Use of polymer-supported Pd reagents for rapid and efficient Suzuki reactions using microwave heating

Article abstract of DOI:10.1021/ol048972p

A rapid and efficient Suzuki coupling protocol has been developed utilizing polymer-supported palladium catalysts and microwave irradiation. It is also shown that solid-phase extraction of excess boronic acids can be rapidly and conveniently accomplished by utilization of a silica-supported carbonate base.

Full text of DOI:10.1021/ol048972p

ORGANIC
LETTERS
2
004
Vol. 6, No. 16
793-2796
Use of Polymer-Supported Pd Reagents
for Rapid and Efficient Suzuki Reactions
Using Microwave Heating
2
Ying Wang and Daryl R. Sauer*
High-Throughput Organic Synthesis Group, Global Pharmaceutical R&D,
Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6113
daryl.r.sauer@abbott.com
Received June 3, 2004
ABSTRACT
A rapid and efficient Suzuki coupling protocol has been developed utilizing polymer-supported palladium catalysts and microwave irradiation.
It is also shown that solid-phase extraction of excess boronic acids can be rapidly and conveniently accomplished by utilization of a silica-
supported carbonate base.
The palladium-catalyzed cross coupling of aryl halides with
boronic acids (Suzuki reaction) is one of the most versatile
and commonly utilized reactions for the construction of
carbon-carbon bonds, in particular for the formation of
transfer reaction mixtures. In addition, removal of Pd and
associated ligands from the resulting product is not always
easily accomplished, resulting in tedious workups.
Supported Pd catalysts are becoming increasingly popular
since the heterogeneous Pd can be easily filtered upon
1
biaryls. The biaryl motif is an important pharmacophore in
2
3
many biologically active compounds, and as such the Suzuki
completion of the reaction. They are also generally air stable
reaction is widely utilized by medicinal chemists in the hit
to lead and lead optimization stages of drug discovery. Its
popularity has been further enhanced due to the increasing
availability of organoboronic reagents, a broad range of
functional group tolerance, and the low toxicity of inorganic
byproducts. The Suzuki reaction is generally performed in
organic solvents such as toluene, DMF, or THF in the
presence of inorganic bases and homogeneous Pd catalysts
and easy to store and handle, making them highly amenable
for both routine and automated synthesis.
Recent advances in microwave heating have greatly
impacted many aspects of chemical synthesis, including
4
applications for transition-metal-catalyzed reactions. It has
been demonstrated that the use of microwave heating can
dramatically cut down reaction times, increase product purity
and yields, and allow precise control of reaction parameters,
all of which are crucial factors to consider when developing
reaction protocols for both routine synthetic transformations
and parallel synthesis.
3 4 3 2 2
such as Pd(PPh ) or Pd(PPh ) Cl . One of the major
problems encountered when performing Suzuki reactions in
automated or semiautomated parallel synthesis results from
the use of these homogeneous palladium catalysts. The Pd
residues may clog probes and frits that are used to filter and
(3) Recent examples include: (a) Yamada, Y. M.; Takada, K.; Takahashi,
H.; Ikegami, S. Org. Lett. 2002, 4, 3371-3374. (b) Mubofu, E. B.; Clark,
J. H.; Macquarrie, D. J. Green Chem. 2001, 3, 23-25. (c) Zhang, T. Y.;
Allen, M. J. Tetrahedron Lett. 1999, 40, 5813-5816.
(4) For recent reviews, see: (a) Lidstr o¨ m, P.; Tierney, J.; Wathey, B.;
Westman, J. Tetrahedron 2001, 57, 9225-9283. (b) Larhed, M.; Moberg,
C.; Hallberg, A. Acc. Chem. Res. 2002, 35, 717-727. (c) Lew, A.; Krutzik,
P. O.; Hart, M. E.; Chamberlin, A. R. J. Comb. Chem. 2002, 4, 95-105.
(d) Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199-9223.
(1) For recent reviews, see: (a) Hassan, J.; S e´ vignon, M.; Gozzi, C.;
Schulz, E.; Lemaire, M. Chem. ReV. 2002, 102, 1359-1470. (b) Kotha, S.;
Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633-9695. (c) Littke, A.
F.; Fu, G. C. Angew. Chem., Int. Ed. Engl. 2002, 41, 4126-4211. (d) Suzuki,
A. J. Organomet. Chem. 1999, 576, 147-168.
(
2) Hajduk, P. J.; Bures, M.; Praestgaard, J.; Fesik, S. W. J. Med. Chem.
2
000, 43, 3443-3447.
1
0.1021/ol048972p CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/14/2004

Although microwave-assisted Suzuki reactions have been
low loading of the catalyst (3 mol %) and short reaction times
5
10
11
reported, there are few reports on the use of polymer-
(110 °C, 600 s). A simple filtration through Si-carbonate
and chromatographic purification afforded the final product
6
supported Pd catalysts in Suzuki reactions. Wishing to take
1
2
full advantage of the complementary nature of these powerful
tools, we have investigated the use of several commercially
available polymer-supported Pd catalysts in microwave-
assisted Suzuki reactions. Herein we report our findings on
the application of polymer-supported Pd catalysts such as
in excellent yield and purity.
Encouraged by these results, and wanting to investigate
the general scope of the method, we picked compound 2 to
carry out additional studies (Table 2). Under microwave
FibreCat (Figure 1)7 and PS-PPh
,8
-Pd in microwave-
9
3
accelerated Suzuki reactions.
Table 2. Suzuki Coupling Reaction of 5-Bromobenzolidine
with Various Catalytic Systems
entry
catalyst
solvent
conversiona
1
2
3
4
5
6
7
8
PdCl2(PPh3)2
PS-PPh3-Pd
FC 1001
FC 1001
FC 1001
FC 1001
FC 1007
FC 1032
DME/EtOH (1:1)
DME/EtOH (1:1)
DME/EtOH (1:1)
DME/EtOH (7:2)
EtOH
EtOH
EtOH
EtOH
88%
81%
85%
50%
97%
100%b
100%
100%
Figure 1. Polyethylene-Supported FibreCat Pd Catalysts.
Compound 1 (Table 1) was initially selected for our model
study. Under microwave heating conditions, both FC 1001
a
Determined by H NMR and LC/MS. b Microwave, 900 s, 110 °C.
1
Table 1. Microwave-Assisted Suzuki Reaction with
Polymer-Supported Pd
heating conditions with K
2
CO
1:1), good conversions were observed when either PdCl
PPh , FC 1001, or PS-PPh -Pd (Table 2, entries 1-3)
3
as the base in DME/EtOH
(
(
2
-
3
)
2
3
was used. Increasing the amount of boronic acid did not
improve the conversion. The reaction was found to be
insensitive to water content, which was varied from 0 to 50%
of the total solvent volume. It was found that utilizing K
CO
were observed when other bases were used, including Na
CO
After screening different solvent systems, it was observed
that increasing amounts of DME decreased the reaction
efficiency (Table 2, entry 4). Optimal reaction conditions
were obtained using 3 mol % catalyst and heating to 110 °C
2
-
3
as the base gave the best yields. Inferior conversions
entry
catalyst
FC 1001
PS-PPh3-Pd
conversiona (isolated yield)
2
-
1
2
100% (99%)
97% (90%)
, organic amines, and various polymer-supported bases.
3
a
1
Determined by H NMR and LC/MS.
and PS-PPh
3
-Pd afforded excellent conversion to the
1
(9) Argonaut Technologies. http://www.argotech.com (accessed July 4,
004).
Suzuki product, as verified by H NMR and LC/MS, with
2
(
10) Microwave reactions were carried out on a Emrys Optimizer (http://
(
5) For recent examples, see: (a) Larhed, M.; Hallberg, A. J. Org. Chem.
www.personalchemistry.com). Wattage was automatically adjusted so as
to maintain the desired temperature.
1
2
6
2
996, 61, 9582-9584. (b) Leadbeater, N. E.; Marco, M. J. Org. Chem.
003, 68, 888-892. (c) Leadbeater, N. E.; Marco, M. J. Org. Chem. 2003,
8, 5660-5667. (d) Leadbeater, N. E.; Marco, M. Org. Lett. 2002, 4, 2973-
976. (e) Gong, Y.; He, W. Org. Lett. 2002, 4, 3803-3805.
(11) SiliCycle, Inc. http://www.silicycle.com (accessed July 4, 2004).
(12) Representative Procedure. A Smith Process vial (2-5 mL) was
charged with a stir bar, 0.2 mmol (36.4 mg) of 4-bromobenzonitrile, 0.24
mmol (32.6 mg) of p-tolylboronic acid, and 2 mL of ethanol. A solution of
1 M K2CO3 (0.24 mL) was added to the solution followed by the polymer-
supported Pd (3 mol % Pd) catalyst. The reaction vessel was sealed and
heated to 110 °C for 600 s under microwave irradiation. After cooling, the
reaction mixture was transferred to a prepacked column of Si-carbonate (2
g, 0.79 mmol/g), which had been conditioned with MeOH/CH2Cl2 (1:1),
and the elutant was collected via gravity filtration. The column was then
washed with MeOH/CH2Cl2 (1:1) (3 × 3 mL). The elutants were combined,
concentrated, and purified by flash chromatography (silica, hexane/ethyl
acetate, 0-10% gradient) to afford 38.3 mg (99%) of analytically pure 4′-
methyl-biphenyl-4-carbonitrile.
(6) (a) Choudary, B. M.; Madhi, S.; Chowdari, N. S.; Kantam, M. L.;
Sreedhar, B. J. Am. Chem. Soc. 2002, 124, 14127-14136. (b) Fenger, I.;
Drian, C. L. Tetrahedron Lett. 1998, 39, 4287-4290. (c) Yamada, Y. M.;
Takeda, K.; Takahashi, H.; Ikegami, S. J. Org. Chem. 2003, 68, 7733-
7
3
741. (d) Uozumi, Y.; Danjo, H.; Hayashi, T. J. Org. Chem. 1999, 64,
384-3388. (e) Zhang, W.; Chen, C. H.-T.; Lu, Y.; Nagashima, T. Org.
Lett. 2004, 6, 1473-1476.
(7) Johnson Matthey. http://www.chemicals.matthey.com (accessed July
4
3
, 2004).
(8) Colacot, T. J.; Gore, E. S.; Kuber, A. Organometallics 2002, 21,
301-3304.
2794
Org. Lett., Vol. 6, No. 16, 2004

for 10-15 min in EtOH with K
entries 5-8).
Unlike the homogeneous system (Table 2, entry 1), the
supported Pd reactions were much cleaner, usually yielding
a colorless solution upon completion of the reaction. Analysis
of the crude reaction mixture by LC-MS showed a single
peak corresponding to the product with no observable
2
CO
3
as the base (Table 2,
acids. This process greatly reduces reaction workup time,
which is one of the bottlenecks in analogue synthesis. When
the desired conversion is quantitative, and after SPE scav-
enging of excess boronic acid, no further purification is
needed. As is shown in Scheme 1, application of the
2 3 2
phosphine byproducts. With PdCl (PPh ) , a brown solution
Scheme 1. Microwave-Accelerated Suzuki Reaction Utilizing
was obtained after heating and triphenylphosphine oxide was
detected in the crude LC/MS.13 FC 1007 and FC 1032,
which are more reactive than FC 1001, gave quantitative
conversions with shorter reaction times (Table 2, entries
FC 1007 and Si-Carbonate
14
5
-8).15 All of the reactions were performed under ambient
atmosphere in sealed microwave tubes, and no observable
difference was found when the reaction was carried out under
nitrogen. This allows for easy sample preparation and is
advantageous for automated parallel synthesis as compared
to the use of homogeneous Pd Suzuki catalysts, most of
which are air sensitive to various extents.
Solid-phase extraction (SPE) techniques have proven to
be useful for scavenging a wide range of excess reagents
1
6
microwave-accelerated FibreCat-catalyzed Suzuki reaction
followed by Si-carbonate SPE afforded the biaryl Suzuki
product after 20 min in high yield and purity. The process
can be easily adapted to automation and, in turn, utilized to
prepare Suzuki libraries via parallel syntheses.
and reaction side-products, including boronic acids. SPE
is especially well suited for parallel synthesis since in many
cases a simple filtration will remove undesired materials,
thereby greatly simplifying reaction workup. It has been
found that the use of silica-supported reagents in SPE can
With a convenient protocol in hand, we examined the
scope of this method, and the results are summarized in Table
greatly decrease the time required for byproduct sequestra-
tion.17 Therefore, Si-carbonate was studied for its effective-
4. It was found that both electron-rich and electron-deficient
ness in scavenging boronic acids. For these experiments, the
desired amount of Si-carbonate was packed into a short
column and subsequently prewetted with MeOH. A solution
of boronic acid in EtOH was passed through the Si-carbonate
column by gravity filtration and washed with additional
MeOH. Compound 1 was added to the boronic acid solution
and used as an internal standard to determine the amount of
boronic acids afforded the desired product in good to
excellent yields. In addition, this method efficiently couples
a wide range of aryl halides, including aryl bromides (entries
1
-3), activated aryl chlorides (entries 4-5), and iodides
(entries 6-8), affording excellent isolated yields. Aryl
triflates can also be accommodated (entry 9). Aryl chlorides
with electron-donating groups are generally challenging
substrates for Suzuki coupling reactions. Under these condi-
tions, moderate yields were obtained with inactivated aryl
chlorides when the most reactive FibreCat, FC 1032, was
used (entries 10 and 11). Many of the entries in Table 4
1
boronic acid in the eluted material by LC/MS and H NMR.
As seen in Table 3, it was found that 10 equiv of Si-carbonate
Table 3. Scavenging of Boronic Acids with a Si-Carbonate
Plug
1
showed quantitative conversion by LC-MS and crude H
NMR. In those cases, passing the crude mixtures through a
plug of Si-carbonate as described previously afforded the
pure products without the need for further purification.
In summary, we have developed a rapid, efficient, and
general Suzuki coupling reaction protocol that utilizes
(
13) Trace amounts (<35 ppm) of Pd were observed (ICP analysis) in
some crude reaction products prepared with the supported catalysts. The
leached Pd was eliminated during the flash chromatography step.
(14) FC 1032 is referred to as “Tuna Cat” in ref 8.
a
(15) Reaction was incomplete after 8 h when carried out in refluxing
EtOH as described in ref 8.
Not determined.
(16) (a) Flynn, D. L.; Devraj, R. V.; Naing, W.; Parlow, J. J.; Weidner,
J. J.; Yang, S. Med. Chem. Res. 1998, 8, 219-243. (b) Flynn, D. L.; Devraj,
R. V.; Parlow, J. J. Curr. Opin. Drug DiscoVery DeV. 1998, 1, 41-50. (c)
Weidner, J. J.; Parlow, J. J.; Flynn, D. L. Tetrahedron Lett. 1999, 40, 239-
242. (d) Lan, P.; Berta, D.; Porco, J. A.; South, M. S.; Parlow, J. J. J. Org.
Chem. 2003, 68, 9678-9686.
efficiently scavenged the boronic acid completely in a single
flow-through. Other solvents can be used effectively in
combination with MeOH. The complete scavenging process
takes less than 10 min and is effective with a range of boronic
(
17) Sauer, D. R.; Kalvin, D.; Phelan, K. M. Org. Lett. 2003, 5, 4721-
4724.
Org. Lett., Vol. 6, No. 16, 2004
2795

Table 4. Suzuki Coupling Reactions Catalyzed by Polymer-Supported Pd under Microwave Irradiation
a
FC 1001 was used. b FC 1032 was used. c Small amount of dehalogenated product was observed in the crude reaction mixture. Reaction conditions:
d
e
f
1
°
.4 equiv of boronic acid was used. Microwave, 110 °C, 900 s. Reaction conditions: microwave, 110 °C, 600 s. Reaction conditions: microwave, 120
C, 600 s. Reaction conditions: 1.5 equiv of boronic acid was used. Microwave, 120 °C, 1500 s. Greater than 97% purity by HPLC (ELSD and UV
g
h
detection) and NMR analysis.
and has been successfully used for routine library generation
in our laboratories.
commercially available polymer-supported Pd catalysts and
microwave heating. Furthermore, it has been demonstrated
that excess boronic acid can be effectively scavenged by Si-
carbonate. The protocol is convenient and uses environmen-
tally benign reagents and solvents. In addition, this Suzuki
reaction procedure is highly amenable for parallel synthesis
Supporting Information Available: General experiment
details and analytical characterization. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL048972P
2796
Org. Lett., Vol. 6, No. 16, 2004