Cu-catalyzed arylation of phenols: Synthesis of sterically hindered and heteroaryl diaryl ethers

Article abstract of DOI:10.1021/jo9026935

"Chemical Equation Presentation" Cu-catalyzed O-arylation of phenols with aryl iodides and bromides can be performed under mild condition in DMSO/K₃PO₄ with use of picolinic acid as the ligand for copper. This method tolerates a variety of functional groups and is effective in the synthesis of hindered diaryl ethers and heteroaryl ethers.

Full text of DOI:10.1021/jo9026935

pubs.acs.org/joc
SCHEME 1. Selected Biologically Active Diaryl Ethers
Cu-Catalyzed Arylation of Phenols: Synthesis of
Sterically Hindered and Heteroaryl Diaryl Ethers
Debabrata Maiti and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139
sbuchwal@mit.edu
Received December 21, 2009
family of antibiotics.11 There has been recent interest in the
synthesis of atropisomeric diaryl ethers12,13 as these may
have application as molecular gears.14
Cu-catalyzed O-arylation of phenols with aryl iodides
and bromides can be performed under mild condition in
DMSO/K3PO4 with use of picolinic acid as the ligand for
copper. This method tolerates a variety of functional
groups and is effective in the synthesis of hindered diaryl
ethers and heteroaryl ethers.
Diaryl ethers are classically made by the Ullmann reac-
tion15 of phenols with aryl halides promoted by stoichio-
metric or greater quantities of copper at high temperatures
(125-300 °C) in polar solvents (typically pyridine or DMF),
conditions which are unsuitable for the construction of
complex molecules.16-21
In an important advance, Lam,22 Chan,23 and Evans24
developed the Cu-catalyzed coupling of arylboronic acids
with phenols.16,25 The ability to use stable, and in some cases
commercially available, boronic acids in these reactions was
a considerable step forward and these reactions have been
applied in the synthesis of a number of complex natural
products.16,19 Despite the advantages of this method a
number of limitations remain, typically an excess of the
boronic acid component is required for optimal yields and
the use of heterocyclic substrates and ortho-substituted
coupling partners in intermolecular reactions is rare.
Furthermore, the required boronic acids, when commer-
cially available, can be expensive. The diaryl ether linkage
can also be forged by an SNAr reaction between a phenol and
The diaryl ether linkage is present in a range of impor-
tant compounds including a number of potential pharma-
ceuticals,1-4 commercially available engineering thermo-
plastics,5,6 and herbicides (Scheme 1).7-9 This motif also
appears in biologically active natural products, notably in
the mammalian hormone thyroxine10 and the vancomycin
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DOI: 10.1021/jo9026935
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Published on Web 02/08/2010
J. Org. Chem. 2010, 75, 1791–1794 1791
2010 American Chemical Society

Maiti and Buchwald
JOCNote
an activated aryl fluoride.26 This method holds promise as it
can be performed in the presence of a weak base and as such
has also seen application in complex molecule synthesis.
Unfortunately, suitable aryl fluoride substrates are not al-
ways readily available and the reaction lacks generality as it
is limited to the coupling of electron-rich or electron-neutral
phenols with highly activated aryl fluorides.
TABLE 1. Comparison of Various Ligands in the Coupling of 2,6-
Dimethylphenol with 2-Iodotoluene
As a result of these problems, efforts continue to find a
general method for formation of diaryl ethers. Much interest
has focused on the metal-catalyzed coupling of phenols with
aryl halides due to the low cost and ready availability of the
starting materials. Pd-catalyzed methods hold considerable
promise, especially in allowing economically attractive aryl
chlorides to be used as substrates; however, a number of
limitations remain.27-32
In 1997 it was shown that the Cu-catalyzed Ullmann-type
coupling of phenols and aryl halides can be performed in the
presence of the weak base Cs2CO3 in nonpolar solvents and
in some cases naphthoic acid was found to promote the
reaction.33 Since this discovery a number of efficient Cu/
ligand systems have been described and the high functional
group tolerance and low air- and moisture-sensitivity has
prompted ongoing interest in these reactions.16-21,34-48
Unfortunately, despite this effort, little progress has been
made in ameliorating some of the key limitations of these
reactions, namely the difficulty in coupling heterocyclic
compounds and the fact that ortho-substituted coupling
partners are often challenging. We set out to attempt to
address these issues and to move closer to a general set of
reaction conditions for the synthesis of diaryl ethers.
(26) Zhu, J. P. Synlett 1997, 133.
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2008, 3351–3355.
We have recently shown that a catalyst system com-
posed of CuI and picolinic acid in combination with
K3PO4/DMSO permits the selective O-arylation of amino-
phenols,49 and we discovered that this system is also expe-
dient in the coupling of 2,6-dimethylphenol with 2-
iodotoluene (Table 1), a cross-coupling reaction that has
not previously been reported with a Cu catalyst. Screening
a range of base/solvent combinations showed K3PO4/
DMSO to be much more efficacious than the more com-
monly used Cs2CO3/1,4-dioxane system (yields 100% and
27%, respectively).17-19,39-46 Using this base/solvent com-
bination pyrrole-2-carboxylic acid and N,N-dimethylglycine
also proved to be effective ligands; however, we elected to
pursue the use of picolinic acid as it is economically more
attractive.50
The scope of the reaction was explored (Table 2) with a
range of ortho-substituted phenols and aryl halides which
are usually difficult substrates for Cu-catalyzed methods (in
contrast to Pd-catalyzed reactions). By using picolinic acid 1
as ligand, o-cresol and 2,6-dimethylphenol could be coupled
with a variety of ortho-substituted aryl halides (entries 1-3,
4, and 5). 2-Methoxyphenol also coupled effectively with
4-iodotoluene (entry 6) as well as with 2-bromotoluene (entry
(47) Lv, X.; Bao, W. L. J. Org. Chem. 2007, 72, 3863–3867.
(48) For a full list of copper-catalyzed diaryl ether formation, see the
Supporting Information.
(49) Maiti, D.; Buchwald, S. L. J. Am. Chem. Soc., 131, 17423-17429.
(50) Current prices from Sigma-Aldrich: picolinic acid $26.4/mol, pyrrole-
2-carboxylic acid $2346/mol, and N,N-dimethylglycine $996/mol.
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Maiti and Buchwald
JOCNote
TABLE 2. Copper-Catalyzed O-Arylation of Phenolsa,54
TABLE 3. Copper-Catalyzed Arylation of Phenols with Heteroaryl
Halidesa,54
aIsolated yield, average of two runs. b90 °C, 10 mol % of CuI,
20 mol % of 1. c105 °C. d10 mol % of CuI, 20 mol % of 1.
7). Note that the reactions of aryl bromides were slower than
those of the analogous aryl iodides and required higher
catalyst loading.
Cross-coupling reactions between phenols and heteroaryl
halides were also investigated (Table 3).35-38,51 Employing
our standard protocol with 1, we were able to obtain
heteroaryl ethers from the reaction of substituted phenols
and 3-bromo-2-formylbenzothiophene (entry 1), 3-iodothio-
phene (entry 2), 5-bromopyrimidine52 (entry 3), and 2- and
3-iodopyridine (entries 4 and 5) in good yield (Table 3).
Heteroaryl halides such as 3-bromoquinolines (entry 6),
aIsolated yield, average of two runs.
5-bromoisoquinolines (entry 7), and 4-bromoisoquinolines
(entry 8) could be coupled with electron-deficient, electron-
neutral, and hindered phenols (Table 3).53 Cu-catalyzed
(51) Corbett, J. W.; Rauckhorst, M. R.; Qian, F.; Hoffman, R. L.;
Knauer, C. S.; Fitzgerald, L. W. Bioorg. Med. Chem. Lett. 2007, 17, 6250–
6256.
(53) The control experiments without catalyst were performed to confirm
these products are not generated by SNAr reaction, but by picolinic acid-
ligated copper-catalyzed C-O bond forming reaction.
(52) Cherng, Y. H. Tetrahedron 2002, 58, 887–890.
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Maiti and Buchwald
JOCNote
TABLE 4. Copper-Catalyzed Synthesis of Heteroaryl Ethersa,54
that by applying our standard protocol based on CuI and
1, 3-hydroxypyridines were successfully coupled with a range
of aryl halides (entries 1, 2, and 3). Furthermore, 6-hydro-
xyquinoline could be arylated with a bromopyridine even in
the presence of free N-H groups (entry 4).49 The O-arylation
of 8-hydroxyquinoline (entry 5) with a substituted pyridine
also proceeded smoothly even though this compound has
previously been employed as an effective ligand for Cu-
catalyzed arylation of phenols.56
In summary, we have devised an efficient, experimentally
simple, and economically attractive method for Cu-cata-
lyzed O-arylation of phenols with aryl iodides and bromides.
This method tolerates a variety of functional groups and
provides a considerable advance in the ability to synthesize
hindered and heteroaryl diaryl ethers by Cu-catalyzed etheri-
fication.
Experimental Procedure
General Procedure for the Synthesis of Diaryl Ether. An oven-
dried screw cap test tube was charged with a magnetic stirbar,
copper(I) iodide (9.5 mg, 0.05 mmol, 5 mol %), picolinic acid 1
(12.3 mg, 0.10 mmol, 10 mol %), aryl halide (if solid; 1.0 mmol),
ArOH (1.2 mmol), and K3PO4 (424 mg, 2.0 mmol). The tube was
then evacuated and backfilled with argon. The evacuation/
backfill sequence was repeated two additional times. Under a
counterflow of argon, remaining liquid reagents were added,
followed by dimethyl sulfoxide (2.0 mL) by syringe. The tube
was placed in a preheated oil bath at 80 °C and the reaction
mixture was stirred vigorously for 24 h. The reaction mixture
was cooled to room temperature. Ethyl acetate (10 mL) and
H2O (1 mL) were added and the mixture was stirred. The organic
layer was separated and the aqueous layer was extracted twice
more with ethyl acetate (10 mL). The combined organic layer
was dried over Na2SO4 and filtered through the pad of silica gel.
The filtrate was concentrated and the resulting residue was
purified via the Biotage SP4 (silica-packed SNAP cartridge,
KP-Sil, 10 g) using hexane:ethyl acetate (3:1).
aIsolated yield, average of two runs.
etherification can also be challenging when electron-with-
drawing groups are present on the phenol component. An
excellent yield of the desired diaryl ether could, however, be
obtained when 4-cyanophenol (entry 9), methyl 4-hydroxy-
benzoate (entry 10), and 4-bromophenol (entry 11) were used
as the nucleophile. We note, however, that 5-membered
ring heteroaryl halides containing two heteroatoms such as
4-bromoisoxazole (entry 12) and 4-bromo-1,3,5-trimethyl-
pyrazole (entry 13) did not provide any of the desired
product under these reaction conditions.
Acknowledgment. This activity is supported by an educa-
tional donation provided by Amgen and by funds from the
National Institutes of Health (Grant GM-58160). We are
grateful to Dr. David Surry for comments and help with this
manuscript. The NMR instruments used for this study were
furnished by funds from the National Science Foundation
(CHE 9808061 and DBI 9729592).
Next we studied the synthesis of diaryl ethers possessing a
heteroaryl moiety on both the nucleophilic and electrophilic
components (Table 4). The construction of such diaryl ethers
by metal-catalyzed cross-coupling is rare.51,55 We found
(54) We found that the reduction of aryl halide (Ar-X to Ar-H) was
obtained as the major side reaction. Thus in Table 2, ethylbenzoate (5%,
entry 2) and benzaldehyde (2%, entry 3) were detected. Similarly, isoquino-
line (10%, entry 7; 5%, entry 8), benzo[b]thiophene-2-carbaldehyde (entry 1),
and pyridine (1%, entry 4) were detected in Table 3 as were quinoline (2%,
entry 3) and a trace of nicotinonitrile in Table 4, entry 5.
Supporting Information Available: Procedural and spectral
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
(56) Fagan, P. J.; Hauptman, E.; Shapiro, R.; Casalnuovo, A. J. Am.
Chem. Soc. 2000, 122, 5043–5051.
(55) Altman, R. A.; Buchwald, S. L. Org. Lett. 2007, 9, 643–646.
1794 J. Org. Chem. Vol. 75, No. 5, 2010