Versatile approach to heteroarylfuroxan derivatives from oximinofuroxans via a one-pot, nitration/thermolysis/[3+2]-cycloaddition cascade

Article abstract of DOI:10.1016/j.tetlet.2017.09.013

A simple, general, and regioselective method has been developed for the synthesis of a series of heteroarylfuroxans, including isoxazolyl-, isoxazolinyl- and (1,2,4-oxadiazolyl)furoxans. The described method is based on a cascade of one-pot processes, inc

Full text of DOI:10.1016/j.tetlet.2017.09.013

Accepted Manuscript
Versatile approach to heteroarylfuroxan derivatives from oximinofuroxans via
a one-pot, nitration/thermolysis/[3+2]-cycloaddition cascade
Alexander A. Larin, Leonid L. Fershtat, Ivan V. Ananyev, Nina N. Makhova
PII:
S0040-4039(17)31131-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.09.013
TETL 49283
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
6 July 2017
31 August 2017
7 September 2017
Please cite this article as: Larin, A.A., Fershtat, L.L., Ananyev, I.V., Makhova, N.N., Versatile approach to
heteroarylfuroxan derivatives from oximinofuroxans via a one-pot, nitration/thermolysis/[3+2]-cycloaddition
cascade, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.09.013
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Versatile approach to heteroarylfuroxan derivatives from oximinofuroxans
via a one-pot, nitration/thermolysis/[3+2]-cycloaddition cascade
Alexander A. Larin,a Leonid L. Fershtat,a Ivan V. Ananyev,b Nina N. Makhovaa*
aN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47, Leninsky
prosp., 119991, Moscow, Russian Federation. Phone: +7 (499) 1355326; Fax: +7 (499)
1355328. e-mail: mnn@ioc.ac.ru
bA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,28
Vavilova str., 119991 Moscow, Russian Federation. Fax: +7 (499) 135 5085.
Abstract
A simple, general, and regioselective method has been developed for the synthesis of a
series of heteroarylfuroxans, including isoxazolyl-, isoxazolinyl- and (1,2,4-
oxadiazolyl)furoxans. The described method is based on a cascade of one-pot processes,
including the nitration of furoxancarbaldehyde oximes, thermolysis of the formed nitrolic acids
to generate furoxancarbonitrile oxides, and [3+2]-cycloaddition with an appropriate
dipolarophile – alkynes, olefins, or activated nitriles.
Keywords: furoxan; isoxazole; nitrolic acids; thermolysis; nitrile oxides; [3+2]-
cycloaddition.
The design of potential drugs with improved pharmacokinetic profiles has in recent years
been focused on the molecular hybridization of diverse compounds with known pharmacological
activities.1 In particular, special efforts have been directed towards the synthesis of
pharmacologically oriented structures comprising of a framework capable of nitric oxide (NO)
release, including 1,2,5-oxadiazole 2-oxides (furoxans) which are capable of exogenous NO
release in the presence of thiol cofactors.2 The incorporation of the furoxan motif as a potential

NO donor into drug candidates with known pharmacological activities has been recently
explored by a number of research groups,3 and new hybrid structures with neuroprotective and
precognitive,4 cytotoxic,5 antihelmintic,6 antibacterial,7 and antiaggregant8 activities have been
reported.
Our research group has significant experience in furoxan chemistry9 and has developed
effective methods for the preparation of new types of hybrid structures, combining a furoxan ring
with various pharmacophoric heterocycles (1,2,3-10a-c and 1,2,4-triazole,10d 1,2,4-,10e 1,2,5-10f,g
and 1,3,4-oxadiazoles,10h tetrazole,10i pyridines,10j tetrahydroisoquinolines,10j and others10k-n),
whereas isoxazolyl- and isoxazolinylfuroxans are practically unknown. Meanwhile, isoxazoles
exhibit various biological activities11 and are a common scaffold of many drugs, such as
flucloxacillin, valdecoxib, and dicloxacillin. The isoxazoline core is also found in numerous
biologically active compounds,12 and the 1,2,4-oxadiazole motif is an important subunit in
advanced materials and bioactive compounds.13 A useful approach for the design of such
structures might involve the [3+2]-cycloaddition of furoxancarbonitrile oxides with alkynes and
olefins, respectively. Additionally, activated nitriles can also be introduced in the cycloaddition
protocol to prepare (1,2,4-oxadiazolyl)furoxans.
Herein, we present the development of a versatile approach for the regioselective
synthesis of hybrid heterocyclic structures combining, in one molecule, furoxan and isoxazole,
isoxazoline, or 1,2,4-oxadiazole heterocycles via a cascade of one-pot processes: the nitration of
furoxancarbaldehyde oximes, thermolysis of the intermediate nitrolic acids to generate
furoxancarbonitrile oxides, and [3+2]-cycloaddition with an appropriate dipolarophile such as
alkynes, olefins, or activated nitriles.
Common methods for the preparation of nitrile oxides include the dehydrochlorination of
hydroximoyl chlorides under the action of bases,14 the oxidation of aldoximes,15 the dehydration
of primary nitroalkanes, and the thermal cycloreversion of furoxans, which are dimers of nitrile
oxides.16 The dimerization of nitrile oxides into furoxans is a common side-process in [3+2]-
cycloaddition reactions. Over the last years, new methods for the generation of nitrile oxides
have been developed. In particular, the water-assisted generation of nitrile oxides from
hydroximoyl chlorides under weakly acidic conditions (pH 4–5) was recently reported.17
Photoredox catalysis was also used for the visible-light-mediated generation of nitrile oxides
from hydroxyimino acids.18 Nitrile oxide intermediates are also formed upon the treatment of
o
substituted aldoximes with alkyl nitrites at 65 C.19 Additionally, a one-pot method for the
generation of furoxancarbonitrile oxides by the thermolysis of furoxanylnitrolic acids, resulting
in terfuroxan formation, was proposed by Gasco and co-workers.20 This research group has also

managed to prepare the first and only example of an isoxazolylfuroxan via the thermolysis of
phenylfuroxanylnitrolic acid in the presence of phenylacetylene.
Recently,10f our group has developed a general method for the preparation of
(chlorohydroxamoyl)furoxans 1 from readily available cyanofuroxans 2 using a two-step
protocol, via their reaction with hydroxylamine and subsequent transformation of the resulting
(aminohydroxamoyl)furoxans 3 into chlorides 1 under the action of NaNO2 in the presence of
HCl (Scheme 1).
Scheme 1. Synthesis of (chlorohydroxamoyl)furoxans 1
Therefore, we initially studied the dehydrochlorination of compounds 1 for the generation
of furoxancarbonitrile oxides using 4-(chlorohydroxamoyl)-3-methylfuroxan 1a as a model
substrate. Detailed screening for the synthesis of furoxanylisoxazole 4a via the base promoted
generation of nitrile oxide 5a from chlorooximinofuroxan 1a in the presence of diethyl
acetylenedicarboxylate 6 is summarized in Table S1 (ESI). Unfortunately, all approaches to
generate nitrile oxide 5a proved to be ineffective. The use of K2CO3 in Et2O in the presence of
dipolarophile 6 (3-4 equiv.) at room temperature was somewhat better (ESI; Table S1, entries 11,
12); however, the undesired terfuroxan 7a was always formed in significant amounts (Scheme
2).
Scheme 2. Generation of nitrile oxide 5a via the dehydrochlorination of furoxan 1a.
Therefore, we decided to study the possibility for the synthesis of isoxazolylfuroxans 4
via generation of nitrile oxides 5 by the thermolysis of furoxanylnitrolic acids 9 in the presence
of an appropriate dipolarophile. It is known20 that nitrolic acids eliminate HNO2 to give nitrile
oxides at elevated temperatures, which was encouraging since nitrile oxide cycloaddition is
usually accelerated under such conditions.15,16 Thus, a set of furoxanylnitrolic acids 9a-c which
were synthesized via nitration of the corresponding oximes 8a-c under the action of N2O4 at 0
oC, and subjected to further transformations without isolation, were selected for investigation.

Oxime 8a and diethyl acetylenedicarboxylate 6 were chosen as model substrates for optimization
of the reaction conditions. The quantities of N2O4 and dipolarophile 6, the solvent, the
temperature, and the reaction time were varied. Nitration of the initial oxime 8a with a 3-5 molar
excess of N2O4 in PhH with subsequent heating at reflux in the presence of dipolarophile 6
afforded the target isoxazole 4a in moderate yield (Table 1, entries 1-3). Replacement of PhH
with CHCl3 and performing the reaction at room temperature did not provide the desired product
o
(Entry 4). Increasing the reaction temperature to 60 C provided isoxazole 4a and varying the
amount of N2O4 revealed the necessary use of excess N2O4 (Entries 5-7). Increasing the excess of
the dipolarophile only slightly altered the yield (Entries 8, 9). At the same time, heating the
reaction mixture at reflux with dipolarophile 6 (1 equiv.) for 2 h gave the highest yield of
isoxazole 4a (Entry 10), while an extended reaction time slightly decreased the yield (Entry 11).
Therefore, the nitration of oxime 8a with N2O4 (5 equiv.) and dipolarophile 6 (1 equiv.) in
CHCl3 for 2 h was the optimal reaction conditions (Entry 10).
Table 1. Reaction conditions screening for the synthesis of isoxazolylfuroxan 4a based on the
[3+2]-cycloaddition of dipolarophile 6 with nitrile oxide 5a, generated by the thermolysis of
furoxanylnitrolic acid 9a.a
O
CO2Et
HON
N
Me
NOH
EtO2C
CO2Et
Me
Me
NO2
N2O4
6
CO2Et
N
N
O
N
N
O
9a
N
N
O
8a
O
O
O
4a
Entry N2O4 (equiv.)
6 (equiv.)
Solvent
T (oC) Time (h)
Yield 4a
(%)b
30
1
2
3
5
5
5
1
3
5
5
5
5
5
1
1
3
3
1
1
1
2
3
1
1
PhH
PhH
PhH
80
80
80
20
60
60
60
60
60
60
60
1
2
1
24
3
2
1
2
2
2
20
33
3
4
5
6
7
8
c
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
-
15
22
52
55
45
64
61
9
10
11
3
a
o
Reagents and conditions: oxime 8a (1 mmol), N2O4, solvent (10 mL), 0 C, 30 min, then
dipolarophile 6, reflux.
b Isolated yield.
c No reaction.
The optimized conditions were suitable for introduction of the in situ formed nitrolic acid
9a into [3+2]-cycloaddition reactions with various C=C, C≡C, and C≡N dipolarophiles to give

the corresponding isoxazolylfuroxans 4a-c, isoxazolinylfuroxans 10a-c, and (1,2,4-
oxadiazolyl)furoxan 11a in good yields. The reaction with terminal olefins and acetylenes
proceeded with high regioselectivity; only single regioisomers 4b,c and 10a were formed (Table
2). The high regioselectivity for the formation of 3,5-disubstituted isoxazoles and isoxazolines
was established on the basis of literature precedence.19,21 1H NMR analysis of isoxazoles 4b and
4c showed characteristic singlets at 7.66 and 7.48 ppm, respectively, for the isoxazole proton
(C4-H), while for compound 10a the isoxazoline proton triplet 5.26 ppm (C5-H) and multiplet
3.72-3.76 ppm (CH2) were observed. The diastereoselectivity of compounds 10b,c was reflected
by the geometry of the initial olefins.
Table 2. Scope for the synthesis of 4-heteroaryl-3-methylfuroxans via the one-pot
nitration/thermolysis/[3+2] cycloaddition cascadea
o
a Reagents and conditions: oxime 8a (1 mmol), N2O4 (5 mmol), CHCl3 (10 mL), 0 C, 30 min,
then dipolarophile (1 mmol), reflux.
b Isolated yield.
The thermolysis of nitrolic acid 9b and subsequent cycloaddition of nitrile oxide 5b with
the same dipolarophiles was more successful in benzene at reflux, resulting in good yields of the
target heteroarylfuroxans. All reactions proceeded with high regioselectivity; however, in the
reaction with methyl propiolate, the second regioisomer 4e’ was also formed in the ratio 4e:4e’ =
4:1 (Table 3). The high regioselectivity for the formation of compounds 4d,e and 10d as well as
the diastereoselectivity of compounds 10e,f were supported by NMR data (see ESI).

Table 3. Scope for the synthesis of 3-heteroaryl-4-phenylfuroxans via the one-pot
nitration/thermolysis/[3+2] cycloaddition cascadea,b
o
a Reagents and conditions: oxime 8b20a (1 mmol), N2O4 (5 mmol), PhH (10 mL), 0 C, 30 min,
distillation of excess N2O4, then dipolarophile (1 mmol), reflux.
b Isolated yields.
Bisnitrolic acid 9c is described in the literature as an isolated explosive complex with
dioxane.22 Therefore, this nitrolic acid was synthesized in situ by the analogous nitration of
oxime 8c under the action of N2O4; the best conditions for thermolysis proved to be in CHCl3 at
reflux. The one-pot cycloaddition of in situ generated bis(nitrile oxide) 5c with the same
dipolarophiles proceeded smoothly and the target products were obtained in good yields (Table
4). In all cases, the cycloaddition occurred at both nitrile oxide motifs and the products of
monocycloaddition were not isolated. Thus, it can be concluded that the reactivity of both
nitrolic acid and nitrile oxide functionalities under thermal conditions does not depend on their
position on the furoxan ring. Compounds 10g-i could be formed as a mixture of diastereomers
(see ESI for the structures of possible stereoisomers), however it was not possible to estimate the
diastereoselective ratios due to overlapping of the proton signals in the 1H NMR spectra.
Table 4. Scope for the synthesis of bis(heteroaryl)furoxans via the one-pot
nitration/thermolysis/[3+2] cycloaddition cascadea,b

a Reagents and conditions: oxime 8c23 (1 mmol), N2O4 (10 mmol), CHCl3 (10 mL), rt, 30 min,
distillation of excess N2O4, then dipolarophile (2 mmol), reflux.
b Isolated yields.
c Obtained as a mixture of diastereoisomers.
All synthesized isoxazoles 4, isoxazolines 10, and 1,2,4-oxadiazoles 11 were
1
characterized by IR, H and 13C NMR, and HRMS. The structure of compound 4c was
additionally confirmed by single-crystal X-ray diffraction (Fig. 1).
Figure 1. General view of compound 4c. Atoms are represented by probability ellipsoids of
atomic vibrations (ρ=50%).
In summary, a general, highly effective, regio- and diastereoselective method for the synthesis of
isoxazolyl-, isoxazolinyl-, and (1,2,4-oxadiazolyl)furoxans has been developed.24 This method
includes a cascade of one-pot reactions: the nitration of furoxancarbaldehyde oximes using
dinitrogen tetraoxide, thermolysis of the formed nitrolic acids to generate furoxancarbonitrile
≡C, C=C, and
oxides, and [3+2]-cycloaddition with an appropriate dipolarophile, containing C

C≡N bonds. It is especially important to note that these reactions are not affected by the position
of the functional group at either the C(3) or C(4) furoxan carbon atom. To the best of our
knowledge, this study represents the first general and comprehensive investigation of the
reactivity of furoxancarbonitrile oxides in cycloaddition processes.
Acknowledgements
This work was supported by the Russian Science Foundation (Project No 14-50-00126).
Supplementary data
Supplementary data associated with this article can be found, in the online version, at
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24. General procedure for the synthesis of heteroarylfuroxans 4, 10, 11: A solution of
dinitrogen tetraoxide (0.46 g, 5.0 mmol for oximes 8a,b and 0.92 g, 10.0 mmol for oxime
8c) in dry CHCl3 or PhH (5 mL) was added dropwise to a magnetically stirred suspension
o
of the corresponding oxime (1.0 mmol) in dry CHCl3 or PhH (5 mL) at 0-5 C. The
reaction mixture was stirred at 0-5 oC for 30 min, then the cooling bath was removed and
the resulting solution concentrated in vacuo to remove excess N2O4 (final volume 4 mL,
in reactions with oxime 8a excess N2O4 was not removed). The appropriate dipolarophile
(1.0 mmol) was added and the resulting mixture was heated at reflux for 3 h. The solvent
was then evaporated and the residue purified by column chromatography.

Highlights
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•
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The cycloaddition reactions of furoxancarbonitrile oxides have been performed.
This approach enables to obtain various N,O-heteroarylsubstituted furoxans.
Target heteroarylfuroxans are formed in good yields with high regioselectivity.