Synthesis of fluorine-containing 6,7-dihydrobenzisoxazolones from 2-(fluorobenzoyl)cyclohexane-1,3-diones and their methyl enol ethers

Article abstract of DOI:10.1007/s10593-018-2198-x

Regioisomeric fluorine-containing 6,7-dihydro-1,2-benzisoxazol-4(5Н)-ones and 6,7-dihydro-2,1-benzisoxazol-4(5Н)-ones were prepared by reactions of 2-(fluorobenzoyl)cyclohexane-1,3-diones or their methyl enol ethers with hydroxylamine.

Full text of DOI:10.1007/s10593-018-2198-x

DOI 10.1007/s10593-018-2198-x
Chemistry of Heterocyclic Compounds 2017, 53(11), 1254–1260
Synthesis of fluorine-containing 6,7-dihydrobenzisoxazolones
from 2-(fluorobenzoyl)cyclohexane-1,3-diones
and their methyl enol ethers
Tat'yana S. Khlebnikova1*, Yurii A. Piveń1, Veronika G. Isakova1,
Alexander V. Baranovsky1, Fedor A. Lakhvich1
1 Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus,
5/2 Akademika Kuprevicha St., Minsk 220100, Belarus;
e-mail: khlebnicova@iboch.bas-net.by
Submitted June 21, 2017
Accepted October 9, 2017
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2017, 53(11), 1254–1260
Regioisomeric fluorine-containing 6,7-dihydro-1,2-benzisoxazol-4(5Н)-ones and 6,7-dihydro-2,1-benzisoxazol-4(5Н)-ones were
prepared by reactions of 2-(fluorobenzoyl)cyclohexane-1,3-diones or their methyl enol ethers with hydroxylamine.
Keywords: 2-(fluorobenzoyl)cyclohexane-1,3-diones, 3-(fluorophenyl)-6,7-dihydrobenzisoxazolones, hydroxylamine hydrochloride,
methyl enol ethers, cyclocondensation, nucleophilic vinylogous substitution.
Isoxazole ring and isoxazole-containing fused ring
systems are found in a large variety of compounds, serving
as the basis for many modern antiviral, antitumor, and anti-
inflammatory drugs, and are also currently used as crop
protection agents.1 Selective introduction of fluorine
substituents and fluoroalkyl groups in biologically active
molecules can substantially affect their physicochemical
properties, reactivity, biological activity and provides an
effective strategy for the design of new pharmaceutical
agents, as well as for enhancing the efficacy of established
drugs.2 The importance of this field is illustrated by the
steadily increasing number of fluorinated active pharma-
ceutical ingredients that have been already approved for
market, or currently undergo clinical trials.3 Fluorine-
containing isoxazoles show a broad spectrum of biological
activity, including antitumor, anti-inflammatory, and other
effects.4 The active development of advanced synthetic
methods provides access to various new fluorine-containing
polyfunctional heterocyclic structures as potential drugs
and crop protection agents.5 One of the most promising
approaches includes the use of polycarbonyl compounds as
building blocks for the preparation of biologically active
fluorine-containing organic compounds. The examples of
such building blocks include cyclic fluoroacyl-β-dike-
tones.6 Due to their polyfunctionality, fluorinated 2-benzoyl-
cyclohexane-1,3-diones 1, similarly to their nonfluorinated
analogs employed as powerful herbicides in agriculture,7 as
well as active molecules in medicinal chemistry,8 can serve
as effective building blocks for the construction of
heterocyclic structures.
Previously we developed an effective method for the
synthesis of 2-(fluorobenzoyl)cyclohexane-1,3-diones 1,9
which included О−С isomerization of 3-oxocyclohex-1-en-
1-yl fluorobenzoates 2 by the action of acetone cyano-
hydrin in the presence of triethylamine in chloroform,
providing access to such compounds and enabling further
investigations of their reactivity. The types of chemical
transformations known for fluorine-containing 2-benzoyl-
cyclohexane-1,3-diones 1 include the reactions of these
compounds or their enol derivatives with amines10 and
N,N-dinucleophiles.11
The aim of this work was to synthesize new 3-(fluoro-
phenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-ones
and
3-(fluorophenyl)-6,7-dihydro-2,1-benzisoxazol-4(5H)-ones
with potential biological activity. The most common
methods for the preparation of nonfluorinated as well as
fluorinated isoxazoles include the condensation of hydr-
oxylamine with various 1,3-dienophiles (1,3-ketoalde-
hydes, 1,3-diketones, 1,3-ketonitriles, and other compounds)
and 1,3-dipolar addition reactions of nitrile oxides to
dipolarophiles – alkenes (followed by spontaneous or oxida-
tive aromatization), alkynes,4,12 1,3-diketones13 and their
0009-3122/17/53(11)-1254©2017 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2017, 53(11), 1254–1260
Scheme 1
derivatives. The result of the reaction between fluorine-
containing 1,3-diketones and hydroxylamine depended on
such factors as the nature of substituents and structure of
β-diketone and the reaction conditions.6 The main chemical
transformations of cyclic β-triketones existing in enol form
could occur at such reactive sites as the exo- and endo-
cyclic carbonyl groups.14 In order to obtain new
regioisomeric fluorophenyl-substituted isoxazolones, we
studied the reaction of hydroxylamine hydrochloride with
2-benzoylcyclohexane-1,3-diones 1a–f containing fluorine
atoms in the aromatic ring or with their methyl enol ethers
3a–f (Scheme 1).
nucleophilic attack by hydroxylamine. As known in the
case of 2-acetylcyclohexane-1,3-diones,15 this can be
achieved by initially converting these triketones into
methyl enol ethers, followed by a reaction of the latter with
hydroxylamine. A range of methods have been proposed
for the synthesis of methyl enol ethers of 2-acylcyclo-
hexane-1,3-diones, including O-alkylation of their silver
salts with iodomethane,16 alkylation of sodium or
tetrabutylammonium salts with dimethyl sulfate,17 as well
as treatment with diazomethane.18 It should be noted,
however, that this led to an intractable mixture of products
in the case of 2-acetylcyclohexane-1,3-dione.19 We
obtained methyl enol ethers of 2-(fluorobenzoyl)cyclo-
hexane-1,3-diones 3a–f by treatment of triketones 1a–f
with diazomethane. The reaction was performed by adding
an excess of ethereal diazomethane solution at 0°С to a
solution of 2-(fluorobenzoyl)cyclohexane-1,3-dione 1a–f in
ether over 5 min, followed by stirring of the reaction
mixture for 3 h at room temperature. Products 3a–f were
obtained in 57–72% yields. The treatment of methyl ethers
3a–f with an equimolar mixture of NH2OH·HCl and NaOH
in methanol for 8 h at room temperature provided 6,7-di-
hydro-2,1-benzisoxazol-4(5H)-ones 5a–f as the only pro-
ducts in 86–95% yields. Under the indicated conditions, as
well as in the case of nonfluorinated 2-acetylcyclohexane-
1,3-diones,14 the reaction of methyl enol ethers 5a–f with
hydroxylamine proceeded according to vinylogous
substitution mechanism with subsequent intramolecular
cyclization.
The treatment of 2-(fluorobenzoyl)cyclohexane-1,3-
diones 1a–f with an equimolar mixture of NH2OH·HCl and
NaOH in methanol for 20 h at room temperature led to the
formation of 6,7-dihydro-1,2-benzisoxazol-4(5H)-ones 4a–f
as the major products. In the case of 2-(4-fluorobenzoyl)-
cyclohexane-1,3-diones 1c,f, the reaction was regio-
selective, leading to the formation of only 1,2-benz-
isoxazolones 4с,f in high yields (89–93%), while the
reactions with 2-(2-fluorobenzoyl)- and 2-(3-fluoro-
benzoyl)cyclohexane-1,3-diones 1a,b,d,e led to the
formation of 1,2-benzisoxazolones 4a,b,d,e as the major
products, accompanied by 2,1-benzisoxazolones 5a,b,d,e
1
as the minor products (according to Н and 19F NMR data,
the following ratios were established – 4a:5a = 17:1, 4b:5b
= 100:1, 4d:5d = 3:1, 4e:5e = 13:1). As the distance of the
fluorine atom of the aromatic ring from the side chain car-
bonyl group was increased, the content of the minor 2,1-benz-
isoxazolones 5a,b,d,e was decreased. Compounds 4a,b,d,e
were isolated in 79, 82, 66, and 75% yields, respectively,
while isoxazolone 5d was obtained in 22% yield. The
cyclocondensation of 2-(fluorobenzoyl)cyclohexane-1,3-di-
ones 1a–f with hydroxylamine hydrochloride under the
indicated conditions proceeded mostly at the most
electrophilic exocyclic carbonyl group, i.e., at the carbonyl
carbon atom bonded to the fluorophenyl group.
The structures of the synthesized compounds 1–5 a–f
were confirmed by using the data of elemental analysis, IR
spectroscopy, as well as 1Н, 13С, and 19F NMR
spectroscopy. IR spectra of methyl ethers 3a–f contained
characteristic absorption bands of two conjugated carbonyl
groups (in the ranges of 1650–1680 and 1630–1640 cm–1)
and the carbon–carbon double bond (in the range of 1595–
1
1610 cm–1). Н NMR spectra (CDCl3) featured a singlet in
In order to obtain fluorophenyl-substituted 6,7-dihydro-
2,1-benzisoxazol-4(5H)-ones that are structural isomers of
isoxazolones 4a–f, it is necessary to alter the direction of
the range of 3.73–3.75 ppm, corresponding to the methoxy
group protons. 13C NMR spectra of compounds 4a–f showed
the signal of carbonyl carbon atom (С-4) and the signals of
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Chemistry of Heterocyclic Compounds 2017, 53(11), 1254–1260
C–О (C-7a) and C=N (C-3) carbon atoms at 190.9–192.3,
180.8–182.5, and 155.2–159.2 ppm, respectively, while the
signals of С-4 (C=O), С-3 (C–О), and С-7a (C=N) carbon
atoms in 13C NMR spectra of isomeric isoxazolones 5a–f
were observed at 191.6–192.7, 166.2–169.8, and 163.8–
165.1 ppm, respectively. The presence of fluorine atoms
bonded to the aromatic ring in structures of compounds
3–5 a–f was confirmed by the observation of a doublet
signal in 13С NMR spectra in the range of 160.0–165.0 ppm
(1JCF = 246–258 Hz) due to the carbon atom bearing a
fluorine substituent, as well as the presence of fluorine
signals in the range from –105.3 to –113.1 ppm in 19F NMR
spectra.
Additional spectral studies were performed in order to
prove the structures of the synthesized isomeric
benzisoxazolones 4–5 a–f. The pair of regioisomers 4c and
5c was selected for spectral analysis using two-dimensional
NMR experiments. The quaternary carbon signals and
nitrogen signals in the benzisoxazole moiety were assigned
based on HMBC data. The signal of С-7а carbon atom was
identified by the presence of a cross peak with the proton
bonded to the С-7 carbon atom, while the signal of С-3
carbon atom was recognized from its coupling to the ortho
proton of aromatic ring. In the case of compound 4c, the
signal of С-7а nucleus was observed at lower field
(182.0 ppm) than for its isomer 5c (164.6 ppm). The
opposite situation was observed for the nucleus of С-3
carbon atom: the signal of benzisoxazole 5c was observed
at lower field (169.5 ppm), while the analogous signal of
compound 4c – at stronger field (159.0 ppm). This trend
was also evident for isomeric isoxazoles reported in the
literature20 and corresponded to the electron density
distribution in the molecule. The assignment of signals was
additionally confirmed by the results of two-dimensional
1H–15N HMBC experiments. In the case of compound 5c,
HMBC spectrum showed a strong cross peak (3J) between
the proton at С-7 carbon atom and the nitrogen nucleus.
This cross peak was also observed for isomer 4c, but it was
significantly weaker (4J). At the same time, no coupling
between the nitrogen nucleus and the ortho proton of
substituent at the С-3 carbon atom (4J) was evident in the
spectrum of compound 4c.
sample temperature in CDCl3. Residual sovent signals were
1
used as internal standards for Н and 13С NMR spectra
1
(7.26 ppm for Н nuclei and 77.16 ppm for 13С nuclei).
External standards were used for 19F NMR (α,α,α-tri-
fluorotoluene signal at –63 ppm) and 15N NMR spectra
(MeNO2 signal at 380 ppm). The two-dimensional NMR
1
1
spectra (1H–13С HSQC, COSY, H–13С HMBC, H–15N
HMBC) were acquired and processed by using the standard
software supplied by Bruker. Melting points were deter-
mined on a Boetius hot stage. Elemental analysis was per-
formed on a EuroVector EA3000 CHNS-O analyzer. The
reaction progress and purity of the obtained compounds
were controlled by a TLC method on Silufol UV–254
plates, with EtOAc–hexane as eluent. Column chromato-
graphy was performed on silica gel (70–230 mesh).
2-(Fluorobenzoyl)cyclohexane-1,3-diones 1a–f were ob-
tained as colorless crystals by О−С isomerization of (3-oxo-
cyclohex-1-en-1-yl) fluorobenzoates 2a–f by the action of
acetone cyanohydrin in the presence of triethylamine in
acetonitrile according to a published procedure.9 The
physicochemical characteristics of 2-(2-fluorobenzoyl)-
5,5-dimethylcyclohexane-1,3-dione (1а), 2-(3-fluorobenzoyl)-
5,5-dimethylcyclohexane-1,3-dione (1b), and 2-(4-fluoro-
benzoyl)-5,5-dimethylcyclohexane-1,3-dione (1c) were in
agreement with the data reported in literature.9
A
compound, described in the work,21 was assigned the
structure of β-triketone 1e. However the spectral data
presented in that study did not confirm the claimed
1
structure. H NMR spectrum of the described compound
lacked the signal of enol proton in the downfield region at
16–17 ppm, which would be characteristic for 2-benzoyl-
cyclohexane-1,3-diones that exist in solutions as enol
tautomers with a strong intramolecular bond.9,22 At the
same time, a signal was present at 6 ppm, which
corresponded to the vinyl proton signal in compound 2e.
13С NMR spectrum contained signals of the carbonyl
carbon atoms at 199.3 and 169.8 ppm, which also matched
the signals in 13C NMR spectrum of compound 2e.
Compounds 1d,23 1f24 have been described in patents
without characterization of their physicochemical
properties.
2-(2-Fluorobenzoyl)cyclohexane-1,3-dione (1d). Yield
2.53 g (80%), mp 46–49°С (Et2O–hexane). IR spectrum,
ν, cm–1: 1685 (С=О conjug.), 1610 (С=О chelate), 1550
(C=C). 1H NMR spectrum, δ, ppm (J, Hz): 2.06 (2Н, quin,
J = 6.4, СН2); 2.49 (2Н, t, J = 6.4, СН2); 2.76 (2Н, t, J = 6.4,
СН2); 7.03–7.06 (1Н, m, Н Ar); 7.20–7.24 (1Н, m, Н Ar);
7.41–7.48 (2Н, m, Н Ar); 16.89 (1H, br. s, ОН). 13C NMR
spectrum, δ, ppm (J, Hz): 19.2; 32.3; 37.8; 114.8; 115.4 (d,
JCF = 22); 124.2; 127.6 (d, JCF = 15); 128.9 (d, JCF = 1);
132.8 (d, JCF = 8), 159.3 (d, JCF = 251); 194.1; 194.2; 195.7.
19F NMR spectrum, δ, ppm: –112.74 (m, F). Found, %:
С 66.61; Н 4.70. C13H11FO3. Calculated, %: C 66.66; H 4.73.
2-(3-Fluorobenzoyl)cyclohexane-1,3-dione (1е). Yield
2.59 g (82%), mp 52–55°С (Et2O–hexane). IR spectrum,
ν, cm–1: 1655 (С=О conjug.), 1610 (С=О chelate), 1570
(C=C). 1H NMR spectrum, δ, ppm (J, Hz): 2.08 (2Н, quin,
J = 6.2, СН2); 2.50 (2Н, t, J = 6.2, СН2); 2.76 (2Н, t,
J = 6.2, СН2); 7.17–7.21 (2Н, m, Н Ar); 7.26–7.28 (1Н, m,
Thus, 2-benzoylcyclohexane-1,3-diones containing fluo-
rine atoms in the aromatic ring participated in cyclo-
condensation reactions with hydroxylamine preferentially
at the most electrophilic exocyclic carbonyl group, forming
3-(fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5Н)-ones
as the major products, while their methyl enol ethers
reacted with hydroxylamine via vinylogous substitution
mechanism followed by intramolecular cyclization, form-
ing 3-fluorophenyl-6,7-dihydro-2,1-benzisoxazol-4(5Н)-ones
as the only products.
Experimental
IR spectra were recorded on a PerkinElmer Spectrum
1
100 FTIR spectrometer in KBr pellets. Н, 19F, 13С, and
15N NMR spectra were acquired on a Bruker Avance 500
instrument (500, 470, 125, and 50 MHz, respectively) by
using a 5 mm probe (QNP) with Z-gradient at 293 K
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Chemistry of Heterocyclic Compounds 2017, 53(11), 1254–1260
Н Ar); 7.34–7.39 (1Н, m, Н Ar); 16.71 (1H, br. s, ОН).
1.7 mmol) was added over 5 min to a solution of triketone
1a–f (1.15 mmol) in diethyl ether (30 ml) with stirring and
cooling to 0°С. The reaction mixture was stirred for 3 h at
room temperature, the solvent was removed by evaporation
at reduced pressure, and the obtained residue was separated
by silica gel column chromatography (eluent EtOAc–
hexane, gradient from 1:10 to 1:3), providing methyl esters
3a–f as colorless crystals. The products were recrystallized
from an Et2O–hexane mixture.
13C NMR spectrum, δ, ppm (J, Hz): 19.1; 32.3; 38.0; 113.2;
115.2 (d, JCF = 23); 118.7 (d, JCF = 21); 123.9 (d, JCF = 2);
129.4 (d, JCF = 8); 140.4 (d, JCF = 7); 162.0 (d, JCF = 247);
194.1; 196.2; 197.9. 19F NMR spectrum, δ, ppm: –113.28
(m, F). Found, %: С 66.59; Н 4.68. C13H11FO3. Calculated, %:
C 66.66; H 4.73.
2-(4-Fluorobenzoyl)cyclohexane-1,3-dione (1f). Yield
2.53 g (80%), mp 164–167°С (Et2O–hexane). IR spectrum,
ν, cm–1: 1665 (С=О conjug.), 1595 (С=О chelate), 1565
2-(2-Fluorobenzoyl)-3-methoxy-5,5-dimethylcyclohex-
2-en-1-one (3а). Yield 0.22 g (57%), mp 84–87°С.
IR spectrum, ν, cm–1: 1650 (C=O), 1640 (C=O), 1605
1
(C=C). H NMR spectrum, δ, ppm (J, Hz): 2.07 (2Н, quin,
J = 6.4, СН2); 2.50 (2Н, t, J = 6.4, СН2); 2.74 (2Н, t,
J = 6.4, СН2); 7.05–7.08 (2Н, m, Н Ar); 7.55–7.58 (2Н, m,
Н Ar); 16.87 (1H, br. s, ОН). 13C NMR spectrum, δ, ppm
(J, Hz): 19.1; 32.4; 38.1; 113.1; 114.9 (d, JCF = 22); 131.2
(d, JCF = 9); 134.2 (d, JCF = 22); 165.1 (d, JCF = 253); 194.3;
196.2; 197.6. 19F NMR spectrum, δ, ppm: –106.81 (m, F).
Found, %: С 66.72; Н 4.76. C13H11FO3. Calculated, %:
C 66.66; H 4.73.
1
(С=С). H NMR spectrum, δ, ppm: 1.18 (6H, s, 2СН3);
2.31 (2Н, s, СН2); 2.52 (2Н, s, СН2); 3.75 (3Н, s, ОCH3);
7.01–7.05 (1Н, m, Н Ar); 7.19–7.23 (1H, m, Н Ar); 7.45–
7.50 (1Н, m, Н Ar); 7.87–7.90 (1H, m, H Ar). 13C NMR
spectrum, δ, ppm (J, Hz): 28.5; 31.9; 40.0; 50.4; 57.0;
116.4 (d, JCF = 23); 121.1; 124.3 (d, JCF = 3); 126.8 (d,
JCF = 10); 130.9; 134.5 (d, JCF = 9); 161.7 (d, JCF = 256);
173.6; 190.8; 196.3. 19F NMR spectrum, δ, ppm: –113.06
(m, F). Found, %: C 69.50; H 6.17. C16H17FO3. Calculated, %:
C 69.55; H 6.20.
3-Oxocyclohex-1-en-1-yl fluorobenzoates 2a–f were
obtained as colorless crystalline products by О-acylation of
dimedone or dihydroresorcinol with fluorobenzoyl
chlorides in the presence of pyridine in chloroform
according to a published procedure.25 The physicochemical
characteristics of 5,5-dimethyl-3-oxocyclohex-1-en-1-yl
2-fluorobenzoate (2а),9 5,5-dimethyl-3-oxocyclohex-1-en-
1-yl 3-fluorobenzoate (2b),9 5,5-dimethyl-3-oxocyclohex-
1-en-1-yl 4-fluorobenzoate (2c),9 and 3-oxocyclohex-1-en-
1-yl 2-fluorobenzoate (2d)26 matched those reported in the
literature.
2-(3-Fluorobenzoyl)-3-methoxy-5,5-dimethylcyclohex-
2-en-1-one (3b). Yield 0.23 g (59%), mp 114–117°С.
IR spectrum, ν, cm–1: 1680 (C=O), 1630 (C=O), 1605
1
(C=C). H NMR spectrum, δ, ppm: 1.22 (6H, s, 2СН3);
2.35 (2Н, s, СН2); 2.55 (2Н, s, СН2); 3.73 (3Н, s, ОСН3);
7.21–7.25 (1Н, m, H Ar); 7.38–7.42 (1H, m, H Ar), 7.52–
7.55 (1Н, m, H Ar); 7.60–7.62 (1H, m, H Ar). 13C NMR
spectrum, δ, ppm (J, Hz): 28.7; 32.2; 39.9; 50.3; 56.8;
115.6 (d, JСF = 22); 118.3; 120.2 (d, JCF =22), 124.9 (d,
JCF = 2); 130.2 (d, JCF = 8); 139.8 (d, JCF = 6); 162.8 (d,
JCF = 247); 173.7; 194.0; 196.3. 19F NMR spectrum,
δ, ppm: –112.7 (m, F). Found, %: C 69.61; H 6.24.
C16H17FO3. Calculated, %: C 69.55; H 6.20.
3-Oxocyclohex-1-en-1-yl 3-fluorobenzoate (2e). Yield
4.31 g (92%), mp 40–43°С (Et2O–hexane). IR spectrum,
ν, cm–1: 1735 (С=О ester), 1670 (С=О conjug.), 1590
1
(С=С). H NMR spectrum, δ, ppm (J, Hz): 2.14 (2Н, quin,
J = 6.5, СН2); 2.48 (2Н, t, J = 6.5, СН2); 2.69 (2Н, td,
J = 1.0, J = 6.5, СН2); 6.06 (1Н, br. s, Н vinyl); 7.33–7.37
(1Н, m, Н Ar); 7.47–7.52 (1Н, m, Н Ar); 7.75–7.78 (1Н,
m, Н Ar); 7.88–7.90 (1H, m, Н Ar). 13C NMR spectrum,
δ, ppm (J, Hz): 21.3; 28.4; 36.8; 117.1 (d, JCF = 23); 118.0;
121.3 (d, JCF = 21); 126.0 (d, JCF = 2); 130.5 (d, JCF = 8);
130.8 (d, JCF = 8); 162.1 (d, JCF = 2); 162.6 (d, JCF = 248);
169.8; 199.4. 19F NMR spectrum, δ, ppm: –111.70 (m, F).
Found, %: С 66.60; Н 4.68. C13H11FO3. Calculated, %:
C 66.66; H 4.73.
2-(4-Fluorobenzoyl)-3-methoxy-5,5-dimethylcyclohex-
2-en-1-one (3c). Yield 0.24 g (60%), mp 115–118°С.
IR spectrum, ν, cm–1: 1675 (С=О), 1640 (С=О), 1600
1
(С=С). H NMR spectrum, δ, ppm: 1.22 (6H, s, 2СН3);
2.35 (2Н, s, СН2); 2.54 (2Н, s, СН2); 3.73 (3Н, s, ОСН3);
7.09–7.12 (2Н, m, Н Ar); 7.86–7.90 (2H, m, Н Ar).
13C NMR spectrum, δ, ppm (J, Hz): 28.7; 32.2; 39.8; 50.3;
56.7; 115.7 (d, JСF = 22); 118.5; 131.8 (d, JСF = 9); 134.1
(d, JСF = 2); 165.9 (d, JСF = 255); 173.5; 193.6; 196.4.
19F NMR spectrum, δ, ppm: –105.3 (m, F). Found, %:
C 69.62; H 6.25. C16H17FO3. Calculated, %: C 69.55; H 6.20.
2-(2-Fluorobenzoyl)-3-methoxycyclohex-2-en-1-one (3d).
Yield 0.22 g (63%), mp 122–124°С. IR spectrum, ν, cm–1:
1665 (С=О), 1640 (С=О), 1610 (С=С). 1H NMR spectrum,
δ, ppm (J, Hz): 2.08 (2H, quin, J = 6.0, CH2); 2.42 (2H, t,
J = 6.7, CH2); 2.66 (2H, t, J = 6.2, CH2); 3.75 (3H, s,
ОCH3); 7.00–7.04 (1H, m, Н Ar); 7.19–7.22 (1H, m,
Н Ar); 7.45–7.49 (1H, m, Н Ar); 7.87–7.91 (1H, m, Н Ar).
13C NMR spectrum, δ, ppm (J, Hz): 20.4; 26.1; 36.5; 56.9;
116.6 (d, JCF = 23); 122.5; 124.4 (d, JCF = 3); 126.6 (d,
JCF = 9); 131.1; 134.7 (d, JCF = 9); 162.0 (d, JCF = 256);
174.8; 191.0; 196.5. 19F NMR spectrum, δ, ppm: –112.6
(m, F). Found, %: C 67.80; H 5.31. C14H13FO3. Calculated, %:
C 67.73; H 5.28.
3-Oxocyclohex-1-en-1-yl 4-fluorobenzoate (2f). Yield
3.94 g (84%), mp 44–47°С (Et2O–hexane). IR spectrum,
ν, cm–1: 1730 (С=О ester), 1670 (С=О conjug.), 1600
1
(С=С). H NMR spectrum, δ, ppm (J, Hz): (2Н, quin,
J = 6.5, СН2); 2.48 (2Н, t, J = 6.5, СН2); 2.70 (2Н, t,
J = 6.5, СН2); 6.06 (1Н, br. s, Н vinyl); 7.16–7.21 (2Н, m,
Н Ar), 8.10–8.14 (2Н, m, Н Ar). 13C NMR spectrum,
δ, ppm (J, Hz): 21.6; 28.4; 36.8; 116.0 (d, JCF = 22); 117.9;
124.9 (d, JCF = 2); 136.0 (d, JCF = 10); 162.2; 166.4 (d,
J
CF = 256); 170.0; 199.4. 19F NMR spectrum, δ, ppm:
–103.46 (m, F). Found, %: С 66.74; Н 4.78. C13H11FO3.
Calculated, %: C 66.66; H 4.73.
Preparation of 2-(fluorobenzoyl)-3-methoxycyclohex-
2-en-1-ones 3a–f (General method). An ethereal diazo-
methane solution (concentration 0.48 mmol/ml) (3.6 ml,
1257

Chemistry of Heterocyclic Compounds 2017, 53(11), 1254–1260
2-(3-Fluorobenzoyl)-3-methoxycyclohex-2-en-1-one (3e).
IR spectrum, ν, cm–1: 1690 (C=O), 1625, 1590, 1515, 1480.
1H NMR spectrum, δ, ppm: 1.20 (6Н, s, 2СН3); 2.50 (2Н,
s, СН2); 2.93 (2Н, s, СН2); 7.16–7.20 (1Н, m, Н Ar); 7.41–
7.46 (1Н, m, Н Ar); 7.88–7.94 (2Н, m, Н Ar). 13C NMR
spectrum, δ, ppm (J, Hz): 28.2; 35.1; 37.0; 53.2; 113.1;
116.2 (d, JCF = 24); 117.5 (d, JCF = 21); 124.9 (d, JCF = 2);
129.4 (d, JCF = 9); 130.0 (d, JCF = 8); 158.8 (d, JCF = 1,
C-3); 162.6 (d, JCF = 246, C-3'); 182.0 (C-7a); 191.5 (C-4).
19F NMR spectrum, δ, ppm: –112.70 (m, F). Found, %:
C 69.57; H 5.49; N 5.48. C15H14FNO2. Calculated, %:
C 69.49; H 5.44; N 5.40.
Yield 0.25 g (72%), mp 156–159°С. IR spectrum, ν, cm–1:
1675 (С=О), 1640 (С=О), 1610 (С=С). 1H NMR spectrum,
δ, ppm (J, Hz): 2.11–2.17 (2H, m, CH2); 2.45 (2H, t,
J = 6.6, CH2); 2.69 (2H, t, J = 6.2, CH2); 3.73 (3H, s,
ОCH3); 7.20–7.24 (1Н, m, Н Ar); 7.37–7.41 (1Н, m,
Н Ar); 7.52–7.54 (1Н, m, Н Ar); 7.61–7.63 (1Н, m, Н Ar).
13C NMR spectrum, δ, ppm (J, Hz): 20.6; 25.8; 36.4; 56.7;
115.7 (d, JCF = 22); 119.6; 120.3 (d, JCF = 22); 125.0 (d,
JCF = 2); 130.3 (d, JCF = 8); 139.6 (d, JCF = 6); 163.0 (d,
JCF = 247); 175.5; 194.1; 196.5. 19F NMR spectrum,
δ, ppm: –112.5 (m, F). Found, %: C 67.68; H 5.24.
C14H13FO3. Calculated, %: C 67.73; H 5.28.
3-(4-Fluorophenyl)-6,6-dimethyl-6,7-dihydro-1,2-benz-
isoxazol-4(5Н)-one (4c). Yield 0.22 g (86%), mp 70–73°С.
IR spectrum, ν, cm–1: 1680, 1610, 1585, 1530, 1460.
1H NMR spectrum, δ, ppm: 1.20 (6Н, s, 2СН3); 2.49 (2Н,
s, 5-СН2); 2.92 (2Н, s, 7-СН2); 7.13–7.17 (2Н, m, Н-3',5');
8.13–8.16 (2Н, m, H-2',6'). 13C NMR spectrum, δ, ppm (J, Hz):
28.4 (2CH3); 35.2 (C-6); 37.2 (C-7); 53.3 (C-5); 113.1
(C-3a); 115.7 (d, JCF = 22, C-3',5'); 123.7 (d, JCF = 3, C-1');
131.5 (d, JCF = 9, C-2',6'); 159.0 (С-3); 164.3 (d, JCF = 251,
C-4'); 182.0 (C-7a); 191.8 (C-4). 19F NMR spectrum, δ, ppm:
–109.90 (m, F). 15N NMR spectrum, δ, ppm: 378. Found, %:
C 69.41; H 5.40; N 5.35. C15H14FNO2. Calculated, %:
C 69.49; H 5.44; N 5.40.
2-(4-Fluorobenzoyl)-3-methoxycyclohex-2-en-1-one (3f).
Yield 0.25 g (72%), mp 102–104°С. IR spectrum, ν, cm–1:
1675 (С=О), 1635 (С=О), 1595 (С=С). 1H NMR spectrum,
δ, ppm (J, Hz): 2.13 (2H, quin, J = 6.0, CH2); 2.45 (2H, t,
J = 6.7, CH2); 2.69 (2H, t, J = 6.2, CH2); 3.73 (3H, s,
ОCH3); 7.06–7.10 (2Н, m, Н Ar); 7.85–7.89 (2Н, m,
Н Ar). 13C NMR spectrum, δ, ppm (J, Hz): 20.6; 25.8;
36.5; 56.6; 115.7 (d, JCF = 22); 119.7; 131.9 (d, JCF = 9);
134.0 (d, JCF = 2); 166.0 (d, JCF = 255); 175.2; 193.8;
196.5. 19F NMR spectrum, δ, ppm: –112.5 (m, F). Found,
%: C 67.65; H 5.23. C14H13FO3. Calculated, %: C 67.73;
H 5.28.
Preparation of 3-(fluorophenyl)-6,7-dihydro-1,2-
benzisoxazol-4(5Н)-ones 4a–f and 3-(fluorophenyl)-6,7-
dihydro-2,1-benzisoxazol-4(5Н)-ones 5a–f (General
method). NH2OH·HCl (1.0 mmol) and NaOH (1.0 mmol)
were added to a solution of the appropriate triketone 1a–f
or methyl ether 3a–f (1.0 mmol) in MeOH (5 ml) with
stirring. The reaction mixture was stirred at room
temperature for 20 h (reactions with triketones) or 8 h
(reactions with methyl ethers). The solvent was removed
by evaporation at reduced pressure, and the residue was
dissolved in CHCl3 (50 ml), washed with saturated
NaHCO3 solution (2×15 ml), water (15 ml), and dried over
anhydrous Na2SO4. The solvent was removed by
evaporation at reduced pressure and the obtained residue
was separated by silica gel column chromatography (eluent
EtOАс–hexane, gradient from 1:10 to 1:3), providing
isoxazolones 4a–f or 5a–f as colorless crystals. The
products were recrystallized from Et2O–hexane mixture.
Compounds 4d,f have been mentioned in patents without a
description of their physicochemical properties.26,27
3-(2-Fluorophenyl)-6,6-dimethyl-6,7-dihydro-1,2-benz-
isoxazol-4(5Н)-one (4a). Yield 0.21 g (79%), mp 87–91°С.
IR spectrum, ν, cm–1: 1695, 1620, 1600, 1525, 1480.
1H NMR spectrum, δ, ppm: 1.19 (6Н, s, 2СН3); 2.46 (2Н,
s, СН2); 2.94 (2Н, s, СН2); 7.17–7.27 (2Н, m, Н Ar); 7.46–
7.50 (1Н, m, Н Ar); 7.61–7.65 (1Н, m, Н Ar). 13C NMR
spectrum, δ, ppm (J, Hz): 28.3; 35.4; 36.9; 52.7; 114.1;
115.8 (d, JCF = 14); 116.0 (d, JCF = 21); 124.0 (d, JCF = 3);
131.2; 132.2 (d, JCF = 8); 155.2 (С-3); 160.4 (d, JCF = 253,
C-2'); 180.8 (C-7a); 190.9 (C-4). 19F NMR spectrum, δ, ppm:
–112.38 (m, F). Found, %: C 69.56; H 5.48; N 5.46.
C15H14FNO2. Calculated, %: C 69.49; H 5.44; N 5.40.
3-(3-Fluorophenyl)-6,6-dimethyl-6,7-dihydro-1,2-benz-
isoxazol-4(5Н)-one (4b). Yield 0.21 g (82%), mp 77–80°С.
3-(2-Fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5Н)-
one (4d). Yield 0.15 g (66%), mp 82–84°С. IR spectrum,
1
ν, cm–1: 1700, 1620, 1600, 1580, 1510, 1470. H NMR
spectrum, δ, ppm (J, Hz): 2.47 (2H, quin, J = 6.5, CH2);
2.54 (2H, t, J = 6.5, CH2); 3.06 (2H, t, J = 6.4, CH2); 7.16–
7.26 (2H, m, H Ar); 7.44–7.49 (1H, m, H Ar); 7.56–7.60
(1H, m, H Ar). 13C NMR spectrum, δ, ppm (J, Hz): 22.2;
23.3; 38.3; 115.1; 116.1 (d, JCF = 21); 121.4 (d, JCF = 5);
124.1 (d, JCF = 3); 131.2; 132.2 (d, JCF = 8); 155.4 (С-3);
160.5 (d, JCF = 253, C-2'); 181.4 (C-7a); 191.6 (С-4).
19F NMR spectrum, δ, ppm: –106.70 (m, F). Found, %:
C 67.60; H 4.42; N 6.14. C13H10FNO2. Calculated, %:
C 67.53; H 4.36; N 6.06.
3-(3-Fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5Н)-
one (4e). Yield 0.17 g (75%), mp 48–50°С. IR spectrum,
1
ν, cm–1: 1685, 1640, 1615, 1590, 1575, 1470. H NMR
spectrum, δ, ppm (J, Hz): 2.26 (2H, quin, J = 6.5, CH2);
2.61 (2H, t, J = 6.5, CH2); 3.07 (2H, t, J = 6.4, CH2); 7.15–
7.19 (1H, m, H Ar); 7.41–7.45 (1H, m, H Ar); 7.83–7.86
(1H, m, H Ar); 7.87–7.89 (1H, m, H Ar). 13C NMR
spectrum, δ, ppm (J, Hz): 22.1; 23.6; 38.8; 114.2; 116.4 (d,
JCF = 24); 117.6 (d, JCF = 24); 125.1 (d, JCF = 3); 129.5 (d,
JCF = 8); 130.1 (d, JCF = 8); 159.1 (С-3); 162.7 (d,
JCF = 246, C-3'); 182.5 (C-7a); 192.1 (С-4). 19F NMR
spectrum, δ, ppm: –112.50 (m, F). Found, %: C 67.59; H 4.40;
N 6.11. C13H10FNO2. Calculated, %: C 67.53; H 4.36;
N 6.06.
3-(4-Fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5Н)-
one (4f). Yield 0.18 g (79%), mp 59–61°С. IR spectrum,
1
ν, cm–1: 1680, 1640, 1610, 1580, 1520, 1465. H NMR
spectrum, δ, ppm (J, Hz): 2.26 (2H, quin, J = 6.4, CH2);
2.60 (2H, t, J = 6.5, CH2); 3.06 (2H, t, J = 6.3, CH2); 7.12–
7.16 (2H, m, H Ar); 8.08–8.10 (2H, m, H Ar). 13C NMR
spectrum, δ, ppm (J, Hz): 22.1; 23.6; 38.9; 114.1; 115.6 (d,
JCF = 22); 123.6 (d, JCF = 2); 131.5 (d, JCF = 8); 159.2
1258

Chemistry of Heterocyclic Compounds 2017, 53(11), 1254–1260
(С-3); 164.3 (d, JCF = 251, C-4'); 182.4 (C-7a); 192.3 (С-4).
3-(3-Fluorophenyl)-6,7-dihydro-2,1-benzisoxazol-4(5Н)-
one (5e). Yield 0.22 g (95%, from compound 3e), mp 88–
90°С. IR spectrum, ν, cm–1: 1680, 1615, 1590, 1570, 1485,
19F NMR spectrum, δ, ppm: –109.70 (m, F). Found, %:
C 67.48; H 4.31; N 6.05. C13H10FNO2. Calculated, %:
C 67.53; H 4.36; N 6.06.
1
1470, 1450. H NMR spectrum, δ, ppm (J, Hz): 2.15–2.20
3-(2-Fluorophenyl)-6,6-dimethyl-6,7-dihydro-2,1-benz-
isoxazol-4(5Н)-one (5а). Yield 0.23 g (88%, from
compound 3а), mp. 66–69°С. IR spectrum, ν, cm–1: 1690,
1625, 1600, 1570, 1510, 1490, 1475, 1465. 1H NMR spectrum,
δ, ppm: 1.15 (6H, s, 2СН3); 2.47 (2Н, s, CH2); 2.85 (2Н, s,
CH2); 7.20–7.24 (1Н, m, Н Ar); 7.27–7.31 (1Н, m, Н Ar);
7.52–7.56 (1Н, m, Н Ar); 7.97–8.00 (1Н, m, Н Ar).
13C NMR spectrum, δ, ppm (J, Hz): 28.1; 34.6; 35.0; 53.6;
113.1; 115.0 (d, JСF = 12); 116.5 (d, JСF = 21); 124.1 (d,
(2H, m, CH2); 2.64 (2H, t, J = 6.4, CH2); 2.98 (2H, t,
J = 6.4, CH2); 7.22–7.26 (1Н, m, Н Ar); 7.46–7.51 (1Н, m,
Н Ar); 8.23–8.26 (2Н, m, Н Ar). 13C NMR spectrum, δ, ppm
(J, Hz): 21.9; 22.3; 40.2; 112.9; 115.7 (d, JСF = 25); 119.4
(d, JСF = 21); 124.5 (d, JСF = 2); 128.2 (d, JСF = 9); 130.5
(d, JСF = 8); 162.7 (d, JСF = 246, C-3'); 165.1 (C-7a); 169.3
(C-3); 192.6 (C-4). 19F NMR spectrum, δ, ppm: –111.30
(m, F). Found, %: C 67.48; H 4.30; N 6.01. C13H10FNO2.
Calculated, %: C 67.53; H 4.36; N 6.06.
JСF = 3); 131.1; 133.7 (d, JСF = 9); 160.0 (d, JСF = 258, C-2');
3-(4-Fluorophenyl)-6,7-dihydro-2,1-benzisoxazol-4(5Н)-
one (5f). Yield 0.21 g (89%, from compound 3f), mp 68–
70°С. IR spectrum, ν, cm–1: 1685, 1675, 1605, 1565, 1520,
163.8 (C-7a); 166.2 (C-3); 191.6 (C-4). 19F NMR spectrum,
δ, ppm: –112.18 (m, F). Found, %: C 69.42; H 5.38;
N 5.34. C15H14FNO2. Calculated, %: C 69.49; H 5.44;
N 5.40.
1
1490, 1460. H NMR spectrum, δ, ppm (J, Hz): 2.16 (2H,
quin, CH2); 2.62 (2H, t, J = 6.4, CH2); 2.97 (2H, t, J = 6.4,
CH2); 7.17–7.21 (2Н, m, Н Ar); 8.48–8.52 (2Н, m, Н Ar).
13C NMR spectrum, δ, ppm (J, Hz): 21.9; 22.3; 40.1; 112.2;
116.1 (d, JСF = 22); 122.8 (d, JСF = 3); 131.4 (d, JСF = 9);
165.1 (C-7a); 165.1 (d, JСF = 255, C-4'); 169.8 (C-3); 192.7
(C-4). 19F NMR spectrum, δ, ppm: –105.50 (m, F). Found,
%: C 67.60; H 4.41; N 6.11. C13H10FNO2. Calculated, %:
C 67.53; H 4.36; N 6.06.
3-(3-Fluorophenyl)-6,6-dimethyl-6,7-dihydro-2,1-benz-
isoxazol-4(5Н)-one (5b). Yield 0.22 g (86%, from
compound 3b), mp 77–80°С. IR spectrum, ν, cm–1: 1690,
1
1610, 1590, 1570, 1475, 1450. H NMR spectrum, δ, ppm:
1.15 (6H, s, 2СН3); 2.51 (2Н, s, CH2); 2.84 (2Н, s, CH2);
7.23–7.27 (1Н, m, Н Ar); 7.48–7.52 (1Н, m, Н Ar); 8.26–
8.29 (2Н, m, Н Ar). 13C NMR spectrum, δ, ppm (J, Hz):
28.1; 34.2; 35.1; 53.9; 111.9; 115.6 (d, JСF = 25); 119.3 (d,
This study received financial support from the
Belarusian Republican Foundation for Fundamental
Research (grant Kh16K-037).
JСF = 21); 124.3 (d, JСF = 2); 128.1 (d, JСF = 9); 130.4 (d,
JСF = 8); 162.6 (d, JСF = 247, C-3'); 164.5 (C-7a); 169.0
(C-3); 192.1 (C-4). 19F NMR spectrum, δ, ppm: –112.28 (m,
F). Found, %: C 69.42; H 5.40; N 5.35. C15H14FNO2.
Calculated, %: C 69.49; H 5.44; N 5.40.
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compound 3c), mp 93–96°С. IR spectrum, ν, cm–1: 1690,
1
1600, 1565, 1520, 1490, 1430. H NMR spectrum, δ, ppm:
1.15 (6H, s, 2СН3); 2.50 (2Н, s, 5-CH2); 2.83 (2Н, s,
7-CH2); 7.18–7.32 (2Н, m, H-3',5'); 8.50–8.55 (2Н, m,
Н-2',6'). 13C NMR spectrum, δ, ppm (J, Hz): 28.2 (2CH3);
34.3 (C-6); 35.3 (C-7); 54.0 (C-5); 111.3 (C-3a); 116.1 (d,
JСF = 22, C-3',5'); 122.8 (d, JСF = 2, C-1'); 131.3 (d, JСF = 9,
C-2',6'); 164.6 (C-7a); 165.2 (d, JСF = 255, C-4'); 169.5 (C-3);
192.3 (C-4). 19F NMR spectrum, δ, ppm: –105.50 (m, F).
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H 5.47; N 5.45. C15H14FNO2. Calculated, %: C 69.49;
H 5.44; N 5.40.
3-(2-Fluorophenyl)-6,7-dihydro-2,1-benzisoxazol-4(5Н)-
one (5d). Yield 0.21 g (91%, from compound 3d), 0.05 g
(22%, from compound 1d), mp. 53–54°С (yellow oil28).
IR spectrum, ν, cm–1: 1690, 1620, 1590, 1580, 1570, 1475,
1
1455. H NMR spectrum, δ, ppm (J, Hz): 2.18 (2H, quin,
J = 6.5, CH2); 2.59 (2H, t, J = 6.4, CH2); 3.00 (2H, t,
J = 6.5, CH2); 7.20–7.30 (2Н, m, Н Ar); 7.51–7.56 (1Н, m,
Н Ar); 7.91–7.95 (1Н, m, Н Ar). 13C NMR spectrum,
δ, ppm (J, Hz): 21.8; 22.5; 39.8; 115.1; 115.7 (d, JСF = 13);
116.6 (d, JСF = 21); 124.2 (d, JСF = 3); 131.3; 133.8 (d,
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СF = 9); 160.2 (d, JСF = 258, C-2'); 164.4 (C-7a); 166.5 (C-3);
192.1 (C-4). 19F NMR spectrum, δ, ppm: –109.40 (m, F).
Found, %: C 67.46; H 4.29; N 6.00. C13H10FNO2.
Calculated, %: C 67.53; H 4.36; N 6.06.
1259

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