Synthesis of pyrazoles with fluorinated side-chain by cyclization of fluoroalkylated triketides

Article abstract of DOI:10.1016/j.tet.2013.02.059

The cyclization of fluoroalkylated 3,5-dioxoesters with hydrazines, carried out in glacial acetic acid, afforded pyrazines with fluoroalkylated side-chain. The cyclization of 3,5-dioxoesters with hydroxylamine afforded hydroxylated fluoroalkylated dihydro

Full text of DOI:10.1016/j.tet.2013.02.059

Tetrahedron 69 (2013) 3459e3464
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of pyrazoles with fluorinated side-chain by cyclization
of fluoroalkylated triketides
,
,
b
a
a,b
Willi Desens a b, Marleen Winterberg a , Stefan Buttner , Dirk Michalik
,
€
Ashot S. Saghyan c y, Alexander Villinger a, Christine Fischer b, Peter Langer a
Institut fur Chemie, Universitat Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
,
d,
,b,
*
a
€
€
b
€
€
Leibniz-Institut fur Katalyse e.V. an der Universitat Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
c Scientific and Production Center “Armbiotechnology” of NAS RA, 14 Gyurjyan Str., 0056 Yerevan, Armenia
d Department of Pharmaceutical Chemistry, Yerevan State University, Alex Manoogian Str. 1, 0025 Yerevan, Armenia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 January 2013
Received in revised form 12 February 2013
Accepted 18 February 2013
Available online 26 February 2013
The cyclization of fluoroalkylated 3,5-dioxoesters with hydrazines, carried out in glacial acetic acid, af-
forded pyrazines with fluoroalkylated side-chain. The cyclization of 3,5-dioxoesters with hydroxylamine
afforded hydroxylated fluoroalkylated dihydroisoxazoles. All reactions proceeded with good to very good
regioselectivity.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Cyclizations
Dianions
Organofluorine compounds
Tautomerism
1,3,5-Tricarbonyl compounds
1. Introduction
are of considerable relevance in medicinal chemistry. For example,
the clinically used drug celecoxib represents a non-steroidal anti-
Fluoroalkylated heterocycles are of considerable relevance in
medicinal and agricultural chemistry, due to their solubility, bio-
availability and metabolic stability.1e4Perfluoroalkylated molecules
are also of importance as liquid crystals5 and as ligands6 in catalytic
reactions in fluorous solvent systems and as organocatalysts.7 Per-
fluoroalkylated 1,3,5-tricarbonyl compounds represent versatile
building blocks for the synthesis of hetero- and carbocycles. Fluori-
rheumatic agent,11 while fipronilÒ is highly active against parasites12
(Scheme 1).
NH2
O
S
O
N
CF3
Cl
N
N
€
nated 1,3,5-triketones were studied by Roschenthaler and co-
S
workers.8 In 2011, we reported a convenient synthesis of fluo-
roalkylated 3,5-dioxoalkanoates based on the condensation of the
dianion of ethyl acetoacetate with perfluoroalkanoates.9 The tauto-
meric equilibria of the products in solution were also analyzed in
detail. The chemistry of these new and potentially useful building
blocks has, to the best of our knowledge, not been studied so far.10
Herein, we report the synthesis of pyrazoles containing per-
fluoroalkyl side chains by cyclization reactions of fluoroalkylated
3,5-dioxoalkanoates with hydrazines. Trifluoromethylated pyrazoles
N
O
N
Me
NH2
F3C
Cl
F3C
Fipronil®
Celecoxib
Scheme 1. Structures of fipronilÒ and celecoxib.
2. Results and discussion
It is known for more than one century that pyrazoles can be
prepared by cyclization of hydrazine with 1,3-diketones.13 The cy-
clization of perfluoroalkylated 3,5-dioxoalkanoates 1b and 1c,
available by condensation of the dianion of ethyl acetoacetate with
* Corresponding author. Tel.: þ49 381 4986410; fax: þ49 381 49864112; e-mail
address: peter.langer@uni-rostock.de (P. Langer).
y
Fax: þ374 10 654183, þ374 10 559355.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.02.059

3460
W. Desens et al. / Tetrahedron 69 (2013) 3459e3464
the corresponding perfluoroalkylated esters,9 with hydrazine hy-
drate (2a) afforded pyrazoles 3a and 3b, respectively (Scheme 2,
Table 1). The reactions were carried out in glacial acetic acid (25 ꢀC,
2 h). The cyclization of 1b and 1c with methyl hydrazine gave
perfluoroalkylated derivatives studied in the present manuscript as
compared to non-fluorinated pyrazoles, because of the strong elec-
tron withdrawing effect of the perfluoroalkyl groups and thus low
stability of a cationic intermediate. In case of the p-nitrophenyl
substituted molecules the elimination is particularly difficult be-
cause of the additional electron withdrawing effect of the aryl group.
In addition, the formation of regioisomers might account to the
moderate yields. The yields could not be improved by elevation of
the temperature. The cyclization of 1aec with p-methylphenyl hy-
drazine (2d) resulted in the formation of pyrazoles 3hej. While CF3-
substituted pyrazole 3h was isolated in good yield, the isolated yield
of 3i was rather low, which can be explained by the formation of
regioisomer 4i and by the low solubility of the 3,5-dioxoalkanoate. In
case of 3j, the regioisomeric side-product could not be completely
separated by chromatography. 3,5-Dioxoalkanoates 1def contain an
additional chloro substituent and were prepared by condensation of
the dianion of ethyl 2-chloroacetoacetate with the corresponding
perfluoroalkanoates.11 The cyclization of ethyl 6,6,6-trifluoro-3,5-
dioxohexanoate (1a) with 2d, carried out in glacial acetic acid at
25 ꢀC for 2 h, afforded pyrazole 3k in good yield and with excellent
regioselectivity.
The structures of compounds 3 and 4 were confirmed by NMR
spectroscopy. For instance, in the NOESY spectra of 3c, 3d and 3i
correlations were found between the protons of the N-methyl
groups (3c, 3d) and the ortho-aromatic protons (3i), respectively,
with the protons of the neighbouring methylene group (Scheme 4).
Such NOESY correlations have not been observed for compounds
4c, 4d and 4i. Typically for these compounds, 1H,13C correlations of
the N-methyl (3c, 3d) and the ortho-aromatic (3i) protons to the
carbon atom F2CC were observed in the 1H,13C HMBC spectra. The
structure of 5 was independently confirmed by X-ray crystal
structure analysis (Fig. 1).14
R
N
O
N
F2n+1Cn
H2N
R
OEt
OEt
N
H
3a-m
X
O
O
O
+
2a-d
F2n+1Cn
OEt
R
X
i
N
N
O
1a-f
F2n+1Cn
X
4a-m
Scheme 2. Synthesis of 3aem; conditions: i, HOAc, 25 ꢀC, 2 h.
Table 1
Synthesis of 3aem
1
2
3,4
CnF2nþ1
X
R
3a
59
55
66
4a
b
c
b
c
a
b
c
a
b
c
d
e
f
a
a
b
b
c
a
b
c
d
e
f
g
h
i
C2F5
C3F7
C2F5
C3F7
CF3
C2F5
C3F7
CF3
C2F5
C3F7
CF3
C2F5
C3F7
H
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
H
H
Me
Me
4-(NO2)C6H4
4-(NO2)C6H4
4-(NO2)C6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
0
0
16
17
0
0
0
0
4
67
37b
35
c
c
31
67
d
d
d
d
d
d
25
j
k
l
20c
75
0
15
70d
20c
m
a
b
c
Yields of isolated products.
Product 5 was isolated as a by-product in 31% yield (structure see Scheme 3).
Unseparable mixture of regioisomers.
The reaction was carried out at 50 ꢀC, 6 h (for 25 ꢀC, 2 h: 42% yield).
CH3
CH2
H3C
N
N
O
d
N
F
2n+1Cn
N
O
F2n+1Cn
OEt
pyrazoles 3c and 3d, respectively, along with small amounts of
regioisomers 4c and 4d, which could be separated by chromatog-
raphy. The predominant formation of products 3c and 3d can be
explained by protonation of the (more basic) nitrogen atom attached
to the methyl group and subsequent regioselective attack of the non-
protonated NH2 group to the keto group neighbouring to the per-
fluoroalkyl group. This keto group is more electrophilic than the
central keto group because of the strong electron withdrawing effect
of the perfluoroalkyl group. The cyclization of 3,5-dioxoalkanoates
1aec with p-nitrophenyl hydrazine afforded pyrazoles 3eeg. The
moderate yields can be explained by formation of the corresponding
hydrates as by-products. In case of the reaction of 1a, product 5 could
be isolated in 31% yield (Scheme 3). This type of hydrates should be
intermediates during the formation of all pyrazoles. In general, it can
be expected that the elimination of water is more difficult for the
OEt
1H,13C HMBC
correlations of 4c,d
1H,1H NOESY
correlations of 3c,d
CH3
H3C
N
N
OEt
N
N
C2F5
O
CH2
OEt
C2F5
O
1H,1H NOESY
correlations of 3i
1H,13C HMBC
correlations of 4i
O2N
Scheme 4. Significant NOESY and HMBC correlations of selected compounds 3 and 4.
The cyclization of 1d with parent hydrazine (2a), carried out in
glacial acetic acid, afforded product 6, containing an exocyclic
double bond, in 58% yield (Scheme 5). The chloride group was
cleaved during the reaction, which might be explained by nucleo-
philic displacement of the chloride by the hydrazine and sub-
N
O
N
F3C
HO
OEt
5
sequent extrusion of nitrogen by
a process related to the
Scheme 3. Compound 5.
WolffeKishner reaction or by another type of reduction.

W. Desens et al. / Tetrahedron 69 (2013) 3459e3464
3461
group attached to the perfluoroalkyl group and subsequent cycli-
zation. In the 1H NMR spectra of compounds 8 the non-equivalent
CH2 protons appear as AB spectra with geminal coupling constants
2J¼18.5e19.5 Hz. For compounds 8def, doubled sets of signals are
observed, because diastereomers are formed due to the presence of
a second asymmetric carbon atom. The structures of 8 were con-
firmed by the 13C NMR spectra, in which a coupling was observed
between the fluorine atoms and the sp3 hybridized carbon atom
attached to the hydroxyl group. For instance, a coupling constant
JC,F¼34.3 Hz, found in case of 8a, is characteristic for a 13C,19
F
coupling about two bonds, by which the alternative regioisomer
can be excluded.
O
OEt
OEt
N
O
HO
F2n+1Cn
X
X
8a-f
i
O
O
O
H2N OH
7
F2n+1Cn
OEt
O
X
1a-f
O
N
OH
F2n+1Cn
Scheme 6. Synthesis of 8aef; conditions: i, HOAc, 25 ꢀC, 2 h.
Table 2
Synthesis of 8aef
8
CnF2nþ1
X
% (8)a
a
b
c
d
e
f
CF3
H
H
H
Cl
Cl
Cl
57
46
51
45
31
26
C2F5
C3F7
CF3
C2F5
C3F7
Fig. 1. Ortep plot of 5 (50% probability level).
H
N
H2N NH2
2a
N
O
O
O
a
Yields of isolated products.
F3C
HO
OEt
F3C
OEt
i
O
Cl
In conclusion, we have reported the synthesis of pyrazines,
containing a fluoroalkylated side-chain, by cyclization of fluo-
roalkylated 3,5-dioxoesters with hydrazines. The cyclization of 3,5-
dioxoesters with hydroxylamine afforded hydroxylated fluoroalky-
lated dihydroisoxazoles. All reactions, which were carried out in
glacial acetic acid, proceeded with good to very good regioselectivity.
1d
6 (58%)
Scheme 5. Synthesis of 6; conditions: i, HOAc, 25 ꢀC, 2 h.
The structure of compound 6 was confirmed by the NMR data.
One of the non-equivalent methylene protons resonating as dou-
bled multiplet at 2.81 ppm shows a coupling to the trifluoromethyl
group (4JH,F¼1.5 Hz). The second methylene proton resonates as
a doublet of a doublet at 3.10 ppm. Except the geminal coupling of
2J¼19.5 Hz, a coupling about four bonds to the olefinic hydrogen
atom (4JH,H¼2.5 Hz) was found. The olefinic hydrogen atom appears
at 6.98 ppm as a triplet with the same coupling constant of 2.5 Hz.
The hydroxyl proton resonates at 4.91 ppm. A 1H,1H NOESY spec-
trum revealed a correlation between the olefinic hydrogen atom
and the methylene protons of the ester group and between the
hydroxyl group and the methylene proton at 2.81 ppm.
The cyclization of 3,5-dioxoalkanoates 1aef with hydroxyl-
amine (7), carried out in glacial acetic acid (25 ꢀC, 2 h), afforded the
hydroxylated dihydroisoxazoles 8aef (Scheme 6, Table 2). It is
important to note that, under the reaction conditions, extrusion of
water and formation of the corresponding isoxazoles was not ob-
served. Extended reaction times resulted in decomposition. Prod-
ucts 8aef were formed with very good regioselectivity. This might
be explained by protonation of the amino group of 7, attack of the
(non-protonated) hydroxyl group to the more electrophilic keto
3. Experimental section
3.1. General
1H NMR spectra (250.13, 300.13 and 500.13 MHz, resp.) and 13
C
NMR spectra (62.9, 75.5 and 125.8 MHz, resp.) were recorded on
Bruker spectrometers AVANCE 250, AVANCE 300 and AVANCE 500.
The chemical shifts are referenced to solvent signals (CDCl3:
d
1H¼7.26,
d
13C¼77.0; DMSO-d6:
d
1H¼2.50,
d
13C¼39.7). The NMR
signals were assigned by DEPT and two-dimensional 1H,1H COSY,
1H,1H NOESYand 1H,13C correlation spectra (HSQC, HETCOR, HMBC)
using standard pulse sequences (standard Bruker software).19F
NMR spectra (282.4 MHz) were recorded on Bruker spectrometer
AVANCE 300 and 19F chemical shifts are referenced to CFCl3.
3.2. Ethyl 2-(3-(perfluoroethyl)-1H-pyrazol-5-yl)acetate (3a)
1H NMR (300.13 MHz, CDCl3):
d
¼1.29 (t, JH,H¼7.2 Hz, 3H,
3
OCH2CH3), 3.79 (s, 2H, CH2), 4.23 (q, 3JH,H¼7.2 Hz, OCH2), 6.46 (s,1H,

3462
W. Desens et al. / Tetrahedron 69 (2013) 3459e3464
CH), 11.72 (br s, 1H, NH). 19F NMR (282 MHz, CDCl3):
d
¼ꢁ84.6 (CF3),
DMSO-d6):
d
¼ꢁ61.1 (CF3). 13C NMR (62.9 MHz, DMSO-d6):
d
¼13.7
2
ꢁ113.0 (CF2). 13C NMR (75.5 MHz, CDCl3):
d
¼14.0 (CH3), 31.1 (CH2),
(CH3), 31.6 (CH2), 61.0 (OCH2), 107.3 (CH), 121.1 (q, JC,F¼269 Hz,
62.0 (OCH2), 104.7 (CH), 110.7 (tq, 1JC,F¼250 Hz, 2JC,F¼39.3 Hz, CF2),
CF3), 124.9, 125.9 (CHAr), 139.6 (Cq), 142.2 (q, JC,F¼37.8 Hz, F3CC),
2
1
2
118.8 (qt, JC,F¼286 Hz, JC,F¼38.0 Hz, CF3), 137.1 (CN), 141.5 (t,
2JC,F¼28.6 Hz, F2CC), 169.5 (CO).
143.3, 147.1 (Cq), 168.2 (CO).
3.9. Ethyl 2-(5-hydroxy-1-(4-nitrophenyl)-5-(tri-
3.3. Ethyl 2-(3-(perfluoropropyl)-1H-pyrazol-5-yl)acetate (3b)
fluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl) acetate (5)
3
3
1H NMR (300.13 MHz, CDCl3):
d
¼1.31 (t, JH,H¼7.2 Hz, 3H,
1H NMR (300.13 MHz, DMSO-d6):
d
¼1.22 (t, JH,H¼7.2 Hz, 3H,
OCH2CH3), 3.81 (s, 2H, CH2), 4.25 (q, 3JH,H¼7.2 Hz, OCH2), 6.45 (s,1H,
OCH2CH3), 3.41, 3.62 (2d, JH,H¼19.5 Hz, 2H, CH2), 3.62 (s, 2H, CH2),
2
CH), 7.73 (br s, 1H, NH). 19F NMR (282 MHz, CDCl3):
d
¼ꢁ80.2 (t,
4.14 (q, JH,H¼7.2 Hz, 2H, OCH2), 7.51 (m, 2H, Ar), 8.16 (m, 2H, Ar),
3
3JF,F¼9.7 Hz, CF3), ꢁ110.9 (CF2), ꢁ127.1 (CF2). 13C NMR (62.9 MHz,
8.70 (s, 1H, OH). 19F NMR (282 MHz, DMSO-d6):
d
¼ꢁ80.1 (CF3). 13
C
CDCl3):
d
¼13.9 (CH3), 31.1 (CH2), 61.9 (OCH2), 104e120 ppm (mul-
NMR (62.9 MHz, DMSO-d6):
d
¼13.9 (CH3), 35.6 (CH2COO), 46.1 (CH2),
tiplets of C3F7), 105.1 (CH), 137.2 (CN), 141.4 (t, 2JC,F¼28.2 Hz, F2CC),
60.9 (OCH2), 92.7 (q, JC,F¼32.3 Hz, F3CC), 114.7 (CHAr), 123.8 (q,
2
169.5 (CO).
1JC,F¼288 Hz, CF3), 124.9 (CHAr), 139.7, 147.7, 149.6 (Cq), 168.4 (CO).
3.4. Ethyl 2-(1-methyl-3-(perfluoroethyl)-1H-pyrazol-5-yl)ac-
3.10. Ethyl 2-(1-(4-nitrophenyl)-3-(perfluoroethyl)-1H-pyr-
etate (3c)
azol-5-yl)acetate (3f)
3
3
1H NMR (300.13 MHz, CDCl3):
d
¼1.28 (t, JH,H¼7.2 Hz, 3H,
1H NMR (300.13 MHz, CDCl3):
d
¼1.24 (t, JH,H¼7.2 Hz, 3H,
OCH2CH3), 3.69 (s, 2H, CH2), 3.89 (s, 3H, NCH3), 4.20 (q, 3JH,H¼7.2 Hz,
OCH2CH3), 3.79 (s, 2H, CH2), 4.17 (q, 3JH,H¼7.2 Hz, 2H, OCH2), 6.76 (s,
OCH2), 6.47 (s, 1H, CH). 19F NMR (282 MHz, CDCl3):
d¼ꢁ84.6 (CF3),
1H, CH), 7.73 (m, 2H, Ar), 8.38 (m, 2H, Ar). 19F NMR (282 MHz,
ꢁ113.0 (CF2). 13C NMR (62.9 MHz, CDCl3):
d
¼14.0 (OCH2CH3), 31.7
CDCl3):
d
¼ꢁ84.3 (CF3), ꢁ113.4 (CF2). 13C NMR (62.9 MHz, CDCl3):
(CH2), 37.3 (NCH3), 61.7 (OCH2),106.3 (m, CH),110.7 (tq, 1JC,F¼250 Hz,
2JC,F¼38.9 Hz, CF2), 118.8 (qt, 1JC,F¼286 Hz, 2JC,F¼38.0 Hz, CF3), 136.9
(CN), 139.7 (t, 2JC,F¼28.8 Hz, F2CC), 168.2 (CO).
d
¼14.0 (CH3), 32.2 (CH2), 62.0 (OCH2), 108.5 (CH), 110.9 (tq,
1JC,F¼251 Hz, JC,F¼39.0 Hz, CF2), 118.9 (qt, JC,F¼286 Hz,
2JC,F¼38.0 Hz, CF3), 124.9, 126.0 (CHAr), 138.0 (Cq), 142.9 (t,
2JC,F¼29.2 Hz, F2CC), 143.4, 147.6 (Cq), 168.0 (CO).
2
1
3.5. Ethyl 2-(1-methyl-5-(perfluoroethyl)-1H-pyrazol-3-yl)ac-
etate (4c)
3.11. Ethyl 2-(1-(4-nitrophenyl)-3-(perfluoropropyl)-1H-pyr-
azol-5-yl)acetate (3g)
3
1H NMR (300.13 MHz, CDCl3):
d
¼1.26 (t, JH,H¼7.2 Hz, 3H,
OCH2CH3), 3.65 (s, 2H, CH2), 3.96 (s, 3H, NCH3), 4.18 (q, 3JH,H¼7.2 Hz,
1H NMR (300.13 MHz, CDCl3):
d
¼1.24 (t, JH,H¼7.2 Hz, 3H,
3
OCH2), 6.59 (s, 1H, CH). 19F NMR (282 MHz, CDCl3):
d¼ꢁ83.9 (CF3),
OCH2CH3), 3.79 (s, 2H, CH2), 4.17 (q, 3JH,H¼7.2 Hz, 2H, OCH2), 6.75 (s,
ꢁ110.3 (CF2). 13C NMR (62.9 MHz, CDCl3):
d
¼14.1 (OCH2CH3), 33.9
1H, CH), 7.73 (m, 2H, Ar), 8.39 (m, 2H, Ar). 19F NMR (282 MHz,
(CH2), 38.7 (m, NCH3), 61.1 (OCH2), 109.1 (m, CH), 110.1 (tq,
1JC,F¼252 Hz, 2JC,F¼39.8 Hz, CF2),118.5 (qt, 1JC,F¼286 Hz, 2JC,F¼37.5 Hz,
CF3), 130.4 (t, 2JC,F¼28.8 Hz, F2CC), 144.7 (CN), 170.1 (CO).
CDCl3):
(62.9 MHz, CDCl3):
d
¼ꢁ80.1 (CF3), ꢁ111.3 (CF2), ꢁ126.9 (CF2). 13C NMR
d
¼14.0 (CH3), 32.2 (CH2), 62.0 (OCH2),
104e120 ppm (multiplets of C3F7), 108.7 (CH), 124.9, 126.0 (CHAr),
138.0 (Cq), 142.9 (t, 2JC,F¼28.8 Hz, F2CC), 143.4, 147.6 (Cq), 168.0 (CO).
3.6. Ethyl 2-(1-methyl-3-(perfluoropropyl)-1H-pyrazol-5-yl)
acetate (3d)
3.12. Ethyl 2-(5-hydroxy-5-(trifluoromethyl)-4,5-dihydro-3H-
pyrazol-3-ylidene)acetate (6)
3
1H NMR (300.13 MHz, CDCl3):
d
¼1.28 (t, JH,H¼7.2 Hz, 3H,
OCH2CH3), 3.70 (s, 2H, CH2), 3.90 (s, 3H, NCH3), 4.20 (q, 3JH,H¼7.2 Hz,
1H NMR (500.13 MHz, CDCl3):
d
¼1.35 (t, JH,H¼7.2 Hz, 3H,
3
2
4
OCH2), 6.47 (s, 1H, CH). 19F NMR (282 MHz, CDCl3):
d
¼ꢁ80.2 (CF3),
OCH2CH3), 2.81 (dm, JH,H¼19.5 Hz, JH,F¼1.5 Hz, 1H), 3.10 (dd,
4
3
ꢁ110.8 (CF2), ꢁ127.0 (CF2). 13C NMR (75.5 MHz, CDCl3):
d
¼14.0
2JH,H¼19.5 Hz, JH,H¼2.5 Hz, 1H, CH2), 4.30 (q, JH,H¼7.2 Hz, 2H,
4
(OCH2CH3), 31.7 (CH2), 37.3 (NCH3), 61.7 (OCH2), 104e120 ppm
OCH2), 4.91 (s, 1H, OH), 6.98 (‘t’, JH,H¼2.5 Hz, 1H, CH). 19F NMR
2
(multiplets of C3F7), 106.6 (CH), 136.8 (CN), 139.7 (t, JC,F¼28.3 Hz,
(282 MHz, CDCl3):
d
¼ꢁ80.8 (CF3). 13C NMR (125.8 MHz, CDCl3):
F2CC), 168.1 (CO).
d
¼14.1 (CH3), 30.1 (CH2), 61.8 (OCH2), 109.4 (q, 2JC,F¼31.0 Hz, F3CC),
122.1 (CH), 122.4 (q, 1JC,F¼285 Hz, CF3), 165.8 (CO), 170.0 (Cq).
3.7. Ethyl 2-(1-methyl-5-(perfluoropropyl)-1H-pyrazol-3-yl)
acetate (4d)
3.13. Ethyl(2-p-tolyl-5-trifluoromethyl-2H-pyrazol-3-yl)ace-
tate (3h)
3
1H NMR (300.13 MHz, CDCl3):
d
¼1.26 (t, JH,H¼7.2 Hz, 3H,
OCH2CH3), 3.66 (s, 2H, CH2), 3.95 (s, 3H, NCH3), 4.17 (q, 3JH,H¼7.2 Hz,
1H NMR (300.13 MHz, CDCl3):
d
¼1.22 (t, JH,H¼7.2 Hz, 3H,
3
OCH2), 6.60 (s, 1H, CH). 19F NMR (282 MHz, CDCl3):
d
¼ꢁ80.1 (CF3),
OCH2CH3), 2.42 (s, 3H, CH3), 3.61 (s, 2H, CH2), 4.13 (q, 3JH,H¼7.2 Hz,
ꢁ108.0 (CF2), ꢁ125.7 (CF2). 13C NMR (75.5 MHz, CDCl3):
¼14.0
d
2H, OCH2), 6.65 (s, 1H, CH), 7.29e7.33 (m, 4H, Ar). 19F NMR
(OCH2CH3), 33.9 (CH2), 38.8 (m, NCH3), 61.1 (OCH2), 104e120 ppm
(282 MHz, CDCl3):
d
¼ꢁ62.5 (CF3). 13C NMR (75.5 MHz, CDCl3):
2
(multiplets of C3F7), 109.6 (m, CH), 130.5 (t, JC,F¼29.0 Hz, F2CC),
d
¼14.0 (OCH2CH3), 21.1 (CH3), 32.1 (CH2), 61.5 (OCH2), 105.6 (q,
1
144.8 (CN), 170.1 (CO).
3JC,F¼2.2 Hz, CH), 121.2 (q, JC,F¼269 Hz, CF3), 125.6, 129.9 (CHAr),
2
135.9, 137.4, 139.5 (Cq), 142.8 (q, JC,F¼38.3 Hz, F3CC), 168.2 (CO).
3.8. Ethyl 2-(1-(4-nitrophenyl)-3-(trifluoromethyl)-1H-pyr-
azol-5-yl)acetate (3e)
3.14. Ethyl (5-pentafluorethyl-2-p-tolyl-2H-pyrazol-3-yl)ace-
tate (3i)
3
1H NMR (300.13 MHz, DMSO-d6):
d
¼1.24 (t, JH,H¼7.2 Hz, 3H,
OCH2CH3), 3.97 (q, 3JH,H¼7.2 Hz, 2H, OCH2), 4.12 (s, 2H, CH2), 7.00 (s,
1H NMR (300.13 MHz, CDCl3):
d
¼1.22 (t, JH,H¼7.2 Hz, 3H,
3
1H, CH), 7.88 (m, 2H, Ar), 8.40 (m, 2H, Ar). 19F NMR (282 MHz,
OCH2CH3), 2.42 (s, 3H, CH3), 3.61 (s, 2H, CH2), 4.14 (q, 3JH,H¼7.2 Hz,

W. Desens et al. / Tetrahedron 69 (2013) 3459e3464
3463
2H, OCH2), 6.68 (s, 1H, CH), 7.30e7.33 (m, 4H, Ar). 19F NMR
3.20. Ethyl 2-chloro-2-(3-pentafluoroethyl-2-p-tolyl-2H-pyr-
azol-5-yl)acetate (4l)
(282 MHz, CDCl3):
CDCl3):
d
¼ꢁ84.4 (CF3), ꢁ113.0 (CF2). 13C NMR (75.5 MHz,
d
¼14.0 (OCH2CH3), 21.1 (CH3), 32.1 (CH2), 61.6 (OCH2), 106.8
(t, 3JC,F¼2.8 Hz, CH), 110.9 (tq, 1JC,F¼251 Hz, 2JC,F¼39.0 Hz, CF2), 118.9
1H NMR (300.13 MHz, CDCl3):
d
¼1.32 (t, JH,H¼7.2 Hz, 3H,
3
1
2
(qt, JC,F¼286 Hz, JC,F¼38.0 Hz, CF3), 125.6, 129.9 (CHAr), 135.9,
OCH2CH3), 2.43 (s, 3H, CH3), 4.31 (m, 3JH,H¼7.2 Hz, 2H, OCH2), 5.51
2
137.6, 139.5 (Cq), 141.3 (t, JC,F¼28.6 Hz, F2CC), 168.5 (CO).
(s, 1H, CHCl), 7.01 (m, 1H, CH), 7.29e7.33 (m, 4H, Ar). 19F NMR
(282 MHz, CDCl3):
CDCl3):
d
¼ꢁ83.4 (CF3), ꢁ106.5 (CF2). 13C NMR (75.5 MHz,
d
¼13.9 (OCH2CH3), 21.2 (CH3), 51.8 (CHCl), 62.8 (OCH2),
3.15. Ethyl (3-pentafluoroethyl-2-p-tolyl-2H-pyrazol-5-yl)ac-
etate (4i)
126.4, 129.5 (CHAr), 140.1 (Cq), 167.2 (CO), not all signals are given.
3.21. Ethyl 2-chloro-2-(5-heptafluoropropyl-2-p-tolyl-2H-
pyrazol-3-yl)acetate (3m)
3
1H NMR (300.13 MHz, CDCl3):
d
¼1.29 (t, JH,H¼7.2 Hz, 3H,
OCH2CH3), 2.41 (s, 3H, CH3), 3.76 (s, 2H, CH2), 4.26 (q, 3JH,H¼7.2 Hz,
2H, OCH2), 6.81 (s, 1H, CH), 7.29e7.32 (m, 4H, Ar). 19F NMR
3
1H NMR (300.13 MHz, CDCl3):
d
¼1.27 (t, JH,H¼7.2 Hz, 3H,
(282 MHz, CDCl3):
CDCl3):
d
¼ꢁ83.4 (CF3), ꢁ106.3 (CF2). 13C NMR (75.5 MHz,
OCH2CH3), 2.45 (s, 3H, CH3), 4.26 (m, ABX3, 3JH,H¼7.2 Hz, 2H, OCH2),
d
¼14.1 (OCH2CH3), 21.2 (CH3), 33.9 (CH2), 61.5 (OCH2), 109.8
5.31 (s, 1H, CHCl), 6.95 (s, 1H, CH), 7.32e7.41 (m, 4H, Ar). 19F NMR
(CH), 126.4, 129.4 (CHAr), 137.0, 139.6, 146.0 (Cq), 170.0 (CO), signals
(282 MHz, CDCl3):
d
¼ꢁ80.2 (CF3), ꢁ110.9 (CF2), ꢁ126.8 (CF2). 13C
not given for C2F5 and F2CC.
NMR (75.5 MHz, CDCl3):
d
¼13.8 (OCH2CH3), 21.2 (CH3), 48.8 (CHCl),
63.3 (OCH2), 104e126 ppm (multiplets of C3F7), 107.4 (t,
3JC,F¼3.0 Hz, CH), 125.7, 130.2 (CHAr), 135.1, 139.7, 140.3 (Cq), 141.8 (t,
2JC,F¼29.0 Hz, F2CC), 165.9 (CO).
3.16. Ethyl (5-heptafluoropropyl-2-p-tolyl-2H-pyrazol-3-yl)
acetate (3j)
3
1H NMR (300.13 MHz, CDCl3):
d
¼1.22 (t, JH,H¼7.2 Hz, 3H,
3.22. Ethyl 2-chloro-2-(3-heptafluoropropyl-2-p-tolyl-2H-
pyrazol-5-yl)acetate (4m)
OCH2CH3), 2.42 (s, 3H, CH3), 3.68 (s, 2H, CH2), 4.14 (q, 3JH,H¼7.2 Hz,
2H, OCH2), 6.67 (s, 1H, CH), 7.25e7.33 (m, 4H, Ar). 19F NMR
¼ꢁ80.2 (CF3), ꢁ111.0, ꢁ126.9 (CF2). 13C NMR
3
1H NMR (300.13 MHz, CDCl3):
d
¼1.32 (t, JH,H¼7.2 Hz, 3H,
(282 MHz, CDCl3):
(75.5 MHz, CDCl3):
d
OCH2CH3), 2.42 (s, 3H, CH3), 4.30 (m, ABX3, 3JH,H¼7.2 Hz, 2H, OCH2),
d
¼14.0 (OCH2CH3), 21.1 (CH3), 32.1 (CH2), 61.6
5.51 (s, 1H, CHCl), 7.03 (s, 1H, CH), 7.24e7.34 (m, 4H, Ar). 19F NMR
(OCH2), 107.1 (CH), 108e120 (ppm multiplets of C3F7), 125.6, 129.9
2
(282 MHz, CDCl3):
d
¼ꢁ80.1 (CF3), ꢁ104.2 (CF2), ꢁ124.9 (CF2). 13C
(CHAr), 135.9, 137.6, 139.5 (Cq), 141.3 (t, JC,F¼28.6 Hz, F2CC), 168.4
(CO).
NMR (75.5 MHz, CDCl3):
d
¼13.9 (OCH2CH3), 21.2 (CH3), 51.8 (CHCl),
62.8 (OCH2), 104e126 ppm (multiplets of C3F7), 109.6 (m, CH),
126.5, 129.4 (CHAr), 132.3 (t, 2JC,F¼29.0 Hz, F2CC), 136.7, 140.1, 148.1
(Cq), 167.1 (CO).
3.17. Ethyl (3-heptafluoropropyl-2-p-tolyl-2H-pyrazol-5-yl)
acetate (4j)
3
1H NMR (300.13 MHz, CDCl3):
d
¼1.28 (t, JH,H¼7.2 Hz, 3H,
3.23. Ethyl (5-hydroxy-5-trifluoromethyl-4,5-dihydroisoxazol-
3-yl)acetate (8a)
OCH2CH3), 2.42 (s, 3H, CH3), 3.76 (s, 2H, CH2), 4.23 (q, 3JH,H¼7.2 Hz,
2H, OCH2), 6.82 (s, 1H, CH), 7.25e7.33 (m, 4H, Ar). 19F NMR
3
1H NMR (300.13 MHz, CDCl3):
d
¼1.30 (t, JH,H¼7.2 Hz, 3H,
(282 MHz, CDCl3):
(75.5 MHz, CDCl3):
d
¼ꢁ80.1 (CF3), ꢁ104.1, ꢁ125.0 (CF2). 13C NMR
2
OCH2CH3), 3.24, 3.52 (2d, JH,H¼19.2 Hz, 2H, CH2), 3.50 (s, 2H,
d
¼14.1 (OCH2CH3), 21.2 (CH3), 34.0 (CH2), 61.1
CH2COO), 4.21 (q, 3JH,H¼7.2 Hz, 2H, OCH2), 5.20 (s, 1H, OH). 19F NMR
(OCH2), 108e120 ppm (multiplets of C3F7), 110.2 (CH), 126.5, 129.3
(282 MHz, CDCl3):
d
¼ꢁ83.0 (CF3). 13C NMR (75.5 MHz, CDCl3):
2
(CHAr), 131.5 (t, JC,F¼28.2 Hz, F2CC), 137.0, 139.6, 146.0 (Cq), 170.0
d
¼13.5 (OCH2CH3), 32.7 (CH2COO), 44.3 (CH2), 62.0 (OCH2), 103.5
(CO).
(q, 2JC,F¼34.3 Hz, F3CC),121.8 (q, 1JC,F¼283 Hz, CF3), 154.0 (CN), 168.4
(CO).
3.18. Ethyl 2-chloro-2-(2-p-tolyl-5-trifluoromethyl-2H-pyr-
azol-3-yl)acetate (3k)
3.24. Ethyl (5-hydroxy-5-pentafluoroethyl-4,5-dihydroisoxazol-
3-yl)acetate (8b)
3
1H NMR (300.13 MHz, CDCl3):
d
¼1.29 (t, JH,H¼7.2 Hz, 3H,
OCH2CH3), 2.45 (s, 3H, CH3), 4.26 (m, ABX3, 3JH,H¼7.2 Hz, 2H, OCH2),
1H NMR (300.13 MHz, CDCl3):
d
¼1.29 (t, JH,H¼7.2 Hz, 3H,
3
5.30 (s, 1H, CHCl), 6.93 (s, 1H, CH), 7.31e7.42 (m, 4H, Ar). 19F NMR
2
OCH2CH3), 3.24, 3.58 (2 d, JH,H¼18.8 Hz, 2H, CH2), 3.50 (s, 2H,
(282 MHz, CDCl3):
d
¼ꢁ62.2 (CF3). 13C NMR (75.5 MHz, CDCl3):
CH2COO), 4.21 (q, 3JH,H¼7.2 Hz, 2H, OCH2), 6.27 (s, 1H, OH). 19F NMR
d
¼14.0 (OCH2CH3), 21.1 (CH3), 48.8 (CHCl), 61.6 (OCH2), 105.6 (q,
(282 MHz, CDCl3):
d
¼ꢁ80.0 (CF3), ꢁ123.4 (d, 2JF,F¼278 Hz, 1F, CF2),
3JC,F¼2.0 Hz, CH), 121.3 (q, JC,F¼268 Hz, CF3), 125.7, 129.9 (CHAr),
1
ꢁ127.9 (d, 2JF,F¼278 Hz, 1F, CF2). 13C NMR (75.5 MHz, CDCl3):
¼13.7
d
2
135.9, 137.4, 139.5 (Cq), 142.8 (q, JC,F¼38.3 Hz, F3CC), 168.5 (CO).
(OCH2CH3), 32.8 (CH2COO), 45.1 (CH2), 62.0 (OCH2), 104.7 (dd,
2
1
2JC,F¼27.0 Hz, JC,F¼25.5 Hz, F2CC), 111.1 (tq, JC,F¼261 Hz,
2JC,F¼36.5 Hz, CF2), 118.3 (qt, 1JC,F¼287 Hz, 2JC,F¼35.2 Hz, CF3), 154.0
(CN), 168.5 (CO).
3.19. Ethyl 2-chloro-2-(5-pentafluoroethyl-2-p-tolyl-2H-pyr-
azol-3-yl)acetate (3l)
3
1H NMR (300.13 MHz, CDCl3):
d
¼1.28 (t, JH,H¼7.2 Hz, 3H,
3.25. Ethyl (5-hydroxy-5-heptafluoropropyl-4,5-dihydroisox-
azol-3-yl)acetate (8c)
OCH2CH3), 2.45 (s, 3H, CH3), 4.26 (m, ABX3, 3JH,H¼7.2 Hz, 2H, OCH2),
5.31 (s, 1H, CHCl) 6.96 (s, 1H, CH), 7.32e7.42 (m, 4H, Ar). 19F NMR
3
(282 MHz, CDCl3):
CDCl3):
d
¼ꢁ84.3 (CF3), ꢁ113.0 (CF2). 13C NMR (75.5 MHz,
1H NMR (300.13 MHz, CDCl3):
d
¼1.29 (t, JH,H¼7.2 Hz, 3H,
2
d
¼13.8 (OCH2CH3), 21.2 (CH3), 48.7 (CHCl), 63.3 (OCH2),
OCH2CH3), 3.27 (d, JH,H¼18.8 Hz, 1H, CH2), 3.51 (s, 2H, CH2COO),
1
2
2
107.2 (CH), 110.5 (tq, JC,F¼251 Hz, JC,F¼39.4 Hz, CF2), 118.5 (qt,
3.60 (d, JH,H¼18.8 Hz, 1H, CH2), 3.81 (s, 1H, OH), 4.22 (q,
1JC,F¼286 Hz, JC,F¼37.5 Hz, CF3), 125.7, 130.2 (CHAr), 135.1, 139.6,
3JH,H¼7.2 Hz, 2H, OCH2). 19F NMR (282 MHz, CDCl3):
¼ꢁ81.0 (‘t’,
d
2
140.3 (Cq), 141.8 (t, 2JC,F¼29.1 Hz, F2CC), 165.9 (CO).
CF3), ꢁ120.2, ꢁ124.1 (2m, 2F, CF2), ꢁ123.9, ꢁ125.2 (2m, 2F, CF2). 13
C

3464
W. Desens et al. / Tetrahedron 69 (2013) 3459e3464
NMR (75.5 MHz, CDCl3):
d
¼13.8 (OCH2CH3), 32.9 (CH2COO), 45.4
NMR (75.5 MHz, CDCl3):
(m, CH2), 50.2, 50.2 (CHCl), 63.8, 63.9 (OCH2), 105e117 ppm (mul-
d
¼13.6, 13.6 (OCH2CH3), 41.8 (m, CH2), 41.9
(CH2), 62.1 (OCH2), 105e114 ppm (multiplets of CF2), 105.2 (‘t’,
2JC,F¼27.0 Hz, F2CC), 112.8 (tt, JC,F¼262 Hz, JC,F¼29.8 Hz,
tiplets of CF2CF2), 105.9 (‘t’, JC,F¼27.0 Hz, F2CC), 117.6 (qt,
1
2
2
CF3CF2CF2), 117.6 (qt, 1JC,F¼288 Hz, JC,F¼33.5 Hz, CF3), 154.0 (CN),
1JC,F¼288 Hz, JC,F¼33.6 Hz, 2CF3), 155.0, 155.3 (CN), 165.5, 165.9
2
2
168.4 (CO).
(CO).
3.26. Ethyl 2-chloro(5-hydroxy-5-trifluoromethyl-4,5-
dihydroisoxazol-3-yl)acetate (8d)
Acknowledgements
Financial support by the State of Mecklenburg-Vorpommern, by
the EU (EFRE program) and by the Volkswagenstiftung (Az86223) is
gratefully acknowledged.
3
1H NMR (300.13 MHz, CDCl3):
d
¼1.33 (t, JH,H¼7.2 Hz, 3H,
3
OCH2CH3), 1.34 (t, JH,H¼7.2 Hz, 3H, OCH2CH3), 3.37 (dm,
2JH,H¼18.5 Hz, 2H, CH2), 3.57 (d, JH,H¼18.5 Hz, 1H, CH2), 3.61 (d,
2
2JH,H¼18.5 Hz, 1H, CH2), 4.31 (q, JH,H¼7.2 Hz, 2H, OCH2), 4.32 (q,
3
References and notes
3JH,H¼7.2 Hz, 2H, OCH2), 5.20 (br, 2H, OH), 5.28 (s, 1H, CHCl), 5.29 (s,
1H, CHCl). 19F NMR (282 MHz, CDCl3):
d
¼ꢁ83.2, ꢁ83.0 (CF3). 13C
1. (a) Fluorine in Bioorganic Chemistry; Filler, R., Ed.; Elsevier: Amsterdam, Neth-
erlands, 1993; (b) Filler, R. Fluorine Containing Drugs in Organofluorine Chemicals
and Their Industrial Application; Pergamon: New York, NY, 1979, Chapter 6; (c)
Hudlicky, M. Chemistry of Organic Fluorine Compounds; Ellis Horwood: Chi-
chester, UK, 1992; (d) Kirsch, P. Modern Fluoroorganic Chemistry; VCH: Wein-
heim, Germany, 2004; (e) Chambers, R. D. Fluorine in Organic Chemistry;
Blackwell CRC: 2004; (f) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V.
Chem. Soc. Rev. 2008, 37, 320.
NMR (75.5 MHz, CDCl3):
d
¼13.5, 13.5 (OCH2CH3), 40.8, 40.8 (CH2),
2
50.2, 50.3 (CH), 63.7, 63.8 (OCH2), 104.2, 104.3 (q, JC,F¼34.7 Hz,
1
F3CC), 121.5 (q, JC,F¼284 Hz, 2CF3), 154.8, 155.0 (CN), 165.6, 165.8
(CO).
3.27. Ethyl 2-chloro(5-hydroxy-5-pentafluoroethyl)-4,5-(di-
2. Heidelberger, C.; Chaudhuri, K. N.; Danneberg, P.; Mooren, D.; Griesbach, L.;
Duschinsky, R.; Schnitzer, J. R. Nature 1957, 179, 663.
hydroisoxazol-3-yl)acetate (8e)
3. Wong, T. D.; Bymaster, P. F.; Engleman, A. E. Life Sci. 1995, 57, 411.
4. Roman, L. D.; Walline, C. C.; Rodriguez, J. G.; Barker, L. Eur. J. Pharmacol. 2003,
479, 53.
5. Reviews: (a) Stegemeyer, H.; Steinkopff, K. Liquid Crystals; Springer: New York,
NY, 1994; (b) Miethchen, R.; Hein, M. Carbohydr. Res. 2000, 327, 169.
6. Reviews: (a) Schneider, S.; Tzschucke, C. C.; Bannwarth, W. Multiphase Ho-
mogeneous Catalysis In. Cornils, B., Ed.; Wiley VCH: 2005, Chapter 4, p 346; (b)
Clarke, D.; Ali, M. A.; Clifford, A. A.; Parratt, A.; Rose, P.; Schwinn, D.; Bannwarth,
W.; Rayner, C. M. Curr. Top. Med. Chem. 2004, 7, 729.
3
1H NMR (300.13 MHz, CDCl3):
d
¼1.33 (t, JH,H¼7.2 Hz, 3H,
3
OCH2CH3), 1.34 (t, JH,H¼7.2 Hz, 3H, OCH2CH3), 3.36 (d,
2JH,H¼18.5 Hz, 2H, CH2), 3.64 (d, JH,H¼18.5 Hz, 1H, CH2), 3.68 (d,
2
2JH,H¼18.5 Hz, 1H, CH2), 4.31 (q, JH,H¼7.2 Hz, 2H, OCH2), 4.32 (q,
3
3JH,H¼7.2 Hz, 2H, OCH2), 5.30 (s, 2H, 2CHCl), 7.30 (br, 2H, OH). 19
F
NMR (282 MHz, CDCl3):
d
¼ꢁ79.9, ꢁ80.0 (2 CF3), ꢁ123.5, ꢁ128.0
7. Reviews: (a) Wittkopp, A.; Schreiner, P. R. The Chemistry of Diens and Polyenes;
John Wiley & Sons Ltd: 2000; Vol. 2; (b) Schreiner, P. R. Chem. Soc. Rev. 2003, 32,
289 see also; (c) Wittkopp, A.; Schreiner, P. R. Chem.dEur. J. 2003, 9, 407; (d)
Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701.
(2d, AB, 2JF,F¼280 Hz, 2F, CF2), ꢁ123.7, ꢁ128.1 (2d, AB, 2JF,F¼280 Hz,
2F, CF2). 13C NMR (75.5 MHz, CDCl3):
d
¼13.6, 13.6 (OCH2CH3), 41.6,
41.7 (CH2), 50.2, 50.2 (CHCl), 63.8, 63.9 (OCH2), 105.3 (dd,
€
8. (a) Chizhov, D. L.; Pashkevich, K. I.; Roschenthaler, G.-V. J. Fluorine Chem. 2003,
2JC,F¼27.5 Hz, JC,F¼25.3 Hz, F2CC), 118.3, 118.3 (qt, JC,F¼287 Hz,
2
1
€
123, 267; (b) Sevenard, D. V.; Kazakova, O.; Chizhov, D. L.; Roschenthaler, G.-V. J.
2JC,F¼35.2 Hz, 2CF3), 110.9, 110.9 (tq, JC,F¼262 Hz, JC,F¼36.9 Hz,
1
2
Fluorine Chem. 2006, 127, 983.
€
9. Buttner, S.; Desens, W.; Michalik, D.; Langer, P. Eur. J. Org. Chem. 2011, 6663.
2CF2), 155.0, 155.3 (CN), 165.5, 165.9 (CO).
10. One exception is the synthesis of methyl 2-(3-(trifluoromethyl)-1H-pyrazol-5-
yl)acetate by cyclization of methyl 6,6,6-trifluoro-3,5-dioxohexanoate with
hydrazine hydrate was previously mentioned in a patent. However, a detailed
procedure and characterization of the product were not provided: Okano, K.;
Takahashi, T.; Itou, H.; Sumitani, N.; Tanaka, K. Patent WO2003057659, 07/
2003.
11. Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell Science: Malden,
2000.
12. US Environmental Protection Agency, www.epa.gov, Efficacy Review, File
65331-R, July 17, 1995.
3.28. Ethyl 2-chloro-(5-hydroxy-5-heptafluoropropyl-4,5-
dihydroisoxazol-3-yl)acetate (8f)
3
1H NMR (300.13 MHz, CDCl3):
d
¼1.33 (t, JH,H¼7.2 Hz, 3H,
3
OCH2CH3), 1.35 (t, JH,H¼7.2 Hz, 3H, OCH2CH3), 3.39 (d,
2JH,H¼18.8 Hz, 2H, CH2), 3.67 (d, JH,H¼18.8 Hz, 1H, CH2), 3.68 (d,
2
2JH,H¼18.8 Hz, 1H, CH2), 4.31 (q, JH,H¼7.2 Hz, 2H, OCH2), 4.31 (q,
3
13. Knorr, L. Ber. Dtsch. Chem. Ges. 1883, 16, 2597.
3JH,H¼7.2 Hz, 2H, OCH2), 5.29 (s, 1H, CHCl), 5.29 (s, 1H, CHCl), 5.55
14. CCDC-925328 contains all crystallographic details of this publication and is
available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or can be
ordered from the following address: Cambridge Crystallographic Data Centre,
12 Union Road, GB-Cambridge CB21EZ; Fax: (þ44)1223-336-033; or deposit@
ccdc.cam.ac.uk.
(br, 2H, OH). 19F NMR (282 MHz, CDCl3):
d
¼ꢁ80.9 (dd, CF3), ꢁ80.9
(dd, CF3), ꢁ120.4 (m, 1F), ꢁ124.2 (m, 1F), (CF2), ꢁ120.6 (m, 1F),
ꢁ124.2 (m, 1F), (CF2), ꢁ124.0 (m, 2F, CF2), ꢁ124.9 (m, 2F, CF2). 13
C