Highly Efficient [3?+?2] Cycloaddition: Click Synthesis of Novel 1H-indol-3-yl-benzo[d]imidazole Bis-triazoles

Article abstract of DOI:10.1002/jhet.3679

A series of novel 1-((1H-1,2,3-triazol-4-yl)methyl)-2-(1-((1H-1,2,3-triazol-4-yl)methyl)-5-substituted-1H-indol-3-yl)-6-substituted-1H-benzo[d]imidazoles 5a–i have been prepared using click chemistry as an ideal strategy where [3?+?2] cycloaddition of azides with terminal alkynes has been developed as the target compounds. In route-II, 5-substituted-1H-indole-3-carbaldehydes 1a–c react with 5-substituted orthophenylenediamine 8 to give desired products, that is, 6-substituted-2-(5-substituted-1H-indol-3-yl)-1H-benzo[d]imidazole 6a–i. Here, 6a–i react with 2?equiv of propargylbromide 7 to give novel 6-substituted 2-(5-substituted-1-(prop-2-yn-1-yl)-1H-indol-3-yl)-1-(prop-2-yn-1-yl)-1H-benzo[d]imidazole 4a–i. 4a–i were reacted with 2?equiv of NaN₃ in t-butanol/water (1:2) and add catalytic amount of CuSO₄.5H₂O. Stir the reaction mixture at room temperature to get the target products 5a–i. Here, obtained products contain four rings, that is, one indole, two triazoles, and one benzimidazole. The main advantages of this method are short reaction times, easy workup, higher yields (88–92%), and no by-products formation.

Full text of DOI:10.1002/jhet.3679

Month 2019 Highly Efficient [3 + 2] Cycloaddition: Click Synthesis of Novel 1H-indol-
3-yl-benzo[d]imidazole Bis-triazoles
*
Mahesh Goud Bakkolla,
Ashok Kumar Taduri, and Rama Devi Bhoomireddy
Department of Chemistry, College of Engineering, Jawaharlal Nehru Technological University Hyderabad, Hyderabad
500 085, Telangana, India
*E-mail: mahesh.bakkolla@gmail.com
Received March 22, 2019
DOI 10.1002/jhet.3679
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel 1-((1H-1,2,3-triazol-4-yl)methyl)-2-(1-((1H-1,2,3-triazol-4-yl)methyl)-5-substituted-
1H-indol-3-yl)-6-substituted-1H-benzo[d]imidazoles 5a–i have been prepared using click chemistry as an
ideal strategy where [3 + 2] cycloaddition of azides with terminal alkynes has been developed as the target
compounds. In route-II, 5-substituted-1H-indole-3-carbaldehydes 1a–c react with 5-substituted
orthophenylenediamine 8 to give desired products, that is, 6-substituted-2-(5-substituted-1H-indol-3-yl)-
1H-benzo[d]imidazole 6a–i. Here, 6a–i react with 2 equiv of propargylbromide 7 to give novel 6-
substituted
2-(5-substituted-1-(prop-2-yn-1-yl)-1H-indol-3-yl)-1-(prop-2-yn-1-yl)-1H-benzo[d]imidazole
4a–i. 4a–i were reacted with 2 equiv of NaN3 in t-butanol/water (1:2) and add catalytic amount of
CuSO4.5H2O. Stir the reaction mixture at room temperature to get the target products 5a–i. Here, obtained
products contain four rings, that is, one indole, two triazoles, and one benzimidazole. The main advantages
of this method are short reaction times, easy workup, higher yields (88–92%), and no by-products formation.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
containing indole moieties always attract the attention of
chemists [7].
Click chemistry is a well-known synthetic methodology
for the syntheses of various drug molecules, allowing the
joining of substrates of choice with specific biomolecules
in drug discovery process. Indoles are one of the most
important nitrogen-containing heteroaryl compounds,
found extensively in biological systems such as
Triazoles are essential molecular entities because of their
unique chemical and physical properties, and a wide variety
of triazoles with structurally diverse and functionalized
groups have gained much attention in organic synthesis
due to their potential as key fragments in drug syntheses
[8–12]. They are well known for their wide selection of
functions in organometallic, organic, medicinal, and
materials chemistry [13–18]. 1,2,3-Triazoles were
discovered to be versatile constructing blocks in natural
synthesis and exhibit very important pharmacological
functions owing to their stability in the presence of light,
moisture, and oxygen [19–21]. The 1,2,3-triazole unit is
currently an exclusive in quite a few bioactive entities
exhibiting fascinating properties corresponding to
antiproliferative, antibacterial, anti-HIV, anti-allergic, anti-
tryptophan which play
a very important role in
biochemical processes. Because the wide range of
biological activities is associated with indole derivatives,
both naturally occurring and synthetic indole derivatives
remain a topic of current interest [1–5]. Among the wide
variety of heterocycles that have been explored for
developing
biochemically
important
molecules,
benzimidazoles played an important role in medicinal
chemistry [6], and the scaffolds of benzimidazole
© 2019 Wiley Periodicals, Inc.

M. G. Bakkolla, A. K. Taduri, and R. D. Bhoomireddy
Vol 000
parasitic, antifungal, antiviral, and antimicrobial actions
[22–25]. Currently, 1,2,3-triazoles have been exploited as
a backbone of bidentate phosphine ligands in the industrial
sector as photosensitizers, dyes, and agrochemicals and
commercially utilized as anticorrosive agents [26,27].
There are various diverse examples of biologically active
molecules containing 1,2,3-triazoles [28–30] that have
been receiving rising prominence concerning their
versatile functions [31–33], and consequently, important
advances have been made in accessing such frameworks
with numerous functionalities which represent one of
many ongoing programs in trendy organic synthesis.
We synthesized a collection of green and novel 1-((1H-
1,2,3-triazol-4-yl)methyl)-2-(1-((1H-1,2,3-triazol-4-yl)
methyl)-5-substituted-1H-indol-3-yl)-6-substituted-1H-
benzo[d]imidazole derivatives 5a–i in two routes with
excellent yields. All the synthesized compounds 5a–i
comprising bis-triazole are considered high biologically
effective because they possess indole and benzimidazole
ring systems. Their structures have been confirmed by
FTIR, 1H-NMR, 13C-NMR, and LC–MS spectroscopic
methods.
cycloaddition reactions in high efficient ways, that is, in
two routes. Here, for the synthesis of 5a, the reaction
parameters were optimized in two routes. In route I
(Scheme 1), for the synthesis of 5a, substituted indole-3-
carbaldehyde is reacted with propargyl bromide using
K2CO3 as base and TBAB as a phase-transfer catalyst
using acetonitrile as the reaction medium resulted N-
propargyl-substitued-indole-3-carbaldehyde 2a which was
further treated with 5-substituted OPDA in ethanol, a
catalytic quantity of Na2S2O5, and allowed to reflux for
1.5 h at 120°C resulted the formation of 3a as a result of
cyclization followed by dehydration under refluxing
conditions. The excess amount of OPDA might be
eliminated by treating the product with hot water. 3a was
further proporgylated using the same conditions for the
synthesis of 2a to prepare the product 4a. Lastly, the
compound 4a was treated with 2 equiv of NaN3
dissolved in t-butanol/water (1:2), with a catalytic
quantity of CuSO4.5 H2O at room temperature for 5 min
followed by the addition of sodium ascorbate resulted the
formation of the target compound 5a with an excellent
yield. Here, NaN3 resulted the formation of 1,2,3-triazole
rings of 5a and CuSO4.5H2O in t-butanol/water promoted
(3 + 2) cycloaddition reactions. Here, the sodium
ascorbate is utilized as a reducing agent which generated
Cu (I) and enhanced the cycloaddition mechanism.
RESULTS AND DISCUSSION
Here, we prepared novel 1H-Indol-3-yl-benzo[d]
imidazole bis-triazoles 5a–i and optimized parameters for
the synthesis of these compounds using (3 + 2)
In route-II (Scheme 2), 1a reacts with 5-substituted
OPDA in ethanol and Na2S2O5, and this reaction mixture
was refluxed at 120°C for 1.5 h resulted the formation of
Scheme 1. Synthesis of novel bis-triazoles.
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Month 2019
Highly Efficient [3 + 2] Cycloaddition
Scheme 2. Alternative route for synthesis novel bis-triazoles.
6a. 6a then treated with 2 equiv of propargyl bromide in
acetonitrile using K2CO3 as base and a catalytic quantity
of TBAB as phase-transfer catalyst at room temperature
yielded 4a. Using standard click chemistry reaction
protocols, the mixture of 4a, CuSO4.5 H2O, 2 equiv
of NaN3 and sodium ascorbate have been dissolved in t-
butanol/water (1:2) and stirred at room temperature for 4 h
followed by neutralization with dil. HCl resulted 5a and
its derivatives. Among these two strategies, Scheme 2 is a
straightforward and environment friendly for the syntheses
of compounds 5a–i as this methodology requires much
less variety of steps and time and obtains better yield.
Table 1
Synthesis of different structurally bis-triazole derivatives of 5a under various conditions.
Entry
Catalyst (mol%) CuSO4.5H2O
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
0
2
2
2
2
5
5
5
10
10
10
15
15
15
20
20
20
10
10
10
10
20
DMF
DMF
DMSO
t-Butanol
t-Butanol/water (1:1)
DMF
DMSO
t-Butanol/water (1:1)
DMF
DMSO
t-Butanol/water (1:1)
DMF
24
6
10
24
20
5
10
17
4
8
15
4
16
15
14
12
15
8
0
62
55
0
60
65
56
65
80
68
72
80
65
70
56
68
68
84
92
78
88
92
9
10
11
12
13
14
15
16
17
18
19
20
21
22
DMSO
t-Butanol/water (1:1)
THF/water (2:1)
THF/water (1:2)
t-Butanol/water (1:1)
t-Butanol/water (2:1)
t-Butanol/water (1:2)
t-Butanol/water (3:1)
t-Butanol/water (1:3)
t-Butanol/water (1:2)
4
10
6
2
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Table 2
Synthesis of compounds 5a–i derivatives.
S. no
Products 5a–i
R
R1
Temperature
RT
Time (h)
10
Yield (%)
1
2
3
4
5
6
H
H
H
H
92
90
88
90
89
5a
5b
5c
5d
5e
NO2
CO-Ph
H
RT
RT
RT
RT
10
12
10
10
12
NO2
NO2
NO2
NO2
CO-Ph
RT
89
(Continues)
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Highly Efficient [3 + 2] Cycloaddition
Table 2
(Continued)
S. no
Products 5a–i
R
R1
Temperature
Time (h)
Yield (%)
5f
5g
5h
5i
7
8
9
Br
Br
Br
H
RT
10
10
12
90
88
90
NO2
RT
CO-Ph
RT
Various conditions have been applied to optimize the
yields for the formation of bis-triazoles (Table 1). The
presence of CuSO4.5H2O was apparent, and no product
formation was observed in its absence (Table 1, entry 1).
Another set of the reaction mixture was enabled to stir at
normal room temperature within the presence of sodium
ascorbate and CuSO4.5H2O in DMF, and the reaction
was accomplished in shorter reaction time with poor yield
(Table 1, entry 2). When dry t-butanol was used as the
solvent, no product formation was noticed (Table 1, entry
4). Apparently, an overabundance of water was beneficial
to this method. The explanation could also be that it is
going to improve the solubility of 4a–i in this reaction
system. It was discovered ultimately that the reaction
proceeded more efficiently when the reaction was
carried out in the presence of CuSO4.5H2O (10 mmol) in
t-butanol/H2O in 1:2 ratio at room temperature to give an
excellent yield of the cycloaddition product. Hence, the
product 5a was isolated with 92% of yield utilizing these
optimum reaction conditions (Table 1, entry 19). Lastly,
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M. G. Bakkolla, A. K. Taduri, and R. D. Bhoomireddy
Vol 000
we examined identical reaction in several catalyst ratios
and solvent systems such as dimethyl sulfoxide (DMSO)
(Table 1, entries 3, 7, and 13), THF/H2O (2:1) (Table 1,
entry 15), THF/H2O (1:2) (Table 1, entry 16), t-butanol/
Water (3:1) (Table 1, entry 20), t-butanol/water (1:3)
(Table 1, entry 21). It is observed that all these reaction
conditions with various solvents mentioned earlier
resulted the products in moderate yields with longer
time. A rise within the quantity of water content
compares to t-butanol within the solvent mixture resulted
in a rise within the yield of the target bis-triazoles. Using
only 10 mol% CuSO4.5H2O is ample to push the reaction
forward, and higher quantities of the catalyst did not
enhance the yields to any better extent (Table 1,
entry 22). Right here, we perceived the scope and the
generality of CuSO4.5H2O and t-butanol/water promoted
(3 + 2) cycloaddition reactions.
imidazole bis-triazole derivatives 5a–i were synthesized in
good yields (88–92%) and represented in Table 2. The
formation of 5a–i were identified by checking thin-layer
chromatography (TLC).
Totally considering the experimental outcomes, a
plausible mechanism for the formation of the 5a
derivatives was proposed in Scheme 3. 6a reacts with
2 equiv propargyl bromide forms product 4a. Right here,
the coordination of the 4a with Cu (I), one ligand has got
displaced and then re-coordination to provide 9a. Within
the subsequent step, the azide displaces one of the ligands,
and the copper complex binds to the nitrogen atom which
is adjacent to the carbon on both the rings to form an
intermediate 10a. Attacking reaction by the terminal
nitrogen atom in 10a on C-2 to form the cyclic six-
membered Cu (III) intermediate 11a which is unstable and
immediately undergoes rearrangement. Rearrangement of
11a provides a five-membered compound 12a which yields
the target compound 5a by the elimination of Cu complex.
Based on the aforementioned conditions, a variety of
structurally divergent novel 1H-indol-3-yl-benzo[d]
Scheme 3. Plausible mechanism for the formation of 5a.
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Highly Efficient [3 + 2] Cycloaddition
CONCLUSION
Synthesis of compounds 5a–i from 4a–i.
To the
compounds of 4a–i (0.3 g, 1 mmol), 2 equiv of sodium
azide (1.2 g 1 mmol), CuSO4.5H2O (10 mol%), and
sodium ascorbate (20 mol%) in t-butyl alcohol/water
(1:2) were added, and the reaction was stirred at room
temperature for 1 h. The progress of the reaction was
monitored by TLC method. The reaction completion
times were varied as per the conditions of the products
that were obtained from previous procedures. Upon
completion of the reaction, the reaction mixture was
poured into ice cold water and neutralized with acetic
acid to obtain the pure target compounds 5a–i.
In summary, a simple, efficient, and green syntheses
of novel l-H-indol-3-yl-benz[d]imidazobis-1,2,3-triazoles
have been developed. An alternative reaction methodology
also has been reported, which also considered an efficient
and environment friendly method. The products were
synthesized in good to higher yields under mild
conditions. Both t-butanol/water and CuSO4.5H2O are
inexpensive and eco-friendly. The route-II has the
advantages of simple procedure, shorter reaction time,
good yields, and easy workup.
General procedure. Synthesis of compounds 6a–i from 1a–
c. The synthetic procedure for the synthesis of 6a–i from
1a–c is the same as mentioned earlier for the synthesis of
3a–i.
EXPERIMENTAL
Synthesis of compounds 4a–i from 6a–i.
To the
Melting points of all newly synthesized compounds
were recorded in Buchi B-540 melting point apparatus.
All required organic chemicals were bought from Sigma
compounds of 6a–i (0.3 g, 1 mmol) (20 mL), added
2 equiv propargyl bromide (0.36 g, 2 mmol), K2CO3
(1.3 g, 3 mmol), and the catalytic amount of TBAB
(1 mmol) in acetonitrile. The entire reaction mixture was
allowed to stir at room temperature for 2 h. The progress
of the reaction was monitored by TLC method. Upon
completion of the reaction, the chemical reaction mixture
was added to ice cold water in a 250-mL beaker to yield
pure solid 4a–i, which was filtered and dried.
1
Aldrich Company. 13C-NMR and H-NMR spectral data
were reported using Bruker-ARX 400 Mega Hertz
Fourier Transmitter-NMR spectrometer using DMSO as
an internal reference solvent to obtain NMR spectra.
Mass spectra of the target products were obtained using
an LC–MS spectrometer of Agilent instrument. The
completion of the reactions were observed using TLC
method, and the target moieties were visualized by UV–
Visible Chamber (254, 365).
Synthesis of compounds 5a–i from 4a–i.
The
methodology for the synthesis of compounds 5a–i is the
same as above for the synthesis of 5a–i from Scheme 1.
General methodology. Synthesis of compounds 2a–c from
1a–c. Compounds of 1a–c (1.45 g, 10 mmol), 1 equiv
propargyl bromide (1.18 g, 10 mmol) in acetonitrile,
K2CO3 (4.14 g, 30 mmol), and catalytic amount of
TBAB (1 mmol) were taken into a round bottom flask of
100-mL quantity. The reaction mixture was allowed to
stir at room temperature for 2 h, and the progress of the
reaction was monitored by TLC. Upon completion of the
reaction, the mixture was poured into crushed ice into a
Acknowledgments. The authors are thankful to the authorities of
Jawaharlal Nehru Technological University, Hyderabad, for
providing laboratory facilities.
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M. G. Bakkolla, A. K. Taduri, and R. D. Bhoomireddy
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Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
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