Practical one-pot synthesis of 5-alkynyl-1,2,3-triazoles via heterogeneous copper(I)-catalyzed tandem three-component click/alkynylation reaction

Article abstract of DOI:10.1002/aoc.5319

An efficient and practical route to 5-alkynyl-1,2,3-triazoles has been developed via heterogeneous tandem CuAAC/alkynylation reaction of organic azides, alkynes and 1-bromoalkynes by using an L-proline-functionalized MCM-41-anchored copper(I) complex [L-P

Full text of DOI:10.1002/aoc.5319

Received: 8 August 2019
DOI: 10.1002/aoc.5319
Revised: 2 October 2019
Accepted: 9 October 2019
F U L L P A P E R
Practical one‐pot synthesis of 5‐alkynyl‐1,2,3‐triazoles via
heterogeneous copper(I)‐catalyzed tandem three‐
component click/alkynylation reaction
Ruonan Zhao | Yang Liao | Tao Yan | Mingzhong Cai
Key Laboratory of Functional Small
Organic Molecule, Ministry of Education
An efficient and practical route to 5‐alkynyl‐1,2,3‐triazoles has been developed
and College of Chemistry & Chemical
via heterogeneous tandem CuAAC/alkynylation reaction of organic azides,
Engineering, Jiangxi Normal University,
Nanchang 330022, China
alkynes and 1‐bromoalkynes by using an L‐proline‐functionalized MCM‐41‐
anchored copper(I) complex [L‐Proline‐MCM‐41‐CuCl] as catalyst under mild
Correspondence
M. Cai, Key Laboratory of Functional
Small Organic Molecule, Ministry of
conditions. The reaction produces a wide variety of 5‐alkynyl‐1,2,3‐triazoles
in mostly good to excellent yields. The new immobilized copper(I) complex
Education and College of Chemistry &
Chemical Engineering, Jiangxi Normal
University, Nanchang 330022, China.
Email: caimzhong@163.com
can be readily prepared from commercially available and inexpensive reagents
and displays the same catalytic activity as CuCl. The L‐Proline‐MCM‐41‐CuCl
catalyst is also easy to recover via a simple filtration process and can be reused
at least seven times without apparent loss of activity.
Funding information
Key Laboratory of Functional Small
Organic Molecule, Ministry of Education,
Grant/Award Number: No. KLFS‐KF‐
201704; National Natural Science
Foundation of China, Grant/Award
Number: No. 21462021
KEYWORDS
5‐alkynyl‐1,2,3‐triazole, alkynylation, click reaction, copper, heterogeneous catalysis
1 | INTRODUCTION
more difficult to react with organic azides to construct
fully substituted triazoles owing to their low reactivity
The copper(I)‐catalyzed azide‐alkyne cycloaddition
(CuAAC) producing 1,4‐disubstituted 1,2,3‐triazoles has
received much attention since the pioneering work of
Sharpless and Meldal groups in 2002.[1] The CuAAC reac-
tion has played a key role in different areas of science,
including organic chemistry,[2] polymer chemistry and
material science,[3] and bioconjugation.[4] In addition,
the 1,2,3‐triazole products of this reaction as a class of
important N‐heterocycles have found wide applications
in organic synthesis,[5] medicinal chemistry,[6] and mate-
rial sciences.[7] Recently, 1,2,3‐triazoles have also been
widely employed as multifunctional ligands for cataly-
sis,[8] supermolecular binding groups,[9] and directing
groups for C–H bond activation catalyzed by transition‐
metals.[10] However, traditional CuAAC reaction is lim-
ited to terminal alkynes, thereby providing only 1,4‐
disubstituted 1,2,3‐triazoles. Internal alkynes are much
and difficulty in regiocontrol. So, the development of an
efficient method for the construction of trisubstituted
triazoles with a high level of regiocontrol is of great
importance. Recently, “the interrupted click chemistry”
strategy has been successfully developed by Xu et al. for
the synthesis of various functionalized trisubstituted
1,2,3‐triazoles.[11]
5‐Alkynyl‐1,2,3‐triazoles are
a class of valuable
multisubstituted 1,2,3‐triazoles since the alkyne moiety
can be further transformed into other useful functional
groups or heterocycles. Traditional methods for the syn-
thesis of 5‐alkynyl‐1,2,3‐triazoles from terminal alkynes
and azides mainly involve the oxidative coupling between
the cuprate‐triazole intermediates formed in situ with the
same alkynes, thus limiting the diversity of the target
products.[12] In addition, these protocols need to use
external oxidizing agents and homocoupling products
Appl Organometal Chem. 2019;e5319.
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ZHAO ET AL.
such as 1,3‐diynes and bistriazoles are often formed as
byproducts.[13] Lauten and coworkers reported a multi-
component multicatalyst reaction (MC)2R of terminal
alknes, azides, and 1‐iodoalkynes with CuI and Xphos‐
Pd‐G3 as the catalysts for constructing 5‐alkynyl‐1,2,3‐
triazoles.[14] This strategy involves a Cu(I)‐catalyzed
chemoselective cycloaddition of azides with 1‐
these issues of environmental and economic concerns in
chemical and pharmaceutical industries. In recent years,
some immobilized copper catalysts have been successfully
applied to many carbon‐heteroatom bond‐forming
reactions.[16a, 17]
Ordered mesoporous material MCM‐41 has been
widely employed as solid support for anchoring various
metal catalysts because of its advantageous properties
over other insoluble supports including extremely high
surface area, big pore volume, uniform pore size, and
excellent thermal stability.[18] To date, some palla-
dium,[19] rhodium,[20] molybdenum,[21] gold,[22] and
copper[17g–k] complexes have been anchored on MCM‐41
for use as catalysts for many organic reactions. As a part
of our continuing interest in developing recyclable cata-
lytic systems for organic synthesis,[17g–k, 19e–g, 22d–f] herein
we report the synthesis of an L‐proline‐modified MCM‐
41‐anchored copper(I) complex [L‐Proline‐MCM‐41‐
CuCl] and its successful application to tandem CuAAC/-
alkynylation reaction of terminal alkynes, organic azides,
and bromoalkynes towards 5‐alkynyl‐1,2,3‐triazoles
[Equation (2), in Scheme 1].
iodoalkynes followed by
a
Pd(0)/Cu(I)‐catalyzed
Sonogashira cross‐coupling with terminal alkynes,
affording 5‐alkynyl‐1,2,3‐triazoles regioselectively with
good yields and a broad scope, but an expensive palla-
dium catalyst was required. Recently, Xu et al. described
a copper(I)‐catalyzed cascade CuAAC/alkynylation reac-
tion of terminal alkynes, azides, and 1‐bromoalkynes for
the construction of 5‐alkynyl‐1,2,3‐triazoles with com-
plete regioselectivity and high yields under mild condi-
tions [Equation. (1), in Scheme 1].[15] This elegant three‐
component reaction involves
a
copper(I)‐catalyzed
chemoselective cycloaddition of azides with alkynes
followed by interception of the cuprate‐triazole interme-
diates formed in situ with electrophilic 1‐bromoalkynes.
However, this reaction requires the use of 20 mol% CuCl
as catalyst to achieve high yields. Although copper is an
inexpensive metal compared to palladium, employment
of high copper loading could result in the formation of a
large amount of waste derived from reaction work‐up
because homogeneous copper catalysts are difficult to
separate from the reaction mixture and cannot be
recycled. What's more, homogeneous catalysis might lead
to unacceptable copper contamination of the desired
product due to the fact that 1,2,3‐triazoles could coordi-
nate with various transition metals such as copper and
gold to form stable complexes,[8,16] thereby limiting its
application in the synthesis of 1,2,3‐triazole‐containing
drug molecules, which have to be free of any residual
metal. Anchoring homogeneous copper catalysts on vari-
ous solid supports, especially porous materials with high
surface areas, could be an effective strategy for solving
2 | RESULTS AND DISCUSSION
The L‐proline‐modified MCM‐41‐anchored copper(I) com-
plex [L‐Proline‐MCM‐41‐CuCl] was readily prepared from
commercially easily available and inexpensive materials
according to the procedure shown in Scheme 2. First, the
condensation of MCM‐41[18a] with 2‐(4‐(chloromethyl)
phenyl)ethyltrimethoxysilane in toluene under reflux,
followed by the treatment with Me3SiCl in toluene at
room temperatureprovided the chloromethyl‐modified
MCM‐41 (ClCH2‐MCM‐41). Subsequent reaction of
ClCH2‐MCM‐41 with N‐Boc‐trans‐4‐hydroxy‐L‐proline in
THF using NaH as base, followed by deprotection with
TFA in CH2Cl2 generated the L‐proline‐modified MCM‐
SCHEME 1 Copper(I)‐catalyzed synthesis of 5‐alkynyl‐1,2,3‐triazoles

ZHAO ET AL.
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SCHEME 2 Preparation of the
L‐Proline‐MCM‐41‐CuCl complex
41 (L‐Proline‐MCM‐41). Finally, the L‐Proline‐MCM‐41
was reacted with CuCl in acetone at room temperature to
afford the L‐Proline‐MCM‐41‐CuCl complex as a pale blue
powder.
relative intensity of lower angle diffraction peak (100)
decreased and two higher angle diffraction peaks (110
and 200) become weak and diffuse after introduction of
the L‐Proline‐CuCl complex, which further confirmed
that the L‐Proline‐CuCl complex was mainly anchored
onto the inner walls of mesoporous channels. The results
above demonstrate that the ordered mesoporous structure
of the starting MCM‐41 remains almost unaltered
through the anchoring copper complex procedure.
The small angle X‐ray powder diffraction (XRD) pat-
terns of the MCM‐41 and the L‐Proline‐MCM‐41‐CuCl
complex are presented in Figure 1. The small angle
XRD pattern of the MCM‐41 displays a very intense dif-
fraction peak (100) at 2θ = 2.37° and two high order dif-
fraction peaks (110 and 200) with low intensity at
2θ = 3.91° and 4.50°, respectively, which can be ascribed
to a well‐ordered mesoporous phase of MCM‐41.[18a] For
modified material L‐Proline‐MCM‐41‐CuCl, its XRD pat-
tern was similar to that of MCM‐41, indicating that L‐Pro-
line‐MCM‐41‐CuCl also has a hexagonal arrangement of
one‐dimensional mesoporous structure. However, the
Figure 2 shows the N2 isotherms of MCM‐41 and the
copper‐containing
recorded at 77 K. The MCM‐41 gave
sample
L‐Proline‐MCM‐41‐CuCl
N2
a
adsorption‐desorption isotherms of type IV[23] (definition
by IUPAC), which is characteristic for mesoporous mate-
rials having 2–50 nm pore diameters. Compared with
MCM‐41, the modified sample L‐Proline‐MCM‐41‐CuCl
also gave a type IV isotherm, but a decreased uptake of
N2 was apparently observed owing to the incorporation
of the silylated L‐Proline‐CuCl complex and the silylation
with Me3SiCl. Figure 3 displays the BJH pore size distri-
butions for the parent MCM‐41 and modified sample L‐
Proline‐MCM‐41‐CuCl. From the Figure 3 it can be seen
that MCM‐41 shows narrow pore size distribution with
average pore diameter of 2.7 nm. But for L‐Proline‐-
MCM‐41‐CuCl, the average pore diameter was reduced
to 2.5 nm and a broad and lower pore size distribution
was observed, which implying that the copper complex
and the Me3Si groups are not uniformly distributed
through the channel surface of MCM‐41 in the modified
sample. The BET specific surface areas of MCM‐41 and
L‐Proline‐MCM‐41‐CuCl were calculated to 927 and
593 m2g−1, respectively. The significant decrease in sur-
face area should be due to the introduction of the organic
moieties into the channels of MCM‐41, which is also
responsible for a reduction of pore diameter. The energy
FIGURE 1 XRD patterns of MCM‐41 (a) and L‐Proline‐MCM‐41‐
CuCl (b)

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ZHAO ET AL.
FIGURE 2 N2 adsorption/desorption
isotherms of MCM‐41 and L‐Proline‐
MCM‐41‐CuCl
FIGURE 3 Pore size distributions of
MCM‐41 and L‐Proline‐MCM‐41‐CuCl
dispersive X‐ray spectroscopy (EDS) analysis of the mate-
rials indicates the presence of various elements with their
respective energy positions. The EDS spectrum of the L‐
Proline‐MCM‐41‐CuCl complex demonstrated the pres-
ence of Si, O, C, N, Cl, and Cu elements (Figure 4), which
further verifying the successful anchoring of the L‐Pro-
line‐CuCl complex onto MCM‐41.
The L‐Proline‐MCM‐41‐CuCl complex was then
employed as the catalyst for the three‐component reac-
tion of terminal alkynes, organic azides and 1‐
bromoalkynes. Initially, the reaction of phenylacetylene
1a with benzyl azide 2a and 1‐(bromoethynyl)‐4‐
methoxybenzene 3a was investigated to optimize reaction
conditions, and the results are summarized in Table 1.
First, the effect of different solvents on the model reaction
was investigated in the presence of 10 mol% of L‐Proline‐
MCM‐41‐CuCl with LiOBut as the base at room tempera-
ture (entries 1–8). The use of hexane, THF, DCE and
DCM as solvents afforded the desired 4a in 62–89% yield.
DCE was the most efficient solvent, giving the target
product 4a in 89% isolated yield along with the byproduct
5a in only 7% yield (entry 6), while other solvents such as
toluene, MeCN, dioxane and i‐PrOH were substantially
less effective and gave lower yields. The effect of different

ZHAO ET AL.
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FIGURE 4 EDS pattern of L‐Proline‐MCM‐41‐CuCl
TABLE 1 Optimization of reaction conditionsa
T (°
C)
Yieldb (%) of
4a
Yieldb (%) of
5a
Entry
Base
Solvent
1
LiOBut
LiOBut
LiOBut
LiOBut
LiOBut
LiOBut
LiOBut
LiOBut
KOBut
NaOBut
NaOMe
K2CO3
Et3N
Hexane
Toluene
MeCN
THF
25
25
25
25
25
25
25
25
25
25
25
25
25
40
60
25
25
68
53
34
62
58
89
76
47
22
45
63
50
41
68
59
62
88
23
18
54
23
26
7
2
3
4
5
Dioxane
DCE
6
7
DCM
i‐PrOH
DCE
13
34
63
19
29
42
45
22
31
4
8
9
10
11
12
13
14
15
16c
17d
DCE
DCE
DCE
DCE
LiOBut
LiOBut
LiOBut
LiOBut
DCE
DCE
DCE
DCE
8
aReaction was carried out with 1a (0.2 mmol), 2a (0.3 mmol), 3a (0.4 mmol), base (0.4 mmol), 4 Å molecular sieves (MS, 150 mg), and the catalyst (10 mol%) in
solvent (2 ml) under N2 atmosphere for 12 hrs.
bIsolated yield.
c5 mol% of L‐Proline‐MCM‐41‐CuCl was used.
d20 mol% of L‐Proline‐MCM‐41‐CuCl was used.

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ZHAO ET AL.
bases on the reaction was also examined (entries 9–13).
When KOBut, NaOBut, NaOMe, K2CO3, and Et3N were
used as bases, the desired 4a was obtained in only low
to moderate yields, so LiOBut as base was the best choice
(entry 6). Further optimization of different temperatures
showed that raising reaction tem‐ perature to 40 or 60°C
led to a decreased yield of 4a (entries 14 and 15). Finally,
copper catalyst loadings were also screened (entries 16
and 17). Reducing the loading of L‐Proline‐MCM‐41‐CuCl
to 5 mol% provided 4a in only 62% yield, whilst increasing
the loading of L‐Proline‐MCM‐41‐CuCl to 20 mol% did
not improve the yield. Thus, the optimized catalytic sys-
tem for this tandem CuAAC/alkynylation reaction was
the use of L‐Proline‐MCM‐41‐CuCl (10 mol%) with LiO-
tBu as base and DCE as solvent at 25 °C under N2 atmo-
sphere for 12 hrs (entry 6).
With the optimized reaction conditions established, we
started to explore the substrate scope of this heteroge-
neous copper‐catalyzed tandem CuAAC/alkynylation
reaction. Firstly, a wide variety of terminal alkynes were
examined and the results are given in Table 2. As shown
in Table 2, both aromatic and aliphatic terminal alkynes
could undergo the three‐component reaction with 2a
and 3a smoothly to afford the corresponding 5‐alkynyl‐
1,2,3‐triazoles in good to excellent yields. For example,
various para‐substituted phenylacetylenes 1b–1f bearing
either electron‐donating or electron‐withdrawing groups
reacted effectively with 2a and 3a, providing the desired
products 4b–4f in 64–92% yields. The reactivity of
electron‐rich phenylacetylenes 1b–1c was higher than
that of electron‐deficient ones 1d–1f. It was observed
that the rigid 4‐ethyl‐4'‐ethynylbiphenyl 1g and bulky 1‐
ethynylnaphthalene 1h also reacted well in this transfor-
mation, thus furnishing the expected 4g and
4h, respectively, in good yields. In addition,
a
heteroarylacetylene such as 2‐ethynylthiophene 1i was
suitable substrate and gave the target product 4i in 85%
yield. It is noteworthy that, various alkylacetylenes 1j–
1m were also compatible with the standard conditions
and underwent the reaction with 2a and 3a smoothly to
give the corresponding products 4j–4m in 85–90% yields.
Interestingly, a conjugated enyne, 1‐ethynylcyclohex‐1‐
ene 1n displayed a good reactivity to afford the desired
product 4n in 83% yield.
We next investigated the scope of this three‐
component reaction with respect to various azides and
TABLE 2 Substrate scope of various terminal alkynesa,b
aReaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), 3a (0.4 mmol), L‐Proline‐MCM‐41‐CuCl (10 mol%), LiOBut (0.4 mmol), 4 Å molecular sieves (MS, 150 mg),
and DCE (2 ml) at room temperature under N2 atmosphere for 12 hrs.
bIsolated yield.

ZHAO ET AL.
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the results are given in Table 3. para‐Substituted benzyl
azides 2b–2c could participate in this transformation
effectively to give the corresponding products 4o–4p in
86–88% yields, but 4‐cyanobenzyl azide 2d bearing a
strong electron‐withdrawing group showed a relatively
lower reactivity and provided the desired 4q in only 66%
yield. Notably, 2‐naphthylmethyl azide 2e and cinnamyl
azide 2f proved to be good substrates and afforded the
expected products 4r and 4s in 78 and 89% yields, respec-
tively. Other aliphatic azides containing octyl 2g,
phthalimide‐protected amine 2h or the indole skeleton
2i were all compatible with the standard conditions
and gave the desired 5‐alkynyl‐1,2,3‐triazoles 4t‐4v in
high yields. The substrate scope of 1‐bromoalkynes was
further examined and the results are also listed in
Table 3. Aryl‐substituted 1‐bromoalkynes 3b‐3d displayed
corresponding products 4w‐4y in 83‐91% yields. A
heteroaryl‐substituted 1‐bromoalkyne 3e was also amena-
ble to this reaction, giving the target product 4z in 88%
yield. In addition, various alkyl‐substituted 1‐
bromoalkynes 3f‐3i were all suitable substrates and
afforded the corresponding 1,2,3‐triazole derivatives
4a'‐4d' in good to high yields. To our delight, the i‐Pr3Si‐
substituted 1‐bromoalkyne 3j also reacted well in this
transformation, providing the desired product 4e' in 88%
yield. The present method is applicable to a wide range
of terminal alkynes, organic azides and 1‐bromoalkynes,
and provides a highly efficient and practical procedure
for construction of 5‐alkynyl‐1,2,3‐triazoles from readily
available starting materials.
To ascertain whether the observed three‐component
reaction was due to the heterogeneous L‐Proline‐MCM‐
41‐CuCl or a soluble copper species leached from L‐
a
similar reactivity with 3a and produced the
TABLE 3 Substrate scope of azides and 1‐bromoalkynesa,b
aReaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), 3 (0.4 mmol), L‐Proline‐MCM‐41‐CuCl (10 mol%), LiOBut (0.4 mmol), 4 Å molecular sieves (MS, 150 mg), and
DCE (2 ml) at room temperature under N2 atmosphere for 12 hrs.
bIsolated yield.

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ZHAO ET AL.
Proline‐MCM‐41‐CuCl in the solution, we conducted the
three‐component reaction of phenylacetylene 1a with
benzyl azide 2a and 1‐(bromoethynyl)‐4‐methoxybenzene
3a and removed the copper catalyst by a simple filtration
of the reaction mixture at approximately 40% conversion
of phenylacetylene 1a. The catalyst‐free filtrate was
allowed to react further with the addition of 4 Å MS at
room temperature under N2 atmosphere for 10 hrs. It
was found that, no increase in conversion of
phenylacetylene 1a was observed in the filtrate, demon-
strating that leached Cu species from L‐Proline‐MCM‐
41‐CuCl (if any) are not related to the observed catalysis.
Besides, no copper species could be detected in the filtrate
based on ICP‐AES analysis, which further excluding the
contribution of homogeneous catalysis from more active
soluble forms of copper. So, the actual catalytic activity
should arise from L‐Proline‐MCM‐41‐CuCl and not from
the soluble Cu species in the solution.
In order to explore the reaction mechanism, two con-
trol experiments were carried out under the optimized
reaction conditions (Scheme 3). Firstly, under the opti-
mized reaction conditions, benzyl azide 2a did not react
with 1‐(bromoethynyl)‐4‐methoxybenzene 3a to form
the 1‐benzyl‐5‐bromo‐4‐((4‐methoxyphenyl)ethynyl)‐1H‐
1,2,3‐ triazole 6, which indicating that terminal alkyne
exhibits much higher reactivity than 1‐bromoalkyne 3a
in this CuAAC reaction [Equation. (1), in Scheme 3]. 1‐
Benzyl‐4‐phenyl‐1H‐1,2,3‐triazole 5a, a major byproduct
SCHEME 3 Control experiments
SCHEME 4 Plausible mechanism for
the formation of product 4

ZHAO ET AL.
9 of 12
TABLE 4 Recycle of the L‐Proline‐MCM‐41‐CuCl catalysta
L‐Proline‐
MCM‐41‐CuCl
Yield
(%)b
L‐Proline‐
MCM‐41‐CuCl
Yield
(%)b
Entry
Entry
1
2
3
4
fresh
92
91
92
90
5
6
7
8
recycle 4
recycle 5
recycle 6
recycle 7
91
90
89
88
recycle 1
recycle 2
recycle 3
aReaction conditions: 1c (0.2 mmol), 2a (0.3 mmol), 3a (0.4 mmol), L‐Proline‐MCM‐41‐CuCl (10 mol%), LiOBut (0.4 mmol), 4 Å molecular sieves (MS, 150 mg),
and DCE (2 ml) at room temperature under N2 atmosphere for 12 hrs.
bIsolated yield.
of this tandem reaction, was subjected to the reaction
with 3a under the optimized conditions, but the desired
4a was not detected [Equation. (2), in Scheme 3], which
verifying that the click reaction and subsequent
copper‐catalyzed C–H activation pathway are impossible.
Based on these experiment results and previous
report,[15] a plausible mechanism for this heterogeneous
tandem CuAAC/alkynylation reaction is proposed and
illustrated in Scheme 4. First, the reaction of L‐Proline‐
MCM‐41‐CuCl with terminal alkyne 1 in the presence of
LiOBut gives an MCM‐41‐anchored copper(I)‐acetylide
intermediate A. Subsequent cycloaddition of intermediate
A with the organic azide 2 forms an MCM‐41‐anchored 5‐
copper(I)‐triazolide intermediate B. Finally, oxidative
addition of 1‐bromoalkyne 3 to intermediate B generates
an MCM‐41‐anchored alkyne‐Cu (III)Br‐triazole complex
intermediate C, which undergoes a reductive elimination
to afford the desired product 4 and regenerate the L‐Pro-
line‐MCM‐41‐CuX catalyst.
To make the present synthetic protocol more econom-
ical, practical and environmentally friendly, it is neces-
sary to investigate the recoverability and recyclability of
the L‐Proline‐MCM‐41‐CuCl complex. The recycle of L‐
Proline‐MCM‐41‐CuCl was then studied in the tandem
three‐component reaction of (4‐methoxyphenyl)acetylene
1c, benzyl azide 2a and 1‐(bromoethynyl)‐4‐
methoxybenzene 3a and the results are listed in Table 4.
After completion of the reaction, the reaction mixture
was diluted with ethyl acetate and the copper catalyst
was readily separated from the product via a simple filtra-
tion process and washed with ethanol, dried at 80 °C in
vacuum, and used directly for the next reaction cycle
without further purification. As shown in Table 4, the
recovered copper catalyst could be recycled and reused
at least seven consecutive trials with almost consistent
activity. The excellent reusability of this heterogeneous
copper(I) catalyst should be attributed to the strong inter-
action between the bidentate L‐proline ligand and copper
and the ordered mesoporous structure of MCM‐41.
3 | CONCLUSION
In summary, we have developed an efficient, practical
and environmentally friendly method for the synthesis
of diverse 5‐alkynyl‐1,2,3‐triazoles through heteroge-
neous copper(I)‐catalyzed tandem three‐component
reaction. The present approach employs easily available
terminal alkynes, organic azides and 1‐bromoalkynes
as starting materials and has many notable features,
including: (1) the substrate scope is broad, and a wide
range of terminal alkynes, organic azides and 1‐
bromoalkynes are allowed; (2) a wide variety of 5‐
alkynyl‐1,2,3‐triazoles were obtained in mostly good to
excellent yields; (3) the reaction conditions were mild
and complete regioselectivity was achieved; (4) this sup-
ported copper catalyst can be readily synthesized from
commercially easily available and inexpensive reagents
and recovered via a simple filtration process, and reused
at least seven times without any significant loss of cata-
lytic activity.
4 | EXPERIMENTAL
Unless otherwise stated, all chemicals were purchased
from different commercial suppliers and used without
further purification. Organic azides and 1‐bromoalkynes
were prepared according to the literature procedure.[15]

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ZHAO ET AL.
All solvents were dried by CaH2 or sodium and distilled
before use. The reaction products were purified by flash
chromatography on silica gel with light petroleum
CH2Cl2 (12 ml) and Et2O (12 ml), and dried under vac-
uum at 100 °C for 3 hrs to provide 1.39 g of modified
material L‐Proline‐MCM‐41 with nitrogen content of
0.89 mmol/g based on elemental analysis.
1
ether/ethyl acetate as eluent. H NMR (400 MHz) and
13C NMR (100 MHz) spectra were recorded on a Bruker
Avance 400 spectrometer with TMS as an internal stan-
dard in CDCl3 as solvent. HRMS spectra were recorded
on an AGILENT 6520 Accurate‐Mass QTOF LC/MS spec-
trometer with the electrospray mode (ES). Melting points
were measured by using a Beijing Tech Instrument Co.,
LTD X‐6 melting point apparatus and are uncorrected.
X‐ray diffraction (XRD) measurements were carried out
at room temperature with a SEIFERT‐FPM XRD7 diffrac-
tometer with Cu Kα radiation at 40 kV and 36 mA. The
content of copper was measured on a Jarrell‐Ash 1100
ICP analysis. Nitrogen adsorption/desorption isotherms
were obtained using a Bel Japan Inc. Belsorp‐HP at the
liquid nitrogen temperature and samples were degassed
at 413 K overnight prior to measurements. Energy disper-
sive spectroscopy (EDS) analysis was performed by using
JEOL JSM‐7600F scan electron microscope. Mesoporous
material MCM‐41 was prepared according to literature
method.[18a]
A mixture of L‐Proline‐MCM‐41 (1.28 g) and CuCl
(0.109 g, 1.1 mmol) in acetone (25 ml) was stirred at room
temperature for 24 hrs under N2 atmosphere. The
resulting product was collected by filtration, washed with
DMF (2 × 20 ml) and acetone (2 × 20 ml), and dried at 80
°C under vacuum for 4 hrs to give 1.358 g of the L‐Proline‐
MCM‐41‐CuCl complex as a pale blue powder. The con-
tent of copper was found to be 0.71 mmol/g based on
ICP‐AES analysis.
4.2 | General procedure for the
heterogeneous copper(I)‐catalyzed
synthesis of 5‐alkynyl‐1,2,3‐triazoles
To a 25 ml Schlenk tube were added L‐Proline‐MCM‐41‐
CuCl (29 mg, 0.02 mmol), LiOBut (0.4 mmol), 4 Å MS
(150 mg), terminal alkyne 1 (0.2 mmol), organic azide 2
(0.3 mmol), 1‐bromoalkyne 3(0.4 mmol) and DCE (2 ml)
under N2 atmosphere. The reaction mixture was stirred at
room temperature for 12 hrs. After the reaction was com-
pleted (monitored by TLC), the reaction mixture was
diluted with 10 ml of EtOAc, and filtered. The L‐Proline‐
MCM‐41‐CuCl catalyst was washed with ethanol
(3 × 5 ml), dried at 80 °C in vacuum and reused in the next
cycle. The filtrate was concentrated under reduced pres-
sure and the residue was purified by flash column chroma-
tography on silica gel (light petroleum ether/ethyl
acetate = 12:1) to give the desired product 4. The character-
ization data and copies of 1H NMR and 13C NMR spectra of
compounds 4a–4e' have been provided in the Supporting
Information.
4.1 | Preparation of L‐Proline‐MCM‐41‐
CuCl
A
mixture of 3.2 g of 2‐(4‐(chloromethyl)phenyl)
ethyltrimethoxysilane and 3.0 g of the MCM‐41 in
160 ml of dry toluene was stirred at 110 °C under N2
atmosphere for 24 hrs. After being cooled to room tem-
perature, the reaction mixture was filtered and the solid
was washed by chloroform (30 ml) and dried in vacuum
at 130 °C for 5 hrs. The solid product was then stirred
with 3.5 g of Me3SiCl in 110 ml of dry toluene at room
temperature for 24 hrs. The resulting product was fil-
tered, washed with acetone (2 × 40 ml) and dried in vac-
uum at 100 °C for 5 hrs to give 4.55 g of modified material
ClCH2‐MCM‐41 as a white powder. The content of chlo-
rine was found to be 1.26 mmol/g based on elemental
analysis.
A mixture of N‐Boc‐trans‐4‐hydroxy‐L‐proline (1.39 g,
6.0 mmol) and NaH (0.30 g, 12.5 mmol) in dry THF
(100 ml) was stirred at room temperature for 1.5 hrs
under N2 atmosphere. Then ClCH2‐MCM‐41 (3.16 g)
was added and the resulting mixture was stirred at 65
°C for 20 hrs. The product was collected by filtration,
washed with distilled water (3 × 25 ml), ethanol
(3 × 25 ml), and dried under vacuum at 100 °C for
5 hrs. The dried product (1.65 g) was stirred with TFA
(7 ml) in CH2Cl2 (12 ml) at 40 °C for 4 hrs and filtered.
The resulting product was washed with Et3N (8 ml),
ACKNOWLEDGEMENTS
We thank the National Natural Science Foundation of
China (No. 21462021) and Key Laboratory of Functional
Small Organic Molecule, Ministry of Education (No.
KLFS‐KF‐201704) for financial support.
ORCID
Mingzhong Cai https://orcid.org/0000-0002-1056-2846
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How to cite this article: Zhao R, Liao Y, Yan T,
Cai M. Practical one‐pot synthesis of 5‐alkynyl‐
1,2,3‐triazoles via heterogeneous copper(I)‐
catalyzed tandem three‐ component
click/alkynylation reaction. Appl Organometal
Chem. 2019;e5319. https://doi.org/10.1002/aoc.5319
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.