RETRACTED ARTICLE: Unexpected Heterocyclization of Electrophilic Alkenes by Tetranitromethane in the Presence of Triethylamine. Synthesis of 5-Nitroisoxazoles

Article abstract of DOI:10.1021/acs.joc.8b03086

A novel reaction of tetranitromethane with electrophilic alkenes in the presence of triethylamine affording substituted 5-nitroisoxazoles is described. Triethylamine reacts with tetranitromethane to generate N-nitrotriethylammonium and trinitromethanide. This process provides the heterocyclization of electrophilic alkenes. A variety of α,β-unsaturated aldehydes, ketones, esters, amides, phosphonates, nitro, and sulfur compounds was involved in the heterocyclization reaction, and a wide range of functionalized 5-nitroisoxazoles was obtained in good to high yields. The scope and limitations of the reaction and the mechanistic proposal are discussed.

Full text of DOI:10.1021/acs.joc.8b03086

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Article
Unexpected heterocyclization of electrophilic alkenes by tetranitromethane
in the presence of triethylamine. Synthesis of 5-nitroisoxazoles
Yulia Alexeevna Volkova, Elena Borisovna Averina, Dmitry A. Vasilenko, Kseniya N.
Sedenkova, Yuri K. Grishin, Per Bruheim, Tamara S. Kuznetsova, and Nikolay S. Zefirov
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03086 • Publication Date (Web): 06 Feb 2019
Downloaded from http://pubs.acs.org on February 7, 2019
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Unexpected heterocyclization of electrophilic alkenes by tetranitromethane in the presence of
triethylamine. Synthesis of 5-nitroisoxazoles
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Yulia A. Volkova,† Elena B. Averina,*† Dmitry A. Vasilenko,† Kseniya N. Sedenkova,†
Yuri K. Grishin,† Per Bruheim,‡ Tamara S. Kuznetsova,† Nikolai S. Zefirov†
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†
Lomonosov Moscow State University, Department of Chemistry, Leninskie Gory, 1-3, Moscow
119992, Russia
‡ Department of Biotechnology, Norwegian University of Science and Technology, Sem Selands vei
6/8, N-7431 Trondheim, Norway
elaver@org.chem.msu.ru
R2
R2
R1
NO2
R1
O2N
R
NO2
C(NO2)4
Et3N
O
R
O
N
N
NO2
O
O
SO2R
PO(OEt)2
38-63%
R = H, Alk
40-49%, R = H, Alk
46-75%, R1, R2 = OAlk, OAr
RO2S
(EtO)2OP
18-64%, R1, R2 = NHAlk,
N
N
NHAr, NAlk2, NHAr2
45-86%, R1, R2 = H, Alk, Ar
NO2
NO2
O
O
25-28%
R = Ph, OPh
76%
Novel reaction of tetranitromethane with electrophilic alkenes in the presence of triethylamine
affording substituted 5-nitroisoxazoles is described. Triethylamine reacts with tetranitromethane to
generate N-nitrotriethylammonium and trinitromethanide. This process provides the
heterocyclization of electrophilic alkenes. A variety of α,β-unsaturated aldehydes, ketones, esters,
amides, phosphonates, nitro- and sulfur compounds was involved in the heterocyclization reaction
and a wide range of functionalized 5-nitroisoxazoles was obtained in good to high yields. The scope
and limitations of the reaction and the mechanistic proposal are discussed.
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Introduction
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Polynitromethanes have been found to be versatile reagents for heterocyclization reactions of
alkenes.1 These reactions discovered in the 1960s2,3 result in five-membered N,O-heterocyclic
compounds, mainly dinitroisoxazolidines. It was mentioned that only nucleophilic alkenes were
used in the heterocyclization with tetranitromethane, moreover “electron-withdrawing groups at
double bond dramatically reduce the nucleophilicity of alkene and exclude its reaction…with
tetranitromethane”. 4
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Studying the reactions of polynitromethanes with alkenes containing small ring, we have
developed one-pot three component heterocyclization reaction with a variety of alkenes and
proposed a preparative approach to highly functionalized nitro-substituted heterocycles, such as
isoxazolidines, as well as piperidones, aziridines, and isoxazolines.5 Moreover, we have found that
the combination of tetranitromethane (TNM) with triethylamine (TEA) may be regarded as a
specific reagent, which was used for the ring opening reaction of oxiranes and N-tosylaziridines
giving β-hydroxy nitrate6 and -tosylamino nitrates,7 respectively. It should be noted that TNM
itself does not cleave the epoxides and the aziridines directly without activation with a basic reagent
(TEA).
In this paper we report a novel reaction of TNM in the presence of TEA with conjugated
functionalized alkenes containing electron-withdrawing group at the double bond, which may be
considered as a general method for the synthesis of substituted 5-nitroisoxazoles.
It is well-known that isoxazoles constitute a class of heterocyclic compounds possessing a
remarkable variety of applications and being versatile building blocks in organic synthesis.8 A wide
range of isoxazoles’ biological activity includes antibacterial, antiviral, antifungal properties; they
can act as various glutamate and GABA receptors ligands, and also display herbicide activity.8d,9
The construction of the isoxazole ring can be achieved by two basic synthetic approaches, including
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the condensations of 1,3-dielectrophiles under the treatment with hydroxylamine and 1,3-dipolar
cycloaddition of nitrile oxides to acetylenes or the reactions of their synthetic equivalents.8
However, both these methods have limited application for the synthesis of 5-nitroisoxazoles.
The only one synthetic approach to 5-nitroisoxazoles has been known until recently, and it
involved 1,3-dipolar cycloaddition of nitrile oxides to nitroethylenes followed by the oxidation of 5-
nitroisoxazoline intermediates into the corresponding 5-nitroisoxazoles.10 An approach based on the
heterocyclization reaction of polynitrocompounds, was also reported,11 but this reaction was studied
on a limited number of substrates and not extended to general procedures.
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Results and Discussion
We have started our studies by examining the reaction of TNM-base complex with α,β-
unsaturated compounds containing carbonyl group. Methyl vinyl ketone (MVK) was chosen as a
model substrate for the optimization of the reaction conditions. Full data concerning the
optimization of the type of base and solvent used and the amounts of the reagents are presented in
Supporting Information. Several tertiary amines (TEA, Bu3N, Py, TMEDA, DBU, DABCO) and
triphenyl phosphine were tested as the bases for heterocyclization in either catalytic or equimolar
amounts. In all cases we have observed the formation of 5-nitroizoxazole 1 as shown in Scheme 1:
SCHEME 1. Heterocyclization of MVK under the treatment of TNM in the presence of base.
Me
O
Me
base
20 oC
+
C(NO2)4
N
NO2
O
O
1
However, in some cases side product, 5,5,5-trinitropentan-2-one, was isolated in 6-10%
yields. TEA was found to be the most effective base to promote the heterocyclization (yield of 1,
80%). The use of other bases such as Bu3N, Py, TMEDA, DBU resulted in moderate yields of
isoxazole 1 (30-40%), and low yields were obtained when employing DABCO and Ph3P (20 and
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6%). Variation of the mole ratio of the reagents in the case of TEA showed that the highest yield of
isoxazole 1 was achieved using MVK, TNM and TEA in 1:2.5:2 ratio. After screening the solvents
we have found that the heterocyclization proceeded smoothly in dioxane at room temperature and
complete conversion of the starting olefin was achieved within 12 h. It should be noted that if the
reaction was carried out in methanol, the trinitropentanone was isolated exclusively. The reaction
protocol involved a slow addition of alkene at 5 oC to a previously prepared complex of TNM with
TEA. The reaction was scaled up using 10 mmol of MVK, 25 mmol of TNM and 20 mmol of TEA
under standard conditions to produce 80% yield of isoxazole 1.
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Having this general optimized protocol in hand, we examined the heterocyclization of series
of α,β-unsaturated ketones and aldehydes. The results are presented in Scheme 2.
SCHEME 2. Heterocyclization of α,β-unsaturated ketones and aldehydes under the treatment
with TNM-TEA (alkene:TNM:TEA in 1:2.5:2 ratio).
R2
R1
R1
O
Et3N
R2
+
C(NO2)4
N
NO2
1,4-dioxane
20 oC, 12 h
O
O
1-7
Me
N
Et
Ph
O
O
O
O
N
N
O
NO2
N
NO2
2
, 86%
NO2
O
NO2
, 77%
O
O
3
, 85%
1
, 80%
4
O
O
N
O
O
Me
NO2
H
H
O
N
N
NO2
NO2
, 52%
O
O
O
, 40%
6
5
7
, 49%
α,β-Unsaturated ketones smoothly reacted with the TNM-TEA complex at room temperature
forming 3-acyl-5-nitroisoxazoles 1-7 in high yields. We also succeeded to involve in the
heterocyclization with TNM-TEA levoglucosenone, a highly functionalized chiral synthon, which is
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an excellent starting material and building block for the synthesis of natural compounds.12 A new
chiral 5-nitroisoxazole 5 was obtained in a good yield. It was found that acrolein and (E)-
crotonaldehyde also reacted with TNM under the same conditions producing 5-carbaldehyde-3-
nitroisoxazoles 6 and 7 in 40 and 49% yields, correspondingly. The lower yields of compounds 6
and 7 can be explained by partial polymerization of starting aldehydes under reaction conditions.
Next, α,β-unsaturated esters were involved in the heterocyclization reaction with TNM-TEA
complex. We have found that methyl acrylate scarcely reacted with TNM-TEA at room temperature
for 12 h giving corresponding 5-nitroisoxazole 8 in a poor yield (10%).13 However, further
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investigation revealed that this reaction proceeded smoothly at 70 C for 2 h affording 8 in 62%
yield. These conditions were found to be optimal for α,β-unsaturated esters and a series of 5-
nitroisoxazole-3-carboxylates 8-16 was obtained in moderate to good yields (Table 1).
TABLE 1. Synthesis of 5-nitroisoxazole-3-carboxylates.a
OR2
R1
O
R1
OR2
Et3N
+
C(NO2)4
N
NO2
O
1,4-dioxane
70 oC, 2 h
O
8-16
5-nitro-
Yieldb,
%
Entry
R1
R2
isoxazole
1
2
3
4
5
6
7
8
H
H
Me
Et
62
75
60
72
60
50
40
9
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12
13
14
H
Bu
H
t-Bu
CH2Ph
Et
H
Me
Et
Et
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(CH2)3Cl
CH2Ph
Et
Et
46
21
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8
9
aalkene:TNM:TEA in 1:2.5:2 ratio; bisolated
yield.
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It is worth noting that increasing the volume of substituents R1 or R2 led to a moderate
decrease of isoxazole yields. For instance, if R1 in the starting ester was changed from proton (table
1, entry 2) to ethyl group (table 1, entry 7) and then to benzyl group (table 1, entry 9) the yields of
corresponding isoxazoles 9, 14 and 16 decreased from 75 to 40 and 20%, respectively. Moreover, it
was found that sterically hindered cumarin and (E)-ethyl 4-methylpent-2-enoate do not react with
complex TNM-TEA under the optimal conditions.
The results of the heterocyclization of N-substituted acryl amides upon the action of TNM-
TEA are summarized in Table 2. We have found that acryl amide in the reaction with the complex
TNM-TEA at room temperature forms 5-nitroisoxazole-3-carboxamide 17a as a sole product in 64%
yield. However the heterocyclization of N-substituted acryl amides led to the mixtures of the desired
nitroisoxazoles 17b-g and the products of trinitromethane Michael addition to the starting amides –
N-substituted 4,4,4-trinitrobutanamides 18b-g. The attempt to optimize the reaction conditions for
hemoselective preparation of 5-nitroisoxazole carbamides was unsuccessful. The mixtures of
compounds 17c and 18c in nearly equal ratio were obtained in the reaction of N-benzyl acryl amide
as a model compound with TNM-TEA complex at room temperature for 48 h or upon heating at 70
oC in dioxane for 2 h. The use of methylene chloride as a solvent in reaction of N-benzyl acryl
amide with TNM-TEA complex at room temperature for 72 h led to trinitroamide 18c as the sole
product in 54% yield. The products 17 and 18 were isolated by column chromatography (Table 2).
TABLE 2. Reaction of acrylamides with TNM-TEA.a
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NR1R2
3
4
5
6
O
NR1R2
Et3N
(O2N)3C
NR1R2
+
+
C(NO2)4
N
NO2
O
O
1,4-dioxane
20 oC, 48 h
O
7
8
17a-f
18b-f
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compounds 17, 18
R1
H
R2
H
Yieldb 17, %
Yieldb 18, %
a
b
c
d
e
f
64
29
20
41
24
23
18
-
H
Bu
21
23
38
19
25
25
H
CH2Ph
H
cy-hexyl
Ph
H
C3H7
C3H7
g
-(CH2)5-
aalkene:TNM:TEA in 1:2.5:2 ratio; bisolated yield.
A similar result was observed in the reaction of α,β-unsaturated sulfone and sulfonate in the
reaction with TNM–TEA complex. It was found that phenyl vinyl sulfone reacted with TNM in the
o
presence of TEA at 70 C in dioxane for 5 h to give the target 5-nitro-3-(phenylsulfonyl)isoxazole
19 along with phenyl trinitropropyl sulfone 20 (Scheme 3). When the reaction was conducted at
room temperature in dioxane for 14 days, only compound 20 was obtained in 38% yield. The
increase of the reaction temperature up to 100 oC (in chlorobenzene as a solvent) afforded 19 and 20
in 2% and 3% yields, respectively, along with a number of unidentified by-products.
SCHEME 3. Reaction of phenyl vinyl sulfone with TNM-TEA complex (alkene:TNM:TEA in
1:2.5:2 ratio).
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PhO2S
3
4
5
6
7
8
(O2N)3C
+
70 oC, 5 h
N
SO2Ph
NO2
O
19
20
, 20%
, 25%
Et3N
+
C(NO2)4
SO2Ph
1,4-dioxane
9
20 oC, 14 d
(O2N)3C
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SO2Ph
, 38%
20
We have found that the reaction of phenyl ethylenesulfonate with TNM-TEA in boiling
dioxane proceed with the formation of trinitromethyl derivative 21 in a 66% yield (Scheme 4),
however, the same reaction in boiling chlorobenzene afford the isoxazole 22 in moderate yield.
SCHEME 4. Reaction of phenyl ethylenesulfonate with complex TNM-TEA (alkene:TNM:TEA
in 1:2.5:2 ratio).
1,4-dioxane
(O2N)3C
70 oC, 2 h
SO3Ph
21
, 66%
Et3N
+
C(NO2)4
SO3Ph
PhO3S
C6H5Cl
110 oC, 1.5 h
N
NO2
O
22
, 28%
It was found that phenyl vinyl sulfoxide in the reaction with TNM-TEA did not afford
expected isoxazole, and only benzenesulfonic acid was formed as a result of the oxidation of starting
alkene by TNM. This result was the same at room temperature and at 70 oC in dioxane.
We were encouraged to find that vinyl phosphonate ester smoothly reacted with TNM-TEA
o
complex in dioxane upon heating at 70 C to form desired 5-nitroisoxazole-3-phosphonate 23 in
high yield (Scheme 5).
SCHEME 5. Synthesis of 5-nitro-3-phosphonate isoxazole (alkene:TNM:TEA in 1:2.5:2 ratio).
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(EtO)2OP
Et3N
3
4
5
6
+
C(NO2)4
N
PO(OEt)2
NO2
, 76%
1,4-dioxane
70 oC, 2 h
O
23
7
8
9
Finally, a series of α,β-unsaturated nitroalkenes were investigated in the reaction with TNM-
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TEA complex. We have found that heterocyclization proceeds smoothly at 70 C in dioxane
affording 3,5-dinitroisoxazoles 24-28 in good yields (Table 3). The yield of 24 was substantially
reduced due to a partial polymerization of starting nitroethylene under the reaction conditions. The
bulky substituents at the double bond have dilatory effect on reactivity of starting olefins. E.g., the
yield of cyclopropylmethyl substitued isoxazole 28 did not exceed 50%, while
isopropylnitroethylene was totally inert in the reaction with TNM in optimized conditions.
TABLE 3. Synthesis of 3,5-dinitroisoxazolesa
O2N
R
Et3N
R
+
C(NO2)4
NO2
N
1,4-dioxane
70 oC, 2 h
NO2
O
24-28
3,5-dinitro-
isoxazole
R
Yieldb, %
24
25
26
27
H
Me
38
63
53
51
Et
(CH2)3Cl
H2C
28
50
b
aalkene:TNM:TEA in 1:2.5:2 ratio; isolated
yield.
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Structures of the obtained products were confirmed by NMR spectroscopy.14,15
4
5
A proposed mechanism for the formation of 5-nitroisoxazoles is outlined on Scheme 6 using
6
7
α,β-unsaturated ketone as a model.16
8
9
SCHEME 6. Proposed mechanism for the heterocyclization affording 5-nitroisoxazoles.
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R
CTC
Et N
C(NO2)3
NO2
C(NO2)4 + Et3N
3
(NO2)3C
O
I
Path B
Path A
NO2
NO2
O
+H
I
(O2N)3C
Et3N
R
(O2N)3C
R
(O2N)3C
R
(O2N)3C
R(O)C
R
H
O
C(NO2)3
-NEt3H
O
O
IV
II
VII
III
R(O)C
R(O)C
NO2
NO2
NO2
NO2
NO2
N
O
C
N
N
-HNO3
NO2
-NO2
O
O
O
O
VI
V
At the first step, the molecule of TNM is polarized upon the reaction with TEA to give
charge-transfer complex (CTC) and then complex I with trinitromethyl group possessing anionic
character, while [Et3N-NO2]+ cation can be considered as a reagent for the electrophilic nitration.
Such reactivity of TNM with electron donor molecules has been reviewed.1a,f It should be
emphasized that TNM does not react with electrophilic alkenes in the absence of the amine.
Subsequent process of heterocyclization involves Michael addition of [C(NO2)3]- as the
nucleophile to give anionic species II. Further nitration of this intermediate (Path A) leads to ketone
III which transforms into IV in the result of deprotonation under the action of TEA. Next,
intramolecular cyclization of IV proceeds accompanied by the elimination of nitrite anion and
HNO3 resulting in 5-nitroisoxazole VI. The indirect proof of the elimination of HNO3 and HNO2
molecules is the successful isolation of Et3N·HNO3 salt and N-nitroso diethylamine from the
reaction mixture. Proceeding the transformation through intermediate V is not proved, but the
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cyclization of substituted 1,1,1,3-tetranitropropanes leading to the formation of the corresponding 5-
nitroisoxazoles is known.11a
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Trinitrosubstituted adducts of type VII could be formed via the protonation of the
intermediate II by a free proton from the solvent or substrate (path B). This is in a good agreement
with the fact that 5,5,5-trinitropentan-2-one was the only product in the reaction of methyl vinyl
ketone with TNM-TEA in methanol. Acrylic acid reacted with TNM-TEA complex at room
temperature in 1,4-dioxane affording the sole product 4,4,4-trinitro-butyric acid in 49% yield.
Although the cyclization of trinitromethyl substituted compounds leading to the formation of the
corresponding 5-nitroisoxazoles is described in the literature,11 our attempts to cyclize the products
of the Michael addition VII were unsuccessful.
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Conclusion
In conclusion, it is has been demonstrated that TNM activated by triethylamine possesses
unusual properties and may be used as an efficient and readily available reagent for numerous
synthetic purposes. The present investigation describes the employment of TNM-TEA complex for
heterocyclization of electrophilic alkenes under mild conditions affording hardly accessible 5-
nitroisoxazoles in good isolated yields. The reaction tolerates a variety of substituents in alkenes.
We have developed a simple general and preparative method for the synthesis of functionalized 5-
nitroisoxazoles which are convenient precursors of pharmacologically active compounds.
Experimental Section
Measurements
1
NMR spectra were recorded on 400.1, 162.0, 100.6 and 28.9 MHz for H, 31P, 13C and 14N,
respectively at room temperature; the chemical shifts  were measured in ppm with respect to the
solvent (1Н: CDCl3,  = 7.26 ppm, DMSO-d6,  = 2.49 ppm, CD3OD,  = 3.31 ppm; 13C: CDCl3,  =
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77.1 ppm, DMSO-d6,  = 39.5 ppm, CD3OD,  = 49.0 ppm). Data are reported as follows: chemical
shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, app=apparent, and
br=broad), coupling constant in Hertz (Hz), and integration. Accurate mass determination (ESI) was
performed on instrument equipped with a dual electrospray ion source. Samples were injected into
the MS using methanol as carrier solvent and analysis was performed as a flow injection analysis
without any chromatographic step. Both negative and positive electrospray and chemical ionization
were conducted. Two reference compounds were continuously injected enabling post-analyses
correction of mass axis. Samples for Infrared spectroscopy were recorded as indicated on film, KBr
pellet or nujol. Melting points (mp) are uncorrected. Analytical thin layer chromatography (TLC)
was carried out with “Silufol” silica gel plates (supported on aluminum); the revelation was done by
UV lamp (254 and 365 nm) and chemical staining (iodine vapor and potassium permanganate
solution in water). Column chromatography was performed on silica gel 60 (230-400 mesh, Merck).
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Materials
All solvents were dried and distillated. 1,4-dioxane and chlorobenzene were stored over molecular
sieves. All bases (triethylamine, tributylamine, pyridine, tetramethylethylenediamine, 1,8-
diazabicyclo[5.4.0]undecene,
1,4-diazabicyclo[2.2.2]octane,
triphenylphosphine)
and
tetranitromethane, methyl vinyl ketone, ethyl vinyl ketone, cyclohex-2-enone, levoglucosenone,
acrolein, crotone aldehyde, methyl acrylate, ethyl acrylate, butyl acrylate, tert-butyl acrylate, benzyl
acrylate, acrylamide, vinylsulfinylbenzene, vinylsulfonylbenzene, phenyl ethenesulfonate, acrylic
acid were commercially available. Tertiary amines (triethylamine, tributylamine, pyridine,
tetramethylethylenediamine) were dried and distillated. Other materials obtained from commercial
suppliers were used without further purification. All reactions with tetranitromethane were carried
out under an atmosphere of argon. 1-Phenylprop-2-en-1-one was obtained in two steps, i.e.
paraformaldehyde Mannich reaction and thermal elimination17. (E)-Methyl but-2-enoate, (E)-methyl
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pent-2-enoate, (E)-methyl 6-chlorohex-2-enoate, (E)-methyl 4-phenylbut-2-enoate were synthesized
by general procedure based on Wittig reaction18. N-Butylacrylamide, N-benzylacrylamide, N-
phenylacrylamide, N-cyclohexylacrylamide were obtained by known procedure19 and N,N-
dipropylacrylamide, 1-(piperidin-1-yl)prop-2-en-1-one by procedure20, both were included reaction
of acryloyl chloride with corresponding amine in the presents of triethylamine. Diethyl
vinylphosphonate was obtained in two steps, i.e. Arbuzov reaction of 1,2-dibromoethane with
triethyl phosphate and dehydrohalogenation of Arbuzov’s product21. Nitroethene was prepared from
2-nitroethanol by treatment of phthalic anhydride22. (E)-1-Nitroprop-1-ene, (E)-1-nitrobut-1-ene,
(E)-5-chloro-1-nitropent-1-ene, (E)-(3-nitroallyl)cyclopropane were synthesized by condensation
aldehydes with nitroethane23.
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General Procedure for the Synthesis of 5-nitroisoxazoles 1-17, 19, 23-28. Triethylamine (0.28
mL, 2 mmol) was added dropwise to a solution of tetranitromethane (0.3 mL, 2.5 mmol) in 1,4-
o
dioxane (2 mL) at 0 C (ice bath). The reaction mixture was stirred for 5 min and alkene (1 mmol)
was added in one portion. Then the cooling was taken off and the mixture was stirred either at room
o
temperature for 12-48 h (for isoxazoles 1-7, 17) or at 70 C for 2-5 h (for isoxazoles 8-16, 19, 23-
28), the reaction time is indicated in Scheme 2-5 and Table 1-3. The solvent was removed under
reduced pressure and the product was isolated by column chromatography.
Caution: Although we did not experience any problem in handling tetranitromethane, full safety
precautions should be taken due to its toxicity and explosive nature.
1-(5-Nitroisoxazol-3-yl)ethanone (1)24,11b Yield 120 mg (80%), colorless solid, mp 70-72 C, Rf
1
0.62 (petroleum ether - EtOAc, 4:1). H NMR (CDCl3) δ 2.69 (s, 3H, CH3), 7.33 (s, 1H, CH);
13C{1H} NMR (CDCl3) δ 26.9 (q, J = 130 Hz, CH3), 100.2 (d, J = 197 Hz, CH), 163.3 (C), 165.7 (br
s, CNO2) , 189.6 (q, JCH = 6 Hz, CO); IR (KBr) 1718 (s), 1544 (s), 1364 (s) cm-1.
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1-(5-Nitroisoxazol-3-yl)propan-1-one (2). Yield 150 mg (86%), pale yellow solid, mp 53-54 C, Rf
0.67 (CHCl3). 1H NMR (CDCl3) δ 1.20 (t, J = 7.3 Hz, 3H, CH3), 3.08 (q, J = 7.3 Hz, 2H, CH2), 7.34
(s, 1H, CH); 13C{1H} NMR (CDCl3) δ 7.0, 33.1, 100.4, 162.9, 165.7 (br s, CNO2), 192.7; IR (KBr)
1710 (s), 1546 (s), 1359 (s) cm-1; Anal. Calcd for C6H6N2O4: C, 42.36; H, 3.55; N, 16.47. Found: C,
42.45; H, 3.54; N, 16.32.
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(5-Nitroisoxazol-3-yl)(phenyl)methanone (3). Yield 190 mg (85%), colorless solid, mp 82-83 C,
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Rf 0.66 (CHCl3). H NMR (CDCl3) δ 7.53 (s, 1H, CH), 7.56-7.60 (m, 2H, Ph), 7.71-7.75 (m, 1H,
13
Ph), 8.31-8.33 (m, 2H, Ph); C{1H} NMR (CDCl3) δ 102.9, 129.0 (2C), 130.8 (2C), 134.3, 135.1,
163.5, 165.5 (br s, CNO2), 182.9; IR (KBr) 1715 (s), 1542 (s), 1325 (s) cm-1; Anal. Calcd for
C10H6N2O4: C, 55.05; H, 2.77; N, 12.84. Found: C, 55.27; H, 2.63; N, 12.88.
3-Nitro-5,6-dihydrobenzo[d]isoxazol-7(4H)-one (4). Yield 140 mg (77%), pale yellow solid, mp
114-115 C, Rf 0.25 (CHCl3). 1H NMR (CDCl3) δ 2.22-2.29 (m, 2H, CH2), 2.73-2.79 (m, 2H, CH2),
3.11-3.17 (m, 2H, CH2); 13C{1H} NMR (CDCl3) δ 20.3, 22.3, 39.8 (CH2), 118.9 (C), 158.9 (C),
160.9 (br s, CNO2), 188.9 (CO); IR (KBr) 1716 (s), 1540 (s), 1357 (s) cm-1; Anal. Calcd for
C7H6N2O4: C, 46.16; H, 3.32; N, 15.38. Found: C, 46.21; H, 3.50; N, 15.19.
(4R,7S)-3-Nitro-4,5-dihydro-4,7-epoxyoxepino[4,5-d]isoxazol-8-one (5). Yield 110 mg (53%),
colorless solid, mp 110-112 C, Rf 0.25 (petroleum ether - EtOAc, 2:1). 1H NMR (CDCl3) δ 4.09 (d,
J = 7.8 Hz, 1H, CH2), 4.20 (dd, J = 4.3, 7.8 Hz, 1H, CH2), 5.65 (s, 1H, CH), 6.02 (d, J = 4.3 Hz, 1H,
CH); 13C{1H} NMR (CDCl3) δ 68.6 (JCH = 156 Hz, CH2), 69.9 (J = 165 Hz, CH), 99.9 (J = 185 Hz,
CH), 117.1 (С), 156.4 (C), 158.4 (br s, CNO2), 179.0 (CO); IR (nujol) 1730 (s), 1535 (s), 1340 (s)
cm-1; Anal. Calcd for C7H4N2O6: C, 39.64; H, 1.90; N, 13.21. Found: C, 39.81; H, 2.07; N, 13.29.
5-Nitroisoxazole-3-carbaldehyde (6).25 Yield 80 mg (60%), pale yellow liquid, Rf 0.75 (petroleum
ether - EtOAc, 2:1). 1H NMR (CDCl3) δ 7.32 (s, 1H, CH), 9.96 (s, 1H, CH); 13C{1H} NMR (CDCl3)
δ 99.7, 163.0, 166.7 (br s, CNO2), 182.5.
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4-Methyl-5-nitroisoxazole-3-carbaldehyde (7). Yield 70 mg (49%), pale yellow liquid, Rf 0.76
(petroleum ether - EtOAc, 2:1). 1H NMR (CDCl3) δ 2.58 (s, 3H, CH3), 10.14 (s, 1H, CH); 13C{1H}
NMR (CDCl3) δ 8.0, 114.1, 161.2, 162.3 (br s, CNO2), 184.4; IR (KBr) 1718 (s), 1542 (s), 1359 (s)
cm-1; Anal. Calcd for C5H4N2O4: C, 38.47; H, 2.58; N, 17.95. Found: C, 38.31; H, 2.60; N, 17.86.
Methyl 5-nitroisoxazole-3-carboxylate (8). Yield 110 mg (62%), colorless solid, mp 71-72 C, Rf
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0.46 (CHCl3). H NMR (CDCl3) δ 4.01 (s, 3H, CH3), 7.40 (s, 1H, CH); C{1H} NMR (CDCl3) δ
53.7 (q, J = 148 Hz, CH3), 102.3 (d, J = 197 Hz, CH), 157.96 (C), 158.04 (C), 165.6 (br s, CNO2);
IR (KBr) 1741 (s), 1550 (s), 1359 (s) cm-1; Anal. Calcd for C5H4N2O5: C, 34.90; H, 2.34; N, 16.28.
Found: C, 34.91; H, 2.19; N, 16.40.
Ethyl 5-nitroisoxazole-3-carboxylate (9). Yield 140 mg (75%), pale yellow liquid, Rf 0.49
(CHCl3). 1H NMR (CDCl3) δ 1.46 (t, J = 7.2 Hz, 3H, CH3), 4.52 (q, J = 7.2 Hz, 2H, CH2), 7.41 (s,
13
1H, CH); C{1H} NMR (CDCl3) δ 14.0, 63.4, 102.3, 157.6, 158.3, 165.6 (br s, CNO2); IR (KBr)
1740 (s), 1552 (s), 1357 (s) cm-1; Anal. Calcd for C6H6N2O5: C, 38.72; H, 3.25; N, 15.05. Found: C,
38.65; H, 3.24; N, 15.25.
Butyl 5-nitroisoxazole-3-carboxylate (10). Yield 130 mg (60%), pale yellow liquid, Rf 0.55
1
(CHCl3). H NMR (CDCl3) δ 0.99 (t, J = 7.3 Hz, 3H, CH3), 1.45-1.51 (m, 2H, CH2), 1.77-1.84 (m,
13
2H, CH2), 4.46 (t, J = 6.7 Hz, 2H, CH2), 7.41 (s, 1H, CH); C{1H} NMR (CDCl3) δ 13.6, 19.0,
30.4, 67.1, 102.3, 157.7, 158.3, 165.6 (br s, CNO2); IR (KBr) 1739 (s), 1550 (s), 1357 (s) cm-1;
Anal. Calcd for C8H10N2O5: C, 44.86; H, 4.71; N, 13.08. Found: C, 44.70; H, 4.57; N, 13.19.
tert-Butyl 5-nitroisoxazole-3-carboxylate (11). Yield 155 mg (72%), colorless solid, mp 57-58 C,
1
Rf 0.60 (CHCl3). H NMR (CDCl3) δ 1.57 (s, 9H, 3×CH3), 7.30 (s, 1H, CH); 13C{1H} NMR
(CDCl3) δ 27.8 (q, J = 127 Hz, 3CH3), 85.5 (C), 102.3 (d, J = 197 Hz, CH), 156.5 (C), 159.3 (d, J =
3 Hz, C), 165.3 (br s, CNO2); IR (KBr) 1736 (s), 1548 (s), 1375 (s) cm-1; Anal. Calcd for
C8H10N2O5: C, 44.86; H, 4.71; N, 13.08. Found: C, 44.98; H, 4.49; N, 13.11.
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Benzyl 5-nitroisoxazole-3-carboxylate (12). Yield 150 mg (60%), colorless solid, mp 61-62 C, Rf
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0.57 (CHCl3). H NMR (CDCl3) δ 5.47 (s, 2H, CH2), 7.37-7.48 (m, 5H, Ph), 7.41 (s, 1H, CH);
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13C{1H} NMR (CDCl3) δ 68.8 (CH2), 102.3 (CH), 128.9 (4СН, Рh), 129.1 (СН, Рh), 134.0 (С, Ph),
157.5(C), 158.1 (C), 165.7 (br s, CNO2); IR (KBr) 1749 (s), 1540 (s), 1355 (s) cm-1; Anal. Calcd for
C11H8N2O5: C, 53.23; H, 3.25; N, 11.29. Found: C, 53.29; H, 3.33; N, 11.24.
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Ethyl 4-methyl-5-nitroisoxazole-3-carboxylate (13). Yield 100 mg (50%), pale yellow liquid, Rf
0.54 (CHCl3). 1H NMR (CDCl3) δ 1.45 (t, J = 7.2 Hz, 3H, CH3), 2.61 (s, 3H, CH3), 4.50 (q, J = 7.2
Hz, 2H, CH2); 13C{1H} NMR (CDCl3) δ 8.6, 14.0, 63.0, 115.6, 157.3, 158.6, 162.1 (br s, CNO2); IR
(KBr) 1736 (s), 1543 (s), 1354 (s) cm-1; Anal. Calcd for C7H8N2O5: C, 42.01; H, 4.03; N, 14.00.
Found: C, 42.30; H, 4.22; N, 14.15.
Ethyl 4-ethyl-5-nitroisoxazole-3-carboxylate (14). Yield 80 mg (40%), pale yellow liquid, Rf 0.47
(CHCl3). 1H NMR (CDCl3) δ 1.27 (t, J = 7.5 Hz, 3H, CH3), 1.47 (t, J = 7.1 Hz, 3H, CH3), 3.08 (q, J
13
= 7.5 Hz, 2H, CH2), 4.51 (q, J = 7.1 Hz, 2H, CH2); C{1H} NMR (CDCl3) δ 13.4 (q, J = 128 Hz,
CH3), 14.0 (q, J = 127 Hz, CH3), 16.3 (t, J = 133 Hz,CH2), 63.0 (t, J = 127 Hz, CH2), 121.3 (C),
157.0 (C), 158.5 (C), 161.8 (br s, CNO2); IR (KBr) 1734 (s), 1539 (s), 1348 (s) cm-1; Anal. Calcd for
C8H10N2O5: C, 44.86; H, 4.71; N, 13.08. Found: C, 44.70; H, 4.75; N, 13.20.
Ethyl 4-(3-chloropropyl)-5-nitroisoxazole-3-carboxylate (15). Yield 120 mg (46%), pale yellow
1
liquid, Rf 0.36 (petroleum ether - EtOAc, 5:1). H NMR (CDCl3) δ 1.48 (t, J = 7.1 Hz, 3H, CH3),
2.11-2.18 (m, 2H, CH2), 3.21-3.25 (m, 2H, CH2), 3.65 (app t, J = 6.3 Hz, 2H, CH2), 4.53 (q, J = 7.1
13
Hz, 2H, CH2); C{1H} NMR (CDCl3) δ 14.0, 20.6, 31.5, 44.0, 63.2, 118.5, 157.1, 158.4, 162.1 (br
s, CNO2); IR (film) 1730 (s), 1540 (s), 1335 (s) cm-1; Anal. Calcd for C9H11ClN2O5: C, 41.16; H,
4.22; N, 10.67. Found: C, 41.21; H, 4.13; N, 10.75.
Ethyl 4-benzyl-3-nitroisoxazole-5-carboxylate (16). Yield 60 mg (21%), pale yellow liquid, Rf
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0.55 (CHCl3). H NMR (CDCl3) δ 1.41 (t, J = 7.2 Hz, 3H, CH3), 4.45-4.50 (m, 4H, 2×CH2), 7.23-
13
7.32 (m, 5H, Ph); C{1H} NMR (CDCl3) δ 14.0, 27.8, 63.1, 118.1, 127.3, 128.6 (2C), 128.8 (2C),
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133.3, 157.0, 158.5, 162.0 (br s, CNO2); IR (KBr) 1739 (s), 1544 (s), 1348 (s) cm-1; HRMS (ESI-
TOF) m/z: [M-H]- Calcd. for C13H11N2O5 275.0674; Found: 275.0676.
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5-Nitroisoxazole-3-carboxamide (17a). Yield 100 mg (64%), colorless solid, mp 159-163 C, Rf
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0.21 (CHCl3). H NMR (CD3OD) δ 7.60 (с, 1H, CH); 13C{1H} NMR (CD3OD) δ 101.0, 159.4,
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160.8, 165.9 (br s, CNO2); IR (KBr) 3369 (s), 1678 (s), 1545 (s), 1344 (s) cm-1; Anal. Calcd for
C4H3N3O4: C, 30.58; H, 1.92; N, 26.75. Found: C, 30.70; H, 2.09; N, 26.85.
N-Butyl-5-nitroisoxazole-3-carboxamide (17b). Yield 70 mg (29%), colorless solid, mp 72-74 C,
Rf 0.40 (petroleum ether - EtOAc, 5:1). 1H NMR (CDCl3) δ 0.97 (t, J = 7.3 Hz, 3H, CH3), 1.39-1.47
(m, 2H, CH2), 1.60-1.67 (m, 2H, CH2), 3.45-3.51 (m, 2H, CH2), 6.88 (br. m, 1H, NH), 7.44 (s, 1H,
13
CH); C{1H} NMR (CDCl3) δ 13.6, 20.0, 31.3, 39.6, 101.7, 156.3, 160.6, 165.6 (br s, CNO2); IR
(nujol) 3315 (w), 1672 (s), 1548 (s), 1320 (s) cm-1; Anal. Calcd for C8H11N3O4: C, 45.07; H, 5.20;
N, 19.71. Found: C, 45.32; H, 5.08; N, 19.92.
N-butyl-4,4,4-trinitrobutanamide (18b). Yield 60 mg (21%), colorless solid, mp 73-75 C, Rf 0.32
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(CНCl3). H NMR (CDCl3) δ 0.93 (t, J = 7.2 Hz, 3H, CH3), 1.30-1.39 (m, 2H, CH2), 1.45-1.52 (m,
2H, CH2), 2.58-2.62 (m, 2H, CH2), 3.22-3.29 (m, 2H, CH2), 3.42-3.45 (m, 2H, CH2), 5.81 (br. m,
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1H, NH); C{1H} NMR (CDCl3) δ 13.5, 20.0, 29.6, 30.0, 31.3, 39.8, 129.5 [C(NO2)3], 168.0; IR
(nujol) 3290 (w), 1620 (s), 1470 (s), 1280 (s) cm-1; Anal. Calcd for C8H14N4O7: C, 34.54; H, 5.07;
N, 20.14. Found: C, 34.49; H, 5.13; N, 19.95.
N-benzyl-5-nitroisoxazole-3-carboxamide (17c). Yield 50 mg (20%), colorless solid, mp 101-105
C, Rf 0.47 (petroleum ether - EtOAc, 5:1). 1H NMR (CDCl3) δ 4.67 (d, J = 6.0 Hz, 2H, CH2), 7.14
13
(br. m, 1H, NH), 7.34-7.39 (m, 5H, Ph), 7.47 (s, 1H, CH); C{1H} NMR (CDCl3) δ 43.9, 101.8,
128.0 (2C), 128.1, 129.0 (2C), 136.6, 156.3, 160.4, 165.6 (br s, CNO2); IR (KBr) 3356 (w), 1668 (s),
1537 (s), 1338 (s) cm-1; Anal. Calcd for C11H9N3O4: C, 53.44; H, 3.67; N, 17.00. Found: C, 53.55;
H, 3.65; N, 16.95.
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N-benzyl-4,4,4-trinitrobutanamide (18c). Yield 70 mg (23%), yellow liquid, Rf 0.39 (petroleum
ether - EtOAc, 5:1). 1H NMR (CDCl3) δ 3.67 (s, 4H, 2×CH2), 4.94 (s, 2H, CH2), 7.19-7.33 (m, 5H,
6
7
13
Ph); C{1H} NMR (CDCl3) δ26: 29.1, 29.6, 42.7, 128.3, 128.7 (2C), 128.8 (2C), 133.8, 172.9; IR
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(KBr) 3345 (w), 1739 (s), 1597 (s), 1303 (s) cm-1; Anal. Calcd for C11H12N4O7: C, 42.31; H, 3.87;
N, 17.94. Found: C, 42.47; H, 3.71; N, 18.07.
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N-cyclohexyl-5-nitroisoxazole-3-carboxamide (17d). Yield 100 mg (41%), colorless solid, mp
1
142-144 C, Rf 0.44 (petroleum ether - EtOAc, 5:1). H NMR (CDCl3) δ 1.19-1.48 (m, 5H, CH2),
1.67-1.71 (m, 1H, CH2), 1.78-1.81 (m, 2H, CH2), 2.02-2.05 (m, 2H, CH2), 3.92-4.01 (m, 1H, CH),
13
6.96 (br s, 1H, NH), 7.45 (s, 1H, CH); C{1H} NMR (CDCl3) δ 24.7 (2C), 25.3, 32.8 (2C), 49.0,
101.8, 155.3, 160.8, 165.6 (br s, CNO2); IR (KBr) 3320 (w), 1670 (s), 1550 (s), 1320 (s) cm-1; Anal.
Calcd for C10H13N3O4: C, 50.21; H, 5.48; N, 17.56. Found: C, 50.39; H, 5.44; N, 17.50.
N-cyclohexyl-4,4,4-trinitrobutanamide (18d). Yield 110 mg (38%), colorless solid, mp 150-152
1
C, Rf 0.52 (CНCl3). H NMR (CDCl3) δ 1.09-1.22 (m, 3H, CH2), 1.33-1.43 (m, 2H, CH2), 1.63-
1.66 (m, 1H, CH2), 1.72-1.75 (m, 2H, CH2), 1.92-1.95 (m, 2H, CH2), 2.57-2.60 (m, 2H, CH2), 3.44-
3.47 (m, 2H, CH2), 3.74-3.81 (m, 1H, CH), 5.42 (br s, 1H, NH); 13C{1H} NMR (DMSO-d6) δ2624.8
(2C), 25.6, 29.2 (2C), 32.7 (2C), 48.2, 167.4; IR (KBr) 3288 (w), 1643 (s), 1594 (s), 1299 (s) cm-1;
Anal. Calcd for C10H16N4O7: C, 39.48; H, 5.30; N, 18.41. Found: C, 39.55; H, 5.19; N, 18.35.
5-Nitro-N-phenylisoxazole-3-carboxamide (17e). Yield 60 mg (24%), colorless solid, mp 105-107
C, Rf 0.21 (petroleum ether - EtOAc, 5:1). 1H NMR (CDCl3) δ 7.24-7.28 (m, 1H, Ph), 7.41-45 (m,
13
2H, Ph), 7.55 (s, 1H, CH), 7.66-7.68 (m, 2H, Ph), 8.48 (br s, 1H, NH); C{1H} NMR (CDCl3) δ
101.8, 120.2 (2C), 125.9, 129.4 (2C), 136.1, 154.0, 160.7, 165.8 (br s, CNO2); MS (ESI) 234
[(М+Н)] +; IR (KBr) 3338 (w), 1680 (s), 1551 (s), 1348 (s) cm-1; Anal. Calcd for C10H7N3O4: C,
51.51; H, 3.03; N, 18.02. Found: C, 51.77; H, 3.14; N, 17.95.
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4,4,4-Trinitro-N-phenylbutanamide (18e). Yield 60 mg (19%), yellow liquid, Rf 0.18 (petroleum
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ether - EtOAc, 5:1). H NMR (CD3OD) δ 2.81-2.85 (m, 2H, CH2), 3.56-3.60 (m, 2H, CH2), 7.06-
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7.09 (m, 1H, Ph), 7.26-7.30 (m, 2H, Ph), 7.47-7.49 (m, 2H, Ph); C{1H} NMR (CD3OD) δ26 31.6,
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32.3, 122.5 (2C), 126.8, 131.1 (2C), 140.3, 170.5; MS (ESI) 299 [(М+Н)] +; IR (KBr) 3262 (w),
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1670 (s), 1602 (s), 1324 (s) cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for C10H11N4O7
299.0622; Found: 299.0627.
5-Nitro-N,N-dipropylisoxazole-3-carboxamide (17f). Yield 50 mg (23%), yellow oil, Rf 0.23
1
(petroleum ether - EtOAc, 5:1). H NMR (CDCl3) δ 0.90 (t, J = 7.4 Hz, 3H, CH3), 0.95 (t, J = 7.4
Hz, 3H, CH3), 1.64-1.73 (m, 4H, 2×СН2), 3.46-3.51 (m, 4H, СН2, 2×CH2), 7.34 (s, 1H, CH);
13C{1H} NMR (CDCl3) δ 11.1, 11.3, 20.7, 21.9, 48.0, 49.3, 103.6, 157.8, 162.4, 165.8 (br s, CNO2);
IR (KBr) 2964 (w), 1648 (s), 1596 (s), 1305 (s) cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for
+
C10H16N3O4 242.1135; Found: 242.1132.
4,4,4-Trinitro-N,N-dipropylbutanamide (18f). Yield 80 mg (25%), yellow liquid, Rf 0.18
1
(petroleum ether - EtOAc, 5:1). H NMR (CDCl3) δ 0.90 (t, J = 7.4 Hz, 3H, CH3), 0.94 (t, J = 7.4
Hz, 3H, CH3), 1.51-1.64 (m, 4H, 2×СН2), 2.71-2.74 (m, 2H, CH2), 3.15-3.19 (m, 2H, CH2), 3.27-
3.31 (m, 2H, CH2), 3.48-3.51 (m, 2H, CH2); C{1H} NMR (CDCl3) δ 11.1, 11.3, 20.7, 21.9, 27.4,
13
30.3, 48.0, 49.3, 129.9, 167.1; MS (ESI) 307 [(М+Н)] +; IR (KBr) 2967 (w), 1646 (s), 1596 (s), 1305
(s) cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for C10H19N4O7 307.1248; Found: 307.1251;
+
Anal. Calcd for C10H18N4O7: C, 39.22; H, 5.92; N, 18.29. Found: C, 39.40; H, 5.85; N, 18.29.
(5-Nitroisoxazol-3-yl)(piperidin-1-yl)methanone (17g). Yield 40 mg (18%), yellow oil, Rf 0.18
1
(petroleum ether - EtOAc, 5:1). H NMR (CDCl3) δ 1.52-1.74 (m, 6H, 3×СН2), 3.71-3.76 (m, 4H,
2×CH2), 7.30 (s, 1H, CH); 13C{1H} NMR (CDCl3) δ 24.3, 25.4, 26.2, 43.3, 46.3, 103.4, 156.5,
161.0, 165.8 (br s, CNO2); IR (KBr) 2954 (w), 1635 (s), 1581 (s), 1307 (s) cm-1; HRMS (ESI-TOF)
+
m/z: [M+H]+ Calcd. for C9H12N3O4 226.0822; Found: 226.0823.
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4,4,4-Trinitro-1-(piperidin-1-yl)butan-1-one (18g). Yield 70 mg (25%), yellow liquid, Rf 0.35
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5
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(CHCl3). H NMR (CD3OD) δ 1.54-1.69 (m, 6H, 3×CH2), 2.84-2.88 (m, 2H, CH2), 3.43-3.45 (m,
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2H, CH2), 3.52-3.56 (m, 2H, CH2), 3.58-3.64 (m, 2H, CH2); C{1H} NMR (CD3OD) δ 24.0, 25.2,
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25.9, 26.9, 29.4, 43.0, 46.1, 130.6, 167.2; IR (KBr) 2950 (w), 1635 (s), 1581 (s), 1305 (s) cm-1;
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HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for C9H15N4O7 291.0935; Found: 291.0939; Anal. Calcd
for C9H14N4O7: C, 37.25; H, 4.86; N, 19.30. Found: C, 37.47; H, 4.73; N, 19.14.
5-Nitro-3-(phenylsulfonyl)isoxazole (19). Yield 60 mg (25%), colorless solid, mp 75-76 C; Rf =
0.42 (petroleum ether - EtOAc, 10:1). 1H NMR (CDCl3) δ 7.42 (s, 1H, CH), 7.68-7.70 (m, 2H, Ph),
7.71-7.83 (m, 1H, CH), 8.10-8.12 (m, 2H, Ph); C{1H} NMR (CDCl3) δ 100.7, 128.2 (2C), 129.1
13
(2C), 135.8 (C), 137.4 (C), 165.4 (br s, CNO2), 168.0; IR (KBr) 1594 (s), 1334 (s), 1294 (s), 1157
(s) cm-1; Anal. Calcd for C9H6N2O5S: C, 42.52; H, 2.38; N, 11.02. Found: C, 42.90; H, 2.60; N,
10.85.
(3,3,3-Trinitropropylsulfonyl)benzene (20). Yield 60 mg (19%), colorless solid, mp 163-165 C;
Rf = 0.39 (petroleum ether - EtOAc, 10:1). 1H NMR (CDCl3) δ 3.44-3.51 (m, 4Н, 2×CH2), 7.66-7.70
(m, 2H, Ph), 7.78-7.85 (m, 1H, Ph), 7.97-7.98 (m, 2H, Ph); C{1H} NMR (CDCl3) δ26 28.4, 50.1,
13
130.0 (4C), 135.0, 137.1; IR (KBr) 1596 (s), 1332 (s), 1294 (s), 1160 (s) cm-1; Anal. Calcd for
C9H9N3O8S: C, 33.86; H, 2.84; N, 13.16. Found: C, 33.83; H, 2.73; N, 13.27.
Phenyl 3,3,3-trinitropropane-1-sulfonate 21. To a solution of tetranitromethane (0.3 ml, 2.5
o
mmol) in 2 ml 1,4-dioxane at 0 C (ice bath) triethylamine (0.28 ml, 2 mmol) dropwise was added.
The mixture was stirred over cooling 5 min, and phenyl ethenesulfonate (0.18 g, 1 mmol) was added
in one portion. The cooling was taken off and the mixture was stirred at 70 C for 2 hours. Solvent
was removed under reduced pressure and 220 mg (yield 66%) of 21 was isolated by column
chromatography with petroleum ether - EtOAc, 5:1. Colorless solid, mp 89-91 C, Rf 0.68
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(petroleum ether - EtOAc, 5:1). H NMR (DMSO-d6) 4.06-4.09 (m, 2H, CH2), 4.15-4.18 (m, 2H,
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CH2), 7.40-7.45 (m, 3H, Ph), 7.49-7.55 (m, 2H, Ph); 13C{1H} NMR (DMSO-d6) δ: 28.2, 45.0, 123.1
(2C), 128.6, 129.8, 131.1(2C), 149.5; IR (nujol) 1490 (s), 1385 (s), 1305 (s), 1200 (s) cm-1; Anal.
Calcd for C9H9N3O9S: C, 32.24; H, 2.71; N, 12.53. Found: C, 32.48; H, 2.73; N, 12.27.
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Phenyl 5-nitroisoxazole-3-sulfonate 22. To a solution of tetranitromethane (0.3 ml, 2.5 mmol) in 2
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ml chlorobenzene at 0 C (ice bath) triethylamine (0.28 ml, 2 mmol) dropwise was added. The
mixture was stirred over cooling 5 min, and phenyl ethenesulfonate (0.18 g, 1 mmol) was added in
one portion. The cooling was taken off and the mixture was stirred at 110 C for 1.5 hours. Solvent
was removed under reduced pressure and 80 mg (yield 28%) of 22 was isolated by column
chromatography with petroleum ether - EtOAc, 5:1. Colorless solid, mp 93-94 C, Rf 0.38
(petroleum ether - EtOAc, 5:1). 1H NMR (CDCl3) δ 7.23-7.24 (m, 2H, Ph), 7.36 (s, 1H, CH), 7.38-
7.48 (m, 3H, Ph); 13C{1H} NMR (CDCl3) δ 101.6, 121.8 (2C), 128.5, 130.4 (2C), 149.1, 162.7,
165.6 (br s, CNO2); IR (nujol) 1596 (s), 1310 (s), 1350 (s), 1200 (s) cm-1; Anal. Calcd for
C9H6N2O6S: C, 40.00; H, 2.24; N, 10.37. Found: C, 40.12; H, 2.30; N, 10.25.
1
Diethyl 5-nitroisoxazol-3-ylphosphonate (23). Colorless liquid, Rf 0.67 (CHCl3-МеОН, 20:1). H
NMR (CDCl3) δ 1.41 (t, J = 7.1 Hz, 6H, 2×CH3), 4.29-4.34 (m, 4H, 2×CH2), 7.27 (s, 1H, CH);
13C{1H} NMR (CDCl3) δ 16.2 (d, JCP = 6 Hz, 2×CH3), 64.6 (d, JCP = 6 Hz, 2×CH2), 104.2 (d, JCP
=
19 Hz, CH), 159.5 (d, JCP = 211 Hz, C), 165.5 (br s, CNO2); Р{1H} NMR (CDCl3) δ -0.12; IR
(KBr) 2987 (s), 1554 (s), 1355 (s), 1220 (s) cm-1; Anal. Calcd for C7H11N2O6Р: C, 33.61; H, 4.43; N,
11.20. Found: C, 33.35; H, 4.30; N, 11.15.
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3,5-Dinitroisoxazole (24).11a,27 Yield 60 mg (38%), colorless solid, mp 51-53 C, Rf = 0.76
(petroleum ether - EtOAc, 5:1). 1H NMR (CDCl3) δ 7.65 (s, 1H, CH); 13C{1H} NMR (CDCl3) δ 97.7
(CH), 165.7 (br. t, JCN = 18 Hz, CNO2), 167.1 (br. t, J CN = 16 Hz, CNO2); 14N{1H} NMR (CDCl3) δ
-38.4, -33.7 (NO2).
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4-Methyl-3,5-dinitroisoxazole (25). Yield 110 mg (63%), pale yellow solid, mp 24-28 C, Rf 0.81
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(CHCl3). H NMR (CDCl3) δ 2.71 (s, 3H, CH3); C{1H} NMR (CDCl3) δ 8.5, 110.7, 165.3 (br s,
CNO2), 166.4 (br s, CNO2); IR (nujol) 1560 (s), 1315 (s) cm-1; Anal. Calcd for C4H3N3O5: C, 27.76;
H, 1.75; N, 24.28. Found: C, 27.90; H, 1.67; N, 24.10.
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4-Ethyl-3,5-dinitroisoxazole (26). Yield 100 mg (53%), pale yellow liquid, Rf 0.75 (petroleum
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ether - EtOAc, 10:1). H NMR (CDCl3) δ 1.35 (t, J = 7.4 Hz, 3H, CH3), 3.14 (q, J = 7.4 Hz, 2H,
13
CH2); C{1H} NMR (CDCl3) δ 13.0, 16.3, 116.0, 162.2, 166.1 (br s, CNO2); IR (KBr) 1558 (s),
1334 (s) cm-1; Anal. Calcd for C5H5N3O5: C, 32.10; H, 2.69; N, 22.46. Found: C, 32.12; H, 2.71; N,
22.41.
4-(3-Chloropropyl)-3,5-dinitroisoxazole (27). Yield 120 mg (51%), pale yellow liquid, Rf 0.42
1
(petroleum ether - EtOAc, 10:1). H NMR (CDCl3) δ 2.16-2.23 (m, 2H, CH2), 3.27-3.31 (m, 2H,
CH2), 3.69 (app t, J = 6.1 Hz, 2H, CH2); 13C{1H} NMR (CDCl3) δ 20.4, 31.0, 43.8, 113.5, 162.3 (br
s, CNO2), 166.2 (br s, CNO2); IR (film) 1540 (s), 1345 (s) cm-1; Anal. Calcd for C6H6ClN3O5: C,
30.59; H, 2.57; N, 17.84. Found: C, 30.77; H, 2.56; N, 17.69.
4-(Cyclopropylmethyl)-3,5-dinitroisoxazole (28). Yield 100 mg (50%), pale yellow liquid, Rf 0.75
1
(petroleum ether - EtOAc, 10:1). H NMR (CDCl3) δ 0.34-0.40 (m, 2H, CH2), 0.55-0.61 (m, 2H,
13
CH2), 1.07-1.14 (m, 1H, CH), 3.07-3.11 (m, 2H, CH2); C{1H} NMR (CDCl3) δ 4.7 (2C), 10.3,
26.5, 114.3, 161.9 (br s, CNO2), 166.3 (br s, CNO2); IR (KBr) 1621 (s), 1558 (s), 1140 (s), 1334 (s)
cm-1; Anal. Calcd for C7H7N3O5: C, 39.44; H, 3.31; N, 19.71. Found: C, 39.45; H, 3.39; N, 19.52.
Experimental data concerning studies of heterocyclization reaction mechanism.
Triethylammonium nitrate was isolated by column chromatography from the reaction of methyl
vinyl ketone and TNM-TEA in dioxane. Pale yellow solid,28 Rf 0.35 (petroleum ether - EtOAc, 1:1).
1H NMR (CD3OD) δ 1.33 (t, J = 7.3 Hz, 3H, CH3), 3.25 (q, J = 7.3 Hz, 2H, CH2). 4.77 (br.s 1H,
NH); 13C{1H} NMR (CD3OD) δ 7.9, 46.6; IR (nujol) 1463 (s), 1376 (s) cm-1; Anal. Calcd for
C6H16N2O3: C, 43.89; H, 9.82; N, 17.06. Found: C, 44.06; H, 10.03; N, 17.08.
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5,5,5-Trinitropentan-2-one29 To a solution of tetranitromethane (0.3 ml, 2.5 mmol) in 2 ml MeOH
at 0 oC (ice bath) triethylamine (0.28 ml, 2 mmol) dropwise was added. The mixture was stirred over
cooling 5 min, and methyl vinyl ketone (0.08 ml, 1 mmol) was added in one portion. The cooling
was taken off and the mixture was stirred at rt for 12 h. Solvent was removed under reduced
pressure and 140 mg (63%) of product was isolated by column chromatography with petroleum
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ether - EtOAc, 5:1. Pale yellow solid, mp 44 C, Rf 0.35 (CHCl3). H NMR (CDCl3) δ 2.21 (s, 3H,
CH3), 2.86-2.90 (m, 2H, CH2), 3.31-3.34 (m, 2H, CH2C(NO2)3); 13C{1H} NMR (CDCl3) δ 28.4,
29.5, 37.0, 129.6, 202.5.
4,4,4-Trinitrobutanoic acid. To a solution of tetranitromethane (0.3 ml, 2.5 mmol) in 2 ml 1,4-
o
dioxane at 0 C (ice bath) triethylamine (0.28 ml, 2 mmol) dropwise was added. The mixture was
stirred over cooling 5 min, and acryl acid (0.07 ml, 1 mmol) was added in one portion. The cooling
was taken off and the mixture was stirred at rt for 3 days. Solvent was removed under reduced
pressure and 110 mg (49%) of product was isolated by column chromatography with petroleum
ether - EtOAc, 4:1. Colorless solid, mp 55-57 C, Rf 0.19 (petroleum ether - EtOAc, 2:1). 1H NMR
(CDCl3) δ 2.86-2.89 (m, 2H, CH2), 3.40-3.43 (m, 2H, CH2), 9.21 (br s, 1H, OH); C{1H} NMR
13
(CDCl3) δ 28.2, 29.4, 128.6, 175.2; IR (nujol) 2900 (s), 1598 (s), 1310 (s), 1245 (s) cm-1; Anal.
Calcd for C4H5N3O8: C, 21.53; H, 2.26; N, 18.83. Found: C, 21.67; H, 2.38; N, 18.71.
Acknowledgment. This work was supported by the Russian Science Foundation, grant no. 17-15-
01455. This study was fulfilled using a STOE STADI VARI PILATUS-100K diffractometer and
NMR spectrometer Agilent 400-MR purchased by MSU Development Program. We are indebted to
Dr. L. D. Konyushkin for а sample of levoglucosenone.
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Supporting Information Available: Copies of NMR spectra for all reaction products, tables with
the information on the optimization of reaction conditions. This material is available free of charge
via the Internet at http://pubs.acs.org.
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1. (a) Altukhov, K. V.; Perekalin, V. V. Chemistry of tetranitromethane. Uspekhi Khimii 1976, 45,
2050–2076; Chem. Abstr. 1977, 86, 71774s. (b) Fridman, A. L.; Surkov, V. D.; Novikov, S. S.
Chemistry of α-halonitroalkanes. Uspekhi Khimii 1980, 49, 2159–2187; Chem. Abstr. 1981, 94,
156194t. (c) Shvekhgeymer, G. A.; Zvolinskii, V. I.; Kobrakov, K. I. Synthesis of heterocycles from
aliphatic nitro compounds. Khim. Heterotsikl. Soed. 1986, 435–452; Chem. Abstr. 1987, 106,
50078j. (d) Nielsen, A. T. in Nitronic acids and esters, Feuer, H., Ed.; Wiley-VCH: New York,
1981, 349. (e) Torssell, K. B. G. in Nitrile oxides, nitrones and nitronates in organic synthesis,
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in yield 36% was evolved as a reaction product.
14. The isoxazole fragments of the compounds present characteristic spectral patterns with small
1
13
variations of the H and C chemical shift values. The C(4)H protons of heterocycles give singlets
at  7.3-7.6 ppm. The signals of the corresponding carbon atoms (C4) are observed in the typical
region at  100 to 104 ppm that reveals weak dependence on substituent at C3. Introduction of the
13
substituent at C4 causes expected downfield shift (Δ 14-20 ppm). Relatively narrow ranges of C
chemical shifts in a series of compounds are found for carbon atoms C3 (at 162 to 167 ppm) and C5
(at 154 to 164 ppm). It is interesting to note the peculiarity of the signals of quaternary carbon atoms
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case of 3,5-dinitroisoxazole 24 resolved C-14N splitting was observed for both CNO2 groups with
JCN equal to 18 and 16 Hz. Nitro groups of this compound give rather narrow resonance signals in
14N NMR spectrum at -33.7 and -38.4 ppm with respect to CH3NO2. The 13C resonance of C(NO2)3
group (at ca 130 ppm) in trinitrosubstituted adducts 18, 21 is upfield shifted compared to C-NO2
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group of 5-nitroisoxazoles. Weak C signal of this group was not found for compounds 18c-e and
20.
15. For conclusive proof of 5-nitroisoxazoles structure we have done X-ray for compounds 2, 4, 5,
13
8, 12 and confirmed the C NMR chemical shifts assignments for the isoxazole ring carbon atoms
(3- vs. 5-nitroisoxazoles) by empirical and DFT computations. For details see: (a) Averina, E. B.;
Volkova, Y. A.; Samoilichenko, Y. V.; Grishin, Y. K.; Rybakov, V. B.; Kutateladze, A. G.;
Elyashberg, M. E.; Kuznetsova, T. S.; Zefirov, N. S. Heterocyclization of electrophilic alkenes with
tetranitromethane revisited: regiochemistry and the mechanism of nitroisoxazole formation
Tetrahedron Lett. 2012, 53, 1472–1475. We also obtained X-ray data for some products of reduction
of 5-nitroisoxazoles: (b) Averina, E. B.; Vasilenko, D. A.; Samoilichenko, Y. V.; Grishin, Y. K.;
Rybakov, V. B.; Kuznetsova, T. S.; Zefirov, N. S. Chemoselective Reduction of Functionalized 5-
Nitroisoxazoles: Synthesis of 5-Amino- and 5-[Hydroxy(tetrahydrofuran-2-yl)amino]isoxazoles.
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Grishin, Y. K.; Rybakov, V. B.; Zefirova, O. N.; Kuznetsova, T. S.; Kuznetsov, S. A.; Zefirov, N. S.
Synthesis and antimitotic activity of novel 5-aminoisoxazoles bearing alkoxyaryl moieties
Mendeleev Commun. 2017, 27, 228–230.
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Signal of group C(NO2)3 was not observed in 13C NMR of compounds 18c, 18d, 18e, 20
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