Copper(ii)-catalyzed C-O coupling of aryl bromides with aliphatic diols: Synthesis of ethers, phenols, and benzo-fused cyclic ethers

Article abstract of DOI:10.1039/c4ob00649f

A highly efficient copper-catalyzed C-O cross-coupling reaction between aryl bromides and aliphatic diols has been developed employing a cheaper, more efficient, and easily removable copper(ii) catalyst. A broad range of aryl bromides were coupled with aliphatic diols of different lengths using 5 mol% CuCl₂ and 3 equivalents of K₂CO₃ in the absence of any other ligands or solvents to afford the corresponding hydroxyalkyl aryl ethers in good to excellent yields. In this newly developed protocol, aliphatic diols have multilateral functions as coupling reactants, ligands, and solvents. The resulting hydroxyalkyl aryl ethers were further readily converted into the corresponding phenols, presenting a valuable alternative way to phenols from aryl bromides. Furthermore, it was demonstrated that they are useful intermediates for more advanced molecules such as benzofurans and benzo-fused cyclic ethers. This journal is

Full text of DOI:10.1039/c4ob00649f

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Biomolecular Chemistry
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PAPER
Copper(II)-catalyzed C–O coupling of aryl
bromides with aliphatic diols: synthesis of ethers,
phenols, and benzo-fused cyclic ethers†
Cite this: Org. Biomol. Chem., 2014,
12, 4747
Yajun Liu, Se Kyung Park, Yan Xiao‡ and Junghyun Chae*
A highly efficient copper-catalyzed C–O cross-coupling reaction between aryl bromides and aliphatic
diols has been developed employing a cheaper, more efficient, and easily removable copper(II) catalyst.
A broad range of aryl bromides were coupled with aliphatic diols of different lengths using 5 mol% CuCl2
and 3 equivalents of K2CO3 in the absence of any other ligands or solvents to afford the corresponding
hydroxyalkyl aryl ethers in good to excellent yields. In this newly developed protocol, aliphatic diols have
multilateral functions as coupling reactants, ligands, and solvents. The resulting hydroxyalkyl aryl ethers
were further readily converted into the corresponding phenols, presenting a valuable alternative way to
phenols from aryl bromides. Furthermore, it was demonstrated that they are useful intermediates for
more advanced molecules such as benzofurans and benzo-fused cyclic ethers.
Received 27th March 2014,
Accepted 9th May 2014
DOI: 10.1039/c4ob00649f
www.rsc.org/obc
for example, copper-cluster as a catalyst, KF/Al2O3 as a base, or
β-amino alcohols as coupling partners. In the case of phenol
Introduction
The C(aryl)–O bond forming reaction is a valuable process for synthesis, copper-catalyzed methods have been very recently
the preparation of various target compounds.1 To this end, developed.11 In 2009, the Taillefer group11a and the You11b
transition metal-catalyzed C–O coupling of aryl halides with group reported independently that metal hydroxide cross-
O-nucleophiles is often sought,2,3 and copper has attracted couples directly with aryl iodides in the presence of CuI and
much attention due to its low cost and less toxicity. While either 1,3-diketone or 1,10-phenanthroline in aqueous DMSO.
copper-catalyzed diaryl ether synthesis using phenolic nucleo- Shortly after these findings, other ligands showing the similar
philes is better established,4 less has been explored on the activity were identified.11c–i
preparation of aryl alkyl ethers and phenols with aliphatic
alcohols and hydroxide as nucleophiles, respectively.
Despite the remarkable advancements in this regard, there
are still several aspects to be addressed for the catalytic C–O
The classical Ullmann reaction for the synthesis of aryl cross-coupling reactions toward aryl alkyl ethers and phenols.
alkyl ethers from aryl halides and alkoxides suffers from First, the catalyst is mostly limited to copper(I) salts, especially
drastic reaction conditions.5 However, significant advance- CuI. Alternative copper salts should be advantageous if they
ment has been made in this area in the past few decades. In are cheaper, more efficient, and readily removable. Second,
2002, the Buchwald group reported the first successful copper- these reactions are highly dependent on specific ligands, most
catalyzed arylation of aliphatic alcohols with aryl iodides using of which are expensive and often used in large amounts as
CuI and 1,10-phenanthroline under mild conditions.6 Later, much as 50 mol%. Third, most protocols have limited sub-
other ligands were reported, including N,N-dimethylglycin,7 strate scopes, where aryl iodides are generally required while
8-hydroxyquinoline,8 and 3,4,7,8-tetramethyl-1,10-phenanthro- more available aryl bromides and chlorides are poor in reacti-
line.9 New protocols are also continuously being developed:10 vity. Herein, we wish to report an efficient copper(II)-catalyzed
C–O cross-coupling reaction between aryl bromides and ali-
phatic diols. To the best of our knowledge, our work is the first
attempt to cross-couple aliphatic diols with aryl halides. To a
Department of Chemistry and Research Institute of Basic Sciences, Sungshin
great extent, this protocol fulfills the above-mentioned require-
ments, as it has a broad substrate scope for various aryl
bromides employing the copper(II) catalyst in the absence of
any extra ligands. In addition, the resulting aryl alkyl ethers
are further readily converted into phenols and benzo-fused
cyclic ethers.
Women’s University, Seoul 136-742, Korea. E-mail: jchae@sungshin.ac.kr;
Fax: +82-2-920-2058; Tel: +82-2-920-7660
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, spectral data, and copies of 1H NMR and 13C NMR spectra. See DOI:
10.1039/c4ob00649f
‡Current address: School of Pharmaceutical Engineering, Shenyang Pharma-
ceutical University, Shenyang 110016, China.
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and 3.0 equiv. of K2CO3 were applied at 130 °C for 20 h, only
65% of 4-bromotoluene was converted into the coupled
Results and discussion
In many copper-catalyzed coupling reactions, a variety of product 2a in 63% yield (entry 2). Such poor conversions and
bidentate ligands including N,N-, N,O-, and O,O-chelators are yields were also observed in cases of most other copper(I) salts
often employed.3a We were particularly intrigued by the O,O- tested. Only CuOAc showed conversion over 90% (entry 6) and
donor ligands such as ethylene glycol12a and 1,1,1-tris(hydroxy- less than 50% conversion was achieved for the others (entries
methyl)ethane.12b We envisioned that they could not only 3–5). For the reactions with CuBr and CuCl, the low yields are
function as ligands, but also couple as O-nucleophiles with attributed to the formation of the reduced by-product, toluene
aryl halides. Particularly, these polyols could be effective in the in 7–20%. Thus, most copper(I) salts seemed not effective
coupling with less reactive aryl halides such as aryl bromides. enough for the desired coupling reaction. However, by chan-
We tested this idea by heating ethylene glycol with 4-iodo- or ging the catalyst to copper(II) salts, the reactivity dramatically
4-bromotoluene without N-nucleophiles under the copper- increased, leading to almost quantitative formation of the
catalyzed C–N coupling conditions published by Buchwald.13 product 2a, showing similar results with all the copper(II) salts
Indeed, for both 4-iodo- and 4-bromotoluene, the C–O coup- tested (entries 8–14). Under the test conditions, we observed
ling occurred, affording a considerable amount of products at that the reaction mixtures with copper(II) salts and CuOAc
a more elevated temperature.
became homogeneous while those with the other copper(I)
Thus, we set out investigating copper-catalyzed systems for salts remained heterogeneous throughout the reaction. The
the C–O coupling between aryl bromides and aliphatic diols. high reactivity with copper(II) salts was sustained even when
Using 4-bromotoluene and ethylene glycol as model sub- the catalyst loading was decreased down to 3–5 mol%. The
strates, a variety of copper-catalytic conditions were examined, observed reactivity difference between copper(I) and copper(II)
studying factors such as copper salt, catalyst loading, base, salts is interesting. In the coupling reactions, it is generally
reaction temperature, and time (Table 1). In order to make the accepted that copper(I) is the real catalyst species and copper(II)
reaction protocol simple and practical, we did not incorporate is converted to copper(I) by in situ reduction by nucleophiles,
any other solvents than ethylene glycol.14 When 10 mol% CuI which explains the slower reaction and/or lower reactivity with
copper(II) salts.15 However, from what we observed with the
reactions, we presume that the apparent higher reactivity of
copper(II) salts under our conditions seems to be due to the
better stabilization and enhanced solubility of copper com-
Table 1 Optimization of Cu-catalyzed coupling reactions of 4-bromo-
toluene with ethylene glycola
plexes. Nonetheless, we think that the reactive catalyst com-
plexes would have copper(I) species reduced from copper(II)
sources by plenty of O-nucleophiles, ethylene glycol. Since, in
general, copper(II) salts have several advantages over copper(I)
salts in respect of cost, air-stability, and water-solubility,
employing copper(II) salts could lead to an economical and
streamlined process; for instance, the easy removal of catalysts
by simple aqueous work-up.16
We further screened a series of inorganic bases and reac-
tion temperatures. Both K2CO3 and Cs2CO3 turned out to be
excellent while K3PO4 and Na2CO3 were less effective
(entries 17–19). Stronger bases such as NaOH and KOtBu pro-
duced 7–8% p-cresol (entries 15 and 16), because they pro-
moted the cleavage of the ethereal bond of 2a (vide infra),
while less than 2% p-cresol was detected in the reactions with
weaker bases. Meanwhile, no trace of the biarylated product of
ethylene glycol was observed. Increasing the amount of ethyl-
ene glycol or base did not improve the reaction. Shortening
the reaction time (entry 20) and lowering the reaction tempera-
ture (entry 22) caused negative effects. After the experiments,
we were able to achieve the optimized conditions: 1 M solution
of aryl bromide in ethylene glycol, 5 mol% CuCl2 as the cata-
lyst, and 3 equivalents of K2CO3 as the base at 130 °C for 20 h.
However, we think users can choose any copper(II) salts avail-
able as there is little reactivity difference among them.
Entry
[Cu]
Base
Conv.b (%)
Yieldb (%)
1
2
3
4
5
6
7
8
—
CuI
CuBr
CuCl
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NaOH
KOtBu
K3PO4
Na2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
0
65
35
42
50
92
0
100
100
99
97
98
95
99
93
100
93
70
100
91
97
63
0
63
28
12
50
92
0
Cu2O
CuOAc
Cu (powder)
Cu(acac)2
CuCl2
99, 85c
99, 99,c 88d
99, 99c
96, 95c
95, 94c
95, 95c
99, 97c
86
9
10
11
12
13
14
15
16
17
18
19
20e
21f
22g
CuBr2
Cu(OAc)2
Cu(OH)2
CuSO4
CuO
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
CuCl2
92
90
70
98
91
97
63
CuCl2
CuCl2
a Reaction conditions: 4-bromotoluene (1.0 mmol), [Cu] (10 mol%),
base (3.0 equiv.) in ethylene glycol (1.0 mL) at 130 °C for 20 h.
b Conversion and yield were determined by GC using n-dodecane as an
internal standard. c 5 mol% [Cu]. d 3 mol% [Cu]. e 5 mol% CuCl2, 12 h.
f 120 °C. g 100 °C.
We then explored the application scopes of our method
using a variety of aryl bromides (Table 2). Compared to aryl
iodides, aryl bromides are more attractive for industrial appli-
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Table 2 Copper(II)-catalyzed C–O coupling reactions of various aryl
bromides with ethylene glycola
Table 2 (Contd.)
Entry
16d
Product
Yieldb
88%
Entry
1
Product
Yieldb
96%
2p
2q
2a
2b
2c
17e
90%
2
3
99%
99%
18e
19
2r
2s
83%
91%
4c
2d
2e
94%
99%
5
20
2t
94%
6
7
2f
95%
96%
21
22
2u
2v
94%
95%
2g
8
2h
94%
23
2w
90%
9
2i
2j
93%
92%
a Reaction conditions: aryl bromide (1.0 mmol), CuCl2 (5 mol%), K2CO3
3.0 equiv.) in 1.0 mL ethylene glycol at 130 °C for 20 h. b Isolated yield
(average of two runs). c 140 °C. d 110 °C, 36 h. e 110 °C.
10
cation, but their usage in the copper-catalyzed C–O coupling
reaction with aliphatic alcohols is rather limited due to their
low reactivity. Only a few examples have been reported.8
However, our new catalytic system is found to be readily appli-
cable to various aryl bromides possessing substituents of elec-
tron-withdrawing, electronically neutral, and electron-donating
groups. Ethylene glycol readily cross-coupled with aryl bro-
mides under the reaction conditions to afford the corres-
ponding arylated products in good to excellent yields. Simple
alkyl or phenyl substituted aryl bromides showed almost quan-
titative reactions (entries 1–6). 1- and 2-Bromonaphthalenes
also reacted with ethylene glycol in excellent yields (entries 7
and 8). It is noteworthy that sterically hindered aryl bromides
such as 2,6-dimethyl bromobenzene successfully cross-coupled
in 94% yield though a little higher temperature was required
(entry 4). In fact, in our developed protocol, the reactivity of
11
12
2k
2l
92%
94%
13
2m
96%
14
15
2n
2o
96%
95%
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substrates seems to be less influenced by ortho-substituents in
terms of steric and electronic factors; 1-bromo-2-methoxy-
benzene, which has an electron-donating group, and 1-acetyl-
2-bromobenzene, which has an electron-withdrawing group,
underwent the reactions at comparable efficiencies (entries 11
and 18). In the case of acetyl bromobenzenes, they all behaved
similarly regardless of their substitution positions, except for
the need for adjusting each reaction temperature and time for
the completion (entries 16–18). It was observed that acetyl bromo-
benzenes were reduced to acetophenones and the coupled
products were further cleaved to the phenolic by-products,
acetyl phenols at 130 °C. Lowering the reaction temperature to
110 °C was helpful in minimizing such side reactions. Yet, the
moderate yields were attributed to the formation of acetyl
phenols up to 8%. Excellent yields were observed in the reac-
tions with 4-fluoro- and 3-, 4-chlorobromobenzene and the
coupling reaction occurred only at the carbon bearing bromine
(entries 13–15). Meanwhile, our catalytic system showed a
good tolerance toward a variety of functional groups. Besides
those described above, functional groups such as trifluoro-
methyl, phenolic hydroxyl, aliphatic hydroxyl, and carboxylic
acid were compatible under the reaction conditions (entries
19–22). Particularly, it is noteworthy that the phenolic hydroxyl
group did not participate in the C–O coupling reaction to give
diaryl ether (entry 20). Heterocyclic compounds such as 3-bro-
mopyridine also afforded the corresponding product in 90%
yield (entry 23). For those reactions showing excellent yields in
Table 2, almost pure products were obtained simply by
aqueous work-up, because all the reagents including copper(II)
chloride, bases, and diols were water-soluble and easily
removed from the organic phase.
We then turned our attention to longer diols for arylation
(Table 3). We assume that the coupling reaction is mediated
via the chelation of diols to the copper catalyst, thus the C–O
bond formation would proceed when the aliphatic diols could
effectively form cyclic bidentate ligands. Therefore, diols
which can form a 5- or 6-membered ring in the copper com-
plexes would be preferred in this reaction, as most reported
bidentate ligands are often 1,2- or 1,3-N,N-, N,O- and O,O-
donors. Not too surprisingly, 1,3-propanediol cross-coupled
with aryl bromides in good yields (entries 1–9), whereas 1,4-
butanediol reacted in lower yields when the same aryl bro-
mides were used (entries 10–14). For both 1,3-propanediol and
1,4-butanediol, Cs2CO3 was a more effective base than K2CO3,
presumably because of the better solubility and basicity of
Cs2CO3. In the case of arylation with 1,4-butanediol, aryl
iodides showed significantly better reaction conversions than
aryl bromides. For both 1,3-propanediol and 1,4-butanediol,
the effects of various substituents of aryl halides were similar
to those observed for ethylene glycol. Diols longer than 1,4-
butanediol such as 1,5-pentanediol and 1,6-hexanediols were
essentially ineffective in this coupling reaction with aryl bro-
mides, showing poor conversions less than 30%. However,
their reactions with aryl iodides showed good conversions up
to 90%. Some branched aliphatic diols were briefly tested. 1,2-
Table 3 Copper(II)-catalyzed C–O coupling reactions of aryl bromides
with aliphatic diols of different lengthsa
Yieldb
Entry
1
Product
X = Br
X = I
d
3b
3c
96%, 90%c
—
d
2
86%, 77%c
—
d
3
4
3f
3j
84%, 82%c
95%, 93%c
—
d
—
d
5
6
3k
3l
90%, 82%c
92%, 86%c
—
—
d
d
d
d
7
8
9
3m
3n
3o
93%, 81%c
87%, 79%c
86%, 82%c
—
—
—
10
11
4a
4e
80%
62%
91%
78%
12
13
14
4i
78%
62%
72%
86%
80%
91%
4n
4o
a Reaction conditions: aryl halide (1.0 mmol), CuCl2 (5 mol%), Cs2CO3
(3.0 equiv.) in 1.0 mL aliphatic diol at 130 °C for 20 h. b Isolated yield
(average of two runs). c K2CO3 was used as the base. d The reaction was
Propanediol and 1,3-butanediol were effectively coupled with not tested.
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Scheme 2 Synthesis of benzofurans from aryl alkyl ethers (2).
less favorable than that of 3- or 5-membered rings. Overall, the
procedure offers a practical alternative route to phenols from
aryl bromides, considering that only a limited number of
direct phenol syntheses from aryl bromides are available.11
Moreover, the scalability of the reaction was further demon-
strated by carrying out the synthesis of phenol from bromo-
benzene in a scale as large as 100 times that of the
optimization. Bromobenzene (1b, 15.7 g, 0.1 mol), CuCl2
(0.67 g, 5 mmol) and K2CO3 (41 g, 0.3 mol) were stirred in
56 mL of ethylene glycol (1.0 mol) under an Ar atmosphere at
130 °C for 20 h. For this larger scale, the reaction concen-
tration was about 2 M, and yet the complete conversion and
quantitative yield were achieved for the first step. Then, the
concentrated crude intermediate was directly used for the next
reaction. Dealkylation of 2b proceeded smoothly in the pres-
ence of KOH (16.8 g, 0.3 mol) in 200 mL of DMSO under a N2
atmosphere. Aqueous work-up followed by distillation of the
concentrated crude product under reduced pressure afforded
8.75 g of phenol 5b as a colorless liquid (93% over 2 steps).
Another example showing the utility of the hydroxyalkyl aryl
ethers is demonstrated by the synthesis of benzo-fused com-
pounds. Benzo-fused cyclic ethers including benzofuran,
benzofuranone, and benzopyranone are widely present in
nature and they often appear as biologically active molecules
and important synthetic intermediates.17 It is conceivable that
these cyclic ethers can be readily prepared from our coupled
products by means of conventional synthetic methods. Indeed,
we were able to synthesize several compounds of those classes
uneventfully. For the synthesis of benzofurans, the terminal
alcohols of hydroxyethyl aryl ethers (2) were oxidized to the
corresponding aldehydes, which underwent intramolecular
cyclization to afford the products (6) (Scheme 2).18 When the
terminal hydroxyl groups of arylated diols, 2, 3, and 4, were
further oxidized to the carboxylic acids and the subsequent
cyclizations were carried out, benzofuranone, benzopyranone,
and benzooxepinone were obtained respectively (Scheme 3).19
As our C–O coupling protocol provides one-step synthesis for
hydroxyalkyl aryl ethers with various functional groups on the
aryl ring, the synthetic route becomes much simplified and a
library of these series can be rapidly generated. Thus, our
method is readily applicable in the research areas where high-
throughput synthesis is necessary.
Scheme 1 Synthesis of phenols from aryl alkyl ethers. Reaction con-
ditions: aryl alkyl ether (2) (1.0 mmol) and KOH (3.0 equiv.) in DMSO
(3.0 mL) at 100 °C for 3 h. aYield from 3, 120 °C, 5 h. bYield from 4.
aryl bromides predominantly at the primary hydroxyl group,
whereas 2,3-butanediol turned out to be less effective under
our reaction conditions, though detailed studies have not been
carried out in this regard.
The hydroxyalkyl aryl ethers resulting from the reactions
can serve as useful intermediates. For instance, the terminal
primary alcohol can be transformed into various functional
groups such as leaving groups for substitution, aldehydes, car-
boxylic acids, and so forth. Moreover, phenols can be liberated
from the ethers by base-mediated intramolecular SN2 reaction
in an analogy to the Payne rearrangement pathway. We believe
that the driving forces of this cleavage reaction are intramole-
cular cyclic ether formation and innate character of phenolate
as a good leaving group. The hydroxyethyl aryl ethers (2) were
treated with 3 equivalents of KOH in DMSO at 100 °C and the
corresponding phenols (5) were obtained in good to excellent
yields (Scheme 1). Most of them were cleaved with great easi-
ness regardless of the substituents on the aryl ring. Similarly,
the ethers derived from 1,4-butanediols (4) were smoothly
transformed to the phenols (5a, 5i and 5o). The ethers (3)
derived from 1,3-propanediols required slightly more heat and
longer reaction time for full conversion (5f, 5l and 5n). One
can assume that formation of a 4-membered ring would be
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1996, vol. 52; (b) F. Theil, Angew. Chem., Int. Ed., 1999, 38,
2345.
2 For reviews on Pd-catalyzed C–O bond formation, see:
(a) A. de Meijere and F. Diederich, Metal-Catalyzed Cross-
Coupling
Reactions,
Wiley-VCH, Weinheim,
2004;
(b) S. Enthaler and A. Company, Chem. Soc. Rev., 2011, 40,
4912; (c) J. Tsuji, Palladium Reagents and Catalysts Inno-
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Formation, Wiley-VCH, Weinheim, 2011, pp. 35–68;
(e) M. Catellani, E. Motti and N. D. Ca’, Acc. Chem. Res.,
2008, 41, 1512.
3 For reviews on Cu-catalyzed C–O bond formation, see:
(a) G. Evano, N. Blanchard and M. Toumi, Chem. Rev.,
2008, 108, 3054; (b) F. Monnier and M. Taillefer, Angew.
Chem., Int. Ed., 2009, 48, 6954; (c) B. C. Ranu, R. Dey,
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4 Selected examples for Cu-catalyzed synthesis of diaryl
ethers: (a) J. F. arcoux, S. Doye and S. L. Buchwald, J. Am.
Chem. Soc., 1997, 119, 10539; (b) Q. Cai, B. Zou and D. Ma,
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M. Oiarbide, R. López and E. Gómez-Bengoa, Chem.
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Scheme 3 Synthesis of benzo-fused cyclic ethers from aryl alkyl ethers
(2–4).
Conclusions
In conclusion, we have developed a highly efficient and practi-
cal C–O coupling reaction between aryl bromides and aliphatic
diols using copper(II) catalysts. When compared to previously
reported C–O(alkyl) coupling reactions, the developed protocol
has the following advantages: (1) CuCl2, the catalyst of choice,
is not only readily available but also very effective in the C–O
coupling. The good solubility of CuCl2 in both reactant diols
and water greatly enhances the reactivity of the catalytic system
by rendering homogeneous reactions and makes it easy to
remove the catalyst by simple aqueous work-up. (2) Our cataly-
tic system is reactive enough so that it is applicable to a broad
range of aryl bromides, which are more economically viable
than aryl iodides. (3) The reaction conditions are very straight-
forward, consisting of the coupling components (aryl bromide
and diol), copper catalyst, and base. It is essentially ligand-free
and no additional solvents or additives are required. Unlike
the coupled product from simple alcohols, the products,
hydroxyalkyl aryl ethers, can be readily converted into more
advanced molecules, for example, benzo-fused cyclic ethers, by
transforming the terminal hydroxyl group. In addition, we
developed a highly effective method to synthesize phenols
from the hydroxyalkyl aryl ethers, presenting a valuable
alternative way to phenols from aryl bromides. Overall, we
believe that our protocol can find wide use both in academia
and industry.
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This work was supported by the Ministry of Trade, Industry,
and Energy and the Korea Institute of Energy Technology
Evaluation and Planning (Project B3-3210).
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