Dinitrofuroxan cycloreversion as a novel general approach for the synthesis of nitroazoles

Article abstract of DOI:10.1007/s11172-015-0878-6

A novel general approach towards various nitroazoles via tandem process involving dinitrofuroxan cycloreversion followed by [3+2] cycloaddition of generated in situ nitroformonitrile oxide is developed. The reaction is promoted by addition of catalytic am

Full text of DOI:10.1007/s11172-015-0878-6

Russian Chemical Bulletin, International Edition, Vol. 64, No. 2, pp. 415—422, February, 2015
415
Dinitrofuroxan cycloreversion as a novel general approach
for the synthesis of nitroazoles*
L. L. Fershtat, D. V. Khakimov, and N. N. Makhova
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: mnn@ioc.ac.ru
A novel general approach towards various nitroazoles via tandem process involving dinitroꢀ
furoxan cycloreversion followed by [3+2] cycloaddition of generated in situ nitroformonitrile
oxide is developed. The reaction is promoted by addition of catalytic amounts of ionic liquids.
Plausible mechanisms of the described processes based on quantum chemical calculations are
proposed.
Key words: dinitrofuroxan, nitroformonitrile oxide, nitroazoles, cycloreversion, [3+2] cycloꢀ
addition, ionic liquids, catalysis, quantum chemical calculations.
1,3ꢀDipolar cycloaddition is a versatile synthetic stratꢀ
egy to construct fiveꢀmembered heterocycles of various
types.2—4 Nitrile oxides are one of the most reactive 1,3ꢀdiꢀ
poles widely used in the synthesis of fiveꢀmembered
N,Oꢀcontaining azoles.5 Like other unstable intermediꢀ
ates, nitrile oxides are usually generated in situ and further
involved in cycloadditions with various dipolarophiles.
Nitrile oxides are mainly generated by dehydrochlorinaꢀ
tion of hydroximoyl chlorides, thermal decomposition of
nitrolic acids, and dehydration of nitroalkanes.5,6
Useful source of nitrile oxides is symmetrical furoxans,
which can be regarded as dimers of nitrile oxides even if
they were synthesized by other methods, for instance, by
oxidation of the corresponding glyoximes.
Thermolysis of symmetrically substituted furoxans proꢀ
ceeds with cycloreversion to give two molecules of nitrile
oxide. Cycloreversion of furoxans bearing aromatic and
aliphatic substituents occurs at high temperatures and can
be accompanied by isomerization of nitrile oxides into
isocyanates. To exclude the possibility of isomerization,
furoxans bearing bulky substituents, e.g., adamantyl fragꢀ
ment,7 or furoxans fused with strained carbocycles8,9 are
mainly used.
addition of NFNO to cyano group of trichloroacetonitrile
and methyl cyanoformate to give two 3ꢀnitroꢀ1,2,4ꢀoxaꢀ
diazole derivatives in low yields. However, our attempts to
involve other dipolarophiles (phenylacetylene, transꢀstilꢀ
bene, and cyclohexene) in similar reactions led to unꢀ
separable product mixtures. Meanwhile, the synthesis of
N,Oꢀcontaining azole derivatives is still a challenge for
organic chemists. For instance, it is well known4 that isoxꢀ
azoles and their partially hydrogenated analogs, isoxazolꢀ
ines, are promising building blocks in organic synthesis.
These compounds possess a wide range of biological activꢀ
ities (antimicrobial, antiviral, antifungal13), can act as the
ligands for a variety of glutamate receptors and ꢀaminoꢀ
butyric acid (GABA) receptors.14,15 3ꢀNitroisoxazoles are
of interest as antimicrobial agents.16
[3+2] Cycloaddition of NFNO with acetylenes and
olefins could be regarded as the simplest approach to
3ꢀnitroisoxazoles and 3ꢀnitroisoxazolines. However, the
known methods for in situ generation of NFNO require
aggressive media (treatment of dinitromethane potassium
salt with either 30% oleum at 20 C or 95% H2SO4 at
100 C; nitration of 2ꢀmethylꢀ1ꢀnitroꢀ1ꢀpropꢀ1ꢀene with
a mixture of concentrated sulfuric and nitric acids)17,18
and cannot be applied in the reactions with dipolarophiles.
The goal of the present work is the development of the
tandem process involving in situ generation of NFNO via
the DNFO cycloreversion with subsequent [3+2] cycloꢀ
addition between thus formed NFNO and different diꢀ
polarophiles.
Cycloreversion of furoxans bearing electronꢀwithdrawing
substituents proceeds at lower temperature (80—110 C)
but accompanies by intramolecular migration of one of
the functional groups at the furoxan cycle.10,11
We earlier have demonstrated12 that dinitrofuroxan
(DNFO) in the CCl4 solution at 20 C exists in equilibriꢀ
um with its monomeric form, nitroformonitrile oxide
(NFNO). We have succeeded to perform [3+2] cycloꢀ
Taking into account the low effectiveness of our previꢀ
ous studies, we started present investigations from quantum
chemical calculations of the possibility of generating
NFNO by thermolysis of DNFO at 20 C in organic solꢀ
* For short communication see Ref. 1.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 0415—0422, February, 2015.
1066ꢀ5285/15/6402ꢀ0415 © 2015 Springer Science+Business Media, Inc.

416
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Fershtat et al.
vent. For the reversible process "dimerization of formoꢀ
nitrile oxide—cycloreversion of unsubstituted furoxan",
two mechanisms ("carbene" and concerted) have been sugꢀ
gested. Turs and coꢀworkers19 calculated potential energy
surface for cyclodimerization of formonitrile oxide (FNO)
by the MNDO and MINDO/3 semiempirical methods.
The authors suggested that the cyclodimerization is a two
stage process involving formation of intermediate cisꢀdiꢀ
nitrosoethylene (DNE) followed by the ring closure of the
intermediate to give furoxan. In the transition state leadꢀ
ing to DNE, two molecules of nitrile oxide are arranged
perpendicular to each other forming the system similar to
the carbenoid species (Scheme 1).
considering both enthalpic and entropic contributions.
Calculations show that the activation energy of the transiꢀ
tion state for the concerted mechanism is very high being
107.7 kcal mol–1 in gas phase (108.44 kcal mol–1 in solꢀ
vent phase) and calculated Gibbs activation energy is
100.52 kcal mol–1. Obviously, the concerted mechanism
of the studied process is unlikely and, therefore, cycloreꢀ
version of DNFO into NFNO was calculated via "carꢀ
bene" mechanism19 using not only the B3LYP/6ꢀ31G(d)
method but also the M05ꢀ2X/6ꢀ31G(d) level of theory.
Energy diagrams of cycloreversion of DNFO to give
two molecules of NFNO were plotted using Gibbs activaꢀ
tion energy calculations in gas phase at 298 K as most
correctly describing the reaction mechanism (Fig. 1).
According to the B3LYP/6ꢀ31G(d) calculations, the barꢀ
riers of the transformation of DNFO into DNE are
35.04 kcal mol–1 in gas phase (the change in the Gibbs
free energy is –6.00 kcal mol–1) and 35.17 kcal mol–1
in the CCl4 solution (the Gibbs activation energy is
31.8 kcal mol–1). The activation energies for the second
stage, transformation of DNE into two molecules of
NFNO, are 19.72 kcal mol–1 in gas phase (the change
in the Gibbs free energy is –6.45 kcal mol–1) and
19.64 kcal mol–1 in solvent phase (the Gibbs activation
energy is 17.87 kcal mol–1). The calculations reveal that
the solvent does not virtually affect the activation energy
of the reaction. Therefore, further M05ꢀ2X/6ꢀ31G(d) calꢀ
culations were carried out only for gas phase (see Fig. 1).
Calculations performed by both methods indicate that
cycloreversion of DNFO is a twoꢀstage process. The first
stage involves the cleavage of the O(1)—N(2) bond, the
weakest bond of the furoxan cycle (transition state TSꢀ1)
to give DNE. On the second stage proceeding via transiꢀ
tion state TSꢀ2, the C(3)—C(4) bond of DNE is cleaved.
Some differences in calculated values have to be noted.
According to the B3LYP/6ꢀ31G(d) calculations, the first
stage is thermodynamically favorable; in contrast, the
M05ꢀ2X/6ꢀ31G(d) calculations show that the second stage
is more favorable. However, the total energies of the proꢀ
cesses calculated by both methods are rather similar.
Calculations indicate that the reverse process (cycloꢀ
dimerization of NFNO into DNFO) is energetically more
favorable. However, the experimental data12 demonstrate
the possibility of cycloreversion, at least for activated
nitriles. Apparently, the driving force of this process is
a considerable energy gain obtained upon formation of
1,2,4ꢀoxadiazole derivatives. Therefore, before the experiꢀ
mental studies of other dipolarophiles, we calculated actiꢀ
vation barriers and reaction energies for [3+2] cycloaddiꢀ
tion between NFNO and three different electronꢀdeficient
dipolarophiles, namely, methyl propiolate (1a), methyl
acrylate (2a), and trichloroacetonitrile (3). Energy diaꢀ
grams for the addition of NFNO to these dipolarophiles
are given in Figs 2—4. Calculations were carried out on
the B3LYP/6ꢀ31G(d) level of theory for both the Michael
Scheme 1
Detailed kinetic study of nitrile oxide dimerization into
furoxans20,21 suggests the bimolecular concerted mechaꢀ
nism of nitrile oxide cyclodimerization of the 1,3ꢀdipolar
cycloaddition type (Scheme 2). However, this mechanism
contradicts the Huisgen rule, which states that the direcꢀ
tion of cycloaddition producing the highest energy gain
upon formation of novel ꢀbonds is favorable.22
Scheme 2
Taking into account the published data, we calculated
cycloreversion of DNFO into two molecules of NFNO
(both cycloreversion of DNFO into NFNO and cycloꢀ
dimerization of NFNO into DNFO were regarded as reꢀ
versible processes). Calculations were performed in gas
phase and solvent phase (B3LYP/6ꢀ31G(d), point estiꢀ
mation with PCM for CCl4 as a solvent). The reaction
mechanisms were evaluated using Gibbs activation energy

Nitroazoles by dinitrofuroxan cycloreversion
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 2, February, 2015
417
Fig. 1. Energy diagram for the DNFO—NFNO cycloreversion. Activation Gibbs energies (kcal mol–1) calculated in gas phase by
B3LYP/6ꢀ31G(d) and M05ꢀ2X/6ꢀ31G(d) are given in roman type and italic, respectively.
(pathway a, TSꢀM) and antiꢀMichael (pathway b,
TSꢀAM) additions. Calculations indicate that for all three
dipolarophiles, antiꢀMichael cycloaddition is an energetiꢀ
cally favorable and produces 5ꢀmethoxycarbonylꢀ3ꢀnitroꢀ
isoxazole (4a), 5ꢀmethoxycarbonylꢀ3ꢀnitroisoxazoline
(5a), and 3ꢀnitroꢀ5ꢀtrichloromethylꢀ1,2,4ꢀoxadiazole (6),
respectively.
According to the energy diagrams (see Figs 2—4), cyꢀ
cloaddition of NFNO with dipolarophiles of all three types
is a oneꢀstage process and proceeds without formation of
any intermediates. It also should be mentioned that forꢀ
mation of nitroazoles 4a, 5a, 6 gains significant energy.
Meanwhile, a comparison of diagrams 2—4 shows noticeꢀ
able differences between trichloroacetonitrile and two
other dipolarophiles upon formation of Michaelꢀtype
cycloadducts. To explain this difference, we calculated
the NPA23 charge distribution on the reacting atoms of
dipolarophiles and NFNO. Calculated charges on the N
and C atoms in trichloroacetonitrile (3) are –0.217 and
+0.213 a.u., respectively. For methyl propiolate (1a) and
methyl acrylate (2a), the charges on the reacting atoms
are similar being –0.13 and –0.14 a.u. for methyl propiꢀ
olate and –0.33 and –0.34 for methyl acrylate. For NFNO,
the charges on the C and O atoms are +0.25 and –0.27 a.u.,
respectively. These data indicate that trichloroacetoꢀ
nitrile (3) cannot react with NFNO following the Michael
type mechanism.
It should be emphasized that in contrast to cycloreverꢀ
sion of DNFO, [3+2] cycloadditions shown on Figs 2—4
are irreversible and no data on the possibility of cycloꢀ
reversion for azoles of type 4—6 have been published.3,4
Therefore, the performed calculations allowed us to exꢀ
pect that generation of NFNO via cycloreversion of DNFO
with subsequent cycloaddition with different dipolarophiles
can be successful.
We started experimental studies from [3+2] cycloꢀ
addition of NFNO in commonly used CCl4 using followꢀ
ing substituted terminal and internal acetylenes and ethylꢀ
enes as dipolarophiles: methyl propiolate (1a), dimethyl
acetylenedicarboxylate (1b), butꢀ2ꢀyneꢀ1,4ꢀdiol (1c), meꢀ
thyl acrylate (2a), dimethyl fumarate (2b), and dimethyl
maleate (2c). Since the concentration of NFNO in the
reaction mixture is very low, dipolarophiles were used in
5ꢀfold excess with respect to DNFO. Dipolarophiles 1a—c
and 2a—c are found to be reactive in cycloaddition leading
to 3ꢀnitroisoxazoles 4a—c and 3ꢀnitroisoxazolines 5a—c
Fig. 2. Energy diagram (free Gibbs energies (kcal mol–1)) for [3+2] cycloaddition of methyl propiolate (1a) to NFNO.

418
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 2, February, 2015
Fershtat et al.
Fig. 3. Energy diagram (free Gibbs energies (kcal mol–1)) for [3+2] cycloaddition of methyl acrylate (2a) to NFNO.
Fig. 4. Energy diagram (free Gibbs energies (kcal mol–1)) for [3+2] cycloaddition of trichloroacetonitrile (3) to NFNO.
(Scheme 3, Table 1). However, in all cases, the reaction
times were relatively long (from 36 h to 10 days, TLC
monitoring of the DNFO consumption) and the product
yields were low (see Table 1). Apparently, under applied
conditions, significant amount of DNFO decomposes
rather than underwent cycloreversion. From other tested
dipolarophiles, only hexafluoroacetone (7) is found to be
reactive to give 3ꢀnitroꢀ1,4,2ꢀdioxazole 8a. Phenyl vinyl
sulfone and diphenyl cyclopropenone do not react under
described conditions. Nevertheless, the obtained experiꢀ
mental data confirm both the correctness of modeled
mechanism of the DNFO decomposition into two NFNO
species and possibility of the generated NFNO to undergo
[3+2] cycloaddition.
In recent years, ionic liquids (ILs) are widely used as
the reaction media and catalysts for various heterolytic
processes. Ionic liquids comprising nonꢀcoordinated ionic
pairs are the ideal ionic surrounding for polar intermediꢀ
ates. Application of ILs leads to noticeable increase in the
rate and selectivity of the reaction.24—26 Ionic liquids posꢀ
sess unique physicochemical properties being nonꢀflamꢀ
mable and nonꢀvolatile. Therefore, ILs favor transformaꢀ
tions that cannot be achieved in common organic solꢀ
vents.27,28 Our research group has a positive experience in
carrying out chemical reactions including 1,3ꢀdipolar
Table 1. [3+2] Cycloaddition of NFNO to dipolarophiles
in CCl4 (method A)
Dipolarophile
Producta
t/h
Yieldb (%)
1a
1b
1c
2a
2b
2c
7
4a
4b
4c
5a
5b
5c
8a
148
148
172
120
168
240
120
19
31
22
50
30
10
14
1
a Structures of all products were established by H, 13C,
and 14N NMR spectroscopy, mass spectrometry, and
microanalysis.
b Isolated yield.

Nitroazoles by dinitrofuroxan cycloreversion
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 2, February, 2015
419
Scheme 3
R1 = H, R2 = COOMe (1a, 2a, 4a, 5a);
R
1 = R2 = COOMe (1b, 2b, 2c, 4b, 5b, 5c), CH2OH (1c, 4c)
cycloaddition29—31 in ILs; therefore, we decided to apply
ILs for promoting cycloaddition between NFNO and difꢀ
ferent dipolarophiles.
Scheme 4
With this aim, we optimized the reaction conditions by
the example of the cycloaddition of DNFO and methyl
acrylate (Scheme 4). As IL, we first used readily available
IL, [bmim]BF4 (bmim is 1ꢀbutylꢀ3ꢀmethylimidazolium).
An attempt to use [bmim]BF4 as the reaction medium
resulted in DNFO explosive decomposition; therefore,
all further reactions were carried out utilizing catalytic
amounts of [bmim]BF4 and CCl4 as a solvent. Optimum
amount of IL was found to be 40 mol.%. The similar
results were obtained in the presence of catalytic amounts
of other ILs ([emim]OTf, [emim]HSO4, emim is 3ꢀethylꢀ
1ꢀmethylimidazolium). Note that the reaction time and
the yield of 3ꢀnitroisoxazoline 2a do not depend on the
nature of IL and all further experiments were carried out
with 40 mol.% [bmim]BF4.
Before starting the studies on the cycloaddition of
NFNO with other dipolarophiles, we performed a screenꢀ
ing of the molar excess of dipolarophile with respect to
DNFO by the example of methyl acrylate carring out the
reaction under above described conditions. A ratio of
dipolarophile : DNFO = 5 : 1 was found to be the optimum.
As expected, the rates of ILꢀcatalyzed 1,3ꢀdipolar
cycloaddition of already studied dipolarophiles 1a—c, 2a—c,
NFNO
DNFO
and 7 with NFNO were noticeably higher (Table 2). Moreꢀ
over, we succeeded to perform cycloadditions with dipoꢀ
larophiles (Fig, 5), which were found inactive in the reacꢀ
tions with NFNO in CCl4 in this work (compounds 2e,f)
and in our previous study (compounds 1d, 2d).12 The corꢀ
responding nitroazoles 4d and 5d—f were obtained in
moderate yields. The reaction rate for cycloaddition inꢀ
volving trichloroacetonitrile (3) was also higher. Among
other carbonyl compounds, 3ꢀacetylꢀ4ꢀaminofuroxan (9)
was reactive in cycloaddition to give nitroazole 8b.
In summary, we developed a novel general approach
towards nitroazoles via [3+2] cycloaddition of different

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Russ.Chem.Bull., Int.Ed., Vol. 64, No. 2, February, 2015
Fershtat et al.
Fig. 5. Structures of dipolarophiles 1d, 2d—f, 9 and products of their [3+2] cycloaddition to NFNO.
dipolarophiles with NFNO generated in situ by cycloꢀ
reversion of DNFO. It was found that catalysis with ILs
significantly accelerates the cycloaddition and allows
involving in the reaction dipolarophiles inactive in orꢀ
ganic solvents. Preliminary quantum chemical calculaꢀ
tions suggest mechanism of the DNFO cycloreversion
and show the possibility to perform cycloaddition of
NFNO generated by the DNFO cycloreversion with diꢀ
polarophiles.
Table 2. ILꢀCatalyzed [3+2] cycloaddition of NFNO to
dipolarophilesa (method B)
Experimental
Dipolarophile
Productb
t/h
Yieldc (%)
1
H, 13C, and 14N NMR spectra were recorded with a Bruker
1a
1b
1c
1d
2a
2b
2c
2d
2e
2f
7
4a
4b
4c
4d
5a
5b
5c
5d
5e
5f
12
12
12
12
36
48
72
72
72
36
48
48
48
22
24
21
26
32
38
32
26
14
23
19
24
23
AMꢀ300 instrument (working frequencies of 300, 75, and
21 MHz, respectively) in CDCl3. The chemical shifts are given
in the  scale relative to the residual proton signal of CDCl3
( 7.27) and signal of the C atom ( 77.0). High resolution
electrospray ionization mass spectra were obtained on a Bruker
micrOTOF II instrument. Melting points were determined with
a Sanyo Gallenkamp apparatus. The course of the reactions were
monitored by TLC on precoated Merck 60 F254 plates. Products
were purified by column chromatography on silica gel 60 A
(0.060—0.200 mm, Acros Organics); elution with CH2Cl2—CCl4
or CHCl3.
Physicochemical data for compounds 4a—d, 5a—f, 6,
and 8a are given in Ref. 1 (see Supporting Information Secꢀ
tion). Compound 8b was first synthesized in the present work.
Dinitrofuroxan was synthesized following the known proceꢀ
dure.18
Synthesis of compounds 4a—c, 5a—c, and 8a (general proceꢀ
dure). Method A. To a stirred solution of dinitrofuroxan (100 mg,
0.57 mmol) in CCl4 (2 mL), the corresponding dipolaroꢀ
phile (2.85 mmol) was added at room temperature. The reacꢀ
H
C
8a
8b
6
9
3
a Structures of dipolarophiles 1d, 2d—f, 9 and products
of their [3+2] cycloaddition to NFNO, compounds 4d,
5d—f, 8b, are given in Fig. 5.
b Structures of all products were established by H, 13C,
1
and 14N NMR spectroscopy, mass spectrometry, and miꢀ
croanalysis.
c Isolated yield.

Nitroazoles by dinitrofuroxan cycloreversion
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 2, February, 2015
421
tion mixture was stirred until complete consumption of the
starting dinitrofuroxan (TLC monitoring), then water (5 mL)
was added, the organic layer was separated, and the
aqueous layer was extracted with CCl4 (3×3 mL). The comꢀ
bined organics were washed with water and dried with
MgSO4. Removal of the solvent in vacuo and purification of the
residue by silica gel column chromatography afforded target
product.
Synthesis of compounds 4a—d, 5a—f, 6, and 8a,b (general
procedure). Method B. To a stirred solution of dinitrofurꢀ
oxan (100 mg, 0.57 mmol) in CCl4 (2 mL), [bmim]BF4
(51 mg, 0.228 mmol) and the corresponding dipolarophile
(2.85 mmol) were added at room temperature. The reaction
was carried out and the products were isolated following the
method A.
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4ꢀAminoꢀ3ꢀ(5ꢀmethylꢀ3ꢀnitroꢀ1,4,2ꢀdioxazolꢀ5ꢀyl)furoxan
(8b). Yield 31 mg (24%, method B). Yellow powder, m.p. 88—89 C.
Rf 0.43 (CHCl3). 1H NMR, : 2.93 (s, 3 H, CH3); 5.24 (br.s, 2 H,
NH2). 13C NMR, : 14.2 (CH3); 110.2 (C(3) furoxan cycle);
139.4 (C(5) dioxazole cycle); 150.2 (C—NH2); 164.8 (C—NO2).
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C5H5N5O6. Calculated, m/z: 232.0273.
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Authors are grateful to Merck KGaA for kindly proꢀ
viding ionic liquids.
This work was financially supported in parts by the
Russian Academy of Sciences (Program "Development of
Methods for the Synthesis of Chemical Compounds and
Design of Novel Materials").
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Received September 22, 2014;
in revised form October 20, 2014