Copper nanoparticles in click chemistry: an alternative catalytic system for the cycloaddition of terminal alkynes and azides

Article abstract of DOI:10.1016/j.tetlet.2009.02.220

Readily prepared copper nanoparticles have been found to effectively catalyse the 1,3-dipolar cycloaddition of a variety of azides and alkynes furnishing the corresponding 1,2,3-triazoles in excellent yields. Both the preparation of the nanoparticles and

Full text of DOI:10.1016/j.tetlet.2009.02.220

Tetrahedron Letters 50 (2009) 2358–2362
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper nanoparticles in click chemistry: an alternative catalytic system for
the cycloaddition of terminal alkynes and azides
Francisco Alonso a,*, Yanina Moglie a,b, Gabriel Radivoy , Miguel Yus
b
a,*
a
Departamento de Química Orgánica, Facultad de Ciencias, and Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
Departamento de Química, Instituto de Química del Sur (INQUISUR), Universidad Nacional del Sur, Avenida Alem 1253, 8000 Bahía Blanca, Argentina
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Readily prepared copper nanoparticles have been found to effectively catalyse the 1,3-dipolar cycloaddi-
tion of a variety of azides and alkynes furnishing the corresponding 1,2,3-triazoles in excellent yields.
Both the preparation of the nanoparticles and the click reaction proceed in short reaction times.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 9 January 2009
Revised 24 February 2009
Accepted 27 February 2009
Available online 5 March 2009
Keywords:
Click chemistry
Cycloaddition
Alkynes
Azides
Copper nanoparticles
Few reactions in organic chemistry have experienced the revival
and great splendour achieved by the Huisgen 1,3-dipolar cycload-
dition reaction of organic azides and alkynes1 in the dawn of the
some issues that should be addressed in order to further improve
the efficiency of the reaction and to fulfil the requirements of a
truly click reaction. For instance, reactions performed in some of
the common solvents used (e.g., water–alcohol solvent mixtures)
can be problematic especially for insoluble reagents or too soluble
products, thus reducing the application scope. Another aspect of
consideration is the reaction time, which, in general, is relatively
rather long if we take into account that many of the protocols need
2
1st century. The enormous attention recently gained by this reac-
2
tion began with the pivotal discovery by the groups of Meldal and
Sharpless, in which copper(I) catalysis was found to dramatically
3
accelerate the reaction under mild conditions at the same time that
a high regioselectivity was achieved towards the 1,4-regioisomer
4
11
of the triazole product. This powerful, highly reliable and selective
12–24 h for completion. The addition of some copper complexes
4
,12
reaction is the paradigm of a click reaction, as it meets the set of
stringent criteria required in click chemistry as defined by Sharp-
or ligands
was found to enhance the reaction rate, but it was
with the application of microwave chemistry (75–140 °C) that
5
4a,13
less et al. Consequently, this protocol has found increasing appli-
reaction times were dramatically reduced to less than 1 h.
4
b,6
4
cation in a variety of disciplines
such as organic chemistry,
New and interesting advances in the title reaction involve hetero-
7
14
drug discovery and medicinal chemistry, polymer and materials
geneous catalysis. Thus, copper(I) in charcoal showed to be an
8
7a,9
science, or bioconjugation.
efficient heterogeneous catalyst for the title reaction in the pres-
In spite of the fact that some copper-free azide-alkyne cycload-
dition strategies have been recently reported, the kinetics is rather
low and the regioselectivity unpredictable.10 Therefore, the cop-
per(I)-catalysed process is still the preferred choice. The sources
of copper(I) include: (a) copper(I) salts, normally in the presence
of a base and/or a ligand, (b) in-situ reduction of copper(II) salts
ence of triethylamine in dioxane at 60 °C, the reaction times being
1
4a
reduced to only 10–120 min.
Copper(I) in zeolite USY was re-
cently found to catalyse the cycloaddition reaction with a wide
substrate scope under ligand-free conditions in toluene (15 h,
1
4b
rt).
Since the discovery that copper metal (turnings or powder in
(
e.g., copper sulfate with sodium ascorbate) and (c) compropor-
stoichiometric quantity) can be a source of the catalytic species,15
an increasing attention has been devoted to the application of cop-
per nanoparticles (CuNPs) as substitutes of bulk copper metal in
order to reduce both the catalyst loading and the reaction times.16
Although the use of CuNPs has shown a general beneficial effect in
the cycloaddition of alkynes and azides, some arguments can cur-
tail the application, competitiveness and general acceptance of
tionation of copper(0) and copper(II), generally limited to special
applications (e.g., biological systems).4 The results obtained by
any of these methods are, in general, excellent. There are, however,
*
Corresponding authors. Fax: +34 965903549 (F.A.).
E-mail addresses: falonso@ua.es (F. Alonso), yus@ua.es (M. Yus).
0
040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.220

F. Alonso et al. / Tetrahedron Letters 50 (2009) 2358–2362
2359
some of these methods, namely: (a) rather tedious CuNPs prepara-
tion due to the multiple steps, long time, high temperatures or use
of non-commercially available reagents; (b) presence of stabilising
agents or solid supports to prevent nanoparticle agglomeration
during the cycloaddition reaction; (c) presence of an additive to
create an acidic medium that induces copper dissolution; (d) lim-
ited substrate scope or (e) insufficient high yields that require
chromatographic purification. Although the reaction times have
been considerably reduced in some cases, they are still relatively
nanoparticles in THF which, in the presence of triethylamine at
65 °C, allows the fast and high yielding 1,3-dipolar cycloaddition
of terminal alkynes and azides.
The CuNPs suspension was instantaneously generated by mix-
ing copper(II) chloride, lithium metal and a catalytic amount of
1
8
DTBB (10 mol %) in THF at room temperature. The CuNPs were
characterised by transmission electron microscopy (TEM), X-ray
photoelectron spectroscopy (XPS) and X-ray powder diffraction
(XRD). Droplets of this suspension analysed by TEM showed
well-defined spherical nanoparticles with a particle size distribu-
tion of ca. 3.0 ± 1.5 nm (Fig. 1). Energy-dispersive X-ray (EDX) anal-
ysis on various regions confirmed the presence of copper, with
energy bands of 8.04, 8.90 keV (K lines) and 0.92 keV (L line) (Sup-
plementary data). The XPS spectrum showed a single Cu 2p3/2 peak
at 932.9 eV, which despite the close proximity of the binding ener-
gies for the Cu(0), Cu(I) and Cu(II) states, it was clearly different
from that obtained for a sample exposed to air during prolonged
time (Supplementary data). The XRD spectrum and selected area
electron diffraction (SAED) pattern were in agreement with the
presence primarily of metallic copper (Supplementary data), albeit
1
6a–d,f
long (2–18 h).
It is noteworthy that the PVP-stabilised CuNPs
reached high product yields for benzyl and aryl azides in very short
reaction times (15–50 min) using formamide as the solvent at
1
6e
room temperature.
On the other hand, and due to our ongoing interest on active
1
7a
metals,
we reported that active copper, generated from cop-
per(II) chloride dihydrate, lithium metal and a catalytic amount
0
of 4,4 -di-tert-butylbiphenyl (DTBB) in THF, was successfully ap-
1
7b
plied to the reduction of carbonyl compounds and imines,
sulfo-
1
7c
nates,
room temperature.
and to the hydrodehalogenation of organic halides, all at
1
7d
We have recently discovered that, under
the above conditions or in the case of using anhydrous copper(II)
chloride, copper nanoparticles are formed. We wish to present
herein a catalytic system composed of readily generated copper
the formation of copper oxides (especially Cu
during the sample handling cannot be ruled out.
Benzyl azide (1a) and cyclohexylacetylene (2a) were used as
model substrates in order to optimise the reaction conditions (Ta-
ble 1). Two blank experiments carried out in the absence of Cu but
under the conditions of generation of the CuNPs (with or without
2
O) on the surface
3 3
Et N) led to the starting 1a and 2a. The presence of Et N was
shown to be indispensable for the reaction to take place (Table 1,
entry 1). The CuNPs in stoichiometric amounts were shown to be
Table 1
Copper-catalysed 1,3-dipolar cycloaddition of benzyl azide and cyclohexylacetylenea
N
N
N
catalyst
Ph
N3
+
Ph
conditions
1a
3
aa
2a
Entry
Catalyst (mol %)
Additive (mmol)
none
T (°C)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
CuNPs (100)
CuNPs (100)
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
65
25
65
65
65
12
1
2
2
2
2
3
3
6
0
98
0
0
0
Et
Et
Et
Et
Et
Et
3
3
3
3
3
3
N (1)
N (1)
N (1)
N (1)
N (1)
N (1)
c
Cu (100)
2
1
1
1
1
1
0
8
6
4
2
0
8
6
4
2
0
CuO (100)
Cu
CuCl
2
O (100)
(100)
2
0
CuCl (100)
CuNPs (100)
CuNPs (20)
CuNPs (10)
CuNPs (5)
CuNPs (2)
CuNPs (1)
CuNPs (10)
CuNPs (10)
CuNPs (10)
CuCl (10)
85d
58
98
98
98
100
100
99
99
100
70
80
75
71
N (1)e
PVP/Et
3
Et
3
Et
3
Et
3
Et
3
Et
3
Et
3
Et
3
Et
3
Et
3
Et
3
Et
3
Et
3
N (1)
N (1)
N (1)
N (1)
N (1)
N (3)
N (2)
N (1)
N (1)
N (1)
N (1)
10
11
12
13
14
15
16
6
24
24
24
0.5
0.5
0.5
24
24
24
24
17
18
CuCl (10)
CuNPs (10)
CuNPs (10)
f
19
20
N (1)g
a
1a (1 mmol) and 2a (1 mmol) in THF.
b
c
d
e
f
GLC yield.
Cu powder (1–5 lm).
Multiple side products were detected.
0
.5 1.0 1.5 2.0 2.5 3.0
3.5 4.0 4.5 5.0 5.5 6.0
diameter (nm)
1
g PVP [poly(1-vinylpyrrolidin-2-one), MW ꢀ 29000].
Figure 1. TEM micrograph and size distribution of the CuNPs. The sizes were
determined for 230 nanoparticles selected at random.
2
Reaction in t-BuOH/H O 1:2.
g
Reaction under air.

2
360
F. Alonso et al. / Tetrahedron Letters 50 (2009) 2358–2362
Table 2
1
,3-Dipolar cycloaddition of azides and alkynes catalysed by CuNPsa
N
1
0 mol% CuNPs
N
R1 N3
R2
R1
N
+
Et N, THF, 65 °C
R2
3
1
2
3
Entry
1
Azide
Alkyne
Time (min)
30
Triazole
Yieldb (%)
N
N
N
Ph
N3 1a
2a
95c
3aa
Ph
N
N
N
N
N
N
2
3
1a
1a
2b
2c
10
10
3ab
3ac
98
5
Ph
Ph
5
98c
Ph
Ph
N
N
N
N
Ph
90d
4
1a
2d
10
N
N
3ad
Ph
Ph
Ph
5
6
1a
1a
2e
2f
30
30
3ae
3af
97c
97c
N
N
OH
N
OH
Ph
Ph
N
N
N
N
N
7
8
Ph–N
3
1b
2a
2c
30
10
3ba
3bc
94
98
N
N
1b
Ph
Ph
Ph
N
N
Ph
9
1b
2g
2c
2c
2c
10
30
30
10
3bg
3cc
3dc
3ec
98
87
88d
97
N3
N
N
1
1
1
0
1
2
1c
Ph
Ph
Ph
N
Ph
N
N
1d
N
EtO C
N3
2
EtO C
Ph
2
N
N
N
1e
Ph
N3
Ph
Ph
a
3
Reaction conditions: 1 (1 mmol), 2 (1 mmol), CuNPs (10 mol %), Et N (1 mmol) in THF at 65 °C.
Isolated yield after crystallisation from Et O.
2
Isolated yield after filtration and solvent evaporation.
Isolated yield after column chromatography.
b
c
d

F. Alonso et al. / Tetrahedron Letters 50 (2009) 2358–2362
2361
superior to other sources of copper, leading to 3aa in the highest
yield and shortest reaction time (Table 1, entries 2–8). The product
yields were also excellent by decreasing the amount of CuNPs up to
tion with Cu(I) on the nanoparticle surface. We have carried out a
series of experiments that demonstrate that dissolution of CuNPs
3 3
did not occur in the absence of Et N and that Et N itself have no
1
mol %, albeit longer reaction times were required (Table 1, en-
capability of dissolution over the CuNPs. In the presence of Et N
3
tries 9–13). It is noteworthy that the addition of >1 equiv Et
3
N
and phenylacetylene but in the absence of an azide, however, the
CuNPs suspension was transformed into a yellow precipitate and
a colourless supernatant. This yellow precipitate could be attrib-
uted to Cu(I) phenylacetylide, which proves that the correspond-
ing copper(I) acetylides are the real intermediate species in the
reactions reported herein.
shortened the reaction time to only 30 min at 25 °C maintaining
an excellent yield (Table 1, entries 14 and 15). This reduction in
time, however, was not generally observed for some other sub-
strates tested at 25 °C but it was at 65 °C, in the case of 1a and
2
2
2
a with the same result (Table 1, entry 16). CuCl, under the above
conditions, or CuNPs in the solvent mixture t-BuOH/H O 1:2 or un-
der air, led to lower product yields and much longer reaction times
Table 1, entries 17–20). Therefore, the reaction conditions in entry
6 were considered the most appropriate in order to have a meth-
2
In conclusion, we have introduced a catalytic system, based on
CuNPs, that effectively catalyses the 1,3-dipolar cycloaddition of
azides and terminal alkynes. The CuNPs are quickly prepared from
commercially available reagents under mild conditions in the ab-
sence of any stabilising additive or support. We believe that the
herein described methodology fulfils the requirements of a truly
click reaction, namely: a) wide in scope, b) simple reaction condi-
tions, c) readily available starting materials and reagents, d) easily
removed solvent and e) simple removal of by-products and prod-
uct isolation. In view of the results presented above, we also be-
lieve that this is one of the fastest procedures ever reported for
the title reaction, comparable to some microwave-based method-
ologies, but involving milder conditions (65 vs 75–140 °C) and
without the inherent limitations of microwave chemistry (e.g.,
generally restricted to small-scale reactions). Further research to
extend the substrate scope and on the reaction mechanism is
underway and will be reported in due course.
(
1
od of more general application maintaining the short reaction time.
The optimised reaction conditions were successfully applied to
a variety of terminal alkynes and azides (Table 2).19 Benzyl azide,
phenyl azide, cyclohexyl azide, ethyl 2-azidoacetate and cinnamyl
azide were combined with several terminal alkynes bearing alkyl,
cycloalkyl, phenyl, alkenyl or hydroxyalkyl substituents. All reac-
tions were highly regioselective towards the 1,4-disubstituted tri-
azoles and were completed in 10–30 min. Furthermore, the
corresponding 1,2,3-triazoles were obtained in excellent isolated
yields, generally, after simple work-up involving filtration and
crystallisation or solvent evaporation. We checked some of the
1
0-min reactions and observed that they really proceeded almost
instantaneously (during the first minute), though a standard time
of 10 min has been given. It is worthwhile mentioning that, under
the reaction conditions, cinnamyl azide did not undergo a [3,3]-sig-
Acknowledgements
2
0
matropic rearrangement leading to the secondary allylic azide,
since compound 3ec was the only detected product (Table 2, entry
2). Moreover, this methodology exhibited the same efficiency for
This work was generously supported by the Spanish Ministerio
de Educación y Ciencia (MEC; grant no. CTQ2007-65218 and Con-
solider Ingenio 2010-CSD2007-00006). Y. M. thanks the Secretaría
General de Ciencia y Tecnología (SeCyT) of the Universidad Nacion-
al del Sur, and the Vicerrectorado de Investigación, Desarrollo e
Innovación of the University of Alicante for a grant.
1
more complex substrates such as 17-ethynyloestradiol (2h), which
by reaction with benzyl azide, under the standard conditions, fur-
nished the corresponding triazole-substituted steroid derivative in
practically quantitative yield after 30 min (Scheme 1).
Unfortunately, the CuNPs could not be reused due to the homo-
geneous nature of the resulting mixture (colourless solution) at the
end of the reaction. The reaction mechanism in the alkyne-azide
cycloaddition catalysed by copper nanoparticles is not well under-
Supplementary data
1
6
Experimental procedures as well as the characterisation of the
copper nanoparticles (TEM, XPS, XRD) and new compounds are
available. Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2009.02.220.
stood. The formation of copper(I) acetylide is generally invoked
(
but not demonstrated) by dissolution of Cu(0) to Cu(I) or by reac-
HO
References and notes
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1.
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H
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2h
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4.
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1
0 mol% CuNPs, 1a
2
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Et N, THF
6
3
5
.
.
5 °C, 30 min
2
6
1
N
N
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HO
N
Ph
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9
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1
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Int. Ed. 2008, 47, 2182–2184.

2
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and DTBB (27 mg, 0.1 mmol) in THF (2 mL) at room temperature under argon.
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diluted with more THF (8 mL).
1
1
19. General procedure for the CuNPs-catalysed 1,3-dipolar cycloaddition of azides and
3
alkynes: Et N (1 equiv), azide (1 equiv) and alkyne (1 equiv) were added over
10 mol % of the CuNPs suspension in THF under argon. The reaction mixture
was warmed up to 65 °C and monitored by TLC until total conversion of the
starting materials. The resulting solution was passed through a pad of Celite or
alternatively subjected to aqueous work-up and extraction with EtOAc. The
2
092.
organic phase was dried over MgSO
the corresponding triazole which was pure enough or was purified by
crystallisation (Et O) or column 2chromatography (hexane/EtOAc) (see
footnotes in Table 2). Triazoles 3ab,
4
and the solvent removed in vacuo to give
1
1
1
4. (a) Lipshutz, B. H.; Taft, B. R. Angew. Chem., Int. Ed. 2006, 45, 8235–8238; (b)
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2
1a
21a
16f
21a
21a
21b
3ac,
3ae,
3af,
3bc,
3bg,
3dc,2 and 3ec,
1c
21c
were characterised by comparison of their physical and
spectroscopic data with those described in the literature.1-Benzyl-4-cyclohexyl-
1H-1,2,3-triazole (3aa): white solid; mp 110.2–112.0 °C; IR (KBr) 3118, 2918,
ꢁ
1
1
6. (a) Durán Pachón, L.; van Maarseveen, J. H.; Rothenberg, G. Adv. Synth. Catal.
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10H); 13C NMR (100 MHz, CDCl
) d 154.1, 134.9, 129.0, 128.5, 127.8, 119.1,
3
; H NMR (400 MHz, CDCl ) d
2
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3
19 3
53.9, 35.3, 32.9, 26.1, 25.9; HRMS (EI) calcd for C15H N 241.1579, found
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3