Transition-metal-free Suzuki-type coupling reactions

Article abstract of DOI:10.1002/anie.200390362

No metal required: The first transition-metal-free Suzuki-type coupling reaction was carried out in water by using tetrabutylammonium bromide (TBAB) as an additive (see scheme). Products were obtained in high yields with a wide range of aryl bromide substrates.

Full text of DOI:10.1002/anie.200390362

Angewandte
Chemie
that aryl bromides can be coupled with phenylboronic acid to
yield biaryl compounds 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 thought to
be twofold: 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 [ArB(OH)3]À[R4N]+.
TBAB has been used recently in conjunction with a palladium
oxime catalyst for the Suzuki coupling of aryl chlorides with
phenylboronic acid in water.[9] We recently reported that it is
possible to couple a range of aryl halides, including chlorides,
with phenylboronic acid in neat water using microwave
heating with palladium acetate as the catalyst and TBAB as
an additive.[10] The total reaction time is between 5 and
10 min, and low palladium loadings are used. Like Badone
and co-workers, we attribute much of the success of our
methodology to the use of TBAB as additive. In our studies to
understand further the role of this additive, we have found
that, using the appropriate conditions, it is possible to perform
Suzuki-type coupling reactions without the need for a
transition-metal catalyst, which we report herein.
As a starting point for the development of our transition-
metal-free aryl-coupling methodology, we chose to study the
microwave-promoted coupling of phenylboronic acid with 4-
bromoacetophenone, as this would act as a sharpening stone
for optimizing reaction conditions. The results from our
optimization studies are presented in Table 1.
Performing the reaction at 1508C in a sealed tube, we
found that optimum yields of product are obtained when a
ratio of aryl bromide to boronic acid of 1:1.3 is used. The
reason that excess boronic acid is required is because, at the
elevated temperatures used in the reactions, there is com-
petitive protodeboronation of the boronic acid to produce
benzene. We found that a microwave power of 100 W is
optimum. Since we were not concerned about deactivation of
a metal catalyst, we used a higher power than that normally
Biaryl Coupling Reactions
Transition-Metal-Free Suzuki-Type Coupling
Reactions**
Nicholas E. Leadbeater* and Maria Marco
The Suzuki reaction (palladium-catalyzed cross coupling of
aryl halides with boronic acids) is one of the most versatile
and utilized reactions for the selective construction of C C
À
bonds, in particular for the formation of biaryl compounds.[1]
As the biaryl motif is found in a range of pharmaceuticals,
herbicides, and natural products, as well as in conducting
polymers and liquid-crystalline materials, development of
improved conditions for the Suzuki reaction has received
much recent attention. Indeed, in the last ten 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. In addition to a range of organic
solvents, there has been considerable recent interest in the use
of water as a reaction medium. Water, which is cheap, readily
available, nontoxic, and nonflammable, has clear advantages
as a solvent for use in chemistry.[2,3] Suzuki coupling reactions
of water-soluble aryl iodides have been performed in water
with simple palladium salts[4,5] or amphiphilic polymer-
supported palladium catalysts.[6] Badone and co-workers
have investigated the effects of solvent, including water, on
the rate of the ligand-free palladium acetate catalyzed Suzuki
reaction of a range of aryl bromides, iodides, and triflates.[7]
They report that when using water as a solvent, the addition of
1 equivalent of tetrabutylammonium bromide (TBAB) to the
reaction mixture greatly accelerates the reaction.[8] They find
Table 1: Microwave-promoted Suzuki-type coupling of 4-bromoaceto-
phenone and phenylboronic acid in water.[a]
TBAB
COMe
B(OH)2
Na2CO3
COMe
+
H2O
microwave
Br
Entry
Reaction conditions[b]
PhB(OH)2 TBAB Na2CO3 Power
Yield[c]
T
t
[equiv]
[equiv] [equiv] [W]
[8C] [min] [%]
1
2
3
4
5
6
7
8
9
1.3
1.3
1.3
1.0
1.1
1.2
1.2
1.2
1.2
1.0
1.0
1.0
1.0
1.0
1.0
0.5
1.0
1.0
3.8
3.8
3.8
3.8
3.8
3.8
3.8
1.9
3.8
60
150
100
100
100
100
100
100
150
150
150
150
150
150
150
150
5
5
5
5
5
5
5
5
97
100
100
82
[*] Dr. N. E. Leadbeater, M. Marco
Department of Chemistry, King's College London
Strand, London, WC2R 2LS (UK)
Fax: (+44)20-7848-2810
95
100 (98)[d]
58
E-mail: nicholas.leadbeater@kcl.ac.uk
[**] We thank the Royal Society for a University Research Fellowship
(N.E.L.) and King's College London for a PhD studentship (M.M.).
Funding from the Royal Society and King'sCollege London is
acknowledged.
84[d]
94[d]
oil bath 150 120
[a] Aryl halide (1 mmol), water (2 mL). Temperature ramped to that
stated and held there for the allotted time. [b] Conditions changed from
entry 1 are highlighted in bold. [c] Determined by 1H NMR spectroscopic
analysis. [d] Yield of isolated product.
Supporting information for thisarticle (NMR data and experimental
details) is available on the WWW under http://www.angewandte.org
or from the author.
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Communications
[a]
Table 2: Suzuki-type coupling of aryl halidesand aryl boronic acidsin water.
used in the palladium-mediated
X
B(OH)2
couplings (60 W). We found that
the amount of base used in the
reaction affects the yield consid-
erably, the optimum quantity
being 3.8 equivalents. The reac-
tion reaches completion in 5 min.
To show that the reaction is
indeed metal-free, we used new
TBAB, Na2CO3
+
H2O, microwave
R
R
X = Cl, Br, I
Entry
1
Aryl halide
Yield [%]
Entry
11
Aryl halide
Yield [%]
71[c]
90[b]
99[b]
glassware,
apparatus,
and
2
3
12
13
99[b]
50[b]
reagents and analyzed the
entire crude product mixture
for palladium content. We
found that there was no palla-
dium in the product mixture to
the level of detection of the
analysis apparatus.[11] This, and
the fact that the reaction is
reproducible argues against cat-
alytic contaminants. We also
checked the levels of other
metals in the product mixture
that could possibly be acting as
catalysts by inductively coupled
plasma atomic absorption (ICP
AA) spectroscopy. None of them
were present in the product mix-
ture in concentrations above the
level of detection of the appara-
tus of 0.5–1 ppm.[12]
98 (91)[b]
4
5
82[b]
61[b]
14
15
76[c]
99[b,d]
6
53[c]
73[b]
55[b]
82[c]
96[c]
16
17
18
19
20
3[c]
7
79[c]
25[c]
0[c]
8
9
In an attempt to broaden the
10
0[c]
scope of the methodology, we
investigated the possibility of
performing the reaction with
conventional heating. We found
that placing a sealed tube in an
oil bath at 1508C offers an easy
way to perform the reaction with
4-bromoacetophenone, a 91%
yield of product being obtained
[a] Aryl halide (1 mmol), boronic acid (1.3 mmol), Na2CO3 (3.8 mmol), TBAB (1.0 mmol), water (2 mL).
Yieldsquoted are for microwave promotion using a microwave power of 100 W. The temperature was
ramped to 1508C and held for 5 min. The yield quoted in parentheses was obtained when using
conventional heating. The sealed tube was placed in an oil bath at 1508C and held for 5 h. [b] Yieldsof
isolated product. [c] Determined by 1H NMR spectroscopic analysis. [d] Reaction using 4-methylben-
zeneboronic acid asthe coupling partner.
after heating for 2 h. However, the reaction of unactivated
and deactivated aryl bromide substrates is not so efficient
under conventional heating, even after heating for extended
periods of time (16 h).
with their bromo counterparts. Aryl chlorides cannot be
coupled by this method (Table 2, entries 19 and 20).
In conclusion, we have shown that the Suzuki-type
coupling of boronic acids and aryl halides is possible without
the need for a transition-metal catalyst. The methodology is
immediately viable for use both in small research and larger
industrial scales. Since the use of transition metals leads to the
generation of waste and has a number of hazards associated
with it, such as the handling of toxic, air- and moisture-
sensitive complexes, the eradication of the transition-metal
catalyst from the Suzuki reaction offers significant advan-
tages. Work is currently underway to investigate the mech-
anism of the coupling reaction.
The methodology is applicable to a wide range of aryl
bromide substrates (Table 2, entries 1–15), with good yields
being obtained in the reaction with phenylboronic acid. A
wide range of functional groups are tolerated in the reaction
and are not affected by the high temperature and aqueous
conditions used. Furthermore, sterically demanding aryl
bromides can be coupled with phenylboronic acid to give
good yields of product (Table 2, entries 8 and 13). To show
that the reaction is regiospecific with respect to both the aryl
bromide and the boronic acid, we screened the reaction of 4-
bromoacetophenone with 4-methylbenzeneboronic acid and
obtained the desired coupling product in excellent yield
(Table 2, entry 15). Representative aryl iodides were also
screened in the coupling reaction using our methodology
(Table 2, entries 16–18), but product yields were lower those
Received: December 16, 2002 [Z50773]
Keywords: aqueouschemistry · biaryl compounds· boron ·
.
cross-coupling · microwave chemistry
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Angewandte
Chemie
[7] D. Badone, M. Baroni, R. Cardamone, A. Ielmini, U. Guzzi, J.
[1] For recent reviews, see: a) J. Hassan, M. SØvignon, C. Gozzi, E.
Schulz, M. Lemaire, Chem. Rev. 2002, 102, 1359; b) A. Suzuki, J.
Organomet. Chem. 1999, 576, 147; c) N. Miyaura, A. Suzuki,
Chem. Rev. 1995, 95, 2457.
[2] For an introduction to the use of water as a solvent in organic
synthesis, see: a) Organic Synthesis in Water (Ed.: P. A. Grieco),
Klewer Academic Publishers, Dordrecht, 1998; b) C.-J. Li, T.-H.
Chan, Organic Reactions in Aqueous Media, Wiley, New York,
1997.
[3] For an introduction to the use of organometallic catalysts in
aqueous-phase catalysis, see: Aqueous-Phase Organometallic
Catalysis, Concepts and Applications (Eds.: B. Cornils, W. A.
Herrmann), Wiley-VCH, Weinheim, 1998.
[4] N. A. Bumagin, V. V. Bykov, Tetrahedron 1997, 53, 14437.
[5] H. Sakurai, T. Tsukuda, T. Hirao, J. Org. Chem. 2002, 67, 2721.
[6] Y. Uozumi, H. Danjo, T. Hayashi, J. Org. Chem. 1999, 64, 3384.
Org. Chem. 1997, 62, 7170.
[8] The use of TBAB in palladium-mediated catalysis has been
reported on a number of occasions, in particular for the Heck
reaction; see, for example: T. Jeffery, Tetrahedron Lett. 1994, 35,
3051.
[9] L. Botella, C. Nꢀjera, Angew. Chem. 2002, 114, 187; Angew.
Chem. Int. Ed. 2002, 41, 179.
[10] N. E. Leadbeater, M. Marco, Org. Lett. 2002, 4, 2973. We have
subsequently shown that it is possible to perform the reaction
conventionally: N. E. Leadbeater, M. Marco J. Org. Chem. 2003,
68, 888
[11] No Pd found down to below 0.1 ppm Pd.
[12] Elements screened: As, Bi, Be, Cd, Ce, Co, Cr, Cu, Dy, Eu, Gd,
Ge, Hf, Hg, Ir, K, La, Li, Mn, Mo, Nd, Ni, Os, P, Pb, Pr, Pt, Re,
Rh, Ru, Sb, Sc, Se, Sm, Sn, Tb, Th, Ti, Tl, Tm, V, Y, Yb, Zn, Zr.
Angew. Chem. Int. Ed. 2003, 42, No. 12
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