Ultrasound-promoted copper-catalyzed azide - alkyne cycloaddition

Full text of DOI:10.1021/cc900150d

J. Comb. Chem. 2010, 12, 13–15
13
MW14 in organic synthesis have been widely described.
Using both simultaneously may be beneficial to the rates,
yields, and selectivity of the reactions, as recent examples
show.15
Ultrasound-Promoted Copper-Catalyzed
Azide-Alkyne Cycloaddition
Giancarlo Cravotto,*,† Valery V. Fokin,‡ Davide Garella,†
Arianna Binello,† Luisa Boffa,† and Alessandro Barge†
Here we describe a process in which metallic copper
efficiently catalyzes azide-alkyne cycloadditions under US
or simultaneous US/MW irradiation. Reactions involving
metals represent the favorite domain of sonochemistry
because US favors mechanical depassivation and enhances
both mass transfer and electron transfer from the metal to
the organic acceptor.16 Although a piece of metal placed
inside a MW oven will lead to dangerous arcing, it is possible
to perform organic reaction using well-dispersed fine metal
particles in a polar high boiling solvent. This was first
demonstrated by Whittaker and Mingos, who opened the
doors to synthetic applications of metals under MW condi-
tions.17 Besides the particle size, other important safety
features are the following: (i) a moderate applied power (it
is directly related to the electric field strength, decreasing
the field strength decreases the risk of arcing, (ii) a low metal
loading, and (iii) an efficient stirring to disperse the metal
powder throughout the solvent. After several years of
experiments under simultaneous US/MW irradiation18 by
using every kind of solvents and solid catalysts, we can
emphasize that this hybrid treatment is probably the most
efficient technique to be applied to heterogeneous metal
catalysis to reduce any risk of arcing. Combined US/MW
irradiation in a single reaction vessel can be achieved inside
a modified MW oven by inserting in it a non-metallic horn
made of quartz, Pyrex, ceramic, or made from engineered
plastics, such as PEEK (poly(etherether ketone)) or PTFE
(poly(tetrafluoroethylene)).15 In a previous study, we found
that the charcoal-supported CuAAC were strongly promoted
by simultaneous US/MW irradiation, as well as by MW alone
(with slightly lower yields).9 In this study, we experimented
with the typical reaction of benzyl azide with phenylacetylene
using metallic copper (fine turnings or wires) or Cu2O as
catalysts. Figure 1 shows the typical setup for sonochemical
reaction and the general scheme of the reaction, while results
are summarized in Table 1.
Dipartimento di Scienza e Tecnologia del Farmaco,
UniVersita` di Torino, Via Giuria 9, 10125 Torino, Italy,
and Department of Chemistry, The Scripps Research
Institute, 10550 North Torrey Pines Road,
La Jolla, California 92037
ReceiVed September 26, 2009
The 1,3-dipolar cycloaddition reaction of azides and
alkynes has been known for over 100 years and was studied
extensively by Huisgen and co-workers in the 1960s.1 The
resurgence of recent interest in the reaction has been
stimulated by the discovery of the copper-catalyzed version
of this process, the copper-catalyzed azide-alkyne cycload-
dition (CuAAC).2 Copper catalysis increases the reaction rate
by up to 107 and results in regioselective formation of 1,4-
disubstituted triazoles. This reaction is generally recognized
as the most striking example of click chemistry.3 What makes
a click reaction so appealing is its application to label
molecules of interest in complex biological samples without
interferences with any other chemical functionalities.4 The
most common catalyst systems for CuAAC employ water
or alcohol solvents and use a Cu(II) salt in the presence of
a reducing agent (often sodium ascorbate or metallic copper)
to generate the required Cu(I) catalyst in situ. Cu(I)
complexes can also be used directly, although the reaction
often suffers from the formation of byproducts of red/ox
processes catalyzed by copper and requires the addition of
ligands to accelerate the cycloaddition.2
Microwave (MW) irradiation was efficiently applied to
accelerate the azide/alkyne click reaction.5 Catalytic activity
of metallic copper was established early on,6 and although
the reaction times were long, the final product was clean,
and the workup consisted of a simple removal of the copper
turnings. Copper clusters7 have also been employed as
precatalysts. Lipshutz et al. found that copper supported on
charcoal (Cu(II)/C) was an efficient catalyst;8 Cu(I)/C was
also successfully employed by Cintas et al. in MW-assisted
protocols.9 Ultrasound (US) has been used to promote the
CuAAC reaction as well. Sreedhar reported a sonochemical
CuI-catalyzed synthesis of triazoles from terminal alkynes
and alkyl/aryl azides, formed in situ.10 Worthy of mention
are the efficient applications of copper nanoparticles as
substitutes of bulk copper metal although their preparation
involves an additional step.11 We studied this reaction under
non-conventional conditions,9,12 namely, power US and MW,
alone or combined. The specific advantages of US13 and
* To whom correspondence should be addressed. E-mail:
giancarlo.cravotto@unito.it.
† Universita` di Torino.
Figure 1. General reaction scheme and setup for US-promoted
reaction.
‡ The Scripps Research Institute.
10.1021/cc900150d CCC: $40.75  2010 American Chemical Society
Published on Web 11/11/2009

14 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Reports
Table 1. Synthesis of 1,2,3-Triazole from Benzylazide and
Phenylacetylene (Dioxane/H2O 8:2, 70°C)
no.
catalyst
method
time (h)
yield (%)
1
2
3
4
oil bath
US
oil bath
oil bath
US
24
5
0.5
24
5
1a-4b
2a-2b
78
90
71
CuSO4/ ascorbic acid
Cu2O
Cu2O
5
6
7
Cu wires
Cu wires
oil bath
24
2
52
64
USc
8
9
10
11
12
13
14
Cu wires
US
oil bath
MW
2
12
2
1.5
2
1
85
76
39
89
25
95
85
Cu turnings
Cu turnings
Cu turnings
Cu turnings
Cu turnings
Cu turnings
US
USd
MW/US
MW/USe
1
a Isomer 1,4. b Isomer 1,5. c US 80W, without oil bath. d Depassi-
vated metal. e Reaction carried out under nitrogen.
Figure 2. General setup for simultaneous US/MW irradiation.
Table 2. Synthesis of 1,2,3-Triazole with Copper Turnings
In all cases the temperature was strictly controlled at 70
°C by two different measurement systems: an IR-pyrometer
and a thermocouple (under US), and an IR-pyrometer and
an optic-fiber thermometer (under combined US/MW).
The US irradiation19 was combined with oil bath heating
to reach the desired temperature. Because of the higher
contact surface, thin copper turnings gave better results than
common electrical wires. A portion of copper turnings was
depassivated by washing with HCl and then with abundant
distilled water. Entry 12 showed that its catalytic activity
dropped, a result that supports our hypothesis that Cu(I)
derives from the red/ox activated by sonication between the
copper metal and the copper oxide on the surface. We suspect
that oxygen dissolved in the solvent has certain effect on
this equilibrium; in fact the same reaction carried out in a
degassed solvent under nitrogen atmosphere gave a slightly
lower yield (entry 14 vs 13). Reactions under conventional
heating catalyzed by Cu2O powder gave excellent yields
(entry 4), while under US required longer reaction times and
gave somewhat lower yields (entry 5 vs 11). In the absence
of any catalyst, a mixture of 1,4- and 1,5-disubstituted
triazole isomers was obtained in 1-4% yield.
Preliminary results showed that an intense short sonication
(10 min, 50 W) of the copper turnings in the solvent mixture
sufficed to accelerate the reaction in comparison to mechan-
ical stirring and conventional heating. The reaction rate
increased further when US and MW irradiation was used
simultaneously. Figure 2 shows the reaction setup for
simultaneous US/MW irradiation in professional multimode
oven, with the Pirex horn into the reaction vessel and a fiber
optic thermometer to monitor the temperature.
no.
reagentsa
method
time(h)
yield(%)
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
31
32
33
34
A/B
oil bath
MW
US
MW/US
oil bath
MW
6
3
2
2
6
3
2
2
16
3
2
2
10
3
2
6
3
2
2
38
21
88
85
34
16
80
86
C/B
D/E
US
MW/US
oil bath
MW
88
41/37b
81c
83c
64
US
MW/US
oil bath
MW
MW/US
oil bath
MW
F/B
55
80
56
68
81
87
G/B
US
MW/US
a A ) 1-azidoctane; B ) phenylacetylene; C ) 1-azidoheptadecane;
D ) benzylazide; E ) 1,3-bis(propargyloxy)benzene; F ) 6-mono-
azido-ꢀ-CD; G ) 6-monoazido-permethyl-ꢀ-CD. b Ratio % mono- and
bis-triazole derivatives. c % bis-triazole.
Scheme 1. 6-Monoazido-ꢀ-CD Transformations (Entries
27-34)
The catalysis with metallic copper was applied to a
series of other substrates (Table 2), among which was the
6-monoazido-ꢀ-cyclodextrin (ꢀ-CD) both in the hydro-
philic native form as well as in the lipophilic permeth-
ylated derivative (Scheme 1). The reaction with 1,3-
bis(propargyloxy)benzene and excess benzylazide (entries
23-26) gave exclusively the monotriazole derivative in
oil bath (23), and the bis-adduct under US and US/MW
irradiation (25, 26). A mixture of both derivatives was
obtained under MW irradiation.
joined by Cu(II) ions in a sandwich-type complex. In this
metal-bridged complex, the CD secondary face which is
masked21 is a strong limitation for further applications. The
CD adducts from Cu(II)/sodium ascorbate catalyzed 1,3-
dipolar cycloaddition showed a typical green-grayish color
due to the complex with copper ions that require time-
consuming purifications by means of competitive chelants.
As reported in the literature, ꢀ-CD forms a stable copper
ion-CD inclusion complex20 in which the two CD tori are

Reports
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 15
(8) Lipshutz, B. H.; Taft, B. R. Angew. Chem., Int. Ed. 2006,
118, 8415–8418.
(9) Cintas, P.; Martina, K.; Robaldo, B.; Garella, D.; Boffa, L.;
Cravotto, G. Collect. Czech. Chem. Commun. 2007, 72, 1014–
1024.
Although we would expect a great influence of water in
radical formation under sonochemical conditions,22 the use
of copper metal as a catalyst in DMF at 100 °C was
extremely advantageous and provided very clean CD-triazole
derivatives as white powder.23 This was probably due to the
higher temperature and the better cavitation. The ICP-MS
analysis of the crude products obtained from reactions
catalyzed with metallic copper turnings, revealed only traces
of the metal in the range of 3-6 ppb.
In conclusion, a US or US/MW-enhanced, efficient and
sustainable metallic copper-catalyzed Huisgen 1,3-dipolar re-
gioselective cycloaddition of azides and alkynes has been
developed. This method could be applied to the production of
large libraries and combinatorial strategies; moreover, US and
MW can now be implemented in flow systems,24 which should
enable large-scale production. Recently click reactions have
been successfully conducted in a modular flow reactor.25
The reaction performs well in aqueous media, avoiding
any pretreatments and the addition of ligands or amines. The
use of copper turnings as a heterogeneous catalyst represents
a much cleaner approach for click reactions that may blossom
into a plethora of applications in pharmaceutical and com-
binatorial chemistry, as well as in biological systems.
(10) Sreedhar, B.; Surendra Reddy, P. Synth. Commun. 2007, 37,
805–812.
(11) (a) Sarkar, A.; Mukherjee, T.; Kapoor, S. J. Phys. Chem. C
2008, 112, 3334–3340. (b) Park, I. S.; Kwon, M. S.; Kim,
Y.; Lee, J. S.; Park, J. Org. Lett. 2008, 10, 497–500. (c)
Alonso, F.; Moglie, Y.; Radivoy, G.; Yus, M. Tetrahedron
Lett. 2009, 50, 2358–2362.
(12) Appukkuttan, P.; Dehaen, W.; Fokin, V. V.; Van der Eycken,
E. Org. Lett. 2004, 6, 4223–4225.
(13) Cravotto, G.; Cintas, P. Chem. Soc. ReV. 2006, 35, 180–196.
(14) Kappe, C. O., Dallinger, D.; Murphree, S. S. Practical
MicrowaVe Synthesis for Organic Chemists. Strategies, Instru-
ments, and Protocols; Wiley-VCH: Weinheim, Germany,
2009.
(15) (a) Cravotto, G.; Cintas, P. Chem.sEur. J. 2007, 13, 1902–
1909. (b) Cravotto, G.; Garella, D.; Calcio Gaudino, E.;
Le´veˆque, J.-M. Chemistry Today 2008, 26, 39–41.
(16) Cintas, P.; Luche, J.-L. Synthetic Organic Sonochemistry;
Luche, J.-L., Ed.; Plenum Press: New York, 1998; pp 167-
234.
(17) Whittaker, A. G.; Mingos, D. M. P. J. Chem. Soc., Dalton
Trans. 2000, 1521–1526.
(18) (a) Palmisano, G.; Bonrath, W.; Boffa, L.; Garella, D.; Barge,
A.; Cravotto, G. AdV. Synth. Catal. 2007, 349, 2338–2344.
(b) Cravotto, G.; Boffa, L.; Le´veˆque, J.-M.; Estager, J.;
Bonrath, W. Aust. J. Chem. 2007, 60, 946–950. (c) Wu, Z.-
L.; Ondruschka, B.; Cravotto, G. EnViron. Sci. Technol. 2008,
42 (21), 8083–8087. (d) Domini, C.; Vidal, L.; Cravotto, G.;
Canals, A. Ultrason. Sonochem. 2009, 16, 564–569.
(19) Sonication conditions. Probe equipped with a titanium horn
(frequency 21.4 kHz, power 25 W).
Acknowledgment. This work was supported by the
University of Turin and the Regione Piemonte (NanoIGT
Project, Converging Technologies 2007).
Supporting Information Available. Characterization data
(1H and 13C NMR, EI-MS, IR and MP) of new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(20) Klufers, P.; Piotrowski, H.; Uhlendorf, J. Chem.sEur. J. 1997,
3, 601–608.
(21) Fuchs, R.; Habermann, N.; Klu¨fers, P. Angew. Chem., Int.
Ed. Engl. 1993, 32, 852–854.
References and Notes
(22) Henglein, A. Ultrason. Sonochem. 1995, 2, 115–121.
(23) Typical Experimental Procedure. All reactions were carried
out in a 50 mL heavy walled pear-shaped two-neck flask with
non-standard taper outer joint. In all cases the temperature
was strictly monitored by two measurement systems: an IR
pyrometer and a thermocouple (under US) or an IR pyrometer
and an optical-fiber thermometer (under MW). The fine
turnings of metallic copper (50 mol %, 100 mol %, for entries
27-34) were suspended in a mixture of dioxane/H2O 8:2 or
in DMF (10 mL). The azido compound (1 mmol, if not
otherwise stated) and the acetylenic derivative (1.05 mmol,
5.0 mmol for entries 27-34) were added, and the mixture
was heated and/or irradiated with MW or MW/US as indicated
in the tables. The reaction outcome was monitored by TLC
or GC/MS until complete conversion of the starting material
was observed; then the copper was filtered off on paper filter.
After evaporation of the solvent under vacuum, the crude
product was purified by flash-chromatography. The residual
copper had a minimal loss of weight (5-7%) and can be
directly reused maintaining almost the same catalytic activity
for a couple of times.
(1) (a) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; Wiley: New York, 1984, pp 1-176. (b)
Padwa, A. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Ed.; Pergamon: Oxford, 1991; Vol. 4, pp 1069-1109.
(2) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem., Int. Ed. 2002, 41, 2596–2599. (b)
Tornoe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem.
2002, 67, 3057–3064.
(3) For reviews see: (a) Bock, V. D.; Hiemstra, H.; van Maarse-
veen, J. H. Eur. J. Org. Chem. 2005, 51–68. (b) Wang, Q.;
Chittaboina, S.; Barnhill, H. N. Lett. Org. Chem. 2005, 2, 293–
301. (c) Moses, J. E.; Moorhouse, A. D. Chem. Soc. ReV. 2007,
36, 1249–1262. (d) Wu, P.; Fokin, V. V. Aldrichimica Acta
2007, 40, 7–17. (e) Hein, C. D.; Liu, X.-M.; Wang, D. Pharm.
Res. 2008, 25, 2216–2230.
(4) Sletten, E. M.; Bertozzi, C. R. Angew. Chem., Int. Ed. 2009,
48, 6974–6998.
(5) (a) Munteanu, M.; Choi, S.; Ritter, H. Macromolecules 2008,
41, 9616–9623. (b) van Dijk, M.; Nollet, M. L.; Weijers, P. L.;
Dechesne, A. C.; van Nostrum, C. F.; Hennink, W. E.; Rijkers,
D. T. S.; Liskamp, R. M. J. Biomacromolecules 2008, 9, 2834–
2843. (c) Vecchi, A.; Melai, B.; Marra, A.; Chiappe, C.;
Dondoni, A. J. Org. Chem. 2008, 7316, 6437–6440.
(6) (a) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.;
Noodleman, L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem.
Soc. 2005, 127, 210–216. (b) Gommermann, N.; Gehrig, A.;
Knochel, P. Synlett 2005, 2796–2798.
(24) Cravotto, G.; Di Carlo, S.; Curini, M.; Tumiatti, V.; Roggero,
C. J. Chem. Tech. Biotech. 2007, 82, 205–208.
(25) Smith, C. D.; Baxendale, I. R.; Lanners, S.; Hayward, J. J.;
Smith, S. C.; Ley, S. V. Org. Biomol. Chem. 2007, 5,
1559–1561.
(7) Pacho`n, L. D.; van Maarseveen, J. H.; Rothenberg, G. AdV.
Synth. Catal. 2005, 347, 811–815.
CC900150D