Ligand-free Stille cross-coupling reaction using Pd/CaCO3 as catalyst reservoir

Article abstract of DOI:10.1016/j.tetlet.2007.08.091

Stille reactions between halobenzenes and other substituted (hetero)arenes and tributylphenyltin were carried out in ethanol-water solution using Pd/CaCO₃ as catalyst in a ligand-free system. The catalyst could be recycled three times without any loss of activity. The ethanol-water solution, after removal of the catalyst and extraction of the product, was found to have catalytic activity, thus showing the presence of soluble Pd(0)/Pd(II) species that can be regarded as the true catalysts.

Full text of DOI:10.1016/j.tetlet.2007.08.091

Tetrahedron Letters 48 (2007) 7671–7674
Ligand-free Stille cross-coupling reaction using Pd/CaCO3
as catalyst reservoir
*
´
Aline V. Coelho, Andrea Luzia F. de Souza, Paulo G. de Lima,
James L. Wardell and O. A. C. Antunes*
Instituto de Quı´mica, Universidade Federal do Rio de Janeiro, Av. Athos da Silveira Ramos 149,
CT Bloco A 641, Cidade Universita´ria, Rio de Janeiro RJ 21941-909, Brazil
Received 13 July 2007; revised 23 August 2007; accepted 24 August 2007
Available online 31 August 2007
Abstract—Stille reactions between halobenzenes and other substituted (hetero)arenes and tributylphenyltin were carried out in
ethanol–water solution using Pd/CaCO3 as catalyst in a ligand-free system. The catalyst could be recycled three times without
any loss of activity. The ethanol–water solution, after removal of the catalyst and extraction of the product, was found to have
catalytic activity, thus showing the presence of soluble Pd(0)/Pd(II) species that can be regarded as the true catalysts.
Ó 2007 Published by Elsevier Ltd.
In recent years there has been much focus and emphasis
on the Stille reaction, the palladium catalyzed coupling
of organotin compounds with haloarenes, for the con-
struction of new carbon–carbon bonds.1 Biaryls and
their hetero analogs are an important class of organic
compounds. The biaryl unit is present in several com-
pounds of current interest including natural products,
polymers and molecules of medicinal interest. In view
of the importance of biaryls, a number of catalytic meth-
ods for forming these molecules from two monoaryl pre-
cursors in cross-coupling reactions have been developed
over the last two decades.2
seven times without any noticeable loss of activity.
Our results combined with the pioneering work of Geneˆt
and co-workers,8 who studied a Heck reaction involving
diazonium salts and olefins using Pd/CaCO3 as catalyst,
indicated that this very insoluble catalyst could be of
general interest.
In addition, the replacement of expensive, toxic, and
flammable organic solvents by water or aqueous systems
is highly desirable for reducing costs and for developing
environmentally benign synthetic reactions that facili-
tate catalyst recycling.9 Various previous examples of
aqueous carbon–carbon bond formations including
Suzuki,10 Sonogashira,11 Heck12, and Stille13 reactions
have been reported. In our search for developing new
processes for cross-coupling reactions,14 this present
Letter reports our results concerning the use of Pd/
CaCO3 as a catalyst in the Stille cross-coupling reaction
for a ligand-free aqueous system.
Our search for new processes involves the use of well-
known heterogeneous catalysts, such as Pd/C3 and other
systems.4 In cross-coupling reactions, particularly in the
Stille reaction, Pd/C, Pd on KF/Al2O3, and Pd on modi-
fied silica have been used as catalysts.5 Pd/CaCO3
(Lindlar’s catalyst), which is effective as a hydrogenation
catalyst6 has been rarely used in these reactions.
Our initial investigation started with the cross-coupling
reaction of iodobenzene and tributylphenyltin15 as a
model system (Scheme 1). The reaction was carried
Recently, our group reported a study with Pd/CaCO3 as
a reservoir for the Miyaura–Suzuki cross-coupling reac-
tion.7 Our results showed that the production of biaryls
in high yields and the catalyst could be reused up to
I
SnBu3
Pd/CaCO3, K2CO3
EtOH/H2O 40%
*
+
Corresponding authors. Tel.: +55 21 2562 7248; fax: +55 21 2562
7559 (A.L.F.S.); tel.: +55 21 2562 7818; fax: +55 21 2562 7559
(O.A.C.A.); e-mail addresses: andrealuziasouza@yahoo.com.br;
octavio@iq.ufrj.br
°
80 C, 24 h
Scheme 1. Stille reaction between iodobenzene and tributylphenyltin.
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.08.091

7672
A. V. Coelho et al. / Tetrahedron Letters 48 (2007) 7671–7674
Table 1. Stille reaction using catalytic Pd/CaCO3 systema
phenone (entry 6) gave a surprisingly moderate yield
and 2-bromopyridine (entry 7) furnished only the homo-
coupled product. As 1 mmol of reagents were used and
0.01 mmol of Pd, then TONs between 60 and 98 were
obtained. All compounds were characterized and
Entry
Pd/CaCO3 (mol %)
Yieldb (%)
1
2
5
1
100
99
3
4c
0.5
5
93
33
1
13
analyzed by GC–MS, H NMR, and C NMR.17
a 1.0 mmol iodobenzene, 1.1 mmol tributylphenyltin, 2 mmol K2CO3,
Pd/CaCO3 in 30 mL of 40% EtOH/H2O at 80 °C for 24 h.
b Determined by GC–MS using an external standard.
c Room temperature.
Recycling experiments were carried out as previously
described.7 The whole reaction medium was recycled
after extraction of the product. Three cycles were possi-
ble with no effect upon the yield (Table 3). To witness
the role of Pd/CaCO3 as a catalyst reservoir, revealing
that leaching occurred to give rise to the true catalytic
species, the solid catalyst source was separated from
solution by centrifugation (5000 rpm) and decantation
of the solution after extraction of the reaction products.
This solution could be reused twice giving yields of 94%
each time. Thus confirming the presence of soluble
Pd(0)/Pd(II) species in solution (also detected via
dimethylglyoxime yellow testing) as the true catalysts.
out in the presence of different amounts of Pd/CaCO3 as
a catalyst reservoir, in a ligand-free system, in 40% aque-
ous ethanol at 80 °C for 24 h. Our results are summa-
rized in Table 1.
The Stille reaction between iodobenzene and tributyl-
phenyltin furnished high yields of biphenyl with very
low loadings of Pd/CaCO3 (Table 1). High yields were
obtained with 5 and 1 mol % of catalyst (entries 1 and
2). Reduction of the catalyst loading to 0.5 mol %
resulted in a small reduction of the yield (entry 3).
The Stille reaction was also carried out using 5 mol %
Pd/CaCO3 at room temperature but the result was not
satisfactory (entry 4), showing that heating is necessary.
Due to the very low solubility of CaCO3 the addition of
K2CO3 to the reaction medium is also required. To
generalize our method, other aryl halides were tested
using tributylphenyltin, K2CO3 and 1 mol % Pd/CaCO3
in aqueous ethanolic solution under reflux for 24 h.16
The results are described in Table 2.
Mechanistically (Scheme 2), an active intermediate is
formed upon very slow oxidative addition of ArI to
the Pd(0), nanoparticles, on the support surface. This
addition would result in the intermediate ArPdI, which
after ligand exchange would form ArPdAr and then
the final product, Ar–Ar, and a very active ‘mono-
nuclear’ Pd(0) species that would react faster with ArI
thus resulting in a homogeneous catalytic cycle. Thus,
Pd/CaCO3 is really acting as a source of soluble Pd(0)/
Pd(II) species.
We initially studied the coupling between 4-nitro-iodo-
benzene and tributylphenyltin using 0.5 mol % of Pd/
CaCO3 that furnished the expected product in 75% yield
(entry 1). Increasing the loading to 1 mol % of catalyst
for this reaction gave 93% yield (entry 2). Due to this
result the same catalyst loading was used in the other
reactions (entries 2–7). Using 4-iodoanisole (entry 3)
resulted in a lower yield due to the electron donating
group effect. The use of bromobenzene did not result
in a decreased yield when compared to iodobenzene
(entry 4), while chlorobenzene, a normally very unreac-
tive, although abundant and low priced feedstock,
afforded a satisfactory yield (entry 5). The 4-bromoaceto-
Table 3. Recycle of the Stille reaction
Run
Yielda,b (%)
1st
2nd
3rd
94
98
98
a 1.0 mmol iodobenzene and 1.1 mmol tributylphenyltin at 80 °C for
24 h.
b Determined by GC–MS using external standard.
ArI
Oxidative
Addition on
the cluster
Table 2. Stille reaction between different aryl halides and
tributylphenyltina
surface.
Pd cluster on CaCO3
Very slow
Entry
Halide
Product
Yieldb (%)
pathway.
1c
2
3
4
5
6
7d
4-IC6H4NO2
4-IC6H4NO2
4-IC6H4OMe
BrC6H5
ClC6H5
4-BrC6H4COCH3
2-Bromopyridine
4-O2NC6H4C6H5
4-O2NC6H4C6H5
4-MeOC6H4C6H5
Biphenyl
Biphenyl
4-CH3COC6H4C6H5
2,20-Bipyridyl
75
93
81
98
60
66
92
Ligand exchange
ArPdPh
ArPh
ArPdI
PhSnBu3
ArI
Fast
Oxidative
Addition
a 1.0 mmol aryl halide, 1.1 mmol tributylphenyltin, 2 mmol K2CO3 and
1 mol % Pd/CaCO3 in 30 mL of 40% EtOH/H2O.
b Determined by GC–MS using external standard.
c 0.5 mol % Pd/CaCO3.
Pd(0)
"Mononuclear"
Scheme 2. Mechanism of the Stille reaction using Pd/CaCO3 as a
d Homocoupling product.
catalyst source.

A. V. Coelho et al. / Tetrahedron Letters 48 (2007) 7671–7674
7673
3. (a) Heidenreich, R. G.; Krauter, J. G. E.; Pietsch, J.;
Ko¨hler, K. J. Mol. Catal. A: Chem. 2002, 182–183, 499;
(b) Ko¨hler, K.; Heidenreich, R. G.; Krauter, J. G. E.;
Pietsch, J. Chem. Eur. J. 2002, 8, 622; (c) Colacot, T. J.;
Gore, E. S.; Kuber, A. Organometallics 2002, 21, 3301; (d)
LeBlond, C. R.; Andrews, A. T.; Sun, Y.; Sowa, J. T., Jr.
Org. Lett. 2001, 3, 1555.
4. (a) Narayanan, R.; El-Sayed, M. A. J. Catal. 2005, 234,
348; (b) Narayanan, R.; El-Sayed, M. A. J. Am. Chem.
Soc. 2003, 125, 8340; (c) Ko¨hler, K.; Wagner, M.;
Djakovitch, L. Catal. Today 2001, 66, 105.
5. Yin, L.; Liebscher, J. Chem. Rev. 2007, 107, 133.
6. (a) Parrish, D. A.; Zou, Z.; Allen, C. L.; Day, C. S.; King,
S. B. Tetrahedron Lett. 2005, 46, 8841; (b) Bogliotti, N.;
Dalko, P. I. Tetrahedron Lett. 2005, 46, 6915; (c) Mura-
kami, M.; Hasegawa, N.; Hayashi, M.; Ito, Y. J. Org.
Chem. 1991, 56, 7356.
The concentration of Pd(0)/Pd(II) species was deter-
mined via atomic absorption and a level of 1.1 mg Lꢀ1
(0.010 mM solution) Pd was found, that is, only 0.17%
Pd(II) was leached from the Pd source.
Considering the use of 30 mL of this solution and 94%
yield on solution recycling experiments an expressive
TON of about 3000 can be calculated. This result is in
agreement with our and other groups findings on the
fact that Pd species leached from the nanoparticles, in
our case from surface, are the true catalysts.7,18,19 The
concentration of Pd found is compatible to the results
of De Vries19 group who entitled such catalytic effect
as homeopathic.
In conclusion, Pd/CaCO3 proved to be a suitable cata-
lyst source for Stille cross-coupling reactions in a
ligand-free aqueous system. Substituted biaryls were
obtained with good yields in this method. Chlorobenz-
ene was found to be a convenient substrate. The catalyst
could be recycled up to three times without any notice-
able loss of activity. Use of the ethanol–water solution
after decantation of the catalyst and product extraction,
afforded high yields of product indicating that the true
catalyst was a soluble species that was formed upon slow
oxidative addition to the insoluble catalyst and repeated
reductive elimination/oxidative addition in homo-
geneous solution. The present phosphine-free system
can be regarded as of industrial interest.
7. Oliveira, B. L.; Antunes, O. A. C. Lett. Org. Chem. 2007,
4, 13.
8. Geneˆt, J. P.; Savignac, M. J. Organomet. Chem. 1999, 576,
305.
9. Brunner, H.; Courey, N. C.; Geneˆt, J. P. Tetrahedron Lett.
1999, 40, 4815.
10. (a) Leadbeater, N. E.; Marco, M. J. Org. Chem. 2003, 68,
´
´
888; (b) Najera, C.; Gil-Molto, J.; Karlstro¨m, S. Adv.
Synth. Catal. 2004, 346, 1798.
´
11. (a) Liang, B.; Daı, M.; Chen, J.; Yang, Z. J. Org. Chem.
2005, 70, 391; (b) Rollet, P.; Kleist, W.; Dufaud, V.;
Djakovitch, L. J. Mol. Catal. A: Chem. 2005, 241, 39.
12. (a) Solabannavar, S. B.; Desai, U. V.; Mane, R. B. Green
Chem. 2002, 4, 347; (b) Li, J.; Hu, X.; Xie, Y. Tetrahedron
2006, 62, 31.
13. Wolf, C.; Lerebours, R. J. Org. Chem. 2003, 68, 7551.
14. (a) Silva, A. C.; Souza, A. L. F.; Antunes, O. A. C. J.
Organometal. Chem. 2007, 692, 3104; (b) Perez, R.;
Veronese, D.; Coelho, F.; Antunes, O. A. C. Tetrahedron
Lett. 2006, 47, 1325.
Acknowledgments
15. General procedure for the production of tributylphenyltin:
In a 200 mL reaction flask containing 52 mL of n-BuLi
1.6 M (84 mmol) ꢀ78 °C, it was added bromobenzene
(76 mmol; 8 mL) for 15 min, under vigorous stirring. The
reaction was maintained for 40 min at ꢀ78 °C under
continuous stirring, while the color of the reaction passed
from yellowish to colorless. After that period, SnBuCl3
(1.1 mmol; 0.35 mL) was added for 15 min and the
reaction was left under stirring overnight. The reactional
mixture was neutralized with saturated solution of
(NH3)2SO4 and the aqueous phase was extracted with
hexane. The tributylphenyltin was purified by Kugelrohr
distillation under reduced pressure. Tributylphenyltin—
Financial support from CNPq, CAPES, and FAPERJ,
Brazilian Governmental Financing Agencies, is grate-
fully acknowledged. We are grateful to Professor Delmo
Santiago Vaitsman and to Ms. Katia Ferreira Cavalcan-
te for carrying out Atomic Absorption analysis and to
Professor Simon Garden for careful revision of the
manuscript.
References and notes
1
colorless oil, 7.6 g (81%). H NMR (CDCl3, 200 MHz) d
1. (a) Stille, J. K. Pure Appl. Chem. 1985, 57, 1771; (b) Stille,
J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508; (c)
Hassa, J.; Savignon, M.; Gozzi, C.; Schulz, E.; Lemaire,
M. Chem. Rev. 2002, 102, 1359; (d) Littke, A. F.; Fu, G. C.
Angew. Chem., Int. Ed. 2002, 41, 4176; (e) Espinet, P.;
Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43, 4704.
2. (a) Nicolaou, K. C.; Li, Y.; Sugita, K.; Monenschein, H.;
Guntupali, P.; Mitchell, H. J.; Fylaktakidou, K. C.;
Vourloumis, D.; Giannakakou, P.; O’Brate, A. J. Am.
Chem. Soc. 2003, 125, 15443; (b) Kadota, I.; Takamura,
H.; Sato, K.; Ohno, A.; Matsuda, K.; Yamamoto, Y. J.
Am. Chem. Soc. 2003, 125, 46; (c) Lin, S.; Chen, C.; Lee,
Y. J. Org. Chem. 2003, 68, 2968; (d) Boger, D. L.;
Ichikawa, S.; Jing, H. J. Am. Chem. Soc. 2000, 122, 12169;
(e) Kuribayashi, T.; Gohya, S.; Mizuno, Y.; Satoh, S. J.
Carbohydr. Chem. 1999, 18, 383; (f) Nicolaou, K. C.;
King, N. P.; Finlay, M. R. V.; He, Y.; Roschangar, F.;
Vourloumis, D.; Vallberg, H.; Sarabia, F.; Ninkovic, S.;
Hepworth, D. Bioorg. Med. Chem. 1999, 7, 665.
0.87–0.92 (t, 9H), 1.03–1.09 (q, 6H), 1.31–1.38 (q, 6H),
1.50–1.61 (m, 6H), 7.31–7.40 (m, 3H), 7.46–7.48 (m, 2H).
13C NMR (CDCl3, 50 MHz) d 7.55, 13.8, 27.5, 29.2, 128.3,
136.6, 142.2.
16. General procedure for Stille reaction: In a 25 mL reaction
flask containing iodobenzene (1 mmol; 0.204 g) in 30 mL
of EtOH/H2O 40%, tributylphenyltin (1.1 mmol; 0.2 mL),
Pd/CaCO3 (0.01 mmol; 0.021 g) and K2CO3 (2 mmol;
0.280 g) were successively added. The reaction was then
kept under stirring at 80 °C for 24 h. The reactional
mixture was extracted with hexane. The organic phase was
washed with water, brine and 1 M KF solution, and dried
over anhydrous magnesium sulfate. Solution was filtered
under CeliteÒ, the solvent was evaporated and crude
product was analyzed by GC–MS, 1H NMR and 13C
NMR. Biphenyl—1H NMR (CDCl3, 200 MHz) d 7.56 (d,
2H), 7.40 (d, 2H), 7.29 (d, 2H). 13C NMR (CDCl3,
50 MHz) d 140.8, 128.4, 126.9, 126.8. GC–MS: m/z 154, 77.

7674
A. V. Coelho et al. / Tetrahedron Letters 48 (2007) 7671–7674
17. 4-Nitro-biphenyl—1H NMR (CDCl3, 200 MHz) d 8.30 (d,
2H), 7.74 (d, 2H), 7.64 (d 2H), 7.52–7.44 (m, 3H). 13C
NMR (CDCl3, 50 MHz) d 147.6, 147.1, 138.8, 129.2, 128.9,
127.8, 127.4, 124.1. GC–MS: m/z 199, 183, 169, 152. 4-
Methoxy-biphenyl—1H NMR (CDCl3, 200 MHz) d 7.54 (t,
(m, 2H), 7.42 (m, 1H), 7.22 (m, 1H). 13C NMR (CDCl3,
50 MHz) d 157.3, 149.6, 139.3, 136.6, 128.8, 128.7, 126.8,
122.0, 120.4. GC–MS: m/z 156, 127, 78.
18. (a) Andrews, S. P.; Stepan, A. F.; Tanaka, H.; Ley, S. V.;
Smith, M. D. Adv. Synth.Catal. 2005, 347, 647; (b) Ji, Y.;
Jain, S.; Davis, R. J. J. Phys. Chem. B 2005, 109, 17232; (c)
Cassol, C. C.; Umpierre, A. P.; Machado, G.; Wolke, S. I.;
Dupont, J. J. Am. Chem. Soc. 2005, 127, 3298; (d) Yu, K.;
Sommer, W.; Richardson, J.; Weck, M.; Jones, C. W. Adv.
Synth. Catal. 2005, 347, 161; (e) Weck, M.; Jones, C. W.
Inorg. Chem. 2007, 46, 1865.
4H), 7.42 (t, 2H), 7.31 (t, 1H), 6.98 (d, 2H), 3.86 (s, 3H). 13
C
NMR (CDCl3, 50 MHz) d 159.1, 140.8, 133.7, 128.7, 128.1,
126.7, 126.6, 114.2, 55.3. GC–MS: m/z 184, 169, 141, 115.
1-Biphenyl-4-yl-ethanone—1H NMR (CDCl3, 200 MHz) d
8.09 (d, 2H), 7.63 (d, 2H), 7.58 (d, 2H), 7.40 (m, 2H), 7.37
(m, 1H), 2.63 (s, 3H). 13C NMR (CDCl3, 50 MHz) d 197.7,
145.7, 139.8, 135.9, 128.9, 128.1, 127.3, 26.2. GC–MS: m/z
196, 181, 153, 77. 2,2’-Bipyridyl—1H NMR (CDCl3,
200 MHz) d 8.69 (m, 1H), 8.0 (m, 2H), 7.73 (m, 2H), 7.49
19. Alimardanov, A.; Schmieder-van de Vondervoort, L.; de
Vries, A. H. M.; de Vries, J. G. Adv. Synth. Catal. 2004,
346, 1812.