J. Am. Chem. Soc. 1997, 119, 3395-3396
3395
Table 1. Synthesis of Aryl Ethers via Pd-Catalyzed and Direct
Nucleophilic Substitution Reactions
Palladium-Catalyzed Intermolecular
Carbon-Oxygen Bond Formation: A New
Synthesis of Aryl Ethers
Michael Palucki, John P. Wolfe, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139
ReceiVed NoVember 20, 1996
Aryl ethers are ubiquitous structural constituents in pharma-
cologically important molecules, and consequently, much
research has been focused on their synthesis.1 Available
methods for the synthesis of aryl ethers via direct nucleophilic
or Cu(I)-catalyzed substitution of an aryl halide with an alcohol
typically require high reaction temperatures and/or a large excess
of the alcohol and are limited in substrate scope.2-4 The need
to employ HMPA, DMSO, or DMF as solvent further dimin-
ishes the applicability of these methods, particularly for large-
scale processes.
Recently we reported the first example of palladium-catalyzed
aromatic carbon-oxygen bond formation; the intramolecular
Pd-catalyzed ipso substitution of an aryl halide with an alcohol
to afford oxygen heterocycles.5,6 This method was used to
synthesize five-, six-, and seven-membered oxygen heterocycles
in moderate to good yields.7 We sought to determine whether
a related catalyst system could be used for the synthesis of aryl
ethers by the intermolecular coupling of alcohols and aryl
bromides (eq 1).8 Herein we report our initial results which
demonstrate the viability of using palladium catalysis for the
intermolecular formation of carbon-oxygen bonds.
a For entries 1-5 and 7-9, reaction conditions: 1.5 mol % Pd2(dba)3,
3.6 mol % Tol-BINAP, 1 equiv of aryl bromide, 1.2 equiv of alcohol,
and 2.0 equiv of NaH. For entry 6: 5 mol % Pd(OAc)2, 6 mol %
Tol-BINAP, 1 equiv of aryl bromide and 2.0 equiv of NaOtBu. b Yields
refer to the average of isolated yields for two runs.
The conditions employed for the intramolecular process (vide
supra) were not immediately applicable to the intermolecular
version. We found, however, that reaction of 2-propanol,
4-bromobenzonitrile, and NaH in the presence of 1.5 mol %
Pd2(dba)3 and 3 mol % (S)-(-)-2,2′-bis(di-p-tolylphosphino)-
1,1′-binaphthyl (Tol-BINAP) at 50 °C afforded 4-isopropoxy-
benzonitrile in 80% isolated yield.9 Although Pd(OAc)2 was
an effective catalyst precursor, use of Pd2(dba)3 afforded superior
ratios of product to reduced side product (benzonitrile) as
determined by GC analyses. Aryl bromides containing electron-
withdrawing substituents (Table 1, entries 1-5) coupled ef-
fectively with a wide variety of alcohols including 2-propanol,
3-pentanol, (1R,2S,5R)-(-)-menthol,10 benzyl alcohol, and
methanol within 24 h using 1.5 mol % Pd2(dba)3 and 3.6 mol
% Tol-BINAP at 70 °C. The Pd-catalyzed coupling of methanol
with 4-bromobenzonitrile is of interest since it has previously
been demonstrated that methanol in combination with catalytic
amounts of Pd(PPh3)4 is effective in reducing aryl halides to
the dehalogenated arene products with concomitant formation
of HCHO.11 Application of this methodology using electron-
rich or -neutral aryl bromides and various alcohols affords the
desired coupling products in good yields only when alkoxides
from tertiary alcohols or cycloalkanols are employed. For
example, reaction of 4-bromo-tert-butylbenzene with 2-propanol
or cyclopentanol afforded predominantly the reduction product
tert-butylbenzene. However, reaction with NaOtBu afforded
(1) For a review of alkenyl and aryl C-O bond-forming reactions, see:
Chiuy, C. K.-F. In ComprehensiVe Organic Functional Group Transforma-
tions; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.; Pergamon
Press: New York, 1995; Vol. 2, Chapter 2.13.
(2) Paradisi, C. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Semmelhack, M. F., Eds.; Pergamon Press: New York, 1991;
Vol. 4, Chapter 2.1 and references therein.
(3) (a) Keegstra, M. A.; Peters, T. H.; Brandsma, L. Tetrahedron 1992,
48, 3633. (b) Yeager, G. W.; Schissel, D. N. Synthesis 1991, 63. (c) Aalten,
H. L.; Van Koten, G.; Grove, D. M.; Kuilman, T.; Piekstra, O. G.; Hulshof,
L. A.; Sheldon, R. A. Tetrahedron 1989, 45, 5565. Pentavalent organobis-
muth reagents have been used in the presence and absence of Cu salts, see:
Barton, D. H. R.; Finet, J.-P.; Khamsi, J.; Pichon, C. Tetrahedron Lett.
1986, 27, 3619.
(4) Electron-deficient transition metal complexes have been used as
activators for the synthesis of aryl ethers: Pearson, A. J.; Gelormini, A.
M. J. Org. Chem. 1994, 59, 4561 and references therein.
(5) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1996,
118, 10333.
(6) After submission of this manuscript, a report from Hartwig describing
related work on palladium-catalyzed formation of tert-butyl ethers appeared.
Mann, G.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 13109.
(7) For examples of nickel-catalyzed synthesis of aryl ethers, see: (a)
Cramer, R.; Coulson, D. R. J. Org. Chem. 1975, 40, 2267. (b) Cristau,
H.-J.; Desmurs, J.-R. Ind. Chem. Libr. 1995, 7, 249.
the aryl ether product in 53% isolated yield (entry 6).12
A
similar reaction of 1-bromonaphthalene with 2-propanol afforded
naphthalene as the major product, while employing cyclohexanol
afforded the aryl ether product in 65% yield (entry 7).
While only preliminary studies of the mechanism of this
process have been carried out, it most likely proceeds via a
(10) Since only one product was detected by GC and TLC analyses,
and the stereochemistry of the carbinol carbon was preserved in the Pd-
catalyzed intramolecular coupling reaction (see ref 5), it is assumed that
the stereochemistry of (1R,2S,5R)-(-)-menthol is preserved during the
course of the reaction.
(11) Zask, A.; Helquist, P. J. Org. Chem. 1978, 43, 1619.
(12) (a) No meta product, as would be expected from benzyne formation,
was observed in this process. (b) Both tert-butylbenzene and 4,4′-di-tert-
butylbiphenyl were side products of the Pd-catalyzed reaction of 4-tert-
butylbromobenzene with NaOtBu. We are uncertain about the mechanism
of formation of tert-butylbenzene in this reaction. (c) In contrast to the
other substrates examined (Table 1), use of tBuOH and NaH in place of
NaOtBu afforded large amounts of arene side products and only traces of
the desired aryl ether product.
(8) It has been reported that treatment of trans-[PdBr(C6H5)(PPh3)2] with
a solution of NaOMe in toluene at 35 °C afforded benzene (80% yield),
HCHO (20% yield), and anisole (trace), see: Yoshida, T.; Okano, T.;
Otsuka, S. J. Chem. Soc., Dalton Trans. 1976, 993.
(9) Either enantiomer of Tol-BINAP can be used as can BINAP.
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