Synthesis of some new biologically active 1,3,4-oxadiazolyl nitroindoles and a modified Fischer indole synthesis of ethyl nitro indole-2-carboxylates

Article abstract of DOI:10.1016/j.bmc.2005.04.068

An efficient and modified synthesis of ethyl-4-nitro/5-nitro/6-nitro and 7-nitroindole-2-carboxylates is described. Carbohydrazides of corresponding ethyl nitroindole-2-carboxylates underwent smooth one-step transformation to 1,3,4-oxadiazolyl nitroindole

Full text of DOI:10.1016/j.bmc.2005.04.068

Bioorganic & Medicinal Chemistry 13 (2005) 4638–4644
Synthesis of some new biologically active 1,3,4-oxadiazolyl
nitroindoles and a modified Fischer indole synthesis of ethyl
nitro indole-2-carboxylates
B. Narayana,a,* B. V. Ashalatha,a K. K. Vijaya Raj,a J. Fernandesb and B. K. Sarojinic
aDepartment of Post-Graduate Studies and Research in Chemistry, Mangalore University, Mangalagangotri 574 199, India
bDepartment of Pharmaceutical Chemistry, N.G.S.M. Institute of Pharmaceutical Sciences, Mangalore 574 005, India
cDepartment of Chemistry, P.A. College of Engineering, Mangalore 574 153, India
Received 2 December 2004; revised 24 April 2005; accepted 26 April 2005
Available online 31 May 2005
Abstract—An efficient and modified synthesis of ethyl-4-nitro/5-nitro/6-nitro and 7-nitroindole-2-carboxylates is described. Carbo-
hydrazides of corresponding ethyl nitroindole-2-carboxylates underwent smooth one-step transformation to 1,3,4-oxadiazolyl nitro-
indoles (4a–l) on reaction with aromatic carboxylic acids in the presence of phosphorus oxychloride. An alternate method to
synthesize 1,3,4-oxadiazolyl nitroindoles is also described. Among the newly synthesized 1,3,4-oxadiazolyl nitroindoles, a few com-
pounds are studied for anti-inflammatory activity.
Ó 2005 Published by Elsevier Ltd.
1. Introduction
2-carboxylate was done by differential recrystallization
in benzene, which is carcinogenic.4,5
The indole derivatives display a wide range of biological
activities. This is exemplified by the amino acid trypto-
phan, the hormones serotonin and melatonin, the anti-
inflammatory drug indomethacin, the psychotropic drug
LSD and the anti-tumour agent vinblastine.1 Accord-
ingly, the synthesis of indole derivatives has long been
a topic of fundamental interest to organic and medicinal
chemists. The Fischer indole synthesis is the most widely
used method for the preparation of indole derivatives.2
However, two major drawbacks of Fischer indole syn-
thesis are lower yield and numerous by-products.3 The
synthesis of ethyl esters of 4/6/5/7-nitro-indole-2-carbox-
ylic acids carried out according to Fischer indole synthe-
sis resulted in mixtures of ethyl 4-nitro/6-nitro-indole-2-
carboxylates, ethyl 5-nitroindole-2-carboxylate and
ethyl 7-nitro indole-2-carboxylate and these cyclizations
were carried out at elevated temperatures (125–195 °C).
The separation between ethyl-4-nitro and 6-nitro indole-
During our initial trials for the cyclization of ethyl pyru-
vate nitrophenyl hydrazones (1a–c) to ethyl-nitroindole-
2-carboxylates (2a–d) as per the reported procedure,4,5
we faced the problem of charring of compounds and
yields obtained were very low. But these cyclizations
when carried out at temperatures in the range of 50–
60 °C and maintained for 4 h, and after workup and
recrystallization from ethyl acetate instead of benzene,
resulted in better yields and purer compounds. These
compounds on reaction with hydrazine hydrate yielded
corresponding acid hydrazides (3a–d). The formation
of acid hydrazides is confirmed by recording the IR
spectrum.
The chemistry of substituted 1,3,4-oxadiazoles and their
derivatives received considerable attention during the
last decade as potential anti-inflammatory, analgesic,
CNS-stimulanting, anticonvulsive, anticancer, diuretic
and antihypertensive agents.6–12 Anti-inflammatory
activity of indole derivatives is extensively studied in re-
cent years.13–16 Incorporation of potential indole moiety
may enhance biological activity of 1,3,4-oxadiazole
derivatives. Hence it is thought worthwhile to synthesize
Keywords: Oxadiazolyl nitroindoles; Fischer indole synthesis; Ethyl
nitroindole-2-carboxylates.
*
Corresponding author. Tel.: +91 8242287262; fax: +91
8242287367; e-mail: nbadiadka@yahoo.co.uk
0968-0896/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.bmc.2005.04.068

B. Narayana et al. / Bioorg. Med. Chem. 13 (2005) 4638–4644
4639
1,3,4-oxadiazolyl nitroindoles and study their anti-in-
flammatory activity.
3. Pharmacology
3.1. Anti-inflammatory activity
2. Chemistry
Six of the newly synthesized compounds 4a, 4c–f and 4k
were evaluated for their anti-inflammatory activity
against carrageenin-induced acute paw edema in rats
weighing 150–200 g.17–20 Carrageenin, 0.1 ml (1% w/v
solution prepared in 0.9% NaCl solution) was injected
underneath the subplantar region. Indomethacin,
1.5 mg/kg body weight per oral (suspended in 0.3%
CMC) was used as the standard drug. Compounds 4a,
4c–f and 4k (5.0 mg/kg body weight) were suspended
in 0.3% CMC and administered to rats by the oral route.
4/6/5/7-Nitroindole-2-carbohydrazides (3a–d) under-
went smooth one-step reaction with aromatic carboxylic
acids in the presence of phosphorus oxychloride (meth-
od-1) to give 2-[5-(aryl)-1,3,4-oxadiazol-2-yl]-4-nitro/6-
nitro/5-nitro/7-nitro indoles (4a–l) (Scheme 1). The
structures of the newly synthesized compounds are con-
1
firmed by recording IR, H NMR, mass spectra and
elemental analysis.
4-Nitroindole-2-carbohydrazide (3a), 6-nitroindole-2-
carbohydrazide (3b), 5-nitroindole-2-carbohydrazide
(3c) and 7-nitroindole-2-carbohydrazide (3d) were trea-
ted with corresponding aromatic aldehydes in chloro-
form with a catalytic amount of acetic acid. The
compounds were confirmed by recording the IR and
mass spectra. The characterization data are given in
Experimental section. The Schiff bases of ethyl-4/6/5/7-
nitroindole-2-carbohydrazides (5a–d) on cyclization in
the presence of FeCl3 (method-2) yielded 4a, 4d, 4f
and 4l. Spectral data of the compounds 4a, 4d, 4f, and
4l are given in Experimental section (Tables 1 and 2).
The animals were weighed and numbered into six
groups and each group contained six animals. A
mark was made on the hind paw (left) just beyond
the tibio-tarsal junction, so that every time the paw
was dipped in the mercury column up to the fixed
mark constant paw volume was ensured. The initial
paw volume of each rat was noted (all the six
groups) by the mercury displacement method. To
the first group was administered saline and to the
second group was administered indomethacin orally.
The third, fourth, fifth, and sixth groups were admin-
istered the test compounds 4a, 4c–f and 4k orally
Scheme 1.

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B. Narayana et al. / Bioorg. Med. Chem. 13 (2005) 4638–4644
Table 1. Characterization data of (4a–l)
Compound no.
Position of NO2
Ar
Yield (%)a
MP (°C)
Nature of crystals
Yellow crystals
% Nitrogen
Found
Calcd
4a
4
80b
69c
180–182
16.5
16.66
4b
4c
4
4
70
226–228
>250
Light yellow crystals
Yellow crystals
21.49
20.49
21.53
20.53
85
87b
72c
4d
4e
6
6
>250
>250
Yellow crystals
Yellow crystals
16.40
16.04
16.47
15.99
75
86b
72c
4f
5
>250
Brown crystals
16.38
16.47
4g
4h
4i
5
5
7
78
76
75
>250
Brown crystals
22.83
20.50
17.43
22.79
20.49
17.48
194–196
222–225
Dark brown crystals
Yellow crystals
4j
7
7
75
60
210–212
240–242
Yellow crystals
Beige crystals
16.48
16.05
16.44
15.99
4k
4l
7
68b
65c
250
Brown micro-crystals
19.56
19.59
a Yields refer to single runs and are given for isolated products.
b Yield by method-1.
c Yield by method-2.
(5.0 mg/kg, suspended in 0.3% CMC). After 30 min,
0.1 ml of 1% (w/v) carrageenin was injected in the
subplantar region of the left paw in all drug-treated
groups (group I–IV). Immediately after the injection
of carrageenin, paw volumes were measured in a
mercury plethysmograph. Thereafter the paw volume
was measured at 1, 2 and 3 h. The amount of edema
in the drug-treated groups was compared in relation
to the control group with the corresponding time
intervals. The percentage of inhibition by the drugs
was calculated using the formula,
% of edema inhibition ¼ 100 ꢀ ðV test=V controlÞ ꢁ 100;
where Vcontrol = volume of paw edema in the control
group; Vtest = volume of paw edema in the drug treated
group.

B. Narayana et al. / Bioorg. Med. Chem. 13 (2005) 4638–4644
4641
Table 2. Characterization data of (5a–d)
Compound No
Position of NO2
Ar
Yield (%)a
MP °C
>250
Nature of crystals
Yellow crystals
% Nitrogen
Found Calcd
5a
5b
4
6
78
75
16.53
16.38
16.55
16.34
>250
Light yellow crystals
5c
5d
5
7
78
78
>250
>250
Light yellow crystals
Light yellow crystals
16.30
19.39
16.34
19.48
a Yields refer to single runs and are given for isolated products.
Table 3. Anti-inflammatory activity screening of compounds 4a, 4c–f and 4k: Carrageenin-induced rat paw edema
Group
Dose
Paw edema volume,
Mean SE (ml)
% Decrease in paw edema
(anti-inflammatory activity)
Control (Carrageenin alone)
Indomethacin
0.1 ml/kg
0.42 0.0089
0.163 0.00843
0.26 0.00549
0.22 0.00281
0.19 0.0033
0.22 0.00840
0.21 0.00343
0.21 0.00666
—
1.5 mg/kg p.o (suspended in 0.3% CMC)
5.0 mg/kg p.o (suspended in 0.3% CMC)
5.0 mg/kg p.o (suspended in 0.3% CMC)
5.0 mg/kg p.o (suspended in 0.3% CMC)
5.0 mg/kg p.o (suspended in 0.3% CMC)
5.0 mg/kg p.o (suspended in 0.3% CMC)
5.0 mg/kg p.o (suspended in 0.3% CMC)
60.04
35.0
46.07
52.5
46.07
48.5
48.5
4a
4c
4d
4e
4f
4k
Vehicle: 5% Gum acacia. Animals: Albino rats. Weights: 150–200 g. Route of administration: Oral. No of animals in each group: 6.
P < 0.001 versus indomethacin.
The results were expressed as % inhibition of edema over
the untreated control group.
ent test compounds. So there is further scope to carry
out the study at different doses and also compare the
activity with other non-steroidal anti-inflammatory
drugs.
Table 3 shows the effect of drug and extract treatment
on carrageenin-induced edema. The percentage of inhi-
bition was compared with that of the standard drug
indomethacin.
5. Experimental
5.1. Preparation of ethyl-4/6-nitro indole-2-carboxylate
(2a–b)5
4. Discussion
An insight into the anti-inflammatory activity with re-
spect to the chemical structure reveals that compounds
4d and 4f bearing a 2-chlorophenyl moiety, and com-
pound 4k bearing a 4-fluoro cinnamyl moiety, exhibited
good anti-inflammatory activity at a dose of 5.0 mg/kg
in comparison with the standard drug indomethacin.
Compound 4c bearing a 2-chloronicotinyl moiety and
compound 4e bearing a 4-fluorocinnamyl moiety have
shown moderate anti-inflammatory activity and the
compound 4a bearing a 3-methoxyphenyl moiety has
shown mild anti-inflammatory activity. There is further
scope to investigate the effect of nitro group and its ori-
entation to the anti-inflammatory activity. In the present
study, the studies are being done at 5.0 mg/kg of differ-
Ethylpyruvate-3-nitro
phenylhydrazone
(2 g,
0.00796 mol) was taken in 10 g polyphosphoric acid
and kept under stirring for proper mixing. The reaction
mass was slowly heated to 50–60 °C and maintained for
4 h. Progress of the reaction was monitored by TLC.
The reaction mass was cooled and 100 ml of DM water
was added to break the lumps till it became a slurry. The
solid was filtered and washed with water. The dried
crude was charcoalized in ethyl acetate filtered over hy-
flo and slowly cooled to room temperature and kept
overnight under stirring. After one more recrystalliza-
tion from ethyl acetate, ethyl-4-nitro indole-2-carboxyl-
ate (2a) was obtained as yellow crystals with a yield of
0.96 g (51%) mp 226–228 °C (lit.,5 228–230 °C).

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B. Narayana et al. / Bioorg. Med. Chem. 13 (2005) 4638–4644
Anal. Calcd for C11H10N2O4: C, 56.4; H, 4.3; N, 11.96.
Found: C, 56.20, H, 4.52; N, 12.04.
Anal. Calcd for C9H8N4O3: C, 49.09; H, 3.66; N, 25.45.
Found: C, 49.1, H, 3.67; N, 25.42.
The ethyl acetate mother liquor from which ethyl-4-ni-
tro indole-2-carboxylate was isolated, was concentrated
and kept under stirring overnight at room temperature.
The solid obtained was filtered and again recrystallized
from ethyl acetate. Ethyl-6-nitro indole-2-carboxylate
(2b) was isolated as light yellow needles with a yield of
0.43 g (24%) mp 194–196 °C (lit.5 195–197 °C).
5.4.2. 6-Nitro indole-2-carbohydrazide (3b). The
product was obtained as yellow micro-crystals with a
yield of 1.65 g (75%), mp 292 °C (dec). Molecular
formula: C9H8N4O3, IR (KBr): 3388 cmꢀ1 (–NH2),
1654 and 1615 cmꢀ1 (–CONH2) and 1546 cmꢀ1
(–NO2).
Anal. Calcd for C9H8N4O3: C, 49.09; H, 3.66; N, 25.45.
Found: C, 49.11, H, 3.65; N, 25.44
Anal. Calcd for C11H10N2O4: C, 56.4; H, 4.3; N, 11.96.
Found: C, 56.38, H, 4.52; N, 12.20.
5.4.3. 5-Nitro indole-2-carbohydrazide (3c). The product
was obtained as brown crystals with a yield of
5.2. Preparation of ethyl-5-nitro indole-2-carboxylate (2c)5
1.76
g
(80%), mp >250 °C. Molecular formula:
Ethylpyruvate-4-nitrophenylhydrazone (2 g, 0.00796 mol)
was taken in 10 g of polyphosphoric acid and kept under
stirring for proper mixing. The reaction mass was slowly
heated to 50–60 °C and maintained for 4 h. Progress of
the reaction was monitored by TLC. The reaction mass
was cooled and 100 ml of DM water was added to break
the lumps till it became a slurry. The solid was filtered
and washed with water. The dried crude was recrystal-
lized from ethyl acetate. The product was obtained as
yellow crystals with a yield of 1.29 g (70%), mp 219–
222 °C (lit.,5 220–223 °C).
C9H8N4O3, IR (KBr): 3324 cmꢀ1 (–NH), 1635 and
1724 cmꢀ1(–CONH2) and 1544 cmꢀ1 (–NO2).
Anal. Calcd for C9H8N4O3: C, 49.09; H, 3.66; N, 25.45.
Found: C, 49.09, H, 3.67; N, 25.41.
5.4.4. 7-Nitro indole-2-carbohydrazide (3d). The product
was obtained as yellow micro-crystals with a yield of
1.65 g (75%), mp 230–232 °C. Molecular formula:
C9H8N4O3, IR (KBr): 3325 cmꢀ1 (–NH2), 1635.5 and
1722.3 cmꢀ1 (–CONH2) and 1544.9 cmꢀ1 (–NO2).
Anal. Calcd for C11H10N2O4: C, 56.4; H, 4.3; N, 11.96.
Found: C, 56.39, H, 4.42; N, 12.04.
Anal. Calcd for C9H8N4O3: C, 49.09; H, 3.66; N, 25.45.
Found: C, 49.06, H, 3.67; N, 25.44.
5.3. Preparation of ethyl-7-nitro indole-2-carboxylate (2d)5
5.5. Preparation of Schiff bases (5a–d)
Ethylpyruvate-2-nitrophenylhydrazone (2 g, 0.00796 mol)
was taken in 10 g of polyphosphoric acid and kept under
stirring for proper mixing. The reaction mass was slowly
heated to 50–60 °C and maintained for 4 h. Progress of
the reaction was monitored by TLC. The reaction mass
was cooled and 100 ml of DM water was added to break
the lumps till it became a slurry. The solid was filtered
and washed with water. The dried crude was recrystal-
lized from ethyl acetate. The product was obtained as
yellow crystals with a yield of 1.39 g (75%), mp 92–
93 °C (lit.,5 92–93 °C).
4/6/5/7-Nitro indole-2-carbohydrazide (2.20 g, 0.01 mol)
in 22 ml of chloroform was refluxed with 0.01 mol of
aromatic aldehydes for 4 h in the presence of one drop
of acetic acid. The solvent was removed by distillation.
The solid was collected and recrystallized from metha-
nol–dimethyl formamide mixture.
5.5.1.
N0-[(3-Methoxyphenyl)methylene]-4-nitro-1H-
indole-2-carbohydrazide (5a). Molecular formula:
C17H14N4O4; MS: m/z 338 (M+, I = 20%), m/z 205
(C9H7N3O3, I = 80%), m/z 188 (C9H5N2O3, I = 100%);
IR (KBr): 3398 cmꢀ1 (–NH–), 3053 cmꢀ1 (–CH3), 2949
and 2848 cmꢀ1 (–CH), 1656 cmꢀ1 (–C@O), 1545 cmꢀ1
(–NO2).
Anal. Calcd for C11H10N2O4: C, 56.4; H, 4.3; N, 11.96.
Found: C, 56.46, H, 4.48; N, 12.02.
5.4. General method for the preparation of 4/6/5/7-nitro
indole-2-carbohydrazide (3a–d)
5.5.2. N0-[(2-Chlorophenyl)methylene]-6-nitro-1H-indole-
2-carbohydrazide
(5b).
Molecular
formula:
C16H11ClN4O3, MS: m/z 342 (M+, I = 10%), m/z 205
(C9H7N3O3, I = 84%), m/z 188 (C9H5N2O3, I = 100%);
IR (KBr): 3399 cmꢀ1 (–NH–), 2945 and 2843 cmꢀ1 (–
CH), 1659 cmꢀ1 (–C@O), 1545 cmꢀ1 (–NO2),
1058 cmꢀ1 (Ar–Cl).
Ethyl-4/6/5/7-nitro indole-2-carboxylate (2.34 g, 0.01 mol)
in 25 ml of absolute ethanol was refluxed with 1.0 ml of
hydrazine hydrate for 2 h. After the completion of the
reaction by TLC, the reaction mixture was cooled to
room temperature. The separated solid was filtered,
washed with cold ethanol and recrystallized from ethanol.
5.5.3. N0-[(2-Chlorophenyl) methylene]-5-nitro-1H-indole-
2-carbohydrazide
(5c).
Molecular
formula:
5.4.1. 4-Nitro indole-2-carbohydrazide (3a). The product
was obtained as yellow micro-crystals with a yield of
1.76 g (80%), mp 280 °C (dec). Molecular formula:
C9H8N4O3, IR (KBr): 3325 cmꢀ1 (–NH2), 1722 and
1635 cmꢀ1 (–CONH2) and 1544.9 cmꢀ1 (–NO2).
C16H11ClN4O3, MS: m/z 342 (M+, I = 12%), m/z
205 (C9H7N3O3, I = 86%), m/z 188 (C9H5N2O3,
I = 100%); IR (KBr): 3399 cmꢀ1 (–NH–), 2945 and
2843 cmꢀ1 (–CH), 1659 cmꢀ1 (–C@O), 1545 cmꢀ1
(–NO2), 1058 cmꢀ1 (Ar–Cl).

B. Narayana et al. / Bioorg. Med. Chem. 13 (2005) 4638–4644
4643
5.5.4. 7-Nitro-N0-[(quinolin-7-yl) methylene]-1H-indole-2-
carbohydrazide (5d). Molecular formula: C19H13N5O3,
MS: m/z 359 (M+, I = 5%), m/z 155 (C10H5N2, I =
40%), m/z 142 (C10H9N, I = 20%); IR (KBr): 3399
cmꢀ1 (–NH–), 2945 and 2843 cmꢀ1 (–CH), 1659 cmꢀ1
(–C@O), 1545 cmꢀ1 (–NO2).
5.6.5. 2-{5-[2-(4-Fluorophenyl)vinyl]-1,3,4-oxadiazol-2-
yl}-6-nitro-1H-indole (4e). Molecular formula:
C18H11FN4O3; MS: m/z 347 (Mꢀ1, I = 15%), m/z 189
(I = 10%, C8H5N3O2); m/z 149 (I = 30%, C9H6FO).
5.6.6.
2-[5-(2-Chlorophenyl)-1,3,4-oxadiazol-2-yl]-5-
nitro-1H-indole (4f). Molecular formula: C16H9ClN4O3;
MS: m/z 340 (M+, I = 5%), m/z 139 (I = 100%,
o-Cl-C6H4CN); IR (KBr): 3297 cmꢀ1 (–NH–),
1589 cmꢀ1 (–NO2), 1342 cmꢀ1 (C–O), 1058 cmꢀ1 (Ar–
Cl).
5.6. Preparation of 2-[5-(aryl)-1,3,4-oxadiazol-2-yl]-4-
nitro-1H-indoles (4a–c), 2-[5-(aryl)-1,3,4-oxadiazol-2-yl]-
6-nitro-1H-indoles (4d–e), 2-[5-(aryl)-1,3,4-oxadiazol-2-
yl]-5-nitro-1H-indoles (4f–h) and 2-[5-(aryl)-1,3,4-oxa-
diazol-2-yl]-7-nitro-1H-indoles (4i–l)
5.6.7. 5-Nitro-2-(5-pyridin-4-yl-1,3,4-oxadiazol-2-yl)-1H-
indole (4g). Molecular formula: C15H9N5O3; MS: m/z
Method-1: A mixture of 4-nitro, 6-nitro, 5-nitro, or
7-nitroindole-2-carbohydrazide (0.001 mol), aromatic
carboxylic acid (0.0015 mol) in 4 ml of phosphorus
oxychloride was refluxed on an oil bath for 6 h. The
excess phosphorus oxychloride was distilled under
reduced pressure. The cooled reaction mass was
then poured into ice cold water with stirring. The
separated solid was filtered and washed with sodium
bicarbonate solution and then with water. The prod-
uct was then recrystallized from ethanol–dimethylform-
amide mixture.
1
307 (M+, I = 50%); H NMR (CDCl3–DMSO): d 7.40
(dd, 2H, Ar–H), d 7.8 (dd, 2H, Ar–H), d 8.0 (dd, 2H,
Ar–H), d 8.8 (s, 1H, Ar–H), d 8.9 (s, 1H, Ar–H),
d13.16 (s, 1H, –NH–).
5.6.8. 2-[5-(2-Chloropyridin-3-yl)-1,3,4-oxadiazol-2-yl]-5-
nitro-1H-indole (4h). Molecular formula: C15H8ClN5O3;
MS: m/z 340 (M+, I = 80%); 1H NMR (CDCl3–DMSO):
d 7.60 (m, 3H, Ar–H), d 7.8 (s, 1H, Ar–H), d 8.02 (dd,
1H, Ar–H), d 8.15 (dd, 1H, Ar–H), d 8.6 (s, 1H, Ar–
H), 12.5 (s, 1H, –NH–).
Method-2: The appropriate Schiff bases (5a–d),
(0.01 mol) were dissolved in glacial acetic acid (100 ml)
and ferric chloride (4 g in 100 ml) was added to it with
stirring. The mixture was stirred for 1 h and diluted
with water. The solid obtained was filtered, washed with
water, dried and recrystallized in ethanol–dimethylform-
amide mixture.
5.6.9. 2-[5-(3-Methyl phenyl)-1,3,4-oxadiazol-2-yl]-7-
nitro-1H-indole (4i). Molecular formula: C17H12N4O3;
MS: m/z 320 (M+, I = 100%), m/z 189 (C9H7N3O2,
I = 16%), m/z 119 (C8H9N, I = 97%), m/z 91 (C7H7,
I = 25%) 1H NMR (CDCl3–DMSO): d 2.48 (s, 3H,
–CH3), d 7.31–7.41 (m, 3H, Ar–H), d 7.52 (s, 1H, Ar–
H), d 7.9 (s, 1H, Ar–H), d 8.15(J = 7.84) (d, 1H, Ar–H),
d 8.24(J = 8.15) (d, 1H, Ar–H), d 8.15 (s, 1H, Ar–H), d
11.9 (s, 1H, –NH–).
5.6.1.
2-[5-(3-Methoxyphenyl)-1,3,4-oxadiazol-2-yl]-4-
nitro-1H-indole (4a). Molecular formula: C17H12N4O4,
MS: m/z 336 (M+, I = 60%); 1H NMR (CDCl3–DMSO);
d 3.89 (s, 3H, –CH3), d 7.07–7.09 (m, 2H, Ar–H), d 7.38
(t, 1H, Ar–H), d 7.52 (s, 1H, Ar–H), d 7.87–7.95 (m, 2H,
Ar–H), d 8.11–8.16 (m, 2H, Ar–H), d 12.73 (s, –NH–).
5.6.10.
2-[5-(2-Chlorophenyl)-1,3,4-oxadiazol-2-yl]-7-
nitro-1H-indole (4j). Molecular formula: C16H9ClN4O3;
MS: m/z 340 (M+, I = 63%), m/z 189 (C9H7N3O2,
I = 25%), m/z 139 (C7H6ClN, I = 100%); IR (KBr):
3298 cmꢀ1 (–NH–), 1598 cmꢀ1 (–NO2), 1342 cmꢀ1 (C–
O), 1054 cmꢀ1 (Ar–Cl).
5.6.2. 4-Nitro-2-[5-(7-nitro-1H-indol-2-yl)-1,3,4-oxadi-
azol-2-yl]-1H-indole
(4b).
Molecular
formula:
C18H10N6O5, MS: m/z 390 (M+, I = 10%), m/z 220
(I = 80%, C9H8N4O3); 1H NMR (CDCl3–DMSO); d
7.27 (t, 1H, Ar–H), d 7.35 (s, 1H, Ar–H), d 8.07(J = 7.8)
(d, 1H, Ar–H), d 8.27(J = 8.1) (d, 1H, Ar–H), d 10.40 (s,
1H, –NH–).
5.6.11. 2-{5-[2-(4-Fluorophenyl)vinyl]-1,3,4-oxadiazol-2-
yl}-7-nitro-1H-indole (4k). Molecular formula: C18H11-
FN4O3; MS: m/z 349 (M+, I = 100%), m/z 189
(C9H7N3O2, I = 40%,) m/z 149 (C9H8FN, I = 66%) m/
1
z 121 (C8H6F, I = 50%); H NMR (CDCl3–DMSO): d
5.6.3. 2-[5-(2-Chloropyridin-3-yl)-1,3,4-oxadiazol-2-yl]-4-
nitro-1H-indole (4c). Molecular formula: C15H8ClN5O3;
MS: m/z 340 (M+, I = 10%), m/z 220 (I = 80%,
C9H8N4O3); IR (KBr): 3427.5 and 3232.5 cmꢀ1 (–NH–),
1330 cmꢀ1 (@C–O–), 1058 cmꢀ1 (Ar–Cl).
7.18 (dd, 2H, –HC@CH–), d 7.35 (t, 1H, Ar–H),
d 7.50 (s, 1H, Ar–H), d 7.72–7.78 (m, 4H, Ar–H), d
8.14(J = 7.73) (d, 1H, Ar–H), d 8.26(J = 8.08) (d, 1H,
Ar–H), d 11.65 (s, 1H, –NH–).
5.6.12.
8-[5-(7-Nitro-1H-indol-2-yl)-1,3,4-oxadiazol-2-
5.6.4.
2-[5-(2-Chlorophenyl)-1,3,4-oxadiazol-2-yl]-6-
yl]quinoline 4l. Molecular formula: C19H11N5O3; MS:
m/z 357 (M+, I = 98%), m/z 311 (MꢀNO2, I = 22%),
m/z 187 (C10H9N3O, I = 20%), m/z 156 (C10H8N2,
I = 100%), m/z 143 (C10H9N, I = 25%); 1H NMR
(CDCl3–DMSO): d 7.35 (t, 1H, Ar–H), d 7.74 (dd, 1H,
Ar–H), d 7.84(J = 7.83) (d, 1H, Ar–H), d 7.89(J = 4.6) (d,
1H, Ar–H), d 8.15(J = 7.95) (d, 1H, Ar–H), d 8.28 (dd,
2H, Ar–H), d 8.57 (m, 2H, Ar–H), d 9.18 (s, 1H, Ar–
H), d 11.76 (s, 1H, –NH).
nitro-1H-indole (4d). Molecular formula: C16H9ClN4O3;
MS: m/z 340 (M+, I = 42%), m/z 139 (I = 100%, o-Cl-
C6H4CN); IR (KBr): 3297 cmꢀ1 (–NH–), 1589 cmꢀ1
(–NO2), 1342 cmꢀ1 (@C–O–), 1058 cmꢀ1 (Ar–Cl); 1H
NMR (CDCl3–DMSO): d 7.47 (s, 1H, Ar–H), d 7.59–
7.75 (m, 3H, Ar–H), d 7.89(J = 8.86) (d, 1H, Ar–H), d
7.97(J = 10.5) (d, 1H, Ar–H), d 8.15(J = 6.28) (d, 1H, Ar–
H), d 8.15 (s, 1H, Ar–H), d 8.13 (s, 1H, –NH–).

4644
B. Narayana et al. / Bioorg. Med. Chem. 13 (2005) 4638–4644
(d) Hughes, D. L. Org. Prep. Proced. Int. 1993, 25, 609–
632.
6. Conclusion
3. Miyata, O.; Kimura, Y.; Muroya, K.; Hiramatsu, H.;
Niato, H. Tetrahedron Lett. 1999, 40, 3601–3604.
4. Singer, H.; Shive, W. J. Org. Chem. 1957, 22, 84–85.
5. Parmerter, S. M.; Cook, G. A.; Dixon, W. B. J. Am.
Chem. Soc. 1958, 80, 4621–4622.
6. Jones, D. H.; Slack, R.; Squires, S. H.; Wooldridge, K. R.
J. Med. Chem. 1965, 8, 676.
7. Ainsworth, C. J. Am. Chem. Soc. 1965, 87, 5800–
5803.
8. Yale, H.; Losee, K. J. Med. Chem. 1966, 9, 478–483.
9. Ghiram, D.; Schwartz, I.; Simity, I. Farmacia 1971, 22,
141.
10. Thomas, J. Ger. Offen. 1974, 2403357. Chem. Abstr. 1974,
81, 136153.
In conclusion, we developed a smooth one-step synthe-
sis of 2-[5-(aryl)-1,3,4-oxadiazol-2-yl]-4-nitro-1H-indoles,
2-[5-(aryl)-1,3,4-oxadiazol-2-yl]-5-nitro-1H-indoles,
2-[5-(aryl)-1,3,4-oxadiazol-2-yl]-6-nitro-1H-indoles and 2-
[5-(aryl)-1,3,4-oxadiazol-2-yl]-7-nitro-1H-indoles. In the
present work, the Fischer indole cyclization was modi-
fied by considerably reducing the temperature to 50–
60 °C and maintaining the reaction for 4–5 h. The syn-
thesized compounds 4d and 4f bearing a 2-chlorophenyl
moiety, and compound 4k bearing a 4-fluoro cinnamyl
moiety, exhibited good anti-inflammatory activity at a
dose of 5.0 mg/kg in comparison with the standard drug
indomethacin.
11. Adelstein, G. W.; Yen, C. H.; Dajani, E. Z.; Bianchi, R.
G. J. Med. Chem. 1976, 19, 1221–1223.
12. Smicius, R.; Jakubkiene, V.; Burbaliene, M. M.; Vainila-
vicius, P. Monatsh. Chem. 2002, 133, 731–734.
13. Misra, U.; Hitkari, K.; Saxena, A. K.; Gurtu, S.; Shankar,
K. Eur. J. Med. Chem. 1996, 31, 629–634.
14. Andreani, A.; Rambaldi, M.; Locatelli, A.; Pifferi, G. Eur.
J. Med. Chem. 1994, 29, 903–906.
15. Ebeid Mohammed, Y.; Lashine Sayed, M.; El-Adl Sobby,
M.; Aboo Kull Mansoor, F. Zagzig J. Pharm. Sci. 1994, 3,
40–48.
Acknowledgments
The authors are thankful to Dr. P. M. Akberali, former
Sr. Vice President, Strides Research and Specialty
Chemicals, Mangalore for providing the necessary facil-
ities. The authors are also thankful to the Director,
RSIC, Punjab University, Chandigarh, and The Head
RSIC, IIT, Chennai for mass and NMR spectra.
16. Preeti Rani; Srivastava, V. K.; Ashok Kumar Eur. J. Med.
Chem. 2004, 39, 449–452.
17. Vogel, H. G.; Vogel, W. H. Drug Discovery and Evaluation
of Pharmacological Assays, 2nd ed.; Springer: Berlin, 2002,
pp. 406–408.
References and notes
18. Kulkarni, S. K. Handbook of Experimental Pharmacology;
Vallabh Publications, 1999, pp 128–131.
1. Murphy, J. A.; Scott, K. A.; Sinclair, R. S.; Lewis, N.
Tetrahedron Lett. 1997, 38, 7295–7298.
19. Winter, C. A.; Risely, E. A.; Nuss, G. W. Proc. Soc. Exp.
Biol. Med. 1962, 111, 544–547.
20. Kasahara, Y.; Hikino, H.; Trusufuji, S.; Watanabe, M.;
Ohuchi, K. Planta Med. 1985, 51, 325–331.
2. Reviews of Fischer Indole synthesis: (a) Robinson, B.
Chem. Rev. 1963, 63, 373–401; (b) Robinson, B. Chem.
Rev. 1969, 69, 227–250; (c) Robinson, B. The Fischer
Indole Synthesis; John Wiley and Sons: New York, 1982;