Nov-Dec 2005
Synthesis of 3-Phenyl-5-(trifluoromethyl)isoxazole
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chloroform): δ (DEPT-135) 43.0 (-), 103.5 (q, J= 34.5 Hz) (0),
121.q (q, J= 283.9 Hz)(0), 127.0(+), 127.7(0), 129.0(+),
131.2(+), 157.0(0); MS m/z (%) 231(57), 162(52), 144(16),
120(36), 119(24), 103(33), 91 (33), 77 (100).
of 1,1,1-trifluro-4-phenylbut-3-yn-2-one (14) [7] with
hydroxylamine according to a modification of a procedure
developed by Linderman [8] for the synthesis of 5-octyl-3-
(trifluromethyl)isoxazole.
3-Phenyl-5-(trifluoromethyl)isoxazole (1).
The products obtained in our laboratory from 13 and 14
were identical and exhibited a melting range of 40-42 ºC,
similar to the value reported by Tanaka [6] but quite differ-
ent from the melting range of the regiosiomer 1. The mass
spectrum of this material also exhibited a molecular ion at
m/z = 213. Unlike the mass spectrum of 1, however, the
major fragmentation pathway for 2 does not result from
cleavage of the trifluoromethyl group but leads to a signal
at m/z 105, most likely due to loss of a benzoyl group
(PhC=O).
A solution of 5-hydroxy-3-phenyl-5-(trifluoromethyl)-4,5-
dihydroxyisoxazole (8) (6.2 g, 16.9 mmol) and p-toluenesulfonic
acid (0.60 g, 3.3mmol) in benzene (120 ml) was refluxed for 12
hr. Most of the benzene was removed by simple distillation and
the gray solid was collected and dissolved in dichloromethane
(180 ml). The solution was filtered, washed with saturated aque-
ous bicarbonate (3 x 50 ml), dried (sodium sulfate), and concen-
trated to dryness. The resulting white solid was recrystallized
from 20% aqueous methanol to yield 1 as white crystals (2.7 g,
12.7 mmol, 47.2%) which was sublimed (40 ºC, 1.5 mm Hg) to
1
1
give white crystals mp 78.0-79.5 ºC, lit [4], 80 ºC; H-NMR
The H-NMR spectrum of 2 exhibited a 1H singlet at δ
(deuteriochloroform): δ 7.01 (s, 1H), 7.49-7.51 (m, 3H), 7.80-
6.73 due to the H4 proton and 3H and 2H multiplets cen-
13
7.83 (m, 2H): C-NMR (deuteriochloroform): δ (DEPT-135)
tered at δ 7.50 and 7.79 due to protons of the phenyl rings.
103.5(+), 117.9 (q, J + 270.2 Hz) (0), 126.9 (+), 127.2 (0), 129.2
(+), 131.0 (+), 159.2 (q, J = 42.6 Hz) (0), 162.6 (0); Ms m/z (%)
213 (45), 144(100), 116(27), 77 (61.5).
13
The C-NMR spectrum of 2 exhibited signals at δ 126.4,
129.7, and 131.7 for the carbons of the phenyl group, a
quartet at 120.0 (J = 271.0 Hz) for the carbon of the triflu-
oromethyl group, and signals at δ 172.8, 156.4 and 97.2 for
the carbons of the isoxazole ring. Surprisingly, the signal
at δ 156.4 appeared as a quartet (J = 38.0 Hz), indicating
long-range coupling with the fluorine nuclei of the trifluo-
romethyl group. Accordingly, in contrast to isomer 1, in
this compound the C5 carbon absorbs furthest downfield
5-Phenyl-3-(trifluoromethyl)isoxazole (2).
4-Phenyl-1,1,1-trifluorobut-3-yn-2-one (14) [7] (0.31 g, 1.6
mmol) was dissolved in glacial acetic acid (2.0 ml). Aqueous
hydrochloric acid (10%, 3 drops) and water (10 drops) were
added. Hydroxylamine hydrochloride (0.11 g, 1.6 mmol) was
added and the solution was stirred at room temperature for 24 hr.
The solution was filtered and the filtrate was extracted with ether
(5 x 10 ml). The combined ether extract was dried (sodium sul-
fate) and concentrated to dryness. The pale yellow residual oil
solidified upon standing at room temperature to provide 2 as a
pale yellow solid (0.32 g, 1.5 mmol, 94%) which was recrystal-
lized from 20% aqueous methanol to give white crystals of 2 mp
13
in the C-NMR spectrum and the absorption due to the C3
carbon appears slightly upfield at δ 156.4 between the sig-
nals for the C5 and C4 carbons.
1
EXPERIMENTAL
41.0-41.8 ºC, lit [6] 44-45.5 ºC; H-NMR (deuteriochloroform):
13
δ 6.74 (s, 1H), 7.51 (m, 3H), 7.81 (m, 2H: C-NMR (deuteri-
1
13
ochloroform): δ (DEPT-135) 96.8 (+), 119.7 (q, J = 270.8 Hz),
126.0 (+), 129.3 (+), 131.3(+), 156.0 (q, J = 38.3 Hz) (0), 172.4
(0); MS m/z (%) 213 (100), 105 (57), 77 (41).
H- and C spectra were recorded at 400.1 and 100.6 MHz in
1
13
deuteriochloroform on a Bruker FT-NMR system. H and
C
chemical shifts were measured relative to internal tetramethylsi-
lane and chloroform respectively. Mass spectra were recorded
with an HP 5970 B mass selective detector interfaced to an
HP588 capillary column gas chromatograph.
REFERENCES AND NOTES
Reactant (3) is commercially available. Compounds (10) and
(13) were synthesized by methods described in [5]. Compound
(14) was prepared by the procedure given in [7].
[1] J. W. Pavlik, H. St. Martin, K. A. Lambert, J. A. Lowell, V. M.
Tsefrikas, C. K. Eddins, and N. Kebede, J. Heterocyclic Chem., 42, 273
(2005).
[2] J. B. Carr, H. G. Durham, and D. K. Hass, J. Med. Chem., 20,
934 (1977).
[3] J. C. Reid and M. Calvin, J. Am. Chem. Soc., 72, 2948 (1950).
[4] J. Diab, A. Laurent, and I. LeDréan, J. Fluorine Chem., 84,
145 (1997).
[5] G. Alvernhe, D. Greif, B. Langlois, A. Laurent, I. LeDréan,
M. Pulst, A. Selmi, and M. Weissenfels, Bull. Soc. Chim. Fr. 131, 167
(1994).
[6] K. Tanaka. H. Masuda, and K. Mitsuhashi, Bull Chem. Soc.,
Jpn., 57, 2184 (1984).
5-Hydroxy-3-Phenyl-5-(trifluoromethyl)-4,5-dihydroisoxazole
(8).
A solution of hydroxylamine hydrochloride (3.8 g, 54.7 mmol)
in water (14.0 ml) was added to a solution of 4,4,4-trifluoro-1-
phenyl-1,3-butanedione (3) (5.6 g, 25.9 mmol) dissolved in a
mixture of 0.5 M hydrochloric acid (50 ml) and ethanol (210 ml).
The solution was stored in a refrigerator for 48 hours and concen-
trated to a volume of 50 ml. Further storage in the refrigerator
overnight gave 8 as white crystals (3.6 g, 15.6 mmol, 60%) mp
[7] R. J. Linderman and M. S. Lonikar, J. Org. Chem., 53, 6013
(1988).
1
140.5-142.0 ºC, lit [3], mp 143.3-144.1 ºC; H-NMR (deuteri-
ochloroform): δ 3.61 (AB quartet, 2H, J = 17.9 Hz), 3.78 (s,
[8] R. J. Linderman and K. S. Kirollos, Tetrahedron Lett., 30,
2049 (1989).
AB
13
1H), 7.42-7.46 (m, 3H), 7.63-7.65 (m, 2H); C-NMR (deuterio-