Regioselective Synthesis of Polyfluoroalkyl Substituted 6,7-Dihydrobenzisoxazolones

Article abstract of DOI:10.1002/jhet.3218

Regioselective methods for synthesis of hitherto unreported both 6,7-dihydro-1,2-benzisoxazol-4(5H)-ones and 6,7-dihydro-2,1-benzisoxazol-4(5H)-ones with perfluoroalkyl or halogenodifluoromethyl substituents have been developed. 3-Polyfluoroalkyl-6,7-dihydro-1,2-benzisoxazol-4(5H)-ones were prepared by the cyclocondensation of 2-polyfluoroalkanoylcyclohexane-1,3-diones with hydroxylamine. The regioisomeric 3-polyfluoroalkyl-6,7-dihydro-2,1-benzisoxazol-4(5H)-ones were synthesized by the transformation of 2-polyfluoroalkanoylcyclohexane-1,3-diones into their vinylogous chlorides, followed by the interaction of obtained crude 3-chloro-2-polyfluoroalkanoyl-2-cyclohexen-1-ones with sodium azide in dimethylformamide.

Full text of DOI:10.1002/jhet.3218

Month 2018
Regioselective Synthesis of Polyfluoroalkyl Substituted 6,7-
Dihydrobenzisoxazolones
a
Tatyana S. Khlebnicova,
Yurii A. Piven’,a Veronica G. Isakova,a Alexander V. Baranovsky,a Fedor A. Lakhvich,a
*
Alexander E. Sorochinsky,b and Igor I. Gerusb
aInstitute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Acad. Kuprevicha Street 5/2, 220141
Minsk, Belarus
bInstitute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Murmanska 1, 02660
Kiev 94, Ukraine
*
E-mail: tkhlebnicova@gmail.com
Received February 21, 2018
DOI 10.1002/jhet.3218
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
Regioselective methods for synthesis of hitherto unreported both 6,7-dihydro-1,2-benzisoxazol-4(5H)-
ones and 6,7-dihydro-2,1-benzisoxazol-4(5H)-ones with perfluoroalkyl or halogenodifluoromethyl substitu-
ents have been developed. 3-Polyfluoroalkyl-6,7-dihydro-1,2-benzisoxazol-4(5H)-ones were prepared by the
cyclocondensation of 2-polyfluoroalkanoylcyclohexane-1,3-diones with hydroxylamine. The regioisomeric
3-polyfluoroalkyl-6,7-dihydro-2,1-benzisoxazol-4(5H)-ones were synthesized by the transformation of 2-
polyfluoroalkanoylcyclohexane-1,3-diones into their vinylogous chlorides, followed by the interaction of
obtained
crude
3-chloro-2-polyfluoroalkanoyl-2-cyclohexen-1-ones
with
sodium
azide
in
dimethylformamide.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
[8,9] and agrochemicals [10]. The selective introduction
of fluorine atoms or polyfluoroalkyl groups into aromatic
or heterocyclic moiety to modify the bioactivity of
biomolecules is a well-established practice [11,12].
Previously synthesized 2-perfluoroalkanoylcyclohexane-
1,3-diones [13] are very reactive compounds because of
the presence of three electrophilic centers (one exocyclic
and two endocyclic carbonyl groups) and can be used as
building blocks in the synthesis of a large series of
perfluoroalkyl-containing heterocyclic compounds. 2-
Perfluoroalkanoylcyclohexane-1,3-diones and their enol
derivatives are known to react with N,N-dinucleophiles
such as phenylhydrazines or o-phenylenediamine to give
corresponding fluorinated indazolones [14] and
benzodiazepinones [15].
Therefore, in view of these observations and in
conjunction with our previous interest in synthesis of
heterocyclic compounds [16,17], we report herein a facile
synthesis of novel regioisomeric 6,7-dihydro-1,2-
benzisoxazol-4(5H)-ones and 6,7-dihydro-2,1-benzisoxazol-
4(5H)-ones with perfluoroalkyl or halogenodifluoromethyl
substituents.
Heterocyclic compounds are an exceedingly important
class of compounds, and they have attracted much
attention for diverse biological studies. Heterocyclic
moiety plays important functions in medicinal chemistry
and serves as key template for development of therapeutic
agents with unique properties [1]. Nitrogen containing
heterocyclic rings with an oxygen atom are considered as
one of the best combination in medicinal chemistry due to
a broad spectrum of pharmacological activities [2,3].
Numerous heterocyclic compounds possessing an
isoxazole ring (both isolated and fused to other mono or
polycyclic systems) have been used as a base structure for
the design of many pharmaceutical [4] and agrochemical
agents [5]. Isoxazole, a five-membered heterocyclic azole
ring, can be found in naturally occurring ibotenic acid
along some of the marketed drugs as valdecoxib,
flucloxacillin, cloxacillin, and dicloxacillin. It is also
significant for showing antipsychotic activity in
risperidone and anticonvulsant activity in zonisamide. The
benzisoxazole scaffold and its analogues are important
pharmacophores that can be found in biologically active
compounds across a number of different therapeutic areas
as anti-HIV, antimicrobial, antipsychotic, anti-
inflammatory, analgesic, anticancer, and so on [6,7]. A
large number of fluorine containing heterocyclic
compounds are well known as important marketed drugs
RESULTS AND DISCUSSION
The most common synthetic approaches used to
construct the fluorinated as well as nonfluorinated
© 2018 Wiley Periodicals, Inc.

T. S. Khlebnicova, Y. A. Piven', V. G. Isakova, A. V. Baranovsky, F. A. Lakhvich,
A. E. Sorochinsky, and I. I. Gerus
Vol 000
isoxazoles up to the date include the condensation of β-
diketones with hydroxylamine and the condensation of
α,β-unsaturated compounds with hydroxylamine and 1,3-
dipolar cycloaddition reactions [18,19]. The reaction of
nitrile oxides with nonfluorinated cyclic β-diketones
provides a regiospecific synthesis of isoxazoles with a wide
variety of substituents [20,21]. However, reaction of nitrile
oxides, generated in situ from trifluoroacetohydroximoyl
bromide etherate, with cyclohexane-1,3-dione gave desired
3-(trifluoromethyl)-6,7-dihydrobenzo-1,2-isoxazol-4(5H)-
one in a poor 29% yield [22]. The result of the reaction
perfluoroalkyl-substituted analogs) was observed when
we used 1,10-carbonyldiimidazole and 2-halogeno-2,2-
difluoroacetic acid for the generation of N-
acylimidazoles. Nevertheless, the previously unknown
2-(2-halogeno-2,2-difluoroacetyl)cyclohexane-1,3-diones
2a,b,f,g were successfully prepared via C-acylation
cyclohexane-1,3-diones 1a,b with N-(2-halogeno-2,2-
difluoroacetyl)imidazoles generated in situ from
corresponding 2-halogeno-2,2-difluoroacetyl chlorides
and imidazole in 63–71% yields.
Next, the reaction of hydroxylamine hydrochloride
with 2-alkanoylcyclohexane-1,3-diones 2a–j containing
perfluoroalkyl or halogenodifluoromethyl substituents
was investigated by us. The treatment of fluorinated
cyclic β-triketones 2b–e,g–j with an equimolar mixture
of NH2OH·HCl and NaOH in methanol at room
temperature for 20 h led to the formation of 6,7-
dihydro-1,2-benzisoxazol-4(5H)-ones 3b–e,g–j in 42–
63% yield. Unfortunately, β-triketones 2a,f containing
bromodifluoromethyl group were unstable at the
reaction conditions, and only the formation of complex
mixture of unidentified products was observed. In fact,
in the reactions of β-triketones 2b–e,g–j with
between
fluorine-containing
1,3-diketones
and
hydroxylamine depended on such factors as the nature of
constituents, the structure of β-diketone, and the reaction
conditions [19,23]. For the synthesis of the target
regioisomeric 6,7-dihydro-1,2-benzisoxazol-4(5H)-ones
and
6,7-dihydro-2,1-benzisoxazol-4(5H)-ones,
the
strategy depicted in Scheme 1 was chosen.
The starting 2-perfluoroalkanoylcyclohexane-1,3-diones
2c–e,h–j were prepared from commercially available
cyclohexane-1,3-diones 1a,b via a one-pot procedure,
developed in our group [13]. The method involved C-
acylation cyclohexane-1,3-diones 1a,b with N-
perfluoroacylimidazoles generated in situ from
perfluorocarboxylic acid or perfluorocarboxylic acid
anhydrides. That contrary to expectations, no formation
of the desired products 2a,b,f,g (unlike their
hydroxylamine,
the
nucleophilic
attack
of
hydroxylamine amino group takes place on the
electrophilic exocyclic carbonyl carbon attached to the
polyfluoroalkyl group, followed by cyclocondensation,
Scheme 1. Synthesis of 6,7-dihydro-1,2-benzisoxazol-4(5H)-ones 3b–e,g–j and 6,7-dihydro-2,1-benzisoxazol-4(5H)-ones 5a–j
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Regioselective Synthesis of Polyfluoroalkyl Substituted 6,7-
Dihydrobenzisoxazolones
which was in conformity with the reaction of
perfluoroalkanoylcyclohexane-1,3-diones 2c–e and 2-(2-
halogeno-2,2-difluoroacetyl)cyclohexane-1,3-diones 2a,
b,f,g were unsuccessful because of their decomposition
during a separation from the reaction mixture by
column chromatography.
nonfluorinated
hydrochloride [24].
To obtain
benzisoxazol-4(5H)-ones
β-triketones
and
hydroxylamine
polyfluoroalkyl
5a–j
6,7-dihydro-2,1-
(regioisomers
of
isoxazolones 3a–j), it is essential that a nucleophilic
attack would be directed at the trigonal C3 center of 2-
polyfluoroalkanoylcyclohexane-1,3-diones 2a–j. It could
be achieved via an initial transformation of β-triketones
2a–j into their enol derivatives (vinylogous chlorides or
methyl ethers). We synthesized diketovinyl chlorides
The structures of all new obtained compounds were
confirmed by their IR, 1H, 13C, and 19F NMR spectra
and data of elemental analysis. From the spectral data,
2-(2-halogeno-2,2-difluoroacetyl)cyclohexane-1,3-diones
2a,b,f,g were completely enolized in solution similar to
2-perfluoroacylcyclohexane-1,3-diones 2c–e,h–j [14].
1H NMR spectra of the triacylmethanes 2a,b,f,g
showed a single enol proton signal as a broad singlet
in the range of δ 15.02–15.27 ppm. Because of an
influence of electronegative halogenopolyfluoroalkyl
group, the strength of an intramolecular hydrogen
bonding was obviously weakened and the resonance of
enolic protons occurred at higher field than its usual
position for 2-acylcyclohexane-1,3-diones (δ 17–
18 ppm) [28]. The 13C NMR spectra of β-triketones
2a,b,f,g revealed a signal of the carbon atom of a
carbonyl group of a halogeno-2,2-difluoroacetyl side
chain at δ 185.3–186.1 ppm and broad signals of
carbon atoms of cyclic carbonyl groups at δ 190.5–
4a–j
and
investigated
their
interaction
with
hydroxylamine hydrochloride. On the treatment of
diketovinyl chlorides 4a–j with an equimolar mixture of
NH2OH·HCl and NaOH in methanol at room
temperature, we observed a formation of the complex
mixture of products that contained trace amounts of
6,7-dihydro-1,2-benzisoxazol-4(5H)-ones 3a–j and 6,7-
dihydro-2,1-benzisoxazol-4(5H)-ones 5a–j (according to
1H and 19F NMR data). Then we investigated the
interaction of chlorides 4a–j with sodium azide; such
type of transformation for 3-chloro-2-acetyl-2-
cyclohexen-1-ones has been reported [25]. As a result,
we developed a facile synthesis of 3-polyfluoroalkyl-
6,7-dihydro-2,1-benzisoxazol-4(5H)-ones
method included conversion
polyfluoroalkanoylcyclohexane-1,3-diones
chlorides 4a–j under an action of oxalyl chloride in the
presence of DMF (as catalyst) in chloroform, followed
by the treatment of obtained crude 3-chloro-2-
5a–j.
of
2a–j
The
2-
into
191.8 ppm and at
broadening was obviously connected with
δ
194.1–197.6 ppm. Such
a
a
fast
exchange of the enolic proton between carbonyl
groups of the cyclohexane-1,3-diones. In the 19F NMR
spectra of compounds 2a,f and 2b,g, singlets at δ
ꢀ61.1 ppm or δ ꢀ63.7 ppm, respectively, were
assigned to the fluorine atoms of a halogeno-2,2-
difluoroacetyl group. The 13C NMR spectra of
isoxazolones 3b–e,g–j revealed a signal of carbonyl
carbon atoms (C4) and the signals of C–O (C7a) and
C=N (C3) at δ 188.1–189.4, 182.4–183.3, and 150.5–
155.4 ppm, respectively, while the signals of C4
(C=O), C3 (C–O), and C7a (C=N) carbon atoms in
13C NMR spectra of isomeric isoxazolones 5a–j were
observed at δ 188.7–190.0, 156.7–162.6, and 164.2–
165.1 ppm, respectively. The presence of fluorine
atoms in structures of compounds 3–5 was confirmed
by the observation of fluorine signals in the
appropriate ranges of their 19F NMR spectra.
polyfluoroalkanoyl-2-cyclohexen-1-ones
4a–j
with
sodium azide in dimethylformamide (method 1). Target
isoxazolones 5a–j were prepared in good yields (72–
76%) as a result of the initial vinylogous substitution
of the trigonal C3 atom in the molecule of chlorides
4a–j and the transformation of the unstable azides into
the isoxazolones 5a–j.
As known in the case of 2-acylcyclohexane-1,3-diones,
the direction of N-nucleophilic attack by hydroxylamine
could be altered by converting of the β-triketones into
methyl enol ethers, followed by a reaction of the latter
with hydroxylamine [24,26]. We synthesized 2-
perfluoroalkanoyl-5,5-dimethyl-3-methoxy-2-cyclohexen-
1-ones 4a–c via O-methylation of compounds 2h–j with
diazomethane in 52–71% yields according to
a
published procedure [27]. The treatment of methyl
ethers 4a–c with an equimolar mixture of
hydroxylamine hydrochloride and NaOH in methanol at
room temperature for 8 h afforded 3-perfluoroalkyl-6,7-
dihydro-2,1-benzisoxazol-4(5H)-ones 5h–j in 67–70%
yields (method 2). The reaction proceeded via a
vinylogous substitution mechanism with subsequent
intramolecular cyclization. It is worthy to mention that
our attempts to synthesize the methyl ethers of 2-
CONCLUSIONS
In conclusion, we have described convenient syntheses
of hitherto unreported both 6,7-dihydro-1,2-benzisoxazol-
4(5H)-ones and 6,7-dihydro-2,1-benzisoxazol-4(5H)-ones
with perfluoroalkyl or halogenodifluoromethyl substituents
in a high regioselectivity. 3-Polyfluoroalkyl-6,7-dihydro-
1,2-benzisoxazol-4(5H)-ones were effectively prepared by
the cyclocondensation of 2-polyfluoroalkanoylcyclohexane-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

T. S. Khlebnicova, Y. A. Piven', V. G. Isakova, A. V. Baranovsky, F. A. Lakhvich,
A. E. Sorochinsky, and I. I. Gerus
Vol 000
1,3-diones with hydroxylamine that proceeded at the most
electrophilic exocyclic carbonyl group. The regioisomeric
3-polyfluoroalkyl-6,7-dihydro-2,1-benzisoxazol-4(5H)-ones
were synthesized by the transformation of 2-
reaction mixture was stirred at room temperature for
2 h, then the solution was washed with 5% solution of
hydrochloric acid (3 × 25 mL) and water (1 × 25 mL)
and dried (Na2SO4). The solution was evaporated in
vacuo to give the title compounds 2a,b,f,g in 63–71%
polyfluoroalkanoylcyclohexane-1,3-diones
into
their
vinylogous chlorides, followed by the vinylogous
substitution with sodium azide in dimethylformamide
and the transformation of unstable azides to the
isoxazolones.
yield.
2-(2-Bromo-2,2-difluoroacetyl)cyclohexane-1,3-dione
(2a). This compound was obtained as colorless crystals,
yield 63%, mp 80–82°С. IR (KBr): 1680 (C=O conjug.
nonchelat), 1615 (C=O chelat.), 1545 (C=C) cmꢀ1. H
1
NMR: δ 2.06 (2Н, qui, J = 6.6 Hz, СН2), 2.57–2.77 (4Н,
m, 2СН2), 15.26 (1Н, brs, OH). 13C NMR: δ 19.0, 32.3
(br), 38.2 (br), 110.2, 113.3 (t, J = 313 Hz), 186.1 (t,
J = 30 Hz), 191.8(br), 197.6 (br). 19F NMR: δ ꢀ61.19 (s,
CF2). Anal. Calcd for C8H7BrF2O3: C, 35.71; H, 2.62.
EXPERIMENTAL
Materials and methods.
All chemicals were
Found: C, 35.75; H, 2.64.
commercially available and used as purchased without
2-(2-Chloro-2,2-difluoroacetyl)cyclohexane-1,3-dione
(2b). This compound was obtained as colorless crystals,
further purification. Solvents were dried and freshly
1
distilled according to common practice. H, 19F, and 13C
yield 65%, mp 57–58°С. IR (KBr): 1680 (C=O conjug.
NMR spectra were recorded on a Bruker Avance 500
spectrometer (500, 470, and 125 MHz, respectively) in
CDCl3 solutions. Residual solvent signals were used as
internal standards for 1H and 13C NMR spectra
1
Nonchelat.), 1620 (C=O chelat.), 1550 (C=C) cmꢀ1. H
NMR: δ 2.05 (2Н, qui, J = 6.6 Hz, СН2), 2.46–2.87 (4Н,
m, 2СН2), 15.16 (1Н, brs, OH). 13C NMR: δ 19.0, 32.2
(br), 38.1 (br), 110.6, 119.4 (t, J = 300 Hz), 185.8 (t,
J = 32 Hz), 191.9 (br), 197.3 (br). 19F NMR: δ ꢀ63.73
(s, CF2). Anal. Calcd for C8H7ClF2O3: C, 42.78; H, 3.14.
Found: C, 42.82; H, 3.17.
2-(2-Bromo-2,2-difluoroacetyl)-5,5-dimethylcyclohexane-
1,3-dione (2f). This compound was obtained as colorless
1
(7.26 ppm for H nuclei and 77.16 ppm for 13C nuclei).
External standard was used for 19F NMR (α,α,α-
trifluorotoluene signal at ꢀ63 ppm for 19F NMR). IR
spectra were recorded on an FTIR PerkinElmer Spectrum
100. The elemental analyses were performed on a
Eurovector EA3000 CHNS-O analyzer. Melting points
were determined on a Boetius hot stage. Column
chromatography was performed on 70–230 mesh silica
gel (eluent ethyl acetate:petroleum ether 1:10–1:5). The
reaction progress and purity of the obtained compounds
were controlled by thin-layer chromatography on pre-
crystals, yield 71%, mp 75–78°С. IR (KBr): 1685 (C=O
conjug. nonchelat), 1625 (C=O chelat.), 1560 (C=C)
1
cmꢀ1. H NMR: δ 1.12 (6Н, s, 2СН3), 2.40–2.63 (4Н, m,
2СН2), 15.27 (1Н, brs, OH). 13C NMR: δ 28.2, 31.2,
46.1 (br), 52.3 (br), 109.3, 112.1 (t, J = 313 Hz), 185.7
(t, J = 29.0 Hz), 193.1 (br,). 19F NMR: δ ꢀ61.09 (s,
CF2). Anal. Calcd for C10H11BrF2O3: C, 40.43; H, 3.73.
coated
silica
gel
F254
plates.
2-
Perfluoroalkanoylcyclohexane-1,3-diones 2c–e,h–j [13],
3-chloro-2-perfluoroalkanoyl-2-cyclohexen-1-ones 4c–e,
h–j [29], 2-perfluoroalkanoyl-5,5-dimethyl-3-methoxy-2-
cyclohexen-1-ones 6a–c [15,27], and 3-(trifluoromethyl)-
6,7-dihydrobenzo-1,2-isoxazol-4(5H)-one (3c) [22] have
been described in literature.
Found: C, 40.48; H, 3.75.
2-(2-Chloro-2,2-difluoroacetyl)-5,5-dimethylcyclohexane-
1,3-dione (2g). This compound was obtained as colorless
crystals, yield 69%, mp 76–78°С. IR (KBr): 1685 (C=O
conjug. nonchelat), 1620 (C=O chelat.), 1565 (C=C)
1
cmꢀ1. H NMR: δ 1.11 (6Н, s, 2СН3), 2.46–2.62 (4Н, m,
General procedure for preparation of 2-(2-halogeno-2,2-
2СН2), 15.04 (1Н, brs, OH). 13C NMR: δ 28.2, 31.1,
48.8 (br), 109.6, 119.3 (t, J = 300 Hz), 185.3 (t,
J = 32 Hz), 190.5 (br), 194.1 (br).19F NMR: δ ꢀ63.67 (s,
CF2).). Anal. Calcd for C10H11ClF2O3: C, 47.54; H, 4.39.
Found: C, 47.50; H, 4.36.
difluoroacetyl)cyclohexane-1,3-diones (2a,b,f,g).
To
a
stirred
solution
of
respective
2-halogeno-2,2-
difluoroacetic acid, namely, 2-bromo-2,2-difluoroacetic
acid or 2-chloro-2,2-difluoroacetic acid (5 mmol), in
dry chloroform (20 mL), oxalyl chloride (0.635 g,
5 mmol) and one drop of dimethylformamide were
added at 0°C. After stirring at 0°C for 2 h, the
obtained reaction mixture was added dropwise to a
solution of imidazole (0.680 g, 10 mmol) in chloroform
(30 mL) at 0°C. To the resultant suspension, a solution
of cyclohexane-1,3-diones 1a,b (3.75 mmol) and
imidazole (0.255 g, 3.75 mmol) in dry chloroform
(30 mL) was added dropwise at room temperature. The
General
3-polyfluoroalkyl-6,7-dihydro-1,2-benzisoxazol-4(5H)-ones
(3b–e,g–j).
procedure
for
preparation
of
To
a
stirred
solution
of
2-
polyfluoroalkanoylcyclohexane-1,3-diones 2a–j (1.0 mmol)
in methanol (25 mL), hydroxylamine hydrochloride
(0.070 g, 1.0 mmol) and NaOH (0.040 g, 1.0 mmol)
were added. After stirring at room temperature for 20 h,
methanol was evaporated in vacuo. The obtained residue
was dissolved in chloroform (40 mL), and the solution
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Regioselective Synthesis of Polyfluoroalkyl Substituted 6,7-
Dihydrobenzisoxazolones
was washed with water (1 × 25 mL) and then dried
(Na2SO4). The solution was evaporated in vacuo and the
crude residue was purified by silica gel column
chromatography to give the title compounds (3b–e,g–j) in
155.4 (t, J = 33 Hz, C3), 182.8 (C7a), 188.7 (C4). 19F
NMR:
C10H10ClF2NO2: C, 48.11; H, 4.04; N, 5.61. Found: C,
48.17; H, 4.07; N, 5.66.
3-(Trifluoromethyl)-6,6-dimethyl-6,7-dihydrobenzo-1,2-
isoxazol-4(5H)-one (3h). This compound was obtained as
δ
ꢀ52.64 (s, CF2). Anal. Calcd for
42–63% yield.
3-(Chlorodifluoromethyl)-6,7-dihydrobenzo-1,2-isoxazol-
4(5H)-one (3b). This compound was obtained as colorless
colorless crystals, yield 55%, mp 40–41°С. IR (KBr):
1
crystals, yield 44%, mp 32–33°С. IR (KBr): 1700 (C=O),
1705 (C=O), 1600, 1480 cmꢀ1. H NMR: δ 1.18 (6Н, s,
1
1595, 1475 cmꢀ1. H NMR: δ 2.29 (2Н, qui, J = 6.4 Hz,
2СН3), 2.47 (2Н, s, СН2), 2.94 (2H, s, СН2). 13C NMR:
δ 28.4, 35.5, 36.8, 52.4, 112.5, 119.2 (q, JC-F = 272 Hz),
151.2 (q, JC-F = 40 Hz, C3), 182.6 (C7a), 188.8 (C4). 19F
NMR: δ ꢀ63.67 (s, CF3). Anal. Calcd for C10H10F3NO2:
C, 51.51; H, 4.32; N, 6.01. Found: C, 51.47; H, 4.30; N,
СН2), 2.60 (2Н, t, J = 6.4 Hz, СН2), 3.09 (2Н, t,
J = 6.4 Hz, CH2). 13C NMR: 21.9, 23.2, 38.1, 112.9,
120.3 (t, J = 289 Hz), 155.5 (t, J = 33 Hz, C3), 183.3
(C7a), 189.2 (C4). 19F NMR: δ ꢀ52.79 (s, CF2). Anal.
Calcd for C8H6ClF2NO2: C, 43.36; H, 2.73; N, 6.32.
Found: C, 43.41; H, 2.76; N, 6.36.
5.95.
3-(Perfluoroethyl)-6,6-dimethyl-6,7-dihydrobenzo-1,2-
isoxazol-4(5H)-one (3i). This compound was obtained as
3-(Trifluoromethyl)-6,7-dihydrobenzo-1,2-isoxazol-4(5H)-
colorless crystals, yield 63%, mp 27–29°С. IR (KBr):
one (3c).
This compound was obtained as colorless
1
1710 (C=O), 1595, 1470 cmꢀ1. H NMR: δ 1.17 (6Н, s,
crystals, yield 57%, mp 43–44°С. IR (KBr): 1702 (C=O),
2СН3), 2.47 (2Н, s, СН2), 2.95 (2H, s, СН2). 13C NMR:
δ 28.1, 35.5, 36.6, 52.5, 109.4 (tq, JC-F = 256, 41 Hz),
113.4, 118.2 (qt, JC-F = 287, 35 Hz), 150.5 (t,
JC-F = 31 Hz, C3), 182.4 (C7a), 188.1 (C4). 19F NMR: δ
ꢀ83.04 (3F, m, CF3), ꢀ112.50 (2F, m, CF2). Anal. Calcd
for C11H10F5NO2: C, 46.65; H, 3.56; N, 4.95. Found: C,
1599, 1495 cmꢀ1. H NMR: δ 2.29 (2Н, qui, J = 6.4 Hz,
1
СН2), 2.61 (2Н, t, J = 6.4 Hz, СН2), 3.10 (2Н, t,
J = 6.4 Hz, CH2). 13C NMR: δ 22.0, 23.1, 38.0, 113.5,
119.2 (q, JC-F = 272 Hz), 151.3 (q, JC-F = 40 Hz, C3),
183.1 (C7a), 189.4 (C4). 19F NMR: δ ꢀ63.79 (s, CF3).
Anal. Calcd for C8H6F3NO2: C, 46.84; H, 2.95; N, 6.83.
46.60; H, 3.52; N, 4.91.
Found: C, 46.80; H, 2.91; N, 6.79.
3-(Perfluoropropyl)-6,6-dimethyl-6,7-dihydrobenzo-1,2-
isoxazol-4(5H)-one (3j). This compound was obtained as
3-(Perfluoroethyl)-6,7-dihydrobenzo-1,2-isoxazol-4(5H)-one
(3d). This compound was obtained as colorless crystals,
colorless oil, yield 52%. IR (film): 1710 (C=O), 1595,
yield 46%, mp 51–53°С. IR (KBr): 1702 (C=O), 1594,
1
1470 cmꢀ1. H NMR: δ 1.17 (6Н, s, 2СН3), 2.46 (2Н, s,
1
1479 cmꢀ1. H NMR: δ 2.28 (2Н, q, J = 6.4 Hz, СН2),
СН2), 2.95 (2H, s, СН2). 13C NMR: δ 28.0, 35.1, 36.6,
52.5, 108.4 (tm, JC-F = 268 Hz), 111.6 (tt, JC-F = 258,
33 Hz), 113.6, 117.6 (qt, JC-F = 288, 34 Hz), 150.7 (t,
JC-F = 30 Hz, C3), 182.5 (C7a), 187.9 (C4). 19F NMR:
δ ꢀ80.18 (3F, m, CF3), ꢀ110.32 (2F, m, CF2),
ꢀ125.63 (2F, m, CF2). Anal. Calcd for C12H10F7NO2:
C, 43.26; H, 3.03; N, 4.20. Found: C, 43.32; H, 3.06;
N, 4.25.
2.60 (2Н, t, J = 6.5 Hz, СН2), 3.11 (2Н, t, J = 6.4 Hz,
CH2). 13C NMR:
δ 21.8, 23.2, 38.3, 109.6 (tq,
JC-F = 256 Hz, 41 Hz), 114.5, 117.2 (qt, JC-F = 287 Hz,
35 Hz), 150.8 (t, J = 31 Hz, C3), 183.0 (C7a), 188.8
(C4). 19F NMR: δ ꢀ82.92 (3F, m, CF3), ꢀ112.49 (2F, m,
CF2). Anal. Calcd for C9H6F5NO2: C, 42.37; H, 2.37; N,
5.49. Found: C, 42.43; H, 2.40; N, 5.53.
3-(Perfluoropropyl)-6,7-dihydrobenzo-1,2-isoxazol-4(5H)-
one (3e).
This compound was obtained as colorless
crystals, yield 45%, mp 29–31°С. IR (KBr): 1707
(C=O), 1592, 1470 cmꢀ1 1H NMR: δ 2.28 (2Н, q,
General procedure for preparation of 3-chloro-2-(2-
halogeno-2,2-difluoroacetyl)-2-cyclohexen-1-ones (4a,b,f,g).
.
To a stirred solution of 2-(2-halogeno-2,2-difluoroacetyl)
cyclohexane-1,3-diones (2a,b,f,g) (1.0 mmol) in dry
chloroform (20 mL), oxalyl chloride (0.635 g, 3.0 mmol)
and one drop of dimethylformamide were added. After
stirring at room temperature for 2 h, chloroform and
residual oxalyl chloride were evaporated in vacuo. The
crude residue was purified by silica gel column
chromatography to give the title compounds 4a,b,f,g in
J = 6.4 Hz, СН2), 2.59 (2Н, t, J = 6.4 Hz, СН2),
3.11 (2Н, t, J = 6.4 Hz, CH2). 13C NMR: δ 21.8,
23.2, 38.3, 108.5 (tm, JC-F = 268 Hz), 111.7 (tt,
JC-F = 258, 33 Hz), 114.7, 117.8 (qt, JC-F = 258,
33 Hz), 151.0 (t, JC-F = 30 Hz, C3), 183.1 (C7a),
188.6 (C4). 19F NMR: δ ꢀ80.10 (3F, m, CF3),
ꢀ110.21 (2F, m, CF2), ꢀ125.45 (2F, m, CF2). Anal.
Calcd for C10H6F7NO2: C, 39.36; H, 1.98; N, 4.59.
75–78% yield.
Found: C, 39.32; H, 1.95; N, 4.55.
3-(Chlorodifluoromethyl)-6,6-dimethyl-6,7-dihydrobenzo-
2-(2-Bromo-2,2-difluoroacetyl)-3-chlorocyclohex-2-en-1-one
(4a). This compound was obtained as colorless oil, yield
1,2-isoxazol-4(5H)-one (3g). This compound was obtained
78%. IR (film): 1755 (C=O), 1685 (C=O), 1620 (C=C)
1
cmꢀ1. H NMR: δ 2.16 (2H, qui, J = 6.3 Hz, CH2), 2.53
as colorless crystals, yield 42%, mp 65–66°С. IR (KBr):
1
1695 (C=O), 1590, 1475 cmꢀ1. H NMR: δ 1.19 (6Н, s,
(2H, t, J = 6.2 Hz, CH2), 2.86 (2H, t, J = 6.1 Hz, CH2).
13C NMR: δ 21.5, 34.7, 36.2, 113.5 (t, J = 319 Hz),
134.7, 159.0, 184.6 (t, J = 31 Hz), 193.0. 19F NMR: δ
2СН3), 2.48 (2Н, s, СН2), 2.94 (2H, s, СН2). 13C NMR:
δ 28.4, 35.5, 36.9, 52.5, 111.9, 120.2 (t, J = 289 Hz),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

T. S. Khlebnicova, Y. A. Piven', V. G. Isakova, A. V. Baranovsky, F. A. Lakhvich,
A. E. Sorochinsky, and I. I. Gerus
Vol 000
ꢀ61.19 (s, CF2). Anal. Calcd for C8H6BrClF2O2: C, 33.42;
resultant residue was purified by silica gel column
chromatography to give the title compounds 5h–j in 67–
H, 2.10. Found: C, 33.38; H, 2.07.
2-(2-Chloro-2,2-difluoroacetyl)-3-chlorocyclohex-2-en-1-one
(4b). This compound was obtained as colorless oil, yield
70% yield.
3-(Bromodifluoromethyl)-6,7-dihydrobenzo-2,1-isoxazol-
77%. IR (film): 1755 (C=O), 1685 (C=O), 1620 (C=C)
4(5H)-one (5a).
This compound was obtained as
colorless crystals, yield 76% (method 1), mp 31–33°С.
IR (KBr): 1705 (C=O), 1615 cmꢀ1 1H NMR: δ 2.20
1
cmꢀ1. H NMR: δ 2.16 (2H, qui, J = 6.2 Hz, CH2), 2.54
(2H, t, J = 6.2 Hz, CH2), 2.85 (2H, t, J = 6.1 Hz, CH2).
13C NMR: δ 21.5, 34.6, 36.2, 119.4 (t, J = 305 Hz),
135.0, 158.7, 184.5 (t, J = 34 Hz), 193.1. 19F NMR: δ
ꢀ64.96 (s, CF2). Anal. Calcd for C8H6Cl2F2O2: C, 39.54;
.
(2Н, qui, J = 6.4 Hz, СН2), 2.62 (2Н, t, J = 6.4 Hz,
СН2), 3.00 (2Н, t, J = 6.4 Hz, CH2). 13C NMR: δ
21.5, 22.2, 39.7, 108.7 (t, JC-F = 304 Hz), 113.2, 162.6
(t, JC-F = 34 Hz, C3), 165.0 (C7a), 189.9 (C4). 19F
NMR: δ ꢀ49.83 (s, CF2). Anal. Calcd for C8H6BrF2NO2:
C, 36.12; H, 2.27; N, 5.26. Found: C, 36.16; H, 2.30;
N, 5.31.
H, 2.49. Found: C, 39.49; H, 2.47.
2-(2-Bromo-2,2-difluoroacetyl)-3-chloro-5,5-
dimethylcyclohex-2-en-1-one (4f).
This compound was
obtained as colorless oil, yield 75%. IR (film): 1755
1
(C=O), 1685 (C=O), 1620 (C=C) cmꢀ1. H NMR: δ 1.15
3-(Chlorodifluoromethyl)-6,7-dihydrobenzo-2,1-isoxazol-
4(5H)-one (5b). This compound was obtained as colorless
(6H, s, 2CH3), 2.39 (2H, s, CH2), 2.72 (2H, s, CH2). 13C
NMR: δ 27.9, 33.8, 48.4, 50.0, 113.5 (t, J = 319 Hz),
133.7, 157.0, 184.4 (t, J = 31 Hz), 193.1. 19F NMR: δ
ꢀ61.08 (s, CF2). Anal. Calcd for C10H10BrClF2O2: C,
crystals, yield 74% (method 1), mp 42–43°С. IR (KBr):
1705 (C=O), 1615 cmꢀ1 1H NMR: δ 2.20 (2Н, qui,
.
J = 6.4 Hz, СН2), 2.62 (2Н, t, J = 6.3 Hz, СН2), 3.01
(2Н, t, J = 6.3 Hz, CH2). 13C NMR: δ 21.5, 22.2, 39.6,
113.9, 118.6 (t, J = 290 Hz), 161.5 (t, J = 38 Hz, C3),
165.1 (C7a), 189.8 (C4). 19F NMR: δ ꢀ52.74 (s, CF2).
Anal. Calcd for C8H6ClF2NO2: C, 43.36; H, 2.73; N,
38.07; H, 3.19. Found: C, 38.01; H, 3.15.
2-(2-Chloro-2,2-difluoroacetyl)-3-chloro-5,5-
dimethylcyclohex-2-en-1-one (4g).
This compound was
obtained as colorless oil, yield 76%. IR (film): 1755
1
(C=O), 1685 (C=O), 1620 (C=C) cmꢀ1. H NMR: δ 1.14
6.32. Found: C, 43.41; H, 2.77; N, 6.35.
3-(Trifluoromethyl)-6,7-dihydrobenzo-2,1-isoxazol-4(5H)-
(6H, s, 2CH3), 2.39 (2H, s, CH2), 2.72 (2H, s, CH2). 13C
NMR: δ 27.9, 33.8, 48.3, 50.0, 119.4 (t, J = 305 Hz),
134.0, 156.8, 184.3 (t, J = 34 Hz), 193.2. 19F NMR: δ
ꢀ64.84 (s, CF2). Anal. Calcd for C10H10Cl2F2O2: C,
44.31; H, 3.72. Found: C, 44.36; H, 3.74.
one (5c).
This compound was obtained as colorless
crystals, yield 73% (method 1), mp 57–59°С. IR (KBr):
1709 (C=O), 1626 cmꢀ1 1H NMR: δ 2.20 (2Н, qui,
.
J = 6.4 Hz, СН2), 2.62 (2Н, t, J = 6.3 Hz, СН2), 3.01
(2Н, t, J = 6.3 Hz, CH2). 13C NMR: δ 21.4, 22.1, 39.5,
115.9 (q, JC-F = 276 Hz), 118.6, 157.5 (q, JC-F = 45 Hz,
C3), 164.9 (C7a), 190.0 (C4). 19F NMR: δ ꢀ63.44 (s,
CF3). Anal. Calcd for C8H6F3NO2: C, 46.84; H, 2.95; N,
General
3-polyfluoroalkyl-6,7-dihydro-2,1-benzisoxazol-4(5H)-ones
(5a–j). a stirred solution of 2-
procedure
for
preparation
of
Method 1. To
polyfluoroalkanoylcyclohexane-1,3-diones 2a–j (1.0 mmol)
in dry chloroform (20 mL), oxalyl chloride (0.635 g,
3 mmol) and one drop of dimethylformamide were
added. After stirring at room temperature for 2 h,
chloroform and residual oxalyl chloride were evaporated
in vacuo to dryness. To a stirred solution of obtained
crude 3-chloro-2-polyfluoroalkanoyl-2-cyclohexen-1-ones
4a–j in dimethylformamide (15 mL), sodium azide
(0.078 g, 1.2 mmol) was added portionwise. The reaction
mixture was stirred at room temperature for 20 h, and
dimethylformamide was evaporated in vacuo. The
obtained residue was dissolved in chloroform (40 mL),
the solution was washed with water (1 × 10 mL) and
dried (Na2SO4). The solution was evaporated in vacuo,
and the crude residue was purified by silica gel column
chromatography to give the title compounds 5a–j in 72–
76% yield.
6.83. Found: C, 46.89; H, 2.97; N, 6.87.
3-(Perfluoroethyl)-6,7-dihydrobenzo-2,1-isoxazol-4(5H)-one
(5d). This compound was obtained as colorless crystals,
yield 72% (method 1), mp 55–57°С. IR (KBr): 1712
(C=O), 1622 cmꢀ1
.
1H NMR: δ 2.20 (2Н, qui,
J = 6.4 Hz, СН2), 2.63 (2Н, t, J = 6.3 Hz, СН2), 3.03
(2Н, t, J = 6.3 Hz, CH2). 13C NMR: δ 21.5, 22.0, 39.8,
108.5 (tq, JC-F = 259 Hz, 42 Hz), 117.8, 118.1 (qt,
JC-F = 287 Hz, 36 Гц), 157.3 (t, JC-F = 34 Hz, C3), 165.1
(C7a), 189.3 (C4). 19F NMR: δ ꢀ83.47 (3F, m, CF3),
ꢀ114.78 (2F, m, CF2). Anal. Calcd for C9H6F5NO2:
C, 42.37; H, 2.37; N, 5.49. Found: C, 42.43; H, 2.40;
N, 5.53.
3-(Perfluoropropyl)-6,7-dihydrobenzo-2,1-isoxazol-4(5H)-
one (5e).
This compound was obtained as colorless
crystals, yield 72% (method 1), mp 41–43°С. IR (KBr):
1712 (C=O), 1614 cmꢀ1 1H NMR: δ 2.20 (2Н, qui,
Method 2. To a stirred solution of 2-perfluoroalkanoyl-
.
5,5-dimethyl-3-methoxy-2-cyclohexen-1-ones
6a–c
J = 6.4 Hz, СН2), 2.61 (2Н, t, J = 6.4 Hz, СН2), 3.03
(2Н, t, J = 6.2 Hz, CH2). 13C NMR: δ 21.5, 22.0, 39.8,
108.4 (tm, JC-F = 268 Hz), 111.5 (tt, JC-F = 261 Hz,
33 Hz), 117.0 (qt, JC-F = 288, 34 Hz), 118.0, 157.2 (t,
JC-F = 34 Hz, C3), 165.1 (C7a), 189.1 (C4). 19F NMR: δ
(1.0 mmol) in methanol (25 mL), hydroxylamine
hydrochloride (0.070 g, 1.0 mmol) and NaOH (0.040 g,
1.0 mmol) were added. After stirring at room temperature
for 20 h, methanol was evaporated in vacuo. The
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Regioselective Synthesis of Polyfluoroalkyl Substituted 6,7-
Dihydrobenzisoxazolones
ꢀ80.32 (3F, m, CF3), ꢀ112.42 (2F, m, CF2), ꢀ125.29 (2F,
m, CF2). Anal. Calcd for C10H6F7NO2: C, 39.36; H, 1.98;
N, 4.59. Found: C, 39.30; H, 1.95; N, 4.55.
Acknowledgments. This work was financially supported by the
Belarusian Republican Foundation for Fundamental Research
(grant Kh16K–037) and by State Fund for Fundamental
Research of Ukraine (grant F73/18–2017).
3-(Bromodifluoromethyl)-6,6-dimethyl-6,7-dihydrobenzo-
2,1-isoxazol-4(5H)-one (5f). This compound was obtained
as colorless crystals, yield 71% (method 1), mp 46–48°С.
IR (KBr): 1700 (C=O), 1615 cmꢀ1 1H NMR: δ 1.13
.
REFERENCES AND NOTES
(6H, s, 2CH3), 2.48 (2Н, s, СН2), 2.85 (2H, s, СН2). 13C
NMR: δ 28.2, 34.8, 34.9, 53.5, 108.6 (t, JC-F = 304 Hz),
112.3, 162.4 (t, JC-F = 35 Hz, C3), 164.5 (C7a), 189.6
(C4). 19F NMR: δ ꢀ49.74 (s, CF2). Anal. Calcd for
C10H10BrF2NO2: C, 40.84; H, 3.43; N, 4.76. Found: C,
[1] Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N.
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40.91; H, 3.47; N, 4.80.
3-(Chlorodifluoromethyl)-6,6-dimethyl-6,7-dihydrobenzo-
2,1-isoxazol-4(5H)-one (5g). This compound was obtained
as colorless crystals, yield 75% (method 1), mp 30–32°С.
IR (KBr): 1710 (C=O), 1620 cmꢀ1 1H NMR: δ 1.13
.
(6H, s, 2CH3), 2.48 (2Н, s, СН2), 2.85 (2H, s, СН2). 13C
NMR: δ 28.2, 34.9, 53.4, 113.1, 118.6 (t, JC-F = 290 Hz),
161.2 (t, JC-F = 38 Hz, C3), 164.6 (C7a), 189.5 (4). 19F
NMR:
δ
ꢀ52.61 (s, CF2). Anal. Calcd for
C10H10ClF2NO2: C, 48.11; H, 4.04; N, 5.61. Found: C,
48.06; H, 4.00; N, 5.56.
3-(Trifluoromethyl)-6,6-dimethyl-6,7-dihydrobenzo-2,1-
isoxazol-4(5H)-one (5h). This compound was obtained as
colorless oil, yield 75% (method 1), 67% (method 2). IR
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thesis, chemistry and applications; John Willey and Sons: New Jersey,
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1
(film): 1714, 1635 cmꢀ1. H NMR: δ 1.12 (6Н, s, 2СН3),
2.47 (2Н, s, СН2), 2.85 (2H, s, СН2). 13C NMR: δ 28.0,
29.6, 34.6, 53.2, 114.8, 117.3 (q, JC-F = 273 Hz), 157.2 (q,
JC-F = 45 Hz, C3), 164.2 (C7a), 189.4 (C4). 19F NMR: δ
ꢀ63.36 (s, CF3). Anal. Calcd for C10H10F3NO2: C, 51.51;
[13] Khlebnicova, T. S.; Isakova, V. G.; Baranovsky, A. V.;
Borisov, E. V.; Lakhvich, F. A. J Fluorine Chem 2006, 127, 1564.
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Lakhvich, F. A. Rus J Gen Chem 2008, 78, 1954.
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Lakhvich, F. A. In Heterocyclic Compounds: Synthesis, Properties and
Applications; Nylund, K.; Jochanson, P., Eds.; Nova Science Publisher:
New York, 2010; pp. 171–182.
H, 4.32; N, 6.01. Found: C, 51.57; H, 4.36; N, 6.04.
3-(Perfluoroethyl)-6,6-dimethyl-6,7-dihydrobenzo-2,1-
isoxazol-4(5H)-one (5i). This compound was obtained as
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A.; Khlebnicova, T. S.; Lakhvich, F. A. Tetrahedron 2012, 68, 6131.
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Chem Soc Jpn 1986, 59, 2631.
colorless crystals, yield 73% (method 1), 67% (method
1
2), mp 26–27°С. IR (KBr): 1714, 1620 cmꢀ1. H NMR:
δ 1.11 (6Н, s, 2СН3), 2.46 (2Н, s, СН2), 2.85 (2H, s,
СН2). 13C NMR: δ 27.8, 34.4, 34.6, 53.3, 108.4 (tq,
JC-F = 259 Hz, 41 Hz), 116.9, 117.9 (qt, JC-F = 288 Hz,
2
36 Hz), 156.7 (t, JC-F 34 Hz, C3), 164.4 (C7a), 188.8
(C4). 19F NMR: δ ꢀ83.67 (3F, m, CF3), ꢀ114.88 (2F, m,
CF2). Anal. Calcd for C11H10F5NO2: C, 46.65; H, 3.56;
N, 4.95. Found: 46.60; H, 3.52; N, 4.91.
3-(Perfluoropropyl)-6,6-dimethyl-6,7-dihydrobenzo-2,1-
isoxazol-4(5H)-one (5j). This compound was obtained as
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colorless oil, yield 75% (method 1), 70% (method 2). IR
1
(film): 1717, 1620 cmꢀ1. H NMR: δ 1.13 (6Н, s, 2СН3),
2.48 (2Н, s, СН2), 2.88 (2H, s, СН2). 13C NMR: δ 27.9,
34.4, 34.7, 53.4, 108.3 (tm, JC-F = 269 Hz), 110.5 (tt,
JC-F = 261 Hz, 33 Hz), 117.1, 117.4 (qt, JC-F = 288 Hz,
33 Hz), 156.7 (t, JC-F = 34 Hz, C3), 164.4 (C7a), 188.7
(C4). 19F NMR: δ ꢀ80.40 (3F, m, CF3), ꢀ112.52 (2F, m,
CF2), ꢀ126.45 (2F, m, CF2). Anal. Calcd for
C12H10F7NO2: C, 43.26; H, 3.03; N, 4.20. Found: C,
43.21; H, 3.98; N, 4.15.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet