Ligand-free, copper-catalyzed, one-pot, three-component synthesis of novel 1,2,3-triazole-linked indoles in magnetized water

Article abstract of DOI:10.1002/jccs.201800287

Magnetized water (MW) is used as a green and new solvent-promoting medium for the one-pot, three-component synthesis of novel 1,2,3-triazole-linked indoles catalyzed by copper iodide. A broad range of 2-aryl-1-(prop-2-ynyl)-1H-indole-3-carbaldehydes were

Full text of DOI:10.1002/jccs.201800287

Received: 23 July 2018
Revised: 4 December 2018
Accepted: 12 December 2018
DOI: 10.1002/jccs.201800287
A R T I C L E
Ligand-free, copper-catalyzed, one-pot, three-component
synthesis of novel 1,2,3-triazole-linked indoles in magnetized
water
Mohammad Bakherad1 | Ali Keivanloo1 | Zohreh Bakherad2 | Zahra Toozandejani1 |
Mohamad Mahdavi3
1Faculty of Chemistry, Shahrood University of
Magnetized water (MW) is used as a green and new solvent-promoting medium for
Technology, Shahrood, Iran
2Food and Drug Laboratories Research Center,
Food and Drug Organization, MOH & ME,
Tehran, Iran
the one-pot, three-component synthesis of novel 1,2,3-triazole-linked indoles
catalyzed by copper iodide. A broad range of 2-aryl-1-(prop-2-ynyl)-1H-indole-
3-carbaldehydes were reacted with alkyl halides and sodium azide via copper-
catalyzed azide–alkyne cycloaddition reactions in MW in the absence of any
ligand. This method offers the advantages of short reaction times, green procedure,
low cost, simple work-up, quantitative reaction yields, and no need for any organic
solvent.
3Endocrinology and Metabolism Research Center,
Endocrinology and Metabolism Clinical Science
Institute, Tehran, Iran
Correspondence
Mohammad Bakherad, Faculty of Chemistry,
Shahrood University of Technology, Shahrood
3619995161, Iran.
KEYWORDS
Email: m.bakherad@yahoo.com
1,2,3-Triazole, Click reaction, Indole, Magnetized water
ring positions of bi- or tri-heterocycle-containing new mole-
cules, interesting physiological proprieties are observed.
1
| INTRODUCTION
Indole is an important material used in organic synthesis, and
its physiological properties have attracted much scientific
attention.[1–3] A variety of 2-phenylindoles have been found
to inhibit the growth of human breast cancer cells by dissimi-
lar mechanisms depending upon the type and position of the
substituents.[4–7] Recently, 2-phenylindole-3-carboxaldehydes
have been proven to exert antimitotic activity in human breast
cancer cells by inhibiting tubulin polymerization.[8,9] More-
over, 2-aryl-indole derivatives have displayed diverse biolog-
ical properties such as anti-estrogen, cytotoxic, and
antimitotic[10–12] activity.
1,2,3-Triazoles play essential functions in organic chem-
istry, medicinal chemistry, agrochemicals, and dyes because
of their ease of preparation by “click chemistry.”[13,14] For
example, some of these compounds display broad pharmaco-
logical properties such as antitubercular,[15] antiviral,[16]
antibacterial and antifungal,[17] and anticancer[18] activity.
On the other hand, when 1,2,3-triazole and indoles are
linked by copper-catalyzed click reactions at the specific
The copper-catalyzed azide–alkyne cycloaddition
(CuAAC) reaction, also known as the “click reaction”, has
become one of the most important reactions used for the
preparation of 1,2,3-triazoles.[19] In 2002, Sharpless[20] and
Meldal[21] independently claimed that copper catalysts dra-
matically hasten the reaction and make it totally regioselec-
tive toward the 1,4-regioisomer. It is well known that the
CuAAC reaction takes place only in the presence of a
Cu(I) species but not in the presence of Cu(II) or
Cu(0) species. However, Cu(I) salts are not susceptible to
redox processes, and thus it is beneficial to protect and stabi-
lize the active copper catalysts during a CuAAC reaction,
and this has led to the discovery of various modified
methods such as the use of Cu(II)/Cu(0) salts with different
additives or ligands.[22–24] Other copper(0) and copper(I)
catalysts, such as copper nano-sized powder,[25] copper
nanoparticles adsorbed on charcoal,[26] and copper
nanoclusters,[27] have also shown good catalytic activity.
However, some of these methods suffer from disadvantages
© 2019 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J Chin Chem Soc. 2019;1–9.
http://www.jccs.wiley-vch.de
1

2
BAKHERAD ET AL.
CHO
Ar
CHO
such as expensive reagents, long reaction times, use of large
quantities of organic solvents, and harsh reaction conditions.
In order to overcome these problems, the development of a
milder, cheaper, more general, and highly efficient as well as
an environmentally benign method is desirable for the prepa-
ration of triazoles.
CuI (0.5 mol %)
NaN3
R
X
+
+
Ar
N
Magnetized water/ 45 o
C
N
R
N
N
N
SCHEME 1 Synthesis of 1,2,3-triazole-linked indoles catalyzed by CuI in
magnetized water
Among the commonly used solvents in organic synthe-
sis, water is nontoxic, and it is the most economical, most
abundant, safest, and most environmentally friendly
medium. Sometimes water shows higher reactivity and
selectivity compared to the other conventional organic sol-
vents because of its strong hydrogen-bonding ability. These
characteristics allow water to act as a solvent, a reactant, or a
catalyst, making it different from conventional organic sol-
vents.[28] Furthermore, reactions in water give enhanced
yields, require shorter reaction times, and show greater ease
of manipulation. Although the majority of CuAAC reactions
proceed either in organic solvents or in their mixtures with
water, a few reactions have been reported in water
itself.[29–32] However, in all these reactions, a suitable ligand
is needed to speed up the reaction rate. In addition, in most
of these methods, high temperatures are needed for the reac-
tion to proceed.
In 1953, Vermeiren reported that an applied magnetic
field can affect the properties of water.[33] The water magne-
tization technique is an easy one without extra energy con-
sumption when a permanent external magnet is used. A
permanent external magnet can be installed on a previously
established water tube system, resulting in no additional
energy requirement for water magnetization. This green
technology is clean and has zero energy consumption. Pure
water, as a polar and associative liquid, can modify its inter-
molecular bonds in an applied magnetic field, changing to a
metastable state but keeping that state for some time.[34]
Based on Mosin and Ignatov's theory,[35,36] the applied mag-
netic field directly affects the structure of water because of
the polarization of water molecules. These molecules are
bound together via low-energy intermolecular Van der
Waals forces, dipole–dipole interactions, and hydrogen
bonding. The magnetic field can deform the hydrogen bonds
and give rise to some partial rupture. In this regard, during
the last few years, many researchers have been interested in
studying the effect of an applied magnetic field on the prop-
erties of water, such as its density, specific heat, refractive
index, electric dipole moment, vaporization enthalpy, sur-
face tension, viscosity, and, especially, hydrogen-bond
distribution.[37]
2
| RESULTS AND DISCUSSION
MW was prepared using a static magnetic system of 0.8T
field strength at different exposure times to the magnetic
field (Figure 1). Distilled water (5 mL) was taken in a test
tube, which was then placed in the magnetic field for
20 min. The tube was subsequently removed from the instru-
ment and used for the reaction.
Then, treatment of 2-aryl-1H-indole-3-carbaldehydes (1)
with propargyl bromide (2) in the presence of potassium car-
bonate in MW at room temperature afforded 2-aryl-1-(prop-
2-ynyl)-1H-indole-3-carbaldehydes (3) in good yields
(Table 1). The 1H NMR spectrum of 2-phenyl-1-(prop-
2-ynyl)-1H-indole-3-carbaldehyde 3a showed a triplet for
the CH proton at δ 3.47, a doublet for the CH2 protons at δ
4.99, a multiplet for the aromatic protons of the indole and
phenyl rings at δ 7.35–8.27, and a singlet at δ 9.45 due to
the CHO proton.
Preliminary experiments were performed using a ligand-
free click reaction of 2-phenyl-1-(prop-2-ynyl)-1H-indole-
3-carbaldehyde 3a, benzyl chloride, and sodium azide in the
presence of 5 mol% of CuI as a model reaction. In order to
find the optimum reaction conditions for the synthesis of
compound 5a, the effects of various solvents and reaction
temperatures were studied, and the results are shown in
Table 2.
As shown in Table 2, several solvents were screened for
the reaction in the presence of a catalytic amount of CuI.
The results obtained showed that the efficiency and yield of
the reaction in MW at 45ꢀC (Table 2, entry 18) were higher
than those obtained in solvents such as CH2Cl2, CH3CN,
THF, DMF, ethyl acetate, methanol, ethanol, and distilled
water in the absence of any ligand (Table 2, entries 1–18).
50 mm
In continuation of our interest in the development of
organic syntheses in magnetized water (MW) as a new
solvent,[38–42] we report here, for the first time, a rapid and
mild protocol for the synthesis of novel 1,2,3-triazole-linked
indoles via the copper-catalyzed click reactions in MW
(Scheme 1).
40 mm
15 mm
FIGURE 1 Pilot for solvent magnetization apparatus

BAKHERAD ET AL.
3
TABLE 1 Synthesis of 2-aryl-1-(prop-2-ynyl)-1H-indole-3-carbaldehydes 3a
CHO
Ar
CHO
K2CO3/ MW
r.t./ 6 h
Ar
+
Br
N
N
H
3
1
Entry
Ar
Product
M.p. (ꢀC)
Yield (%)b
1
Ph
3a
3b
3c
3d
3e
145–147
98
1a
2
3
4
5
4-BrC6H4-
167–169
163–165
142–144
148–150
85
82
92
90
1b
4-ClC6H4-
1c
4-MeC6H4-
1d
4-MeOC6H4-
1e
a
Reaction condition: 1 (1 mmol), propargyl bromide (1.2 mmol), K2CO3 (2 mmol), MW (5 mL), room temperature, 6 hr.
Isolated yield.
b
TABLE 2 Synthesis of compound 5a in different solventsa
CHO
CHO
Ph
Solvent
PhCH Cl
NaN3
+
Ph
+
2
N
N
CH2Ph
N
3a
5a
N
N
Entry
1
Solvent
CH2Cl2
CH2Cl2
CH3CN
CH3CN
THF
Temp. (ꢀC)
Yield (%)b
—
rt
2
45
rt
—
3
10
4
45
rt
23
5
12
6
THF
45
rt
25
7
DMF
15
8
DMF
45
rt
34
9
Ethyl acetate
Ethyl acetate
MeOH
—
10
11
12
13
14
15
16
17
18
19
45
rt
—
17
MeOH
45
rt
45
EtOH
20
EtOH
45
rt
52
Distilled water
15
Distilled water
45
rt
40
Magnetized water (MW)c
Magnetized water (MW)c
Magnetized water (MW)c
60
45
94
95
60
a
b
c
Reaction conditions: 3a (1.0 mmol), benzyl chloride (1.0 mmol), sodium azide (1.0 mmol), CuI (5 mol%), solvent (5 mL) for 30 min.
Isolated yield.
Magnetization time 20 min.

4
BAKHERAD ET AL.
Also, increasing the temperature did not improve the reac-
tion yield (Table 2, entry 19).
systems without employing a ligand is an attractive field of
research. For this purpose, we decreased the amount of the
copper catalyst. Surprisingly, we found that with 0.5 mol%
of CuI catalyst, the click reaction proceeded effectively and
reached completion to afford the desired product in 98%
yield in 20 min (Table 3, entry 13). Furthermore, the volume
of MW used had a great effect on the reaction yield
(Table 3, entries 15–17). When a small amount of MW
(1 mL) was used, the reagents were insoluble in it, and the
product was formed in low yield (Table 3, entry 17). Thus
the optimal reaction conditions were 0.5 mol% of CuI, at
45ꢀC, in 3 mL of MW (Table 3, entry 15).
Based on the results obtained (Table 2, entry 18), we
tried to optimize the reaction conditions using MW that
could help reduce the reaction time and improve the yield of
the target product (Table 3). Various parameters including
different catalysts, magnetization time, catalyst concentra-
tion, reaction time, and volume of MW were studied. From
Table 3, it is obvious that the use of CuI results in the best
reaction condition (Table 3, entry 4). It seems that the mag-
netization time of water plays an important role in achieving
the product 5a in high yield (Table 3, entries 4–6). As indi-
cated in Table 3, increasing the water magnetization time to
30 min showed no substantial improvement in the reaction
yield (Table 3, entry 5), whereas the yield decreased on
decreasing the water magnetization time to 10 min (Table 3,
entry 6).
A substantial amount of a heavy-metal catalyst is utilized
in the classic copper-catalyzed click reactions. The Cu salts
pollute the biologically relevant compounds, they are toxic,
and their full removal from the reaction mixture is hard.
These problems can be overcome by the use of click reac-
tions in biomedicine. In the recent years, numerous modifi-
cations have been reported for reducing the amount of the
copper catalyst required for click reactions, such as the use
of ligands.[43,44]
It should be noted that the synthesis of 1,2,4-triazoles via
CuAAC reactions is generally carried out in the presence of
base ligands or heterogeneous catalytic systems with the aid
of organic or aqueous solvents.[45–52]
Clearly, these reported methods not only generate a lot
of organic or inorganic wastes during the work-up procedure
but also result in the complication of carrying away trace
amounts of the residual ligand or metal species from the tar-
get compound when they are used in pharmaceutical synthe-
sis. Performing the model reaction in MW not only offers a
ligand- and base-free click reaction and excellent reaction
yield but also avoids the generation of harmful wastes, the
use of a great amount organic solvents or catalysts, and a
tedious post-treatment. We, therefore, believe that our pro-
posed system is an attractive strategy for the synthesis of the
product from the viewpoint of green synthesis.
One of the roles of such ligands is to increase the solubil-
ity of the copper complex in water to deliver higher solution
concentrations of the necessary Cu(I) species. Fortunately,
since copper iodide is completely soluble in MW, the addi-
tion of a ligand to the reaction is not necessary. For environ-
mental and economic reasons, the development of catalytic
After the optimized conditions were found (Table 3,
entry 15), the scope of the reaction was explored with
2-aryl-1-(prop-2-ynyl)-1H-indole-3-carbaldehyde (3), benzyl
or alkyl halides, and sodium azide (Table 4). As shown in
TABLE 3 Synthesis of 5a in MW under various conditionsa
Entry
1
Solvent (mL)
MW (5)
MW (5)
MW (5)
MW (5)
MW (5)
MW (5)
MW (5)
MW (5)
MW (5)
MW (5)
MW (5)
MW (5)
MW (5)
MW (5)
MW (3)
MW (2)
MW (1)
Catalyst (mol%)
CuSO4 (5)c
Magnetization time (min)
Reaction time (min)
Yield (%)b
70
20
20
20
20
30
10
20
20
20
20
20
20
20
20
20
20
20
30
30
30
30
30
30
30
30
30
30
30
30
20
10
20
20
20
c
2
Cu(OAc)2
88
3
CuCl (5)
CuI (5)
82
4
99
5
CuI (5)
98
6
CuI (5)
85
7
CuI (3)
99
8
CuI (2)
99
9
CuI (1)
98
10
11
12
13
14
15
16
17
CuI (0.5)
CuI (0.4)
CuI (0.2)
CuI (0.5)
CuI (0.5)
CuI (0.5)
CuI (0.5)
CuI (0.5)
98
90
75
98
93
98
72
60
a
b
c
Reaction conditions: 3a (1.0 mmol), benzyl chloride (1.0 mmol), sodium azide (1.0 mmol), CuI, magnetized water, 45ꢀC.
Isolated yield.
Sodium ascorbate (10 mol%).

BAKHERAD ET AL.
5
TABLE 4 Syntheses of novel 1,2,3-triazole-linked indoles 5a
CHO
CHO
Ar
CuI (0.5 mol %)
R
X
+
Ar
NaN3
+
Magnetized water/ 45 o
C
N
N
R
N
3
4
5
N
N
Entry
Substrate
R-X
Product
5a
m.p (ꢀC)
Yieldb (%)
1
3a
PhCH2Cl
4a
115–117
98
2
3
3a
3a
4-cl-C6H4CH2Cl
5b
5c
75–77
95
92
4b
C4H9Br
4c
102–104
4
3b
3b
3b
3c
3c
3c
3d
3d
3e
3e
3e
4a
5d
5e
5f
118–120
70–72
93
90
87
90
88
82
96
89
95
86
91
5
4b
6
4c
92–94
7
4a
5g
5h
5i
131–133
88–90
8
4b
9c
10
11
12
13
14c
4c
95–97
4a
5j
83–85
4b
5k
5l
75–77
4c
120–122
68–70
4b
5m
5n
4c
88–90
a
Reaction conditions: 3 (1.0 mmol), organic halide (1.0 mmol), sodium azide (1.0 mmol), CuI (0.5 mol%), magnetization time (10 min), MW (3 mL), 45ꢀC, reaction
time (20 min).
Isolated yield.
Reaction time (120 min).
b
c
Table 4, the corresponding 1-([1-alkyl-1H-1,2,3-triazol-4-yl]
methyl)-2-aryl-1H-indole-3-carbaldehyde derivatives (5)
were isolated as products in high to excellent yields under
the present reaction conditions from the reaction of various
2-aryl-1-(prop-2-ynyl)-1H-indole-3-carbaldehydes (3) and
benzyl or alkyl halides with sodium azide.
What is interesting is that all the solid reagents dissolve
in MW, whereas after completion of the reaction, the reac-
tion product is insoluble in MW.
internal standard, and the J-values are given in hertz. Micro-
analysis was performed on
microanalyzer.
a
Perkin-Elmer 240-B
3.2 | Preparation of MW
In order to prepare the MW sample according to Figure 1,
5 mL distilled water was first taken in a test tube, which was
then placed between two neodymium magnets NdFeB
(10 cm × 5 cm × 4 cm) with a magnetic field of 0.8 T. The
test tube was subsequently removed from the magnetic field
and used for the reaction.
3
| EXPERIMENTAL
3.3 | Synthesis of 2-aryl-1-(prop-2-ynyl)-1H-indole-
3-carbaldehydes 3a–e
3.1 | General
The reagents and solvents used were supplied from Merck,
Fluka, or Aldrich. Melting points were determined using an
Electrothermal C14500 apparatus. The reaction progress and
purity of the compounds were monitored using thin-layer
chromatography (TLC) using analytical silica gel plates
A mixture of 2-aryl-1H-indole-3-carbaldehyde (1) (1 mmol)
and K2CO3 (2 mmol, 0.27 g) in MW (5 mL) was stirred for
10 min. Then propargyl bromide (1.2 mmol, 0.15 g) was
added, and the solution was stirred for 6 hr at room tempera-
ture. After completion of the reaction (monitored by TLC),
the crude product was washed with water, and the precipitate
formed was purified by recrystallization from ethanol to
afford the pure title compound.
(Merck 60F250). The H NMR (300 MHz) and 13C NMR
(75 MHz) spectra were obtained using a Bruker Avance
DPX-250 FT-NMR spectrometer. The chemical shifts are
given as δ values against tetramethylsilane (TMS) as the
1

6
BAKHERAD ET AL.
3.3.1
|
2-Phenyl-1-(prop-2-yn-1-yl)-1H-indole-
3.3.5
|
2-(4-Methoxyphenyl)-1-(prop-2-yn-1-yl)-1H-indole-
3-carbaldehyde (3a)
3-carbaldehyde (3e)
IR (KBr): 3,216 (m), 2,320 (m), 1,657 (s), 1,414 (m), 1,372
w), 1,097 (s) cm−1; 1H NMR (300 MHz, DMSO-d6) δ: 3.47
(t, 1H, J = 2.4 Hz, C-H), 4.99 (s, 2H, CH2), 7.35–7.47 (m,
2H, Ar-H), 7.66–7.73 (m, 5H, Ar-H), 7.76 (d, 1H,
J = 7.8 Hz, Ar-H), 8.27 (dd, 1H, J = 7.2 Hz, 1.2 Hz, Ar-H),
9.65 (s, 1H, CHO). 13C NMR (75 MHz, DMSO-d6) δ: 31.1,
34.1, 39.1, 39.4, 39.7, 40.0, 40.2, 40.5, 40.8, 76.4, 78.7,
111.7, 115.5, 121.5, 123.7, 124.5, 125.1, 128.0, 129.3,
130.6, 131.2, 136.4, 150.9, 186.0; MS (m/z): 259 (M)+;
Anal. calcd for C18H13NO: C, 83.37; H, 5.05; N, 5.40%;
Found: C, 83.52; H, 5.14; N, 5.53%.
IR (KBr): 3,213 (m), 2,327 (m), 1,653 (s), 1,417 (m), 1,370
1
(w), 1,095 (m) cm−1; H NMR (300 MHz, DMSO-d6) δ:
3.49 (t, 1H, J = 2.4 Hz, C-H), 4.99 (d, 2H, J = 2.4 Hz,
ch2), 7.23 (d, 2H, J = 8.7 Hz, Ar-H), 7.34–7.39 (m, 1H, Ar-
H), 7.40–7.45 (m, 1H, Ar-H), 7.64 (d, 2H, J = 8.7 Hz, ar-h),
7.74 (d, 1H, J = 7.8 Hz, Ar-H), 8.25 (d, 1H, J = 7.2 Hz,
Ar-H), 9.65 (s, 1H, CHO). 13C NMR (75 MHz, DMSO-d6)
δ: 34.0, 55.8, 76.4, 78.9, 111.6, 114.9, 115.3, 119.9, 121.4,
123.6, 124.4, 125.2, 132.7, 136.4, 151.1, 161.1, 186.1; MS
(m/z): 289 (M)+; Anal. calcd for C19H15NO2: C, 78.87; H,
5.23; N, 4.84%; Found: C, 78.69; H, 5.14; N, 4.99%.
3.4 | General procedure for the synthesis of
1,2,3-triazole-linked indoles 5a–n
3.3.2
| 2-(4-Bromophenyl)-1-(prop-2-yn-1-yl)-1H-indole-
3-carbaldehyde (3b)
IR (KBr): 3,210 (m), 2,322 (m), 1,651 (s), 1,420 (m), 1,377
To a 10-mL round-bottomed flask equipped with a magnetic
stirrer bar and containing MW (3 mL) were added 2-aryl-
1-(prop-2-ynyl)-1H-indole-3-carbaldehyde (3) (1.0 mmol),
an organic halide (1.0 mmol), and sodium azide (1.0 mmol,
0.065 g). The reaction mixture was stirred at 45ꢀC, and the
reaction progress was monitored by TLC using chloroform
as the eluent. After completion of the reaction, the precipi-
tate formed was filtered and purified by recrystallization
from ethanol to afford the desired product.
(w), 1,092 (s) cm−1 1H NMR (300 MHz, DMSO-d6) δ:
;
3.36 (s, 1H, C-H), 5.01 (s, 2H, CH2), 7.35–7.40 (m, 1H, Ar-
H), 7.42–7.48 (m, 1H, Ar-H), 7.66 (d, 2H, J = 8.4 Hz, Ar-
H), 7.77 (d, 1H, J = 8.1 Hz, Ar-H), 7.88 (d, 2H, J = 8.4 Hz,
Ar-H), 8.28 (D, 1H, J = 7.5 Hz, AR-H), 9.64 (s, 1H, CHO).
13C NMR (75 MHz, DMSO-d6) δ: 34.1, 76.5, 78.7, 111.7,
115.7, 121.5, 123.8, 124.53, 124.7, 125.0, 127.3, 132.3,
133.3, 136.5, 149.4, 185.9; MS (m/z): 337 (M)+; Anal.calcd
for C18H12BrNO: C, 63.92; H, 3.58; N, 4.14%; Found: C,
63.74; H, 3.50; N, 4.27%.
3.4.1
| 1-([1-Benzyl-1H-1,2,3-triazol-4-yl]methyl)-2-phenyl-
1H-indole-3-carbaldehyde (5a)
IR (KBr): 3,072 (w), 2,944 (m), 2,384 (m), 1,651 (s), 1,536
3.3.3
| 2-(4-Chlorophenyl)-1-(prop-2-yn-1-yl)-1H-indole-
(m), 1,462 (m), 1,420 (w) cm−1 1H NMR (300 MHz,
;
3-carbaldehyde (3c)
DMSO-d6) δ: 5.42 (s, 2H, CH2), 5.54 (s, 2H, CH2),
7.22–7.24 (m, 2H, Ar-H), 7.30–7.40 (m, 5H, Ar-H),
7.58–7.63 (m, 3H, Ar-H), 7.68–7.74 (m, 3H, Ar-h), 8.02 (s,
1H, C-H), 8.22–8.25 (m, 1H, Ar-H), 9.61 (s, 1H, CHO). 13C
NMR (75 MHz, DMSO-d6) δ: 53.2, 111.9, 115.3,
121.4123.3, 124.1, 124.3, 125.2, 128.2, 128.4, 128.5, 129.1,
129.1, 130.4, 131.5, 136.3, 136.7, 143.0, 151.7, 185.9; MS
(m/z): 392 (M)+; Anal. calcd for C25H20N4O: C, 76.51; H,
5.14; N, 14.28%; Found: C, 76.70; H, 5.23; N, 14.12%.
IR (KBr): 3,221 (m), 2,329 (m), 1,655 (s), 1,418 (m), 1,369
(w), 1,089 (s) cm−1 1H NMR (300 MHz, DMSO-d6) δ:
;
3.47 (t, 1H, J = 2.4 Hz, C-H), 5.02 (d, 2H, J = 2.4 Hz,
CH2), 7.35–7.40 (m, 1H, Ar-H), 7.42–7.47 (m, 1H, Ar-H),
7.74–7.78 (m, 5H, Ar-H), 8.26 (d, 1H, J = 7.5 Hz, Ar-H),
9.65 (s, 1H, CHO). 13C NMR (75 MHz, DMSO-d6) δ: 34.1,
76.5, 78.7, 111.7, 115.7, 121.5, 123.8, 124.7, 125.0, 126.9,
129.4, 133.0, 135.7, 136.5, 149.4, 185.9; MS (m/z):
293 (M)+; Anal. calcd for C18H12CLNO: C, 73.60; H,
4.12; N, 4.77%; Found: C, 73.78; H, 4.21; N, 4.63%.
3.4.2
| 1-((1-[4-Chlorobenzyl]-1H-1,2,3-triazol-4-yl)methyl)-
2-phenyl-1H-indole-3-carbaldehyde (5b)
3.3.4
| 1-(Prop-2-yn-1-yl)-2-(p-tolyl)-1H-indole-
IR (KBr): 3,070 (w), 2,940 (m), 2,379 (m), 1,650 (s), 1,530
3-carbaldehyde (3d)
(m), 1,460 (m), 1,422 (w) cm−1 1H NMR (300 MHz,
;
IR (KBr): 3,211 (m), 2,318 (m), 1,659 (s), 1,416 (m), 1,369
DMSO-d6) δ: 5.43 (s, 2H, CH2), 5.55 (s, 2H, CH2),
7.22–7.28 (m, 1H, Ar-H), 7.33–7.35 (m, 2H, Ar-H),
7.43–7.51 (m, 3H, Ar-H), 7.61–7.74 (m, 6H, Ar-H), 8.04 (s,
1H, C-H), 8.25 (d, 1H, J = 6 Hz, Ar-H), 9.62 (s, 1h, CHO).
13C NMR (75 MHz, DMSO-d6) δ: 52.4, 111.9, 115.5,
121.4, 123.5, 124.3, 124.3, 125.2, 128.4, 129.1, 129.1,
130.2, 130.4, 130.7, 131.5, 133.3, 135.3, 136.7, 143.1,
151.7, 185.9; MS (m/z): 426 (M)+; Anal. Calcd for
C25H19ClN4O: C, 70.34; H, 4.49; N, 13.12%; Found: C,
70.51; H, 4.39; N, 13.27%.
(w), 1,090 (m) cm−1; H NMR (300 MHz, DMSO-d6) δ:
1
2.46 (s, 3H, CH3), 3.47 (s, 1H, C-H), 4.98 (s, 2H, CH2),
7.34–7.49 (m, 4H, Ar-H), 7.57–7.60 47 (m, 2H, Ar-H), 7.75
(d, 1H, J = 8.1 Hz, Ar-H), 7.76 (d, 1H, J = 7.5 Hz, Ar-H),
9.65 (s, 1H, CHO). 13C NMR (75 MHz, DMSO-d6) δ: 21.4,
34.1, 76.4, 78.8, 111.7, 115.4, 121.5, 123.7, 124.5, 125.0,
125.1, 129.9, 131.1, 136.4, 140.4, 151.1, 186.0; MS (m/z):
273 (M)+; Anal. calcd for C19H15NO: C, 83.49; H, 5.53; N,
5.12%; Found: C, 83.66; H, 5.62; N, 5.27%.

BAKHERAD ET AL.
7
3.4.3
| 1-([1-Butyl-1H-1,2,3-triazol-4-yl]methyl)-2-phenyl-1H-
132.1, 133.5, 136.8, 142.5, 150.2, 185.8; MS (m/z):
436 (M)+; Anal. calcd for C22H21BrN4O: C, 60.42; H,
4.84; N, 12.81%; Found: C, 60.60; H, 4.94; N, 12.97%.
indole-3-carbaldehyde (5c)
IR (KBr): 3,077 (w), 2,945 (m), 2,380 (m), 1,652 (s), 1,535
(m), 1,459 (m), 1,420 (w) cm−1 1H NMR (300 MHz,
;
3.4.7
| 1-([1-Benzyl-1H-1,2,3-triazol-4-yl]methyl)-
DMSO-d6) δ: 0.77 (t, 3h, j = 7.2 Hz, CH3), 1.02–1.09 (m,
2H, CH2), 1.58–1.68 (m, 2H, ch2), 4.20 (t, 2H, J = 7.2 Hz,
CH2), 5.31 (s, 2H, CH2), 7.23–7.28 (m, 2H, Ar-H),
7.54–7.61 (m, 4H, Ar-H), 7.66–7.69 (m, 2H, Ar-H), 7.89 (s,
2-(4-chlorophenyl)-1H-indole-3-carbaldehyde (5g)
IR (KBr): 3,078 (w), 2,961 (m), 2,387 (m), 1,655 (s), 1,536
(m), 1,461 (m), 1,410 (w) cm−1 1H NMR (300 MHz,
;
1H, C-H), 8.13–8.16 (m, 1H, Ar-H), 9.53 (s, 1H, CHO). 13
C
DMSO-d6) δ: 5.43 (s, 2H, CH2), 5.55 (s, 2H, CH2),
7.23–7.25 (m, 2H, Ar-H), 7.25–7.38 (m, 5H, Ar-H), 7.66 (d,
2H, J = 8.1 Hz, Ar-H), 7.71–7.74 (m, 1H, Ar-H), 7.77 (d,
2H, J = 8.4 Hz, Ar-H), 8.08 (s, 1H, C-H), 8.23–8.26 (m,
1H, Ar-H), 9.62 (s, 1H, CHO). 13C NMR (75 MHz, DMSO-
d6) δ: 53.2, 112.0, 115.7, 121.4, 123.6, 124.1, 124.4, 125.1,
127.3, 128.5, 129.1, 129.2, 133.3, 135.5, 136.3, 136.8,
142.9150.1, 185.8; MS (m/z): 426 (M)+; Anal.calcd for
C25H19CLN4O: C, 70.34; H, 4.49; N, 13.12%; Found: C,
70.51; H, 4.58; N, 13.27%.
NMR (75 MHz, DMSO-d6) δ: 13.7, 19.4, 34.1, 49.5, 111.7,
115.5, 121.5, 123.7, 124.6, 125.1, 128.0, 129.1, 129.3,
130.6, 131.2, 131.5, 136.4, 150.9, 186.0; MS (m/z):
358 (M)+; Anal. calcd for C22H22N4O: C, 73.72; H, 6.19; N,
15.63%; Found: C, 73.90; H, 6.30; N, 15.80%.
3.4.4
| 1-([1-Benzyl-1H-1,2,3-triazol-4-yl]methyl)-
2-(4-bromophenyl)-1H-indole-3-carbaldehyde (5d)
IR (KBr): 3,069 (w), 2,960 (m), 2,382 (m), 1,650 (s), 1,530
(m), 1,460 (m), 1,417 (w) cm−1 1H NMR (300 MHz,
;
3.4.8
| 1-((1-[4-Chlorobenzyl]-1H-1,2,3-triazol-4-yl)methyl)-
DMSO-d6) δ: 5.43 (s, 2H, CH2), 5.55 (s, 2H, CH2),
7.23–7.25 (m, 2H, Ar-H), 7.30–7.41 (m, 5H, Ar-H),
7.68–7.74 (m, 3H, Ar-H), 7.78–7.81 (m, 2H, Ar-H), 8.08 (s,
2-(4-chlorophenyl)-1H-indole-3-carbaldehyde (5h)
IR (KBr): 3,076 (w), 2,946 (m), 2,383 (m), 1,652 (s), 1,533
(m), 1,460 (m), 1,416 (w) cm−1 1H NMR (300 MHz,
;
1H, C-H), 8.23–8.26 (m, 1H, Ar-H), 9.62 (s, 1H, CHO). 13
C
DMSO-d6) δ: 5.43 (s, 2H, CH2), 5.55 (s, 2H, CH2),
7.25–7.33 (m, 2H, Ar-H), 7.33–7.38 (m, 2H, Ar-H),
7.41–7.53 (m, 2H, Ar-H), 7.64–7.67 (m, 2H, Ar-H),
7.71–7.74 (m, 1H, Ar-H), 7.75–7.78 (m, 2H, Ar-H), 8.06 (s,
NMR (75 MHz, DMSO-d6) δ: 53.2, 112.0, 115.6, 121.4,
123.6, 124.1, 124.3, 124.4, 125.1, 127.7, 128.2, 128.5,
129.1, 132.1, 133.5, 136.3, 136.8, 142.9, 150.1, 185.8; MS
(m/z): 470 (M)+; Anal. calcd for C25H19BrN4O: C, 63.70; H,
4.06; N, 11.89%; Found: C, 63.53; H, 4.15; N, 11.74%.
1H, C-H), 8.22–8.25 (m, 1H, Ar-H), 9.62 (s, 1H, CHO). 13
C
NMR (75 MHz, DMSO-d6) δ: 52.4, 112.0, 115.7, 121.4,
123.5, 124.1, 124.4, 125.1, 127.3, 129.2, 130.2, 130.7,
133.3, 135.3, 135.5, 136.8, 143.0, 150.1, 185.8; MS (m/z):
460 (M)+; Anal. calcd for C25H18Cl2N4O: C, 65.09; H,
3.93; N, 12.14%; Found: C, 65.26; H, 3.85; N, 12.29%.
3.4.5
| 2-(4-Bromophenyl)-1-((1-[4-chlorobenzyl]-1H-
1,2,3-triazol-4-yl)methyl)-1H-indole-3-carbaldehyde (5e)
IR (KBr): 3,073 (w), 2,951 (m), 2,385 (m), 1,649 (s), 1,525
(m), 1,458 (m), 1,418 (w) cm−1 1H NMR (300 MHz,
;
DMSO-d6) δ: 5.43 (s, 2H, CH2), 5.55 (s, 2H, CH2),
7.25–7.28 (m, 2H, Ar-H), 7.32–7.38 (m, 3H, Ar-H),
7.43–7.49 (m, 2H, Ar-H), 7.68–7.73 (m, 3H, Ar-H),
7.78–7.88 (m, 2H, Ar-H), 8.07 (s, 1H, C-H), 8.23–8.25 (m,
1H, Ar-H), 9.62 (s, 1H, CHO). 13C NMR (75 MHz, DMSO-
d6) δ: 52.4, 112.0, 115.7, 121.4, 123.6, 124.1, 124.3, 124.4,
125.1, 127.7, 129.2, 130.2, 132.1, 132.3, 133.3, 133.5,
135.3, 136.8, 143.0, 150.1, 185.8; MS (m/z): 503 (M)+;
Anal. calcd for C25H18BrClN4O: C, 59.37; H, 3.59; N,
11.08%; Found: C, 59.55; H, 3.67; N, 11.25%.
3.4.9
| 1-([1-Butyl-1H-1,2,3-triazol-4-yl]methyl)-
2-(4-chlorophenyl)-1H-indole-3-carbaldehyde (5i)
IR (KBr): 3,073 (w), 1,939 (m), 2,375 (m), 1,657 (s), 1,532
(m), 1,455 (m), 1,428 (w) cm−1 1H NMR (300 MHz,
;
DMSO-d6) δ: 0.86 (t, 3H, J = 7.2 Hz, ch3), 1.11–1.23 (m,
2H, CH2), 1.67–1.77 (m, 2H, CH2), 4.29 (t, 2H, J = 6.9 Hz,
CH2), 5.41 (s, 2H, CH2), 7.32–7.38 (m, 2H, Ar-H),
7.68–7.72 (m, 2H, Ar-H), 7.72–7.75 (m, 1H, Ar-H),
7.78–7.82 (m, 2H, Ar-H), 8.02 (s, 1H, C-H), 8.22–8.27 (m,
1H, Ar-H), 9.62 (s, 1H, CHO). 13C NMR (75 MHz, DMSO-
d6) δ: 13.7, 19.4, 32.0, 49.5, 112.0, 115.6, 121.4, 121.5,
123.5, 123.8, 124.4, 125.1, 127.3, 129.2, 129.4, 133.1,
133.3, 135.5, 136.8, 142.5, 150.1, 185.8; MS (m/z):
392 (M)+; Anal. calcd for C22H21ClN4O: C, 67.26; H,
5.39; N, 14.26%; found: C, 67.07; H, 5.29; N, 14.42%.
3.4.6
| 2-(4-Bromophenyl)-1-([1-butyl-1H-1,2,3-triazol-4-yl]
methyl)-1H-indole-3-carbaldehyde (5f)
IR(KBr): 3,080 (w), 2,940 (m), 2,371 (m), 1,651 (s), 1,520
(m), 1,460 (m), 1,419 (w) cm−1 1H NMR (300 MHz,
;
DMSO-d6) δ: 0.86 (t, 3H, J = 7.2 Hz, CH3), 1.11–1.21 (m,
2H, CH2), 1.67–1.77 (m, 2H, CH2), 4.29 (t, 2H, J = 7.2 Hz,
CH2), 5.41 (s, 2H, CH2), 7.30–7.38 (m, 2H, Ar-H),
7.70–7.76 (m, 3H, Ar-H), 7.82–7.85 (m, 2H, Ar-H), 8.02 (s,
3.4.10
| 1-([1-Benzyl-1H-1,2,3-triazol-4-yl]methyl)-2-(p-tolyl)-
1H-indole-3-carbaldehyde (5j)
1H, C-H), 8.22–8.25 (m, 1H, Ar-H), 9.62 (s, 1H, CHO). 13
C
IR (KBr): 3,079 (w), 2,937 (m), 2,380 (m), 1,653 (s), 1,531
NMR (75 MHz, DMSO) δ: 13.7, 19.4, 32.0, 49.5, 112.0,
(m), 1,469 (m), 1,427 (w) cm−1 1H NMR (300 MHz,
;
115.6, 121.4, 123.5, 123.8, 124.3, 124.5, 125.1, 127.7,
DMSO-d6) δ: 2.43 (s, 3H, CH3), 5.41 (s, 2H, CH2), 5.54 (s,

8
BAKHERAD ET AL.
3.4.14
| 1-([1-Butyl-1H-1,2,3-triazol-4-yl]methyl)-
2H, CH2), 7.23–7.41 (m, 9H, Ar-H), 7.60–7.69 (m, 3H, Ar-
H), 8.03 (s, 1H, C-H), 8.23–8.25 (m, 1H, Ar-H), 9.62 (s, 1H,
CHO). 13C NMR (75 MHz, DMSO-d6) δ: 21.4, 53.2, 111.9,
115.4, 121.4, 123.4, 124.0, 124.2, 125.2, 125.4, 128.2,
128.5, 128.9, 129.1, 129.7, 131.4, 136.4, 136.7, 140.2,
143.1, 151.9, 185.9; MS (m/z): 406 (M)+; Anal. calcd for
C26H22N4O: C, 76.83; H, 5.46; N, 13.78%; Found: C,
76.65; H, 5.55; N, 13.94%.
2-(4-methoxyphenyl)-1H-indole-3-carbaldehyde (5n)
IR (KBr): 3,077 (w), 2,940 (m), 2,376 (m), 1,656 (s), 1,530
(m), 1,440 (m), 1,426 (w) cm−1;1H NMR (300 MHz,
DMSO-d6) δ: 0.86 (t, 3H, J = 7.2 Hz, CH3), 1.11–1.24 (m,
2H, CH2), 1.68–1.77 (m, 2H, CH2), 3.88 (s, 3H, OCH3),
4.29 (t, 2H, J = 7.2 Hz, CH2), 5.40 (s, 2H, CH2), 7.17–7.24
(m, 2H, Ar-H), 7.28–7.35 (m, 2H, Ar-H), 7.62–7.67 (m, 1H,
Ar-H), 7.69–7.74 (m, 2H, Ar-H), 8.01 (s, 1H, C-H),
8.21–8.26 (m, 1H, Ar-H), 9.65 (s, 1H, CHO). 13C NMR
(75 MHz, DMSO-d6) δ: 13.7, 19.4, 32.0, 49.5, 55.8, 111.9,
114.6, 115.3, 120.3, 121.3, 123.7, 124.1, 125.3, 133.0,
136.7, 142.7, 151.9, 160.9, 186.0; MS (m/z): 388 (M)+;
Anal.calcd for C23H24N4O2: C, 71.11; H, 6.23; N, 14.42%;
Found: C, 71.29; H, 6.30; N, 14.26%.
3.4.11
| 1-((1-[4-Chlorobenzyl]-1H-1,2,3-triazol-4-yl)methyl)-
2-(p-tolyl)-1H-indole-3-carbaldehyde (5k)
IR (KBr): 3,081 (w), 2,940 (m), 2,388 (m), 1,655 (s), 1,540
(m), 1,450 (m), 1,414 (w) cm−1 1H NMR (300 MHz,
;
DMSO-d6) δ: 2.44 (s, 3H, CH3), 5.41 (s, 2H, CH2), 5.55 (s,
2H, CH2), 7.25–7.29 (m, 2H, Ar-H), 7.31–7.36 (m, 2H, Ar-
H), 7.39–7.43 (m, 2H, Ar-H), 7.46–7.48 (m, 2H, Ar-H),
7.60 (d, 2H, J = 7.8 Hz, Ar-H), 7.67–7.70 (m, 1H, Ar-H),
8.00 (s, 1H, C-H), 8.21–8.24 (m, 1H, Ar-H), 9.61 (s, 1H,
CHO). 13C NMR (75 MHz, DMSO-d6) δ: 21.4, 52.4, 111.9,
115.4, 121.3, 123.4, 124.0, 124.2, 125.2, 125.4, 125.1,
129.7, 130.2, 131.3, 133.3, 135.3, 136.7, 140.2, 143.1,
151.9, 185.9; MS (m/z): 442 (26), 440 (M)+; Anal. calcd for
C26H21ClN4O: C, 70.82; H, 4.80; N, 12.71%; found: C,
70.99; H, 4.89; N, 12.86%.
4
| CONCLUSIONS
We have developed a highly efficient, inexpensive, green,
and one-pot protocol for the synthesis of 1,2,3-triazole-
linked indoles using MW as a new solvent. This method not
only offers significant improvements in the reaction rates
and yields but also avoids (i) the production of harmful
wastes, (ii) the use of a large amount of organic solvents or
catalysts, and (iii) tedious post-treatment. In addition, the
promising points for the presented methodology are its effi-
ciency, generality, short reaction time, mild reaction condi-
tions, easy work-up, excellent yield, low copper catalyst
loading, and finally, agreement with green chemistry proto-
cols, making it a useful and attractive process for the synthe-
sis of 1,2,3-triazole-linked indoles. Most importantly, this
protocol does not require any additional reducing agent or
ligand.
3.4.12
| 1-([1-benzyl-1H-1,2,3-triazol-4-yl]methyl)-
2-(4-methoxyphenyl)-1H-indole-3-carbaldehyde (5l)
IR (KBr): 3,077 (w), 1,953 (m), 2,377 (m), 1,645 (s), 1,530
(m), 1,451 (m), 1,417 (w) cm−1 1H NMR (300 MHz,
;
DMSO-d6) δ: 3.87 (s, 3H, OCH3), 5.42 (s, 2H, CH2), 5.56
(s, 2H, CH2), 7.15 (d, 3H, J = 8.4 Hz, Ar-H), 7.24–7.26 (m,
2H, Ar-H), 7.31–7.37 (m, 5H, Ar-H), 7.68 (d, 3H,
J = 8.1 Hz, Ar-H), 8.06 (s, 1H, C-H), 8.23–8.26 (m, 1H,
Ar-H), 9.64 (s, 1H, CHO). 13C NMR (75 MHz, DMSO-d6)
δ: 53.2, 55.8, 111.9, 114.6, 115.4, 120.2, 121.3, 123.4,
124.1, 125.3, 128.2, 128.5, 129.1, 132.9, 136.4, 136.7,
143.1, 151.9, 160.9, 186.0; MS (m/z): 422 (M)+; Anal. calcd
for C26H22N4O2: C, 73.92; H, 5.25; N, 13.26%; Found: C,
73.74; H, 5.33; N, 13.41%.
ACKNOWLEDGMENT
This work was supported by the Research Council of the
Shahrood University of Technology.
3.4.13
| 1-((1-[4-Chlorobenzyl]-1H-1,2,3-triazol-4-yl)methyl)-
ORCID
2-(4-methoxyphenyl)-1H-indole-3-carbaldehyde (5m)
Mohammad Bakherad https://orcid.org/0000-0003-3139-2249
IR (KBr): 3,083 (w), 2,936 (m), 2,369 (m), 1,654 (s), 1,533
(m), 1,456 (m), 1,428 (w) cm−1 1H NMR (300 MHz,
;
REFERENCES
DMSO-d6) δ: 3.87 (s, 3H, OCH3), 5.42 (s, 2H, CH2), 5.56
(s, 2H, CH2), 7.65 (d, 2H, J = 8.7 Hz, Ar-H), 7.26–7.29 (m,
2H, Ar-H), 7.31–7.33 (m, 2H, Ar-H), 7.43–7.48 (m, 3H, Ar-
H), 7.67 (d, 3H, J = 8.7 Hz, Ar-H), 8.05 (s, 1H, C-H),
8.21–8.24 (m, 1H, Ar-H), 9.62 (s, 1H, CHO). 13C NMR
(75 MHz, DMSO-d6) δ: 52.4, 55.8, 111.8, 114.6, 115.4,
120.2, 121.3, 123.4, 124.1, 124.1, 125.2, 129.1, 130.2,
130.7, 132.9, 133.3, 135.3, 136.7, 143.2, 151.8, 160.9,
186.0; MS (m/z): 456 (M)+; Anal. calcd for
C26H21CLN4O2: C, 68.34; H, 4.63; N, 12.26%; Found: C,
68.52; H, 4.55; N, 12.42%.
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SUPPORTING INFORMATION
Additional supporting information may be found online in
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How to cite this article: Bakherad M, Keivanloo A,
Bakherad Z, Toozandejani Z, Mahdavi M. Ligand-
free, copper-catalyzed, one-pot, three-component
synthesis of novel 1,2,3-triazole-linked indoles in
magnetized water. J Chin Chem Soc. 2019;1–9.
https://doi.org/10.1002/jccs.201800287