Synthesis of cyanofuroxans from 4-nitrofuroxans via C–C bond forming reactions

Article abstract of DOI:10.1016/j.tetlet.2017.07.015

A substitution reaction of 4-nitrofuroxans to prepare 4-cyanofuroxans is described. This substitution reaction was complicated by the reverse reaction and a judicious choice of cyanide source was important to enable this direct synthesis process. The optimized reaction conditions showed an excellent applicability for the synthesis of a range of 4-cyanofuroxans. 3-Cyanofuroxans, known to be thiol-mediated nitric oxide donors, could also be obtained by the thermal or photochemical isomerization of 4-cyanofuroxans. The developed cyanation of furoxans is a rare example of C–C bond-forming reaction on a furoxan ring.

Full text of DOI:10.1016/j.tetlet.2017.07.015

Accepted Manuscript
Synthesis of cyanofuroxans from 4-nitrofuroxans via C–C bond forming reac-
tions
Ryosuke Matsubara, Akihiro Ando, Masahiko Hayashi
PII:
S0040-4039(17)30851-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.015
TETL 49097
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
2 June 2017
24 June 2017
3 July 2017
Please cite this article as: Matsubara, R., Ando, A., Hayashi, M., Synthesis of cyanofuroxans from 4-nitrofuroxans
via C–C bond forming reactions, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.07.015
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Synthesis of cyanofuroxans from 4-
nitrofuroxans via C–C bond forming
reactions
Ryosuke Matsubara, * Akihiro Ando, Masahiko Hayashi

1
Tetrahedron Letters
journal homepage: www.els evier.com
Synthesis of cyanofuroxans from 4-nitrofuroxans via C–C bond forming reactions
Ryosuke Matsubara, ∗ Akihiro Ando and Masahiko Hayashi
Department of Chemistry, Graduate School of Science, Kobe University, Nada, Kobe, 657-8501, Japan.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A substitution reaction of 4-nitrofuroxans to prepare 4-cyanofuroxans is described. This
substitution reaction was complicated by the reverse reaction and a judicious choice of cyanide
source was important to enable this direct synthesis process. The optimized reaction conditions
showed an excellent applicability for the synthesis of a range of 4-cyanofuroxans. 3-
Cyanofuroxans, known to be thiol-mediated nitric oxide donors, could also be obtained by the
thermal or photochemical isomerization of 4-cyanofuroxans. The developed cyanation of
furoxans is a rare example of C–C bond-forming reaction on a furoxan ring.
Available online
Keywords:
Furoxan
Nitric oxide
Cyanation
Addition reaction
Cyanide
2009 Elsevier Ltd. All rights reserved
.
———
∗ Corresponding author. Tel.: +0-000-000-0000; fax: +0-000-000-0000; e-mail: author@university.edu

2
Tetrahedron
In the last two decades, 1,2,5-oxadiazole-2-oxides (furoxans)
few of these reactions are known so far.11 Herein, the first direct
cyanation of furoxans is reported.
have drawn increased attention due to their unique ability to
release nitric oxide (NO) under physiological conditions through
the mediation of thiol.1 Because NO has a spectrum of biological
We previously reported the synthesis of fluorofuroxans from
the corresponding nitrofuroxans using Bu4NF.12 On the basis of
this knowledge, we set out to investigate the cyanation of
nitrofuroxans with Bu4NCN.13 Soon after the investigation was
commenced, we found that the SNAr reaction of 3-aryl-4-
nitrofuroxan with Bu4NCN proceeded at 0 °C (entry 1, Table 1);
however, several byproducts were formed. The addition of MS
4Å suppressed the formation of the unidentified byproducts, but
primary amide 3 was generated instead (entry 2, Table 1),
probably due to the adventitious contamination by water and
somewhat basic nature of the reaction conditions employed.
activities,
including
immune
response,
vasodilation,
neurotransmission, and inhibition of platelet aggregation,2
a
series of molecules with a furoxan module have been synthesized
and applied as pharmacologically active compounds. The NO-
releasing ability highly depends on the substituent on the furoxan
ring; specifically, the electronegative substituent on the 3-
position of the furoxan ring provides the molecule with the thiol-
mediated NO-releasing ability. In this context, 3-cyanofuroxans
have been intensively investigated as powerful NO donors,
following the pioneering work of Gasco and coworkers.3 3-
Cyanofuroxans are also known to be therapeutic agents against
−78 °C was effective in
Decreasing the reaction temperature to
suppressing the formation of any byproduct and complete
conversion of 1a to 2a was observed by 1H NMR analysis of the
solution before aqueous work-up (entry 3, Table 1).14 However,
after aqueous work-up, a mixture of 1a and 2a (ca. 1:1) was
obtained (entry 4, Table 1).15 We surmised that the reaction of 1a
with Bu4NCN is reversible, and that 1a was regenerated from 2a
and Bu4NNO2 upon addition of water. In order to avoid
detrimental aqueous work-up, concentration of the reaction
mixture under reduced pressure was conducted, but then the
formation of byproduct 3 was observed (entry 5, Table 1). The
direct loading of the reaction mixture onto a silica-gel column led
to the formation of byproducts (data not shown). For removing
the coproduct Bu4NNO2, oxidation and silyl trapping of the
nitrite anion were tried (entries 6–8, Table 1). However, no
beneficial effects were observed. The use of polymer-supported
ammonium cyanide (PSA CN), with the expectation that the
coproduct ammonium nitrite would be removed by filtration
instead of aqueous work-up, resulted in the successful isolation
of pure product 2a (entry 9, Table 1). However, the reaction time
was sacrificed. Eventually a combination of NaCN and a
catalytic amount of Bu4NBr proved to be suitable (entry 10,
Table 1). The reaction was completed in 3 h at room temperature,
and product 2a remained untouched after aqueous work-up. The
use of KCN in lieu of NaCN or the exclusion of Bu4NBr caused a
decrease on the reaction rate (entries 11–13, Table 1).
parasitic
diseases
including
trypanosomiasis4
and
schistosomiasis5, as well as cytotoxic agents.6 Besides, both
regioisomers of cyanofuroxans can be the precursors of new
energetic nitrogen-rich molecules and potential pharmacophores
via azole formation from the cyano group.7
Despite their usefulness, only a limited number of synthesis
methods for cyanofuroxans have been reported so far. Although a
standard procedure for the formation of furoxans involves the
treatment of the corresponding alkenes with N2O3,8 the reaction
of acrylonitrile with N2O3 fails to form the furoxan ring due to the
−C double bond; therefore, the
electron-deficient nature of C
cyano group on the furoxan is generally formed by standard
functional group manipulation after the formation of the furoxan
ring. The two major pathways employed so far are dehydration
reactions from the corresponding oximes and amides using
dehydrating reagents such as thionyl chloride and trifluoroacetic
anhydride.3,5b,9 In both cases, the corresponding precursors need
to be tediously synthesized in several steps. From the viewpoint
of atom economy and step economy, direct cyanation on the
furoxan ring via a C–C bond-forming reaction is preferable.
However, C–C bond-forming reactions on furoxan rings have
often been cumbered by their fragile nature toward nucleophilic
attack, leading to ring-opening decomposition;10 therefore, only
Table 1
Optimization of the reaction conditions for the cyanation of 4-nitrofuroxan 1a
Product Ratio (%)a
e
ntry
reagents
Bu4NCN
te
mp.
ti
(
work-up
2a
3
1a
me
procedure
(°
C)
h)
1
2
(1.3
(1.3
0
1
1
–
–
(74
(79
(
(
(0)
(0)
b
equiv)
)
)
9)
Bu4NCN
equiv)
0
21)
MS 4Åc
3
Bu4NCN
(1.3
−
1
–
(10
(
(0)
equiv)
78
0)
0)
MS 4Åc

3
4
5
6
7
8
9
1
1
Bu4NCN
equiv)
(1.3
(1.3
(1.3
(1.3
(1.3
−
1
1
1
1
1
1
3
2
aqueous work-up
45–
65
0
3
0
0
0
0
0
0
49–
0
78
78
78
78
78
51
55
MS 4Åc
Bu4NCN
equiv)
−
solvent evaporation
5
MS 4Åc
Bu4NCN
equiv)
−
DDQ (1 equiv), 2 h
56
44
4–
then aqueous work-up
MS 4Åc
Bu4NCN
equiv)
−
Oxone (1.5 equiv), 4 h
42–
96d
58d
then aqueous work-up
MS 4Åc
Bu4NCN
−
Me3SiCl (1.5 equiv), 30
min
43–
88d
12–
57d
equiv)
MS 4Åc
PSA CN (2
then aqueous work-up
filtration
26
26
26
100
0
equiv)e
18
MS 4Åc
NaCN (2 equiv)
aqueous work-up
aqueous work-up
100
82
0
0
1
Bu4NBr
equiv)
(0.1
KCN (2 equiv)
Bu4NBr (0.1
equiv)
18
4
1
1
KCN (2 equiv)
26
26
2
2
aqueous work-up
aqueous work-up
11
84
0
0
89
16
2
3
4
4
NaCN (2 equiv)
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The substrate scope was next evaluated using 4-nitrofuroxans
with different types of aryl and alkyl groups at the 3-position.
The results are summarized in Table 2. A range of different
electron-withdrawing and electron-donating substituents on the
aryl group were tolerated (products 2a–h). Sterical hindrance
caused by bis-substitution at the ortho positions did not affect the
reactions (products 2i and 2j). Some heteroaryl variants were also
obtained in good yields (products 2m and 2n). The cyanation
reaction of 3-alkyl 4-nitrofuroxan was low yielding due to the
formation of byproducts (product 2o).
Table 2
Substrate scopea

4
Tetrahedron
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It is known that regioisomers of furoxans isomerize into each
other under thermal and photochemical conditions.16 With a
widely applicable method to prepare 4-cyanofuroxans in hand,
we examined the isomerization of 4-cyanofuroxans to 3-
cyanofuroxans, which are known to be biologically active
compounds. The isomeric ratios at the thermal and
photochemical equilibrium states in an aromatic hydrocarbon
solvent are listed in Table 3. Under both isomerization
conditions, 3-cyanofuroxans 4 were obtained as the major
products. Thus, a straightforward synthesis method for both
regioisomers of cyanofuroxans has been established.
As mentioned in Table 1, the anomalous reverse reaction was
observed in the cyanation of 4-nitrofuroxan using Bu4NCN as
cyanide source. Starting material 4-nitrofuroxan 1a was not
1
observed in the H NMR analysis of the reaction mixture before
aqueous work-up; however, a significant amount of 1a was
obtained after aqueous work-up. To clarify the reaction
mechanism, several probe reactions were conducted. At first,
cyanated product 2a was treated with an equimolar amount of
1
Bu4NNO2 (Figure 1a). H NMR analysis of the reaction mixture
before and after aqueous work-up confirmed that no formation of
1a occurred. Next, crossover experiments were carried out. 4-
Nitrofuroxan 1a was treated with Bu4NCN to form 2a, then 4-
cyanofuroxan 2m was added (Figure 1b). While 1a was not
observed before work-up, 1a was regenerated after aqueous
work-up, however, 1m was not obtained. A similar experiment
was conducted using 1m and 2a instead of 1a and 2m (Figure
1c). As a result, 1m was regenerated after aqueous work-up while
1a was not observed. The lack of formation of crossover products
suggests that the regeneration of the starting 4-nitrofuroxans in
the cyanation reaction using Bu4NCN after aqueous work-up is
not ascribed to the simple reverse reaction of the 4-
cyanofuroxans with Bu4NNO2 coproduct. The use of less than 1
equiv of Bu4NCN resulted in two sets of independent signals
ascribed to 1a and 2a (Figure 1d). This result clearly denies the
rapid equilibrium between 1a and 2a in the NMR sample before
work-up, which would result in the observation of averaged
single species. Although the rationalization for this anomalous
reverse reaction is proposed based on the above results (see
Supplementary Material), further investigation needs to be
conducted to fully unravel the mechanism.
Table 3
Thermal and photochemical isomerization of 4-cyanofuroxans 2a
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5
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4. Boiani, L.; Aguirre, G.; González, M.; Cerecetto, H.; Chidichimo,
In conclusion, this paper demonstrates a direct cyanation
reaction of furoxans, one of the rare examples of a C–C bond
forming reaction on a furoxan ring. Due to the reverse reaction, a
choice of cyanating reagent was important to obtain the 4-
cyanofuroxans in high yield. The regioisomeric 3-cyanofuroxans,
known to have several biological activities, could be readily
generated from 4-cyanofuroxans via thermal or photochemical
isomerization, making the developed method a straightforward
approach for the construction of a library of biologically
applicable candidates based on a furoxan architecture.
A.; Cazzulo, J. J.; Bertinaria, M.; Guglielmo, S. Bioorg. Med.
Chem. 2008, 16, 7900–7907.
5. (a) Rai, G.; Sayed, A. A.; Lea, W. A.; Luecke, H. F.; Chakrapani,
H.; Prast-Nielsen, S.; Jadhav, A.; Leister, W.; Shen, M.; Inglese,
J.; Austin, C. P.; Keefer, L.; Arnér E. S. J.; Simeonov, A.;
Maloney, D. J.; Williams, D. L.; Thomas, C. J. J. Med. Chem.
2009, 52, 6474–6483; (b) Rai, G.; Thomas, C. J.; Leister, W.;
Maloney, D. J. Tetrahedron Lett. 2009, 50, 1710–1713; (c) Sayed,
A. A.; Simeonov, A.; Thomas, C. J.; Inglese, J.; Austin, C. P.;
Williams, D. L. Nature Med. 2008, 14, 407–412; (d) Guglielmo,
S.; Cortese, D.; Vottero, F.; Rolando, B.; Kommer, V. P.;
Williams, D. L.; Fruttero, R.; Gasco, A. Eur. J. Med. Chem. 2014,
84, 135–145.
Acknowledgments
6. (a) Aguirre, G.; Boiani, M.; Cerecetto, H.; Fernández, M.;
González, M.; León, E.; Pintos, C.; Raymondo, S.; Arredondo, C.;
Pacheco, J. P.; Basombrío, M. A. Pharmazie 2006, 61, 54–59; (b)
Boiani, M.; Cerecetto, H.; González, M.; Risso, M.; Olea-Azar,
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Monge-Vega, A. Eur. J. Med. Chem. 2001, 36, 771–782.
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Epishina, M. A.; Ovchinnikov, I. V.; Kachala, V. V.; Makhova, N.
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8. (a) Dinh, N. H.; Ly, N. T.; Hoan, P. V. J. Heterocycl. Chem. 2006,
43, 1657; (b) Gasco, A. M.; Fruttero, R.; Sorba, G.; Gasco, A.
Liebigs Ann. Chem. 1991, 1211; (c) Fruttero, R.; Ferrarotti, B.;
Serafino, A.; Di Stilo, A.; Gasco, A. J. Heterocycl. Chem. 1989,
26, 1345; (d) Matsubara, R.; Saeki, Y.; Li, J.; Eda, K. Synthesis
2013, 45, 1524–1528; (e) Matsubara, R.; Ando, A.; Saeki, Y.;
Eda, K.; Asada, N.; Tsutsumi, T.; Shin, Y.-S.; Hayashi, M. J.
Heterocycl. Chem. 2016, 53, 1094–1105.
We thank Prof. Atsunori Mori and Prof. Kentaro Okano for
their help on mass analysis. This work was financially supported
by JSPS KAKENHI Grant Numbers JP16K18844 and
JP17J00025, Futaba Electronics Memorial Foundation, Suzuken
Memorial Foundation, Inamori Foundation, and Daiichi Sankyo
Foundation of Life Science. A.A. wishes to thank the JSPS for
Research Fellowships for Young Scientists.
References and notes
1. For recent reviews of furoxan, see; (a) Cerecetto, H.; González,
M. Top Heterocycl. Chem. 2007, 10, 265–308; (b) Sheremetev, A.
B.; Makhova, N. N. Adv. Heterocycl. Chem. 2001, 78, 65–188; (c)
Cerecetto, H.; Porcal, W. Mini-Rev. Med. Chem. 2005, 5, 57–71;
(d) Nikonov, G. N.; Bobrov, S. In Comprehensive Heterocyclic
Chemistry III, 2008, 5, 315–395; Paton, R. M. In Science of
Synthesis; Storr, R. C.; Gilchrist, T. L., Eds.; Georg Thieme:
Stuttgart, 2004; Vol. 13, pp185–218.
2. (a) Culotta, E.; Koshland, D. E. Science 1992, 258, 1862–1868;
(b) Carpenter, A. W.; Schoenfisch, M. H. Chem. Soc. Rev. 2012,
41, 3742–3752; (c) McCleverty, J. A. Chem. Rev. 2004, 104, 403–
418; (d) Toledo Jr., J. C.; Augusto, O. Chem. Res. Toxicol. 2012,
25, 975–989.
9. (a) Zhao, J.-Q.; Zhou, M.-Q.; Zuo, J.; Xu, X.-Y.; Zhang, X.-M.;
Yuan, W.-C. Tetrahedron 2015, 71, 1560–1565; (b) Tamboli, Y.;
Lazzarato, L.; Marini, E.; Guglielmo, S.; Novelli, M.; Beffy, P.;
Masiello, P.; Fruttero, R.; Gasco, A. Bioorg. Med. Chem. Lett.
2012, 22, 3810–3815; (c) Fruttero, R.; Ferrarotti, B.; Serafino, A.;
Gasco, A. Liebigs Ann. Chem. 1990, 335–338.
3. Medana, C.; Ermondi, G.; Fruttero, R.; Di Stilo, A.; Ferretti, C.;
Gasco, A. J. Med. Chem. 1994, 37, 4412–4416.

6
Tetrahedron
10. (a) Angeli, A. Gazz. Chim. Ital. 1916, 46, 300; (b) Bigiavi, D.
15. Similar results were obtained even if the reactions were quenched
by NaHCO3 aq., or NH4Cl aq.
Gazz. Chim. Ital. 1921, 51, 324; (c) Ponzio, G.; Longo, G. Gazz.
Chim. Ital. 1930, 60, 893.
11. (a) Gasco, E. D.; Boschi, D.; Lazzarato, L.; Cena, C.; Di Stilo, A.;
Fruttero, R.; Moro, S.; Gasco, A. Chem. Biodivers. 2005, 2, 886;
(b) Matsubara, R.; Eguchi, S.; Ando, A.; Hayashi, M. Org.
Biomol. Chem. 2017, 15, 1965–1969.
16. Gasco, A.; Boulton, A. J. J. Chem. Soc. Perkin 2 1973, 1613–
1617.
Supplementary Material
12. Ando, A.; Matsubara, R.; Takazawa, S.; Shimada, T.; Hayashi, M.
Asian J. Org. Chem. 2016, 5, 886–890.
Supplementary Material (experimental procedures and
spectral data) associated to this article can be found in the online
version, at http://dx.doi.org/xxxxxx.
13. Bu4NCN purchased from Sigma-Aldrich contained Bu4NOiPr
(<5%), which resulted in the formation of 4-isopropoxyfuroxan.
Pure Bu4NCN was synthesized from commercially available
Bu4NOH•30H2O and KCN according to the literature; Dobbs, K.
D.; Marshall, W. J.; Grushin, V. V. J. Am. Chem. Soc. 2007, 129,
30–31.
Click here to remove instruction text...
14. The sample for NMR analysis was prepared by taking an aliquot
out of the reaction followed by direct dilution by CDCl3 (without
evaporation).

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