Synthesis of 4-Nitroisoxazoles via NO/NO2 -Mediated Heterocyclization of Aryl-Substituted α,β-Unsaturated Ketones

Article abstract of DOI:10.1055/s-0039-1690053

A straightforward approach for the synthesis of 4-nitroisoxazoles has been developed via heterocyclization of aryl/hetaryl-substituted α,β-unsaturated ketones upon treatment with tetranitromethane-triethylamine (TNM-TEA) complex or t -BuONO. This strategy features high efficiency and wide substrate tolerance under simple reaction conditions.

Full text of DOI:10.1055/s-0039-1690053

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–I
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D. A. Vasilenko et al.
Paper
Synthesis
Synthesis of 4-Nitroisoxazoles via NO/NO2-Mediated Hetero-
cyclization of Aryl-Substituted ,-Unsaturated Ketones
Dmitry A. Vasilenkoa
Kirill S. Sadovnikova
Kseniya N. Sedenkovaa,b
Anastasiya V. Kurovaa
Yuri K. Grishina
Tamara S. Kuznetsovaa
Victor B. Rybakova
Yulia A. Volkovaa,c
R
NO2
t-BuONO-H2O
or
R
R1
C(NO2)4-Et3N
N
R1
O
O
1,4-dioxane
60 °C, 2 h
R = Ar, Hetaryl
R
19 examples
up to 80% yield
1 = Alk, Ar
Elena B. Averina*a,b
a Department of Chemistry, Lomonosov Moscow State University,
Leninskie Gory 1 bd. 3, Moscow 119991, Russian Federation
elaver@med.chem.msu.ru
b Institute of Physiologically Active Compounds, Severny Proezd 1,
Chernogolovka, Moscow Region 142432, Russian Federation
c N.D. Zelinsky Institute of Organic Chemistry RAS, Leninsky Prospect,
47, Moscow 119991, Russian Federation
Received: 10.12.2019
Accepted after revision: 13.01.2020
Published online: 03.02.2020
H
O
O
S
O
N
H2N
S
H2N
NH
N
H
O
O
DOI: 10.1055/s-0039-1690053; Art ID: ss-2019-t0671-op
N
N
N
CH3
O
CH3
O
O
Sulfamethoxazole
(antibiotic)
Zonisamide
(anticonvulsant)
Isocarboxazid
(antidepressant)
Abstract A straightforward approach for the synthesis of 4-nitroisox-
azoles has been developed via heterocyclization of aryl/hetaryl-substi-
tuted ,-unsaturated ketones upon treatment with tetranitrometh-
ane-triethylamine (TNM-TEA) complex or t-BuONO. This strategy
features high efficiency and wide substrate tolerance under simple reac-
tion conditions.
Figure 1 Examples of isoxazole-containing marketed drugs
4-nitroisoxazoles have broad applicability as nucleophiles
in enantioselective synthesis of complex isoxazole contain-
ing structures.18 The products of condensation of 5-methyl-
4-nitroisoxazoles with carbonyl compounds – 4-nitro-5-
styrylisoxazoles – were employed in catalytic asymmetric
processes such as Sharpless dihydroxylation,19 aza-Diels–
Alder reaction,20 1,3-dipolar cycloaddition,21 Michael addi-
tion,22 and domino Michael/cyclization reactions.23
The synthesis of the 4-nitroisoxazoles can be accom-
plished via four major approaches.24 The first one, the di-
rect nitration of isoxazoles, not substituted at position 4, is
the best-known method for the synthesis of 4-nitroisoxaz-
oles, though it lacks regioselectivity when an isoxazole con-
tains a (het)aryl moiety. The second method is ring-closure,
involving -nitroketones or their oximes and usually used
for the synthesis of 3,5-diaryl-substituted 4-nitroisoxaz-
oles. The 1,3-dipolar cycloaddition of nitrile oxides to ni-
troalkenes and heterocyclization of acetylene derivatives
under the treatment with sodium nitrite have also found
their application, though limited by the affordability of
starting compounds.
Key words 4-nitroisoxazoles, alkenes, ketones, heterocycles, ring
closure, tert-butyl nitrite, heterocyclization, tetranitromethane
Isoxazoles possess a variety of applications both as ver-
satile building blocks in organic synthesis1 and as the com-
pounds with remarkably diverse bioactivity.2 Isoxazole
moiety is present in natural psychoactive molecules such as
AMPA, muscimol, and ibotenic acid. Synthetic derivatives of
isoxazole are known as marketed antibiotics,3 anticonvul-
sants,4 antipsychotics,5 antidepressants,6 anti-inflammato-
ry,7 and antirheumatic8 drugs (Figure 1). A variety of bioac-
tive isoxazoles, including regulators of immune functions,9
cognitive enhancers,10 antitumor agents,11 antiviral
agents,12 various glutamate13 and GABA receptors14 ligands,
inhibitors of apoptosis,15 and antifungals16 have been found,
making these compounds the object of continued interest
for medicinal chemistry.
Among various nitro-substituted isoxazoles the chemis-
try of 4-nitro regioisomers has attracted a lot of attention
of chemists in the past few decades.17 Particularly, 5-alkyl-
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
D. A. Vasilenko et al.
Paper
Synthesis
Taking into account the topicality of investigations in
chemistry of 4-nitroisoxazoles, the elaboration of novel
preparative approaches to these heterocycles starting from
available compounds remains highly relevant.
amounts, solvents, and the reaction temperature (Table 2).
We initiated our optimization studies by treating alkene 1a
with NaNO2 (10 equiv) in a mixture of AcOH and 1,4-diox-
ane at 60 °C for 2 hours (Table 2, entry 1). Under these reac-
tion conditions only traces of the isoxazole 2a were ob-
served. By varying the reaction temperature or the number
of NaNO2 equivalents the yield of 2a was slightly affected
(entries 1–5). Only 20% conversion of alkene 1a to isoxazole
2a has been achieved using NaNO2/AcOH as a reagent of
heterocyclization (entry 2), and after four-fold re-entry of
the alkene 1a in the reaction 80% conversion of the starting
material has been achieved. It is likely that low conversion
of the unsaturated ketone 1a is due to the proceeding of the
reaction in heterophase conditions.
The use of t-BuONO (20 equiv) in the presence of water
(3 mL) proved to be more effective compared to
NaNO2/AcOH system (Table 2, entry 6). In these conditions,
55% conversion of alkene 1a into the target heterocycle 2a
took place. To improve the efficiency of heterocyclization
different co-solvents, such as EtOH, EtOAc, THF, MeCN, 1,4-
dioxane, were tested (entries 7–11,13), and 1,4-dioxane has
been found to be the most preferred additional solvent. Af-
ter screening the reaction temperature, we found that heat-
ing at 60 °C is optimal for heterocyclization (entries 13–16).
It was found that the number of t-BuONO equivalents, its
concentration, and the water-1,4-dioxane ratio also affect
the efficiency of heterocyclization (entries 17–25).
Previously we have elaborated a novel preparative
method for the synthesis of functionalized 5-nitroisoxaz-
oles via the reaction of tetranitromethane (TNM) with elec-
trophilic alkenes in the presence of triethylamine (TEA).25
Now we have found that application of the same reaction
conditions to aryl substituted ,-unsaturated ketones af-
forded exclusively 4-nitroisoxazoles (Scheme 1). Brief opti-
mization of the heterocyclization of model alkene 1a upon
treatment with TNM-TEA complex showed that previously
used conditions (Table 1, entry 3)25d were optimal, while
the change of the solvent or base reduced the yield of 4-ni-
troisoxazole 2a (Table 1).
our previous works
EWG
R
C(NO2)4-Et3N
EWG
R
N
NO2
O
EWG = NO2, C(O)R1, C(O)OR1,
C(O)N(R1)2, P(O)(OR1)2, SO2R1
R = H, Alk
our present work
R
NO2
C(NO2)4-Et3N
R
R1
or
N
R1
t-BuONO-H2O
O
O
R = Ar, Hetaryl
The complete conversion of 1a into isoxazole 2a was
achieved using t-BuONO (10 equiv) in a solution in 1,3-di-
oxane-water (0.25 mL/0.75 mL) at 60 °C for 2 hours (Table 2,
entry 24). In these conditions, 4-nitroisoxazole 2a was ob-
tained in 78% isolated yield.
Scheme 1 Varied reactions of electrophilic alkenes with nitration/
nitrosation reagents
Table 1 Optimization of the Conditions for the Reaction of 1a with
TNMa
With the optimal conditions of heterocyclization in
hand, we investigated the scope of ,-unsaturated ketones
bearing aryl/hetaryl substituents. Starting alkenes 1a–r
were easily available either via condensation of methyl ke-
tones with the corresponding aldehydes or by Wittig reac-
tion. As shown in Scheme 2, both procedures (A and B) per-
mitted to achieve close results. The electronic nature of
substituents in aromatic ring had slight effect on the reac-
tivity of ,-unsaturated ketones 1a–n, although electron-
donating groups in aryl moiety, in principle, were more fa-
vorable for the heterocyclization (1a,d–f) than electron-
withdrawing ones, such as CHO (1i) or NO2 (1j). When pol-
yaromatic naphthalene and biphenyl substrates were em-
ployed, the desired isoxazoles 2k and 2l were obtained in
55% and 47% yield, respectively. Heteroaryl-substituted ,-
unsaturated ketones were also investigated giving good iso-
lated yields of isoxazoles 2m,n. However, the influence of
steric hindrance was more pronounced. For example, the
heterocyclization of ketone 1c bearing bulky ortho-substi-
tuted aromatic ring upon the treatment with TNM-Et3N re-
sulted in complex mixture of oxidation side-products, the
major of which was 2-methoxybenzaldehyde. Target isox-
MeO
MeO
NO2
base
C(NO2)4
+
solvent
Me
Me
temp
N
O
O
1a
2a
Entry
Base
Solvent
Temp (°C)
Yield (%)b
1
2
3
4
5
pyridine
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
CH2Cl2
80
80
60
20
40
0
52
76
0
Et3N
Et3N
Et3N
Et3N
0
a The reaction was carried out using 0.5 mmol of 1a, 1.25 mmol TNM, and
1 mmol of a base in 2 mL of a solvent under argon atmosphere.
b Isolated yields after chromatographic purification.
Studying the mechanistic aspects of this reaction we re-
vealed that heterocyclization of model alkene 1a also pro-
ceeded using NaNO2/AcOH system or t-BuONO in the pres-
ence of water. In this connection, the reaction optimization
was carried out for these reagents, by varying their
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

C
D. A. Vasilenko et al.
Paper
Synthesis
Table 2 Optimization of the Conditions for the Reaction of 1a with NaNO2 or t-BuONOa
MeO
MeO
NO2
solvent
reagent
+
Me
temp
Me
N
O
O
1a
2a
Entry
Reagent (equiv)
Solvent
Temp (°C)
Conversion of 1a (%)b,c(isolated yield, %)d
1
2
NaNO2 (10)
AcOH/1,4-dioxane (5 mL/5 mL)
AcOH/1,4-dioxane (5 mL/5 mL)
AcOH/1,4-dioxane (5 mL/5 mL)
AcOH/1,4-dioxane (5 mL/5 mL)
AcOH/1,4-dioxane (5 mL/5 mL)
H2O (3 mL)
60
80
100
80
80
60
60
60
60
60
60
60
60
20
40
80
60
60
60
60
60
60
60
60
60
traces
20 (15)
0
NaNO2 (10)
3
NaNO2 (10)
4
NaNO2 (20)
21 (15)
12 (–)
5
NaNO2 (5)
6
t-BuONO (20)
t-BuONO (20)
t-BuONO (20)
t-BuONO (20)
t-BuONO (20)
t-BuONO (20)
t-BuONO (20)
t-BuONO (20)
t-BuONO (20)
t-BuONO (20)
t-BuONO (20)
t-BuONO (20)
t-BuONO (20)
t-BuONO (20)
t-BuONO (20)
t-BuONO (20)
t-BuONO (10)
t-BuONO (10)
t-BuONO (10)
t-BuONO (5)
55 (50)
0
7
EtOH/H2O (3 mL/3 mL)
8
EtOAc/H2O (3 mL/3 mL)
32 (25)
79 (50)
53 (45)
74 (50)
traces
9
AcOH/H2O (3 mL/3 mL)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
THF/H2O (3 mL/3 mL)
MeCN/H2O (3 mL/3 mL)
1,4-dioxane (3 mL)
1,4-dioxane/H2O (3 mL/3 mL)
1,4-dioxane/H2O (3 mL/3 mL)
1,4-dioxane/H2O (3 mL/3 mL)
1,4-dioxane/H2O (3 mL/3 mL)
1,4-dioxane/H2O (2 mL/3 mL)
1,4-dioxane/H2O (1 mL/3 mL)
1,4-dioxane/H2O (0.5 mL/3 mL)
1,4-dioxane/H2O (1.5 mL/1.5 mL)
1,4-dioxane/H2O (0.5 mL/1.5 mL)
1,4-dioxane/H2O (3 mL/3 mL)
1,4-dioxane/H2O (0.75 mL/0.75 mL)
85 (55)
30 (2)
38 (18)
86 (50)
84 (54)
85 (60)
84 (62)
95 (66)
100 (70)
75 (61)
100 (76)
100 (78)
76 (60)
1,4-dioxane/H2O (0.25 mL/0.75 mL)
1,4-dioxane/H2O (0.25 mL /0.75 mL)
a The reaction was carried out using 0.5 mmol of 1a under argon atmosphere.
b Conversion of 1a into 2a was estimated via 1H NMR spectra.
c The formation of 10–20% 4-methoxybenzaldehyde as a by-product was observed when using t-BuONO as the reagent.
d Isolated yields after chromatographic purification.
azole 2c was isolated from this mixture in poor yield (21%),
while the application of t-BuONO permitted to avoid the
formation of side-products and to isolate 2c in 80% yield.
To probe the synthetic utility of our approaches to 4-ni-
troisoxazoles, diaryl-substituted vinyl ketones 1o–r were
used in heterocyclization. As the result, a series of 3,5-di-
aryl-4-nitroisoxazoles 2o–r were obtained in moderate
yields. Also it was demonstrated that the reaction can be
exploited to the synthesis of bis(isoxazole) 2s, which can be
interesting as a precursor of bivalent ligands with increased
bioactivities.26
The structures of the obtained 4-nitroisoxazoles were
additionally confirmed by X-ray diffraction analysis on the
example of compounds 2a and 2o (see Supporting Informa-
tion).
As expected, cyclohexyl-substituted alkene 1t was not
involved in heterocyclization upon treatment with either
TNM-TEA or t-BuONO-H2O, that additionally confirms the
demand for aryl substituent in -position of the double
bond for this process.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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D. A. Vasilenko et al.
Paper
Synthesis
R1
NO2
O
Method A or B
Method A: C(NO2)4-Et3N, 1,4-dioxane, 60 °C, 2 h
R1
R2
Method B: t-BuONO, 1,4-dioxane/H2O (1:3), 60 °C, 2 h
N
R2
O
1a–s
2a–s
MeO
MeO
MeO
MeO
NO2
NO2
NO2
NO2
NO2
MeO
N
N
N
N
N
Me
Me
Me
Me
Me
O
O
O
O
O
2a
76% (A), 78% (B)
2b
2c
2d
34% (A), 65% (B)
2e
70% (A), 68% (B)
67% (A), 70% (B)
21% (A), 80% (B)
OMe
MeO
MeO
F
Br
H(O)C
O2N
NO2
NO2
NO2
NO2
NO2
NO2
N
N
N
N
N
N
Me
Me
Me
Me
Me
O
Me
O
O
O
O
O
2f
71% (A), 71% (B)
2g
52% (A), 56% (B)
2h
70% (A), 76% (B)
2i
2j
2k
54% (A), 60% (B)
39% (A). 67% (B)
55% (A), 64% (B)
MeO
NO2
O
NO2
S
NO2
NO2
NO2
N
N
N
Me
N
Me
O
O
O
O
N
Me
2m
2l
2n
2o
2p
O
47% (A), 39% (B)
42% (A), 49% (B)
43% (A), 48% (B)
38% (A), 42% (B)
68% (A). 47% (B)
NO2
NO2
O2N
NO2
Me
Me
NO2
OMe
N
N
O
O
O
O
N
N
N
Me
O
OMe
2q
21% (A), 20% (B)
2s
52% (A), 68% (B)
2t
2r
OMe
30% (A), 33% (B)
–
Scheme 2 Synthesis of 4-nitroisoxazoles 2a–s
To demonstrate the practical utility of our synthetic
method gram-scale synthesis of 4-nitroisoxazoles (6 mmol
1a or 1e) was carried out. In standard reaction conditions,
heterocycles 2a and 2e were obtained in 73% and 64% iso-
lated yield, respectively (Scheme 3).
participation of NO/NO2 radicals. It is described that ther-
mal decomposition of TNM leads to the complex mixture of
products containing NO/NO2 radicals.27 The possibility of
homolytic TNM nitration of aromatic hydrocarbons and nu-
cleophilic double bonds of alkenes is well known and re-
viewed.27a,b Also, there are evidences in the literature that
polynitromethanes may produce nitrosation agent(s) in the
presence of nucleophiles.27a,b,28 At the same time, t-BuONO
can be employed as a source of NO and NO2 radicals, which
are formed in aerobic thermal homolysis or hydrolysis.29
The heterocyclization of unsaturated ketone is initiated by
the attack of NO2-radical to -carbon of double bond and
generation of the stable benzyl radical A. Subsequent nitro-
gen monoxide trapping leads to the formation of nitroso in-
termediate B followed by tautomerization reaction giving
oxime C. The intramolecular cyclization of oximino deriva-
tive C proceeds accompanied by elimination of water from
D with the formation of 4-nitroisoxazole 2. The possibility
H2O/1,4-dioxane
(7.2 mL/2.4 mL)
O
Ar
NO2
+
t-BuONO
Ar
Me
60 °C, 2 h
N
Me
1a,e
6 mmol
60 mmol
O
2a, 1.02 g, 73%
2e, 1.01 g, 63%
MeO
MeO
MeO
Ar =
(1a),
(1e)
Scheme 3 Gram-scale preparation of 2a and 2e
A putative mechanism is outlined in Scheme 4. We sup-
pose that heterocyclization of ,-unsaturated ketone in
both procedures (A and B) includes a radical pathway with
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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D. A. Vasilenko et al.
Paper
Synthesis
of the formation of 4-nitroisoxazole from chalcones and di-
nitrogen trioxide has been demonstrated.30 In addition, we
have found that heterocyclization of alkene 1a in both con-
ditions (A and B) is suppressed in the presence of the radi-
cal scavenger 2,2,6,6-tetramethyl-1-piperidinoxyl (TEMPO,
0.5 equiv) that indirectly confirms the radical nature of het-
erocyclization.
dard for 19F NMR. Chemical shifts () are given in ppm; J values are
given in hertz (Hz). When necessary, assignments of signals in NMR
spectra were made using 2D techniques. Accurate mass measure-
ments (HRMS) were performed on a Bruker micrOTOF II instrument
using electrospray ionization (ESI). The measurements were done in a
positive ion mode (interface capillary voltage 4500 V) or in a negative
ion mode (3200 V). Analytical TLC was carried out with Silufol alumi-
num-backed silica gel plates; the detection was done by UV lamp (254
and 365 nm) and chemical staining (5% aq KMnO4). Column chroma-
tography was performed on silica gel (230–400 mesh, Merck).
t-BuONO + H2O
NO2 + NO
C(NO2)4 + Et3N
Compounds 1a,31 1b,32 1c,33 1d,34 1e,f,35 1s36 were synthesized by the
known procedure.35 Compounds 1g,h,l,37 1i,38 1j,39 1k,33 1m,40 1n,41
1t42 were synthesized by the known procedure.39 Compounds 1o,43
1p,44 1q,45 1r46 were synthesized by the known procedure.43 All other
starting materials were commercially available. All reagents except
commercial products of satisfactory quality were purified by litera-
ture procedures prior to use.
O2N
R
O
R
O2N
Ar
R
O
NO2
NO
Ar
O
Ar
Ar
O
N
A
B
O2N
O2N
O2N
R
R
R
OH
Compounds 2a–s; General Procedures
Ar
Ar
O
– H2O
O
O
N
N
Method A: To a solution of C(NO2)4 (0.28 mL, 590 mg, 2.50 mmol) in
1,4-dioxane (3.0 mL) was added Et3N (0.28 mL, 202 mg, 2 mmol)
dropwise under argon atmosphere at –10 to –5 °C. The resulting mix-
ture was stirred at this temperature for 5 min and then the corre-
sponding alkene 1 (1.0 mmol) in 1,4-dioxane (1.0 mL) was added
dropwise. The reaction mixture was stirred at 60 °C for 2 h and then
the solvent was evaporated in vacuo. The residue was purified by pre-
parative column chromatography on silica gel.
N
OH
2
D
C
Scheme 4 Plausible pathway accounting for 4-nitroisoxazoles 2
As follows from the above data and previously pub-
lished results,25 the reactivity of electrophilic alkenes to-
wards TNM-TEA complex strongly depends on their struc-
ture. As we have shown earlier, -unsubstituted electro-
philic alkenes or alkenes, bearing primary alkyl
substituents in -position, react with TNM-TEA affording 5-
nitroisoxazoles. This reaction proceeds through the Michael
Method B: To a solution of the corresponding alkene 1 (1.0 mmol) in a
mixture of 1,4-dioxane (0.4 mL) and H2O (1.2 mL) was added t-BuONO
(1.18 mL, 1.30 g, 10.0 mmol) dropwise under argon atmosphere over
1 h at 60 °C. The resulting mixture was stirred at this temperature for
1 h and then cooled down to rt. The mixture was poured into H2O (10
mL) and extracted with CH2Cl2 (4 × 10 mL). The combined organic lay-
ers were washed with brine (20 mL) and dried (anhyd MgSO4). The
solvent was evaporated in vacuo and the residue was purified by pre-
parative column chromatography on silica gel.
–
addition of C(NO2)3 to double bond and subsequent intra-
molecular cyclization. The specific reactivity of -aryl vinyl
ketones towards TNM-TEA is defined by the following rea-
sons: (i) electrophilic alkenes with bulky substituents in -
position do not react with –C(NO2)3 anion because of steric
hindrance,25 (ii) for these substrates there is a possibility of
formation of a stable benzyl radical (type A, Scheme 4), and
(iii) keto group, present in the molecule, may participate in
the intramolecular cyclization allowing 4-nitroisoxazoles.
In summary, a general straightforward and regioselec-
tive method for the synthesis of 4-nitroisoxazoles in good
to high isolated yields from readily available and inexpen-
sive alkenes has been developed. A wide range of -
aryl/hetaryl-substituted vinyl ketones may be successfully
involved in the reactions with TNM-TEA or cheap and prac-
ticable t-BuONO, including gram-scale protocols. Therefore,
the elaborated method provides easy access to 4-nitro-
isoxazoles, bearing a variety of substituents, that represent
valuable precursors in organic and medicinal chemistry.
3-(4-Methoxyphenyl)-5-methyl-4-nitroisoxazole (2a)18b
White solid; yield: 178 mg (0.76 mmol, 76%) via method A; yield: 183
mg (0.78 mmol, 78%) via method B; mp 127–129 °C; Rf = 0.41 (PE–
EtOAc, 10:1).
1H NMR (CDCl3, 400.0 MHz):  = 2.85 (s, 3 H, CH3), 3.86 (s, 3 H, CH3O),
6.96–7.02 (m, 2 H, 2 × CH), 7.55–7.60 (m, 2 H, 2 × CH).
13С NMR (CDCl3, 100.6 MHz):  = 14.3 (CH3), 55.5 (CH3O), 114.1 (2 ×
СH), 118.0 (CAr), 129.7 (CNO2), 130.9 (2 × CH), 157.4 (С), 161.6 (СAr),
172.9 (С).
Anal. Calcd for С11Н10N2O4: C, 56.41; H, 4.30; N, 11.96. Found: C,
56.47; H, 4.44; N, 11.65.
5-Methyl-4-nitro-3-phenylisoxazole (2b)47
White solid; yield: 137 mg (0.67 mmol, 67%) via method A; yield: 143
mg (0.70 mmol, 70%) via method B; mp 92–93 °C; Rf = 0.62 (PE–EtOAc,
10:1).
1H NMR (CDCl3, 400.0 MHz):  = 2.89 (s, 3 H, CH3), 7.47–7.56 (m, 3 H,
3 × СН), 7.60–7.63 (m, 2 H, 2 × СН).
13С NMR (CDCl3, 100.6 MHz):  = 13.9 (CH3), 125.9 (C, C6H5), 128.5 (2 ×
NMR spectra were recorded on spectrometer Agilent 400-MR (400.0
MHz for 1H; 100.6 MHz for 13C, 376.3 MHz for 19F) at room tempera-
ture; chemical shifts () were measured with reference to the solvent
CDCl3 for 1Н ( = 7.26), 13C ( = 77.16) and to CFCl3 as external stan-
CH), 129.2 (2 × CH), 129.6 (CNO2), 130.7 (CH), 157.7 (C), 172.8 (C).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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Synthesis
3-(2-Methoxyphenyl)-5-methyl-4-nitroisoxazole (2c)
1H NMR (CDCl3, 400.0 MHz):  = 2.87 (s, 3 H, CH3), 7.14–7.21 (m, 2 H,
2 × CH), 7.57–7.66 (m, 2 H, 2 × CH).
Light-yellow oil; yield: 49 mg (0.21 mmol, 21%) via method A; yield:
13С NMR (CDCl3, 100.6 MHz):  = 14.2 (CH3), 115.8 (3JC,F = 22 Hz, 2 ×
СH), 122.0 (4JC,F = 4 Hz, CAr), 129.7 (CNO2), 131.6 (2JC,F = 8.8 Hz, 2 × CH),
157.0 (С), 164.5 (1JC,F = 251 Hz, СAr), 173.1 (С).
187 mg (0.80 mmol, 80%) via method B; Rf = 0.43 (PE–CH2Cl2, 10:1).
1H NMR (CDCl3, 400.0 MHz):  = 2.85 (s, 3 H, CH3), 3.77 (s, 3 H, OCH3),
7.00 (dd, 3J = 8.4 Hz, 4J = 1.0 Hz, 1 H, CH), 7.08 (ddd, 3J = 7.8 Hz, 3J = 7.6
Hz, 4J = 1.0 Hz, 1 H, CH), 7.48 (dd, 3J = 7.6 Hz, 4J = 1.8 Hz, 1 H, CH), 7.53
(ddd, 3J = 8.4 Hz, 3J = 7.6 Hz, 4J = 1.8 Hz, 1 H, CH).
3
4
19F NMR (CDCl3, 376.3 MHz):  = –109.2 (tt, JH,F = 8.5 Hz, JH,F = 5.1
Hz).
13С NMR (CDCl3, 100.6 MHz):  = 13.6 (CH3), 55.6 (CH3O), 111.1 (CH),
115.6 (СAr), 120.9 (CH), 130.2 (CH), 131.0 (СNO2), 132.4 (CH), 155.8
(CAr), 157.6 (C), 170.9 (С).
Anal. Calcd for С10Н7FN2O3: C, 54.06; H, 3.18; N, 12.61. Found: C,
53.96; H, 3.12; N, 12.51.
HRMS (ESI): m/z [M + H]+ calcd for C11H11N2O4+: 235.0713; found:
3-(4-Bromophenyl)-5-methyl-4-nitroisoxazole (2h)18b
235.0710.
White solid; yield: 198 mg (0.70 mmol, 70%) via method A; yield: 215
mg (0.76 mmol, 76%) via method B; mp 121–123 °C; Rf = 0.22 (PE–
EtOAc, 10:1).
3-(3-Methoxyphenyl)-5-methyl-4-nitroisoxazole (2d)
1H NMR (CDCl3, 400.0 MHz):  = 2.88 (s, 3 H, CH3), 7.52 (d, 3J = 8.7 Hz,
2 H, 2 × CH), 7.66 (d, 3J = 8.7 Hz, 2 H, 2 × CH).
Light-yellow oil; yield: 80 mg (0.34 mmol, 34%) via method A; yield:
152 mg (0.65 mmol, 65%) via method B; Rf = 0.25 (PE–EtOAc, 10:1).
1H NMR (CDCl3, 400.0 MHz):  = 2.87 (s, 3 H, CH3), 3.84 (s, 3 H, OCH3),
7.07 (ddd, 3J = 8.3 Hz, 4J = 1.0 Hz, 4J = 2.6 Hz, 1 H, CH), 7.14 (dd,
4J = 1.2 Hz, 4J = 2.6 Hz, 1 H, CH), 7.18 (ddd, 3J = 7.6 Hz, 4J = 1.2 Hz,
4J = 1.0 Hz, 1 H, CH), 7.40 (dd, 3J = 8.3 Hz, 3J = 7.6 Hz, 1 H, CH).
13С NMR (CDCl3, 100.6 MHz):  = 14.2 (CH3), 55.5 (CH3O), 114.6 (CH),
116.8 (СH), 121.7 (CH), 127.1 (CAr), 129.7 (CH), 129.7 (СNO2), 157.7
(CAr), 159.6 (C), 172.8 (С).
13С NMR (CDCl3, 100.6 MHz):  = 14.3 (CH3), 124.9 (CAr), 125.6 (СAr),
129.7 (CNO2), 131.0 (2 × СH), 131.9 (2 × CH), 157.1 (С), 173.2 (С).
Anal. Calcd for С10Н7BrN2O3: C, 42.43; H, 2.49; N, 9.90. Found: C,
42.36; H, 2.71; N, 9.72.
4-(5-Methyl-4-nitroisoxazol-3-yl)benzaldehyde (2i)
White solid; yield: 125 mg (0.54 mmol, 54%) via method A; yield: 139
mg (0.60 mmol, 60%) via method B; mp 101–102 °C; Rf = 0.16 (PE–
EtOAc, 10:1).
HRMS (ESI): m/z [M + H]+ calcd for C11H11N2O4+: 235.0713; found:
235.0714.
1H NMR (CDCl3, 400.0 MHz):  = 2.90 (s, 3 H, CH3), 7.76–7.79 (m, 2 H,
2 × CH), 7.98–7.82 (m, 2 H, 2 × CH), 10.08 (s, 1 H, CHO).
Anal. Calcd for С11Н10N2O4: C, 56.41; H, 4.30; N, 11.96. Found: C,
56.42; H, 4.34; N, 11.96.
13С NMR (CDCl3, 100.6 MHz):  = 14.2 (CH3), 129.6 (CNO2), 129.7 (2 ×
СH), 130.2 (2 × CH), 131.7 (CAr), 137.7 (СAr), 157.0 (С), 173.3 (С), 191.6
(CHO).
HRMS (ESI): m/z [M + Na]+ calcd for C11H8N2O4Na+: 255.0376; found:
255.0368.
3-(3,4-Dimethoxyphenyl)-5-methyl-4-nitroisoxazole (2e)
White solid; yield: 185 mg (0.70 mmol, 70%) via method A; yield: 180
mg (0.68 mmol, 68%) via method B; mp 153–155 °C; Rf = 0.33 (PE–
EtOAc, 3:1).
1H NMR (CDCl3, 400.0 MHz):  = 2.86 (s, 3 H, CH3), 3.90 (s, 3 H, CH3O),
3.94 (s, 3 H, CH3O), 6.96 (d, 3J = 8.4 Hz, 1 H, CH), 7.15 (d, 4J = 2.0 Hz, 1
H, CH), 7.23 (dd, 3J = 8.4 Hz, 4J = 2.0 Hz, 1 H, CH).
13С NMR (CDCl3, 100.6 MHz):  = 14.3 (CH3), 56.07 (CH3O), 56.12
(CH3O), 110.9 (CH), 112.2 (CH), 118.0 (CAr), 122.7 (СH), 129.8 (СNO2),
148.9 (CAr), 151.2 (СAr), 157.4 (C), 173.0 (С).
5-Methyl-4-nitro-3-(4-nitrophenyl)isoxazole (2j)48
Light-yellow solid; yield: 97 mg (0.39 mmol, 39%) via method A;
yield: 167 mg (0.67 mmol, 67%) via method B; mp 152–153 °C; Rf =
0.16 (PE–EtOAc, 7:1).
1H NMR (CDCl3, 400.0 MHz):  = 2.93 (s, 3 H, CH3), 7.79–7.85 (m, 2 H,
2 × CH), 8.32–8.38 (m, 2 H, 2 × CH).
13С NMR (CDCl3, 100.6 MHz):  = 14.3 (CH3), 123.7 (2 × СH), 129.7
HRMS (ESI): m/z [M + H]+ calcd for C12H13N2O5+: 265.0819; found:
265.0821.
(CNO2), 130.8 (2 × CH), 132.3 (CAr), 149.3 (СArNO2), 156.3 (С), 173.6
(С).
5-Methyl-4-nitro-3-(3,4,5-trimethoxyphenyl)isoxazole (2f)
White solid; yield: 209 mg (0.71 mmol, 71%) via method A; yield: 209
mg (0.71 mmol, 71%) via method B; mp 160–162 °C; Rf = 0.16 PE–EtOAc,
7:1).
1H NMR (CDCl3, 400.0 MHz):  = 2.85 (s, 3 H, CH3), 3.86 (s, 6 H, 2 ×
5-Methyl-3-(naphthalen-1-yl)-4-nitroisoxazole (2k)18b
White solid; yield: 140 mg (0.55 mmol, 55%) via method A; yield: 163
mg (0.64 mmol, 64%) via method B; mp 97–98 °C; Rf = 0.12 (PE–EtOAc,
10:1).
CH3O), 3.89 (s, 3 H, CH3O), 6.84 (s, 2 H, 2 × CH).
13С NMR (CDCl3, 100.6 MHz):  = 14.2 (CH3), 56.3 (2 × CH3O), 61.0
(CH3O), 106.8 (2 × CH), 120.9 (СAr), 129.7 (СNO2), 140.2 (CAr), 153.2 (2
× СAr), 157.5 (C), 173.0 (С).
3
1H NMR (CDCl3, 400.0 MHz):  = 2.95 (s, 3 H, CH3), 7.48 (ddd, J = 8.2
3
4
3
3
Hz, J = 6.9 Hz, J = 1.6 Hz, 1 H, CH), 7.53 (ddd, J = 8.1 Hz, J = 6.7 Hz,
4J = 1.5 Hz, 1 H, CH), 7.54–7.61 (m, 3 H, 3 × CH), 7.95 (br d, 3J = 8.2 Hz,
1 H, CH), 8.01–8.08 (m, 1 H, CH).
HRMS (ESI): m/z [M + H]+ calcd for C13H15N2O6+: 295.0925; found:
13С NMR (CDCl3, 100.6 MHz):  = 14.2 (CH3), 123.6 (CAr), 124.4 (CH),
125.0 (CH), 126.6 (CH), 127.3 (CH), 128.3 (CH), 128.8 (CH), 130.9
(CNO2), 131.1 (СH), 131.5 (СAr), 133.4 (CAr), 157.3 (С), 172.5 (С).
295.0926.
3-(4-Fluorophenyl)-5-methyl-4-nitroisoxazole (2g)
HRMS (ESI): m/z [M + H]+ calcd for C14H11N2O3+: 255.0764; found:
255.0769.
White solid; yield: 115 mg (0.52 mmol, 52%) via method A; yield: 124
mg (0.56 mmol, 56%) via method B; mp 99–102 °C; Rf = 0.63 (PE–EtOAc,
10:1).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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Synthesis
3-Biphenyl-4-yl-5-methyl-4-nitroisoxazole (2l)
4-Nitro-3-phenyl-5-(3,4,5-trimethoxyphenyl)isoxazole (2q)
Light-yellow solid; yield: 132 mg (0.47 mmol, 47%) via method A;
yield: 110 mg (0.39 mmol, 39%) via method B; mp 108–109 °C; Rf =
0.4 (PE–EtOAc, 3:1).
White solid; yield: 75 mg (0.21 mmol, 21%) via method A; yield: 71
mg (0.20 mmol, 20%) via method B; mp 100–102 °C; Rf = 0.37 (PE–
EtOAc, 4:1).
1H NMR (CDCl3, 400.0 MHz):  = 2.88 (s, 3 H, CH3), 7.38–7.44 (m, 1 H,
СH), 7.46–7.51 (m, 2 H, 2 × СH), 7.64–7.68 (m, 1 H, СH), 7.70–7.75 (m,
4 H, 4 × СH).
1H NMR (CDCl3, 400.0 MHz):  = 3.94 (s, 6 H, 2 × CH3), 3.97 (s, 3 H,
CH3), 7.24 (s, 2 H, 2 × CH), 7.48–7.60 (m, 3 H, 3 × CH), 7.62–7.67 (m, 2
H, 2 × CH).
13С NMR (CDCl3, 100.6 MHz):  = 14.2 (CH3), 124.7 (C), 127.2 (2 × СН),
127.3 (2 × СН), 128.0 (СН), 129.0 (2 × CH), 129.6 (CNO2), 129.8 (2 ×
CH), 140.1 (СAr), 143.6 (СAr), 157.5 (С), 172.9 (С).
13С NMR (CDCl3, 100.6 MHz):  = 56.5 (2 × CH3), 61.2 (CH3), 106.6 (2 ×
CH), 119.4 (C), 126.1 (C), 128.88 (2 × CH), 128.90 (2 × CH), 129.5
(CNO2), 131.0 (CH), 142.1 (C), 153.5 (2 C), 158.9 (C), 167.8 (C).
Anal. Calcd for С16Н12N2O3: C, 68.56; H, 4.32; N, 9.99. Found: C, 68.36;
HRMS (ESI): m/z [M + H]+ calcd for C18H17N2O6+: 357.1081; found:
H, 4.36; N, 9.30.
357.1079.
3-(Furan-2-yl)-5-methyl-4-nitroisoxazole (2m)
5-([1,1'-Biphenyl]-4-yl)-3-phenyl-4-nitroisoxazole (2r)
White solid; yield: 81 mg (0.42 mmol, 42%) via method A; yield: 95
mg (0.49 mmol, 49%) via method B; mp 95–97 °C; Rf = 0.28 (PE–EtOAc,
10:1).
Light-yellow solid; yield: 103 mg (0.30 mmol, 30%) via method A;
yield: 113 mg (0.33 mmol, 33%) via method B; mp 206–207 °C; Rf =
0.14 (PE–CH2Cl2, 2:1).
1H NMR (CDCl3, 400.0 MHz):  = 2.87 (s, 3 H, CH3), 6.59 (dd, 3J = 1.8
Hz, 3J = 3.6 Hz, 1 Н, СН), 7.43 (dd, 3J = 3.5 Hz, 4J = 0.7 Hz, 1 Н, СН), 7.64
(dd, 3J = 1.8 Hz, 4J = 0.7 Hz, 1 Н, СН).
1H NMR (CDCl3, 400.0 MHz):  = 7.41–7.46 (m, 1 H, CH), 7.48–7.58 (m,
5 H, 5 × CH), 7.65–7.69 (m, 4 H, 4 × CH), 7.78–7.82 (m, 2 H, 2 × CH),
8.01–8.05 (m, 2 H, 2 × CH).
13С NMR (CDCl3, 100.6 MHz):  = 14.3 (СН3), 112.1 (CH), 117.2 (CH),
128.8 (СNO2), 140.2 (C), 145.5 (CH), 148.5 (C), 173.2 (C).
13С NMR (CDCl3, 100.6 MHz):  = 123.4 (СAr), 126.1 (СAr), 127.4 (2 ×
СH), 127.7 (2 × СH), 128.6 (CH), 128.9 (2 × CH), 129.0 (2 × CH), 129.2
(2 × CH), 129.2 (CNO2), 129.5 (2 × СH), 131.0 (СH), 139.6 (СAr), 145.6
(СAr), 158.7 (С), 168.2 (С).
Anal. Calcd for С8Н6N2O4: C, 49.58; H, 3.25; N, 14.41. Found: C, 49.49;
H, 3.12; N, 14.43.
HRMS (ESI): m/z [M + H]+ calcd for C22H17N2O4+: 343.1077; found:
343.1066.
5-Methyl-4-nitro-3-(thiophen-2-yl)isoxazole (2n)
White solid; yield: 143 mg (0.68 mmol, 68%) via method A; yield: 99
mg (0.47 mmol, 47%) via method B; mp 67–69 °C; Rf = 0.35 (PE–EtOAc,
10:1).
1H NMR (CDCl3, 400.0 MHz):  = 2.87 (s, 3 H, CH3), 7.18 (dd, 3J = 3.8
Hz, 3J = 5.1 Hz, 1 Н, СН), 7.56 (dd, 4J = 1.1 Hz, 3J = 5.1 Hz, 1 Н, СН), 7.88
(dd, 4J = 1.1 Hz, 3J = 3.8 Hz, 1 Н, СН).
1,4-Bis(5-methyl-4-nitroisoxazol-3-yl)benzene (2s)
Light-yellow solid; yield: 172 mg (0.52 mmol, 52%) via method A;
yield: 224 mg (0.68 mmol, 68%) via method B; mp 214–216 °C. Com-
pound 2s crystallized after the addition of MeOH to the reaction mix-
ture and required no additional purification.
1H NMR (CDCl3, 400.0 MHz):  = 2.92 (s, 6 H, CH3), 7.77 (s, 4 Н, 4 ×
СН).
13С NMR (CDCl3, 100.6 MHz):  = 14.3 (2 × СН3), 128.4 (2 × CAr), 129.6
(4 × CH), 130.2 (CNO2), 157.2 (C), 173.2 (C).
HRMS (ESI): m/z [M + H]+ calcd for C14H10N4O6+: 331.0673; found:
13С NMR (CDCl3, 100.6 MHz):  = 14.4 (СН3), 125.8 (С), 127.9 (CH),
129.3 (CNO2), 130.1 (CH), 132.0 (CH), 152.0 (C), 173.5 (C).
Anal. Calcd for С8Н6N2O3S: C, 45.82; H, 2.85; N, 13.19; S, 15.40. Found:
C, 45.71; H, 2.88; N, 13.33; S, 15.25.
4-Nitro-3,5-diphenylisoxazole (2o)47
331.0673.
White solid; yield: 114 mg (0.43 mmol, 43%) via method A; yield: 127
mg (0.48 mmol, 48%) via method B; mp 55–57 °C; Rf = 0.41 (PE–EtOAc,
5:1).
1H NMR (CDCl3, 400.0 MHz):  = 7.48–7.66 (m, 8 H, 8 × СН), 7.89–7.93
(m, 2 H, 2 × СН).
Gram-Scale Synthesis of 2a and 2e
To the solution of alkene 1 (6 mmol) in a mixture of 1,4-dioxane (2.4
mL) and H2O (7.2 mL) was added t-BuONO (7.2 mL, 6.24 g, 60 mmol)
dropwise under argon atmosphere over 1 h at 60 °C. The resulting
mixture was stirred at this temperature for 1 h and then cooled down
to r.t. The mixture was poured into H2O (20 mL) and extracted with
CH2Cl2 (4 × 20 mL). The combined organic layers were washed with
brine (30 mL) and dried (anhyd MgSO4). The solvent was evaporated
in vacuo and the crude product was purified by prepared column
chromatography.
3-(4-Methoxyphenyl)-4-nitro-5-phenylisoxazole (2p)
White solid; yield: 112 mg (0.38 mmol, 38%) via method A; yield: 124
mg (0.42 mmol, 42%) via method B; mp 121–122 °C; Rf = 0.26 (PE–
EtOAc, 8:1).
1H NMR (CDCl3, 400.0 MHz):  = 3.88 (s, 3 H, CH3O), 7.00–7.05 (m, 2
H, 2 × CH), 7.54–7.66 (m, 5 H, 5 × CH), 7.88–7.93 (m, 2 H, 2 × CH).
Compound 2a
13С NMR (CDCl3, 100.6 MHz):  = 55.5 (CH3O), 114.4 (2 × CH), 118.0
(CAr), 124.8 (CAr), 128.9 (2 × CH), 129.0 (CNO2), 129.1 (2 × CH), 130.5 (2
× CH), 132.7 (CH), 158.1 (С), 161.8 (СAr), 168.3 (С).
HRMS (ESI): m/z [M + Na]+ calcd for C16H12N2O4Na+: 319.0689; found:
319.0787.
White solid; yield: 1.02 g (4.38 mmol, 73%).
Compound 2e
White solid; yield: 1.01 g (3.84 mmol, 64%).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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D. A. Vasilenko et al.
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Synthesis
Synthesis of 2a Using NaNO2 and Acetic Acid
adelphia, 2015, 263. (b) Farrington, M. In Clinical Pharmacology,
11th ed; Bennett, P. N.; Brown, M. J.; Sharma, P., Ed.; Elsevier
Ltd: Churchill Livingstone, 2012, 173.
To the solution of alkene 1a (100 mg, 0.57 mmol) in a mixture of 1,4-
dioxane (2.5 mL) and AcOH (2.5 mL) was added NaNO2 (393 mg, 5.7
mmol) in one portion under argon atmosphere at 60 °C. The resulting
mixture was stirred at this temperature for 2 h and then cooled down
to r.t. The mixture was poured into H2O (10 mL) and extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers were washed with
sat. aq NaHCO3 and dried (anhyd MgSO4). The solvent was evaporated
in vacuo to give 96 mg of the crude product. According the 1H NMR
spectra, the resulting mixture was composed of alkene 1a (80%) and
isoxazole 2a (20%).
(4) Leppik, I. E. Seizure 2004, 13S1, S5.
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2724. (b) Averina, E. B.; Vasilenko, D. A.; Gracheva, Y. A.; Grishin,
Y. K.; Radchenko, E. V.; Burmistrov, V. V.; Butov, G. M.;
Neganova, M. E.; Serkova, T. P.; Redkozubova, O. M.; Shevtsova,
E. F.; Milaeva, E. R.; Kuznetsova, T. S.; Zefirov, N. S. Bioorg. Med.
Chem. 2016, 24, 712.
Funding Information
This work was supported by the Russian Science Foundation, grant
no. 19-73-00145.
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n
c
e
F
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n
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ati
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Acknowledgment
This study was fulfilled using a STOE STADI VARI PILATUS-100K dif-
fractometer and NMR spectrometer Agilent 400-MR purchased by
MSU Development Program.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690053.
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Primary Data
for this article are available online at https://doi.org/10.1055/s-0039-
1690053 and can be cited using the following DOI: 10.4125/pd0113th.
(14) Jorgensen, A. T.; Tagmose, L.; Stensbol, T. B.; Vestergaard, H. T.;
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