2-Polyfluoroalkylchromones 10. Synthesis of regioisomeric 3-(2-hydroxyaryl)-5-polyfluoroalkyl- and 5-(2-hydroxyaryl)-3-polyfluoroalkylisoxazoles and determination of their structures by 1H, 19F, and 13C NMR spectroscopy

Article abstract of DOI:10.1023/A:1020908831426

The reactions of 2-hydroxy-2-polyfluoroalkylchroman-4-ones with hydroxylamine yield, through Δ²-isoxazolines as intermediate products, 3-(2-hydroxyaryl)-5-polyfluoroalkylisoxazoles. Analogous reactions with 2-polyfluoroalkylchromones afford β-diketone monooximes, which in an acidic medium undergo cyclodehydration into 5-(2-hydroxyaryl)-3-polyfluoroalkylisoxazoles. The structures of regioisomeric 3- and 5-polyfluoroalkylisoxazoles were determined using ¹H, ¹⁹F, and ¹³C NMR spectroscopy.

Full text of DOI:10.1023/A:1020908831426

1270
Russian Chemical Bulletin, International Edition, Vol. 51, No. 7, pp. 1270—1279, July, 2002
2ꢀPolyfluoroalkylchromones
10.* Synthesis of regioisomeric 3ꢀ(2ꢀhydroxyaryl)ꢀ5ꢀpolyfluoroalkylꢀ and
5ꢀ(2ꢀhydroxyaryl)ꢀ3ꢀpolyfluoroalkylisoxazoles and determination of their structures by
19
13
1H, F, and C NMR spectroscopy
ꢀ
V. Ya. Sosnovskikh, A. Yu. Sizov, and B. I. Usachev
A. M. Gorky Ural State University,
51 prosp. Lenina, 620083 Ekaterinburg, Russian Federation.
Fax: +7 (343 2) 61 5978. Eꢀmail: Vyacheslav.Sosnovskikh@usu.ru
The reactions of 2ꢀhydroxyꢀ2ꢀpolyfluoroalkylchromanꢀ4ꢀones with hydroxylamine yield,
2
through ∆ ꢀisoxazolines as intermediate products, 3ꢀ(2ꢀhydroxyaryl)ꢀ5ꢀpolyfluoroalkylꢀ
isoxazoles. Analogous reactions with 2ꢀpolyfluoroalkylchromones afford βꢀdiketone monoꢀ
oximes, which in an acidic medium undergo cyclodehydration into 5ꢀ(2ꢀhydroxyaryl)ꢀ3ꢀ
polyfluoroalkylisoxazoles. The structures of regioisomeric 3ꢀ and 5ꢀpolyfluoroalkylisoxazoles
1
were determined using H, 19F, and 13C NMR spectroscopy.
Key words: 2ꢀhydroxyꢀ2ꢀpolyfluoroalkylchromanꢀ4ꢀones, 2ꢀpolyfluoroalkylchromones,
2
hydroxylamine hydrochloride, 5ꢀhydroxyꢀ5ꢀpolyfluoroalkylꢀ∆ ꢀisoxazolines, 5ꢀpolyfluoroꢀ
alkylisoxazoles, βꢀdiketone monooximes, 3ꢀpolyfluoroalkylisoxazoles; 1H, 19F, and 13C NMR
spectroscopy.
In recent years, much attention has been given to the
fluoromethylisoxazoles are obtained by 1,3ꢀdipolar cycloꢀ
addition of trifluoroacetonitrile Nꢀoxide to alkenes,17,18
alkynes,17,18 βꢀdiketones,19 βꢀoxo esters,19 βꢀacyl pyruꢀ
vates,20 and malononitrile.21 Regioisomeric 3ꢀ and
5ꢀtrifluoromethylisoxazoles have been synthesized from
trifluoroacetylalkynes22 and a trifluoroacetyl derivative
of 4ꢀhomoadamantanone,23 while 3ꢀ and 5ꢀtrifluoroꢀ
development of efficient methods for the synthesis of
trifluoromethylated heterocycles,2 which are of interest
as potential bioactive compounds.3 However, informaꢀ
tion on the regiocontrolled syntheses that afford regioꢀ
isomeric CF3ꢀcontaining heterocycles, including isoxazoꢀ
les, in good yields is very scarce. Isoxazoles play an
important part in medicinal and agricultural chemistry,4
and the reductive opening of the isoxazole ring affords
various polyfunctional compounds.5,6 It is known5,7 that
the reactions of hydroxylamine with βꢀdiketones bearing
a fluorinated substituent at one of the carbonyl groups
and with ethers of the enol form of βꢀdiketones (βꢀalkoxyꢀ
vinyl trifluoromethyl ketones)8—10 give, through the forꢀ
2
methylꢀ∆ ꢀisoxazolines, from 3,3ꢀdialkylꢀ6ꢀtrifluoroꢀ
methylꢀ2,3ꢀdihydroꢀ4ꢀpyrones.24
In the present work, the reactions of hydroxylamine
with adducts of 2ꢀhydroxyacetophenones and RFCO2Et
(RF = CF3, CF2CF2H, and CF2H) and with 2ꢀpolyꢀ
fluoroalkylchromones obtained from these adducts were
studied with the aim of synthesizing regioisomeric
3ꢀ(2ꢀhydroxyaryl)ꢀ5ꢀpolyfluoroalkylꢀ and 5ꢀ(2ꢀhydroxyꢀ
aryl)ꢀ3ꢀpolyfluoroalkylisoxazoles. For the first time, we
performed comparative analysis of the 1H, 19F, and
13C NMR data for 5ꢀRFꢀ and 3ꢀRFꢀisoxazoles and reꢀ
vealed some of their characteristic spectral features for
clearcut distinction between these compounds.
2
mation of 5ꢀhydroxyꢀ5ꢀpolyfluoroalkylꢀ∆ ꢀisoxazolines,
5ꢀRFꢀisoxazoles, which make them quite accessible comꢀ
pounds, as distinct from their 3ꢀRFꢀregioisomers. In adꢀ
dition, 5ꢀtrifluoromethylisoxazoles have been synthesized
in two steps from perfluoroethyl iodide, monosubstituted
acetylenes, and hydroxylamine,11 while 5ꢀperfluoroꢀ
alkylisoxazoles, by the reactions of fluorineꢀcontaining
βꢀdicarbonyl compounds with nitrile Nꢀoxides.12 Analoꢀ
gous reactions of nitrile Nꢀoxides with fluorinated alkynes
give a mixture of 4ꢀ and 5ꢀperfluoroalkylisoxazoles,13—16
while those with alkenes yield 5ꢀperfluoroalkylisoxazoꢀ
Results and Discussion
Earlier,25 enol structure 1 has been assigned to adꢀ
ducts of substituted 2ꢀhydroxyacetophenones with ethyl
trifluoroacetate; they were shown to react with hydroxyꢀ
lamine to give monooximes 2 containing the oxime group
at the aromatic substituent. Later,26 it was determined
2
lines.16 3ꢀTrifluoromethylꢀ∆ ꢀisoxazolines and 3ꢀtriꢀ
* For Part 9, see Ref. 1.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1175—1183, July, 2002.
1066ꢀ5285/02/5107ꢀ1270 $27.00 © 2002 Plenum Publishing Corporation

3ꢀ(2ꢀHydroxyaryl)ꢀ5ꢀRFꢀisoxazoles
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 7, July, 2002
1271
Scheme 1
that these adducts have structures of cyclic chromanones 3
both in the crystalline state and in solution. We found
that the reactions of hydroxylamine with 2ꢀhydroxyꢀ2ꢀ
polyfluoroalkylchromanꢀ4ꢀones 3a—f (compounds 3c,d
containing the (CF2)2H group exist in CDCl3 as a mixꢀ
ture of tautomers 1 and 3), afford 5ꢀRFꢀisoxazolines 4
rather than open oximes 2 as believed previously,25 which
is due to a high electrophilicity of the carbonyl C atom
bound to the RF group (Scheme 1). The cyclic structure
of compounds 4a—f was confirmed by 1H NMR spectra,
which show a characteristic AB system of the methylene
protons at δ 3.59—3.71 (JAB = 17.7—17.9 Hz) (Table 1).
For compounds 4a and 4e, the higherꢀfield doublet of
the AB system for the cisꢀproton with respect to the RF
group (the proton that is cis to the hydroxy group is
deshielded more strongly27), splits into two quartets
(4JH,F = 1.1 Hz) and two triplets (4JH,F = 1.5 Hz), reꢀ
spectively.
Isoxazolines 4a—f are resistant to dehydration; they
were converted into 5ꢀRFꢀisoxazoles 5a—f in 59—93%
yields only by the reactions with SOCl2 in boiling toluꢀ
ene in the presence of pyridine for 5—10 min. The reacꢀ
tion duration should not be extended because of possible
side reactions at the aromatic ring. Attempts at dehyꢀ
drating compounds 4 both with conc. H2SO4 at ∼20 °C
for a day or at 70 °C for 0.5 h and with several drops of
conc. HCl in boiling acetic acid failed. Isoxazolines 4
were recovered upon the dilution of the reaction mixture
with ice water.
The reactions of hydroxylamine with 2ꢀpolyfluoroꢀ
alkylchromones 6a—f obtained by the dehydration of
chromanones 3a—f involve the C(2) atom rather than
the carbonyl group, as in the case of the latter. The
opening of the pyrone ring gives monooximes 7a—f
(Scheme 1). In these compounds, the oxime group is
adjacent to the electronꢀwithdrawing RF group, which
decreases the nucleophilicity of the oxime OH group
and stabilizes the open form 7. Earlier,24 it was shown
that aliphatic analogs of oximes 7 in the crystalline state
2
and in CDCl3 exist as 3ꢀtrifluoromethylꢀ∆ ꢀisoxazolines,
while in DMSOꢀd6 they exist as an equilibrium mixture
1
of the oxime and isoxazoline forms. The H NMR specꢀ
tra of aromatic oximes 7a—f in CDCl3 (see Table 1)
show only one set of signals corresponding to their
open form 7 (a singlet for the CH2 group appears at
δ 4.18—4.26), while the cyclic isoxazoline form 8 was
not detected, which is due to a lower reactivity of the
carbonyl group conjugated with the aromatic ring (see
Ref. 24). The existence of compounds 7a—f in the open
rather than cyclic form was also confirmed by the chemiꢀ
cal shifts of signals for the benzene protons in isomeric
compounds 4 and 7. Signals for the most strongly
deshielded H(4) and H(6) protons in oximes 7 are shifted
downfield by 0.14—0.16 and 0.58—0.63 ppm, respecꢀ
tively, compared to those for isoxazolines 4 (see Table 1).
RF
CF3
CF3
R
H
Me
H
RF
(CF2)2H
CF2H
R
Me
H
a
b
c
d
e
f
(CF2)2H
CF2H
Me
i. AcOH, HCl; ii. NH2OH•HCl, AcONa, EtOH, H2O;
iii. SOCl2, PhMe, Py
This can be associated with an anisotropic effect of the
C=O group in compounds 7. The chemical shifts of
signals for the H(3) and H(5) protons (whose shielding is

1272
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 7, July, 2002
V. Ya. Sosnovskikh et al.
1
Table 1. H NMR and IR spectra of isoxazolines 4a—f and monooximes 7a—f
Comꢀ
pound
1H NMR (CDCl3, δ, J/Hz)
IR,
ν/cm–1
CH3
CH2
3.71а,b
(J = 17.7,
∆δ = 0.17)
H(3)
H(4)
H(5)
H(6)
OH
RF
4а
4b
4c
4d
4e
4f
7.07 (dd,
Jo = 8.3,
Jm = 0.9)
7.39 (ddd,
Jo = 8.3, 7.3,
Jm = 1.6)
6.96 (ddd,
Jo = 7.8, 7.3, Jo = 7.8,
Jm = 0.9)
7.16 (dd,
3.9c br.s;
9.1d br.s
1580, 1610,
1625, 3350
Jm = 1.6)
6.93e (d,
Jm = 1.0)
2.29 s 3.70а
(J = 17.7,
6.96 (d,
Jo = 8.4)
7.18 (dd,
Jo = 8.4,
Jm = 1.6)
3.7c br.s;
9.07d s
1580, 1610,
1630, 3350
∆δ = 0.17)
3.70а
(J = 17.9,
∆δ = 0.34)
f
7.05 (dd,
Jo = 8.3,
Jm = 1.0)
7.37 (ddd,
Jo = 8.3, 7.3,
Jm = 1.6)
6.94 (ddd,
Jo = 7.8, 7.3, Jo = 7.8,
Jm = 1.0)
7.14 (dd,
6.15 (tt,
2J = 52.8,
3J = 5.6)
1570, 1605,
1625, 3345
Jm = 1.6)
6.91e (d,
Jm = 1.4)
2.29 s 3.69а
6.95 (d,
Jo = 8.4)
7.17 (dd,
Jo = 8.4,
Jm = 1.7)
3.91c s;
9.13d s
6.15 (tt,
2J = 52.8,
3J = 5.7)
1580, 1610,
1635, 1655,
3200, 3430
(J = 17.9,
∆δ = 0.35)
3.59a,g
(J = 17.7,
∆δ = 0.21)
7.06 (dd,
Jo = 8.4,
Jm = 1.0)
7.37 (ddd,
Jo = 8.4, 7.0,
Jm = 1.6)
6.95 (ddd,
Jo = 7.8, 7.0, Jo = 7.8,
Jm = 1.0)
7.16 (dd,
3.63c;
9.40d
5.95 (t,
1575, 1605,
2J = 54.9) 1620, 3350
Jm = 1.6)
6.95e s
2.30 s 3.59а
6.95 (d,
Jo = 8.4)
7.17 (dd,
Jo = 8.4,
Jm = 1.9)
3.50c s;
9.20d s
5.94 (t,
1580, 1610,
2J = 55.0) 1630, 3350
(J = 17.7,
∆δ = 0.21)
7а
7b
7c
7d
7e
7f
4.24 s
7.02 (dd,
Jo = 8.5,
Jm = 0.9)
7.53 (ddd,
Jo = 8.5, 7.2,
Jm = 1.5)
6.95 (ddd,
Jo = 8.1, 7.2, Jo = 8.1,
Jm = 0.9)
7.74 (dd,
8.51h s;
11.68d s
–70.8 si
1590, 1625,
1645, 1670,
3350
Jm = 1.5)
7.51e s
2.33 s 4.23 s
6.92 (d,
Jo = 8.5)
7.33 (dd,
Jo = 8.5,
Jm = 1.7)
8.81h s;
11.51d s
1575, 1615,
1635, 3280,
3390
4.26 s
2.33 s 4.25 s
4.20 s
7.02 (dd,
Jo = 8.5,
Jm = 1.0)
7.52 (ddd,
Jo = 8.5, 7.1,
Jm = 1.4)
6.95 (ddd,
Jo = 8.1, 7.1, Jo = 8.1,
Jm = 1.0)
7.75 (dd,
8.26h s;
11.70d s
6.17 (tt,
2J = 52.8,
3J = 5.1)
1580, 1635,
1665, 3200,
3450
Jm = 1.4)
7.52e (d,
Jm = 1.1)
6.92 (d,
Jo = 8.5)
7.33 (dd,
Jo = 8.5,
Jm = 2.0)
8.37h s;
11.53d s
6.17 (tt,
2J = 52.8,
3J = 5.1)
1595, 1620,
1640, 1670,
3320
7.02 (dd,
Jo = 8.5,
Jm = 1.0)
7.52 (ddd,
Jo = 8.5, 7.1,
Jm = 1.6)
6.95 (ddd,
Jo = 8.1, 7.1, Jo = 8.1,
Jm = 1.0)
7.79 (dd,
8.15h s;
11.78d s
6.22 (t,
2J = 54.5) 1645, 3200,
1585, 1620,
Jm = 1.6)
7.55e (d,
Jm = 1.2)
3400
2.33 s 4.18 s
6.92 (d,
Jo = 8.5)
7.33 (dd,
Jo = 8.5,
Jm = 2.0)
7.86h s;
11.59d s
6.22 (t,
2J = 54.5) 1645, 3180,
1590, 1625,
3470
a Center of the AB system.
b Each signal of the higherꢀfield part of the AB system is split into a quartet with JH,F = 1.1 Hz.
c A signal for the hemiketal OH proton in DMSOꢀd6 appears at δ 8—9.
d For the phenolic OH proton.
4
e The broadening of the signal is due to oꢀbenzyl splitting with JH(6),CH ≈ 0.5 Hz.
4
3
f Hemiketal and phenolic OH protons were not detected.
g Each signal of the higherꢀfield part of the AB system is split into a triplet with JH,F = 1.5 Hz.
4
h For the oxime OH proton.
i The 19F NMR spectrum with reference to CFCl3.
mainly determined by the effect of the 2ꢀhydroxy subꢀ
stituent) remain virtually the same; therefore, the pheꢀ
nolic OH group is not involved in the ringꢀchain tauꢀ
tomerism resulting in a chromanone structure of type 3.
It is worth noting that compounds 7a—f exist in CDCl3
as Eꢀisomers (7a: 19F NMR, δ: –70.8 (CF3)). According
to the literature data,28—30 a signal for this group in
trifluoromethylated oximes and hydrazones appears at
δ –64 to –66 for Zꢀisomers and at δ –67 to –71 for
Eꢀisomers.

3ꢀ(2ꢀHydroxyaryl)ꢀ5ꢀRFꢀisoxazoles
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 7, July, 2002
1273
Oximes 7a—f are dehydrated under milder condiꢀ
tions compared to isoxazolines 4a—f. Their cycloꢀ
dehydration in boiling acetic acid with a few drops of
conc. HCl gave 3ꢀRFꢀisoxazoles 9a—f in 86—98% yields
within 3—5 min. Unlike regioisomeric 5ꢀRFꢀisoxazoles
5a—f, the latter are highꢀmelting substances and insoluble
in most organic solvents.
signal for the trifluoromethyl group at
δ
–65.1
4
(d, JF,H = 0.9 Hz) and δ –64.4 (s), respectively. Earꢀ
lier,5,22 close values have been reported for 3ꢀphenylꢀ
and 3ꢀhexylꢀ5ꢀtrifluoromethylisoxazoles (δ –65.0) and
for 5ꢀhexylꢀ3ꢀtrifluoromethylisoxazole (δ –64.0),22 alꢀ
though the 5ꢀCF3ꢀisomers gave no doublet signals for
the CF3 group. In nonsubstituted 5ꢀtrifluoromethylꢀ
isoxazole, a signal for this group appears at δ –64.6 (dd,
Thus, the direction of the nucleophilic attack changes
in passing from chromanones 3 to chromones 6. This
makes it possible to obtain regioisomeric 5ꢀ and 3ꢀpolyꢀ
fluoroalkylisoxazoles 5 and 9. Note that chromanones
3a—c and chromones 6a—c regiospecifically react with
NH2OH•HCl to give products 4a—c and 7a—c, which
are converted into regioisomers 5a—c and 9a—c. Howꢀ
ever, the regioselectivity decreases when passing from
trifluoromethyl and tetrafluoroethyl derivatives to diꢀ
fluoromethylchromanones 3e,f and ꢀchromones 6e,f.
Thus the reactions of compounds 3e,f with NH2OH•HCl
afford products containing, along with isoxazolines 4e,f,
oximes 7e,f (2—3%) (1H NMR data). Chromone 6e yields
a mixture of compounds 7e and 4e in the 94 : 6 ratio,
while difluoromethylchromone 6f containing a donor
methyl group in position 6 proved to react even less
regioselectively, giving isoxazoline 4f (12%) along with
oxime 7f. The cyclization of compound 7d yielded a
mixture of isoxazole 9d and chromone 6d in the 7 : 3
ratio (1H NMR data); this outcome suggests that an
alternative reaction direction involving the phenolic
OH group and the C=N bond is more pronounced in
this case.
The high regioselectivity of the above reactions is
characteristic of only 2ꢀpolyfluoroalkylchromanones
and ꢀchromones since 2ꢀnonsubstituted chromones,31—33
2ꢀmethylchromones,32,34 and flavones35,36 react with hyꢀ
droxylamine ambiguously to give a complex mixture of
products usually including isomeric isoxazoles or one of
them. Nonfluorinated analogs of isoxazoles 5 and 9,
namely, 3ꢀ(2ꢀhydroxyaryl)ꢀ5ꢀmethylꢀ and 5ꢀ(2ꢀhydroxyꢀ
aryl)ꢀ3ꢀmethylisoxazoles, have been described previꢀ
ously.32,34,37
4JF,H(4)
≈
5JF,H(3) ≈ 1 Hz),10 while for disubstituted
5ꢀCF3ꢀisoxazoles a singlet was observed at δ –63.5 to
–64.4.12,38 Hence, the chemical shift of a signal for the
CF3 group provides no reliable criterion for the distincꢀ
tion between 5ꢀ and 3ꢀCF3ꢀisoxazoles. Whereas a signal
for this group in regioisomeric Nꢀsubstituted 5ꢀ and
3ꢀCF3ꢀpyrazoles appears at δ ∼–58 and ∼–62, respecꢀ
tively,39 which is used as an argument while proving the
structures of trifluoromethylated pyrazoles.40,41 The
4
constant JF,H = 0.8—1.0 Hz can be useful only for
4ꢀnonsubstituted isoxazoles. It should be kept in mind
that although the presence of a spinꢀspin coupling beꢀ
tween the H(4) proton and the polyfluoroalkyl F atoms
makes it possible to sufficiently strictly classify a comꢀ
pound among 5ꢀRFꢀisoxazoles, its absence does not yet
indicate that this compound is a 3ꢀRFꢀisoxazole.
1H NMR spectra. The H(4) proton of the isoxazole
ring gives a quartet (4JH,F = 0.9 and 0.7 Hz, respectively)
in the spectra of 5ꢀCF3ꢀisoxazoles 5a,b and a triplet
(4JH,F = 1.0 Hz) in the spectra of 5ꢀH(CF2)2ꢀisoxazoles
5c,d, whereas for 3ꢀRFꢀisoxazoles 9a—d its signal does
not split but appears as a singlet. The H(4) proton in
difluoromethylisoxazoles 5e,f and 9e,f manifests itself as
a singlet at any arrangement of the double bonds in the
ring (see Table 2); this is probably due to a decreased
population of rotamers in which the H(4) atom and the
fluorine atoms are spatially close. This is evidence in
favor of the spatial mechanism of 1H...19F spinꢀspin couꢀ
pling transfer. In the literature, the H(4) proton in both
5ꢀCF3ꢀ3ꢀPhꢀ5,11 and 3ꢀCF3ꢀ5ꢀPhꢀisoxazoles18 is reported
to give a singlet; however, we found that a signal for the
H(4) proton in 3ꢀphenylꢀ, 3ꢀstyrylꢀ, 3ꢀ(2ꢀthienyl)ꢀ, and
3ꢀtertꢀbutylꢀ5ꢀCF3ꢀisoxazoles is split into a quartet with
4JH,F = 0.8—0.9 Hz. A signal for this proton has
As a rule, the IR spectra of 5ꢀRFꢀisoxazoles 5 usually
contain two mediumꢀintensity absorption bands at
1590—1630 cm–1, while those of 3ꢀRFꢀisoxazoles 9 show
three absorption bands at 1580—1620 cm–1 (Table 2).
Obviously, these data preclude reliable assignment of the
compound under study to one or the other series. Unlike
the IR spectra of regioisomeric isoxazoles 5 and 9, their
1H, 19F, and 13C NMR spectra in CDCl3 have a number
of characteristic features, which enable one to easily disꢀ
tinguish between these compounds (Tables 2—4). In this
respect, for trifluoromethylated isoxazoles 19F NMR specꢀ
troscopy proved to be least informative, while 13C NMR
spectroscopy was most informative.
been described for nonsubstituted 5ꢀCF3ꢀisoxazole
3
(dq, JH,H
≈
4JH,F ≈ 1.0 Hz)10 and 3ꢀCF3ꢀisoxazole
(d, 3JH,H = 1.8 Hz)17. The constants 4JH,F = 0.7—1.0 Hz
found for 5ꢀRFꢀisoxazoles correlate well with the data
for trisubstituted alkenes with geminal alkoxy and
trifluoromethyl groups (4JH,F = 0.7—1.1 Hz, regardless
of the configuration of the double bond).42 It should also
be noted that the spectra of compounds 5a and 9a in
DMSOꢀd6 show a singlet for the H(4) proton.
The data in Table 3 indicate that a signal for the H(4)
proton in 3ꢀtrifluoromethylisoxazole is shielded more
strongly (∆δH(4) = 0.55 ppm) than the corresponding
signal for 5ꢀtrifluoromethylisoxazole. Apparently, this is
19F NMR spectra. The 19F NMR spectra of
5ꢀCF3ꢀisoxazole 5a and 3ꢀCF3ꢀisoxazole 9a show a

1274
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 7, July, 2002
V. Ya. Sosnovskikh et al.
1
Table 2. H NMR and IR spectra of 5ꢀRFꢀisoxazoles 5a—f and 3ꢀRFꢀisoxazoles 9a—f
Comꢀ
pound
1H NMR (CDCl3, δ, J/Hz)
IR,
ν/cm–1
CH3
=CH
H(3)
H(4)
H(5)
H(6)
OH
RF
5а
7.13 (q,
7.11 (ddd,
7.40 (ddd,
Jo = 8.4, 7.3,
Jm = 1.6)
7.01 (ddd,
Jo = 7.8, 7.3,
Jm = 1.1)
7.51 (ddd,
Jo = 7.8,
Jm = 1.6,
Jp = 0.3)
8.97 s
–65.1a (d,
1590, 1610,
4JH,F = 0.9) Jo = 8.4,
Jm = 1.1,
4JF,H = 0.9) 1625, 3190
Jp = 0.3)
5аb
5b
5c
5d
5е
5f
7.72 s
7.06 (dd,
Jo = 8.3,
Jm = 1.0)
7.39 (ddd,
Jo = 8.3, 7.3,
Jm = 1.7)
6.95 (ddd,
Jo = 7.8, 7.3,
Jm = 1.0)
7.75 (dd,
Jo = 7.8,
Jm = 1.7)
7.28c (d,
10.46 s
8.77 s
9.01 s
8.80 s
9.14 s
8.94 s
5.90 s
10.94 s
5.69 s
5.99 s
5.94 s
6.11 s
5.91 s
2.34 s 7.12 (q,
7.01 (d,
7.21 (dd,
Jo = 8.4,
Jm = 2.0)
1595, 1625,
3210
4JH,F = 0.7) Jo = 8.4)
Jm = 1.6)
7.11 (t,
4JH,F = 1.0) Jo = 8.3,
Jm = 1.1)
7.11 (dd,
7.40 (ddd,
Jo = 8.3, 7.3,
Jm = 1.6)
7.01 (ddd,
Jo = 7.8, 7.3,
Jm = 1.1)
7.51 (dd,
Jo = 7.8,
Jm = 1.6)
7.30c (d,
6.13 (tt,
1595, 1630,
3280
2J = 53.1,
3J = 2.8)
2.34 s 7.11 (t,
7.00 (d,
7.20 (dd,
Jo = 8.4,
Jm = 2.1)
6.12 (tt,
2J = 53.1,
3J = 2.8)
1595, 1635,
3300
4JH,F = 1.0) Jo = 8.4)
Jm = 2.1)
7.00 s
2.34 s 6.99 s
7.01 s
7.11 (dd,
Jo = 8.4,
Jm = 0.9)
7.39 (ddd,
Jo = 8.4, 7.1,
Jm = 1.5)
7.00 (ddd,
Jo = 7.8, 7.1,
Jm = 0.9)
7.51 (dd,
Jo = 7.8,
Jm = 1.5)
7.29c s
6.83 (t,
2J = 53.6)
1580, 1625,
3160, 3240
7.00 (d,
Jo = 8.3)
7.19 (dd,
Jo = 8.3,
Jm = 1.8)
6.82 (t,
2J = 53.6)
1590, 1630,
3140, 3250
9а
9аb
9b
9c
9d
9e
9f
6.95 (dd,
Jo = 8.2,
Jm = 1.0)
7.38 (ddd,
Jo = 8.2, 7.4,
Jm = 1.6)
7.08 (ddd,
Jo = 7.9, 7.4,
Jm = 1.0)
7.88 (dd,
Jo = 7.9,
Jm = 1.6)
–64.4a s
1580, 1600,
1620, 3230
7.30 s
7.09 (dd,
Jo = 8.3,
Jm = 1.0)
7.41 (ddd,
Jo = 8.3, 7.2,
Jm = 1.7)
7.00 (ddd,
Jo = 8.0, 7.2,
Jm = 1.0)
7.85 (dd,
Jo = 8.0,
Jm = 1.7)
7.67c (d,
2.35 s 6.99 s
7.00 s
6.84 (d,
Jo = 8.3)
7.17 (dd,
Jo = 8.3,
Jm = 1.9)
1580, 1605,
1625, 3210
Jm = 1.7)
6.95 (dd,
Jo = 8.2,
Jm = 1.0)
7.37 (ddd,
Jo = 8.2, 7.4,
Jm = 1.6)
7.16d (ddq,
Jo = 8.3,
7.07 (ddd,
Jo = 7.9, 7.4,
Jm = 1.0)
7.86 (dd,
Jo = 7.9,
Jm = 1.6)
7.64c (d,
6.18 (tt,
2J = 53.1,
3J = 4.0)
1575, 1605,
1625, 3200,
3440
2.35 s 6.99 s
6.96 s
6.85 (d,
Jo = 8.3)
6.17 (tt,
2J = 53.1,
3J = 4.0)
1585, 1615,
1630, 3240
Jm = 1.5)
Jm = 2.1)
6.96 (dd,
Jo = 8.2,
Jm = 0.9)
7.36 (ddd,
Jo = 8.2, 7.4,
Jm = 1.6)
7.15e (ddq,
Jo = 8.3,
7.06 (ddd,
Jo = 7.9, 7.4,
Jm = 0.9)
7.83 (dd,
Jo = 7.9,
Jm = 1.6)
7.61c (d,
6.82 (t,
2J = 53.8)
1580, 1620,
3190
2.34 s 6.93 s
6.85 (d,
Jo = 8.3)
6.82 (t,
2J = 53.8)
1580, 1600,
1625, 3230,
3550
Jm = 1.5)
Jm = 2.2)
a The 19F NMR spectrum with reference to CFCl3.
b In DMSOꢀd6.
4
c The broadening of the signal is due to oꢀbenzyl splitting with JH(6),CH ≈ 0.5 Hz.
3
d 4
J
J
= 0.5 Hz.
H(4),CH
3 = 0.6 Hz.
e 4
H(4),CH
3

3ꢀ(2ꢀHydroxyaryl)ꢀ5ꢀRFꢀisoxazoles
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 7, July, 2002
1275
of the other 5(3)ꢀRFꢀisoxazoles (∆δH(4) = 0.11—0.12 ppm
for RF = (CF2)2H and ∆δH(4) = 0.14—0.16 ppm for
RF = CF2H). Because of this, δH(4) cannot be regarded
as a reliable criterion for identification of a regioisomer
belonging to the (oꢀhydroxyaryl)isoxazole series if only
one is present. However, if both regioisomers are availꢀ
able, then the lowerꢀfield signal will most probably be
related to 5ꢀRFꢀisoxazole. This rule is also true for
solutions in DMSOꢀd6; for compounds 5a and 9a,
∆δH(4) = 0.42 ppm (see Table 2). Earlier,43 it has been
found that a signal for the H(4) proton is shifted downfield
by 0.23—0.46 ppm when passing from 1ꢀRꢀ3ꢀCF3ꢀ to
1ꢀRꢀ5ꢀCF3ꢀpyrazoles.
Table 3. Chemical shifts of the signal for the H(4) proton in
3ꢀRꢀ5ꢀCF3ꢀ and 5ꢀRꢀ3ꢀCF3ꢀisoxazoles in CDCl3
R
δ
4JH,F/Hz Reference
R
δ
Reference
H(4)
H(4)
H
6.65 dq
6.98 s
7.00 q
7.13 q
∼1.0
10
11
b
H
6.10 d
17
18
Ph
Ph
5а
Ph 6.67а s
0.9
0.9
b
b
9а 7.01 s
a In CCl4.
b This study.
In CDCl3, the phenolic proton in isoxazoles 9a—f
gives a singlet at δ 5.7—6.1, which disappears immediꢀ
ately upon the addition of CD3CO2D. In the spectra of
compounds 5a—f, an analogous signal is significantly
shifted downfield (δ 8.8—9.1), and this proton slowly
exchanges for deuterium with CD3CO2D, indicating its
involvement in intramolecular hydrogen bonding via the
N atom of the isoxazole ring. Based on these data, one
can conclude that the O—H...N= hydrogen bond occurꢀ
ring in 5ꢀRFꢀisoxazoles 5 is stronger than the O—H...O
bond in 3ꢀRFꢀisoxazoles 9. Thus, the chemical shift of a
signal for the phenolic proton is quite indicative in CDCl3
and can be useful while determining the structures of
regioisomeric (oꢀhydroxyaryl)isoxazoles.
partially due to the electronꢀwithdrawing effect of the CF3
group, which is more pronounced in the 5ꢀCF3ꢀisomer
containing an adjacent double bond. As expected, in the
spectra of 5(3)ꢀphenylꢀ3(5)ꢀCF3ꢀisoxazoles, this signal
is shifted downfield since the H(4) proton is deshielded
by the benzene ring, especially in the 3ꢀCF3ꢀisomer,
which reduces ∆δH(4) to 0.33 ppm. When the phenyl
substituent contains an oꢀhydroxy group (compounds 5a
and 9a), the rings are conjugated more efficiently through
an intramolecular hydrogen bond, which will hinder the
rotation about the C(1´)—C(3/5) bond and thus stabiꢀ
lize the coplanar conformer. As a result, the H(4) proꢀ
tons in regioisomeric isoxazoles 5 and 9 are deshielded to a
larger extent; again, this effect is more pronounced for the
3ꢀCF3ꢀisomer, and ∆δH(4) is reduced to 0.12—0.13 ppm
for 5a,b and 9a,b. An analogous pattern is characteristic
The aromatic protons in isomeric isoxazoles also
manifest themselves differently. A signal for the H(6)
proton in compounds 9a—f is shifted downfield by
Table 4. 13C NMR spectra of isoxazoles 5a and 9a (δ, J/Hz)
Comꢀ C(3)
pound
C(4)
C(5)
CF3
C(1´)
C(2´)
C(3´)
C(4´)
C(5´)
C(6´)
5aа 162.5 (t,
103.3 (dq,
158.3 (qd, 117.8 (qd, 111.8 (dd, 156.6 118.0 (dd, 132.8 (ddd, 120.2 (ddd, 128.0 (ddd,
3JH
2JH
=
=
= 4.5)
1JH = 187.0, 2JF = 42.9, 1JF
=
3JH ≈ 7.6, (tm, 1JH = 161.0, 1JH = 160.0, 1JH = 163.3, 1JH = 157.6,
3JF = 2.1)
2JH = 8.5) 270.7,
3JH ≈ 6.0) 3JH
≈
3JН = 6.5) 3JH = 8.8,
2JH = 1.4)
3JH = 8.1,
2JH = 0.8)
3JH = 8.7,
2JH = 1.4)
3JH = 0.5)
8.0)
9ab 156.1 (q,
2J = 38.0)
100.0
169.1
119.9 (q,
1J = 271.1)
113.4
153.1 116.9
132.4
121.5
127.9
9ac 155.1 (qd, 99.9 (dd,
2JF = 37.1, 1JH = 191.7, 3JH = 8.7, 1JF
2JH = 5.4) 4JН = 1.1) 2JH = 4.5, 271.0)
4JH = 2.0)
169.3 (ddd, 119.8 (q,
112.4
(br.s)
155.2 116.6 (dd, 132.7 (ddd, 119.6 (dd,
127.0 (ddd,
=
(t,
1JH = 160.4, 1JH = 160.4, 1JH = 163.5, 1JH = 161.0,
3JH
8.9)
≈
3JН = 7.7) 3JH = 8.9,
2JH = 1.7)
3JH = 7.8)
3JH = 8.5,
2JH = 2.0)
a In CDCl3.
b In CDCl3 with proton decoupling (9a is insoluble in CDCl3).
c In DMSOꢀd6.

1276
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 7, July, 2002
V. Ya. Sosnovskikh et al.
0.32—0.39 ppm compared to its position in the spectra
of 5a—f, while a signal for the H(3) proton is shifted
upfield by 0.15—0.17 ppm. However, when CDCl3 is
replaced by DMSOꢀd6, the chemical shifts of the aroꢀ
matic protons in, e.g., regioisomeric compounds 9a and
5a become virtually identical (∆δ = 0.02—0.10 ppm).
The same relates to signals for the phenolic proton,
which forms intermolecular hydrogen bonds with polar
DMSOꢀd6 molecules (δ 10.94 for 9a and δ 10.46 for 5a).
Thus, the above signals are useless while distinguishing
between these regioisomers. If one takes into account
that the isoxazole proton in both isomers gives a singlet
while recording their spectra in this solvent, then δH(4) is
the sole criterion for their identification (δH(4) 7.30 for
9a and δH(4) 7.72 for 5a) (see Table 2).
crease, but the overlap of the above ranges makes this
constant a less valuable criterion for the distinction beꢀ
tween regioisomeric trifluoromethylpyrazoles. It is also
noteworthy that a signal for the C(4) atom in isoxazole
9a appears as a singlet at δ 100.0, while the correspondꢀ
ing signal in the 13C NMR spectrum of compound 5a is
3
a quartet (δ 103.3, JC,F = 2.1 Hz). Such a coupling
constant is obviously lower than those for other comꢀ
pounds with the cisꢀH—C=C—CF3 fragment (alkenes
and sixꢀmembered nitrogenꢀ and oxygenꢀcontaining hetꢀ
3
erocycles, JC,F = 2.8—7.1 Hz)42,46 and lies in the range
3
characteristic of the transꢀfragment (alkenes, JC,F
=
1.5—3.3 Hz).42,46
The 13C NMR spectra recorded without proton
decoupling and the literature data for similar sysꢀ
tems11,47,48 (with consideration of the constants JC,H
n
Regioisomeric isoxazoles 5c,d and 9c,d containing
the (CF2)2H group can be easily distinguished by the
(n = 1—4)) were used to assign signals for the benzene C
atoms and the isoxazole carbon atom having no C—F
coupling. While comparing the chemical shifts of signals
for the C(3)—C(5) atoms in 3,5ꢀdiphenylisoxazole
(δC(3) 162.2, δC(4) 98.3, and δC(5) 169.3),47 3ꢀphenylꢀ5ꢀ
trifluoromethylisoxazole (δC(3) 162.7, δC(4) 103.5, and
δC(5) 159.4),5,11,49 and compounds 5a and 9a (see
Table 4), one can note that the C(5) atom bearing a
trifluoromethyl group instead of the phenyl group is
shielded by ∼10 ppm, while the C(4) atom becomes
deshielded by ∼5 ppm. An analogous replacement at the
C(3) atom causes shielding of this atom by ∼6 ppm and
deshielding of the C(4) atom by ∼2 ppm. The direct
3
coupling constants JH,F = 2.8 and 4.0 Hz for 5c,d and
9c,d, respectively (the chemical shifts of signals for the
tetrafluoroethyl proton differ only by 0.05 ppm). Note
that 3JH,F of isoxazoles 5c,d is exactly half as high as that
of isoxazolines 4c,d (5.6 versus 2.8 Hz), while the
cyclodehydration of oximes 7 into isoxazoles 9 decreases
its value from 5.1 to 4.0 Hz. The 3JH,F values determined
for the isoxazole systems supplement the data reported
3
in Ref. 44 (in this paper, variations in the constant JH,F
of the (CF2)2H group with the nearest environment of
its adjacent carbon atom have been analyzed and some
generalization made).
13C NMR spectra. In the protonꢀdecoupled 13C NMR
spectra of isoxazoles 5a and 9a (see Table 4), the couꢀ
pling constants nJC,F (n = 1—3) are of primary note. The
constant JC(4),H (191.7 Hz for 9a) is indicative of an
1
increased electron deficiency of the isoxazole ring conꢀ
taining the trifluoromethyl group.50 Note a decrease in
1
2
direct constants JC,F for compounds 5a and 9a are alꢀ
2JC,H (along with JC,F) from 8.5 to 5.4 Hz for the same
most the same (270.7 and 271.1 Hz, respectively), while
the constant JC,F decreases from 42.9 to 38.0 Hz in
carbon atom in compound 9a compared to 5a. In addiꢀ
tion, unlike a quartet for the trifluoromethyl C atom in
isoxazole 9a, the corresponding signal for compound 5a
appears as a quartet of doublets due to additional splitꢀ
2
passing from 5a to 9a, which is probably characteristic of
regioisomeric 5ꢀ and 3ꢀCF3ꢀisoxazoles and can be of
diagnostic interest for their 13C NMR identification. Inꢀ
3
ting at the vicinal hydrogen atom with JC,H = 0.5 Hz.
2
deed, JC,F = 42.1 Hz in 3ꢀphenylꢀ5ꢀtrifluoromethylꢀ
Earlier,46 it has been reported that compounds with the
isoxazole,11 while for various disubstituted 5ꢀ and
3ꢀCF3ꢀisoxazoles, this constant has been reported to be
40—45 and 36—39 Hz, respectively.12,21,23,38 Moreover,
cisꢀH atom relative to the CF3 group have JC,H
=
3
1.8—8.0 Hz.
Thus, we developed the new method for the synthesis
of regioisomeric fluorineꢀcontaining isoxazoles from
2ꢀhydroxyacetophenones and polyfluorocarboxylates. The
structures of the compounds obtained were determined
2
a similar decrease in JC,F has been noted earlier for
Nꢀsubstituted 5(3)ꢀCF3ꢀpyrazoles. For example, for the
C(5) and C(3) atoms in 3,5ꢀbis(trifluoromethyl)ꢀ1ꢀ(4ꢀ
2
1
methylquinolinꢀ2ꢀyl)pyrazole the JC,F values are 42.9
by H, 19F, and 13C NMR spectroscopy. Analysis of the
and 38.6 Hz, respectively.39 However, the constant 2JC,F
in this series of pyrazoles more strongly depends on the
nature of substituents, and the C(5) and C(3) atoms
in, e.g., 3,5ꢀbis(trifluoromethyl)ꢀ1ꢀ(4ꢀnitrophenyl)pyrꢀ
azole are characterized by the same value (40.0 Hz).41
essential NMR features of 5ꢀ and 3ꢀRFꢀisoxazoles showed
that these regioisomers can be most reliably distinguished
using 13C NMR spectroscopy. In particular, the conꢀ
stant 2JC,F is of diagnostic value for structure determinaꢀ
tion of trifluoromethylated isoxazoles. The 3(5)ꢀarylꢀ5(3)ꢀ
polyfluoroalkylisoxazoles obtained are of interest both as
compounds with potential biological activity and as startꢀ
ing reagents for construction of more complex heterocyꢀ
clic systems with fluorinated substituents.
2
On the whole, the constant JC,F for Nꢀsubstituted
5ꢀCF3ꢀpyrazoles ranges from 38 to 43 Hz,12,38,39,45 while
that for 3ꢀCF3ꢀpyrazoles is known to vary from 36 to
40 Hz.21,38,39,45 Hence, this constant still tends to deꢀ

3ꢀ(2ꢀHydroxyaryl)ꢀ5ꢀRFꢀisoxazoles
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 7, July, 2002
1277
1
known procedures.5,54 The H, 19F, and 13C NMR data and IR
spectra of compounds 4a—f and 7a—f are given in Table 1;
those for compounds 5a—f and 9a—f are presented in Tables 2
and 4. The 1H NMR data and IR spectra of chromanones 3c—f
and chromones 6c,d,f are given in Table 5. The yields, melting
points, and elemental analysis data of the compounds obtained
are summarized in Table 6. The yields are given for nonꢀ
recrystallized products since their melting points remained virꢀ
tually unchanged upon recrystallization.
Experimental
IR spectra were recorded on an IKSꢀ29 instrument (Vaseline
oil). 1H and 13C NMR spectra were recorded on a Bruker
DRXꢀ400 spectrometer (400.13 and 100.62 MHz, respectively)
in CDCl3 with Me4Si as the internal standard. 19F NMR specꢀ
tra were recorded on a Tesla BSꢀ587A instrument (75.3 MHz)
with CFCl3 as the internal standard. The 1H NMR spectra of
the starting compounds 3c—f and 6c,d,f were recorded on Bruker
WMꢀ250 and Tesla BSꢀ587A instruments (250 and 100 MHz,
respectively).
Compounds 3a,b and 6a,b,e have been characterized earꢀ
lier.25,51,52 Chromanones 3c—f and chromones 6c,d,f were obꢀ
tained as described in Ref. 53, while 3ꢀphenyl(styryl, 2ꢀthienyl,
or tertꢀbutyl)ꢀ5ꢀtrifluoromethylisoxazoles were prepared by the
5ꢀHydroxyꢀ3ꢀ(2ꢀhydroxyaryl)ꢀ5ꢀRFꢀ∆ ꢀisoxazolines (4a—f)
2
and 1ꢀ(2ꢀhydroxyaryl)ꢀ3ꢀRFꢀpropaneꢀ1,3ꢀdione 3ꢀoximes (7a—f)
(general procedure). Chromanone 3 or chromone 6 (2 mmol),
hydroxylamine hydrochloride (4 mmol), and sodium acetate
(6 mmol) were dissolved with heating in 5 mL of aqueous
ethanol (water : ethanol = 1 : 1). The resulting solution was
refluxed for 1 h, cooled, and diluted with water. The crystalline
1
Table 5. H NMR and IR spectra of chromanones 3c—f and chromones 6c,d,f
Comꢀ
pound
1H NMR (CDCl3, δ, J/Hz)
IR,
ν/cm–1
CH3
CH2
3.09c
(J = 16.7,
∆δ = 0.15)
=CH
H(5)
H(6)
H(7)
H(8)
OH
RF
3cа,b
3dd,е
3ea
7.89 (dd,
Jo = 7.6,
Jm = 1.5)
7.13 (t,
Jo = 7.3)
7.56 (ddd,
Jo = 8.3, 7.0, Jo = 8.3)
Jm = 1.5)
7.02 (d,
4.00 s
6.27 (tt,
2J = 52.7,
3J = 5.9)
1585, 1610,
1680, 3220
2.30 s 3.04c
(J = 16.9,
7.64f (d,
Jm = 1.6)
7.35f (dd,
Jo = 8.4,
Jm = 1.6)
6.90 (d,
Jo = 8.4)
4.36
(br.s)
6.25 (tt,
2J = 52.7,
3J = 5.9)
1585, 1620,
1670, 3300
∆δ = 0.15)
2.96c,
J = 16.8,
∆δ = 0.08)
7.86 (dd,
Jo = 7.9,
Jm = 1.7)
7.08 (t,
Jo = 7.5)
7.54 (ddd,
Jo = 8.6, 7.0, Jo = 8.6)
Jm = 1.7)
7.02 (d,
4.15 s
3.95 s
5.85 (t,
1580, 1610,
2J = 55.0) 1685, 3340
3f d,g
6cd,h
6dd
2.30 s 2.94 s
7.65f (d,
Jm = 1.6)
7.35f (dd,
Jo = 8.4,
Jm = 2.1)
6.91 (d,
Jo = 8.4)
5.83 (t,
1580, 1620,
2J = 55.0) 1675, 3200,
3330
6.71 s
6.69 s
6.55 s
8.19 (dd,
Jo = 7.8,
Jm = 1.8) Jm = 0.9)
7.45 (ddd,
Jo = 7.6,
7.74 (ddd,
Jo = 7.8,
Jm = 1.8)
7.51 (dd,
Jo = 8.2,
Jm = 0.9)
6.15 (tt,
2J = 52.9,
3J = 3.6)
1615, 1645,
1660
2.45 s
2.43 s
7.96 br.s
7.54 (dd,
Jo = 8.5,
Jm = 2.1)
7.38 (d,
Jo = 8.5)
6.14 (tt,
2J = 53.0,
3J = 3.8)
1620, 1640,
1660
6f d
7.93 br.s
7.51 (dd,
Jo = 8.6,
Jm = 2.0)
7.35 (d,
Jo = 8.6)
6.43 (t,
1615, 1640,
2J = 53.8) 1665, 3110
a For an operating frequency of 250 MHz.
1
b According to the H and 19F NMR data, this compound exists as a mixture of 3c (88%) and 1c (12%). For 1c: 1H NMR, δ: 6.10
2
3
(tt, 1 H, CF2CF2H, JH,F = 52.8 Hz, JH,F = 5.0 Hz); 6.73 (s, 1 H, =CH); 6.96 (t, 1 H, H(5), Jo = 7.8 Hz); 7.72 (d, 1 H, H(6),
Jo = 7.8 Hz); 11.57 (s, 1 H, OH phenol); 14.36 (br.s, 1 H, OH enol); signals for the H(3) and H(4) protons coincide with those for
2
3
the H(6) and H(7) protons of the cyclic form 3c. 19F NMR (CFCl3), δ: –139.0 (dt, 2 F, CF2H, JF,H = 52.7 Hz, JF,F = 7.1 Hz);
3
3
–126.6 (dt, 2 F, CF2, JF,F = 7.1 Hz, JF,H = 4.9 Hz).
c Center of the AB system.
d For a operating frequency of 100 MHz.
e According to the 19F NMR data, the compound exists as a mixture of 3d (92%) and 1d (8%). For 1d: 19F NMR (CFCl3), δ: –138.9
(dt, 2 F, CF2H, JF,H = 52.8 Hz, JF,F = 7.1 Hz); –126.4 (dt, 2 F, CF2, JF,F = 7.1 Hz, JF,H = 4.9 Hz).
2
3
3
3
4
f The broadening of the signal is due to oꢀbenzyl splitting with JH(6),CH ≈ 0.5 Hz.
3
g 19F NMR (CFCl3), δ: –135.8 (the AB part of the ABX system, 2 F, CF2H, JF,F = 287.4 Hz, JF,H = 54.9 Hz).
h 19F NMR (CFCl3), δ: –136.9 (dt, 2 F, CF2H, JF,H = 53.0 Hz, JF,F = 5.4 Hz); –122.9 (dt, 2 F, CF2, JF,F = 5.4 Hz,
2
2
2
3
3
3JF,H = 3.4 Hz).

1278
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 7, July, 2002
V. Ya. Sosnovskikh et al.
Table 6. Main physicochemical characteristics of compounds 3c—f, 4a—f, 5a—f, 6c,d,f, 7a—f, and 9a—c,e,f
Comꢀ Yield
pound (%)
M.p.
/°C
Molecular
formula
Found
Calculated
Comꢀ Yield
pound (%)
M.p.
/°C
Molecular
formula
Found
Calculated
(%)
(%)
С
Н
N
С
Н
N
3c
3d
3e
3f
70
68
84
48
90
94
90
96
75
83
65
59
85
93
72
117—118 C11H8F4O3
113—114 C12H10F4O3
123—124 C10H8F2O3
126—127 C11H10F2O3
50.08 3.34
50.01 3.05
51.67 3.73
51.81 3.62
56.16 3.64
56.08 3.77
57.77 4.39
57.90 4.42
—
—
—
—
5f
82
91
94
90
87
91
92
31
67
90
92
62—63
C11H9F2NO2 58.55 4.05 5.93
58.67 4.03 6.22
6c
6d
6f
100—101 C11H6F4O2
53.55 2.52
53.67 2.46
55.37 3.03
55.40 3.10
62.76 3.90
62.86 3.84
—
—
—
95—96
95—96
C12H8F4O2
C11H8F2O2
a
7a
7b
7c
7d
7ed
7fe
9a
9b
9c
9e
9f
118—119 C10H8F3NO3 48.54 3.27 5.84
48.59 3.26 5.67
142—143 C11H10F3NO3 50.79 3.71 5.22
50.58 3.86 5.36
4a
4bb
4c
4d
4e
4f
122—123 C10H8F3NO3 48.54 3.42
48.59 3.26
141—142 C11H10F3NO3 50.48 3.70
50.58 3.86
—
—
c
93—94
C11H9F4NO3 47.02 3.08 4.96
47.32 3.25 5.02
89—90
C11H9F4NO3 47.28 2.99 4.92
47.32 3.25 5.02
C12H11F4NO3 48.89 3.57 4.51
49.16 3.78 4.78
102—103 C12H11F4NO3 49.15 3.58 4.65
49.16 3.78 4.78
109—112 C10H9F2NO3 52.61 4.13 6.37
52.41 3.96 6.11
132—135 C11H11F2NO3 54.31 4.49 6.05
54.32 4.56 5.76
213—215 C10H6F3NO2 52.42 2.66 6.26
52.41 2.64 6.11
85—86
126—127 C10H9F2NO3 52.27 4.04 6.20
52.41 3.96 6.11
151—152 C11H11F2NO3 54.24 4.60 5.72
54.32 4.56 5.76
5a
5b
5c
5d
5e
98—99
84—85
48—49
60—61
73—74
C10H6F3NO2 52.35 2.72 6.03
52.41 2.64 6.11
C11H8F3NO2 54.44 3.42 5.69
54.33 3.32 5.76
C11H7F4NO2 50.58 2.66 5.49
50.59 2.70 5.36
C12H9F4NO2 52.45 3.14 5.19
52.37 3.30 5.09
97 subl. >210 C11H8F3NO2 54.59 3.51 5.92
54.33 3.32 5.76
91
86
86
161—163 C11H7F4NO2 50.56 2.60 5.48
50.59 2.70 5.36
173—176 C10H7F2NO2 57.05 3.26 6.50
56.88 3.34 6.63
162—164 C11H9F2NO2 58.64 4.25 6.45
58.67 4.03 6.22
C10H7F2NO2 56.77 3.27 6.48
56.88 3.34 6.63
a Found (%): F, 22.86. Calculated (%): F, 23.06.
b Ref. 25: m.p. 140 °C.
c Found (%): F, 21.96. Calculated (%): F, 21.82.
d The content of isoxazoline 4e in oxime 7e is 6%.
e The content of isoxazoline 4f in oxime 7f is 12%.
product (in some cases, gradually solidifying oil) that formed
was filtered off, washed with water, dried, and recrystallized
from hexane—chloroform for isoxazolines 4 and from ethaꢀ
nol—water (2 : 1) for oximes 7.
3ꢀ(2ꢀHydroxyaryl)ꢀ5ꢀRFꢀisoxazoles (5a—f) (general proceꢀ
dure). Isoxazoline 4 (4 mmol) was dissolved with slight heating
in 3 mL of toluene. Then two drops of pyridine and thionyl
chloride (0.6 mL, 1.0 g, 8.1 mmol) were added. The reaction
mixture was refluxed for 5—10 min. All volatile substances
were removed in vacuo (waterꢀjet pump), and the solid residue
was recrystallized from hexane with a small amount of chloꢀ
roform.
3—5 min, cooled, and diluted with water. The precipitate that
formed was filtered off and dried.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 99ꢀ03ꢀ32960)
and in part by the US Civilian Research and Developꢀ
ment Foundation (CRDF, Grant RECꢀ005).
References
5ꢀ(2ꢀHydroxyaryl)ꢀ3ꢀRFꢀisoxazoles (9a—f) (general proceꢀ
dure). Three to five drops of conc. HCl were added to 2 mL of
glacial acetic acid. Oxime 7 (0.8 mmol) was dissolved in the
resulting mixture. The reaction mixture was refluxed for
1. V. Ya. Sosnovskikh, I. I. Vorontsov, and V. A. Kutsenko,
Izv. Akad. Nauk, Ser. Khim., 2001, 1360 [Russ. Chem. Bull.,
Int. Ed., 2001, 50, 1430].
2. P. Lin and J. Jiang, Tetrahedron, 2000, 56, 3635.

3ꢀ(2ꢀHydroxyaryl)ꢀ5ꢀRFꢀisoxazoles
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 7, July, 2002
1279
3. Organofluorine Compounds in Medicinal Chemistry and Bioꢀ
medical Applications, Eds. R. Filler, Y. Kobayashi, and L. M.
Yagupolskii, Elsevier, Amsterdam, 1993.
4. P. KrogsgaardꢀLarsen, Med. Res. Rev., 1988, 8, 27.
5. C. P. Filix, N. Khatimi, and A. J. Laurent, J. Org. Chem.,
1995, 60, 3907.
32. W. Basiñski and Z. Jerzmanowska, Pol. J. Chem., 1979,
53, 229.
33. V. Szabó, J. Borbély, E. Theisz, and S. Nagy, Tetrahedron,
1986, 42, 4215.
34. W. Basiñski and Z. Jerzmanowska, Rocz. Chem., 1974,
48, 989.
6. A. A. Akhrem, F. A. Lakhvich, and V. A. Khripach, Khim.
Geterotsikl. Soedin., 1981, 1155 [Chem. Heterocycl. Compd.,
1981 (Engl. Transl.)].
7. C. Massyn and A. Cambon, J. Fluorine Chem., 1975, 5, 67.
8. A. Colla, M. A. P. Martins, G. Clar, S. Krimmer, and
P. Fischer, Synthesis, 1991, 483.
9. M. A. P. Martins, A. F. C. Flores, R. A. Freitag, and
N. Zanatta, J. Heterocycl. Chem., 1996, 33, 1223.
10. I. I. Gerus, M. G. Gorbunova, S. I. Vdovenko, Yu. L.
Yagupol´skii, and V. P. Kukhar´, Zh. Org. Khim., 1990, 26,
1877 [J. Org. Chem. USSR, 1990, 26 (Engl. Transl.)].
11. X.ꢀQ. Tang, and C.ꢀM. Hu, J. Fluorine Chem., 1995, 73, 133.
12. P. Bravo, D. Diliddo, and G. Resnati, Tetrahedron, 1994,
50, 8827.
13. E. S. Turbanova, N. P. Stepanova, V. B. Lebedev, V. A.
Galishev, and A. A. Petrov, Zh. Org. Khim., 1983, 19, 221
[J. Org. Chem. USSR, 1983, 19 (Engl. Transl.)].
14. G. Meazza, L. Capuzzi, and P. Piccardi, Synthesis,
1989, 331.
35. W. Basiñski and Z. Jerzmanowska, Rocz. Chem., 1976,
50, 1067.
36. C. Morin and R. Beugelmans, Tetrahedron, 1977, 33, 3183.
37. W. Basiñski and Z. Jerzmanowska, Rocz. Chem., 1974,
48, 2217.
38. D. V. Sevenard, Ph. D. Thesis, University of Bremen,
2000, 258 p.
39. S. P. Singh, J. K. Kapoor, D. Kumar, and M. D. Threadgill,
J. Fluorine Chem., 1997, 83, 73.
40. S. P. Singh and D. Kumar, J. Chem. Res. (S), 1997, 142.
41. S. P. Singh, D. Kumar, B. G. Jones, and M. D. Threadgill,
J. Fluorine Chem., 1999, 94, 199.
42. J.ꢀP. Bégué, D. BonnetꢀDelpon, D. Mesureur, and
M. Ourévitch, Magn. Reson. Chem., 1991, 29, 675.
43. S. P. Singh, D. Kumar, and J. K. Kapoor, J. Chem. Res. (S),
1993, 163.
44. V. Ya. Sosnovskikh, Izv. Akad. Nauk, Ser. Khim., 2001,
1166 [Russ. Chem. Bull., Int. Ed., 2001, 50, 1223].
45. A. B. Denisova, T. V. Glukhareva, G. P. Andronnikova,
V. S. Mokrushin, W. Dehaen, I. Luyten, V. Y. Sosnovskikh,
L. van Meervelt, and V. A. Bakulev, J. Chem. Res. (S),
2001, 12.
15. Y. Shen, J. Zheng, and Y. Huang, Synthesis, 1985, 970.
16. N. Naji, M. Soufiaoui, and P. Moreau, J. Fluorine Chem.,
1996, 79, 179.
17. D. P. Del´tsova, E. S. Ananyan, and N. P. Gambaryan,
Izv. Akad. Nauk SSSR, Ser. Khim., 1971, 362 [Bull. Acad.
Sci. USSR, Div. Chem. Sci., 1971, 20 (Engl. Transl.)].
18. K. Tanaka, H. Masuda, and K. Mitsuhashi, Bull. Chem.
Soc. Jpn., 1984, 57, 2184.
19. K. Tanaka, M. Kishida, S. Maeno, and K. Mitsuhashi,
Bull. Chem. Soc. Jpn., 1986, 59, 2631.
20. J. N. Kim and E. K. Ryu, Heterocycles, 1990, 31, 663.
21. K. Tanaka, T. Suzuki, S. Maeno, and K. Mitsuhashi, Bull.
Chem. Soc. Jpn., 1987, 60, 4480.
46. M. Guillaume, C. Maliverney, J.ꢀP. Declercq, and
B. Tinant, Magn. Reson. Chem., 1996, 34, 960.
47. A. L. Baumstark, D. R. Chrisope, R. A. Keel, and D. W.
Boykin, J. Heterocycl. Chem., 1980, 17, 1719.
48. J. Catalán, F. Fabero, R. M. Claramunt, M. D. Santa
Maria, M. C. FocesꢀFoces, F. H. Cano, M. Martinezꢀ
Ripoll, J. Elguero, and R. Sastre, J. Am. Chem. Soc., 1992,
114, 5039.
49. M. A. P. Martins, R. Freitag, and N. Zanatta, Spectrosc.
Lett., 1994, 27, 1227.
22. R. J. Linderman and K. S. Kirollos, Tetrahedron Lett., 1989,
30, 2049.
50. A. de la Hoz, M. C. Pardo, J. Elguero, and A. Fruchier,
Magn. Reson. Chem., 1989, 27, 603.
23. A. Umada, T. Okano, and S. Eguchi, Synthesis, 1994, 1457.
24. V. Ya. Sosnovskikh, M. Yu. Mel´nikov, and S. A. Pogozhikh,
Izv. Akad. Nauk, Ser. Khim., 1999, 1334 [Russ. Chem. Bull.,
1999, 48, 1323 (Engl. Transl.)].
25. W. B. Whalley, J. Chem. Soc., 1951, 3235.
26. E. Morera and G. Ortar, Tetrahedron Lett., 1981, 22, 1273.
27. R. Escale, F. Petrus, and J. Verducci, Bull. Soc. Chim. Fr.,
1974, 725.
51. V. Ya. Sosnovskikh and I. S. Ovsyannikov, Zh. Org. Khim.,
1993, 29, 89 [Russ. J. Org. Chem., 1993, 29, 74 (Engl.
Transl.)].
52. K. Tamura, T. Ishihara, and H. Yamanaka, J. Fluorine
Chem., 1994, 68, 25.
53. V. Ya. Sosnovskikh and B. I. Usachev, Izv. Akad. Nauk,
Ser. Khim., 2001, 434 [Russ. Chem. Bull., Int. Ed., 2001,
50, 453].
28. J.ꢀP. Bouillon, A.ꢀM. FrisqueꢀHesbain, Z. Janousek, and
H. G. Viehe, Heterocycles, 1995, 40, 661.
54. J. C. Reid and M. Calvin, J. Am. Chem. Soc., 1950, 72, 2948.
29. F. J. Weigert, J. Org. Chem., 1972, 37, 1314.
30. G. Shi and Y. Xu, J. Fluorine Chem., 1989, 44, 161.
31. R. Beugelmans and C. Morin, J. Org. Chem., 1977, 42, 1356.
Received August 9, 2001;
in revised form March 5, 2002