Convenient synthesis of 5-perfluoroalkylsubstituted isoxazoles

Article abstract of DOI:10.1016/S0040-4020(01)00522-1

5-Perfluoroalkylsubstituted isoxazoles are prepared readily from the reaction of nitrile oxide generated in situ from RCH₂NO₂, TEA and POCl₃ with ethyl 3-perfluoroalkyl-3-pyrrolidino-acrylates, which were obtained by treat

Full text of DOI:10.1016/S0040-4020(01)00522-1

TETRAHEDRON
Pergamon
Tetrahedron 57 82001) 5781±5784
Convenient synthesis of 5-per¯uoroalkylsubstituted isoxazoles
Peng Weimin, Zhu Shizhengp and Jin Guifang
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, People's Republic of China
Received 19 January 2001; revised 20 April2001; accepted 10 May 2001
AbstractÐ5-Per¯uoroalkylsubstituted isoxazoles are prepared readily from the reaction of nitrile oxide generated in situ from RCH2NO2,
TEA and POCl3 with ethyl 3-per¯uoroalkyl-3-pyrrolidino-acrylates, which were obtained by treatment of a-per¯uoroalkyl ethyl acetate with
pyrrolidine in the presence of base. q 2001 Elsevier Science Ltd. All rights reserved.
Isoxazoles are well known compounds and structural parts
of numerous naturalproducts, drugs, poylmers and other
1. Result and discussion
1
usefulcompounds.
Owing to their unique biological
It is well known that 1,3-dipolar cycloaddition reactions
between an open chain building block including a double
bond, and nitrile oxide as dipole produced in situ is a
versatile route to isoxazoles. An electron donating group
on one side of the double bond controls the regioselectivity
in the reaction.7 We therefore synthesized a ¯uorine-
containing building block with an electron donating group
attached to one end of the double bond. A preparation of
ethyl 3-tri¯uoromethyl-3-pyrrolidino-acrylate has been
reported.8 However, the starting material8ethyl4,4,4-
tri¯uoroacetoacetate) is comparatively an expensive
reagent.
activities such as pharmaceuticals and agrochemicals,2 and
the novelchemicaland physicalproperties, as dyes, electric
insulating oils and high temperature lubricants,3 many
methods have been developed for their preparation.1 We
are interested in synthesis of ¯uorine-containing isoxazoles
as they could be key intermediates in the preparation of
¯uorine-containing b-amino alcohol, b-hydroxylketone
and other ¯uorine-containing heterocycles which are
1,4
intriguing targets for medicaltreatment.
However, some methods for preparation of isoxazoles do
not work well for ¯uorine-containing analogues.5 Recently
we have reported the preparation of a series of 5-per¯uoro-
alkyl-1,3-oxazoles via the rhodium catalyzed hetero-
cycloaddition of ethyl 2-diazo-¯uoroalkylacetoacetate
with nitrile 8Scheme 1):6
Firstly, we prepared a-¯uoroalkyl substituted ethyl acetates
3 from the reaction of vinylethylether 2 and readily avail-
able per¯uoroalkylhalide 1 using the method of Huang.9
Under basic conditions treatment of 3 with pyrrolidine at
ambient temperature gave ethyl 3-per¯uoroalkyl-3-pyrroli-
dino-acrylates 4 as a mixture of Z and E isomers in high
yield 8Scheme 2).
Herein we wish to report the synthesis of ethyl3-per¯uoro-
alkyl-3-pyrrolidino-acrylates and their reactions with nitrile
oxides obtained in situ from nitro compounds to give
5-per¯uoroalkylsubstituted isoxazoles.
The formation of per¯uoroalkylated acrylates 4 from 3
involves three reaction steps in one pot: 8i) elimination of
HX; 8ii) Michael addition of pyrrolidine to the acrylate ester
and 8iii) elimination of HY.
It was noted that in the preparation of 4 8Scheme 2) two
stereoisomers 84Z/4E) are formed. For example, when 3c
was treated with pyrrolidine, 19F NMR spectra showed
two peaks at 260.2 and 265.5 ppm, respectively, in a
ratio of 7:6 after 3c was consumed. According to the litera-
ture,10 when the CF3 and ester groups are trans, the chemical
shift of the CF3 is at higher ®eld, so in our case the higher
®eld chemical shift 8at 265.5 ppm) should arise from the Z
isomer.
Scheme 1.
Keywords: synthesis; ¯uorine-containing isoxazole; nitrile oxide; 1,3 di-
polar cycloaddition; enamine.
p
Attempts to separate the two isomers by ¯ash chromato-
graphy using silica gel 8washed with TEA before use) failed.
Corresponding author. Tel.: 186-21-6416-3300; fax: 186-21-6416-
6128; e-mail: zhusz@pub.sioc.ac.cn
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020801)00522-1

5782
P. Weimin et al. / Tetrahedron 57 -2001) 5781±5784
Scheme 2. Reaction conditions and reagents: 8i) Na2S2O4, NaHCO3, C2H5OH, 508C; 8ii) 8NH4)2S2O8/H2SO4/H2O; 8iii) TEA, NaHCO3, pyrrolidine/diethyl
ether.
room temperature for three days, then excess TEA was
added to quench the reaction. The solvent was then evapo-
rated, and 1N HClwas added to the residue. The remaining
acrylate was hydrated to the F-alkyl b-keto ester after
severalhours, then the reaction mixture was extracted
with diethylether. After generalwork up, chromatography
afforded the expected isoxazoles 6.
Table 1. Reaction of a-¯uoroalkyl ethyl acetates 3 with pyrrolidine in the
presence of base
Entry
Reactant 83)
Product 84)
E:Za
Yield 8%)b
1
2
3
3a
3b
3c
4a
4b
4c
1:2
2:5
7:6
83
75
74
a
Determined by 19F NMR spectroscopy.
Isolated yield 8Z isomer only after Vacuum distillation).
The addition product A from 1,3 dipole nitrile oxide with
¯uoroalkylated acrylates 4 could not been detected by 19F
NMR spectroscopy or TLC analysis 8Scheme 3). Conse-
quently, the pyrrolidine moiety was readily lost after the
concerted cycloaddition reaction. The moderate conversion
should be attributed to the comparatively low reactivity of
the acrylate to the nitrile oxide because of the electron with-
drawing character of the per¯uoroalkyl group and the
comparatively high liability of nitrile oxide to dimerisa-
tion.11 It can also explain the fact that a-nitro acetate acid
methylester had no reaction with the ¯uorinated acrylates 4.
The conversions were 60, 55 and 35% for the 4c 8RfˆCF3±),
4b 8RfˆBrCF2±) and 4a 8RfˆClC3F6±), respectively. The
different steric effect of per¯uoroalkyl groups could account
for the difference in the conversion. The preparation of 5-per-
¯uoroalkyl substituted isoxazoles is summarised in Table 2.
b
It was found that the E isomer transformed partly to the Z
isomer on the silica gel column. It was also observed that the
ratio of Z isomer in the two isomers mixture increased after
standing for severaldays at room temperature. The Z isomer
is thermodynamically more stable. Eventually, vacuum
distillation gave pure acrylates 4 as the Z isomer alone.
The reaction result of a-¯uoroalkyl ethyl acetates 3 with
pyrrolidine is tabulated in Table 1.
The reaction of ethyl 3-per¯uoroalkyl-3-pyrrolidino-
acrylates 4 with nitrile oxide formed in situ from the reac-
tion of RCH2NO2 with TEA and POCl3 proceeded smoothly
as shown by TLC analysis. However, the conversions of the
acrylates observed by 19F NMR spectroscopy were ranged
from 30 to 60%. Even by raising the reaction temperature or
prolonging the reaction time, the ¯uorinated acrylates did
not react more completely. Addition of more reagents or
changing the ratio of RCH2NO2, TEA and POCl3, did not
increase the conversion. As it is known that the nitrile oxide
is liable to dimerisation, 11 we tried to reduce its concentra-
tion in the reaction system by slowing down the speed of
addition of phosphorus oxychloride and increasing the amount
of solvent used. The conversions increased only a little.
Table 2. Preparation of 5-per¯uoroalkyl substituted isoxazoles 6
Entry
Reactant 84)
Regent 85)
Product 86)a
Yield 8%)b
1
2
3
4
5
6
7
8
9
4a
4a
4a
4b
4b
4b
4c
4c
4c
5a
5b
5c
5a
5b
5c
5a
5b
5c
6aa
6ab
6ac
6ba
6bb
6bc
6ca
6cb
6cc
85
92
81
84
61
72
76
69
89
The optimum reaction conditions are described in the
experimentalsection. The reaction mixture was stirred at
a
The reaction conditions are described in the Experimentalsection.
Isolated yield based on the conversions.
b
In summary we have synthesized a series of ethyl
3-per¯uoroalkyl-3-pyrrolidino-acrylates 4 in high yield
and with high steroselectivity. They readily undergo 1,3-
dipolar cycloaddition with nitrile oxide produced in situ to
afford 5-per¯uoroalkyl substituted isoxazoles 6.
2. Experimental
1H- and 19F NMR spectra were recorded on Varian-360L
Scheme 3.

P. Weimin et al. / Tetrahedron 57 -2001) 5781±5784
5783
spectrometer instruments with TMS and TFA 8dCFCl3
TFA276.8 ppm, with high ®eld negative) as internal and
externalstandards, respectivye.l NMR spectra were
ˆ
1.28 83H, t, Jˆ11.0 Hz, ±OCH2CH3); dF 854.7 MHz,
CDCl3) 264.6 [dFˆ259.6 for E-4b]; m/z 8EI): 237 822.10
M1), 192 837.04), 208 8100.00%).
d
recorded in CDCl3 unless otherwise stated. The IR spectra
were obtained with a Perkin±Elmer 983G spectro-photo-
meter on KBr disks. Low and high resolution mass spectra
were obtained in a HP 5989a and Finngan MAT Instru-
ments, respectively. This institute performed elemental
analysis. Solvent and reagents were commercially available
and puri®ed before use.
2.2. General procedure for the synthesis of 5-per¯uoro-
alkylsubstituted isoxazoles 6
Under nitrogen atmosphere and with stirring, to a mixture of
ethyl 3-per¯uoroalkyl-3-pyrrolidino-acrylate 4 81.0 mmol),
primary nitro compound 5 81.1 mmol) and triethylamine
80.42 mL, 3.0 mmol) in anhydrous chloroform 815 mL) at
08C was added for about 3 h, via dropping funnel, a solution
of phosphorus oxychloride 80.11 mL, 1.2 mmol) in
anhydrous chloroform 810 mL). The mixture was stirred at
ambient temperature for about 72 h before TEA 85 mL) was
added to quench the reaction. The solvent was evaporated
out in vacuo, the residue was submitted to 19F NMR spectro-
scopy, then poured into 1N HCl825 mL) and stirred for
7±8 h at room temperature. The organic layer was sepa-
rated, the water layer was extracted with CH2Cl2
825 mL£3). The organic layers were combined, washed
with brine 840 mL£2) and dried 8Na2SO4). After removal
of solvent, column chromatography 8with petroleum ether
and ethyl acetate as the eluent) afforded the title compounds.
2.1. General procedure for preparation of the ethyl
3-per¯uoroalkyl-3-pyrrolidino-acrylates 4
To a suspension of a-per¯uoroalkyl ethyl acetate 3
810.0 mmol), sodium bicarbonate 81.26 g, 15.0 mmol) and
triethylamine 82.09 mL, 15.0 mmol) in diethyl ether
850 mL) at 0±58C, with stirring, added a solution of pyrro-
lidine 81.00 mL, 12.0 mmol) in diethyl ether 810 mL) by
drop funnelin 1 h, then the mixture was stirred at ambient
temperature for 24 h. 19F NMR spectroscopy showed the
reaction was completed. Then the mixture was poured into
water 860 mL), the organic layer was separated, the water
layer was extracted with diethyl ether 840 mL£3). The
organic layers were combined, washed with brine
840 mL£2) and dried 8Na2SO4). After removalof sovlent,
vacuum distillation afforded the ethyl 3-per¯uoroalkyl-3-
pyrrolidino-acrylates.
2.2.1. 4-Ethoxycarbonyl-3-methyl-5-'3-chloro-1,1,2,2,3,
3-hexa¯uoropropyl)-isoxazole 6aa. Eluent: n-hexane/
ethylacetate 30:1 8 Rfˆ0.2±0.3); 8yield: 85%); light yellow
oil; [Found: C, 35.60; H, 2.31; N, 4.30. C10H8ClF6NO3
requires C, 35.37; H, 2.37; N, 4.12%]; nmax 8liquid ®lm)
2986, 1728, 1615, 1125±1306, 776 cm21; dH 860 MHz,
CDCl3) 4.40 82H, q, Jˆ7.2 Hz, ±OCH2CH3), 2.17 83H, s,
±CH3), 1.28 83H, t, Jˆ7.2 Hz, ±OCH2CH3); dF 854.7 MHz,
CDCl3) 266.8 82F, s, ClCF2CF2CF2±), 2108.8 82F, s,
ClCF2CF2CF2±), 2119.2 82F, s, ClCF2CF2CF2±); m/z
8EI): 339/341 87.19/2.29 M1), 331/333 87.38/8.36), 294/
296 8100.00/32.81), 154 815.41%).
2.1.1. 'Z) Ethyl 3-'3-chloro-1,1,2,2,3,3-hexa¯uoropropyl)-
3-pyrrolidino-acrylate 4a. 8Yield: 83%); light yellow oil;
bp 888C/0.5 Torr; [Found: C, 40.69; H, 3.99; N, 4.11.
C12H14ClF6NO2 requires C, 40.75; H, 3.99; N, 3.96%];
nmax 8liquid ®lm) 2979, 1681, 1597, 1047±1287,
789 cm21; dH 860 MHz, CDCl3) 5.18 81H, s, CvCH),
4.13 82H, q, Jˆ9.3 Hz, ±OCH2CH3), 3.28±3.68 84H, m,
2£NCH2CH2±), 1.73±2.23 84H, m, 2£NCH2CH2±), 1.28
83H, t, Jˆ9.3 Hz, ±OCH2CH3); dF 854.7 MHz, CDCl3)
266.4 82F, s, ClCF2CF2CF2±), 2105.5 82F, s,
ClCF2CF2CF2±) [dFˆ2102.4 for E-4a], 2119.8 82F, s,
ClCF2CF2CF2±) [dFˆ2116.4 for E-4a]; m/z 8EI): 353/355
88.56/2.93 M1), 324/326 8100.00/33.35), 308/310 834.78/
11.45), 280/282 810.27/3.39%).
2.2.2. 4-Ethoxycarbonyl-3-ethyl-5-'3-chloro-1,1,2,2,3,3-
hexa¯uoropropyl)-isoxazole 6ab. Eluent: n-hexane/ethyl
acetate 15:1 8Rfˆ0.2±0.3); 8yield: 92%); light yellow oil;
[Found: C, 37.61; H, 2.89; N, 4.19. C11H10ClF6NO3 requires
C, 37.36; H, 2.85; N, 3.95%]; nmax 8liquid ®lm) 2920, 1729,
1600, 1093±1293, 786 cm21; dH 860 MHz, CDCl3) 4.40
82H, q, Jˆ6.2 Hz, ±OCH2CH3), 3.00 82H, q, Jˆ7.1 Hz
±CH2CH3), 1.09±1.54 86H, m, ±OCH2CH3 and
±CH2CH3); dF 854.7 MHz, CDCl3) 266.5 82F, s, ClCF2
CF2CF2±), 2108.2 82F, s, ClCF2CF2CF2±), 2118.4 82F,
s, ClCF2CF2CF2±); m/z 8EI): 354/356 857.32/18.25 M1),
326/328 814.99/4.77), 307/309 895.59/34.72), 94
8100.00%).
2.1.2. 'Z) Ethyl 3-bromodi¯uoromethyl-3-pyrrolidino-
acrylate 4b. 8Yield: 75%); light yellow oil; bp 1008C/
1 Torr; [Found: C, 40.42; H, 4.77; N, 4.85. C10H14BrF2NO2
requires C, 40.28; H, 4.73; N, 4.70%]; nmax 8liquid ®lm)
2976, 1693, 1597, 1145±1262 cm21; dH 860 MHz, CDCl3)
5.10 81H, s, CvCH), 4.08 82H, q, Jˆ10.0 Hz, ±OCH2CH3),
3.26±3.64 84H, m, 2£NCH2CH2±), 1.73±2.08 84H, m,
2£NCH2CH2±), 1.23 83H, t, Jˆ10.0 Hz, ±OCH2CH3); dF
854.7 MHz, CDCl3) 246.1 [dFˆ243.0 for E-4b]; m/z
8EI): 298/300 810.10/8.80 M1), 268/270 89.44/9.34), 252/
254 847.38/43.62), 188 8100.00%).
2.2.3. 4-Ethoxycarbonyl-3-phenyl-5-'3-chloro-1,1,2,2,3,
3-hexa¯uoropropyl)-isoxazole 6ac. Eluent: n-hexane/
ethylacetate 30:1 8 Rfˆ0.2±0.3); 8yield: 81%); light yellow
oil; [Found: C, 45.08; H, 2.65; N, 3.67. C15H10ClF6NO3
requires C, 44.85; H, 2.51; N, 3.48%]; nmax 8liquid ®lm)
2985, 1737, 1623, 1124±1309, 774 cm21; dH 860 MHz,
CDCl3) 7.33±7.73 85H, m, Ph), 4.33 82H, q, Jˆ6.2 Hz,
±OCH2CH3), 1.28 83H, t, Jˆ6.2 Hz, ±OCH2CH3); dF
854.7 MHz, CDCl3) 266.3 82F, s, ClCF2CF2CF2±),
2109.1 82F, s, ClCF2CF2CF2±), 2119.1 82F, s,
ClCF2CF2CF2±); m/z 8EI): 401/403 872.00/27.82 M1),
2.1.3. 'Z) Ethyl 3-tri¯uoromethyl-3-pyrrolidino-acrylate
4c. 8Yield: 74%); light yellow oil; bp 788C/3 Torr; [Found:
C, 50.31; H, 6.02; N, 6.00. C10H14F3NO2 requires C, 50.67;
H, 5.95; N, 5.91%]; nmax 8liquid ®lm) 2980, 1681, 1615,
1123±1274 cm21; dH 860 MHz, CDCl3) 5.21 81H, s,
CvCH), 4.14 82H, q, Jˆ11.0 Hz, ±OCH2CH3), 3.26±3.78
84H, m, 2£NCH2CH2±), 1.76±2.15 84H, m, 2£NCH2CH2±),

5784
P. Weimin et al. / Tetrahedron 57 -2001) 5781±5784
356/358 861.97/21.52), 216 875.00), 77 845.85), 114
8100.00%).
8liquid ®lm) 2961, 1732, 1617, 1023±1298 cm21; dH
860 MHz, CDCl3) 4.25 82H, q, Jˆ10.0 Hz, ±OCH2CH3),
2.85 82H, q, Jˆ10.0 Hz ±CH2CH3), 1.10±1.46 86H, m,
±OCH2CH3 and ±CH2CH3); dF 854.7 MHz, CDCl3) 261.8
8s, CF3); m/z 8EI): 238 86.96 M111), 209 85.13), 191
8100.00), 164 865.13), 69 817.82%).
2.2.4. 4-Ethoxycarbonyl-3-methyl-5-bromodi¯uoromethyl-
isoxazole 6ba. Eluent: n-hexane/ethylacetate 20:1
8Rfˆ0.2±0.3); 8yield: 84%); light yellow oil; [Found: C,
33.75; H, 2.89; N, 4.71. C15H10BrF2NO3 requires C,
33.83; H, 2.84; N, 4.93%]; nmax 8liquid ®lm) 2920, 1731,
1600, 1140±1290 cm21; dH 860 MHz, CDCl3) 4.40 82H, q,
Jˆ7.2 Hz, ±OCH2CH3), 2.53 83H, s, ±CH3), 1.40 83H, t,
Jˆ7.2 Hz, ±OCH2CH3); dF 854.7 MHz, CDCl3) 247.3 8s,
BrCF2); m/z 8EI): 284/286 87.89/7.37 M1), 238/240 823.68/
23.16), 204 822.19), 176 8100.00%).
2.2.9. 4-Ethoxycarbonyl-3-phenyl-5-tr¯uoromethyl-isoxa-
zole 6cc. Eluent: n-hexane/ethylacetate 30:1 8 Rfˆ0.2±0.3);
8yield: 89%); light yellow oil; [Found: C, 55.05; H, 3.79; N,
5.21. C13H10F3NO3 requires C, 54.70; H, 3.53; N, 4.91%];
nmax 8liquid ®lm) 2920, 1730, 1600, 1160±1319 cm21; dH
860 MHz, CDCl3) 7.37±7.87 85H, m, Ph), 4.24 82H, q,
Jˆ7.5 Hz, ±OCH2CH3), 1.20 83H, t, Jˆ7.5 Hz,
±OCH2CH3); dF 854.7 MHz, CDCl3) 261.0 8s, CF3); m/z
8EI): 285 85.29 M1), 240 83.38), 216 85.80), 149 8100), 69
813.46%).
2.2.5. 4-Ethoxycarbonyl-3-ethyl-5-bromodi¯uoromethyl-
isoxazole 6bb. Eluent: n-hexane/ethylacetate 20:1
8Rfˆ0.2±0.3); 8yield: 61%); light yellow oil; [Found: C,
36.42; H, 3.59; N, 5.04. C9H10BrF2NO3 requires C, 45.10;
H, 2.91; N, 4.00%]; nmax 8liquid ®lm) 2910, 1720, 1600,
1142±1290 cm21; dH 860 MHz, CDCl3) 4.40 82H, q,
Jˆ8.0 Hz, ±OCH2CH3), 2.97 82H, q, Jˆ7.1 Hz
±CH2CH3), 1.23±1.53 86H, m, ±OCH2CH3 and
±CH2CH3); dF 854.7 MHz, CDCl3) 246.9 8s, BrCF2); m/z
8EI): 298/300 811.87/11.02 M1), 251/253 818.42/19.63),
224/226 822.98/19.99), 162 8100.00%).
Acknowledgements
The authors thank the NationalNaturalScience Foundation
of China 8NNSFC) 8No. 20072049) and Innovation
Foundation of Chinese Academy of Science for ®nancial
support.
2.2.6. 4-Ethoxycarbonyl-3-phenyl-5-bromodi¯uoromethyl-
isoxazole 6bc. Eluent: n-hexane/ethylacetate 20:1
8Rfˆ0.2±0.3); 8yield: 72%); light yellow oil; [Found: C,
45.26; H, 3.11; N, 4.30. C13H10BrF2NO3 requires C,
36.30; H, 3.38; N, 4.70%]; nmax 8liquid ®lm) 2910, 1730,
1600, 1130±1297 cm21; dH 860 MHz, CDCl3) 7.37±7.90
85H, m, Ph), 4.37 82H, q, Jˆ7.4 Hz, ±OCH2CH3), 1.52
83H, t, Jˆ7.4 Hz, ±OCH2CH3); dF 854.7 MHz, CDCl3)
246.6 8s, BrCF2); m/z 8EI): 345/347 834.72/34.94 M1),
317/319 81.22/1.21), 300/302 816.77/16.52), 216 875.68),
144 8100.00%).
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0.3); 8yield: 69%); light yellow oil; [HMRS 8EI): M1,
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