯uorinated pyrazole derivatives from
b-alkoxyvinyl tri¯uoroketones
Li-ping Songb, Qian-li Chua, Shi-zheng Zhua,*
aShanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, PR China
bDepartment of Chemistry, Shanghai University, Shanghai 201800, PR China
Received 11 July 2000; accepted 16 September 2000
Abstract
1,1,1-Tri¯uoro-4-ethoxy-3-butene-2-one, 3-tri¯uoroacetyl-3, 4-dihydro-2H-pyran or furan reacted readily with penta¯uorophenylhy-
drazine or per(poly)¯uoroacectylhydrazine RfCO±NHNH2 (Rf: BrCF2, C3F7) to give N-substituted-5-hydroxy-5-tri¯uoromethyl
heterocycles Y N NˆCH CHꢀR†CꢀOH†CF3 (Y: H, Arf or RfCO), which were dehydrated by treatment with P2O5 or SOCl2 to form
N-substituted 5-tri¯uoromethyl pyrazoles Y N NˆCH CꢀR†ˆC CF3 (Y: H, Arf or RfCO) in good yields.
# 2001 Elsevier Science B.V. All rights reserved.
Keywords: b-Alkoxyvinyl tri¯uoromethylketone; Penta¯uorophenylhydrazine; Per(poly)¯uoroacectyl-hydrazine; Fluorinated pyrazole derivatives
1. Introduction
a,b-Unsaturated ketones with a tri¯uoromethyl substi-
tuent represent interesting building blocks for the synthesis
of tri¯uoromethyl containing compounds, especially hetero-
cyclic systems, which often show high biological activities
[1±3]. In recent years, the synthesis of ¯uorinated N-hetero-
cyclic compounds have drawn much more attention, the
literature has reported a series of CF3-substituted pyridines,
pyrazoles and quinolines obtained from the reactions of
b-ethoxyvinyl-tri¯uoromethyl ketone or diethylamino-
methylene hexa¯uoromethylacetone Et2NCH=C(COCF3)2
with the corresponding nitrogen nucleophiles [4±6],
Jones et al. [7] have reported 2 reacted with hydrazine
thus:
gave 3-(3-tri¯uoromethyl-1H-pyrazol-4-yl)propanol and
2-(3-tri¯uoromethyl-1H-pyrazol-4-yl)ethanol, respectively.
We have also worked with the b-alkoxyvinyltri¯uoro-
* Corresponding author.
methyl ketones and found that they are sensitive to
0022-1139/01/$ ± see front matter # 2001 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 0 ) 0 0 3 4 8 - 1

108
L.-p. Song et al. / Journal of Fluorine Chemistry 107 (2001) 107±112
nucleophilic attack, and in some case the products are
heterocyclic products containing tri¯uoromethyl or tri¯uor-
oacetyl groups [8].
In continuation of our work on these reactive ¯uorinated
vinylketones we recently found that they reacted readily
with hydrazine derivatives to form ¯uorinated pyrazole
derivatives. Herein, we report on this simple method for
the preparation of 5-tri¯uoromethyl pyrazoles from the
readily available b-alkoxyvinyltri¯uoromethyl ketones.
pyrazole. For example: the product obtained from the reac-
tion of 1 with C6F5NHNH2 is a stable colorless solid. It is
readily crystallized from CH2Cl2 and was characterized (by
spectroscopic data and X-ray diffraction analysis) as
C6F5N NˆCHCH2CꢀOH† CF3 5. In the 19F NMR spec-
trum the chemical shift of the CF3 is at 79.9 ppm indicat-
ing that this CF3 group is bonded to a saturated carbon atom.
For compounds 3 or 4 in which the CF3 group is bonded to a
carbon±carbon double bond, the chemical shift of the CF3
group is at 54.5 and 55.6 ppm, respectively. The mole-
cular structure of 5 is shown in Fig. 1. Selected bond angles
and bond lengths are summarized in Table 1.
2. Results and discussion
The differences between the reaction of C6H5NHNH2 and
C6F5NHNH2 with 1 should been due to the different basi-
cities of C6H5NHNH2 and C6F5NHNH2. In the case of
C6F5NHNH2 or HC6F4NHNH2 it give the undehydrated
products, thus:
1,1,1-Tri¯uoro-4-ethoxy-3-butene-2-one EtOCH=CH-
1,
COCF3
3-tri¯uoroacetyl-3,4-di-hydro-2H-pyrane
CH2CH2CH2OCHˆCCꢀO†CF3 2b reacted smoothly with
phenylhydrazine in ethanol to give the corresponding tri-
¯uoromethyl substituted pyrazoles. The undehydrated pro-
duct 4,5-dihydro-1-phenyl-5-(tri¯uoromethyl)-1H-pyrazol-
5-ol was also synthesized in high yield [9] and shows the
reaction occurred via two steps.
Compounds 6 and 8a were identi®ed by 1H NMR spectro-
scopy (400 MHz) and by other techniques as appropriate.
For example, the 1H NMR spectrum of 6 displayed the
dihydropyrazole 4±CH2 protons as an AB system (doublets
at dA 3.49 and dB 3.33 with the geminal coupling constant
J ˆ 19), which corresponds with the work of Singh et al.,
reported previously [10].
However, under the same reaction condition treatment 1
or 2 with penta¯uorophenyl-hydrazine or tetra¯uorophenyl-
hydrazine did not give the expected N-¯uorinated phenyl
Fig. 1. Molecular structure of 5.

L.-p. Song et al. / Journal of Fluorine Chemistry 107 (2001) 107±112
109
Reactions of 1 with BrCF2CONHNH2 in ethanol are
straightforward yielding 5-tri¯uoromethyl-stubstituted
pyrazoles:
other cases a dehydration process with P2O5 or SOCl2 is
needed.
3. Experimental
Melting points were measured on a Temp-Melt apparatus
1
and are uncorrected. Solvents were dried before use. H
NMR and 19F NMR spectra were recorded on a Varian-360 l
instrument or Bruker DRX-400 spectrometer with TMS and
TFA (dCFCl ˆ dTFA ‡ 76:8 ppm) as the internal and exter-
3
nal standards and the up®eld as negative. IR spectra were
obtained with an IR-440 Shimadzu spectrophotometer.
Lower resolution mass spectra and high resolution mass
For the formation of compound 9, a possible reaction path
was proposed as follows:
But when 1 or 2 were treated with C3F7CONHNH2 the
products are: C3F7CꢀO†N NˆCH CHꢀR† CꢀOH†CF3.
spectra (HRMS) were obtained on a Finnigan GC-MS 4021
and Finnigan MAT-8430 instrument, respectively. The X-ray
structure analysis was performed with a Rigaku/AFC 7R
Diffractometer. Elemental analyses were performed by this
Institute. Compounds 1 and 2 were prepared according to the
literature methods [12,13].
3.1. Reaction of 1 with hydrazine derivatives general
procedure
Treatment of compounds 7b and 8b with P2O5 or PCl3
gave. The corresponding dehydrated products N-substituted
5-tri¯uoromethyl pyrazoles:
1,1,1-Tri¯uoro-4-ethoxy-3-butene-2-one (5 mmol) was
added dropwise into a 50 ml ¯ask containing a solution
of hydrazine (5 mmol) and EtOH (30 ml). After additions
Table 1
Ê
Selected bond lengths (A) and bond angles (8) of compound 5
Ê
Bond length (A)
N(1)±N(2)
N(2)±C(7)
C(7)±C(8)
C(8)±C(9)
C(9)±N(1)
N(2)±C(6)
C(9)±C(10)
C(9)±O
1.423 (4)
1.266 (4)
1.499 (5)
1.538 (5)
1.473 (4)
1.419 (4)
1.520 (5)
1.399 (4)
Under the same reaction conditions, however, the com-
pound 12b did not form the eliminated product 15. Treat-
ment of compound 12b with SOCl2 and pyridine gave. The
corresponding dehydrated product N-substituted 5-tri¯uor-
omethyl pyrazole:
Bond angle (8)
C(9)±N(1)±N(2)
N(1)±N(2)±C(7)
N(2)±C(7)±C(8)
C(7)±C(8)±C(9)
C(8)±C(9)±N(1)
C(8)±C(9)±C(10)
N(1)±C(9)±C(10)
O±C(9)±C(10)
109.8 (3)
108.8 (3)
114.7 (3)
101.6 (3)
102.7 (4)
112.4 (3)
108.8 (3)
109.4 (3)
In summary, a series of new ¯uorinated pyrazole deriva-
tives are prepared from the reaction of b-alkoxyvinyltri-
¯uoromethyl ketone with hydrazine derivatives such
as C6H5NHNH2, ArfNHNH2 and RfCONHNH2. In some
cases this reaction gave directly the pyrazole product, in

110
L.-p. Song et al. / Journal of Fluorine Chemistry 107 (2001) 107±112
Table 2
Preparation of fluorinated pyrazole derivatives
Entry
Reactants
Reaction condition
Product
mp (8C)
Yield(%)
a
1
2
1 ‡ C6H5NHNH2
1 ‡ C6F5NHNH2
1 ‡ HC6F4NHNH2
1 ‡ BrCF2CONHNH2
1‡BrCF2CONHNH2
1 ‡ C3F7CONHNH2
2a ‡ C6F5NHNH2
2a ‡ HC6F4NHNH2
2a ‡ BrCF2CONHNH2
2a ‡ C3F7CONHNH2
2b ‡ C6H5NHNH2
2b ‡ C6F5NHNH2
2b ‡ HC6F4NHNH2
2b ‡ BrCF2CONHNH2
2b ‡ C3F7CONHNH2
7b
EtOH, reflux, 24 h
EtOH, reflux, 24 h
EtOH, rt, 24 h
3
5
±
79
80
130±132
140±142
47±48b
47±48b
3
6
72
4
EtOH, rt, 24 h
9
78
5
DMSO, rt, 24 h
EtOH, rt, 24 h
9
73
62
6
11
7a
8a
10a
12a
4 (2b)
7b
8b
10b
12b
13
14
15
56±58
7
EtOH, reflux, 24 h
EtOH, reflux, 24 h
EtOH, reflux, 24 h
EtOH, reflux, 24 h
EtOH, reflux, 24 h
EtOH, reflux, 24 h
EtOH, reflux, 24 h
EtOH, reflux, 24 h
EtOH, reflux, 24 h
CHCl3/P2O5
134±136
130±132
114±116c
128±130
71
8
70
66
9
10
11
12
13
14
15
16
17
18
55
a
±
36 (40)
46
55
122±124
172±174
90±92c
50±52
61
47
a
±
68
65
8b
12b
CHCl3/P2O5
106±108
144±146
CHCl3/SOCl2/py
66
a Liquid at room temperature.
b Product 9 is known compound, see [11].
c Products 10a and 10b are known compounds, see [10], melting points were measured after recrystallization with petroleum and ethyl acetate.
this reaction mixture was re¯uxed in EtOH for 24 h, the
solvent was evaporated, and the obtained crude product was
puri®ed by column chromatography to give the pure pro-
duct. The reaction yields are shown in Table 2.
square refinement was based on 1384 observed reflections
(I > 2:00sꢀI†) and 191 variable parameters. The final R
and Rw value were 0.052 and 0.054, respectively. All
calculations were performed using the teXsan crystal-
lographic software package of Molecular Structure
Corporation Table 1.
3.1.1. 5-Hydroxy-1-pentafluorophenyl-5-trifluoromethyl-
4,5-dihydropyrazole, 5
IR (nmax, cm 1): 3612 (s, O±H), 2955 (m, C±H), 1509 (s,
C=N), 1199, 1152 (vs, C±F); 1H NMR (90 MHz, (CD3)2CO)
d (ppm): 6.98 (s, 1H, pyrazole 3-H), 3.28 (s, 2H pyrazole 4-
H), 3.20 (br, 1H, OH); 19H NMR (56.4 MHz, (CD3)2CO) d
(ppm): 79.9 (s, CF3); 142.9 (d, Ar±F, F2, F6), 155.5 (t,
3.1.2. 5-Hydroxy-1-(2,3,5,6, tetrafluorophenyl)-5-
trifluoromethyl-4,5-dihydropyrazole, 6
IR (nmax, cm 1): 3100 (m, O±H), 1510 (s, C=N), 1195,
1
1145 (vs, C±F); H NMR (400 MHz,(CD3)2CO) d (ppm):
7.57 (m, 1H, H±C6F4), 7.15 (s, 1H, pyrazole 3±H), 3.49 (d,
1H, J ˆ 19 Hz, pyrazole 4±H), 3.33 (d, 1H, J ˆ 19 Hz,
pyrazole 4±H), 3.22 (br, 1H, OH); 19F NMR (56.4 MHz,
CDCl3 ‡ ꢀCD3†2CO)d (ppm): 79.4 (s, CF3); 140.8 (d,
Ar±F, F2, F6), 143.4(d, Ar±F, F3, F5); MS (m/z, %): 302
‡
Ar±F, F-4), 164.9(t, Ar±F, F3, F5); MS (m/z, %): 320 (M ,
‡
‡
‡
6.32), 319 (M ±H, 36.62), 302 (M ±H2O, 6.81), 251 (M ±
‡
‡
CF3, 100.00), 181 (C6F5N , 90.88), 167 (C6F5 , 36.18);
HRMS for C10H4F8N2O: Calculated: 320.01959; Found:
320.02354.
‡
‡
‡
(M , 35.60), 285 (M ±OH, 6.68), 233 (M ±CF3, 100.00),
‡
‡
‡
163 (HC6F4N , 49.42), 149 (HC6F4 , 13.75), 69 (CF3 ,
3.1.1.1. Crystal structure analysis. C10H4ON2F8: MW ˆ
320:14, monoclinic, space group p21/c (#14), a ˆ 10:924
14.13); Elemental analyses for C10H5F7N2O: Anal. Calcu-
lated: N, 9.27%; H, 1.66%; C, 39.74%; Found: N, 9.16%; H,
1.71%; C, 39.69%.
ꢁ
Ê
Ê
Ê
(4) A, b ˆ 9:437 (4) A, c ˆ 11:813 (4) A, b ˆ 114:99ꢀ2† ;
3
Ê 3
V ˆ 1103:7 (7) A , Z ˆ 4, Dc ˆ 1:927 g/cm , Fꢀ0 0 0† ˆ
Ê
632:00. Radiation, Mo Ka (l ˆ 0:71069 A). Crystal
3.1.3. 1-Heptafluorobutanoyl-5-hydroxy-5-trifluoromethyl-
4,5-dihydropyrazole, 11
dimension, 0:20 mm  0:20 mm  0:30 mm. Intensity data
were collected at 208C with
a
Ragaku AFC 7R
IR (nmax, cm 1): 3400 (s, O±H), 1705 (s, C=O), 1490 (s,
1
diffractometer using graphite-monochromated Mo Ka
radiation (m ˆ 2:18 cm 1). A total of 2826 independent
reflection were measured in the range 18:7 < 2y <
21:4ꢁ.The structure was solved by direct methods and
referred using Fourier techniques. The nonhydrogen
atoms were refined anisotropically, hydrogen atoms were
included but not refined. The final cycle of full matrix least-
C=N), 1168 (vs, C±F); H NMR (60 MHz, (CD3)2CO) d
(ppm): 7.30 (s, 1H, pyrazole 3-H), 5.10 (br, 1H, O±H), 3.46
(s, 2H, pyrazole 4-H) 19F NMR (56.4 MHz, (CD3)2CO) d
(ppm): 79.6 (s, CF3), 80.3 (s, CF3); 113.6 (s, CF2),
‡
‡
124.3 (s, CF2); MS (m/z, %): 350 (M , 0.8), 333 (M ±OH,
‡
‡
‡
16.23), 281 (M ±CF3, 22.23), 169 (C3F7 , 36.18), 69 (CF3
100.00); Elemental analyses for C8H4F10N2O2: Anal.
,

L.-p. Song et al. / Journal of Fluorine Chemistry 107 (2001) 107±112
111
Calculated: N, 8.00%; H, 1.14%; C, 27.43%; Found: N,
7.69%; H, 1.11%; C, 27.31%.
3.2.4. 5-Hydroxy-4-(2-hydroxyethyl)-1-(2,3,5,6-tetra-
fluorophenyl)-5-trifluoromethyl-4,5-dihydro-pyrazole, 8a
IR (nmax, cm 1): 3300 (s, O±H), 3050 (m, H±C6F4)
1500(s, C=N), 1180, 1145 (vs, C±F); 1H NMR
(400 MHz, (CD3)2CO) d (ppm): 7.57 (m, 1H, H±C6F4),
7.21 (s, 1H, pyrazole 3-H), 3.80 (m, 2H, CH2±O), 3.80
(br, 1H, ±OH), 3.17 (br, 1H, OH), 2.20 (m, 1H, pyrazole 4-
H), 2.12 (m, 2H, pyrazole±CH2); 19F NMR (56.4 MHz,
CDCl3 ‡ ꢀCD3†2CO) d (ppm): 80.8 (s, CF3); 141.3
(d, Ar±F, F2, F6), 143.8 (s, Ar±F, F3, F5); MS (m/z,
3.2. Reaction of 2 with hydrazine derivatives general
procedure
3-Tri¯uoroacetyl-3,4-dihydro-2H-pyran or furan (5 mmol)
was added into a 50 ml ¯ask containing a solution of
hydrazine (5 mmol) and EtOH (30 ml). This reaction mix-
ture was re¯uxed in EtOH for 24 h, the solvent was evapo-
rated and the crude product was puri®ed by column
chromatography.
‡
‡
‡
%): 346 (M , 36.36), 328 (M ±H2O, 24.74), 277 (M ±
‡
‡
CF3, 96.59), 259 (M ±CF3±H2O, 90.26), 163 (HC6F4N ,
‡
‡
100.00), 149 (HC6F4 , 46.65), 69 (CF3 , 77.04); Elemental
analyses for C12H9F7N2O2: Anal. Calculated: N, 8.09%; H,
2.60%; C, 41.62%; Found: N, 8.02%; H, 2.56%; C, 41.78%.
3.2.1. 4-(3-Hydroxypropyl)-1-phenyl-5-trifluoromethyl-
pyrazole, 4
IR (nmax, cm 1): 3394 (s, O±H), 2949 (m, C±H), 1597 (vs,
C=C), 1499 (s, C=N), 1129, 1099 (vs, C±F); 1H NMR
(90 MHz, CDCl3) d (ppm): 7.70 (s, 1H, pyrazole 3-H),
7.57 (m, 5H, Ar±H), 3.73 (t, 2H, CH2±O), 3.73 (br, 1H,
OH), 2.85 (t, 2H, pyrazole±CH2), 1.99 (m, 2H, CH2CH2);
19F NMR (56.4 MHz, CDCl3) d (ppm): 54.5 (s, CF3); MS
3.2.5. 5-Hydroxy-4-(3-hydroxypropyl)-1-(2,3,5,6-tetra-
fluorophenyl)-5-trifluoromethyl-4,5-di-hydropyrazole, 8b
IR (nmax, cm 1): 3320 (s, O±H), 3050 (m, H±C6F4), 2990
1
(m, C±H), 1500 (s, C=N), 1185, 1155 (vs, C±F); H NMR
(60 MHz, CDCl3 ‡ ꢀCD3†2CO) d (ppm): 7.20 (m, 1H, H±
C6F4), 6.94 (s, 1H, pyrazole 3-H), 3.73 (t, 2H, CH2±O), 3.50
(br, 1H, ±OH), 3.02 (br, 1H, OH), 2.01 (m, 1H, pyrazole 4-
H), 1.83 (m, 4H, CH2CH2); 19F NMR (56.4 MHz, CDCl3‡
ꢀCD3†2CO) d (ppm): 79.8 (s, CF3); 140.8 (t, Ar±F, F2,
‡
‡
‡
(m/z, %): 270 (M , 68.31), 252 (M ±H2O, 69.75), 225 (M ±
‡
‡
CH2CH2OH, 100.00), 201 (M ±CF3, 9.25), 183 (M ±CF3±
H2O, 23.94); HRMS for C13H13F3N2O: Calculated:
270.0980; Found: 270.0988.
‡
F6), 143.3 (s, Ar-F, F3, F5); MS (m/z, %): 360 (M , 8.26),
‡
‡
‡
‡
342 (M ±H2O, 8.91), 291 (M ±CF3, 100.00), 273 (M ±
‡
3.2.2. 5-Hydroxy-4-(2-hydroxyethyl)-1-pentafluorophenyl-
5-trifluoromethyl-4,5-dihydropyrazole, 7a
CF3±H2O, 90.26), 163 (HC6F4N , 75.34), 149 (HC6F4
,
‡
‡
29.71), 69 (CF3 , 77.04), 41 (C3H5 , 24.97); Elemental
analyses for C13H11F7N2O2 Anal. Calculated: N, 7.78%;
H, 3.06%; C, 43.33%; Found: N, 7.74%; H, 3.10%; C,
43.26%.
IR (nmax, cm 1): 3280 (s, O±H), 2800 (m, C±H), 1500 (s,
C=N), 1180, 1168 (vs, C±F); 1H NMR (60MHz, (CD3)2CO)
d (ppm): 6.86 (s, 1H, pyrazole 3-H), 3.55 (t, 2H, O±CH2),
3.55 (br, 1H, OH), 2.85 (br, 1H, OH), 1.90 (m, 1H, pyrazole
4-H), 1.73 (m, 2H, pyrazole±CH2); 19F NMR (56.4 MHz,
(CD3)2CO) d (ppm): 81.9 (s, CF3); 144.8 (d, Ar±F, F2,
F6), 157.8 (t, Ar±F, F4), 166.8 (t, Ar±F, F3, F5); MS (m/
3.2.6. 4-(2-hydroxyethyl)-5-trifluoromethylpyrazole, 10a
IR (nmax, cm 1): 3230 (s, O±H), 3100 (s, N±H), 2779 (s,
C±H), 1458 (s, C=N), 1140, 1050 (vs, C±F); 1H NMR
(60 MHz, CDCl3 ‡ ꢀCD3†2CO) d (ppm): 7.53 (s, 1H, pyr-
azole 3-H), 3.67 (t, 2H, CH2O), 2.83 (t, 2H, pyrazole±CH2),
2.13 (br, 1H, ±OH); 19F NMR (56.4 MHz, CDCl3‡
ꢀCD3†2CO) d (ppm): 59.8 (s, CF3); MS (m/z, %): 180
‡
‡
‡
z, %): 364 (M , 43.59), 346 (M ±H2O, 29.34), 295 (M ±
‡
‡
‡
CF3 , 100.00), 181 (C6F5N , 73.62), 167 (C6F5 , 40.95), 69
‡
(CF3 , 56.12); Elemental analyses for C12H8F8N2O2: Anal.
Calculated: N, 7.69%; H, 2.20%; C, 39.56%; Found: N,
7.62%; H, 2.18%; C, 39.80%.
‡
‡
‡
(M , 13.2), 149 (M ±CH2OH, 100.00), 111 (M ±CF3,
‡
2.01), 69 (CF3
,
12.19); Elemental analyses for
3.2.3. 5-Hydroxy-4-(3-hydroxypropyl)-1-pentafluoro-
phenyl-5-trifluoromethyl-4,5-dihydro-pyrazole 7b
C6H7F3N2O: Anal. Calculated: N, 15.56%; H, 3.89%; C,
40.00%; Found: N, 15.36%; H, 3.89%; C, 40.25%.
IR (nmax, cm 1): 3370 (s, O±H), 2954 (m, C±H), 1522 (s,
C=N), 1260, 1056 (vs, C±F); 1H NMR (90 MHz, (CD3)2CO)
d (ppm): 6.65 (s, 1H, pyrazole 3-H), 3.14 (t, 2H, CH2O), 3.14
(br, 1H, OH), 2.92 (br, 1H, OH), 1.55 (m, 1H, pyrazole 4-H),
1.35 (m, 4H, CH2CH2); 19F NMR (56.4 MHz, (CD3)2CO) d
(ppm): 80.8 (s, CF3); 144.1 (d, Ar±F, F2, F6), 157.5 (t,
3.2.7. 4-(3-Hydroxypropyl)-5-trifluoromethylpyrazole, 10b
IR (nmax, cm 1): 3100 (s, O±H, N±H), 2880 (s, C±H),
1480 (s, C=N), 1250, 1140 (vs, C±F); H NMR (60 MHz,
1
CDCl3) d (ppm): 7.79 (s, 1H, pyrazole 3-H), 4.06 (t, 2H,
CH2O), 3.09 (m, 2H, pyrazole±CH2), 2.24 (m, 2H,
CH2CH2), 1.53 (br, 1H, ±OH); 19F NMR (56.4 MHz,
CDCl3) d (ppm): 59.8 (s, CF3); MS (m/z, %): 195
‡
Ar±F, F4), 166.4 (t, Ar±F, F3, F5); MS (m/z, %): 378 (M ,
‡
‡
4.15), 360 (M ±H2O, 5.33), 309 (M ±CF3, 39.02), 181
‡
‡
‡
‡
‡
‡
‡
(C6F5N , 40.70), 167 (C6F5
,
23.94), 41 (C3H5
,
(M ‡ 1, 28.19), 176 (M ±H2O, 96.33), 149 (M ±
100.00); Analysis for C13H10F8N2O2: Calculated: N,
7.41%; H, 2.64%; C, 41.27%; Found: N, 7.08%; H, 2.41
%; C, 41.10%.
CH2CH2OH, 100.00), 69 (CF3 , 12.49); Elemental analyses
for C7H9F3N2O: Anal. Calculated: N, 14.43%; H, 4.64%; C,
43.30%; Found: N, 14.26%; H, 4.59%; C, 43.09%.

112
L.-p. Song et al. / Journal of Fluorine Chemistry 107 (2001) 107±112
3.2.8. 1-Heptafluorobutanoyl-5-hydroxy-4-(2-hydroxy-
ethyl)-5-trifluoromethyl-4,5-dihydro-pyrazole, 12a
3.3.2. 4-(3-Hydroxypropyl)-1-(2,3,5,6-tetrafluorophenyl)-
5-trifluoromethylpyrazole, 14
IR (nmax, cm 1): 3200 (s, O±H), 1705 (s, C=O), 1200,
1160 (vs, C±F); 1H NMR (60 MHz, CD3Cl ‡ ꢀCD3†2CO) d
(ppm): 7.90 (d, 1H, pyrazole 3-H), 4.00 (br, 1H, OH), 4.00 (t,
2H, CH2O), 3.20 (m, 1H, pyrazole 4-H), 3.20 (br, 1H, OH),
2.10 (m, 2H, pyrazoleCH2); 19F NMR (56.4 MHz,
CD3Cl ‡ ꢀCD3†2CO) d (ppm): 80.6 (s, CF3), 83.3 (s,
CF3); 120.6 (s, CF2), 126.8 (s, CF2); MS (m/z, %): 395
IR (nmax, cm 1): 3410 (s, O±H), 3070 (m, H±C6F4), 2980
(m, C±H), 1500 (s, C=N), 1184, 1139 (vs, C±F), H NMR
1
(60 MHz, CDCl3) d (ppm): 7.93 (s, 1H, pyrazole 3-H), 7.50
(m, 1H, H±C6F4), 3.30 (t, 2H, CH2O), 2.96 (t, 2H, pyrazole±
CH2), 2.13 (m, 2H, CH2CH2), 2.13 (br, 1H, OH); 19F NMR
(56.4 MHz, CDCl3) d (ppm): 61.8 (s, CF3); 136.8 (t, Ar±
‡
F, F2, F6), 144.8 (s, Ar±F, F3, F5); MS (m/z, %): 342 (M ,
‡ ‡
‡
‡
‡
(M ‡ 1, 4.22), 377 (M ±OH, 68.57), 280 (M ±CF3±
100.00), 324 (M ±H2O, 1.34), 273 (M ±CF3, 12.13), 163
‡
‡
‡
‡
‡
CH2CH2OH, 23.68), 169 (C3F7 , 12.58), 83 (C3H3N2O ,
(HC6F4N , 25.94), 149 (HC6F4 , 28.01), 69 (CF3 , 23.51);
HRMS for C13H9F7N2O: Calculated: 342.06031; Found:
342.05654.
‡
‡
49.11), 69 (CF3 , 77.48), 68 (C2N2O , 100); Elemental
analyses for C10H8F10N2O3: Anal. Calculated: N, 7.11 %;
H, 2.03%; C, 30.46%; Found: N, 7.10%; H, 2.11%; C,
30.17%.
3.3.3. 4-(3-Hydroxypropyl)-1-heptafluorobutanoyl-5-
trifluoromethylpyrazole, 15
3.2.9. 1-Heptafluorobutanoyl-5-hydroxy-4-(3-hydroxy-
propyl)-5-trifluoromethyl-4,5-dihydro-pyrazole, 12b
IR (nmax, cm 1): 3100 (s, O±H), 1710 (s, C=O), 1160,
IR (nmax, cm 1): 3180, 3050 (m, =CH), 1700 (s, C=O),
1
1210, 1130 (vs, C±F); H NMR (90 MHz, (CD3)2CO) d
(ppm): 8.20 (s, 1H, pyrazole 3-H), 3.90 (t, 2H, CH2O), 2.60
(s, 1H, OH), 1.63 (m, 4H, CH2CH2); 19F NMR (56.4 MHz,
CDCl3) d (ppm): 61.8 (s, CF3), 79.4 (s, CF3); 119.8 (s,
1
1100 (vs, C±F); H NMR (60 MHz, CD3Cl) d (ppm): 7.90
(d, 1H, pyrazole 3-H), 4.60 (br, 1H, O±H), 4.05 (m, 2H,
CH2O), 2.45 (m, 1H, OH), 2.30 (m, 1H, pyrazole 4-H), 1.95
(m, 4H, CH2CH2); 19F NMR (56.4 MHz, CD3Cl) d (ppm):
79.7 (s, CF3), 83.2 (s, CF3); 120.2 (s, CF2), 125.8 (s,
‡
CF2), 126.1 (s, CF2); MS (m/z, %): 391 (M ‡ 1, 45.26),
‡
‡
390 (M , 43.76), 177 (M ‡ 1±C3F7CO±OH, 100.00), 169
‡
‡
(C3F7 , 21.30), 108 (M ‡ 1±C3F7CO±OH±CF3, 70.16), 69
‡
‡
‡
‡
CF2); MS (m/z, %): 408 (M , 3.72), 391 (M ±OH, 24.52),
‡
(CF3 , 54.29); HRMS for C12H8F10O2N2: Calculated:
390.04261, Found: 390.04264.
294 (M ±CF3±CH2CH2OH, 8.62), 239 (M ±C3F7, 7.02),
‡
‡
‡
169 (C3F7 , 36.18), 97 (C4H5N2O , 59.65), 69 (CF3
,
‡
100.00), 41 (C3H5 , 46.77); Elemental analyses for
C11H10F10N2O3: Anal. Calculated: N, 8.00%; H, 1.14%;
C, 27.43%; Found: N, 7.69%; H, 1.11%; C, 27.31%.
Acknowledgements
The authors thank the National Natural Science Founda-
tion of China (NNSFC) (No. 29872051) and Innovation
Foundation of Chinese Academy of Sciences for ®nancial
support.
3.3. General procedure for the preparation of fluorinated
pyrazole derivatives by a dehydration process
References
At room temperature 1-substituted-5-(tri¯uoromethyl)-5-
hydroxy-4,5-dihydro pyrazole (2 mmol) was added into a
25 ml ¯ask containing a mixture of P2O5 (2.5 mmol) and
chloroform (15 ml). After re¯ux for 8 h, the residue was
removed by ®ltration. The solvent was washed with water
and dried with anhydrous Na2SO4 and evaporated. The
crude product was puri®ed by column chromatography.
[1] M. Hudlicky, Chemistry of Organic Fluorine Compounds, Ellis
Horwood, Chichester, 1992.
[2] J.T. Welch, Tetrahedron 43 (1987) 3123.
[3] R.E. Bank, Organofluorine Chemistry, Principles and Commercial
Application, New York, 1994.
[4] I.I. Gerus, M.G. Gorbunova, V.P. Kukhar, J. Fluorine Chem. 69
(1994) 195.
[5] I.I. Gerus, S.I. Vdovenko, M.G. Gorbunova, V.P. Kukhar, Khim.
Geterots. Soedin. 4 (1991) 502.
3.3.1. 4-(3-Hydroxypropyl)-1-pentafluorophenyl-5-trifluor-
omethylpyrazole, 13
[6] M. Soufyane, C. Mirand, J. Levy, Tetrahedron Lett. 34 (1993) 7737.
[7] B.G. Jones, S.K. Branch, A.S. Thompson, M.D. Threadgill, J. Chem.
Soc., Perkin Trans. 1 (1996) 2685.
IR (nmax, cm 1): 3420 (s, O±H), 2950 (m, C±H), 1510 (s,
N=H), 1255, 1050 (vs, C±F); 1H NMR (60 MHz, CDCl3) d
(ppm): 8.07 (s, 1H, pyrazole 3-H), 4.10 (t, 2H, CH2O), 3.13
(m, 2H, pyrazole±CH2), 2.30 (m, 2H, CH2CH2), 2.30 (br,
1H, OH); 19F NMR (56.4 MHz, CDCl3) d (ppm): 57.2 (s,
CF3); 144.7 (d, Ar±F, F2, F6), 149.3 (t, Ar±F, F4),
[8] S.Z. Zhu, G.L. Xu, C.Y. Qin, Q.L. Chu, Y. Xu, Monatsh. Chem. 130
(1999) 671.
[9] M.E.F. Braibante, G. Clar, M.A.P. Martins, J. Heterocyclic Chem. 30
(1993) 1159.
[10] S.P. Singh, D. Kumar, B.G. Jones, M.D. Threadgill, J. Fluorine
Chem. 94 (1999) 199.
‡
160.6 (t, Ar±F, F3, F5); MS (m/z, %): 360 (M , 0.65),
‡
‡
[11] J.H. Atherton, R. Fields, J. Chem. Soc. C (1968) 1507.
[12] M. Hojo, R. Masuda, Y. Kokuryo, H. Shioda, S. Matsuo, Chem. Lett.
(1976) 499.
342 (M ±H2O, 100.00), 315 (M ±CH2CH2OH, 42.53), 273
‡
‡
‡
(M ±H2O±CF3, 25.80), 167 (C6F5 , 5.96), 69 (CF3 ,
11.42); HRMS for C13H8F8N2O: Calculated: 360.05089;
Found: 360.05306.
[13] H. Yoshioka, C. Takayama, N. Mastuo, J. Synth. Org. Chem. Jpn. 42
(1984) 809.