Dearomatization of oxa- or selenadiazolopyridines with neutral nucleophiles as an efficient approach to pharmacologically relevant nitrogen compounds

Article abstract of DOI:10.1016/j.mencom.2018.11.025

Highly electrophilic 6-nitro-4-azabenzofuroxan and 6-nitro-4-azabenzo[1,2,5]selenadiazole add π-excessive (het)arenes and other neutral nucleophiles at 7-position to give C–C and N–C-bonded adducts, 1,4-dihydropyridines fused with furoxan or selenadiazole ring.

Full text of DOI:10.1016/j.mencom.2018.11.025

Mendeleev
Communications
Mendeleev Commun., 2018, 28, 638–640
Dearomatization of oxa- or selenadiazolopyridines
with neutral nucleophiles as an efficient approach
to pharmacologically relevant nitrogen compounds
Alexey M. Starosotnikov,*a Dmitry V. Shkaev,a Maxim A. Bastrakov,a
Ivan V. Fedyanin,b Svyatoslav A. Sheveleva and Igor L. Dalingera
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. E-mail: alexey41@list.ru
b A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow,
Russian Federation
DOI: 10.1016/j.mencom.2018.11.025
R
EDG
O2N
Highly electrophilic 6-nitro-4-azabenzofuroxan and 6-nitro-
4-azabenzo[1,2,5]selenadiazole add p-excessive (het)arenes
and other neutral nucleophiles at 7-position to give C–C-
and N–C-bonded adducts, 1,4-dihydropyridines fused with
furoxan or selenadiazole ring.
N
N
(O)n
(O)n
(O)n
EDG
O2N
O2N
N
N
X
N
N
X
N
azole
X
MeCN,
20 °C
MeCN (EtOH),
20 °C
N
N
H
N
N
H
X = O, n = 1
X = Se, n = 0
This work continues our ongoing project on synthesis of complex
hybrid compounds combining several pharmacophoric moieties
in the same molecule, interesting from the standpoint of design
of novel pharmaceuticals.1 In particular, approaches to poly-
cyclic furoxan-containing potential nitric oxide donors comprising
heterocyclic pharmacophoric fragments and biologically important
furoxan ring have been elaborated.2 Furoxans are considered as
exogenic NO-donors and therefore extensively studied.3
Recently,4 we have discovered that 6-nitro-4-azabenzofuroxan
1 reacts with CH-acids to afford carbon-bonded 1,4-adducts. In
case of most acidic b-diketones, the reactions can proceed in the
absence of bases, which would emphasize the highly electrophilic
character of compound 1.
In products 3a–c, a new bond was formed between C7 of 1
and C4 of the aniline. The yield of adduct with 2-naphthol was
51%. Anisole, 1,3-dimethoxybenzene and 2,4-dimethyl-6-nitro-
aniline did not give any adduct with substrate 1.
Ar
O
O
O2N
O2N
N
N
7
ArH
6
5
O
O
4
MeCN or EtOH,
~20 °C
N
N
N
N
H
1
3a Ar = 4-H2NC6H4, 56%
3b Ar = 3-Me-4-H2NC6H3, 55%
3c Ar = 4-Me2NC6H4, 76%
3d Ar = 2-hydroxy-1-naphthyl, 51%
Here we report on dearomatization of oxadiazolopyridine 1
with p-excessive (het)arenes. Related 6-nitro-4-azabenzo[1,2,5]
selenadiazole 2 was also examined in reactions with both CH-
acids and p-donor arenes. To the best of our knowledge, the
reactions of fused pyridines with substituted anilines, phenols
and p-donor azoles leading to 1,4-adducts have not been pre-
viously described. The only analogous example of the aniline
adduct formation in reaction with benzonaphthiridine system
was reported.5
We found that oxadiazolopyridine 1 readily reacted with
p-excessive benzenoid compounds. Addition of equimolar amounts
of a certain arene to its solution in MeCN or EtOH resulted in
rapid formation of adducts 3a–d after 15–20 min stirring at room
temperature† (Scheme 1).
Scheme 1
Pyrazole and its derivatives bearing electron-donor groups
afforded 1,4-adducts 4a–c via N–C-bond formation (Scheme 2).†
As expected, in case of N-methylpyrazole, formation of the adduct
n/cm–1): 529, 739, 815, 1204, 1256, 1311, 1341, 1496, 1546, 1600, 3048,
3317. HRMS (ESI), m/z: 230.9425 [C5H2N4O2Se + H]+ (calc., m/z:
230.9416).
Synthesis of compounds 3–5 (general procedure). A nucleophile (1 mmol)
was added to a solution of compound 1 or 2 (1 mmol) in MeCN or EtOH
(10 ml) and the mixture was stirred at room temperature for 30 min (for
adducts with 1) or 2–24 h (for adducts with 2). The precipitated product
was filtered off, washed with the same solvent (5 ml) and dried in air to
give beige or brown solid adduct.
†
6-Nitro-4-azabenzofuroxan 14 and 2,3-diamino-5-nitropyridine6 were
7-(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)-6-nitro-4,7-dihydro[1,2,5]oxa-
diazolo[3,4-b]pyridine 1-oxide 4d: yield 70%, mp 195–196°C (decomp.).
1H NMR (DMSO-d6, 300.13 MHz) d: 2.33 (s, 3H, Me), 2.86 (s, 3H,
Me), 7.30 (s, 1H), 8.84 (s, 1H), 12.54 (br.s, 1H, NH). IR (KBr, n/cm–1):
471, 758, 832, 1006, 1174, 1239, 1312, 1363, 1486, 1568, 1583, 1643,
2848, 2977, 3087. HRMS (ESI), m/z: 346.0493 [C10H9N7O6 + Na]+ (calc.,
m/z: 346.0507).
prepared as previously described.
6-Nitro-4-azabenzo[1,2,5]selenadiazole 2. Selenium dioxide (1.22 g,
11 mmol) was added to a solution of 2,3-diamino-5-nitropyridine (1.7 g,
11 mmol) in EtOH (35 ml) and acetic acid (15 ml). The mixture was
stirred under reflux for 4 h, cooled to room temperature and poured into
water (200 ml). The precipitated product was filtered off and dried in air
to give 1.49 g (59%) of compound 2 as brown solid, mp 123–124°C.
1H NMR (DMSO-d6, 300.13 MHz) d: 9.23 (s, 1H), 9.70 (s, 1H). 13C NMR
(DMSO-d6, 75.47 MHz) d: 127.5, 142.6, 149.1, 150.5, 165.2. IR (KBr,
For characteristics of compounds 3a–d, 4a–c,e,f and 5a–g, see Online
Supplementary Materials.
© 2018 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
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Mendeleev Commun., 2018, 28, 638–640
O(1)
N(3)
N(2)
C(2)
R
X
O(2)
N(6)
C(10)
N
C(7)
O(5)
H(1A)
R
O
N
O
C(3)
C(8)
R
N(1)
N(8)
O(6)
O2N
X
N(5)
C(4)
O2N
N
N
N
MeCN
20 °C
C(9)
C(11)
+
O
N
O
R
C(6)
N
N
N
C(5)
N
H
H
1
4a–f
N(4)
O(3)
O(4)
R
H
X
Yield (%)
a
b
c
d
e
f
CH
30
65
Figure 1 General view of molecule 4d in crystal. Anisotropic displacement
parameters are drawn with 50% probability, only the major component of
the disordered heterocyclic moiety is shown.
Me CH
Me C–CH2CO2H 51
Me C–NO2
H
H
70
43
32
C–CHO
N
compounds 4d,e with electron-withdrawing groups in pyrazole
moieties.
Scheme 2
The structure of product 4d was confirmed by single-crystal
X-ray diffraction (Figure 1).‡ In crystal, the pyridofuroxan fragment
is disordered by two positions due to its pseudo symmetric
geometry (Figure S1, see Online Supplementary Materials). The
refined bond lengths and angles are typical of the corresponding
fragments.
did not occur. When unsubstituted imidazole was used, a complex
mixture was formed, while 4-nitroimidazole, benzimidazole and
benzotriazole were inert towards compound 1.
Pyrazoles with electron-withdrawing substituents readily
added to oxadiazolopyridine 1 with formation of products 4d,e
(see Scheme 2) which precipitated from the reaction mixture.
However, their 1H NMR spectra in DMSO-d6 contained two sets of
signals attributed to the expected adduct and the starting reactants.
Similar phenomenon was observed in case of [1,2,4]triazole
adduct 4f. It seems likely that this was a result of reversibility of
the transformations in DMSO-d6 solution. Compound 4f is poorly
soluble in all common solvents used for NMR spectroscopy,
therefore we were unable to record spectra in aprotic low-polar
solvents. In DMSO solution, the adduct/reactants ratio was about
60:40. Interestingly that 1H NMR spectrum recorded in CF3COOD
contained signals of only compound 1 (d 8.75 and 9.38 ppm)
and [1,2,4]triazole (8.99 ppm) indicating complete decay of the
adduct into the starting compounds. Apparently, polar solvents
favor reverse reaction characteristic of re-aromatization of the
pyridine ring. We believe that the same situation arises in case of
New 6-nitro-4-azabenzo[1,2,5]selenadiazole 2 was synthesized
from 2,3-diamino-5-nitropyridine6 (Scheme 3).† This compound
readily added various nucleophiles at its pyridine moiety even in
1
the absence of bases, which afforded products 5a–f. H NMR
spectrum of adduct 5a contains one set of signals which was
attributed to the enol form. On the contrary, products 5b and 5c
existed in DMSO-d6 solution mainly in dioxo form. Adduct 5d
was formed upon treatment of compound 2 with equimolar amount
of malononitrile in EtOH/H2O mixture. 3,5-Dimethylpyrazole
gave adduct 5g in 62% yield, however this reaction was found to
be reversible analogously to reactions of oxadiazolopyridine 1
with low-nucleophilic pyrazoles (see above).
O2N
NH2
NH2
O2N
N
SeO2, EtOH
AcOH,
Se
N
N
N
2, 59%
Nu
‡
Crystal data for 4d. X-ray diffraction data were collected on a Bruker
O2N
N
N
APEX DUO diffractometer [l(MoKa) = 0.71073 Å, w-scans, 2q < 60.00°].
Yellow crystals of C10H9N7O6 at 120(2) K are monoclinic, space group
P21/n, a = 13.2684(8), b = 7.2207(5) and c = 13.7670(9) Å, b =
= 100.0790(10)°, V = 1298.62(15) Å3, Z = 4 (Z' = 1), dcalc = 1.653 g cm–3.
Intensities of 3783 independent reflections (Rint = 0.0407) out of 14844
collected were used in structure solution and refinement. The structure was
solved by direct methods with SHELXT program13 and refined by the
full-matrix least-squares technique against F2 in the anisotropic approxi-
mation. The analysis of Fourier maps revealed the disorder of pseudo-
symmetric pyridofuroxan heterocyclic fragment by two positions, so
that the nitro substituent of one component is superimposed by O–N–O
fragment of the furoxan moiety of the second component; the super-
imposed fragments are apparently inverted, so the position of the saturated
C(4) atom is almost the same on both components. The relative occupancy
of the disordered positions was refined to be 0.76:0.24; the only restraints
applied were restrictions on the anisotropic displacement parameters of
the atoms of the minor component [EADP for C(4) and C(4') atoms and
ISOR for all other atoms]. Hydrogen atoms connected to nitrogen atoms
were found from difference Fourier synthesis and refined isotropically.
All other H atoms were placed in calculated positions and refined in
the riding model with Uiso(H) equal to 1.5Ueq(C) and 1.2Ueq(C) of the
connected methyl and other carbon atoms. The refinement converged to
R1 = 0.0411 [calculated for 2810 observed reflections with I > 2s(I)],
wR2 = 0.0928 and GOF = 1.029. The refinement was performed with
SHELX software package.14
NuH
Se
MeCN or EtOH,
20 °C
N
H
5a–g
Nu
Yield (%)
Nu
Yield (%)
95
O
[MeC(O)]2CH
(NC)CH
c
d
e
f
Me
Me
a
73
75
45
45
77
4-Me2NC6H4
OH
O
Me
5-methoxy-
3-indolyl
N
N
O
b
g
3,5-dimethyl- 62
pyrazol-1-yl
Me
O
Scheme 3
The new selenadiazole derivatives can be of special interest
due to their potent biological properties since compounds of this
class possess antibacterial, fungicidal and antioxidant activities7,8
as well as high citotoxicity,7 and are able to inhibit multiplication
and to stimulate apoptosis of various types of cancer cells.8,9
Antitumor activity of some [1,2,5]selenadiazoles exceeds that of
standard medicinal preparations thus allowing one to consider them
as potential cancer therapy agents.9 In addition to substituents
CCDC 1837203 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via http://www.ccdc.cam.ac.uk.
– 639 –

Mendeleev Commun., 2018, 28, 638–640
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1,4-dihydropyridines.
In conclusion, reactions of 6-nitro-4-azabenzofuroxan and
6-nitro-4-azabenzoselenadiazole with p-excessive (het)arenes
brought about C–C- and N–C-bonded 1,4-adducts, namely,
1,4-dihydropyridines fused with furoxan or selenadiazole ring.
The resulting compounds combine pharmacologically important
fragments in one molecule and therefore can be considered as
prospective platforms for the design of pharmacology-oriented
heterocyclic systems.
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This work was supported by the Russian Science Foundation
(grant no. 14-50-00126).
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Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2018.11.025.
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Received: 15th June 2018; Com. 18/5611
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