Transition-metal-free Suzuki-type coupling reactions: Scope and limitations of the methodology

Article abstract of DOI:10.1021/jo034230i

The scope and limitations of the transition-metal-free Suzuki-type coupling of aryl halides and arylboronic acids to form biaryls are presented. Confirmation that the reaction is indeed metal-free is presented. The effects of changing base, solvent, reaction temperature, phase-transfer catalyst, and substrate are shown and the implications of these results discussed in terms of their impact on the synthetic versatility of the methodology. The main findings are that the reaction works well for aryl bromides, water is necessary as a solvent for the reaction, the optimum temperature for the reaction is 150 °C, the reaction is best performed by using microwave promotion with the exception of an electron-poor aryl bromide example where conventional heating may be used, only limited boronic acids can be used as coupling partners, sodium carbonate is the best base for the reaction, tetrabutylammonium bromide proves to be the best phase-transfer catalyst for the reaction, the reaction is limited to couplings between aryl halides and aryl boronic acids with sp²-sp³ couplings proving ineffective, and NaBPh₄ can be used in the place of phenylboronic acid as a phenylating agent.

Full text of DOI:10.1021/jo034230i

Tr a n sition -Meta l-F r ee Su zu k i-Typ e Cou p lin g Rea ction s: Scop e
a n d Lim ita tion s of th e Meth od ology
Nicholas E. Leadbeater* and Maria Marco
Department of Chemistry, King’s College London, Srand, London WC2R 2LS, United Kingdom
nicholas.leadbeater@kcl.ac.uk
Received February 21, 2003
The scope and limitations of the transition-metal-free Suzuki-type coupling of aryl halides and
arylboronic acids to form biaryls are presented. Confirmation that the reaction is indeed metal-
free is presented. The effects of changing base, solvent, reaction temperature, phase-transfer catalyst,
and substrate are shown and the implications of these results discussed in terms of their impact
on the synthetic versatility of the methodology. The main findings are that the reaction works well
for aryl bromides, water is necessary as a solvent for the reaction, the optimum temperature for
the reaction is 150 °C, the reaction is best performed by using microwave promotion with the
exception of an electron-poor aryl bromide example where conventional heating may be used, only
limited boronic acids can be used as coupling partners, sodium carbonate is the best base for the
reaction, tetrabutylammonium bromide proves to be the best phase-transfer catalyst for the reaction,
2
3
the reaction is limited to couplings between aryl halides and aryl boronic acids with sp -sp
couplings proving ineffective, and NaBPh
phenylating agent.
4
can be used in the place of phenylboronic acid as a
In tr od u ction
of efficient and selective synthesis in water has been
exemplified as the rates, yields, and selectivities observed
for many reactions in water have begun to match or, in
The Suzuki reaction (palladium-catalyzed cross cou-
pling of aryl halides with boronic acids) is one of the most
versatile and utilized reactions for the selective construc-
tion of carbon-carbon bonds, in particular for the forma-
3
many cases, surpass those in organic solvents. Water
also offers practical advantages over organic solvents. It
is cheap, readily available, nontoxic, and nonflammable.
The use of water as a solvent for metal-mediated syn-
1
tion of biaryls. As the biaryl motif is found in a range of
pharmaceuticals, herbicides, and natural products as well
as in conducting polymers and liquid crystalline materi-
als, development of improved conditions for the Suzuki
reaction has received much recent attention. Indeed, in
the last 10 years, there have been over 700 publications
on the area of aryl-aryl bond formation. A wide range
of metal complexes have been used as catalysts in these
coupling reactions, attention particularly being focused
on palladium. Suzuki couplings are used daily not only
in research laboratories but also on industrial scales.2
4
thesis has attracted considerable research interest.
Suzuki couplings of water-soluble aryl iodides have been
5
,6
performed in water by using simple palladium salts or
7
amphiphilic polymer-supported palladium catalysts. Ba-
done and co-workers have investigated the effects of
solvent, including water, on the rate of the ligandless
palladium acetate catalyzed Suzuki reaction of a range
8
of aryl bromides, iodides, and triflates. They report that
when using water as a solvent the addition of 1 equiv of
tetrabutylammonium bromide (TBAB) to the reaction
mixture greatly facilitates the reaction. They find that
activated aryl bromides can be coupled with phenylbo-
ronic acid to yield biaryls fairly rapidly (1 h) and in good
yields whereas with aryl iodides the reaction does not
reach completion. The role of the ammonium salts is
In addition to a range of organic solvents, there has
been considerable recent interest in the use of water as
a reaction medium. Over the last 5-10 years, the concept
(3) For a general introduction to organic synthesis in water see: (a)
Organic synthesis in water; Grieco, P. A., Ed.; Blackie Academic and
Professional: London, UK, 1998. (b) Li, C.-J .; Chen, T.-H. Organic
Reactions in Aqueous Media; Wiley: Dordrecht, The Netherlands, 1997.
(4) 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, Germany, 1998.
(5) Bumagin, N. A.; Bykov, V. V. Tetrahedron 1997, 53, 14437.
(6) Sakurai, H.; Tsukuda, T.; Hirao, T. J . Org. Chem. 2002, 67, 2721.
(7) Uozumi, Y.; Danjo, H.; Hayashi, T. J . Org. Chem. 1999, 64, 3384.
(8) Badone, D.; Baroni, M.; Cardamone, R.; Ielmini, A.; Guzzi, U. J .
Org. Chem. 1997, 62, 7170.
*
Corresponding author.
(1) For recent reviews see: (a) Hassan, J .; S e´ vignon, M.; Gozzi, C.;
Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359. (b) Kotha, S.;
Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633. (c) Suzuki, A.
J . Organomet. Chem. 1999, 576, 147. (d) Miyaura, N.; Suzuki, A. Chem.
Rev. 1995, 95, 2457.
(
2) See for example: Ennis, D. S.; McManus, J .; Wood-Kaczmar, W.;
Richardson, J .; Smith, G. E.; Carstairs, A. Org. Proc. Res. Dev. 1999,
, 248.
3
1
0.1021/jo034230i CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/18/2003
5
660
J . Org. Chem. 2003, 68, 5660-5667

Transition-Metal-Free Suzuki-Type Coupling Reactions
thought to be 2-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 activating the boronic acid to reaction by formation
to understand further the role of the water and the
TBAB, we have found that, using the appropriate condi-
tions, it is possible to perform Suzuki-type couplings
1
9
without the need for a transition-metal catalyst. Since
the use of metals leads to the generation of waste and
can have a number of problems associated with it, the
eradication of the catalyst from the Suzuki reaction offers
significant advantages. This runs true even with today’s
-
+
3 4
of a boronate complex [ArB(OH) ] [R N] . TBAB has
been used recently in conjunction with a palladium oxime
catalyst for the Suzuki coupling of aryl chlorides with
9
phenylboronic acid in water and as a promoter in the
Pd(PPh
3
)
4
-catalyzed Suzuki coupling reaction of 4-bro-
20
21
highly active or recyclable metal catalysts for the
reaction. The preparation of these catalysts, their extrac-
tion, and product purification can be time-consuming and
costly. This is of particular importance when considering
the synthesis of fine chemicals such as pharmaceuticals
where contamination of the product with heavy metals
is highly undesirable. In this paper we discuss the scope
and limitations of this transition-metal-free methodology.
mobenzonitrile and phenylboronic acid in organic sol-
vents.10
With its high dielectric constant water is also poten-
tially a very useful solvent for microwave-mediated
synthesis. The use of microwave ovens as tools for
1
1,12
synthetic chemistry is a fast growth area.
Since the
first reports of microwave-assisted synthesis in 1986,1
the technique has been accepted as a method for reducing
reaction times often by orders of magnitude and for
3,14
increasing yields of product compared to conventional
methods.1
5,16
Much of the work in the field to date has
been conducted with use of modified domestic microwave
ovens. There are, however, problems associated with this,
in particular poor reproducibility of reactions and the fact
that it is hard to control the reaction precisely. In the
last year or so, with the advent of scientific focused
microwave systems, many of these problems can be
overcome. By using these scientific microwaves it is
possible to control the temperature, pressure, microwave
power, and reaction times very easily and with a high
degree of reproducibility. As a result, this has opened up
the possibility of optimizing new reactions in a very short
time. 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.17 The total reaction time is between 5 and
Resu lts a n d Discu ssion
In our initial communication, we reported a general
method for microwave-promoted transition-metal-free
Suzuki-type couplings of aryl bromides and aryl boronic
acids in water using sodium carbonate as a base and
TBAB as an additive. (Ca u tion : 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 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.) A wide
range of functional groups are tolerated in the reaction
and sterically demanding aryl bromides can be coupled
with phenylboronic acid to give good yields of product
(Table 1, entries 1-15). Representative aryl iodides were
also screened in the coupling reaction by using our
methodology, but product yields were lower than their
bromo counterparts (Table 1, entries 16-18). Aryl chlo-
rides could not be coupled. Reactions are run with a 1:1.3
molar ratio of aryl halide to boronic acid and take 5 min;
the only organic materials found at the end of the
reaction are the biaryl product, unreacted aryl halide,
and traces of benzene. This highlights one of the problems
with working at elevated temperatures, namely that
there is competitive protodeboronation of the boronic acid
to produce benzene (most of which is removed in the
1
0 min and low palladium loadings are used. The
reactions can be performed on small (1 mmol) scales,
using sealed tubes, or larger scales (20 mmol), using open
reaction vessels. We have found subsequently that it is
possible to perform the coupling reactions using aryl
bromides and iodides equally well and in similar short
times with conventional heating.18 However, the reaction
does not work for aryl chloride substrates. In our studies
(
9) Botella, L.; N a´ jera, C. Angew. Chem., Int. Ed. Engl. 2002, 41,
79.
10) Castanet, A.-S.; Colobert, F.; Desmurs, J .-R.; Schlama, S. J . Mol.
Catal. 2002, 182-183, 481.
11) For reviews on the area see: (a) Larhed, M.; Moberg, C.;
1
(
(
Hallberg, A. Acc. Chem. Res. 2002, 35, 717. (b) Lew, A.; Krutzik, P.
O.; Hart, M. E.; Chamberlin, A. R. J . Comb. Chem. 2002, 4, 95. (c)
Lindstr o¨ m, P.; Tierney, J .; Wathey B.; Westman, J . Tetrahedron 2001,
5
7, 9225. (d) Perreux L.; Loupy, A. Tetrahedron 2001, 57, 9199. (e)
Deshayes, S.; Liagre, M.; Loupy, A.; Luche, J .-L.; Petit, A. Tetrahedron
999, 55, 10851.
12) For reviews on the concepts see: (a) Gabriel, C.; Gabriel, S.;
Grant, E. H.; Halstead, B. S.; Mingos, D. M. P. Chem. Soc. Rev. 1998,
7, 213. (b) Mingos, D. M. P. Chem. Soc. Rev. 1991, 20, 1.
13) Gedye, R.; Smith, F.; Westaway, K.; Humera, A.; Baldisera, L.;
Laberge, L.; Rousell, L. Tetrahedron Lett. 1986, 27, 279.
14) Giguere, R.; Bray, T. L.; Duncan, S. M.; Majetich, G. Tetrahe-
dron Lett. 1986, 27, 4945.
15) For some recent examples see: (a) Westman, J . Org. Lett. 2001,
, 3745. (b) Kuhnert, N.; Danks, T. N. Green Chem. 2001, 3, 98. (c)
1
(
2
(
(19) Leadbeater, N. E.; Marco, M. Angew. Chem., Int. Ed. Engl.
2003, 42, 1407.
(20) For examples see: (a) Bedford, R. B.; Cazin, C. S. J .; Hazelwood,
S. L. A. Angew. Chem., Int. Ed. Engl. 2002, 41, 4120. (b) Bedford, R.
B.; Cazin, C. S. J . Chem. Commun. 2001, 1540.
(21) (a) Choudary, B. M.; Madhi, S.; Chowdari, N. S.; Kantam, M.
L.; Sreedhar, B. J . Am. Chem. Soc. 2002, 124, 14127. (b) Brase, S.;
Dahmen, S.; Lauterwasser, F.; Leadbeater, N. E.; Sharp, E. L. Bioorg.
Med. Chem. Lett. 2002, 12, 1849. (c) Heidenreich, R. G.; Kohler, K.;
Krauter, J . G. E.; Pietsch, J . Synlett 2002, 1118. (d) Akiyama, R.;
Kobayashi, S. Angew. Chem., Int. Ed. Engl. 2001, 40, 3469.
(
(
3
Loupy, A.; Regnier, S. Tetrahedron Lett. 1999, 40, 6221. (d) Danks, T.
N. Tetrahedron Lett. 1999, 40, 3957.
(16) Stadler, A.; Kappe, A. C. Eur. J . Org. Chem. 2001, 919.
(17) Leadbeater, N. E.; Marco, M. Org. Lett. 2002, 4, 2973.
(18) Leadbeater, N. E.; Marco, M. J . Org. Chem. 2002, 68, 888.
J . Org. Chem, Vol. 68, No. 14, 2003 5661

Leadbeater and Marco
TABLE 1. Su zu k i-Typ e Cou p lin g of Ar yl Ha lid es a n d Bor on ic Acid s in Wa ter a
a
1
mmol of aryl halide, 1.3 mmol of boronic acid, 3.8 mmol of Na2CO3, 1.0 mmol of TBAB, 2 mL of water. Yields quoted are for microwave
promotion, using a microwave power of 100 W. The temperature is ramped to 150 °C and held for 5 min. Isolated yield. c Determined
b
1
by H NMR.
workup procedure and hence only traces are observed).22
We find that addition of additional equivalents of boronic
acid to the reaction mixture does not have an appreciable
effect on the overall product yield. Of interest is that no
homocoupling of either the aryl halide or boronic acid is
observed during the course of any of the reactions.
We were keen next to explore the range of boronic acids
that can be used in the coupling protocol and so we
screened a number of substrates bearing different func-
tional groups (Table 1, entries 19-26). However, we find
(
22) This competitive deboronation of boronic acids in basic aqueous
media has been reported on a number of occasions. For a study of the
reaction see: (a) Kuvila, H. G.; Reuwer, J . F.; Mangravite, J . A. J .
Am. Chem. Soc. 1964, 86, 2666. (b) Kuvila, H. G.; Nahabedian, K. V.
J . Am. Chem. Soc. 1961, 83, 2159.
5
662 J . Org. Chem., Vol. 68, No. 14, 2003

Transition-Metal-Free Suzuki-Type Coupling Reactions
that the methodology is limited to electron-poor or
electron-neutral boronic acids; electron-rich or heterocy-
clic examples not reacting with our conditions. This
shows one of the limitations of the current methodology
but we believe that after further optimization it may be
possible to expand the scope of boronic acids that can be
used in the transition-metal-free protocol. However, like
with phenylboronic acid, in those cases where coupling
does occur the reaction is very clean, no homocoupling
of either the aryl halide or boronic acid being observed.
These studies also allowed us to probe the regioselectivity
of the reaction. Looking at the coupling of 4-bromoac-
etophenone with 4-methylboronic acid (Table 1, entry 19),
we obtain pure 4-acetyl-4′-methylbiphenyl in 99% iso-
lated yield with no evidence for formation of any other
regioisomers. This illustrates that the reaction is totally
regioselective.
Effects of Tem p er a tu r e on th e Rea ction . Having
shown that the reaction is not transition-metal mediated
we were next interested in looking at the components in
the reaction mixture individually together with the
reaction conditions. We looked first at the temperature
at which the reaction is performed. In our initial experi-
ments we used a reaction temperature of 150 °C, using
a microwave power of 100 W. The reaction mixture takes
approximately 50 s: 1 min to reach the target temper-
ature that is then held for 5 min. To assess the effects of
temperature on the reaction we have performed the
coupling of 4-bromotoluene and phenylboronic acid at a
range of different temperatures. We find that decreasing
the temperature to 130 °C has the effect of stopping the
reaction, no biaryl being formed. Increasing the temper-
ature to 170 °C does not lead to an improvement in
reaction yields and indeed is slightly deleterious. As
already mentioned, one of the problems with working at
elevated temperatures is that there is competitive pro-
todeboronation of the boronic acid to produce benzene.
However, running the reaction at 150 °C seems to have
the effect of facilitating the coupling reaction while
limiting the protodeboronation. Indeed at this tempera-
ture the coupling reaction must be significantly faster
than the competing deboronation.
These results impact on the possibility of performing
the reaction with conventional heating. We find that
placing a sealed tube into an oil bath at 150 °C offers an
easy way to perform the coupling reaction of phenylbo-
ronic acid with 4-bromoacetophenone, a 91% yield of
product being obtained after heating for 2 h. (Ca u tion :
A blast shield should be in place and vessels designed to
withhold elevated pressures must be used. After comple-
tion of an experiment, the vessel must be allowed to cool
before being opened to the atmosphere.) However, with
electron-rich and electron-neutral aryl bromide sub-
strates it is not possible to perform the reaction so
efficiently with conventional heating. With 4-bromotolu-
ene a conversion of only 29% is obtained after heating
for 16 h, while with 4-bromoanisole, no product is
obtained after a similar reaction time. By inserting a
thermal probe into the reaction mixtures we found that
the solutions were not reaching more than 130 °C which,
as we knew from our microwave studies, was not suf-
ficient to promote biaryl formation. However, we find that
increasing the temperature of the oil bath from 150 to
An a lysis of th e Rea ction Mixtu r e. To show that the
reaction is indeed transition-metal free, we used new
glassware, apparatus, reagents (not only were new
bottles of reagents used but also a range of suppliers’
reagents were screened in the reaction and all found to
1
lead to the same yields of biaryl formation), and spatula
and analyzed the entire crude product mixture from a
reaction for palladium content. We found that there was
no palladium in the mixture down to the level of detection
of the analytical apparatus (less than 0.1 ppm). This, and
the fact that the reaction is reproducible argues against
catalytic contaminants. But to show that other metals
that could possibly catalyze the reaction are present in
too small amounts we have subsequently analyzed reac-
tion mixtures for the presence of a wide range of ele-
ments. The results are shown in the Supporting Infor-
2
3
mation. Possible catalyst candidates include nickel,
platinum,24 copper,25,26 and ruthenium since all of these
metals have been shown to act as catalysts for the Suzuki
reaction either individually or together. However, none
of these metals were present in the product mixture in
concentrations above 1 ppm. We perform the reactions
in 10-mL glass tubes sealed with a Teflon septum and
the pressure of the reaction mixture is measured by a
25
1
85 °C offers improvements in product yield for bromo-
toluene, a 100% conversion being obtained after 16 h of
heating at this higher temperature. However, with 4-bro-
moanisole there was still no reaction. Since the start of
the field of microwave-assisted synthesis, far shorter
times for reactions as compared to those with “conven-
tional” heating have been reported and this has sparked
2
load cell connected to the vessel via an SiO -coated steel
needle that penetrates just below the septum surface. A
further postulate was that the reaction could be catalyzed
by any metal exposed on the needle. To show that this
was not the case, we performed the reaction in a vessel
with a noninvasive pressure monitor and found that we
still obtained the desired biaryl product.
27
debate into the nature of the microwave heating. The
acceleration of reactions could simply be an effect of the
thermal energy generated by the microwaves interacting
with the substrates or could be an effect specific to
microwave heating. In most cases the observed differ-
ences between microwave and conventional heating can
be attributed to simple thermal effects and our results
show that this is the case with our coupling reactions.
(
23) (a) Zim, D.; Monteiro, A. L. Tetrahedron Lett. 2002, 43, 4009.
(
(
b) Griffiths, C.; Leadbeater, N. E. Tetrahedron Lett. 2000, 41, 2487.
c) Lipshutz, B. H.; Sclafani, J . A.; Blomgren, P. A. Tetrahedron 2000,
5
1
6, 2139. (d) Leadbeater, N. E.; Resouly, S. M. Tetrahedron 1999, 55,
1889.
(
24) Bedford, R. B.; Hazelwood, S. L.; Albisson, D. A. Organometal-
lics 2002, 21, 2599.
25) Thathagar, M. B.; Beckers, J .; Rothenberg, G. J . Am. Chem.
Soc. 2002, 124, 2159.
26) (a) Liu, X. X.; Deng, M. Z. Chem. Commun. 2002, 622. (b)
Savarin, C.; Liebeskind, L. S. Org. Lett. 2001, 3, 2149.
(
(
(27) For a review see: Perreux, L.; Loupy, A. Tetrahedron 2001, 57,
9199.
J . Org. Chem, Vol. 68, No. 14, 2003 5663

Leadbeater and Marco
The microwave methodology offers a facile and very
efficient method for holding the reaction mixture at a
high temperature constantly thereby promoting the
reaction.
TABLE 2. Effects of th e Ba se on th e
Micr ow a ve-P r om oted Su zu k i-Typ e Cou p lin g of
-Br om oa cetop h en on e a n d P h en ylbor on ic Acid in Wa ter
a
4
We also investigated the possibility of activating aryl
chlorides in the microwave-promoted methodology by
using elevated temperatures. In our Pd-mediated Suzuki
coupling protocol we find that aryl chlorides can be used
entry
base
product conversion (%)b
1
2
3
4
5
6
7
8
9
Li2CO3
Na2CO3
K2CO3
Cs2CO3
Mg2CO3
CaCO3
(NH4)2CO3
NaOH
0
100
17
89
11
9
as substrates only when the temperature is increased
from 150 °C up to 175 °C.17 We screened the reaction of
4
-chlorotoluene with phenylboronic acid at temperatures
up to 175 °C but no product was obtained indicating that,
with the metal-free coupling protocol, simply increasing
the temperature does not allow us to increase the
substrate scope of the methodology.
c
0
0
33
4
47
0
NaHCO3
NaOAc
K3PO4
1
0
Effects of Solven t Va r ia tion on th e Rea ction . In
our initial experiments we ran all the reactions using
water as solvent. In contrast to many other solvents,
water not only provides a medium for solution chemistry
but often participates in elementary chemical events on
a molecular scale. To explore the solvent scope of the
reaction, we screened a number of other solvents in the
coupling of 4-bromoacetophenone with phenylboronic
acid. We find that running the reaction using dimethyl-
formamide or methanol as solvent leads to significantly
less coupling product (6% and 42% conversions, respec-
tively). If a 1:1 mixture of water and DMF is used, no
biaryl product is formed. The same is true if a 1:1 mixture
of water and methanol is used. This clearly demonstrates
that the use of water as a solvent is central to the success
11
1
2
KF
a
1
mmol of 4-bromoacetophenone, 1.3 mmol of phenylboronic
acid, 1 mmol of TBAB, 3.7 mmol of base, 2 mL of water.
Temperature ramped to 150 °C and held there for 5 min.
b
Determined by 1H NMR. c No TBAB used.
Effects of P h a se-Tr a n sfer Ca ta lyst on th e Rea c-
tion . We have assessed a number of phase-transfer
catalysts in the reaction and attempted to probe their
role in the reaction. The results are summarized in Table
. The addition of phase-transfer catalysts such as
tetraalkylammonium salts has been shown to improve
3
8
,9
yields of Suzuki reactions in both water
and polar
organic solvents.28 The role of the ammonium salts is
thought to be 2-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 activating the boronic acid to reaction by formation
of the reaction. Running the reaction in D
similar yields of coupling product as with H
2
O leads to
O although
2
all of the protons of the methyl group of the methyl
ketone functionality are exchanged for deuterium.
-
+
3 4
of [ArB(OH) ] [R N] . We felt that both of these factors
Effects of Ba se on th e Rea ction . In the absence of
any base, the reaction does not proceed, indicating that
it is essential to the procedure although its role is not
currently fully understood. In our initial experiments we
would help reduce the extent of hydrodeboronation in our
experiments since increased solubility of the organic
substrates in the water would mean increased concentra-
tion of reactive species and the formation of a complex
between the boronic acid and the ammonium salt would
favor Suzuki-type couplings over hydrodeboronation.
Using 4-bromoacetophenone and phenylboronic acid as
substrates, we find that optimal product yields are
obtained when using a stoichiometric ratio of aryl bro-
mide to TBAB of 1:1. Use of less TBAB results in a
significant decrease in product yield (Table 3, entries 1,
2 3
used Na CO as base, finding that optimal product yields
were obtained by using 3.7 equiv with respect to the aryl
halide. Use of less than this results in a significant
reduction in product yield. Using 4-bromoacetophenone
and phenylboronic acid as substrates, we have screened
a range of other metal carbonates in the reaction together
with (NH
find that, of the group 1 metal carbonates, Na
Cs CO are the only two that result in acceptable yields
of product (Table 2, entries 2 and 4), Li CO and K CO
3
4
)
2
CO
3
. The results are shown in Table 2. We
2
CO and
3
2
, and 3). To determine whether the TBAB was playing
2
3
an integral role in the reaction mechanism we attempted
to couple a more water soluble aryl bromide with a more
water soluble arylboronic acid. We find that the reaction
between 4-bromobenzoic acid and 4-carboxybenzenebo-
ronic acid can be effected in the absence of TBAB giving
a conversion of 27% (Table 3, entries 3 and 4). Although
this is low, it is comparable to that obtained when using
TBAB (Table 3, entry 5). It therefore does show that the
reaction can occur without TBAB. This is further con-
firmed by the observation that, using 4-bromoacetophe-
none and phenylboronic acid as substrates, replacement
of TBAB by poly(ethylene glycol) (PEG) as a phase-
transfer catalyst results only in a slight decrease in
product yield (Table 3, entry 6). To determine whether
2
3
2
proving inactive (Table 2, entries 1 and 3). Group 2 metal
carbonates are not effective bases for the reaction, nor is
4 2 3
(NH ) CO (Table 2, entries 5, 6, and 7). As all the metal
carbonates screened have similar basicity, the results
suggest that there may be a cation effect in the reaction,
sodium being particularly good. To see if this was indeed
the case we screened a number of other sodium-contain-
ing bases and found that anion is also important: NaOH
3
proving inactive, NaHCO and NaOAc leading to some
product formation but only small quantities (Table 2,
entries 8, 9, and 10). We also screened potassium
phosphate and potassium fluoride as both of these are
well-known bases in coupling reactions. We obtained a
3 4
moderate yield with K PO , while KF was inactive (Table
(28) Zim, D.; Monteiro, A. L.; Dupont, J . Tetrahedron Lett. 2000,
2
, entries 11 and 12).
41, 8199.
5
664 J . Org. Chem., Vol. 68, No. 14, 2003

Transition-Metal-Free Suzuki-Type Coupling Reactions
TABLE 3. Effects of th e P h a se-Tr a n sfer Ca ta lyst on th e Micr ow a ve-P r om oted Su zu k i-Typ e Cou p lin g of Ar yl Ha lid es
a n d Bor on ic Acid s in Wa ter a
a
1
mmol of aryl halide, 1.3 mmol of boronic acid, phase-transfer catalyst, 3.7 mmol of Na2CO3, 2 mL of water. Temperature ramped
to 150 °C and held there for 5 min. Determined by H NMR. c 1 equiv of NaBr added.
b
1
the bromide anion in the TBAB is important in the
reaction we screened the chloro and iodo analogues,
TBACl and TBAI, in the reaction and found that the use
of either of these results in a decrease in product yield
(Table 3, entries 7, 8, and 9). This clearly shows that not
only does the bromide ion in the TBAB play a role in the
reaction but the use of TBACl or TBAI actually has a
deleterious effect. The role of bromide ion was further
J . Org. Chem, Vol. 68, No. 14, 2003 5665

Leadbeater and Marco
illustrated in the reaction of 4-bromobenzoic acid and
phenylboronic acid with NaBr as an additive. A conver-
sion of 78% is obtained, this being higher than when
NaBr is omitted (Table 3, entries 10 and 11). This led us
to investigate the possibility of increasing the scope of
the reaction to aryl iodides and chlorides by selection of
appropriate phase-transfer catalysts. We screened the
reaction of 4-iodoacetophenone with benzeneboronic acid
using TBACl, TBAB, and TBAI as phase transfer cata-
lysts (Table 3, entries 12, 13, and 14). We find that, again,
the use of TBAB leads to the highest conversion to the
desired biaryl product.
explore the possibility of varying the boron-containing
component, using group 1 metal tetraaryl borates in place
of boronic acids. These would be less prone to hydrode-
boronation and also would increase the scope of reagents
that can be used in the coupling reaction. Borates such
4
as NaBPh have been used in the palladium-mediated
Suzuki reaction previously, working well in water and
5
transferring all four aryl rings. Sodium tetraphenylbo-
rate has been used as a phenylation reagent for micro-
3
1
wave-mediated aqueous-phase biaryl synthesis. Our
interest comes about from their solubility in neat water
and thus opening up the possibility of performing our
coupling reaction in the absence of a phase-transfer
catalyst. We find that it is possible to couple 4-bromoac-
Exp a n sion of th e Su bstr a te Scop e of th e Rea ction
to In cor p or a te Alk yl Ha lid es a n d Alk ylbor on ic
Acid s. We have already shown that, when using aryl
bromides, a wide range of functional groups are tolerated
in the reaction and sterically demanding aryl bromides
can be coupled with phenylboronic acid to give good yields
of product. We wanted to determine whether, using our
optimal reaction conditions, it was possible to perform
4
etophenone and NaBPh in 58% yield, using a stoichio-
metric ratio of the two reagents of 4:1, respectively (Table
4, entry 1). The reaction is performed under the same
conditions as for the couplings of aryl halides with boronic
acids except that no TBAB is used. We have extended
the methodology to encompass aryl bromides ranging
from electron rich to electron poor, good yields of the
desired biaryl being formed in each case (Table 4, entries
2, 3, and 4). We find that the product yields obtained
2
3
sp -sp coupling reactions of either alkylboronic acids
with aryl halides or arylboronic acids with alkyl halides.
These reactions have proven the focus of much recent
research activity within the transition-metal mediated
catalysis community because of the challenge associated
with this but also the potential use of this methodology
in the synthetic chemist’s portfolio.29,30 We screened the
reaction of 1-bromopropane and with phenylboronic acid
but no product was obtained. Similar observations were
made when using the secondary alkyl halide 2-bromopro-
pane. We next screened the reaction of butaneboronic
acid with 4-bromoacetophenone again with no success.
This suggests that the methodology in its current form
is limited to use only with aryl-aryl coupling reactions.
4
when using NaBPh are all lower than in the correspond-
ing examples when using boronic acids. We attribute this
to the poor solubility of the aryl bromides in the water.
However, it is not possible to improve product yields by
adding TBAB to the reaction mixture since this reacts
+
-
4 4
with the borate in situ to form [Bu N] [BPh ] and NaBr,
the former of which precipitates out of solution and is
inactive in the coupling reaction (Table 4, entry 5). We
have used KBPh in place of NaBPh but find that this
4 4
results in a significant decrease in product yield (Table
4, entry 6).
Con clu sion s
We have presented in detail here our methodology for
transition-metal-free coupling of aryl bromides with
boronic acids using water as a solvent and in the presence
of a base and a phase-transfer catalyst. We have dis-
cussed the scope and limitations of the methodology. In
summary, the key observations are the following: the
methodology is indeed transition-metal free as shown by
analysis of the reaction mixtures by ICP-AA; the reaction
works well for a range of aryl bromides; water is
necessary as a solvent for the reaction, the use of other
media such as organic solvents resulting in no product
being formed; the optimum temperature for the reaction
is 150 °C above which protodeboronation is observed and
below which no coupling reaction occurs; the reaction is
best performed by using microwave promotion with the
exception of an electron-poor aryl bromide example where
conventional heating may be used; only limited boronic
acids can be used as coupling partners; Na
to be the best base for the reaction, other metal carbon-
ates together with NaOH, NaHCO , and NaOAc being
2 3
CO proves
Exp a n sion of th e Su bstr a te Scop e of th e Rea ction
to In cor p or a te Tetr a ta r ylbor a tes. We next wanted to
3
less active; tetrabutylammonium bromide is shown to be
the best phase-transfer catalyst for the reaction, presum-
ably due to the fact that it also interacts with the boronic
acid present, but other phase-transfer catalysts can be
(
29) For a review see: Luh, T. Y.; Leung, M. K.; Wong, K. T. Chem.
Rev. 2000, 100, 3187.
30) (a) Kirchhoff, J . H.; Netherton, M. R.; Hills, I. D.; Fu, G. C. J .
(
Am. Chem. Soc. 2002, 124, 13662. (b) Netherton, M. R.; Fu, G. C.
Angew. Chem., Int. Ed. Engl. 2002, 41, 3910. (c) Kirchhoff, J . H.; Dai,
C. Y.; Fu, G. C. Angew. Chem., Int. Ed. Engl. 2002, 41, 1945. (d)
Soderquist, J . A.; Leon, G.; Colberg, J . C.; Martinez, I. Tetrahedron
Lett. 1995, 36, 3119.
(31) Villemin, D.; G o´ mez-Escalonilla M. J .; Saint-Clair, J .-F. Tet-
rahedron Lett. 1996, 37, 8219.
5
666 J . Org. Chem., Vol. 68, No. 14, 2003

Transition-Metal-Free Suzuki-Type Coupling Reactions
TABLE 4. Micr ow a ve-P r om oted Su zu k i-Typ e Cou p lin g of Ar yl Ha lid es a n d Tetr a p h en ylbor a tes in Wa ter a
a
1
mmol of aryl halide, 0.25 mmol of tetraphenylborate, 3.7 mmol of Na2CO3, 2 mL of water. Temperature ramped to 150 °C and held
there for 5 min. Conversion determined by H NMR. c Isolated yield. d 1 equiv of TBAB added.
b
1
used with slight decreases in product yield observed; the
reaction is limited in the scope of the boronic acids that
can be used and is limited to couplings between aryl
were added and the organic material extracted and removed.
After further extraction of the aqueous layer with ether,
combining the organic washings and drying them over MgSO
the ether was removed in vacuo leaving the crude product.
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 while under a vacuum on a Schlenk line.
Gen er a l P r oced u r e for Con ven tion a lly Hea ted Rea c-
tion s. The method was as for the microwave-assisted proce-
dure except that after the tube was sealed with a septum it
was placed into an oil bath preheated to the desired temper-
ature rather than into the microwave cavity. The reaction
mixture was held in the oil for the specified time before being
removed, the vessel and contents were allowed to cool, and
then the product was extracted and purified in an identical
manner to that in the microwave protocol.
4
,
2
3
halides and arylboronic acids, sp -sp couplings proving
ineffective; and NaBPh can be used in place of phenyl-
4
boronic acid as an phenylating agent.
In terms of scope and conditions used, this transition-
metal-free coupling procedure compares favorably with
many of the palladium-mediated methodologies found in
the literature. It of course has the major advantage that
no metal catalyst is needed. Work is now underway to
determine the mechanism of the coupling reaction and
to apply the methodology to other reactions that are
traditionally palladium mediated.
Exp er im en ta l Deta ils
Ack n ow led gm en t. 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 the Royal Society and King’s College London is
acknowledged. Frontier Scientific is thanked for the
generous supply of boronic acids. R. S. Grainger and M.
M. Salter are thanked for useful discussions.
Gen er a l P r oced u r e for th e Micr ow a ve-Assisted Rea c-
tion s. In a 10-mL glass tube was placed aryl halide (1.0 mmol),
arylboronic acid (1.3 mmol), Na CO (400 mg, 3.8 mmol),
2 3
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 100 W was used, the temperature being ramped
from rt to the desired temperature. Once this was reached,
the reaction mixture was held at that temperature for 5 min.
After allowing the mixture 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)
Su p p or tin g In for m a tion Ava ila ble: Elemental analysis
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O034230I
J . Org. Chem, Vol. 68, No. 14, 2003 5667