(2-Pyridyl)acetone-promoted Cu-catalyzed O-arylation of phenols with aryl iodides, bromides, and chlorides

Article abstract of DOI:10.1021/jo9012157

(Chemical Equation Presented) Employing (2-pyridyl)acetone as a new supporting ligand, the copper-catalyzed coupling reactions of aryl chlorides, aryl bromides, and aryl iodides with various phenols successfully proceeded in good yields under mild conditions. This reaction displays great functional groups compatibility and excellent reactive selectivity.

Full text of DOI:10.1021/jo9012157

pubs.acs.org/joc
preparations of diaryl ethers.3-5 Despite the high efficiency
(2-Pyridyl)acetone-Promoted Cu-Catalyzed
O-Arylation of Phenols with Aryl Iodides, Bromides,
and Chlorides
of the Pd-catalyzed methods, the use of expensive palladium
and elaborate phosphorated ligands would limit its applica-
tions to large- or industrial-scale production. The classical
copper-catalyzed synthesis of diaryl ethers, however, suffers
from the requirements of high temperature (125-220 ꢀC)
and stoichiometric amounts of catalysis.6 In the past years,
much progress have been achieved for the copper-catalyzed
synthesis of diaryl ethers. With the carefully selected combi-
nations of copper sources, bases, and supporting ligands,
aryl bromides and aryl iodides had been reported to couple
with phenols with excellent yields under mild conditions.4
Recently, a successful coupling of chlorobenzenes with
substituted phenols was reported under the catalysis of
10% CuBr and 80% 2,2,6,6-tetramethyl-3,5-heptanedione
(TMHD).5b In spite of the significant improvements
achieved, examples for the coupling of aryl chlorides with
phenols are rare.1,4i,4n,5b It is still highly desirable to develop
new efficient catalytic systems to further improve the effi-
ciency and generality of the copper-catalyzed coupling of
phenols with aryl halides.
Qi Zhang,†,‡ Deping Wang,†,§,^ Xianyang Wang,‡ and
Ke Ding*,§
‡Jiangsu Provincial Institute of Materia Medica, Nanjing
University of Technology, Nanjing, China, §Key Laboratory of
Regenerative Biology and Institute of Chemical Biology,
Guangzhou Institute of Biomedicine and Health, Chinese
Academy of Sciences, International Business Incubator A-3,
Guangzhou Science Park, Guangzhou 510663, China, and
^Graduate School of the Chinese Academy of Sciences,
Chinese Academy of Sciences. †Z.Q. and W.D. contributed
equally to this work.
ding_ke@gibh.ac.cn
Received June 11, 2009
Recently we identified 2-pyridyl β-ketones as new efficient
supporting ligands for the copper-catalyzed C-N coupling
reaction at room temperature.7 In this paper, we report that
2-pyridyl acetone (Figure 1, L1), a simple and commercially
available 2-pyridyl β-ketone analogue, successfully pro-
motes the copper-catalyzed C-O coupling of substituted
aryl chlorides, aryl bromides, and aryl iodides with various
phenols under mild conditions.
(3) For selected examples of Pd-catalyzed C-O coupling reactions, see:
(a) Mann, G.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 13109–13110.
(b) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118,
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Wolfe, J. P.; Sadighi, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121,
4369–4378. (e) Mann, G.; Incarvito, C.; Rheigold, A. L.; Hartwig, J. F.
J. Am. Chem. Soc. 1999, 121, 3224–3225. (f) Kataoka, N.; Shelby, Q.;
Stambuli, J. P.; Hartwig, J. F. J. Org. Chem. 2002, 67, 5553–5556. (g) Prim,
D.; Campagne, J.-M.; Joseph, D.; Andrioletti, B. Tetrahedron 2002, 58,
2041–2075. (h) Vorogushin, A. V.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2005, 127, 8146–8149. (i) Burgos, C. H.; Barder, T. E.; Huang, X.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 4321–4326.
Employing (2-pyridyl)acetone as a new supporting
ligand, the copper-catalyzed coupling reactions of
aryl chlorides, aryl bromides, and aryl iodides
with various phenols successfully proceeded in good
yields under mild conditions. This reaction displays great
functional groups compatibility and excellent reactive
selectivity.
(4) For selected examples of Cu-catalyzed C-O coupling reactions, see:
(a) Marcoux, J.-F.; Doye, S.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119,
10539–10540. (b) Fagan, P. J.; Hauptman, E.; Shapiro, R.; Casalnuovo, A. J.
Am. Chem. Soc. 2000, 122, 5043–5051. (c) Gujadhur, R. K.; Bates, C. G.;
Venkataraman, D. Org. Lett. 2001, 3, 4315–4317. (d) Buck, E.; Song, Z. J.;
Tschaen, D.; Dormer, P. G.; Volante, R. P.; Reider, P. J. Org. Lett. 2002, 4,
1623–1626. (e) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 3799–3802.
(f) Ouali, A.; Spindler, J.-F.; Cristau, H.-J.; Taillefer, M. Adv. Synth. Catal.
2006, 348, 499–505. (g) Cai, Q.; Zou, B.; Ma, D. Angew. Chem., Int. Ed. 2006,
45, 1276–1279. (h) Cristau, H. J.; Cellier, P. P.; Hamada, S.; Spindler, J. F.;
Tailefer, M. Org. Lett. 2004, 6, 913–916. (i) Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.;
Zhao, Y. Chem.;Eur. J. 2006, 12, 3636–3646. (j) Lv, X.; Bao, W. J. Org.
Chem. 2007, 72, 3863–3867. (k) Chen, Y.; Chen, H. Org. Lett. 2006, 8, 5609–
5612. (l) Niu, J.; Zhou, H.; Li, Z.; Xu, J.; Hu, S. J. Org. Chem. 2008, 73, 7814–
7817. (m) Naidu, A. B.; Jaseer, E. A.; Sekar, G. J. Org. Chem. 2009, 74, 3675–
3679. (n) Zhang, J.; Zhang, Z.; Wang, Y.; Zheng, X.; Wang, Z. Eur. J. Org.
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Diaryl ethers represent an important class of intermediates
for pharmaceuticals, agrochemicals, and polymers.1,2 Tran-
sitional metal catalyzed coupling reactions of aryl halides
and phenols are the most straightforward methods for the
(1) For reviews, see: (a) Lindley, J. Tetrahedron 1984, 40, 1433–1456.
(b) Theil, F. Angew. Chem., Int. Ed. 1999, 38, 2345–2347. (c) Sawyer, J. S.
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Chem., Int. Ed. 2003, 42, 5400–5449. (e) Kunz, K.; Scholz, U.; Ganzer, D.
Synlett 2003, 15, 2428–2439. (f) Beletskaya, I. P.; Cheprakov, A. V. Coord.
Chem. Rev. 2004, 248, 2337–2364. (g) Monnier, F.; Taillefer, M. Angew.
Chem., Int. Ed. 2008, 47, 3096–3099.
(2) For selected examples of medicinally important diaryl ethers, see:
(a) Jung, M. E.; Rohloff, J. C. J. Org. Chem. 1985, 50, 4909–4913. (b) Singh,
S. B.; Pettit, G. R. J. Org. Chem. 1990, 55, 2797–2800. (c) Deshpande, V. E.;
Gohkhale, N. J. Tetrahedron Lett. 1992, 33, 4213–4216. (d) Evans, D. A.;
DeViries, K. M. In Glycopeptide Antibiotics, Drugs and the Pharmaceutical
Sciences; Nagarajan, R., Ed.; Marcel Decker: New York, 1994; pp 63-104.
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2003, 59, 7859–7870.
(5) For Fe-catalyzed C-O coupling reactions, see: (a) Bistri, O.; Correa,
A.; Bolm, C. Angew. Chem., Int. Ed. 2008, 47, 586–588. (b) Xia, N.; Taillefer,
M. Chem.;Eur. J. 2008, 14, 6037–6039.
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DOI: 10.1021/jo9012157
r
Published on Web 08/12/2009
J. Org. Chem. 2009, 74, 7187–7190 7187
2009 American Chemical Society

Zhang et al.
JOCNote
TABLE 2. Cu-Catalyzed Coupling Reaction of Aryl Iodides or Aryl
Bromides with Phenolsa
FIGURE 1. Structures of ligands L1-L4.
TABLE 1. Copper-Catalyzed O-Arylation of 2-Naphthol with
4-Iodoanisole: Optimization of the Reaction Conditionsa
entry
[Cu]
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl
Cu(acac)2
Cu2O
ligand
base
solvent
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
a
L2
L3
L4
L1
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
dioxane
DMSO
toluene
CH3CN
DMSO
DMSO
DMSO
DMSO
DMSO
71
66
60
82
23
44
42
73
89
30
80
89
84
80
63
0
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
Reaction conditions: CuBr (0.05 mmol), ligand (0.10 mmol), aryl-I
(1.0 mmol), phenol (1.2 mmol), bases (2.0 mmol), solvents (1.5 mL),
80 ꢀC.
The investigation was initiated by using the coupling of
4-iodoanisole and 2-naphthol as a model reaction. Since the
conformation-constrained 1-(5,6,7,8-tetrahydroquinolin-
8-yl)ethanones displayed great activity to promote CuI-
catalyzed C-N bond fortmation,7 we first evaluated the
catalytic efficiency of these compounds (L2-L4) for the
O-arylation of 2-naphthol. As shown in Table 1, these ligands
showed moderate potency for the copper-catalyzed coupling
of 4-iodoanisole and 2-naphthol. For instance, a 71% yield
was obtained when the coupling was performed under the
combination of 5% CuI, 10% L2 (1-(5,6,7,8-tetrahydroqui-
nolin-8-yl)ethanone), and 200% cesium carbonate in DMF at
80 ꢀC (Table 1, entry 1). Interestingly, 2-pyridyl acetone (L1),
one of the simplest and commercially available 2-pyridyl
β-ketone analogues, displayed the best catalytic efficiency
(Table 1, entry 4). Further conditional optimization revealed
that Cs2CO38 and DMSO were the optimal base and solvent,
respectively (Table 1, entries 6-11). The potential catalytic
efficiency of several other copper salts was also evaluated. As
shown in Table 1 (entries 12-15), almost all the copper salts
displayed good catalytic activity except for the fact that Cu2O
was less active (entry 15). Therefore, the combination of less
expensive CuBr (5%), 10% 2-pyridylacetone (L1), and 200%
Cs2CO3 in DMSO at 80 ꢀC was chosen as the optimal
conditions for further exploration.
a
Reaction conditions: CuBr (0.10 mmol), L1 (0.20 mmol), aryl-Br
(1.0 mmol), phenol (1.2 mmol), Cs2CO3 (2.0 mmol), DMSO (1.5 mL),
90 ꢀC. bCuBr (0.05 mmol), L1 (0.10 mmol), 80 ꢀC. cThe reaction was carried
out in the absence of CuBr and L1.
The scope of the copper-catalyzed C-O bond formation
was explored by using a variety of aryl iodides or aryl
bromides with substituted phenols under the optimized
conditions. As shown in Table 2, the coupling reactions were
performed well for all the aryl iodides examined with
(8) For an over view of the so-called “cesium effect”, see: (a) Dijkstra, G.;
Kruizinga, W. H.; Kellogg, R. M. J. Org. Chem. 1987, 52, 4230–4234.
(b) Galli, C. Org. Prep. Proced. Int. 1992, 24, 287–307. (c) Flessner, T.; Doye,
S. J. Prakt. Chem. 1999, 341, 793–796.
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Zhang et al.
JOCNote
TABLE 3. Cu-Catalyzed Coupling Reaction of Heteroaromatic Ha-
lides with Phenolsa
TABLE 4. Cu-Catalyzed Coupling Reaction of Aryl Chlorides with
Phenolsa
a
Reaction conditions: CuBr (0.10 mmol), L1 (0.20 mmol), aryl-Br (1.0
mmol), phenol (1.2 mmol), Cs2CO3 (2.0 mmol), DMSO (1.5 mL), 90 ꢀC.
bCuBr (0.05 mmol), L1 (0.10 mmol), 80 ꢀC.
excellent yields (Table 2, entries 1-4). Less active aryl
bromides were also successfully coupled with phenols under
the catalysis of 10% CuBr and 20% L1 (Table 2, entries
5-23). More importantly, the CuBr/L1 combination was
able to be recycled at least 3 times without significantly losing
the catalytic efficiency (Supporting Information).9
The results revealed that an electron-withdrawing group
in the aryl bromide favored the coupling reactions (Table 2,
entries 9-13). For example, 1-bromo-4-nitrobenzene suc-
cessfully coupled with 4-methoxyphenol with an excellent
yield without the presence of copper catalyst and supporting
ligand, which might be due to a nucleophilic aromatic
substitution mechanism (Table 2, entry 12).4m,5b The results
also clearly showed that the CuBr/L1 combination signifi-
cantly improved the reaction efficiency in most cases
(Supporting Information).9 The coupling of electron-defi-
cient phenols with aryl bromides also proceeded smoothly in
good yields (Table 2, entries 16-19) with the exception of
p-nitrophenol, which led to a total failure for the coupling
reaction (Table 2, entry 20). This might be due to the stronger
decreased nucleophilicity of phenols induced by the nitro
group.4d,h,10 The results also indicated that steric hindrance
had a huge influence on the coupling reaction (Table 2,
entries 22 and 23). For instance, only 50% yield was obtained
when 2-methylphenyl bromide coupled with the correspond-
ing phenol (Table 2, entry 22). It was noteworthy that
2-acetylphenyl bromide, a problematic substrate in a pre-
vious report for the Pd-catalyzed synthesis of diaryl ether,3i
coupled with the corresponding phenol in an acceptable
yield (52%) (Table 2, entry 21), which highlighted the high
catalytic efficiency of the CuBr/L1 combination. In addition,
a
Reaction conditions: CuBr (0.10 mmol), L1 (0.20 mmol), aryl-Cl
(1.0 mmol), phenol (1.2 mmol), Cs2CO3 (2.0 mmol), DMSO (1.5 mL),
120 ꢀC. bAt 90 ꢀC. cProduct of diether/polyether: 42:10. dCuBr (0.1
mmol), L1 (0.2 mmol), aryl-Cl (2.0 mL), phenol (1.0 mmol), Cs2CO3 (2.0
mmol), 150 ꢀC. eCuBr (0.1 mmol), N-methylglycine (0.2 mmol), aryl-Cl
(2.0 mL), phenol (1.0 mmol), Cs2CO3 (2.0 mmol), 150 ꢀC.
the reaction also displayed a great tolerance to multiple
functional groups such as ketone, nitrile, nitro, carboxylic
ester, and free amido or hydroxyl groups. To the best of our
knowledge, the examples for Pd- or Cu-catalyzed diaryl ether
synthesis with substrates bearing a free amido or hydroxyl
substituents were relatively rare.3,4b,11
The catalytic efficiency of the CuBr/L1 combination
for the coupling of heteroaromatic iodides or bromides
(9) For details about the coupling of the other electron-deficient aromatic
halides with phenols in the absence of Cu and ligand, see the Supporting
Information.
(10) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39,
2937–2940.
(11) For examples, see: (a) Thomas, S.; Alexander, Z.; Alain, C.;
Nikolaus, M.; Matthias, B. Tetrahedron Lett. 2008, 49, 1851–1855.
(b) Thomas, S.; Alexander, Z.; Alain, C.; Nikolaus, M.; Matthias, B. Org.
Process Res. Dev. 2008, 12, 537–539. (c) Ghosh, R.; Samuelson, A. G. New J.
Chem. 2004, 28, 1390–1393.
J. Org. Chem. Vol. 74, No. 18, 2009 7189

Zhang et al.
JOCNote
with the corresponding phenols was also evaluated. As shown
in Table 3, various heteroaromatic halides, including pyridine,
quinoline, and benzothioazole bromides, successfully coupled
with phenols in good-to-excellent yields (Table 3).
Experimental Section
General Procedure for the Coupling of Aryl Halides with
Phenols. A test tube equipped with a Teflon valve was charged
with a magnetic stir bar, CuBr (5-10 mol %), Cs2CO3 (650 mg,
2 mmol), and any remaining solid phenols (1.2 mmol) and aryl
halides (1.0 mmol). The tube was evacuated and backfilled with
argon (this procedure was repeated three times). Under a counter
flow of argon, 1.2 mmol of phenols (if liquid), 1 mmol of aryl
halides (if liquid), DMSO (1.5 mL), and L1 (10-20 mol %) were
added by syringe. The tube was evacuated and backfilled with
argon again (this procedure was repeated three times) and sealed.
The reaction mixture was heated to the indicated temperature
(80-120 ꢀC) for the required time period. After cooling to room
temperature, the mixture was diluted with ethyl acetate (10 mL)
then passed through a fritted glass filter to remove the inorganic
salts and the solventwas removedunder vacuum. The residue was
purified by column chromatography on silica gel and the product
was dried under high vacuum for at least 1 h.
Because of their low cost and ready availability, aryl chlor-
ides are much more attractive substrates for the industrial
production and laboratory preparation of diaryl ethers.1,5b
We further investigated the potential catalytic efficiency of
the CuBr/L1 system for the coupling between aryl chlorides
and phenols. As summarized in Table 4, CuBr/L1 combina-
tion successfully promoted the coupling reaction with good
or moderate yields for most of the substrates examined. For
example, a 52% yield was obtained when 1-(4-chlorophenyl)-
ethanone was reacted with phenol at 90 ꢀC. The yield was
improved to 71% when the reaction was carried out at 120 ꢀC
(Table 4, entry 1). The other electron-deficient aromatic
chlorides tested also gave good yields (61-97%) under the
catalysis of CuBr/L1 at 120 ꢀC (Table 4, entries 2-6). It is
noteworthy that significantly lower yields were obtained for
the coupling of aryl chlorides with phenols when the copper
catalyst and ligand were absent (Supporting Information).9
The cross-coupling of chloropyridines and chloroquinoline
with phenols also took place smoothly with satisfactory
yields (Table 4, entries 7-9). Furthermore, acceptable yields
were also obtained for the substrates with electron-donating
groups when excessive aryl chlorides were applied (Table 4,
entries 10-17).
N-(4-phenoxyphenyl)acetamide (Table 2, entry 8): white solid;
1H NMR (400 MHz, CDCl3) δ 8.34 (1H, s), 7.46 (2H, d, J=7.2
Hz), 7.30-7.32 (2H, m), 7.05 (1H, t, J=7.6 Hz), 6.93 (4H, t, J=
8.4 Hz), 2.15 (3H, s); 13C NMR (100 MHz, CDCl3) δ 169.1,
157.5, 153.5, 133.5, 129.8, 123.1, 122.0, 119.5, 118.5, 24.2; GC/
MS rt=8.99 min, m/z 227.
Acknowledgment. We thank the 100-talent program of
CAS, National Natural Science Foundation (grant no.
90813033), and National High Technology Research and
Development Program (grant nos. 2008AA02Z420 and
2009CB940904) for their financial support.
In summary, an efficient Cu-catalyzed synthesis of diaryl
ethers from various aromatic or heteroaromatic iodides,
bromides, and chlorides was developed by using (2-pyridyl)-
acetone (L1) as the ligand. The Cu/L1 catalytic system
displays excellent functional group compatibility and high
chemical selectivity in the presence of a broad range of
functional groups at moderate temperature. Our report
provides an attractive addition to the strategies for the
synthesis of diaryl ether derivatives.
Supporting Information Available: Typical experimental
procedure, characterization data, and copies of 1H and 13C
NMR spectra for all of the coupling products with additional
HRMS spectra for the unknown compounds. This material
is available free of charge via the Internet at http://pubs.
acs.org.
7190 J. Org. Chem. Vol. 74, No. 18, 2009