General synthesis of (1-substituted-1H-1,2,3-triazol-4-ylmethyl)- dialkylamines via a copper(I)-catalyzed three-component reaction in water

Article abstract of DOI:10.1016/j.tet.2005.07.060

A copper(I)-catalyzed three-component reaction to form (1-substituted-1H-1, 2,3-triazol-4-ylmethyl)-dialkylamines based on the Huisgen cycloaddition using amine, propargyl halide and azide in water was proposed. The process showed considerable synthetic advantages in terms of high atom economy, low environmental impact, atmospheric oxygen, wide substrate scope, mild reaction condition and good yields.

Full text of DOI:10.1016/j.tet.2005.07.060

Tetrahedron 61 (2005) 9331–9337
General synthesis of (1-substituted-1H-1,2,3-triazol-4-
ylmethyl)-dialkylamines via a copper(I)-catalyzed
three-component reaction in water
Ze-Yi Yan,a Ya-Bin Zhao,a Ming-Jin Fan,a Wei-Min Liub and Yong-Min Lianga,
*
aState Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, People’s Republic of China
bLanzhou Institute of Physics, Chinese Academy of Science, Lanzhou 730000, People’s Republic of China
Received 27 May 2005; revised 15 July 2005; accepted 18 July 2005
Available online 9 August 2005
Abstract—A copper(I)-catalyzed three-component reaction to form (1-substituted-1H-1,2,3-triazol-4-ylmethyl)-dialkylamines based on the
Huisgen cycloaddition using amine, propargyl halide and azide in water was proposed. The process showed considerable synthetic
advantages in terms of high atom economy, low environmental impact, atmospheric oxygen, wide substrate scope, mild reaction condition
and good yields.
q 2005 Published by Elsevier Ltd.
1. Introduction
application than simple 1,2,3-triazole derivatives.4 Due to
the limited number of commercially available alkynes and
azides, the complex triazoles are usually synthesized in
multi-step sequences. Multi-component reactions have been
proven to be a very elegant and rapid way to access complex
structures from simple building blocks. As a one-pot
reaction, multi-component reactions generally afford good
yields and are fundamentally different from two-component
reactions in several aspects.8 Over the past decade, various
advanced sequential multi-component reactions have been
developed in three- and four-component reactions involving
Passerini-,9 Ugi-,10 and Mannich-type11 reactions. In the
case of Huisgen cycloaddition reaction, some more recent
examples were reported using a one-pot procedure to
prepare 1,2,3-triazole derivatives based on the three-
component coupling reaction.1e,12
1,2,3-Triazole derivatives have received much attention
because of their wide range of applications1 and biological
activities such as anti-HIV,2 antimicrobial agents3 and
b3-adrenergic receptor agonist.4 The most popular method
for the construction of 1,2,3-triazoles frameworks is the
1,3-dipolar Huisgen cycloaddition reaction of azides with
alkynes.1a,5 However, the early Huisgen cycloaddition
process required a strong electron-withdrawing substituent
either on azide or on alkyne, and were often conducted at
high temperature for a prolonged period of time, and usually
led to the isolation of a mixture of 1,4-disubstituted- and
1,5-disubstituted-1,2,3-triazoles.1e,5 Therefore, it is desir-
able to develop a new, convenient and regiocontrolled
synthetic approach for the formation of triazoles. Recently,
some important concepts and transition-metal catalysts to
overcome the above drawbacks have been proposed.6
Furthermore, triazoles have been utilized as a backbone of
a bidentate phosphine ligand, and some new compounds
have been synthesized.7 These potent usefulness exhibited
that the use of triazoles for organic synthetic purposes has
been growing in scope and importance.
The increasing environmental consciousness of the
chemical community has led to the search for more efficient
and environmentally friendly methods for chemical
syntheses.13 Although it would be best not to use any
solvent, frequently a solvent is required for a reaction
because of various reasons. In such cases, the use of some
solvents such as water is desirable.14 In the last decade,
there has been increasing recognition that organic reactions
in water may offer advantages over those occurring in
organic solvents.15 The use of water as a solvent offers
practical convenience as it alleviates the need to handle
flammable, and reduce or eliminate environment damage
caused by organic solvents. Water is the cheapest and safest
After extensively reviewed, we found both N-substituted
and 4- or 5-substituted 1,2,3-trizoles had more potential
Keywords: Copper(I)-catalyzed; Three-component reaction; Water;
Huisgen cycloaddition.
Corresponding author. Tel.: C86 931 8912596; fax: C86 931 8912582;
e-mail: liangym@lzu.edu.cn
*
0040–4020/$ - see front matter q 2005 Published by Elsevier Ltd.
doi:10.1016/j.tet.2005.07.060

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Z.-Y. Yan et al. / Tetrahedron 61 (2005) 9331–9337
Table 1. The effect of solvent and catalyst on three-component reactiona
solvent available, and frequently better selectivity is
obtained in water. It also simplifies the tedious protection–
deprotection sequence for molecules containing acidic
protons, and increases the overall synthetic efficiency.15
Then, there is a general agreement about the future of the
use of water as a solvent.16
Entry Catalyst
Condition
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
CuSO4/Vc
CuSO4/Vc
CuSO4/Vc
CuCl
H2O–t-BuOH (1/1)
H2O
H2O–THF (1/1)
H2O
H2O
H2O
H2O
H2O–THF (1/1)
H2O–DMF (1/1)
THF
13
14
14
10
10
10
10
10
10
10
24
70
40
61
77
84
80
88
89
85
86
54
CuBr
CuCN
CuI
CuI
CuI
CuI
On the other hand, 5-aminomethyl-substituted 1,2,3-triazol-
4-yl-N,N-dimethylmethaneamine hydrochloride analogues
was reported to be a human neurokinin-1 receptor
antagonist with a solubility in water, and the preparation
of these analogues generally involved the prior reaction of
amine and alkyne to form propargylamine, followed by
other two-step transformations to product 1,2,3-triazole.17
The most attractive access of propargylamines is the
classical mannich reaction. However, the efficient prepa-
ration of propargylamines was hindered by rather harsh
conditions, moderate yields and complex workup and
purification procedures.18 Therefore, it is desirable to
develop a new, convenient and regiocontrolled synthetic
approach for the formation of triazoles-4-yl-methanamine.
On the other hand, (1-benzyl-, and 1-phenyl-1H-[1,2,3]tri-
azol-4-ylmethyl)-diethylamines were, respectively, pre-
pared from various starting materials using the ‘click’
chemistry approach.6d,12c These promoted us to initiate a
corresponding study of three-component reaction. Herein,
we wish to report an efficient and facile one-pot reaction
of amines, propargyl halide and azides to generate
(1-substituted-1H-1,2,3-triazol-4-ylmethyl)-dialkylamines
in the presence of Cu(I) in water at room temperature
(Scheme 1).
9
10
11b
Cu
H2O
a All reactions were performed with 2 mmol of Et3N, 1.2 mmol of
diethylamine, 2 mL of solvent, 1.2 mmol of propargyl bromide, 1.0 mmol
of azide, and 10 mol% catalyst at room temperature, unless otherwise
noted.
b Stoichiometric copper powder was used.
such as CuSO4, CuCl2, Cu(OAc)2 in the absence of a
reducing agent, were also evaluated, and negative results
were observed. Other catalysts such as ZnCl2, InCl3, AgCl,
AgI, and silver metal, were also investigated, which were
not effective or non-active for the three-component reaction.
However, a number of observations were worth high-
lighting, as they underscored the unusual reactivity aspects
of the system. In other words, this was a very surprised
process, which could effectively be catalyzed by either
Cu(I) or copper metal. Finally, CuI was found to be the most
effective in catalyzing the three-component reaction of
amine, propargyl halide and azide (Table 1, entries 7–10).
Under the optimized conditions, a number of substrates
were investigated (Table 2). A variety of substituents,
aromatic, benzyl, and aliphatic, were readily used in this
transformation. Both electron-rich and -poor aromatic
groups were tolerated in three-component reaction. Gener-
ally, the reaction was highly dependent on both electronic
and steric effects. An evident steric effect was observed
when we compared the yield of bulky diisopropylamine
with that of dimethylamine (entries 1–3). On the whole, the
better yields were obtained with cyclic amines in a short
period of time (entries 4 and 6). Both aromatic azides
bearing electron-withdrawing substituent Cl– and NO2–
group afforded the product in excellent yields (entries
12–15). Compared the propargyl bromide, the reaction of
propargyl chloride, amines, and azide gave a slightly low
yields (entries 5 and 11). Phenyl azide provided better
results than electron-donating methylphenyl azide under
the present reaction conditions (entries 16–18). The reaction
was also tolerated with various functional groups. In
addition to electron-rich and electron-poor C-aryl-substi-
tuted azides, benzyl azide, and even the less electrophilic
phenoxyethyl azide could react to form the corresponding
compounds in good yields, although the reaction time might
be prolonged (entries 19–20). Moreover, this methodology
could also be extended to the primary aliphatic amine (entry
2. Results and discussion
In preliminary experiments, we investigated the template
reaction of diethylamine, propargyl bromide and benzyl
azide using CuSO4$5H2O–sodium ascorbate (Vc) system in
a 2:1 mixture of water and tert-butyl alcohol (the ‘click’
chemistry condition),6d and the reaction only gave the
corresponding compound 4b in moderate yield (Table 1,
entry 1). Encouraged by this positive result, an optimum
reaction condition was explored using various solvents and
catalysts. We were pleased to find Cu(I) could catalyze the
three-component reaction in water in the presence of
triethylamine without other co-solvent. Common Cu(I)
salts, for example, CuCN, CuCl, CuBr, and CuI all gave
good yields (entries 4–7). The reaction did not proceed in
the presence of catalytic amount of copper powder.
However, when the reaction was treated with stoichiometric
copper powder (under 100 mol% amount of metal), a decent
yield was obtained (entry 10). It was indicated that copper
metal could also catalyze the three-component reaction,
although it required a large amount of catalyst and extended
reaction time, which was in good agreement with the
previous results reported.19 Furthermore, some Cu(II) salts,
Scheme 1.

Z.-Y. Yan et al. / Tetrahedron 61 (2005) 9331–9337
Table 2. The reaction of amine, propargyl halide and azide catalyzed by Cu(I) in watera
9333
Entry
Propargyl halide
Amine
Azide
Time (h)/
medium
Product isolated
Yield
(%)
1
8/water
92
(4a)
(4b)
2
3
10/water
88
75
14/water
(4c)
(4d)
(4d)
(4e)
4
5
6
7/water
12/water
7/water
95
89
93
7b
10/water
14/water
89
86
(4f)
8b
(4g)
(4h)
(4h)
9c
16/water
16/water
24/water
75
78
70
10d
11c
(4h)
(4i)
12
13
14
15
16
7/water
7/water
10/water
10/water
9/water
98
95
98
96
93
(4j)
(4k)
(4l)
(4m)

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Z.-Y. Yan et al. / Tetrahedron 61 (2005) 9331–9337
Table 2 (continued)
Entry
Propargyl halide
Amine
Azide
Time (h)/
medium
Product isolated
Yield
(%)
17
18
10/water
13/water
90
83
(4n)
(4o)
19
20
16/water
16/water
94
91
(4p)
(4q)
a Typical procedure can be seen in ‘Section 4’, unless otherwise noted.
b Et3N (3 mmol), 0.5 mmol of amine, 1.2 mmol of propargyl bromide and 1.2 mmol azide were used.
c Et3N (2 mmol), 2 mmol of amine, 1 mmol of propargyl halide and 1 mmol azide were used.
d Et3N (3 mmol), 0.5 mmol of amine, 2 mmol of propargyl bromide and 2 mmol azide were used; no disubstituted product was isolated.
8). Compared to secondary amines, the reaction of primary
amines led to the disubstituted products in good yields when
using an excess of Et3N (3 equiv). For phenyl amine, only
mono-substituted product was isolated even large excesses
of propargyl bromide and phenyl azide were participated in
the reaction (entries 9–11). It was presumed due to steric
hindrance of bulk benzene ring. Diphenylamine, on the
other hand, did not give the reaction even larger excess of
base was used, presumably due to steric hindrance and/or
weak nucleophilicity.
investigated. Triethylamine showed better yields and no
byproducts were observed. Moreover, it was known that, in
the presence of a base and Cu(I) salts, terminal acetylenes
could be converted to the corresponding alkynylides in
water; if oxygen was not excluded, Cu(I)–acetylides could
participate in oxidative Glaser coupling.21 However, in our
study, no coupling products were obtained, probably, six-
membered copper(III) metallacycle was a preferable
intermediate rather than alkynyl free radical one in Glaser
coupling reaction (see below). We also observed that the
three-component reaction in two-step gave higher yields in
contrast to one-step procedure.22 It was indicated that first
the formation of propargylamines effectively suppressed the
oxidative coupling reaction.
Herein, the effect of basicity was very vital in the three-
component reaction. On the one hand, it could drive the
rapid formation of propargyl amines and avoid self-
coupling product of terminal alkynes. On the other hand,
it was also known that copper(I) could readily inserts into
terminal alkynes in the presence of base to promote the
reaction.20 Some inorganic and organic bases were
A tentative mechanism for the Cu(I)-catalyzed three-
component reaction to form triazole derivatives was
illustrated in Scheme 2, which may involve two possible
Scheme 2. Tentative mechanism for the three-component reaction of amine, propargyl bromide and azide.

Z.-Y. Yan et al. / Tetrahedron 61 (2005) 9331–9337
9335
pathway: A and B. For pathway B, in the first step, the
4.2. General procedure
reaction between propargyl bromide and a nucleophilic
amine to form propargyl amine followed by the formation of
copper(I) acetylide by displacing one of the H2O ligands.
The acetylide thus generated was reacted with azide to give
the six-membered copper(III) metallacycle intermediate.
After the ring contraction, a five-membered triazolyl-copper
derivative was formed.6d,19 Proteolysis of triazolyl-copper
derivative released the triazole compound and regenerated
the Cu(I) specie catalyst for further reactions. In further
study, we prepared 1-phenyl-4-bromomethyl-1,2,3-triazole
by a mixture of phenyl azide and propargyl bromide. Under
the similar condition, the reactions of 1-phenyl-4-bromo-
methyl-1,2,3-triazole and several secondary amines were
investigated, and expected products were obtained with
lower yields. It was indicated that the early formation of
4-bromomethyl-1,2,3-triazole intermediates followed by the
coupling of triazoles with amines to yield preferable
compounds, was also an alternative mechanism (pathway
A). Based on the above results, we proposed that pathway B
was the preferable process. Herein, the formation of
propargyl amine is a crucial factor for completion of the
reaction in water because propargyl amine has a weak
solubility in water, but the non-polar propargyl halide is not
soluble in water.
The reaction was carried out in micro scale: a mixture of
2 mL of water, 2 mmol of Et3N, 1.2 mmol of amine and
1.2 mmol of propargyl halide was stirred vigorously for
60 min at room temperature.21 Then, 1.0 mmol of azide and
10 mol% of CuI were added into the mixture until complete
consumption of the starting materials monitored by TLC.17
The reaction mixture was diluted with 25 mL of water,
cooled in ice, and extracted with CH2Cl2 (3!15 mL). The
combined organic extracts were washed with brine, and
dried (MgSO4). After removal of the solvent under reduced
pressure, the residue was purified on silica gel with
petroleum–ethyl acetate (8:1–1:10).
4.3. Data of spectra
4.3.1. (1-Phenyl-1H-[1,2,3]triazol-4-ylmethyl)-dimethyl-
amine (4a). Solid, mp 75–77 8C; 1H NMR (300 MHz,
CDCl3) d 7.94 (s, 1H), 7.71 (d, JZ8.4 Hz, 2H), 7.49 (t, JZ
7.2, 8.4 Hz, 2H), 7.39 (t, JZ7.2 Hz, 1H), 3.68 (s, 2H), 2.31
(s, 6H); 13C NMR (75 MHz, CDCl3) d 145.8, 137.0, 129.6,
128.5, 120.5, 120.3, 54.3, 45.1; IR (KBr, cmK1) 2942, 2821,
2773, 1599, 1504, 1462, 1039; EI-MS m/z 202 (MC), 202,
159, 130, 77; HRMS (EI) found [M]CZ202.1208,
C11H14N4 requires 202.1213.
4.3.2. (1-Phenyl-1H-[1,2,3]triazol-4-ylmethyl)-diethyl-
3. Conclusions
1
amine (4b). 12cSticky oil; H NMR (300 MHz, CDCl3) d
7.95 (s, 1H), 7.75 (d, JZ8.4 Hz, 2H), 7.52 (t, JZ6.9,
8.4 Hz, 2H), 7.45–7.4 (m, 1H), 3.88 (s, 2H), 2.61 (q, JZ6.9,
7.2, 7.5 Hz, 4H), 1.12 (t, JZ6.9, 7.2 Hz, 6H); 13C NMR
(75 MHz, CDCl3) d 146.1, 137.1, 129.6, 128.5, 120.5,
120.3, 47.6, 46.8, 11.8; IR (KBr, cmK1) 2970, 1599, 1504,
1465, 1041; EI-MS m/z 230 (MC), 215, 159, 130, 77.
In summary, we have demonstrated a new three-component
protocol of amine, propargyl halide and azide in one-pot
procedure for the synthesis of (1-substituted-1H-1,2,3-
triazol-4-ylmethyl)-dialkylamine derivatives in the
presence of copper(I) in water. The process showed the
considerable synthetic advantages in terms of air, products
diversity, mild reaction condition, simplicity of the reaction
procedure, and good to excellent yields. The convenience
with readily accessible starting materials (commercially
available amines and propargyl halide) and simple
experimental procedure as well as the simplicity of the
reaction conditions (room temperature, water) can provide
an access to a class of compounds that can serve as useful
building blocks for synthesis. The rich array of functionality
displayed by these products can provide opportunities for
the creation of unique combinatorial libraries.
4.3.3. (1-Phenyl-1H-[1,2,3]triazol-4-ylmethyl)-diisopro-
pylamine (4c). Solid, mp 45–47 8C; H NMR (300 MHz,
1
CDCl3) d 7.86 (s, 1H), 7.73 (d, JZ7.8 Hz, 2H), 7.49 (t, JZ
7.2, 7.8 Hz, 2H), 7.42–7.38 (m, 1H), 3.83 (s, 2H), 3.09 (m,
2H), 1.04 (d, JZ6.6 Hz, 12H); 13C NMR (75 MHz, CDCl3)
d 152.1, 137.5, 129.9, 128.6, 120.6, 120.4, 49.1, 41.4, 21.0;
IR (KBr, cmK1) 2966, 1599, 1503, 1464, 1226, 1036;
EI-MS m/z 258 (MC), 243, 215, 159, 130, 100, 77; HRMS
(EI) found [M]CZ258.1840, C15H22N4 requires 202.1839.
4.3.4. (1-Phenyl-1H-[1,2,3]triazol-4-ylmethyl)-piperidine
(4d). Solid, mp 95–97 8C; H NMR (300 MHz, CDCl3) d
1
4. Experimental
7.92 (s, 1H), 7.70 (d, JZ7.8 Hz, 2H), 7.45 (t, JZ7.8,
7.2 Hz, 2H), 7.41–7.38 (m, 1H), 3.70 (s, 2H), 2.47 (br s,
4H), 1.56 (m, 4H), 1.40 (m, 2H); 13C NMR (75 MHz,
CDCl3) d 145.5, 137.0, 129.6, 128.5, 120.6, 120.3, 54.3,
54.0, 25.8, 24.0; IR (KBr, cmK1) 2934, 1599, 1504, 1465,
1231, 1042; EI-MS m/z 242 (MC), 159, 130, 84, 77; HRMS
(EI) found [M]CZ242.1528, C14H18N4 requires 242.1526.
4.1. General remarks
Column chromatography was carried out on silica gel.
Melting points were measured using an electrothermal
melting point apparatus, and uncorrected. The H and 13C
1
NMR spectra were recorded at 300 and 75 MHz, respect-
ively. The 1H chemical shifts were reported in ppm relative
to tetramethylsilane, using the residual solvent signal as an
internal reference and 13C with CDCl3 as internal standard.
IR spectra were obtained using an FT IR spectrometer and
only major peaks were reported in cmK1. Mass spectra were
recorded by the EI method or FAB method. All reagents
were used directly as unless otherwise noted.
4.3.5. (1-Phenyl-1H-[1,2,3]triazol-4-ylmethyl)-morpho-
line (4e). Solid, mp 88–90 8C; 1H NMR (300 MHz,
CDCl3) d 7.93 (s, 1H), 7.71 (d, JZ8.4 Hz, 2H), 7.49 (t,
JZ6.9, 8.4 Hz, 2H), 7.42–7.37 (m, 1H), 3.72 (s, 2H), 3.70
(t, JZ7.8, 6.9 Hz, 4H), 2.55 (t, JZ4.2 Hz, 4H); 13C NMR
(75 MHz, CDCl3) d 144.8, 136.9, 129.6, 128.6, 120.7,
120.3, 66.8, 53.6, 53.4; IR (KBr, cmK1) 2959, 2923, 2856,

9336
Z.-Y. Yan et al. / Tetrahedron 61 (2005) 9331–9337
2815, 1599, 1504, 1454, 1116; EI-MS m/z 244 (MC), 226,
214, 201, 159, 130, 77; HRMS (EI) found [MKN2H]CZ
215.1179, C13H15N2O requires 215.1179.
4.3.12.
(1-[4-Nitro-phenyl]-1H-[1,2,3]triazol-4-yl-
methyl)-morpholine (4l). Solid, mp 195–197 8C; 1H
NMR (300 MHz, CDCl3) d 8.43 (d, JZ8.7 Hz, 2H), 8.10
(s, 1H), 8.00 (d, JZ8.7 Hz, 2H), 3.74–3.80 (m, 6H), 2.61 (br
s, 4H); 13C NMR (75 MHz, CDCl3) d 147.1, 145.9, 141.1,
125.5, 120.7, 120.3, 66.7, 53.5 (2C); IR (KBr, cmK1) 1523,
1343, 1113, 856; EI-MS m/z 289 (MC), 246, 204, 129, 86;
HRMS (EI) found [M–N2H]CZ260.1028, C13H14N3O3
requires 260.1030.
4.3.6. 1,4-Bis-(1-phenyl-1H-[1,2,3]triazol-4-ylmethyl)-
piperazine (4f). Solid, mp 158–160 8C; 1H NMR
(300 MHz, CDCl3) d 8.12 (s, 2H), 7.71 (d, JZ7.8 Hz,
4H), 7.50 (t, JZ7.8, 7.2 Hz, 4H), 7.39 (t, JZ7.2 Hz, 2H),
3.90 (s, 4H), 2.83 (br s, 8H); 13C NMR (75 MHz, CDCl3) d
137.1, 130.0, 129.1, 122.1, 120.9, 120.7, 52.9, 52.1; IR
(KBr, cmK1) 1598, 1503, 1461, 1045; FAB-MS m/z 401.3
[MC1]C; HRMS (EI) found [M]CZ400.2117, C22H24N8
requires 400.2118.
4.3.13. (1-[4-Methyl-phenyl]-1H-[1,2,3]triazol-4-yl-
methyl)-piperidine (4m). Solid, mp 109–111 8C; 1H
NMR (300 MHz, CDCl3) d 7.90 (s, 1H), 7.58 (d, JZ
7.8 Hz, 2H), 7.27 (d, JZ7.8 Hz, 1H), 3.68 (s, 2H), 2.46 (br
s, 4H), 2.38 (s, 3H), 1.56 (br s, 4H), 1.41 (br s, 2H); 13C
NMR (75 MHz, CDCl3) d 145.3, 138.5, 134.7, 130.1, 120.7,
120.2, 54.2, 54.0, 25.7, 24.0, 21.0; IR (KBr, cmK1) 2938,
1528, 1113; EI-MS m/z 256 (MC), 173, 91, 84; HRMS (EI)
found [M]CZ256.1684, C15H20N4 requires 256.1682.
4.3.7. Bis-(1-[4-chloro-phenyl]-1H-[1,2,3]triazol-4-yl-
methyl)-butylamine (4g). Solid, mp 88–90 8C; H NMR
1
(300 MHz, CDCl3) d 8.03 (s, 2H), 7.61 (m, 4H), 7.37 (m,
4H), 3.79 (s, 4H), 2.50 (t, JZ7.2 Hz, 2H), 1.54 (m, 2H),
1.24 (m, 2H), 0.82 (m, 3H); 13C NMR (75 MHz, CDCl3) d
145.3, 135.2, 134.0, 129.6, 126.3, 121.2, 121.0, 53.3, 47.4,
29.2, 20.2, 13.8; IR (KBr, cmK1) 2956, 2930, 1501, 1226,
1096, 1043; FAB-MS m/z 456.2 [M] C; HRMS (EI) found
[M]CZ455.1389, C22H23N7Cl2 requires 455.1387.
4.3.14. (1-[4-Methyl-phenyl]-1H-[1,2,3]triazol-4-yl-
methyl)-morpholine (4n). Solid, mp 102–103 8C; 1H
NMR (300 MHz, CDCl3) d 7.89 (s, 1H), 7.59 (d, JZ
8.1 Hz, 2H), 7.30 (d, JZ8.1 Hz, 2H), 3.73 (s, 2H), 3.72
(t, JZ4.5 Hz, 4H), 2.56 (br s, 4H), 2.41 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 145.0, 139.0, 135.0, 130.5, 121.0,
120.6, 67.1, 53.9, 53.7, 21.3; IR (KBr, cmK1) 1521, 1449,
1113; EI-MS m/z 258 (MC), 240, 228, 215, 173, 144, 91;
HRMS (EI) found [M–N2H]CZ229.1378, C14H17N2O
requires 229.1335.
4.3.8. (1-Phenyl)-1H-[1,2,3]triazol-4-ylmethyl)-phenyl-
amine (4h). Solid, mp 138–140 8C; H NMR (300 MHz,
1
CDCl3) d 7.88 (s, 1H), 7.69 (d, JZ8.1 Hz, 2H), 7.53–7.40
(m, 3H), 7.26–7.18 (m, 2H), 6.78–6.70 (m, 3H), 4.55 (s,
2H); 4.32 (br s, 1H); 13C NMR (75 MHz, CDCl3) d 147.4,
147.0, 137.0, 129.7, 129.3, 128.7, 120.4, 119.8, 118.1,
113.1, 39.9; IR (KBr, cmK1) 1598, 1462, 1320, 1105;
EI-MS m/z 250 (MC), 221, 130, 77; HRMS (EI) found
[M]CZ250.1210, C15H14N4 requires 250.1213.
4.3.15. (1-[4-Methyl-phenyl]-1H-[1,2,3]triazol-4-yl-
methyl)-diethylamine (4o). Oil; 1H NMR (300 MHz,
CDCl3) d 7.91 (s, 1H), 7.57 (d, JZ8.1 Hz, 2H), 7.26 (d,
JZ8.1 Hz, 2H), 3.85 (s, 2H), 2.59 (q, 4H), 2.37 (s, 3H), 1.09
(t, JZ7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3) d 145.6,
138.9, 135.1, 130.4, 121.0, 120.5, 47.9, 47.0, 21.3, 11.9; IR
(KBr, cmK1) 2970, 1520, 1459, 1226, 1042; EI-MS m/z 244
(MC), 229, 215, 201, 187, 173, 144, 91, 72; HRMS (EI)
found [M]CZ244.1678, C14H20N4 requires 244.1682.
4.3.9.
(1-[4-Chloro-phenyl]-1H-[1,2,3]triazol-4-yl-
1
methyl)-piperidine (4i). Solid, mp 120–122 8C; H NMR
(300 MHz, CDCl3) d 7.93 (s, 1H), 7.70 (d, JZ8.7 Hz, 2H),
7.41 (d, JZ8.7 Hz, 2H), 3.72 (s, 2H), 2.50 (br s, 4H), 1.60
(m, 4H), 1.45 (m, 2H); 13C NMR (75 MHz, CDCl3) d 145.6,
135.5, 134.2, 129.8, 121.4, 120.7, 54.3, 53.9, 25.7, 23.9; IR
(KBr, cmK1) 2936, 1502, 1440, 1098, 1048; EI-MS m/z 276
(MC), 247, 193, 84; HRMS (EI) found [M]CZ276.1136,
C14H17N4Cl requires 276.1136.
4.3.16. (1-Benzyl-1H-[1,2,3]triazol-4-ylmethyl)-piperi-
dine (4p). Solid, mp 97–99 8C; 1H NMR (300 MHz,
CDCl3) d 7.41 (s, 1H), 7.38–7.34 (m, 2H), 7.28 (m, 3H),
5.51 (s, 2H), 3.62 (s, 2H), 2.43 (br s, 4H), 1.58–1.53 (m,
4H), 1.43–1.41 (d, 2H); 13C NMR (75 MHz, CDCl3) d
145.1, 134.6, 129.0, 128.6, 128.0, 122.4, 54.2 (2C), 54.0,
25.7, 24.0; IR (KBr, cmK1) 2931, 2771, 1445, 1306, 1050;
EI-MS m/z 256 (MC), 173, 91, 84; HRMS (EI) found
[M]CZ256.1682, C15H20N4 requires 256.1682.
4.3.10. (1-[4-Chloro-phenyl]-1H-[1,2,3]triazol-4-yl-
methyl)-morpholine (4j). Solid, mp 119–121 8C; 1H
NMR (300 MHz, CDCl3) d 7.95 (s, 1H), 7.70 (d, JZ
8.7 Hz, 2H), 7.50 (d, JZ8.7 Hz, 2H), 3.72–3.75 (m, 6H),
2.58 (br s, 4H); 13C NMR (75 MHz, CDCl3) d 145.4, 135.7,
134.7, 130.1, 121.8, 121.0, 67.0, 53.8, 53.7; IR (KBr, cmK1
)
2925, 1502, 1115; EI-MS m/z 278 (MC), 235, 193, 164;
HRMS (EI) found [M–N2H]CZ249.0786, C13H14N2ClO
requires 249.0789.
4.3.17. (1-Phenoxyethyl-1H-[1,2,3]triazol-4-ylmethyl)-
piperidine (4q). Solid, mp 103–104 8C; 1H NMR
(300 MHz, CDCl3) d 7.71 (s, 1H), 7.28 (t, JZ8.4, 7.5 Hz,
2H), 6.97 (t, JZ8.4, 7.5 Hz, 1H), 6.86 (d, JZ9.0 Hz, 2H),
4.74 (t, JZ4.8 Hz, 2H), 4.35 (t, JZ4.8 Hz, 2H), 3.66 (s,
2H), 2.45 (br s, 4H), 1.62–1.54 (m, 4H), 1.45–1.41 (m, 2H);
13C NMR (75 MHz, CDCl3) d 157.7, 144.6, 129.5, 123.8,
121.5, 114.4, 66.2, 54.1, 53.9, 49.6, 25.7, 24.0; IR (KBr,
cmK1) 2930, 2770, 1596, 1497, 1460, 1252, 1118, 1047;
EI-MS m/z 286 (MC), 203, 84; HRMS (EI) found [M]CZ
286.1785, C16H22N4O requires 286.1788.
4.3.11.
(1-[4-Nitro-phenyl]-1H-[1,2,3]triazol-4-yl-
1
methyl)-piperidine (4k). Solid, mp 109–111 8C; H NMR
(300 MHz, CDCl3) d 8.42 (d, JZ8.7 Hz, 2H), 8.09 (s, 1H),
8.00 (d, JZ8.7 Hz, 2H), 3.75 (s, 2H), 2.51 (br s, 4H), 1.61
(m, 4H), 1.46 (m, 2H); 13C NMR (75 MHz, CDCl3) d 147.0,
146.8, 141.2, 125.5, 120.5, 120.2, 54.4, 53.9, 25.8, 24.0; IR
(KBr, cmK1) 2938, 1600, 1528, 1507, 1447, 1343, 1111,
1042, 909; EI-MS m/z 287 (MC), 204, 129, 84; HRMS (EI)
found [M]CZ287.1380, C14H17N5O2 requires 287.1377.

Z.-Y. Yan et al. / Tetrahedron 61 (2005) 9331–9337
9337
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Acknowledgements
We thank the NSF-20021001, NSF-20172024 and the
‘Hundred Scientist Program’ from the Chinese Academy
of Sciences for the financial support of this work.
10. (a) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1995,
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