Palladium-catalyzed formation of aryl tert-butyl ethers from unactivated aryl halides

Full text of DOI:10.1021/jo001426z

2498
J . Org. Chem. 2001, 66, 2498-2500
tolylphosphino)-1,1′-binaphthyl (tol-BINAP) as the ligand,
P a lla d iu m -Ca ta lyzed F or m a tion of Ar yl
provided the product in moderate yield. As anticipated,
it was found that sterically hindered di-tert-butylphos-
phinobiphenyl ligands led to highly active catalysts for
Pd-catalyzed C-O bond formation, as seen for the
preparation of diaryl ethers.9 It is believed that such
bulky ligands facilitate reductive elimination to form the
C-O bond. Recent reports on the Pd-catalyzed synthesis
of aryl tert-butyl ethers have indeed supported this
hypothesis. Work by Hartwig10 and Watanabe11 has
provided several examples of aryl tert-butyl ether forma-
tion in the presence of di-tert-butylphosphinoferrocene
and tri-tert-butylphosphine ligands, respectively. These
phosphine ligands are, however, air sensitive and thus
require special handling techniques. The scope of sub-
strates utilized in this reaction is also still limited.
Although the use of unactivated aryl bromides has been
described, the use of electron-rich aryl bromides, save one
recent example by Hartwig,10b has only been reported in
low yield.11 In addition, few examples describing unac-
tivated aryl chlorides as substrates have been published.
As aryl tert-butyl ethers are precursors to phenols,12 it
was worthwhile to search for a more general and less
sensitive catalyst for their formation. We report herein
the palladium-catalyzed preparation of aryl tert-butyl
ethers in good to excellent yields based on air-stable
dialkylphosphinobiphenyl ligands that allows for the use
of unactivated and even electron-rich aryl bromides or
chlorides as substrates.
ter t-Bu tyl Eth er s fr om Un a ctiva ted Ar yl
Ha lid es
Cynthia A. Parrish and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139
sbuchwal@mit.edu
Received October 2, 2000
Alkyl aryl ethers are key constituents in numerous
natural products and pharmaceuticals and are often
utilized as phenol precursors.1 Methods for their prepara-
tion complementary to the traditional Williamson ether
synthesis include direct nucleophilic substitution2 and the
Cu(I)-catalyzed cross-coupling of alkoxides with aryl
halides.3 However, these methods are limited in that they
typically require activated aryl halides, large excesses of
alkoxides, high reaction temperatures, or undesirable
solvents. Recently, the palladium-catalyzed intra- and
intermolecular cross-coupling reaction of aryl halides
with alcohols has been reported as an alternative method
for the formation of the aryl-oxygen bond.4-6 Although
able to avoid many of the limitations stated above, the
intermolecular reaction has been most successful using
activated aryl halides. There are limited examples that
utilize unactivated aryl halides as substrates. For such
substrates, tertiary alcohols or cycloalkanols have pro-
vided the best results in the cross-coupling reaction.7
Other methods for the synthesis of tertiary alkyl aryl
ethers from aryl halides are currently limited to the
nucleophilic substitution of activated aryl halides,2b,d aryl
Grignard addition to tert-butylperoxybenzoate,8 and the
Cu(I)-catalyzed cross-coupling.3a The Pd-catalyzed C-O
bond-forming reaction represents an attractive alterna-
tive method, especially with application to unactivated
aryl halide substrates.
Our initial studies indicated that the di-tert-butylphos-
phinobiphenyl ligands provided active palladium cata-
lysts that couple aryl halides with sodium tert-butoxide
to form aryl tert-butyl ethers (eq 1). These ligands are
Previously, we reported the first example of a pal-
ladium-catalyzed cross-coupling reaction between a ter-
tiary alcohol and an unactivated aryl bromide.5 The
procedure, based on a catalyst using 2,2′-bis(di-p-
air stable and are either commercially available13 or
readily prepared in a one-pot procedure.14 Experiments
performed in the presence of commercially available
ligand 1 provided moderate to good results in the pal-
ladium-catalyzed aryl tert-butyl ether formation (Table
1, entries 1, 3, and 6). It was found that the use of
Pd2(dba)3 and reaction temperatures of 110 °C gave the
best results with ligand 1. However, for most examples,
excess palladium (g3 mol %), especially when using aryl
chlorides, was required, incomplete conversions were
(1) For example, see: Comprehensive Natural Products Chemistry;
Barton, D., Nakanishi, K., Meth-Cohn, O., Eds.; Elsevier Science:
Oxford, UK, 1999; Vols. 1, 3, 8.
(2) (a) DeVries, V. G.; Moran, D. B.; Allen, G. R.; Riggi, S. J . J . Med.
Chem. 1976, 19, 946. (b) Hamilton, J .; Mahaffy, C. A. L. Synth. React.
Inorg. Met. Org. Chem. 1986, 16, 1363. (c) Pearson, A. J .; Gelormini,
A. M. J . Org. Chem. 1994, 59, 4561. (d) Woiwode, T. F.; Rose, C.;
Wandless, T. J . J . Org. Chem. 1998, 63, 9594, and references therein.
(3) (a) Whitesides, G. M.; Sadowski, J . S.; Lilburn, J . J . Am. Chem.
Soc. 1974, 96, 2829. (b) Lindley, J . Tetrahedron 1984, 40, 1433. (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. (d)
Keegstra, M. A.; Peters, T. H. A.; Brandsma, L. Tetrahedron 1992, 48,
3633. (e) Capdevielle, P.; Maumy, M. Tetrahedron Lett. 1993, 34, 1007.
(4) (a) Palucki, M.; Wolfe, J . P.; Buchwald, S. L. J . Am. Chem. Soc.
1996, 118, 10333. (b) Torraca, K. E.; Kuwabe, S.-I.; Buchwald, S. L. J .
Am. Chem. Soc. 2000, 122, 12907.
(9) Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J . P.; Sadighi, J .
P.; Buchwald, S. L. J . Am. Chem. Soc. 1999, 121, 4369.
(10) (a) Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J . F. J .
Am. Chem. Soc. 1999, 121, 3224. (b) Shelby, Q.; Kataoka, N.; Mann,
G.; Hartwig, J . F. J . Am. Chem. Soc. 2000, 122, 10718.
(11) Watanabe, M.; Nishiyama, M.; Koie, Y. Tetrahedron Lett. 1999,
40, 8837.
(12) Greene, T. W.; Wuts, P. G. M. In Protective Groups in Organic
Synthesis, 2nd ed.; Wiley & Sons: New York, 1991.
(13) 2-Dicyclohexylphosphinobiphenyl, 2-di-tert-butylphosphinobi-
phenyl, and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl
are commercially available from Strem Chemicals, Inc.
(14) Tomori, H.; Fox, J . M.; Buchwald, S. L. J . Org. Chem. 2000,
65, 5334.
(5) Palucki, M.; Wolfe, J . P.; Buchwald, S. L. J . Am. Chem. Soc. 1997,
119, 3395.
(6) (a) Mann, G.; Hartwig, J . F. J . Am. Chem. Soc. 1996, 118, 13109.
(b) Mann, G.; Hartwig, J . F. J . Org. Chem. 1997, 62, 5413.
(7) The use of tertiary alcohols precludes â-H elimination from the
intermediate palladium-alkoxide. For a discussion of this, see ref 5.
(8) Conlon, D. A.; Crivello, J . V.; Lee, J . L.; O’Brien, M. J .
Macromolecules 1989, 22, 509, and references therein.
10.1021/jo001426z CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/10/2001

Notes
J . Org. Chem., Vol. 66, No. 7, 2001 2499
Ta ble 1. P d -Ca ta lyzed F or m a tion of Ar yl ter t-Bu tyl
Difficulty was encountered in attempting to utilize
more hindered aryl halides such as 2-bromo-p-xylene or
2-chloro-p-xylene. Although complete conversion was
observed using 2.5 mol % Pd(OAc)2, product yields were
moderate, and significant formation of diaryl ether was
observed.9 Despite our previous work that indicated the
use of dicyclohexylphosphinobiphenyl ligands would not
be effective in C-O bond-forming reactions,9 such ligands
were tested. In contrast to our earlier findings, the use
of the commercially available and less bulky dicyclohexyl-
phosphine ligand 3 allowed for the conversion of 2-bromo-
p-xylene or 2-chloro-p-xylene to product using 2.5 mol %
palladium (Table 1, entries 11 and 12). Under these
conditions, 2-tert-butoxy-p-xylene was produced in good
yield and, more importantly, with negligible amounts of
diaryl ether formation.
Eth er sa
In conclusion, we describe here a palladium-catalyzed
synthesis of aryl tert-butyl ethers in the presence of
commercially available or readily prepared air-stable
dialkylphosphinobiphenyl ligands. The ether products are
obtained in very good yield from unactivated aryl bro-
mides or chlorides. Furthermore, we have demonstrated
efficient C-O bond formation using an electron-rich aryl
bromide or chloride with catalysts based on these ligands.
This procedure represents the simplest, most general,
and most effective conditions known to date for the Pd-
catalyzed preparation of aryl tert-butyl ethers from a
variety of unactivated aryl bromides or chlorides.
Exp er im en ta l Section
a
Reaction conditions: 1.0 equiv of aryl halide, 1.3 equiv of
NaOt-Bu, catalytic Pd(OAc)2, ligand (1.2:1 L/Pd), toluene (0.5 M
solution), 100 °C, 17-23 h (reaction times have not been mini-
mized). Yields (average of two or more experiments) represent
isolated yields of products estimated to be of >95% purity as
Gen er a l Con sid er a tion s. All reactions were carried out
under an argon atmosphere in oven-dried resealable Schlenk
tubes. Toluene was distilled under nitrogen from molten sodium.
Palladium acetate and tris(dibenzylideneacetone)dipalladium-
(0) were purchased from Strem Chemicals, Inc. Ligands 1-3
were prepared as reported in the literature.14,15 Aryl halides were
purchased from commercial sources and were used as received.
Sodium tert-butoxide was purchased from Sigma-Aldrich; the
bulk of this material was stored under nitrogen in a Vacuum
Atmospheres glovebox. Small (1-2 g) portions were removed
from the glovebox in glass vials and stored in a desiccator for
use up to 1 week. Standard elemental analyses were performed
by Atlantic Microlabs Inc., Norcross, GA. The procedures
described in this section are representative, and thus, yields may
differ from those given in Table 1.
b
indicated by 1H NMR and GC analysis. Pd2(dba)3 was used
instead of Pd(OAc)2; the temperature was increased to 110 °C.c The
yield of one of the experiments was determined by GC against an
d
internal standard. Pd2(dba)3 was used instead of Pd(OAc)2.
observed, and only moderate yields of product were
obtained (for example, entry 6).
Gen er a l Rea ction P r oced u r e. An oven-dried resealable
Schlenk tube was charged with ligand (12 µmol, 1.2 mol %), Pd-
(OAc)2 (2.2 mg, 10 µmol, 1.0 mol %), and sodium tert-butoxide
(125 mg, 1.30 mmol, 1.3 equiv). The flask was evacuated,
backfilled with argon, and sealed with a septum. Toluene (1.00
mL), aryl halide (1.00 mmol, 1 equiv), and additional toluene
(1.00 mL) were added sequentially via syringe. Dodecane (225
µL, 1.00 mmol, 1.00 equiv) was often added as an internal
standard. The septum was replaced with a Teflon screwcap, and
the flask was sealed and placed into a 100 °C oil bath. The
reaction mixture was stirred for 17-23 h. After cooling, the
mixture was diluted with ether (5 mL), filtered through Celite,
rinsed with ether (2 × 5 mL), and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel (2%
EtOAc/hexanes).
1-ter t-Bu toxy-4-ter t-bu tylben zen e (En tr y 2).16 The gen-
eral procedure using 1-bromo-4-tert-butylbenzene (175 µL) and
ligand 2 (3.7 mg) provided 183 mg (89%) of the title compound
as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.26 (d, 2H, J )
8.9 Hz), 6.91 (d, 2H, J ) 8.9 Hz), 1.35 (s, 9H), 1.31 (s, 9H); 13C
NMR (75 MHz, CDCl3) δ 152.9, 145.9, 125.7, 123.6, 78.1, 34.5,
Better results were obtained when the palladium
catalyst was based on ligand 2. Although ligand 2 is not
commercially available, it can easily be prepared in 48%
overall yield in the one-pot sequence.14 Experiments
performed with ligand 2 showed that the use of this
catalyst provided products in higher yields, under milder
conditions, and displayed a more general substrate
tolerance. For example, the conversion of unactivated aryl
bromides to aryl tert-butyl ethers proceeded readily in
the presence of sodium tert-butoxide, ligand 2, and 1.0-
2.5 mol % Pd(OAc)2 at 100 °C in very good yield (Table
1, entries 2, 4, and 7). Under these conditions, the
successful use of unactivated aryl chlorides was also
demonstrated (entries 5 and 8). Furthermore, an electron-
rich aryl bromide or chloride also readily underwent
cross-coupling to afford the aryl tert-butyl ether (entries
9 and 10), representing the first high-yielding example
utilizing an aryl bromide and the first successful example
utilizing the less reactive aryl chloride.
(15) Wolfe, J . P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J . Am.
Chem. Soc. 1999, 121, 9550.
(16) Cai, L.; Mahmoud, H.; Han, Y. Tetrahedron: Asymmetry 1999,
10, 411.

2500 J . Org. Chem., Vol. 66, No. 7, 2001
Notes
31.8, 29.1; IR (neat, cm-1) 2967, 1507, 1364, 1244, 1170, 900.
Anal. Calcd for C14H22O: C, 81.48; H, 10.77. Found: C, 81.26;
H, 10.61.
5-ter t-Bu toxy-m -xylen e (En tr y 4). The general procedure
using 5-bromo-m-xylene (135 µL) and ligand 2 (3.7 mg) afforded
the title compound as a yellow oil (146 mg, 82%): 1H NMR (300
MHz, CDCl3) δ 6.73 (s, 1H), 6.63 (s, 2H), 2.29 (s, 6H), 1.35 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 155.3, 138.3, 125.1, 121.9, 78.1,
29.2, 21.6; IR (neat, cm-1) 2977, 1596, 1473, 1364, 1304, 1181,
1144, 859. Anal. Calcd for C12H18O: C, 80.84; H, 10.20. Found:
C, 80.56; H, 10.03.
mol %), and ligand 2 (9.4 mg, 30 µmol, 3.0 mol %) gave the title
compound as a colorless oil (154 mg, 86%): 1H NMR (300 MHz,
CDCl3) δ 6.93 (d, 2H, J ) 8.9 Hz), 6.80 (d, 2H, J ) 9.0 Hz), 3.79
(s, 3H), 1.32 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 155.8, 148.6,
125.4, 113.8, 78.1, 55.6, 28.9; IR (neat, cm-1) 2976, 1504, 1365,
1227, 1167, 1038, 896, 845. Anal. Calcd for C11H16O2: C, 73.29;
H, 8.96. Found: C, 73.47; H, 8.84.
4-ter t-Bu toxya n isole (En tr y 10). The general procedure
using 4-chloroanisole (120 µL), Pd(OAc)2 (5.6 mg, 25 µmol, 2.5
mol %), and ligand 2 (9.4 mg, 30 µmol, 3.0 mol %) afforded the
title compound as a colorless oil (157 mg, 87%).
1-ter t-Bu toxy-4-n -bu tylben zen e (En tr y 5). The general
procedure using 1-n-butyl-4-chlorobenzene (170 µL), Pd(OAc)2
(5.6 mg, 25 µmol, 2.5 mol %), and ligand 2 (9.4 mg, 30 µmol, 3.0
mol %) gave the title compound as a yellow oil (187 mg, 91%):
1H NMR (300 MHz, CDCl3) δ 7.06 (d, 2H, J ) 8.2 Hz), 6.90 (d,
2H, J ) 8.4 Hz), 2.57 (t, 2H, J ) 7.7 Hz), 1.62-1.54 (m, 2H),
1.40-1.30 (m, 2H), 1.34 (s, 9H), 0.94 (t, 3H, J ) 7.3 Hz); 13C
NMR (75 MHz, CDCl3) δ 153.1, 137.9, 128.7, 124.2, 78.2, 35.2,
34.0, 29.1, 22.7, 14.3; IR (neat, cm-1) 2976, 2930, 1506, 1365,
1236, 1164, 899. Anal. Calcd for C14H22O: C, 81.48; H, 10.77.
Found: C, 81.56; H, 10.65.
3-ter t-Bu toxya n isole (En tr y 7). The general procedure
using 3-bromoanisole (125 µL) and ligand 2 (3.7 mg) provided
the title compound as a colorless oil (155 mg, 86%): 1H NMR
(300 MHz, CDCl3) δ 7.17 (t, 1H, J ) 8.2 Hz), 6.63 (m, 2H), 6.56
(t, 1H, J ) 2.3 Hz), 3.80 (s, 3H), 1.37 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 160.2, 156.6, 129.2, 116.5, 110.2, 108.9, 78.7, 55.4, 29.2;
IR (neat, cm-1) 2977, 1599, 1485, 1366, 1281, 1142, 1044, 964.
Anal. Calcd for C11H16O2: C, 73.29; H, 8.96. Found: C, 73.47;
H, 8.86.
2-ter t-Bu toxy-p-xylen e (En tr y 11). The general procedure
using 2-bromo-p-xylene (140 µL), Pd2(dba)3 (11.4 mg, 12.5 µmol,
1.25 mol %), and ligand 3 (11.8 mg, 30.0 µmol, 3.00 mol %)
provided the title compound as a yellow oil (135 mg, 76%): 1H
NMR (300 MHz, CDCl3) δ 7.04 (d, 1H, J ) 7.5 Hz), 6.84 (s, 1H),
6.78 (d, 1H, J ) 7.6 Hz), 2.30 (s, 3H), 2.20 (s, 3H), 1.39 (s, 9H);
13C NMR (75 MHz, CDCl3) δ 154.2, 135.7, 130.6, 128.9, 123.5,
123.2, 78.9, 29.5, 21.4, 17.1; IR (neat, cm-1) 2978, 2925, 1504,
1365, 1260, 1178, 1122, 998, 806. Anal. Calcd for C12H18O: C,
80.84; H, 10.20. Found: C, 80.99; H, 10.09.
2-ter t-Bu toxy-p-xylen e (En tr y 12). The general procedure
using 2-chloro-p-xylene (135 µL), Pd(OAc)2 (5.6 mg, 25 µmol, 2.5
mol %), and ligand 3 (11.8 mg, 30.0 µmol, 3.00 mol %) afforded
the title compound as a yellow oil (154 mg, 87%).
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (GM58160) for financial support. Ad-
ditional unrestricted funds from Pfizer and Merck are
also greatly appreciated. C.A.P. was a trainee of the
National Cancer Institute (Grant CA09112), to whom
we are indebted. We also thank Dr. J ohn P. Wolfe for
initial experiments on this project.
3-ter t-Bu toxya n isole (En tr y 8). The general procedure
using 3-chloroanisole (120 µL) and ligand 2 (3.7 mg) afforded
the title compound as a colorless oil (152 mg, 85%).
4-ter t-Bu toxya n isole (En tr y 9). The general procedure
using 4-bromoanisole (125 µL), Pd(OAc)2 (5.6 mg, 25 µmol, 2.5
J O001426Z