Synthesis of polyfluorophenyl substituted-4,5-dihydropyrazole derivatives via 1,3-dipolar cycloaddition of nitrile imine with ethyl acrylate

Article abstract of DOI:10.1016/j.jfluchem.2003.08.005

Oxidation of aldehyde 4-chloro-2,3,5,6-tetrafluorophenylhydrazones (1) with [bis(acetoxy)iodo]benzene leads to the formation of nitrile imines (2) which reacted in situ with ethyl acrylate to produce 3-substituted-1-(4-chloro-2,3,5,6-tetrafluorophenyl)-5-

Full text of DOI:10.1016/j.jfluchem.2003.08.005

Journal of Fluorine Chemistry 124 (2003) 211–217
Synthesis of polyfluorophenyl substituted-4,5-dihydropyrazole
derivatives via 1,3-dipolar cycloaddition of nitrile imine
with ethyl acrylate
Li-Ping Songa,b, Shi-Zheng Zhub,*
aSchool of Chemistry and Pharmaceutics, East China University of Science and Technology, Shanghai 200237, China
bLaboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai 200032, China
Received 20 May 2003; received in revised form 13 August 2003; accepted 15 August 2003
Abstract
Oxidation of aldehyde 4-chloro-2,3,5,6-tetrafluorophenylhydrazones (1) with [bis(acetoxy)iodo]benzene leads to the formation of nitrile
imines (2) which reacted in situ with ethyl acrylate to produce 3-substituted-1-(4-chloro-2,3,5,6-tetrafluorophenyl)-5-ethoxycarbonyl-4,5-
dihydropyrazoles (3) in moderate to good yields. The structures of new compounds were fully confirmed by their spectral data, elemental
analyses and X-ray diffraction (XRD) analysis. A plausible reaction mechanism for the synthesis of title compounds is presented.
# 2003 Elsevier B.V. All rights reserved.
Keywords: 1,3-Dipolar cycloaddition; Nitrile imine; Ethyl acrylate; 4,5-Dihydropyrazole derivatives
1. Introduction
also be formed by reaction of a(azobenzyl)hydroperoxide
formed on auto oxidation of an aldehyde hydrazone with
triethylamine [12]. These results prompted us to use the
methodology to aldehyde 4-chloro-2,3,5,6-tetrafluorophenyl-
hydrazones (1). In previous work [13], we reported the
preparation of 5-cyano-4,5-dihydropyrazoles. In continuation
of our studies on the application of nitrile imine, we inves-
tigatedthereactionofnitrileiminewithethylacrylate.Herein,
we wish to report the generation of nitrile imines from the
oxidation of aldehyde 4-chloro-2,3,5,6-tetrafluorophenylhy-
drazones with [bis(acetoxy)iodo]benzene in situ, and their
simultaneous trapping with ethyl acrylate to produce a
series of 3-substituted-1-(4-chloro-2,3,5,6-tetrafluorophe-
nyl)-5-ethoxycarbonyl-4,5-dihydropyra-zole derivatives (3).
Recently, there has been a growing interest in the synth-
esis of fluorine-containing heterocyclic compounds because
of their potential biological activities [1]. 4,5-Dihydropyr-
azole derivatives have been studied extensively due to their
diverse chemical reactivity, broad spectrum of biological
activity and variety of industrial application [2]. In addition,
it is known that 4,5-dihydropyrazole derivatives were useful
compounds not only as intermediates in the synthesis of
pyrazoles, but also as effective chemical bleaching agents,
luminescent and fluorescent substances [3]. In terms of
biological activity, substituted 4,5-dihydropyrazoles were
used as anti-inflammatory or anti-coagulating agent [4].
Thus, the synthesis of 4,5-dihydropyrazole derivatives is
of current importance. These compounds were generally
prepared via 1,3-dipolar cycloaddition reaction of nitrile
imines with alkene [5]. A series of useful methods for
generating nitrile imine intermediates in situ have been
mentioned by Rai and Hassner [6]. Dehydrogenation of
an aldehyde hydrazone with Chloramine-T (CAT) [7],
[bis(acetoxy)iodo]benzene [8], polymer supported [bis(ace-
toxy)iodo]benzene [9], lead tetraacetate [10] or mercuic
acetate [11] also lead to nitrile imines. Nitrile imine can
2. Results and discussion
Aldehyde 4-chloro-2,3,5,6-tetrafluorophenylhydrazones
(1) were readily prepared by the reaction of aldehydes
and 4-chloro-2,3,5,6-tetrafluorophenylhydrazine in EtOH
at room temperature (Scheme 1). After recrystallization
from petroleum-ethyl acetate, they were purified enough
to be used. XRD analysis of compound 1a showed that due
to the fluorine atoms in one of aromatic ring, there exists
Hꢀ ꢀ ꢀF inter molecular hydrogen bonds between two mole-
cules, resulting in the formation of cross-stacking of two
* Corresponding author. Fax: þ86-21-6416-6128.
E-mail address: zhusz@mail.sioc.ac.cn (S.-Z. Zhu).
0022-1139/$ – see front matter # 2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2003.08.005

212
L.-P. Song, S.-Z. Zhu / Journal of Fluorine Chemistry 124 (2003) 211–217
F
F
F
F
F
EtOH r.t.
Cl
NHNH2
R-CHO
Cl
NHN CHR
+
F
F
F
1 (a-k)
1a R =
1b R =
CH CH
O2N
1i
R =
1e R =
H3C
CH3 CH CH
1f R =
1g R =
F
1j R =
1k R =
H3C
1c R = H3CO
1d R = Br
O
CH3
1h R =
Scheme 1.
Oxidation of 1 with [bis(acetoxy)iodo]benzene in the
presence of ethyl acrylate (Scheme 2) occurred smoothly
at 0 8C for 4 h, after general work-up, giving the expected
1,3-disubstituted 5-ethoxycarbonyl-4,5-dihydropyrazoles in
moderated to good yields.
The method is not only applicable to aromatic aldehyde
bearing electron-donating substituent or electron-withdraw-
ing substituent, but also a,b-unsaturated aromatic aldehyde,
fused aromatic aldehyde and heterocyclic aldehyde. How-
ever, the results showed that the electron-withdrawing sub-
stituted group on phenyl ring affected the reaction activity of
nitrile imine. For example, in most cases, the reactions were
carried out at 0 8C, and TLC analysis showed the reaction
was completed within 4 h. In the case of 1e, under the same
conditions, treatment of 1e with [bis(acetoxy)iodo]benzene
in the presence of ethyl acrylate, the starting material 1e was
not disappeared completely within 4 h at 0 8C (monitored by
TLC). The completion of reaction must be carried out at
room temperature for another 3 h, which means the reaction
occurred at higher temperature when 1e was used as starting
material. Furthermore, by comparison, the alternative
compound pentafluoroaledhyde 4-nitro-phenylhydrazone
(4) was synthesized to be investigated the relation between
the reaction condition and electronic effect of substituent on
phenyl group. Similar result was observed by mean of
reaction of pentafluoroaledhyde 4-nitro-phenylhydrazone
(4) with [bis(acetoxy)iodo]benzene in the presence of ethyl
acrylate (Scheme 3). Expected compound 5 was obtained in
56% yield after 4 h stirring at room temperature. The
different reaction condition can be attributed to the strong
electron-withdrawing effect of nitro group.
Fig. 1. Molecular structure of 1a, showing the existence of Hꢀ ꢀ ꢀF
hydrogen bond.
molecules in the unit cell. Molecular structure of compound
1a is shown in Fig. 1. The stacking diagram of compound 1a
is shown in Fig. 2. The crystal data and refinement details are
summarized in Table 2. Selected bond lengths and bond
angles of compound 1a are listed in Table 3.
On the other hand, it was noted that in the cases of 1j and
1k, when the aliphatic aldehyde hydrazones were used as
starting materials, the yields of the expected products were
Fig. 2. The stacking diagram of 1a.

L.-P. Song, S.-Z. Zhu / Journal of Fluorine Chemistry 124 (2003) 211–217
213
R
F
F
F
N
CO2Et
F
N
PhI(OAc)2 / CH2Cl2
+
CH2 CH CO2Et
F
F
Cl
NHN CHR
0
OC
F
F
Cl
1 (a-k)
3
Scheme 2.
F
PhI(OAc)2 CH2Cl2
r.t. 4 h
N
CO2Et
N
CH=N-NH
NO2
F
CH2=CHCO2Et
+
4
NO2
56%
5
Scheme 3.
rather lower (see Table 1, entries 10, 11). This can be
attributed to the unstability of nitrile imine intermediate,
in which there were no aromatic cycles conjugated in the
dipole system. The reaction conditions and reaction results
are summarized in Table 1.
It is known that 1,3-dipolar cycloaddition reaction of nitrile
imines to acrylonitrile is a regioselective reaction, yielding
5-cyano-4,5-dihydropyrazoles exclusively [14]. The same
regioselective reaction was observed when ethyl acrylate
was employed. The structures of the products were fully
confirmed by their elemental analyses and spectral data.
For instance, in their 1H NMR spectra, the five-position
proton in the 4,5-dihydropyrazole was found as doublet of
doublet in the region d 5.00–5.20, whereas the four-position
protons in the compound 3 were found as ABX system in
the region d 3.50–3.70. The mass spectra of compound 3
showed a very similar fragmentation pattern, and in most
cases, the base peak was Mþ À CO2Et peak. The 19F NMR
spectra of 4,5-dihydropyrazole showed a very similar pattern
in the region d À140 to À141 and À146 to À147 for the four
fluorine atoms, respectively. It should be indicated that, the
reaction of trifluoroacetonitrile phenylimine with allyloxy-
benzene gave two regio-isomeric products in the ratio of 7:1,
approximately [15]. However, in our cases, the title com-
pounds were obtained exclusively, without the formation of
regio-isomeric products. The structure of 4,5-dihydropyra-
zole 3 was further confirmed by XRD analysis. A fine crystal
of 3i suitable for X-ray diffraction (XRD) analysis was
obtained from chromatography following recrystallization
from petroleum-ethyl acetate. Fig. 3 shows the molecular
Table 1
Preparation of compounds 3
Entry
R
Conditiona
Product
Yield
(%)b
Temperature
Time
(h)
(8C)
1
C6H5–
0
4
4
4
4
3
4
4
4
4
4
4
3a
3b
3c
3d
3e
3f
65
53
51
56
54
71
62
69
56
25
20
2
p-CH3C6H4–
p-CH3OC6H4–
p-BrC6H4–
p-O2NC6H4–
C6F5–
0
3
0
4
0
5
RT
0
6
7
Furfuryl–
0
3g
3h
3i
8
Naphthyl-1–
C6H5CH¼CH–
Propenyl–
iso-Butyl–
0
9
0
10
11
0
3j
3k
0
a All reactions were carried out in CH2Cl2.
b Isolated yield based on 1.
Fig. 3. Molecular structure of compound 3i.

214
L.-P. Song, S.-Z. Zhu / Journal of Fluorine Chemistry 124 (2003) 211–217
Table 2
Table 3
˚
Crystal data and details of structural determination for 1a and 3i
Compound 1a Compound 3i
13H7ClF4N2
Selected bond lengths (A) and bond angles (8) of compounds 1a and 3i
Compound 1a
Compound 3i
˚
Formula
C
C20H15ClF4N2O2
426.79
Bond length (A)
C(4)–N(1)
N(1)–N(2)
Formula weight
Crystal size (mm3)
306.66
1.372(3)
1.364(2)
1.276(3)
1.456(3)
0.860
N(1)–N(2)
1.389(3)
1.466(4)
1.529(4)
1.492(4)
1.291(4)
1.444(4)
1.512(4)
1.377(4)
0.578 ꢁ 0.498
ꢁ 0.156
Triclinic
P-1 (no. 2)
6.432(1)
7.531(1)
12.887(1)
92.22(1)
96.17(1)
90.87(1)
620.04(14)
2
0.156 ꢁ 0.467
ꢁ 0.311
Monoclinic
P21/n (no. 14)
9.245(2)
21.544(4)
9.824(2)
90.00
N(2)–C(17)
C(16)–C(17)
C(15)–C(16)
N(1)–C(15)
C(14)–C(15)
C(17)–C(18)
N(2)–C(7)
N(2)–C(7)
Crystal system
Space group
C(7)–C(18)
N(1)–H(1)
F(3)ꢀ ꢀ ꢀH(1A)
F(3)ꢀ ꢀ ꢀH(1A)–N(1A)
˚
a (A)
2.323
˚
b (A)
˚
c (A)
3.103
a (8)
b (8)
g (8)
Bond angle (8)
105.76(3)
90.00
N(4)–N(1)–N(2)
N(1)–N(2)–C(7)
N(2)–C(7)–C(8)
F(3)ꢀ ꢀ ꢀH(1A)–N(1A)
102.9(2)
115.4(2)
121.7(2)
151.01
C(15)–N(1)–N(2)
N(1)–N(2)–C(17)
N(2)–C(17)–C(16)
108.2(2)
112.2(2)
102.9(2)
3
˚
V (A )
1884.0(7)
4
Z
C(17)–C(16)–C(15) 102.2(2)
C(16)–C(15)–N(1) 114.4(3)
Dcalcd
1.621
1.505
2y range (8)
2–50
2–50
m (mmÀ1
F(0 0 0)
)
0.347
304
0.261
872
indicating polyfluorophenyl substituted-4,5-dihydropyra-
zole derivatives have moderate biological activity as embry-
otoxic, uricosuric, interleukin antagonist, complement
inhibitor and metabolic, etc. A further chemical transforma-
tion of the new compounds 3 is under investigation.
Total reflections
4128
5368
Unique reflections
2850
(Rint ¼ 0.0182)
1735
4315
(Rint ¼ 0.0335)
2205
Observed reflections
(I > 2s(I))
Data/restraints/parameters
Goodness of fit on F2
Final R indices (I > 2s(I))
2850/0/183
1.078
4315/0/286
0.947
R1 ¼ 0.0574,
wR2 ¼ 0:1375
R1 ¼ 0.0862,
wR2 ¼ 0:1616
R1 ¼ 0.0672,
wR2 ¼ 0:1489
R1 ¼ 0.1306,
wR2 ¼ 0:1843
3. Experimental
R indices (all data)
Melting points were measured on a Temp-Melt apparatus
and are uncorrected. Solvents were dried before use. 1H NMR
and 19F NMR spectra were recorded on a Bruker AM-300
spectrometer with Me4Si and CFCl3 (with upfield negative) as
the internal and external standards, respectively. IR spectra
were obtained with a Nicolet AV-360 spectrophotometer.
Lower resolution mass spectra or high resolution mass spectra
(HRMS) were obtained on a Finnigan GC-MS 4021 or a
Finnigan MAT-8430 instrument respectively. Elemental ana-
lyses were performed by this Institute. X-ray diffraction
crystal structure analysis was obtained on Bruker P4 instru-
ment. [Bis(acetoxy)iodo]benzene was purchased from Acros.
Data were collected at 293(2) K on Bruker P4 diffractometer with graphite
˚
monochromator and Mo Ka radiation (l ¼ 0:71073 A). Refinement
method: full-matrix least-squares on F2.
structure of compound 3i. The crystal data and refinement
details are summarized in Table 2. Selected bond lengths and
bond angles of compound 3i are listed in Table 3.
A plausible mechanism for the generation of nitrile imines
is analogous to the oxidation of the aldehyde hydrazones
with lead tetracetate [8] as well as mercuric acetate [11] and
is illustrated in Scheme 4.
In summary, a series of 3-substituted-1-(4-chloro-2,3,5,6-
tetrafluorophenyl)-5-ethoxycarbonyl-4,5-dihydropyrazoles
(3) were prepared by oxidation of aldehyde 4-chloro-
2,3,5,6-tetrafluorophenylhydrazones (1) with [bis(acetox-
y)iodo]benzene in the presence of ethyl acrylate. The bio-
logical activity of typical compounds was measured,
3.1. A general procedure for the preparation of
4,5-dihydropyrazoles
A solution of [bis(acetoxy)iodo]benzene (0.322 g,
1 mmol) in CH2Cl2 (5 ml) was added dropwise to a 20 ml
H
-PhI
+
+
PhI(OAc)2
]
[
ClC6F4-N-N=C-R
ClC6F4-N-N C-R
ClC6F4N-N=C-R
I
ClC6F4NHN=CHR
-HOAc
-HOAc
2
CH2=CHCO2Et
AcO
Ph
1
R
N
CO2Et
N
C6F4Cl
3
Scheme 4.

L.-P. Song, S.-Z. Zhu / Journal of Fluorine Chemistry 124 (2003) 211–217
215
flask containing aldehyde 4-chloro-2,3,5,6-tetrafluorophe-
nylhydrazone (1) (1 mmol) and ethyl acrylate (5 ml). After
stirring at 0 8C for 4 h, TLC analysis shown the reaction was
completed. The reaction mixture was then concentrated
under vacuum. To the residue was added 20 ml of CH2Cl2
and the organic layer was washed with 5% aq. Na2CO3
solution (10 ml), brine (10 ml), and dried with anhydrous
MgSO4. After evaporation of the solvent, the crude material
was purified by column chromatography on silica gel using
petroleum-ethyl acetate as eluent. The reaction yields are
shown in Table 1.
Ar–F, F3, F5); EIMS (probe) 70 eV, m/z (rel. int.): 432/430
[M]þ (9/25), 359/357 [M À CO2Et]þ (35/100), 148 [C6F4]þ
(18); Anal. Calcd. for C19H15ClF4N2O3: C, 52.98; H, 3.51;
N, 6.50. Found: C, 53.02; H, 3.36; N, 6.31.
3.1.4. 3-(4-Bromophenyl)-1-(4-chloro-2,3,5,6-
tetrafluoro)phenyl-5-ethoxycarbonyl-4,5-dihydropyrazole
(3d)
m.p. 136–138 8C; IR (KBr): n 2992, 1731, 1637, 1502,
1487, 1219, 1161, 1106 cmÀ1 1H NMR spectral data
;
(300 MHz, CDCl3): d 7.57–7.51 (m, 4H, Ar–H), 5.03 (dd,
J ¼ 11:7 Hz, J ¼ 7:2 Hz, 1H, pyrazole 5-H), 4.16 (q,
J ¼ 7:2 Hz, 2H, –OCH2–), 3.66–3.48 (m, ABX system,
2H, pyrazole 4-H), 1.20 (t, J ¼ 7:2 Hz, 3H, –CH3); 19F
NMR (282 MHz, CDCl3): d À142.2 (d, 2F, J ¼ 15:0 Hz,
Ar–F, F2, F6), À147.7 (d, 2F, J ¼ 15:0 Hz, Ar–F, F3, F5);
EIMS (probe) 70 eV, m/z (rel. int.): 482/480/478 [M]þ (5/21/
16), 409/407/405 [M À CO2Et]þ (26/100/78), 328/326
[M À CO2Et–Br]þ (8/25); Anal. Calcd. for C18H12BrClF4-
N2O2: C, 45.07; H, 2.52; N, 5.84. Found: C, 45.03; H, 2.45;
N, 5.88.
3.1.1. 1-(4-Chloro-2,3,5,6-tetrafluoro)phenyl-5-
ethoxycarbonyl-3-phenyl-4,5-dihydropyrazole (3a)
m.p. 116–118 8C; IR (KBr): n 2996, 1731, 1636, 1506,
1488, 1220, 1165, 1112 cmÀ1 1H NMR spectral data
;
(300 MHz, CDCl3): d 7.71–7.67 (m, 2H, Ar–H), 7.42–
7.39 (m, 3H, Ar–H), 5.02 (dd, J ¼ 11:7 Hz, J ¼ 7:2 Hz,
1H, pyrazole 5-H), 4.16 (q, J ¼ 7:2 Hz, 2H, –OCH2–), 3.69–
3.50 (m, ABX system, 2H, pyrazole 4-H), 1.20 (t,
J ¼ 7:2 Hz, 3H, –CH3); 19F NMR (282 MHz, CDCl3):
d À142.4 (d, 2F, J ¼ 15:0 Hz, Ar–F, F2, F6), À147.8 (d,
2F, J ¼ 15:0 Hz, Ar–F, F3, F5); EIMS (probe) 70 eV, m/z
(rel. int.): 402/400 [M]þ (7/19), 329/327 [M À CO2Et]þ (33/
100), 77 [C6H5]þ (7); Anal. Calcd. for C18H13ClF4N2O2: C,
53.95; H, 3.27; N, 6.99. Found: C, 54.09; H, 3.21; N, 6.88.
3.1.5. 1-(4-Chloro-2,3,5,6-tetrafluoro)phenyl-5-
ethoxycarbonyl-3-(4-nitrophenyl)-4,5-dihydro-pyrazole
(3e)
m.p. 118–120 8C; IR (KBr): n 2986, 1737, 1638, 1597,
1573, 1505, 1489, 1343, 1157, 1107 cmÀ1; 1H NMR spectral
data (300 MHz, CDCl3): d 8.14 (d, J ¼ 9:0 Hz, 2H, Ar–H),
7.73 (d, J ¼ 9:0 Hz, 2H, Ar–H), 5.05 (dd, J ¼ 12:0 Hz,
J ¼ 7:2 Hz, 1H, pyrazole 5-H), 4.08 (q, J ¼ 7:2 Hz, 2H,
–OCH2–), 3.62–3.43 (m, ABX system, 2H, pyrazole 4-H),
1.12 (t, J ¼ 7:2 Hz, 3H, –CH3); 19F NMR (282 MHz,
CDCl3): d À141.9 (d, 2F, J ¼ 15:0 Hz, Ar–F, F2, F6),
À147.7 (d, 2F, J ¼ 15:0 Hz, Ar–F, F3, F5); EIMS (probe)
70 eV, m/z (rel. int.): 447/445 [M]þ (6/16), 374/372
[M À CO2Et]þ (35/100), 328/326 [M À CO2Et–NO2]þ
(11/33); Anal. Calcd. for C18H12ClF4N3O4: C, 48.50; H,
2.71; N, 9.43. Found: C, 48.68; H, 2.78; N, 9.35.
3.1.2. 1-(4-Chloro-2,3,5,6-tetrafluoro)phenyl-5-
ethoxycarbonyl-3-(4-methylphenyl)-4,5-dihydropyrazole
(3b)
m.p. 118–120 8C; IR (KBr): n 2992, 1733, 1634, 1486,
1216, 1162, 1107 cmÀ1; H NMR spectral data (300 MHz,
1
CDCl3): d 7.57 (d, J ¼ 8:4 Hz, 2H, Ar–H), 7.21 (d,
J ¼ 8:4 Hz, 2H, Ar–H), 5.01 (dd, J ¼ 12:0 Hz, J ¼
7:2 Hz, 1H, pyrazole 5-H), 4.16 (q, J ¼ 7:2 Hz, 2H,
OCH2), 3.67–3.48 (m, ABX system, 2H, pyrazole 4-H),
2.38 (s, 1H, Ar–CH3), 1.19 (t, J ¼ 7:2 Hz, 3H, –CH3); 19F
NMR (282 MHz, CDCl3): d À142.5 (d, 2F, J ¼ 15:0 Hz,
Ar–F, F2, F6), À147.8 (d, 2F, J ¼ 15:0 Hz, Ar–F, F3, F5);
EIMS (probe) 70 eV, m/z (rel. int.): 416/414 [M]þ (7/18),
343/341 [M À CO2Et]þ (34/100), 91 [CH3Ph]þ (14); Anal.
Calcd. for C19H15ClF4N2O2: C, 55.02; H, 3.65; N, 6.75.
Found: C, 55.04; H, 3.45; N, 6.61.
3.1.6. 1-(4-Chloro-2,3,5,6-tetrafluoro)phenyl-5-
ethoxycarbonyl-3-(pentafluorophenyl)-4,5-dihydropyrazole
(3f)
m.p. 106–108 8C; IR (KBr): n 1733, 1530, 1484, 1224,
1157, 1115, 1107 cmÀ1; H NMR spectral data (300 MHz,
1
3.1.3. 1-(4-Chloro-2,3,5,6-tetrafluoro)phenyl-5-
ethoxycarbonyl-3-(4-methoxyphenyl)-4,5-dihydropyrazole
(3c)
CDCl3): d 5.01 (dd, J ¼ 11:7 Hz, J ¼ 6:9 Hz, 1H, pyrazole
5-H), 4.17 (q, J ¼ 7:2 Hz, 2H, –OCH2–), 3.76–3.60 (m,
ABX system, 2H, pyrazole 4-H), 1.23 (t, J ¼ 7:2 Hz, 3H, –
CH3); 19F NMR (282 MHz, CDCl3): d À138.3 (d,
J ¼ 15:0 Hz, 2F, C6F5–, F2, F6), À141.7 (d, J ¼
15; 0 Hz, 2F, ClC6F4–, F2, F6), À147.3 (d, J ¼ 15:0 Hz,
2F, ClC6F4–, F3, F5), À152.5 (t, J ¼ 24:0 Hz, 1F, C6F5–,
F4), À161.2 to À161.3(m, 2F, C6F5–, F3, F5); EIMS (probe)
70 eV, m/z (rel. int.): 492/490 [M]þ (4/13), 419/417
[M À CO2Et]þ (33/100), 197 [ClC6F4]þ (6); Anal. Calcd.
for C18H8ClF9N2O2: C, 44.06; H, 1.64; N, 5.71. Found: C,
44.15; H, 1.62; N, 5.65.
m.p. 120–122 8C; IR (KBr): n 2996, 1730, 1637, 1608,
1489, 1265, 1218, 1165, 1111 cmÀ1; 1H NMR spectral data
(300 MHz, CDCl3): d 7.63 (d, J ¼ 9:0 Hz, 2H, Ar–H), 6.92
(d, J ¼ 9:0 Hz, 2H, Ar–H), 4.98 (dd, J ¼ 11:4 Hz,
J ¼ 7:2 Hz, 1H, pyrazole 5-H), 4.16 (q, J ¼ 7:2 Hz, 2H,
–OCH2–), 3.84 (s, 1H, ArOCH3), 3.66–3.47 (m, ABX
system, 2H, pyrazole 4-H), 1.20 (t, J ¼ 7:2 Hz, 3H, –
CH3); 19F NMR (282 MHz, CDCl3): d À142.5 (d, 2F,
J ¼ 15:0 Hz, Ar–F, F2, F6), À147.8 (d, 2F, J ¼ 15:0 Hz,

216
L.-P. Song, S.-Z. Zhu / Journal of Fluorine Chemistry 124 (2003) 211–217
3.1.7. 1-(4-Chloro-2,3,5,6-tetrafluoro)phenyl-5-
–OCH2–), 3.41–3.23 (m, ABX system, 2H, pyrazole 4-H),
1.92 (d, J ¼ 6:9 Hz, 3H, –CH3), 1.20 (t, J ¼ 7:2 Hz, 3H, –
CH3); 19F NMR (282 MHz, CDCl3): d À142.8 (d, 2F,
J ¼ 15:0 Hz, Ar–F, F2, F6), À148.2 (d, 2F, J ¼ 15:0 Hz,
Ar–F, F3, F5); EIMS (probe) 70 eV, m/z (rel. int.): 366/364
[M]þ (6/17), 293/291 [M À CO2Et]þ (34/100); Anal. Calcd.
for C15H13ClF4N2O2: C, 49.40; H, 3.59; N, 7.68. Found: C,
49.40; H, 3.52; N, 7.60.
ethoxycarbonyl-3-(furfur-2-yl)-4,5-dihydropyrazole (3g)
m.p. 110–112 8C; IR (KBr): n 3149, 2994, 1731, 1639,
1505, 1486, 1217, 1173, 1111 cmÀ1; 1H NMR spectral data
(300 MHz, CDCl3): d 7.52 (d, J ¼ 1:6 Hz, 1H, furfuryl-H),
6.68 (d, J ¼ 3:6 Hz, 1H, furfuryl-H), 6.50–6.49 (m, 1H,
furfuryl-H), 4.96 (dd, J ¼ 11:1 Hz, J ¼ 7:8 Hz, 1H, pyra-
zole 5-H), 4.17 (q, J ¼ 7:2 Hz, 2H, –OCH2–), 3.64–3.50 (m,
ABX system, 2H, pyrazole 4-H), 1.20 (t, J ¼ 7:2 Hz, 3H, –
CH3); 19F NMR (282 MHz, CDCl3): d À142.2 (d, 2F,
J ¼ 15:0 Hz, Ar–F, F2, F6), À147.2 (d, 2F, J ¼ 15:0 Hz,
Ar–F, F3, F5); EIMS (probe) 70 eV, m/z (rel. int.): 392/390
[M]þ (11/32), 319/317 [M À CO2Et]þ (33/100); Anal.
Calcd. for C16H11ClF4N2O3: C, 49.19; H, 2.84; N, 7.17.
Found: C, 49.41; H, 2.75; N, 7.12.
3.1.11. 1-(4-Chloro-2,3,5,6-tetrafluoro)phenyl-5-
ethoxycarbonyl-3(2-methylpropyl)-4,5-dihydropyrazole
(3k)
sticky oil; IR (liquid film): n 2960, 1744, 1636, 1493,
1200, 1168, 1027 cmÀ1; H NMR spectral data (300 MHz,
1
CDCl3): d 4.74 (dd, J ¼ 10:8 Hz, J ¼ 7:8 Hz, 1H, pyrazole
5-H), 4.14 (q, J ¼ 7:2 Hz, 2H, –OCH2–), 3.24–3.07 (m,
ABX system, 2H, pyrazole 4-H), 2.26 (d, J ¼ 7:8 Hz, 2H, –
CH2–), 2.05–1.90 (m, J ¼ 6:6 Hz, 1H, –CH–, 1.19 (t,
J ¼ 7:2 Hz, 3H, –CH3), 0.99 (d, J ¼ 6:6 Hz, 6H,
2 ꢁ CH3); 19F NMR (282 MHz, CDCl3): d À143.1 (d, 2F,
J ¼ 18:0 Hz, Ar–F, F2, F6), À147.7 (d, 2F, J ¼ 18:0 Hz,
Ar–F, F3, F5); EIMS (probe) 70 eV, m/z (rel. int.): 382/380
[M]þ (3/7), 309/307 [M À CO2Et]þ (22/63), 57 [C4H9]þ
(41), 43 [C3H7]þ (100); HRMS Calcd. for C16H17ClF4N2O2:
380.09147. Found: 380.08944.
3.1.8. 1-(4-Chloro-2,3,5,6-tetrafluoro)phenyl-5-
ethoxycarbonyl-3-(naphth-1-yl)-4,5-dihydropyrazole (3h)
m.p. 96–98 8C; IR (KBr): n 2982, 1755, 1638, 1506, 1489,
1191, 1138, 1109 cmÀ1; H NMR spectral data (300 MHz,
1
CDCl3): d 9.25 (d, J ¼ 8:4 Hz, 1H, naphthyl-H), 7.88 (d,
J ¼ 8:4 Hz, 2H, naphthyl-H), 7.66–7.45 (m, 4H, naphthyl-
H), 5.07 (dd, J ¼ 12:3 Hz, J ¼ 6:0 Hz, 1H, pyrazole 5-H),
4.17 (q, J ¼ 7:2 Hz, 2H, –OCH2–), 3.93–3.66 (m, ABX
system, 2H, pyrazole 4-H), 1.21 (t, J ¼ 7:2 Hz, 3H, –CH3);
19F NMR (282 MHz, CDCl3): d À141.9 (d, 2F, J ¼ 15:0 Hz,
Ar–F, F2, F6), À147.7 (d, 2F, J ¼ 15:0 Hz, Ar–F, F3, F5);
EIMS (probe) 70 eV, m/z (rel. int.): 452/450 [M]þ (10/29),
379/377 [M À CO2Et]þ (34/100), 127 [C10H7]þ (63); Anal.
Calcd. for C22H15ClF4N2O2: C, 58.61; H, 3.35; N, 6.21.
Found: C, 58.73; H, 3.31; N, 6.10.
3.1.12. 5-Ethoxycarbonyl-1-(4-nitrophenyl)-3-
pentafluorophenyl-4,5-dihydropyrazole (5)
m.p. 148–150 8C; IR (KBr): n 2992, 1751, 1595, 1508,
1488, 1317, 1112 cmÀ1; H NMR spectral data (300 MHz,
1
CDCl3): d 8.18 (d, J ¼ 9:3 Hz, 2H, Ar–H), 7.13 (d,
J ¼ 9:3 Hz, 2H, Ar–H), 4.98 (dd, J ¼ 12:9 Hz,
J ¼ 5:4 Hz, 1H, pyrazole 5-H), 4.26 (q, J ¼ 7:2 Hz, 2H,
OCH2), 3.91–3.57 (m, ABX system, 2H, pyrazole 4-H), 1.26
(t, J ¼ 7:2 Hz, 3H, –CH3); 19F NMR (282 MHz, CDCl3): d
À137.9 (d, 2F, J ¼ 15:0 Hz, Ar–F, F2, F6), À151.6 (t, 1F,
J ¼ 21:6 Hz, Ar–F, F4), À160.9 to À161.1 (m, 2F, Ar–F, F3,
F5); EIMS (probe) 70 eV, m/z (rel. int.): 429 [M]þ (20), 356
[M À CO2Et]þ (100), 310 [M À CO2Et-NO2]þ, (54); Anal.
Calcd. for C18H12F5N3O4: C, 50.36; H, 2.82; N, 9.79. Found:
C, 50.39; H, 2.78; N, 9.83.
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary pub-
lication nos. CCDC 204060–204061. Copies of the data can
be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: þ44-1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk).
3.1.9. 1-(4-Chloro-2,3,5,6-tetrafluoro)phenyl-5-
ethoxycarbonyl-3-styryl-4,5-dihydropyrazole (3i)
m.p. 148–150 8C; IR (KBr): n 2997, 1740, 1637, 1507,
1491, 1212, 1133, 1121 cmÀ1 1H NMR spectral data
;
(300 MHz, CDCl3): d 7.50–7.49 (m, 2H, Ar–H), 7.41–
7.32 (m, 3H, Ar–H), 7.12 (d, J ¼ 16:5 Hz, 1H, ¼CH–),
6.74 (d, J ¼ 16:5 Hz, 1H, ¼CH–), 5.03 (dd, J ¼ 11:1 Hz,
J ¼ 6:9 Hz, 1H, pyrazole 5-H), 4.18 (q, J ¼ 7:2 Hz, 2H, –
OCH2–), 3.58–3.42 (m, ABX system, 2H, pyrazole 4-H),
1.22 (t, J ¼ 7:2 Hz, 3H, –CH3); 19F NMR (282 MHz,
CDCl3): d À142.5 (d, 2F, J ¼ 15:0 Hz, Ar–F, F2, F6),
À148.3 (d, 2F, J ¼ 15:0 Hz, Ar–F, F3, F5); EIMS (probe)
70 eV, m/z (rel. int.): 428/426 [M]þ (10/29), 355/353
[M À CO2Et]þ (33/100), 103 [C6H5CH¼CH]þ (24), 77
[C6H5]þ (16); Anal. Calcd. for C20H15ClF4N2O2: C,
56.28; H, 3.54; N, 6.56. Found: C, 56.17; H, 3.40; N, 6.41.
3.1.10. 1-(4-Chloro-2,3,5,6-tetrafluoro)phenyl-5-
ethoxycarbonyl-3-propenyl-4,5-dihydropyrazole (3j)
m.p. 72–74 8C; IR (KBr): n 3134, 2999, 1744, 1638, 1509,
Acknowledgements
1493, 1214, 1181, 1119 cmÀ1
;
1H NMR spectral data
The authors thank the National Natural Science Founda-
tion of China (NNSFC) (Nos. 20032010 and 20072049) and
Innovation Foundation of Chinese Academy of Sciences for
financial support.
(300 MHz, CDCl3): d 6.43 (d, J ¼ 15:6 Hz, 1H, ¼CH–),
6.05–5.93 (m, 1H, ¼CH–), 4.89 (dd, J ¼ 11:4 Hz,
J ¼ 7:5 Hz, 1H, pyrazole 5-H), 4.16 (q, J ¼ 7:2 Hz, 2H,

L.-P. Song, S.-Z. Zhu / Journal of Fluorine Chemistry 124 (2003) 211–217
217
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