Environmental friendly azide-alkyne cycloaddition reaction of azides, alkynes, and organic halides or epoxides in water: Efficient "click" synthesis of 1,2,3-triazole derivatives by Cu catalyst

Article abstract of DOI:10.1002/cjoc.201280012

An efficient click synthesis of 1,2,3-triazole derivatives from benzyl halides or alkyl halides, epoxides, terminal alkynes, and sodium azides in the presence of copper salts and relative benzimidazole salts have been developed. This procedure eliminates the need to handle potentially organic azides, which are generated in situ. A broad spectrum of substrates can participate in the process effectively to produce the desired products in good yields.

Full text of DOI:10.1002/cjoc.201280012

FULL PAPER
DOI: 10.1002/cjoc.201280012
Environmental Friendly Azide-Alkyne Cycloaddition Reaction
of Azides, Alkynes, and Organic Halides or Epoxides in Water:
Efficient “Click” Synthesis of 1,2,3-Triazole Derivatives by Cu
Catalyst
Liu, Jianming(刘建明)
Liu, Muwen(刘慕文)
Yue, Yuanyuan(岳园园)
Yao, Meihuan(姚美焕)
Zhuo, Kelei*(卓克垒)
Key Laboratory of Green Chemical Media and Reactions (Ministry of Education), School of Chemistry and Envi-
ronmental Science, Henan Normal University, Xinxiang, Henan 453007, China
An efficient click synthesis of 1,2,3-triazole derivatives from benzyl halides or alkyl halides, epoxides, terminal
alkynes, and sodium azides in the presence of copper salts and relative benzimidazole salts have been developed.
This procedure eliminates the need to handle potentially organic azides, which are generated in situ. A broad spec-
trum of substrates can participate in the process effectively to produce the desired products in good yields.
Keywords copper catalyst, benzimidazole salts, 1,2,3-triazole derivatives, click chemistry, cycloaddition
Introduction
catalytic systems have serious shortcoming in the broad
tolerance of substrate and indispensability of additives
such as reducing agents and bases. In this content, the
developing of efficient catalysts, the broadening of the
scope of substrates, and without adding any additives is
desirable from the standpoint of green chemistry. In
connection with the recent work in benzimidazole and
related ligands and copper-catalyzed “click” chemis-
try,[14-16] we report herein an efficient catalyst system in
situ prepared easily from Cu(I) and Cu(II) species in
combination with benzimidazole salts. The catalyst sys-
tem exhibits excellent catalytic performance for cop-
per-catalyzed “click” chemistry for synthesis of
1,2,3-triazole framework.
Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC)
reaction has undergone a rapid development since its
discovery in 2002.[1,2] Wide substrate scope, high syn-
thetic efficiency and mild reaction condition have made
it
a fast and efficient approach to synthesize
1,4-disubstituted 1,2,3-triazoles, which is an important
class of heterocyclic compounds due to its wide appli-
cation in the preparation of dyes, photostabilizers, ag-
rochemicals, biochemicals and organometallics.[3-5]
In this click reaction, many achievements have
demonstrated that copper(I)[6-10] and copper(II) cata-
lysts[11,12] are required for the reaction, respectively.
However, using copper(I) and copper(II) salts combined
with the same benzimidazolium salts as catalysts simul-
taneously has been rarely reported to the best of our
knowledge. Furthermore, most of the aforementioned
methods inherently suffer from harsh conditions such as
organic azides, organic solvents and a large amount of
strong base. Although organic azides are generally sta-
ble against most reaction conditions such as water and
oxygen, the isolation or purification of lower concentra-
tion organic azides or polyazides can be difficult to
handle. It is therefore desirable to develop a methodol-
ogy that avoids the isolation of organic azides.[13]
Results and Discussion
The cycloaddition of phenylacetylene, benzyl bro-
mide and sodium azide was used as model reaction to
establish the optimum conditions. Initially, catalytic
activities of different ligands were examined with 1.0
mol% CuI as catalytic precursor in water at room tem-
perature. Generally, all the used ligands 1—3 gave gen-
erally high yields, and up to 95% yield of the product
1,4-disubstituted 1,2,3-triazoles was achieved by using
ligand 1 (Table 1, Entries 1—3). With this promising
lead, a systematic screening of catalysts and solvents
were carried out. The results were summarized in Table
1. It was found that the use of copper(I) catalytic pre-
cursor gave more than 90% yield of the products (Table
Additionally, it is beneficial to develop an efficient
catalyst system in water medium instead of organic sol-
vents from the standpoint of green chemistry. As for the
1,3-dipolar cycloaddition, most of the reported copper
*
E-mail: klzhuo@263.net; Fax: 00863733326336
Received May 20, 2011; accepted October 20, 2011.
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Efficient “Click” Synthesis of 1,2,3-Triazole Derivatives by Cu Catalyst
1, Entries 1, and 4—6). In comparison, in the presence
of copper(II) catalyst, the reaction yield was still very
good, and the isolated yield was 88% (Table 1, Entries
7—12). During our optimization studies, screening dif-
ferent solvents (Table 1, Entries 13—14) revealed that
the reaction was not dependent on the nature of the sol-
vent.
with alkynes bearing different alkyl groups in para po-
sition. In all cases, the cycloaddition reactions pro-
ceeded well, producing the desired products in high
yields.
Table 2 One-pot synthesis of 1,2,3-triazoles from alkyl bro-
mide, alkynes, and sodium azidea
Cu(I)/L1
Table 1 Screening of the different catalysts and conditions for
Br
R1
+
+
NaN3
azide-alkyne cycloadditiona
R2
R1
Cu catalyst
Br
N
N
+ NaN3
+
N
R2
Entry R1
R2
Product
Yieldb/%
95
N
N
N
N
1
2
H
H
H
N
N
N
p-Me
94
92
N
N
N
N
N
N
N
N
I-
Cl-
L2
N
L1
N
3
m-Cl
H
H
N
N
Cl
N
4
5
6
o-F
93
94
93
N
N
N
F
N
N
I-
N
L3
H
p-Me
N
N
Entry
Cat.
Ligand
Solvent
Yieldb/%
95
N
p-Me p-Me
m-Cl p-Me
1
CuI
L1 H2O
L2 H2O
L3 H2O
L1 H2O
L1 H2O
L1 H2O
L1 H2O
L1 H2O
L1 H2O
L1 H2O
L1 H2O
L1 H2O
N
N
2
CuI
92
N
3
CuI
91
N
7
8
9
92
85
91
N
4
CuCl
CuBr
Cu2O
91
Cl
5
90
N
6
90
o-F
p-Me
N
N
N
7
Cu(OAc)2
CuSO4
88
F
8
87
N
9
Cu(acac)2
CuCl2•2H2O
Cu(NO3)2•3H2O
CuO
84
N
m-F p-Me
10
11
12
13c
14c
86
F
87
N
10
11
H
H
p-Bu
94
92
84
N
N
CuI
L1 H2O/CH3CN
L1 H2O/THF
91
N
OMe
CuI
85
p-OMe
N
N
a Reaction conditions: copper catalyst (0.02 mmol), ligand (0.024
mmol), benzyl bromide (2.0 mmol), phenylacetylene (2.4 mmol),
sodium azide (2.4 mmol), 24 h, solvent (5.0 mL), r.t. Isolated
yield. c A 1∶4 ratio of solvent.
a Reaction conditions: CuI (0.02 mmol), L1 (0.024 mmol), benzyl
bromides (2.0 mmol), alkynes (2.4 mmol), sodium azide (2.4
mmol), H2O (5.0 mL), 24 h, r.t. b Isolated yield.
b
In an attempt to broaden the scope of our methodol-
ogy, the possibility of performing the reaction with al-
kyl halides and alkyl bromides instead of benzyl bro-
mides derivatives was also investigated under N2 at-
mosphere. In this way, the reaction between benzyl hal-
ides and phenylacetylene, p-methyl-phenylacetylene
afforded the corresponding products in 86% and 89%
Having established the effective catalytic system, we
next examined the azide-alkyne cycloaddition reactions
of a variety of benzyl bromides derivatives with alkynes
to explore the reaction scope, and the results are sum-
marized in Table 2. It was found that the reaction was
applicable to various benzyl bromides with both elec-
tron-donating and electron-withdrawing substituents
Chin. J. Chem. 2012, 30, 644—650
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645

Liu et al.
FULL PAPER
yields, respectively (Table 3, Entries 1, 3). This meth-
odology could be extended to heterocyclic halides, such
as 2-chloromethyl pyridine and 2-chloromethyl-1-
methyl-benzimidazole, and the high yields of the tar-
geted products were obtained (Table 3, Entries 4—6).
The results indicated that the obtained products were
useful bidentate ligands for complex formation and ca-
talysis. Next, the reactions of alkyl bromides,
phenylacetylene and sodium azide were also investi-
gated, and the reactions afforded the corresponding
products smoothly with moderate yields (Table 3, En-
tries 7—10).
To probe the reaction scope and performance of
copper(II) catalyst, we also examined other alkyl halides
and epoxy compound under the optimized reaction con-
dition. In comparison to copper(I) catalyst system, no
significant difference was observed by using benzyl
bromide, benzyl chloride and 2-chloromethyl pyridine
(Table 4, Entries 1—3). However, phenylacetylene, so-
dium azides, and n-butyl bromide exhibited much lower
reactivities (Table 4, Entry 4). Under the above opti-
mized condition, the Cu(OAc)2/L1 was applied to the
reactions of terminal alkynes and epoxides to produce
regioselectively β-hydroxy-1,4-disubstituted 1,2,3-tri-
azoles up to 91% yields (Table 4, Entries 5—8).
Conclusions
In conclusion, we have developed an efficient pro-
cedure for the copper-catalyzed azide-alkyne cycloaddi-
tion reaction of alkyl halides or epoxides, alkynes and
sodium azide, which employed low loading of copper
species in combination with benzimidazole salts as
catalyst. The simple methodology avoided isolation and
handling of potentially unstable organic azides and pro-
vided many corresponding 1,2,3-triazole derivatives in
water medium. The studies here exhibit broad applica-
bility to understand reactivities of different functional
groups, such as benzyl bromides, benzyl halides, alkyl
bromides, heterocyclic halides, and epoxies.
Table 3 CuI combined with L1 catalyzed azide-alkyne cycloaddition to synthesize 1,2,3-triazolesa
R1
Cu(I)/L1
R1
N
N
+
+ NaN3
X
R2
R2
N
Entry
1
R1-X
R2
H
Time/h
48
Product
Yieldb/%
86
Cl
Cl
Cl
Cl
Cl
N
N
N
N
N
2
3
H
24
48
24
24
50
89
84
88
N
N
p-Me
H
N
N
N
4c
5c
N
N
N
N
N
N
p-Me
N
N
N
N
Cl
N
N
6c
H
24
90
N
N
N
N
n-C4H9
n-C5H11
n-C6H13
n-C8H17
N
7d
8d
n-C4H9Br
n-C5H11Br
n-C6H13Br
n-C8H19Br
H
H
H
H
48
48
48
48
48
71
72
57
N
N
N
N
N
N
9d
N
N
N
10d
N
N
a Reaction conditions: CuI (0.04 mmol), L1 (0.048 mmol), alkyl halides (2.0 mmol), alkynes (2.4 mmol), sodium azide (2.4 mmol), H2O
(5.0 mL), 48 h, N2 atmosphere, r.t. b Isolated yield. c CuI (0.02 mmol), L1 (0.024 mmol). d A 1∶4 ratio of H2O/CH3CN.
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Efficient “Click” Synthesis of 1,2,3-Triazole Derivatives by Cu Catalyst
Table 4 Azide-alkyne cycloaddition catalyzed by copper(II) catalysta
R1
Cu(II)/L1
N
N
R1
+
+ NaN
X
3
R2
R2
N
R3
Cu(II)/L1
O
HO
+
+
NaN3
N
R3
R1
R2
R1
N
R2
N
Entry
1
R1-X
R2
Product
Yieldb/%
88
Br
Cl
Cl
N
H
H
H
H
N
N
N
N
N
2
3
88
86
28
N
N
N
N
N
n-C4H9
4c
n-C4H9Br
N
N
N
HO
N
O
N
5
6
7
8
H
86
91
90
90
N
Ph
HO
N
O
N
p-Me
H
N
Ph
O
O
N
OH
N
N
p-Me
N
OH
N
N
a Reaction conditions: Cu(OAc)2•H2O (0.02 mmol), L1 (0.024 mmol), alkyl halides (2.0 mmol), alkynes (2.4 mmol), sodium azide (2.4
mmol), H2O (5.0 mL), 24 h, r.t. b Isolated yield. c A 1∶4 ratio of H2O/CH3CN, N2 atmosphere.
7.23—7.39 (m, 1H), 6.02 (s, 2H), 5.83 (s, 2H); 13C
NMR (CDCl3, 100 MHz) δ: 151.84, 149.70, 142.37,
137.68, 132.21, 131.82, 131.01, 129.41, 129.34, 128.36,
127.24, 127.21, 123.98, 123.77, 114.40, 113.52, 52.41,
Experimental
Synthesis of benzimidazole and related ligands
Synthesis of 1-benzyl-3-picolylbenzimidazole io-
51.62. HRMS calcd for C20H18N3 (M－I－) 300.1495,
dide (L1) To a solution of picolyl chloride, prepared
found 300.1494 (M－I－).
Synthesis of 1-picolyl-3-picolylbenzimidazole io-
dide (L2) To a solution of picolyl chloride, prepared
by basifying of picolyl chloride hydrochloride (9.26 g,
56.4 mmol) in 100 mL acetone were added 1-benzyl-
1H-benzo[d]imidazole (2.63 g, 12.6 mmol) and NaI
(9.26 g, 61.8 mmol). After the mixture was stirred for
by basifying of picolyl chloride hydrochloride (9.26 g,
48 h, volatiles were removed in vacuo. The solid was
56.4 mmol) in 100 mL of acetone were added 1-picolyl-
dissolved in dichloromethane (50 mL), and the solution
1H-benzo[d]imidazole (2.64 g, 12.6 mmol) and NaI
filtered through Celite. Addition of diethyl ether (200
(9.26 g, 61.8 mmol). After the mixture was stirred for
48 h, volatiles were removed in vacuo. The solid was
mL) caused a solid to precipitate. The residual mixture
was chromatographed on silica gel to give the desired
dissolved in dichloromethane (50 mL), and the solution
product.
1-Benzyl-3-picolylbenzimidazole iodide (L1) 1H
filtered through Celite. Addition of diethyl ether (200
mL) caused a solid to precipitate. The residual mixture
was chromatographed on silica gel to give the desired
product.
NMR (CDCl3, 400 MHz) δ: 11.24 (s, 1H), 8.47 (d, J＝
4.8 Hz, 1H), 7.88 (J＝4.8, 2.0 Hz, 2H), 7.72—7.76 (m,
1H), 7.58 (dd, J＝6.8, 1.6 Hz, 5H), 7.48—7.55 (m, 3H),
Chin. J. Chem. 2012, 30, 644—650
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1-Picolyl-3-picolylbenzimidazole iodide (L2) 1H
NMR (CDCl3, 400 MHz) δ: 11.19 (s, 1H), 8.48 (d, J＝
4.8 Hz, 2H), 7.84 —7.87 (m, 4H), 7.71—7.75 (m, 2H),
7.51 (dd, J＝6.4, 2.8 Hz, 2H), 7.23—7.26 (m, 2H), 5.98
(s, 4H); 13C NMR (CDCl3, 100 MHz) δ: 151.87, 149.75,
142.52, 137.70, 131.49, 127.20, 124.00, 123.75, 114.13,
52.58. HRMS calcd for C19H17N4 (M－I－) 301.1448,
found 301.1448 (M－I－).
Synthesis of 1-benzyl-3-picolylbenzimidazole
chloride (L3) To a solution of 1-picolyl-1H-benzo[d]-
imidazole (4.67 g, 22.2 mmol) in toluene (20 mL) was
added benzyl chloride (7.5 mL, 65.4 mmol). After re-
flux for 12 h, the solvent was removed in vacuo. The
product was obtained by recrystallization in ethyl alco-
hol.
1-Benzyl-3-picolylbenzimidazole chloride (L3)
1H NMR (DMSO-d6, 400 MHz) δ: 10.40 (s, 1H), 8.48
(d, J＝4.8 Hz, 1H), 7.90—8.00 (m, 3H), 7.69 (d, J＝7.6
Hz, 1H), 7.61—7.63 (m, 2H), 7.52 (d, J＝6.8 Hz, 2H),
7.36—7.45 (m, 4H), 5.98 (s, 2H), 5.88 (s, 2H); 13C
NMR (DMSO-d6, 100 MHz) δ: 153.42, 150.00, 144.04,
137.97, 134.57, 131.92, 131.21, 129.43, 129.13, 128.65,
127.23, 127.10, 124.13, 123.24, 114.47, 51.30, 50.26.
HRMS calcd for C20H18N3 (M－Cl－) 300.1495, found
300.1494 (M－Cl－).
1-(4-Methylbenzyl)-4-phenyl-1H-1,2,3-triazole[12b]
1H NMR (CDCl3, 400 MHz) δ: 7.80 (dd, J＝1.2, 7.2 Hz,
2H), 7.66 (s, 1H), 7.19—7.42 (m, 7H), 5.54 (s, 2H),
2.37 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 148.09,
138.71, 131.60, 130.53, 129.78, 128.76, 128.11, 125.66,
119.40, 54.02, 21.15. EI-MS m/z: 249 (M＋).
1-(3-Chlorobenzyl)-4-phenyl-1H-1,2,3-triazole
1H NMR (CDCl3, 400 MHz) δ: 7.82 (dd, J＝1.2, 7.2 Hz,
2H), 7.72 (s, 1H), 7.18—7.44 (m, 7H), 5.56 (s, 2H); 13C
NMR (CDCl3, 100 MHz) δ: 148.38, 136.61, 135.00,
130.44, 130.30, 128.97, 128.83, 128.28, 128.04, 126.04,
125.70, 115.96, 53.47. HRMS calcd for C15H13ClN3
(M＋H＋) 270.0793, found 290.0782 (M＋H＋).
1-(2-Fluorobenzyl)-4-phenyl-1H-1,2,3-triazole[15a]
1H NMR (CDCl3, 400 MHz) δ: 7.82 (d, J＝7.2 Hz, 2H),
7.79 (s, 1H), 7.13—7.46 (m, 7H), 5.65 (s, 2H); 13C
NMR (CDCl3, 100 MHz) δ: 161.73, 159.27, 148.17,
130.95, 130.87, 130.57, 130.53, 130.37, 128.79, 128.20,
125.70, 124.89, 124.85, 122.01, 121.86, 119.70, 115.92,
115.71, 47.73, 47.69. EI-MS m/z: 253 (M＋).
1-Benzyl-4-p-tolyl-1H-1,2,3-triazole[9c] 1H NMR
(CDCl3, 400 MHz) δ: 7.70 (d, J＝8.0 Hz, 2H), 7.65 (s,
1H), 7.21—7.43 (m, 7H), 5.58 (s, 2H), 2.38 (s, 3H); 13C
NMR (CDCl3, 100 MHz) δ: 137.99, 134.72, 129.47,
129.11, 128.72, 128.04, 127.67, 125.57, 54.18, 21.26.
EI-MS m/z: 249 (M＋).
General procedure
1-(4-Methylbenzyl)-4-p-tolyl-1H-1,2,3-triazole
1H NMR (CDCl3, 400 MHz) δ: 7.69 (d, J＝8.0 Hz, 2H),
7.61 (s, 1H), 7.19—7.22 (m, 6H), 5.53 (s, 2H), 2.37 (s,
6H); 13C NMR (CDCl3, 100 MHz) δ: 148.16, 138.65,
137.92, 131.69, 129.76, 129.44, 128.10, 127.74, 125.56,
119.07, 53.96, 21.25, 21.15. HRMS calcd for C17H18N3
(M＋H＋) 264.1495, found 264.1499 (M＋H＋).
1-(3-Chlorobenzyl)-4-p-tolyl-1H-1,2,3-triazole
1H NMR (CDCl3, 400 MHz) δ: 7.70 (d, J＝8.0 Hz, 2H),
7.69 (s, 1H), 7.17—7.33 (m, 6H), 5.53 (s, 2H), 2.38 (s,
3H); 13C NMR (CDCl3, 100 MHz) δ: 148.40, 138.18,
136.65, 134.97, 130.42, 129.51, 128.93, 128.04, 127.42,
126.05, 125.61, 119.26, 53.45, 21.27. HRMS calcd for
C16H15ClN3 (M＋H＋) 284.0949, found 284.0943 (M＋
H＋).
1-(2-Fluorobenzyl)-4-p-tolyl-1H-1,2,3-triazole
1H NMR (CDCl3, 400 MHz) δ: 7.72 (d, J＝6.8 Hz, 2H),
7.70 (s, 1H), 7.12—7.38 (m, 6H), 5.63 (s, 2H), 2.38 (s,
3H); 13C NMR (CDCl3, 100 MHz) δ: 161.72, 159.25,
148.27, 138.03, 130.89, 130.81, 130.55, 130.52, 129.46,
127.58, 125.60, 124.86, 124.83, 122.08, 121.93, 119.32,
115.90, 115.69, 47.67, 47.62, 21.25. HRMS calcd for
C16H15FN3 (M＋H＋) 268.1245, found 268.1244 (M＋
H＋).
1-(3-Fluorobenzyl)-4-p-tolyl-1H-1,2,3-triazole
1H NMR (CDCl3, 400 MHz) δ: 7.70 (d, J＝8 Hz, 2H),
7.68 (s, 1H), 7.22—7.24 (m, 6H), 5.57 (s, 2H), 2.38 (s,
3H); 13C NMR (CDCl3, 100 MHz) δ: 164.21, 161.75,
148.42, 138.14, 137.14, 137.07, 130.80, 130.72, 129.50,
127.48, 125.60, 123.51, 123.48, 119.24, 115.83, 115.62,
115.06, 114.84, 53.48, 21.26. HRMS calcd for
C16H15FN3 (M＋H＋) 268.1245, found 268.1247 (M＋
General procedure for azide-alkyne cycloaddition
reaction of benzyl bromides derivatives and alkynes
and sodium azide in the presence of Cu(I), Cu(II)
and L1 Benzyl bromides derivatives (2.0 mmol), al-
kynes (2.4 mmol) and sodium azide (2.4 mmol) were
added and stirred in water (5.0 mL) in the presence of
copper salts (0.02 mmol) and L1 (0.024 mmol) at room
temperature in a schlenk. After completion of the reac-
tion, the water was removed in vacuo. The residual
mixture was chromatographed on silica gel to give the
desired product.
General procedure for azide-alkyne cycloaddition
reaction from alkyl halides, alkyl bromides, alkynes,
and sodium azide in the presence of CuI and L1
Alkyl bromides derivatives (2.0 mmol), alkynes (2.4
mmol) and sodium azide (2.4 mmol) were added and
stirred in solvents (5.0 mL) in the presence of CuI (0.02
mmol) and L1 (0.024 mmol) at room temperature in a
schlenk under N2 atmosphere. After completion of the
reaction, the water was removed in vacuo. The residual
mixture was chromatographed on silica gel to give the
desired product.
Characterization of products
1-Benzyl-4-phenyl-1H-1,2,3-triazole[9b] 1H NMR
(CDCl3, 400 MHz) δ: 7.82 (d, J＝7.6 Hz, 2H), 7.72 (s,
1H), 7.32—7.44 (m, 4H), 7.00—7.10 (m, 4H), 5.58 (s,
2H); 13C NMR (CDCl3, 100 MHz) δ: 148.34, 137.05,
130.75, 130.31, 128.83, 128.28, 125.70, 123.51, 119.60,
115.87, 115.66, 115.05, 114.85, 53.52. EI-MS m/z: 235
(M＋).
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Efficient “Click” Synthesis of 1,2,3-Triazole Derivatives by Cu Catalyst
H＋).
1-Hexyl-4-phenyl-1H-1,2,3-triazole
1H NMR
1-Benzyl-4-(4-tert-butylphenyl)-1H-1,2,3-triazole
1H NMR (CDCl3, 400 MHz) δ: 7.74 (d, J＝8.4 Hz, 2H),
7.66 (s, 1H), 7.30—7.45 (m, 7H), 5.59 (s, 2H), 1.35 (s,
9H); 13C NMR (CDCl3, 100 MHz) δ: 151.27, 148.20,
134.76, 129.10, 128.70, 127.97, 127.64, 125.70, 125.41,
119.29, 54.15, 34.63, 31.26. HRMS calcd for C19H22N3
(M＋H＋) 292.1808, found 292.1803 (M＋H＋).
1-Benzyl-4-(4-methoxyphenyl)-1H-1,2,3-triazole[9b]
1H NMR (CDCl3, 400 MHz) δ: 7.73 (d, J＝8.8 Hz, 2H),
7.59 (s, 1H), 7.33—7.38 (m, 5H), 6.93 (d, J＝8.8 Hz,
2H), 5.57 (s, 2H), 3.84 (s, 3H); 13C NMR (CDCl3, 100
MHz) δ: 159.56, 148.05, 134.75, 129.10, 128.71, 128.01,
126.97, 123.23, 118.71, 114.17, 55.28, 54.15. EI-MS
m/z: 275 (M＋).
2-((4-Phenyl-1H-1,2,3-triazol-1-yl)methyl)pyri-
dine[15a] 1H NMR (CDCl3, 400 MHz) δ: 8.60 (d, J＝
4.0 Hz, 1H), 7.95 (s, 1H), 7.2 (d, J＝7.2 Hz, 2H),
7.67—7.72 (m, 1H), 7.39 (dd, J＝7.2, 1.2 Hz, 2H),
7.23—7.34 (m, 3H), 5.71 (s, 2H); 13C NMR (CDCl3,
100 MHz) δ: 154.43, 149.68, 148.19, 137.44, 130.48,
128.78, 128.15, 125.68, 123.45, 122.46, 120.21, 55.63.
EI-MS m/z: 237 (M＋).
(CDCl3, 400 MHz) δ: 7.84 (d, J＝7.6 Hz, 2H), 7.77 (s,
1H), 7.32—7.45 (m, 3H), 4.39 (t, J＝7.2 Hz, 2H),
1.92—1.99 (m, 2H), 1.27—1.34 (m, 6H), 0.88 (t, J＝6.8
Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 147.60,
130.64, 128.80, 128.06, 125.65, 119.45, 50.43, 31.13,
30.28, 26.13, 22.39, 13.92. HRMS calcd for C14H20N3
(M＋H＋) 230.1652, found 230.1642 (M＋H＋).
1-Octyl-4-phenyl-1H-1,2,3-triazole
1H NMR
(CDCl3, 400 MHz) δ: 7.84 (d, J＝7.6 Hz, 2H), 7.76 (s,
1H), 7.32—7.46 (m, 3H), 4.39 (t, J＝6.8 Hz, 2H),
1.92—1.97 (m, 2H), 1.28—1.36 (m, 12H), 0.87 (t, J＝
7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 147.32,
130.69, 128.79, 128.03, 125.64, 50.41, 31.67, 30.32,
29.02, 28.94, 26.46, 22.57, 14.04. HRMS calcd for
C16H24N3 (M＋H＋) 258.1965, found 258.1962 (M＋
H＋).
1-Phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)etha-
nol[12c] 1H NMR (CDCl3, 400 MHz) δ: 8.82 (s, 1H),
7.86 (d, J＝7.6 Hz, 2H), 7.31—7.47 (m, 9H), 5.82—
5.85 (m, 1H), 4.30—4.36 (t, J＝10 Hz, 1H), 4.02—4.06
(m, 1H); 13C NMR (CDCl3, 100 MHz) δ: 146.63,
137.75, 131.26, 129.32, 129.14, 128.71, 128.25, 127.56,
125.53, 121.34, 66.87, 63.59. EI-MS m/z: 265 (M＋).
1-Phenyl-2-(4-p-tolyl-1H-1,2,3-triazol-1-yl)etha-
nol 1H NMR (CDCl3, 400 MHz) δ: 8.76 (s, 1H), 7.74
(d, J＝8.0 Hz, 2H), 7.24—7.41 (m, 7H), 5.80—5.84 (m,
1H), 5.35 (t, J＝5.2 Hz, 1H), 4.29—4.36 (m, 1H),
4.01—4.06 (m, 1H), 2.32 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ: 146.69, 137.79, 137.51, 129.86, 129.12,
128.69, 128.51, 127.56, 125.48, 120.89, 66.83, 63.59,
21.26. HRMS calcd for C17H18N3O (M＋H＋) 280.1444,
found 280.1438 (M＋H＋).
2-((4-p-Tolyl-1H-1,2,3-triazol-1-yl)methyl)pyri-
dine 1H NMR (CDCl3, 400 MHz) δ: 8.60 (d, J＝4.4
Hz, 1H), 7.90 (s, 1H), 7.66—7.73 (m, 3H), 7.20—7.26
(m, 4H), 5.69 (s, 2H), 2.36 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ: 154.50, 149.63, 148.26, 137.98, 137.44,
129.46, 127.66, 125.59, 123.42, 122.44, 119.87, 55.59,
21.25. HRMS calcd for C15H15N4 (M＋H＋) 251.1291,
found 251.1286 (M＋H＋).
1-Methyl-2-((4-phenyl-1H-1,2,3-triazol-1-yl)meth-
yl)-1H-benzo[d]imidazole
1H NMR (CDCl3, 400
MHz) δ: 7.96 (s, 1H), 7.77 (t, J＝8.0 Hz, 3H), 7.32—
7.42 (m, 6H), 5.93 (s, 2H), 3.86 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ: 148.59, 142.00, 136.05, 130.04,
128.81, 128.36, 125.65, 123.84, 122.88, 120.09, 119.81,
109.86, 46.78, 30.33. HRMS calcd for C13H18N3 (M＋
H＋) 216.1495, found 216.1498 (M＋H＋). HRMS calcd
for C17H16N5 (M＋H＋) 290.1400, found 290.1401 (M＋
H＋).
2-(4-Phenyl-1H-1,2,3-triazol-1-yl)cyclohexanol[12c]
1H NMR (CDCl3, 400 MHz) δ: 8.58 (s, 1H), 7.83 (d,
J＝7.6 Hz, 2H), 7.42 (t, J＝7.6 Hz, 2H), 7.32 (t, J＝7.6
Hz, 1H), 4.99 (d, J＝5.6 Hz, 1H), 4.20—4.26 (m, 1H),
3.76—3.80 (m, 1H), 3.34 (s, 1H), 1.36—2.01 (m, 8H);
13C NMR (CDCl3, 100 MHz) δ: 146.08, 131.58, 129.29,
128.03, 125.41, 120.95, 71.77, 66.45, 35.18, 32.40,
24.87, 24.31. EI-MS m/z: 243 (M＋).
2-(4-p-Tolyl-1H-1,2,3-triazol-1-yl)cyclohexanol
1H NMR (CDCl3, 400 MHz) δ: 8.51 (s, 1H), 7.71 (d,
J＝7.6 Hz, 2H), 7.24 (d, J＝7.6 Hz, 2H), 4.99 (d, J＝
5.6 Hz, 1H), 4.20 (t, J＝8.4 Hz, 1H), 3.78 (s, 1H), 2.32
(s, 3H), 1.36—2.00 (m, 8H); 13C NMR (CDCl3, 100
MHz) δ: 146.14, 137.25, 129.83, 128.83, 125.37, 120.51,
71.77, 66.41, 35.20, 32.42, 24.88, 24.32, 21.25. HRMS
calcd for C15H20N3O (M ＋ 2H ＋ ) 258.1601, found
258.1604 (M＋2H＋).
1-Butyl-4-phenyl-1H-1,2,3-triazole
1H NMR
(CDCl3, 400 MHz) δ: 7.84 (dd, J＝7.2, 1.2 Hz, 2H),
7.762 (s, 1H), 7.34—7.45 (m, 3H), 4.39 (t, J＝7.6 Hz,
2H), 1.92—1.96 (m, 2H), 1.37—1.43 (m, 2H), 0.96 (t,
J＝7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 147.66,
130.67, 128.79, 128.04, 125.65, 119.41, 50.11, 32.28,
19.68, 13.44. HRMS calcd for C12H16N3 (M＋H＋ )
202.1339, found 202.1347 (M＋H＋).
1-Pentyl-4-phenyl-1H-1,2,3-triazole
1H NMR
(CDCl3, 400 MHz) δ: 7.84 (d, J＝7.6 Hz, 2H), 7.77 (s,
1H), 7.32—7.45 (m, 3H), 4.38 (t, J＝7.2 Hz, 2H),
1.93—2.00 (m, 2H), 1.31—1.41 (m, 4H), 0.87—1.27
(m, 3H); 13C NMR (CDCl3, 100 MHz) δ: 147.64,
132.44, 130.72, 128.78, 128.43, 128.02, 125.63, 119.49,
50.37, 30.00, 28.55, 22.07, 13.82. HRMS calcd for
C13H18N3 (M＋H＋) 216.1495, found 216.1498 (M＋
H＋).
Acknowledgement
This work was supported by the National Natural
Science Foundation of China (Nos. 20973055,
21103044).
Chin. J. Chem. 2012, 30, 644—650
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
649

Liu et al.
FULL PAPER
Hu, Y. Y.; Hu, J.; Wang, X. C.; Guo, L. N.; Shu, X. Z.; Niu, Y. N.;
Liang, Y. M. Tetrahedron 2010, 66, 80; (g) Saha, B.; Sharma, S.;
Sawant, D.; Kundu, B. Synlett 2007, 10, 1591; (h) Lu, P.; Wang, Y.
G. Synlett 2010, 2, 165.
References
[1] Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67,
3057.
[2] Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596.
[10] (a) Zhou, Y. H.; Lecourt, T.; Micouin, L. Angew. Chem., Int. Ed.
2010, 122, 2661; (b) Chattopadhyay, B.; Vera, C. R.; Chuprakov, S.;
Gevorgyan, V. Org. Lett. 2010, 12, 2166; (c) Buckley, B. R.; Dann,
S. E.; Heaney, H. Chem. Eur. J. 2010, 16, 6278; (d) Wu, Y. M.;
Deng, J.; Fang, X.; Chen, Q. Y. J. Fluorine Chem. 2004, 125, 1415.
[11] (a) Candelon, N.; Lastécouères, D.; Diallo, A. K.; Aranzaes, J. R.;
Astruc, D.; Vincent, J.-M. Chem. Commun. 2008, 741; (b) Yousuf, S.
K.; Mukherjee, D.; Singh, B.; Maityc, S.; Taneja, S. C. Green Chem.
2010, 10, 1568; (c) Jin, S.; Choudhary, G.; Cheng, Y. F.; Dai, C. F.;
Li, M. Y.; Wang, B. H. Chem. Commun. 2009, 5251; (d) Camp-
bell-Verduyn, L. S.; Szymański, W.; Postema, C. P.; Dierckx, R. A.;
Elsinga, P. H.; Janssen, D. B.; Fering, B. L. Chem. Commun. 2010,
898.
[12] (a) Pachón, L. D.; Van Maarseveen, J. H.; Rothenberg, G. Adv.
Synth. Catal. 2005, 347, 811; (b) Sharghi, H.; Khalifeh, R.;
Doroodmanda, M. M. Adv. Synth. Catal. 2009, 351, 207; (c) Sharghi,
H.; Beyzavi, M. H.; Safavi, A.; Doroodmanda, M. M.; Khalifeh, R.
Adv. Synth. Catal. 2009, 351, 2391; (d) Lee, C. T.; Huang, S. L.;
Lipshutz, B. H. Adv. Synth. Catal. 2009, 351, 3139.
[13] Scriven, E. F. V.; Turnbull, K. Chem. Rev., 1988, 2, 351.
[14] (a) Feldman, A. K.; Colasson, B.; Fokin, V. V. Org. Lett. 2004, 6,
3897; (b) Appukkuttan, P.; Dehaen, W.; Fokin, V. V.; Van der
Eycken, E. Org. Lett. 2004, 6, 4223; (c) Ackermann, L.; Potukuchi,
H. K.; Landsberg, D.; Vicente, R. Org. Lett. 2008, 10, 3081; (d)
Namitharan, K.; Kumarraja, M.; Pitchumani, K. Chem. Eur. J. 2009,
15, 2755.
[15] (a) Li, F. W.; Hor, T. S. A. Chem. Eur. J. 2009, 15, 10585; (b) Li, F.
W.; Bai, S. Q.; Hor, T. S. A. Organometallics 2008, 27, 672; (c)
McGuinness, D.; Cavell, K. J. Organometallics 2000, 19, 741; (d)
Wang, X.; Liu, S.; Jin, G. X. Organometallics 2004, 23, 6002.
[16] Lin, I. J. B.; Vasam, C. S. Coord. Chem. Rev. 2007, 254, 642.
[3] (a) Wang, Q.; Chan, T. R.; Hilgraf, R.; Fokin, V. V.; Sharpless, K.
B.; Finn, M. G. J. Am. Chem. Soc. 2003, 125, 3192; (b) Speers, A. E.;
Adam, G. C.; Cravatt, B. F. J. Am. Chem. Soc. 2003, 125, 4686.
[4] (1) Anderson, J. C.; Schultz, P. G. J. Am. Chem. Soc. 2003, 125,
11782; (2) Link, A. J.; Tirrell, D. A. J. Am. Chem. Soc. 2003, 125,
11164.
[5] (a) Wu, P.; Feldman, A. K.; Nugent, A. K.; Hawker, C. J.; Scheel,
A.; Voit, B.; Pyun, J.; Frechet, J. M. J.; Sharpless, K. B.; Fokin, V.
V. Angew. Chem., Int. Ed. 2004, 43, 3928; (b) Collman, J. P.;
Devaraj, N. K.; Chidsey, C. E. D. Langmuir 2004, 20, 1051.
[6] (a) Rodionov, V. O.; Presolski, S. I.; Gardinier, S.; Lim, Y. H.; Finn,
M. G. J. Am. Chem. Soc. 2007, 129, 12696; (b) Rodionov, V. O.;
Presolski, S. I.; Dìaz, D. D.; Fokin, V. V.; Finn, M. G. J. Am. Chem.
Soc. 2007, 129, 12705.
[7] (a) Hein, J. E.; Fokin, V. V. Chem. Soc. Rev. 2010, 39, 1302; (b)
Kappe, C. O.; Eycken, E. V. Chem. Soc. Rev. 2010, 39, 1280.
[8] (a) Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V. Org. Lett.
2004, 6, 2853; (b) Girard, C.; Önen, E.; Aufort, M.; Beauvière, S.;
Samson, E.; Herscovici, J. Org. Lett. 2006, 8, 1689; (c) Chassaing,
S.; Kumarraja, M.; Sido, A. S. S.; Pale, P.; Sommer, J. Org. Lett.
2007, 9, 883; (d) Oezcubukcu, S.; Ozkal, E.; Jimeno, C.; Pericas, M.
A. Org. Lett. 2009, 11, 4680.
[9] (a) Díez-González, S.; Correa, A.; Cavallo, L.; Nolan, S. P. Chem.
Eur. J. 2006, 12, 7558; (b) Teyssot, M. L.; Chevry, A.; Traïkia, M.;
El-Ghozzi, M.; Avignant, D.; Gautier, A. Chem. Eur. J. 2009, 15,
6322; (c) Yamaguchi, K.; Oishi, T.; Katayama, T.; Mizuno, N.
Chem. Eur. J. 2009, 15, 10464; (d) Zhao, Y. B.; Yan, Z. Y.; Liang,
Y. M. Tetrahedron Lett. 2006, 47, 1545; (e) Yan, Z. Y.; Zhao, Y. B.;
Fan, M. J.; Liu, W. M.; Liang, Y. M. Tetrahedron 2005, 61, 9331; (f)
(E1105201 Zhao, X.; Lu, Z.)
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