Fluorination of 4-nitroisoxazoline salts. Synthesis of 4-fluoro-4- nitroisoxazolines and 4-fluoroisoxazoles

Article abstract of DOI:10.1007/s11172-009-0300-3

Methods for the synthesis of hitherto unknown 4-fluoro-4-nitroisoxazolines by fluorination of 4-nitroisoxazoline salts with FClO₃ in MeOH and 4-fluoroisoxazoles by treatment of fluoronitroisoxazolines bearing the hydrogen atom bound to the C(5)

Full text of DOI:10.1007/s11172-009-0300-3

Russian Chemical Bulletin, International Edition, Vol. 58, No. 10, pp. 2182—2184, October, 2009
2182
Fluorination of 4ꢀnitroisoxazoline salts.
Synthesis of 4ꢀfluoroꢀ4ꢀnitroisoxazolines and 4ꢀfluoroisoxazoles
G. Kh. Khisamutdinov,a L. V. Okhlobystina,b and A. A. Fainzil´bergb†
aState Scientific Research Institute "Krislall",
6 ul. Zelenaya, 606007 Dzerzhinsk, Nizhny Novgorod Region, Russian Federation.
Fax: +7 (8313) 24 4085. Eꢀmail: kristall@sinn.ru
bN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328
Methods for the synthesis of hitherto unknown 4ꢀfluoroꢀ4ꢀnitroisoxazolines by fluorination
of 4ꢀnitroisoxazoline salts with FClO3 in MeOH and 4ꢀfluoroisoxazoles by treatment of fluoꢀ
ronitroisoxazolines bearing the hydrogen atom bound to the C(5) atom of the isoxazole ring
with MeONa in MeOH were developed.
Key words: 4ꢀnitroisoxazolines and their salts, 4ꢀfluoroꢀ4ꢀnitroisoxasolines, 4ꢀfluoroꢀ
isoxazoles, perchloryl fluoride, fluorination, synthesis, elimination, nitrous acid.
Scheme 2
In continuation of our research on chemical transforꢀ
mations of 4ꢀnitroisoxazolines 1 (see Refs 1—3), in the
present work we studied fluorination of their salts 2
(Scheme 1). It was found that fluorination of 4ꢀnitroisoxꢀ
azoline salts 2a—j with FClO3 in MeOH resulted in hithꢀ
erto unknown 4ꢀfluoroꢀ4ꢀnitroisoxazolines 3a—j in good
yields (75—88%). This reaction is general and can be used
as a preparative method for the synthesis of fluoronitroisoxꢀ
azolines. In the reaction mixtures along with isoxazoꢀ
lines 3, small amounts of 4ꢀnitroisoxazolines 1a—j (due to
acid hydrolysis of salts 2a—j) and isoxazolꢀ4ꢀones 4a—c
(due to oxidation of salts 2h—j) were also detected by TLC
and IR spectroscopy (see Ref. 2; Schemes 1 and 2).
Scheme 1
1—3: R = R´ = Me (h); R—R´ = (CH2)4 (i), (CH2)5 (j)
4: R = R´ = Me (a); R—R´ = (CH2)4 (b), (CH2)5 (c)
The formation of ketones along with fluoronitro comꢀ
pounds has previously been documented for the fluorinaꢀ
tion of 5ꢀnitroꢀ6ꢀphenylnorbornene salt with perchoryl
fluoride.4
The purity of the synthesized fluoronitroisoxazolines
3a—j was demonstrated by TLC and their structures were
established based on the data from 19F NMR and IR specꢀ
troscopy and elemental analysis.
The IR spectra of compounds 3a—j contained the
vibration bands characteristic of the geminal aliphatic
fluoronitro compounds in the range of 1350 and
1570—1575 cm–1 (NO2), and 1140—1160 cm–1 (C—F).5,6
The 19F NMR spectra of compounds 3a—e and 3g bearing
the hydrogen atom bound to the C(5) atom of the isoxꢀ
R = Me (a), Et (b), Ph (c), pꢀMeOC6H4 (d), pꢀBrC6H4 (e),
pꢀO2NC6H4 (f), mꢀFC6H4 (g)
† Deceased.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2117—2119, October, 2009.
1066ꢀ5285/09/5810ꢀ2182 © 2009 Springer Science+Business Media, Inc.

Fluorination of 4ꢀnitroisoxazoline salts
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 10, October, 2009
2183
(%)
Table 1. Physicochemical characteristics of synthesized compounds 3a—j
Comꢀ Yield М.p./°C or
Found
Calculated
Molecular
formula
Rf
19F NMR
(δ, J/Hz)
cisꢀ3
(%)
pound (%)
B.p./°C
(p/Torr)
transꢀ3
С
H
N
F
δ (JF,H
)
δ (JF,H
)
trans
1
2
cis
3a
3b
83
85
87—89(3)a
98—99(3)b
53.93 4.53 12.94
53.58 4.04 12.50
55.03 4.78 11.65
55.46 4.65 11.76
8.43
8.47
7.92
7.97
C10H9FN2O3
C11H11FN2O3
0.84
0.88
49.29(21) 43.03(30)
50.23(21) 42.43(30)
80
20
70
30
3с
3d
3e
3f
90
87
88
75
87
85
88
86
71—73
69—70
63.43 4.83 9.78
62.94 3.87 9.79
60.62 4.21 8.77
60.76 4.14 8.86
49.39 3.03 7.26
49.34 2.76 7.67
54.45 3.17 12.26
54.39 3.04 12.69
6.66
6.64
6.26
6.01
5.44
5.20
5.27
5.73
C15H11FN2O3
C16H13FN2O4
0.82
0.69
41.04(20) 40.78(28)
40.78(20) 41.13(28)
40.42(20) 40.33(28)
30
70
46
54
46
54
100
0
55—56
C15H10BrFN2O3 0.85
91—92
C15H10FN3O5
C15H10F2N2O3
C11H11FN2O3
C13H13FN2O3
C14H15FN2O3
0.70
0.87
0.76
0.90
0.85
40.69(20)c
41.4(20)
52.20
—
40.8(28)
—
3g
3h
3i
67—69
59.78 3.03 9.37 12.00
59.22 3.31 9.20 12.48
62
38
—
172—173(2)d
82—83
55.64 4.30 12.51
55.46 4.62 11.76
58.96 5.66 10.74
59.08 4.96 10.60
60.82 5.62 9.31
60.41 5.43 10.06
7.84
7.97
7.44
7.19
6.92
6.82
48.43
—
—
—
3j
68—69
53.72
—
a nD20 1.534; d420 1.270; b nD20 1.531; d420 1.258; c in (CD3)2 C=O; d nD20 1.530; d420 1.245.
azole ring exhibited two doublets with coupling constants
JF—H of 20 and 30 Hz suggesting that these compounds
exist as two structural isomers (cis and trans). The isomer
ratio depends on the substituent at the C(5) atom. In the
case of compound 3f, the 19F NMR spectrum contained
only one doublet with JF—H = 20 Hz (cis isomer).
No separation of the mentioned isomers could
be achieved by TLC on Silufol UVꢀ254 plates (chloroꢀ
form—benzene, 1 : 1 and CH2Cl2—hexane, 1 : 1).
Treatment of fluoronitroisoxazolines 3c—g with Meꢀ
ONa in MeOH resulted in elimination of HNO2 to give
the corresponding 4ꢀfluoroisoxazoles 5c—g. In contrast to
4ꢀchloroꢀ4ꢀnitroisoxazolines,3 no formation of 4ꢀniꢀ
troisoxazoles was observed (Scheme 3).
The purity of fluoroisoxazoles 5a—e was demonstrated
by TLC, their structures were confirmed based on the data
from elemental analysis and in the case of compounds
5a—c from 19F NMR spectroscopy as well. In the 19F
NMR spectra of compounds 5a—c, the singlet signals at
δ 99.29, 106.29, and 97.87, respectively, were observed,
Physicochemical data and the yields of the synthesized
fluoronitroisoxazolines 3a—j are given in Table 1.
Table 2. Physicochemical characteristics of synthesized fluoroisoxazoles 5c—g
Comꢀ
pound
Yield
(%)
M.p./°C
Found
Calculated
Molecular
formula
Rf
(%)
С
H
N
F
5a
90
121—123
74.87
75.33
4.55
4.11
6.00
5.85
7.52
7.94
C15H10FNO
0.96
5b
5c
5d
5e
92
89
93
87
91—92
123—124
202—203
86—87
71.40
71.51
56.47
56.07
63.00
63.32
69.17
69.98
4.89
4.45
3.27
2.88
5.77
5.20
5.03
4.40
7.24
7.06
5.77
5.97
6.32
6.68
14.06
14.77
C16H12FNO2
C15H9BrFNO
C15H9FN2O3
C15H9F2NO
0.74
0.97
0.73
0.96
3.48 10.24
3.17
3.61
2.50
9.85
5.83
5.44

2184
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 10, October, 2009
Khisamutdinov et al.
Scheme 3
chloryl fluoride was passed for 1—1.5 h, and the mixture was
poured into cold water (200 mL). In the case of 1c—g and 1i,j,
the heavy viscous oils that formed crystallized on standing, the
resulting crystals were filtered off, washed with water, and dried.
Fluorination of salts 1a,b and 1h resulted in the oily products,
which were extracted with diethyl ether (2×50 mL), the comꢀ
bined organic layer was washed with water (2×50 mL), dried
with MgSO4, and the solvent was removed in vacuo.
The resulting mixtures of 3a—j, 1a—j, and 4a—c were sepaꢀ
rated by column chromatography (silica gel, CH2Cl2—hexane
(1 : 1)).
3: R = Ph (c), pꢀMeOC6H4 (d), pꢀBrC6H4 (e), pꢀO2NC6H4 (f),
mꢀFC6H4 (g)
5: R = Ph (a), pꢀMeOC6H4 (b), pꢀBrC6H4 (c), pꢀO2NC6H4 (d),
mꢀFC6H4 (e)
4ꢀFluoroisoxazoles (general procedure). To a solution of comꢀ
pound 3c—g (0.01 mmol) in MeOH (30 mL), MeONa (0.01 mol,
10% MeONa solution in MeOH) was added and the mixture was
stirred at room temperature for 30 min. The solvent was reꢀ
moved in vacuo, the residue was treated with water, and the
precipitate that formed was filtered off. Recrystallization from
hexane afforded compounds 5a—c and 5e. Compound 5d was
only washed with chloroform.
which were attributed to the fluorine atom bound to the
C(4) atom of the isoxazole ring.
Physicochemical data and the yields of compounds
5a—e are given in Table 2.
In summary, the reaction studied can be regarded as
a convenient preparative synthetic method toward hitherꢀ
to unknown 4ꢀfluoroisoxazoles, which may otherwise be
difficult to obtain.
References
1. L. A. Demina, G. Kh. Khisamutdinov, S. V. Tkachev, A. A.
Fainzil´berg, Zh. Org. Khim., 1979, 15, 735 [J. Org. Chem.
USSR (Engl. Transl.), 1979, 15].
Experimental
2. G. Kh. Khisamutdinov, L. A. Demina, G. E. Cherkasova,
B. G. Klimenko, Zh. Org. Khim., 1979, 15, 2436 [J. Org. Chem.
USSR (Engl. Transl.), 1979, 15].
3. T. V. Trusova, N. G. Maluyta, G. Kh. Khisamutdinov, Zh. Org.
Khim., 1987, 23, 1313 [J. Org. Chem. USSR (Engl. Transl.),
1987, 23].
4. J. P. Freemann, J. Am. Chem. Soc., 1960, 82, 3869.
5. V. Grakauskas, K. Baum, J. Org. Chem., 1968, 33, 3080.
6. F. Ya. Natsibullin, G. V. Oreshko, L. T. Eremenko, Izv. Akad.
Nauk SSSR, Ser. Khim., 1971, 2344 [Bull. Acad. Sci. USSR,
Div. Chem. Sci. (Engl. Transl.), 1971, 20, 2230].
Melting points were determined in capillaries. The IR specꢀ
tra were recorded on a URꢀ20 spectrometer in KBr pellets. The
19F NMR spectra were obtained on a Varian DPꢀ60 instrument
at 56.5 MHz in CDCl3, the chemical shifts are given in the δ
scale relative to CF3COOH as the external standard. TLC was
performed on Silufol UV–254 plates in chloroform—benꢀ
zene (1 : 1).
The starting 4ꢀnitroisoxazolines (1a—j) were synthesized by
the known methods.1
4ꢀFluroꢀ4ꢀnitroisoxazolines 3a—j (general procedure). To
a suspension of compound 1a—g (0.01 mol) in dry MeOH
(14 mL), MeONa (0.01 mol, 10% solution in MeOH) was added
and the mixture was stirred for 1—1.5 h until clear solution was
formed. After the reaction mixture was cooled to 3—5 °C, perꢀ
Received May 20, 2009;
in revised form August 10, 2009