Straightforward Access to the Nitric Oxide Donor Azasydnone Scaffold by Cascade Reactions of Amines

Article abstract of DOI:10.1002/chem.201903526

A novel one-pot cascade method for the assembly of valuable NO-donor azasydnone scaffold has been developed. The construction strategy involves a diazotization/azo coupling/elimination/double rearrangement cascade sequence of readily available amines. The

Full text of DOI:10.1002/chem.201903526

DOI: 10.1002/chem.201903526
Communication
&
Nitrogen Heterocycles
Straightforward Access to the Nitric Oxide Donor Azasydnone
Scaffold by Cascade Reactions of Amines
Egor S. Zhilin,[a] Dmitry M. Bystrov,[a] Ivan V. Ananyev,[b] Leonid L. Fershtat,*[a] and
Nina N. Makhova[a]
olates) are considered as promising NO-donor prodrugs which
Abstract: A novel one-pot cascade method for the assem-
bly of valuable NO-donor azasydnone scaffold has been
release NO under physiological conditions and do not cause
tolerance upon continuous exposure. Several azasydnones
developed. The construction strategy involves a diazotiza-
were found to possess antihypertensive[7] and antiaggregant[8]
tion/azo coupling/elimination/double rearrangement cas-
properties. Furthermore, recently, the azasydnone scaffold was
cade sequence of readily available amines. The current
revealed as a powerful explosive which was successfully incor-
protocol enables the generation of a diverse array of aza-
porated in a structure of environmentally benign high-energy
sydnones, including previously hardly accessible heteroar-
materials.[9] Although mesoionic heterocyclic systems are ex-
yl substituted azasydnones (25 examples, 70–97% yield)
tensively studied in a last decade as promising candidates for
with a good functional group tolerance under very mild
drug development[10] or in bioorthogonal click-and-release
conditions. Preliminary NO-releasing studies revealed an
methodology,[11] 1,2,3,4-oxatriazolium-5-olates remain rather
ability of azasydnones to produce NO in a wide range of
neglected. Arguably, inefficient and multi-step procedures for
concentrations. This method provides a new approach to
the construction of the mesoionic azasydnone motif bring seri-
nitrogen-oxygen heterocycles with potential applications
ous limitations on the extensive study of functional properties
in medicine and material science.
of these compounds.
In a series of nitrogenÀoxygen heterocyclic systems, 1,2,5-
oxadiazoles (furazans) and their N-oxides (furoxans) became
Nitrogen heterocycles correspond to the most frequently oc-
curring structural motifs in various pharmaceuticals.[1] Recent
analysis of a database of U.S. FDA approved drugs revealed
that 59% of clinically used small-molecule pharmaceuticals in-
corporate a nitrogen heterocycle subunit.[2] However, the con-
struction of individual pharmaceutical scaffolds using known
synthetic methodologies often involves multi-step and energy-
consuming procedures or suffers from a lack of reproducibility
and scalability. Therefore, a creation of novel step-economy
protocols for the assembly of various nitrogen-containing het-
erocyclic scaffolds remains highly important.[3]
emergent pharmacologically oriented scaffolds, which proved
to be stable under ambient conditions.[12] In addition, furoxans
exhibit NO-releasing properties and have a wide range of bio-
logical activities.[13–16] Moreover, furazans and furoxans are
useful building blocks in the construction of numerous eco-
friendly high-energy density materials.[17] In this regard, 1,2,5-
oxadiazole-azasydnone hybrids may represent a huge potential
both as energetic materials and pharmacologically active NO-
donor prodrugs. Therefore, we intended to develop an easy
synthetic methodology to access 1,2,5-oxadiazole-azasydnone
di-heteroaryl derivatives.
One of the important subclasses of heterocyclic
pharmaceutical ingredients are nitric oxide donors (NO
donors).[4] NO is a crucial gaseous signaling molecule which
mediates various physiological processes and may be useful
for cancer treatment.[5] Various classes of nitrogenÀoxygen or-
ganic systems are known for their ability to release NO.[6]
Among them, mesoionic azasydnones (1,2,3,4-oxatriazolium-5-
Azasydnones correspond to the rare heterocyclic mesoionic
motifs so far: A comprehensive search through Reaxys and Sci-
Finder databases revealed less than 50 synthesized compounds
incorporating azasydnone subunit. One of the methods for the
synthesis of azasydnones includes a nitrosation of monosubsti-
tuted semicarbazides with subsequent thermally-induced cycli-
zation (Scheme 1a).[18] Unfortunately, this approach involves
the utilization of pre-functionalized substrates and suffers from
a lack of functional group tolerance, which results in a narrow
scope of synthesized azasydnones. Azo coupling of arenedi-
azonium salts with bromonitromethane,[9a,11a,19] trinitro-
methane[20] or diazomethanedisulfonate[21] followed by elimina-
tion/rearrangement sequence also affords target azasydnones
(Scheme 1b). The main drawbacks of this method include a
necessary isolation of hazardous intermediates and a utilization
of pre-functionalized substrates. Also, only stable arenediazoni-
um salts can be introduced in this reaction. In this sense, a
direct one-pot protocol for the assembly of azasydnone scaf-
[a] E. S. Zhilin, D. M. Bystrov, Dr. L. L. Fershtat, Prof. Dr. N. N. Makhova
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences
Leninsky Prospect 47, 119991 Moscow (Russia)
E-mail: fershtat@bk.ru
Homepage: https://nc-lab.ru/
[b] Dr. I. V. Ananyev
A. N. Nesmeyanov Institute of Organoelement Compounds
Russian Academy of Sciences, Vavilova str. 28, 119991 Moscow (Russia)
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/chem.201903526.
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Table 1. Optimization of the reaction conditions.[a]
Entry Diazotization Solvent
reagent
Nitro
Additive
Yield
[%][b]
compound (equiv)
1
2
3
4
NaNO2
NaNO2
NaNO2
NaNO2
H2SO4-
H3PO4
H2SO4-
H3PO4
H2SO4-
H3PO4
H2SO4-
H3PO4
[bmim]BF4
MeCN
TFA
KC(NO2)3
HC(NO2)3
–
16
[c]
Py (8.6)
–
[c]
NaCH(NO2)2 NH4NO3
(2.0)
CH2BrNO2
–
[d]
NH4NO3
(2.0)
–
–
–
–
BF3·Et2O
(0.5)
ZnCl2 (0.25) 86[f]
–
[c]
5
6
7
8
9
tBuONO
NOBF4
NOBF4
NOBF4
NOBF4
KC(NO2)3
KC(NO2)3
KC(NO2)3
KC(NO2)3
KC(NO2)3
–
33
72[e]
81[f]
75[f]
TFA
TFA
10
NOBF4
TFA
KC(NO2)3
[a] Reaction conditions: 1a (1 mmol), diazotization reagent (1 mmol), sol-
vent (2 mL), 08C, 1 h, then nitro compound (2 mmol), 208C, 10 min, then
additive, 12 h, 208C. [b] Isolated yields. [c] Trace amounts of azasydnone
2a were detected by TLC. [d] Decomposition of starting material was ob-
served. [e] AcOH (2 mL) was added after an azo coupling. [f] AcOH (1 mL)
and HCOOH (1 mL) were added after an azo coupling. See more reaction
conditions in Table S1.
system (entries 7–10). Further solvent and Lewis acid screening
(see Table S1 in the Supporting Information) indicated that an
addition of AcOH and HCOOH was required to increase the
yield of azasydnone 2a, while ZnCl2 (0.25 equiv) was the best
catalyst of choice (entry 10).
To demonstrate the efficiency and generality of this ZnCl2-
mediated cascade reaction, we investigated the transformation
of various aminofuroxans under the same conditions
(Scheme 2). An incorporation of electron-donor alkyl and
alkoxy groups at the benzene ring had no effect on the reac-
tion outcome and azasydnones 2b,c were obtained in high
yields. Various aryl-substituted aminofuroxans bearing a halo-
gen atom (fluoro, chloro, bromo) located ortho, meta or para
to the furoxan moiety were also compatible with our condi-
tions, as exemplified by the formation of azasydnones 2d–h
with excellent yields. To our delight, the reaction of aminofur-
oxan 1i incorporating a strong electron-withdrawing CF3-
group at the para-position of the benzene ring proceeded
smoothly with an excellent yield of target azasydnone 2i. The
protocol was also suitable for the aminofuroxans bearing dif-
ferent cyclic and acyclic aliphatic substituents, as was demon-
strated by the formation of azasydnones 2j–l in 70–95%
yields. Ester and amide functionalities well tolerated the reac-
tion conditions and target azasydnones 2m–o were obtained
in good and high yields.
Scheme 1. Synthesis of azasydnones.
fold would be highly desirable considering the functional
group tolerance, utilization of readily available compounds, as
well as enabling an incorporation of 1,2,5-oxadiazole motif to
the azasydnone backbone. Herein, we disclose a straightfor-
ward approach to azasydnones based on the diazotization/azo
coupling/elimination/double rearrangement cascade reactions
of amines (Scheme 1c).
Recently, amino-1,2,5-oxadiazoles became a readily accessi-
ble class of organic substrates.[22] Therefore, our investigations
towards the cascade process began by using aminofuroxan 1a
as a model substrate. Various diazotization reagents, solvents,
nitro compounds as azo coupling partners and additives were
varied (Table 1). Diazotization of a substrate 1a with NaNO2 in
acidic media followed by an azo coupling with KC(NO2)3 afford-
ed target azasydnone 2a in a low yield (entry 1), while other
substituted nitromethanes were ineffective (entries 2–4). Uti-
lization of tBuONO for diazotization was unsuccessful due to
the very low nucleophilicity of the amino group in compound
1a (entry 5).[23] NOBF4 in TFA was a more effective diazotization
Subsequently, we surveyed the scope of this transformation
by replacing the furoxan motif with a furazan one and the re-
sults are summarized in Scheme 3. It was found, that for ami-
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of arylazasydnones (Scheme 4). In particular, 4-fluoro- and 4-
chloroanilines 5a,b successfully underwent the cascade pro-
cess and afforded azasydnones 6a,b in synthetically useful
yields. It should be noted, that 3-(4-chlorophenyl)azasydnone
was previously used as a mesoionic precursor in bioorthogonal
Scheme 4. Synthesis of arylazasydnones and gram-scale experiment.
reactions.[11a] Our approach enabled the synthesis of this useful
compound in a higher yield and in milder conditions. However,
unsubstituted aniline and p-toluidine did not provide corre-
sponding azasydnones arguably due to the absence of elec-
tron-withdrawing substituents. We also performed the reaction
with aminofuroxan 1a on a gram scale under the standard re-
action conditions. To our delight, our protocol showed good
scalability and the target azasydnone 2a was prepared in a
high yield (Scheme 4).
Scheme 2. Substrate scope for the synthesis of furoxanylazasydnones.
All compounds were fully characterized by IR and multinu-
clear (1H, 13C, 14N, 15N) NMR spectroscopy as well as high-reso-
lution mass spectrometry. The structures of azasydnones 2a,j,l
were further confirmed by X-ray diffraction study (Figure 1).
The distribution of bond lengths of heterocycles is similar with
previously reported structures.[9,12,17,23] To gain a deeper insight
into the conjugation between furoxan and azasydnone rings
some DFT calculations were performed with the Gaussian09
software package.[24] According to the geometry optimization
of isolated molecules (see Figure S1–S3 in the Supporting In-
formation for more details), the nearly planar structure of 2j
molecule (the N5N3C2N2 torsion angle is 8.5(2)8 in crystal) is
only slightly affected by crystal packing effects: the r.m.s. devi-
Scheme 3. Substrate scope for the synthesis of furazanylazasydnones.
nofurazans 3 the reaction temperature should be raised up to
358C on the final step of the cascade process to achieve the
full conversion of intermediate products. Under these condi-
tions, all investigated aminofurazans 3a–f bearing different ar-
omatic substituents underwent the target transformation with
excellent yields of furazanylazasydnones 4a–f. Importantly,
aminofurazan 3g incorporating a reactive propargyloxy moiety
also reacted smoothly to produce azasydnone 4g, further illus-
trating the applicability of the current method.
Figure 1. Structures of 2a (upper left), 2j (bottom) and 2l (upper right) mol-
ecules in crystals (probability ellipsoids for non-hydrogen atoms at p=0.5
level).
To further demonstrate the synthetic utility of the developed
protocol, we extended this transformation to several examples
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ation between crystal and isolated structures is 0.08 ꢁ. Note,
that mentioned torsion angle is larger in the isolated state
(18.08) that implies smaller p-conjugation between the furoxan
and azasydnone cycles. The 2a and 2l structures are pro-
nouncedly less rigid (r.m.s. deviations are 0.30 and 0.15 ꢁ, re-
spectively): again, the furoxan–azasydnone conjugation is
more favorable in crystals while the rotations of hydrocarbon
substituents can be simply rationalized by intermolecular
CH···O interactions in 2l and by CH···O and phenyl–heterocycle
stacking interactions in 2a.
To elucidate the reaction mechanism, several control experi-
ments were performed. Recently, we have shown that amino-
1,2,5-oxadiazoles undergo mild diazotization upon treatment
with NOBF4 in TFA affording corresponding diazonium salts in
nearly quantitative yields.[23] We synthesized diazonium tetra-
fluoroborate 7a and, to our delight, its azo coupling with
KC(NO2)3 followed by ZnCl2-promoted rearrangement/cycliza-
tion sequence afforded azasydnone 2a in a good yield
(Scheme 5). Thus, it may be concluded that diazonium salt 7a
fords azo compound B. Intermediate B is rather unstable and
undergoes fast elimination of NO2+. This process is similar to a
known solvolytic dissociation of tetranitromethane.[25] Further
À
elimination of NO2 generates nitrilimine C. A nitrilimine nitro-
gen atom and a nitro group oxygen atom coordinate with a
Lewis acid (ZnCl2 or H+) forming chelate D. Higher yields upon
using ZnCl2 may be attributed to a more effective chelation of
both heteroatoms with ZnCl2 which has been described else-
where.[26] Such chelation promotes the subsequent nitro–nitrite
rearrangement which is known to proceed for nitro groups lo-
cated on the carbenium center.[27] It is also well established,
that such rearrangement is facilitated by electron-withdrawing
groups linked to the carbenium ion.[28] In our case, we ob-
served a similar correlation since azasydnones bearing strong
electron-withdrawing substituents (e.g., a furoxan ring) were
produced at room temperature, while those bearing aryl moi-
eties were formed at elevated temperatures. Finally, an intra-
molecular nitroso group transfer in nitrite E followed by cycli-
zation of an intermediate F furnishes final azasydnone scaffold.
Since both furoxan and azasydnone motifs are known to
possess NO-donor properties, we investigated an ability to re-
lease NO for the synthesized bi-heteroaryl compounds
(Figure 2). A well-known NO-donor compound 3-carbamoyl-4-
Scheme 5. Control experiments: a) Isolation of an intermediate and b) 15N la-
beling study.
is an intermediate in the cascade process for the formation of
an azasydnone motif. Furthermore, we explored the origin of
the N4 atom of the azasydnone ring by employing Na15NO2 for
the diazotization step. 15N-Labeled azasydnone 2p was synthe-
sized in a good yield (similar to entry 26 in Table S1) and, ac-
cording to NMR, no other 15N-labeled azasydnone was formed
(see the Supporting Information for details). This fact clearly
shows, that a terminal nitrogen atom of a diazonium function-
ality in the intermediate 7b becomes an N4 atom of the aza-
sydnone motif.
Based on the existing literature[19,23] and relying on the reac-
tion scope and control experiments, we proposed a plausible
mechanism for this cascade one-pot process (Scheme 6). Di-
azotization of initial amine with NOBF4 generates a diazonium
tetrafluoroborate A which upon azo coupling with KC(NO2)3 af-
Figure 2. NO release data.
(hydroxymethyl)furoxan (CAS-1609)[12a,13b,29] was used as a ref-
erence. The formation of nitrite-anion as a result of NO oxida-
tion may be quantified according to Griess assay and thus may
serve as a reliable tool for measuring the amount of NO re-
À
lease. The amounts of NO2 produced of the synthesized aza-
sydnones under physiological conditions (pH 7.4; 378C) after
1 h incubation were measured via the Griess reaction using a
spectrophotometric technique. According to the Griess test re-
sults, it was found that furoxanylazasydnones 2a–i bearing ar-
omatic substituents released high fluxes of NO (39–94%) while
those incorporating aliphatic substituents 2j–l released lower
amounts of NO (29–37%) on the same level as CAS-1609. Im-
portantly, furoxanylazasydnones 2m–o possessing additional
functional groups demonstrated the highest NO-donor ability
(163–195%). Since either furoxan or azasydnone scaffolds may
release only one stoichiometric equivalent of NO, these data
indicate that compounds 2m–o undergo both furoxan and
Scheme 6. Plausible reaction mechanism.
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laou, C. R. H. Hale, C. Nilewski, H. A. Ioannidou, Chem. Soc. Rev. 2012, 41,
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azasydnone ring cleavage with a subsequent NO release. For
comparison, corresponding furazanylazasydnones 4a–g
showed moderate NO-donor ability (17–48%) which is compat-
ible with a fact that a furazan subunit is not able to release
NO. It should also be pointed out, that furoxanyl- and furaza-
nylazasydnones are stable under ambient conditions, soluble
in various organic solvents (CHCl3, THF, MeCN, DMF, DMSO),
slightly soluble in water and do not decompose upon pro-
longed storage (neat or as solutions in CHCl3 or DMSO). Over-
all, synthesized azasydnones have good physicochemical prop-
erties and release NO in a wide range of concentrations which
is useful for various biomedical insights.[4,12,15]
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In summary, we have developed a straightforward one-pot
approach to the construction of azasydnone scaffold based on
cascade reactions of amines. A wide array of azasydnones were
produced with very good functional group tolerance (25 exam-
ples, up to 97% yield). It is especially important, that this syn-
thetic protocol affords 1,2,5-oxadiazole-substituted azasydnone
derivatives in good and high yields and may be realized on a
gram scale. In addition, synthesized azasydnones demonstrat-
ed good NO-donor profiles releasing NO in a wide range of
concentrations. Therefore, a combination of the facile synthesis
and NO-donor ability of azasydnones has application potential
for materials and pharmaceuticals.
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Acknowledgements
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This work was supported by the Russian Foundation for Basic
Research (grant #18-33-20030). I.V.A. is grateful to the Russian
Science Foundation (project #18-73-10131) for the financial
support of X-ray diffraction studies.
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Conflict of interest
The authors declare no conflict of interest.
Keywords: azasydnone · cascade reactions · homogeneous
catalysis · nitrogen heterocycles · NO-donors
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Manuscript received: August 2, 2019
Accepted manuscript online: September 11, 2019
Version of record online: && &&, 0000
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ÝÝ These are not the final page numbers!

Communication
COMMUNICATION
&
Nitrogen Heterocycles
E. S. Zhilin, D. M. Bystrov, I. V. Ananyev,
L. L. Fershtat,* N. N. Makhova
&& – &&
Straightforward Access to the Nitric
Oxide Donor Azasydnone Scaffold by
Cascade Reactions of Amines
Five heteroatoms—one ring: An opera-
tionally simple one-pot approach to the
assembly of the rare mesoionic azasyd-
none framework has been established.
This method has a broad substrate
bi-heteroaryl derivatives in high yields.
The heterocycles correspond to a prom-
ising rediscovered class of organic NO-
donor compounds with application po-
tential in materials and medicine.
scope and enables the preparation of
Chem. Eur. J. 2019, 25, 1 – 7
www.chemeurj.org
7
ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ