Simple and efficient protocol for catalyst recycling and product recovery in the Pd-catalyzed homogeneous Suzuki reaction

Article abstract of DOI:10.1016/j.tetlet.2004.04.198

Poly(ethylene oxide) (PEO)/methanol can be used as solvent medium for the Pd-catalyzed Suzuki cross-coupling reaction under mild conditions. After the end of the reaction the product is extracted with heptane and the polar phase can be reused several times without any change in the activity. Pure biaryl products are obtained from the nonpolar phase in excellent isolated yields (>90%). The same catalyst-containing polar phase was used to coupling different aryl halides furnishing the biaryl products in good to high isolated yields.

Full text of DOI:10.1016/j.tetlet.2004.04.198

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6527–6530
Simple and efficient protocol for catalyst recycling and
product recovery in the Pd-catalyzed homogeneous Suzuki reaction
Sabrina M. Nobre, Silvana I. Wolke, Ricardo G. da Rosa and Adriano L. Monteiro*
´
Group of Molecular Catalysis, Instituto de Quımica––UFRGS, Av.Bento Gonc¸alves,
9500 Porto Alegre 91501-970––CP 15003 RS, Brazil
Received 13 April 2004; revised 22 April 2004; accepted 28 April 2004
Available online 20 July 2004
Abstract—Poly(ethylene oxide) (PEO)/methanol can be used as solvent medium for the Pd-catalyzed Suzuki cross-coupling reaction
under mild conditions. After the end of the reaction the product is extracted with heptane and the polar phase can be reused several
times without any change in the activity. Pure biaryl products are obtained from the nonpolar phase in excellent isolated yields
(>90%). The same catalyst-containing polar phase was used to coupling different aryl halides furnishing the biaryl products in good
to high isolated yields.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The palladium-catalyzed Suzuki cross-coupling reaction
is one of the most efficient methods for the construction
of Caryl–Caryl bonds and has found widespread use in or-
ganic synthesis.1 A plethora of palladium catalyst pre-
cursors promote the coupling of aryl halides with
organoboron compounds.2 One of the major drawbacks
of homogeneous Suzuki cross-coupling reactions is the
separation of the reaction product from the catalyst.
The expensive palladium catalysts are difficult to recover
and recycle. On the other hand, in order to obtain a pure
biaryl product tedious and expensive workups are usu-
ally necessary. To overcome these problems, several het-
erogeneous Pd-catalyzed Suzuki coupling systems have
been described in the last years, such as Pd/C,3 polymer
supported Pd-catalysts,4 and the use of aqueous media,5
and other systems.6 However, in homogeneous catalysis,
solvents play a critical role in rendering the reaction
homogeneous and allowing more efficient molecular
interactions and, in several cases, the heterogenization
of the catalyst results in reduced activity. In this context,
a homogenous coupling reaction that, at the end of the
reaction, the catalyst can be easily separated from the
product phase and recycled would be desirable. One
example of this strategy was the use of ionic liquids as
solvents for the Suzuki reaction.7 The products are sep-
arated from the solvent by extraction with diethyl ether
and the catalytic solution can be reused three times with-
out loss of activity. However, the ionic solution needs to
be washed with water and dried in vacuo before reuse.
An alternative to the ionic liquids consists of using a
mixture of organic solvents and poly(ethylene oxide)
(PEO). In fact, ternary mixtures of PEO, heptane and
one of the three organic solvents (MeOH, CH2Cl2 or
CHCl3) may be interchanged between homogeneous
and biphasic regions by either composition or tempera-
ture alterations.8 These characteristics have been used to
achieve efficient separation and easy catalyst recycling in
hydrogenation,9 epoxidation10 reactions by using PEO
as polymer, and in cross-coupling reactions of aryl
iodides (Heck and Suzuki reactions)4b by using triden-
tate SCS-Pd(II) catalyst bound to poly(N-isopropyl-
acrylamide) or PEG. Otherwise, the application of
poly(ethylene glycol) (PEG) as a reusable solvent has
been described for the Heck reaction.11 In this case, after
the end of the first run, the reaction mixture was
extracted with dry ether and the PEG and Pd(OAc)2
were solidified and subjected to five recycles (yields:
88%, 82%, 80%, 74%, 73%, 70%). We wish to report here
the application of PEO/MEOH as an efficient and reus-
able medium for Pd-catalyzed Suzuki reactions.
Initially, the coupling of 4-bromotoluene with phenylbo-
ronic acid was investigated. In order to test our system
we chose a very simple catalyst system composed of
Pd(OAc)2 and PPh3. Preliminary screening of solvent
Keywords: Suzuki reaction; Palladium catalyst; Recycle; Poly(ethyl-
eneoxide).
*
Corresponding author. Tel.: +55-51-33166303; fax: +55-51-
33167304; e-mail: almonte@iq.ufrgs.br
0040-4039/$ - see front matter ꢀ 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.198

6528
S.M.Nobre et al./ Tetrahedron Letters 45 (2004) 6527–6530
Table 1. Recycling experiments for the Pd-catalyzed Suzuki cross-couplinga
Reaction 1
Reaction 2
Reaction 3
p-MeC6H4Br
MeOH
Reaction 4
p-MeC6H4I
PEO/MeOH
Pd(OAc)2/PPh3
Yield (%)
ArX
Solvent
Catalyst
p-MeC6H4Br
PEO/MeOH
Pd(OAc)2/PPh3
Yield (%)b
p-MeC6H4Br
PEO/MeOH
Pd(OAc)2
Yield (%)b
Pd(OAc)2/PPh3
Yield (%)b
Run
1
70
37
13
0
100
100
61
90
100 (91)
100 (81)
2
100
100
3
498
5
36
100 (92)
98
0
100 (98)
100 (93)
100 (95)
6
100 (93)
96
98
7
8
9
93
94
10
11
12
97
97
a Reactions conditions: 0.25mmol of aryl halide, 0.375mmol of phenylboronic acid, 0.5mmol of K3PO4, Pd(OAc)2 (0.005mmol), PPh3 (0.015mmol),
MeOH (4mL), PEO (1g), 60 ꢁC, 24h for 4-bromotoluene and 3h for 4-iodotoluene.
b GC yield (isolated yields are given in parentheses).
media and reaction conditions demonstrated that a mix-
ture of MeOH/PEO was effective and that heating to
60ꢁC was sufficient.12 Under these reaction conditions,
the coupling of 4-bromotoluene was carried out in the
presence of 2mol% Pd catalyst and K3PO4 as base for
24h furnishing 4-methylbiphenyl in 70% yield ( Table
1, reaction 1, run 1). Then, the product was extracted
under argon with n-heptane. The polar phase was reused
in further runs by the addition of 4-bromotoluene, phen-
ylboronic acid and K3PO4 in each run. For the first
recycle the biphenyl product was obtained in quantita-
tive yield, and eleven catalytic runs were performed
without any significant loss of catalytic activity (Table
1, reaction 1, runs 2–12). The crude products of the first
reaction were analyzed for Pd content by ICP-MS. For
the first run a leaching of 5% of the palladium species
from the polar phase was observed, but this leaching
was lower for the following runs (>2%).
plete conversion in the first run, only four catalytic
runs could be performed. These results indicate that
the role of PEO is to increase the partitioning selectivity
of the catalyst for the polar phase.
4-Iodotoluene was also efficiently coupled following this
protocol (Table 1, reaction 4). As observed for the aryl
bromide, incomplete conversion was observed in the
first run. For the further runs complete conversion was
achieved within 3h. The workup procedure to isolate
the biphenyl product is very simple. The apolar phase
was washed with aqueous NaOH and brine and then
dried over MgSO4. After evaporation of the solvent 4-
methylbiphenyl was obtained in 95% purity as judged
1
by H NMR and GC. The only side-reaction product
observed was the biphenyl formed from the homocou-
pling of phenylboronic acid (2–5%).
In order to demonstrate the versatility of the catalyst
recycling and product recovery in our protocol, the syn-
thesis of different cross-coupled products using the same
catalyst-containing polar phase was performed (Table 2).
In the first run, 4-iodotoluene was coupled with phenyl-
boronic acid to furnish 4-methylbiphenyl in 83% isolated
yield (Table 2, run 1). Then, at the polar phase of this
reaction, 1-bromonaphthalene, phenylboronic acid and
K3PO4 were added and the coupling reaction afforded
1-phenylnaphthalene in 81% isolated yield (Table 2, run 2).
Using this strategy we were able to obtain six different
coupled products from the same catalyst solution.
It is worth to note that ligandless Pd(OAc)2 catalytic
system efficiently promotes the coupling of aryl bro-
mides with arylboronic acids using DMF as solvent.13
However in the case of PEO/MeOH solvent media the
presence of triphenylphosphine is necessary. In the ab-
sence of triphenylphosphine, only 37% yield was ob-
tained in the first run and the reaction stopped in the
third run (Table 1, reaction 2).
The coupling reaction was carried out using only meth-
anol as solvent (Table 1, reaction 3). Despite the com-

S.M.Nobre et al./ Tetrahedron Letters 45 (2004) 6527–6530
6529
Table 2. Recycling experiments for the Pd-catalyzed Suzuki cross-
coupling changing the aryl halide in each recyclea
Org.Chem. 2002, 67, 5588; (f) Bedford, R. B.; Cazin, C. S.
J.; Coles, S. J.; Gelbrich, T.; Horton, P. N.; Hursthouse,
M. B.; Light, M. E. Organometallics 2003, 22, 987; (g)
Rosa, G. R.; Ebeling, G.; Dupont, J.; Monteiro, A. L.
Synthesis 2003, 2894; (h) Zapf, A.; Jackstell, R.; Rata-
boul, F.; Riermeier, T.; Monsees, A.; Furhmann, C.;
Shaik, N.; Dingerdissen, U.; Belle, M. Chem.Commun.
2004, 38; (i) Walker, S. D.; Barder, T. E., Dr.; Martinelli,
Run
1
Substrate
Product
Yield (%)b
92 (83)
I
Ph
Br
J. R.; Buchwald, S. L. Angew.Chem,. Int.Ed.
1871.
2004, 43,
2
100 (81)
3. (a) Marck, G.; Villiger, A.; Buchecker, R. Tetrahedron
Lett. 1994, 35, 3277; (b) LeBlond, C. R.; Andrews, A. T.;
Sowa, J. R. Org.Lett. 2001, 3, 1555; (c) Sakurai, H.;
Tsukuda, T.; Hirao, T. J.Org.Chem. 2002, 67, 2721; (d)
Heiderich, R. G.; Kohler, K.; Krauter, J. G. E.; Pietsch, J.
Synlett 2002, 7, 1118.
4. (a) Jang, S.-B. Tetrahedron Lett. 1997, 38, 1793; (b)
Fenger, I.; Le Drian, C. Tetrahedron Lett. 1998, 39, 4287;
(c) Zhang, T. Y.; Allen, M. J. Tetrahedron Lett. 1999, 40,
5813; (d) Bergbreiter, D. E.; Osburn, P. L.; Wilson, A.;
Sink, E. M. J.Am.Chem.Soc. 2000, 122, 9058; (e) Parrish,
C. A.; Buchwald, S. L. J.Org.Chem. 2001, 66, 3820; (f)
Buchmeiser, M. R.; Schareina, T.; Kempe, R.; Wurst, K.
Ph
Br
3
4
100 (83)
88 (62)
F3C
F3C
Br
Br
5
6
75 (68)
J.Organomet.Chem.
2001, 634, 39; (g) Akiyama, R.;
MeO
MeO
100 (71)
Br
Kobayashi, S. Angew.Chem,. Int.Ed. 2001, 40, 3469; (h)
Yamada, Y. M. A.; Takeda, K.; Takahashi, H.; Ikegami,
S. Org.Lett. 2002, 4, 3371; (i) Datta, A.; Ebert, K.; Plenio,
H. Organometallics 2003, 22, 4685; (j) Lin, C.-A.; Luo,
F.-T. Tetrahedron Lett. 2003, 44, 7565; (k) Byun, J. W.;
Lee, Y. S. Tetrahedron Lett. 2004, 45, 1837.
a Reactions conditions: 0.25mmol of aryl or benzyl halide, 0.375mmol
of phenylboronic acid, 0.5mmol of K3PO4, MeOH (4mL), PEO (1g),
24h.
b GC yield (isolated yields are given in parentheses).
5. (a) Genet, J. P.; Linquist, A.; Blart, E.; Mouries, V.;
Savignac, M.; Vaultier, M. Tetrahedron Lett. 1995, 36,
1443; (b) Uozumi, Y.; Danjo, H.; Hayashi, T. J.Org.
Chem. 1999, 64, 3384; (c) Paetzold, E.; Oeheme, G. J.Mol.
Catal.A: Chem. 2000, 152, 69; (d) Li, Y.; Hong, X. M.;
Collard, D. M.; El-Sayed, M. A. Org.Lett. 2000, 2, 2385;
(e) Dupuis, C.; Adiey, K.; Charruault, L.; Michelet, V.;
Savignac, M.; Genet, J. P. Tetrahedron Lett. 2001, 42,
6523.
6. For other recent developments and improvements for
heterogeneous catalysis of the Suzuki–Miyaura reaction,
see: (a) Mubofu, E. B.; Clark, J. H.; Macquarrie, D. J.
Green Chem. 2001, 3, 23; (b) Schneider, S.; Bannwarth, W.
Helv.Chim.Acta 2001, 84, 735; (c) Kosslick, H.; Mo¨nnich,
In summary, we have developed a simple and efficient
protocol for catalyst recycling and product recovery un-
der homogenous Suzuki reaction conditions. At the end
of the reaction the mixture is extracted with heptane and
the polar phase can be reused several times without any
significant loss of catalytic activity. Pure biaryl products
are obtained from the nonpolar phase in excellent iso-
lated yields (>90%). The same catalyst-containing polar
phase can be reused in order to couple different aryl
halides furnishing biaryl products in good to high iso-
lated yields. This strategy has potential for combinato-
rial chemical investigations.
I.; Paetzold, E.; Fuhrmann, H.; Fricke, R.; Muller, D.;
¨
Oehme, G. Micropor.Mesopor.Mater. 2001, 44, 537; (d)
Bedford, R. B.; Cazin, C. S. J.; Hursthouse, M. B.; Light,
M. E.; Pike, K. J.; Wimperis, S. J.Organomet.Chem.
2001, 633, 173; (e) Corma, A.; Garcia, H.; Leyva, A. Appl.
Catal.A 2002, 236, 179; (f) Smith, M. D.; Stepan, A. F.;
Ramarao, C.; Brennan, P. E.; Ley, S. V. Chem.Commun.
2003, 2652.
Acknowledgements
We thank PADCT-CNPq and CNPq for partial finan-
cial support. We also thank Professor Dirce Pozebon
for helping in the ICP-MS analysis, and Dr. John Spen-
cer (UK) for proofreading the manuscript.
7. Mathews, C. J.; Smith, P. J.; Welton, T. Chem.Commun.
2000, 14, 1249.
8. (a) da Silva, L. H. M.; Loh, W. Chem.Commun. 1998, 787;
(b) Spitzer, M.; da Silva, L. H. M.; Loh, W. J.Braz.Chem.
Soc. 2000, 11, 375; (c) Spitzer, M.; Sabadini, E.; Loh, W.
J.Braz.Chem.Soc. 2002, 13, 7.
References and notes
9. Da Rosa, R. G.; Martinelli, L.; da Silva, L. H. M.; Loh,
W. Chem.Commun. 2000, 33.
10. Dallmann, K.; Buffon, R.; Loh, W. J.Mol.Cat.A: Chem.
2002, 178, 4 3.
1. Suzuki, A. J.Organomet.Chem. 1999, 576, 147; Kotha, S.;
Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633.
2. For some examples of recent developments and improve-
ments for the Pd-catalyzed Suzuki reaction, see: (a) Littke,
11. Chandrasekhar, S.; Narsihmulu, Ch.; Sultana, S. S.;
Reddy, N. R. Org.Lett. 2002, 4, 4399.
A. F.; Dai, C.; Fu, G. C. J.Am.Chem.Soc.
2000, 122,
4020; (b) Zim, D.; Gruber, A. S.; Ebelin, G.; Dupont, J.;
Monteiro, A. L. Org.Lett. 2000, 2, 2881; (c) Feuerstein,
M.; Laurenti, D.; Doucet, H.; Santelli, M. Synthesis 2001,
2320; (d) Grasa, G. A.; Viciu, M. S.; Huang, J. K.; Zhang,
C. M.; Trudell, M. L.; Nolan, S. P. Organometallics 2002,
21, 2866; (e) Alonso, D. A.; Najera, C.; Pacheco, M. C. J.
12. In a typical experiment an oven-dried resealable Schlenk
flask was evacuated and back filled with argon and
charged with Pd(OAc)2 (0.005mmol), PPh3 (0.015mmol),
K3PO4 (0.5mmol), PEO 3350 (1g) and phenylboronic acid
(0.375mmol). The flask was evacuated and back filled with

6530
S.M.Nobre et al./ Tetrahedron Letters 45 (2004) 6527–6530
argon and then the aryl halide (0.25mmol) and methanol
GC. For the recycle reactions, the polar phase was trans-
ferred to a an oven dried resealable Schlenk flask under
argon. Then, the aryl halide (0.25mmol), phenylboronic
acid (0.375mmol) and K3PO4 (0.5mmol) were added. The
reaction mixture was stirred at 60ꢁC for the desired time
and the product was isolated as described above.
13. Zim, D.; Monteiro, A. L.; Dupont, J. Tetrahedron Lett.
2000, 41, 8199.
(4mL) were added. The reaction mixture was stirred at
60ꢁC for the desired time. The coupling product was
extracted under argon with n-heptane (4mL ·5–8 extrac-
tions depending on the biaryl product). The apolar phase
was washed with aqueous NaOH (1M, 5mL) and brine
(2·5mL), and then dried over MgSO4. The biaryl product
was obtained in 95% purity as judged by 1H NMR and