Synthesis of Isoxazolylvinyl Ketones from Substituted Furans

Article abstract of DOI:10.1007/s10593-020-02841-y

[Figure not available: see fulltext.] A new method for the preparation of isoxazolylvinyl ketones related to potential cytotoxic agents has been developed. In the first step, the reaction of furfuryl ketones with hydroxylamine hydrochloride affords the corresponding oximes. Further, the oxidative ring opening – ring closure reaction of oximes leads to isoxazoles with an α, β-unsaturated carbonyl motif. The developed procedure is metal-free and does not require expensive starting materials.

Full text of DOI:10.1007/s10593-020-02841-y

DOI 10.1007/s10593-020-02841-y
Chemistry of Heterocyclic Compounds 2020, 56(11), 1477–1484
Synthesis of isoxazolylvinyl ketones from substituted furans
1
1
2,3
Olga V. Serdyuk *, Frank Hampel , Vladimir T. Abaev
1
Department of Chemistry and Pharmacy, Institute of Organic Chemistry I,
Friedrich-Alexander University of Erlangen-Nürnberg,
1
0 Nikolaus-Fiebiger-St., Erlangen 91058, Germany; e-mail: olga@serdyuk.de
2
3
North Ossetian State University named after K. L. Khetagurov,
3–46 Vatutina St., Vladikavkaz 362025, Russia
Department of Chemistry, North Caucasus Federal University,
a Pushkina St., Stavropol 355009, Russia
4
1
Published in Khimiya Geterotsiklicheskikh Soedinenii,
020, 56(11), 1477–1484
Submitted October 13, 2020
Accepted November 11, 2020
2
A new method for the preparation of isoxazolylvinyl ketones related to potential cytotoxic agents has been developed. In the first step,
the reaction of furfuryl ketones with hydroxylamine hydrochloride affords the corresponding oximes. Further, the oxidative ring opening – ring
closure reaction of oximes leads to isoxazoles with an α,β-unsaturated carbonyl motif. The developed procedure is metal-free and does
not require expensive starting materials.
Keywords: chalcone, furan, isoxazole, ring opening – ring closure reaction.
Cancer is the second leading cause of death worldwide.
In 2018, 18.1 million new cases and 9.6 million cancer
deaths were reported according to the World Health
sation, the discovery of new cytotoxic agents based on
chalcone scaffold has long been focused on easily available
8,9
heterocyclic aldehydes and ketones. To the best of our
knowledge, the only isoxazole-chalcones that have been
reported up to now are those depicted in Figure 1.
1
Organization. Despite of the huge breakthroughs in the
development of anticancer drug therapy, some drawbacks,
e.g., high toxicity of anticancer agents toward normal cells
and the rise of multidrug resistance, remain. Therefore, the
discovery of new effective cytotoxic agents is still highly
desired.2
Isoxazole derivatives are known to reveal promising
activity against breast cancer (MCF-7), prostate cancer
11
We suggested that easily available furfuryl ketones 1
could serve as a starting point for the synthesis of
isoxazolylvinyl ketones employing a ring opening – ring
closure (RORC) strategy (Scheme 1). Recently, we have
shown that compounds 1 afford pyrazole-chalcones upon
the reaction with arylhydrazine hydrochlorides in a single
step. The reported protocol does not require the use of
expensive materials and metal catalysis, representing a
3
4
(
PC3), the human central nervous system glioma (SNB-19),
5
lung adenocarcinoma (A549), colon cancer (Colo-205),
6
12
and other tumor cell lines.
valuable alternative to the Claisen–Schmidt condensation.
In medicinal chemistry, chalcones and their heterocyclic
Herein, we describe a new synthesis of isoxazolylvinyl
ketones from substituted furans.
analogs bearing α,β-unsaturated fragments are known as
7
important scaffolds with potent anticancer activity. In
particular, isoxazolylvinyl ketones and isoxazole-chalcones
demonstrate activity against lung cancer cell lines H1792,
8
H157, A549, Calu-1 and prostate DU-145 cancer cell lines
(
Fig. 1).9
Additionally, the enone motif in these structures can be
further modified, giving access to various linked hetero-
cycles. We have recently reviewed application of this
concept to some related systems through functionalization
1
0
of the enone fragment. Since the common approach to
heterocyclic chalcones is the Claisen–Schmidt conden-
Figure 1. Common structures of reported isoxazole-chalcones and
their anticancer activity.
0
009-3122/20/56(11)-1477©2020 Springer Science+Business Media, LLC
1477

Chemistry of Heterocyclic Compounds 2020, 56(11), 1477–1484
Scheme 1. Possible pathways to isoxazolylvinyl ketones
Scheme 4. Acid-catalyzed transformation
of tetrahydrofurooxazines
15
The target isoxazole (E,Z)-3a was obtained through the
reaction of oxime 2a with m-CPBA followed by treatment
of the reaction mixture with TFA (Table 1). Product 3a was
isolated as a mixture of (E,Z)-isomers in moderate yield at
room temperature. Importantly, adding TFA at low
temperature (0°C (entry 2) and –10°C (entry 3)) allowed
sufficient improvement of the yield of ketone 3a along
with much better stereoselectivity in favor of the (Z)-isomer.
A quantitative isomerization of mixture (E,Z)-3a into the
stable (E)-isomer (Fig. 2) was easily performed under
To prepare the target isoxazole derivatives, we decided
to test the conditions established earlier for the synthesis of
1
1
pyrazoles from furans. Specifically, we have shown
that treatment of furfuryl ketones 1 with hydrazine deriva-
tives led to the corresponding pyrazoles in one step
16
heating with catalytic amount of I (6.4 mol %).
2
(
Scheme 2).11
To illustrate the scope of the reaction, a series of oximes
2
a–j have been synthesized on a 2 mmol scale (Scheme 5) and
Scheme 2. Synthesis of pyrazole-chalcones from furans
subjected to the optimized reaction conditions (Table 1,
Table 1. Synthesis of isoxazolylvinyl ketone 3a
under oxidative conditions: a model reaction*
Accordingly, we have studied the reaction of furfuryl
ketone 1a with hydroxylamine hydrochloride and NaOAc
in EtOH. However, prolonged heating (24 h) of ketone 1a
at 80°C led exclusively to oxime 2a instead of the expected
isoxazole, presumably due to the reduced nucleophilicity of
the hydroxylamino group in compound 2a (Scheme 3).
Entry
Temperature, °C
Yield, %
E/Z ratio**
1:1.0
1:30.4
1
2
3
rt
0
–10
56
80
79
1:30.0
*
*
The reaction was carried out on 2 mmol scale.
* The E/Z ratio was determined by H NMR spectroscopy.
1
Scheme 3. Synthesis of ketone 1a and its condensation
with NH
NH
2
OH·HCl. Conditions: furfuryl ketone 1a (2 mmol),
2
OH·HCl (2 mmol), NaOAc (4 mmol), EtOH (5 ml)
In 2017, Pinho e Melo et al. reported two examples of
isoxazole synthesis from tetrahydrofurooxazines via the
formation of corresponding oximes as intermediates
(
Scheme 4).13 This acid-catalyzed reaction afforded a
mixture containing substituted 4-(isoxazol-5-yl)butan-
2
-ones as major products. We aimed to obtain isoxazolyl-
vinyl ketones as the major products and decided to study
the transformation of compound 2a under oxidative
conditions.14
Figure 2. Monitoring of E/Z isomerization: selected sections of
1
the H NMR (600 MHz) spectra of compound (E)-3a (bottom)
3
and mixture (E,Z)-3a (top) in CDCl .
1
478

Chemistry of Heterocyclic Compounds 2020, 56(11), 1477–1484
Scheme 5. Synthesis of oximes 2a–j
entry 2) with m-CPBA and TFA (Scheme 6). Each product
a–j was prepared on a 0.5 mmol scale in a pure (E)-form
and fully characterized.
group were comparable in the range of 60–70%. The same
transformation of oximes 2h,i containing butyl group
proceeded in lower yields and gave mixtures of products
3
through the isomerization with I
2
1
The reaction worked well for substrates 2a–j bearing
electronically neutral hydrogen atom, electron-donating
methyl and methoxy groups, and halogens in the aromatic
that required further purification. When R was a p-bromo-
phenyl group, we could not isolate the target isoxazole 3j.
Probably, the aryl group can alter the regiochemistry due to
steric and electronic reasons, and m-CPBA attacks the C=C
double bond proximate to the oxime function, resulting in
alternative reaction pathways (see also the mechanism,
Scheme 7).
Importantly, the synthesis of isoxazolylvinyl ketones 3
can be performed on a gram-scale in high yields as it was
demonstrated for compound 3a (Scheme 6). The structure
of isoxazole (E)-3g was confirmed by single crystal X-ray
diffraction (Fig. 3).
2
ring of R substituent. The corresponding isoxazoles 3a–i
1
were isolated in 50–82% yields. With respect to R substituent,
the methyl group was more favorable. The desired products
3
a,b were obtained in 82 and 65% yields, respectively. The
reaction of oximes 2a,b proceeded in a very clean manner,
and products 3a,b did not require any purification.
The NMR spectra of the crude reaction mixtures
indicated the presence of only isomers of the target
isoxazoles 3a,b. The yields of compounds 3c–g with ethyl
Scheme 6. Synthesis of isoxazolylvinyl ketones 3a–i. The E/Z ratio was determined by NMR spectra of crude products (E/Z)-3a–i
1
479

Chemistry of Heterocyclic Compounds 2020, 56(11), 1477–1484
opening – ring closure (RORC) reaction under acidic
conditions to produce new isoxazole with α,β-unsaturated
fragment. The reaction worked well for substrates bearing
diverse groups in aromatic ring, but strongly depends on
the substituent in the furan ring. The best results were
observed for substituted methylfurans. These experiments
proceeded so clean that target isoxazoles did not required
any purification.
Figure 3. Molecular structure of compound (E)-3g with atoms
represented as thermal vibration ellipsoids of 50% probability.
Experimental
A proposed mechanism for the transformation of oximes
2
into isoxazoles 3 is presented in Scheme 7. The key step
IR spectra were recorded on a PerkinElmer Spectrum
1
13
includes epoxidation of the furan double bond with m-CPBA
resulting in the formation of bicyclic epoxide A. An
intermediacy of similar oxidized products was reported
BX spectrophotometer. H and C NMR spectra were
recorded on Bruker AV-600 (600 and 151 MHz, respec-
tively), Bruker AV-500 (500 and 126 MHz, respectively),
or Bruker AV-400 (400 and 101 MHz, respectively)
17
earlier. Further, the treatment with TFA induces intra-
molecular attack of nucleophilic hydroxylamine O atom
onto C-2 atom of the furan ring with proton-assisted
epoxide ring opening giving rise to the spirocyclic inter-
mediate B. The subsequent ring opening of intermediate B
and aromatization yield the final isoxazole 3.
spectrometers in CDCl , using TMS or solvent residual
3
1 13
peak (7.20 ppm and 77.2 ppm for H and C nuclei,
respectively) as internal standard. High-resolution mass
spectra were recorded on a Bruker micrOTOF-Q ESI-Qq-
TOF mass spectrometer. TLC analyses were performed on
Merck 60 F254 Aluminum silica gel plates in combination
with UV detection (254 nm). Flash chromatography was
performed on silica gel 200–300 mesh using i-hexane–
EtOAc system as eluent. Melting points were determined
on a Mel-Temp II Laboratory Devices apparatus. All com-
mercial reagents and solvents were used without further
purification. All reactions were run under air. The reactions
Scheme 7. Proposed mechanism for the transformation
of oximes 2 into isoxazoles 3
®
under microwave irradiation were carried out in a Biotage
Robot Eight microwave synthesis reactor using sealed
microwave reaction vessels.
1
1a,c
Synthesis of furfuryl ketones 1a–j (General method).
12
A solution of the corresponding xanthogenate (12.5 mmol)
and furan derivative (80 mmol for 2-methylfuran and 2-ethyl-
furan; 13 mmol for 2-butylfuran and 2-(4-bromophenyl)-
furan) in DMSO (30 ml) was cooled (5–10°C) and treated
with FeSO ·7H O (1.74 g, 6.25 mmol). Then, 34% aqueous
Since hetaryl-substituted isoxazoles that could be
obtained from compounds 3 are known as the second gene-
1
8
ration RORγ inhibitors, we decided to study the reaction
of compound (E)-3f with hydroxylamine hydrochloride and
NaOAc in EtOH to obtain a bisisoxazole. We have found
that under conditions applied for the synthesis of oximes 2,
4
2
H O (2.5 ml, 25 mmol) was dropwise added. After adding
2
2
H O , the reaction mixture was stirred for 30 min at 5–10°C,
2
2
compound (E)-3f yielded the corresponding oxime 4
then for 2 h at room temperature (TLC control). Once the
reaction was complete, the mixture was poured into H O
1
(
Scheme 8). The H NMR spectrum of compound 4
2
demonstrated two doublets of the vinylic protons at 6.80
and 6.98 ppm with J = 16.6 Hz. In the IR spectrum, we
could not observe the signal of a carbonyl group. Instead, a
(300 ml), extracted with EtOAc (4×50 ml), the combined
extracts were washed with saturated aqueous NaCl
solution, dried over anhydrous Na SO , and evaporated to
2
4
–1
new peak of the NOH group was detected at 3202 cm .
Further study of this reaction and synthesis of bisisoxazole
from compounds 3 is underway.
dryness. The residue was purified by flash chromatography
using i-hexane–EtOAc, 8:1, as eluent.
2-(5-Methylfuran-2-yl)-1-phenylethan-1-one
(1a).
19
Yield 1.6 g (64%), pale-yellow oil. IR spectrum (NaCl),
Scheme 8. Synthesis of oxime 4
–1
1
ν, cm : 784, 1021, 1220, 1597, 1693 (C=O). H NMR
spectrum (600 MHz), δ, ppm: 2.28 (3H, br. s, CH ); 4.27
2H, s, CH ); 5.93–5.94 (1H, m, H Fur); 6.12–6.13 (1H, m,
H Fur); 7.47–7.50 (2H, m, H Ph); 7.57–7.60 (1H, m, H Ph);
.03–8.04 (2H, m, H Ph). 13C NMR spectrum (101 MHz),
δ, ppm: 13.6; 38.6; 106.6; 109.1; 128.7 (4C); 133.3; 136.3;
3
(
2
8
+
1
46.3; 151.7; 195.4. Found, m/z: 201.0752 [M+H] . C13
H
13
2
O .
Calculated, m/z: 201.0910.
2
-(5-Methylfuran-2-yl)-1-(p-tolyl)ethanone (1b) was
In summary, we have developed a new method for the
synthesis of isoxazolylvinyl ketones that are related to
compounds with anticancer activity. We have demonstrated
that oximes of furfuryl ketones undergo oxidative ring
isolated as a mixture with 5% of starting xanthogenate and
1
used further without additional purification. H NMR
spectrum (400 MHz), δ, ppm: 2.24 (3H, br. s, CH
3
); 2.36
(3H, s, CH
C
3 6
H
4
); 4.20 (2H, s, CH
2
); 5.88–5.90 (1H, m,
1
480

Chemistry of Heterocyclic Compounds 2020, 56(11), 1477–1484
H Fur); 6.07–6.08 (1H, m, H Fur); 7.89–7.91 (2H, m,
CH ); 7.23–7.24 (2H, m, CH ).
spectrum (500 MHz), δ, ppm (J, Hz): 0.90 (3H, t, J = 7.4,
CH CH CH CH ); 1.29–1.34 (2H, m, CH CH CH CH );
1.55–1.61 (2H, m, CH CH CH CH ); 2.56–2.59 (2H, m,
CH CH CH CH ); 4.25 (2H, s, CH ); 5.90–5.91 (1H, m,
3
C
6
H
4
3
C
6
H
4
2
2
2
3
2
2
2
3
2-(5-Ethylfuran-2-yl)-1-phenylethan-1-one (1c). Yield
2
2
2
3
1
9
–1
1
7
.87 g (70%), brownish oil. IR spectrum (NaCl), ν, cm :
2
2
2
3
2
1
79, 1013, 1181, 1219, 1597, 1686 (C=O). H NMR
H Fur); 6.09–6.10 (1H, m, H Fur); 7.44–7.48 (2H, m,
H Ph); 7.55–7.56 (1H, m, H Ph); 8.00–8.02 (2H, m, H Ph).
spectrum (600 MHz), δ, ppm (J, Hz): 1.19 (3H, t, J = 7.6,
1
3
CH
CH
7
8
2
CH
3
); 2.60 (2H, q, J = 7.5, CH
2
CH
3
); 4.25 (2H, s,
C NMR spectrum (126 MHz), δ, ppm: 13.8; 22.2; 27.7;
2
); 5.90–5.92 (1H, m, H Fur); 6.10–6.11 (1H, m, H Fur);
30.1; 38.7; 105.6; 108.7; 128.6 (4C); 133.2; 136.3; 146.1;
156.2; 195.3. Found, m/z: 243.1379. [M+H] . C16
Calculated, m/z: 243.1380.
+
.45–7.47 (2H, m, H Ph); 7.54–7.57 (1H, m, H Ph); 8.00–
H
19
2
O .
1
3
.02 (2H, m, H Ph). C NMR spectrum (151 MHz),
δ, ppm: 11.9; 21.2; 38.4; 104.8; 108.6; 128.4 (2C); 128.5
2-(5-Butylfuran-2-yl)-1-(4-fluorophenyl)ethan-1-one (1i).
12 1
(
2
2C); 133.1; 136.2; 146.0; 157.2; 195.1. Found, m/z:
Yield 1.33 g (41%), yellow oil. H NMR spectrum (400 MHz),
δ, ppm (J, Hz): 0.89 (3H, t, J = 7.3, CH CH CH CH ); 1.29–
1.35 (2H, m, CH CH CH CH ); 1.50–1.61 (2H, m,
CH CH CH CH ); 2.54–2.58 (2H, m, CH CH CH CH );
4.22 (2H, s, CH ); 5.90–5.91 (1H, m, H Fur); 6.09–6.10
(1H, m, H Fur); 7.08–7.14 (2H, m, FC ); 8.01–8.06 (2H,
). C NMR spectrum (101 MHz), δ, ppm (J, Hz):
+
15.1065 [M+H] . C14
H
15
O
2
. Calculated, m/z: 215.1067.
2
2
2
3
2
-(5-Ethylfuran-2-yl)-1-(p-tolyl)ethan-1-one (1d). Yield
2
2
2
3
12
1
(
.42 g (50%), white solid, mp 42–44°C. IR spectrum
2
2
2
3
2
2
2
3
–1
1
NaCl), ν, cm : 776, 1181, 1223, 1606, 1684 (C=O). H NMR
2
spectrum (600 MHz), δ, ppm (J, Hz): 1.19 (3H, t, J = 7.6,
6
H
4
13
CH
CH
2
CH
CH
3
); 2.40 (3H, s, CH
); 4.22 (2H, s, CH
3
C
6
H
4
); 2.60 (2H, q, J = 7.5,
); 5.89–5.91 (1H, m, H Fur);
);
). C NMR spectrum (101 MHz),
6
m, FC H
4
2
3
2
13.8; 22.2; 27.7; 30.1; 38.7; 105.7; 108.8; 115.5 (d,
J = 21.9, 2C); 131.3 (d, J = 9.5, 2C); 132.7 (d, J = 3.4);
145.9; 156.3; 165.8 (d, J = 255.1); 193.8.
6
7
.08–6.10 (1H, m, H Fur); 7.25–7.26 (2H, m, CH
3 6
C H
4
1
3
.90–7.92 (2H, m, CH
3
C
6
H
4
δ, ppm: 12.1; 21.4; 21.7; 38.6; 104.9; 108.7; 128.8 (2C);
2-[5-(4-Bromophenyl)furan-2-yl]-1-(4-fluorophenyl)-
ethanone (1j). Yield 1.79 g (40%), yellow solid, mp 84–
1
2
29.3 (2C); 133.8; 144.2; 146.4; 157.4; 195.0. Found, m/z:
+
–1
29.1220 [M+H] . C15
H
17
O
2
. Calculated, m/z: 229.1223.
88°C. IR spectrum (ATP), ν, cm : 817, 993, 1068, 1113,
1
2
-(5-Ethylfuran-2-yl)-1-(4-methoxyphenyl)ethanone (1e).
1152, 1229, 1328, 1405, 1539, 1589, 1689 (C=O). H NMR
–1
Yield 2.07 g (68%), brownish oil. IR spectrum (NaCl), ν, cm :
99, 833, 1025, 1173, 1224, 1260, 1601, 1681 (C=O).
spectrum (400 MHz), δ, ppm (J, Hz): 4.32–4.33 (2H, m,
7
CH ); 6.31–6.32 (1H, m, H Fur); 6.58–6.60 (1H, m, H Fur);
2
1
H NMR spectrum (400 MHz), δ, ppm (J, Hz): 1.19 (3H, t,
J = 7.6, CH CH ); 2.57–2.63 (2H, m, CH CH ); 3.87 (3H,
s, OCH ); 4.20–4.21 (2H, m, CH ); 5.90–5.91 (1H, m,
H Fur); 6.08–6.09 (1H, m, H Fur); 6.91–6.95 (2H, m,
7.12–7.16 (2H, m, FC
8.02–8.07 (2H, m, FC
6
H
H
4
4
); 7.43–7.47 (4H, m, BrC
6
H
4
);
13
2
3
2
3
6
). C NMR spectrum (101 MHz),
3
2
δ, ppm (J, Hz): 38.6; 106.7; 110.7; 115.9 (d, J = 21.9, 2C);
120.9; 125.1 (2C); 129.6; 131.3 (d, J = 9.4, 2C); 131.7
1
3
CH
3
6
OC H
4
); 7.98–8.02 (2H, m, CH
3
6
OC H
4
). C NMR
(2C); 132.6 (d, J = 2.9); 148.1; 152.5; 165.9 (d, J = 255.6);
193.1. Found, m/z: 359.0079 [M+H] . C18
lated, m/z: 359.0078.
+
spectrum (101 MHz), δ, ppm: 12.1; 21.3; 38.4; 55.5; 104.9;
H
13BrFO . Calcu-
2
1
1
08.5; 113.7 (2C); 129.3; 131.0 (2C); 146.6; 157.3; 163.6;
+
93.9. Found, m/z: 245.1175 [M+H] . C15
H
17
O
3
. Calcu-
Synthesis of oximes 2a–j (General method). Hydroxyl-
amine hydrochloride (139 mg, 2 mmol) and anhydrous
NaOAc (32.8 mg, 4 mmol) were added to a solution of
furfuryl ketone 1a–j (2 mmol) in EtOH (5 ml), and the
mixture was stirred for 24 h at 80°C (TLC and LC-MS
lated, m/z: 245.1172.
1
-(4-Chlorophenyl)-2-(5-ethylfuran-2-yl)ethanone (1f).
Yield 2.17 g (70%), pale-yellow oil. IR spectrum (NaCl),
–1
ν, cm : 779, 833, 1012, 1092, 1219, 1399, 1589, 1688
1
(
(
4
C=O). H NMR spectrum (400 MHz), δ, ppm (J, Hz): 1.19
3H, t, J = 7.6, CH CH ); 2.54–2.67 (2H, m, CH CH );
.22 (2H, s, CH ); 5.91–5.92 (1H, m, H Fur); 6.09–6.11
1H, m, H Fur); 7.42–7.45 (2H, m, ClC ); 7.93–7.97
). C NMR spectrum (101 MHz), δ, ppm:
2.1; 21.4; 38.7; 105.0; 108.9; 129.0 (2C); 130.1 (2C);
34.6; 139.8; 145.8; 157.6; 194.2. Found, m/z: 249.0679
control). Then, the reaction mixture was poured into H O
2
2
3
2
3
(100 ml) and extracted with EtOAc (4×25 ml). The
2
combined organic phases were washed with brine, dried over
(
(
6
H
4
anhydrous Na
2
SO , filtered, and evaporated under reduced
4
13
2H, m, ClC
6
H
4
pressure. The resulting crude product was purified by flash
1
1
chromatography using i-hexane–EtOAc, 4:1, as eluent.
15
2-(5-Methylfuran-2-yl)-1-phenylethan-1-one oxime (2a).
+
[
M+H] . C14
H
14ClO2. Calculated, m/z: 249.0677.
Yield 610 mg (~100%), white solid, mp 90–92°C. IR spectrum
–1
2
-(5-Ethylfuran-2-yl)-1-(4-fluorophenyl)ethan-1-one (1g).
(NaCl), ν, cm : 960, 1016, 1168, 1321, 1461, 1495, 1568,
1
2
1
Yield 1.30 g (45%), brownish oil. IR spectrum (NaCl),
2922, 3241 (N–OH). H NMR spectrum (600 MHz),
–
1
1
ν, cm : 845, 1158, 1233, 1599, 1693 (C=O). H NMR
spectrum (600 MHz), δ, ppm (J, Hz): 1.19 (3H, t, J = 7.6,
δ, ppm (J, Hz): 2.24 (3H, s, CH
3
); 4.13 (2H, s, CH ); 5.82–
2
5.84 (1H, m, H Fur); 5.91–5.92 (1H, m, H Fur); 7.36–7.37
13
CH
5
7
2
CH
3
); 2.60 (2H, q, J = 7.5, CH
2
CH
3
); 4.22 (2H, s, CH
2
);
(3H, m, H Ph); 7.67–7.69 (2H, m, H Ph). C NMR
.90–5.92 (1H, m, H Fur); 6.09–6.11 (1H, m, H Fur); 7.11–
spectrum (101 MHz), δ, ppm: 13.6; 25.5; 106.3; 107.5;
1
3
.15 (2H, m, FC
6
H
4
); 8.02–8.06 (2H, m, FC
6
H
4
). C NMR
126.4 (2C); 128.5 (2C); 129.4; 135.3; 147.9; 150.9; 155.2.
–
spectrum (151 MHz), δ, ppm (J, Hz): 12.1; 21.3; 38.7;
Found, m/z: 214.0862 [M–H] . C13
H
13NO . Calculated, m/z:
2
1
1
05.0; 108.9; 115.7 (d, J = 21.9, 2C); 131.4 (d, J = 9.5, 2C);
32.7 (d, J = 3.4); 145.9; 157.5; 165.8 (d, J = 255.1), 193.7.
-(5-Butylfuran-2-yl)-1-phenylethanone (1h). Yield 1.30 g
214.0874.
2-(5-Methylfuran-2-yl)-1-(p-tolyl)ethanone oxime (2b).
2
Yield 389 mg (85%), white solid, mp 84–86°C. IR spectrum
–1
–1
(
43%), pale-yellow oil. IR spectrum (ATR), ν, cm : 780, 1013,
(ATP), ν, cm : 793, 915, 952, 1015, 1065, 1185, 1289,
1
1
147, 1219, 1273, 1333, 1448, 1562, 1597 (C=O). H NMR
1319, 1439, 1511, 1566, 2920, 1609, 3236, 3281 (N–OH).
1
481

Chemistry of Heterocyclic Compounds 2020, 56(11), 1477–1484
1
H NMR spectrum (500 MHz), δ, ppm (J, Hz): 2.23 (3H, s,
CH ); 2.35 (3H, s, CH ); 4.12 (2H, s, CH ); 5.82–5.83
1H, m, H Fur); 5.90–5.91 (1H, m, H Fur); 7.16–7.17 (2H,
m, CH ); 7.55–7.57 (2H, m, CH ); 9.00 (1H, br. s,
(400 MHz), δ, ppm (J, Hz): 1.17 (3H, t, J = 7.6, CH
2.55–2.61 (2H, m, CH CH ); 4.11–4.13 (2H, m, CH ); 5.87–
5.88 (1H, dt, J = 3.1, J = 1.1, H Fur); 5.95–5.96 (1H, m,
H Fur); 7.05–7.09 (2H, m, FC ); 7.67–7.70 (2H, m,
2
CH );
3
3
C
3 6
H
4
2
2
3
2
(
3
C
6
H
4
3
C
6
H
4
6
H
4
1
3
13
NOH). C NMR spectrum (101 MHz), δ, ppm: 13.5; 21.3;
FC
6
H ). C NMR spectrum (101 MHz), δ, ppm (J, Hz):
4
2
1
C
5.4; 106.3; 107.4; 126.3 (2C); 129.2 (2C); 132.4; 139.4;
12.1; 21.3; 25.5; 104.7; 107.4; 115.4 (d, J = 22.0, 2C);
128.4 (d, J = 8.5, 2C); 131.5 (d, J = 3.8); 147.5; 154.5;
+
48.0; 150.8; 155.0. Found, m/z: 230.1178. [M+H] .
+
14
2
H
16NO
2
. Calculated, m/z: 230.1176.
156.8; 163.4 (d, J = 249.3). Found, m/z: 248.1083 [M+H] .
-(5-Ethylfuran-2-yl)-1-phenylethanone oxime (2c).
Yield 370 mg (80%), yellow solid, mp 52–55°C.IR spectrum
C
14
H
15FNO . Calculated, m/z: 248.1081.
2
2-(5-Butylfuran-2-yl)-1-phenylethanone oxime (2h).
–1
–1
(
NaCl), ν, cm : 966, 1012, 1180, 1366, 1446, 1497, 1563,
Yield 364 mg (71%), yellow oil. IR spectrum (ATP), ν, cm :
1
2
973, 3292 (N–OH). H NMR spectrum (400 MHz),
δ, ppm (J, Hz): 1.20 (3H, t, J = 7.5, CH CH ); 2.61 (2H,
); 4.17 (2H, d, J = 1.0, CH );
.86–5.87 (1H, m, H Fur); 5.93–5.99 (1H, m, H Fur); 7.39–
949, 1012, 1061, 1175, 1287, 1445, 1561, 1607, 2864,
1
2
3
2928, 3242 (N–OH). H NMR spectrum (500 MHz), δ, ppm
qd, J = 7.5, J = 1.0, CH
2
CH
3
2
(J, Hz): 0.89 (3H, t, J = 7.3, CH
2
CH
CH
); 2.55 (2H, t, J = 7.6, CH
2
CH
2
CH ); 1.56 (2H,
3
5
7
quint, J = 7.5, CH
CH CH CH CH
4.14 (2H, br. s, CH ); 5.82–5.84 (1H, m, H Fur); 5.92–5.93
2
CH
2
CH
2
3
); 1.47–1.67 (2H, m,
13
.41 (3H, m, H Ph); 7.69–7.71 (2H, m, H Ph). C NMR
2
2
2
3
2
CH CH CH );
2
2
3
spectrum (101 MHz), δ, ppm: 12.1; 21.4; 25.6; 104.7;
2
1
1
07.3; 126.5 (2C); 128.5 (2C); 129.3; 135.4; 147.8; 155.3;
(1H, d, J = 3.1, H Fur); 7.31–7.44 (3H, m, H Ph); 7.66 (2H,
+
13
56.7. Found, m/z: 230.1174 [M+H] . C14
H16NO2. Calcu-
m, H Ph). C NMR spectrum (126 MHz), δ, ppm: 13.8;
lated, m/z: 230.1176.
22.2; 25.6; 27.7; 30.1; 105.4; 107.3; 126.5 (2C); 128.5 (2C);
2
-(5-Ethylfuran-2-yl)-1-(p-tolyl)ethanone oxime (2d).
129.3; 135.4; 147.7; 155.4 (2C). Found, m/z: 258.1492
–1
+
Yield 351 mg (73%), yellow oil. IR spectrum (NaCl), ν, cm :
[M+H] . C16
H
20NO . Calculated, m/z: 258.1489.
2
9
2
66, 1012, 1060, 1185, 1365, 1435, 1515, 1563, 1610,
2-(5-Butylfuran-2-yl)-1-(4-fluorophenyl)ethanone oxime
1
923, 2973, 3292 (N–OH). H NMR spectrum (400 MHz),
(2i). Yield 380 mg (69%), yellow solid, mp 64–65°C.
–1
δ, ppm (J, Hz): 1.18 (3H, t, J = 7.5, CH
2
CH
3
); 2.35 (3H, s,
IR spectrum (ATP), ν, cm : 969, 1010, 1057, 1158, 1226,
1
CH
CH
3
C
2
6
H
4
); 2.55–2.61 (2H, m, CH ); 4.13 (2H, d, J = 1.0,
); 5.85–5.87 (1H, m, H Fur); 5.94–5.95 (1H, m, H Fur);
2
CH
3
1438, 1509, 1597, 2862, 2928, 3216 (N–OH). H NMR
spectrum (500 MHz), δ, ppm (J, Hz): 0.89 (3H, t, J = 7.4,
7
.18–7.21 (2H, m, CH
3
C
6
H
4
); 7.59–7.61 (2H, m, CH
3
C
6
H
4
).
CH
2
CH
2
CH
2
CH
3
); 1.31–1.35 (2H, m, CH
2
CH
2
CH
2
CH );
3
1
3
C NMR spectrum (101 MHz), δ, ppm: 12.1; 21.3 (2C);
1.52–1.58 (2H, m, CH
CH CH CH CH ); 4.12 (2H, d, J = 1.0, CH
(1H, m, H Fur); 5.92–5.93 (1H, m, H Fur); 7.02–7.06 (2H,
2
CH
2
CH
2
CH
3
); 2.53–2.56 (2H, m,
2
1
C
5.5; 104.6; 107.2; 126.3 (2C); 129.2 (2C); 132.5; 139.4;
2
2
2
3
2
); 5.83–5.84
+
47.9; 155.2; 156.6. Found, m/z: 244.1332 [M+H] .
15
H
18NO2. Calculated, m/z: 244.1332.
m, FC
6
H
4
); 7.62–7.65 (2H, m, FC
6
H ); 8.85 (1H, br. s,
4
1
3
2
-(5-Ethylfuran-2-yl)-1-(4-methoxyphenyl)ethanone
NOH). C NMR spectrum (126 MHz), δ, ppm (J, Hz):
13.8; 22.2; 25.6; 27.7; 30.1; 105.4; 107.4; 115.5 (d, J = 21.6,
2C); 128.5 (d, J = 8.3, 2C); 131.5 (d, J = 3.3); 147.4; 154.6;
oxime (2e). Yield 399 mg (77%), yellow oil. IR spectrum
–
1
(
NaCl), ν, cm : 836, 966, 1012, 1030, 1179, 1253, 1515,
1
–
1
607, 2936, 2970, 3292 (N–OH). H NMR spectrum
400 MHz), δ, ppm (J, Hz): 1.20 (3H, t, J = 7.6, CH CH );
O); 4.15 (2H,
); 5.86–5.87 (1H, m, H Fur); 5.95–5.96 (1H,
OC ); 7.65–7.68 (2H,
). C NMR spectrum (101 MHz), δ, ppm:
2.1; 21.4; 25.4; 55.3; 104.7; 107.2; 113.9 (2C); 127.9
2C); 128.3; 147.9; 155.0; 156.6; 160.5. Found, m/z:
155.6; 163.4 (d, J = 249.2). Found, m/z: 274.1245 [M–H] .
(
2
3
C
16
H
18FNO . Calculated, m/z: 274.1249.
2
2
.58–2.64 (2H, m, CH
2
CH
3
); 3.84 (3H, s, CH
3
2-[5-(4-Bromophenyl)furan-2-yl]-1-(4-fluorophenyl)-
d, J = 1.0, CH
2
ethanone oxime (2j). Yield 522 mg (70%), white solid,
1
m, H Fur); 6.89–6.93 (2H, m, CH
3
6
H
4
mp 151–154°C. H NMR spectrum (400 MHz), δ, ppm
13
m, CH
3
6
OC H
4
(J, Hz): 4.22 (2H, d, J = 1.0, CH ); 6.14 (1H, dt, J = 3.3,
2
1
J = 1.0, H Fur); 6.52–6.54 (1H, m, H Fur); 7.05–7.09 (2H,
m, FC ); 7.42–7.47 (4H, m, BrC ); 7.67–7.71 (2H, m,
FC ); 8.05 (1H, br. s, NOH). C NMR spectrum
(
6
H
4
6
H
4
+
13
2
60.1282 [M+H] . C15
-(4-Chlorophenyl)-2-(5-ethylfuran-2-yl)ethanone oxime
2f). Yield 426 mg (81%), white solid, mp 78–80°C.
H
18NO3. Calculated, m/z: 260.1281.
6
H
4
1
(101 MHz), δ, ppm (J, Hz): 25.5; 106.5; 109.3; 115.6 (d,
J = 21.8, 2C); 120.8; 124.9 (2C); 128.3 (d, J = 8.3, 2C);
129.7; 131.3 (d, J = 3.5); 131.8 (2C); 149.8; 151.9; 153.9;
(
–
1
IR spectrum (NaCl), ν, cm : 834, 967, 1012, 1094, 1180,
291, 1315, 1494, 1563, 1595, 2937, 2973, 3292 (N–OH).
+
1
163.5 (d, J = 249.7). Found, m/z: 374.0079 [M+H] .
1
H NMR spectrum (400 MHz), δ, ppm (J, Hz): 1.17 (3H, t,
J = 7.6, CH CH ); 2.55–2.61 (2H, m, CH CH ); 4.11–4.12
2H, m, CH ); 5.83–5.85 (1H, m, H Fur); 5.92–5.93 (1H,
m, H Fur); 7.31–7.35 (2H, m, ClC ); 7.59–7.62 (2H, m,
C
18
H
14BrFNO . Calculated, m/z: 374.0187.
2
2
3
2
3
Synthesis of isoxazolylvinyl ketones 3a–i (General
method). m-CPBA (77% w/w, 0.135 g, 0.6 mmol) was
added to a solution of oxime 2a–i (0.5 mmol) in CH Cl
(
2
6
H
4
2
2
13
ClC
6
H
4
). C NMR spectrum (101 MHz), δ, ppm: 12.1;
(2 ml) at 0°C. The reaction mixture was stirred at the same
temperature for 1 h. Then TFA (0.038 ml, 0.05 mmol) was
added. The reaction mixture was allowed to reach room
temperature and stirred for 20 h. Once the reaction was
2
1
1.4; 25.4; 104.7; 107.5; 127.8 (2C); 128.7 (2C); 133.8;
+
35.4; 147.4; 154.5; 156.9. Found, m/z: 264.0788 [M+H] .
C
14
H
15ClNO2. Calculated, m/z: 264.0786.
2
-(5-Ethylfuran-2-yl)-1-(4-fluorophenyl)ethanone oxime
complete, the mixture was washed with Na
and then with brine. CH Cl was dried over anhydrous
Na SO , filtered, and evaporated under reduced pressure to
give a pure respective product (E,Z)-3a–i.
2 2
S
O solution
3
(
2g). Yield 340 mg (70%), yellow solid, mp 75–78°C.
2
2
–
1
IR spectrum (NaCl), ν, cm : 967, 1012, 1159, 1234, 1364,
2
4
1
1
563, 1603, 2939, 2974, 3356 (N–OH). H NMR spectrum
1
482

Chemistry of Heterocyclic Compounds 2020, 56(11), 1477–1484
Isomerization of compounds (E,Z)-3a–i into com-
1116, 1181, 1258, 1407, 1528, 1633 (C=C enone), 1690
1
pounds (E)-3a–i (General method). Microwave reaction
vessel was charged with compound (E,Z)-3a–i (0.2 mmol),
(C=O). H NMR spectrum (600 MHz), δ, ppm (J, Hz): 1.18
(3H, t, J = 7.3, CH
3.86 (3H, s, OCH
J = 16.1, (O)CCH=CH); 6.97–6.99 (2H, m, CH
7.39 (1H, d, J = 16.1, (O)CCH=CH); 7.74–7.76 (2H, m,
2
CH
3
); 2.70 (2H, q, J = 7.3, CH
2
CH );
3
I
2
(3.4 mg, 0.013 mmol), and PhMe (2 ml). The reaction
3
); 6.73 (1H, s, H isoxazole); 6.95 (1H, d,
OC );
mixture was stirred at 140°C in a microwave reactor for 2 h.
3
6
H
4
After completion of the reaction, PhMe and I were
2
1
3
removed under reduced pressure. The resulting product was
CH
3
OC
6
H ). C NMR spectrum (151 MHz), δ, ppm: 7.9;
4
purified by flash chromatography using i-hexane–EtOAc,
35.3; 55.4; 104.4; 114.4 (2C); 120.9; 124.6; 128.2 (2C);
4
:1, as eluent.
129.7; 161.3; 162.6; 166.2; 199.8. Found, m/z: 258.1127
1
5
+
(
E)-4-(3-Phenylisoxazol-5-yl)but-3-en-2-one ((E)-3a).
[M+H] . C15
H
16NO . Calculated, m/z: 258.1125.
3
Yield 87 mg (82%), white solid, mp 130–132°C. IR spectrum
(E)-1-[3-(4-Chlorophenyl)isoxazol-5-yl]pent-1-en-3-one
((E)-3f). Yield 91 mg (70%), yellow solid, mp 142–144°C.
–1
(
(
NaCl), ν, cm : 769, 952, 983, 1268, 1439, 1560, 1637
1
–1
C=C enone), 1664 (C=O). H NMR spectrum (600 MHz),
IR spectrum (NaCl), ν, cm : 809, 832, 949, 972, 1092,
δ, ppm (J, Hz): 2.41 (3H, s, CH
3
); 6.80 (1H, s,
1020, 1120, 1258, 1428, 1557, 1633 (C=C enone), 1696
1
H isoxazole); 6.95 (1H, d, J = 16.2, (O)CCH=CH); 7.40
(C=O). H NMR spectrum (600 MHz), δ, ppm (J, Hz): 1.18
(
7
1H, d, J = 16.2, (O)CCH=CH); 7.47–7.49 (3H, m, H Ph);
(3H, t, J = 7.3, CH
2
CH
3
); 2.71 (2H, q, J = 7.3, CH
2
CH );
3
1
3
.81–7.83 (2H, m, H Ph). C NMR spectrum (151 MHz),
6.76 (1H, s, H isoxazole); 6.97 (1H, d, J = 16.1,
(O)CCH=CH); 7.40 (1H, d, J = 16.1, (O)CCH=CH); 7.45–
δ, ppm: 28.5; 104.5; 125.4; 126.8 (2C); 128.4; 129.1; 130.4
(
[
2C); 130.8; 163.1; 166.3; 197.0. Found, m/z: 214.0861
7.46 (2H, m, ClC
6
H
4
); 7.75–7.76 (2H, m, ClC
6
4
H ).
+
13
M+H] . C13
H
12NO2. Calculated, m/z: 214.0863.
C NMR spectrum (151 MHz), δ, ppm (J, Hz): 7.8; 35.4;
(
E)-4-[3-(p-Tolyl)isoxazol-5-yl]but-3-en-2-one ((E)-3b).
104.2; 124.3; 126.9; 128.1 (2C); 129.3 (2C); 130.0; 136.4;
+
Yield 74 mg (65%), white solid, mp 133–136°C. IR spectrum
162.1; 166.8; 199.6. Found, m/z: 262.0631 [M+H] .
–
1
(
1
ATP), ν, cm : 803, 963, 1162, 1256, 1299, 1355, 1424,
C
14
H
13ClNO . Calculated, m/z: 262.0629.
2
1
523, 1557, 1624 (C=C enone), 1688 (C=O). H NMR
spectrum (400 MHz), δ, ppm (J, Hz): 2.43 (3H, s, CH );
.43 (3H, s, CH ); 6.80 (1H, s, H isoxazole); 6.94 (1H,
d, J = 16.2, (O)CCH=CH); 7.28–7.32 (2H, m, CH );
.38 (1H, dd, J = 16.3, J = 0.4, (O)CCH=CH); 7.71–7.74
(E)-1-[3-(4-Fluorophenyl)isoxazol-5-yl]pent-1-en-3-one
3
((E)-3g). Yield 77 mg (63%), yellow solid, mp 139–140°C.
–1
2
C
3 6
H
4
IR spectrum (NaCl), ν, cm : 810, 846, 1225, 1435, 1523, 1633
1
3 6
C H
4
(C=C enone), 1694 (C=O). H NMR spectrum (400 MHz),
7
δ, ppm (J, Hz): 1.18 (3H, t, J = 7.2, CH
2
CH ); 2.71 (2H, q,
3
1
3
(
2H, m, CH
3
C
6
H
4
). C NMR spectrum (101 MHz), δ, ppm:
J = 7.3, CH
J = 16.1, (O)CCH=CH); 7.14–7.19 (2H, m, FC
(1H, d, J = 16.1, (O)CCH=CH); 7.79–7.83 (2H, m, FC
13
2
CH
3
); 6.76 (1H, s, H isoxazole); 6.96 (1H, d,
); 7.40
).
2
1
1.5; 28.5; 104.5; 125.5 (2C); 126.7 (2C); 129.7 (2C);
6
H
4
30.7; 140.6; 163.0; 166.1; 197.1. Found, m/z: 228.0970
6
H
4
+
[
M+H] . C14
H
14NO
2
. Calculated, m/z: 228.1019.
C NMR spectrum (151 MHz), δ, ppm (J, Hz): 7.8; 35.3;
(
E)-1-(3-Phenylisoxazol-5-yl)pent-1-en-3-one ((E)-3c).
104.2; 116.2 (d, J = 22.2, 2C); 124.3; 124.6 (d, J = 3.8);
Yield 70 mg (61%), white solid, mp 127–130°C. IR spectrum
128.8 (d, J = 8.8, 2C); 130.0; 162.1; 164.0 (d, J = 250.5);
–1
+
(
(
NaCl), ν, cm : 764, 951, 981, 1297, 1403, 1562, 1632
166.6; 199.6. Found, m/z: 246.0926 [M+H] . C14
H
13FNO .
2
1
C=C enone), 1693 (C=O). H NMR spectrum (600 MHz),
Calculated, m/z: 246.0925.
δ, ppm (J, Hz): 1.21 (3H, t, J = 7.3, CH
2
CH
3
); 2.73 (2H, q,
); 6.81 (1H, s, H isoxazole); 6.99 (1H, d,
(E)-1-(3-Phenylisoxazol-5-yl)hept-1-en-3-one ((E)-3h).
J = 7.3, CH
2
CH
3
Yield 64 mg (50%), pale-beige solid, mp 113–116°C.
–1
J = 16.1, (O)CCH=CH); 7.43 (1H, d, J = 16.1, (O)CCH=CH);
IR spectrum (ATP), ν, cm : 763, 979, 1056, 1127, 1294, 1397,
1
7
.49–7.50 (3H, m, H Ph); 7.83–7.85 (2H, m, H Ph).
1461, 1557, 1628 (C=C enone), 1688 (C=O). H NMR
1
3
C NMR spectrum (151 MHz), δ, ppm: 7.9; 35.3; 104.5;
spectrum (400 MHz), δ, ppm (J, Hz): 0.93 (3H, t, J = 7.3,
1
1
24.5; 126.8 (2C); 128.4; 129.0 (2C); 129.9; 130.3; 163.1;
CH
2
CH
2
CH
2
CH
3
); 1.32–1.41 (2H, m, CH
2
CH
2
CH
2
CH );
3
+
66.5; 199.7. Found, m/z: 228.1021 [M+H] . C14
H
14NO
2
.
1.62–1.69 (2H, m, CH
2
CH
2
CH
2
CH ); 2.63–2.67 (2H, m,
3
Calculated, m/z: 228.1019.
CH
2
CH
2
CH
2
CH ); 6.77 (1H, s, H isoxazole); 6.95 (1H, d,
3
(
E)-1-[3-(p-Tolyl)isoxazol-5-yl]pent-1-en-3-one ((E)-3d).
J = 16.1, (O)CCH=CH); 7.38 (1H, d, J = 16.1, (O)CCH=CH);
Yield 72 mg (60%), white solid, mp 130–132°C. IR spectrum
7.45–7.46 (3H, m, H Ph); 7.79–7.81 (2H, m, H Ph).
–1
13
(
NaCl), ν, cm : 807, 948, 974, 1119, 1296, 1359, 1428,
C NMR spectrum (101 MHz), δ, ppm: 13.9; 22.4; 26.1;
1
1
558, 1632 (C=C enone), 1696 (C=O). H NMR spectrum
600 MHz), δ, ppm (J, Hz): 1.18 (3H, t, J = 7.3, CH CH );
); 6.76
41.8; 104.5; 124.5; 126.8 (2C); 128.4; 129.1 (2C); 130.1;
+
(
2
3
130.4; 163.1; 166.5; 199.5. Found, m/z: 256.1336 [M+H] .
2
.41 (3H, s, CH
C
3 6
H
4
); 2.71 (2H, q, J = 7.3, CH
2
CH
3
C
16
H
18NO . Calculated, m/z: 256.1332.
2
(
1H, s, H isoxazole); 6.96 (1H, d, J = 16.1, (O)CCH=CH);
.26–7.28 (2H, m, CH ); 7.40 (1H, d, J = 16.1,
O)CCH=CH); 7.70–7.71 (2H, m, CH
spectrum (151 MHz), δ, ppm: 7.9; 21.5; 35.3; 104.5; 124.5;
25.5; 126.7 (4C); 129.8; 140.6; 163.0; 166.3, 199.8.
(E)-1-[3-(4-Fluorophenyl)isoxazol-5-yl]hept-1-en-3-one
7
3
6
C H
4
((E)-3i). Yield 80.6 mg (59%), yellow solid, mp 117–119°C.
1
3
–1
(
3
6
C H
4
). C NMR
IR spectrum (ATP), ν, cm : 813, 929, 968, 1011, 1100,
1159, 1229, 1375, 1432, 1522, 1602 (C=C enone), 1655
1
1
(C=O). H NMR spectrum (500 MHz), δ, ppm (J, Hz): 0.95
+
Found, m/z: 242.1177 [M+H] . C15
H
16NO
2
. Calculated, m/z:
(3H, t, J = 7.4, CH
2
CH
2
CH
2
CH ); 1.35–1.42 (2H, m,
3
2
42.1176.
E)-1-[3-(4-Methoxyphenyl)isoxazol-5-yl]pent-1-en-
-one ((E)-3e). Yield 77 mg (60%), pale-beige solid, mp 118–
CH
2.66–2.69 (2H, m, CH
H isoxazole); 6.97 (1H, dd, J = 16.1, J = 0.4, (O)CCH=CH);
7.15–7.19 (2H, m, FC ); 7.39 (1H, dd, J = 16.1, J = 0.4,
2
CH
2
CH
2
CH
3
); 1.64–1.70 (2H, m, CH
2
CH
2
CH
2
CH
3
);
(
2
CH CH CH ); 6.75 (1H, br. s,
2
2
3
3
1
–
1
20°C. IR spectrum (NaCl), ν, cm : 810, 842, 968, 1033,
6
H
4
1
483

Chemistry of Heterocyclic Compounds 2020, 56(11), 1477–1484
1
3
(
O)CCH=CH); 7.79–7.83 (2H, m, FC
6
H
4
). C NMR
4. Gajewski, M. P.; Beall, H.; Schnieder, M.; Stranahan, S. M.;
Mosher, M. D.; Rider, K. C.; Natale, N. R. Bioorg. Med.
Chem. Lett. 2009, 19, 4067.
spectrum (151 MHz), δ, ppm (J, Hz): 13.9; 22.4; 26.1;
4
1.9; 104.3; 116.2 (d, J = 21.8, 2C); 124.4; 124.6 (d,
5
. Kumbhare, R. M.; Kosurkar, U. B.; Ramaiah, M. J.;
Dadmal, T. L.; Pushpavalli, S. N. C. V. L.; Pal-Bhadra, M.
Bioorg. Med. Chem. Lett. 2012, 22, 5424.
J = 3.3); 128.8 (d, J = 8.4, 2C); 130.2; 162.1; 164.0 (d,
+
J = 250.6); 166.7; 199.4. Found, m/z: 274.1243 [M+H] .
C
16
(
H
17FNO . Calculated, m/z: 274.1238.
2
6
. (a) Rajanarendar, E.; Nagi Reddy, M.; Rama Krishna, S.;
Govardhan Reddy, K.; Reddy, Y. N.; Rajam, M. V. Eur. J.
Med. Chem. 2012, 50, 344. (b) Güiza, F. M.; Duarte, Y. B.;
Mendez-Sanchez, S. C.; Romero Bohórquez, A. R. Med.
Chem. Res. 2019, 28, 1182. (c) Wang, H.; Ma, Y.; Lin, Y.;
Liu, J.; Chen, R.; Xu, B.; Liang, Y. Molecules 2019, 24, 2335.
1E)-1-[3-(4-Chlorophenyl)isoxazol-5-yl]pent-1-en-3-one
oxime (4). Hydroxylamine hydrochloride (0.0132 g,
0
.19 mmol) and anhydrous NaOAc (0.0311 g, 0.38 mmol)
were added to a solution of isoxazole 3f (0.05 g, 0.19 mmol) in
EtOH (1 ml), and the mixture was stirred for 24 h at reflux
(
d) Xue, X.; Zhang, Y.; Wang, C.; Zhang, M.; Xiang, Q.;
(
H
TLC control). Then, the reaction mixture was poured into
Wang, J.; Wang, A.; Li, C.; Zhang, C.; Zou, L.; Wang, R.;
Wu, S.; Lu, Y.; Chen, H.; Ding, K.; Li, G.; Xu, Y. Eur. J.
Med. Chem. 2018, 152, 542. (e) Bondarenko, O. B.; Zyk, N. V.
Chem. Heterocycl. Compd. 2020, 56, 694. [Khim. Geterotsikl.
Soedin. 2020, 56, 694.]
. (a) Rani, A.; Anand, A.; Kumar, K.; Kumar, V. Expert Opin.
Drug Discovery 2019, 14, 249. (b) Zhuang, C.; Zhang, W.;
Sheng, C.; Zhang, W.; Xing, C.; Miao, Z. Chem. Rev. 2017,
117, 7762. (c) Gomes, M. N.; Muratov, E. N.; Pereira, M.;
Peixoto, J. C.; Rosseto, L. P.; Cravo, P. V. L.; Andrade, C. H.;
Neves, B. J. Molecules 2017, 22, 1210. (d) Singh, P.; Anand, A.;
Kumar, V. Eur. J. Med. Chem. 2014, 85, 758. (e) Sharma, V.;
Kumar, V.; Kumar, P. Anti-Cancer Agents Med. Chem. 2013,
13, 422.
2
O (50 ml) and extracted with EtOAc (4×15 ml). The
combined organic phases were washed with brine, dried
over anhydrous Na
2
SO , filtered, and evaporated under
4
reduced pressure. The resulting crude product 4 was
purified by flash chromatography. Yield 26 mg (50%), pale-
7
–1
yellow solid, mp 143–148°C. IR spectrum (ATP), ν, cm :
7
(
88, 832, 959, 1080, 1185, 1295, 1375, 1429, 1557, 1602
1
C=C enone), 2853, 2921, 3202 (N–OH). H NMR
spectrum (400 MHz), δ, ppm (J, Hz): 1.17 (3H, t, J = 7.6,
CH CH ); 2.63 (2H, q, J = 7.6, CH CH ); 6.59 (1H, s,
2
3
2
3
H isoxazole); 6.80 (1H, d, J = 16.6, (O)CCH=CH); 6.98
(
7
1H, d, J = 16.6, (O)CCH=CH); 7.43–7.46 (2H, m, ClC
6 4
H );
13
.74–7.76 (2H, m, ClC
6
H
4
). C NMR spectrum (101 MHz), δ,
8
9
1
. Wan, M.; Xu, L.; Hua, L.; Li, A.; Li, S.; Lu, W.; Pang, Y.;
Cao, C.; Liu, X.; Jiao, P. Bioorg. Chem. 2014, 54, 38.
. Thiriveedhi, A.; Nadh, R. V.; Srinivasu, N.; Kaushal, K. Lett.
Drug Des. Discovery 2018, 15, 576.
ppm: 10.9; 30.2; 100.1; 116.8; 124.5; 127.4; 128.1 (2C);
1
[
29.3 (2C); 131.3; 136.2; 160.7; 161.8. Found, m/z: 277.0739
+
M+H] . C14
H
14ClN
2
O Calculated, m/z: 277.0738.
2
X-ray structural investigation of compound (E)-3g.
0. Trushkov, I. V.; Uchuskin, M. U.; Abaev, V. T.; Serdyuk, O. V.
Synthesis 2019, 787.
Single colorless block-shaped crystals were recrystallized
from a mixture of EtOAc and i-hexane by solvent layering.
11. (a) Abaev, V. T.; Bosikova, K. V.; Serdyuk, O. V.; Butin, A. V.
Chem. Heterocycl. Compd. 2009, 45, 611. [Khim. Geterotsikl.
Soedin. 2009, 772.] (b) Serdyuk, O. V.; Chalikidi, P. N.;
Butin, A. V. Chem. Heterocycl. Compd. 2012, 48, 1281.
3
A suitable crystal 0.23 × 0.14 × 0.10 mm was selected and
mounted on a mylar loop in perfluoroether oil. The data
were collected on an Agilent SuperNova diffractometer
equipped with an Atlas dual CCD detector at 153.00(10) K
using CuKa radiation. The crystal was kept at a steady
[
Khim. Geterotsikl. Soedin. 2012, 1376.] (c) Chalikidi, P. N.;
Nevolina, T. A.; Uchuskin, M. G.; Abaev, V. T.; Butin, A. V.
Chem. Heterocycl. Compd. 2015, 51, 621. [Khim. Geterotsikl.
Soedin. 2015, 51, 621.]
1
53.00(10) K during data collection. The complete
crystallographic information on compound (E)-3g has been
1
2. Sawengngen, N.; Chalikidi, P. N.; Araby, S.; Hampel, F.;
Gmeiner, P.; Serdyuk, O. V. Org. Biomol. Chem. 2019, 17,
4850.
deposited at the Cambridge Crystallographic Data Center
(deposit CCDC 1943861).
1
3. Alves, A. J. S.; Lopes, S. M. M.; Henriques, M. S. C.; Paixão, J. A.;
Pinho e Melo, T. M. V. D. Eur. J. Org. Chem. 2017, 4011.
4. (a) Merino, P. In Organic Reactions; John Wiley & Sons,
1
Supplementary information file containing H and
C NMR spectra of the synthesized compounds and X-ray
data of compound (E)-3g is available at the journal website
1
3
1
2
015, Vol. 87. DOI: 10.1002/0471264180.or087.01.
(
b) Merino, P.; Tejero, T.; Delso, J. I.; Matute, R. Curr. Org.
at http://link.springer.com/journal/10593.
Chem. 2007, 11, 1076. (c) Makarov, A. S.; Uchuskin, M. U.;
Trushkov, I. V. Synthesis 2018, 3059.
This work was supported by the scholarship ''Promotion
of Equal Opportunities for Women in Research and
Teaching (FFL)'' offered by the Free State of Bavaria,
Germany. We also thank the Russian Foundation for Basic
Research for the support (grant 19-03-01027).
1
5. Sawengngen, N.; Kolodina, A. A.; Serdyuk, O. V. Molbank
2
019, M1081. DOI: 10.3390/M1081.
1
1
6. Dugave, C.; Demange, L. Chem. Rev. 2003, 103, 2475.
7. (a) Makarov, A. S.; Merkushev, A. A.; Uchuskin, M. G.;
Trushkov, I. V. Org. Lett. 2016, 18, 2192. (b) Manfredi, K. P.;
Jennings, P. W. J. Org. Chem. 1989, 54, 5186. (c) Ruzo, L. O.;
Casida, J. E.; Holden, I. J. Chem. Soc. Chem. Commun. 1985, 1642.
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