Novel synthesis of 5-substituted-3-phenylindole-2-(1,2,4-triazole) derivatives

Article abstract of DOI:10.1080/00397910801914160

Various substituted 3-phenylindole 2-carboxylates (1a-c) were prepared according to the literature methods. These carboxylates (1a-c) on reaction with thiosemicarbazide yielded 5-substituted-3-phenylindol-2-(1,2,4-triazole-3- thione) (2a-c) on refluxing in pyridine for 8 h. The 5-substituted-3- phenylindole-2-[1,2,4-triazolo-3-thioacetic acid] (3a-c) were prepared from 5-substituted-3-phenyl indole-2-[1,2,4-triazole-3-thione] (2a-c) on reaction with an appropriate alkylating agent and sodium acetate in acetic acid. Further, (3a-c) were reacted with acetic anhydride to bring about a cyclocondensation reaction to yield 5-substituted-3-phenylindol-2-thiazolo(2,3-b)-triazole (4a-c). The 5-substituted-3-phenylindole-2-[1,2,4-triazolo-3-acetic acid] (3a-c) were reacted with o-phenylenediamino dihydrochloride in ethylene glycol to yield 5-substituted-3-phenylindole-1,2,4-triazolo-3′-yl-thiomethyl) benzimidazoles (5a-c). Copyright Taylor & Francis Group, LLC.

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Novel Synthesis of
5‐Substituted‐3‐phenylindole‐2‐(1,2,4‐triazole)
Derivatives
P. M. Veeresha Sharma a & M. G. Purohit b
a Department of Organic Chemistry, Indian Institute of Science, Bangalore,
India
b Department of Chemistry, Gulbarga University, Gulbarga, India
Published online: 25 Apr 2008.
To cite this article: P. M. Veeresha Sharma & M. G. Purohit (2008): Novel Synthesis of
5‐Substituted‐3‐phenylindole‐2‐(1,2,4‐triazole) Derivatives, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 38:9, 1381-1388
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Synthetic Communicationsw, 38: 1381–1388, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801914160
Novel Synthesis of 5-Substituted-
3-phenylindole-2-(1,2,4-triazole) Derivatives
P. M. Veeresha Sharma1 and M. G. Purohit2
1Department of Organic Chemistry, Indian Institute of Science,
Bangalore, India
2Department of Chemistry, Gulbarga University, Gulbarga, India
Abstract: Various substituted 3-phenylindole 2-carboxylates (1a–c) were prepared
according to the literature methods. These carboxylates (1a–c) on reaction with thiose-
micarbazide yielded 5-substituted-3-phenylindol-2-(1,2,4-triazole-3-thione) (2a–c) on
refluxing in pyridine for 8 h. The 5-substituted-3-phenylindole-2-[1,2,4-triazolo-3-thioa-
cetic acid] (3a–c) were prepared from 5-substituted-3-phenyl indole-2-[1,2,4-triazole-3-
thione] (2a–c) on reaction with an appropriate alkylating agent and sodium acetate in
acetic acid. Further, (3a–c) were reacted with acetic anhydride to bring about a cyclo-
condensation reaction to yield 5-substituted-3-phenylindol-2-thiazolo(2,3-b)-triazole
(4a–c). The 5-substituted-3-phenylindole-2-[1,2,4-triazolo-3-acetic acid] (3a–c) were
reacted with o-phenylenediamino dihydrochloride in ethylene glycol to yield 5-substi-
tuted-3-phenylindole-1,2,4-triazolo-30-yl-thiomethyl)benzimidazoles (5a–c).
Keywords: 3-Phenylindole-2-carboxylates, thiosemicarbazides, alkylating agents,
cyclocondensation
INTRODUCTION
A literature survey reveals that indole and its derivatives represent one of
the most pharmcologically active classes of compounds. Still, there is
an immense research interest in preparing indole derivatives because of
their efficient use in anti-HIV activity and varied biodynamic properties.
The indole nucleus is present in number of physiologically significant
Received October 11, 2007
Address correspondence to M. G. Purohit, Department of Chemistry, Gulbarga
University, Gulbarga 585106, India. E-mail: murleedhar_purohit@hotmail.com
1381

1382
P. M. V. Sharma and M. G. Purohit
compounds. For example, indole-3-acetic acid (heteroauxin) is a naturally
occurring plant growth hormone. Tryptophan is a naturally occurring
essential amino acid, which plays a vital role in the biosynthesis of cellular
proteins and porphyrins in animals. Reserpine is an indole alkaloid that
reduces the concentration of serotonin in central nervous tissue. In recent
years, there are increasing numbers of reports on the synthesis of indole
analogs for their agrochemical anthelmintic activity and also COX-II
enzyme inhibitory activity.[1,2]
The triazoles also exhibit broad-spectrum pesticidal activities. Certain
heterocyclic compounds with a 1,2,4-triazole nucleus are reported to
possess fungicidal, insecticidal, and antimicrobial activities. Some of the
triazole derivatives have been synthesized for possible anticonvulsants, anti-
depressant plant growth hormone, and antitubercular molecules.[3,4]
A literature survey reveals that benzimidazole and its derivatives possess
diverse pharmacological properties such as analgesic, anti-inflammatory, tran-
quilizing anticonvulsant, and central nervous system (CNS) inhibition
activity.[5]
In this article, we report the novel preparation and characterization of
5-substituted-3-phenylindole-2-(1,2,4-triazole) derivatives.
RESULTS AND DISCUSSION
On reaction with thiosemicarbazide, the indole-2-carboxylates (1a–c) yielded
5-substituted-3-phenylindol-2-(1,2,4-triazole-3-thione) (2a–c). The formation
of these compounds was confirmed by their IR, NMR, and mass spectral
data. The IR spectrum of 2a displayed an absorption peak at 3328 cm21 as
a result of NH of indole. Another peak at 3280 cm21 can be assigned for
triazole NH. The 1H NMR spectrum of 2a exhibits a sharp singlet
downfield at 9.2 ppm because of the resonance of H of indole NH. Another
singlet at 8.6 ppm may be due to the proton of SH group. A single proton
present on the triazole moiety has shown a peak at 7.8 ppm. The multiplet
from 7.2 to 7.6 ppm is expected to be due to the protons of aromatic region.
These spectral data of 2a described previously confirms the structure
assigned to 2a obtained by the reaction of 1a with thiosemicarbazide in
pyridine. Other compounds (2b and 2c) also exhibit the spectral properties
as per the discussion mentioned before. Hence, the structure assigned to
2a–c obtained by the reaction with 1a–c is in conformity with the expected
structure.
The 5-substituted-3-phenylindole-2-[1,2,4-triazolo-3-thioacetic acid]
(3a–c) were prepared from 5-substituted-3-phenylindole-2-[1,2,4-triazole-3-
thione] (2a–c) with an appropriate alkylating agent and sodium acetate in
acetic acid. The structures of 3a–c were confirmed by their spectral data.
The IR spectrum of 3a exhibits absorption peaks at 3312, 2987, and
1682 cm21, attributable to NH/NH, C55O, and functional groups present in

5-Substituted-3-phenylindole-2-(1,2,4-triazole)
1383
1
the molecule. H NMR of 3b shows a peak at 10.0 ppm for H of COOH.
Another peak at 9.1 ppm was attributed to H of indole NH and a singlet
peak at 7.8 ppm to triazole NH. The multiplet from 7.3 to 7.6 ppm is for the
protons of aromatic ring. The peak at 4.3 ppm is due to -CH2 protons as a
singlet. The other compounds (3b and 3c) exhibit identical spectral data
with respect to 3a. Hence, structures assigned to 3a–c are in conformity
with the proposed structures.
Further 3a–c was reacted with acetic anhydride to bring about a cyclo-
condensation reaction to yield 5-substituted-3-phenylindol-2-thiazolo (2,3-b)
triazole (4a–c). The IR spectrum of 4a displays absorption peaks at
Scheme 1.

1384
P. M. V. Sharma and M. G. Purohit
3311 cm21 for indole NH functional group, and at 1685 cm21 for cyclic C55O
1
group. H NMR spectrum of 4a exhibits a peak at 12.1 ppm for H of indole
NH. The peak due to H of triazole NH appeared in the precursor has disap-
peared in the spectrum of 4a. This observation supports the cyclization to
yield expected compound 5. Two protons of the thiazole ring appear as a
singlet at 4.2 ppm. The aromatic protons appear as a multiplet from 7.3 to
7.6 ppm (Scheme 1).
These spectral data of 4a confirm the structures of 4a–c from 3a–c. All
other compounds (4a–c) exhibit identical spectral data with respect to 4a. The
5-substituted-3-phenylindole-2-[1,2,4-triazolo-3-acetic acid] (3a–c) was
reacted with O-phenylenediamino dihydrochloride in ethylene glycol to
yield 5-substituted-3-phenyl indole-1,2,4-triazolo-30-yl-thio methyl) benzimi-
dazoles (5a–c). The spectrum of 5b shows a broad peak at 3313 cm21 for the
1
absorption of NH/NH functionality of indole and triazole. The H NMR
spectrum of 5b exhibits a downfield peak at 9.1 ppm, due to the resonance
of H of indole NH. The H of triazole NH appears as a singlet at 7.8 ppm.
The multiplet in the region from 7.2 to 7.6 ppm is due to aromatic protons.
The protons of -CH2 appear as a singlet at 4.3 ppm. Furthermore, the
structure of 5b is supported by its mass spectra. Other derivatives (5a–c)
also exhibit identical spectral properties, confirmed by their spectral data
(Table 1).
EXPERIMENTAL
Ethyl 3,5-Disubstituted Indole-2-carboxylates (1a–c)
Ethyl a-benzylaceto acetate: Anhydrous ethanol (780 mL) was placed in a
three-necked flask (2 L), filled with reflux condenser, mercury-sealed stirrer,
and a dropping funnel. Small pieces of sodium (38.8 g, 1.6 mol) were added
and dissolved to form sodium ethoxide. Ethylacetoacetate (21 g, 1.6 mol)
was added to this with stirring for 2 h, followed by benzyl chloride (208 g,
1.7 mol). The reaction mixture was heated under reflux on a water bath for
4–5 h and kept for 4 h at room temperature. Ethanol was distilled off under
reduced pressure, and the residue was diluted with water (1 L). The oil
separated after cooling and was extracted with ether. The extract was dried
on Na2SO4, and the solvent was removed by distillation. Distillation of
residual oil under reduced pressure gave ethyl a-benzylacetoacetate as a
colorless oil, yield 60%.
Ethyl Phenyl Pyruvate Phenylhydrazones
Ice-cold solution of potassium hydroxide (125 mL, 51%) was added to a vig-
orously stirred solution of ethyl a-benzyl acetoacetate (82.55 g, 0.375 mol) in

Table 1. Synthesis of some 5-substituted-3-phenylindole-2-(1,2,4-triazole) derivatives
Found (cald.)
MP Yield
(8C)
Compound
(%) Molecular formula
C
H
N
IR (cm21
)
1H NMR (ppm)
2a
162
70
64
C16H11N4SBr
C16H11N4SCl
C17H14N4S
51.75 (51.62) 2.96 (2.90) 15.00 (15.09)
58.80 (58.89) 3.30 (3.37) 17.10 (17.17)
66.65 (66.66) 4.50 (4.57) 18.28 (18.30)
3328, 3280 NH/NH
3312 NH, 3260 NH
3316, 3260 NH/NH
9.2 (s, 1H, indole NH),
8.6 (dH), 7.8 (s, triazole
NH), 7.2–7.6 (Ar-H)
9.1 (s, 1H, indole NH),
8.7 (stio), 7.6 (s, triazole
NH), 7.3–7.8 (Ar-H)
2b
173
2c
3a
168
148
68
75
C18H13N4O2SBr 50.32 (50.34) 3.00 (3.03) 13.00 (13.05) 3312 NH, 1682 (C55O) 9.1 (s, 1H, indole NH),
7.7 (s, triazole NH),
7.3–7.6 (Ar-H)
C18H13N4O2SCl 56.20 (56.25) 3.36 (3.38) 14.56 (14.58) 3216 NH, 1690 (C55O) 9.3 (s, 1H, indole NH),
3b
155
68
7.5 (s, triazole NH),
7.16–7.5 (Ar-H)
3c
4a
153
180
76
62
C19H16N4O2S 62.60 (62.63) 4.30 (4.39) 15.35 (15.38) 3318 NH, 1659 (C55O)
C18H11N4SOBr 52.50 (52.55) 2.60 (2.67) 13.60 (13.62) 3311 (NH), 1685 (C55O) 12.1 (s, 1H, indole NH),
3.3 (triazole CH2),
7.3–7.6 (Ar-H)
(continued)

Table 1. Continued
Found (cald.)
H
MP Yield
(8C) (%) Molecular formula
Compound
C
N
IR (cm21
)
1H NMR (ppm)
4b
160
70
C18H11N4SOCl 59.05 (59.01) 3.12 (3.00) 15.32 (15.30) 3317 (NH), 1690 (C55O) 12.2 (s, 1H, indole NH),
3.4 (triazole CH2),
7.3–7.59 (Ar-H)
4c
5a
166
188
63
56
C19H14N4SO
C24H17N6SBr
65.85 (65.89) 4.02 (4.04) 16.20 (16.18) 3318 (NH), 1596 (C55O)
57.42 (57.48) 3.35 (3.39) 16.72 (16.76) 3313 (indole NH), 2988
(triazole NH)
9.1 (indole NH), 7.8
(benzimidazole NH)
5b
5c
196
190
59
60
C24H17N6SCl
C25H20N6S
63.14 (63.15) 3.70 (3.72) 18.40 (18.42) 3260 (indole NH), 2860 9.36 (indole NH), 7.9
(triazole NH)
(benzimidazole NH),
7.3–7.8 (Ar-H)
68.50 (68.80) 4.50 (4.58) 19.22 (19.26) 3317 (indole NH), 2890
(triazole NH)

5-Substituted-3-phenylindole-2-(1,2,4-triazole)
1387
absolute alcohol (375 mL), maintained at 0 8C, followed by the addition of ice
water (700 mL). Immediately the diazonium solution (which was prepared from
substituted anilines, 0.375 mol; concentrated hydrochloric acid, 150 mL; water,
225 mL; and sodium nitrite, 26.3 g, in 80 mL of water) was added, and stirring
continued for 30 min. Ethyl phenyl pyruvate phenylhydrazone separated as red
oil, was extracted with ether, and was distilled off. The red oil obtained was dried
in a vacuum over P2O5 and used directly for the next stage.
Dry hydrogen chloride gas was passed into a solution of the hydrazone
(0.16 mol) in superdry alcohol (200 mL) with occasional shaking until the sep-
aration of ammonium chloride was complete. It was then allowed to stand for
2 h. The reaction mixture was poured into crushed ice. The separated solid
was filtered, washed thoroughly with water, dried, and crystallized from
absolute alcohol to obtain ethyl substituted indole-2-carboxylates (1a–c).
5-Substituted-3-phenylindol-2-[1,2,4-triazole-3-thione] (2a–c)
3-Phenyl-indole-2-carboxylate (0.01 mol) on reaction with thiosemicarbazide
(0.01 mol) was refluxed for 8 h in 30 ml of pyridine. The solution was poured
1
into ice/HCl. The separated solid was filtered dried and recrystallized. H
NMR data: 9.2 (s, 1H, indole NH), 8.6 (dH), 7.8 (s, triazole NH), 7.2–7.6 (Ar-H).
5-Substituted-3-phenylindol-2-[1,2,4-triazolo-3-thioacetic Acid] (3a–c)
5-Substituted-indole-2-[1,2,4-triazole-3-thione] (2a–c) (1 g) in acetic anhydride
(10 ml) was refluxed for 3 h, then cooled and poured into water. The formed
1
product was collected and recrystallized. H NMR data: 9.1 (s, 1H, indole
NH), 7.7 (s, 1H, triazole NH), 7.3–7.6 (Ar-H).
5-Substituted-3-phenylindole-2-thiazolo [2,3-b] Triazole (4a–c)
5-Substituted-3-phenylindole-2-[1,2,4-triazolo-3-thioacetic acid] (3a–c)
(0.01 mol), chloroacetic acid (0.03 mol), and sodium acetate (3 g) in acetic
acid (30 ml) was refluxed for 5 h, and then the solution was evaporated.
The residue was washed with a little water and recrystallized. 1H NMR
data: 12.1 (s, 1H, indole NH), 3.3 (s, 2H, triazole CH2), 7.3–7.6 (Ar-H).
5-Substituted-3-phenylindole-1,2,4-triazolo[30-yl Sulfanyl Methyl]
Benzimidazole (5a–c)
5-Substituted-3-phenylindole-2-[1,2,4-triazolo-3-acetic acid] (3a–c) (0.01 mol)
and orthophenylenediamine dihydrochloride (i) (0.01 mol) in ethyleneglycol

1388
P. M. V. Sharma and M. G. Purohit
(20 ml) was refluxed for 5 h. The reaction mixture was cooled to room temp-
erature and poured into water (100 ml). The obtained solid was filtered and
suspended in water. The pH of the solution was adjusted to 7 by the
addition of sodium bicarbonate. It was filtered, washed, dried, and recrystal-
1
lized. H NMR data: 9.1 (s, 1H, indole NH), 7.8 (s, 1H, benzimidazol NH).
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