Tetraphosphine/palladium-catalysed Suzuki cross-coupling with sterically hindered aryl bromides and arylboronic acids

Article abstract of DOI:10.1016/S0040-4039(01)01360-0

cis,cis,cis-1,2,3,4-Tetrakis(diphenylphosphinomethyl)cyclopentane/[PdCl(C ₃H₅)]₂ system efficiently catalyses the Suzuki cross-coupling of sterically hindered substrates. Very high turnover numbers can be obtained for the

Full text of DOI:10.1016/S0040-4039(01)01360-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6667–6670
Tetraphosphine/palladium-catalysed Suzuki cross-coupling with
sterically hindered aryl bromides and arylboronic acids
Marie Feuerstein, Henri Doucet* and Maurice Santelli*
Laboratoire de Synth e` se Organique associ e´ au CNRS, Facult e´ des Sciences de Saint J e´ r oˆ me,
Avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex 20, France
Received 16 July 2001; revised 25 July 2001; accepted 26 July 2001
Abstract—cis,cis,cis-1,2,3,4-Tetrakis(diphenylphosphinomethyl)cyclopentane/[PdCl(C H )] system efficiently catalyses the Suzuki
3
5 2
cross-coupling of sterically hindered substrates. Very high turnover numbers can be obtained for the coupling of sterically
hindered aryl bromides with benzeneboronic acid or for the coupling of bromobenzene with sterically hindered arylboronic acids.
On the other hand the formation of tri-ortho-substituted biaryl adducts requires higher catalyst loading. © 2001 Elsevier Science
Ltd. All rights reserved.
Atropisomerism in biaryl derivatives is important due
to their biological properties; therefore their prepara-
tuted arylbromides and arylboronic acids has not been
reported.
1
tion is an important goal. Palladium-catalysed Suzuki
2
cross-coupling reaction between sterically hindered
The nature of phosphine ligands on complexes has a
tremendous influence on the rate of catalysed reactions.
In order to obtain highly stable palladium catalysts
aryl halides and arylboronic acids is one of the most
efficient methods for the synthesis of these compounds.
In general, these palladium catalysts are associated with
6
we have prepared the new tetraphosphine ligand,
3
the triphenylphosphine ligand. Even if the catalyst
cis,cis,cis - 1,2,3,4 - tetrakis(diphenylphosphinomethyl)-
7
formed by association of this ligand with palladium
complexes is efficient in terms of yield of adduct, the
efficiency in terms of ratio substrate/catalyst is gener-
ally low and 1–10% of the catalyst must be used. In
recent years, a few bulky monodentate ligands have
been successfully used for Suzuki cross-coupling reac-
cyclopentane or Tedicyp (Fig. 1) in which four
diphenylphosphino groups are stereospecifically bound
to the same face of a cyclopentane ring. The presence of
these four phosphines close to the metal centre seems to
increase the coordination of the ligand to the metal
centre and therefore increase the stability of the cata-
lyst. We have recently reported the first results obtained
4
tion. However, most of the results, which have been
8
9
described with these ligands, were obtained for the
coupling of meta- or para-substituted aryl halides or
arylboronic acids. Few results have been reported using
in allylic substitution, for Heck reaction and for
10
Suzuki cross-coupling using Tedicyp as the ligand.
7
For example, a turnover number (TON) of 2.8×10 for
the coupling of 4-bromobenzophenone with ben-
zeneboronic acid had been observed. A high efficiency
was also observed for the cross-coupling of activated
5
ortho-substituted substrates. One of the most active
catalysts for such substrates is Herrmann’s palladacy-
5
a
cle. A very efficient catalyst has also been prepared
5
b
11
with the bulky ligand (o-biphenyl)P(t-Bu)2. Another
aryl chlorides. In this paper, we wish to report on
efficient catalytic system uses a palladium–phosphite
Suzuki cross-coupling in the presence of sterically hin-
dered aryl bromides and arylboronic acid using Tedicyp
as the ligand.
5
d
complex. Finally, a sulfur-containing palladacycle and
a ferrocene derivative also efficiently promote the cross-
5e,f
coupling of sterically demanding substrates.
How-
ever, to our knowledge, the efficiency of tetraphosphine
ligands for the coupling of ortho- and di-ortho-substi-
Ph2P
PPh2
Ph2P
PPh2
Tedicyp
*
Corresponding authors. Tel.: 00-33-4-91-28-84-16; fax: 00-33-4-91-
8-38-65 (H.D.); tel.: 00-33-4-91-28-88-25 (M.S.); e-mail:
henri.doucet@lso.u-3mrs.fr; m.santelli@lso.u-3mrs.fr
9
Figure 1.
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01360-0

6
668
M. Feuerstein et al. / Tetrahedron Letters 42 (2001) 6667–6670
First, we tried to evaluate the importance of the pres-
ence of one ortho substituent on the arylbromide on the
rate of the reaction. For this study, based on our
previous results, xylene was chosen as the solvent and
potassium carbonate as the base. The reactions were
performed at 140°C in the presence of a 1/2 ratio of
zeneboronic acid in the presence of a 0.00001% catalyst
led to the biaryl adduct in 88% yield (TON 8.8×10 )
6
(Scheme 1, Table 1, entry 6). A conversion of 75% was
obtained using similar conditions with 4-methylbro-
1
0
6
mobenzene (TON 7.5×10 ) (entry 4). With 1-fluoro-2-
bromobenzene, 2-bromoanisole, 2,4-dimethoxy-bromo-
benzene or 1-bromonaphthalene similar reaction rates
[
Pd(C H )Cl] /Tedicyp as catalyst. Although this cata-
3 5 2
9
5
6
lyst is quite air-stable, the reactions were performed
under argon. Using these conditions, we observed that
the coupling of 2-methylbromobenzene with ben-
were observed (TONs 7.1×10 –4.3×10 ) (entries 7–13).
Next, we tried to evaluate the difference of reaction rate
between mono- and di-ortho-substituted arylbromides,
R1
R3
R1 R3
[
Pd(C H )Cl] /tedicyp
3 5 2
Br + (HO)2B
xylene, K CO , 130°C
2
3
R2
R4
R2 R4
Scheme 1.
Table 1. Suzuki cross-coupling catalysed by the Tedicyp–palladium complex (Scheme 1)
12
Entry
Aryl bromide
Boronic acid
Ratio substrate/catalyst
Yield (%)a
1
2
3
4
5
6
7
8
9
Bromobenzene
Bromobenzene
4-Bromotoluene
4-Bromotoluene
2-Bromotoluene
2-Bromotoluene
1-Bromo-2-fluorobenzene
1-Bromo-2-fluorobenzene
2-Bromoanisole
1-Bromo-2,4 dimethoxybenzene
1-Bromo-2,4 dimethoxybenzene
1-Bromonaphthalene
1-Bromonaphthalene
1-Bromo-2,6-dimethylbenzene
1-Bromo-2,6-diethylbenzene
1-Bromo-2,4,6-triisopropylbenzene
9-Bromoanthracene
9-Bromoanthracene
1-Bromo-2-methylnaphthalene
Bromobenzene
Bromobenzene
2-Bromotoluene
Benzeneboronic acid
Benzeneboronic acid
Benzeneboronic acid
Benzeneboronic acid
Benzeneboronic acid
Benzeneboronic acid
Benzeneboronic acid
Benzeneboronic acid
Benzeneboronic acid
Benzeneboronic acid
Benzeneboronic acid
Benzeneboronic acid
Benzeneboronic acid
Benzeneboronic acid
Benzeneboronic acid
Benzeneboronic acid
1 000 000
10 000 000
1 000 000
10 000 000
1 000 000
10 000 000
1 000 000
10 000 000
1 000 000
1 000 000
5 000 000
1 000 000
10 000 000
1 000 000
1 000 000
1 000 000
1 000 000
10 000 000
1 000 000
1 000 000
10 000 000
1 000 000
1000
100b
75
100
b
75
91
88
87
43
71
b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
100
28
82
42
88
88
92
93
Benzeneboronic acid
Benzeneboronic acid
Benzeneboronic acid
b
32
60
88
43
2-Methylphenylboronic acid
2-Methylphenylboronic acid
2-Methylphenylboronic acid
2-Methylphenylboronic acid
2-Methylphenylboronic acid
2,6-Dimethylphenylboronic acid
2,6-Dimethylphenylboronic acid
2,6-Dimethylphenylboronic acid
2,6-Dimethylphenylboronic acid
2,6-Dimethylphenylboronic acid
2,6-Dimethylphenylboronic acid
1-Naphthaleneboronic acid
1-Naphthaleneboronic acid
1-Naphthaleneboronic acid
1-Naphthaleneboronic acid
1-Naphthaleneboronic acid
1-Naphthaleneboronic acid
1-Naphthaleneboronic acid
1-Naphthaleneboronic acid
1-Naphthaleneboronic acid
b
85
83
89
78
43
100
1-Bromo-2,6-dimethylbenzene
1-Bromo-2-methoxynaphthalene
Bromobenzene
Bromobenzene
2-Bromotoluene
1000
10 000
100 000
100
1000
b
b
2-Bromotoluene
12
36
0
1-Bromonaphthalene
1-Bromo-2,6-dimethylbenzene
Bromobenzene
Bromobenzene
Bromobenzene
2-Bromotoluene
2-Bromotoluene
1-Bromo-2,6-dimethylbenzene
1-Bromo-2-methylnaphthalene
1-Bromo-2-methylnaphthalene
1-Bromo-2-methoxynaphthalene
100
50
b
100 000
1 000 000
10 000 000
1 000 000
10 000 000
100
100
92
50
b
90
43
85
b
b
100
1000
1000
94
82
90
Conditions: catalyst [Pd(C H )Cl] /ligand 1/2 see: Ref. 7, ArBr (1 equiv.), ArB(OH) (2 equiv.), K CO (2 equiv.), xylene, 140°C, 20 h.
3
5
2
2
2
3
a
Isolated yields.
GC yields.
b

M. Feuerstein et al. / Tetrahedron Letters 42 (2001) 6667–6670
6669
and we observed that even very hindered aryl bro-
mides could be coupled efficiently with ben-
this catalyst, the rate-determining step of the reaction
is not the oxidative addition of the arylbromide. The
rate-determining step seems to be the transmetallation
of the boronic acid with the palladium centre due to
a sterically hindered ortho-subtituted aryl-Pd interme-
diate. However, a slower CꢀC bond formation from
the Pd-biaryl intermediate due to a steric effect is also
possible.
zeneboronic
acid.
For
example,
with
9
-bromoanthracene, 1-bromo-2,6-dimethylbenzene, 1-
bromo-2,6-diethylbenzene and 1-bromo-2,4,6-triiso-
propylbenzene high conversions were obtained in the
5
6
presence of 0.0001% catalyst (TONs 8.8×10 –3.2×10 )
entries 14–18) showing a not very significant effect of
(
the ortho-substituents of the aryl bromide on the rate
of the reaction. In all cases, only traces (<3%) of
homocoupling of the boronic acid were observed.
In conclusion, the use of the tetradentate ligand Tedi-
cyp associated with a palladium complex provides a
convenient catalyst for the cross-coupling of sterically
hindered aryl bromides with arylboronic acids. This
catalyst is more efficient than the complex formed
with triphenylphosphine and related ligands. This
efficiency probably comes from the presence of the
four diphenylphosphinoalkyl groups stereospecifically
bound to the same face of the cyclopentane ring,
which probably increases the coordination of the lig-
and to the metal and prevents precipitation of the
catalyst. As expected, both the steric hindrance of the
arylbromides and the steric hindrance of the boronic
acids have an effect on the rate of this reaction. If
the presence of one ortho substituent on one of the
substrates has almost no influence on the rate of the
reaction, the presence of two ortho substituents on
one of the substrates or one ortho substituent on both
substrates has some influence on the rate of the reac-
tion. However, with all these substrates, high TONs
are generally observed. The reaction can be per-
formed with as little as 0.00001% catalyst without
further optimisation of the reaction conditions. Due
to the high price of palladium, the practical advan-
tage of such low catalyst loading reactions can
become increasingly important for industrial pro-
cesses. On the other hand, the formation of tri-ortho-
substituted biaryl compounds led to much lower
reaction rates and the presence of 0.1–1% catalyst is
required, showing a very significant steric effect on
the rate of the reaction. These results represent an
environmentally friendly procedure. Further applica-
tions of this ligand will be reported in due course.
Next, we studied the influence of hindered aryl-
boronic acids for this reaction, and we noticed that
similar reaction rates were obtained for the cross-cou-
pling of bromobenzene with 2-methylbenzene boronic
6
acid (TON 4.3×10 ) (entry 21) than for the coupling
of 2-bromotoluene with benzeneboronic acid (TON
6
8
.8×10 ) (entry 6). This result indicates that the
transmetallation of sterically hindered boronic acids
with the palladium centre occurs very rapidly. High
reaction rates were also observed for the coupling of
bromobenzene with the sterically hindered 2,6-
dimethylphenylboronic acid and 1-naphthaleneboronic
acid (entries 25, 26, 32 and 33).
On the other hand, a very important steric effect for
the cross-coupling of ortho-subtituted arylbromides
with di-ortho-substituted arylboronic acids or for di-
ortho-subtituted arylbromides with ortho-substituted
arylboronic acids was observed. For example, the
coupling of 1-bromo-2,6-dimethylbenzene with 2-
methylbenzeneboronic acid led to the biaryl adduct in
a TON of 830 (entry 23). Finally, we tried the cou-
pling of 1-bromo-2,6-dimethylbenzene with 2,6-
dimethylbenzeneboronic acid in the presence of 2%
catalyst; however, no coupling adduct was observed
due to a very fast decomposition of the catalyst. In
order to obtain more information on the influence of
the steric factors on the rate of this reaction, we per-
formed a competitive reaction using an equimolar
mixture of benzeneboronic acid and 2,6-dimethyl-ben-
zeneboronic acid in the presence of 1-bromo-2,6-
dimethylbenzene (Scheme 2). We only observed the
formation of the coupling products with ben-
zeneboronic acid and in this case the decomposition
of the catalyst was not observed.
Acknowledgements
We thank the CNRS for providing financial support
and M.F. is grateful to the Minist e` re de la Recherche
et de la Technologie for a grant.
The respective rates of these reactions with sterically
hindered substrates suggest that, in the presence of
Me
Me
Me Me
Me
[
Pd(C H )Cl] /tedicyp
3 5 2
Ratio S/C: 100 000
Br
+
(HO) B
+ (HO) B
+
2
2
xylene, K CO ,
2
3
1
40°C, 20h
Me
Me
Me Me
0%
Me
1
0 mmol
20 mmol
20 mmol
100%
Scheme 2.

6
670
M. Feuerstein et al. / Tetrahedron Letters 42 (2001) 6667–6670
1995, 34, 1848; (b) Wolfe, J.; Singer, R.; Yang, B.;
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7
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4
1
1
1. Feuerstein, M.; Doucet, H.; Santelli, M. Synlett 2001, in
press.
2. As a typical experiment, the reaction of 2,4,6-triisopropyl
bromobenzene (2.83 g, 10 mmol), benzeneboronic acid
(
2.44 g, 20 mmol) and K CO (2.76 g, 20 mmol) at 140°C
2 3
for 20 h in dry xylene (10 mL) in the presence of
cis,cis,cis-1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclo-
2
413; (f) Bedford, R.; Welch, S. Chem. Commun. 2001,
1
29; (g) Gibson, S.; Foster, D.; Eastham, G.; Tooze, R.;
Cole-Hamilton, D. Chem. Commun. 2001, 779.
pentane/[PdCl(C H )] complex (0.00001 mmol) under
3 5 2
5
. For examples of cross-coupling with sterically hindered
substrates, see: (a) Beller, M.; Fischer, H.; Herrmann, A.;
.
Ofele, K.; Brossmer, C. Angew. Chem., Int. Ed. Engl.
argon affords the corresponding biaryl product after
evaporation and filtration on silica gel in 92% (2.57 g)
isolated yield.