Low catalyst loadings for copper-catalyzed O-arylation of phenols with aryl and heteroaryl halides under mild conditions

Article abstract of DOI:10.1055/s-0031-1290110

A practical and mild strategy has been developed for the cross-coupling of O-arylation of phenol with differently substituted aryl halides and heteroaryl iodides using low catalyst loading of copper iodide under low operating temperature in DMF with TMHD as the ligand and Cs₂CO₃ as the base. This method tolerates a variety of functional groups including sterically hindered phenols and heteroaryl iodides to afford products in good to excellent yields (up to 95%). Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0031-1290110

LETTER
101
Low Catalyst Loadings for Copper-Catalyzed O-Arylation of Phenols with
Aryl and Heteroaryl Halides under Mild Conditions
LowCatalyst
uoadings for
i
Coppe
-
r-Catalyz
F
edO-Arylatio
o
n
of Phenol
n
g Yong,a Yong-Chua Teo,*a Yaw-Kai Yan,a Guan-Leong Chuab
a
Natural Sciences and Science Education, National Institute of Education, Nanyang Technological University,
1 Nanyang Walk, Singapore 637616, Singapore
b
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
21 Nanyang Link, Singapore 637371, Singapore
E-mail: yongchua.teo@nie.edu.sg
Received 26 September 2011
Thus, there is still a need to develop an optimized ligand-
metal and catalytic system to improve further the efficien-
cy and generality of the copper-catalyzed coupling of phe-
nols with aryl halides.
Abstract: A practical and mild strategy has been developed for the
cross-coupling of O-arylation of phenol with differently substituted
aryl halides and heteroaryl iodides using low catalyst loading of
copper iodide under low operating temperature in DMF with
TMHD as the ligand and Cs2CO3 as the base. This method tolerates
a variety of functional groups including sterically hindered phenols
and heteroaryl iodides to afford products in good to excellent yields
(up to 95%).
Recently, Bolm7 reported efficient Cu2O-catalyzed cross-
couplings with parts-per-million catalyst loadings and
emphasized the importance of high ligand-to-metal ratios
in the protocol. Therefore, the exploration of an optimized
ligand-to-metal ratio for the O-arylation reaction, espe-
cially for heteroaryl halides, that operates efficiently at
low reaction temperature remains highly attractive. In
continuation of our endeavors devoted to the development
of more economical and efficient catalytic systems for di-
aryl synthesis and from the viewpoint of cost effective-
ness and atom economy, herein, we wish to report an
optimized low-loading copper-ligand catalytic system for
the cross-coupling of aryl halides and heteroaryl iodides
with a wide variety of phenols.
Key words: cross-coupling, mild conditions, low catalyst loading,
copper-catalyzed, O-arylations, phenol
Diaryl ethers represent a very important class of organic
compounds in pharmaceutical, agricultural and polymer
industries.1 The Ullmann ether formation reaction2 has
been extensively used as it has emerged as one of the most
versatile strategies to access diaryl ethers directly. How-
ever, the harsh conditions of the classical Ullmann ether
synthesis has limited its utility due to the use of stoichio-
metric amounts of copper reagents and high reaction tem-
peratures.3 In recent years, it has been reported that the use
of additives or ligands enables the reaction to be per-
formed under milder conditions and in the presence of cat-
alytic amounts of the copper catalyst.4 Buchwald
demonstrated that the Cu-catalyzed coupling of phenols
and aryl halides can be performed in the presence of the
weak base Cs2CO3 in nonpolar solvents.5 Song further re-
ported that the use of 2,2,6,6,-tetramethylheptane-3,5-di-
one (TMHD) as ligand greatly accelerated the rate of
diaryl ether formation from aryl bromides or iodides and
phenols.6 However, the use of high ratios of CuCl (50
mol%) at 120 °C was required for this protocol. Despite
these advances, a number of limitations remains; typical-
ly, high catalyst loadings (10–20 mol%) and high reaction
temperatures are required for optimal yields and the use of
heteroaryl halides as the electrophilic precursors for the
cross-coupling reaction remains limited. In some cases,
the need for time-consuming and uneconomical transfor-
mations associated with the synthesis of specially de-
signed ligands bring additional disadvantages to the
method.
In our initial study, we examined the merits of various
copper salts for the O-arylation reaction using m-cresol (1
equiv) and iodobenzene (1.5 equiv) as model substrates
(Table 1, entries 1–6). Among them, the reaction cata-
lyzed by CuI (1 mol%) in combination with TMHD (10
mol%) and Cs2CO3 (2 equiv) in DMF at 60 °C gave the
best yield of 92% (Table 1, entry 6). The use of Cu(I) re-
agent was crucial for the success of this reaction as other
copper reagents gave significantly lower yields. Next, we
probed the ligand effect using a series of commercially
available ligands such as L-proline (L2, entry 7), trans-
1,2-diaminocyclohexane (L3, entry 8), N,N¢-dimethyleth-
ylenediamine (DMEDA, L4, entry 9) and N,N,N¢,N¢-tet-
ramethylethylenediamine (TMEDA, L5, entry 10). It was
shown that TMHD was the best ligand as it clearly accel-
erated the reaction even at low temperature and catalyst
loading. Further experiments revealed that the choice of
DMF as the solvent was important for this coupling reac-
tion, since the use of toluene or DMSO resulted in only
traces and 68% yield, respectively (entries 11 and 12).
Lower yields were obtained when the ligand loading was
reduced to 5 mol% or on lowering the reaction tempera-
ture to 50 °C (entries 13 and 14). In summary, the opti-
mized conditions for this mild and low catalyst copper-
catalyzed O-arylations were achieved using a combina-
tion of CuI (1 mol%), TMHD (10 mol%) and Cs2CO3 (2
equiv) in DMF at 60 °C for 24 hours. It is noteworthy that
SYNLETT 2012, 23, 101–106
x
x.
x
x.
2
0
1
1
Advanced online publication: 13.12.2011
DOI: 10.1055/s-0031-1290110; Art ID: D29711ST
© Georg Thieme Verlag Stuttgart · New York

102
F.-F. Yong et al.
LETTER
the cross-coupling reaction operated efficiently at low cat- observed for both meta- and para-substituted aryl iodides
alyst loading with an optimal metal-ligand ratio (1:10) and (entries 5–11) except for when a methoxy substituent was
low reaction temperature of 60 °C. Compared to most cat- present when a lower yield was obtained (entry 8). This
alytic systems, this system afforded the products in com- protocol was not only limited to aryl iodides, as good to
parable, if not, higher yields.
excellent yields were achieved using aryl bromides when
the reaction temperature was elevated to 100 °C (entries
12–19).
Table 1 Optimization Studies of Cross-Coupling of m-Cresol and
Iodobenzenea
Table 2 CuI-Catalyzed O-Arylation of m-Cresol with Aryl Halidesa
[Cu](1 mol%)
ligand (10 mol%)
O
OH
I
+
CuI (1 mol%)
Cs2CO3 (2 equiv)
DMF, 60 °C
air, 24 h
TMHD (10 mol%)
O
OH X
+
Cs2CO3 (2 equiv)
R
R
1
2
3
DMF, 60 °C
air, 24 h
O
O
1
2
3a–k
COOH
N
H
L2
H2N
NH2
Entry ArX
Product
Yield
(%)b
L1
L3
MeHN
Me2N
NHMe
NMe2
O
L4
L5
I
1
3a
3b
92
50
Entry
1
[Cu] source
CuO
Cu2O
CuCl
CuBr
Cu
Ligand
L1
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
toluene
DMSO
DMF
DMF
Yield (%)b
11
F
2
L1
76
O
I
2
3
L1
87
4
L1
85
Cl
Cl
5
L1
33
O
I
3
3c
19
12
6
CuI
L1
92
7
CuI
L2
48
F
8
CuI
L3
39
F
O
O
O
I
4
3d
9
CuI
L4
45
10
11
12
13
14
CuI
L5
20
CuI
L1
tracec
68c
64d
77e
I
5
3e
3f
90
91
CuI
L1
CuI
L1
I
CuI
L1
6
a Unless otherwise shown, the reaction was carried out with m-cresol
(2.21 mmol), iodobenzene (1.47 mmol), Cs2CO3 (2.94 mmol), Cu
source (1 mol%), ligand (10 mol%) in DMF (0.3 mL) at 60 °C for 24 h.
b Isolated yield after column chromatography.
Cl
Cl
O
I
7
3g
92
c The reaction was performed with TMHD (20 mol%).
d The reaction was performed at 50 °C.
CF3
CF3
e The reaction was performed with TMHD (5 mol%).
O
O
I
44
8
3h
3i
74c
To investigate the generality of this protocol, a variety of
functionalized aryl halides was coupled with m-cresol un-
der the optimized condition. The results are summarized
in Table 2. In general, good to excellent yields were ob-
tained for cross-coupling of sterically unhindered aryl
halides. Ortho-substituted aryl halides gave poor to mod-
erate yields (Table 2, entries 2–4) due to the sterically hin-
dered substituent. No significant electronic effects were
OMe
Cl
OMe
Cl
I
9
91
Synlett 2012, 23, 101–106
© Thieme Stuttgart · New York

LETTER
Low Catalyst Loadings for Copper-Catalyzed O-Arylation of Phenols
103
Table 2 CuI-Catalyzed O-Arylation of m-Cresol with Aryl Halidesa
(continued)
To expand the scope of this catalytic system, the protocol
was tested for cross-coupling between a series of phenols
and iodobenzene. The results are summarized in Table 3.
In general, good to excellent yields were obtained regard-
less of the electronic nature of the substituted phenols.
Ortho-substitution of the phenols did not hamper the
cross-coupling reactions, affording products in excellent
yields (entries 2 and 9) and no significant electronic ef-
fects were observed for para-substituted phenols (entries
3–6). Arylation reactions using 1-naphthol or 2-naphthol
also afforded the products in good yields (entries 7 and 8).
In addition, the arylation of a representative heteroaryl
phenol, 3-hydroxypyridine gave the corresponding O-ary-
lated product in a good yield of 74% under the reaction
conditions (entry 10).
CuI (1 mol%)
TMHD (10 mol%)
Cs2CO3 (2 equiv)
+
O
OH X
R
R
DMF, 60 °C
air, 24 h
1
2
3a–k
Entry ArX
Product
Yield
(%)b
O
O
O
O
I
10
3j
76
95
F
F
I
Next, the cross-coupling reactions between differently
substituted phenols and heteroaryl iodides were investi-
gated using the optimized conditions. As shown in
Table 4, both m-cresol and neutral phenols were excellent
nucleophilic partners for the coupling reactions with dif-
ferently substituted iodopyridines, which afforded the
corresponding heteroaryl ethers in good to excellent
yields (Table 4, entries 1–8). The presence of an electron-
withdrawing group on the phenols resulted in moderate
yields for the coupling reactions with 3- or 4-iodopy-
ridines (entries 10 and 11).
11
3k
3a
CF3
CF3
83c
66d
Br
12
Br
13
3l
73c
OMe
OMe
O
O
O
In summary, we have developed a cost-effective, versatile
and operationally simple strategy for diaryl ether synthe-
sis under mild conditions. This protocol is general and can
be applied to a wide variety of nucleophilic and electro-
philic substrates.8 In addition, we have expanded the
scope of the O-arylations to include the use of both nitro-
gen-containing heteroaryl halides and phenols. In most in-
stances, the O-arylated derivatives were obtained in good
to excellent yields. The mild reaction conditions and easy
availability of the copper source as well as the TMHD
ligand are attractive features of this protocol. Further in-
vestigation of this economical and practical catalytic sys-
tem for other cross-coupling reactions is ongoing.
Br
14
3h
3i
34c
84c
OMe
Cl
OMe
Cl
Br
15
Br
16
3g
3e
3f
3j
86c
84c
86c
73c
CF3
CF3
O
O
Br
17
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Br
18
Acknowledgment
Cl
Cl
We thank the National Institute of Education and Nanyang Techno-
logical University for their generous financial support.
O
Br
19
F
F
References and Notes
a Unless otherwise shown, the reaction was carried out with m-cresol
(2.21 mmol), aryl halide (1.47 mmol), Cs2CO3 (2.94 mmol), CuI (1
mol%), TMHD (10 mol%) in DMF (0.3 mL) at 60 °C for 24 h.
b Isolated yield after column chromatography.
(1) For representative papers on pharmaceutical compounds,
see: (a) Evans, D. A.; Devries, K. M. In Glycopeptide
Antibiotics, Drugs and the Pharmaceutical Sciences, Vol.
63; Nagarajan, R., Ed.; Marcel Decker, Inc.: New York,
1994, 63–104. (b) Rao, A. V.; Rama Gurjar, M. K.; Reddy,
L.; Rao, A. S. Chem. Rev. 1995, 95, 2135. (c) Wada, C. K.;
Holms, J. H.; Curtin, M. L.; Dai, Y.; Florjancic, A. S.;
Garland, R. B.; Guo, Y.; Heyman, H. R.; Stacey, J. R.;
Steinman, D. H.; Albert, D. H.; Bouska, J. J.; Elmore, I. N.;
c The reaction was performed at 100 °C.
d The reaction was performed at 80 °C.
© Thieme Stuttgart · New York
Synlett 2012, 23, 101–106

104
F.-F. Yong et al.
LETTER
Table 3 CuI-Catalyzed O-Arylation of Selected Phenols with Iodobenzenea
CuI (1 mol%)
TMHD (10 mol%)
O
OH
X
Cs2CO3
R1
R1
+
R2
R2
DMF, 60 °C
air, 24 h
4a–j
1
2
Entry
1
Phenols
ArX
Product
Yield (%)b
85
OH
OH
I
O
O
4a
4b
I
2
90
O
I
I
I
I
O
3
4
5
6
4c
4d
4e
4f
87
73
56
83
Cl
OH
O
MeO
Cl
MeO
Cl
OH
O
OH
O
O
F
F
I
7
4g
62
OH
OH
OH
I
I
O
8
9
4h
4i
78
94
74
O
OH
O
I
10
4j
N
N
a Unless otherwise shown, the reaction was carried out with phenol (2.21 mmol), aryl halide (1.47 mmol), Cs2CO3 (2.94 mmol), CuI (1 mol%),
TMHD (10 mol%) in DMF (0.3 mL) at 60 °C for 24 h.
b Isolated yield after column chromatography.
Goodfellow, C. L.; Marcotte, P. A.; Tapang, P.; Morgan, D.
W.; Michaelides, M. R.; Davidsen, S. K. J. Med. Chem.
2002, 45, 219. (d) Hodous, B. L.; Feuns-Meyer, S. D.;
Hughes, P. E.; Albrecht, B. K.; Bellon, S.; Bready, J.;
Caenepeel, S.; Cee, V. J.; Chaffee, S. C.; Coxon, A.; Emery,
M.; Fretland, J.; Gallant, P.; Gu, Y.; Hoffman, D.; Johnson,
R. E.; Kendall, R.; Kim, J. L.; Long, A. M.; Morrison, M.;
Olivieri, P. R.; Patel, V. F.; Polverino, A.; Rose, P.; Tempest,
P.; Wang, L.; Whittington, D. A.; Zhao, H. L. J. Med. Chem.
2007, 50, 611. (e) Liu, L. B.; Siegmund, A.; Xi, N.; Kaplan-
Lefko, P.; Rex, K.; Cheti, A.; Lin, J.; Moriguchi, J.; Berry,
L.; Huang, L.; Teffera, Y.; Yang, Y. I.; Zhang, Y. H.; Bellon,
S. F.; Lee, M.; Shimanovich, R.; Bak, A.; Dominguez, C.;
Norman, M. H.; Harmange, J. C.; Dussault, I.; Kimt, T. S.
J. Med. Chem. 2008, 51, 3688. (f) Caron, S.; Do, N. M.;
Sieser, J. E.; Whritenour, D. C.; Hill, P. D. Org. Process Res.
Dev. 2009, 13, 324. For representative papers on
agricultural compounds, see: (g) Draper, W. M.; Casida, J.
E. J. Agric. Food Chem. 1983, 31, 1201. (h) The Pesticide
Manual, 10th ed.; Tomlin, C., Ed.; British Crop Protection
Council: Farnham, 1994. (i) Scrano, L.; Bufo, S. A.;
D’Auria, M.; Meallier, P.; Behechti, A.; Shramm, K. W.
J. Environ. Qual. 2002, 31, 268. For representative papers
on polymer industries, see: (j) Labadie, J. W.; Hedrick, J.
L.; Ueda, M. Am. Chem. Soc. Symp. Ser. 1996, 624, 210.
(k) Theil, F. Angew. Chem. Int. Ed. 1999, 38, 2345.
(l) Laskoski, M.; Dominguez, D. D.; Keller, T. M. J. Polym.
Sci., Part A: Polym. Chem. 2006, 44, 4559.
(2) Ullmann, F. Chem. Ber. 1904, 37, 853.
(3) (a) Lindley, J. Tetrahedron 1984, 40, 1433. (b) Paul, S.;
Gupta, M. Tetrahedron Lett. 2004, 45, 8825.
Synlett 2012, 23, 101–106
© Thieme Stuttgart · New York

LETTER
Low Catalyst Loadings for Copper-Catalyzed O-Arylation of Phenols
105
Table 4 CuI-Catalyzed O-Arylation of Phenols with Selected Heterocyclic Aryl Halidesa
CuI (1 mol%)
TMHD (10 mol%)
O
OH
I
Cs2CO3
+
R1
R1
N
N
DMF, 60 °C
air, 24 h
1
2
4a–j
Entry
1
Phenols
ArX
Product
Yield (%)b
95
O
O
O
O
N
OH
I
I
I
I
N
5a
5b
5c
5d
N
N
N
2
3
4
85
77
92
N
N
Cl
Cl
N
N
I
I
I
I
N
O
O
O
O
N
OH
5
6
7
8
9
6a
4j
94
71
78
88
80
N
6c
6d
7a
N
N
N
N
Cl
Cl
OH
O
N
I
I
I
I
N
Cl
Cl
Cl
Cl
Cl
O
O
O
N
N
10
11
12
7b
7c
7d
53
42
85
N
N
N
N
Cl
Cl
a Unless otherwise shown, the reaction was carried out with phenol (2.21 mmol), N-containing heteroaryl halide (1.47 mmol), Cs2CO3 (2.94
mmol), CuI (1 mol%), TMHD (10 mol%) in DMF (0.3 mL) at 60 °C for 24 h.
b Isolated yield after column chromatography.
(4) (a) Marcoux, J.-F.; Doye, S.; Buchwald, S. L. J. Am. Chem.
Soc. 1997, 119, 10539. (b) Fagan, P. F.; Hauptman, E.;
Shapiro, R.; Casalnuovo, A. J. Am. Chem. Soc. 2000, 122,
5043. (c) Gujadhur, R.; Venkataraman, D. Synth. Commun.
2001, 31, 2865. (d) Gujadhur, R. K.; Bates, C. G.;
Angew. Chem. Int. Ed. 2006, 45, 1276. (g) Chen, Y.-J.;
Chen, H.-H. Org. Lett. 2006, 8, 5609. (h) Ouali, A.;
Spindler, J. F.; Cristau, H. J.; Taillefer, M. Adv. Synth. Catal.
2006, 348, 499. (i) Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.; Zhao,
Y. Chem. Eur. J. 2006, 12, 3636. (j) Lv, X.; Bao, W. J. Org.
Chem. 2007, 72, 3863. (k) Naidu, A. B.; Raghunath, O. R.;
Prasad, D. J. C.; Sekar, G. Tetrahedron Lett. 2008, 49, 1057.
Venkataraman, D. Org. Lett. 2001, 3, 4315. (e) Ma, D.; Cai,
Q. Org. Lett. 2003, 5, 3799. (f) Cai, Q.; Zou, B.; Ma, D.
© Thieme Stuttgart · New York
Synlett 2012, 23, 101–106

106
F.-F. Yong et al.
LETTER
mmol), TMHD (0.147 mmol), Cs2CO3 (2.94 mmol) was
(l) Niu, J.; Zhou, H.; Li, Z.; Xu, J.; Hu, S. J. Org. Chem.
2008, 73, 7814. (m) Liu, Y.-H.; Li, G.; Yang, L.-M.
Tetrahedron Lett. 2009, 50, 343. (n) Maiti, D.; Buchwald,
S. L. J. Am. Chem. Soc. 2009, 131, 17423. (o) Zhang, Q.;
Wang, D.; Wang, X.; Ding, K. J. Org. Chem. 2009, 74,
7187. (p) Maiti, D.; Buchwald, S. L. J. Org. Chem. 2010, 75,
1791.
dissolved in DMF (0.3 mL). Subsequently, the aryl halide
(1.47 mmol) and the phenol (2.21 mmol) were added to the
reaction vial and a screw cap was fitted to it. The reaction
mixture was stirred under air in a closed system at 60 °C for
24 h and the heterogeneous mixture was then cooled to r.t.
and diluted with EtOAc. The resulting solution was directly
filtered through a pad of Celite. The organic extracts were
washed with H2O twice. The combined organic extracts
were dried with anhyd Na2SO4 and the solvent was removed
under reduced pressure. The crude product was purified by
silica gel column chromatography to afford the O-arylated
product. The identity and purity of known products were
confirmed by 1H NMR and 13C NMR spectroscopic analysis.
(5) Marcoux, J.-F.; Doye, S.; Buchwald, S. L. J. Am. Chem. Soc.
1997, 119, 10539.
(6) Buck, E.; Song, Z. J.; Tschaen, D.; Dormer, P. G.; Volante,
R. P.; Reider, P. J. Org. Lett. 2002, 4, 1623.
(7) Larsson, P.-F.; Correa, A.; Carril, M.; Norrby, P.-O.; Bolm,
C. Angew. Chem. Int. Ed. 2009, 48, 5691.
(8) Representative Procedure for O-Arylation of Phenols: A
mixture of CuI (Sigma-Aldrich, 99.99% purity, 0.0147
Synlett 2012, 23, 101–106
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