A general and mild Ullmann-type synthesis of diaryl ethers

Article abstract of DOI:10.1021/ol036290g

(Equation presented) An efficient method for the synthesis of diaryl ethers under particularly mild conditions is described. Inexpensive ligands were found to greatly accelerate the Ullmann-type coupling of aryl bromides or iodides with phenols. A series of diaryl ethers were obtained with excellent yields in acetonitrile in the presence of Cs₂CO₃ and catalytic copper(I) oxide. The reaction tolerates substrates with unfavorable substitution patterns, such as sterically hindered coupling partners or electron-rich aryl halides.

Full text of DOI:10.1021/ol036290g

ORGANIC
LETTERS
2
004
Vol. 6, No. 6
13-916
A General and Mild Ullmann-Type
Synthesis of Diaryl Ethers
Henri-Jean Cristau,* Pascal P. Cellier, Samy Hamada, Jean-Francis Spindler, and
Marc Taillefer*
9
†
Laboratoire de Chimie Organique (CNRS UMR 5076), Ecole Nationale Sup e´ rieure de
Chimie de Montpellier, 8 rue de l’Ecole Normale, 34296 Montpellier Cedex 5, France
cristau@cit.enscm.fr; taillefe@cit.enscm.fr
Received November 24, 2003
ABSTRACT
An efficient method for the synthesis of diaryl ethers under particularly mild conditions is described. Inexpensive ligands were found to
greatly accelerate the Ullmann-type coupling of aryl bromides or iodides with phenols. A series of diaryl ethers were obtained with excellent
yields in acetonitrile in the presence of Cs
2 3
CO and catalytic copper(I) oxide. The reaction tolerates substrates with unfavorable substitution
patterns, such as sterically hindered coupling partners or electron-rich aryl halides.
Diaryl ethers form an important class of organic compounds
throughout the polymer and life sciences industries. A num-
ness of this method for large-scale or industrial applications.
Therefore, less costly alternatives are needed.
1
ber of them have been reported to have significant biological
activity, like natural products of the isodityrosine family and
its derivatives (e.g., the antibiotic vancomycin and the anti-
The copper-mediated arylation of phenols with aryl
halides, discovered by Ullmann in 1904, appears to be the
6
method of choice, but its traditional conditions are rather
2
7
tumoral bouvardin). The diaryl ether structural unit is also
drastic. Considerable efforts have been devoted in the past
3
prevalent in numerous weed-killing chemicals.
few years to the discovery of more attractive Ullmann
O-arylation methods. Several authors showed that certain
The most straightforward way to synthesize diaryl ethers
8
involves the direct formation of an aryl-oxygen bond from
additives, which probably act as copper ligands, enhance
4
an aryl halide. Efficient palladium-catalyzed arylations of
reaction rates and allow the couplings to be carried out at
milder temperatures, in the presence of reduced amounts of
copper or with a larger substrate scope. Thus, ethylene glycol
phenols or their sodium salts have been developed in recent
5
years. Nevertheless, the use of expensive palladium and
9
a
9b,c
9d
noncommercial sophisticated phosphines limit the attractive-
diacetate, 8-hydroxyquinoline, 1-naphthoic acid, triphen-
9e
9f
ylphosphine, neocuproine, or 2,2,6,6-tetramethylheptane-
†
Current address: RHODIA Organique Fine, Centre de Recherches de
8
a
Lyon (CRL), 85 avenue des Fr e` res Perret, BP 62, 69192 Saint-Fons Cedex,
France.
3,5-dione were successfully used as promoters. It has been
suggested that such additives would increase the solubility
(1) Theil, F. Angew. Chem., Int. Ed. 1999, 38, 2345.
(
2) (a) Zhu, J. Synlett 1997, 133. (b) Boger, D. L.; Patane, M. A.; Zhou,
J. J. Am. Chem. Soc. 1994, 116, 8544.
3) The Pesticide Manual, 10th ed.; Tomlin, C., Ed.; Crop Protection
Publications: Farnham, UK, 1994.
4) For reviews, see: (a) Sawyer, J. S. Tetrahedron 2000, 56, 5045. (b)
(6) (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1904, 37, 853. (b) Hassan,
J.; S e´ vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. ReV. 2002,
102, 1359. (c) Thomas, A. W.; Ley, S. V. Angew. Chem. Int. Ed. 2003, 42,
5400.
(
(
Lindley, J. Tetrahedron 1984, 40, 1433. (c) Moroz, A. A.; Shvartsberg, M.
S. Russ. Chem. ReV. 1974, 43, 679. (d) Reference 1.
(7) (a) Tomita, M.; Fujitani, K.; Aoyagi, Y. Chem. Pharm. Bull. 1965,
13, 1341. (b) Jung, M. E.; Jachiet, D.; Rohloff, J. C. Tetrahedron Lett.
1989, 30, 4211.
(
5) (a) Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J.
P.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369. (b) Kataoka, N.;
Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem. 2002, 67, 5553
and references therein. (c) Ding, S.; Gray, N. S.; Ding, Q.; Schultz, P. G.
Tetrahedron Lett. 2001, 42, 8751.
(8) (a) Buck, E.; Song, Z. J.; Tschaen, D.; Dormer, P. G.; Volante, R.
P.; Reider, P. J. Org. Lett. 2002, 4, 1623. (b) Goodbrand, H. B.; Hu, N.-X.
J. Org. Chem. 1999, 64, 670. (c) Lu, Z.; Twieg, R. J.; Huang, S. D.
Tetrahedron Lett. 2003, 44, 6289.
1
0.1021/ol036290g CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/20/2004

of copper salts and prevent their aggregation.10 They could
also enhance reactivity by increasing electronic density on
the catalytic species. However, these advances in the field
of Ullmann ether formation were not sufficient because
general methods still required high temperatures (at least 100
Table 1. Effect of Ligand, Catalyst, Base, and Solvent on the
Coupling of 3,5-Dimethylphenol with Iodobenzenea
9d-f
8a
°C)
and in some cases high catalyst loading (50 mol %).
After completion of this work, Ma reported that the use of
N,N-dimethylglycine as a ligand allowed the lowering of
copper
source
GC
11
reaction temperature to 90 °C. Alternative arylating agents
entry
ligand
base
solvent
yield (%)
12a
12b
such as arylboronic anhydrides, esters or acids, aryltri-
1
2
3
4
5
6
7
8
9
Cu2O
Cu2O
Chxn-Py-Al
Salox
DMG
Salox
Salox
Salox
Salox
Salox
Salox
Cs2CO3
Cs2CO3
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
97
96
87
97
67
57
0
67
69
12
1
3
14
fluoroborate salts, or arylbismuth derivatives can be em-
ployed at room temperature in copper-catalyzed reactions,
but these methods suffer either from high cost or from limited
commercial availability of functionalized reagents. Thus, it
was of interest to develop a simultaneously mild, general
and cost-effective catalytic procedure for the synthesis of
diaryl ethers from aryl halides.
Cu O
2
Cs CO3
2
CuI
CuBr
CuO
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
Cu2O
Cu2O
Cu2O
MeCN
MeCN
We recently disclosed that compounds of the oxime and
Schiff base types serve as powerful ligands in the copper-
1
0
Salox
K2CO3
a
Reaction conditions: 0.75 mmol of ArI, 0.5 mmol of ArOH, 1.0 mmol
1
5
catalyzed arylation of pyrazoles with aryl halides. This
success prompted us to examine whether our newly discov-
ered catalysts could be used for the formation of aryl-oxygen
bonds. In this report, we extend the usefulness of these air-
stable and in situ-generated catalyst systems for the synthesis
of diaryl ethers from functionalized phenols and aryl iodides,
under milder reaction conditions than those previously
reported.16
of base, 5 mol % copper catalyst, 20 mol % ligand, 150 mg of activated
and powdered 3 Å molecular sieves, solvent (300 µL), 82 °C, under N2.
entries 2, 4-6). No reaction was observed in their absence
(entry 7). Among these copper sources, CuI and Cu O were
2
1
7
the most effective. The air-stable and less expensive Cu O
2
was used in experiments aimed at investigating the effect of
A variety of multidentate chelating ligands were examined
using iodobenzene and 3,5-dimethylphenol as model sub-
strates, copper(I) oxide as the precatalyst, acetonitrile as the
solvent, and cesium carbonate as the base. Many ligands that
have, to our knowledge, never been used in Ullmann-type
O-arylation reactions proved to be successful. Among these
were Chxn-Py-Al 1, salicylal-doxime 2, and dimethylgly-
oxime 3 (Figure 1 and Table 1, entries 1-3). Almost quan-
solvent and base on the coupling reaction outcome. Aryla-
tions conducted in acetonitrile were faster than those con-
ducted in DMF (entry 8), while cesium carbonate was more
efficient than K PO and K CO (entries 9-10). Cesium
3
4
2
3
phenoxides are indeed more dissociated and more soluble
in organic solvents than their potassium counterparts.9
No side reaction involving 3,5-dimethylphenol was ob-
served. The selectivity with respect to the aryl halide was
high too, provided that an appropriate drying agent was
used to reduce the competing process of water arylation,19
d,18
(
10) Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. Tetrahedron Lett.
1
999, 40, 2657.
(
11) Ma, D.; Cai, Q. Org. Lett. 2003, 5, 3799.
(12) (a) Chan, D. M. T.; Monaco, K. L.; Li, R.; Bonne, D.; Clark, C.
G.; Lam, P. Y. S. Tetrahedron Lett. 2003, 44, 3863. (b) Evans, D. A.; Katz,
J. L.; West, T. R. Tetrahedron Lett. 1998, 39, 2937.
(
13) Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 1381.
(14) (a) Barton, D. H. R.; Finet, J.-P.; Khamsi, J.; Pichon, C. Tetrahedron
Lett. 1986, 27, 3619. (b) Barton, D. H. R.; Finet, J.-P.; Khamsi, J.
Tetrahedron Lett. 1987, 28, 887.
(
15) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Eur. J.
Org. Chem. 2004, 695−709.
16) These results, obtained more than two years ago, appear only now
Figure 1. Additional chelating ligands used in this work.
(
in the literature due to the regular time required for patent protection.
Taillefer, M.; Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F. FR Patent 2833947
(
WO Patent 03/050885), Rhodia Chimie, 2003; Chem. Abstr. 2003, 139,
9290. Taillefer, M.; Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F. Patent
titative yields were observed in the presence of 2 and 3 within
6
24 h at 82 °C.
priority number FR 03 10253. Taillefer, M.; Cristau, H.-J.; Cellier, P. P.;
Spindler, J.-F.; Ouali, A. Patent priority number FR 02 06717 (International
application number PCT/FR03/01647), Rhodia Chimie, 2003.
A preliminary survey had shown that Cu salts such as CuI,
CuBr, CuO, and Cu O were effective precatalysts (Table 1,
2
(17) Stabilized form sold by Aldrich was used.
(
18) For a discussion of the so-called “cesium effect”; see: (a) Dijkstra,
(
9) (a) Weingarten, H. J. Org. Chem. 1964, 29, 3624. (b) Oi, R.;
G.; Kruizinga, W. H.; Kellogg, R. M. J. Org. Chem. 1987, 52, 4230. (b)
Galli, C. Org. Prep. Proced. Int. 1992, 24, 287.
(19) Thermal decomposition of cesium hydrogen carbonate produced
during the coupling leads to the formation of water or cesium hydroxide,
as underlined by Greiner: Greiner, A. Synthesis 1989, 312. For an example
of such byproduct formation, see: Beletskaya, I. P.; Davydov, D. V.;
Gorovoi, M. S.; Kardashov, S. V. Russ. Chem. Bull. 1999, 48, 1533.
Shimakawa, C.; Takenaka, S. Chem. Lett. 1988, 899. (c) Fagan, P. J.;
Hauptman, E.; Shapiro, R.; Casalnuovo, A. J. Am. Chem. Soc. 2000, 122,
043. (d) Marcoux, J.-F.; Doye, S.; Buchwald, S. L. J. Am. Chem. Soc.
997, 119, 10539. (e) Gujadhur, R. K.; Venkataraman, D. Synth. Commun.
001, 31, 2865. (f) Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. Org.
5
1
2
Lett. 2001, 3, 4315.
914
Org. Lett., Vol. 6, No. 6, 2004

Table 2. Effect of Additives on Diphenyl Ether and Phenol
Byproduct Formationa
Table 5. Ullmann-Type Couplings in the Presence of the
Ligand Chxn-Py-Al (Optimized Reactions Conditions )
a
GC yield PhOH yield PhOPh yield
entry
additive
(%)
(%)
(%)
1
2
3
4
97
92
99
96
2
1.5
<1
<1
9
9
6
3
MgSO4
3 Å MSb
powdered 3 Å MS
a
Reaction conditions: as in Table 1, with 150 mg of additive per mmol
of Cs2CO3. The yields of byproducts are calculated with respect to
b
iodobenzene. MS: Molecular sieves.
Table 3. Reactivity Comparison of Aryl Iodides after 24
Hoursa
entry
R
GC yield (%)
1
2
3
4
5
H
2-Me
4-CN
4-CF3
4-MeO
96
43
quantitativeb
quantitativeb
90b
a
Reaction conditions: see Table 1. b Chxn-Py-Al as the ligand.
Table 4. Reactivity Comparison of Phenols after 24 Hoursa
entry
R
GC yield (%)
1
2
3
4
5
6
7
3,5-Me2
4-t-Bu
4-MeO
H
2-Me
2,4-Cl2
4-NO2
96
99
98
quantitative
91
45
0
a
Reaction conditions: see Table 1.
leading to the formation of phenol and, further, to diphenyl
ether. In our case, the desiccant efficiency of activated and
powdered 3 Å molecular sieves (MS) was better than that
of the nonpowdered one or that of magnesium sulfate (Table
a
Reaction conditions: 3 mmol of ArX, 2 mmol of Ar′OH, 4 mmol of
2). While making the purification of products by column
Cs2CO3, 5 mol % Cu2O, 20 mol % Chxn-Py-Al, 600 mg of powdered 3 Å
b
c
molecular sieves, MeCN (1.2 mL), under N2. Isolated yield. GC yield.
chromatography significantly easier, this additive led to only
a slight decrease in the reaction rate. In all reactions,
hydrodehalogenation products were formed in small amounts
d
Without molecular sieves. e Salox ligand was used. In DMF. Phenol
f
g
conversion: 49%.
Org. Lett., Vol. 6, No. 6, 2004
915

(
less than 5%). Homocoupling of the aryl halide was never
temperature (Table 5, entry 10). This result, already stated
4
c,8a,9e
observed.
in previous work,
could be explained by the formation
20
The optimized reaction conditions were used to examine
C-O bond formations involving functionalized coupling
partners. Reactivity comparisons were made by interrupting
the reactions after 24 h (Tables 3 and 4), while optimized
reaction times and isolated yields of purified products are
given in Table 5.
No spectacular electronic effects were observed when 3,5-
dimethylphenol was submitted to coupling with para-
substituted aryl iodides (Table 3, entries 3-5). Only a slight
decrease in the reaction rate was noted with the electron-
rich 4-iodoanisole (entry 5). Cyano, nitro, and trifluoromethyl
groups are well tolerated on the aryl iodide (Table 5, entries
of an electron-poor and consequently less reactive copper-
8
a,12b
phenoxide
complex.
Since the reactions were totally selective with respect to
the phenols, the use of a moderate excess of the aryl halide
partner allowed couplings involving electron-rich or -neutral
phenols to be driven to completion and the corresponding
diaryl ethers to be isolated with excellent yields (above 90%,
Table 5). Chxn-Py-Al 1 was found to be more practical than
salicylaldoxime 2 as a ligand, since it proved to be less
reactive toward aryl iodides and led to cleaner reactions.
We were pleased to note that we could quantitatively
couple the hindered ortho-cresol with the hindered 2-iodo-
toluene in DMF at 110 °C (Table 5, entry 17), a rather
challenging substrate combination. We have also shown that
our conditions were superior to those based on the use of
1
2, 13, 18). 2-Iodotoluene, as usually observed in the
9e,f
literature with hindered aryl halides, gave lower conver-
sions after 24 h (entry 2), and the arylation required longer
reaction times to go to completion (Table 5, entry 16).
Extension of this arylation process to aryl bromides yielded
interesting results: The use of bromobenzene in place of
iodobenzene afforded only 39% of diaryl ether after 24 h at
9f
3
the copper(I) complex Cu(neocup)(PPh )Br for bromoben-
zene substitution: we obtained a better GC yield of diphenyl
ether after 36 h (80%, Table 5, entry 3) than the one reported
in the literature (51%) at the same temperature with the same
9
f
8
2 °C, but this weaker reactivity could be overcome by
amount of copper catalyst.
increasing the reaction temperature to 110 °C and changing
the solvent to DMF (Table 5, entries 1-4). Good yields were
generally obtained after 36 h. Additionally, 2-bromopyridine
can be cleanly transformed in less than 24 h at 110 °C (Table
In summary, we have devised an efficient, experimentally
simple, and economically attractive copper-catalyzed O-ary-
lation of phenols with aryl iodides. Inexpensive and air-stable
2 2
precatalyst systems Cu O/2 and Cu O/1, which we recently
5
, entry 15).
developed for pyrazole N-arylation, allow aryl-oxygen bond
formation to occur with high yields and selectivity at the
lowest temperature reported to date (82 °C). Aryl bromides
can also be used at 110 °C. This method shows broad
functional group tolerance on both coupling partners, with
the exception of electron-poor phenols, and provides an in-
teresting alternative to palladium chemistry. Efforts to expand
the utility of our new catalyst systems to other classes of
nucleophiles have been rewarded and will be reported in due
course.
Phenol reactivity was compared using iodobenzene as an
arylating agent (Table 4). The rates of reactions were
comparable with electron-rich, electron-neutral, and ortho-
substituted phenols (entries 1-5). We also demonstrated that
the coupling was favored by electron-donating groups thanks
to a competitive arylation involving iodobenzene (0.5 mmol),
phenol (0.5 mmol), and 4-methoxyphenol (0.5 mmol). After
24 h at 82 °C under our standard reaction conditions, 59%
conversion to 4-methoxydiphenyl ether and 28% conversion
to diphenyl ether were observed.
Acknowledgment. P.P.C. thanks Rhodia Organique Fine
for a Ph.D. grant, and the Laboratoire de Chimie Organique
is grateful to the same company for financial support of this
work.
2,4-Dichlorophenol proved to be a significantly less effec-
tive coupling partner, due to its poor nucleophilicity and its
steric hindrance (Table 4, entry 6), while 4-nitrophenol,
which bears a strong electron-withdrawing group, does not
undergo the desired O-arylation reaction, even at high
Note Added after ASAP Posting. The last sentence of
the Abstract was incomplete in the version posted ASAP
February 20, 2004; the corrected version was posted February
(20) Typical Procedure. After standard cycles of evacuation and back-
filling with nitrogen, an oven-dried Schlenk tube equipped with a magnetic
stirring bar was charged with Cu2O (0.1 mmol), Chxn-Py-Al (0.4 mmol),
Cs2CO3 (4.0 mmol), activated and powdered 3 Å molecular sieves (600
mg), the phenol (2 mmol), if a solid, and the aryl halide (3.0 mmol), if a
solid. The tube was capped with a rubber septum. If liquids, the phenol
and the aryl halide were added by syringe, followed by anhydrous
acetonitrile (1.2 mL). The septum was removed and the tube sealed under
positive pressure of nitrogen and stirred in an oil bath preheated to 82 °C
for the required time period. The reaction mixture was allowed to cool to
room temperature, diluted with CH2Cl2, and filtered through a plug of Celite.
The solvent was removed in vacuo to yield the crude product, which was
purified by silica gel chromatography.
2
5, 2004.
Supporting Information Available: Detailed experi-
mental procedures and complete characterization data for
each diaryl ether and for ligand 1. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL036290G
916
Org. Lett., Vol. 6, No. 6, 2004