A general copper-catalyzed synthesis of diaryl ethers

Full text of DOI:10.1021/ja971901j

J. Am. Chem. Soc. 1997, 119, 10539-10540
10539
Scheme 1
A General Copper-Catalyzed Synthesis of Diaryl
Ethers
Jean-Franc¸ois Marcoux, Sven Doye, and
Stephen L. Buchwald*
coupling procedures with unactivated aryl bromide substrates
in DMF. To the best of our knowledge, the use of cesium
carbonate for the Ullmann diaryl ether synthesis has never been
reported. These results prompted us to try the reaction in less
polar solvents to avoid the problems associated with the use of
toxic, high-boiling or water-soluble solvents such as DMF and
pyridine. Toluene was found to be the most effective solvent
when a catalytic amount of ethyl acetate (5 mol %) was included
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139
ReceiVed June 10, 1997
Diaryl ethers are useful intermediates in organic synthesis1
and are found in a large number of biologically active
compounds.2 The Ullmann ether synthesis3 has been extensively
used for the formation of diaryl ethers.4,5 However, the harsh
reaction conditions (125-220 °C in neat phenol or solvents such
as pyridine, collidine, or DMF), the usual requirement for
stoichiometric (or greater) quantities of the copper complex,
and the fact that unactivated aryl halides usually react in low
yields have limited the utility of this reaction.4 Recent efforts
to develop procedures which are applicable to more complex
synthetic intermediates have met with only limited success5a,6
or require the use of an activating group.7
We now report a general procedure for the formation of diaryl
ethers from the reaction of aryl bromides and iodides with a
variety of phenols (Scheme 1). The new procedure is character-
ized by the following features: (a) its use of a catalytic amount
of a copper complex (0.25 to 2.5 mol %), (b) its use of cesium
carbonate as a base, which eliminates the need to form the
phenoxide anion prior to the reaction, (c) its ability to employ
a nonpolar solvent (toluene) and lower reaction temperatures
than previous reactions, and (d) its use of a stoichiometric
amount of a carboxylic acid in the reactions of unactivated aryl
halides with less soluble phenols and phenols containing
electron-withdrawing groups.
in the reaction mixture.8,9
A survey of reactions with a number
of other bases (Et3N, DIPEA, DBU, 1,2,2,6,6-pentamethylpi-
peridine, dicyclohexylmethylamine), including other carbonates,
such as K2CO3, Li2CO3, Na2CO3, and BaCO3, confirmed that
cesium carbonate is a key element responsible for the improved
reaction conditions. The choice of the copper catalyst did not
appear to be critical; CuCl, CuBr, CuI, CuBr2, and CuSO4 gave
similar results. The use of (CuOTf)2‚benzene led to slightly
accelerated reaction rates, presumably due to the higher solubil-
ity of (CuOTf)2‚benzene in toluene, compared to other copper
salts, increasing the rate of formation of the reactive copper
catalyst. A slight excess of the phenol was employed (0.4-
1.0 equiv excess) since the use of 1.0 equiv resulted in very
slow conversion as the reaction neared completion.
As shown in Table 1, the procedure employing cesium
carbonate as base is extremely effective in coupling phenols
with both activated and unactivated aryl bromides and iodides.
Consistent with previous studies, aryl iodides react faster than
aryl bromides, and aryl chlorides are unreactive.4,10 The reaction
conditions are compatible with a wide range of functionalized
substrates, including those containing ethers, ketones, carboxylic
acids, esters, dialkylamines, nitriles, nitro groups, and aryl
chlorides, whereas those containing primary and secondary
amides were found to be poor substrates. This method is
particularly suitable for unactivated aryl halides and ortho-
substituted phenols; e.g., coupling of the sterically demanding
2-isopropylphenol with 2-iodo-p-xylene proceeds in high yield
(entry 15). Reactions employing 2,6-dimethylphenol were
inefficient, and reductive homocoupling of the 5-iodo-m-xylene
was the major reaction observed (entry 13). Surprisingly,
p-cresol was less reactive than o-cresol or 3,4-dimethylphenol
(entries 8-10), and the use of phenol or p-chlorophenol
produced only small amounts of the desired ethers (entries 18,-
20). In these cases, we surmised that the lower solubility of
the corresponding cesium phenolate or of the phenoxide-copper
complex may account for the lack of reactivity. To circumvent
this limitation, we investigated the use of different additives
that could help solubilize the key intermediates. We found that
stoichiometric quantities of certain carboxylic acids,11 particu-
larly 1-naphthoic acid, in the presence of molecular sieves12
promoted the reaction of less reactive phenols. The resulting
new procedure allowed for the first time the successful Ullmann
coupling of unactivated aryl halides and less reactive phenols,
During a study directed toward finding new catalytic methods
for the preparation of diaryl ethers, we discovered that cesium
carbonate was particularly effective as a base in Ullmann
(1) Pello´n, R. F.; Carrasco, R.; Milia´n, V.; Rodes, L. Synth. Commun.
1995, 25, 1077 and references cited therein.
(2) (a) Evans, D. A.; DeVries, K. M. In Glycopeptide Antibiotics, Drugs
and the Pharmaceutical Sciences; Nagarajan, R., Ed.; Marcel Decker,
Inc.: New York, 1994; Vol. 63, pp. 63-104. (b) Itokama, H.; Takeya, K.
Heterocycles 1993, 35, 1467. (c) Kase, H.; Masami, K.; Yamada, K. J.
Antibiot. 1987, 40, 450. (d) Sano, S.; Ikai, K.; Kuroda, H.; Nakamura, T.;
Obayashi, A.; Ezure, Y.; Enomoto, H. J. Antibiot. 1986, 39, 1674. (e) Sano,
S.; Ikai, K.; Katayama, K.; Takesako, K.; Nakamura, T.; Obayashi, A.;
Ezure, Y.; Enomoto, H. J. Antibiot. 1986, 39, 1685. (f) Jolad, S. D.;
Hoffmann, J. J.; Torrance, S. J.; Wiedhopf, R. M.; Cole, J. R.; Arora, S.
K.; Bates, R. B.; Gargiulo, R. L.; Kriek, G. R. J. Am. Chem. Soc. 1977, 99,
8040. (g) Itokawa, H.; Takeya, K.; Mihara, K.; Noboru, M.; Hamanaka,
T.; Sonobe, T.; Iitaka, Y. Chem. Pharm. Bull. 1983, 31, 1424. (h) Itokawa,
H.; Takeya, K.; Mori, N.; Hamanaka, T.; Sonobe, T.; Mihara, K. Chem.
Pharm. Bull. 1984, 32, 284. (i) Williams, D. H. Acc. Chem. Res. 1984, 17,
364. (j) Pearson, A. J.; Bignan, G.; Zhang, P.; Chelliah, M. J. Org. Chem.
1996, 61, 3940. (k) Janetka, J. W.; Raman, P.; Satyshur, K.; Flentke, G.
R.; Rich, D. H. J. Am. Chem. Soc. 1997, 119, 441.
(3) Ullmann, F. Chem. Ber. 1904, 37, 853.
(4) General reviews: (a) Moroz, A. A.; Shvartsberg, M. S. Russ. Chem.
ReV. 1974, 43, 679. (b) Lindley, J. Tetrahedron 1984, 40, 1433.
(5) (a) Evans, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1989, 111, 1063.
(b) Boger, D. L.; Yohannes, D. J. Org. Chem. 1990, 55, 6000. (c) Boger,
D. L.; Patane, M. A.; Zhou, J. J. Am. Chem. Soc. 1994, 116, 8544. (d)
Carruthers, W. In ComprehensiVe Organometallic Chemistry; Wilkinson,
G., Ed.; Pergamon Press: New York, 1982; Vol. 7, p 690.
(8) The formation of more soluble copper(I) complexes, resulting from
the formation of an adduct between the added ester and the alkoxide, has
been proposed to be responsible for the rate enhancement. Capdevielle, P.;
Maumy, M. Tetrahedron Lett. 1993, 34, 1007.
(9) Addition of more than 5 mol % of ethyl acetate resulted in lower
conversions.
(10) Weingarten, H. J. Org. Chem. 1964, 29, 977.
(11) 2-Thiophenecarboxylic acid has been reported to enhance the
reductive homocoupling of aryl iodides: Zhang, S.; Zhang, D.; Liebeskind,
L. S. J. Org. Chem. 1997, 62, 2312.
(12) The reaction between 1-naphthoic acid and cesium carbonate leads
to the formation of some water. The addition of 5 Å molecular sieves
increases the rate of the reaction by removing the water thus formed.
(6) (a) Boger, D. L.; Sakya, S. M.; Yohannes, D. J. Org. Chem. 1991,
56, 4204. (b) Boger, D. L.; Yohannes, D. Tetrahedron Lett. 1989, 30, 2053.
(c) Jung, M. E.; Jachiet, D.; Rohloff, J. C. Tetrahedron Lett. 1989, 30,
4211. (d) Nogradi, M.; Vermes, B.; Kajiar-Peredy, M. Tetrahedron Lett.
1987, 28, 2899. (e) Tomita, M.; Fujitami, K.; Aoyagi, Y. Chem. Pharm.
Bull. 1965, 13, 1341.
(7) For selected examples with ortho-activating groups, see: (a) Nicolaou,
K. C.; Boddy, C. N. C.; Natarajan, S.; Yue, T.-Y.; Li, H.; Bra¨se, S.;
Ramanjulu, J. M. J. Am. Chem. Soc. 1997, 119, 3421. (b) Rozanel’skaya,
N. A.; Stepanov, B. I. Zhur. Obshch, Khim. 1961, 31, 758. (c) Reference
1.
S0002-7863(97)01901-X CCC: $14.00 © 1997 American Chemical Society

10540 J. Am. Chem. Soc., Vol. 119, No. 43, 1997
Communications to the Editor
Table 1. Copper(I) Triflate-Catalyzed Formation of Diaryl Ethers
Scheme 2
in Toluene in the Presence of Cesium Carbonateh
suggests that the reaction conditions are sufficiently mild to
prevent the undesired reduction of copper(I) species to copper-
(0).14a,15
It has been proposed that copper-catalyzed nucleophilic
substitution proceeds Via the formation of a complex between
the aryl halide and the copper.4 As previously reported,4,16 we
observed that the rate of the reaction was not greatly influenced
by the presence of electron-donating or electron-withdrawing
groups on the aryl halide or phenol substrates (in the latter case,
this refers to reactions in the presence of 1-naphthoic acid). This
observation, combined with the fact that aryl triflates and
unactivated aryl chlorides failed to react, does not support a
mechanism in which a negative charge develops on the aromatic
ring resulting from the direct attack of the phenolate.4b It has
recently been proposed that the methoxylation of aryl bromides
involves the formation of an active cuprate-like intermediate
of the general structure [(RO)2Cu]-M+.14b We believe that the
nature of the cation plays an important role during the formation
or the solubilization of such an intermediate. Cesium phenox-
ides and carboxylates are relatively soluble in organic solvents.17
Their use could enhance the solubility of the possible key
reaction intermediates 1 and 2 (Scheme 2), as compared to their
potassium and sodium counterparts. Based on a recent report,11
we suggest that in the presence of less nucleophilic phenols,
the cesium naphthoate participates in the formation of the
reactive intermediate 2, thereby increasing its solubility and the
rate of its subsequent reaction.
In summary, we have developed a general procedure for the
copper-catalyzed coupling of a wide range of activated and
unactivated aryl bromides and iodides with phenols, using
cesium carbonate as a base. In addition, the use of 1-naphthoic
acid as an additive for the efficient coupling of less soluble
phenoxides is important in that it extends the generality of the
reaction, rendering it more useful in organic synthesis.
Acknowledgment. J.-F.M. thanks the Natural Sciences and Engi-
neering Research Council (NSERC, Canada) for a postdoctoral fel-
lowship. S.D. thanks the Deutsche Forschungsgemeinschaft (DFG) for
a postdoctoral fellowship. We thank the National Science Foundation,
Eastman Kodak, and Pfizer for financial support. This paper is
dedicated with admiration to Professor Dieter Seebach on the occasion
of his 60th birthday.
a All reactions were conducted in toluene at 110 °C in the presence
of 1.4 or 2.0 equiv of Cs2CO3, 2.5 mol % of (CuOTf)2‚PhH (5 mol %
Cu) and 5 mol % of EtOAc for 12-26 h. b An equimolar amount of
1-naphthoic acid (compared to the cesium carbonate) and 250 mg/mmol
of activated 5 Å molecular sieves were added to the mixture. c 0.25
mol % of (CuOTf)2‚PhH was used. d The partial hydrolysis of the ester
could be avoided by adding 250 mg/mmol of activated 5 Å molecular
sieves to the mixture. e 0.05 mol % of (CuOTf)2‚PhH was used.
f Approximate yield because the product was contaminated with ∼25%
of a byproduct resulting from the reductive homocoupling of the aryl
iodide. g GC yields. h Unless otherwise noted, the yields refer to the
average of at least two isolated yields of >95% purity as determined
Supporting Information Available: Detailed experimental pro-
cedures including analytical and spectroscopic data for all compounds
(9 pages). See any current masthead page for ordering and Internet
access instructions.
1
JA971901J
by GC, H NMR, and/or elemental analysis.
(14) (a) Aalten, H. L.; van Koten, G.; Grove, D. M.; Kuilman, T.;
Piekstra, O. G.; Hulshof, L. A.; Sheldon, R. A. Tetrahedron 1989, 45, 5565.
(b) These authors also suggest that the cuprate-like copper complex M+
[(RO)2Cu]- is in equilibrium with the unreactive dimer [M+[(RO)2Cu]-]2.
The nature of the cation could also have an effect on this equilibrium.
(15) Under the conditions described, no diaryl ethers were observed for
unactivated aryl bromides (entries 2-4, 11, and 18) in the absence of copper
catalyst, whereas 23% and 1% GC yields of the corresponding diaryl ethers
were obtained for entries 1 and 17, respectively.
such as phenol and chlorophenol (entries 18 and 20).13 The
good yield obtained for the coupling of p-cresol and 2-bro-
moanisole (entry 16) is also noteworthy compared with the 44%
reported by Boger for the same product using the more reactive
iodide in the presence of an excess of sodium hydride and of
CuBr (2.0 equiv).6b Furthermore, the fact that the use of a
catalyst level as low as 0.05 to 0.25 mol % of (CuOTf)2‚benzene
resulted in only a slight decrease in yield (entries 1, 3, and 20)
(16) Lituak, V. V.; Shein, S. M. Zh. Org. Khim. 1974, 10, 550; Engl.
Ed. 1974, 2373.
(17) (a) Hennings, D. D.; Imasa, S.; Rawal, V. R. J. Org. Chem. 1997,
62, 2. (b) Kwizinga, W. H.; Kellogg, R. M. J. Chem. Soc., Chem. Commun.
1979, 286. (c) Zaugg, H. E. J. Org. Chem. 1976, 41, 3419.
(13) To the best of our knowledge no general study of the reactions of
unactivated aryl halides has appeared in the literature.