Ionic liquid-promoted [3+2]-cycloaddition reactions of nitroformonitrile oxide generated by the cycloreversion of dinitrofuroxan

Article abstract of DOI:10.1016/j.tetlet.2014.02.112

A new approach to the synthesis of 3-nitroisoxazoles and 3-nitroisoxazolines based on the [3+2]-cycloaddition of nitroformonitrile oxide (NFNO), generated by the cycloreversion of dinitrofuroxan (DNFO), to acetylene and ethylene derivatives, under ionic liquid catalysis is developed. The approach is of a general nature and applicable to cycloaddition reactions with other dipolarophiles.

Full text of DOI:10.1016/j.tetlet.2014.02.112

Tetrahedron Letters 55 (2014) 2398–2400
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ionic liquid-promoted [3+2]-cycloaddition reactions
of nitroformonitrile oxide generated by the cycloreversion
of dinitrofuroxan
⇑
Leonid L. Fershtat, Igor V. Ovchinnikov, Nina N. Makhova
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47, Leninsky prosp., 119991 Moscow, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
A new approach to the synthesis of 3-nitroisoxazoles and 3-nitroisoxazolines based on the [3+2]-cyclo-
addition of nitroformonitrile oxide (NFNO), generated by the cycloreversion of dinitrofuroxan (DNFO), to
acetylene and ethylene derivatives, under ionic liquid catalysis is developed. The approach is of a general
nature and applicable to cycloaddition reactions with other dipolarophiles.
Received 23 January 2014
Revised 5 February 2014
Accepted 26 February 2014
Available online 6 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Dinitrofuroxan
Nitroformonitrile oxide
Cycloreversion
Cycloaddition
Ionic liquid
The 1,3-dipolar cycloaddition of 1,3-dipoles to dipolarophiles is
one of the most convenient and general methods for the synthesis
of five-membered heterocyclic compounds of various classes,1
which are widely used as medical and crop protection agents.2 Ni-
trile oxides are amongst the most reactive 1,3-dipoles employed to
construct five-membered N,O-containing heterocycles (isoxazoles,
isoxazolines and 1,2,4-oxadiazoles).3 It is well-known that isoxaz-
oles, and their partially hydrogenated analogues, isoxazolines, con-
acids generated from propargyl halides7 or 1,3-dihalopropanes8
and sodium nitrite. Another method is based on the reaction of
chloronitrolic acids with Grignard derivatives of acetylene.9 An
interesting approach to the synthesis of mono- and disilyl-substi-
tuted 3-nitroisoxazoles is via the reaction of tetranitroethylene
with trimethylsilyl-substituted acetylenes.10 Recently,
a new
method for the preparation of 3-nitroisoxazoles based on the het-
erocyclization of electrophilic alkenes under the action of tetrani-
tromethane activated by Et3N was published.11 However, the
authors later refuted this information and unambiguously estab-
lished that the reaction products were 5-nitroisoxazoles.12
The best approach for the synthesis of 3-nitroisoxazoles or
3-nitroisoxazolines might be via the [3+2]-cycloaddition of nitro-
formonitrile oxide (NFNO) to the appropriate dipolarophiles. How-
ever, the known methods for NFNO generation (treatment of
dinitromethane potassium salt with 30% fuming sulfuric acid at
20 °C, or 95% H2SO4 at 100 °C and nitration of 2-methyl-1-nitro-
1-propene with a sulfuric-nitric acid mixture)13a,b cannot be used
for our purpose.
stitute classes of heterocycles possessing
a wide range of
applications as versatile building blocks in organic synthesis.4
Their biological activity includes antibacterial, antiviral and anti-
fungal behaviour.5a Also, they can act as glutamate and GABA
receptor ligands and display herbicide activity.5b,c Along with the
1,3-dipolar cycloaddition of nitrile oxides to acetylene and ethyl-
ene derivatives, the reaction of hydroxylamine with 1,3-diketones
or a,b-unsaturated ketones is applied to construct isoxazoles with
various substituents.5a However, no reports on the synthesis of 3-
nitrosubstituted isoxazoles and isoxazolines by either of the meth-
ods are available in the literature. Meanwhile these compounds are
important as antibacterial agents.6
Here we present our research on a new approach for the synthe-
sis of 3-nitrosubstituted isoxazoles 1 and isoxazolines 2 via the
[3+2]-cycloaddition reaction of acetylene and ethylene derivatives
to NFNO, generated in situ by the cycloreversion of dinitrofuroxan
(DNFO) under the catalysis of ionic liquids (ILs).
Only a few synthetic approaches for the preparation of 3-nitro-
substituted isoxazoles have been described. These compounds can
be obtained by intramolecular cyclization of substituted nitrolic
The nitrile oxides for the heterocycle construction are usually
prepared in situ in the presence of the corresponding
dipolarophiles. Typical pathways to nitrile oxides are the
⇑
Corresponding author. Tel.: +7 (499) 1355326; fax: +7 (499) 1355328.
E-mail address: mnn@ioc.ac.ru (N.N. Makhova).
http://dx.doi.org/10.1016/j.tetlet.2014.02.112
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

L. L. Fershtat et al. / Tetrahedron Letters 55 (2014) 2398–2400
2399
O2N
O2N
NO2
O2N
NO2
O2N
R1
R2
R1
R2
CO2Me
O2N
N O
O2N
N O
N
N
N
N
N
N
CO2Me
O
CCl4, cat. IL, r.t.
O
O
2a
O
O
O
1a-d
NFNO
NFNO
R1
R1
R2
DNFO
C
DNFO
C
l
3C
N
(
C
O2N
F
3
)
N
2
C
R2
Scheme 1. Synthesis of isoxazoline 2a.
O
IL = [bmim][BF4] (40 mol%)
O2N
N
CCl3
O
4
O2N
O
O
CF3
CF3
N
N
O
dehydrochlorination of hydroxamic acid chlorides under the action
of bases, thermolysis of nitrolic acids and dehydration of
nitroalkanes.3,4 An important approach to nitrile oxides is the
cycloreversion of symmetrically substituted 1,2,5-oxadiazol-2-oxi-
des (furoxans) resulting in two molecules of the nitrile oxides, from
which the furoxans were originally constructed. As a rule, a cyclo-
reversion proceeds at high temperature,14,15 though, as we found
earlier,16 the cycloreversion of DNFO in CCl4 can occur at room
temperature to afford an equilibrium mixture of DNFO and its
monomeric form–NFNO, where the cyclic form predominates
dramatically.
The reactions between DNFO and activated nitriles (trichloro-
acetonitrile, methoxycarbonyl cyanide) in CCl4 allowed the synthe-
sis of two representative 3-nitro-1,2,4-oxadiazoles. The reactions
were completed in seven days at rt (TLC monitoring) and the final
products were obtained in low yields (21% and 23%), whilst
remaining DNFO decomposed under the reaction conditions. An in-
crease in the reaction temperature did not promote the cycloaddi-
tion, but accelerated DNFO decomposition. Attempts to synthesize
3-nitroisoxazoles or 3-nitroisoxazolines by the reaction of DNFO
with appropriate dipolarophiles, in particular phenylacetylene
and trans-stilbene, failed under the above-mentioned conditions.
Evidently, the rate of DNFO decomposition exceeded that of the
DNFO cycloaddition to the dipolarophiles.
Ionic liquids (ILs) are widely used as reaction media or catalysts
for the promotion of many reactions (especially heterolytic exam-
ples). ILs have become beneficial in modern ‘green’ chemistry ow-
ing to their useful physicochemical properties (non-flammability,
low vapour pressure, possible recovery, etc.).17 ILs consisting of
non-coordinated ions form an ideal environment for 1,3-dipolar
intermediates, which may lead to an unprecedented increase in
the rate and selectivity of these processes.18 Nitrile oxide cycload-
dition reactions with olefins in the ILs, [bmim]BF4 and [bmim]PF6,
have been exemplified.19
To this end, we decided to study these reactions using ILs as the
reaction media or catalysts, with a view to develop methods for the
preparation of 3-nitroisoxazoles 1 or 3-nitroisoxazolines 2 on the
basis of the [3+2]-cycloaddition of NFNO, generated by the cyclore-
version of DNFO, to the appropriate dipolarophiles. To optimize the
3
2a-f
Scheme 2. Synthesis of 3-nitroheterocycles by [3+2]-cycloaddition of NFNO to
dipolarophiles.
reaction conditions we used methyl acrylate as a dipolarophile,
which was added in considerable excess (5 mol per 1 mol DNFO)
because of the low NFNO concentration (Scheme 1, Table 1). An at-
tempt to perform the reaction between DNFO and methyl acrylate
in 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]BF4)
caused an explosion! Therefore, in subsequent experiments, the
ILs were used in catalytic amounts and reactions were carried
out in CCl4 since DNFO had been obtained in this solvent13
(Scheme 1, Table 1). Different ILs were added to the reaction mix-
tures in amounts from 20 to 100 mol % (entries 2–5). The comple-
tion of the reaction was determined by the disappearance of DNFO
in the reaction mixture (TLC monitoring). The optimum amount of
IL was found to be 40 mol % (entry 3) and both the reaction time
and 3-nitroisoxazoline 2a yield did not depend on the IL structure
(entries 3,
6 and 7). For further investigations we selected
[bmim]BF4 as the IL because of its ready availability and low cost.
By varying the amount of the dipolarophile, a value of 5 mol of
dipolarophile per 1 mol of DNFO was found to be optimum. The
yield of the final compound 2a was lower on both decreasing
and increasing the amount of methyl acrylate (entries 8–12).
Using the optimized conditions, both terminal and internal
acetylene and ethylene derivatives successfully reacted with DNFO
(Scheme 2, Table 2, entries 1–10), including those dipolarophiles
that had been inactive in our previous research16 (entries 4 and
8). The corresponding 3-nitroisoxazoles 1 and 3-nitroisoxazolines
2 were obtained in moderate yields in all cases. Moreover, the reac-
tion was found to be general as the carbonyl group participated in
the cycloaddition with NFNO (compound 3, entry 11), whereas the
reaction with diphenylcyclopropenone only occurred on the dou-
ble bond (entry 10). As expected, the rate of the reaction with tri-
chloroacetonitrile (compound 4) increased under IL catalysis
(entry 12). The low yields of the final products could be attributed
to partial decomposition of DNFO under the reaction conditions.
Table 1
Optimization of the [3+2]-cycloaddition reaction of NFNO to methyl acrylate under IL catalysis
Entry
Solvent
IL (mol %)
Methyl acrylate/DNFO (mol/mol)
Time (h)
Yielda (%) 2a
1
2
3
4
5
6
7
8
9
[bmim]BF4 as solvent
5.0
5.0
5.0
5.0
5.0
5.0
5.0
1.0
2.0
3.0
4.0
6.0
Explosion!
60
36
36
36
36
36
240
240
160
50
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
[bmim]BF4 (20)
30
32
28
25
31
29
[bmim]BF4 (40)
[bmim]BF4 (60)
[bmim]BF4 (100)
[emim]OTf (40)
[emim]HSO4 (40)
[bmim]BF4 (40)
[bmim]BF4 (40)
[bmim]BF4 (40)
[bmim]BF4 (40)
[bmim]BF4 (40)
Traceb
4c
10
11
12
9c
14c
30
36
a
b
c
Isolated yield after purification.
Determined by 1H NMR spectroscopy.
Some DNFO was recovered.

2400
L. L. Fershtat et al. / Tetrahedron Letters 55 (2014) 2398–2400
Table 2
Supplementary data
Reaction of DNFO with different dipolarophiles under [bmim]BF4 catalysis
Entry
1
Dipolarophile
CO2Me
Producta
Time
Yieldb (%)
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2014.02.112.
O2N
12 h
22 (1a)
N
O
O2N
CO2Me
CO2Me
References and notes
MeO2C
HOH2C
CO2Me
CH2OH
2
3
4
5
6
7
8
9
12 h
12 h
12 h
36 h
48 h
3 d
24 (1b)
21 (1c)
26 (1d)
32 (2a)
38 (2b)
32 (2c)
26 (2d)
14 (2e)
N
O
O2N
CO2Me
CH2OH
1. (a) Huisgen, R. Angew. Chem. 1963, 2, 565; (b) Huisgen, R.; Knorr, R.; Mobins, L.;
Szeimies, G. Chem. Ber. 1965, 98, 4014; (c) Pellissier, H. Tetrahedron 2007, 63,
3235; (d) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.;
Wiley: New-York, 1984; p 1.
N
O
O2N
CH2OH
2. (a)Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Scriven, E.
F. V., Eds.; Pergamon: Oxford, 1996; Vol. 3,
p 932; (b)Comprehensive
Ph
Heterocyclic Chemistry; Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V.,
Taylor, R. J. K., Eds.; Elsevier: Oxford, 2008; Vol. 4, p 1304.
N
O
O2N
Ph
3. Padwa, A.; Pearson, W. H. In Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry toward Heterocycles and Natural Products; Feuer, H., Ed.; Wiley-VCH:
New-York, 2002; p 363.
4. Grünanger, P.; Vita-Finzi, P. Isoxazoles, Part I In The Chemistry of Heterocyclic
Compounds; Taylor, E. C., Weissberger, A., Eds.; Wiley: NewYork, 1991; Vol. 49,
p 1.
5. (a) Giomi, D.; Cordero, F. M.; Machetti, F. Isoxazoles In Comprehensive
Heterocyclic Chemistry; Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V.,
Taylor, R. J. K., Eds.; Elsevier: Oxford, 2008; Vol. 4, p 365; (b) Pieroni, M.;
Lilienkampf, A.; Wan, B.; Wang, Y.; Franzblau, S. G.; Kozikowski, A. P. J. Med.
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Sulimov, I. G.; Usik, N. V.; Mladenov, I.; Perekalin, V. V. J. Org. Chem. USSR 1980,
16, 1148.
8. Diamantini, G.; Duranti, E.; Tontini, A. Synthesis 1993, 1104.
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CO2Me
N
O
CO2Me
CO2Me
O2N
CO2Me
MeO2C
MeO2C
N
O
O2N
CO2Me
CO2Me
CO2Me
Ph
N
O
CO2Me
O2N
Ph
3 d
Ph
N
Ph
O
O
O2N
SO2Ph
3 d
N
SO2Ph
O
O
O
Ph
O2N
10
36 h
23 (2f)
N
Ph
Ph
O
Ph
O2N
O
CF3
11
12
F3C
N
CF3
48 h
48 h
19 (3)
23 (4)
N
O
CF3
CCl3
O2N
N
N
CCl3
O
All products were characterized from 1H, 13C and 14N NMR and MS spectral data
and by elemental analysis.
a
15. (a) Brittelli, D. R.; Boswell, G. A. J. Org. Chem. 1981, 46, 316; (b) Marchand, A. P.;
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Shlyapochnikov, V. A. Mendeleev Commun. 1995, 231.
b
Isolated yield after purification.
17. (a)For selected examples, see: Ionic Liquids in Synthesis 1; Wasserscheid, P.,
Welton, T., Eds.; Wiley-VCH GmbH & Co. KGaA: Weinheim, Germany, 2008; p
367; (b)Ionic Liquids in Synthesis 2; Wasserscheid, P., Welton, T., Eds.; Wiley-
VCH GmbH & Co. KGaA: Weinheim, Germany, 2008; p 353; (c) Zlotin, S. G.;
Makhova, N. N. Russ. Chem. Rev. 2010, 79, 543; (d) Siddiqui, I. R.; Shamim, S. S.;
Waseem, M. A.; Abumhdi, A. A. H.; Srivastava, A.; Srivastava, A. Tetrahedron
Lett. 2013, 54, 5083; (e) Chakraborty, B.; Sharma, C. D. Tetrahedron Lett. 2013,
54, 5532; (f) Shen, Z.-L.; Goh, K. K. K.; Wong, C. H. A.; Loo, W.-Y.; Yang, Y.-S.; Lu,
J.; Loh, T.-P. Chem. Commun. 2012, 5856; (g) Gholap, A. R.; Venkatesan, K.;
Daniel, T.; Lahoti, R. J.; Srinivasan, K. V. Green Chem. 2004, 6, 147.
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5327; (b) Rodriquez, M.; Sega, A.; Taddei, M. Org. Lett. 2003, 5, 4029; (c) Rosella,
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In conclusion, we have reported a new approach for the synthe-
sis of substituted 3-nitroisoxazoles 1 and 3-nitroisoxazolines 2
from dinitrofuroxan–a unique source of nitroformonitrile oxide–
via its [3+2]-cycloaddition with acetylene and ethylene derivatives
under ionic liquid catalysis.20 The developed method is the first
general synthetic route to 3-nitroisoxazoles and 3-nitroisoxazo-
lines, which has allowed us to enlarge libraries of these com-
pounds. In addition, the described approach to the preparation of
NFNO is general and can be extended to cycloaddition reactions
with other dipolarophiles. Such investigations are now in progress.
20. General procedure for the synthesis of 1 and 2: [bmim]BF4 (0.051 g, 0.228 mmol)
and the appropriate dipolarophile (2.85 mmol) were added to the DNFO
solution (0.57 mmol) in CCl4 (2 ml) with stirring at room temperature. The
mixture was stirred for the time indicated in Table 2. Next, H2O (5 ml) was
added, and the organic layer was separated and dried over MgSO4. The solvent
was evaporated under reduced pressure and the residue was purified by
column chromatography on silica gel (eluent–CH2Cl2/CCl4). Caution!
Dinitrofuroxan must be used only as a solution in CCl4 due to its propensity
to explode.
Acknowledgements
This work was partially supported by the Russian Foundation
for Basic Research, Russia (Grant No. 12-03-12012 ofi-m) and the
Program of the Russian Academy of Sciences: ‘Development of
methods for synthesizing chemical compounds and creating new
materials’. Ionic liquids were provided by Merck KGaA.