A copper(I) isonitrile complex as a heterogeneous catalyst for azide-alkyne cycloaddition in water

Article abstract of DOI:10.1021/ol103134c

A structurally well-defined copper(I) isonitrile complex is shown to be an efficient, heterogeneous catalyst for the Huisgen azide-alkyne 1,3-dipolar cycloaddition under mild conditions in water. Notably, this catalyst can also be utilized in a three-component reaction of halides, sodium azide and alkynes to form 1,4-disubstituted 1,2,3-triazoles in high yields. Furthermore, it can be readily recovered by precipitation and filtration and recycled for at least five runs without significant loss of activity.(Figure Presented)

Full text of DOI:10.1021/ol103134c

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1102–1105
A Copper(I) Isonitrile Complex as a
Heterogeneous Catalyst for
Azide-Alkyne Cycloaddition in Water
Meina Liu and Oliver Reiser*
€
€
Institut fu€r Organische Chemie, Universitat Regensburg, Universitatsstr. 31,
93053 Regensburg, Germany
oliver.reiser@chemie.uni-regensburg.de
Received December 25, 2010
ABSTRACT
A structurally well-defined copper(I) isonitrile complex is shown to be an efficient, heterogeneous catalyst for the Huisgen azide-alkyne 1,3-
dipolar cycloaddition under mild conditions in water. Notably, this catalyst can also be utilized in a three-component reaction of halides, sodium
azide and alkynes to form 1,4-disubstituted 1,2,3-triazoles in high yields. Furthermore, it can be readily recovered by precipitation and filtration
and recycled for at least five runs without significant loss of activity.
Click chemistry is a chemical philosophy introduced by
Sharpless in 2001, emphasizing reactions that generate
substances quickly and reliably by joining small units
together.1 The copper(I)-catalyzed Huisgen [3 þ 2] dipolar
cycloaddition (CuAAC)2 between alkynes and azides has
arguably become the most popular ligation reaction that
has been widely applied in many areas such as polymer and
drug discovery, advanced material science, etc.3
in situ by reduction of Cu(II) salts,2b oxidation of Cu(0)
metal,4 or Cu(II)/Cu(0) comproportionation.5 Copper(I)
salts are less used because of their general thermodynamic
instablility,2c,6 with copper(I) iodide being a notable ex-
ception. The latter, however, requires the employment of
amines as additives.7 In recent studies, the CuAAC has
been proven to be accelerated by Cu(I) species supported
by nitrogen,8 sulfur,9 NHC,10 and polydentate ligands,11
since those serve both to protect the copper(I) center from
oxidation or dispropotionation and to enhanceits catalytic
activity. However, such supported copper(I) catalysts are
not always easily prepared. Moreover, reusability of cop-
per catalysts for the CuAAC is scarcely studied12 because
of the generally homogeneous nature of these catalysts,
Much attention has been paid to the development of
copper(I) catalytic systems for CuAAC reactions. Most
of the reported copper(I) catalytic species were prepared
(1) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
2001, 40, 2004.
(2) (a) Tornøe, C. W.; Meldal, M. Peptidotriazoles: Copper(I)-cata-
lyzed 1,3-dipolar cycloadditions on solid-phase. In Peptides: The Wave of
the Future; Lebl, M., Houghten, R. A., Eds.; American Peptide Society and
Kluwer Academic Publishers: San Diego, 2001; pp 263-264. (b) Rostovtsev,
V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed.
2002, 41, 2596. (c) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org.
Chem. 2002, 67, 3057.
(3) (a) Moses, J. E.; Moorhouse, A. D. Chem. Soc. Rev. 2007, 36,
1249. (b) Dondoni, A. Chem.;Asian J. 2007, 2, 700. (c) Lutz, J.-F.
Angew. Chem., Int. Ed. 2007, 46, 1018. (d) Meldal, M.; Tornøe, C. W.
Chem. Rev. 2008, 108, 2952.
(4) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman,
L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210.
(5) (a) Wang, Q.; Chittaboina, S.; Barnhill, H. N. Lett. Org. Chem.
2005, 2, 293. (b) Quader, S.; Boyd, S. E.; Jenkins, I. D.; Houston, T. A.
J. Org. Chem. 2007, 72, 1962.
(6) Aucagne, V.; Leigh, D. A. Org. Lett. 2006, 8, 4505.
(7) Lo1ber, S.; Rodriguez-Loaiza, P.; Gmeiner, P. Org. Lett. 2003, 5,
1753.
(8) (a) Rodionov, V. O.; Presolski, S. I.; Gardinier, S.; Lim, Y. H.;
Finn, M. G. J. Am. Chem. Soc. 2007, 129, 12696. (b) Rodionov, V. O.;
Presolski, S. I.; Diaz, D. D.; Fokin, V. V.; Finn, M. G. J. Am. Chem. Soc.
2007, 129, 12705. (c) Lewis, W. G.; Magallon, F. G.; Fokin, V. V.; Finn,
M. G. J. Am. Chem. Soc. 2004, 126, 9152. (d) Chan, T. R.; Hilgraf, R.;
Sharpless, K. B.; Fokin, V. V. Org. Lett. 2004, 6, 2853.
(9) Wang, W.; Hua, F.; Jiang, Y. Y.; Zhao, Y. F. Green Chem. 2008,
10, 452.
ꢀ
(10) Dıez-Gonzalez, S.; Nolan, S. P. Angew. Chem., Int. Ed. 2008, 47,
8881.
(11) Li, F. W.; Hor, T. S. A. Chem.;Eur. J. 2009, 15, 10585.
r
10.1021/ol103134c
Published on Web 02/10/2011
2011 American Chemical Society

Table 1. Solvent and Catalyst Optimization Studiesa
Scheme 1. Synthesis and X-ray Structure of 2a
entry
catalyst
solvent
yield (%)b
1
2
2
2
2
2
2
2
2
2
THF
H2O
85
98c
94
34
42
61
59
48
78
32
4
2c
3
H2O/t-BuOH (1:1)
i-PrOH
MeOH
DMF
4
5
6
7
acetone
DMSO
neat
8
9
10
11
12
13
14d
15e,f
CuCl
H2O
CuI
H2O
CuBr
H2O
15
22
50
95
CuCN
CuCl
H2O
H2O
[(CuOAc)2]n
H2O
a Color code: Cu, cyan; Cl, green; O, red; N, blue; C, grey.
a Reagents and reaction conditions: 3a (1.05 mmol), 4a (1.0 mmol),
and catalyst (5 mol %) in the given solvent was stirred at roomtemperature
for 1 h unless otherwise stated.b Isolated yields as an average of at least two
independent experiments. c Reaction time(10 min). d 50 mol % CuCl, 24 h.
e Taken from ref 19. f Reaction time (11 min).
which renders their recovery and recycling difficult. Con-
sidering the virtues of ligands and heterogeneous catalysts,
we set out to develop a practical, heterogeneous, ligand-
supported copper(I) catalyst without the need of immobi-
lization on a polymeric or an inorganic support.
aerobic Wacker oxidations15 and asymmetric transfer
hydrogenations.16 As part of our continued interest in
copper-catalyzed transformations and click chemistry,17
we describe here a readily prepared and structurally well-
defined copper(I) isonitrile complex 2, which exhibits
excellent activity to CuAAC reaction under mild reaction
conditions in water. Notably, 2 is heterogeneously
dispersed in most solvents and can therefore be readily
recovered and recycled without significant loss of activity.
The isonitrile ligand 1 was prepared following literature
procedures.18 Upon treatment of 1 with CuCl in THF, the
off-white complex 2 was obtained in 95% yield, being
stable in air or water for several months. Furthermore, 2 is
insoluble in water and common organic solvents such as
THF, ethanol, acetone, and ethyl acetate but soluble in
acetonitrile and DMF. Complex 2 was characterized by
NMR spectroscopy as well as X-ray crystallographic
analysis. The latter revealed (Scheme 1) that each Cu(I)
center is coordinated to an isonitrile ligand and possesses
three bridging chloride atoms that coordinate to another
Cu(I) center of the next entity. Hence the [CuLCl] units are
Isonitriles are recognized as valuable synthons in organ-
ic synthesis13 but have been less frequently applied as
ligands for metal catalysts, although they are known to
coordinate to a broad variety of transition metal com-
plexes.14 Owing to their electronic properties, being strong
σ-donor ligands comparable to N-heterocyclic carbenes,
the exploration of metal isonitrile complexes appears to
be promising. We recently reported chiral palladium-
and iron-bis(isonitrile) complexes as efficient catalyst for
ꢀ
(12) (a) Girard, C.; Onen, E.; Aufort, M.; Beauviere, S.; Samson, E.;
Herscovici, J. Org. Lett. 2006, 8, 1689. (b) Lipshutz, B. H.; Taft, B. R.
Angew. Chem., Int. Ed. 2006, 45, 8235. (c) Chassaing, S.; Kumarraja, M.;
Sani Souna Sido, A.; Pale, P.; Sommer, J. Org. Lett. 2007, 9, 883.
(13) (a) Ozaki, S. Chem. Rev. 1972, 72, 457. (b) Ito, Y. Pure Appl.
Chem. 1990, 62, 583. (c) Zhu, J. Eur. J. Org. Chem. 2003, 1133.
€
(d) Domling, A. Chem. Rev. 2006, 106, 17. (e) Gulevich, A. V.; Zhdanko,
A. G.; Orru, R. V. A.; Nenajdenko, V. G. Chem. Rev. 2010, 110, 5235.
(14) Representative examples: (a) Murakami, M.; Suginome, M.;
Fujimoto, K.; Nakamura, H.; Anderson, P. G.; Ito, Y. J. Am. Chem.
Soc. 1991, 113, 3987. (b) Nile, T. A.; Adams, K. P.; Joyce, J. A.; Patel,
A. I.; Reid, C. D.; Walters, J. M. J. Mol. Catal. 1985, 29, 201.
(c) Haiwara, T.; Taya, K.; Yamamoto, Y.; Yamazaki, H. J. Mol. Catal.
1989, 54, 165. (d) Trost, B. M.; Merlic, C. A. J. Am. Chem. Soc. 1990,
€
112, 9590. (e) Hahn, F. E.; Tamm, M.; Lugger., T. Angew. Chem., Int.
Ed. 1994, 33, 1356. (f) Suginome, M.; Nakamura, H.; Ito, Y. Tetrahedron
Lett. 1997, 38, 555. (g) Suginome, M.; Matsunaga, S.-i.; Iwanami, T.;
Matsumoto, A.; Ito, Y. Tetrahedron Lett. 1996, 37, 8887. (h) Braune, S.;
Kazmaier, U. J. Organomet. Chem. 2002, 641, 26. (i) Mancuso, J.;
Lautens, M. Org. Lett. 2003, 5, 1653. (j) Tanabiki, M.; Tscuchiya, K.;
Kumanomido, Y.; Matsubara, K.; Motoyama, Y.; Nagashima, H.
Organometallics 2004, 23, 3976. (k) Villemin, D.; Jullien, A.; Bar, N.
Tetrahedron Lett. 2007, 48, 4191. (l) Engelman, K. L.; White, P. S.;
Templeton, J. L. Organometallics 2010, 29, 4943.
ꢀ
(17) (a) Gissibl, A.; Padie, C.; Hager, C. M.; Jaroschik, F.; Rasappan,
R.; Cuevas-Yanz, E.; Turrin, C.-O.; Caminade, A.-M.; Majoral, J.-P.;
ꢁ
Reiser, O. Org. Lett. 2007, 9, 2895. (b) Fraile, J. M.; Perez, I.; Mayoral,
J. A.; Reiser, O. Adv. Synth. Catal. 2006, 348, 1680. (c) Werner, H.;
Herrerias, C. I.; Glos, M.; Gissibl, A.; Fraile, J. M.; Perez, I.; Mayoral,
J. A.; Reiser, O. Adv. Synth. Catal. 2006, 348, 125. (d) Rasappan, R.;
Olbrich, T.; Reiser, O. Adv. Synth. Catal. 2009, 351, 1961. (e) Gissibl, A.;
€
Finn, M. G.; Reiser, O. Org. Lett. 2005, 7, 2325. (f) Schatz, A.; Gras,
R. N.; Stark, W. J.; Reiser, O. Chem.;Eur. J. 2008, 14, 8262.
(18) (a) Hosseini-Sarvari, M.; Sharghi, H. J. Org. Chem. 2006, 71,
6652. (b) Kamijo, S.; Jin, T.; Yamamoto, Y. Angew. Chem., Int. Ed.
2002, 41, 1780.
(15) Naik, A.; Liu, M.; Zabel, M.; Reiser, O. Chem.;Eur. J. 2010, 16,
1624.
(16) Naik, A.; Maji, T.; Reiser, O. Chem. Commun. 2010, 46, 4475.
Org. Lett., Vol. 13, No. 5, 2011
1103

linked into an extended one-dimensional chain polymer,
contrasting an earlier report on copper(CNArMes2) (Mes =
2,4,6-Me3C6H2)19 for which a bridging dichloro dimer
rather than a one-dimensional chain structure was found.
Complex 2 was investigated in the CuAAC of benzyl
azide (4a) and phenylacetylene (3a). A first screening of
different solvents revealed exceptional activity of 2 in
water, giving rise to the cycloadduct 5a in virtually quanti-
tative yield within a reaction time of only 10 min. In
contrast, other copper(I) salts (CuI, CuCl, CuBr, CuCN)
gave far inferior results under the same conditions (Table
1, entries 10-14) with the exception of [(CuOAc)2]n (entry
15) that was recently reported to be a highly efficient
catalyst for this reaction as well.20
Table 4. Azide-Alkyne Cycloaddition Catalyzed with 2a
Table 2. CuAAC with Different Loading of Catalyst 2a
entry
2 (mol %)
time (min)
yield (%)b
1
2
3
5
10
30
5
98
91
94
0.5
2
a Reagents and reaction conditions: 3a (1.05 mmol), 4a (1.0 mmol),
and catalyst 2 (0.5-5 mol %), water. b Isolated yields after complete con-
version of the starting materials as an average of at least two independent
experiments.
Table 3. Recyclability Experimentsa
time
yield
(%)b
recovery of catalyst based
on the initial amount (%)
entry
run
(min)
1
2
3
4
5
1
2
3
4
5
10
10
10
10
10
98
96
96
97
93
92
83
72
62
50
a Reagents and reaction conditions: 3a (15.75 mmol), 4a (15.0 mmol),
and catalyst 2 (78 mg, 0.30 mmol, 2 mol %). b Isolated yields.
Having identified water as the best solvent for the reac-
tion, we next investigated catalyst loading and recyclability
for the title reaction (Table 2). Gratifyingly, upon lowering
the catalyst concentration to 0.5 mol % the reaction still
proceeded within 30 min in 91% yield (entry 2). A catalyst
a Reagents and reaction conditions: 3 (1.05 mmol), 4 (1.0 mmol), and
catalyst 2 (5 mg), water. b Isolated yields as an average of at least two
independent experiments.
(19) Fox, B. J.; Sun, Q. Y.; DiPasquale, A. G.; Fox, A. R.; Rheingold,
A. L.; Figueroa, J. S. Inorg. Chem. 2008, 47, 9010.
(20) Shao, C.; Cheng, G.; Su, D.; Xu, J.; Wang, X.; Hu, Y. Adv.
Synth. Catal. 2010, 352, 1587.
1104
Org. Lett., Vol. 13, No. 5, 2011

loading of 2 mol % appeared to be optimal with respect to
yield and short reaction times (entries 3).
high yields (Table 4, entries 1-17). A broad variety of
azides equipped with various functional moieties such as
alcohol, ketone, pyridine, nitrile, and fluoride was success-
fully employed. A dialkyne was also found to be a suitable
substrate to afford the triazole 5p (entry 16), which sug-
gests that catalyst 2 has potential for the synthesis of
bidentate ligands.
Inspired by the recent workof Hor et al.,11 we turnedour
attention toward the three-component (alkyl halide, so-
dium azide, and alkyne) azide-alkyne cycloaddition reac-
tion (Table 5). Catalyst 2 again performed well in water to
give the desired products (entries 1-11) in good to ex-
cellent isolated yields (84-97%).
In conclusion, the structurally well-defined copper(I)
isonitrile complex 2 was successfully synthesized and de-
veloped as a heterogeneous catalyst for the copper-cata-
lyzed azide-alkyne cycloaddition under mildconditionsin
water. This catalyst shows considerable synthetic advan-
tages in terms of facile and sustainable reaction setup
(aerobic conditions in water, no additives are necessary),
wide scope, and high reactivity. The catalyst 2 is also
efficient in the three-component (alkyl halide, sodium
azide, and alkyne) azide-alkyne cycloaddition. Further-
more, it can be readily recovered by filtration and recycled
for at least five runs without significant loss of activity.
The reason for the high activity that is conferred by the
isonitrile ligands for the CuAAC is under further investi-
gation by us. We reason, however, that these ligands are
similar in their electronic properties like nucleophilic
carbenes that have shown to give excellent results for the
title reaction.10
Starting with a catalyst loading of 2 mol %, the reaction
was performed through 5 cycles on a 15 mmol scale each
(Table 3). After each cycle the heterogeneous catalyst was
recovered by simple filtration and reused without further
purification. High yields (93-98%) were achieved at every
run, and after five runs 50% of the initial amount of 2 was
still recovered. We attribute the overall loss of the catalyst
to transfer operations between the filter and the reaction
flask.
Having optimized the reaction conditions, catalyst 2 was
applied to the cycloaddition reaction of electron-rich,
electron-poor, hindered, and dialkynes at room tempera-
ture in water to give the corresponding triazoles 5a-5q in
Table 5. Azide-Alkyne Cycloaddition Catalyzed with 2a
Acknowledgment. We gratefully acknowledge the
Fonds der Chemischen Industrie for funding.
a 3 (1.05 mmol), NaN3 (1.05 mmol), alkyl halide 6 (1.0 mmol), and
catalyst 2 (5 mg, 2 mol %). b Isolated yields as an average of at least two
independent experiments. c Alkyl halide = ethyl 2-iodoethanoate.
d Alkyl halide = benzyl chloride.
Supporting Information Available. Experimental pro-
cedures and spectral data for all compounds. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
Org. Lett., Vol. 13, No. 5, 2011
1105