Nitrosylsulfuric acid as an oxidant in the synthesis of 3,5-diarylisoxazoles

Article abstract of DOI:10.1007/s11172-018-2103-x

By six examples, it was demonstrated that nitrosylsulfuric acid can be successfully used for oxidation of 3,5-diaryl-4,5-dihydroisoxazoles to the corresponding 3,5-diarylisoxazoles. If the starting isoxazolines contain the aromatic substituents activated towards electrophilic substitution, nitration of both newly formed isoxazole and substituted benzene rings occurred.

Full text of DOI:10.1007/s11172-018-2103-x

Russian Chemical Bulletin, International Edition, Vol. 67, No. 3, pp. 517—520, March, 2018
517
Nitrosylsulfuric acid as an oxidant in the synthesis of 3,5-diarylisoxazoles*
O. B. Bondarenko,a A. I. Komarov,a L. I. Kuznetsova,a S. N. Nikolaeva,a A. Yu. Gavrilova,a and N. V. Zyka,b
aDepartment of Chemistry, M. V. Lomonosov Moscow State University,
1 Leninskie Gory, 119992 Moscow, Russian Federation.
Fax: +7 (495) 939 4652. E-mail: k527.5msu@gmail.com
bInstitute of Physiologically Active Compounds, Russian Academy of Sciences,
1 Severnyi proezd, Chernogolovka, 142432 Moscow Region, Russian Federation
By six examples, it was demonstrated that nitrosylsulfuric acid can be successfully used for
oxidation of 3,5-diaryl-4,5-dihydroisoxazoles to the corresponding 3,5-diarylisoxazoles. If the
starting isoxazolines contain the aromatic substituents activated towards electrophilic substitu-
tion, nitration of both newly formed isoxazole and substituted benzene rings occurred.
Key words: 3,5-diaryl-4,5-dihydroisoxazoles, nitrosylsulfuric acid, oxidation, 3,5-diaryl-
isoxazoles, nitration.
3,5-Diarylisoxazoles are widely used stable compounds
consisting of three conjugated aromatic rings. A scope of
application of these compounds is very broad. Due to the
presence of isoxazole moiety, 3,5-diarylisoxazoles are of
interest for medicine and medicinal chemistry. These
compounds exhibit antimicrobial,1 antituberculosis,2
antitumor3 and other types of biological activities4—7 and
are selective estrogen receptor modulators.8,9 3,5-Di-
phenylisoxazole derivatives are the platforms for the design
of the liquid-crystal materials10,11 and light-harvesting
systems.12
3,5-Diarylisoxazoles could be accessed by two major
approaches, namely, by 1,3-dipolar cycloaddition of nitrile
oxides to alkynes13,14 and by condensation of hydroxyl-
amine with either -diketones or their synthetic equiva-
lents.15,16 Another method for synthesizing 3,5-diaryl-
isoxazoles is oxidation (dehydrogenation) of 4,5-dihydro-
isoxazoles (isoxazolines). This method is of particular
interest since the construction of the 4,5-dihydroisoxazole
ring by the conventional methods is more simple and ef-
ficient due to more readily proceeding reactions, higher
yields of target heterocycles, and greater variety of the
starting compounds. Oxidation of isoxazolines to isox-
azoles can be effected with nickel peroxide,17 chromic
acid, potassium permanganate, chloranil, air oxygen,18
DDQ,19 and -manganese dioxide.20 In the present work,
we applied nitrosylsulfuric acid for the conversion of
isoxazolines to isoxazoles. It should be noted that readily
available nitrosylsulfuric acid is widely used in organic
synthesis. The efficacy of nitrosylsulfuric acid as dehydro-
genating agent for the aromatization of hydroaromatic
compounds has been reported.21
We found that nitrosylsulfuric acid efficiently oxidizes
3,5-diaryl-4,5-dihydroisoxazoles 1a—e to the correspond-
ing 3,5-diarylisoxazoles 2a—e (Scheme 1). The reactions
were carried out at room temperature for 15—20 h using
a 1.5—2-fold excess of nitrosylsulfuric acid. On the model
oxidation of 3,5-diphenylisoxazoline (1a), we revealed that
the reaction between the equimolar amounts of the start-
ing reagents is very slow. Thus, 5 h after the reaction onset
the conversion of isoxazoline 1a to isoxazole 2a was only
22% (1H NMR spectral data of the reaction mixture). The
reaction conditions and the yields of isoxazoles 2a—e are
given in Table 1. From Table 1 follows that the selected
conditions gives 3,5-diarylisoxazoles 2 in high yields and
high purity.
Scheme 1
Compounds 1 and 2
R1
H
Br
F
NO2
H
R2
H
4-Br
4-F
H
a
b
c
d
e
2-F
If isoxazoline 1 contains the aromatic substituents
activated towards electrophilic substitution (e.g., isoxazo-
line 1f), the reaction is accompanied with nitration of
* Dedicated to Academician of the Russian Academy of Sciences
I. P. Beletskaya.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 0517—0520, March, 2018.
1066-5285/18/6703-0517 © 2018 Springer Science+Business Media, Inc.

518
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 3, March, 2018
Bondarenko et al.
Table 1. Oxidation of isoxazolines 1a—e to isoxazoles 2a—e
with nitrosylsulfuric acid in nitromethane at 20 C
reaction conditions (see Table 2). It was found that even
at 0 C oxidation of isoxazoline 1f occurs at a significant
rate. At that, by 30 min of the reaction all three isoxazoles
(2f, 3, and 4) were presented in the reaction mixture
(see Table 2, entry 1). The highest selectivity for isoxazole
2f was achieved by adding equimolar amount of nitrosyl-
sulfuric acid to a cooled nitromethane solution of isoxa-
zoline 1f (0 C) and further carrying the reaction at room
temperature (see Table 2, entry 3).
In summary, in the present work we revealed that
nitrosylsulfuric acid efficiently oxidizes 3,5-diaryl-4,5-
dihydroisoxazoles to the corresponding 3,5-diarylisox-
azoles.
Compo- NOHSO4
Product
(yield (%))
M.p./C
und 1
(equiv.)
1a
1b
1c
1d
1e
2.0
1.5
2.0
1.5
2.0
2a (86)
2b (80)
2c (85)
2d (97)
2e (75)
140 (141—14316,22)
218 (217.5—218.511,23
)
188 (19024
)
221 (220—22125
91—92
)
both newly formed isoxazole and substituted benzene rings
(Scheme 2, Table 2, entry 4). Spectral and physicochem-
ical properties of isoxazoles 2f and 3 agree with those
published earlier.22,26 The composition of isoxazole 4 was
confirmed by elemental analysis data, its structure was
established by 1H and 13C NMR spectroscopy. The loca-
tion of the nitro substituent at the ortho position for the
MeO group is confirmed by a significant upfield shift of the
C(NO2) quaternary carbon atom signal ( 129.1). Note that
nitration of aromatic moieties of compounds on treatment
with the nitrosating agents is a well-known fact.27
Experimental
1H, 13C, and 19F NMR spectra were recorded with Bruker
Avance-400 and Agilent 400-MR spectrometers (working fre-
quencies of 400.13, 100.67, and 376.29 MHz, respectively) in
CDCl3. The chemical shifts are given in the  scale relative to
internal standards of hexamethyldisiloxane for 1H and 13C nuclei
and CFCl3 for 19F nucleus. Electron impact mass spectrometry
was performed with a Thermo Scientific TSQ 8000 system
(Germany) (a capillary column SPB™-5 (15 m0.25 mm), car-
rier gas was helium at a flow rate of 1 mL•min–1), energy of
ionizing electrons was 70 eV); temperature was programmed as
follows: maintaining at 70 C for 2 min, heating with the rate of
20 C•min–1, maintaining at 280 C for 5 min. IR spectra were
recorded on a Nicolet IR200 FT-IR spectrometer (Thermo
Scientific) equipped with an attenuated total reflection (ATR)
accessory using ZnSe crystal plate; reflection angle of 45; spec-
tral resolution of 4 cm–1; 20 scans were collected. Melting points
of the synthesized compounds were measured with a Mel-Temp II
apparatus and are given uncorrected. The course of the reactions
was monitored by TLC on Silufol plates. Nitrosylsulfuric acid
was synthesized by the known procedure.29
Scheme 2
Oxidation of 3,5-diaryl-4,5-dihydroisoxazoles 1a—f (general
procedure). A flask equipped with a magnetic stirring bar and
a ground glass stopper was charged with 3,5-diaryl-4,5-di-
hydroisoxazole (1) (0.4 mmol), nitromethane (4 mL), and
nitrosylsulfuric acid (51 mg, 0.4 mmol) in this order. After 1 h
stirring at room temperature, additional portion of nitrosylsul-
furic acid (0.2—0.4 mmol) was added and stirring was continued
until complete consumption of compound 1. The products were
R = 4-MeOC6H4
We studied the compositions of the reaction mixtures
obtained by oxidation of isoxazoline 1f under different
Table 2. Composition of the reaction mixtures obtained by oxidation of isoxazoline 1f depending on the reac-
tion conditions
Entry
NOHSO4
(equiv.)
T/C
t/h
Reaction mixture composition (%)a
1f
2f
3
4
1
2
3
4
1.1
1.2
1.2
1.2
0
0
0.5
2
15b
5с
45
—
55
20
20
45
25
45
15
40
20
35
0—20
20
1
—
1
—
a 1H NMR data.
b Reaction mixture contained ca. 5% of 5-(4-methoxy-3-nitrophenyl)-3-phenylisoxazoline.28
c Reaction mixture contained ca. 10% of 5-(4-methoxy-3-nitrophenyl)-3-phenylisoxazoline.

NOHSO4 in the synthesis of 3,5-diarylisoxazoles
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 3, March, 2018
519
isolated by flash-column chromatography (SiO2 40/100, elution
with chloroform). The obtained isoxazoles were additionally
purified by recrystallization from ethanol if required.
5-(4-Methoxyphenyl)-3-phenylisoxazole (2f). Yield 0.13 g
(50%), Rf 0.43, m.p. 128 C (cf. Ref. 22 and 26: m.p. 128—129).
1H NMR, : 3.83 (s, 3 H, CH3O); 6.68 (s, 1 H, C(4)His); 6.97
(d, 2 H, Ar, 3J = 8.8 Hz); 7.45 (m, 3 H, Ph); 7.75 (d, 2 H, Ar,
3J = 8.8 Hz); 7.85 (m, 2 H, Ph).
5-(4-Methoxy-3-nitrophenyl)-3-phenylisoxazole (4). Yield
0.04 g (14%), Rf 0.18, m.p. 158 C. IR, /cm–1: 2850 (MeOAr),
1626 (C=N), 1618 (C=C), 1531 (NO2), 1342 (NO2). 1H NMR,
: 4.05 (s, 3 H, CH3O); 6.85 (s, 1 H, C(4)His); 7.23 (d, 1 H, Ar,
3J = 8.8 Hz); 7.50 (m, 3 H, Ar); 7.87 (m, 2 H, Ar); 8.03 (dd,
1 H, Ar, 3J = 8.8 Hz, 4J = 2.2 Hz); 8.31 (d, 1 H, Ar, 4J = 2.2 Hz).
13C NMR, : 56.8 (CH3O), 97.7 (C(4)is), 114.1 (HC(5)Ar), 120.2
(C(1)Ar), 123.3 (HC(2)Ar), 126.8 (2 CH), 128.7 (C(1´)Ar), 129.0
(2 CH), 129.1 (C(3)ArNO2), 130.2 (C(6)ArH), 131.2 (HC(4´)Ar),
154.0 (C(4)ArOCH3), 163.2 (Cis=N), 167.8 (=Cis—O). Found (%):
C, 65.26; H, 4.29; N, 9.18. C16H12N2O4. Calculated (%):
C, 64.86; H, 4.08; N, 9.46.
3,5-Bis(4-fluorophenyl)isoxazole (2c). 1H NMR, : 6.76
(s, 1 H, C(4)His); 7.20 (m, 4 H, Ar); 7.86 (m, 4 H, Ar). 13C NMR,
: 97.1 (C(4)His); 116.0 (d, 2 CHAr
,
2JCF = 22.1 Hz); 116.2
4
(d, 2 CHAr ,2JCF = 22.9 Hz); 123.7 (d, C(1)Ar, JCF = 3.8 Hz);
125.2 (d, C(1)Ar, , =
4JCF = 3.8 Hz); 127.9 (d, 2 CHAr 3JCF
= 9.2 Hz); 128.7 (d, 2 CHAr, 3JCF = 8.4 Hz); 162.1 (C=N); 163.82
(d, FC(4)Ar, 1JCF = 251.8 Hz); 163.84 (d, FC(4)Ar, 1JCF = 250.3 Hz);
169.6 (C—O). 19F NMR, : –110.4 (m, 1 F); –109.3 (m, 1 F).
Found (%): C, 70.18; H, 3.74; N, 5.44. C15H9F2NO. Calculat-
ed (%): C, 70.04; H, 3.53; N, 5.45.
3-(4-Nitrophenyl)-5-phenylisoxazole (2d). 1H NMR, : 6.91
(s, 1 H, C(4)His); 7.53 (m, 3 H, Ar); 8.87 (m, 2 H, Ar); 8.07
(d, 2 H, Ar, 3J = 8.8 Hz); 8.36 (d, 2 H, Ar, 3J = 8.8 Hz). MS (EI,
70 eV), m/z (Irel (%)): 266 [M]+ (40), 207 (50), 105 [PhCO]+
(100), 77 [Ph]+ (57).
5-(2-Fluorophenyl)-3-phenylisoxazole (2e). 1H NMR, : 7.05
The authors would like to acknowledge Thermo Fisher
Scientific Inc., MS Analytica (Moscow, Russia), and
personally Prof. A. A. Makarov for providing mass spectro-
metry equipment for this work. The authors are also grate-
ful to L. G. Saginova for kindly providing 3,5-diaryl-4,5-
dihydroisoxazoles used in the present work.
5
3
(d, 1 H, C(4)His, JHF = 3.7 Hz); 7.23 (ddd, 1 H, Ar, JHF
=
= 10.9 Hz, J = 7.8 Hz, J = 1.0 Hz); 7.31 (dt, 1 H, Ar, J = 7.8 Hz,
J = 1.0 Hz); 7.42—7.47 (m, 1 H, Ar); 7.48—7.50 (m, 3 H, Ar);
7.91 (m, 2 H, Ar); 8.03 (dt, 1 H, Ar, J = 7.8 Hz, J = 1.7 Hz).
4
13C NMR, : 101.7 (d, C(4)His, JCF = 11.2 Hz); 115.9 (d, C(1)Ar
,
2JCF = 12.1 Hz); 116.3 (d, C(3)HAr
,
2JCF = 21.7 Hz); 124.7
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 15-03-04260).
(d, CHAr, JCF = 3.2 Hz); 126.9 (2 CHPh); 127.7 (d, CHAr
,
JCF = 2.4 Hz); 129.0 (2 CHPh); 129.02 (C(1)Ph); 130.1 (CHPh);
131.6 (d, CHAr, 3JCF = 8.8 Hz); 159.2 (d, C—F, 1JCF = 253.0 Hz);
163.2 (C=N); 164.2 (d, C—O, JCF = 3.2 Hz). 19F NMR, :
3
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Received December 28, 2017;
in revised form January 16, 2018;
accepted January 18, 2018