Suzuki Coupling Reaction in Water
of microwave-assisted synthesis in 1986,19,20 the tech-
nique has been accepted as a method for reducing
reaction times often by orders of magnitude and for
increasing yields of product compared to conventional
methods.21,22 As a result, this has opened up the possibil-
ity of optimizing new reactions in a very short time. With
microwave promotion, efficient heating of the sample
itself is possible, whereas transfer of heat through
reaction vessel walls is necessary with conventional
heating systems, e.g., an oil bath. This internal heat
transfer results in minimized wall effects (no thermal
boundary layer), and reaction mixtures can be heated to
high temperatures rapidly. The first reports of Suzuki
couplings using microwave promotion were by Larhed
and Hallberg, using Pd(PPh3)4 as the catalyst, homoge-
neous and polymer-supported aryl iodides and bromides
as substrates, and a mixture of water, ethanol, and DME
as solvent.23,24 With reaction times of only approximately
3-4 min, good yields of product were obtained. There
have been reports of microwave-assisted solvent-free
Suzuki coupling protocols using palladium-doped alu-
mina25 and KF on alumina in conjunction with palladium
catalysts.26 Microwave heating has been used to facilitate
the coupling in water of arylboronic acids with the poly-
(ethylene glycol) esters of an aryl iodide and triflate and
also a bromothiophene.27 In the same report, 4-iodoben-
zoic acid methyl ester was coupled with a range of boronic
acids in water/poly(ethylene glycol) mixtures. Sodium
tetraphenylborate has been used as a phenylation re-
agent for microwave-mediated aqueous-phase biaryl
synthesis.28 We have recently reported that it is possible
to couple a range of aryl halides, including chlorides, with
phenylboronic acid in neat water using microwave heat-
ing with palladium acetate as the catalyst and TBAB as
an additive.29 The total reaction time is between 5 and
10 min, and low palladium loadings are used. We were
next interested in extending the methodology, comparing
our reactions performed using microwave heating with
those using conventional thermal heating and in inves-
tigating the effects on the yields and reaction times of
scaling up the reaction to make larger quantities of
biaryls. We report the results of these studies here.
specifically, monitoring temperature, pressure, and reac-
tion times. This meant that we were able to screen a wide
range of conditions very fast and with close monitoring.
As a result, we could optimize the reaction very easily.
Our initial investigations were undertaken using 1 mmol
of aryl halide and 1 mmol of boronic acid, the reactions
being performed in 10 mL sealed tubes using 2 mL of
water. When using aryl iodides and bromides, we find
that the best yields of biaryl are formed when the
temperature is ramped from room temperature to 150
°C and then held at this temperature for 5 min.30 The
time taken for the reaction mixture to reach the target
temperature of 150 °C varies depending on the aryl
halide substrate but is within the period of 30-40 s. For
aryl chlorides we find that it is necessary to increase the
temperature to 175 °C to obtain reasonable yields of
biaryl product. At temperatures above 150-175 °C we
observe significant deactivation of the catalyst and the
onset of decomposition of the organic substrates and
products. We find that the optimum catalyst loading is
0.4 mol %. At the high temperatures used in the reac-
tions, if higher catalyst loadings are used, there is a
problem with competitive hydrodeboronation of the bo-
ronic acid, giving, in the case of phenylboronic acid,
benzene. This obviously leads to poor yields of the desired
biaryl. The microwave power used is very important. We
find that the optimum power is 60 W, above which rapid
deactivation of the catalyst occurs and below which yields
of biaryl drop significantly and extended reaction times
are required. We find that although good yields of product
are formed using 0.5 equiv of TBAB, it is better to use 1
equiv of TBAB. The conditions used are applicable to a
wide range of substrates bearing different functional
groups.
We were keen to develop the methodology for the
preparation of grams of material. As a starting point for
the scale-up of the reaction from 1 to 10 mmol, we chose
to study the coupling of 4-bromoacetophenone with
phenylboronic acid. Due to the quantity of starting
materials required, we moved from performing the reac-
tions in sealed 10 mL tubes to using larger open vessels.
A 50 mL round-bottomed flask was placed inside the
microwave cavity and a double-surface reflux condensor
attached to this. In the initial experiment, a ratio of aryl
halide to phenylboronic acid to TBAB to Pd(OAc)2 to
Na2CO3 identical to that in the optimized 1 mmol
reaction, namely, 1:1:1:0.004:3.8, respectively, was used.
A volume of 10 mL of water was used. The reaction was
performed using a continuous microwave power of 60 W
and the reaction run for a total time of 10 min, stirring
the reaction mixture throughout. The temperature in-
creased from room temperature to a maximum of 110 °C
over a period of 3.5 min and then stayed at this temper-
ature for the remainder of the time. A yield of 4-acetyl-
biphenyl of 90% was obtained, this comparing with a
yield of 91% when the reaction is performed on a 1 mmol
scale in a sealed tube. Having shown that it was possible
Micr ow a ve-Assisted Su zu k i Cou p lin gs
A key advantage of modern scientific microwave ap-
paratuses is the ability to control reaction conditions very
(18) For a review on the concepts see: Gabriel, C.; Gabriel, S.; Grant,
E. H.; Halstead, B. S.; Mingos, D. M. P. Chem. Soc. Rev. 1998, 27,
213.
(19) Gedye, R.; Smith, F.; Westaway, K.; Humera, A.; Baldisera, L.;
Laberge, L.; Rousell, L. Tetrahedron Lett. 1986, 26, 279.
(20) Giguere, R.; Bray, T. L.; Duncan, S. M.; Majetich, G. Tetrahe-
dron Lett. 1986, 27, 4945.
(21) For some recent examples see: (a) Westman, J . Org. Lett. 2001,
3, 3745. (b) Kuhnert, N.; Danks, T. N. Green Chem. 2001, 3, 98. (c)
Loupy, A.; Regnier, S. Tetrahedron Lett. 1999, 40, 6221.
(22) Stadler, A.; Kappe, A. C. Eur. J . Org. Chem. 2001, 919.
(23) Hallberg, A.; Larhed, M. J . Org. Chem. 1996, 61, 9582.
(24) Hallberg, A.; Lindeberg, G.; Larhed, M. Tetrahedron Lett. 1996,
37, 8219.
(25) Kabalka, G. W.; Pagni, R. M.; Wang, L.; Namboodiri, V.; Hair,
C. M. Green Chem. 2000, 2, 120.
(26) Villemin, D.; Caillot, F. Tetrahedron Lett. 2001, 42, 639.
(27) Blettner, C. G.; Konig, W. A.; Stenzel, W.; Schotten, T. J . Org.
Chem. 1999, 64, 3885.
(28) Villemin, D.; Go´mez-Escalonilla M. J .; Saint-Clair, J .-F. Tet-
rahedron Lett. 1996, 37, 8219.
(29) Leadbeater, N. E.; Marco, M. Org. Lett. 2002, 4, 2973.
(30) Caution: The water is heated well above its boiling point, so
all necessary precautions should be taken when such experiments are
performed. 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 being opened to the atmosphere.
J . Org. Chem, Vol. 68, No. 3, 2003 889