Isoxazolo[4,3-e]indazole as a new heterocyclic system: Design, synthesis, spectroscopic characterization, and antibacterial activity

Article abstract of DOI:10.1007/s10593-016-1833-7

The new heterocyclic system isoxazolo[4,3-e]indazole was synthesized via the nucleophilic substitution of a hydrogen in 1-methyl-5-nitro-1H-indazole with different aryl acetonitriles in basic medium. The fluorescence properties and antibacterial activitie

Full text of DOI:10.1007/s10593-016-1833-7

DOI 10.1007/s10593-016-1833-7
Chemistry of Heterocyclic Compounds 2016, 52(1), 52–57
Isoxazolo[4,3-e]indazole as a new heterocyclic system: design, synthesis,
spectroscopic characterization, and antibacterial activity
Masoumeh Ghaemi1, Mehdi Pordel1*
1
Department of Chemistry, Mashhad Branch, Islamic Azad University,
Mashhad, Iran; e-mail: mehdipordel58@mshdiau.ac.ir
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2016, 52(1), 52–57
Submitted December 10, 2015
Accepted after revision January 25, 2016
Cl
N
NO2
O
N
O
N
N
N
N
Me
Me
Antibacterial
Fluorescent
The new heterocyclic system isoxazolo[4,3-e]indazole was synthesized via the nucleophilic substitution of a hydrogen in 1-methyl-
5-nitro-1H-indazole with different aryl acetonitriles in basic medium. The fluorescence properties and antibacterial activities of the new
compounds against Gram-positive and Gram-negative bacterial species were also studied.
Keywords: indazole, isoxazole, antibacterial activity, emission and absorption spectra, fluorescence.
Heterocycles constitute the largest group of organic
compounds and are becoming ever more significant in all
aspects of pure and applied chemistry. Many natural pro-
ducts, such as hormones, vitamins, alkaloids, antibiotics, as
well as pharmaceuticals, herbicides, dyes, and other
products of technical importance (corrosion inhibitors,
sensitizers, stabilizing agents, etc.) include heterocycles in
their structure. Among numerous heterocycles, isoxazoles
are an important class of heterocyclic pharmaceuticals and
bioactive natural products because of their broad spectrum
of biological activities, including potent and selective
antagonism of the NMDA receptor1 and antiHIV activity.2
On the other hand, indazole derivatives exhibit inte-
resting biological properties, such as antidepressant,3 anti-
inflammatory,4,5 analgesic and antipyretic,6 antidopaminer-
gic,7 antitumor,8 anti-emetic,9 and antiHIV activities.10 In
addition, indazole ring system is present in many other
compounds, such as herbicides, dyes or sweeteners, as
guanidine-1H-indazole.11–13 Recently, indazole scaffold has
become of interest as parent structure of dyes14 and
fluorescent substances.15–18 A combination of the indazole
moiety with the isoxazole nucleus may provide compounds
with interesting optical and biological properties.
pounds,15–18,22,23 we have synthesized a new heterocyclic
system isoxazolo[4,3-e]indazole via the nucleophilic
substitution of hydrogen24 in 1-methyl-5-nitro-1H-indazole
with various aryl acetonitriles in basic medium with the
purpose to study spectral and fluorescence properties.
Antibacterial activity of the obtained compounds against
Gram-positive and Gram-negative bacterial species has
been also studied.
Synthesis and structure of isoxazolo[4,3-e]indazoles.
Previously, we attempted to obtain isoxazolo[4,3-e]-
indazoles from the reaction of 1-alkyl-5-nitro-1H-indazoles
125 with aryl acetonitriles 2 under different conditions. As
we have reported, such reaction led to the formation of
uncyclized green dyes 2-(1-alkyl-5-hydroxyimino-1,5-dihydro-
4H-indazolylidene)-2-arylacetonitriles 314 and fluorescent
pyrazolo[4,3-a]acridines 416–18 under reflux and room
temperature conditions, respectively (Scheme 1).
In the current work, we found out that the best method
for the synthesis of isoxazolo[4,3-e]indazoles 5a–e, pro-
ducing 45–65% yields, was the reaction of 1-methyl-5-nitro-
1H-indazole 1 (R1 = Me) with different aryl acetonitriles 2
in saturated KOH solution in MeOH at reflux for 48 h
(Scheme 1). As by-products, pyrazolo[4,3-a]acridines 4a–e
were obtained in 9–17% yields. The work-up procedure
and isolation of compounds 5a–e and 4a–e, which turned
out to be very simple, were performed by filtration of the
Taking into consideration the available literature data
and in continuation of our studies on the synthesis of new
biologically active19–21 and fluorescent heterocyclic com-
0009-3122/16/5201-0052©2016 Springer Science+Business Media New York
52

Chemistry of Heterocyclic Compounds 2016, 52(1), 52–57
Scheme 1
precipitated product after the neutralization of the reaction
mixture with dilute HCl solution and washing the crude
precipitate with cold acetone. Compounds 5a–e are quite
soluble in acetone, and the removal of the solvent from the
filtrate and then recrystallization from MeOH give pure
products 5a–e while pyrazolo[4,3-a]acridines 4a–e are
nearly insoluble in cold acetone and remain in the
precipitate.
A proposed mechanism to explain the formation of com-
pounds 5a–e and 4a–e is shown in Scheme 2.26 The
different result with respect to the previously reported14,16–18 is
likely caused by the different conditions (refluxing the
reaction mixture in combination with the high concen-
tration of KOH), which leads to the preferential trans-
formation of intermediate A into anion B, the precursor to
isoxazolo[4,3-e]indazoles 5a–e as the major products. The
pathway from intermediate A through compound 3 is
disfavored and results in formation of pyrazolo[4,3-a]-
acridines 4a–e as the minor products (yields 9–17%)
(Scheme 2).
When R is an electron-withdrawing group such as NO2
group, the yield of the reaction is very low because the
corresponding conjugated base is a weak nucleophile.
However, the nitration of compound 5a with a mixture of
sulfuric acid and potassium nitrate led to the formation of
compound 5f by the introduction of nitro group at the para
position of the phenyl ring (Scheme 3).
Scheme 3
NO2
O
N
KNO3, H2SO4
O
N
rt, 1 h
84%
N
N
N
Me
N
Me
5a
5f
Structural assignments of the new compounds 5a–f were
based on their spectral and microanalytical data. For
1
example, in the aromatic region of the H NMR spectrum
Scheme 2
53

Chemistry of Heterocyclic Compounds 2016, 52(1), 52–57
Figure 1. The expanded 1H NMR spectrum of compound 5d in downfield region.
of compound 5d, there are two signals of an AA'BB'
fluorescence quantum yield of compound 5f was deter-
mined via comparison methods, using fluorescein as a
standard sample in 0.1 M NaOH and MeOH solution.27 The
used value of the fluorescein emission quantum yield is
0.79, and the obtained emission quantum yield of the
compound 5f is 0.29.
The absorption band of compound 5f with λabs 405–430 nm
in different solvents can be attributed to π–π* transition
from the electron-donating (N-6 atom) to electron-
accepting groups (nitro group). The fluorescence emission
of the new compound 5f can be explained in terms of the
extended conjugation pathway.15–18 Comparing the resonance
structures of compounds 5a–e and 5f demonstrates that
π-electron delocalization in compound 5f can occur much more
easily than in compounds 5a–e.
Antibacterial studies of compounds 5a–f. The antibac-
terial activity of compounds 5a–f was tested against two
standard strains of Gram-positive (Staphylococcus aureus
ATCC 29213 and Bacillus subtilis ATCC 6633) and two
strains of Gram-negative bacteria (Escherichia coli ATCC
10538 and Salmonella typhimurium ATCC 14028) species
(Table 2), using the broth microdilution method as pre-
system at 8.01 and 7.62 ppm attributed to four aromatic
protons of the 4-chlorophenyl ring and two doublet signals
at 7.56 and 7.50 ppm assigned to two aromatic protons in
the C-4 and C-5 positions, as well as a singlet signal at
8.20 ppm linked to the proton of the pyrazole ring (Fig. 1).
The 1H NMR spectra of the corresponding open-chain
compounds 3 are markedly different (Supplementary infor-
mation Fig. S1 and S2). Also there are 13 different carbon
atom signals in the 13C NMR spectrum of compound 5d.
All this evidence taken in conjunction with molecular ion
peak at m/z 283 [M(35Cl)]+ supports the tricyclic structure
of compound 5d. The products 4a–e were characterized by
comparison of their spectroscopic and physical data with
those of samples synthesized by the procedure given in the
literature16–18 (Supplementary information).
Photophysical properties of compounds 5a–f. Com-
pounds 5a–f were spectrally characterized by UV-Vis and
fluorescence spectroscopy in the wavelength range of 200–
1000 nm. The emission spectra of compounds 5a–e did not
show any fluorescence emission peak even at high
concentrations while compound 5f produced fluorescence
at concentration 1×10–4 mol/l in chloroform allowing to
investigate its solvatochromic properties in different
solvents (Table 1, Fig. 2). The fluorescence absorption and
emission bands of compound 5f undergo a bathochromic
shift with increasing polarity of solvent. Increasing the
solvent polarity stabilizes the excited state of the molecule
relative to the ground state causing the experimentally
observed red shift of the absorption maximum (Table 1).
For example, in the absorption and emission spectra of
compound 5f, the maxima of the absorption (λabs) and
emission (λflu) spectra shift from 405 to 430 nm and 455 to
560 nm, respectively, as the solvent changes from cyclo-
hexane to MeOH (Table 1).
Table 1. Spectroscopic data for compound 5f
at 298 K in different solvents*
Solvent
MeOH
λabs, nm
430
ε × 10–3, mol × l–1 × cm–1
λflu, nm
560
8.7
8.4
7.3
6.0
6.4
5.0
DMF
425
550
MeCN
420
545
Chloroform
1,4-Dioxane
Cyclohexane
420
505
415
495
405
455
The values of extinction coefficient (ε) were calculated
as the slope of the plot of absorbance vs concentration. The
* λabs – Absorption maximum wavelength, ε – extinction coefficient at
λabs, λflu – fluorescence maximum wavelength with excitation at λabs
.
54

Chemistry of Heterocyclic Compounds 2016, 52(1), 52–57
Figure 2. UV-Vis absorption spectra (left) (5×10–4 mol/l) and fluorescence emission spectra (right) (1×10–4 mol/l)
of compound 5f in different solvents with excitation at λabs
.
viously described.27 We used amoxicillin and ciprofloxacin
as reference compounds in the evaluation of antibacterial
activity. The lowest concentration of the antibacterial agent
that prevents growth of the test organism, as detected by
lack of visual turbidity (matching the negative growth
control), is defined as the minimum inhibitory concent-
ration (MIC). Experimental details of the tests can be found
in our earlier study.21
The antibacterial tests performed on compounds 5a–f
confirmed that they were effective only against the two
Gram-negative species. Also the test results revealed that
compound 5d, which has chlorine substituent, showed
higher antibacterial activity against the Escherichia coli
ATCC 10538 and Salmonella typhimurium ATCC 14028
species compared to the well-known antibacterial agent
amoxicillin (Table 2). We propose that the chlorine
substituent might change the binding characteristics of the
ligand to their respective receptors and, thereby, improve
the biological activity.
scopic characterization, fluorescence properties, and anti-
bacterial activity of the new compounds against Gram-
positive and Gram-negative bacterial species were also
studied. The results showed that the compound containing
4-nitrophenyl substituent produces fluorescence while the
one with 4-chlorophenyl substituent shows the highest
antibacterial activity among other synthesized compounds.
Experimental
Absorption and fluorescence spectra were recorded on a
Varian 50-bio UV-Visible spectrophotometer and a Varian
Cary Eclipse spectrofluorophotometer. UV–Vis and fluo-
rescence scans were recorded from 200 to 1000 nm. All
measurements were carried out at room temperature. IR (as
KBr discs) spectra were obtained on a Tensor 27 spectro-
1
meter and only noteworthy absorptions are listed. H and
13C NMR spectra (400 and 100 MHz, respectively) were
recorded on a Bruker Avance DRX-400 FT spectrometer in
CDCl3. Chemical shifts are reported in ppm downfield from
TMS as internal standard. Electron impact ionization mass
spectra were recorded on a Varian Mat CH-7 at 70 eV.
Elemental analysis was performed on a Thermo Finnigan
Flash EA microanalyzer. Melting points were measured on
an Electrothermal type 9100 melting point apparatus.
In conclusion, we have synthesized a new heterocyclic
system isoxazolo[4,3-e]indazole via the nucleophilic sub-
stitution of hydrogen reaction of 1-methyl-5-nitro-1H-
indazole with different aryl acetonitriles in saturated
methanolic KOH solution at room temperature. Spectro-
Table 2. Antibacterial activity of compounds 5a–f (MIC, μg/ml)
Staphylococcus aureus
Bacillus subtilis
ATCC 6633
Escherichia coli
ATCC 10538
Salmonella typhimurium
Compound
ATCC 29213
ATCC 14028
–
–
–
–
75
45
35
10
45
32
1
50
75
5a
5b
–
–
50
5c
–
–
25
5d
5e
–
–
65
–
–
65
5f
Ciprofloxacin
Amoxicillin
16
25
0.05
0.06
>128
>128
150
55

Chemistry of Heterocyclic Compounds 2016, 52(1), 52–57
Amoxicillin, ciprofloxacin, and potassium hydroxide
H 4.67; N 14.93. C16H13N3O2. Calculated, %: C 68.81;
were purchased from Sigma–Aldrich. Other reagents and
solvents were purchased from Merck. All solvents were
dried according to standard procedures. Compound 1 was
synthesized according to a literature procedure.25 The
microorganisms Staphylococcus aureus ATCC 29213,
Bacillus subtilis ATCC 6633, Escherichia coli ATCC
10538, Salmonella typhimurium ATCC 14028 were
purchased from the Pasteur Institute of Iran.
H 4.69; N 15.05.
1-(4-Chlorophenyl)-6-methyl-6H-isoxazolo[4,3-e]-
indazole (5d). Pale-yellow crystals (EtOH), mp 147–149°C.
1H NMR spectrum, δ, ppm (J, Hz): 4.05 (3H, s, N–CH3);
7.50 (1H, d, J = 10.0, H Ar); 7.56 (1H, d, J = 10.0, H Ar);
7.62 (2H, d, J = 8.8, H Ar); 8.01 (2H, d, J = 8.8, H Ar);
8.20 (1H, s, H Ar). 13C NMR spectrum, δ, ppm: 35.7
(NCH3); 107.4; 112.3; 114.6; 117.2; 117.7; 125.2; 129.8;
134.1; 137.3; 141.4; 155.3; 163.5 (C-1). Mass spectrum, m/z
(Irel, %): 285 [M(37Cl)]+ (1), 283 [M(35Cl)]+ (3), 249 (17),
235 (21), 234 (35), 91 [C7H7]+ (100). Found, %: C 63.29;
H 3.52; N 14.99. C15H10ClN3O. Calculated, %: C 63.50;
H 3.55; N 14.81.
Synthesis of compounds 5a–e (General method).
1-Alkyl-5-nitro-1H-indazole 1 (1.77 g, 10 mmol) and
nitrile 2a–e (12 mmol) were added with stirring to a
solution of KOH (30 g, 535 mmol) in methanol (70 ml).
The mixture was refluxed for 48 h and then poured into
water. The precipitate was filtered off, washed with water,
and air-dried to give crude product 5a–e with admixture of
side product 4a–e. Washing the crude product with
acetone, evaporation of the filtrate, and recrystallization of
the residue from MeOH gave pure compound 5a–e, while
crude compound 4a–e remained as precipitate on the filter.
Compound 4a–e was purified by recrystallization from
EtOH.
1-(4-Bromophenyl)-6-methyl-6H-isoxazolo[4,3-e]-
indazole (5e). Pale-yellow crystals (EtOH), mp 153–155°C.
IR spectrum, ν, cm–1: 3105, 3049 and 3004 (C–H Ar); 2956
1
(C–H); 1643, 1559 (C=C Ar). H NMR spectrum, δ, ppm
(J, Hz): 4.09 (3H, s, N–CH3); 7.55 (1H, d, J = 9.8, H Ar);
7.62 (1H, d, J = 9.8, H Ar); 7.68 (2H, d, J = 8.6, H Ar);
8.15 (2H, d, J = 8.6, H Ar); 8.19 (1H, s, H Ar). 13C NMR
spectrum, δ, ppm: 36.1 (NCH3); 108.8; 112.5; 114.5; 117.9;
118.8; 123.8; 127.3; 132.9; 134.9; 141.0; 155.5; 163.9
(C-1). Mass spectrum, m/z (Irel, %): 329 [M(81Br)]+ (6), 327
[M(79Br)]+ (7), 249 (15), 234 (21), 91 [C7H7]+ (100).
Found, %: C 54.78; H 3.06; N 12.73. C15H10BrN3O.
Calculated, %: C 54.90; H 3.07; N 12.80.
6-Methyl-1-phenyl-6H-isoxazolo[4,3-e]indazole (5a).
Pale-yellow crystals (MeOH), mp 155–157°C. IR spect-
rum, ν, cm–1: 3101, 3043 and 3007 (C–H Ar); 2958 (C–H);
1
1643, 1553 (C=C Ar). H NMR spectrum, δ, ppm (J, Hz):
4.25 (3H, s, NCH3); 7.56 (1H, d, J = 9.6, H Ar); 7.64 (1H,
d, J = 9.6, H Ar); 7.75–7.86 (5H, m, H Ar); 8.24 (1H, s,
H Ar). 13C NMR spectrum, δ, ppm: 37.5 (NCH3); 106.1;
111.5; 115.2; 117.0; 124.9; 125.2; 128.1; 133.6; 137.3;
140.3; 157.3; 163.3 (C-1). Mass spectrum, m/z (Irel, %): 249
[M]+ (1), 248 (5), 235 (19), 158 (11), 119 (25), 91 [C7H7]+
(100). Found, %: C 71.94; H 4.41; N 16.65. C15H11N3O.
Calculated, %: C 72.28; H 4.45; N 16.86.
3-Methyl-3H-pyrazolo[4,3-a]acridine-11-carbonitrile
(4a). Shiny yellow needles, mp 250–253°C (EtOH) (mp
251–253°C17).
3,8-Dimethyl-3H-pyrazolo[4,3-a]acridine-11-carbo-
nitrile (4b). Shiny yellow needles, mp 263–265°C (EtOH)
(mp 261–264°C16).
8-Methoxy-3-methyl-3H-pyrazolo[4,3-a]acridine-
11-carbonitrile (4c). Shiny yellow needles, mp 323–325°C
(EtOH) (mp 325–327°C16).
6-Methyl-1-(p-tolyl)-6H-isoxazolo[4,3-e]indazole (5b).
Pale-yellow crystals (MeOH), mp 181–183°C. IR spectrum,
ν, cm–1: 3095, 3041 and 3005 (C–H Ar); 2957 (C–H); 1638,
8-Chloro-3-methyl-3H-pyrazolo[4,3-a]acridine-11-carbo-
nitrile (4d). Shiny yellow needles, mp 232–235°C (EtOH)
1
1557 (C=C Ar). H NMR spectrum, δ, ppm (J, Hz): 2.51
1
(3H, s, CH3); 4.16 (3H, s, N–CH3); 7.44 (2H, d, J = 8.1,
H Ar); 7.47 (1H, d, J = 9.6, H Ar); 7.54 (1H, d, J = 9.6,
H Ar); 7.97 (2H, d, J = 8.1, H Ar); 8.21 (1H, s, H Ar).
13C NMR spectrum, δ, ppm: 21.6 (CH3); 36.4 (NCH3);
106.8; 111.8; 115.4; 117.4; 125.8; 126.8; 129.9; 132.6;
137.3; 140.4; 157.3; 163.0 (C-1). Mass spectrum, m/z (Irel, %):
263 [M]+ (1), 262 (3), 249 (21), 235 (23), 234 (31), 91
[C7H7]+ (100). Found, %: C 72.78; H 4.95; N 16.11.
C16H13N3O. Calculated, %: C 72.99; H 4.98; N 15.96.
1-(4-Methoxyphenyl)-6-methyl-6H-isoxazolo[4,3-e]-
indazole (5c). Pale-yellow crystals (MeOH), mp 193–195°C.
IR spectrum, ν, cm–1: 3103, 3043 and 3000 (C–H Ar); 2953
(mp 231–233°C18). H NMR spectrum, δ, ppm (J, Hz):
4.25 (3H, s, CH3); 7.78 (1H, dd, J = 8.8, J = 2.0, H Ar);
7.93 (1H, d, J = 9.2, H Ar); 8.07 (1H, d, J = 9.2, H Ar);
8.35 (1H, d, J = 1.5, H Ar); 8.39 (1H, d, J = 8.8, H Ar);
9.19 (1H, s, H Ar).
8-Bromo-3-methyl-3H-pyrazolo[4,3-a]acridine-11-carbo-
nitrile (4e). Shiny yellow needles, mp 268–270°C (EtOH)
(mp 266–268°C17).
6-Methyl-1-(4-nitrophenyl)-6H-isoxazolo[4,3-e]indazole
(5f). Potassium nitrate (0.71 g, 7 mmol) dissolved in con-
centrated sulfuric acid (2 ml) was added with stirring to a
solution of compound 5a (1.2 g, 5 mmol) in concentrated
sulfuric acid (4 ml) over 30 min at 0–5°C. After the
addition was completed, the mixture was allowed to warm
to room temperature while stirring for 30 min. After
pouring this mixture onto crushed ice and water (200 ml),
the solid that precipitated was removed by filtration,
washed with water, and dried to give crude product that
was recrystallized from MeOH. Shiny yellow crystals, mp
250–252°C. IR spectrum, ν, cm–1: 1345, 1540 (NO2).
1H NMR spectrum, δ, ppm (J, Hz): 4.18 (3H, s, NCH3);
1
(C–H); 1648, 1555 (C=C Ar). H NMR spectrum, δ, ppm
(J, Hz): 3.93 (3H, s, OCH3); 4.07 (3H, s, N–CH3); 7.15
(2H, d, J = 8.6, H Ar); 7.55 (1H, d, J = 9.6, H Ar); 7.60
(1H, d, J = 9.6, H Ar); 7.72 (2H, d, J = 8.6, H Ar); 8.16
(1H, s, H Ar). 13C NMR spectrum, δ, ppm: 35.0 (NCH3);
56.4 (O-CH3); 108.3; 112.1; 114.4; 115.4; 117.9; 125.1;
132.9; 137.1; 140.9; 155.5; 159.7; 163.8 (C-1). Mass
spectrum, m/z (Irel, %): 279 [M]+ (3), 278 (7), 264 (31), 250
(25), 235 (14), 91 [C7H7]+ (100). Found, %: C 68.70;
56

Chemistry of Heterocyclic Compounds 2016, 52(1), 52–57
10. Bermudez, J.; Fake, C. S.; Joiner, G. F.; Joiner, K. A.;
7.52 (1H, d, J = 9.6, H Ar); 7.59 (1H, d, J = 9.6, H Ar);
8.22 (1H, s, H Ar); 8.24 (2H, d, J = 8.7, H Ar); 8.49 (2H, d,
J = 8.7, H Ar). 13C NMR spectrum, δ, ppm: 36.7 (NCH3);
109.3; 112.1; 114.5; 119.3; 119.9; 124.0; 129.7; 133.4;
139.4; 148.0; 155.3; 162.2 (C-1). Mass spectrum, m/z (Irel, %):
294 [M]+ (2), 280 (15), 249 (9), 235 (18), 234 (37), 91
[C7H7]+ (100). Found, %: C 61.04; H 3.40; N 18.89.
C15H10N4O3. Calculated, %: C 61.22; H 3.43; N 19.04.
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Rees, C. W., Eds.; Pergamon Press: Oxford, 1984, vol. 5,
p. 167.
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Supplementary information file to this article containing
selected 1H and 13C NMR spectra of the synthesized compounds
is available online at http://link.springer.com/journal/10593.
14. Pordel, M.; Beyramabadi, S. A.; Mohammadinejad, A. Dyes
Pigm. 2014, 102, 46.
15. Alikhani, E.; Pordel, M.; Daghigh, L. R. Spectrochim. Acta,
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We would like to express our sincere gratitude to
Mashhad Islamic Azad University for financial support of
this work. We must also acknowledge Maryam Jajarmi
(Khorasan Razavi Rural Water and Wastewater Co.) for
her assistance in antibacterial studies.
16. Pakjoo, V.; Roshani, M.; Pordel, M.; Hoseini, T. ARKIVOC
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17. Daghigh, L. R.; Pordel, M.; Davoodnia, A. J. Chem. Res.
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