Copper-catalyzed Synthesis of N-alkylated 2-(4-substituted-1H-1,2,3-triazol-1-yl)-1H-indole-3-carbaldehyde by Step-wise and One-pot Three-component Huisgen's 1,3-dipolar Cycloaddition Reaction

Article abstract of DOI:10.1002/jhet.2918

An efficient method for the synthesis of N-alkylated 2-(4-substituted-1H-1,2,3-triazol-1-yl)-1H-indole-3-carbaldehyde has been developed starting from oxindole and indole using Huisgen's 1,3-dipolar cycloaddition reaction of organic azides to alkynes. The effect of catalysts and solvent on these reactions has been investigated. Among all these conditions, while using CuSO₄·5H₂O, DMF was found to be the best system for this reaction. It could also be prepared in a one-pot three-component manner by treating equimolar quantities of halides, azides, and alkynes. The Huisgen's 1,3-dipolar cycloaddition reaction was performed using CuSO₄·5H₂O in DMF with easy work-up procedure.

Full text of DOI:10.1002/jhet.2918

Month 2017
Copper-catalyzed Synthesis of N-alkylated 2-(4-substituted-1H-1,2,3-
triazol-1-yl)-1H-indole-3-carbaldehyde by Step-wise and One-pot Three-
component Huisgen’s 1,3-dipolar Cycloaddition Reaction
Vijay Kumar Reddy Avula,a,b Swetha Vallela, Jaya Shree Anireddy, and Naga Raju Chamarthi
b
b
a
*
aDepartment of Chemistry, Sri Venkateswara University, Tirupati, Andhra Pradesh, India
bCentre for Chemical Science and Technology, IST, Jawaharlal Nehru Technological University, Hyderabad, Telangana,
India
*
E-mail: rajuchamarthi10@gmail.com
Received January 24, 2017
DOI 10.1002/jhet.2918
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
An efficient method for the synthesis of N-alkylated 2-(4-substituted-1H-1,2,3-triazol-1-yl)-1H-indole-3-
carbaldehyde has been developed starting from oxindole and indole using Huisgen’s 1,3-dipolar
cycloaddition reaction of organic azides to alkynes. The effect of catalysts and solvent on these reactions
has been investigated. Among all these conditions, while using CuSO4·5H2O, DMF was found to be the best
system for this reaction. It could also be prepared in a one-pot three-component manner by treating
equimolar quantities of halides, azides, and alkynes. The Huisgen’s 1,3-dipolar cycloaddition reaction was
performed using CuSO4·5H2O in DMF with easy work-up procedure.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
cycloaddition (CuACC) reaction has been traditionally
implemented with advantages are however the
methodologies in which the organic azides are generated
in situ from organic halides [19], (three-component azide-
alkyne cycloaddition) because hazards derived from their
isolation and handling are minimized, time-consuming,
and waste-generating additional synthetic steps are
avoided. The common organic solvents utilized (e.g.,
dioxane, toluene, DMF, dichloromethane, and THF) can
be replaced by neat water. In this vain, efforts have been
recently devoted to develop new catalytic systems, which
allow the CuAAC from other azide. Sahu et al. reported
regioselectivity of vinyl sulfone-based 1,3-dipolar
cycloaddition reactions with sugar azides by
computational and experimental studies [20]. Wua et al.
described base-mediated reaction of vinyl bromides with
aryl azides: one-pot synthesis of 1,5-disubstituted 1,2,3-
triazoles [21]. Li et al. described facile one-pot synthesis
Oxindole derivatives [1] have demonstrated significant
potential for use in a wide range of biological applications
such as NMDA antagonist [2], calcium channel blockers
[3], antiangiogenic [4], anticancer [5], and analgesic
effects [6]. The indole nucleus is the core structure in a
great number of tubulin polymerization inhibitors [7,8].
Indole [9] is the parent substance of a large number of
important compounds that occur in nature. Synthetic
indole alkaloids with different substitutions at the C-1,
C-6, and C-7 positions, some of which are widely
distributed in many plants and mammals and exhibit a
wide spectrum of biological activities [10,11].
1,2,3-Triazoles are important heterocycles [12], which
are widely used in pharmaceuticals and agrochemicals.
1,2,3-Triazoles have a wide spectrum of biological
activities [13], such as antibacterial [14], herbicidal,
fungicidal, antiallergic, and anti-HIV [15] properties.
4-Aryl-1H-1,2,3-triazoles have been used as human
methionine aminopeptidase (hMetAP2) and indoleamine
2,3-dioxygenase (IDO) inhibitors and are expected to
become medicines to treat cancers, AIDS, Alzheimer’s
disease, tristimania, cataracts, and some other serious
diseases [16].
of
4,5-disubstituted
1,2,3-(NH)-triazoles
through
Sonogashira coupling/1,3-dipolar cycloaddition of acid
chlorides, terminal acetylenes, and sodium azide [22].
Favi et al. reported one-pot copper (II)-catalyzed Aza–
Michael addition of trimethylsilyl azide to 1,2-diaza-1,3-
dienes and copper(I)-catalyzed 1,3-dipolar cycloaddition
of the in situ generated α-azido hydrazones with alkynes
[23]. However, alkynes are the most commonly used
starting materials that can provide a carbon framework.
Murthy et al. [24] described one-pot three-component
syntheses of triazoles from organic azides and
phenylacetylene using sodium ascorbate as a catalyst in
Huisgen 1,3-dipolar cycloaddition of organic azides to
alkynes is one of the most important synthetic routes
to 1,2,3-triazole derivatives [17], which have been
utilized as dyes, photo stabilizers, agrochemicals, and
biochemicals [18]. The Cu-catalyzed azide-alkyne
© 2017 Wiley Periodicals, Inc.

V. K. R. Avula, S. Vallela, J. S. Anireddy, and N. R. Chamarthi
Vol 000
ethanol at room temperature. Reddy et al. reported p-TsOH-
mediated, versatile, and efficient approach for the synthesis
of triazolyl-carbazoles from nitrovinylcarbazoles and azide
via 1,3-dipolar cycloaddition [25]. Alonso et al. described
alkenes as azido precursors for the one-pot synthesis of
1,2,3-triazoles catalyzed by copper nanoparticles on
activated carbon [26]. Wang et al. reported copper-
catalyzed synthesis of 4-aryl-1H-1,2,3-triazoles from 1,1-
dibromoalkenes and sodium azide [27]. Based on the
aforementioned literature we have synthesized, the title
compounds in a step-wise and one-pot method from azide
and acetylenic compounds.
In order to synthesize the target compounds of triazoles,
by using azide with phenyl acetylene in the presence of
sodium ascorbate as an additive and copper halide as a
catalyst in DMF solvent for 8 h at room temperature
resulted in triazoles 7a albeit in low yield 30%.
However, generally, it did not exceed 30% (Table 1,
entry 1). When CuSO4·5H2O was used as a catalyst
(Table 1, entry 9), the reaction was proceeded and gave
90% yield at room temperature in 10 min. Unfortunately,
the obtained title compounds were very unstable, so
these compounds were immediately analyzed by
recording NMR, otherwise decomposed. Among all
conditions used, CuSO4·5H2O was found to be the best
catalyst and DMF as the best solvent in terms of reaction
time and yield of the product formed. Thus, using
CuSO4·5H2O-DMF system, we synthesized the title
compounds in good to excellent yields. The structures of
all these compounds were confirmed by the analytical
and spectral data.
RESULTS AND DISCUSSION
As outlined in Scheme 1, the commercially available
oxindole was taken as a starting material, which on
reaction with Vilsmeier reagent yielded the corresponing
key β-haloaldehyde intermediate
2
[28]. This on
As shown in Scheme 2, it was thought of interest to
synthesize the title compounds 7a–f by one-pot synthesis.
Compounds 8a–d on treatment with sodium azide in
DMSO solvent for 12 h at 20°C resulted in the formation
of azide intermediate compounds. This reaction mixture
was treated with phenyl acetylene, sodium ascorbate as
an additive and copper halides as a catalyst in DMF
solvent at room temperature for 12–13 h resulted in the
treatment with alkylating agents such as methyl iodide,
ethyl bromide in acetone at room temperature using
K2CO3 as a base afforded the corresponding N-alkylated
β-haloaldehyde intermediates 3 and 4 [29]. This on
reaction with sodium azide in DMSO as a solvent at
20°C for 12 h gave N-alkylated β-azide aldehyde
intermediates 5 and 6 [30].
Scheme 1. Synthesis of N‐alkylated 2‐(4‐benzyl‐1H‐1,2,3‐triazol‐1‐yl)‐1H‐indole‐3‐carbaldehydes from indolin‐2‐one. [Color figure can be viewed at
wileyonlinelibrary.com]
Table 1
Catalyst optimization for the synthesis of triazoles from indolin‐2‐one.
Entry
Solvent
Catalyst
Temperature (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CuI
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
8
6
5
8
6
5
3
0
20
20
0
0
0
0
0
90
40
CuBr
CuCl
Cu2O
Cu(PPh3)2NO3
Cu(PPh3)2Cl
Cu(PPh3)2Br
[Cu(Phen)(PPh3)2]NO3
CuSO4·5H2O
Cu(AcO)2
7
10–30 min
4
10
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Copper-catalysed synthesis of N-alkylated indole-3-carbaldehydes
Scheme 2. One‐pot synthesis of N‐alkylated 2‐(4‐benzyl‐1H‐1,2,3‐triazol‐1‐yl)‐1H‐indole‐3‐crbaldehydes from 1‐alkyl‐2‐halo‐1H‐indole‐3‐
carbaldehyde. [Color figure can be viewed at wileyonlinelibrary.com]
formation of N-alkylated 2-(4-benzyl-1H-1,2,3-triazol-1-
yl)-1H-indole-3-carbaldehyde in low yields 20% (Table 2,
entries 1–3).
sodium ascorbate as an additive and CuSO4·5H2O as a
catalyst in DMF solvent for 2–3 h at room temperature to
obtain the products in good yields.
On further screening of catalyst in DMF (Table 2, entries
4–8), the reaction was failed. When CuSO4·5H2O was used
as a catalyst (Table 2, entry 9), the reaction was achieved in
80% at room temperature for 1–3 h. Among all observed
conditions, here also CuSO4·5H2O was found to be the
best catalyst and DMF as the best solvent in terms of
reaction time and the yield of product formed. Thus,
using CuSO4·5H2O-DMF system, we synthesized the title
compounds in good yields.
As shown in Scheme 4, compounds 22, 23 were
prepared by using the method of reference [32].
Compound 18 on reaction with alkylating agents such as
methyl iodide, ethyl bromide gave 19 and 20, which on
further coupling with 4-phenyl triazole (21) in the
presence of iodosuccinimide as a catalyst and K2CO3 as a
base at room temperature for 1 h resulted in the
formation of compounds 22 and 23 [33]. Preliminary
mechanistic investigation was carried out to understand
this mechanism at the combination of 3-indolylaldehyde
and 4-phenyltriazole by reference [32] and provided in
Figure 1.
As shown in Scheme 3, by adopting the method of
reference [31], compounds 9–13 were synthesized.
Reactions were conducted on 14, 15 with phenyl azide,
Table 2
Optimization of catalysts for the synthesis of triazoles from 1‐alkyl‐2‐halo‐1H‐indole‐3‐carbaldehyde.
Entry
Solvent
Catalyst
Temperature (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CuI
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
9
6
6
20
15
10
0
0
0
0
0
80
40
CuBr
CuCl
Cu2O
Cu(PPh3)2NO3
Cu(PPh3)2Cl
7
10
12
10
16
1–3
8
Cu(PPh3)2Br
[Cu(Phen)(PPh3)2]NO3
CuSO4·5H2O
Cu(AcO)2
10
The aforementioned step‐wise method gave excellent yields when compared with one‐pot method by using different azides and acetylenes in short
reaction time and yields are good.
Scheme 3. Synthesis of N‐alkylated 2‐(4‐benzyl‐1H‐1,2,3‐triazol‐1‐yl)‐1H‐indole‐3‐carbaldehydes from 2‐bromo‐1H‐indole‐3‐carbaldehyde. [Color
figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

V. K. R. Avula, S. Vallela, J. S. Anireddy, and N. R. Chamarthi
Vol 000
Scheme 4. Synthesis of N‐alkylated 2‐(4‐benzyl‐1H‐1,2,3‐triazol‐1‐yl)‐1H‐indole‐3‐carbaldehyde from 1H‐indole‐3‐carbaldehyde.
Figure 1. Plausible mechanism for the formation of compounds 22 and 23.
CONCLUSIONS
5 min at room temperature, 1.0 mmol of sodium ascorbate
and 1.0 mmol of CuSO4·5H2O were added. The reaction
was stirred up to completion of reaction as indicated by
the TLC. Crushed ice was added to the crude reaction
mass. Then aqueous layer was extracted with ethyl acetate
(3 × 20 mL). The combined organic layers were dried
over Na2SO4, filtered, and concentrated under reduced
pressure. Product was purified by column chromatography
on silica gel (eluent: hexane/ethyl acetate). All the
compounds were characterized by the spectral studies and
the representative spectra (Compounds 5, 7b and 22) have
been provided in the supporting information.
In conclusion, we have developed a new efficient
method for the synthesis of triazole-linked indole
aldehyde by step-wise and one-pot method by Huisgen’s
1,3-dipolar cycloaddition of azide and alkynes under click
reaction. A series of N-alkylated 2-(4-subtituted-1H-1,2,3-
triazol-1-yl)-1H-indole-3-carbaldehydes were prepared in
good to excellent yields, using different copper catalysts
in DMF solvent. For these reactions, CuSO4·5H2O was
found to be the best catalyst in terms of reaction time,
yields of the products and easy work-up procedure.
Spectral data for title compounds. 2-(4-(Bromomethyl)-
1H-1,2,3-triazol-1-yl)-1-methyl-1H-indole-3-carbaldehyde
EXPERIMENTAL
(7b).
Brown solid, yield: 90%, mp: 120–222°C; IR
(KBr): 2958, 2861, 2240, 1720, 1582, 1444, 1356, 1243,
805; H NMR (400 MHz, CDCl3) δ: 3.50 (s, 3H, CH3),
All the commercially available starting materials,
reagents, catalysts, and solvents were used without
purification unless stated otherwise. All products were
purified by silica gel (200–300) column chromatography.
Melting points are uncorrected and were determined in
open capillary tubes using Guna melting point apparatus.
TLC analyses were run on silica gel-G, and visualization
was performed using UV lamp or iodine. 1H and 13C
NMR spectra were recorded on Bruker 400 MHz
instrument in CDCl3 or DMSO-d6 using TMS as an
internal standard using 400 and 100 MHz, respectively.
Mass spectra were recorded on Agilent-LCMS instrument.
1
6.58 (s, 2H, Ar–CH2), 7.14–7.11 (t, J = 7.6 Hz, 4H,
Ar–H), 7.65–7.64 (d, J = 6.4 Hz, 1H, Ar–H), 9.94
(s, 1H, Ar–CHO); 13C NMR (100 MHz, CDCl3) δ: 27.4,
29.7, 108.4, 115.2, 121.1, 122.2, 126.3, 134.5, 152.9,
181.4; MS (positive mode) m/z: 321[M
+
H]+;
Anal. Calcd (%) for C13H11BrN4O; C, 48.92; H, 3.47; N,
17.55; found: C, 48.85; H, 3.36; N, 17.45.
2-(4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl)-1-methyl-1H-
indole-3-carbaldehyde (7c). White solid, yield: 85%, mp:
100–102°C; IR (KBr): 3058, 2961, 2140, 1710, 1592,
1
1454, 1366, 1253, 705; H NMR (400 MHz, CDCl3) δ:
General procedure for the title compounds. In a round
bottom flask equipped with a magnetic stirring bar,
1.0 mmol of 2-azido-3-carbaldehyde was stirred with
1.0 mmol of phenyl acetylene in DMF. After stirring for
3.55(s, 3H, CH3), 4.25 (s, 1H, OH) 6.48 (s, 2H,
Ar–CH2), 7.26–7.24 (t, J = 9.6 Hz, 4H, Ar–H), 7.63–
7.61 (d, J = 8.1 Hz, 1H, Ar–H), 10.1 (s, 1H, Ar–CHO);
13C NMR (100 MHz, CDCl3) δ: 27.2 29.3, 108.6, 114.5,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Copper-catalysed synthesis of N-alkylated indole-3-carbaldehydes
122.3, 123.4, 125.4, 133.5, 153.9, 185.4. MS (positive
mode) m/z: 257 [M + H]+; Anal. Calcd (%) for
C13H12N4O2; C, 60.93; H, 4.72; N, 21.86; found: C,
60.97; H, 4.70; N, 20.84.
2-(4-(Bromomethyl)-1H-1,2,3-triazol-1-yl)-1-ethyl-1H-
indole-3-carbaldehyde (7e). Brown solid, yield: 85%, mp:
Acknowledgments. Acknowledgements are due to UGC
networking resource center program and funding under
networking scheme and Dr. R. Nagarajan, Associate Professor,
School of Chemistry, University of Hyderabad, for providing
laboratory facilities.
110–112°C; IR (KBr): 2988, 2851, 2120, 1715, 1682,
1
CONFLICTS OF INTEREST
1442, 1356, 1253, 815; H NMR (400 MHz, CDCl3) δ:
1.80–1.78 (t, J = 8.4 Hz, 3H, CH3), 4.30–4.26 (q, 2H,
CH2), 6.55 (s, 2H, Ar–H), 7.14–7.12 (t, J = 8.0 Hz, 4H,
Ar–H), 7.63–7.62 (d, J = 5.6 Hz, 2H, Ar–H), 10.2
(s, 1H, Ar–CHO); 13C NMR (100 MHz, CDCl3) δ: 14.6,
27.5, 38.5, 109.2, 110.7, 122.1, 123.5, 124.4, 135.6,
153.9, 185.6; MS (positive mode) m/z: 334 [M + H]+;
Anal. Calcd (%) for C14H13BrN4O; C, 50.47; H, 3.93; N,
We state we have no conflicts of interest.
REFERENCES AND NOTES
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16.82; found: C, 50.43; H, 3.95; N, 16.84.
1-Ethyl-2-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)-1H-
indole-3-carbaldehyde (7f). White solid, yield: 80%, mp:
93–95°C; IR (KBr): 3026, 2970, 2150, 1715, 1582, 1454,
1367, 1253, 705; 1H NMR (400 MHz, CDCl3):
1.80–1.78 (t, J = 8.4 Hz, 3H, CH3), 4.30–4.26 (q, 2H,
CH2), 4.15 (s, 1H, OH) 6.15 (s, 2H, Ar–CH2), 7.15–7.13
(t, J = 8.2,Hz, 4H, Ar–H), 7.53–7.51 (d, J = 8.1 Hz, 1H,
Ar–H), 10.3 (s, 1H, Ar–CHO); 13C NMR (100 MHz,
CDCl3) δ: 14.2, 27.3, 39.5, 108.3, 114.1, 122.5, 123.4,
125.5, 133.2, 153.8, 186.4; MS (positive mode) m/z: 271
[M + H]+; Anal. Calcd (%) for C14H14N4O2; C, 62.21; H,
5.22; N, 20.73; found: C, 62.15; H, 5.25; N, 20.76.
1-Methyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)-1H-indole-3-
carbaldehyde (22).
Pale yellow solid, yield: 90%, mp:
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Tew, D.; Meek, T. D.; Hofmann, G. A.; Schulz, P. C. K.; Smith, W. W.;
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148–150°C; IR (KBr): 3095, 3051, 1660, 1610, 1561,
1479, 1369, 1228, 1128, 1030, 739; H NMR (400 MHz,
1
CDCl3) δ: 3.74 (s, 3H, CH3), 7.53–7.26 (m, 6H, Ar–H),
7.97–795 (d, J = 7.6 Hz, 2H, Ar–H), 8.27 (s, 1H, Ar–H),
8.40–8.38 (d, J = 8.0 Hz, 1H, Ar–H) 9.89 (s, 1H,
Ar–CHO); 13C NMR (100 MHz, CDCl3) δ: 30.6, 110.3,
110.9, 122.3, 122.6, 124.3,125.5, 126.0, 128.3, 129.1,
129.1, 129.2, 132.1, 135.2, 137.3, 148.2, 183.1; MS
(positive mode) m/z: 303 [M + H]+; Anal. Calcd (%) for
C18H14N4O; C, 71.51; H, 4.67; N, 18.53; found: C,
71.48; H, 4.61; N, 18.45.
1-Ethyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)-1H-indole-3-
carbaldehyde (23).
Pale yellow solid, yield: 85%, mp:
130–132°C; IR (KBr): 3032, 3010, 1651, 1601, 1542,
1
1469, 1351, 1215, 1120, 1010, 751; H NMR (400 MHz,
CDCl3) δ: 1.50–1.48 (t, J = 8.2 Hz, 3H, CH3), δ
4.44–4.38 (q, 2H, CH2), 7.51–7.22 (m, 6H, Ar–H),
7.91–789 (d, J = 8.4 Hz, 2H, Ar–H), 8.23 (s, 1H, Ar–H),
8.38–8.36 (d, J = 8.3 Hz, 1H, Ar–H) 10.2 (s, 1H,
Ar–CHO); 13C NMR (100 MHz, CDCl3) δ: 14.2, 37.5,
109.3, 110.9, 121.3, 122.6, 123.2, 125.3, 125.1, 127.3,
128.1, 129.4, 129.5, 132.5, 134.2, 136.3, 147.2, 185.1;
MS (positive mode) m/z: 317 [M + H]+; Anal. Calcd (%)
for C19H16N4O; C, 72.13; H, 5.10; N, 17.71; found: C,
72.10; H, 5.11; N, 17.73.
[17] Huisgen, R. In 1,3-Dipolar Cycloaddition ChemistryPadwa, A.
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