Pd nanoparticles as efficient catalysts for Suzuki and Stille coupling reactions of aryl halides in ionic liquids

Article abstract of DOI:10.1021/jo050801q

Pd-catalyzed Suzuki and Stille cross-couplings of aryl bromides and chlorides were carried out in quaternary ammonium salts as solvents under mild conditions and with the recycling of the catalyst.

Full text of DOI:10.1021/jo050801q

Pd Nanoparticles as Efficient Catalysts for Suzuki and Stille
Coupling Reactions of Aryl Halides in Ionic Liquids
Vincenzo Calo`,†,‡ Angelo Nacci,*,‡ Antonio Monopoli,§ and Floriana Montingelli‡
CNR-ICCOM and Department of Chemistry, University of Bari, via Orabona, 4-70126 Bari, Italy, and
Istituto Centrale Repressione Frodi Alimentari-Lab. di Modena, Via J. Cavedone, 29-41100 Modena, Italy
nacci@chimica.uniba.it
Received April 20, 2005
Pd-catalyzed Suzuki and Stille cross-couplings of aryl bromides and chlorides were carried out in
quaternary ammonium salts as solvents under mild conditions and with the recycling of the catalyst.
Introduction
this methodology allows us to achieve simultaneously the
advantages of the elimination of highly toxic solvents,
the ease of workup, and the possibility of recycling the
catalyst.3 In addition, it has been widely demonstrated
that ILs can play a greater role than merely solubilizing
the reagents, as their ability to affect the nature of the
catalytically active species was shown to be dependent
on the structure of both cation and anion.4
In this context, during the past few years we reported
a series of highly efficient Pd-catalyzed Heck arylations
of mono- and disubstituted olefins by using a tetraalky-
lammonium salt as the solvent and phosphanes-free
catalysts in both homogeneous5 and heterogeneous condi-
tions.6 In particular, while searching for a Pd-catalyzed
In the past three decades, palladium chemistry has
emerged as one of the most powerful tools for the
formation of carbon-carbon and carbon-heteroatom
bonds. Special interest has been devoted to the pal-
ladium-catalyzed cross-couplings of aryl and vinyl halides
with either olefins (Mizoroki-Heck reactions) or orga-
nometallic reagents (Suzuki, Stille, Sonogashira, Negishi,
Kumada, Hiyama, etc. reactions), due to their tolerance
toward a wide range of functional groups, which permits
them to synthesize highly complex molecules.1
Despite the synthetic elegance, these processes suffer
from two serious limitations that have precluded a wide
use in industry: (i) the need for the use of toxic and/or
expensive phosphine ligands, which are necessary to
stabilize the catalytically active Pd(0) species, and (ii) the
very low reactivity of aryl chlorides, which are arguably
the most useful class of substrates, because of their lower
cost and the wider variety of available compounds in
comparison with the more reactive iodides and bromides.2
More recently, palladium-centered catalysis in ionic
liquids (ILs) has gained considerable importance, since
(2) For reviews and articles dealing with the activation of aryl
chlorides in palladium-catalyzed cross-coupling reactions, see: (a) Fu,
G. C.; Littke, A. F. Angew. Chem., Int. Ed. 2002, 41, 4176-4211. (b)
Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2005, 127, 4685-4696. (c) Kataoka, N.; Shelby, Q.;
Stambuli, J. P.; Hartwig, J. F. J. Org. Chem. 2002, 67, 5553-5566.
(3) For reviews on ionic liquids, see: (a) Wilkes, J. S. J. Mol. Catal.
A: Chem. 2004, 214, 11-17. (b) Welton, T. Coord. Chem. Rev. 2004,
248, 2459-2477. (c) Ionic Liquids in Synthesis; Wasserscheid, P.,
Welton, T., Eds.; Wiley-VCH: Weinheim, Germany, 2003. (d) Dupont,
J.; de Souza, R. F.; Suarez, P. A. Z. Chem. Rev. 2002, 102, 3667-3692.
(e) Olivier-Bourbigou, H.; Magna, L. J. Mol. Catal. A: Chem. 2002,
182-183, 419-437. (f) Zhao, D.; Wu, M.; Kou, Y.; Min, E. Catal. Today
2002, 74, 157-189. (g) Tzschucke, C. C.; Markert, C.; Bannwarth, M.;
Roller, S.; Hebel, A.; Haag, R. Angew. Chem., Int. Ed. 2002, 41, 3964-
4000. (h) Zhao, H.; Malhotra, S. V. Aldrichimica Acta 2002, 35, 75-
83. (i) Gordon, C. M. Appl. Catal., A 2001, 222, 101-117. (j) Wasser-
scheid, P.; Keim, W. Angew. Chem., Int. Ed. 2000, 39, 3772-3789. (k)
Welton, T. Chem. Rev. 1999, 99, 2071-2084.
† CNR-ICCOM, Department of Chemistry, University of Bari.
‡ Department of Chemistry, University of Bari.
§ Istituto Centrale Repressione Frodi Alimentari-Lab. di Modena.
(1) (a) Blaser, H.-U.; Indolese, A.; Naud, F.; Nettekoven, U.; Schny-
der, A. Adv. Synth. Catal. 2004, 346, 1583-1598. (b) Herrmann, W.
A.; O¨ fele, K.; Preysing, D. v.; Schneider, S. K. J. Organomet. Chem.
2003, 687, 229-248. (c) de Vries, J. G. In Encyclopedia of Catalysis;
Horvat, I. T., Ed.; Wiley & Sons: New York, 2003; Vol. 3, p 295. (d)
Beller, M.; Zapf, A. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E., de Meijere, A., Eds.; Wiley & Sons:
Hoboken, NJ, 2002; Vol. 1, p 1209.
(4) See, for example: (a) Gu, Y.; Shi, F.; Deng, Y. J. Org. Chem.
2004, 69, 391-394. (b) Dupont, J.; Spencer, J. Angew. Chem., Int. Ed.
2004, 43, 5296-5297. (c) Calo`, V.; Nacci, A.; Monopoli, A.; Lopez, L.;
di Cosmo, A. Tetrahedron 2001, 57, 6071-6077.
10.1021/jo050801q CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/24/2005
6040
J. Org. Chem. 2005, 70, 6040-6044

Pd NPs as Efficient Catalysts for Coupling Reactions
but tetraalkylammonium salts were generally added as
phase transfer agents.15
Pd nanoparticles were also used as a catalyst for the
Suzuki reaction, but they were generally stabilized by
incorporation into polymers, dendrimers, or inorganic
supports.16 In most of these applications, iodo- and
bromoarenes reacted, but only at elevated temperature,
while aryl chlorides were almost unreactive. On the
contrary, only a few articles reported the activation of
bromides and chlorides by Pd NPs under mild condi-
tions.17
With this aim, we tested the activity of the free
monodisperse Pd nanoparticles in a biphasic medium
consisting of an ionic liquid, generally a melt tetraalkyl-
ammonium bromide containing both reagents and cata-
lyst, and an aqueous solution of a source of hydroxide
anions (OH-), which are necessary to activate the boronic
acid. Under these conditions, although the IL is water-
soluble, it forms a biphasic system as already found by
other groups.18
FIGURE 1. (a) TEM characterization of a palladium colloidal
dispersion synthesized as described in the text. (b) Histogram
representing size distribution of the palladium nanoparticle
core. (c) Core-shell structure representation of a nanoparticle.
regio- and stereoselective Heck arylation of cinnamates7
and methacrylates8 in ILs, we found that by dissolving
palladium acetate in melt tetrabutylammonium bromide
(TBAB) and using tetrabutylammonium acetate (TBAA)
as base, the rapidly formed dark suspension of Pd
nanoparticles (Pd NPs) efficiently catalyzed the reaction
of aryl bromides and chlorides.
Of particular importance was the modality of prepara-
tion of Pd nanocolloids, carried out by adding to Pd(OAc)2,
dissolved in the IL, an excess of tetrabutylammonium
acetate and heating the reaction mixture at 90 °C until
a homogeneous dark red mixture was obtained (see
Supporting Information).
The first experiments were devoted to investigating the
efficiency of the catalytic system composed by Pd NPs,
TBAB, and aqueous Na2CO3 on halobenzenes. At high
temperatures, bromobenzene was rapidly converted into
diphenyl (Table 1, entry 1), but the catalyst activity
dropped fast when either the reaction temperature was
lowered or the less reactive chlorobenzene was used as
the substrate (entries 2 and 3). Ascribing this scarce
Reactions occurred at the surface of the monodisperse
nanoparticles, formed by chemical reduction of Pd(OAc)2
by TBAA,9 whose structure, defined “core-shell”, is
composed of a metallic core (∼3.3 nm in size) surrounded
by a stabilizing shell containing tetrabutylammonium
cations and Br- and [PdBr4]2- species (Figure 1).
Although the effectiveness of these nanosized catalysts
has been widely demonstrated in the Heck couplings, the
use of ILs as reaction media for other Pd NP-catalyzed
coupling reactions is a relatively unexplored area.
We report here the applications of free Pd nanopar-
ticles as catalyst for the Suzuki and Stille cross-coupling
reactions of aryl bromides and chlorides carried out in
ILs under mild conditions, with the recycling of the
catalyst for aryl bromides.
(11) (a) McLachlan, F.; Mathews, C. J.; Smith, P. J.; Welton, T.
Organometallics 2003, 22, 5350-5357. (b) Revell, J. D.; Ganesan, A.
Org. Lett. 2002, 4, 3071-3073.
Results
(12) (a) Corma, A.; Garcia, H.; Leyva, A. Tetrahedron 2004, 60,
8553-8560. (b) Alonso, D. A.; Najera, C.; Pacheco, M. C. J. Org. Chem.
2002, 67, 5588-5594.
Our investigations started with the study of Suzuki-
Myiaura cross-coupling reaction, an extremely important
methodology for the generation of new carbon-carbon
(13) (a) Liu, S.; Fukuyama, T.; Sato, M.; Ryu, I. Synlett 2004, 10,
1814-1816. (b) Rajagopal, R.; Jarikote, D. V.; Srinivasan, K. V. Chem.
Commun. 2002, 6, 616-617.
bonds specially applied to the synthesis of biaryls.10
A
(14) Mathews, C. J.; Smith, P. J.; Welton, T. J. Mol. Catal. A: Chem.
2004, 214, 27-32.
typical procedure employs aryl halides as electrophiles
and boronic acids as nucleophilic counterpart, these latter
being widely available and air- and moisture-stable.
Concerning the Suzuki reaction carried out in ionic
liquids, a number of articles have described the use of
Pd catalysts based on phosphanes,11 palladacycles,12
carbenes,13 and N-donor14 ligands, dissolved in ILs de-
rived from imidazolium cation. In some other cases, both
ligand-free Pd catalysts and water solvents were used,
(15) (a) Arvela, R. K.; Leadbeater, N. E.; Sangri, M. S.; Williams,
V. A.; Granados, P.; Singer, R. D. J. Org. Chem. 2005, 70, 161-168.
(b) Arcadi, A.; Cerichelli, G.; Chiarini, M.; Correa, M.; Zorzan, D. Eur.
J. Org. Chem. 2003, 4080-4086. (c) Deng, Y.; Gong, L.; Mi, A.; Liu,
H.; Jiang, Y. Synthesis 2003, 337. (d) Zim, D.; Monteiro, A. L.; Dupont,
J. Tetrahedron Lett. 2000, 41, 8199-8202.
(16) (a) Corma, A.; Garcia, H.; Leyva, A. J. Mol. Catal. A: Chem.
2005, 230, 97-105. (b) Kim, N.; Kwon, M. S.; Park, C. M.; Park, J.
Tetrahedron Lett. 2004, 45, 7057-7059. (c) Narayanan, R.; El-Sayed,
M. A. J. Phys. Chem. B 2004, 108, 8572-8580. (d) Liu, Y.; Khemtong,
C.; Hu, J. Chem. Commun. 2004, 4, 398-399. (e) Gopidas, K. R.;
Whitesell, J. K.; Fox, M. A. Nano Lett. 2003, 3, 1757-1760. (f)
Pittelkow, M.; Moth-Poulsen, K.; Boas, U.; Christensen, J. B. Langmuir
2003, 19, 7682-7684. (g) Narayanan, R.; El-Sayed, M. A. J. Am. Chem.
Soc. 2003, 125, 8340-8347. (h) Strimbu, L.; Liu, J.; Kaifer, A. E.
Langmuir 2003, 19, 483-485. (i) Ramarao, C.; Ley, S. V.; Smith, S.
C.; Shirley, I. M.; DeAlmeida, N. Chem. Commun. 2002, 10, 1132-
1133. (j) Pathak, S.; Greci, M. T.; Kwong, R. C.; Mercado, K.; Prakash,
G. K. S.; Olah, G. A.; Thompson, M. E. Chem. Mater. 2000, 12, 1985-
1989.
(17) (a) Lu, F.; Ruiz, J.; Astruc, D. Tetrahedron Lett. 2004, 45, 9443-
9445. (b) Choudary, M. B.; Madhi, S.; Chowdari, N. S.; Kantam, M.
L.; Sreedhar, B. J. Am. Chem. Soc. 2002, 124, 14127-14136. (c)
McNulty, J.; Capretta, A.; Wilson, J.; Dyck, J.; Adjabeng, G.; Robertson,
A. Chem. Commun. 2002, 17, 1986-1987.
(18) (a) Zou, Y.; Wang, Q. R.; Tao, F. G.; Ding, Z. B. Chin. J. Chem.
2004, 22, 215. (b) Zou, G.; Wang, Z.; Zhu, J.; Tang, J.; He, M. Y. J.
Mol. Catal. A: Chem. 2003, 206, 193-198.
(5) Calo`, V.; Nacci, A.; Monopoli, J. Mol. Catal. A: Chem. 2004, 214,
45-56 and references therein.
(6) Calo`, V.; Nacci, A.; Monopoli, A.; Fornaro, A.; Sabbatini, L.; Cioffi,
N.; Ditaranto, N. Organometallics 2004, 23, 5154-5158.
(7) Calo`, V.; Nacci, A.; Monopoli, A.; Laera, S.; Cioffi, N. J. Org.
Chem. 2003, 68, 2929-2933.
(8) Calo`, V.; Nacci, A.; Monopoli, A.; Detomaso, A.; Iliade, P.
Organometallics 2003, 22, 4193-4197.
(9) (a) Reetz, M. T.; Maase, M. Adv. Mater. 1999, 11, 773-777. (b)
Moreno-Mao`as, M.; Pleixats, R. Acc. Chem. Res. 2003, 36, 638-643.
(10) For reviews, see: (a) Hassan, J.; Se´vignon, M.; Gozzi, C.; Schulz,
E.; Lemaire, M. Chem. Rev. 2002, 102, 1359. (b) Khota, S.; Lahiri, K.;
Kashinath, D. Tetrahedron 2002, 58, 9633. (c) Suzuki, A. J. Organomet.
Chem. 1999, 576, 147. (d) Stanforth, S. P. Tetrahedron 1998, 54, 263.
(e) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
J. Org. Chem, Vol. 70, No. 15, 2005 6041

Calo` et al.
TABLE 1. Screening of ILs and Bases in Pd
TABLE 2. Pd NP-Catalyzed Suzuki Reaction of
Substituted Aryl Bromides and Chlorides in ILsa
NP-Catalyzed Cross-Coupling of Suzuki Reaction in ILsa
convb yieldsb
T
t
(h)
convb yieldsc
T
t
R1
IL
(°C) (h)
(%)
(%)
entry
X
IL
base(aq) (°C)
(%)
(%)
entry
R
1
2
Br TBAB
Br TBAB
Cl TBAB
Cl TBAB
Cl TBAB
Na2CO3
Na2CO3
Na2CO3
KOH
110
0.5 >99
95
-
1
2
3
4
5
6
7
CH3CO
CH3CO
NO2
H
H
H
TBAB
THeptAB
THeptAB
60 16
60 16
69
>99
>99
>99
>99
55
50
90
90
83
78
40
56
60 16
<1
15
36
93
98
57
89
<1
3
140 16
90 16
90
90
70
70
-
60
60
60
3
5
5
4
20
86
92
45
83
-
CH3CO OCH3 THeptAB
5
NBu4OH
3
NO2
CH3O
CH3
OCH3 THeptAB
H
H
6
Cl THeptAB NBu4OH
3
THeptAB 110 16
THeptAB 110 16
7
Cl TBAB
NBu4OH
4.5
4.5
69
8
Cl THeptAB NBu4OH
Cl THeptAB NBu4OH
Br THeptAB NBu4OH
a Reaction conditions: IL (6 mmol), phenylboronic acid (1.1
mmol), aryl halide (1 mmol), tetrabutylammonium hydroxide (2
9
60 16
60
10
1.5 >99
93
mmol in 1.5 mL of H2O), cat. Pdnanopart. [2.5 mol % Pd(OAc)2
+
a Reaction conditions: IL (6 mmol), phenylboronic acid (1.1
mmol), aryl halide (1 mmol), base (2 mmol in 1.5 mL of H2O), cat.
Pdnanopart. [2.5 mol % Pd(OAc)2 + 12.5 mol % TBAA]. b Determined
by GLC using dodecane as internal standard. c Isolated yields.
12.5 mol % TBAA]. b Determined by GLC using dodecane as
internal standard. c Isolated yields.
efficiency to a low OH- concentration in the IL phase,
we replaced sodium carbonate with concentrate solutions
of either KOH or tetrabutylammonium hydroxide. Excel-
lent results were obtained only in the latter case, where
the chlorobenzene was almost completely converted at
90 °C in only 3 h (entries 4 and 5).
In addition to the high value of [OH-], this result could
also be explained by the analogous high concentration
of tetraalkylammonium cations realized into the water
phase, which can contribute, by means of the partitioning
equilibrium, to keeping constant the concentration of
+
NR4 into the IL phase, thus preserving the protecting
shell of nanoparticles.
However, as the presence of the aqueous phase seemed
to accelerate the Pd NP aggregation, and consequently
the catalyst inactivation, we thought to use a water-
insoluble IL also possessing alkyl chains longer than
TBAB. These chains should limit, by means of stronger
hydrophobic interactions, the NPs growing into larger
metal particles (the inactive “Pd black”). Among the
various ILs investigated, tetraheptylammonium bromide
(THeptAB) provided better performances than TBAB also
at 70 °C (entries 5-8). When the reaction temperature
was further lowered, the activity dropped again (entry
9), except with the more reactive bromobenzene, which
was successfully converted also at 60 °C (entry 10).
We next applied the reaction to substituted chloroare-
nes to obtain unsymmetrical biphenyls. The better per-
formances of THeptAB with respect to TBAB as stabi-
lizing agent for Pd NPs were confirmed also in this case,
as shown by the results reported in Table 2. Thus,
p-chloroacetophenone was completely converted at 60 °C
after 16 h (entries 1 and 2). These relatively mild
conditions could successfully be applied to activated
electron-poor chlorides (entries 3-5), while higher tem-
peratures (at least 110 °C) were required in the case of
deactivated electron-rich aryl chlorides (entries 6 and 7).
Recycling experiments, carried out on p-bromotoluene
with Na2CO3 as base, showed that the catalytic system
could be reused for three runs with a slight decrease in
product yields (Figure 2).
FIGURE 2. Recycling experiments for the Suzuki cross-
coupling of Pd NPs in IL.
carbon-carbon bond-forming reaction used for the prepa-
ration of a wide variety of molecules ranging from biaryls
and polyenes to aromatic carbonyl compounds.19 As for
the Suzuki process, the organometallic coupling partner,
an organostannane, is air- and moisture-stable, and thus
it is compatible with IL media. In addition, this process
does not require bases or other additives; as a conse-
quence, product separation and recycling of catalyst
should be simplified.
A number of articles describing the use of ionic liquids
as reaction media have been published,20 but only in a
few cases Pd nanoparticles have been employed as
catalyst;21 in addition, very rarely these catalysts were
able to activate chloroarenes.17b Therefore, we applied our
(19) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508-
524. (b) Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997,
50, 1-652. For a recent review on the Stille reaction, see: (c) Espinet,
P.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43, 4704-4734.
(20) (a) Chiappe, C.; Imperato, G.; Napolitano, E.; Pieraccini, D.
Green Chem. 2004, 6, 33-36. (b) Handy, S. T.; Zhang, X. Org. Lett.
2001, 3, 233-236. (c) Liu, S.; Fukuyama, T.; Sato, M.; Ryu, I. Synlett
2004, 1814-1816.
(21) See, for example: (a) Garcia-Martinez, J. C.; Lezutekong, R.;
Crooks, R. M J. Am. Chem. Soc. 2005, 127, 5097-5103. (b) Zhao, D.;
Fei, Z.; Geldbach, T. J.; Scopelliti, R.; Dyson, P. J. J. Am. Chem. Soc.
2004, 126, 15876-15882.
To further expand the catalytic scope of Pd NPs, we
investigated the Stille reaction, another very important
6042 J. Org. Chem., Vol. 70, No. 15, 2005

Pd NPs as Efficient Catalysts for Coupling Reactions
TABLE 3. Stille Cross-Coupling Catalyzed by Pdnanopart.
in ILa
nanopartcicles’ stabilization, not only by protecting the
metal core but also by sterically inhibiting its access; on
the other hand, due to its nucleophilicity the bromide
anion can play the double role of cocatalyst, by entering
into the metal sphere and forming more active Pd(0)
anionic species as already reported by us,4c and also as
accelerating agent, by assisting the transmetalation step
as already shown by other authors20a for the Stille
reaction in imidazolium-based ILs.
entry
R
X
T (°C)
convb (%)
yieldsc (%)
1
2
3
4
5
6
7
H
Br
Br
Cl
Cl
Cl
Cl
Cl
90
90
97
97
75
98
70
27
57
86
90
68
91
52
10
40
CH3
H
90
NO2
CH3CO
CH3
90
90
110
130
Conclusions
CH3O
The results of our study show that our ligand-free
catalyst, composed of Pd NPs stabilized by tetraalkylam-
monium salts bearing long alkyl chains, behaves ef-
ficiently in important C-C bond-forming reactions such
as the Suzuki and Stille cross-couplings. In the former
process, the use of tetrabutylammonium hydroxide as
base gets to a remarkable catalyst activity enhancement,
permitting the reactions to proceed smoothly under
relatively mild conditions (ranging from 60 °C for acti-
vated chlorides, to 90 °C for unreactive electron-rich
chlorides). In addition, the catalytic system can be
recycled a number of times, and the essential role of both
anion and cation of the IL in determining the catalyst
life and the reaction rate has been evidenced.
a Reaction conditions: IL (1 g), organostannane (1.2 mmol), aryl
halide (1 mmol), cat. Pdnanopart. [2.5 mol % Pd(OAc)2 + 5% TBAA].
b Determined by GLC after 16 h by using dodecane as internal
standard. c Isolated yields.
Experimental Section
Typical Procedure for the Pd NP-Catalyzed Suzuki
Reaction. A 25-mL round-bottom flask, equipped with a
magnetic bar, was charged with tetraalkylammonium bromide
(6 mmol), Pd(OAc)2 (5.6 mg, 0.025 mmol), and tetrabutylam-
monium acetate (38 mg, 0.125 mmol). The mixture was melted
and stirred at 90° C until a homogeneously dark red mixture
was obtained (at least 15 min). The temperature was then set
to the fixed value (see Tables 1 and 2), and the aryl halide (1
mmol), boronic acid (1.1 mmol), and a solution of the base (2
mmol in 1.5 mL of water) were added. Conversion of the
substrate was monitored by GLC for a maximum of 16 h using
dodecane as the internal standard. After cooling to room
temperature, the reaction mixture was extracted with cyclo-
hexane (5 × 10 mL). The extracted phases were collected and
washed with dilute HCl to remove the trialkylammine deriving
from the IL decomposition. After removal of the solvent in
vacuo, the mixture was chromatographed on a silica pad using
diethyl ether/petroleum ether in different ratios depending on
the nature of the product to afford the diaryl derivatives in
high purity as shown by 1H NMR and reported in the
Supporting Information.
Typical Procedure for the Pd NP-Catalyzed Stille
Reaction. The preparation of the Pd NPs in the tetraalky-
lammonium salt was carried out following the procedure
reported above. Then, aryl halide (1 mmol) and tributylphe-
nylstannane (404 mg, 1.1 mmol) were added to the reaction
mixture and stirred at the reaction temperature (see Table
3). Conversion of the substrate was monitored by GLC for a
maximum of 16 h. Then, after cooling to room temperature,
the reaction mixture was extracted with cyclohexane (5 × 10
mL). The extracted phases were collected and washed with
dilute HCl to remove trialkylammine derived from the IL
decomposition. After the solvent removal, in vacuo, the mixture
was chromatographed on a silica pad, affording diaryl deriva-
tives in high purity as shown by 1H NMR and reported in the
Supporting Information.
FIGURE 3. Recycling experiments for the Stille cross-
coupling of Pd NPs in IL.
protocol using THeptAB as solvent in the Stille coupling
between aryl bromides and chlorides and tributylphenyl
stannane. Results are summarized in Table 3.
As in the case of the Suzuki reaction, the process
afforded high product yields starting from aryl bromides,
as well as simple or activated aryl chlorides. These
substrates were in fact successfully converted at 90 °C
for 16 h (entries 1-5), while deactivated electron-rich aryl
chlorides turned out to be significantly less reactive and
afforded modest yields of biaryls even working at 110-
130 °C (entries 6 and 7).
Since the initial goal of this research effort was to
develop a highly recyclable solvent/catalyst system, we
further investigated the possibility to recycle the catalyst
on the model reaction between p-bromotoluene and
phenyltributylstannane. The results obtained show that
the catalyst system can be used at least five times with
little loss in activity (Figure 3).
These results, as well as those concerning the Suzuki
process, confirm the superiority of tetraalkylammonium
salts as reaction media for Pd NP-catalyzed processes.
As anticipated, the nature of both cation and anion of
the IL markedly influences the reaction outcome: on the
one hand, the longer alkyl chains of cation ensure the
Procedure for the Catalyst Recycling of the Suzuki
Coupling. After completion of the reaction and after cooling
to room temperature, the products and the unreacted reagents
were extracted with cyclohexane (5 × 10 mL). After removal
J. Org. Chem, Vol. 70, No. 15, 2005 6043

Calo` et al.
of the residual organic solvent under vacuum, the resulting
biphasic mixture was charged with fresh reagents (aryl halide,
boronic acid, and 2 equiv of solid Na2CO3) heated at the
required temperature with stirring for the proper time (Table
2).
Procedure for the Catalyst Recycling of the Stille
Coupling. After completion of the reaction and after cooling
to room temperature, the products and the unreacted reagents
were extracted with cyclohexane (5 × 10 mL). After removal
of the residual organic solvent under vacuum, the resulting
viscous mixture was charged with fresh reagents (aryl halide
and tributylphenylstannane) and heated at the required
temperature with stirring for the proper time (Table 3).
Acknowledgment. This work was financially sup-
ported by the Ministero dell’Universita` e della Ricerca
Scientifica e Tecnologica, Rome, Italy, and the Univer-
sity of Bari (National Project: “Stereoselezione in Sin-
tesi Organica: Metodologie ed Applicazioni”).
Supporting Information Available: 1H NMR spectra of
the reaction products. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO050801Q
6044 J. Org. Chem., Vol. 70, No. 15, 2005