Ligand-free palladium catalysis of the Suzuki reaction in water using microwave heating

Article abstract of DOI:10.1021/ol0263907

(figure presented) We report the ligand-free palladium catalysis of the Suzuki reaction in water using microwave heating. Our methodology uses low palladium loadings (0.4 mol %), is fast (5-10 min reaction time), and is useful for couplings involving boronic acids and aryl iodides, bromides, and chlorides.

Full text of DOI:10.1021/ol0263907

ORGANIC
LETTERS
2002
Vol. 4, No. 17
2973-2976
Ligand-Free Palladium Catalysis of the
Suzuki Reaction in Water Using
Microwave Heating
Nicholas E. Leadbeater* and Maria Marco
Department of Chemistry, King’s College London, Strand, London WC2R 2LS, U.K.
nicholas.leadbeater@kcl.ac.uk
Received June 19, 2002
ABSTRACT
We report the ligand-free palladium catalysis of the Suzuki reaction in water using microwave heating. Our methodology uses low palladium
loadings (0.4 mol %), is fast (5−10 min reaction time), and is useful for couplings involving boronic acids and aryl iodides, bromides, and
chlorides.
Water is a cheap, readily available nontoxic solvent for use
in chemistry.1 As well as for organic chemistry, water has
also been used for metal-mediated organic synthesis.2 There
are, however, problems with the use of water, such as
solubility of substrates and stability of the metal catalysts in
water, but these problems have to some extent been overcome
by the use of phase-transfer catalysts and water-soluble
phosphine ligands or the design of novel heterogeneous
catalysts.3 With its high dielectric constant, water is also
potentially a very useful solvent for microwave-mediated
synthesis.4,5 As well as benefiting from the rate enhancement
effects found when using microwave heating, when water
is heated well above its boiling point in sealed vessels,
organic substrates can become more soluble.6
The Suzuki reaction (palladium-catalyzed cross coupling
of aryl halides or triflates with boronic acids) is one of the
most versatile and utilized reactions for the selective
construction of carbon-carbon bonds, in particular for the
formation of biaryls.7 There have been a number of reports
of the palladium-mediated Suzuki reaction being performed
using water as a solvent,8,9 which relate to the coupling of
aryl boronic acids with aryl iodides or activated bromides,
with only one recent exception. This reports the coupling of
aryl chlorides but involves the use of an oxime-carbapalla-
dacycle as the catalyst.10 There have also been a number of
reports of the use of water as a cosolvent for the reaction,
(5) For recent reviews on the use of microwaves in organic synthesis
see: (a) Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002, in
press. (b) Lew, A.; Krutzik, P. O.; Hart, M. E.; Chamberlin, A. R. J. Comb.
Chem. 2002, 4, 95. (c) Lindstro¨m, P.; Tierney, J.; Wathey B.; Westman, J.
Tetrahedron 2001, 57, 9225. (d) Perreux L.; Loupy, A. Tetrahedron 2001,
57, 9199. (e) S. Deshayes, S.; Liagre, M.; Loupy, A.; Luche, J.-L.; Petit,
A. Tetrahedron 1999, 55, 10851.
(6) Katritzky, A. R.; Siskin, M. Chem. ReV. 2001, 101, 837.
(7) For recent reviews, see: (a) Hassan, J.; Se´vignon, M.; Gozzi, C.;
Schulz, E.; Lemaire, M. Chem. ReV. 2002, 102, 1359. (b) Suzuki, A. J.
Organomet. Chem. 1999, 576, 147. Miyaura, N.; Suzuki, A. Chem. ReV.
1995, 95, 2457.
(1) For an introduction to the use of water as a solvent in organic
synthesis see: (a) Organic Synthesis in Water; Greico, P. A., Ed.; Blackie
Academic & Professional: London, 1998. (b) Li, C.-J.; Chen, T.-H. Organic
Reactions in Aqueous Media; Klewer Academic Publishers: Dordrecht,
1997.
(2) For an introduction to the use of organometallic catalysts in aqueous-
phase catalysis, see: Aqueous-Phase Organometallic Catalysis, Concepts
and Applications; Cornils, B., Herrmann, W. A., Eds; Wiley-VCH:
Weinheim, 1998.
(3) For recent examples, see: (a) Gulyas, H.; Szollosy, A.; Hanson, B.
E.; Bakos, J. Tetrahedron Lett. 2002, 43, 2543. (b) Brauer, D. J.; Hingst,
M.; Kottsieper, K. W.; Like, C.; Nickel, T.; Tepper, M.; Stelzer, O.;
Sheldrick, W. S. J. Organomet. Chem. 2002, 645, 14.
(4) See, for example: (a) Baudel, V.; Cazier, F.; Woisel, P.; Surpateanu,
G. Eur. Polymer. J. 2002, 38, 615. (b) An, J. Y.; Bagnell, L.; Cablewski,
T.; Strauss, C. R.; Trainor, R. W. J. Org. Chem. 1997, 62, 2505.
(8) For a review of palladium-catalyzed reactions in water, see: Geneˆt,
J.-P.; Savignac, M. J. Organomet. Chem. 1999, 576, 305.
(9) (a) Sakurai, H.; Tsukuda, T.; Hirao, T. J. Org. Chem. 2002, 67, 2721.
(b) Badone, D.; Baroni, M.; Cardamone, R.; Ielmini, A.; Guzzi, U. J. Org.
Chem. 1997, 62, 7170. (c) Bumagin, N A.; Bykov, V. V. Tetrahedron 1997,
53, 14437.
(10) Botella, L.; Na´jera, C. Angew. Chem., Int. Ed. 2002, 41, 179.
10.1021/ol0263907 CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/30/2002

again focusing on the use of aryl iodides or activated
bromides,11 and one recent report12 of the use of aryl
chlorides in a 20:1 DMA/water mix. The first reports of
microwave-mediated Suzuki reactions came in 1996, using
Pd(PPh3)4 as a catalyst both for homogeneous13 and solid-
phase14 biaryl synthesis. More recently, microwave heating
has been used to facilitate the coupling in water of aryl
boronic acids with the poly(ethylene glycol) esters of an aryl
iodide, triflate, and a bromothiophene.15 In the same report,
4-iodobenzoic acid methyl ester was also coupled with a
range of boronic acids in water/poly(ethylene glycol) mix-
tures. Sodium tetraphenylborate has recently been used as a
phenylation reagent for microwave-mediated aqueous-phase
biaryl synthesis.16
A range of palladium catalysts have been used in these
studies, and in many cases it is possible to perform the
reaction ligand-free using varying amounts of palladium salts9
or palladium on charcoal.9a,12 Although much attention has
been focused on water-soluble aryl halides, non-water-soluble
halides have also been coupled, but in the presence of a
phase-transfer catalyst.9b,10
In this Letter we present the results from our investigations
into the ligand-free palladium catalysis of the Suzuki reaction
in pure water using microwave heating. The methodology
we report here uses low palladium loadings (0.4 mol %), is
fast (5-10 min reaction time), and is useful for Suzuki
coupling reactions involving a range of aryl iodides and
bromides. In addition, we report that aryl chlorides can also
be coupled, although in slightly lower yields than their
bromo-counterparts.
As a starting point for the development of our microwave-
mediated methodology, we chose to study the coupling of
phenylboronic acid with 4-iodobenzoic acid. We found that
using 5 mol % Pd(OAc)2, Na2CO3 as base, and 1 mL water,
it was possible to obtain an isolated yield of 95% of
4-phenylbenzoic acid after 10 min of microwave irradiation.17
Using a microwave power of 60 W we ramped the temper-
ature from room temperature to 200 °C, which took 30-40
s, and then held it at this temperature for 5 min.18 Our
attention then turned to the coupling of phenylboronic acid
with the non-water-soluble substrate 4-bromotoluene as this
would act as a sharpening stone for optimizing reaction
conditions (Table 1). Using the same conditions as for
Table 1. Microwave-Mediated Suzuki Coupling of
4-bromotoluene and Phenylboronic Acid in Water Using
a
Pd(OAc)2
product
yield %c
entry
1
reaction conditionsb
5 mol % Pd(OAc)2,
32
T ) 200 °C, hold time 5 min
5 m ol % P d Cl2,
2
3
4
5
6
16
40
14
40
87
T ) 200 °C, hold time 5 min
0.4 m ol % P d (OAc)2,
T ) 200 °C, hold time 5 min
0.2 m ol % P d (OAc)2,
T ) 200 °C, hold time 5 min
0.4 m ol % P d (OAc)2,
T ) 150 °C, hold time 5 min
0.4 m ol % P d (OAc)2,
T ) 150 °C, hold time 5 min,
0.5 equ iv TBAB
7
8
0.4 m ol % P d (OAc)2,
T ) 150 °C, hold time 5 min,
1 equ iv TBAB
0.4 m ol % P d (OAc)2,
T ) 150 °C, h old tim e 10 m in ,
1 equ iv TBAB
96
92
a 1 mmol of aryl halide, 1 mmol of PhB(OH)2, 3 mmol of Na2CO3, 2
mL of water. Microwave irradiation ) 60 W; temperature ramped to that
stated and held there for the allotted time. b Conditions changed from entry
1
1 are highlighted in bold. c Determined by H NMR.
4-iodobenzoic acid, we obtained a yield of 4-phenyltoluene
of 32% (Table 1, entry 1). Our first thought was that the
low yield was attributed to the poor solubility of 4-bromo-
toluene in water, even at these high temperatures. In working
up this reaction, we found that all of the boronic acid had
been consumed. Further investigation showed that at the
temperatures we were using there was competitive proto-
deboronation of the boronic acid to produce benzene. This
indicates that the low yield of Suzuki product obtained in
the reaction is not solely due to poor substrate solubility.
Changing the palladium complex from Pd(OAc)2 to PdCl2
had deleterious results, a lower yield of product being
obtained (Table 1, entry 2). To overcome the problems of
deboronation, we studied the effects of temperature and
Pd(OAc)2 loading on the reaction (Table 1, entries 3-5).
(11) (a) Shaughnessy, K. H.; Booth, R. S. Org. Lett. 2001, 3, 2757. (b)
Dupuis, C.; Adiey, K.; Charruault, L.; Michelet, V.; Savignac, M.; Genet,
J.-P. Tetrahedron Lett. 2001, 42, 6523. (c) Campi, E. M.; Jackson, W. R.;
Marcuccio, S. M.; Naeslund, C. G. M. J. Chem. Soc., Chem. Commun.
1994, 2395.
(12) LeBlond, C. R., Andrews, A. T.; Sun, Y.; Sowa, J. R. Org. Lett.
2001, 3, 1555.
(13) Hallberg, A.; Larhed, M. J. Org. Chem. 1996, 61, 9582.
(14) Hallberg, A.; Lindeberg, G.; Larhed, M. Tetrahedron Lett. 1996,
37, 8219.
(15) Blettner, C. G.; Konig, W. A.; Stenzel, W.; Schotten, T. J. Org.
Chem. 1999, 64, 3885.
(16) Villemin, D.; Go´mez-Escalonilla M. J.; Saint-Clair, J.-F. Tetrahedron
Lett. 1996, 37, 8219.
(17) Microwave reactions were conducted using a CEM Discover
Synthesis Unit (CEM Corp., Matthews, NC). The machine consists of a
continuous focused microwave power delivery system with operator-
selectable power output from 0 to 300 W. Reactions were performed in
glass vessels (capacity 10 mL) sealed with a septum. The pressure is
controlled by a load cell connected to the vessel via a 14-gauge needle,
which penetrates just below the septum surface. The temperature of the
contents of the vessel was monitored using a calibrated infrared temperature
control mounted under the reaction vessel. All experiments were performed
using a stirring option whereby the contents of the vessel are stirred by
means of a rotating magnetic plate located below the floor of the microwave
cavity and a Teflon-coated magnetic stir bar in the vessel.
(18) CAUTION: The water is heated well above its boiling point so all
necessary precautions should be taken when performing such experiments.
Vessels designed to withhold elevated pressures must be used. The
microwave apparatus used here incorporates a protective metal cage around
the microwave vessel in case of explosion. After completion of an
experiment, the vessel must be allowed to cool to a temperature below the
boiling point of the solvent before removal from the microwave cavity and
opening to the atmosphere.
2974
Org. Lett., Vol. 4, No. 17, 2002

a
Table 2. Microwave-Mediated Suzuki Coupling of Aryl Halides and Aryl Boronic Acids in Water Using Pd(OAc)2
a 1 mmol of aryl halide, 1 mmol of boronic acid, 3 mmol of Na2CO3, 0.4 mol % Pd(OAc)2, 1.0 mmol of TBAB, 2 mL of water. Microwave irradiation
) 60 W; temperature ramped to 150 °C (taking 30-40 s) and held for 5 min. b Determined by 1H NMR. c Without TBAB. d On a 3 mmol scale. e Microwave
irradiation ) 60 W; temperature ramped to 175 °C (taking 30-40 s) and held for 5 min.
Our thoughts were that by lowering the temperature and the
catalyst loading, it would be possible to favor the Suzuki
coupling reaction. This was borne out in our results. We
found that reduction of the catalyst loading from 5 to 0.4
mol % improved the yield of the Suzuki product, as did
decreasing the temperature from 200 to 150 °C, with both
of these modifications producing a yield of 40% of 4-phen-
yltoluene.
We next addressed the issue of substrate solubility.
Previous reports have shown the addition of phase-transfer
catalysts, such as tetraalkylammonium salts, can greatly
improve yields of Suzuki reactions in both water9b,10,19 and
polar organic solvents.20 The role of ammonium salts is
thought to be two-fold. First, they facilitate solvation of the
organic substrates in the solvent medium. Second, they are
thought to enhance the rate of the coupling reaction by
Org. Lett., Vol. 4, No. 17, 2002
2975

activating the boronic acid to reaction by formation of
[ArB(OH)3]-[R4N]+.9b We felt that both of these factors
would help to reduce the extent of hydrodeboronation in our
experiments since increased solubility of organic substrates
in water would mean increased concentration of reactive
species, and the formation of a complex between the boronic
acid and the ammonium salt would favor Suzuki-type
couplings over hydrodeboronation. We found that addition
of 0.5 equiv of tetrabutylammonium bromide (TBAB)
increases the yield of product in the coupling of phenyl-
boronic acid and 4-bromo toluene from 40% to 87% (Table
1, entry 6). Use of 1 equiv of TBAB instead of 0.5 equiv
takes this yield to 94% (Table 1, entry 7). We find that
increasing the hold time from 5 to 10 min has a marginal
effect on product yields (Table 1, entry 8).
With our optimized reaction conditions in hand, we
screened a range of aryl bromides together with some aryl
iodides and chlorides in the Suzuki reaction.21 All reactions
have been performed using 1:1 stoichiometric ratio of aryl
halide and boronic acid, as compared to the 1:1.2 or 1:1.5
ratios often used in aqueous Suzuki coupling reactions.9-11
In addition, the reactions were performed in air and without
degassing the water prior to use. The results are shown in
Table 2.
being obtained in the reaction with phenylboronic acid. A
wide range of functional groups are tolerated in the reaction
and not affected by the high temperature and aqueous
conditions used. In addition, sterically demanding aryl
bromides can be coupled with phenylboronic acid to give
good yields of product (Table 2, entries 5, 6, and 9).
To show that the reaction can be scaled up without
compromising the yield, the reaction of 4-bromotoluene and
phenylboronic acid was repeated on a 3 mmol scale (Table
2, entry 19).22 The isolated yield of product is 76%, almost
identical to that when the reaction is performed on a 1 mmol
scale (79%).
Representative aryl iodides were also screened in the
coupling reaction using our methodology (Table 2, entries
20-22). The good results obtained are noteworthy. When
using conventional heating, it is often the case that non-water-
soluble aryl iodides give incomplete conversion when
reactions are performed in aqueous media, even in the
presence of tetraalkylammonium salts.9b
It is possible to couple some aryl chlorides with phenyl-
boronic acid using our methodology (Table 2, entries 23-
25), but we find that this is best achieved by raising the
reaction temperature from 150 to 175 °C. Even the electron-
rich aryl chloride 4-chloroanisole can be coupled in accept-
able yield. Our results with chloro substrates are certainly
as good as those in the literature to date,10,12 and in the case
of 4-chloroanisole, they are better.
The methodology is applicable to a wide range of aryl
bromide substrates (Table 2, entries 1-19) with good yields
(19) Jeffrey, T. Tetrahedron Lett. 1994, 35, 3051.
In conclusion, we have developed a methodology for the
ligand-free microwave-mediated Suzuki coupling of boronic
acids and aryl halides in water and have shown the
application of this to the synthesis of a number of biaryls
starting from a range of aryl halides. The methodology has
the advantage of low catalyst loadings, rapid reaction times,
ease of reaction (no need for anaerobic conditions), and use
of a nontoxic, nonflammable solvent. The methodology is
currently being used in other C-C coupling reactions, and
we anticipate that further enhancements in reactivity will be
possible.
(20) Zim, D.; Monteiro, A. L.; Dupont, J. Tetrahedron Lett. 2000, 41,
8199.
(21) General Procedure. In a 10-mL glass tube were placed aryl halide
(1.0 mmol), phenylboronic acid (122 mg, 1.0 mmol), Na2CO3 (315 mg, 3
mmol), Pd(OAc)2 (1 mg, 0.004 mmol), tetrabutylammonium bromide (322
mg, 1.0 mmol), 2 mL of water, and a magnetic stir bar. The vessel was
sealed with a septum and placed into the microwave cavity. Microwave
irradiation of 60 W was used, the temperature being ramped from room
temperature to 150 °C. Once 150 °C was reached, the reaction mixture
was held at this temperature for 5 min. After the mixture was allowed to
cool to room temperature, the reaction vessel was opened and the contents
poured into a separating funnel. Water and diethyl ether (30 mL of each)
were added, and the organic material was extracted and removed. After
further extraction of the aqueous layer with ether, combining of the organic
washings and drying over MgSO4, the ether was removed in vacuo, leaving
the crude product. In optimizing experiments the 1H NMR spectrum of the
product mixture was recorded and the product yield determined by
integration of the peaks due to biaryl and aryl halide starting material taking
[∫(biaryl)/∫(biaryl + aryl halide)] × 100. In the screening experiments,
the product was purified and isolated by chromatography after, in the cases
where the starting aryl halide was a liquid, first removing unreacted aryl
halide by heating the crude residue whilst under a vacuum on a Schlenk
line. 1H and 13C NMR spectra of the products were obtained and found to
be identical to authentic samples.
Acknowledgment. The Royal Society is thanked for a
University Research Fellowship (N.E.L.) and King’s College
London for a Ph.D. studentship (M.M.). Funding from
Hoffmann La Roche and King’s College London is
acknowledged.
(22) This is the largest scale reaction possible using the 10-mL sealed
glass tubes.
OL0263907
2976
Org. Lett., Vol. 4, No. 17, 2002