Synthesis of 1,4-Disubstituted 1,2,3-Triazoles via 1,3-Dipolar Cycloaddition/C–N Coupling of Propargyl Alcohols/amines and Aryl Azides

Article abstract of DOI:10.1002/jhet.3325

1,4-Disubstituted 1,2,3-triazoles are prepared through the 1,3-dipolar cycloaddition of propargyl (alcohols/amines) and aryl azides in the presence of a mixture of Cu(OAc)₂.H₂O and NaAs as the catalyst. This method offers the advantages of mild experimental conditions, operational simplicity, and high-to-excellent reaction yields.

Full text of DOI:10.1002/jhet.3325

Month 2018
Synthesis of 1,4-Disubstituted 1,2,3-Triazoles via 1,3-Dipolar
Cycloaddition/C–N Coupling of Propargyl Alcohols/amines and Aryl
Azides
*
Mohammad Bakherad,
Ahmad Kakavand Ghalenoei, and Ali Keivanloo
Faculty of Chemistry, Shahrood University of Technology, Shahrood, Iran
*E-mail: m.bakherad@yahoo.com
Received May 5, 2018
DOI 10.1002/jhet.3325
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
1,4-Disubstituted 1,2,3-triazoles are prepared through the 1,3-dipolar cycloaddition of propargyl (alco-
hols/amines) and aryl azides in the presence of a mixture of Cu(OAc)2.H2O and NaAs as the catalyst. This
method offers the advantages of mild experimental conditions, operational simplicity, and high-to-excellent
reaction yields.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
regioisomer [c]. The copper-catalyzed region selective
1,3-dipolar cycloaddition (“click reaction”) is now used
for the syntheses of various complex materials [24–28].
Recently, various copper catalysts such as Cu2O [29],
CuI [30,31], CuSO4.5H2O [32,33], CuBr (PPh3)3 [34],
polymeric imidazole-Cu (II) [35], Cu/SiO2 [36], Cu/C
[37], and polymer-capped Cu/Cu2O [38] have been
investigated for this purpose. In this letter, we wish to
report the synthesis of new derivatives of 1,4-disubstituted
1,2,3-triazol via 1,3-dipolar cycloaddition/C–N coupling of
propargyl (alcohols/amines) and aryl azides in the
presence of a mixture of Cu(OAc)2.H2O and NaAs at
60°C in ethanol as the solvent.
The nitrogen ligands allow the use of copper catalysts in
reduced amounts compared with the original classic
catalyst (Cu(OAc)2.H2O and sodium ascorbate), which is
still the most commonly utilized catalyst but in much
larger quantities that are often even stoichiometric or
superior to stoichiometry [39]. Ligands have been applied
to (a) avoid the formation of unreactive polynuclear
copper(I) acetylides; (b) render ease coordination of the
azide to the copper center at the ligand exchange step;
and (c) develop the solubility of the copper complex to
gain higher solution concentrations of the necessary
It has been noticed that triazol has different usages in
research works as a building block for complex chemical
compounds like pharmaceutical drugs such as the
antibacterial, antifungal, antiviral, anticancer, antimicrobial,
antidepressant, anticonvulsant, central nervous system
modulators, and anti-inflammatory ones [1–5]. Several
methods have been claimed for the synthesis of 1,2,3-
triazoles. A widespread method used for the synthesis of
1,2,3-triazoles is the addition of organoazides to alkynes
[6–17]. This well-appointed method is utilized for the
synthesis of the 1,2,3-triazol system based on the thermal
1,3-dipolar Huisgen cycloaddition of organic azides with
alkynes (Scheme 1). The Huisgen 1,3-dipolar cycloaddition
of organic azides to alkynes is one of the most significant
synthetic ways to the 1,2,3-triazol derivatives [18],
applied as dyes, photostabilizers, biochemicals, and
agrochemicals [19–21]. This transformation indicates a
high chemoselectivity because many functional groups do
not respond to azides or alkynes.
However, Huisgen cycloaddition usually requires a
high-reaction temperature and results in the formation of
a mixture of 1,4- and 1,5-regioisomers. In 2002, the
Sharpless [22] and Meldal [23] teams have independently
claimed that copper catalysts dramatically fasten the
reaction and make it totally regioselective to the 1,4-
Cu(I)-species [40].
A number of researchers have
effectively decreased the required amount of the copper
catalyst for the click reactions by the usage of ligands
© 2018 Wiley Periodicals, Inc.

M. Bakherad, A. K. Ghalenoei, and A. Keivanloo
Vol 000
Scheme 1. Synthesis of 1,2,3-triazol system based on thermal 1,3-dipolar Huisgen cycloaddition of organic azides with alkynes.
[41–43]. Recently, Deraedt et al. have used the dendrimer
ligand to decrease the copper catalyst used to the ppm scale
in simple click reactions [44].
concentration were studied, and the results obtained
were tabulated in Table 1. As shown in this table, the
click reaction was most effective in the presence of
10 mol% of Cu(OAc)2.H2O and 20 mol% of sodium
ascorbate in ethanol at 60°C, giving the product 8b
with an excellent yield (95%) (Table 1, entry 12). Also,
the effect of temperature on the click reaction was
checked, and the results obtained were tabulated in
Table 1. Increasing the temperature did not improve the
reaction yield (Table 1, entry 13). It is obvious that at
room temperature, a low product yield was formed
(Table 1, entry 14). Moreover, increasing the amount of
catalyst to 20 mol% showed no substantial improvement
in the yield (Table 1, entry 15). However, decreasing
the loading of the catalyst to 5 mol% lowered the
reaction yield dramatically (Table 1, entry 16).
A large amount of a heavy metal catalyst is used in the
classic copper-catalyzed click reactions, whereas Cu salts are
toxic, pollute the biologically relevant compounds, and their
complete removal from the reaction products is difficult.
This problem inhibits the utilization of the click reactions in
the biomedicine science. In order to decrease the amount of
the copper catalyst, we decided to use the Schiff base
ligands salen (L1), salophen (L2), metformine (L3) and
ethylenediamine (L4), and O-phenylenediamine (L5), as
additive in the reaction. Surprisingly, in the presence of L2
and with 2.5 mol% of Cu(OAc)2.H2O, this reaction
proceeded accordingly and was completed to gain the
estimated outcome in a 95% yield (Table 1, entry 22). As a
result, the most suitable cases were 2.5 mol% of Cu(OAc)2.
H2O, 5 mol% of sodium ascorbate, and 2.5 mol% of
salophen (L2) at 60°C in ethanol (Table 1, entry 22).
Propargyl (alcohols/amines) were prepared according to
a reported procedure [45]. On one hand, the treatment of
calcium carbide 1 with various aldehydes or ketones 2 in
dimethyl sulfoxide (DMSO)/H2O (50:1) in the presence
of Cs2CO3, as a base, afforded propargyl alcohols 3 in
good yields (Scheme 2). On the other hand, the reaction
of calcium carbide 1, benzaldehyde 4, an amine 5, and
CuI (as the catalyst) in CH3CN at 80°C afforded a
propargyl amine 6 in a good yield (Scheme 3).
Then, we chose the reaction of a propargyl alcohol (R═H,
3a) (1 equiv.) with 1-azido-4-nitrobenzene 7b (1 equiv.), as
a model reaction, using 10 mol% of Cu(OAc)2.H2O and
20 mol% of sodium ascorbate as the catalyst. The effects
of solvent, ligand, reaction temperature, and catalyst
Scheme 2. Synthesis of propargyl alcohols by reaction of calcium carbide
with various ketones in dimethyl sulfoxide (DMSO)/H2O. [Color figure
can be viewed at wileyonlinelibrary.com]
Scheme 3. Synthesis of propargyl amines by reaction of calcium carbide,
benzaldehyde, and an amine in CH3CN. R1R2NH, dimethylamine,
diethylamine, diperidine, morpholine. [Color figure can be viewed at
wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
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Month 2018
Synthesis of 1,4-Disubstituted 1,2,3-Triazoles via 1,3-Dipolar Cycloaddition/C–N
Coupling of Propargyl Alcohols/amines and Aryl Azides
Table 1
Effects of various amounts of catalyst and solvent, and temperature and ligand on reaction of propargyl alcohol 3a with 1-azido-4-nitrobenzene 7b.a [Color
table can be viewed at wileyonlinelibrary.com]
Entry
Catalyst (mol%)
Additive
Solvent
Temp. (°C)
Time (h)
Yieldb (%)
1c
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
CuI (10)
CuI (10)
CuI (10)
CuI (10)
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
L1
L2
L3
L4
L5
L2
L2
L2
CH3CN
DMF
H2O
EtOH
CH3CN
DMF
H2O
EtOH
CH3CN
DMF
H2O
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
60
60
60
60
60
60
60
60
60
60
60
60
78
RT
60
60
60
60
60
60
60
60
60
RT
4
4
5
4
4
6
10
6
3
4
5
2
2
10
2
10
2
2
2
2
81
80
70
89
76
74
65
85
87
82
78
95
95
64
96
63
75
96
77
82
80
95
77
80
CuSO4.5H2O (10)
CuSO4.5H2O (10)
CuSO4.5H2O (10)
CuSO4.5H2O (10)
Cu(OAc)2.H2O (10)
Cu(OAc)2.H2O (10)
Cu(OAc)2.H2O (10)
Cu(OAc)2.H2O (10)
Cu(OAc)2.H2O (10)
Cu(OAc)2.H2O (10)
Cu(OAc)2.H2O (20)
Cu(OAc)2.H2O (5)
Cu(OAc)2.H2O (5)
Cu(OAc)2.H2O (5)
Cu(OAc)2.H2O (5)
Cu(OAc)2.H2O (5)
Cu(OAc)2.H2O (5)
Cu(OAc)2.H2O (2.5)
Cu(OAc)2.H2O (1)
Cu(OAc)2.H2O (2.5)
2
2
4
5
DMF, dimethylformamide; RT, room temperature.
aReaction conditions: compound 3a (1.0 mmol), 1-azido-4-nitrobenzene 7b (1.0 mmol), copper salt, sodium ascorbate (twice the amount of copper salt),
ligand (equal to copper salt), solvent (5 mL).
bIsolated yield.
cWithout sodium ascorbate.
In order to explore the scope and generality of this
protocol, a number of propargyl alcohols 3a–b were
reacted with aryl azied 8a–i in the presence of Cu(OAc)2.
H2O at 60°C in ethanol. The desired products, 1,4-
disubstitued 1,2,3-triazoles 8a–i, were obtained in
moderate-to-good yields. The results obtained are shown in
Table 2. As shown in this table, the click reactions of
compound 3 with aryl azides bearing an electron-donating
(Table 2, entries 7 and 8) or electron-withdrawing group
were obtained in high yields.
The structural assignments of compounds 8a–i are based
on the NMR spectroscopic and mass analysis data. The 1H
NMR spectrum for compound 8b showed two doublets at δ
8.24 and δ 8.45, which were assigned to the four protons
on the phenyl ring. Moreover, the singlet at δ 8.87 was
due to the triazol ring. In the aliphatic region, we
observed a singlet at δ 5.13, which is related to the OH
group, and the three multiples at δ 1.40, 1.75, and 1.94
were assigned to the cyclohexanone group.
To extend the scope of our work, we next investigated
the click reaction of propargyl amines 6 with aryl azides
7, which afforded new 1,4-disubstituted 1,2,3-triazoles 9
in a good yield.
Initially, we chose the click reaction of N,N-diethyl-1-
phenylprop-2-yn-1-amine 6a with 1-azido-4-nitrobenzene
7a in the presence of 5 mol% of Cu(OAc)2.H2O and
10 mol% of sodium ascorbate as the model reaction. In
order to find the optimal reaction conditions for the
synthesis of compound 9a, the effects of various solvents,
catalysts, and ligands were studied, and the results obtained
were tabulated in Table 3. As shown in this table, the
reaction was most effective in the presence of 2.5 mol% of
Journal of Heterocyclic Chemistry
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M. Bakherad, A. K. Ghalenoei, and A. Keivanloo
Vol 000
Table 2
Synthesis of new 1,4-disubstituted 1,2,3-triazoles.a [Color table can be viewed at wileyonlinelibrary.com]
Entry
1
Propargyl alcohol
Aryl azide
Time (h)
3
Product
Yieldb (%)
3a
93
2
3
3a
3a
2
5
95
82
4
5
3a
3a
6
8
83
75
6
7
3a
3a
8
3
70
98
8
3b
6
95
(Continues)
Journal of Heterocyclic Chemistry
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Month 2018
Synthesis of 1,4-Disubstituted 1,2,3-Triazoles via 1,3-Dipolar Cycloaddition/C–N
Coupling of Propargyl Alcohols/amines and Aryl Azides
Table 2
(Continued)
Entry
9
Propargyl alcohol
Aryl azide
Time (h)
5
Product
Yieldb (%)
80
3b
aReaction conditions: 3 (1 mmol), 7 (1 mmol), Cu(OAc)2.H2O (2.5 mol%), sodium ascorbate (5 mol%), salophen (2.5 mol%), ethanol (5 mL), 60°C.
bIsolated yield.
Table 3
Effects of various catalysts and solvents and temperature and ligands on reaction of compound 6a with 1-azido-4-nitrobenzene 7a.a [Color table can be
viewed at wileyonlinelibrary.com]
Entry
Catalyst (mol%)
Additive
Solvent
Temp. (°C)
Time (h)
Yieldb (%)
1c
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
CuI (10)
CuI (10)
CuI (10)
CuI (10)
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
L1
L2
L3
L4
L5
L1
L1
CH3CN
DMF
H2O
EtOH
CH3CN
DMF
H2O
EtOH
CH3CN
DMF
H2O
EtOH
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Reflux
60
Reflux
Reflux
Reflux
60
Reflux
Reflux
Reflux
60
Reflux
Reflux
90
RT
60
60
60
60
60
60
60
6
6
6
6
5
8
8
8
5
2
5
6
3
8
2
10
3
3
3
3
3
3
4
76
80
70
85
81
83
60
78
86
95
67
77
95
56
97
72
97
79
67
80
75
97
80
CuSO4.5H2O (10)
CuSO4.5H2O (10)
CuSO4.5H2O (10)
CuSO4.5H2O (10)
Cu(OAc)2.H2O (10)
Cu(OAc)2.H2O (10)
Cu(OAc)2.H2O (10)
Cu(OAc)2.H2O (10)
Cu(OAc)2.H2O (10)
Cu(OAc)2.H2O (10)
Cu(OAc)2.H2O (20)
Cu(OAc)2.H2O (5)
Cu(OAc)2.H2O (5)
Cu(OAc)2.H2O (5)
Cu(OAc)2.H2O (5)
Cu(OAc)2.H2O (5)
Cu(OAc)2.H2O (5)
Cu(OAc)2.H2O (2.5)
Cu(OAc)2.H2O (1)
60
60
DMF, dimethylformamide; RT, room temperature.
aReaction conditions: compound 6a (1.0 mmol), 1-azido-4-nitrobenzene 7a (1.0 mmol), copper salt, sodium ascorbate (twice the amount of copper salt),
ligand (equal copper salt), solvent (5 mL).
bIsolated yield.
cWithout sodium ascorbate.
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M. Bakherad, A. K. Ghalenoei, and A. Keivanloo
Vol 000
Cu(OAc)2.H2O, 5 mol% of sodium ascorbate, and 2.5 mol%
of salen (L1) at 60°C in dimethylformamide, giving the
desired product with a 97% yield (Table 3, entry 22).
Using the aforementioned optimized conditions, the
scope of the aryl azides was then examined. As shown in
Table 4, various aryl azides performed well in the
developed catalytic system. The corresponding products
were isolated in good-to-high yields. The electronic
effects of the substituents in aryl azides seemed to have a
little effect on the reaction (Table 4).
The copper-catalyzed click reaction mechanism
comprises the multi-general steps shown in Scheme 4: (a)
formation of copper(I) acetylide A; this step occurs
through a π-alkyne copper complex intermediate; (b) the
Table 4
Synthesis of new 1,4-disubstituted 1,2,3-triazoles.a [Color table can be viewed at wileyonlinelibrary.com]
Entry
1
Propargyl amine
Aryl azide
Time (h)
3
Product
Yieldb (%)
97
2
5
90
3
4
6
6
90
85
5
6
3
6
83
87
aReaction conditions: compound 6 (1.0 mmol), aryl azide 7 (1.0 mmol), copper acetate (2.5 mol%), sodium ascorbate (5 mol%), salen (2.5 mol%),
dimethylformamide (3 mL), 60°C.
bIsolated yield.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis of 1,4-Disubstituted 1,2,3-Triazoles via 1,3-Dipolar Cycloaddition/C–N
Coupling of Propargyl Alcohols/amines and Aryl Azides
Scheme 4. Proposed mechanism for copper-catalyzed click reactions. [Color figure can be viewed at wileyonlinelibrary.com]
azide is activated by coordination to copper(I), framing
intermediate B; (c) the first C–N bond formation affords
the six-membered ring copper metallacycle C; (d)
cyclization takes place to yield the copper triazol
intermediate D; (e) proteolysis of the Cu–C bond gives
the triazol product and regenerates the catalyst. Each
stage involves a multi-nuclear Cu species [46].
In conclusion, we demonstrated an efficient and successful
click reaction protocol for the synthesis of new 1,4-
disubstituted 1,2,3-triazoles via 1,3-dipolar cycloaddition/C–
N coupling of propargyl alcohols/amines and aryl azides.
This methodology offers several advantages like one-pot
synthesis of a wide range of 1,2,3-triazol derivatives starting
from propargyl alcohols/amines, simple reaction conditions,
and readily available starting materials.
cyclohexanone (1 mmol), and 3 mL (DMSO/H2O, 50:1).
The mixture was bubbled with argon for 10 min, and the
reaction was stirred at 60°C for 8 h. The resulting
product was extracted with 20 mL ethyl acetate. The
organic layer was dried over Na2SO4 and concentrated in
vacuo, and the crude product obtained was purified by
column chromatography (hexane/ethyl acetate: 5/1) [41].
General procedure for synthesis of propargyl amines (6).
General procedure for A3 coupling: A mixture of calcium
carbide (1.2 mmol, 77 mg), benzaldehyde (1.0 mmol,
106 mg), diisopropylamine (1.5 mmol, 151.5 mg), and
CuI catalyst (0.1 mmol, 20.0 mg) was added to a reaction
tube (10 mL) with 2 mL CH3CN. After stirring at 80°C
for 18 h, the mixture was diluted with H2O (10 mL), and
the aqueous layer was extracted with diethyl ether
(2 × 10 mL), dried over Na2SO4, and concentrated under
vacuum to give the crude product. This crude product
was further purified by column chromatography on silica
gel (ethyl acetate/hexane, 1:4) to afford the corresponding
pure aminopropyne [42].
EXPERIMENTAL
General.
The solvents and reagents used were all
General procedure for synthesis of 2-subsituted-1-(1-aryl-
supplied from Merck (Darmstadt, Germany) or Fluka
(Switzerland) and used without any further purification.
Melting points were recorded on a thermocouple digital
melting point apparatus. Fourier transform infrared
spectra were obtained as potassium bromide pellets in the
range of 400–4000 cmÀ1 on a Bomem MB series
spectrometer (Germany). NMR spectra were recorded on
a Bruker 300 MHz 1H NMR, 75 MHz 13C NMR
spectrometer (Billerica, MA). Mass spectra were recorded
1H-1,2,3-triazol-4-yl)
cyclohexanol
(8a–i).
1-
Ethynylcyclohexan-1-ol (1.5 mmol), an aryl azide
(1 mmol), Cu(OAc)2.H2O (10 mol%), and sodium
ascorbate (20 mol%) were mixed in ethanol at 60°C. The
mixture was extracted with ethyl acetate (3 × 10 mL),
dried over Na2SO4, and concentrated under vacuum to
give the crude product. The crude product was further
purified by column chromatography on silica gel (ethyl
acetate/hexane, 1:4) to afford the corresponding pure
on
a 5975C spectrometer supplied from Agilent
1,2,3-triazol as the eluent (Table 2).
Technologies Company (Santa Clara, CA).
1-(1-Phenyl-1H-1,2,3-triazol-4-yl)cyclohexan-1-ol (8a).
Yellow solid; mp 178–180°C; 1H NMR (300 MHz,
DMSO-d6): δ 1.41–1.62 (m, 4H, CH2 of cyclohexane),
1.69–1.81 (m, 4H, CH2 of cyclohexane), 1.92–1.96 (m,
General procedure for coupling reaction to synthesize
propargyl alcohols (3). To a vial was added 163 mg of
Cs2CO3 (0.5 mmol), 200 mg CaC2 (2.5 mmol),
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M. Bakherad, A. K. Ghalenoei, and A. Keivanloo
Vol 000
2H, CH2 of cyclohexane), 5.06 (s, 1H, OH), 7.47 (t,
J = 9 Hz, 1H, CH aromatic), 7.59 (t, J = 9 Hz, 2H, CH
aromatic), 7.93 (d, J = 9 Hz, 2H, CH aromatic), 8.62 (s,
1H, CH of triazol); 13C NMR (75 MHz, DMSO-d6): δ
23.00, 25.42, 38.12, 73.81, 117.69, 122.14, 127.74,
130.06, 136.32, 153.13; IR (KBr): 3369, 3099, 3057,
2933, 2854, 1595, 1549, 1498, 1068 cmÀ1; MS (EI), m/z
[M]+ 244.14; Anal. Calcd for C14H17N3O: C, 69.11; H,
OH), 8.02 (d, J = 8.7 Hz, 1H, CH aromatic), 8.32 (d,
J = 8.8 Hz, 1H, CH aromatic), 8.72 (s, 1H, CH
aromatic), 8.84 (s, 1H, CH of triazol); 13C NMR
(75 MHz, DMSO-d6): δ 22.13, 25.66, 38.06, 68.42,
117.12, 120.35, 124.50, 124.83, 133.59, 136.48, 148.59,
157.73; IR (KBr): 3216, 3112, 3041, 2917, 2821, 1585,
1519, 1437, 1101 cmÀ1; MS (EI), m/z [M]+ 323.2; Anal.
Calcd for C14H15ClN4O3: C, 52.10; H, 4.68; N, 17.36%;
7.04; N, 17.27%; Found: C, 69.25; H, 7.19; N, 17.35%.
Found: C, 52.21; H, 4.78; N, 17.44%.
1-(1-(4-Chloro-2-nitrophenyl)-1H-1,2,3-triazol-4-yl)
1-(1-(4-Nitrophenyl)-1H-1,2,3-triazol-4-yl)cyclohexan-1-ol
1
Light brown solid; mp 209–210°C; 1H NMR
cyclohexan-1-ol (8f). Yellow solid; mp 139–140°C; H
(8b).
NMR (300 MHz, DMSO-d6): δ 1.29–1.51 (m, 4H, CH2
of cyclohexane), 1.70–1.85 (m, 4H, CH2 of cyclohexane),
1.95–2.02 (m, 2H, CH2 of cyclohexane), 5.15 (s, 1H,
OH), 7.96 (d, J = 8.4 Hz, 1H, CH aromatic), 8.10 (d,
J = 8.4 Hz, 1H, CH aromatic), 8.44 (s, 1H, CH of
triazol), 8.55(s, 1H, CH aromatic); 13C NMR (75 MHz,
DMSO-d6): δ 22.10, 25.65, 38.17, 68.44, 122.90, 125.83,
128.50, 129.01, 134.41, 135.05, 144.82, 157.07; IR
(KBr): 3216, 3115, 3042, 2915, 2819, 1581, 1520, 1437,
1101 cmÀ1; MS (EI), m/z [M]+ 323.2; Anal. Calcd for
(300 MHz, DMSO-d6): δ 1.34–1.47 (m, 4H, CH2 of
cyclohexane), 1.70–1.81 (m, 4H, CH2 of cyclohexane),
1.93–1.96 (m, 2H, CH2 of cyclohexane), 5.13 (s, 1H,
OH), 8.25 (d, J = 8.9 Hz, 2H, CH aromatic), 8.44 (d,
J = 8.9 Hz, 2H, CH aromatic), 8.87 (s, 1H, CH of
triazol); 13C NMR (75 MHz, DMSO-d6): δ 22.10, 25.65,
38.00, 68.41, 120.29, 120.69, 126.04, 141.53, 146.87,
157.87; IR (KBr): 3224, 3116, 3074, 2939, 2854, 1597,
1527, 1442, 1047 cmÀ1; MS (EI), m/z [M]+ 289.2; Anal.
Calcd for C14H16N4O3: C, 58.32; H, 5.59; N, 19.43%;
C14H15ClN4O3: C, 52.10; H, 4.68; N, 17.36%; Found: C,
C, 52.28; H, 4.74; N, 17.49%.
Found: C, 58.22; H, 5.41; N, 19.34%.
1-(1-(3-Nitrophenyl)-1H-1,2,3-triazol-4-yl)cyclohexan-1-ol
(8c). Yellow solid; mp 194–195°C; 1H NMR (300 MHz,
1-(1-(p-Tolyl)-1H-1,2,3-triazol-4-yl)cyclohexan-1-ol (8g).
Brown solid; mp 148–150°C; 1H NMR (300 MHz,
DMSO-d6): δ 1.32–1.98 (m, 10H, CH2 of cyclohexane),
5.07 (s, 1H, OH), 7.89 (t, J = 7.95 Hz, 1H, CH
aromatic), 8.30 (d, J = 7.5 Hz, 1H, CH aromatic), 8.43
(d, J = 7.5 Hz, 1H, CH aromatic), 8.75 (s, 1H), 8.90 (s,
1H, CH of triazol); 13C NMR (75 MHz, DMSO-d6): δ
22.16, 25.68, 38.05, 68.41, 114.86, 120.33, 123.19,
126.19, 131.95, 137.88, 149.01, 157.60; IR (KBr): 3220,
DMSO-d6): δ 1.37–1.52 (m, 4H, CH2 of cyclohexane),
1.68–1.80 (m, 4H, CH2 of cyclohexane), 1.92–1.95 (m,
2H, CH2 of cyclohexane), 2.38 (s, 3H, CH3) 5.02 (s,
1H, OH), 7.38 (d, J = 8.4 Hz, 2H, CH aromatic), 7.79
(d, J = 8.4 Hz, 2H, CH aromatic), 8.56 (s, 1H, CH of
triazol); 13C NMR (75 MHz, DMSO-d6): δ 22.16,
25.70, 38.12, 68.41, 88.197, 119.62, 120.13, 130.66,
135.06, 138.33, 157.14; IR (KBr): 3401, 3128, 3045,
2921, 2852, 1640, 1516, 1445, 1110 cmÀ1; MS (EI),
m/z [M]+ 258.2; Anal. Calcd for C15H19N3O: C, 70.01;
H, 7.44; N, 16.33%; Found: C, 70.12; H, 7.51; N,
3119, 3054, 2925, 2830, 1585, 1519, 1438, 1051 cmÀ1
;
MS (EI), m/z [M]+ 289.2; Anal. Calcd for C14H16N4O3:
C, 58.32; H, 5.59; N, 19.43%; Found: C, 58.30; H, 5.55;
N, 19.39%.
1-(1-(3-Chlorophenyl)-1H-1,2,3-triazol-4-yl)cyclohexan-1-ol
1
(8d). White solid; mp 201–203°C; H NMR (300 MHz,
16.47%.
CDCl3): 1H NMR (300 MHz, DMSO-d6): δ 1.30–1.47
(m, 4H, CH2 of cyclohexane), 1.66–1.81 (m, 4H, CH2 of
cyclohexane), 1.92–1.99 (m, 2H, CH2 of cyclohexane),
5.07 (s, 1H, OH), 7.54 (d, J = 9 Hz, 1H, CH aromatic),
7.62 (t, J = 7.5 Hz, 1H, CH aromatic), 7.95 (d, J = 6 Hz,
1H, CH aromatic), 8.08 (t, J = 7.5 Hz, 1H, CH aromatic),
8.74 (s, 1H, CH of triazol); 13C NMR (75 MHz,
DMSO-d6): δ 22.15, 25.67, 38.05, 68.38, 118.07, 119.97,
120.03, 128.59, 132.08, 134.66, 138.33, 157.35; IR
(KBr): 3226, 3103, 3059, 2933, 2854, 1668, 1591, 1485,
1153 cmÀ1; MS (EI), m/z [M]+ 278.2; Anal. Calcd for
C14H16ClN3O: C, 60.54; H, 5.81; N, 15.13%; Found: C,
2-Methyl-1-(1-(p-tolyl)-1H-1,2,3-triazol-4-yl)cyclohexan-1-ol
1
(8h). White solid; mp 160–162; H NMR (300 MHz,
1
CDCl3): H NMR (300 MHz, DMSO-d6): δ 0.685 (dd,
J = 6.9 Hz, 3H, CH3), 1.30–1.55 (m, 3H, CH2 of
cyclohexane), 1.60–2.08 (m, 6H, CH2 of cyclohexane),
2.35 (s, 3H, CH3), 5.21 (s, 1H, OH), 7.37 (d, J = 8.4 Hz,
2H, CH aromatic), 7.72 (d, J = 8.7 Hz, 2H, CH
aromatic), 8.32 (s, 1H, CH of triazol); 13C NMR
(75 MHz, DMSO-d6): δ 15.78, 23.69, 25.65, 29.83,
39.84, 41.80, 73.39, 88.19, 119.61, 120.11, 130.65,
135.04, 138.33, 157.12; IR (KBr): 3408, 3130, 3049,
2925, 2856, 1641, 1518, 1446, 1113 cmÀ1; MS (EI), m/z
[M]+ 272.17; Anal. Calcd for C16H21N3O: C, 70.82; H,
7.80; N, 15.49%; Found: C, 70.72; H, 7.69; N, 15.37%.
60.67; H, 5.96; N, 15.25%.
1-(1-(4-Chloro-3-nitrophenyl)-1H-1,2,3-triazol-4-yl)
cyclohexan-1-ol (8e). Light yellow solid; mp 197–198°C;
2-Methyl-1-(1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)
1
1H NMR (300 MHz, DMSO-d6): δ 1.46–1.56 (m, 4H, CH2
of cyclohexane), 1.66–1.81 (m, 4H, CH2 of cyclohexane),
1.93–2.00 (m, 2H, CH2 of cyclohexane), 5.09 (s, 1H,
cyclohexan-1-ol (8i).
Yellow solid; mp 126–128°C; H
NMR (300 MHz, CDCl3): 1H NMR (300 MHz,
DMSO-d6): δ 0.833 (dd, J = 6.9 Hz, 3H, CH3), 1.40–
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis of 1,4-Disubstituted 1,2,3-Triazoles via 1,3-Dipolar Cycloaddition/C–N
Coupling of Propargyl Alcohols/amines and Aryl Azides
1.55 (m, 3H, CH2 of cyclohexane), 1.60–2.08 (m, 6H, CH2
of cyclohexane), 5.21 (s, 1H, OH), 8.01 (d, J = 8.4 Hz, 2H,
CH aromatic), 8.07 (s, 1H, CH of triazol), 8.44 (d,
J = 8.7 Hz, 2H, CH aromatic); 13C NMR (75 MHz,
DMSO-d6): δ 15.82, 23.70, 25.65, 29.85, 39.88, 41.88,
73.41, 119.09, 120.35, 125.54, 141.29, 147.11, 157.14;
IR (KBr): 3365, 3134, 3089, 2925, 2856, 1599, 1516,
1448, 1107 cmÀ1; MS (EI), m/z [M]+ 272.17; Anal.
Calcd for C15H18N4O3: C, 59.59; H, 6.00; N, 18.53%;
Found: C, 59.46; H, 5.91; N, 18.45%.
NMR (300 MHz, DMSO-d6): δ 2.36 (m, 4H, CH2
morpholine), 3.60 (m, 4H, CH2 morpholine), 4.73 (s, 1H,
CH), 7.28 (t, J = 7.2 Hz, 1H, CH aromatic), 7.36 (t,
J = 7.35 Hz, 2H, CH aromatic), 7.53 (d, J = 7.2 Hz, 2H,
CH aromatic), 7.89 (t, J = 8.25 Hz, 1H, CH aromatic),
8.32 (d, J = 8.1 Hz, 1H, CH aromatic), 8.44 (d,
J = 8.1 Hz, 1H, CH aromatic) 8.78 (s, 1H, CH aromatic),
9.1 (s, 1H, CH of triazol); 13C NMR (75 MHz,
DMSO-d6): δ 51.98, 66.72, 67.46, 115.16, 122.34,
123.46, 126.49, 127.94, 128.93, 128.97, 131.91, 137.73,
140.33, 148.95, 149.41; IR (KBr): 3093, 2962, 2924,
2858, 1641, 1541, 1452, 1351, 1190 cmÀ1; MS (EI), m/z
[M]+ 366.2; Anal. Calcd for C19H19N5O3: C, 62.46; H,
General procedure for synthesis of (1-aryl-1H-1,2,3-triazol-
4-yl)-N,N-dialkyl (phenyl) methanamine (9a–f). Propargyl
amine 6 (1.0 mmol), an aryl azide (1.2 mmol), CuI
(10 mol%), and N-ethyldiisopropylamine (15 mol%) were
mixed in dimethylformamide at 60°C. The mixture was
extracted with diethyl ether (2 × 10 mL), dried over
Na2SO4, and concentrated under vacuum to give the crude
product. This crude product was further purified by column
chromatography on silica gel (ethyl acetate/hexane, 1:4) to
afford the corresponding pure title compounds. All
5.24; N, 19.17%; Found: C, 62.53; H, 5.33; N, 19.24%.
4-((1-(4-Chloro-3-nitrophenyl)-1H-1,2,3-triazol-4-yl)(phenyl)
methyl) morpholine (9d). Yellow solid; mp 154–156°C;
1H NMR (300 MHz, DMSO-d6): δ 2.36 (m, 4H, CH2
morpholine), 3.60 (m, 4H, CH2 morpholine), 5.20 (s, 1H,
CH), 7.29 (t, J = 7.2 Hz, 1H, CH aromatic), 7.37 (t,
J = 7.00 Hz, 2H, CH aromatic), 7.51 (d, J = 7.0 Hz, 2H,
CH aromatic), 8.01 (d, J = 9 Hz, 1H, CH aromatic), 8.32
(d, J = 8.7 Hz, 1H, CH aromatic), 8.74 (s, 1H, CH
aromatic), 8.99 (s, 1H, CH of triazol); 13C NMR
(75 MHz, DMSO-d6): δ51.95, 66.74, 67.38, 117.37,
122.33, 124.68, 125.07, 127.94, 128.92, 128.94, 133.49,
136.35, 140.22, 148.51, 149.49; IR (KBr): 3171, 3095,
products gave satisfactory spectroscopic data.
N-Ethyl-N-((1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)(phenyl)
1
methyl) ethanamine (9a). White solid; mp 97–98°C; H
NMR (300 MHz, DMSO-d6): δ 0.99 (t, 6H, 2CH3), 2.32–
2.44 (m, 2H, CH2), 2.52–2.61 (m, 2H, CH2), 5.22 (s, 1H,
CH), 7.26 (t, J = 7.2 Hz, 1H, CH aromatic), 7.34 (t,
J = 7.2 Hz, 2H, CH aromatic), 7.48 (d, J = 7.5 Hz, 2H,
CH aromatic), 8.28 (d, J = 7.75 Hz, 2H, CH aromatic),
8.45 (d, J = 9.3 Hz, 2H, CH aromatic) 9.03 (s, 1H, CH
of triazol); 13C NMR (75 MHz, DMSO-d6): δ12.54,
31.175, 43.52, 61.44, 120.86, 122.39, 126.01, 127.51,
128.60, 128.68, 141.42, 141.81, 146.98, 149.08; IR
(KBr): 3130, 3093, 2951, 2858, 1624, 1535, 1452, 1346,
1198 cmÀ1; MS (EI), m/z [M]+ 352.2; Anal. Calcd for
C19H21N5O2: C, 64.94; H, 6.02; N, 19.93%; Found: C,
2958, 2921, 2812, 1591, 1518, 1450, 1345, 1191 cmÀ1
;
MS (EI), m/z [M]+ 400.2; Anal. Calcd for C19H18ClN5O3:
C, 57.08; H, 4.54; N, 17.52%; Found: C, 57.16; H, 4.61;
N, 17.55%.
N,N-Dimethyl-1-(1-(3-nitrophenyl)-1H-1,2,3-triazol-4-yl)-1-
1
phenylmethanamine (9e). Yellow solid; mp 96–98°C; H
NMR (300 MHz, DMSO-d6): δ 2.15 (s, 6H, 2CH3), 4.65
(s, 1H, CH), 7.26 (t, J = 7.2 Hz, 1H, CH aromatic), 7.35
(t, J = 7.00 Hz, 2H, CH aromatic), 7.50 (d, J = 7.0 Hz,
2H, CH aromatic), 7.88 (t, J = 8.1 Hz, 1H, CH aromatic),
8.32 (d, J = 8.7 Hz, 1H, CH aromatic), 8.45 (d,
J = 8.7 Hz, 1H, CH aromatic), 8.79 (s, 1H, CH
aromatic), 9.11 (s, 1H, CH of triazol); 13C NMR
(75 MHz, DMSO-d6): δ43.73, 67.94, 115.05, 122.11,
123.42, 126.37, 127.78, 128.74, 128.82, 131.93, 137.75,
141.29, 148.98, 149.96; IR (KBr): 3135, 3095, 2954,
2850, 1626, 1531, 1455, 1341, 1190 cmÀ1; MS (EI), m/z
[M]+ 324.2; Anal. Calcd for C17H17N5O2: C, 63.15; H,
64.83; H, 5.97; N, 19.86%.
N-((1-(4-Chloro-3-nitrophenyl)-1H-1,2,3-triazol-4-yl)
(phenyl)methyl)-N-ethylethan-amine (9b). Brown solid; mp
1
134–136°C; H NMR (300 MHz, DMSO-d6): δ 0.99 (t,
6H, CH3), 2.34–2.43 (m, 2H, CH2), 2.55–2.59 (m, 2H,
CH2), 5.20 (s, 1H, CH), 7.25 (t, J = 7.2 Hz, 1H, CH
aromatic), 7.34 (t, J = 7.35 Hz, 2H, CH aromatic), 7.47
(d, J = 7.2 Hz, 2H, CH aromatic), 8.02 (d, J = 9 Hz, 1H,
CH aromatic), 8.34 (d, J = 8.7 Hz, 1H, CH aromatic),
8.76 (s, 1H CH aromatic), 8.98 (s, 1H, CH of triazol);
13C NMR (75 MHz, DMSO-d6): δ12.59, 43.49, 61.43,
117.26, 122.41, 124.61, 124.94, 127.51, 128.60, 128.68,
133.53, 136.34, 141.79, 148.52, 148.97; IR (KBr): 3157,
3086, 2968, 2927, 2817, 1597, 1516, 1454, 1342,
1171 cmÀ1; MS (EI), m/z [M]+ 386.2; Anal. Calcd for
C19H20ClN5O2: C, 59.14; H, 5.22; N, 18.15%; Found: C,
59.20; H, 5.24; N, 18.21%.
5.30; N, 21.66%; Found: C, 63.24; H, 5.37; N, 21.71%.
1-((1-(3-Nitrophenyl)-1H-1,2,3-triazol-4-yl)(phenyl)methyl)
1
piperidine (9f). Yellow solid; mp 159–161°C; H NMR
(300 MHz, DMSO-d6): δ 1.36–1.37 (m, 2H, CH2 of
piperidine), 1.52 (m, 4H, CH2 of piperidine), 2.34 (m,
4H, CH2 of piperidine), 5.09 (s, 1H, CH), 7.26 (t,
J = 7.05 Hz, 1H, CH aromatic), 7.34 (t, J = 7.35 Hz, 2H,
CH aromatic), 7.48 (d, J = 7.2 Hz, 2H, CH aromatic),
7.88 (t, J = 8.25 Hz, 1H, CH aromatic), 8.32 (d,
J = 8.1 Hz, 1H, CH aromatic), 8.45 (d, J = 8.1 Hz, 1H,
4-((1-(3-Nitrophenyl)-1H-1,2,3-triazol-4-yl)(phenyl)methyl)
1
morpholine (9c). Light yellow solid; mp 150–152°C; H
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Bakherad, A. K. Ghalenoei, and A. Keivanloo
Vol 000
[20] Genine, M. J.; David, D. A.; Anderson, J.; Barbachyn, M. R.;
Emmert, D. E.; Garmon, S. A.; Graber, D. R.; Grega, K. C.; Hester, J. B.;
Hutchinson, D. K.; Morris, J.; Reischer, R. J.; Ford, C. W.; Zurenko, G.
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[21] Brik, A.; Lin, Y. C.; Elder, J.; Wong, C. H. Chem Biol
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[22] Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew Chem, Int Ed 2002, 41, No. 14.
CH aromatic), 8.78 (s, 1H, CH aromatic), 9.04 (s, 1H, CH
of triazol); 13C NMR (75 MHz, DMSO-d6): δ 24.58, 26.18,
52.19, 67.31, 115.08, 122.21, 123.37, 126.41, 127.62,
128.73, 128.79, 131.90, 137.78, 140.90, 149.00, 149.51;
IR (KBr): 3161, 3095, 2960, 2931, 2812, 1590, 1516,
1457, 1343, 1112 cmÀ1; MS (EI), m/z [M]+ 363.2; Anal.
Calcd for C20H21N5O2: C, 66.10; H, 5.82; N, 19.27%;
Found: C, 66.13; H, 5.89; N, 19.32%.
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Acknowledgment. We wish to express our thanks to the
Research Council of the Shahrood University of Technology for
the financial support of this work.
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Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet