Practical synthesis of new and highly efficient ligands for the Suzuki reaction of aryl chlorides

Article abstract of DOI:10.1039/b311268n

A practical synthesis of a novel class of phosphine ligands, phosphino substituted N-aryl pyrroles (PAP ligands), has been developed. These ligands are applied in the palladium-catalyzed coupling of a variety of aryl and heteroaryl chlorides with phenylboronic acid showing exceedingly high turnover numbers at mild reaction temperatures and even at room temperature.

Full text of DOI:10.1039/b311268n

Practical synthesis of new and highly efficient ligands for the Suzuki
reaction of aryl chlorides
a
a
a
b
b
Alexander Zapf, Ralf Jackstell, Franck Rataboul, Thomas Riermeier, Axel Monsees, Christa
a
a
b
a
Fuhrmann, Nadim Shaikh, Uwe Dingerdissen and Matthias Beller*
Leibniz-Institut für Organische Katalyse an der Universität Rostock e.V., Buchbinderstr. 5-6, 18055
Rostock, Germany
a
b
Degussa AG, Creavis Technologies & Innovation, Project House Catalysis, Industriepark Höchst, G830,
65926 Frankfurt am Main, Germany
Received (in Cambridge, UK) 15th September 2003, Accepted 28th October 2003
First published as an Advance Article on the web 28th November 2003
A practical synthesis of a novel class of phosphine ligands,
phosphino substituted N-aryl pyrroles (PAP ligands), has been
developed. These ligands are applied in the palladium-cata-
lyzed coupling of a variety of aryl and heteroaryl chlorides with
phenylboronic acid showing exceedingly high turnover numbers
at mild reaction temperatures and even at room temperature.
ligands 1–3 were tested in the coupling of 2-chlorotoluene with
phenylboronic acid under various reaction conditions.
The screening of PAP–Ph (1), PAP–Cy (2) and PAP-t-Bu (3) in
2 2 3
the presence of 0.1 mol% Pd(OAc) or 0.05 mol% Pd dba (L/Pd =
2/1, toluene) and different bases demonstrates the importance of
basic substituents on the phosphorus atom: almost no yield (and
conversion) is observed if 1 is applied as ligand. On the other hand,
with 2 and 3 as ligands high yields ( > 90%) have been observed.
Advantageously, best yields have been obtained using potassium
phosphate or cheap potassium carbonate as base.
Biaryls constitute important building blocks for the synthesis of
biologically active substances, e.g. pharmaceuticals and herbi-
1
cides. Currently, the most versatile method for the synthesis of
substituted biaryls is the cross-coupling reaction of aryl halides and
arylboronic acids (Suzuki reaction). Suzuki cross-coupling reac-
The general usefulness of our new catalyst systems is shown in
Table 1. 15 different aryl and heteroaryl chlorides gave the
corresponding biaryls in good to excellent yield (74 to > 99%) at
low catalyst concentration (0.05 mol% Pd or below). While a
number of substrates have been tested in the presence of all
synthesized ligands, most often PAP–t-Bu (3) gave the best results.
For example para-substituted chloroarenes are coupled efficiently
in the presence of only 0.01 mol% palladium and 0.02 mol% 3.
Utilizing 3 electron rich aryl chlorides (entries 5 and 7; 80–99%)
are coupled as smoothly as electron deficient ones (entries 1 and 2;
> 99%). Consistently, chlorobenzene yields biphenyl in 96% yield
under the same conditions (entry 3). Noteworthy are the mild
reaction conditions (60 °C) under which the different coupling
reactions proceed. Even at room temperature good yields of biaryl
products can be obtained in the presence of 0.1 mol% Pd. To the
best of our knowledge the obtained turnover number of 800 for the
coupling of a non-activated aryl chloride (4-chlorotoluene; entry 4)
at room temperature is the highest ever reported. When the reaction
temperature is increased to 100 °C the catalyst concentration can be
reduced to 0.005 mol% without any decrease in yield, resulting in
a TON of almost 20,000 (entry 6). However, when the catalyst
concentration is further lowered (0.001 mol% of catalyst) the
activity breaks down and product yields are generally below
40%.
In the case of ortho-substituted aryl chlorides the catalytic
efficiency is strongly dependent on the bulk of the substituent.
Relatively large or rigid groups result in the need of a higher
catalyst concentration (0.05 mol%) or higher reaction temperatures
(100 °C) in order to obtain good yields even if the electronic nature
of the substituent leads to a formal activation of the substrate
(acetyl, cyano, trifluoromethyl groups; entries 8–11). Ortho-
substituents that do not interfere with the metal complex, e.g. fluoro
or methoxy groups (entries 12 and 13), have no detrimental effect
on the reaction outcome. However, when two ortho-methyl
substituents are present in the chloroarene, dicyclohexylphosphino
substituted ligands, especially 2, result in more efficient catalysts
than the more bulky tert-butyl or adamantyl derivatives (entries
2
tions of aryl halides have been extensively studied in organic
synthesis and the methodology has been significantly enlarged in
the last decade. Recently, even catalyst-free Suzuki reactions of
aryl bromides and iodides were developed using microwave
3
technology. However, less reactive chloroarenes, which are easily
accessible with a variety of substituents and are often the most
economically interesting substrates do not react under these
conditions. Notable catalyst developments for the use of aryl
chlorides have been reported by Bedford, Buchwald,6 Fu,
4
5
7
Herrmann,8 Nolan, us and others. Our main interest is
concerned with the practical application of palladium-catalyzed
coupling reactions.12 In this respect the most active ligands for
Suzuki reactions, which are composed of sterically demanding
basic phosphines, still have significant drawbacks such as the high
sensitivity towards oxygen and/or the price (availability) of the
ligand. Therefore the development of more efficient ligands, which
lead to highly active catalyst systems and can easily be prepared
and modified on a larger scale, is still an important topic in this area.
Here, we describe for the first time the synthesis and application of
new 2-phosphino-1-arylpyrrole ligands 1–6 (PAP ligands, Fig. 1),
which fulfil these criteria.
9
10
11
Faigl and co-workers have shown that N-aryl pyrroles can be
13
deprotonated selectively at the a-position to the nitrogen atom.
We thought that reaction of these carbanions with chlorophos-
phines should give access to novel ligands, which would be
sterically demanding because of their biaryl backbone and electron
rich, if suitable chlorophosphines were chosen. Indeed lithiation of
different N-aryl pyrroles, with n-BuLi/TMEDA and subsequent
reaction with chlorodiphenylphosphine, chlorodicyclohexylphos-
phine, di-1-adamantylchlorophosphine and di-tert-butylchloro-
phosphine gave the PAP ligands 1–6 directly in one step. Initially,
1
4–18).
Fig. 1 A novel ligand family: PAP ligands.
Scheme 1 Suzuki coupling of aryl chlorides with phenylboronic acid.
3
8
C h e m . C o m m u n . , 2 0 0 4 , 3 8 – 3 9
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Heteroaryl chlorides can also be arylated efficiently using the
new PAP ligands. For example, 3-chloropyridine yields 99% of
from N-aryl pyrroles. Hence, ligand synthesis of the PAP family is
comparably easy and the shown PAP ligands will be commercially
available on the 100 g-scale.14 The new ligand family allows highly
efficient coupling reactions of electron rich as well as electron poor
aryl chlorides with phenylboronic acid under mild conditions. In
general, excellent yields are obtained at very low catalyst
concentrations.
Financial support by the state of Mecklenburg-Western Pomer-
ania, the BMBF, and Degussa AG are gratefully acknowledged. We
thank OMG for gifts of palladium compounds. The authors thank
Mr. M. Hoff (Degussa AG) for his excellent technical assistance.
3
2
-phenylpyridine in the presence of 0.01 mol% catalyst (entry 19).
-Chloroquinoline requires some more catalyst (0.05 mol%) to be
coupled well (87%, entry 20), because of a supposed dimerization
of the oxidative addition product via coordination of the nitrogen
atom to a second palladium center. For the coupling of 5-chlor-
oindole and 5-chlorofurfural, respectively, the reaction temperature
needs to be increased to 100 °C. Then, almost quantitative yields
(
> 97%) are obtained (entries 21 and 22).
In summary, we have shown that monodentate 2-phosphino-
-arylpyrrole ligands 1–6 (PAP ligands) can be prepared directly
1
Table 1 Suzuki coupling of aryl and heteroaryl chlorides with phenyl-
boronic acid
References and notes
Cat.
conc.
1 (a) N. Yasuda, J. Organomet. Chem., 2002, 653, 279; (b) H.-U. Blaser,
A. F. Indolese and A. Schnyder, Curr. Sci., 2000, 78, 1336.
2 (a) A. Suzuki, J. Organomet. Chem., 1999, 576, 147; (b) N. Miyaura and
A. Suzuki, Chem. Rev., 1995, 95, 2457.
Temp. Yield
Entry Aryl chloride
1
Ligand [mol%] [°C]
[%]
TON
3
(a) N. E. Leadbeater and M. Marco, J. Org. Chem., 2003, 68, 5660; (b)
N. E. Leadbeater and M. Marco, Angew. Chem., 2003, 115, 1445.
A. F. Littke and G. C. Fu, Angew. Chem., 2002, 114, 4350.
3
3
3
0.01
0.01
0.01
60
60
60
> 99
10,000
4
5
(a) R. B. Bedford, Chem. Commun., 2003, 1787; (b) R. B. Bedford, C.
S. J. Cazin, S. J. Coles, T. Gelbrich, P. N. Horton, M. B. Hursthouse and
M. E. Light, Organometallics, 2003, 22, 2810; (c) R. B. Bedford, M. E.
Blake, C. P. Craig and D. Holder, Chem. Commun., 2003, 466; (d) R. B.
Bedford, C. S. J. Cazin, S. J. Coles, T. Gelbrich, P. N. Horton, M. B.
Hursthouse and M. E. Light, Organometallics, 2003, 22, 987; (e) R. B.
Bedford, C. S. J. Cazin and S. L. Hazelwood, Angew. Chem., 2002, 114,
2
3
> 99
96
10,000
9600
4
294.
6
7
8
(a) J. P. Wolfe and S. L. Buchwald, Angew. Chem., 1999, 111, 2570; (b)
J. P. Wolfe, R. A. Singer, B. H. Yang and S. L. Buchwald, J. Am. Chem.
Soc., 1999, 121, 9550.
(a) S.-Y. Liu, M. J. Choi and G. C. Fu, Chem. Commun., 2001, 2408; (b)
A. F. Littke, C. Dai and G. C. Fu, J. Am. Chem. Soc., 2000, 122, 4020;
4
5
6
3
3
3
0.1
0.01
0.005
r.t.
60
100
80
99
98
800
9900
19,600
7
8
9
3
3
3
0.01
0.05
0.05
60
60
60
80
8000
1600
(c) A. F. Littke and G. C. Fu, Angew. Chem., 1998, 110, 3586.
(a) C. W. K. Gstöttmayr, V. P. W. Böhm, E. Herdtweck, M. Grosche and
W. A. Herrmann, Angew. Chem., 2002, 114, 1421; (b) V. P. W. Böhm,
C. W. K. Gstöttmayr, T. Weskamp and W. A. Herrmann, J. Organomet.
Chem., 2000, 595, 186.
(a) M. S. Viciu, R. F. Germaneau, O. Navarro-Fernandez, E. D. Stevens
and S. P. Nolan, Organometallics, 2002, 21, 5470; (b) G. A. Grasa, M.
S. Viciu, J. Huang, C. Zhang, M. L. Trudell and S. P. Nolan,
Organometallics, 2002, 21, 2866; (c) A. C. Hillier, G. A. Grasa, M. S.
Viciu, H. M. Lee, C. Yang and S. P. Nolan, J. Organomet. Chem., 2002,
80
9
> 99
10,000
1
1
0
1
3
3
0.05
0.01
60
100
90
91
1800
9100
6
53, 69; (d) C. Zhang, J. Huang, M. L. Trudell and S. P. Nolan, J. Org.
Chem., 1999, 64, 3804.
1
0 (a) A. Zapf and M. Beller, Chem. Eur. J., 2000, 6, 1830; (b) A. Zapf, A.
Ehrentraut and M. Beller, Angew. Chem., 2000, 112, 4315; (c) M.
Gómez Andreu, A. Zapf and M. Beller, Chem. Commun., 2000, 2475;
12
3
0.01
60
97
9700
(d) M. Beller, H. Fischer, W. A. Herrmann, K. Öfele and C. Broßmer,
Angew. Chem., 1995, 107, 1992.
1
3
3
0.01
60
97
9700
11 (a) R. A. Singer, S. Caron, R. E. McDermott, P. Arpin and N. M. Do,
Synthesis, 2003, 1727; (b) Q.-S. Hu, Y. Lu, Z.-Y. Tang and H.-B. Yu, J.
Am. Chem. Soc., 2003, 125, 2856; (c) J. P. Stambuli, R. Kuwano and J.
F. Hartwig, Angew. Chem., 2002, 114, 4940; (d) A. Schnyder, A. F.
Indolese, M. Studer and H.-U. Blaser, Angew. Chem., 2002, 114, 3820;
(e) G. Y. Li, J. Org. Chem., 2002, 67, 3643; (f) L. Botella and C. Najera,
Angew. Chem., 2002, 114, 187; (g) A. Fürstner and A. Leitner, Synlett,
1
1
1
1
1
4
5
6
7
8
2
3
4
5
6
0.05
0.05
0.05
0.05
0.05
60
60
60
60
60
72
16
15
55
35
1440
320
300
1100
700
2
001, 290; (h) G. Y. Li, Angew. Chem., 2001, 113, 1561; (i) C. Zhang
and M. L. Trudell, Tetrahedron Lett., 2000, 41, 595; (j) X. Bei, T.
Crevier, A. S. Guram, B. Jandeleit, T. S. Powers, H. W. Turner, T. Uno
and W. H. Weinberg, Tetrahedron Lett., 1999, 40, 3855.
2 (a) M. Beller and A. Zapf, Top. Catal., 2002, 19, 101; (b) M. Beller, A.
Zapf and W. Mägerlein, Chem. Eng. Technol., 2001, 24, 575; (c) J. G.
de Vries, Can. J. Chem., 2001, 79, 1086.
3 (a) F. Faigl, K. Fogassy, E. Szucs, K. Kovács, G. M. Keseru, V. Harmat,
Z. Böcskei and L. Toke, Tetrahedron, 1999, 55, 7881; (b) F. Faigl, K.
Fogassy, A. Thurner and L. Toke, Tetrahedron, 1997, 53, 4883; (c) F.
Faigl and M. Schlosser, Tetrahedron, 1993, 49, 10271.
1
9
0
3
3
0.01
0.05
60
60
99
87
9900
1740
1
1
2
2
2
1
2
3
3
0.05
0.05
100
100
97
99
1940
1980
1
4 CataCXium® P, Degussa Homogeneous Catalysts, Degussa AG,
Düsseldorf.
C h e m . C o m m u n . , 2 0 0 4 , 3 8 – 3 9
39