Amphiphilic self-assembled polymeric copper catalyst to parts per million levels: Click chemistry

Article abstract of DOI:10.1021/ja3036543

Self-assembly of copper sulfate and a poly(imidazole-acrylamide) amphiphile provided a highly active, reusable, globular, solid-phase catalyst for click chemistry. The self-assembled polymeric Cu catalyst was readily prepared from poly(N-isopropylacrylami

Full text of DOI:10.1021/ja3036543

Article
pubs.acs.org/JACS
Amphiphilic Self-Assembled Polymeric Copper Catalyst to Parts per
Million Levels: Click Chemistry
Yoichi M. A. Yamada,*,† Shaheen M. Sarkar,† and Yasuhiro Uozumi*,†,‡
†RIKEN Advanced Science Institute, Wako, Saitama 351-0198, Japan
‡Institute for Molecular Science, and the Graduate School for Advanced Studies, Okazaki, Aichi 444-8787, Japan
S
* Supporting Information
ABSTRACT: Self-assembly of copper sulfate and a poly-
(imidazole−acrylamide) amphiphile provided a highly active,
reusable, globular, solid-phase catalyst for click chemistry. The
self-assembled polymeric Cu catalyst was readily prepared
from poly(N-isopropylacrylamide-co-N-vinylimidazole) and
CuSO4 via coordinative convolution. The surface of the
catalyst was covered with globular particles tens of nanometers
in diameter, and those sheetlike composites were layered to
build an aggregated structure. Moreover, the imidazole units in the polymeric ligand coordinate to CuSO4 to give a self-
assembled, layered, polymeric copper complex. The insoluble amphiphilic polymeric imidazole Cu catalyst with even 4.5−45 mol
ppm drove the Huisgen 1,3-dipolar cycloaddition of a variety of alkynes and organic azides, including the three-component
cyclization of a variety of alkynes, organic halides, and sodium azide. The catalytic turnover number and frequency were up to
209000 and 6740 h−1, respectively. The catalyst was readily reused without loss of catalytic activity to give the corresponding
triazoles quantitatively.
poly(N-isopropylacrylamide-co-N-vinylimidazole) (1) and cop-
per sulfate (2) via a molecular convolution method.7
Incorporation of an aqueous solution of 2 into a chloroform
solution of 1 drove the self-assembly to provide a polymeric
copper composite 3 (Scheme 1). The resulting precipitate 3 was
INTRODUCTION
■
Copper metalloenzymes are supramolecular metal−organic
hybrids of imidazole-containing polypeptides and copper ions,
which are essential proteins in vital activity to promote high-
efficiency enzymatic reactions.1,2 Complexation of polymeric
imidazoles in histidine and copper species provides not only
Lewis acidic−Brϕnsted basic catalytic sites but also a supra-
molecular tertiary structure. Therefore, to go even further and
also ensure high catalytic activity, stability, and reusability, the
development of self-assembled polymeric imidazole-supported
copper catalysts is one of the most interesting topics in organic,
organometallic, and supramolecular chemistry.3−5
Scheme 1. Preparation of a Self-Assembled Polymeric
Imidazole−Cu Catalyst 3, a Photographic Image of 1 (left)
and 3 (right), and a SEM Image of 3 (center)
We envisaged that our concept for the preparation of
convoluted polymeric imidazole−metal catalysts would offer
high catalytic activities with reusability for click reactions:6
Amphiphilic polymeric imidazole units coordinate to Cu species
through the self-assembly to provide the supramolecular
polymeric metal composite with thermodynamic stability and
insolubility. Here, we report the development of a novel self-
assembled poly[(acrylamide−imidazole)−copper] catalyst. A
catalyst in amounts of 0.00045 mol % (4.5 mol ppm) to 0.25 mol
% promoted the Huisgen 1,3-dipolar cycloaddition of organic
azides and terminal alkynes efficiently with a TON of up to
>200000, and it was reused without loss of catalytic activity or
leaching of copper species.
barely soluble in water, tert-butanol, ethyl acetate, toluene, and
ether, whereas the starting polymer 1 was soluble in water,
methanol, chloroform, tetrahydrofuran, and N,N-dimethylfor-
RESULTS AND DISCUSSION
■
Preparation of a Self-Assembled Polymeric Imidazole-
Copper Catalyst. A novel self-assembled polymeric imidazole−
copper catalyst 3 was prepared from a linear amphiphilic polymer
Received: February 7, 2012
Published: May 15, 2012
© 2012 American Chemical Society
9285
dx.doi.org/10.1021/ja3036543 | J. Am. Chem. Soc. 2012, 134, 9285−9290

Journal of the American Chemical Society
Article
Figure 1. Images of 3 before and after use: SEM images of 3 before (a) and after use (e); HR-SEM images of 3 before (b) and after use (f); EDX/SEM
images of 3 before (c) and after use (g); XPS images of 3 before (d) and after use (h).
mamide. An SEM image showed that the composite 3 formed a
macroaggregated lump several hundreds of micrometers thick
(Figure 1). HR-SEM revealed that the surface of 3 was covered
with globular particles tens of nanometers in diameter and that
sheetlike composites were layered to build an aggregated
structure. EDX/SEM analysis of the sheetlike composites
showed the existence of copper and sulfur species. XPS analysis
of Cu 2p3/2 and S 2p3/2 showed peaks at 934.8 and 167.9 eV,
respectively; these are assigned to Cu(II) and S(IV) (CuSO4). A
UV−vis spectrum of 3 exhibited a new single absorption at 694
nm that was assigned as that of Cu-imidazole.8 These results
suggest that the imidazole units in 1 coordinate to CuSO4 to give
a self-assembled, layered, polymeric copper complex. Elemental
analysis and ICP-AES analysis of copper and sulfur supported the
structure of 3.
Huisgen 1.3-Dipolar Cycloaddition of a Self-As-
sembled Polymeric Imidazole-Copper Catalyst. The
amphiphilic polymeric imidazole−copper composite 3 was
used in an investigation of the Huisgen 1,3-dipolar cycloaddition
of organic azides and terminal alkynes (Table 1). A copper-
catalyzed Huisgen 1,3-dipolar cycloaddition of organic azides
and terminal alkynes, also known as a “click reaction”, has
become one of the most important reactions for the preparation
of 1,2,3-triazoles.9,10 High catalytic efficiency of immobilized
catalysts for click reactions is important in terms of sustainable
and process chemistries as well as in organic syntheses. There
have been some pioneering reports on click chemistry with
immobilized copper catalysts.3 Recently, Mizuno, Yus, Yama-
moto, and Santoyo-Gonzaleza developed heterogeneous Cu
catalysts for this reaction with TONs of 800, 198, 990, and 746,
respectively, as the highest TONs.4 The development of
heterogeneous immobilized polymeric metal catalysts11 with
high efficiencies and reusabilities for this purpose still remains a
major challenge.
Table 1. Huisgen 1,3-Dipolar Cycloaddition of Organic
Azides and Terminal Alkynes with 3
a
b
entry
4 (R1)
4a (Ph)
5 (R2)
5a (Ph)
6 yield (%)
1
6a 99
6a 99
6a 96
6a 99
6a 97
6b 97
6c 96
6d 97
6e 97
6f 94
6g 97
6h 96
6i 97
6j 97
6k 96
6l 96
6m 96
6n 96
6o 97
6p 95
6q 96
6r 98
6s 97
6t 97
6u 96
6v 96
c
2
4a
5a
d
3
4a
5a
e
4
4a
5a
f
5
4a
5a
6
4a
5b (4-NO2C6H4)
7
4a
5c (4-FC6H4)
8
4a
5d (4-MeC6H4)
9
4a
5e (4-MeOC6H4)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
4a
5f (2-naph)
4b (4-MeC6H4)
5a
4b
5g (PhCH2)
4b
5h (n-C9H19)
4c (HO-(CH2)4)
5a
5b
5c
5d
5e
5f
4c
4c
4c
4c
4c
4c
5g
5h
5a
5a
5a
5a
5a
4c
4d [c-(CH2)5C]OH
4e ((EtO)2CH)
4f (NMe2CH2)
4g (Cl-(CH2)3)
4h (n-C4H9)
a
When the cyclization of phenylacetylene (4a) and benzyl azide
(5a) was carried out with 3 (0.25 mol % Cu) in a t-BuOH/H2O
solution of sodium ascorbate (10 mol %) at 50 °C for 1.5 h, 3
drove the reaction smoothly to afford 1-benzyl-4-phenyl-1H-
1,2,3-triazole (6a) in 99% yield (entry 1). All the triazoles 6 were
isolated by crystallization. The color of the catalyst changed from
blue to green during the reaction. The catalyst was recovered by
Conditions: 4 (0.50 mmol), 5 (0.50 mmol), 3 (0.25 mol %), sodium
ascorbate (10 mol %), t-BuOH (0.5 mL), H2O (1.5 mL), 50 °C, 1.5 h.
b
c
d
e
Isolated yield by crystallization. First reuse. Second reuse. Third
f
reuse. Fourth reuse.
picking it up, and it was reused in the same reaction under similar
conditions without loss of catalytic activity (second use 99%,
9286
dx.doi.org/10.1021/ja3036543 | J. Am. Chem. Soc. 2012, 134, 9285−9290

Journal of the American Chemical Society
Article
third use 96%, fourth use 99%, fifth use 97%) (entries 2−5).
There was no leaching of Cu species in the reaction mixture in
cyclizations with the reused catalyst (ICP-AES analysis) (entry
5). A hot filtration test was conducted to prove that the insoluble
catalyst promotes the reaction under heterogeneous conditions
and that no copper species were released out in the reaction
mixture (Figure 2).12 SEM observations of fresh and reused 3
Table 2. Three-Component Cyclization of Alkyl Halides,
Sodium Azide, and Alkynes
a
b
entry
4 (R1)
4a (Ph)
7 (R2, X)
7a (Ph, Br)
6 yield (%)
1
6a 99
6a 99
6a 98
6a 97
6a 96
6a 97
6b 97
6b 94
6c 96
6d 98
6f 95
c
2
4a
7a (Ph, Br)
d
3
4a
7a (Ph, Br)
e
4
4a
7a (Ph, Br)
f
5
4a
7a (Ph, Br)
6
4a
7b (Ph, Cl)
7
4a
7c (4-NO2C6H4, Br)
8
4a
7d (4-NO2C6H4, Cl)
9
4a
7e (4-FC6H4, Br)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
4a
7f (4-MeC6H4, Br)
4a
7g (2-naph, Br)
Figure 2. Hot filtration test in the reaction of 4a and 5a. The reaction
mixture was filtered at 50 °C after 50 min, at which 3 and the
precipitated product 6a were readily removed. The resulting filtrate did
not promote the reaction.
4a
7h (CO2Et, Br)
6w 97
6x 97
6g 97
6y 94
6z 97
6aa 94
6bb 98
6cc 81
6dd 94
6ee 86
6ff 96
6j 96
4a
7i (trans-cinnamyl chloride)
4b (4-MeC6H4)
7a
7c
7f
4b
4b
indicated that the morphology of the catalyst was undamaged
and unchanged under the reaction conditions (Figure 1b, d, f, h).
EDX/SEM analysis showed that the sulfur peak disappeared
because Cu(II) was reduced by sodium ascorbate to a Cu(I)
species. The sulfate should be washed away, and the ascorbate
became the counterion of the Cu ions instead. In XPS analysis of
Cu 2p3/2 of the catalyst before and after use, peaks were observed
at 934.8 and 934.6 eV (Figure 1d and h).13 The UV−vis spectra
of 3 before and after use exhibited a similar single absorption at
694−6 nm that should be assigned as that of Cu-imidazole.
These results indicated that the catalyst 3 was intact and stable
under the reaction conditions.
4b
7g
7h
7c
7f
4b
4i (6-MeO-2-naph)
4i
4i
7g
7h
7a
7c
7d
7e
7f
4i
4c (HO-(CH2)4)
4c
6k 97
6k 96
6I 97
4c
4c
4c
6m 96
60 95
6gg 96
6gg 94
4c
7g
7a
7b
Electron-withdrawing- and electron-donating-group-substi-
tuted benzyl azides 5b−e and 2-naphthylmethyl azide (5f)
reacted efficiently with 4a under similar conditions to afford the
corresponding triazoles 6b−f in yields of 94−97% (entries 6−
10). The reactions of 4-tolylacetylene (4b) with benzyl azide
(5a) and with the alkyl azides 1-azido-2-phenylethane (5g) and
1-azidodecane (5h) led to complete conversion, giving the
cyclized products 6g−i in yields of 96−97% (entries 11−13). An
aliphatic alkynol, hex-5-yn-1-ol (4c), readily reacted with a
variety of benzylic and aliphatic azides 5a−h to give the
corresponding triazoles 6j−q in 95−97% yields (entries 14−21).
The Cu catalyst 3 also promoted the reaction of alkynes bearing
tertiary alcohol, acetal, amine, and chloro moieties (4d−g) and
an unmodified aliphatic compound 1-pentyne (4h) with 5a to
give the corresponding products 6r−v in 96−98% yields (entries
22−26). In these cyclization reactions, the alcohol, acetal, amine,
and chloro groups remained intact and did not affect the
reactivity.
Since 3 efficiently drove the click reaction of alkynes and
organic azides, the three-component cyclization of alkyl halides,
sodium azide, and alkynes was investigated (Table 2). The
reaction of phenylacetylene (4a), benzyl bromide (7a), and
sodium azide was carried out under similar conditions to those in
Table 1, affording the triazole 6a in 99% yield (entry 1). The
polymeric imidazole Cu catalyst 3 was reused four times without
loss of catalytic activity (entries 2−5). The reaction of benzyl
chloride (7b) was completed within 2.5 h to give 6a in 97% yield
4j (HO−CH2)
4j
a
Conditions: 4 (0.50 mmol), 7 (0.50 mmol), 3 (0.25 mol %), sodium
ascorbate (10 mol %), t-BuOH (0.5 mL), H2O (1.5 mL), 50 °C, 2.5 h.
b
c
d
e
Isolated yield by crystallization. First reuse. Second reuse. Third
f
reuse. Fourth reuse.
(entry 6). A variety of benzylic halides with substituents were also
converted to the corresponding triazoles 6b−d in yields of 94−
98% (entries 7−10). The catalyst 3 promoted the cyclization
with 2-naphthylmethyl bromide (7g), ethyl bromoacetate (7h),
and cinnamyl chloride (7i) to afford 95−97% yields of the
cyclized products 6f, 6w, and 6x (entries 11−13). All the
reactions of arylacetylenes, i.e., 4-tolylacetylene (4b) and 6-
methoxynaphthylacetylene (4i), and aliphatic alkynes, i.e., hex-5-
yn-1-ol (4c) and propargyl alcohol (4j), with a variety of halides
7a−h proceeded smoothly under similar conditions to those
above to give the corresponding triazoles 6g−gg in 81−98%
yields (entries 14−30). These results indicate that the catalytic
systems can be readily applied to the combinatorial synthesis of
triazole compounds.
The catalyst 3 was used to prepare functional materials, namely
a carbohydrate, a steroid, and a ligand (Scheme 2). The reaction
of an N-acetylglucosamine derivative bearing an azide moiety 5i
with 4a was performed with 3 under similar conditions to those
previously described to afford the triazole-linked N-acetylglucos-
9287
dx.doi.org/10.1021/ja3036543 | J. Am. Chem. Soc. 2012, 134, 9285−9290

Journal of the American Chemical Society
Article
frequency (TOF) of the catalyst reached 209000 and 6740 h−1,
respectively; these are, as far as we know, the highest TON and
TOF obtained for a heterogeneous-catalyst-promoted Huisgen
cycloaddition. This catalytic system was readily applied to the
reaction of alphatic substrates and reactants
Scheme 2. Application of 3 to the Synthesis of Functional
Materials
Moreover, ligand and metal effects for the Huisgen cyclo-
addition were evaluated (Scheme 4). Thus, the reaction of 4a and
Scheme 4. Comparison of the Catalytic Activity of Polymeric
Imidazole/Phosphine Cu/Pd Complexes
amine 6hh in 96% yield. Ethynylestradiol (4k) reacted with 5a to
give the triazole-linked estradiol 6ii in 96% yield. The
multicyclization of 7j with 4a led to the formation of a
tris(triazole) ligand 6jj in 95% yield.
To investigate the highest catalytic activity obtainable for the
cycloaddition, reactions with 4.5−45 mol ppm Cu were
performed (Scheme 3). 3 (45 mol ppm Cu) promoted the
reaction of 4a with 5a to give 6a in 95% yield. The three-
component reaction of 4a, 7a, and NaN3 in the presence of 45
mol ppm, based on Cu, of 3 gave 6a in 96% yield. We also found
that 4.5 mol ppm, based on Cu, of 3 drove the cyclization of 4a
and 5a to provide 6a in 94% yield. The TON and the turnover
5a with 3 (0.25 mol %) at 50 °C for 1.5 h gave 6a in 99% yield. In
c o n t r a s t , p o l y [ ( N - i s o p r o p y l a c r y l a m i d e - c o -
styryldiphenylphosphine)CuSO4] could not be prepared as an
insoluble composite but a soluble one. When the polymeric Pd
catalysts polym-Im-Pd and polym-P-Pd were used for the
reaction under similar conditions,6 no reactions took place.
These results indicated that the use of both the polymeric
imidazole ligand 1 and Cu species 2 in the catalytic composite
was important to prepare a highly active and insoluble catalyst for
the efficient Huisgen cycloaddition.
Scheme 3. Lower Catalytic Loadings (4.5−45 ppm) in the
Huisgen Reaction
Plausible Catalytic Pathway. The plausible reaction
pathway is as follows (Figure 3). The Cu(I) species reacts with
an alkyne to give a copper acetylide. The 1,3-dipolar cyclization
of the resulting Cu acetylide and an organic azide followed by the
protonation provided the formation of a triazole and the
regeneration of Cu(I) catalyst.14 To prove the formation of the
Cu acetylide from the catalyst 3 and the alkyne 4 in the presence
or absence of sodium ascorbate, the IR observation was
conducted (Figures S-1−3 of the Supporting Information).
Thus, the reaction of the catalyst 3 and 4a in the presence of
sodium ascorbate afforded a green-colored catalyst. Gratifyingly,
the vibrational absorption of CuCC in the heterogeneous
composite was observed at 1936 cm−1. In contrast, a similar
reaction in the absence of sodium ascorbate gave an unchanged
blue-colored catalyst where no peaks of CuCC were
observed. These results indicate that the heterogeneous Cu(II)
catalyst was reduced by sodium ascorbate to give the Cu(I)
catalyst. The resulting Cu(I) catalyst reacted with an alkyne 4a to
give the Cu acetylide.
9288
dx.doi.org/10.1021/ja3036543 | J. Am. Chem. Soc. 2012, 134, 9285−9290

Journal of the American Chemical Society
Article
layers were dried over MgSO4 and concentrated under reduced pressure
to give the corresponding 1,2,3-triazole 6. Purification of the obtained
triazole was accomplished by a recrystallization process (EtOAc/
hexane).
General Procedure for the Three-Component [3 + 2]
Cycloaddition Reaction. A 2.5-mL glass vessel was charged with 3
(3 mg, 0.25 mol %), sodium ascorbate (10 mg, 10 mol %), an alkyne 4
(0.5 mmol), sodium azide (0.5 mmol), and an alkyl halide 7 (0.5 mmol)
in water and tert-butyl alcohol (1.5/0.5 mL each). The reaction vessel
was shaken using a PetiSyzer (HiPep Laboratories, Japan) at 50 °C for
2.5 h, during which a colorless triazole was precipitated out. The reaction
mixture was diluted with water and EtOAc. The polymeric Cu catalyst 3
was recovered by picking-up with a pair of tweezers. The organic layer
was separated, and the aqueous layer was extracted with EtOAc (3 × 2
mL). The combined organic layers were dried over MgSO4 and
concentrated under reduced pressure to give the corresponding 1,2,3-
triazole 6. Purification of the obtained triazole was accomplished by a
recrystallization process (EtOAc/hexane).
Figure 3. Plausible reaction pathway of the Huisgen cycloaddtion.
ASSOCIATED CONTENT
* Supporting Information
Experimental details, compound data, and NMR charts. This
material is available free of charge via the Internet at http://pubs.
acs.org.
■
CONCLUSION
■
S
In conclusion, we developed a reusable metalloprotein-inspired
polymeric imidazole−copper catalyst, 3, that formed sheetlike
composites with globular polymeric particles. The catalyst 3
efficiently promoted the Huisgen 1,3-dipolar cycloaddition of a
variety of alkynes and organic azides, including the three-
component cyclization of a variety of alkynes, organic halides,
and sodium azide. The catalyst 3 provides the highest TON and
TOF so far obtained for a heterogeneous catalyst-promoted
Huisgen 1,3-dipolar cycloaddition.
AUTHOR INFORMATION
Corresponding Author
ymayamada@riken.jp; uo@ims.ac.jp
■
Notes
The authors declare no competing financial interest.
EXPERIMENTAL SECTION
■
ACKNOWLEDGMENTS
Preparation of Imidazole Polymer 1. A solution of N-
vinylimidazole (1 g, 10.62 mmol) and N-isopropylacrylamide (6.01 g,
53.13 mmol) in toluene (40 mL) was degassed for 30 min under Ar
atmosphere. AIBN (16.4 mg, 0.1 mmol) was added to the reaction
mixture, which was then degassed for a further 30 min under Ar
atmosphere. The solution was then heated at 70 °C for 12 h, during
which colorless powders were precipitated out. They were filtered off
through a glass filter and washed with toluene. The resulting colorless
solid was dried under reduced pressure to give 1 in 83% yield. 1H NMR
(CDCl3, 500 MHz): δ = 7.18−6.93 (m, 3 H), 4.12−3.81 (m, 5 H), 2.92
(m, 5 H), 2.09 (m, 5 H), 1.30−1.85 (m, 13 H), 1.12 (m, 30 H); 13C
NMR (CDCl3, 125 MHz) δ = 174.2, 129.7, 129.0, 128.2, 42.5, 41.3, 27.5,
22.6; IR (KBr) 3294, 2971, 2932, 2878, 1650, 1543, 1458, 1386, 1367,
1228, 1173, 1131, 1079, 915, 816, 667 cm−1; Anal. Calcd for
C35H61N7O5·2H2O: C, 60.40; H, 9.41; N, 14.09. Found: C, 60.73; H,
9.38; N, 13.55.
■
We thank the RIKEN ASI Advanced Technology Support
Division for elementary (Dr. Yoshio Sakaguchi), TEM (Ms.
Tomoka Kikitsu), XPS (Dr. Aiko Nakao), and ICP (Dr. Yoshio
Sakaguchi) analyses, respectively, and Ms. Aya Ohno (our team)
for measurement of SEM and EDS. We gratefully acknowledge
financial support from JSPS (Grant-in-Aid for Scientific Research
#20655035; Grant-in-Aid for Scientific Research on Innovative
Areas #2105) and RIKEN ASI (Fund for Seeds of Collaborative
Research). We also thank the CREST program.
REFERENCES
■
(1) Karlin, K. D.; Cruse, R. W.; Gultneh, Y.; Farooq, A.; Hayes, J. C.;
Zubieta, J. J. Am. Chem. Soc. 1987, 109, 2668.
(2) Sadava, D.; Hillis, D. M.; Heller, H. C.; Berenbaum, M. R. Life: The
Science of Biology: Evolution, Diversity, and Ecology; W H Freeman & Co.:
New York, 2009.
(3) (a) Coelho, A.; Diz, P.; Caamano, O.; Sotelo, E. Adv. Synth. Catal.
́
2010, 352, 1179. (b) Girard, C.; Onen, E.; Aufort, M.; Beauviere, S.;
Samson, E.; Herscovici, J. Org. Lett. 2006, 8, 1689. (c) Park, I. S.; Kwon,
M. S.; Kim, Y.; Lee, J. S.; Park, J. Org. Lett. 2008, 10, 497. (d) Lipshutz, B.
H.; Taft, B. R. Angew. Chem., Int. Ed. 2006, 45, 8235. (e) Chassaing, S.;
Sido, A. S. S.; Alix, A.; Kumarraja, M.; Pale, P.; Sommer, J. Chem.Eur. J.
2008, 14, 6713. (f) Chassaing, S.; Kumarraja, M.; Sido, A. S. S.; Pale, P.;
Sommer, J. Org. Lett. 2007, 9, 883. (g) Namitharan, K.; Kumarraja, M.;
Pitchumani, K. Chem.Eur. J. 2009, 15, 2755. (h) Wang, Y.; Liu, J.; Xia,
C. Adv. Synth. Catal. 2011, 353, 1534. (i) Liu, M.; Reiser, O. Org. Lett.
2011, 13, 1102.
(4) (a) Yamaguchi, K.; Oishi, T.; Katayama, T.; Mizuno, N. Chem.
Eur. J. 2009, 15, 10464. (b) Alonso, F.; Moglie, Y.; Radivoy, G.; Yus, M.
Adv. Synth. Catal. 2010, 352, 3208. (c) Jin, T.; Yan, M.; Menggenbateer;
Minato, T.; Bao, M.; Yamamoto, Y. Adv. Synth. Catal. 2011, 353, 3095.
Preparation of 3. To a solution of the imidazole polymer 1 (1 g,
1.51 mmol) in chloroform (10 mL) was slowly added an aqueous
solution of CuSO4·5H2O (2) (189.2 mg, 0.757 mmol; 10 mL) at 25 °C.
The resulting blue suspension was heated at 70 °C for 12 h before the
precipitates were filtered off through a glass filter. The precipitates were
filtered off, washed with chloroform and water on the glass filter, and
dried under reduced pressure to give 3 (950 mg, 80%). Anal. Calcd for
C105H183N21O19CuS·2H2O: C, 57.97; H, 8.66; N, 13.52; Cu, 2.92; S,
1.47. Found: C, 57.75; H, 8.59; N, 13.92; Cu, 2.66; S, 1.32. IR (KBr):
3303, 2971, 2940, 2873, 1645, 1537, 1457, 1387, 1367, 1234, 1172,
1131, 1037, 835, 667 cm−1.
General Procedure for the Two-Component [3 + 2] Cyclo-
addition Reaction. A 2.5-mL glass vessel was charged with 3 (3 mg,
0.25 mol %), sodium ascorbate (10 mg, 10 mol %), an alkyne 4 (0.5
mmol), and an organic azide 5 (0.5 mmol) in water and tert-butyl
alcohol (1.5/0.5 mL each). The reaction vessel was shaken using a
PetiSyzer (HiPep Laboratories, Japan) at 50 °C for 1.5 h, during which a
colorless triazole was precipitated out. The reaction mixture was diluted
with water and EtOAc. The Cu catalyst 3 was recovered by picking-up
with a pair of tweezers. The organic layer was separated, and the aqueous
layer was extracted with EtOAc (3 × 2 mL). The combined organic
̃
̈
(d) Megia-Fernandez, A.; Ortega-Munoz, M.; Lopez-Jaramillo, J.;
Hernandez-Mateo, F.; Santoyo-Gonzaleza, F. Adv. Synth. Catal. 2010,
352, 3306.
̃
9289
dx.doi.org/10.1021/ja3036543 | J. Am. Chem. Soc. 2012, 134, 9285−9290

Journal of the American Chemical Society
Article
(5) (a) Chen, W.; Boven, G.; Challa, G. Macromolecules 1991, 24, 3982.
(b) Zeitler, K.; Mager, I. Adv. Synth. Catal. 2007, 349, 1851. (c) Arai, T.;
Mizukami, T.; Yanagisawa, A. Org. Lett. 2007, 9, 1145. (d) Arai, T.;
Yokoyama, N.; Yanagisawa, A. Chem.Eur. J. 2008, 14, 2052.
(6) (a) Sarkar, S. M.; Uozumi, Y.; Yamada, Y. M. A. Angew. Chem., Int.
Ed. 2011, 50, 9437. (b) Yamada, Y. M. A.; Sarkar, S. M.; Uozumi, Y. J.
Am. Chem. Soc. 2012, 134, 3190.
(13) These peaks are both assigned as Cu(II) species. The resulting
Cu(I) catalytic species could be oxidized to Cu(II) under atmospheric
conditions.
(14) (a) Shao, C.; Cheng, G.; Su, D.; Xu, J.; Wang, X.; Hu, Y. Adv.
Synth. Catal. 2010, 352, 1587−1592. (b) Khairul, W. M.; Fox, M. A.;
Zaitseva, N. N.; Gaudio, M.; Yufit, D. S.; Skelton, B. W.; White, A. H.;
Howard, J. A. K.; Bruce, M. I.; Low, P. J. Dalton Trans. 2009, 610−620.
(7) (a) Yamada, Y. M. A. Chem. Pharm. Bull. 2005, 53, 723. For recent
examples, see: (b) Yamada, Y. M. A.; Uozumi, Y. Org. Lett. 2006, 8, 1375.
(c) Uozumi, Y.; Yamada, Y. M. A.; Beppu, T.; Fukuyama, N.; Ueno, M.;
Kitamori, T. J. Am. Chem. Soc. 2006, 128, 15994. (d) Yamada, Y. M. A.;
Maeda, Y.; Uozumi, Y. Org. Lett. 2006, 8, 4259. (e) Yamada, Y. M. A.;
Guo, H.; Uozumi, Y. Org. Lett. 2007, 9, 1501. (f) Yamada, Y. M. A.;
Uozumi, Y. Tetrahedron 2007, 63, 8492. (g) Yamada, Y. M. A.; Jin, C.;
Uozumi, Y. Org. Lett. 2010, 12, 4540. (h) Yamada, Y. M. A.; Watanabe,
T.; Torii, K.; Beppu, T.; Fukuyama, N.; Uozumi, U. Chem.Eur. J.
2010, 16, 11311. (i) Ohta, H.; Uozumi, Y.; Yamada, Y. M. A. Org. Lett.
2011, 13, 3892.
(8) (a) Sarkar, B.; Wigfield, Y. J. Biol. Chem. 1967, 242, 5572. (b) Peral,
F.; Gallego, E. J. Mol. Struct. 1997, 415, 187.
(9) (a) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002,
67, 3057. (b) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K.
B. Angew. Chem., Int. Ed. 2002, 41, 2596. (c) Huisgen, R. Angew. Chem.,
Int. Ed. 1963, 2, 565. (d) Kolb, H. C.; Finn, M. G.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2001, 40, 2004. (e) Bock, V. D.; Hiemstra, H.; van
Maarseveen, J. H. Eur. J. Org. Chem. 2006, 51. (f) Lutz, J.-F. Angew.
Chem., Int. Ed. 2007, 46, 1018.
(10) (a) Xiao, J. P.; Tolbert, T. J. Org. Lett. 2009, 11, 4144.
(b) Mohapatra, D. K.; Maity, P. K.; Shabab, M.; Khan, M. I. Bioorg. Med.
Chem. Lett. 2009, 19, 5241. (c) Pearson, D.; Downard, A. J.; Muscroft-
Taylor, A.; Abel, A. D. J. Am. Chem. Soc. 2007, 129, 14862. (d) Aragao-
̃
Leoneti, V.; Campo, V. L.; Gomes, A. S.; Field, R. A.; Carvalho, I.
Tetrahedron 2010, 66, 9475. (e) Iha, R. K.; Wooley, K. L.; Nystrcm, A.
M.; Burke, D. J.; Kade, M. J.; Hawker, C. J. Chem. Rev. 2009, 109, 5620.
(f) Xia, Y.; Li, W.; Qu, F.; Fan, Z.; Liu, X.; Berro, C.; Rauzy, E.; Peng, L.
Org. Biomol. Chem. 2007, 5, 1695. (g) Brik, A.; Wu, C. Y.; Wong, C. H.
Org. Biomol. Chem. 2006, 4, 1446. (h) Kolb, H. C.; Sharpless, K. B. Drug
Discovery Today 2003, 8, 1128. (i) Lee, S. M.; Chen, H.; O’Halloran, T.
V.; Nguyen, S. T. J. Am. Chem. Soc. 2009, 131, 9311. (j) Chernykh, A.;
Agag, T.; Ishida, H. Polymer 2009, 50, 382. (k) Li, B. L.; Liu, Z. T.; He, Y.
M.; Pan, J.; Fan, Q. H. Polymer 2008, 49, 1527. (l) Whittaker, M. R.;
Urbani, C. N.; Monteiro, M. J. J. Am. Chem. Soc. 2006, 128, 11360.
(m) Lutz, J.-F. Angew. Chem., Int. Ed. 2007, 46, 1018. (n) Sommer, S.;
Weikart, N. D.; Brockmeyer, A.; Janning, P.; Mootz, H. D. Angew. Chem.,
Int. Ed. 2011, 50, 9888. (o) Lallana, E.; Riguera, R.; Fernandez-Megia, E.
́
Angew. Chem., Int. Ed. 2011, 50, 8794. (p) Clave, G.; Campidelli, S.
Chem. Sci. 2011, 2, 1887. (q) Binder, W. H.; Sachsenhofer, R. Macromol.
Rapid Commun. 2007, 28, 15.
(11) For reviews on polymer-supported metal catalysts, see:
(a) Uozumi, Y.; Hayashi, T. Solid-Phase Palladium Catalysis for High-
throughput Organic Synthesis. In Handbook of Combinatorial Chemistry;
Nicolaou, K. C., Hanko, R., Hartwig, W., Eds.; Wiley-VCH: Weinheim,
2002. (b) Franzel, T.; Solodenko, W.; Kirschning, A. Solid-Phase Bound
Catalysts: Properties and Applications. In Polymeric Materials in Organic
Synthesis and Catalysis; Buchmeiser, M. R., Ed.; Wiley-VCH: Weinheim,
2003. (c) Uozumi, Y. Top. Curr. Chem. 2004, 242, 77. (d) Wennemers,
H. Combinatorial Methods for the Discovery of Catalysts. In Highlights
in Bioorganic Chemistry; Schmuck, C.; Wennemers, H., Eds.; Wiley-
VCH: Weinheim, 2004; p 436. (e) Wang, Z.; Chen, G.; Ding, K. Chem.
Rev. 2009, 109, 322. (f) Lu, J.; Toy, P. H. Chem. Rev. 2009, 109, 815.
(g) Baer, K.; Krausser, M.; Burda, E.; Hummel, W.; Berkessel, A.;
Groger, H. Angew. Chem., Int. Ed. 2009, 48, 9355. (h) Uozumi, Y.;
̈
Yamada, Y. M. A. Chem. Rec. 2009, 9, 51. (i) Lamblin, M.; Nassar-Hardy,
L.; Hierso, J.-C.; Fouquet, E.; Felpin, F.-X. Adv. Synth. Catal. 2010, 352,
33. (j) Yamada, Y. M. A.; Uozumi, Y. J. Synth. Org. Chem. Jpn. 2011, 69,
542.
(12) For a review, see: Phan, N. T. S.; Van Der Sluys, M.; Jones, C. W.
Adv. Synth. Catal. 2006, 348, 609.
9290
dx.doi.org/10.1021/ja3036543 | J. Am. Chem. Soc. 2012, 134, 9285−9290