An efficient copper-catalyzed etherification of aryl halides

Article abstract of DOI:10.1055/s-0030-1260761

An efficient and mild copper-catalyzed ether formation from aryl halides and aliphatic alcohols has been developed. The key to the successful coupling is the use of lithium alkoxide, directly or in situ generated by lithium tert-butoxide, and the corresponding alcohol as solvent. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260761

LETTER
1419
An Efficient Copper-Catalyzed Etherification of Aryl Halides
C
opper-Ca
i
talyze
n
k
H
u
a
lide
s
n Huang,* Ying Chen, Johann Chan, Mike L. Ronk, Robert D. Larsen, Margaret M. Faul
Chemical Process R&D, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
E-mail: jhuang@amgen.com
Received 24 December 2010
by Zheng, Wang, and co-workers.8 In the same year Chan
et al. developed a ligand-free CuI-catalyzed etherification
process in which tetrabutylammonium bromide (10
mol%) was employed as an additive, K3PO4 as base at
high temperature (in refluxing DMF).9 This later protocol
only gives good yields for coupling of aryl iodide with
phenols, but much less effective with alcohols as shown
by their low yields. Such a ligand-free process is highly
desirable due to its obvious advantages associated with
ligand cost and ligand removal in large-scale production.
Herein, we report the discovery of an efficient copper-cat-
alyzed coupling of aryl halides with aliphatic alcohols
without use of any external ligand.10
Abstract: An efficient and mild copper-catalyzed ether formation
from aryl halides and aliphatic alcohols has been developed. The
key to the successful coupling is the use of lithium alkoxide, direct-
ly or in situ generated by lithium tert-butoxide, and the correspond-
ing alcohol as solvent.
Key words: ligand-free, copper, etherification, aryl halides
There is a continuing interest in the development of gen-
eral and cost-effective methods to provide diverse scaf-
folds of pharmaceutically active compounds. The
transition-metal-catalyzed functionalization of aryl ha-
lides (or their equivalents) serves as a powerful tool by
forming C–C and C–X (X = heteroatom) bonds.1 Driven
by the need for the synthesis of aryl ethers, we became in-
terested in etherification of aryl halides.2 The classical
copper-mediated Ullmann etherification is useful but suf-
fers from a number of drawbacks such as harsh reaction
conditions, limited scope of substrates, and high loading
of a copper salt.3 Significant progress in the past 15 years
has been made in selective couplings employing a catalyt-
ic amount of a transition metal, mainly copper4 or palladi-
um.5 Although palladium catalyzed C–O bond formations
are successful to certain extent, the copper-based proto-
cols are more attractive. Unlike palladium, which typical-
ly requires a bulky and often expensive phosphine ligand,
copper catalyzes the Ullmann etherification through addi-
tion of a broad range of ligands based mostly on straight-
forward bidentate nitrogen and oxygen derivatives.6 A
great variety of structural scaffolds are employed bearing
moieties, such as bipyridines,6a phenathrolines,6b–d Schiff
bases,6e bishydrazones,6f b-diketone,6g b-keto ester,6h 1,1¢-
binaphthyl-2,2¢-diamine,6i amino acids,4c,6j 8-hydroxy-
quinoline,6k and 1-naphthoic acid,6l providing active
ligands to facilitate the copper-catalyzed coupling of aryl
halides with phenols or aliphatic alcohols. This phenome-
non of ligand diversity might be attributed to the compli-
cated mechanism of copper-catalyzed coupling reactions
and the various binding modes of copper complexes.4d
Therefore, continuing ligand searching is attractive but
challenging.7 On the other hand, in general, yet mild
Table 1 Optimization of Cu(I)-Catalyzed Etherification
Br
O
Me
base (3.0 equiv)
n-C5H11
+
solvent, 100 °C, 18 h
Me
n-C5H11 OH
Entry Catalyst
Base
Solvent
Conv. Yield
(%)a (%)b
1
2
CuI/8-HQ
K3PO4
n-C5H11OH
n-C5H11OH
n-C5H11OH
n-C5H11OH
n-C5H11OH
n-C5H11OH
n-C5H11OH
n-C5H11OH
n-C5H11OH
n-C5H11OH
n-C5H11OH
DMF
60
12
5
54
8
CuI
K3PO4
3
CuI
Cs2CO3
NaOt-Bu
LiOt-Bu
LiHDMS
LiOt-Bu
LiOt-Bu
LiOt-Bu
none
3
4
CuI
99c
100
20
99
100
94
0
6
5
CuI
>99
18
96
94
89
0
6
CuI
7
CuBr
Cu(OAc)2
CuI/8-HQ
CuI
8
9
10
11
12
none
CuI
LiOt-Bu
LiOt-Bu
LiOt-Bu
LiOt-Bu
LiOt-Bu
0
0
94d
53
22
75
51
41
21
72
ligand-free copper-catalyzed etherification processes are 13
CuI
dioxane
rare. In 2008, a ligand-free Ullman coupling of phenols
with aryl halides using 10 mol% nano-CuO as catalyst,
Cs2CO3 or KOH as base in DMSO at 110 °C was reported
14
CuI
toluene
15
CuI
t-BuOH
a Conversion was measured by HPLC.
b Yield was determined by HPLC using product as standard.
c Toluene was the major product.
SYNLETT 2011, No. 10, pp 1419–1422
Advanced online publication: 26.05.2011
DOI: 10.1055/s-0030-1260761; Art ID: S10110ST
x
x
.x
x
.2
0
1
1
d A complicated mixture was formed.
© Georg Thieme Verlag Stuttgart · New York

1420
J. Huang et al.
LETTER
In the development of a copper-catalyzed etherification (Table 1, entries 7 and 8).14 Solvent screening disclosed
for one of our drug candidates, we found that an external the solvent can be the corresponding coupling alcohol,
ligand was not required when LiOt-Bu was used as base.11 which was pentanol in this case. The reaction in DMF
To examine the generality of the protocol, 4-bromotolu- only gave a moderate yield of the desired ether with for-
ene was selected as the model substrate to synthesize 4- mation of toluene as a major byproduct from reduction of
pentyloxytoluene (Table 1). At the outset of the screening, the substrate together with some polymeric species even
a recently reported CuI catalytic system employing 8- though high conversion was achieved. Although LiOt-Bu
hydroxyquinoline (8-HQ) as ligand and K3PO4 as base un- was used in excess, 4-tert-butyloxytoluene was not detect-
der slightly milder conditions,12 which proceeded in mod- ed, even where tert-butanol was used as solvent (Table 1,
erate yield (Table 1, entry 1), was set as a benchmark. To entry 15) due to its greater acidity and bulkiness. Further-
our surprise, by replacing K3PO4 with LiOt-Bu as base, more, reduction to toluene and hydrolysis to cresol from
the yield was significantly increased (Table 1, entry 9). 4-bromotoluene was minimized in this coupling process
More strikingly, when LiOt-Bu was used as base, the CuI- when LiOt-Bu was the base.
catalyzed coupling reaction worked smoothly to give
With the optimal conditions in hand, we examined the
nearly quantitative yield of the desired product without
couplings of a variety of aryl halides with different alco-
addition of an external ligand (Table 1, entry 5). Examina-
hols (Table 2). The synthesis of aryl ethers by this method
tion of other bases showed either lower conversion
was demonstrated to be quite general for a broad scope of
(Table 1, entries 2, 3, and 6) or significant reduction of 4-
both coupling partners. The reactions of 4-tolyl halides
(X = Cl, OTf, Br, and I) with 1-pentanol indicate tolyl
bromide is as competitive as its iodo counterpart, although
bromotoluene (Table 1, entry 4) resulted.13 Both LiOt-Bu
and a catalytic amount of Cu(I) salt are important for the
successful coupling at a reasonable rate. The absence of
copper-catalyzed ether formation generally favors aryl
either one led to no reaction and only starting material was
iodide as coupling partner.
recovered (Table 1, entries 10 and 11). The reaction is not
very sensitive to the anion of the Cu(I) salt. For example,
CuBr or Cu(OAc) is as competitive as CuI as catalyst
Table 2 Scope of Cu(I)-Catalyzed Etherification
X
O
CuI (10 mol %)
R2
R1
R1
R2 OH
+
base (3.0 equiv)
solvent, 110 °C, 18–28 h
ether
ArX
Entry
ArX
R2OH
Base
Ether
Yield (%)a,b
X = Cl, 12
X = OTf, 27
X = Br, 97
X = I, 94
X
O
n-H11C5
1
n-C5H11OH
LiOt-Bu
Me
Me
Me
Me
Br
O
O
n-H11C5
n-H11C5
2
3
4
5
n-C5H11OH
n-C5H11OH
n-C5H11OH
n-C5H11OH
LiOt-Bu
LiOt-Bu
LiOt-Bu
LiOt-Bu
96
64
98
94
Br
Me
Me
O
Br
n-H11C5
n-H11C5
n-H11C5
t-Bu
MeO
F3C
t-Bu
OMe
CF3
Br
O
O
Br
6
7
n-C5H11OH
n-C5H11OH
LiOt-Bu
LiOt-Bu
58
90
O
Br
n-H11C5
HO
N
N
OH
Synlett 2011, No. 10, 1419–1422 © Thieme Stuttgart · New York

LETTER
Copper-Catalyzed Etherification of Aryl Halides
1421
Table 2 Scope of Cu(I)-Catalyzed Etherification (continued)
X
O
CuI (10 mol %)
R2
R1
R1
R2 OH
+
base (3.0 equiv)
solvent, 110 °C, 18–28 h
ether
ArX
Entry
8
ArX
R2OH
Base
Ether
Yield (%)a,b
Br
O
N
n-C5H11OH
n-H11C5
N
N
LiOt-Bu
92
95
55
HO
N
N
OH
Br
O
MeO
9
LiOt-Bu
LiOt-Bu
OH
MeO
N
O
Br
OH
OH
10
CF3
F3C
Br
O
3
11
LiOt-Bu
EtOt-Bu
MeOLi
EtOLi
85
74
95
93
3
MeO
OMe
Br
Br
Br
EtO
MeO
EtO
12c
13c
14c
EtOH
MeOH
EtOH
N
N
N
Br
O
15
LiOt-Bu
98
OH
N
a Isolated yield.
b Reaction time and temperature are not optimized.
c Reaction run at 80 °C.
However, the corresponding chloride is less reactive and etherification can be efficiently carried out with the same
triflate is less tolerable by this process (Table 2, entry 1). combination of CuI and LiOt-Bu using dioxane as solvent
A variety of aliphatic alcohols including the ones bearing (Scheme 1).
double bond (Table 2, entries 11 and 15) are suitable for
In conclusion, we have developed a mild and efficient
the coupling reaction. Secondary alcohols are less active
copper-catalyzed etherification of aryl halides. This pro-
(Table 2, entry 10) and tertiary alcohols are not effective.
cess has been shown to be general for the synthesis of a
Aryl bromides are generally excellent coupling partners.
wide range of aryl ethers.16 This new protocol should be a
Heterocycles and hydroxyl-bearing heterocycles are toler-
welcomed addition as a straightforward approach to pre-
ated affording high yields of the product (Table 2, entries
paring a variety of aryl alkyl ethers without the need for
7–9, 14, and 15). A particularly noticeable feature for the
added, often costly ligands.
hydroxyl-bearing substrates is that aryl–aryl ether bond
formation is completely suppressed by this process. How-
OH
CuI (10 mol%)
ever, the trifluoromethyl group is less stable to the condi-
tions leading to lower yields (Table 2, entries 6 and 10).15
LiOt-Bu (3.0 equiv)
dioxane, 100 °C
O
Br
Although other lithium alkoxides are equally effective
(Table 2, entries 12–14), in most cases LiOt-Bu is the base
of choice since it can generate a broad range of alkoxides
in situ and does not form the corresponding tert-butyl aryl
ether as byproduct. When most of the couplings were run
at 100–110 °C, lower reaction temperature (80 °C,
Table 2, entries 12–14) was effective. Intramolecular
96%
Scheme 1 Intramolecular CuI-catalyzed etherification
Acknowledgment
We thank Dr. Xiang Wang for his insightful suggestions and discus-
sions during the preparation of this manuscript.
Synlett 2011, No. 10, 1419–1422 © Thieme Stuttgart · New York

1422
J. Huang et al.
LETTER
(9) Chang, J. W. W.; Chee, S.; Mak, S.; Burananprasertsuk, P.;
Chavasiri, W.; Chan, P. W. H. Tetrahedron Lett. 2008, 49,
2018.
(10) A multikilogram process has been successfully carried out
by us based on this protocol.
(11) In our original process for the particular drug candidate, the
very expensive 3,4,7,8-tetramethyl-1,10-phenanathroline
(20 mol%, MW = 236.3. $63.9/g, from Aldrich) was used as
ligand.
(12) For the consideration of less stable substrate, intead of
110 °C as the original literature reported (ref. 6k), 100 °C
was chosen for screening purpose.
References and Notes
(1) (a) Metal-Catalyzed Cross-Coupling Reactions; Dieterich,
F.; Stang, P. J., Eds.; Wiley-VCH: New York, 1998.
(b) Modern Arylation Methods; Ackermann, L., Ed.; Wiley-
VCH: Weinheim, 2009.
(2) Among the 22 small molecules marketed theraputic new
molecular entities (NMEs) in 2009 alone, seven of them
contain either aryl aryl or aryl alkyl ether bonds. For details,
see: Hegde, S.; Schmidt, M. In Annual Reports in Medicinal
Chemistry, Vol. 45; Macor, J. E., Ed.; Academic Press:
London, 2010, 467.
(3) Ullmann, F. Ber. Dtsch. Chem. Ges. 1904, 37, 853.
(4) For excellent reviews regarding copper-mediated couplings,
see: (a) Monnier, F.; Taillefer, M. Angew. Chem. Int. Ed.
2009, 48, 6954. (b) Ley, S. V.; Thomas, A. W. Angew.
Chem. Int. Ed. 2003, 42, 5400. (c) Ma, D.; Cai, Q. Acc.
Chem. Res. 2008, 41, 1450. (d) Lindley, J. Tetrahedron
1984, 40, 1433.
(13) In the case of NaOt-Bu, toluene is detected as the major
product from reduction of 4-bromotoluene. Bacon, R. G.;
Ressison, S. C. J. Chem. Soc. C 1969, 312.
(14) Cu(II) salts were found slightly less effective.
(15) The presence of other functional groups such as ester,
carboxylic acid, nitro, and cyano were not successful under
this protocol.
(5) For examples of palladium-catalyzed C–O bond formation,
see: (a) Mann, G.; Hartwig, J. F. J. Am. Chem. Soc. 1996,
118, 13019. (b) Palucki, M.; Wolfe, J. P.; Buchwald, S. L.
J. Am. Chem. Soc. 1996, 118, 10333. (c) Shelby, Q.;
Kataoka, N.; Mann, G.; Hartwig, J. F. J. Am. Chem. Soc.
2000, 122, 10178. (d) Parrish, C. A.; Buchwald, S. L. J. Org.
Chem. 2001, 66, 2498.
(6) (a) Niu, J.; Zhou, H.; Li, Z.; Xu, J.; Hu, S. J. Org. Chem.
2008, 73, 7814. (b) Wolter, M.; Nordmann, G.; Job, G. E.;
Buchwald, S. L. Org. Lett. 2002, 4, 973. (c) Lipshutz,
B. H.; Unger, J. B.; Tat, B. R. Org. Lett. 2007, 9, 1089.
(d) Shafir, A.; Lichtor, P. A.; Buchwald, S. L. J. Am. Chem.
Soc. 2007, 129, 3490. (e) Cristau, H. J.; Cellier, P. P.;
Hamada, S.; Spindler, J. F.; Tailefer, M. Org. Lett. 2004, 6,
913. (f) Liu, Y.-H.; Li, G.; Yang, L.-M. Tetrahedron Lett.
2009, 50, 343. (g) Buck, E.; Song, Z. J.; Tschaen, D.;
Dormer, P. G.; Volante, R. P.; Reider, P. J. Org. Lett. 2002,
4, 1623. (h) Lv, X.; Bao, W. J. Org. Chem. 2007, 72, 3863.
(i) Naidu, A. B.; Sekar, G. Tetrahedron Lett. 2008, 49,
3147. (j) Cai, Q.; Zou, B.; Ma, D. Angew. Chem. Int. Ed.
2006, 45, 1276. (k) Niu, J.; Guo, P.; Kang, J.; Li, Z.; Xu, J.;
Hu, S. J. Org. Chem. 2009, 74, 5075. (l) Marcoux, J.-F.;
Doye, S.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119,
10539.
(16) General Procedure for the Etherification of
Arylbromides
To a 10 mL seal tube were charged alcohol (2.0 mL) and
LiOt-Bu (480 mg, 6.0 mmol). The resulting suspension was
stirred at r.t. for 5 min to form a clear solution. Arylbromide
(2.0 mmol) and CuI (38 mg, 0.2 mmol) were added to the
above solution. The mixture was stirred at r.t. for 5 min to
form a nearly clear solution which was sealed and stirred at
80–110 °C for 18–28 h. The reaction was cooled to r.t. and
quenched with AcOH (pH = 7–8) and diluted with CH2Cl2.
The mixture was washed with H2O (2 × 5 mL) and solvent
removed. The crude residue was purified by silica gel
column chromatography to give the desired product. The
identity and purity of the products are confirmed by 1H
NMR, 13C NMR, and HRMS spectroscopic analysis.
5-(Pentyloxy)pyrimidin-2-ol (Table 2, Entry 8)
Off-white solid. 1H NMR (400 MHz, CDCl3): d = 8.04 (s, 2
H), 3.86 (t, J = 8 Hz, 2 H), 1.77 (m, 2 H), 1.40–1.45 (m, 4 H),
0.94 (t, J = 8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
d = 157.9, 144.8, 142.2, 70.5, 28.7, 28.0, 22.4, 14.0 ppm.
HRMS: m/z calcd for C9H14N2O2: 182.1055; found:
182.1053.
3-(2-Methoxyethoxy)pyridine (Table 2, Entry 9)
Colorless oil. 1H NMR (400 MHz, CDCl3): d = 8.35 (s, 1 H),
8.23 (m, 1 H), 7.23 (m, 2 H), 4.17 (t, J = 4 Hz, 2 H), 3.77
(t, J = 4 Hz, 2 H), 3.46 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): d = 155.0, 142.4, 138.0,. 123.8, 121.4, 70.9, 67.7,
59.3 ppm. HRMS: m/z calcd for C8H11NO2: 153.0790;
found: 153.0785.
(7) For recent examples of continuing efforts to search for better
ligands, see: (a) Altman, R. A.; Shafir, A.; Choi, A.; Lichtor,
P. A.; Buchwald, S. L. J. Org. Chem. 2008, 73, 284.
(b) Maiti, D.; Buchwald, S. L. J. Org. Chem. 2010, 75, 1791.
(8) Zhang, J.; Zhang, Z.; Wang, Y.; Zheng, X.; Wang, Z. Eur. J.
Org. Chem. 2008, 5112.
Synlett 2011, No. 10, 1419–1422 © Thieme Stuttgart · New York