A Facile Synthesis of Novel (Z)-ethyl-3-(5-substituted-1-alkyl/aryl-1H-indol-3-yl)-2-(1H-tetrazol-5-yl)acrylate

Article abstract of DOI:10.1002/jhet.3375

A novel route was developed for synthesis of high potential 1H-tetrazoles by using conventional method. Tetrazole scaffold is a promising pharmacophore fragment, frequently used in the development of various novel drugs. Here, the novel (Z)-3-(N-alkyl-indol-3-yl)-2-(1H-tetrazole-5-yl)acrylates 5 (a–i) have been synthesized from (Z)-ethyl-3-(1H-indol-3-yl)2-(1H-tetrazol-5-yl)acrylates 4 (a–c) by using various alkylating agents such as Dimethyl Sulphate (DMS), Diethyl Sulphate (DES), and benzyl chloride; 4 (a–c) were synthesized from sodium azide in the presence of copper sulfate in dimethylformamide; 3 (a–c) have been prepared by Knoevenagel condensation of indole-3-carbaldehyde 1 (a–c) and ethylcyanoacetate 2 in the presence of L-Proline as a catalyst at room temperature in ethanol for an hour. This is an efficient and clean click chemistry method that has various advantages such as easy workup, higher yields, shorter reaction times, and more economical.

Full text of DOI:10.1002/jhet.3375

Month 2018
A Facile Synthesis of Novel (Z)-ethyl-3-(5-substituted-1-alkyl/aryl-1H-
indol-3-yl)-2-(1H-tetrazol-5-yl)acrylate
*
Mahesh Goud Bakkolla,
Ashok Kumar Taduri, and Rama Devi Bhoomireddy
Department of Chemistry, Jawaharlal Nehru Technological University Hyderabad, College of Engineering, Kukatpally,
Hyderabad, Telangana 500 085, India
*E-mail: mahesh.bakkolla@gmail.com
Received June 26, 2018
DOI 10.1002/jhet.3375
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A novel route was developed for synthesis of high potential 1H-tetrazoles by using conventional method. Tet-
razole scaffold is a promising pharmacophore fragment, frequently used in the development of various novel
drugs. Here, the novel (Z)-3-(N-alkyl-indol-3-yl)-2-(1H-tetrazole-5-yl)acrylates 5 (a–i) have been synthesized
from (Z)-ethyl-3-(1H-indol-3-yl)2-(1H-tetrazol-5-yl)acrylates 4 (a–c) by using various alkylating agents such
as Dimethyl Sulphate (DMS), Diethyl Sulphate (DES), and benzyl chloride; 4 (a–c) were synthesized from so-
dium azide in the presence of copper sulfate in dimethylformamide; 3 (a–c) have been prepared by Knoevenagel
condensation of indole-3-carbaldehyde 1 (a–c) and ethylcyanoacetate 2 in the presence of L-Proline as a catalyst
at room temperature in ethanol for an hour. This is an efficient and clean click chemistry method that has various
advantages such as easy workup, higher yields, shorter reaction times, and more economical.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
investigation especially from the nitrile functionality,
which is widely recognized as a useful intermediate in
organic synthesis [16]. Synthetic, medicinal, and
pharmaceutical applications of tetrazoles are well
explored and documented in the literature [17]. Biphenyl
tetrazoles are also well known and used to synthesize
certain family drugs [18]. The other class of its use
includes propellants [19], explosives, and in photography.
[20] In addition to the above, it is found useful in
agriculture as plant growth regulators and in crop
protection [21]. Its derivatives play a key role as
herbicides and fungicides [22]. The synthesis of 5-
substituted-1H-tetrazoles was found fascinating, and
many new processes and revisions of existing processes
since Finnegan’s invention have appeared. The basic
principle of most of them is almost common, that is,
cycloaddition of nitrile with an azide moiety, under the
influence of several efficient catalysts and different
solvent conditions. Number of new catalysts have also
been investigated till date and among those which serve
the purpose are [23] copper triflates [24], Fe (OAc)2 [25],
zinc (II) salts, and Lewis acids such as [26] AlCl3 [27],
The chemistry of heterocyclic compounds has acquired
immense importance in recent years. The tetrazole
functionality is metabolically stable and has a closer
similarity with the acidic character of the carboxylic acid
group that has been inspired medicinal chemists to
synthesize substituted tetrazoles as potential medicinal
agents. 5-Substituted tetrazoles are reported to possess [1]
antibacterial [2], antifungal [3], antiviral, [4] analgesic
[5], anti-inflammatory [6], antiulcer, and [7]
antihypertensive activities. Also [8,9], this functional
group has efficient roles in coordination chemistry as a
ligand and in various material science applications
including propellants and explosives. Furthermore [10],
tetrazole moieties are important synthons in synthetic
organic chemistry [11,12]. Therefore, a number of
methods have been reported for the preparation of
tetrazoles [13,14], one of the major synthetic routes to
tetrazole formation is the [2+3] cycloaddition of an
organonitrile and an azide salt [15]. The preparations of
substituted tetrazoles have been the subject of intense
© 2018 Wiley Periodicals, Inc.

M. G. Bakkolla, A. K. Taduri, and R. D. Bhoomireddy
Vol 000
BF3–OEt2 [28], FeCl3 [29], TBAF [30], heterogeneous
catalysis COY zeolites[31], mesoporous ZnS nanospheres
[32], Cu2O, and [33] CuFe2O4 nanoparticles [25]. Acid
catalysts are also used for the synthesis of tetrazoles via
cycloaddition. Recently, many chemists have reported the
use of transition elements and their salts as catalysts for
the synthesis of tetrazoles [25]. Sharpless and coworkers
were reported an innovative procedure for the preparation
of 5-substituted-1H-tetrazoles from the corresponding
nitriles and NaN3 in the presence of a stoichiometric
amount of 50 mol% of Zn (II) salts.
Herein, we report a novel methodology for the synthesis
of (Z)-ethyl-3-(5-substituted-1-alkyl/aryl-1H-indol-3-yl)-2-
(1H-tetrazol-5-yl)acrylate derivatives and their structures
were confirmed by chemical and spectroscopic methods
such as FTIR,1H NMR, 13C NMR, and HRMS.
RESULTS AND DISCUSSION
The synthetic pathway for the newly synthesized
compounds
(Z)-3-(N-alkyl-indol-3-yl)-2-(1H-tetrazole-
Shortly, an efficient method for the synthesis of tetrazoles
was reported by the reaction of nitriles with TMSN3 using
50 mol% of TBAF as catalyst. However, many of the
aforementioned protocols have some disadvantages, like
use of toxic metals, strong Lewis acids, expensive reagents,
low yields, harsh reaction conditions, water sensitivity, and
the usual separation and toxicity problems associated with
small alkyl tin reagents. In addition to this, in some cases,
formation of highly volatile and toxic hydrazoic acid as by
product warrants the safety of the method.
5-yl)acrylate 5 (a–i) derivatives starts from indole-3-
carbaldehydes 1 (a–c), on reaction with ethylcyanoacetate
2 in the presence of L-Proline as a catalyst. The reaction
has been done at room temperature in ethanol for an hour
gave (Z)-ethyl-2-cyano-3-(1H-indol-3-yl)acrylates 3 (a–
c);
3 (a–c) were reacted with sodium azide in
dimethylformamide (DMF) containing catalytic amount
of copper sulfate resulted the formation of products 4 (a–
c); 4 (a–c) were reacted with various alkylating agents
such as DMS, DES, and benzyl chloride gave the target
Scheme 1. Synthesis of Z-ethyl-3-(1H-indol-3-yl)2-(1H-tetrazol-5-yl)acrylate derivatives.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
A Facile Synthesis of Novel (Z)-ethyl-3-(5-substituted-1-alkyl/aryl-1H-indol-3-
yl)-2-(1H-tetrazol-5-yl)acrylate
Scheme 2. Plausible mechanism for the formation of 5 (a–i) in the presence of CuSO4.5H2O.
compounds, that is, novel (Z)-3-(N-alkyl-indol-3-yl)-2-
(1H-tetrazole-5-yl)acrylates 5 (a–i) (Scheme 1).
Table 1
Synthesis of 4 (a–c) and 5 (a–i) using various mol% of CuSO4.5H2O and
Another possible route for the syntheses of 5 (a–i) using
(Z)-ethyl-2-cyano-3-(5-substituted-1-aryl/alkyl-1H-indol-
3-yl)acrylates 7 (a–i) that were prepared from 5-
substituted-1-alkyl/aryl-1H-indol-3-carbaldehydes 6 (a–i)
and (2) in the presence of L-Proline as a catalyst. The
reaction has been done at room temperature in ethanol for
1 h; 6 (a–i) were obtained by the same procedure
mentioned earlier for the formation of 4 (a–c); 7 (a–i)
were reacted with sodium azide in DMF containing
catalytic amount of copper sulfate resulted the formation
of the final products 5 (a–i) (Scheme 1).
The reaction conditions have been optimized for the
formation of 4 (a–c) and 5 (a–i) under various conditions
using different solvents such as H2O, DMF, DMSO,
ethanol, acetonitrile, and toluene. It was found that DMF
is the best suitable solvent which resulting high yields of
products around 90%. CuSO4.5H2O has been chosen as
the catalyst, and various molar amounts of it has been
used and it was found that only 2 mol% of the catalyst is
solvents.
Catalyst
(mol%)
Time
(h)
Temp
(°C)
Yield
(%)
S. no.
1.
Solvent
H2O
0
2
5
0
2
5
0
2
5
0
2
5
0
2
5
0
2
5
24
24
24
24
100
100
120
120
120
120
0
0
0
0
2.
3.
4.
5.
6.
EtOH
PhCH3
CH3CN
DMF
24
1.5
1.5
24
2
0
95
86
0
74
62
DMSO
2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. G. Bakkolla, A. K. Taduri, and R. D. Bhoomireddy
Vol 000
Table 2
Synthesis of different structurally tetrazole derivatives of 4 (a–c) and 5 (a–i) in the presence of CuSO4.5H2O in DMF.
S. no.
1
Product
Time (h)
1.5
Yield %
90
M.P
220–224
235–238
2
3
4
5
1.5
1.5
1.5
1.5
88
89
85
81
224–228
205–208
218–224
6
1.5
76
210–215
7
1.5
81
215–218
(Continues)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
A Facile Synthesis of Novel (Z)-ethyl-3-(5-substituted-1-alkyl/aryl-1H-indol-3-
yl)-2-(1H-tetrazol-5-yl)acrylate
Table 2
(Continued)
S. no.
8
Product
Time (h)
1.5
Yield %
78
M.P
238–240
9
1.5
1.5
1.5
72
86
82
220–225
218–224
205–210
10
11
12
1.5
80
204–208
sufficient to obtain best results when 1:2 ratio of
intermediate 3 (a–c) and sodium azide has been taken.
Generally, with the catalysis of CuSO4.5H2O in DMSO
(Table 1, entries 6), the reaction gave good yields, whereas
in the absence of catalyst, (Z)-ethyl-3-(5-substituted-N-
CuSO4.5H2O (Table 1). No product was obtained when the
reaction was performed in ethanol, water, toluene, and
acetonitrile (Table 1, entries 1–4). As shown in Table 1,
among all the different solvents tested, DMF was found to
be the solvent of choice, because the excellent yield was
obtained in DMF at 120°C in a very short time by applying
2 mol% of CuSO4.5H2O and 1:2 molar ratio of (Z)-ethyl 2-
cyano-3-(5-substituted-1-aryl/alkyl-1H-indol-3-yl)acrylates
7 (a–i) and sodium azide (Scheme 2, Table 1).
aryl/alkyl-1H-indol-3-yl)2-(1H-tetrazol-5-yl)acrylates
5
(a–i) was not obtained (Table 1, entries 1–4). On the
basis of data from Table 1, the best amount of
CuSO4.5H2O as catalyst is 2 mol% (Table 1, entries 6).
In an effort to develop better reaction conditions, different
solvents were tested for the preparation of 5 (a–i) from the
reaction of (Z)-ethyl-2-cyano-3-(1H-indol-3-yl)acrylates 3
(a–c) with sodium azide in the presence of 2 mol% of
The
formation
of
(Z)-ethyl-3-(1H-indol-3-yl)2-
(1H-tetrazol-5-yl)acrylate derivatives, that is, 4 (a–c) and
(Z)-ethyl-3-(5substituted-N-aryl/alkyl-1H-indol-3-yl)2-
(1H-tetrazol-5-yl)acrylate derivatives
5
(a–i) were
Journal of Heterocyclic Chemistry
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M. G. Bakkolla, A. K. Taduri, and R. D. Bhoomireddy
Vol 000
2. Tetrazole formation:
determined by thin-layer chromatography (TLC), and the
structures of these newly synthesized compounds were
Route I: A mixture of 3a (1 mmol) and sodium azide
(2 mmol) in DMF (10 mL) with catalytic
amount of CuSO4.5H2O added shown in
(Table 1). The reaction mixture was refluxed
for 1.5 h and the completion of the reaction
indicated by TLC. The reaction mixture was
poured into crushed ice, and the separated
crude product was filtered. To the filtrate,
15 mL of 2N HCl was added with vigorous
stirring causing the tetrazoles to precipitate.
The precipitate was filtered and dried to ob-
tain product 4 (a) in pure form.
1
characterized by FTIR, H NMR, 13C NMR, and mass
spectral analysis methods.
To understand the scope and the generality of
CuSO4.5H2O promoted (3+2) cycloaddition reactions, a
variety of structurally divergent Z-ethyl-3-(1H-indol-3-
yl)2-(1H-tetrazol-5-yl)acrylates and a wide range of
alkylating agents were chosen and the results are
presented in Table 2.
CONCLUSION
Route II: Another possible route for the preparation of
5 (a–i) from 7 (a–i). The procedure is same as
earlier.
In conclusion, an efficient and conventional method for
the preparation of novel (Z)-ethyl-3-(5-substituted-1-
alkyl/aryl-1H-indol-3-yl)-2-(1H-tetrazol-5-yl)acrylates
5
(a–i) has been presented. The synthetic method is very
simple, with shorter reaction times within 0.5–1.5 h that
has given excellent product yields up to 90%. This
environmental friendly method is very attractive as it is
very safe process with simple workup, use of
inexpensive, and readily available catalyst.
3. N-alkylation reaction:
Route I: A mixture of 1 (a–c) (1 mmol), alkylating
agent (3 mmol), acetonitrile (20 mL), K2CO3
(5 mmol), and TBAB (0.1 g) was stirred at
room temperature for 2 h. The completion of
reaction was checked by TLC. At the end of
this period, the reaction mixture was diluted
with water (40 mL) and extracted with ethyl
acetate (30 mL). The separated organic layer of
ethyl acetate was collected and was dried over
anhy. Na2SO4 (0.2 g) and the solvent was re-
moved with vacuum. The obtained product
was washed with hexane and recrystallized by
using a suitable solvent to give pure 6 (a–i).
Route II: Another possible route for the preparation of
5 (a–i) from 4 (a–i) is same as earlier.
EXPERIMENTAL
Melting points were determined using open capillary
tubes in sulfuric acid bath, TLC were run on silica gel-G,
and visualization was performed using iodine or UV
light, IR spectra were recorded using PerkinElmer
1
spectrum version 10.03.02 instrument in KBr Pellets. H
NMR spectra were recorded in CDCl3/DMSO using
400 MHz instrument. Mass spectra were recorded on an
Agilent LC–MS instrument giving only M+ values in
(Q + 1) mode.
All the chemicals were obtained from commercial
sources and used without purification.
Another possible route for the preparation of 7 (a–i)
from 3 (a–c) is same as earlier.
General procedure.
Synthesis of target molecules 5
Acknowledgment. The authors are thankful to the authorities of
Jawaharlal Nehru Technological University, Hyderabad, for
providing laboratory facilities.
(a–i) have been done basically by following three types
of reactions in both route I and route II.
1. Knovenagel condensation:
Route I: A mixture of indole-3-carbaldehyde 1 (a–c)
(5 mmol), ethylcyanoacetate 2 (6.5 mmol,
0.69 mL), and L-Proline (40 mol%, 0.288 g) in
ethanol (20 mL) was stirred at room tempera-
ture for 1 h. After completion (as shown by
TLC) of the reaction, the mixture was poured
into ice cold water. The separated solid was
filtered, washed with water, and dried to obtain
the crude product 3a in pure form.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
A Facile Synthesis of Novel (Z)-ethyl-3-(5-substituted-1-alkyl/aryl-1H-indol-3-
yl)-2-(1H-tetrazol-5-yl)acrylate
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet