An efficient Ullmann-type C-O bond formation catalyzed by an air-stable copper(I)-bipyridyl complex

Article abstract of DOI:10.1021/jo801002c

(Chemical Equation Presented) An efficient O-arylation of phenols and aliphatic alcohols with aryl halides was developed that uses an air-stable copper(I) complex as the catalyst. This arylation reaction can be performed in good yield in the absence of Cs₂CO₃. A variety of functional groups are compatible with these reaction conditions with low catalyst loading levels.

Full text of DOI:10.1021/jo801002c

moisture sensitivity, costly metal catalysts, and environmental
toxicity. The harsh classical conditions of the Ullmann ether
synthesis also have limitations in its application because of the
high temperatures required, poor substrate scope, and the use
of stoichiometric amounts of copper reagents.4 During the past
few years, some significant modifications have been made for
the Ullmann ether synthesis. It has been observed that certain
additives, such as 8-hydroxyquinoline,5a 1-naphthoic acid,5b
2,2,6,6-tetramethylheptane-3,5-dione,5c amino acids,5d-f Schiff
base,5g PPAMP,5h phosphazene P4-t-Bu base,5i ꢀ-keto ester,5j
tripod,5k and some copper(I) complexes,5l,m can accelerate the
rate of these reactions, and therefore, the reactions can be
performed under milder conditions. In the coupling of aryl
halides and aliphatic alcohols catalyzed by copper systems, both
Buchwald and Ma groups reported that using CuI as copper
source and adding proper ligand could accomplish the
reactions.6a-d Even though most of these systems work reason-
ably well for aryl ether synthesis, the use of moisture-sensitive
Cs2CO3 is crucial to the success of the reaction.5b-i,6a-d Also,
there are few reports that copper-based protocols can be used
for the synthesis of both diaryl ethers and aryl alkyl ethers.
Herein, we report a very active and air-stable copper(I)
complex that can efficiently catalyze the O-arylation of both
phenols and aliphatic alcohols with aryl halides by using
potassium phosphate as base.
An Efficient Ullmann-Type C-O Bond
Formation Catalyzed by an Air-Stable
Copper(I)-Bipyridyl Complex
Jiajia Niu,† Hua Zhou,† Zhigang Li,† Jingwei Xu,*,† and
Shaojing Hu*,‡
Changchun Institute of Applied Chemistry, Chinese Academy
of Sciences, Graduate School of Chinese Academy of
Sciences, Changchun 130022, P. R. China, and Institute for
Diabetes DiscoVery, Branford, Connecticut 06405
jwxu@ciac.jl.cn; shaojing_hu@betapharma.com
ReceiVed June 2, 2008
After carefully examining all of the reported ligands used in
copper-based Ullmann ether synthesis, it appears that the
selection of bidentate nitrogen ligands or triphenylphosphine
may be crucial for the success of this type of reaction. Based
on this assumption, we prepared three types of copper(I)
complexes 1-3.7 Complex 1 has been reported before,5h and 2
is a close analogue of a reported copper complex catalyst.5i
However, 3,8 according to our knowledge, has never been
applied in this type C-O formation before and can be easily
An efficient O-arylation of phenols and aliphatic alcohols
with aryl halides was developed that uses an air-stable
copper(I) complex as the catalyst. This arylation reaction can
be performed in good yield in the absence of Cs2CO3. A
variety of functional groups are compatible with these
reaction conditions with low catalyst loading levels.
(3) For examples of palladium-catalyzed diaryl ethers, see: (a) Aranyos, A.;
Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.; Buchwald, S. L. J. Am.
Chem. Soc. 1999, 121, 4369–4378. (b) Kataoka, N.; Shelby, Q.; Stambuli, J. P.;
Hartwig, J. F. J. Org. Chem. 2002, 67, 5553–5556. For examples of palladium-
catalyzed aryl aliphatic ethers, see: (c) Mann, G.; Hartwig, J. F. J. Am. Chem.
Soc. 1996, 118, 13109–13110. (d) Palucki, M.; Wolfe, J. P.; Buchwald, S. L.
J. Am. Chem. Soc. 1996, 118, 10333–10334.
Aryl ethers are very important structural motifs of numerous
biologically active natural products and important pharmaceuti-
cal compounds and polymers in the material science industries.1,2
The palladium-catalyzed coupling reaction of aryl halides with
phenols or alcohols is one of the two major methods available
for aryl ether synthesis.3 The other one is the copper-mediated
Ullmann ether synthesis. However, palladium-based protocols,
although successful, have some inherent limitations such as
(4) Ullmann, F. Ber. Dtsch. Chem Ges. 1903, 36, 2382–2384.
(5) (a) Fagan, P. J.; Hauptman, E.; Shapiro, R.; Casalnuovo, A. J. Am. Chem.
Soc. 2000, 122, 5043–5051. (b) Marcoux, J.-F.; Doye, S.; Buchwald, S. L. J. Am.
Chem. Soc. 1997, 119, 10539–10540. (c) Buck, E.; Song, Z. J.; Tschaen, D.;
Dormer, P. G.; Volante, R. P.; Reider, P. J. Org. Lett. 2002, 4, 1623–1626. (d)
Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 3799–3802. (e) Cai, Q.; Zou, B.;
Ma, D. Angew. Chem., Int. Ed. 2006, 45, 1276–1279. (f) Cai, Q.; He, G.; Ma,
D. J. Org. Chem. 2006, 71, 5268–5273. (g) Cristau, H. J.; Cellier, P. P.; Hamada,
S.; Spindler, J. F.; Tailefer, M. Org. Lett. 2004, 6, 913–916. (h) Rao, H.; Jin,
Y.; Fu, H.; Jiang, Y.; Zhao, Y. Chem.sEur. J. 2006, 12, 3636–3646. (i) Palomo,
C.; Oiarbide, M.; Lopez, R.; Gomez-Bengoa, E. Chem. Commun. 1998, 2091–
2092. (j) Lv, X.; Bao, W. J. Org. Chem. 2007, 72, 3863–3867. (k) Chen, Y.;
Chen, H. Org. Lett. 2006, 8, 5609–5612. (l) Gujadhur, R.; Venkataraman, D.
Synth. Commun. 2001, 31, 2865–2879. (m) Gujadhur, R. K.; Bates, C. G.;
Venkataraman, D. Org. Lett. 2001, 3, 4315–4317.
(6) (a) Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Org. Lett.
2002, 4, 973–976. (b) Zhang, H.; Ma, D.; Cao, W. Synlett 2007, 243–246. (c)
Altman, R. A.; Shafir, A.; Choi, A.; Lichtor, P. A.; Buchwald, S. L. J. Org.
Chem. 2008, 73, 284–286. (d) Shafir, A.; Lichtor, P. A.; Buchwald, S. L. J. Am.
Chem. Soc. 2007, 129, 3490–3491.
(7) The synthesis details of the three complexes, see the Supporting
Information.
† Changchun Institute of Applied Chemistry.
‡ Institute for Diabetes Discovery.
(1) For reviews, see: (a) Lindley, J. Tetrahedron 1984, 40, 1433–1456. (b)
Sawyer, J. S. Tetrahedron 2000, 56, 5045–5065. (c) Theil, F. Angew. Chem.,
Int. Ed. 1999, 38, 2345–2347. (d) Thomas, A. W.; Ley, S. V. Angew. Chem.,
Int. Ed. 2003, 42, 5400–5449.
(2) For examples of medicinally important diaryl ethers, see: (a) Zenitani,
S.; Tashiro, S.; Shindo, K.; Nagai, K.; Suzuki, K.; Imoto, M. J. Antibiot. 2003,
56, 617–621. (b) Cristau, P.; Vors, J.-P.; Zhu, J. Tetrahedron 2003, 59, 7859–
7870. (c) Evans, D. A.; DeViriesK. M. In Glycopeptide Antibiotics, Drugs and
the Pharmaceutical Sciences; Nagarajan, R., Ed.;Marcel Decker: New York,
1994; pp 63-104. (d) Deshpande, V. E.; Gohkhale, N. J. Tetrahedron Lett. 1992,
33, 4213–4216. (e) Singh, S. B.; Pettit, G. R. J. Org. Chem. 1990, 55, 2797–
2800. (f) Jung, M. E.; Rohloff, J. C. J. Org. Chem. 1985, 50, 4909–4913. For
examples of agriculturally important diaryl ethers, see: (g) Sheldon, R. A.
Chirotechnology; Marcel Dekker: New York, 1998; p 6265.
(8) Lang, H.; Zoufala, P.; Klaib, S.; Villar, A.; Rheinwald, G. J. Organomet.
Chem. 2007, 692, 4168–4176.
7814 J. Org. Chem. 2008, 73, 7814–7817
10.1021/jo801002c CCC: $40.75 2008 American Chemical Society
Published on Web 09/05/2008

TABLE 1. The Coupling Reaction of Unhindered Aryl Iodides
and Aryl Bromides with Phenols Using Catalyst 3a
FIGURE 1. Copper(I) complexes for diaryl ether formation.
FIGURE 2. Comparison in different copper(I) sources. Reaction
conditions: PhBr (1.0 mmol), phenol (1.5 mmol), K3PO4 (2 mmol),
and 5 mol % of copper(I) were added to a screw-capped test tube
followed by the addition of 0.5 mL of anhydrous DMF. The reaction
was stirred at 90 °C under argon. Conversion was measured by GC
using p-methyldiphenyl ether as internal standard.
prepared by the addition of 2,2′-bipyridyl to a solution of
Cu(CH3CN)4BF4 in acetonitrile at room temperature.
The kinetic study was carried out by using four different
copper catalysts for the synthesis of Ullmann diaryl ether,
bromobenzene, and phenol as model substrates, 5 mol % catalyst
loading, potassium phosphate as base, and DMF as solvent
(Figures 1 and 2). According to the kinetic profiles shown in
Figure 2, CuBr proved to be a better catalyst than complex 1 in
the coupling reaction, which suggested that raising the solubility
of the copper salt might not always enhance the Ullmann diaryl
ether synthesis. One monobipyridyl ligand modified complex,
2, proved to be superior to the simple copper salt CuBr and the
copper complex 1. The most effective catalyst in this coupling
reaction was the bis-bipyridyl ligand modified complex 3. While
the coupling did not approach completion with 1 or 2, 95%
conversion of aryl bromide was achieved after 24 h by using 3.
In our control experiments, both K2CO3 and K3PO4 were found
to be effective bases for the diaryl ether formation. Other bases,
including Cs2CO3, Na2CO3, and some organic bases such as
TMG or Et3N, gave much lower yields.9 Furthermore, with
K3PO4 as base, we were able to use a variety of polar aprotic
solvents (e.g., EtCN, n-PrCN, and NMP).
a General reaction conditions: 1.5 mmol of phenol, 1.0 mmol of ArX,
2.0 mmol of K3PO4, 0.5 mL of anhydrous DMF. b 48 h.
products in good to excellent yields. Aryl bromides or aryl
iodides substituted with electron-withdrawing groups, such as
m-nitrile, p-nitro, and p-keto, are particularly good substrates,
which could be coupled with phenol at much lower catalyst
loadings (3, 0.5 mol %) at fairly low temperature (entries 3-6).
We were pleased to note that the coupling of two poor
substrates, 4-iodoanisole and 4-chlorophenol, with complex 3
(entry 2) gave 63% GC yield after 24 h, and a higher yield
(81%) was obtained by prolonging the reaction time to 48 h.
It is known that sterically hindered components are particu-
larly poor substrates for the copper-catalyzed C-O bond
formation.10 With the highly efficient copper catalyst complex
3 in hand, we decided to examine the scope of this coupling
reaction further in the reactions of hindered phenols with
hindered aryl halides (Table 2). The reaction of ortho-substituted
aryl halides was, in some cases, slightly more demanding than
that for ortho-substituted phenols; for example, the coupling of
2-iodotoluene with phenol carried out with 5 mol % of 3 for
48 h gave 70% yield of the desired product, but the coupling
of 2-methyphenol proceeded more readily (entries 10 and 11).
We expanded our investigation to explore the scope of the
complex 3 as a catalyst in the Ullmann diaryl ether synthesis
of meta- and para-substituted aryl halides. As shown in Table
1, 5 mol % of 3 was sufficient to effect the coupling reaction.
Electron-rich, -neutral, and -deficient aryl halides all provided
(10) (a) Altman, R. A.; Buchwald, S. L. Org. Lett. 2007, 9, 643–646. (b)
Mederski, W. W. K. K. R.; Lefort, M.; Germann, M.; Kux, D. Tetrahedron
1999, 55, 12757–12770. (c) Lam, Y. S. P.; Clark, C. G.; Sauber, S.; Adams, J.;
Averill, K. M.; Chan, D. M. T.; Combs, A. Synlett 2000, 674–676.
(9) GC yield of the desired product after 24 h for the reactions using another
base: K2CO3 (74%), Na2CO3 (5%), Cs2CO3 (20%), TMG, and Et3N (no more
than 10%).
J. Org. Chem. Vol. 73, No. 19, 2008 7815

TABLE 2. Coupling Reaction of Hindered Phenol-Aryl Halide
TABLE 3. Coupling Reaction of Aryl Iodides with Aliphatic
Alcohols under Catalysis of 3a
Combinations under Catalysis of 3a
a General reaction conditions: 1.0 mmol of ArX, 1 mL of R2OH, 2.0
mmol of K3PO4 under argon in a sealed test tube. b 48 h. c Reaction
temperature of 80 °C. d Cs2CO3 as base.
a General reaction conditions: 1.5 mmol of phenol, 1.0 mmol of ArX,
2.0 mmol of K3PO4, 0.5 mL of anhydrous DMF.
In conclusion, we have described the use of a new air-stable
copper(I)-bipyridyl catalyst for the O-arylation of phenols and
alcohols, which displays increased reactivity, requires lower
levels of catalyst loading, and does not require the use of more
expensive and moisture-sensitive bases such as Cs2CO3. This
catalytic system is not only capable of coupling hindered
substrate combinations but also tolerates a broad range of a
series of functional groups.
The same trend was also observed in entries 13 and 14. More
sterically hindered phenols such as 2-isopropylphenol and
2-phenylphenol were almost quantitatively coupled with bro-
mobeneze by using this catalytic system (entries 15 and 16).
The synthesis of o,o,o′-trimethyl-substituted diaryl ether rep-
resents a great challenge. Upon loading with 3 mol % of 3, the
coupling of 2,6-dimethylphenol and 2-bromotoluene can be
accomplished in 48 h with 42% yield (entry 17).
Experimental Section
Using the copper complex 3-potassium phosphate-alcohol
procedure, we examined the C-O coupling reaction between
aryl iodides and aliphatic alcohols (Table 3). In a preliminary
survey, a variety of different reaction conditions were examined.
Our standard conditions, 5 mol % complex loading, potassium
phosphate as base, and alcohol as solvent, proved to be the best.
It was found that primary alcohols such as butanol could be
successfully coupled with different aryl iodides in excellent
yield. It was not successful when we tried to couple aryl
bromides and aliphatic alcohols, which may be due to the
intrinsic reactivity differences of aryl halides in Cu-catalyzed
reactions (I > Br . Cl > F).1,11 We were able to exploit this
point to couple iodide selectively rather than bromide with an
-OH group (entry 4). The system was also compatible with
alkenyl alcohol; 85% product was obtained after 24 h with no
coupled side products (entry 5).
General Procedure for the O-Arylation of Phenols under
Catalysis of 3. Compound 3 (0.5-5 mol %), phenol (1.5 mmol),
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 (three cycles). Aryl halide
(if liquid, 1.0 mmol) and dry DMF (0.5 mL) were added by syringe
at room temperature. The reaction mixture was stirred at needed
temperature (90 or 110 °C) for 24 h. The reaction mixture was
allowed to reach room temperature and then diluted with dichlo-
romethane (10 mL). The slurry was filtered, and 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.
(11) For examples of Cu-catalyzed amination reactions, see: (a) Beletskaya,
I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004, 2337–2364. (b) Kunz, K.;
Scholz, U.; Ganzer, D. Synlett 2003, 2428–2439.
7816 J. Org. Chem. Vol. 73, No. 19, 2008

1
General Procedure for the O-Arylation of Aliphatic Alcohols
under Catalysis of 3. Compound 3 (5 mol %), 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 (three cycles). Aryl halide (if liquid, 1.0
mmol) and 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 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.
Diaryl Ether (Table 1, Entry 1). 1H NMR (600 MHz, CDCl3):
δ 7.32-7.35 (m, 4H) 7.10 (t, J ) 7.2 Hz, 2H), 7.01 (dd, J ) 9.0,
1.2 Hz, 4H). 13C NMR (600 MHz, CDCl3): δ 157.2, 129.7, 123.2,
118.9. MS m/z 170 (M+), 141, 77, 65, 51, 39. Anal. Calcd for
C12H10O: C, 84.68; H, 5.92. Found: C, 84.56; H, 5.90.
4-Chloro-4′-methoxydiphenyl Ether (Table 1, Entry 2). H
NMR (600 MHz, CDCl3): δ 7.23-7.25 (m, 2H), 6.95-6.97 (m,
2H), 6.86-6.89 (m, 4H), 3.80 (s, 3H). 13C NMR (600 MHz,
CDCl3): δ 157.2, 156.1, 149.8, 129.5, 127.3, 120.8, 118.7, 114.9,
55.6. MS m/z 236, 234 (M+), 221, 219, 140, 111, 95, 75, 63, 50.
Anal. Calcd for C13H11ClO2: C, 66.53; H, 4.72. Found: C, 66.49;
H, 4.85.
Acknowledgment. We thank the Changchun Institute of
Applied Chemistry Chinese Academy of Sciences for support
of this work. We also thank Wenbin Xie and Baofeng Liu for
their important contributions in the sample analysis of this work.
Supporting Information Available: Crystallographic infor-
mation files. NMR spectra of coupling products. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO801002C
J. Org. Chem. Vol. 73, No. 19, 2008 7817