The actual active species of sulfur-modified gold-supported palladium as a highly effective palladium reservoir in the suzuki-miyaura coupling

Article abstract of DOI:10.1002/adsc.201000820

The actual active species of the recently developed sulfur-modified, gold-supported palladium material, S-modified Au-supported Pd (SAPd), with one of the lowest Pd-releasing levels and high recyclability in the Suzuki-Miyaura coupling, was investigated. Also, SAPd was found to work repeatedly as an excellent Pd reservoir for liquid-phase combinatorial synthesis. Copyright

Full text of DOI:10.1002/adsc.201000820

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DOI: 10.1002/adsc.201000820
The Actual Active Species of Sulfur-Modified Gold-Supported
Palladium as a Highly Effective Palladium Reservoir in the
Suzuki–Miyaura Coupling
Naoyuki Hoshiya,a,b Satoshi Shuto,a and Mitsuhiro Arisawaa,*
a
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812, Japan
Fax : (+81)-11-706-3769; e-mail: arisawa@pharm.hokudai.ac.jp
Furuya Metal Company Limited, Tokyo 170-0005, Japan
b
Received: October 30, 2010; Revised: January 18, 2011; Published online: March 15, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000820.
Abstract: The actual active species of the recently an excellent Pd reservoir for liquid-phase combinato-
developed sulfur-modified, gold-supported palladium rial synthesis.
material, S-modified Au-supported Pd (SAPd), with
one of the lowest Pd-releasing levels and high recy-
clability in the Suzuki–Miyaura coupling, was investi- Keywords: C C coupling; combinatorial chemistry;
gated. Also, SAPd was found to work repeatedly as green chemistry; heterogeneous catalysis; palladium
À
Introduction
in the Suzuki–Miyaura coupling, this is one of the
best Pd materials developed thus far. Because SAPd
Liquid-phase combinatorial parallel synthesis[1] is an leaches extremely low levels of Pd into reaction mix-
effective method for the generation of a diverse li- tures, removal of the residual Pd becomes unnecessa-
brary of small molecules, and it has been used not ry, even in the syntheses of pharmaceutical ingredi-
only in the field of drug discovery[2] but also in organ- ents.
ic materials.[3]
With this background, we continued our chemical
Palladium-catalyzed reactions allow for the rapid experiments to determine how SAPd works in the
access to a diverse range of compounds, but they also Suzuki–Miyaura coupling. Thus, the actual active spe-
present a problem in that the palladium can often be cies of SAPd and its application to liquid-phase com-
retained in the product even after the purification binatorial chemistry were investigated. It is notewor-
steps. For pharmaceutically active ingredients, there thy that SAPd has proven to be a very effective Pd
are typically strict guidelines to limit the levels of con- material for liquid-phase combinatorial synthesis and
taminating heavy metals, including palladium, in the SAPd is repeatedly used for synthesizing structurally
drug.[4]
diverse molecules by the Suzuki–Miyaura coupling
In an effort to create re-usable, Pd leach-free cata- without contamination of substrates or products. Here
lysts, many heterogeneous catalysts have been devel- we report the results of these studies.
oped with Pd immobilized on supports such as acti-
vated carbon, inorganic solids and polymers.[5] Yet
À
few of these immobilized Pd catalysts for C C bond Results and Discussion
formations can claim both high recyclability (more
than 10 cycles) and low Pd leaching (less than 1 ppm). The Actual Active Species of SAPd
Furthermore, there have been no palladium catalysts,
which repeatedly work well in liquid-phase combina- In the development of a novel heterogeneous catalyst,
torial synthesis with low Pd leaching.
identification of the actual active species is highly im-
Most recently, our group has developed a practical portant. First, we performed kinetic studies/filtration
Pd material, namely S-modified Au-supported Pd, tests and compared the time conversion plots by fol-
SAPd [6]. Due to the lowest recorded Pd-releasing lowing 3 reactions to investigate whether the leached
levels (less than 1 ppm in 3 mL of solvent, TON up to Pd species had catalytic activity for the Suzuki–
2,760,000) and high recyclability (more than 10 cycles) Miyaura coupling (Figure 1).[7] A mixture of 1a
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without SAPd for 10.5 h (reaction b). Reaction c was
carried out in the same manner except that SAPd was
removed after 30 min from the start (reaction c). In
reaction c, only a trace amount of 3a resulted (less
than 3%). On the other hand, in reaction b, the prod-
uct increased time-dependently, after removal of the
catalyst from the reaction mixture, and the yield of 3a
reached almost 80% after 12 h. Hence, the yield of 3a
continuously increased even in the absence of SAPd.
Moreover, a lag time is observed in reactions a and b.
Thus, it is conceivable that it takes time for the actual
active Pd species to be released to the reaction mix-
ture from SAPd. These results suggest that SAPd
might work as an effective Pd reservoir for the follow-
ing reasons. It is known that Pd is strongly retained in
SAPd, and during the Suzuki–Miyaura coupling, a
trace of the Pd species is released from SAPd into the
reaction mixture. The released Pd species has an ex-
tremely high catalytic activity in the Suzuki–Miyaura
coupling, since the reaction is complete with only a
trace[8] amount of the Pd species.
Next, we performed a three-phase test[9] to deter-
mine which soluble or insoluble species is the actual
active catalyst by carrying out a metal-catalyzed reac-
tion with a substrate immobilized on a polymer. We
prepared the immobilized iodobenzene 6 according to
the Daviesꢃ protocol.[9a] The immobilized 6 is known
Figure 1. Filtration test.
(0.5 mmol), 2a (1.5 equiv.), K2CO3 (2 equiv.), and to be inactive with the insoluble Pd catalyst but active
SAPd (14 mmꢁ12 mm), which contained 38Æ9 mg of with the soluble Pd catalyst. Therefore we investigat-
Pd, was heated at 808C in EtOH (3 mL) without stir- ed the Suzuki–Miyaura coupling using 6. After the re-
ring for 12 h (reaction a). The coupling proceeded ef- action, the resulting mixture was treated with an
ficiently to give the product 3a in 92% yield after excess of trifluoroacetic acid (TFA) to remove the de-
12 h. The same reaction was performed for 1.5 h and, sired coupling product from the polymer by breaking
after cooling the mixture to room temperature, SAPd the amide bond. The Suzuki–Miyaura coupling of 2b
was removed from the ꢂcoldꢃ mixture. Then, the re- and 6 was performed in the presence of SAPd and
sulting solution was heated continuously at 808C K2CO3 in EtOH (Figure 2, [case 1] and entry 1). After
Figure 2. Three-phase test.
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The Actual Active Species of Sulfur-Modified Gold-Supported Palladium
Figure 3. Plausible mechanism of SAPd.
heating the reaction mixture at 808C for 12 h, we mixture. The released Pd species has an extremely
then removed the catalyst and filtered the resulting high catalytic activity in the Suzuki–Miyaura coupling,
reaction mixture through Celite 545. The resin was since the reaction was completed with only a trace of
treated with TFA at room temperature for 2 h to give the Pd species. Furthermore, the three-phase test
only the iodobenzene derivative 7 in 78% yield. As a might suggest that a soluble iodobenzene, such as 1b,
control, we carried out the Suzuki–Miyaura coupling could be a key participant in the mechanism of the Pd
of 2b in the presence of two other iodobenzenes, 1b release, probably at the oxidative addition step, be-
and 6, for 12 or 24 h under the same reaction condi- cause 8 was not obtained without 1b (Figure 2, [case
tions ([case 2] and entries 2 and 3). In both cases, the 1]). Soluble boronic acid does not affect the results
coupling product 8 was obtained in 6% and 32% (Figure 2, [cases 1 and 2]).[10] Thus, as shown in
yields, respectively. These results are identical with Figure 3, it is possible that the oxidative addition of
those of the previous filtration tests, namely Pd is 1b to the Pd supported on SAPd initiates the release
strongly retained in SAPd. Furthermore, during the of the active Pd species into the reaction mixture. The
Suzuki–Miyaura coupling, a trace amount of the Pd reaction rate in repeatedly use was also examined
species was released from SAPd into the reaction (Figure 4).
Figure 4. Reaction rate in repeated use.
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Table 1. Examples of liquid phase combinatorial chemistry
SAPd as a Pd Reservoir for Liquid-Phase
Combinatorial Synthesis
using SAPd.[a]
It is widely known that, when polymer-supported Pd
is used, the reaction suffers from contamination prob-
lems and the catalyst has to be washed very carefully
due to the strong absorption of the starting material
and/or the product to the polymer. In dramatic con-
trast, SAPd has a much smaller surface area and
could absorb many fewer organic compounds, includ-
ing starting materials or products, than those of poly-
mer-supported Pd, due to its low affinity for organic
molecules. Moreover, the Au mesh, used as the sup-
port for Pd in SAPd, is malleable and easy to handle
with a pair of tweezers. Combinatorial synthesis is an
important technique in medicinal chemistry and is
widely used for drug development. However, no prac-
tical solid-supported Pd, which can be repeatedly
used for different kinds of coupled products synthesis,
was known until now.[11] Considering the above-men-
tioned advantages, SAPd may indeed be an ideal
solid catalyst for combinatorial synthesis. Consequent-
ly, we tried liquid-phase combinatorial synthesis with
SAPd by changing the iodobenzene derivatives as the
substrates.
When SAPd was used in the Suzuki–Miyaura cou-
pling of phenylboronic acid 2b and ten different iodo-
benzenes with K2CO3 in EtOH, as shown in Table 1,
the yields for runs 1 to 10 were excellent to quantita-
tive in all cases (Table 1). In these reactions, products
with high purity[12] were obtained after the usual
aqueous work-up. Not only did the aromatic iodide
(runs 1–7) react with 2b to give the coupling products
in quantitative yields but also both the heterocyclic
iodides (runs 8 and 9) and the styrenyl iodide reacted
(run 10). This was likewise the case when the boronic
[a]
The SAPd was repeatedly used to the above Suzuki–
Miyaura couplings. A solution of SAPd (ca. 1 cm2), phe-
nylboronic acid 2b (1.5 equiv.), an aryl iodide (0.5 mmol)
and K2CO3 (2 equiv.) was heated in EtOH (3 mL) at
808C for 12 h. After usual aqueous work-up, the corre-
sponding high quality product 3 was obtained. SAPd was
taken out from the reaction mixture and used repeatedly.
acid derivative was changed (Table 2). Therefore it phase combinatorial synthesis. One preparation of
was found that SAPd was an effective Pd reservoir SAPd can be repeatedly used for different kinds of
for this kind of synthesis without any contamination substrates while furnishing the desired products with-
with other products or starting materials.
out any contamination.
SAPd was repeatedly used in the above Suzuki–
Miyaura couplings. A solution of SAPd (ca. 1 cm2),
phenylboronic acid 2b (1.5 equiv.), an aryl bromide Experimental Section
(0.5 mmol), and K2CO3 (2 equiv.) was heated in
EtOH (3 mL) at 808C for 12 h. After the usual aque- Preparation of SAPd
ous work-up, the corresponding product 3 was ob-
tained in high purity. The SAPd was removed from A 14ꢁ12 mm2 (100 mesh) sample of Au was placed in
the reaction mixture and used repeatedly.
35% H2O2 aqueous solution (1 mL) and concentrated
H2SO4 (3 mL) for 3 min and then rinsed in succession
with H2O (3 mLꢁ10) and EtOH (3 mLꢁ5). The
sample was placed in a flask and dried for 10 min
under reduced pressure (ca. 6 mmHg). The resulting
Conclusions
In summary, we have demonstrated that SAPd, with sulfur-modified Au [S-Au] was placed in a solution of
the lowest Pd-releasing levels and high recyclability in Pd(OAc)2 (5.3 mg, 0.023 mmol) in xylene (3 mL) and
AHCTUNGTRENNUNG
the Suzuki–Miyaura coupling, works as a Pd reservoir stirred at 1008C for 12 h under an argon atmosphere.
and releases the catalytically active Pd species, which Then the plate was rinsed with xylene (3 mLꢁ100)
renders it one of the best Pd materials for liquid- and dried under vacuum. The sample was placed in
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The Actual Active Species of Sulfur-Modified Gold-Supported Palladium
Table 2. Examples of liquid phase combinatorial chemistry
with EtOH. The reaction mixture was poured into
2M aqueous NaOH and extracted with AcOEt. The
organic layer was washed saturated aqueous NH4Cl,
and satuarted aqueous NaCl, dried over anhydrous
MgSO4, concentrated under vacuum to give biphenyl
in quantitative yield as a colorless solid.
using SAPd.[a]
The recovered SAPd was again subject to the
above reaction conditions as a 2nd run. This proce-
dure was repeated a total 10 runs.
Acknowledgements
This research was supported by a Grant-in-Aid from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy (MEXT), and Adaptable and Seamless Technology
Transfer Program through target-driven R & D, Japan Sci-
ence and Technology Agency (JST), Japan.
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[a]
The SAPd was repeatedly used to the above Suzuki–
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xylene (3 mL) and heated at 1358C for 12 h. The
sample was rinsed with xylene (3 mLꢁ50) and dried
under vacuum for 10 min to give SAPd (Pd: 38Æ
9 mg).
Typical Experimental Procedure of Successively
Suzuki–Miyaura Coupling Changed Substrates for
Each Reaction [Table 1, 1st Run]
A mixture of iodobenzene (102 mg, 0.5 mmol), phe-
nylboronic acid (91.4 mg, 0.75 mmol), and K2CO3
(138 mg, 1.0 mmol) in EtOH (3 mL) was heated in
the presence of SAPd (14ꢁ12 mm, Pd: 38Æ9 mg) at
808C for 12 h under an argon atmosphere without
stirring. After the reaction mixture had been cooled
to room temperature, the SAPd plate was removed
from the reaction mixture and rinsed several times
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1
[10] When 5 mol% of Pd
8 was obtained quantitatively. When the amount of
Pd(OAc)2 was reduced to less than 0.07 mol%, no 8
was obtained.
ACHTUNGRTEN(NUNG OAc)2 was used instead of SAPd,
[12] The products were pure enough by H NMR spectros-
copy. See Supporting Information.
ACHTUNGTRENNUNG
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