An efficient catalyst system for diaryl ether synthesis from aryl chlorides

Article abstract of DOI:10.1016/j.tetlet.2005.03.033

The combination of 2-phosphino-substituted N-arylpyrroles or related indoles (cataCXiumP) and Pd(OAc)₂ allows for efficient cross-coupling reactions of aryl chlorides and phenols to give diaryl ethers. A variety of aryl and heteroaryl chlorides can be coupled with substituted phenols showing unprecedented catalyst turnover numbers.

Full text of DOI:10.1016/j.tetlet.2005.03.033

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3237–3240
An efficient catalyst system for diaryl ether synthesis
from aryl chlorides
Surendra Harkal,a Kamal Kumar,a Dirk Michalik,a Alexander Zapf,a Ralf Jackstell,a
Franck Rataboul,a Thomas Riermeier,b Axel Monseesb and Matthias Bellera,*
aLeibniz-Institut fu¨r Organische Katalyse an der Universita¨t Rostock e.V. (IfOK), Buchbinderstr. 5-6, D-18055 Rostock, Germany
bDegussa AG, Degussa Homogeneous Catalysts (DHC), Rodenbacher Chaussee 4, D-63457 Hanau, Germany
Received 27 January 2005; revised 2 March 2005; accepted 7 March 2005
Available online 28 March 2005
Abstract—The combination of 2-phosphino-substituted N-arylpyrroles or related indoles (cataCXiumÒP) and Pd(OAc)2 allows for
efficient cross-coupling reactions of aryl chlorides and phenols to give diaryl ethers. A variety of aryl and heteroaryl chlorides can be
coupled with substituted phenols showing unprecedented catalyst turnover numbers.
Ó 2005 Published by Elsevier Ltd.
The diaryl ether moiety is present in numerous naturally
occurring and biologically active compounds. Important
medicinal products having this structural motif include
polycyclic glycopeptide antibiotics like vancomycin1 or
teicoplanin,2 and the antineoplastic agent combretasta-
tin D-2.3 Until recently, the most general method for
the synthesis of diaryl ethers was the classic copper-medi-
ated Ullmann coupling of aryl bromides/iodides and
phenols with the drawback of harsh reaction conditions
and the need of a stoichiometric amount of metal.4 Due
to these problems significant efforts have been under-
taken in the last decade to develop more efficient and
environmentally benign coupling processes of phenols.
For example, an interesting copper-catalyzed Ullmann
coupling has been described by Buchwald and co-work-
ers.5 Palladium-catalysts have also been used for the
synthesis of diaryl ethers.6–10 Important contributions
to that came mainly from Buchwald and co-workers6,7
and Hartwig and co-workers.8,9 So far it has been shown
that electron-poor arylphosphines give good results for
the coupling of activated aryl bromides with phenols.8
On the other hand it has been demonstrated that
electron-rich and bulky phosphines are more suitable
ligands for palladium-catalyzed C–O bond forming
reactions of deactivated aryl bromides and aryl chlo-
rides.7,9 Until now only little attention has been paid
to the efficiency (productivity) of the respective palla-
dium catalysts in such reactions. Hence, in general cata-
lyst turnover numbers (TON) in the range 5–80 are
obtained,11 although it is well known that TONs of
around 1000 are required to consider further practical
application.12
Here, we report for the first time successful C–O cou-
pling reactions of aryl chlorides, which fulfil the require-
ments for fine chemical syntheses and work in general at
comparatively low catalyst concentration (0.1–0.5 mol %
Pd).
For some time we have been interested in catalytic
refinement reactions of aryl chlorides, which are often
economically more attractive substrates than similar
bromides and iodides.13 Very recently, we reported on
PR2
PR2
N
N
1: R = Cy
2: R = tBu
3: R = 1-Ad
4: R = Cy
5: R = tBu
6: R = 1-Ad
Keywords: Aryl chlorides; Aryl ethers; Etherification; Palladium;
Phosphines.
*
Figure 1. Selected examples of 2-phosphino-N-arylpyrroles and -indoles
(cataCXiumÒP ligands).
Corresponding author. Tel.: +49 0381 466930; fax: +49 0381
4669324; e-mail: matthias.beller@ifok.uni-rostock.de
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.03.033

3238
S. Harkal et al. / Tetrahedron Letters 46 (2005)3237–3240
the synthesis of novel monophosphine ligands based on
2-phosphino-N-arylpyrrole and -indole structures (so-
called cataCXiumÒP ligands, e.g., 1–6, Fig. 1).
typical reaction conditions, which have been used previ-
ously for C–O coupling reactions. Selected results are
summarized in Table 1. In general, an increasing steric
bulk of the electron-rich ligand facilitates the coupling
reaction. For example, ligands having tert-butyl and
1-adamantyl groups on the phosphorus atom gave best
results (Table 1, entries 2, 3, 5 and 6), while ligands bear-
ing cyclohexyl groups provided significant conversions
but almost no expected product (Table 1, entries 1 and
4).15 Interestingly, when we started to decrease the cata-
lyst concentration to 0.1 mol % Pd(OAc)2 similarly good
results were obtained, which led to the highest turnover
numbers obtained for this type of reaction.
These ligands lead to efficient catalysts for Suzuki and
Sonogashira cross-couplings as well as Buchwald–Hart-
wig aminations of aryl chlorides and bromides.14
Because of the performance, the easy synthesis and
tunability of this class of ligands we became also inter-
ested in testing them in the reaction of aryl chlorides
and phenols. As a starting point of our investigation
we examined the reaction of 4-chloroacetophenone
(activated aryl chloride) and phenol as a model system
(Scheme 1, Table 1).
Next, the general usefulness of our ligands was
examined and is shown in Table 2. Activated (electron
deficient) aryl chlorides such as 4-chloroacetophenone,
4-chlorobenzonitrile and 1-chloro-3-(trifluoromethyl)-
benzene react with phenol or o-cresol at 0.1 mol %
Pd(OAc)2 and 1 mol % ligand giving good to excellent
yields (84–99%) of the corresponding diaryl ethers and
unprecedented turnover numbers up to ca. 1000 (Table
2, entries 1–4). Nonactivated and electron-rich aryl chlo-
rides require somewhat higher catalyst concentrations
(0.5 mol % Pd(OAc)2, 1 mol % ligand) in order to get
high yields. Hence, 4-chlorotoluene and o-cresol
provided the desired diaryl ether in 93% yield (Table
2, entry 5), while 4-chloroanisole gave 87% of the corre-
sponding product (Table 2, entry 7). Again, to the best
of our knowledge the obtained TON is the highest ever
reported for a C–O coupling reaction of a deactivated
aryl chloride. Even sterically more hindered 2,20-di-
methyl substituted diaryl ethers can be obtained in the
presence of 0.5 mol % palladium catalyst (Table 2, entry
6).
At first the influence of the ligand structure was studied
in the presence of 2 mol % Pd(OAc)2 and 4 mol % ligand
with K3PO4 as the base in toluene at 120 °C. These are
Scheme 1. Coupling reaction of 4-chloroacetophenone and phenol.
Table 1. Variation of ligands for the coupling reaction of 4-chloro-
acetophenone and phenola
Entry
1
Ligand
Conv. [%]b
63
Yield [%]b
0
Furthermore, heteroaryl chlorides reacted well, and the
diaryl ether products were obtained in >80% yield
(Table 2, entries 9 and 10). Apart from intermolecular
coupling reactions, intramolecular C–O bond formation
is also possible. For example, 2,3-dihydrobenzofuran
can be synthesized in moderate yield at low tempera-
ture (60 °C).
2
3
99
99
91
92
In most cases the tert-butyl-substituted phosphine 5
proved to form the most productive catalyst. However,
in few cases the 1-adamantyl-substituted pyrrole ligand
3 gave slightly higher yields in the tested reactions.
A comparison of 5 and the commercially available
ÔstandardÕ Buchwald ligand 2-(di-tert-butylphosphino)-
biphenyl for the reaction of 4-chloroacetophenone,
4-chlorobenzonitrile, 4-chlorotoluene and 4-chloro-
anisole with phenol or o-cresol (0.1–2.0 mol % Pd(OAc)2,
Table 2, entries 12–15) demonstrates the increased
efficiency of our novel ligands.
4
5
6
67
99
99
0
95
96
In summary, we have shown that the cataCXiumÒP
ligand family allows for an efficient diaryl ether synthesis
from aryl chlorides and phenols. Good to excellent
yields are obtained at low catalyst concentration. The
catalyst productivities are the best ever reported for
any metal-catalyzed C–O coupling reaction: turnover
numbers up to 1000 have been observed. Due to the
a Conditions: 1 mmol 4-chloroacetophenone, 1.2 mmol PhOH, 2 mmol
K3PO4, 2 mol % Pd(OAc)2, 4 mol % ligand, 3 mL toluene, 120 °C,
20 h.
b Average of 2 runs, determined by GC using hexadecane as internal
standard.

S. Harkal et al. / Tetrahedron Letters 46 (2005)3237–3240
Table 2. Palladium-catalyzed coupling of aryl chlorides and phenolsa
3239
Entry
Aryl chloride
Pd(OAc)2 [mol %]
Ligand
Product
Yield [%]b
TON
1
0.1
5
96
960
2
3
4
0.1
0.1
0.1
5
5
5
86
99
84
860
990
840
5
6
0.5
0.5
5
3
93
92
186
184
7
0.5
2.0
3
5
87
68
174
34
8c
9
0.1
2.0
5
5
84
82
840
41
10c
11c
12c
2.0
2.0
5
51
96
25
48
L
13
14
0.1
0.5
L
L
76
4
760
8
15
0.5
L
<2
<4
a Conditions: 1 mmol aryl chloride, 1.2 mmol ArOH, 2 mmol K3PO4, 1 mol % ligand, 3 mL toluene, 120 °C, 20 h. L = 2-(di-tert-
butylphosphino)biphenyl.
b Average of 2 runs, determined by GC using hexadecane as internal standard.
c 4 mol % ligand.

3240
S. Harkal et al. / Tetrahedron Letters 46 (2005)3237–3240
modular synthesis of cataCXiumÒP ligands14 a fine tun-
ing of the ligand properties for other substrates is easily
possible and should lead to further improved catalyst
performance.
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Acknowledgements
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This work has been financed by the State of Mecklen-
burg-Vorpommern, the Bundesministerium fur Bildung
¨
und Forschung (BMBF) and Degussa AG. We thank
Professor M. Michalik, Dr. W. Baumann, Mrs. H.
Baudisch, Mrs. A. Lehmann, Mrs. C. Mewes and Ms.
K. Reincke (all IfOK) for excellent analytical support.
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Supplementary data
11. To the best of our knowledge there is only one example
reported using 4-bromoacetophenone as substrate in the
presence of 0.1 mol % Pd(OAc)2, for details see Ref. 7a.
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Supplementary data with a general procedure for C–O
coupling reactions and the analytical data of the newly
synthesized ethers (Table 2, entries 4 and 9) is available
online and with this article can be found in the online
version, at doi:10.1016/j.tetlet.2005.03.033.
13. For an excellent review see: (a) Littke, A. F.; Fu, G. C.
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