Copper(I)-catalyzed aryl bromides to form intermolecular and intramolecular carbon-oxygen bonds

Article abstract of DOI:10.1021/jo900600m

(Chemical Equation Presented) A highly efficient Cu-catalyzed C-O bond-forming reaction of alcohol and aryl bromides has been developed. This transformation was realized through the use of copper(I) iodide as a catalyst, 8-hydroxyquinoline as a ligand, and K3PO4 as a base. A variety of functionalized substrates were found to react under these reaction conditions to provide products in good to excellent yields.

Full text of DOI:10.1021/jo900600m

Hartwig, as well as others, in the palladium-mediated Ullmann
ethers synthesis. The intermolecular and intramolecular carbon-
oxygen bond was formed by using aryl bromides and aryl
chlorides as substrate.4 Nevertheless, these systems still suffer
from some limitations because of the need to prepare and use
environmentally unfriendly PR3 ligands.
Copper(I)-Catalyzed Aryl Bromides To Form
Intermolecular and Intramolecular
Carbon-Oxygen Bonds
Jiajia Niu,† Pengran Guo,† Juntao Kang,† Zhigang Li,†
Jingwei Xu,*,† and Shaojing Hu*,‡
The traditional Ullmann-type Cu(I)-catalyzed cross-coupling
of alkoxides with aryl halides is limited by unfavorable
conditions, such as high temperatures, a large amount of the
alkoxide, and stoichiometric quantities of the copper salt.5,6
During the past few years, some significant modifications have
been made for the synthesis of aryl ethers. In 2002, Buchwald’s
group first reported that using 10 mol % of CuI in conjunction
with 20 mol % of 1,10-phenanthroline could make C-O bond
formation between aryl iodides and aliphatic alcohols successful
under mild reaction conditions (Cs2CO3/110 °C/18-38 h);7a
however, aryl bromides were unreactive in this system. Sub-
sequently reported catalyst systems that employ butyronitrile
as solvent, amino acids as ligands, KF/Al2O3 as the base, or
microwave irradiation also succeeded in coupling different aryl
iodides and aliphatic aolchols.7b-e Although a recently devel-
oped procedure that use modified 1,10-henanthroline was applied
in the coupling of highly active benzyl alcohol with aryl
bromide, low active aliphatic alcohols still required higher
temperature.7f So it is necessary to expand the scope of substrate
under mild conditions.
State Key Laboratory of Electroanalytical Chemistry,
Changchun Institute of Applied Chemistry, Chinese Academy
of Sciences, Changchun 130022, People’s Republic of China,
Graduate School of Chinese Academy of Sciences,
Changchun 130022, People’s Republic of China, and Institute
for Diabetes DiscoVery, Branford, Connecticut 06405
jwxu@ciac.jl.cn; shaojing_hu@betapharma.com
ReceiVed March 20, 2009
Prompted by our current interest in C-O coupling reactions
and the success of these reported process, we decided to
investigate the copper-catalyzed C-O formation between aryl
bromides and aliphatic alcohols via the utilization of air-stable
copper salt and readily available ligands.8
A highly efficient Cu-catalyzed C-O bond-forming reaction
of alcohol and aryl bromides has been developed. This
transformation was realized through the use of copper(I)
iodide as a catalyst, 8-hydroxyquinoline as a ligand, and
K3PO4 as a base. A variety of functionalized substrates were
found to react under these reaction conditions to provide
products in good to excellent yields.
Herein, we report a simple, inexpensive, and effective
catalytic system for the synthesis of aryl-aliphatic ethers under
mild reaction conditions. More importantly, by employing this
system, both intermolecular and intramolecular C-O bond
formation was achieved successfully.
Aryl ethers, including oxygen heterocycles, are key constitu-
ents in numerous natural products and pharmaceuticals1 and aryl
aliphatic ethers are often utilized as phenol precursors.2
Recently, transition metal-catalyzed C-O bond-forming
reactions have become important methods for the preparation
of oxygen-containing compounds.3 Major advancements have
been made in this area by both the groups of Buchwald and
(3) For review, see: (a) Prim, D.; Campagna, J.-M.; Joseph, D.; Andrioletti,
B. Tetrahedron 2002, 58, 2041. (b) Hartwig, J. F. Angew. Chem., Int. Ed. 1998,
37, 2046.
(4) For some recent reports on palladium-catalyzed aryl ether synthesis, see:
(a) Vorogushin, A. V.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2005,
127, 8146. (b) Kataoka, N.; Shelby, Q.; Stambuli, J.; Hartwig, J. F. J. Org. Chem.
2002, 67, 5553. (c) Kuwabe, S.; Torraca, K. E.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 12202. (d) Torraca, K.; Huang, X.; Parrish, C.; Buchwald, S. L.
J. Am. Chem. Soc. 2001, 123, 10770. (e) Parrish, C. A.; Buchwald, S. L. J. Org.
Chem. 2001, 66, 2498. (f) Shelby, Q.; Kataoka, N.; Mann, G.; Hartwig, J. F.
J. Am. Chem. Soc. 2000, 122, 10718. (g) Palucki, M.; Wolfe, J. P.; Buchwald,
S. L. J. Am. Chem. Soc. 1997, 119, 3395. (h) Palucki, M.; Wolfe, J. P.; Buchwald,
S. L. J. Am. Chem. Soc. 1996, 118, 10333. (i) Mann, G.; Hartwig, J. F. J. Am.
Chem. Soc. 1996, 118, 13109.
† Chinese Academy of Sciences.
‡ Institute for Diabetes Discovery.
(1) (a) Ellis, G. P. In The Chemistry of Heterocyclic Compounds; Weissberger,
A., Taylor, E. C., Eds.; John Wiley & Sons: New York, 1977; Vol 31. (b)
Mustafa, A. In The Chemistry of Heterocyclic Compounds; Weissberger, A.,
Taylor, E. C., Eds.; John Wiley & Sons: New York, 1974; Vol 29. (c) Yamazaki,
N.; Washio, I.; Shibasaki, Y.; Mitsuru Ueda, M. Org. Lett. 2006, 8, 2321. (d)
Asano, M.; Inoue, M.; Katoh, T. Synlett 2005, 2599. (e) Jiang, H.; Leger, J.-M.;
Huc, I. J. Am. Chem. Soc. 2003, 125, 3448. (f) Bolm, C.; Hildebrand, J. P.;
Mun˜iz, K.; Hermanns, N. Angew. Chem., Int. Ed. 2001, 40, 3284. (g) Gu, W. X.;
Jing, X. B.; Pan, X. F.; Chan, A. S. C.; Yang, T. K. Tetrahedron 2000, 41,
6079. (h) Matsumoto, Y.; Uchida, W.; Nakahara, H.; Yanagisawa, I.; Shibanuma,
T.; Nohira, H. Chem. Pharm. Bull. 2000, 48, 428. (i) Temal-La¨ıb, T.; Chastanet,
J.; Zhu, J. J. Am. Chem. Soc. 2002, 124, 583. (j) Thompson, A.; Delaney, A.;
James, M.; Hamby, J.; Schroeder, M.; Spoon, T.; Crean, S.; Showalter, H. D. H.;
Denny, W. J. Med. Chem. 2005, 48, 4628.
(5) Ullmann, F. Chem. Ber. 1904, 37, 853.
(6) For reviews, see: (a) Lindley, J. Tetrahedron 1984, 40, 1433. (b) Kunz,
K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428. (c) Frlan, R.; Kikelj, D. Synthesis
2006, 2271. (d) Beletskaya, I.; Cheprakov, A. Coord. Chem. ReV. 2004, 248,
2337. (e) Ley, S.; Thomas, A. Angew. Chem., Int. Ed. 2003, 42, 5400.
(7) (a) Wolter, M.; Nordmann, G. E.; Buchwald, S. L. Org. Lett. 2002, 4,
973. (b) Job, G.; Buchwald, S. L. Org. Lett. 2002, 4, 3703. (c) Zhang, H.; Ma,
D.; Cao, W. Synlett 2007, 243. (d) Hosseinzadeh, R.; Tajbakhsh, M.; Mohad-
jerani, M.; Alikarami, M. Synlett 2005, 1101. (e) Manbeck, G. F.; Lipman, A.,
Jr.; Stockland, R. A.; Freidl, A.; Hasler, A.; Stone, J.; Guzei, I. J. Org. Chem.
2005, 70, 244. (f) Altman, R. A.; Shafir, A.; Choi, A.; Lichtor, P. A.; Buchwald,
S. L. J. Org. Chem. 2008, 73, 284.
(2) For example, see: ComprehensiVe Natural Products Chemistry; Barton,
D., Nakanishi, K., Meth-Cohn, O., Eds.; Elsevier Science: Oxford, UK, 1999;
Vols. 1, 3, and 8.
(8) Niu, J.; Zhou, H.; Li, Z.; Xu, J.; Hu, S. J. Org. Chem. 2008, 73, 7814.
10.1021/jo900600m CCC: $40.75  2009 American Chemical Society
Published on Web 05/28/2009
J. Org. Chem. 2009, 74, 5075–5078 5075

TABLE 1. Comparison of Different Bases for the Copper
SCHEME 1. Sceening of Ligands for CuI-Catalyzed C-O
Coupling
Iodide-Catalyzed C-O Couplinga
entry
base
PhOnBu
PhOPh
In the primary screening experiments, a series of ligands were
examined in the reaction of bromobenzene and n-butyl alcohol,
using the following catalyst system: 5 mol % CuI/10 mol %
ligand/K3PO4/110 °C/24 h and n-butyl alcohol itself as solvent
(Scheme 1). The results of screening experiments were presented
in Figure 1. From the results, it was apparent that 8-hydrox-
yquinoline showed the most activity. Comparing bars 7, 8, and
9, it was found that the presence of the -OH group was the
key element of the success. When the proton was replaced by
a methyl or acetyl group, the yield was decreased obviously.
Some ligands, such as 1,10-phenanthroline and amino acids,
which were used in the coupling between aryl iodides and
alcohols successfully, could not proceed in aryl bromides or in
a low yield, which was consistent with the substrate activity
order of I > Br .Cl > F.6
Further experiments were performed to examine the influence
of base on conversion and selectivity. A set of bases were
examined in the reaction of bromobenzene and n-butyl alcohol,
under the following reaction condition: 5 mol % CuI/10 mol %
8-hydroxyquinoline/110 °C/24 h and n-butyl alcohol itself as
solvent. As shown in Table 1, although Na2CO3, K2CO3, and
some organic base gave a quite low conversion, when K3PO4
and Cs2CO3 were used as base the starting material was nearly
transformed completely after 24 h, at the same time biphenyl
ether was produced as a byproduct, presumably because
nucleophilic displacement of the -OH group of n-butyl alcohol
1
2
3
4
5
6
7
Na2CO3
K2CO3
K3PO4
Cs2CO3
NEt3
3
5
95
68
4
<1
<1
3
28
<1
<1
<1
pyridine
6
11
a Reaction conditions: PhBr (1.0 mmol), CuI (0.05 mmol, 5 mol %),
8-hydroxyquinoline (0.1 mmol, 10 mol %), and base (2 mmol) were
added to a screw-capped test tube followed by the addition of 1 mL of
n-butyl alcohol. The reaction was stirred 24 h at 110 °C under argon.
Conversion was measured by GC, with phenyl ethyl ether as internal
standard.
yielded phenol, with which cross-coupled bromobenzene suc-
cessionally. This process could be inhibited by selecting the
proper base. By using K3PO4 as base, only a minute (3%)
amount of the undesired symmetrical biphenyl ether was
detected (Table 1, entry 3).
To determine the scope of the catalytic system, the present
protocol was applied in reactions of a range of commercially
available aryl bromides and aliphatic alcohols. As shown in
Table 2, the coupling of aliphatic alcohols with different aryl
bromides was successful, leading to the desired products in good
yields. The protocol was tolerant to electron-withdrawing and
-donating functional groups and also to the presence of a group
in the ortho-position of the aryl bromides (Table 2, entries 2,
4, 5, and 6). Moreover, the reactions showed interesting
chemoselectivity; see entry 6 for preferred C-O coupling in
the presence of an -NH2 group, which could be coupled with
aryl bromides potentiality to form a C-N bond. We could also
utilize the intrinsic reactivity of aryl halides to selectively couple
the -Br group when both -Br and -Cl existed in the aromatic
ring (Table 2, entry 8). Functional groups that were compatible
with Cu-catalyzed alcohol arylation protocol include thioether,
keto, and nitro.
The carbon-oxygen bond formation reaction was also tested
employing tethered ortho-bromide aryl alcohols. As can be seen
in Table 3, the intramolecular O-arylation aryl halides could
be carried out successfully under mild reaction conditions by
using a similar protocol. It appeared that the yield was decreased
greatly without adding the ligand (Table 3, entry 1). The choice
of Cs2CO3 as base was more effective than K3PO4, which might
be because the existence of Cs2CO3 was helpful in forming
phenoxides.9,10 Both five- and six-membered ring formations
could be accomplished with aryl bromide substrate at 110 °C.
The reaction of aryl chloride substrate was slightly more
demanding, and a good yield was obtained by raising the
reaction temperature (Table 3, entry 2).
In summary, we have developed an efficient, mild, and
inexpensive Cu-catalyzed coupling reaction of aliphatic alcohols
and aryl bromides at 110 °C that uses commercially available
components and readily available ligand. A variety of functional
FIGURE 1. Comparison in different ligands. Reaction conditions: PhBr
(1.0 mmol), CuI (0.05 mmol, 5 mol %), ligand (0.1 mmol, 10 mol %),
and K3PO4 (2 mmol) were added to a screw-capped test tube followed
by the addition of 1 mL of n-butyl alcohol. The reaction was stirred
24 h at 110 °C under argon. Conversion was measured by GC, with
phenyl ethyl ether as internal standard.
(9) Take entry 2 in Table 3 for example: 65% GC yield obtained when K3PO4
was used as base in the same reaction conditions.
(10) (a) Dijkstra, G.; Kruizinga, W. H.; Kellogg, R. M. J. Org. Chem. 1987,
52, 4230. (b) Flessner, T.; Doye, S. J. Prakt. Chem. 1999, 341, 186. (c) Galli,
C. Org. Prep. Proced. Int. 1992, 24, 287.
5076 J. Org. Chem. Vol. 74, No. 14, 2009

TABLE 2. Copper-Catalyzed Coupling of Aryl Bromides with
Aliphatic Alcoholsa
TABLE 3. Copper-Catalyzed Syntheses of Cyclic Aryl Ethersa
a General reaction conditions: intramolecular alcohol-ArBr/Cl
substrate (1.0 mmol), CuI (0.01-0.05 mmol, 1-5 mol %),
8-hydroxyquinoline (0.02-0.1 mmol, 2-10 mol %), and Cs2CO3 (2.0
mmol) in toluene (1 mL) under argon were added to a sealed test tube.
b Yield of >95% purity as determined by GC and 1H NMR. c 120 °C
and 1 mL of xylene as solvent.
aryl halide (if solid, 1 mmol), and K3PO4 (425 mg, 2.0 mmol) were
added to a screw-capped Schlenk tube under argon. The tube was
then evacuated and backfilled with argon (3 cycles). Aryl halide
(if liquid, 1.0 mmol) and aliphatic alcohol (1 mL) were added by
syringe at room temperature. The reaction mixture was stirred at
110 °C for 24 h. The reaction mixture was allowed to reach room
temperature and then diluted with dichloromethane (10 mL). The
slurry was filtered and the filter cake was washed with 10 mL of
dichloromethane. The solvent was removed in vacuo, and the
residue was purified by column chromatography on silica gel to
afford the desired product.
General Procedure for the Copper-Catalyzed Syntheses of
Cyclic Aryl Ethers. CuI (1-5 mol %), 8-hydroxyquinoline (2-10
mol %), and Cs2CO3 (651 mg, 2.0 mmol) were added to a screw-
capped Schlenk tube under argon. The tube was then evacuated
and backfilled with argon (3 cycles). Aryl halide (1.0 mmol) and
toluene (1 mL) were added by syringe at room temperature. The
reaction mixture was stirred at 110 °C for 24 h. The reaction mixture
was allowed to reach room temperature and then diluted with
dichloromethane (10 mL). The slurry was filtered and the filter cake
was washed with 10 mL of dichloromethane. The solvent was
removed in vacuo, and the residue was purified by column
chromatography on silica gel to afford the desired product.
n-Butyl phenyl ether (Table 2, entry 1): 1H NMR (400 MHz,
CDCl3) δ 7.25-7.29 (m, 2H), 6.88-6.94 (m, 3H), 3.96 (t, J ) 6.0
Hz, 2H), 1.73-1.78 (m, 2H), 1.47-1.53 (m, 2H), 0.97 (t, J ) 6.0
Hz, 3H) ppm; 13C NMR (400 MHz, CDCl3) δ 159.1, 129.2, 120.3,
114.4, 67.3, 31.3, 19.2, 13.7 ppm; MS m/z 150 (M+), 94, 77, 66,
57, 51, 41, 29. Anal. Calcd for C10H14O: C, 79.96; H, 9.39. Found:
C, 79.73; H, 9.52.
a General reaction conditions: ArBr (1.0 mmol), CuI (0.02-0.05
mmol, 2-5 mol %), 8-hydroxyquinoline (0.04-0.1 mmol, 4-10 mol %),
and K3PO4 (2.0 mmol) in 1 mL of R2OH and 2.0 mmol of K3PO4 under
argon were added to a sealed test tube. b Yield of >95% purity as
determined by GC and H NMR. c CS2CO3 as base. d 48 h.
1
groups are compatible with these reaction conditions. The mild
reaction conditions and increased scope relative to previous ones
would render this protocol attractive to synthetic chemists.
Experimental Section
1
Allyl 2-tolyl ether (Table 2, entry 2): H NMR (400 MHz,
General Procedure for the O-Arylation of Aliphatic
Alcohols. CuI (2-5 mol %), 8-hydroxyquinoline (4-10 mol %),
CDCl3) δ 7.12-7.15 (m, 2H), 6.80-6.87 (m, 3H), 6.03-6.12 (m,
1H), 5.45 (dd, J ) 17.2 Hz, J ) 1.9 Hz, 1H), 5.27 (dd, J ) 10.6
J. Org. Chem. Vol. 74, No. 14, 2009 5077

Hz, J ) 2.0 Hz, 1H), 4.54 (m, 2H), 2.25 (s, 3H) ppm; 13C NMR
(400 MHz, CDCl3) δ 156.7, 133.7, 130.7, 126.9, 126.7, 120.5,
116.8, 111.3, 68.6, 16.2 ppm; MS m/z 148 (M+), 133, 107, 91, 79,
77, 65, 51, 41, 39. Anal. Calcd for C10H12O: C, 81.04; H, 8.16.
Found: C, 81.22; H, 8.19.
of this work. We also thank Zunshi He and Jie Zhang for their
important contributions in the sample analysis of this work.
Supporting Information Available: NMR spectra of cou-
pling products. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. We thank the Changchun Institute of
Applied Chemistry Chinese Academy of Sciences for support
JO900600M
5078 J. Org. Chem. Vol. 74, No. 14, 2009