Ionic polymer supported copper(I): A reusable catalyst for Huisgen's 1,3-dipolar cycloaddition

Article abstract of DOI:10.1055/s-2008-1078245

A series of CuI-immobilized polymeric supports having quaternary ammonium salts were prepared as recyclable heterogeneous catalysts with evaluation of their ability in Cu(I)-catalyzed Huisgen's 1,3-dipolar cycloaddition of azides and terminal alkynes, a '

Full text of DOI:10.1055/s-2008-1078245

2326
LETTER
Ionic Polymer Supported Copper(I): A Reusable Catalyst for Huisgen’s
1,3-Dipolar Cycloaddition
Ionic Polymer
S
up
t
ported
h
Copper(I
)
aiwan Sirion,a Yu Jin Bae,a Byoung Se Lee,a,b Dae Yoon Chi*a,b
a
Department of Chemistry, Inha University, 253 Yonghyundong Namgu, Inchon 402-751, Korea
Fax +82(32)8675604; E-mail: dychi@inha.ac.kr
b
Research Institute of Labeling, FutureChem Co. Ltd., 388-1 Pungnap-2-dong, Songpagu, Seoul 138-736, Korea
Received 1 April 2008
molecular modifications. Several efforts have been made
for an efficient removal and reuse of Cu(I) catalysts by
utilizing ionic liquids7 or solid supports. Copper iodide
was immobilized onto dimethylaminomethyl polystyrene
Abstract: A series of CuI-immobilized polymeric supports having
quaternary ammonium salts were prepared as recyclable heteroge-
neous catalysts with evaluation of their ability in Cu(I)-catalyzed
Huisgen’s 1,3-dipolar cycloaddition of azides and terminal alkynes,
a ‘click reaction’. An ionic polymer possessing an acetate anion was based support by Girard et al., who reported reuse of this
suitable as the solid support for immobilization of CuI and CuI-im-
heterogeneous CuI over four cycles without a decrease in
yield.8 However, Smith et al. reported on a modular-flow
mobilized compound showed negligible leaching levels of CuI, pro-
viding 1,4-disubstituted 1,2,3-triazoles in good yields, regio-
reactor system composed of three continuous columns
selectively. The CuI-immobilized compound was also reused not
containing different polymer resins,9 whereby the second
only up to ten times without any loss of yield or catalytic activity,
column was used to remove CuI slightly leached from the
first column filled with CuI-immobilized Amberlyst A-
21, indicating that the polymer-bound CuI is somewhat
released into the solution during the reaction.
but also for twelve different click reactions.
Key words: Huisgen 1,3-dipolar cycloaddition, click reaction,
CuI-immobilized ionic polymer, recyclable solid catalyst
Alternative polymeric supports, ionic polymers having
quaternary ammonium salts, are also available as a useful
and effective class of solid support for the immobilization
of metal catalysts. Since Yb(OTf)3-immobilized ionic
polymer showed good catalytic activity over ten reuses
without any loss of yield,10 it has been extended to other
metal catalysts.11
Being one of the most versatile metals for catalysis, cop-
per has been widely used in a variety of organic reactions
for several decades,1 especially the Cu(I)-catalyzed Huis-
gen’s 1,3-dipolar cycloaddition reaction, referred to as a
‘click reaction’. This click reaction has become a very
useful carbon–heteroatom bond-forming reaction because
of i) mild reaction conditions (at room temperature and
neutral pH); ii) reaction specificity (reacts only between
azide and terminal alkyne); and iii) water tolerance (bio-
molecular-friendly reaction).2 Presently, click reactions
are of growing interest in most applied organic chemistry
such as small molecule synthesis,3 bioconjugation,4 poly-
merization,5 radiolabeling reaction,6 and so forth. Howev-
er, copper metal and some additives such as sodium
ascorbate, amine bases, and ligands remain in the mixture
after the reaction and must be removed, particularly for an
automation system of high-throughput synthesis and bio-
Herein we report the preparation of a series of CuI-immo-
bilized ionic polymers, and their catalytic activities and
reusability, for the benefit of Huisgen’s 1,3-dipolar cy-
cloaddition reaction, and for the sake of high-throughput
synthesis of 1,4-disubstituted 1,2,3-triazoles.
To make a series of ionic polymers having quaternary am-
monium salts, high chloromethyl-loaded (2.44 mmol/g)
Merrifield resins were prepared by suspension radical po-
lymerization of styrene, vinylbenzyl chloride, and 2% di-
vinylbenzene (DVB), followed by quaternization with
Cl
Et3N
Cl
MX
NEt3
PS
PS
MX = NaBF4, NaOMs, KOAc
ion exchange
DMF
60 °C, overnight
quaternization
polystyrene
1a, PS[NEt3][Cl]
X
Cl
1b, PS[NEt3][BF4]
1c, PS[NEt3][OMs]
1d, PS[NEt3][OAc]
NEt3
PS
NMe3
PS
1e, DOWEX-Cl
Scheme 1 Preparation of ionic polymers 1a–e
SYNLETT 2008, No. 15, pp 2326–2330
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5
.0
9
.2
0
0
8
Advanced online publication: 31.07.2008
DOI: 10.1055/s-2008-1078245; Art ID: U02708ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Ionic Polymer Supported Copper(I)
2327
Table 1 Catalytic Activity of CuI Resins in the Click Reactiona
2a–e (13 mol%)
N3
N
DMF–H2O (4:1)
MeO
r.t., 3 h
N
N
MeO
3
4
5
Resin
X
2a
2b
2c
2d
2e
Cl
71
BF4
93
OMs
100
OAc
85
Cl
58
Conversion (%)b
a All reactions were carried out on a 0.20 mmol scale of azide 3 and 1.2 equiv of alkyne 4 using 13 mol% of Cu(I)-catalysts (2a–e, 100 mg) in
DMF–H2O (4:1, 1 mL).
b Determined by HPLC.
excess triethylamine at 60 °C overnight. Consecutively, To investigate the catalytic ability of these CuI-immobi-
the corresponding chloride ion (counteranion of the qua- lized ionic polymers 2a–e, the Cu(I)-catalyzed Huisgen
ternary ammonium salt) was exchanged with three differ- 1,3-dipolar cycloaddition of 4-methoxybenzyl azide (3)
ent anions by simple ion-exchange process to afford and phenylacetylene (4) was performed using 13 mol% of
tetrafluoroborate 1b, mesylate 1c, and acetate resins 1d, Cu(I)-catalysts in DMF–H2O (4:1) at room temperature
respectively. In addition, we purchased commercially for 3 hours. All catalyst resins were easily separated by
available ion-exchange resin, DOWEX® 1 × 2-200, a 2% simple filtration and washed with THF. The resultant or-
DVB cross-linked polystyrene (PS)-based trimethylben- ganic filtrates were analyzed by HPLC to determine per-
zylammonium chloride resin (1e in Scheme 1). This mois- cent of conversion. In all cases, the 1,4-disubstituted
turized, swollen resin was washed with acetone to remove product was regioselectively obtained with no 1,5-disub-
water inside resin and dried under vacuum before use.
stituted byproduct. As a result, we observed that the order
of catalytic activities of the five solid CuI catalysts was
2c > 2b > 2d > 2a > 2e, translating to, OMs >BF4 >
OAc > Cl > DOWEX®-Cl (Table 1).
These prepared ionic polymers 1a–e were suspended in
DMF–MeCN (1:1) with CuI (5 wt% compared to resin),
and shaken well for 3 hours (Scheme 2). In all cases, most
CuI was immobilized onto the ionic polymers and verified However, two resins having BF4 (2b) and OMs (2c)
by weight increase of the corresponding resins. Anions of showed slight CuI leaching compared to Cl (2a and 2e)
ionic polymers are thought to coordinate with CuI as and OAc resins (2d). It could be roughly and easily deter-
shown in Scheme 2,11b forming sufficient immobilization mined by comparing CuI spots on TLC (CuI is visualized
of CuI into resins. The color of copper-containing resins on UV lamp at 254 nm and PMA staining). Generally, cat-
varies depending on counteranions; dark green for chlo- alyst leaching is a very critical factor to validate solid cat-
ride, light yellow-green for BF4, dark brown for OMs, and alyst. The CuI leaching indicates that most of the reaction
light blue for OAc.
may occur homogeneously, and it may contaminate the
product. In contrast to BF4 (2b) and OMs (2c), there was
very small amount of CuI leaching with the Cl (2a and 2e)
and OAc (2d) resins, where the OAc resin (2d) provided
better conversion. CuI-DOWEX®-Cl gave the worst result
with 58% conversion, likely due to less swelling proper-
ties than other polystyrene resins made in our lab. From
this experiment, we chose the CuI-immobilized OAc resin
as a recyclable solid catalyst for further study.
All CuI-immobilized resins except DOWEX® chloride 2e
exhibited overall good swelling properties in polar sol-
vents such as DMF, DMSO, MeCN, acetone, and t-BuOH
for sufficient access to inside resin. Consequently, we ob-
tained 0.25 mmol/g of CuI loaded ionic polymers 2a–e.
An immobilization of CuSO4 onto DOWEX® chloride
resins was also attempted using the same procedure with
aqueous CuSO4 solution. However, a very small amount
of CuSO4 was found immobilized onto the polymer.
To optimize reaction conditions, several solvents contain-
ing 20% water such as MeCN, acetone, DMF, DMSO,
and t-BuOH were tested in the same standard reaction in
the presence of 5 mol% of catalyst 2d for 12 hours at room
temperature (entries 1–5 in Table 2). Thin-layer chroma-
tography was used to monitor the reactions and conver-
sion (%) was determined by HPLC after 12 hours. This
experiment revealed that t-BuOH–H2O (4:1) is the best
solvent due to the lack of any detectable CuI leaching,
whereas tiny leaching was observed in DMF–H2O (4:1)
and considerable leaching in MeCN–H2O (4:1) and
DMSO–H2O (4:1). Better solubility of CuI in MeCN,
DMF, and DMSO perhaps makes it easier for CuI to be re-
CuI (5 wt%)
NR3
NR3
NR3
X
X
X
MeCN–DMF (1:1)
PS
PS
CuI
shaking
r.t., 3 h
NR3
X
0.25 mmol/g
1a–e
2a, PS[NEt3][Cl](CuI)
2b, PS[NEt3][BF4](CuI)
2c, PS[NEt3][OMs](CuI)
2d, PS[NEt3][OAc](CuI)
2e, DOWEX-Cl(CuI)
Scheme 2 Immobilization of CuI onto ionic polymers
Synlett 2008, No. 15, 2326–2330 © Thieme Stuttgart · New York

2328
U. Sirion et al.
LETTER
Table 2 Optimization of Heterogeneous Click Reaction Using 2da
2d
N3
N
solvent
MeO
N
N
MeO
3
4
5
Entry
Solvent (4:1)
DMF–H2O
2d (mol%)
Temp (°C)
Time (h)
12.0
12.0
12.0
12.0
12.0
1.0
Conversion (%)b
1
2
5
r.t.
r.t.
r.t.
r.t.
r.t.
80
60
60
60
60
100
63
MeCN–H2O
DMSO–H2O
acetone–H2O
t-BuOH–H2O
t-BuOH–H2O
t-BuOH–H2O
t-BuOH–H2O
t-BuOH–H2O
t-BuOH–H2O
5
3
5
100
100
100
100
100
100
100
37
4
5
5
5
6
5
7
5
1.5
8
2.5
1.25
0.5
2.0
9
3.0
10
5.0
a All reactions were carried out on a 0.20 mmol scale of azide 3 and 1.2 equiv of alkyne 4.
b Determined by HPLC.
leased from the resin, whereas CuI leaching in t-BuOH or last entry in Table 2, using 0.5 mol%, which showed 37%
acetone is not allowed due to poor solubility of CuI. How- conversion in 5.0 hours.
ever, acetone–H2O (4:1) gave a mixture of products, in-
cluding small amounts of undesired 1,5-disubstituted
Subsequently, resin 2d was repeatedly used at two differ-
ent temperatures up to ten times to ensure reliable reus-
triazole. In addition, for quantitative detection of copper
ability.
leaching, each filtrate of entries 4 and 5 was analyzed by
After each reaction, resin 2d was recovered for the next
ICP-AES after dilution with 0.1 M HCl solution. Only
run by filtration, washing with acetone and THF, and dry-
negligible amount less than detection limit was observed.
ing under vacuum. As shown in Scheme 3, every run was
performed under the same reaction conditions, and
showed 100% conversion on average. Usually, solid cata-
We also repeated the reaction in t-BuOH–H2O (4:1) at two
elevated temperatures 60 °C and 80 °C to obtain further
information on the effect of reaction temperature and cat-
lyst may lose its inherent activity at high temperature due
alyst amount. Copper-free Huisgen 1,3-dipolar cycloaddi-
to physical damage or change to an inactive metal species,
tion has been usually performed at reflux temperature or
such as oxidation of Cu(I) to Cu(II). Interestingly, reitera-
tively used resin 2d, after the tenth run at 60 °C, main-
tained initial catalytic activity. It should be also noted that
after three months under air contact, 2d showed the same
100 °C for longer than overnight. However, the reaction
proceeded much faster and finished within 1.0 hour and
1.5 hours at 80 °C and 60 °C, respectively, when using 5
mol% of catalyst (entries 6 and 7 in Table 2). Less amount
of catalyst also performed sufficiently, allowing the reac-
tion to be completed within 3.0 hours at 60 °C, except the
catalytic performance, indicating significant air-stable.
The relative amount of Cu inside resin 2d before and after
the 10th run was analyzed using XRF (X-ray fluores-
N3
t-BuOH–H2O
N
MeO
N
N
3
MeO
5
10 recycles
4
Conditions
Average conversion (%)
2d (5 mol%)
r.t., 12 h
60 °C, 1.5 h
100
100
Scheme 3 Reusability of 2d in the click reaction. Reaction conditions were the same as entries 5 and 7 in Table 2, respectively.
Synlett 2008, No. 15, 2326–2330 © Thieme Stuttgart · New York

LETTER
Ionic Polymer Supported Copper(I)
2329
Table 3 Various Heterogeneous Click Reactionsa
R1
R2
2d (5 mol%)
R2
N
R1N3
+
t-BuOH–H2O (4:1)
r.t., 2.5–24 h
N
N
R1 N3
R2
Entry
1
Time (h)
2.5
Yield (%)b
N3
N3
99
99
2
3
3.0
O
O
N3
24.0
99
N
O
N3
N3
4
5
4.0
3.0
99
99
MeO
MeO
O
O
N3
6
24.0
85
N
MeO
O
N3
7
8
24.0
5.0
95
85
HO
HO
O
O
N3
O
O
N3
9
24.0
82
N
HO
O
O
AcO
10
11
24.0
24.0
94
91
O
AcO
AcO
N3
N3
AcO
AcO
AcO
AcO
O
O
O
AcO
AcO
12
24.0
36
AcO
AcO
N3
O
AcO
a All reactions were carried out on a 1.00 mmol scale of azide using 1.1 equiv of alkyne and 5 mol% of resin 2d in t-BuOH–H2O (4:1, 3 mL).
b Isolated yield.
cence) spectroscopy to determine the leaching degree af- or nanoparticle formation of the Cu, indicating that the in-
ter the 10th run. Figure 1 illustrates that most of the Cu herent catalyst capabilities of 2d are not changed during
catalyst remained inside the resin 2d, showing constant reiterate experiments.
catalytic activity. In addition, we obtained a TEM image
(see Supporting Information for picture) of 2d after the
10th run, revealing an absence of any visual aggregation
neous click reactions with a cross combination of four
After validation of 2d as a recyclable catalyst, we subse-
quently investigated its general applicability in heteroge-
Synlett 2008, No. 15, 2326–2330 © Thieme Stuttgart · New York

2330
U. Sirion et al.
LETTER
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
This work was supported by a Korea Science and Engineering
Foundation (KOSEF) grant funded by the Korean government
(MOST) (2007-02236) and Korea Health 21 R&D Project, Ministry
of Health & Welfare (A062254). High-resolution mass spectra,
ICP-AES, and XRF analysis were carried out at the Korea Basic
Science Institute.
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Figure 1 An XRF spectrum (Cu) before (blue line) and after (red
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azido compounds and three alkyne compounds (Table 3).
All reactions using 5 mol% of 2d at room temperature
successfully yielded the corresponding regioselective
product with a high yield after various periods of time
(2.5–24 hours). After each reaction was complete, the
polymer catalyst was collected by filtration with a plastic
syringe equipped with polyethylene frit and washed with
acetone and THF three times. Crude products were puri-
fied by column chromatography. We also found that the
rate of reactions trend to be slow in the case of polar sub-
stances. For instance, the reaction of glucosyl azide and
N-propargyl phthalimide was not complete within 24
hours and only 36% of triazole product was yielded (entry
12 in Table 3).
It is noteworthy that all twelve reactions were performed
using the same polymer catalyst 2d which was recovered
and reused from entry 1 to entry 12. To check whether the
used polymer catalyst 2d possessed the same catalytic ac-
tivity as in the first reaction, it was finally reused in the re-
action of benzyl azide and phenylacetylene (entry 1 in
Table 3) again after completion of all reactions. Gratify-
ingly, the same result was obtained.
In conclusion, we developed a novel ionic polymer sup-
ported Cu(I) catalyst possessing an OAc anion as a recy-
clable solid catalyst for click reactions. Robust
immobilization of CuI and constantly maintained catalyt-
ic activity of 2d was certified through ICP-AES, XRF
spectroscopic analysis, and reusability studies. Polymer
catalyst 2d was reused uneventfully without any bases in
twelve click reactions involving four azido and three
alkyne compounds in cross manner. Copper iodide immo-
bilized 2d is also remarkably stable under atmosphere.
We expect that it will be applicable to high-throughput
syntheses of triazole as well as other Cu(I)-catalyzed reac-
tions.
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Synlett 2008, No. 15, 2326–2330 © Thieme Stuttgart · New York