Suzuki cross-coupling of arylboronic acids mediated by a hydrosoluble Pd(0)/TPPTS catalyst

Article abstract of DOI:10.1016/S0040-4039(01)01301-6

Suzuki cross-coupling reactions between a range of aryl bromides and boronic acids using a water-soluble Pd(0)/TPPTS catalyst occur under mild conditions with high efficiency. The process tolerates electron-rich and electron-poor substituents and provides an efficient access to sterically hindered biaryls. Good turnovers are observed and the catalyst can be recycled three times without loss of activity.

Full text of DOI:10.1016/S0040-4039(01)01301-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6523–6526
Suzuki cross-coupling of arylboronic acids mediated by a
hydrosoluble Pd(0)/TPPTS catalyst
Christophe Dupuis, Kouacou Adiey, Lise Charruault, Ve´ronique Michelet, Monique Savignac* and
Jean-Pierre Geneˆt*
Laboratoire de synthe`se se´lective et produits naturels, associe´ au CNRS UMR 7573,
Ecole Nationale Supe´rieure de Chimie de Paris, 11, rue Pierre et Marie Curie, F-75231 Paris Cedex, France
Received 17 July 2001; accepted 19 July 2001
Abstract—Suzuki cross-coupling reactions between a range of aryl bromides and boronic acids using a water-soluble Pd(0)/TPPTS
catalyst occur under mild conditions with high efficiency. The process tolerates electron-rich and electron-poor substituents and
provides an efficient access to sterically hindered biaryls. Good turnovers are observed and the catalyst can be recycled three times
without loss of activity. © 2001 Elsevier Science Ltd. All rights reserved.
Compounds which contain a biaryl linkage have found
applications in areas ranging from pharmaceutical
intermediates to materials science.1 Their preparation,
when effected through the palladium-catalyzed Suzuki
cross-coupling of aryl halides with arylboronic acids, is
both extremely versatile and very convenient: boronic
acids, being generally non-toxic, thermally stable and
insensitive to air and moisture, are much easier to
handle than other commonly used cross-coupling
reagents.2 As well as aryl chlorides,3 arenediazonium
salts can also act as electrophiles and our group has
recently described an efficient palladium-catalyzed
cross-coupling between arylboronic acids or aromatic
potassium tetrafluoroborates which produces biaryls
under mild conditions.4
Previously we have described the Suzuki cross-coupling
of a wide range of arylboronic acids or esters with aryl
or vinyliodides and shown that diisopropylamine is a
very effective base in this medium.7 The principal draw-
back to this protocol lies in its use of expensive arylio-
dide electrophiles. We envisaged an extension to
arylbromides and arylchlorides, which are attractive
because of their low cost and wide availability.
Recently, we have shown that a water-soluble Ni(0)
catalyst formed from NiCl2(dppe) and TPPTS catalyzed
the cross-coupling of a variety of arylchlorides and
arylboronic acids to afford good yields of biaryls8
(Scheme 1). Here, we wish to report our recent results
in Suzuki cross-coupling of arylbromides carried out
with the water-soluble catalyst Pd/TPPTS.9
We have been engaged in a program of organometallic
catalysis in organoaqueous media which uses the water-
soluble ligand, sodium triphenylphosphinometatrisul-
fonate (TPPTS) in combination with palladium for
deprotective group chemistry and cross-coupling reac-
tions.5 These hydrosoluble systems show the dual
advantages of operating under mild conditions and
allowing an easy separation of the products from the
catalyst, which greatly facilitates the work-up. More-
over water is an economical and environmentally
friendly solvent which, under appropriate conditions,
also allows new reactions such as carbohydroxy
palladation6 as well as recycling the catalyst.
R
R'
R
Br
Pd(OAc)2
TPPTS
base
+
CH3CN/H2O
R'
(HO)2B
Scheme 1.
Catalyst performance was optimized in the reaction of
2-bromobenzaldehyde with phenylboronic acid. It was
found that the nature of the palladium source,
Pd(OAc)2 or PdCl2, has no influence on the course of
the reaction. The optimal TPPTS/Pd(OAc)2 ratio was
3:1; 1 equiv. of the phosphine being used to reduce
Pd(II) to Pd(0) and the others to stabilize the palla-
Keywords: Suzuki coupling; water-soluble catalyst; recycling.
* Corresponding authors. E-mail: savignac@ext.jussieu.fr; genet@
ext.jussieu.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01301-6

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C. Dupuis et al. / Tetrahedron Letters 42 (2001) 6523–6526
dium.10 The homogeneity of the reaction mixture was
crucially important to the success of the reaction and
diisopropylamine was found to be the base of choice
(Scheme 2).
substituents are nicely tolerated. The reaction times are
short, except in the cases of 2-bromophenol and 2-bro-
moaniline, where some chelation to palladium may be
occurring (entries 7 and 9). The reaction was chemospe-
cific for aryl bromide in the presence of the correspond-
ing chloride (entries 4 and 5).
R
5% Pd(OAc)2
15% TPPTS
R
Br
As shown in Table 2, the Suzuki coupling of heteroaryl-
bromides with phenylboronic acid is completed in good
yield within 8 h (entries 1 and 2). The slightly lower
conversions observed when electron-donating sub-
stituents are present could be improved by employing
longer reaction times and more polar solvents such as
NMP (entry 4). Under these conditions, it was possible
to generate excellent yields of biaryls having three
ortho-substituents which are difficult to prepare using
the Suzuki coupling in anhydrous conditions (entry 6).
2.5 equiv iPr2NH
CH3CN/H2O 3:1
80 °C
+
(HO)2B
Scheme 2.
Representative cross-coupling reactions using both elec-
tron-rich and electron-poor bromoarenes were investi-
gated under these optimized conditions.11 The results
are summarized in Table 1.
ortho-Biaryls have peculiar biological activity which
may reflect the ability of the gauche conformation,
(generated by intermolecular repulsions) to interact
with proteins; consequently, they show a rather broad
band of pharmacological activity. The value of our
process is exemplified in a two-step synthesis of
xenalipin (Scheme 3), a non-natural product which
reduces cholesterol and triglyceride levels in plasma.12,13
Coupling of 2-bromobenzaldehyde with 4-trifl-
uoromethylphenyl boronic acid under our standard
Table 1. Scope of Suzuki cross-couplings of arylbromides
Entry
R
Time (h)
Yield (GC conversion %)
1
2
3
4
5
6
7
6
8
9
2-OHC
4-OHC
4-Ph-CO
3-Cl
4-Cl
4-CH3
2-HO
2-MeO
2,4-diMeO
2-H2N
4
0.5
1
1
2
1
72
2
3
12
92 (100)
90 (100)
80 (100)
78 (87)
82 (100)
53 (100)
60 (72)
75 (64)
68 (84)
64 (100)
conditions
afforded
2-(4-trifluoromethylphenyl)-
benzaldehyde in 73% yield within 4 h. Xenalipin was
then obtained straightforwardly in a second step
through mild KMnO4 oxidation in 73% yield. This
result may be compared with our earlier procedure
employing a Suzuki coupling of diazonium and tetra-
fluoroborate salts.4 With the new protocol, the 2-(4-
trifluoromethyphenyl)benzaldehyde intermediate was
efficiently prepared in a shorter time (5 min).
It is clear that the cross-coupling is efficient over a
broad spectrum of ortho- and para-substituted aryl
bromides and that variations in electronic nature of the
Table 2. Suzuki cross-coupling of a variety of arylbromides and boronic acids

C. Dupuis et al. / Tetrahedron Letters 42 (2001) 6523–6526
6525
CHO
Pd(OAc)2 /TPPTS
+
Br
(HO)2B
CF3
CHO
CH3CN/H2O, 80° C, 4 h
73%
CF3
CHO
BF3K
Pd2(µ-OAc)2[P(o-tol)3]2
+
F4BN2
CF3
MeOH, rt, 5 min
70%
CO2H
1.5 equiv KMnO4
Xenalipin
CF3
acetone/H2O, 50° C, 2 h
73%
Scheme 3.
The effect of lowering of catalyst loading was also
studied under our standard conditions in the model
coupling of 4-bromobenzaldehyde and boronic acid
(Scheme 4).
that homocoupling reactions were suppressed (<1%
GC).15
Finally, it was possible to recycle the catalyst for use in
the same coupling reaction by using 5 mol% Pd and 4
equiv. of TPPTS to increase catalyst stability (Table 4).
5% Pd(OAc)2
Br
OHC
15% TPPTS
CHO
Table 4 shows that a decrease in the degree of conver-
sion only appears in the fourth generation catalyst.
Reaction times increased upon recycling, perhaps
because of the accumulation of salts in the mixture.
2.5 equiv iPr2NH
CH3CN/H2O 3:1
+
80 ˚C
(HO)2B
Scheme 4.
To conclude, a water-soluble palladium catalyst has
been shown to have high efficiency and turnover num-
bers for the Suzuki coupling of a wide range of aryl
bromides to boronic acids. Furthermore, the catalyst
can be recycled three times without loss of activity.
Reducing the mole fraction of palladium from 5×10−2
mol Pd to 1×10−2 mol still gave a quantitative yield
with no increase in the reaction time (Table 3, entry 1).
However, a small fall in conversion was observed after
4 h when using 1×10−3 mol of catalyst (entry 2). The
turnover number at 10−4 mol concentrations is good
(6400), thus proving that our water-soluble catalyst is
competitive with the most recent methods which gener-
ally use palladacycles (entry 4).14 It is also noteworthy
Acknowledgements
We thank Rhodia for the generous gifts of TPPTS and
financial support to C.D. (Ph.D. Fellowship 1996–
1999).
Table 3. Suzuki with low catalyst loadinga
Entry
Pd (mol)
Time (h)
Conversion (%)b TON
References
1
2
3
4
0.01
0.5
4
22
17
100
88
64
m
100
880
6400
1. Review: Stanfort, S. P. Tetrahedron 1998, 54, 263–303
and references cited therein.
0.001
10−4
10−5
2. For recent reviews, see: (a) Miyaura, N.; Suzuki, A.
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P. J., Eds.; Wiley-VCH: New York; 1998; pp. 49–97; (c)
Stanforth, S. P. Tetrahedron 1998, 54, 263–303.
a Reaction conditions: 1 mmol arylbromide, 1.2 equiv. boronic acid,
[arylbromide]=2.5 M.
b Conversion was determined by GC.
Table 4. Parameters relating to the recycling of the water-soluble catalysta

6526
C. Dupuis et al. / Tetrahedron Letters 42 (2001) 6523–6526
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11. Typical procedure: Water and acetonitrile were degassed
under vacuum. Pd(OAc)2 (5 mol%, 0.025 mmol, 5.6 mg),
TPPTS (15%; 0.075 mmol, 128 mg of a 33% wt solution
in water) and 0.16 mL of water were placed in a flask
under argon and warmed at 60°C for 15 min. A solution
of 4-bromobenzaldehyde (1 equiv., 0.5 mmol, 58 mL) and
phenylboronic acid (1.2 equiv., 0.6 mmol, 73 mg) in 0.5
mL of acetonitrile was added in the flask. Diisopropy-
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the flask and the resulting mixture was stirred 4 h at
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with 5 mL of saturated NaCl solution and extracted by
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vacuo. Purification of crude product by flash chromatog-
raphy on silica gel afforded 77 mg of 4-phenylbenzalde-
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MHz, l ppm): 7.44–7.56 (3H, m); 7.67 (2H, dd); 7.73
(2H, d); 7.98 (2H, d); 10.1 (1H, s, CHO); 13C (CDCl3, 50
MHz, d ppm): 127.3; 127.6; 128.4; 128.9; 130.2; 135.1;
139.6; 147.1; 191.8 (CHO).
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