Supported copper precatalysts for ligand-free, palladium-free Sonogashira coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2007.10.005

Copper(II) oxide and Cu metal, highly dispersed on inert oxides (silica, alumina), have been employed as precatalysts in ligand-free, palladium-free Sonogashira coupling reactions. Best results were obtained with highly dispersed Cu metal on alumina, whic

Full text of DOI:10.1016/j.tetlet.2007.10.005

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 8761–8764
Supported copper precatalysts for ligand-free, palladium-free
Sonogashira coupling reactions
a
b,
c
Andrea Biffis,a,* Elena Scattolin, Nicoletta Ravasio and Federica Zaccheria
*
a
`
Dipartimento di Scienze Chimiche, Universita di Padova, Via Marzolo 1, I-35131 Padova, Italy
bCNR-ISTM, Via Golgi 19, I-20133 Milano, Italy
`
Dipartimento di Chimica Inorganica, Metallorganica e Analitica, Universita di Milano, Via Venezian 21, I-20133 Milano, Italy
c
Received 30 July 2007; revised 25 September 2007; accepted 1 October 2007
Available online 5 October 2007
Abstract—Copper(II) oxide and Cu metal, highly dispersed on inert oxides (silica, alumina), have been employed as precatalysts in
ligand-free, palladium-free Sonogashira coupling reactions. Best results were obtained with highly dispersed Cu metal on alumina,
which exhibited high reactivity with aryl iodides. Electron-rich alkynes, in particular arylacetylenes, act as the most effective alkyne
substrates. The present catalytic system appears attractive in view of its ease of application and low cost, due to the use of a readily
available non-noble metal catalyst combined with the absence of ligands.
Ó 2007 Elsevier Ltd. All rights reserved.
Metal-catalyzed carbon–carbon and carbon–hetero-
atom cross-coupling reactions have nowadays become
one of the most important reaction classes in chemical
synthesis, having been developed to reach a very high
degree of synthetic usefulness.1 However, since most of
these reactions need a noble metal catalyst (albeit in
extremely low amount in some cases2), the cost of the
catalyst may become an issue for their technological
application. Therefore, a flourishing area of research is
the quest for catalysts made out of less noble metals,
which exhibit comparable catalytic efficiency.
much more interesting for economical reasons, related
both to the higher cost of palladium as well as to the dif-
ficulties in removing the metal (and its ligands) from the
reaction product. Indeed, it is a common industrial prac-
tice to avoid, whenever possible, the use of Pd catalysts
in the last steps of the synthesis of a complex molecule.
Although it was early recognized that copper(I) acety-
lides could effectively react with organic halides in a stoi-
chiometric fashion,11 only a limited number of copper-
based catalysts for the Sonogashira reaction has been
described up to now. Most reports deal with copper(I)
complexes containing phosphine ligands, which are
quite effective catalysts with aryl iodide substrates; how-
ever, such catalysts have to be employed in quite large
amounts (usually 10 mol %), which causes difficulties
in the subsequent purification of the reaction product
from the catalyst and especially from the phosphine
ligand.5 More recently, alternative nitrogen-containing
ligands,6 supported copper complexes,7 as well as
ligand-free copper nanoparticles8 have been described
as effective catalysts for this reaction. In this contribu-
tion, we wish to report on a novel class of solid, easy
to handle copper-based catalysts for ligand-free,
palladium-free Sonogashira coupling reactions.
Copper-based catalysts have been occasionally proposed
as an alternative to the more commonly employed palla-
dium-based catalysts for technologically relevant C–C
coupling reactions, such as Heck,3 Suzuki,4 and most
notably for Sonogashira couplings.5–8 The latter reac-
tion is routinely performed using a palladium-based
catalyst and a copper(I) salt as a cocatalyst.9 The role
of the copper cocatalyst is to form an intermediate
copper acetylide that subsequently transmetallates to
the palladium centre. In recent years, many different
copper-free, palladium-based catalytic systems have
been proposed for this reaction,10 but on the other hand
efficient palladium-free systems would obviously be
As previously shown by some of us, pre-reduced CuO/
SiO2 and CuO/Al2O3 materials with a copper loading
of 5–8% are very effective catalysts for a series of organic
*
Corresponding authors. Tel.: +39 049 8275216; fax: +39 049 8275223
(A.B.); tel.: +39 02 50314382; fax: +39 02 50313927 (N.R.); e-mail
addresses: andrea.biffis@unipd.it; n.ravasio@istm.cnr.it
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.005

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A. Biffis et al. / Tetrahedron Letters 48 (2007) 8761–8764
Cu
+
COCH3
I
H3COC
Scheme 1.
synthesis transformations.12 These two materials, both
in oxidized and reduced form,13, were therefore used
as catalyst in preliminary tests run on a standard Sono-
gashira reaction, namely the coupling of iodoacetophe-
none with phenylacetylene (Scheme 1).
made it clear that in the latter case 8 h of reaction is
already sufficient to reach 90% yield. The existence of
an induction period was also apparent from the sigmoi-
dal shape of the curve, which suggests that CuO/Al acts
in fact as a precatalyst generating the true catalytically
active species in situ (see below).
Using this test reaction, an optimization of the reaction
conditions for the silica-supported catalyst in oxidized
form was carried out. We started by investigating the
standard reaction conditions described in the works of
Venkantaraman and co-workers (toluene, 110 °C,
K2CO3 as the base)5c and of Rothenberg and co-workers
(DMF, 110 °C, tetrabutylammonium acetate, TBAA as
the base).8 The results are reported in Table 1.14
Catalyst CuO/Al was subsequently employed to per-
form a systematic evaluation of the generality of the
reaction with respect to the aryl halide, the alkyne and
the metal oxidation state. Reduction of the CuO phase
under mild experimental conditions (H2, 270 °C) leads
to well-formed Cu(0) crystallites very active in catalytic
reactions.12 Therefore, we also examined the activity of
the fully reduced material (Cu/Al) under the same exper-
imental conditions.
It is apparent from the reported results that the reaction
conditions employed by Rothenberg for copper nano-
particles turned out to be the best also in the case of
our catalysts. Using them, yields up to 48% could be
achieved, while only 17% yield was obtained under the
conditions of Venkantaraman et al. Quite remarkably,
using TBAA in toluene or K2CO3 in DMF no product
formation at all was observed, which highlights the
importance of choosing the right solvent/base pair for
this reaction. We also found that the nature of the cata-
lyst support had a marked influence on the reaction
outcome. Switching from silica to alumina significantly
increased the catalytic efficiency of the catalyst, allowing
to obtain an almost quantitative yield (entry 5). Further-
more, determination of the conversion curve (Fig. 1)
As can be derived from the results reported in Table 2,
the reaction appears to be limited to aryl iodides. Reac-
tions with aryl bromides or chlorides gave poor yields
(entries 4–7) with both catalysts, whereas deactivated
aryl iodides turned out to be much more active in the
presence of the pre-reduced Cu/Al (entries 8–11).
Remarkably, in no case we obtained evidence for the
formation of significant quantities of the alkyne head-
to-head homocoupling product (Hay coupling),15 that
was reportedly produced in substantial amounts using
other catalytic systems.6 Concerning the alkyne, best
results were obtained with phenylacetylene. Alkynes
with more electron-donating substituents gave lower
yields (entry 13) whereas no reaction was observed with
electron-poor alkynes such as ethyl propiolate (entry
14). Therefore, the scope of our supported copper
Table 1. Optimization of the reaction conditions
Catalyst
Solvent
Base
Yield (%)
1
2
3
4
5
CuO/Si
CuO/Si
CuO/Si
CuO/Si
CuO/Al
Toluene
Toluene
DMF
DMF
DMF
K2CO3
TBAA
TBAA
K2CO3
TBAA
17
0
48
0
Table 2. Sonogashira reactions with reduced and unreduced copper on
alumina catalysts
95
Catalyst Aryl halide
Alkyne
Yield
(%)
Reaction conditions: 1 equiv iodoacetophenone, 1.2 equiv phenyl-
1
2
3
4
5
6
7
8
9
CuO/Al Iodoacetophenone
Phenylacetylene
95
100
90
15
10
5
acetylene, 1 equiv base, 20 mol % Cu, 110 °C, 24 h.
Cu/Al
Cu/Ala
’’
’’
’’
’’
’’
’’
’’
’’
’’
CuO/Al Bromoacetophenone
Cu/Al ’’
CuO/Al Chloroacetophenone
Cu/Al ’’
CuO/Al Iodotoluene
Cu/Al
100
80
60
40
20
0
0
80
100
5
70
95b
50
0
10 CuO/Al Iodoanisole
11 Cu/Al ’’
12 CuO/Al Iodopentafluorobenzene ’’
13 CuO/Al Iodoacetophenone
14 CuO/Al ’’
’’
’’
1-Octyne
Ethyl propiolate
0
10
20
30
Reaction conditions: 1 equiv iodoacetophenone, 1.2 equiv alkyne,
1 equiv TBAA, 20 mol % Cu, DMF, 110 °C, 24 h.
a 10 mol % Cu.
b Isolated yield.
Time (h)
Figure 1.

A. Biffis et al. / Tetrahedron Letters 48 (2007) 8761–8764
8763
catalyst appears to be similar to that of most soluble
copper-based catalysts reported to date, whose applica-
tion is generally limited to aryl iodides and arylacetyl-
enes as substrates.
recovery, make this reaction attractive from the
synthetic point of view. We are currently aiming at opti-
mizing the catalytic performance with different electron-
rich alkynes as well as at extending the application of
catalysts of this kind to other coupling reactions.
In the case of activated iodoarenes such as iodoaceto-
phenone, it is possible to lower the amount of catalyst
to 10 mol % while maintaining a very high yield by using
the pre-reduced catalyst (entry 3). Remarkably, sup-
ported copper metal appears to be oxidized in the course
of the reaction (the color of the catalyst turns from dark
brown to yellow) even upon working with a carefully
deoxygenated solvent. This is in contrast with the obser-
vation of Rothenberg et al.,8 who claimed stability of
their copper nanocluster catalysts under reaction condi-
tions, and may indicate that the reaction mechanism is
similar both with oxidized and reduced catalyst.
References and notes
1. de Meijere, A. In Metal-Catalysed Cross-Coupling Reac-
tions; Diederichs, F., Ed., 2nd ed.; Wiley-VCH: Weinheim,
2004.
2. Farina, V. Adv. Synth. Catal. 2004, 346, 1553.
3. (a) Declerck, V.; Martinez, J.; Lamaty, F. Synlett 2006,
`
3029, and references cited therein; (b) Calo, V.; Nacci, A.;
Monopoli, A.; Ieva, E.; Cioffi, N. Org. Lett. 2005, 7,
617.
4. (a) Thathagar, M. B.; Beckers, J.; Rothenberg, G. J. Am.
Chem. Soc. 2002, 124, 11858; (b) Thathagar, M. B.;
Beckers, J.; Rothenberg, G. Adv. Synth. Catal. 2003, 345,
979.
5. (a) Okuro, K.; Furuune, M.; Enna, M.; Miura, M.;
Nomura, M. J. Org. Chem. 1993, 58, 4716; (b) Cacchi, S.;
Fabrizi, G.; Parisi, L. M. Org. Lett. 2003, 5, 3843; (c)
Saejueng, P.; Bates, C. G.; Venkantaraman, D. Synthesis
2005, 1706, and references cited therein.
6. (a) Ma, D.; Liu, F. Chem. Commun. 2004, 1934; (b) Deng,
C.-L.; Xie, Y.-X.; Yin, D.-L.; Li, J.-H. Synthesis 2006,
3370.
7. Zhang, L. Y.; Li, P. H.; Wang, L. Lett. Org. Chem. 2006,
3, 282.
8. Thathagar, M. B.; Beckers, J.; Rothenberg, G. Green
Chem. 2004, 6, 215.
9. Sonogashira, K. In Comprehensive Organic Synthesis;
Trost, B. M., Ed.; Pergamon Press: Oxford, 1999; Vol.
3, pp 521.
10. See for example (a) Bo¨hm, V. P. W.; Herrmann, W. A.
Eur. J. Org. Chem. 2000, 3679; (b) Ruiz, J.; Cutillas, N.;
Lopez, F.; Lopez, G.; Bautista, D. Organometallics 2006,
25, 5768; (c) Alonso, D. A.; Najera, C.; Pacheco, M. C.
Tetrahedron Lett. 2002, 43, 9365.
An unexpected activity of copper(0)-containing catalysts
has already been observed by some of us in the oxidative
coupling of 2,6-dimethylphenol.16 This reaction is
homogeneously catalyzed by a copper(II) complex
prepared by autooxidation of CuCl, but replacement
of cuprous chloride by the corresponding copper(II) salt
under the same conditions results in an inactive system,
indicating that the oxidation of CuCl must yield a prod-
uct, which cannot be described in the usual terms17 as
far as the oxidation state is concerned. In a similar
way, the CuO/Si catalyzed oxidative coupling takes
place only in the presence of the pre-reduced catalyst.16
The higher catalytic activity observed in Sonogashira
couplings when using the pre-reduced material may sug-
gest that also in this case interaction of the catalyst with
the substrate and other reactants triggers its evolution to
a more suitable configuration concerning both geometry
and oxidation state with respect to the unreduced cata-
lyst. Indeed, a heterogeneous catalyst containing almost
exclusively supported Cu(I) as isolated copper ions18
was found to exhibit poor activity, reaching as the best
result 18% yield in the coupling between iodoaceto-
phenone and phenylacetylene under the optimized reac-
tion conditions for the CuO-based catalysts.
11. Stephens, R. D.; Castro, C. E. J. Org. Chem. 1963, 28,
2163.
12. (a) Zaccheria, F.; Ravasio, N.; Fusi, A.; Psaro, R.
Tetrahedron Lett. 2005, 46, 3695; (b) Zaccheria, F.;
Ravasio, N.; Rodondi, M.; Fusi, A.; Psaro, R. Adv.
Synth. Catal. 2005, 347, 1267; (c) Zaccheria, F.; Ravasio,
N.; Fusi, A.; Psaro, R. Chem. Eur. J. 2006, 12, 6426; (d)
Ravasio, N.; Zaccheria, F.; Fusi, A.; Psaro, R. Appl.
Catal. A: Gen. 2006, 315, 114.
13. Catalyst preparation. The employed catalysts (8% w/w Cu)
were prepared as already reported12 starting from a
[Cu(NH3)4]2+ aqueous solution. Al2O3 (BET = 280 m2/g,
PV = 1.75 mL/g) and SiO2 (BET = 313 m2/g, PV =
1.79 mL/g) were kindly supplied by GRACE Davison
(Worms, Germany). The obtained catalyst on Al2O3 was
subsequently reduced at 270 °C with H2 (1 atm), removing
the formed water under reduced pressure.
14. General procedure for the catalytic tests. An oven-dried
Schlenk tube equipped with a magnetic stirring bar was
charged with 40 mg catalyst, heated under air for 15 min
at about 200 °C, and then under vacuum for another
15 min. After cooling to room temperature, 0.25 mmol of
aryl halide and 0.25 mmol of base were quickly added. The
tube was closed with a rubber septum, evacuated and filled
with argon. Alkyne (0.3 mmol) and solvent (3 mL) were
subsequently injected, and the tube was placed in an oil
bath preheated at 110 °C. The reaction mixture was stirred
The active catalytic species in the reaction investigated
in this work was found to be actually a soluble one,
released into solution from the supported catalyst. In
fact, separation of the heterogeneous catalyst by filtra-
tion at the reaction temperature after the first 2.5 h of
reaction pointed out that the reaction continued unal-
tered in the solution. Metal leaching at the end of the
reaction was found to amount to 62.7% of the total
copper present, determined by ICP-AAS spectroscopy.
Consequently, the catalyst was not reusable; however,
a simple filtration on Celite afforded a solution contain-
ing only the product, the eventual unreacted substrate
and the base.
Summarizing the results obtained in this work, we can
state that highy dispersed copper(II) oxide and, most
notably, Cu metal on alumina act as efficient precata-
lysts for Sonogashira coupling reactions of aryl iodides.
The use of a readily available non-noble metal catalyst
and the absence of ligands, allowing a simpler product

8764
A. Biffis et al. / Tetrahedron Letters 48 (2007) 8761–8764
at 110 °C for 24 h, after which it was cooled to room
16. (a) Boccuzzi, F.; Martra, G.; Partipilo Papalia, C.;
Ravasio, N. J. Catal. 1999, 184, 327; (b) Ercoli, M.; Fusi,
A.; Psaro, R.; Ravasio, N.; Zaccheria, F. J. Mol. Catal.
2003, 204–205, 729.
17. Finkbeiner, F. H.; Hay, A. S.; Blanchard, H. S.; Endres,
G. F. J. Org. Chem. 1966, 31, 549.
18. Gervasini, A.; Manzoli, M.; Martra, G.; Ravasio, N.;
Sordelli, L.; Zaccheria, F. J. Phys. Chem. B 2006, 110,
7851.
temperature and diluted with 5 mL dichloromethane. The
resulting suspension was filtered and the solvent was
removed under vacuum to give a brown solid. The
1
reaction yield was determined by H NMR spectroscopy.
In the case of iodopentafluorobenzene as reagent, the
product was isolated by flash chromatography (eluent: n-
hexane:diethylether 9:1).
15. Hay, A. S. J. Org. Chem. 1962, 27, 3320.