Study on the 1,3-dipolar cycloaddition reaction of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one with nitrile oxides

Article abstract of DOI:10.1016/j.tet.2006.12.059

1,3-Dipolar cycloaddition (1,3-DC) reaction of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one 1 with nitrile oxides was studied. It was found that besides its C{double bond, long}C participating in the formation of isoxazole rings, trifluoromethyl activated C{dou

Full text of DOI:10.1016/j.tet.2006.12.059

Tetrahedron 63 (2007) 2315–2319
Study on the 1,3-dipolar cycloaddition reaction of
4-ethoxy-1,1,1-trifluoro-3-buten-2-one with nitrile oxides
Huiling Jiang,a Weimin Yue,b Huihong Xiaob and Shizheng Zhua,
*
aKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
bEast China University of Science and Technology, 130 Meilong Road, PO Box 363, Shanghai 200237, China
Received 21 November 2006; revised 19 December 2006; accepted 19 December 2006
Available online 22 December 2006
Abstract—1,3-Dipolar cycloaddition (1,3-DC) reaction of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one 1 with nitrile oxides was studied. It was
found that besides its C]C participating in the formation of isoxazole rings, trifluoromethyl activated C]O also underwent 1,3-DC reaction
with nitrile oxides to afford 1,4,2-dioxazole rings. Single crystal diffraction analysis also evidenced the diheterocyclic configuration.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Heterocycles are an important class of compounds, not only
because of their natural abundance, but also because of their
chemical, biological, and technical significances. Above all
the heterocycles, isoxazole is one of the most useful com-
pounds, which was found as an important unit in many bio-
logically active compounds.1 Most of them are important as
drugs or biocides, including the human neurokinin NK-1 re-
ceptors sulfonamide sulfamethoxazole,2 the Xenopus laevis
oocytes,3 the guinea pig tracheal strips,4 and so on. Further-
more, isoxazoles have a considerable synthetic potential as
masked 1,3-dicarbonyl systems due to their ring-opening
reactions,5 and have attracted increasing attention. The
development of isoxazole chemistry has recently advanced
to the discovery of new synthetic methods. Most of these
are based on the capacity of the substance containing the
Trifluoromethyl-containing a,b-unsaturated ketone 4-ethoxy-
1,1,1-trifluoro-3-buten-2-one 1 is very robust and can react
easily with several kinds of nucleophiles, electrophiles, and
dipoles. Many literatures have reported the chemical trans-
formation of compound 1 and a large number of trifluoro-
methylated heterocyclic molecules have been obtained.9
Our group has described several cycloaddition reactions of
compound 1, such as DA reaction with vinyl ether affording
six-membered heterocycles,9b and 1,3-dipolar reaction with
pyridinium N-ylide10 and C-arylnitrones9b giving the fluo-
rine-containing five-membered heterocycles. As a continua-
tion of our research interest in chemical transformation of
fluorinated a,b-unsaturated ketones, we investigated the
1,3-dipolar cycloaddition (1,3-DC) reaction of compound 1
with nitrile oxides. It was found that the reaction afforded
bicycloaddition products, in which isoxazole and 1,4,2-di-
oxazole rings were formed simultaneously.
þ
ꢀ
highly reactive group ꢀC^ Nꢀ O, which is found in
nitrile oxides6 and fulminic acid,7 to react with aliphatic tri-
ple and double bonds to afford the isoxazole and isoxazoline
rings, respectively. Fluorine, due to its unique electronic
property and its similar atom radius as hydrogen, quite
often imparts specific beneficial properties to organic mole-
cules.8 As a consequence of these characteristics, a group
containing fluorine could be utilized to substitute a non-fluo-
rinated one in a biologically active molecule, which might
dramatically change the activity of the compound. Thus de-
velopment of efficient methodology for the synthesis of fluo-
rine-containing heterocycles is an active area of research.
Due to the circumstance that dimerization always occurs in
the isoxazole synthesis from the nitrile oxide, hydroxamyl
chloride is usually utilized to prepare nitrile oxide in situ
to avoid its dimerization.11 It is well known that hydroxamyl
chlorides are easily converted into nitrile oxides in the pres-
ence of base, usually using triethylamine (TEA). To our dis-
appointment, in the presence of TEA only dimer 4a was
isolated from the reaction mixture, though materials 1 and
2a were consumed completely (Table 1, entry 1). Other in-
organic bases were examined and it was found that sodium
hydrogen carbonate, sodium carbonate, and potassium car-
bonate could successfully promote the reaction and the
expected product 3a was obtained though in low yields
(Table 1, entries 2, 5, and 6). Solvent optimization indicated
that this reaction proceeded most readily in benzene and no
Keywords: 1,3-Dipolar cycloaddition reaction; Fluorine-containing alkene;
Isoxazole; Dioxazole; Nitrile oxide.
* Corresponding author. Tel.: +86 21 54925184; fax: +86 21 64166128;
e-mail: zhusz@mail.sioc.ac.cn
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.12.059

2316
H. Jiang et al. / Tetrahedron 63 (2007) 2315–2319
Table 1. Optimization of conditions for the reaction between compounds 1 and 2a
Br
Br
N
O
OH
O
O
N
base
solvent, T,
N
Br
+
+
OEt
N
O
F3C
Cl
O
N
F3C
O
Br
Br
1
2a
3a
4a
3a (%)a
Entry
Material (1:2a)
Base
Et3N
NaHCO3
NaHCO3
NaHCO3
Na2CO3
K2CO3
Solvent
4a (%)a
1
2
3
4
5
6
7
1:2
1:2
1:2
1:2
1:2
1:2
1:4
CH2Cl2
Benzene
THF
—
23
—
—
12
18
61
40
17
42
37
22
27
21
DMF
Benzene
Benzene
Benzene
NaHCO3
a
Isolated yield.
product was discovered when using THF and DMF as sol-
vents (Table 1, entries 3 and 4). Interestingly, the yield was
increased obviously with addition of hydroxamyl chloride
2a (Table 1, entry 7), which resulted in more intermediate
nitrile oxide participating in the expected 1,3-DC reaction.
The optimized conditions (Table 1, entry 7) were applied
to the 1,3-DC addition reaction of other hydroxamyl chlo-
rides (2b–i) and the results are summarized in Table 2.
corresponding aliphatic diheterocycles when employing
other aliphatic materials under the same reaction conditions.
Compound 3b formed a fine crystal after recrystallization
from CH2Cl2 and ether, and then single crystal diffraction
analysis was carried on it (Fig. 1). It clearly showed that
isoxazole ring did not lie in the same plane with phenyl
and the torsion angle is 82.29ꢁ. In the crystal, molecules
were separated into two parts, which oriented in opposite
directions. Furthermore, O4 and O5 of nitrophenyl formed
intermolecular hydrogen bond with H4 on the isoxazole ring
and intermolecular halogen bond with F3 of the trifluoro-
methyl in the other molecule, respectively. Therefore, every
molecule was connected with each other by these inter-
molecular hydrogen bonds and halogen bonds and then
boundless chains were formed. All these chains were also
packed with each other by the hydrogen bonds that existed
between two chains, and the distances were 2.646 and
Just like 2a, other substituted-phenyl hydroxamyl chlorides
underwent 1,3-DC reaction smoothly with compound 1 in
the presence of sodium hydrogen carbonate to give corre-
sponding diheterocycles 3b–i in moderate to good yields
(Table 2, entries 2–8). From our early studies, we found
that it was difficult for nitrile oxides containing strong
electron-withdrawing group to react with fluorine-containing
optically active imines.12 Differently, hydroxamyl chlorides
2b and 2f substituted by nitro group could react with com-
pound 1 on the occasion and afford the isoxazole derivatives
3b and 3f although with low yield down to 27% (Table 1, en-
try 2). Furthermore, aliphatic hydroxamyl chloride 2i could
also afford the diheterocycle in a considerable yield (Table
2, entry 9). Unfortunately, it was a failure synthesizing
˚
2.718 A.
In order to examine the substitution effect of fluorine atoms,
non-fluorine-containing analogue compound was chosen
to be employed to react with hydroxamyl chloride 2a. Un-
fortunately, preparation of non-fluorine-containing a,b-
unsaturated methyl ketone was unsuccessful. So (E)-ethyl
3-ethoxyacrylate 4 was employed instead in this case. It was
found that only the double bond underwent the 1,3-DC reac-
tion and formed the single-heterocycle product 5 in excellent
yield (Scheme 1). Furthermore, the reaction could also pro-
ceed smoothly using TEA as the base. It means that without
the electron-withdrawing effect of the trifluoromethyl the
carbonyl was unable to react with nitrile oxide.
Table 2. NaHCO3-mediated 1,3-DC addition reaction of compound 1a
R
N
O
O
R
NaHCO3
benzene, r.t
2d
O
N
N
OH
+
F3C
OEt
:
Cl
O
R
F3C
1
2
3
1
4
Entry
Nitrile oxide (R¼)
3b (%)
Br
1
2
3
4
5
6
7
8
9
2a (p-BrC6H4)
2b (p-NO2C6H4)
2c (p-FC6H4)
2d (p-MeC6H4)
2e (o-FC6H4)
2f (m-NO2C6H4)
2g (o-ClC6H4)
2h (C6H5)
3a (61)
3b (27)
3c (45)
3d (46)
3e (43)
3f (32)
3g (79)
3h (71)
3i (42)
O
OH
O
N
EtO
+
Br
N
O
EtO
OEt
Cl
5
4
2a
1
:
4
2i (CH]CHC6H5)
a
Corresponding by-products were isolated in each case.
Isolated yield.
Scheme 1. (1) NaHCO3, benzene, rt, 2 d, >99%; (2) Et3N, CH2Cl2, rt,
1 d, 78%.
b

H. Jiang et al. / Tetrahedron 63 (2007) 2315–2319
2317
Figure 1. (a) Structure of 3b (R¼C6H4NO2); (b) packing map.
3. Conclusion
4.2. Experimental procedure
In summary, 1,3-DC reaction of compound 1 with nitrile
oxides was studied and the reaction formed a series of
bicycloaddition products in moderate to good yields. More-
over, single crystal diffraction analysis of the product 3b
indicated that hydrogen bonds and halogen bonds deter-
mined the molecular configuration together. Compared to
fluorine-containing compound, similar hydrocarbon with-
out the activation of trifluoromethyl only reacted at the
double bond and afforded single-heterocycle compound.
At the same time, mild reaction conditions, easy manipula-
tion, straightforward procedure, and considerable yields of
useful products make this transformation potentially useful
in organic synthesis.
The mixture of 1 (0.3 mmol) and hydroxamyl chloride 2a
(1.2 mmol) in 2 mL of benzene was added slowly into the
mixture of NaHCO3 (0.6 mmol) in 1 mL benzene at 0 ꢁC.
Then the mixture was warmed to room temperature. TLC
analysis was used to monitor the reaction. After one day, the
reactionwas complete. Aftergeneral work-up, the residuewas
purified by column chromatography on silica gel (hexane/
AcOEt¼40:1) to give the product 3a in a yield of 61%.
4.2.1. 3-(4-Bromophenyl)-5-(3-(4-bromophenyl)isoxazol-
4-yl)-5-(trifluoromethyl)-1,4,2-dioxazole 3a. Yellow solid,
mp: 81–83 ꢁC, yield: 61%. 1H NMR (CDCl3): d 8.80 (1H, s,
CH]), 7.65–7.26 (8H, m, Ph). 19F NMR (CDCl3): d ꢀ83.21
(s, CF3). 13C NMR (CDCl3): d 160.2 (C5), 159.6 (C4),
158.2 (C3), 132.4 (Ph), 131.7 (Ph), 130.6 (Ph), 129.2 (Ph),
128.2 (Ph), 127.6 (Ph), 126.4 (Ph), 124.7 (Ph), 120.7
4. Experimental
4.1. General
1
(CF3, JCF¼230 Hz), 111.5 (C1), 106.9 (C2). MS (m/z, %):
519 (M+, 14.61), 450 (M+ꢀCF3, 12.52), 320 (M+ꢀ
p-BrC6H4CNO, 12.97), 251 (M+ꢀp-BrC6H4CNOꢀCF3,
60.37), 69 (CF3, 41.84). IR (cmꢀ1): 1634, 1594, 1489,
1402, 1205, 1098, 1010. HRMS calcd for C18H9Br2F3N2O3:
515.8932; found 515.8947.
Melting points were measured on a Temp-Melt apparatus
1
and are uncorrected. H, 13C, and 19F NMR spectra were
recorded on Bruker AM-300 or AM-400 instruments with
Me4Si and CFCl3 as the internal standards, respectively.
FTIR spectra were obtained with a Nicolet AV-360 spectro-
photometer. Low resolution mass spectra (LRMS) or high
resolution mass spectra (HRMS) were obtained on a Finni-
gan GC–MS 4021 or a Finnigan MAT-8430 instrument using
the electron impact ionization technique (70 eV), respec-
tively. Single crystal X-ray structure analysis was performed
on a Bruker P4 instrument.
4.2.2. 3-(4-Nitrophenyl)-5-(3-(4-nitrophenyl)isoxazol-4-
yl)-5-(trifluoromethyl)-1,4,2-dioxazole 3b. Yellow solid,
1
mp: 110–112 ꢁC, yield: 27%. H NMR (CDCl3): d 8.92
(1H, s, CH]), 8.39–8.20 (4H, m, Ph), 7.84–7.72 (4H, m,
Ph). 19F NMR (CDCl3): d ꢀ83.25 (s, CF3). 13C NMR
(CDCl3): d 160.3 (C5), 159.2 (C4), 157.4 (C3), 150.3 (Ph),
148.9 (Ph), 133.6 (Ph), 130.3 (Ph), 129.6 (Ph), 129.4 (Ph),

2318
H. Jiang et al. / Tetrahedron 63 (2007) 2315–2319
1
127.6 (Ph), 124.3 (Ph), 125.8 (CF3, JCF¼248 Hz), 121.9
(C1), 111.3 (C2). MS (m/z, %): 450 (M+, 6.64), 381
(M+ꢀCF3, 2.45), 379 (M+ꢀCF3ꢀ2H, 57.44), 284 (M+ꢀp-
NO2C6H4CNOꢀ2H, 11.93), 216 (M+ꢀp-NO2C6H4CNOꢀ
CF3ꢀH, 100), 69 (CF3, 35.01). IR (cmꢀ1): 1596, 1525,
1348, 1198, 1098, 854. HRMS calcd for C18H9F3N4O7:
450.0423; found 450.0422.
4.2.7. 3-(3-Nitrophenyl)-5-(3-(3-nitrophenyl)isoxazol-4-
yl)-5-(trifluoromethyl)-1,4,2-dioxazole 3f. Yellow solid,
1
mp: 88–90 ꢁC, yield: 32%. H NMR (CDCl3): d 8.93 (1H,
s, CH]), 8.44–7.97 (4H, m, Ph), 7.74–7.66 (4H, m, Ph).
19F NMR (CDCl3): d ꢀ83.27 (s, CF3). 13C NMR (CDCl3):
d 160.5 (C5), 158.9 (C4), 157.3 (C3), 135.0 (Ph), 132.7
(Ph), 132.4 (Ph), 130.5 (Ph), 130.2 (Ph), 129.8 (Ph), 127.4
(Ph), 127.3 (Ph), 125.0 (Ph), 124.1 (Ph), 122.4 (Ph),
1
4.2.3. X-ray data of compound 3b. C18H9F3N4O7: FW¼
450.29; temperature 293(2) K; monoclinic, P2(1)/c;
121.8 (Ph), 128.4 (CF3, JCF¼286 Hz), 111.3 (C1), 106.0
(C2). MS (m/z, %): 450 (M+, ESI). IR (cmꢀ1): 1655, 1541,
1535, 1087, 805. HRMS calcd for C18H9F3N4O7+Na+:
473.0316; found 473.0325.
˚
˚
˚
wavelength 0.71 A; a¼23.378(3) A, b¼10.1309(13) A,
ꢁ
ꢁ
ꢁ
˚
c¼7.7185(10) A, a¼90.00 , b¼90.00 , g¼90.00 ; V¼
3
3
˚
1828.1(4) A ; Z¼4, Dc¼1.636 Mg/m ; absorption coeffi-
cient 0.147 mmꢀ1; F(000)¼912; 1.74<q<27.00; reflections
collected 10,384; absorption correction empirical; transmis-
sion 1.000max–0.7516min. Final R indices R1¼0.0395, wR2¼
0.0744. The CCDC number is 621809.
4.2.8. 3-(2-Chlorophenyl)-5-(3-(2-chlorophenyl)isoxazol-
4-yl)-5-(trifluoromethyl)-1,4,2-dioxazole 3g. Yellow oil,
yield: 79%. 1H NMR (CDCl3): d 8.83 (1H, s, CH]), 7.60–
7.31 (8H, m, Ph). 19F NMR (CDCl3): d ꢀ83.27 (s, CF3).
13C NMR (CDCl3): d 159.8 (C5), 157.7 (C4), 154.7 (C3),
135.3 (Ph), 134.4 (Ph), 132.6 (Ph), 131.3 (Ph), 130.9 (Ph),
130.4 (Ph), 129.7 (Ph), 129.1 (Ph), 128.4 (Ph), 128.0 (Ph),
126.8 (Ph), 123.3 (CF3, 1JCF¼274 Hz), 111.4 (C1), 97.5 (C2).
MS (m/z, %): 429 (M+, 2.06), 360 (M+ꢀCF3, 2.52), 276
(M+ꢀm-ClC6H4CNO, 0.57), 205(M+ꢀm-ClC6H4CNOꢀCF3,
14.63), 152 (m-ClC6H4CNO, 15.22), 69 (CF3, 22.23). IR
(cmꢀ1): 1634, 1602, 1492, 682. HRMS calcd for
C18H9F3Cl2N2O3: (M++H) 429.0015; found 429.0024.
4.2.4. 3-(4-Fluorophenyl)-5-(3-(4-fluorophenyl)isoxazol-
4-yl)-5-(trifluoromethyl)-1,4,2-dioxazole 3c. Yellow solid,
mp: 107–108 ꢁC, yield: 45%. 1H NMR (CDCl3): d 8.66 (1H,
s, CH]), 8.21–7.88 (4H, m, Ph), 7.22–7.15 (4H, m, Ph).
19F NMR (CDCl3): d ꢀ83.20 (s, CF3), ꢀ102.3 (s, 1F),
ꢀ105.1 (s, 1F). 13C NMR (CDCl3): d 161.3 (C5), 159.2
(C4), 155.4 (C3), 134.2 (Ph), 132.0 (Ph), 131.4 (Ph), 129.2
1
(Ph), 124.3 (Ph), 123.9 (Ph), 121.8 (CF3, JCF¼231 Hz),
112.4 (C1), 109.0 (C2). MS (m/z, %): 396 (M+, 0.12),
395 (M+ꢀH, 0.59), 259 (M+ꢀp-FC6H4CNO, 1.35), 194
(M+ꢀp-FC6H4CNOꢀCF3, 1.48), 69 (CF3, 4.22). IR
(cmꢀ1): 1602, 1506, 1380, 1200, 837. HRMS calcd for
C18H9F5N2O3: 396.0533; found 396.0517.
4.2.9. 3-Phenyl-5-(3-phenylisoxazol-4-yl)-5-(trifluoro-
methyl)-1,4,2-dioxazole 3h. White oil, yield: 71%.
1H NMR (CDCl3): d 8.72 (1H, s, CH]), 7.47–7.44 (5H,
m, Ph), 7.31–7.25 (5H, m, Ph). 19F NMR (CDCl3):
d ꢀ83.14 (s, CF3). 13C NMR (CDCl3): d 161.1 (C5), 159.4
(C4), 158.7 (C3), 132.5 (Ph), 129.9 (Ph), 129.1 (Ph), 128.8
(Ph), 128.3 (Ph), 127.0 (Ph), 126.9 (Ph), 120.6 (CF3,
1JCF¼289 Hz), 111.6 (C1), 97.7 (C2). MS (m/z, %): 360
(M+, 7.58), 359 (M+ꢀH, 15.27), 291 (M+ꢀCF3, 28.30),
242 (M+ꢀC6H5CNO, 1.25), 173 (M+ꢀHꢀC6H5CNOꢀCF3,
6.40), 69 (CF3, 15.63). IR (cmꢀ1): 1635, 1577, 1450,
1017. HRMS calcd for C18H11F3N2O3: 360.0722; found
360.0725.
4.2.5. 3-p-Tolyl-5-(3-p-tolylisoxazol-4-yl)-5-(trifluoro-
methyl)-1,4,2-dioxazole 3d. Yellow oil, yield: 46%.
1H NMR (CDCl3): d 8.78 (1H, s, CH]), 7.48 (4H, dd,
3JHH¼1.8, 8.4 Hz, Ph), 7.18 (4H, dd, JHH¼1.8, 8.4 Hz,
3
Ph), 2.40 (3H, s, Me), 2.30 (3H, s, Me). 19F NMR
(CDCl3): d ꢀ83.23 (s, CF3). 13C NMR (CDCl3): d 161.1
(C5), 159.3 (C4), 158.8 (C3), 150.3 (Ph), 143.2 (Ph), 139.9
(Ph), 129.5 (Ph), 128.9 (Ph), 129.4 (Ph), 127.2 (Ph), 124.5
1
(Ph), 119.4 (Ph), 120.9 (CF3, JCF¼288 Hz), 111.7 (C1),
101.4 (C2). MS (m/z, %): 388 (M+, 22.60), 387 (M+ꢀH,
32.33), 318 (M+ꢀHꢀCF3, 22.19), 255 (M+ꢀp-
MeC6H4CNO, 1.49), 202 (CF3+M+ꢀp-MeC6H4CNO,
3.86), 186 (M+ꢀp-MeC6H4CNOꢀCF3, 100), 69 (CF3,
11.91). IR (cmꢀ1): 1611, 1591, 1520, 1438, 1257,
835. HRMS calcd for C20H15F3N2O3: 388.1035; found
388.1034.
4.2.10. 3-(E)-Styryl-5-(3-(E)-styrylisoxazol-4-yl)-5-(tri-
fluoromethyl)-1,4,2-dioxazole 3i. Yellow oil, yield: 42%.
1H NMR (CDCl3): d 8.80 (1H, s, CH]), 7.74 (1H, d,
3JHH¼16 Hz, CH]), 7.69–7.50 (10H, m, Ph), 7.44 (1H, d,
3
3JHH¼16 Hz, CH]), 7.10 (1H, d, JHH¼17 Hz, CH]),
3
6.80 (1H, d, JHH¼16 Hz, CH]). 19F NMR (CDCl3):
d ꢀ83.69 (s, CF3). 13C NMR (CDCl3): d 159.0 (C5), 158.7
(C4), 157.7 (C3), 141.0 (Ph), 139.9 (Ph), 137.4 (Ph), 135.6
(Ph), 130.5 (Ph), 130.1 (Ph), 129.2 (Ph), 129.0 (CH), 128.8
4.2.6. 3-(2-Fluorophenyl)-5-(3-(2-fluorophenyl)isoxazol-
4-yl)-5-(trifluoromethyl)-1,4,2-dioxazole 3e. Yellow oil,
yield: 43%. 1H NMR (CDCl3): d 8.78 (1H, s, CH]),
7.47–7.24 (4H, m, Ph), 7.13–6.91 (4H, m, Ph). 19F NMR
(CDCl3): d ꢀ83.55 (s, CF3), ꢀ105.45 (s, 1F), ꢀ112.5 (s,
1F). 13C NMR (CDCl3): d 160.2 (C5), 159.6 (C4), 158.1
(C3), 132.4 (Ph), 131.7 (Ph), 130.6 (Ph), 128.2 (Ph), 127.6
(Ph), 126.3 (Ph), 124.7 (Ph), 119.2 (Ph), 120.7 (CF3,
1JCF¼231 Hz), 111.5 (C1), 106.1 (C2). MS (m/z, %): 396
(M+, 9.16), 326 (M+ꢀHꢀCF3, 40.48), 259 (M+ꢀo-
FC6H4CNO, 5.14), 194 (M+ꢀo-FC6H4CNOꢀCF3, 80.76),
69 (CF3, 30.21). IR (cmꢀ1): 1630, 1594, 1499, 759.
HRMS calcd for C18H9F5N2O3: 396.0533; found
396.0533.
1
(CH), 127.7 (CH), 127.3 (CH), 120.9 (CF3, JCF¼288 Hz),
106.9 (C1), 97.7 (C2). MS (m/z, %): 412 (M+, 9.18), 267
(M+ꢀC6H5CHCHCNO, 1.64), 103 (C6H5CHCHCNO,
100), 69 (CF3, 62.31). IR (cmꢀ1): 1643, 1292, 1021.
HRMS calcd for C22H15F3N2O3: 412.1035; found 412.1032.
The mixture of 4 (0.3 mmol) and hydroxamyl chloride 2a
(1.2 mmol) in 2 mL of benzene was added slowly into the
mixture of NaHCO3 (0.6 mmol) in 1 mL benzene at 0 ꢁC.
Then the mixture was warmed to room temperature. TLC
analysis was used to monitor the reaction. After one day,
the reaction was over completely. After general work-up,
the residue was purified by column chromatography

H. Jiang et al. / Tetrahedron 63 (2007) 2315–2319
2319
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257; (b) Quilico, A.; Stagno d’Alcontres, G. Gazz. Chim. Ital.
1949, 79, 703–711; (c) Quilico, A.; Stagno d’Alcontres, G.
Nature 1950, 166, 226–227.
7. Quilico, A.; Speroni, G. Gazz. Chim. Ital. 1939, 69, 508–512.
8. Gladysz, J. A.; Curran, D. P.; Horvath, I. T. Handbook of
Fluorous Chemistry; Wiley-VCH: Weinheim, Germany, 2004.
9. (a) Gerus, I. I.; Tolmachova, N. A.; Vdovenko, S. I.; Froehlich,
R.; Haufe, G. Synthesis 2005, 8, 1269–1278; (b) Zhu, S. Z.; Jin,
G. F.; Peng, W. M.; Huang, Q. C. Tetrahedron 2003, 59, 2899–
2906; (c) Peng, W. M.; Zhu, S. Z. J. Fluorine Chem. 2002, 116,
81–86; (d) Song, L. P.; Chu, Q. L.; Zhu, S. Z. J. Fluorine Chem.
2001, 107, 107–112.
4.2.11. Ethyl 3-(4-bromophenyl) isoxazole-4-carboxylate.
White solid, mp: 54–56 ꢁC, yield: >99%. 1H NMR (CDCl3):
d 9.00 (1H, s, CH]), 7.68 (2H, d, 3JHH¼8 Hz, Ph), 7.60 (2H,
d, 3JHH¼8 Hz, Ph), 4.30 (2H, dd, 3JHH¼6, 13 Hz, CH2), 1.34
3
(3H, t, JHH¼6 Hz, CH3). 13C NMR (CDCl3): d 164.0
(C]O), 160.5 (C]N), 160.1 (C–O), 131.2 (Ph), 130.8
(Ph), 121.6 (Ph), 124.6 (Ph), 112.7 (C]C), 61.0 (CH2),
13.9 (CH3). MS (m/z, %): 296 or 294 (M+, 62.37 or
67.11), 224 or 222 (M+ꢀCF3, 66.15 or 64.9), 251 or 249
(M+ꢀC2H5, 22.42 or 13.25), 69 (CF3, 45.46). IR (cmꢀ1):
3076, 1728, 1305, 1143. HRMS calcd for C12H10BrNO3:
294.9844; found 294.9855.
Acknowledgements
Financial support for this project was provided by The
National Natural Science Foundation of China (NNSFC)
(Nos. 20472106 and 20532040).
10. Zhu, S. Z.; Qin, C. Y.; Wang, Y. L.; Chu, Q. L. J. Fluorine
Chem. 1999, 99, 183–187.
11. (a) Molteni, G.; Buttero, P. D. Tetrahedron: Asymmetry 2005,
16, 1983–1987; (b) Gerald, E.; Claude, T.; Claude, D.; Yves,
C. Tetrahedron: Asymmetry 2005, 16, 2459–2474; (c) Xu,
W. M.; Tang, E.; Huang, X. Tetrahedron 2005, 61, 501–506.
12. Jiang, H. L.; Zhao, J. W.; Han, X. B.; Zhu, S. Z. Tetrahedron
2006, 62, 11008–11011.
References and notes
1. Weissberger, A. Chem. Heterocycl. Compd. 1962.
2. Bleicher, K. H.; Nettekoveh, M.; Peters, J.-U.; Wyler, R.
Chimia 2004, 58, 588–600.