Novel electron-rich bulky phosphine ligands facilitate the palladium-catalyzed preparation of diaryl ethers

Article abstract of DOI:10.1021/ja990324r

A general method for the palladium-catalyzed formation of diaryl ethers is described. Electron-rich, bulky aryldialkylphosphine ligands, in which the two alkyl groups are either tert-butyl or 1-adamantyl, are the key to the success of the transformation. A wide range of electron-deficient, electronically neutral and electron-rich aryl bromides, chlorides, and triflates can be combined with a variety of phenols with the use of sodium hydride or potassium phosphate as base in toluene at 100 °C. The bulky yet basic nature of the phosphine ligand is thought to be responsible for increasing the rate of reductive elimination of the diaryl ether from palladium.

Full text of DOI:10.1021/ja990324r

J. Am. Chem. Soc. 1999, 121, 4369-4378
4369
Novel Electron-Rich Bulky Phosphine Ligands Facilitate the
Palladium-Catalyzed Preparation of Diaryl Ethers
Attila Aranyos, David W. Old, Ayumu Kiyomori, John P. Wolfe, Joseph P. Sadighi, and
Stephen L. Buchwald*
Contribution from the Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
ReceiVed February 1, 1999
Abstract: A general method for the palladium-catalyzed formation of diaryl ethers is described. Electron-
rich, bulky aryldialkylphosphine ligands, in which the two alkyl groups are either tert-butyl or 1-adamantyl,
are the key to the success of the transformation. A wide range of electron-deficient, electronically neutral and
electron-rich aryl bromides, chlorides, and triflates can be combined with a variety of phenols with the use of
sodium hydride or potassium phosphate as base in toluene at 100 °C. The bulky yet basic nature of the phosphine
ligand is thought to be responsible for increasing the rate of reductive elimination of the diaryl ether from
palladium.
Introduction
procedure has been demonstrated,7 but the scope of the reported
process was limited to the reaction of electron-deficient aryl
bromides. Moreover, the procedures usually required the use
of the sodium salt of the phenol and in most cases the yields
were only moderate.
Herein we report that a wide range of electron-deficient,
electronically neutral and electron-rich aryl halides and sul-
fonates can be combined with a variety of phenols by using
palladium catalysis, representing a substantial improvement in
generality and utility of these couplings (eq 1). Critical to the
A variety of naturally occurring and medicinally important
compounds contain a diaryl ether moiety.1 Of the methods used
for the preparation of diaryl ethers, the classic Ullmann ether
synthesis is the most important, but it is often limited by the
need to employ harsh reaction conditions and stoichiometric
amounts of copper.2 While a number of interesting and useful
techniques for diaryl ether formation have been reported in
recent years,3 a need for general methods for their preparation
remains. Recently, we reported a general copper-catalyzed
preparation of diaryl ethers which constitutes a significant
improvement to the Ullmann ether synthesis.4 The use of
palladium catalysis for the combination of phenols and aryl
halides or sulfonates is a desirable extension of other recently
reported carbon-heteroatom bond-forming techniques.5,6 This
success of the method is the use of electron-rich, sterically bulky
aryldialkylphosphines as ligands.8 Specifically, only the use of
catalyst systems with ligands containing a phosphorus center
substituted with two tert-butyl or 1-adamantyl groups effects
efficiently the desired transformation.
(1) For examples of medicinally important diaryl ethers, see: (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) Deshpande, V. E.; Gohkhale, N. J.
Tetrahedron Lett. 1992, 33, 4213-4216. (c) Singh, S. B.; Pettit, G. R. J.
Org. Chem. 1990, 55, 2797-2800. (d) Pettit, G. R.; Singh, S. B.; Niven,
M. L. J. Am. Chem. Soc. 1988, 110, 8539-8540. (e) Jung, M. E.; Rohloff,
J. C. J. Org. Chem. 1985, 50, 4909-4913. (f) Atkinson, D. C.; Godfrey,
K. E.; Myers, P. L.; Philips, N. C.; Stillings, M. R.; Welbourn, A. P. J.
Med. Chem. 1983, 26, 1361-1364; For examples of agriculturally important
diaryl ethers, see: (g) Seldon, R. A. Chirotechnology; Marcel Dekker Inc.:
New York, 1998; pp 62-65.
Results and Discussion
We recently reported that 2-dicyclohexylphosphino-2′-dimeth-
ylaminobiphenyl (1) (Figure 1) serves as an excellent ligand
for the palladium-catalyzed amination of aryl halides and for
room-temperature Suzuki coupling reactions of aryl chlorides
and bromides.8e Our results demonstrated that room-temperature
(2) (a) Ullmann, F. Chem. Ber. 1904, 37, 853-854. (b) Lindley, J.
Tetrahedron 1984, 40, 1433-1456. (c) Moroz, A. A.; Shvartsberg, M. S.
Russ. Chem. ReV. 1974, 43, 679-689.
(3) For examples of recent work in diaryl ether formation, see: (a) Evans,
D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 2937-2940. (b)
Sawyer, J. S.; Schmittling, E. A.; Palkowitz, J. A.; Smith, W. J. J. Org.
Chem. 1998, 63, 6338-6343. (c) Janetka, J. W.; Rich, D. H. J. Am. Chem.
Soc. 1997, 119, 6488-6495. (d) Palomo, C.; Oairbide, M.; Lo´pez, R.;
Go´mez-Bengoa, E. Chem. Commun. 1998, 19, 2091-2092. (e) Beugelmans,
R.; Zhu, J.; Husson, N.; Bois-Choussy, M.; Singh, G. P. Chem. Commun.
1994, 439-440.
(6) (a) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc.
1996, 118, 10333-10334. (b) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J.
Am. Chem. Soc. 1997, 119, 3395-3396. (c) Mann, G.; Hartwig, J. F. J.
Org. Chem. 1997, 67, 5413-5418. (d) Mann, G.; Hartwig, J. F. J. Am.
Chem. Soc. 1996, 118, 13109-13110.
(7) (a) Mann, G.; Hartwig, J. F. Tetrahedron Lett. 1997, 38, 8005-8008.
(b) Doye, S.; Buchwald, S. L., unpublished Results.
(8) For other examples of bulky, electron-rich ligands for Pd-catalyzed
carbon-heteroatom bond forming reactions, see: (a) Nishiyama, M.;
Yamamoto, T.; Koie, Y. Tetrahedron Lett. 1998, 39, 617-620. (b)
Yamamoto, M.; Nishiyama, M.; Koie, Y. Tetrahedron Lett. 1998, 39, 2367-
2370. (c) Reddy, N. P.; Tanaka, M. Tetrahedron Lett. 1998, 39, 617-620.
(d) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 7369-
7370. (e) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc.
1998, 120, 9722-9723.
(4) Marcoux, J.-F.; Doye, S.; Buchwald, S. L. J. Am. Chem. Soc. 1997,
119, 10539-10540.
(5) For reviews, see: (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.;
Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805-818. (b) Hartwig, J. F.
Angew. Chem., Int. Ed. 1998, 37, 2046-2067. (c) Hartwig, J. F. Synlett
1997, 329-340. (d) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852-860.
(e) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem., in press.
10.1021/ja990324r CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/27/1999

4370 J. Am. Chem. Soc., Vol. 121, No. 18, 1999
Aranyos et al.
Figure 3.
Figure 1.
in moderate yield. The reaction of the in situ generated
aryllithium reagent with di-tert-butylchlorophosphine is quite
slow, and we believe that the stability of the aryllithium reagent
in ether relative to THF15 is the key to the success of the
increased yield of 2.
We initially examined the use of 2 in the reaction of 2-chloro-
p-xylene and sodium t-butoxide (eq 2). We were surprised to
Figure 2.
oxidative addition of aryl chlorides to palladium centers can be
achieved by using simple electron-rich phosphines.9,10 Our
findings suggested that when this new ligand was used, the rate-
limiting step in the catalytic cycle of a cross-coupling process
may be shifted from oxidative addition of the aryl halide to a
Pd(0) complex to either Pd-N bond formation or the reductive
elimination leading to the C-N bond formation.
find in addition to the expected product A, that 19% (uncorrected
GC yield) of diaryl ether B was formed. This result encouraged
us to explore the use of 2 in coupling reactions to form diaryl
ethers. In fact, we found that a smooth reaction of 2-chloro-p-
xylene and 3,4-dimethylphenol using 1.5 mol % Pd(0) and 2.25
mol % 2 occurred in the presence of sodium hydride in toluene
at 100 °C to give the desired diaryl ether in 78% isolated yield
(eq 3).
In our initial studies to extend these results to find improved
catalysts for carbon-oxygen bond formation, we sought to
utilize 1 for the combination of NaOt-Bu and 2-chloro-p-xylene
to afford the corresponding tert-butyl ether. Unfortunately, our
efforts were met with little success. We reasoned that the
problem was due to the recalcitrant nature of the C-O bond
reductive elimination from the Pd center.6d,11 This was predi-
cated on previous studies which suggested that in Pd-catalyzed
carbon-oxygen bond-forming reactions, the rate-limiting step
most likely involves the formation of the carbon-oxygen bond
via reductive elimination.6c-d,7a,11 It is known that increasing
the steric bulk of ligands can facilitate reductive elimination
processes.12 We felt that by increasing the size of the dialkyl-
phosphino group, the desired transformation might be induced
to occur.13 With this in mind, we prepared 2 (Figure 2) from
2-bromo-2′-dimethylaminobiphenyl8e and commercially avail-
able di-tert-butylchlorophosphine.14 Attempts to prepare 2 using
the same conditions developed for the synthesis of 1 (1.1 equiv
n-BuLi, THF, -78 °C f rt) were unsuccessful. We found,
however, that switching to diethyl ether as the solvent gave 2
This result led us to undertake a survey of reaction variables
to ascertain the optimum conditions for the transformation. We
found that Pd(OAc)2 and Pd2(dba)3 catalyzed these reactions
with comparable efficiency. While in many instances sodium
hydride proved to be a suitable base, its use required preheating
it with the phenol prior to the addition of the other reaction
components.16 This somewhat tedious protocol led us to examine
alternative bases for the coupling reaction. Screening a variety
of bases, we found that CsF and K3PO4 were both effective for
diaryl ether formation. With respect to the reaction rate, yield,
and cost, K3PO4 is clearly superior to CsF. Other bases,
including Cs2CO3, K2CO3, KF, and n-BuLi were much less
efficient for the process. Comparing K3PO4 and sodium hydride
revealed that reactions with K3PO4 are significantly slower but
often more efficient than those which use sodium hydride in
terms of both the product distribution and the yield. We found
that toluene was the only solvent in which the reaction was
efficient; THF, DME, dioxane, and NMP provided the product
in less than 5% yield.
(9) Typically, oxidative addition of aryl chlorides to Pd(0) requires
temperatures of 60-140 °C. (a) Grushin, V. V.; Alper, H. Chem. ReV. 1994,
94, 1047-1062. (b) Herrmann, W. A.; Brossmer, C.; Priermeier, T.; O¨ fele,
K. J. Organomet. Chem. 1994, 481, 97-108. (c) Parshall, G. W. J. Am.
Chem. Soc. 1974, 96, 2360-2366. (d) Huser, M.; Youinou, M.-T.; Osborn,
J. A. Angew. Chem., Int. Ed. 1989, 28, 1386-1388.
(10) (a) It is well-known that the use of electron-rich phosphine ligands
accelerates the rate of oxidative addition of aryl halides to Pd(0). See:
Spessard, G. O.; Meissler, G. L. Organometallic Chemistry; Prentice Hall:
Upper Saddle River, New Jersey, 1996; pp 171-175. (b) In his pioneering
studies, Milstein demonstrated oxidative addition of aryl chlorides to Pd-
(dippp)2 (dippp ) 1,3-bis(diisopropylphosphino)propane) at 38 °C. Portnoy,
M.; Milstein, D. Organometallics 1993, 12, 1665-1673.
(11) (a) Bryndza, H. E.; Tam, W. Chem. ReV. 1988, 88, 1163-1188.
(b) Widenhoefer, R. A.; Zhong, H. A.; Buchwald, S. L. J. Am. Chem. Soc.
1997, 119, 6787-6795. (c) Widenhoefer, R. A.; Buchwald, S. L. J. Am.
Chem. Soc. 1998, 120, 6504-6511. (d) Hillhouse has reported C-O bond
forming reductive elimination from nickel complexes. Han, R.; Hillhouse,
G. L. J. Am. Chem. Soc. 1997, 119, 8135-8136.
As a control experiment we prepared 2-(di-tert-butylphos-
phino)biphenyl (3) (Figure 3) and were surprised and pleased
to find that it is equally efficient in the transformation shown
in eq 3, providing the desired diaryl ether product in 77%
(12) (a) Jones, W. D.; Kuykendall, V. L. Inorg. Chem. 1991, 30, 2615-
2622. (b) Hartwig, J. F.; Richards, S.; Baranano, D.; Paul, F. J. Am. Chem.
Soc. 1996, 118, 3626-3633.
(13) We have previously speculated that improved results in Pd-catalyzed
aryl C-O bond forming reactions might be obtained with the use of bulky,
electron-deficient, chelating phosphine ligands; see ref 6b.
(15) Schlosser, M. in Organometallics in Synthesis; Schlosser, M., Ed.;
John Wiley and Sons: Chichester, 1994; pp 129-133.
(16) Premixing of sodium hydride and the phenol is required to avoid
palladium-catalyzed hyride reduction of the aryl halide; Pd-catalyzed
reduction of vinyl triflates by LiH and KH has been previously observed:
Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033-3040.
(14) Di-tert-butylchlorophosphine is the bulkiest dialkylchlorophosphine
which is commercially available.

Pd-Catalyzed Preparation of Diaryl Ethers
J. Am. Chem. Soc., Vol. 121, No. 18, 1999 4371
Table 1. Diaryl Ether Formation from Electron-Deficient Aryl
the corresponding diaryl ether in 88% yield; the product results
from chemoselective substitution of the bromide substituent
(Table 1, entry 7).
Halides Using 3/Pda
In terms of the phenol component of the reaction, the use of
substrates bearing an ortho alkyl substituent (e.g., o-cresol and
2-isopropylphenol) were found to give the highest yields. In
the reactions of aryl halides which contain a more weakly
electron-withdrawing group on the aromatic ring, only reactions
with ortho-substituted phenols are high yielding. The coupling
of N,N-diethyl 4-bromobenzamide with o-cresol is one such case
(Table 1, entry 5). This example is particularly significant
because copper-mediated procedures with N,N-diethyl 4-bro-
mobenzamide fail to yield the desired coupling product.4
The reactions of aryl halides having an electron-withdrawing
group in the ortho position (e.g., 2-bromoacetophenone and
2-bromobenzonitrile) gave low yields of the desired product with
the present catalyst system.19 At present we have no explanation
for these results. The search for a catalyst which will effect
these transformations is currently underway in our laboratories.
Synthesis of Diaryl Ethers from Phenols and Electroni-
cally Neutral or Electron-Rich Aryl Halides and Triflates.
We have also examined the reactions of electronically neutral
and electron-rich aryl halides and sulfonates in the palladium-
catalyzed diaryl ether-forming reaction using 3 and related (vide
infra) ligands. These classes of aryl halides were poor, or in a
few cases moderately good substrates in previously reported
palladium-catalyzed C-O bond-forming processes.6,7a A variety
of aryl halides which are unsubstituted at the ortho position are
efficiently coupled with a diverse set of phenols using the simple
monodentate ligand 3 (Table 2, entries 3-6, 14). Consistent
with our results with activated halides, reactions of ortho-
substituted phenols with unactivated halides give the highest
yields (e.g., Table 2, entries 5-6, 13-14). There are, however,
several cases in which ligand 3 is ineffective or affords the
desired product in reduced yields. Continuing our search for
improved ligands for the synthesis of diaryl ethers, we prepared
and evaluated the use of ligands 4-6 in cases for which the
use of 3 was unsatisfactory (Scheme 1).
a Reaction conditions: 1.0 equiv aryl halide, 1.2 equiv phenol, 1.4
equiv NaH or 2.0 equiv K3PO4, 2.0 mol % Pd(OAc)2, 3.0 mol % 3,
toluene (3 mL), 100 °C, 14-24 h; reaction times were not optimized.
b Reaction run with 0.1 mol % Pd(OAc)2, 0.15 mol % 3. c Reaction
run with 5.0 mol % Pd(OAc)2, 7.5 mol % 3. d Reaction run with 1.95
equiv 2-isopropylphenol.
isolated yield.17 While preparation of 2 requires a multistep
sequence, 3 can be obtained in one step from commercially
available 2-bromobiphenyl and di-tert-butylchlorophosphine.
Further study showed that this ligand is quite effective in a wide
range of palladium-catalyzed diaryl ether-forming reactions.
Synthesis of Diaryl Ethers from Phenols and Electron-
Poor Aryl Halides and Triflates. In our examination of the
use of 3 for the combination of electron-poor aryl halides with
a variety of phenols, we found that aryl halides or triflates
substituted in the para position with electron-withdrawing groups
can be coupled with a wide variety of phenols to give the desired
product in good to excellent yields (see Table 1). The fact that
these activated aryl halides are particularly good substrates is
consistent with the results of our previous mechanistic study in
which we showed that the presence of para electron-withdrawing
groups allow the delocalization of the negative charge which
may build up in the transition state of the reductive elimination
of the diaryl ether from an intermediate L2Pd(OAr)Ar′ [L2 )
chelating phosphine] complex.11c The results are also in line
with Hartwig’s previous findings in the palladium-catalyzed
formation of diaryl ethers7a and other carbon-heteroatom bond-
forming processes.5d,25 With 4-bromoacetophenone, use of as
little as 0.1 mol % Pd was effective; the diaryl ether product
was obtained in 95% yield (Table 1, entry 2).18 Electron-
deficient aryl chlorides are also good substrates; the combination
of 4-chlorobenzonitrile with 3-isopropylphenol afforded a 91%
yield of the desired product (Table 1, entry 6). Most impressive
is that 4-chlorobromobenzene, while only slightly electron-
deficient, could be combined with 2-isopropylphenol to give
We were pleased to find that binaphthyl ligand 4 was quite
effective for the processing of electronically neutral ortho-
substituted aryl halides with phenols of several different
substitution patterns (Table 2, entries 1, 8-10). In reactions
involving these ortho-substituted aryl halides, 4 is generally
more efficient than 3.20
There are several other difficult cases in which procedures
employing 3 and 4 are not satisfactory. For instance, the
coupling of an aryl halide lacking an ortho substituent with
phenol does not proceed to completion using ligands 3 or 4.
However, using terphenyl ligand 5, combining 5-bromo-m-
xylene and phenol afforded the corresponding diaryl ether in
83% yield (Table 2, entry 2). This ligand was also quite effective
in a number of other cases (Table 2, entries 12, 15-16). Ligands
3, 4, and 5, unfortunately, are not effective in the reactions of
highly electron-rich aryl chlorides (e.g., 4-chloroanisole). For
these transformations, only ligand 6 has been shown to give
synthetically useful yields. The 1-adamantyl group was chosen
since it occupies a greater volume of space and hence is bulkier
than a tert-butyl group. We believe that this is the key to the
success of 6 in these reactions; 4-chloroanisole and o-cresol
(17) Previously8e we employed dicylclohexylphenylphosphine in a control
reaction due the commercial availability of this compound.
(18) Control experiments were carried out in the absence of a palladium
salt. For the reaction of 4-bromoacetophenone and phenol with potassium
phosphate in toluene at 100 °C, none of the desired product was detected;
in DMF at 100 °C, 32% (GC, corrected) of the starting halide was consumed,
and a 5% GC yield of the desired product was observed.
(19) An exception is the reaction of 2-bromobenzotrifluoride and o-cresol
to provide the corresponding diaryl ether in 75% isolated yield; the reaction
of 2-bromoacetophenone and o-cresol proceeded to 25% conversion (GC)
with ligand 4, affording <20% of the desired product.
(20) Yields are typically 15-20% higher, and improved product/arene
ratio is observed.

4372 J. Am. Chem. Soc., Vol. 121, No. 18, 1999
Aranyos et al.
Table 2. Palladium-Catalyzed Diaryl Ether Formation from
Scheme 2. Proposed Catalytic Cycle
Electronically Neutral and Electron-Rich Aryl Halidesa
the diaryl ether product with concomitant regeneration of the
active LnPd(0) species. While the oxidative addition and
transmetalation may be expected to be relatively facile,21 the
reductive elimination to form the C-O bond is disfavored due
to the Pd-C (LUMO) and Pd-O (HOMO) energy gap22
(Scheme 2).
The palladium-catalyzed diaryl ether-forming reactions re-
quire only a slight excess of ligand to palladium, and reactions
in which the ratio of L/Pd was varied from 1/1 to 1.5/1 to 2/1
gave similar results. This provides circumstantial evidence that
the key intermediates in the catalytic cycle are monophosphine
palladium complexes.23 Mechanistic studies by Hartwig of
carbon-nitrogen bond-forming reactions catalyzed by palladium
complexes with bulky triarylphosphine ligands demonstrated
that the key intermediates in the catalytic cycle were mono-
phosphine palladium complexes.5b-c,24
While the exact mechanism(s) for the key reductive elimina-
tion step remains unknown, we have previously developed
several mechanistic hypotheses for related processes which can
be used to account for the observed results. For electron-deficient
aryl halides, we still favor a mechanism involving transfer of
the phenolate from palladium to the ipso carbon of the aryl
halide to form a zwitterionic intermediate which converts to
the diaryl ether and a palladium(0) complex.7a,11c,25 For elec-
tronically neutral and electron-rich aryl halides, however, we
suggest that a different mechanism for reductive elimination to
form the carbon-oxygen bond most likely involves a three-
centered transition state.11c In these cases, the bulkier ligands
are necessary to destabilize the ground state of the LnPd(OAr)-
a Reaction conditions: 1.0 equiv aryl halide, 1.2 equiv phenol, 1.4
equiv NaH or 2.0 equiv K3PO4, 2.0 mol % Pd(OAc)2, 3.0 mol % ligand,
toluene (3 mL), 100 °C, 14-26 h; reaction times were not optimized.
b 1.2 equiv of the phenolate salt was used, 110 °C. c 1.2 equiv of the
phenolate salt was used, 1.25 mol % Pd2(dba)3, 3.75 mol % 4, toluene
(2 mL), 115 °C. d 4.0 mol % Pd(OAc)2, 6.0 mol % 5, 2.0 equiv phenol,
2.2 equiv NaH, 115 °C.
Scheme 1. New Ligands for Diaryl Ether Formation
(21) (a) Oxidative addition is presumed to be facile based on the utility
of 1 in Suzuki couplings at room-temperature; see ref 8e; (b) transmetalation
of alkali metal alkoxides to LnPd(Ar)X complexes has been shown to occur
at room temperature when L ) BINAP or DPPF.; see ref 6d, 11b-c.
(22) Ba¨ckvall, J. E.; Bjo¨rkman, E. E.; Petterson, L.; Siegbahn, P. J. Am.
Chem. Soc. 1984, 106, 4369-4373.
(23) We cannot rule out a situation where not all of the palladium is
ligated in the reaction mixture and the reactions are proceeding through
bis(phosphine) intermediates.
are converted to the desired product in 73% yield using 6 (Table
2, entry 11), a significantly higher yield than when 3, 4, or 5
were employed.
(24) (a) Hartwig, J. F.; Paul, F. J. Am. Chem. Soc. 1995, 117, 5373-
5374. (b) Paul, F.; Patt, J.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116,
5969-5970. (c) Louie, J.; Hartwig, J. F. J. Am. Chem. Soc. 1995, 117,
11598-11599. (d) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1995,
117, 4708-4709. (e) Louie, J.; Paul, F.; Hartwig, J. F. Organometallics
1996, 15, 2794-2805.
(25) Hartwig has proposed a similar mechanism to account for electronic
effects in C-S and C-N bond forming reductive elimination reactions.
(a) Baranano, D.; Hartwig, J. F. J. Am. Chem. Soc. 1995, 117, 2937-2938.
(b) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 8232-
8245.
Discussion
Our proposed catalytic cycle for diaryl ether formation is
similar to that proposed for other palladium-catalyzed carbon-
carbon and carbon-heteroatom bond-forming processes.5,6,7a
The catalytic cycle consists of three distinct stages: (1) oxidative
addition of the aryl halide to LnPd(0), (2) formation of the Pd-
aryloxide complex from the Pd-halide adduct via transmeta-
lation of a metal phenolate, and (3) reductive elimination of

Pd-Catalyzed Preparation of Diaryl Ethers
J. Am. Chem. Soc., Vol. 121, No. 18, 1999 4373
Experimental Section
Ar′ complex, forcing the palladium-bound aryl and aryloxy
groups closer together. In this way, the complex is distorted
toward the three-centered transition state.26
General. All reactions were performed under argon in oven- or
flame-dried glassware. Toluene was distilled under nitrogen from molten
sodium. Ethyl ether and THF were distilled under argon from sodium
benzophenone ketyl. Reagents were purchased from commercial sources
and were used without further purification, unless otherwise noted.
Tribasic potassium phosphate was purchased from Fluka Chemical
Company. Tetrakis(triphenylphosphine)palladium, palladium acetate,
tris(dibenzylideneacetone)dipalladium(0), and 2,2′-dibromo-1,1′-bi-
naphthyl were purchased from Strem Chemicals, Inc. 2-Bromobiphenyl
was purchased from Lancaster Synthesis Inc. Di-tert-butylchlorophos-
phine was purchased from either Aldrich Chemical Co. or Strem
Chemicals, Inc. Solutions of tert-butyllithium were purchased from
Aldrich Chemical Co. Sodium salts of phenols were prepared using a
slight excess of sodium metal in refluxing THF.29 Elemental analyses
were performed by E & R Microanalytical Laboratory Inc., Parsippany,
NJ. IR spectra were obtained by placing neat samples directly on the
DiComp probe of an ASI REACTIR in situ IR instrument. Yields in
the tables refer to isolated yields (average of at least two runs) of
compounds which are g95% pure as determined by 1H NMR and GC
analysis, or combustion analysis. The products of entries 1,30,31 3,30
and 432 from Table 1, and entries 1,4 4,4 and 164 from Table 2 have
been described in the literature and were characterized by comparison
It is informative to compare the results reported here with
the reaction of the approximately isosteric primary aniline with
the same substrates. The latter processes (using appropriate
ligands) are substantially more general and appear to be
essentially insensitive to the size or the electronic nature of the
substituents on either substrate.5,27 The rate of reductive
elimination to form C-O bonds is significantly slower than the
corresponding rate to form C-N bonds.6d,7a We speculate that
the relatively sluggish rate of this process in the C-O bond-
forming reactions, even with ligands (e.g., 3-6) which give
improved results, is the reason for the discrepancy between the
efficiencies of the diaryl ether- and diarylamine-forming
processes.
What is more complicated is the unraveling of the various
factors which contribute to make some of these reactions so
facile, while others are inefficient or give none of the desired
product. It is clear that ortho substitution in either the phenol
or the aryl halide is beneficial to the success of the reaction.
There are many possible explanations for this observation,
including enhanced steric interaction of the aryl group(s) with
the bulky ligands or improved solubility of key intermediate
complexes.28 While we have significantly expanded the scope
of palladium-catalyzed diaryl ether formation, it is not obvious
to us, for example, why the presence of ortho electron-
withdrawing group on the aryl halide should decrease the
efficiency of the process. Additionally, aryl halides bearing a
strongly electron-donating group at the ortho position (e.g.,
2-bromoanisole, which is a good substrate for related amination
reactions)5,27 and electron-deficient phenols (e.g., 4-hydroxy-
acetophenone) do not give good results in these coupling
reactions.
1
of their H NMR spectra to the previously reported data; their purity
was confirmed by GC analysis. The procedures described in this section
are representative; thus, the yields may differ slightly from those given
in Tables 1 and 2.
Ligand Syntheses. 2-(N,N-Dimethylamino)-2′-di-tert-butylphos-
phinobiphenyl (2). An oven-dried Schlenk tube was purged with argon
and charged with 2-(N,N-dimethylamino)-2′-bromobiphenyl8e (1.104
g, 4.0 mmol). The tube was purged with argon and ether (18 mL) was
added via syringe. The resulting solution was cooled to -78 °C and
n-butyllithium in hexanes (1.6 M, 2.75 mL, 4.4 mmol) was added
dropwise with stirring. The mixture was stirred at -78 °C for 30 min,
then warmed to 0 °C. Di-tert-butylchlorophosphine (0.96 mL, 5.0 mmol)
was added via syringe, and the mixture was allowed to slowly warm
to room temperature overnight (17 h). The mixture was quenched with
saturated aqueous ammonium chloride (10 mL), diluted with ether (40
mL), and transferred to a separatory funnel. The layers were separated
and the aqueous layer was extracted with ether (1 × 20 mL). The
combined organic layers were dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo. The resulting oil was taken up in
a small amount of hot methanol (ca. 10 mL), the bottom of the flask
was scratched with a spatula, and crystallization was allowed to occur
slowly in a -20 °C freezer. The resulting crystals were washed with
cold methanol and dried under vacuum to afford 683 mg (50%) of a
Conclusion
The current procedure enhances the utility of palladium-
catalyzed coupling reactions of phenols with aryl halides in
several respects.7a These include: (1) for most substrate
combinations, the use of preformed sodium phenolates is
obviated; (2) the reactions are, in general, more efficient with
respect to quantity of catalyst required and the yields obtained;
(3) a much wider range of substrates can be utilized including
electron-rich and electronically neutral aryl halides and triflates;
(4) a higher level of functional group compatibility can be
realized. For example, aryl halides containing simple esters or
enolizable ketones are now tolerated. Moreover, o-substituted
phenols, even those with a bulky substituent, are excellent
substrates; (5) only 2 mol % Pd(OAc)2 and 3 mol % ligand is
required as the catalyst and in special cases a level as low as
0.1 mol % was effective; (6) the mild and inexpensive base
K3PO4 is effective in a large majority of these reactions; and
(7) inexpensive and readily available aryl chlorides may be used
as substrates. We are currently working to improve the scope
and generality of palladium-catalyzed diaryl ether formation.
We anticipate that existing difficulties will be overcome through
the development of new palladium catalyst systems. These
efforts and their application to organic synthesis will be reported
in due course.
1
white solid, mp 116-117 °C. H NMR (300 MHz, CDCl3) δ 7.80-
7.75 (m, 1H), 7.40-7.26 (m, 4H), 7.00-6.90 (m, 3H), 2.44 (s, 6H),
1.26 (d, 9H, J ) 11.4 Hz), 0.90 (d, 9H, J ) 11.2 Hz); 31P NMR (121
MHz, CDCl3) δ 25.3; 13C NMR (75 MHz, CDCl3) δ 151.53, 151.5,
150.3, 149.8, 137.1, 137.0, 136.9, 136.7, 135.6, 135.5, 132.7, 131.0,
130.9, 128.7, 127.8, 125.2, 120.9, 117.4, 43.2, 33.4, 33.1, 31.5, 31.3,
31.1, 30.0, 29.8 (observed complexity due to P-C splitting; definitive
assignments have not yet been made); IR (neat, cm-1) 2941, 1416, 947,
745. Anal. Calcd for C22H32NP: C, 77.38; H, 9.45. Found: C, 77.16;
H, 9.56.
2-(Di-tert-butylphosphino)biphenyl (3). An oven dried round-
bottomed flask equipped with a magnetic stirbar and a rubber septum
was allowed to cool to room temperature under an argon purge. The
flask was charged with magnesium turnings (617 mg, 25.4 mmol) and
a small crystal of iodine. The flask was purged with argon and a solution
of 2-bromobiphenyl (5.38 g, 23.1 mmol) in THF (40 mL) was added.
The mixture was heated to reflux with stirring for 2 h and then allowed
to cool to room temperature. The septum was removed, and anhydrous
copper(I) chloride (2.40 g, 24.2 mmol) was added. The flask was capped
with the septum and purged with argon for 2 min. Di-tert-butylchlo-
(26) Brown, J. M.; Guiry, P. J. Inorg. Chim. Acta 1994, 220, 249-259.
(27) Sadighi, J. P.; Harris, M. C.; Buchwald, S. L. Tetrahedron Lett.
1998, 39, 5327-5330.
(29) Brandt, K. J. Org. Chem. 1981, 46, 1918-1920.
(30) Yeager, G. W.; Schissel, D. N. Synthesis 1991, 63-68.
(31) This compound is also available from Aldrich Chemical Co.
(32) Haga, N., Takayanagi, H. J. Org. Chem. 1996, 61, 735-745.
(28) We thank Dr. Joseph Fox for this suggestion.

4374 J. Am. Chem. Soc., Vol. 121, No. 18, 1999
Aranyos et al.
rophosphine (5.0 g, 27.7 mmol) was added via syringe, and the mixture
was heated to reflux with stirring for 8 h. The mixture was cooled to
room temperature and diluted with 1:1 hexanes/ether (200 mL). The
resulting suspension was filtered, and the solids were washed with
hexanes (60 mL). The solid material was transferred to a flask
containing 1:1 hexane/ethyl acetate (150 mL), and water (100 mL) and
30% aqueous ammonium hydroxide (60 mL) were added. The resulting
slurry was stirred at room temperature for 5 min and then transferred
to a separatory funnel. The layers were separated, and the organic phase
was washed with brine (100 mL), dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo. The resulting solid was recrystallized
from methanol (2 crops of crystals were collected) to afford 4.46 g
(67%) of a white solid, mp 86-86.5 °C. 1H NMR (300 MHz, CDCl3)
δ 7.95-7.85 (m, 1H), 7.40-7.21 (m, 8H), 1.15 (d, 18H, J ) 11.6 Hz);
31P NMR (121 MHz, CDCl3) δ 18.7; 13C NMR (75 MHz, CDCl3) δ
151.4, 150.9, 143.6, 143.5, 135.6, 135.2, 135.0, 130.5, 130.4, 130.1,
128.3, 127.0, 126.7, 126.5, 126.2, 126.0, 125.6, 32.7, 32.4, 30.8, 30.6
(observed complexity due to P-C splitting; definitive assignments have
not yet been made); IR (neat, cm-1) 2956, 1459, 1362, 1173. Anal.
Calcd for C20H27P: C, 80.50; H, 9.12. Found: C, 80.67; H, 9.36.
2-N,N-Dimethylamino-2′-di-tert-butylphosphino-1,1′-binaph-
thyl (4). An oven-dried round-bottomed flask was purged with argon
and charged with 2,2′-dibromo-1,1′-binaphthyl (5.0 g, 12.1 mmol),
benzophenone imine (2.90 g, 15.7 mmol), NaOt-Bu (1.70 g, 18.0
mmol), Pd2(dba)3 (110 mg, 0.12 mmol), 2,2′-bis(diphenylphosphino)-
1,1′-diphenyl ether33 (129 mg, 0.24 mmol), and toluene (50 mL). The
flask was fitted with a reflux condenser, the mixture was stirred for 18
h at 100 °C and then cooled to room temperature, and two-thirds of
the solvent was removed under reduced pressure. Ethanol (25 mL) and
water (3 mL) were added to the resulting mixture. The yellow crystals
were collected on a Bu¨chner funnel and washed with ethanol (10 mL)
to afford 5.7 g (92%) of crude 2-(diphenyl-methylene-amino)-2′-bromo-
1,1′-binaphthyl which was used in the following reaction without further
purification.
of 2-N,N-(dimethylamino)-2′-di-tert-butylphosphino-1,1′-binaphthyl as
colorless crystals, mp 188-189 °C. H NMR (500 MHz, CDCl3) δ
1
8.03 (broad d, 1H, J ) 8.5 Hz), 7.92-7.75 (m, 3H), 7.75 (broad d,
1H, J ) 8.2 Hz), 7.48-7.43 (m, 2H), 7.31 (broad d, 1H, J ) 8.5 Hz),
7.24-7.16 (m, 2H), 6.98 (m, 1H), 6.74 (broad d, 1H, J ) 8.6 Hz),
2.46 (s, 6H), 1.26 (d, 9H, J ) 11.3 Hz), 0.75 (d, 9H, J ) 11.3 Hz); 31
P
NMR (121 MHz, CDCl3) δ 26.2; 13C NMR (125 MHz, CDCl3) δ 149.6,
145.8, 145.5, 136.5, 136.3, 134.6, 134.1, 134.0, 133.4, 132.96, 132.94,
129.2, 128.7, 128.03, 128.01, 127.7, 127.5, 127.1, 126.6, 126.5, 126.0,
125.8, 125.4, 124.9, 122.8, 119.0, 43.3, 32.8, 32.6, 31.8, 31.5, 31.4,
31.3, 30.3, 30.1 (observed complexity due to P-C splitting; definitive
assignments have not yet been made); IR (neat, cm-1) 3060, 2941, 1596,
1474, 1173. Anal. Calcd for C30H36NP: C, 81.60; H, 8.22. Found: C,
81.59; H, 8.60.
1-(Di-tert-butylphosphino)-o-terphenyl (5). An oven-dried Schlenk
tube was cooled to room temperature under an argon purge and was
charged with magnesium turnings (267 mg, 11.0 mmol), ether (7 mL),
and 1,2-dibromoethane (38 µL). The mixture was stirred at room
temperature until gas evolution ceased, and then a solution of
2-bromobiphenyl (1.7 mL, 10.0 mmol) in ether (5 mL) was added
dropwise. The mixture was stirred at room temperature for 1.75 h. The
solution was then transferred via cannula to a separate flask containing
an ice-cooled solution of triisopropyl borate (4.6 mL, 20.0 mmol) in
THF (20 mL). The mixture was stirred at 0 °C for 15 min and then
warmed to room temperature and stirred for 21 h. The reaction was
quenched with 1 M HCl (40 mL) and stirred at room temperature for
10 min. The solution was basified to pH 14 with 6 M NaOH and then
extracted with ether (1 × 10 mL). The organic phase was discarded,
and the aqueous phase was acidified to pH 2 with 6 M HCl and
extracted with ether (3 × 50 mL). The combined organic layers were
dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo.
The crude material was recrystallized from ether/pentane at -20 °C to
afford 1.0 g (51%) of o-biphenyl boronic acid as a white, crystalline
solid, which was used without further purification.
The crude imine (3.0 g, 5.9 mmol) was suspended in dichloromethane
(100 mL) in a round-bottomed flask. Concentrated hydrochloric acid
(1.5 mL, 17.6 mmol) was added to the suspension which became
homogeneous within 15 min. The reaction mixture was stirred for 18
h at room temperature during which time a precipitate formed. The
mixture was then treated with 1 M NaOH (25 mL), and the layers were
separated. The aqueous layer was extracted with additional dichlo-
romethane (10 mL). The combined organic layers were washed with
brine, dried over anhydrous magnesium sulfate, filtered, and concen-
trated in vacuo. The crude material was then purified by flash
chromatography on silica gel to give 1.5 g (73%) of 2-amino-2′-bromo-
1,1′-binaphthyl as colorless crystals.
A round-bottomed flask was charged with 2-amino-2′-bromo-1,1′-
binaphthyl (480 mg, 1.4 mmol), iodomethane (0.25 mL, 4.2 mmol),
sodium carbonate (318 mg, 3.0 mmol), and DMF (8 mL) and then
purged with argon. The mixture was heated to 50 °C and stirred until
the starting material had been completely consumed. The reaction
mixture was diluted with ether (5 mL) and water (1 mL) and then passed
through a plug of silica gel. The filtrate was dried over anhydrous
magnesium sulfate, filtered, and concentrated in vacuo to give 473 mg
(91%) of 2-N,N-(dimethylamino)-2′-bromo-1,1′-binaphthyl as colorless
crystals.
An oven-dried round-bottomed flask was charged with 2-N,N-
(dimethylamino)-2′-bromo-1,1′-binaphthyl (376 mg, 1.0 mmol) and
purged with argon. DME (5 mL) was added, the resulting solution was
cooled to 0 °C, and then tert-butyllithium in hexanes (1.7 M, 1.2 mL,
2.0 mmol) was added dropwise. The solution was warmed to room
temperature and stirred for 30 min. Di-tert-butylchlorophosphine (0.417
mL, 2.2 mmol) was then added dropwise, and the reaction was stirred
at room temperature for 18 h. Saturated aqueous ammonium chloride
(2 mL) was added, and the reaction mixture was extracted with ether
(2 × 10 mL). The combined organic extracts were dried over anhydrous
magnesium sulfate, filtered, and concentrated in vacuo. The crude
material was recrystallized from ether/methanol to give 295 mg (67%)
An oven-dried Schlenk flask was cooled to room temperature under
an argon purge and was charged with tetrakis(triphenylphosphine)-
palladium (289 mg, 0.25 mmol, 5 mol %), sodium carbonate (2.86 g,
27 mmol), and o-biphenyl boronic acid (1.0 g, 5.0 mmol). The flask
was purged with argon, and DME (50 mL), ethanol (2 mL), water (15
mL), and 2-bromoiodobenzene (0.83 mL, 6.05 mmol) were added
through a rubber septum. The mixture was heated to 85 °C with stirring
for 3 d. After cooling to room temperature, the reaction mixture was
diluted with ether (100 mL) and poured into a separatory funnel. The
layers were separated, and the organic phase was washed with 1 M
NaOH (2 × 50 mL) and brine and then dried over anhydrous
magnesium sulfate, filtered, and concentrated in vacuo. The crude
material was purified by flash chromatography on silica gel to afford
1.23 g (79%) of 1-bromo-o-terphenyl as a colorless oil.
An oven-dried Schlenk tube was cooled to room temperature under
an argon purge and was charged with magnesium turnings (54 mg, 2.2
mmol), THF (2 mL), and 1,2-dibromoethane (9 µL). The mixture was
stirred at room temperature for 15 min, and then a solution of 1-bromo-
o-terphenyl (618 mg, 2.0 mmol) in THF (1 mL) was added dropwise.
The mixture was stirred at room temperature for 1 h, and then the
septum was removed from the flask, and copper(I) chloride (283 mg,
2.1 mmol) was added. The tube was capped with the septum and purged
with argon for 1 min. The tube was charged with di-tert-butylchloro-
phosphine (0.46 mL, 2.4 mmol) and additional THF (1 mL). The
mixture was heated to 60 °C with stirring for 26 h. The mixture was
cooled to room temperature and filtered, and the solids were washed
with ether/hexanes (50 mL, 1/1 v/v). The organic fraction was poured
into a separatory funnel, washed with 30% aqueous ammonium
hydroxide (3 × 50 mL) and brine (50 mL), dried over anhydrous sodium
sulfate, filtered, and concentrated. The crude material was recrystallized
from hot methanol to afford 191 mg (26%) of the title compound as a
white, crystalline solid, mp 95-97 °C. 1H NMR (300 MHz, CDCl3) δ
7.56 (d, 1H, J ) 7.5 Hz), 7.54-7.07 (m, 12H), 0.92 (d, 9H, J ) 11.1
Hz), 0.68 (d, 9H, J ) 11.1 Hz); 31P NMR (121 MHz, CDCl3) δ 20.9;
13C NMR (75 MHz, CDCl3) δ 150.1, 149.8, 142.4, 141.4, 141.3, 140.95,
140.92, 135.8, 135.65, 135.63, 135.6, 132.8, 132.0, 131.9, 130.6, 130.0,
127.9, 127.8, 127.2, 126.1, 125.9, 125.6, 33.5, 33.3, 31.8, 30.89, 30.88,
(33) Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M.; Goubitz, K.; Fraanje, J. Organometallics 1995, 14,
3081-3089.

Pd-Catalyzed Preparation of Diaryl Ethers
J. Am. Chem. Soc., Vol. 121, No. 18, 1999 4375
30.8, 30.0, 29.8 (observed complexity due to P-C splitting; definitive
assignments have not yet been made); IR (neat, cm-1) 2946, 1459, 1362,
1173. Anal. Calcd for C26H31P: C, 83.39; H, 8.34. Found: C, 83.40;
H, 8.40.
General Procedure B. An oven-dried resealable Schlenk tube was
charged with sodium hydride (dry 95%, 36 mg, 1.4 mmol) in a nitrogen-
filled glovebox. The tube was sealed and removed from the glovebox,
fitted with a septum, and purged with argon. The phenol (1.0 mmol)
and toluene (2.5 mL) were added, and the resulting mixture was stirred
at 100 °C for 15 min under argon. The reaction mixture was allowed
to cool to room temperature, the septum was then removed, and the
tube was charged with palladium acetate (4.5 mg, 0.02 mmol, 2.0 mol
%) and ligand (3 (9.0 mg) or 4 (13.2 mg) or 5 (11.2 mg), 0.03 mmol,
3.0 mol %). The tube was capped with the septum and purged with
argon. The aryl halide (1.0 mmol) and additional toluene (0.5 mL) were
added, the tube was sealed with a Teflon screwcap, and the reaction
mixture was stirred at 100 °C for 14-24 h (reaction times were not
optimized). The reaction was then subjected to workup method 1 or 2
(see below).
2-[Di-(1-adamantyl)phosphino]biphenyl (6). An oven-dried, round-
bottomed flask was charged with magnesium turnings (15.3 g, 0.63
mol) and 1-bromoadamantane (9.0 g, 0.041 mol). The flask was purged
with argon, ethyl ether (45 mL) was then added, and the mixture was
gently refluxed for 15 h, without stirring.34 A separate flame-dried,
two-necked, round-bottomed flask equipped with a reflux condenser
was charged with PCl3 (0.9 mL, 10 mmol) and ether (15 mL) and was
cooled to -40 °C. To this solution was added the solution of the
Grignard reagent via syringe, slowly enough so that the reaction
temperature was kept below -25 °C. The resulting mixture was stirred
for 30 min at -45 °C, the cooling bath was removed, and the reaction
mixture was allowed to warm slowly to room temperature. After the
mixture stirred for an additional 30 min at room temperature, the
reaction vessel was placed into a 37 °C oil bath, and the solution was
allowed to gently reflux for 22 h. The mixture was cooled to room
temperature and then was cannula-filtered into a separate flask. The
solvent and some of the adamantane byproduct were removed in vacuo,
without exposing the product to air, to afford a crude mixture of di-
(1-adamantyl)chlorophosphine and di-(1-adamantyl)bromophosphine.
This mixture was used in the next step without further purification.
Workup Method 1. The reaction mixture was allowed to cool to
room temperature and was then diluted with ether (40 mL), filtered,
and concentrated. The crude material was purified by flash chroma-
tography on silica gel.
Workup Method 2. The reaction mixture was allowed to cool to
room temperature and was then diluted with ether (40 mL) and poured
into a separatory funnel. The mixture was washed with 1 M NaOH
(20 mL) and brine (20 mL), and then the organic fraction was dried
over anhydrous magnesium sulfate or sodium sulfate, filtered, and
concentrated. The crude material was purified by flash chromatography
on silica gel.
An oven-dried Schlenk tube was charged with magnesium turnings
(240 mg, 9.89 mmol) and 2-bromobiphenyl (1.55 mL, 7.5 mmol). The
tube was purged with argon, THF (15 mL) was added through a rubber
septum, and the reaction mixture was heated to a mild reflux for 3 h.
The reaction mixture was then cooled to room temperature, the septum
was removed, and copper(I) chloride (930 mg, 9.45 mmol) was added.
The tube was capped with a septum and purged with argon, and then
a solution of the di-(1-adamantyl)chlorophosphine/di-(1-adamantyl)-
bromophosphine mixture (prepared above) in THF (5 mL) was added.
The reaction mixture was heated to reflux for 3 h and allowed to cool
to room temperature, and ether (50 mL) and pentane (50 mL) were
added. The resulting suspension was stirred for 10 min, during which
time a heavy dark-brown precipitate formed. The suspension was
filtered, and the solid was collected on a fritted funnel. The solid was
partitioned between ethyl acetate/ether (100 mL, 1/1 v/v) and 38%
aqueous ammonium hydroxide (50 mL) and water (50 mL). The mixture
was vigorously shaken several times over 30 min, and the layers were
separated. The aqueous layer was washed with ether/ethyl acetate (2
× 100 mL, 1/1 v/v), and the combined organic layers were washed
with brine (2 × 50 mL), dried over anhydrous magnesium sulfate,
decanted, and concentrated in vacuo. The product was crystallized from
toluene/methanol to afford 450 mg (6%) of the title compound as a
2,3′,4′,5-Tetramethyldiphenyl Ether (the Reaction Shown in eq
3 Using Ligand 2). An oven-dried resealable Schlenk tube was charged
with sodium hydride (dry 95%, 36 mg, 1.4 mmol) in a nitrogen-filled
glovebox. The tube was sealed and removed from the glovebox, fitted
with a rubber septum, and purged with argon. Toluene (1 mL) was
added, followed by a solution of 3,4-dimethylphenol (147 mg, 1.2
mmol) in toluene (2 mL). The mixture was stirred at room temperature
for 2 min and then heated to 100 °C with stirring for 15 min. The
reaction mixture was allowed to cool to room temperature, the septum
was removed, and Pd2(dba)3 (6.9 mg, 0.0075 mmol, 1.5 mol % Pd)
and 2 (7.7 mg, 0.0225 mmol, 2.25 mol %) were added. The tube was
capped with the septum and purged with argon. 2-Chloro-p-xylene
(0.135 mL, 1.0 mmol) and additional toluene (1 mL) were added, and
the tube was sealed with a Teflon screwcap. The mixture was heated
to 100 °C with stirring until the starting aryl halide had been completely
consumed as judged by GC analysis (19 h). The mixture was cooled
to room temperature, diluted with ether (30 mL), filtered through Celite,
and concentrated in vacuo. The crude material was purified by flash
chromatography on silica gel to afford 177 mg (78%) of the title
compound as a colorless oil.
1
white solid, mp 222-224 °C. H NMR (300 MHz, CDCl3) δ 7.92-
2,3′,4′,5-Tetramethyldiphenyl Ether (the Reaction Shown in eq
3 Using Ligand 3). An oven-dried resealable Schlenk tube was charged
with sodium hydride (dry 95%, 36 mg, 1.4 mmol) in a nitrogen-filled
glovebox. The tube was sealed and removed from the glovebox, fitted
with a rubber septum, and purged with argon. 3,4-Dimethylphenol (147
mg, 1.2 mmol) and toluene (2.0 mL) were added, and the resulting
mixture was stirred at 100 °C for 15 min under argon. The reaction
mixture was allowed to cool to room temperature, the septum was
removed, and Pd2(dba)3 (6.9 mg, 0.0075 mmol, 1.5 mol % Pd) and 3
(6.7 mg, 0.0225 mmol) were added. The tube was capped with the
septum and purged with argon. 2-Chloro-p-xylene (135 µL, 1.0 mmol)
was added, the tube was sealed with a Teflon screwcap, and the reaction
mixture was stirred at 100 °C for 14 h. The mixture was allowed to
cool to room temperature, water (5 mL) and ether (40 mL) were added,
and the resulting solution was poured into a separatory funnel. The
organic phase was separated, dried over anhydrous magnesium sulfate,
filtered, and concentrated in vacuo. The crude material was purified
by flash chromatography on silica gel to afford 175 mg (77%) of the
title compound as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 7.12
(d, 1H, J ) 7.5 Hz), 7.05 (d, 1H, J ) 8.1 Hz), 6.85 (d, 1H, J ) 8.1
Hz), 6.74 (d, 1H, J ) 3.0 Hz), 6.70 (broad s, 1H), 6.64 (dd, 1H, J )
8.1, 3.0 Hz), 2.27 (s, 3H), 2.23 (s, 6H), 2.21 (s, 3H); 13C NMR (CDCl3,
125 MHz) δ 155.8, 154.7, 138.0, 136.9, 131.0, 130.42, 130.41, 126.4,
124.2, 119.9, 118.8, 114.7, 21.0, 20.0, 18.9, 15.8; IR (neat, cm-1) 2923,
7.87 (m, 1H), 7.41-7.16 (m, 8H), 1.95-1.79 (m, 18H), 1.69-1.62
(m, 12H); 31P NMR (121 MHz, CDCl3) δ 21.5; 13C NMR (75 MHz,
CDCl3) δ 151.9, 151.5, 143.9, 143.8, 136.53, 136.49, 133.1, 132.8,
130.6, 130.55, 130.49, 129.0, 128.15, 128.08, 128.07, 127.0, 126.2,
125.2, 42.0, 41.8, 37.5, 37.14, 36.9, 28.9, 28.78 (observed complexity
due to P-C splitting; definitive assignments have not yet been made);
IR (neat, cm-1) 2898, 1443, 1343, 697. Anal. Calcd for C32H39P: C,
84.54; H, 8.65. Found: C, 84.40; H, 8.57.
Pd-Catalyzed Coupling of Aryl Halides with Phenols. General
Procedure A. An oven-dried resealable Schlenk tube was fitted with
a rubber septum and was cooled to room temperature under an argon
purge. The septum was removed, and the tube was charged with
palladium acetate (4.5 mg, 0.02 mmol, 2.0 mol %), ligand (3 (9.0 mg)
or 4 (13.2 mg) or 5 (11.2 mg) or 6 (13.6 mg), 0.03 mmol, 3.0 mol %),
potassium phosphate (424 mg 2.0 mmol), the phenol (1.2 mmol) and
the aryl halide (1.0 mmol). The tube was capped with the septum and
purged with argon, and then toluene (3 mL) was added through the
septum. The tube was sealed with a Teflon screwcap, and the reaction
mixture was stirred at 100 °C for 14-26 h (reaction times were not
optimized). The reaction was then subjected to workup method 1 or 2
(see below).
(34) Molle, G.; Bauer, P.; Dubios, J. E. J. Org. Chem. 1982, 47, 4120-
4128.

4376 J. Am. Chem. Soc., Vol. 121, No. 18, 1999
Aranyos et al.
1495, 1256. Anal. Calcd for C16H18O: C, 84.91; H, 8.02. Found: C,
84.67; H, 8.03.
4-Phenoxyacetophenone (Table 1, Entry 1).30,31 General procedure
A (workup method 2, ligand 3) was used to convert 4-bromoacetophe-
none and phenol in 16 h to 188 mg (89%) of the title compound, which
was obtained as a white solid, mp 50-51 °C (lit.30 mp 51 °C).
4-(2′-Methylphenoxy)acetophenone (Table 1, Entry 2).35 General
procedure A (workup method 2, ligand 3) was used to convert
4-bromoacetophenone and o-cresol in 15 h to 213 mg (96%) of the
title compound, which was obtained as a white solid, mp 34.5-35.5
°C (lit.35 oil). 1H NMR (CDCl3, 300 MHz) δ 7.94-7.89 (m, 2H), 7.30-
7.12 (m, 3H), 6.99 (broad d, 1H, J ) 7.5 Hz), 6.91-6.87 (m, 2H),
2.57 (s, 3H), 2.19 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 196.5, 162.1,
152.8, 131.6, 131.2, 130.5, 130.4, 127.4, 125.2, 120.9, 115.8, 26.5,
16.2; IR (neat, cm-1) 1675. Anal. Calcd for C15H14O2: C, 79.62; H,
6.24. Found: C, 79.75; H, 6.55.
4-(2′-Methylphenoxy)acetophenone (Table 1, Entry 8).35 General
procedure A (workup method 2, ligand 3) was used to convert
4-acetylphenyl triflate and o-cresol in 14 h to 188 mg (83%) of the
title compound as a white solid, mp 35-36 °C (lit.35 oil). See data
above (Table 1, entry 2).
3-(2′-Methylphenoxy)acetophenone (Table 1, Entry 9). General
procedure A (workup method 2, ligand 3) was used to convert
3′-bromoacetophenone and o-cresol in 19 h to 170 mg (75%) of the
title compound, which was obtained as a colorless oil. 1H NMR (CDCl3,
300 MHz) δ 7.63 (ddd, 1H, J ) 8.0, 1.5, 1.0 Hz), 7.49 (dd, 1H, J )
2.6, 1.5 Hz), 7.39 (t, 1H, J ) 8.0 Hz), 7.27 (broad d, 1H, J ) 7.3 Hz),
7.19 (dt, 1H, J ) 7.3, 1.5 Hz), 7.11 (dd, 1H, J ) 8.0, 1.5 Hz), 7.09
(ddd, 1H, J ) 8.0, 2.6, 1.0 Hz), 6.91 (dd, 1H, J ) 8.0, 1.5 Hz), 2.57
(s, 3H), 2.23 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 197.8, 158.5,
154.0, 139.0, 131.9, 130.3, 130.1, 127.6, 124.8, 122.5, 121.9, 120.1,
116.8, 27.0, 16.4; IR (neat, cm-1) 1686, 1578, 1437, 1264. Anal. Calcd
for C15H14O2: C, 79.62; H, 6.24. Found: C, 80.02; H, 6.28.
2,2′,5-Trimethyldiphenyl Ether (Table 2, Entry 1).4 General
procedure A (workup method 1, ligand 4) was used to convert 2-bromo-
p-xylene and o-cresol in 24 h to 206 mg (96%) of the title compound
which was obtained as a colorless oil.
4-(2′-Methylphenoxy)acetophenone (Table 1, Entry 2, using 0.1
mol % Pd).35 General procedure A (workup method 2, ligand 3) was
employed, with the following changes in the amount of materials
used: palladium acetate (1.0 mg, 0.004 mmol, 0.10 mol %), ligand 3
(2.0 mg, 0.007 mmol, 0.15 mol %), 4-bromoacetophenone (890 mg,
4.47 mmol), o-cresol (0.55 mL, 5.33 mmol), potassium phosphate (1.90
g, 8.95 mmol) in toluene (13 mL) for 24 h. The title compound (955
mg, 95%) was obtained as a white solid, mp 34.5-35.5 °C (lit.35 oil).
4-(4′-tert-Butylphenoxy)acetophenone (Table 1, Entry 3).30 Gen-
eral procedure A (workup method 2, ligand 3) was used to convert
4-bromoacetophenone and 4-tert-butylphenol in 15 h to 247 mg (92%)
of the title compound, which was obtained as a colorless oil.
Methyl 4-phenoxybenzoate (Table 1, Entry 4).32 General procedure
A (workup method 2, ligand 3) was used to convert methyl 4-bro-
mobenzoate and phenol in 24 h to 201 mg (88%) of the title compound,
which was obtained as a white solid, mp 59.5-60 °C (lit.32 mp 62.5-
63 °C).
3,5-Dimethyldiphenyl Ether (Table 2, entry 2).36 General proce-
dure A (workup method 1, ligand 5) was used to convert 5-bromo-m-
xylene and phenol in 24 h to 164 mg (83%) of the title compound,
1
which was obtained as a colorless oil. H NMR (CDCl3, 300 MHz) δ
7.35-7.30 (m, 2H), 7.11-6.98 (m, 3H), 6.74 (broad s, 1H), 6.63 (broad
s, 2H), 2.28 (broad s, 6H); 13C NMR (CDCl3, 75 MHz) δ 157.3, 157.0,
139.4, 129.5, 124.9, 122.8, 118.7, 116.5, 21.3; IR (neat, cm-1) 2919,
1584, 1490, 1218. Anal. Calcd for C14H14O: C, 84.81; H, 7.12.
Found: C, 84.78; H, 6.94.
2,3′,5′,6-Tetramethyldiphenyl Ether (Table 2, Entry 3).4 General
procedure B (workup method 1, ligand 3) was used to convert 5-bromo-
m-xylene and 2,6-dimethylphenol in 24 h to 157 mg (70%) of the title
1
compound, which was obtained as a colorless oil. H NMR (CDCl3,
N,N-Diethyl-4-(2′-methylphenoxy)benzamide (Table 1, Entry 5).
General procedure B (workup method 2, ligand 3) was used except
that palladium acetate (11 mg, 0.05 mmol, 5.0 mol %) and 3 (22 mg,
0.075 mmol, 7.5 mol %) were employed to convert 4-bromo-N,N-
diethylbenzamide and o-cresol in 22 h to 230 mg (81%) of the title
300 MHz) δ 7.12-7.03 (m, 3H), 6.62 (broad s, 1H), 6.37 (broad s,
2H), 2.24 (s, 6H), 2.13 (s, 6H); 13C NMR (CDCl3, 125 MHz) δ 157.8,
151.1, 139.4, 131.5, 128.8, 124.8, 123.1, 112.2, 21.4, 16.4; IR (neat,
cm-1) 2921, 1600, 1194. Anal. Calcd for C16H18O: C, 84.91; H, 8.02.
Found: C, 84.68; H, 8.18.
3,3′,4′,5-Tetramethyldiphenyl Ether (Table 2, Entry 4).4 General
procedure B (workup method 1, ligand 3) was used to convert 5-bromo-
m-xylene and 3,4-dimethylphenol in 24 h to 188 mg (84%) of the title
compound, which was obtained as a colorless oil.
1
compound, which was obtained as a colorless oil. H NMR (CDCl3,
300 MHz) δ 7.35-7.30 (m, 2H), 7.27-7.25 (m, 1H), 7.19 (td, 1H, J
) 8.0, 1.9 Hz), 7.10 (td, 1H, J ) 7.2, 1.2 Hz), 6.94 (dd, 1H, J ) 8.0,
1.2 Hz), 6.90-6.85 (m, 2H), 3.41 (broad s, 4H), 2.21 (s, 3H), 1.18
(broad s, 6H); 13C NMR (CDCl3, 75 MHz) δ 171.0, 158.9, 153.8, 131.7,
131.1, 130.4, 128.4, 127.4, 124.7, 120.5, 116.7, 43.0, 39.0, 16.4, 13.0;
IR (neat, cm-1) 1627, 1584, 1424, 1237. Anal. Calcd for C18H21NO2:
C, 76.28; H, 7.47. Found: C, 76.11; H, 7.42.
4-tert-Butyl-2′-methyldiphenyl Ether (Table 2, Entry 5). General
procedure A (workup method 1, ligand 3) was used to convert 4-tert-
butylbromobenzene and o-cresol in 14 h to 204 mg (85%) of the title
1
compound, which was obtained as a colorless oil. H NMR (CDCl3,
4-(3′-Isopropylphenoxy)benzonitrile (Table 1, Entry 6). General
procedure A (workup method 2, ligand 3) was used to convert p-chloro
benzonitrile and m-isopropylphenol in 24 h to 218 mg (91%) of the
300 MHz) δ 7.32 (d, 2H, J ) 9.0 Hz), 7.25 (dd, 1H, J ) 8.1, 1.5 Hz),
7.15 (dt, 1H, J ) 7.5, 1.5 Hz), 7.04 (dt, 1H, J ) 7.5, 1.2 Hz), 6.89 (dd,
1H, J ) 8.1, 1.2 Hz), 6.84 (d, 2H, J ) 9.0 Hz), 2.26 (s, 3H), 1.31 (s,
9H); 13C NMR (CDCl3, 125 MHz) δ 155.6, 155.1, 145.4, 131.5, 130.0,
1
title compound, which was obtained as a pale yellow oil. H NMR
127.2, 126.6, 123.8, 119.6, 117.2, 34.4, 31.7, 16.4; IR (neat, cm-1
)
(CDCl3, 300 MHz) δ 7.61-7.57 (m, 2H), 7.32 (t, 1H, J ) 7.8 Hz),
7.11 (d, 1H, J ) 7.8 Hz), 7.02-6.97 (m, 2H), 6.95-6.93 (m, 1H),
6.87 (ddd, 1H, J ) 8.1, 2.4, 0.9 Hz), 2.92 (sept, 1H, J ) 6.6 Hz), 1.25
(d, 6H, J ) 6.6 Hz); 13C NMR (CDCl3, 75 MHz) δ 161.7, 154.6, 151.6,
134.0, 129.9, 123.3, 118.7, 118.4, 117.7, 117.6, 105.5, 34.0, 23.9; IR
(neat, cm-1) 2962, 2227, 1245. Anal. Calcd for C16H15NO: C, 80.98;
H, 6.37. Found: C, 80.93; H, 6.64.
2929, 1586, 1237. Anal. Calcd for C17H20O: C, 84.95; H, 8.39.
Found: C, 84.84; H, 8.72.
4-n-Butyl-2′-isopropyldiphenyl Ether (Table 2, Entry 6). General
procedure A (workup method 1, ligand 3) was used to convert 1-bromo-
4-n-butylbenzene and 2-isopropylphenol in 24 h to 246 mg (92%) of
1
the title compound, which was obtained as a colorless oil. H NMR
4-Chloro-2′-isopropyldiphenyl Ether (Table 1, Entry 7). General
procedure A (workup method 1, ligand 3) was used to convert
4-cholorobromobenzene and o-isopropylphenol (260 µL, 1.95 mmol)
in 24 h to 223 mg (90%) of the title compound, which was obtained as
(CDCl3, 300 MHz) δ 7.34-7.31 (dd, 1H, J ) 7.0, 2.4 Hz), 7.13-7.06
(m, 4H), 6.86-6.82 (m, 3H), 3.31 (sept, 1H, J ) 7.0 Hz), 2.57 (t, 2H,
J ) 7.7 Hz), 1.63-1.53 (m, 2H), 1.42-1.29 (m, 2H), 1.23 (d, 6H, J )
7.0 Hz), 0.93 (t, 3H, J ) 7.3 Hz); 13C NMR (CDCl3, 75 MHz) δ 156.0,
154.0, 140.0, 136.9, 129.4, 126.7, 126.6, 123.7, 119.2, 117.6, 34.9,
33.9, 27.1, 23.0, 22.4, 14.0; IR (neat, cm-1) 2960, 1505, 1486, 1231.
Anal. Calcd for C19H24O: C, 85.03; H, 9.01. Found: C, 84.88; H, 9.06.
2-Isopropyl-4′-methoxydiphenyl Ether (Table 2, Entry 7). General
procedure A (workup method 1, ligand 6) was used to convert
p-bromoanisole and o-isopropylphenol in 24 h to 213 mg (88%) of the
1
a colorless oil. H NMR (CDCl3, 300 MHz) δ 7.38-7.33 (m, 1H),
7.28-7.23 (m, 2H), 7.20-7.12 (m, 2H), 6.90-6.82 (m, 3H), 3.25 (sept,
1H, J ) 6.9 Hz), 1.22 (d, 6H, J ) 6.9 Hz); 13C NMR (CDCl3, 75
MHz) δ 156.9, 153.0, 140.2, 129.5, 127.15, 127.05, 126.9, 124.5, 119.8,
118.5, 27.1, 23.0; IR (neat, cm-1) 2964, 1482, 1092. Anal. Calcd for
C15H15ClO: C, 73.02; H, 6.13. Found: C, 73.00; H, 5.86.
(35) Horii, Z.; Kiuchi, T. J. Pharm. Soc. Jpn. 1937, 57, 683-688; Chem.
Abstr. 1938, 129.
(36) Smith, K.; Jones, D. J. Chem. Soc., Perkin Trans. 1 1992, 407-
408.

Pd-Catalyzed Preparation of Diaryl Ethers
J. Am. Chem. Soc., Vol. 121, No. 18, 1999 4377
title compound, which was obtained as a colorless oil. 1H NMR (CDCl3,
300 MHz) δ 7.32 (dd, 1H, J ) 6.9, 2.1), 7.15-7.04 (m, 2H), 6.94-
6.84 (m, 4H), 6.79 (dd, 1H, J ) 7.5, 2.1 Hz), 3.80 (s, 3H), 3.37 (sept,
1H, J ) 6.6 Hz), 1.26 (d, 6H J ) 6.6 Hz); 13C NMR (CDCl3, 75 MHz)
δ 155.1, 154.8, 151.3, 139.2, 126.7, 126.6, 123.2, 119.4, 118.1, 114.7,
55.7, 27.1, 23.0; IR (neat, cm-1) 2962, 1503, 1036. Anal. Calcd for
C16H18O2: C, 79.31; H, 7.49. Found: C, 79.39; H, 7.30.
4-n-Butyl-3′,4′-dimethyldiphenyl Ether (Table 2, Entry 12).
General procedure B (workup method 1, ligand 5) was used to convert
1-chloro-4-n-butylbenzene and 3,4-dimethylphenol in 22 h to 201 mg
(79%) of the title compound, which was obtained as a colorless oil. 1H
NMR (CDCl3, 300 MHz) δ 7.14-7.03 (m, 3H), 6.92-6.86 (m, 2H),
6.80 (broad d, 1H, J ) 2.4 Hz), 6.80 (broad dd, 1H, J ) 8.4, 2.4 Hz),
2.57 (app t, 2H, J ) 7.8 Hz), 2.22 (s, 6H), 1.66-1.52 (m, 2H), 1.35
(sext, 2H, J ) 7.8 Hz), 0.92 (t, 3H, J ) 7.6 Hz); 13C NMR (CDCl3,
125 MHz) δ 155.5, 155.3, 138.1, 137.4, 131.2, 130.5, 129.4, 120.1,
118.4, 116.0, 34.9, 33.8, 22.3, 19.9, 19.0, 14.0; IR (neat, cm-1) 2927,
1495, 1218. Anal. Calcd for C18H22O: C, 84.99; H, 8.72. Found: C,
85.27; H, 8.99.
2,5-Dimethyldiphenyl Ether (Table 2, Entry 8).37 General proce-
dure B (workup method 1, ligand 4) was used to convert 2-chloro-p-
xylene and phenol in 19 h to 157 mg (79%) of the title compound,
1
which was obtained as a colorless oil. H NMR (CDCl3, 300 MHz) δ
7.31 (dd, 2H, J ) 7.5, 8.6 Hz), 7.14 (d, 1H, J ) 7.7 Hz), 7.05 (t, 1H,
J ) 7.5 Hz), 6.93-6.89 (m, 1H), 6.91 (d, 2H, J ) 8.6 Hz), 6.76 (s,
1H), 2.29 (s, 3H), 2.21 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 158.2,
154.3, 137.3, 131.3, 129.8, 127.0, 125.0, 122.4, 120.7, 117.4, 21.2,
16.0; IR (neat, cm-1) 2923, 1590, 1490, 1252, 1216, 1117. Anal. Calcd
for C14H14O: C, 84.81; H, 7.12. Found: C, 85.02; H, 7.14.
2-Isopropyl-4′-t-butyldiphenyl Ether (Table 2, Entry 13). General
procedure A (workup method 1, ligand 3) was used to convert 4-tert-
butylphenyl triflate and o-isopropylphenol in 24 h to 230 mg (86%) of
1
the title compound, which was obtained as a colorless oil. H NMR
(CDCl3, 300 MHz) δ 7.36-7.30 (m, 1H), 7.33 (d, 2H, J ) 8.6 Hz),
7.18-7.08 (m, 2H), 6.90-6.85 (m, 1H), 6.88 (d, 2H, J ) 8.8 Hz),
3.33 (sept, 1H, J ) 6.9 Hz), 1.33 (s, 9H), 1.25 (d, 6H, J ) 6.9 Hz);
13C NMR (CDCl3, 125 MHz) δ 155.8, 154.0, 145.2, 140.0, 126.8, 126.7,
126.4, 123.8, 119.4, 117.2, 34.2, 31.5, 27.0, 23.0; IR (neat, cm-1) 2962,
1509, 1486, 1233. Anal.Calcd for C19H24O: C, 85.03; H, 9.01. Found:
C, 84.82; H, 8.76.
2,5-Dimethyl-4′-methoxydiphenyl Ether (Table 2, Entry 9). An
oven-dried resealable Schlenk tube was charged with the sodium salt
of p-methoxyphenol (88 mg, 0.6 mmol) in a nitrogen-filled glovebox.
The tube was sealed, removed from the glovebox, fitted with a septum,
and purged with argon. The septum was removed, and then palladium
acetate (2.2 mg, 0.02 mmol, 2.0 mol %) and 4 (6.6 mg, 3.0 mol %)
were added. The tube was capped with a septum and purged with argon.
Toluene (1.5 mL) and 2-chloro-p-xylene (67 µL, 0.5 mmol) were added
via syringe, then the tube was sealed with a Teflon screwcap, and the
reaction mixture was stirred at 110 °C for 24 h. The reaction mixture
was allowed to cool to room temperature and was then diluted with
ether (20 mL), filtered, and concentrated. The crude material was
purified by flash chromatography on silica gel to afford 113 mg (99%)
3-Methoxy-2′-methyldiphenyl Ether (Table 2, Entry 14).39 General
procedure A (workup method 1, ligand 3) was used to convert
3-bromoanisole and o-cresol in 19 h to 186 mg (87%) of the title
1
compound, which was obtained as a colorless oil. H NMR (CDCl3,
300 MHz) δ 7.26 (d, 1H, J ) 7.3 Hz), 7.22-7.16 (m, 2H), 7.08 (dt,
1H, J ) 7.3, 1.3 Hz), 6.95 (dd, 1H, J ) 8.0, 1.3 Hz), 6.61 (ddd, 1H,
J ) 8.5, 2.4, 1.3 Hz), 6.50 (d, 1H, J ) 1.3 Hz), 6.48 (ddd, 1H, J )
8.5, 2.4, 1.3 Hz), 3.78 (s, 3H), 2.25 (s 3H); 13C NMR (CDCl3, 125
MHz) δ 161.1, 159.4, 154 4, 131.6, 130.3, 130.2, 127.4, 124.4, 120.3,
109.6, 108.0, 103.6, 55.5, 16.3; IR (neat, cm-1) 1580, 1486, 1227. Anal.
Calcd for C14H14O2: C, 78.48; H, 6.59. Found: C, 78.56; H, 6.84.
4-n-Butyldiphenyl Ether (Table 2, Entry 15). General procedure
B (workup method 2, ligand 5) was used, except that the quantities of
phenol (2.0 mmol), sodium hydride (2.4 mmol), palladium acetate (9.0
mg, 0.04 mmol, 4.0 mol %), and ligand 5 (22 mg, 0.06 mmol, 6.0 mol
%) were employed to convert 4-n-butyl-1-chlorobenzene and phenol
in 24 h at 115 °C to 142 mg (63%) of the title compound, which was
1
of the title compound as an off-white solid, mp 55-56 °C. H NMR
(CDCl3, 300 MHz) δ 7.11 (broad d, 1H, J ) 7.7 Hz), 6.91-6.81 (m,
5H), 6.62 (broad s, 1H), 3.80 (s, 3H), 2.25 (s, 3H), 2.23 (s, 3H); 13C
NMR (CDCl3, 75 MHz) δ 155.5, 155.1, 151.2, 136.9, 131.0, 125.8,
123.8, 119.2, 118.7, 114.7, 55.6, 21.0, 15.8; IR (neat, cm-1) 2923, 1501,
1030. Anal. Calcd for C15H16O2: C, 78.92; H, 7.06. Found: C, 79.01;
H, 7.24.
2,2′,5,6′-Tetramethyldiphenyl Ether (Table 2, Entry 10). An oven-
dried resealable Schlenk tube was charged with sodium 2,6-dimeth-
ylphenolate (89 mg, 0.62 mmol) in a nitrogen-filled glovebox. The tube
was sealed and removed from the glovebox, fitted with a septum, and
purged with argon. The septum was removed, and then Pd2(dba)3 (5.9
mg, 0.0125 mmol, 2.5 mol % Pd) and 4 (8.5 mg, 3.75 mol %) were
added. The tube was capped with a septum and purged with argon.
Toluene (1.5 mL) and 2-chloro-p-xylene (70 µL, 0.515 mmol) were
added via syringe, and then the tube was sealed with a Teflon screwcap
and placed in a 115 °C oil bath and stirred for 24 h. The reaction mixture
was allowed to cool to room temperature and was then diluted with
ether (20 mL), filtered, and concentrated. The crude material was
purified by flash chromatography on silica gel to afford 97 mg (83%)
1
obtained as a colorless oil. H NMR (CDCl3, 300 MHz) δ 7.33 (dd,
2H, J ) 8.7, 7.4 Hz), 7.15 (d, 2H, J ) 8.6 Hz), 7.08 (t, 1H, J ) 7.4
Hz), 7.00 (dd, 2H, J ) 8.7, 1.0 Hz), 6.34 (d, 2H, J ) 8.6 Hz), 2.60 (t,
2H, J ) 7.4 Hz), 1.61 (quint, 2H, J ) 7.4 Hz), 1.37 (sext, 2H, J ) 7.4
Hz), 0.95 (t, 3H, J ) 7.4 Hz); 13C NMR (CDCl3, 125 MHz) δ 157.7,
154.8, 137.9, 129.6, 129.5, 122.8, 118.9, 118.4, 34.9, 33.8, 22.3, 14.0;
IR (neat, cm-1) 2929, 1590, 1488, 1235. Anal. Calcd for C16H18O: C,
84.91; H, 8.02. Found: C, 84.89; H, 7.88.
3,4′,5-Trimethyldiphenyl Ether (Table 2, Entry 16).4 General
procedure B (workup method 1, ligand 5) was used to convert 5-bromo-
m-xylene and p-cresol in 24 h to 186 mg (88%) of the title product,
which was obtained as a colorless oil.
1
of the title compound as a colorless oil. H NMR (CDCl3, 500 MHz)
δ 7.15-7.07 (m, 4H), 6.72 (broad d, 1H, J ) 7.5 Hz), 6.10 (broad s,
1H), 2.42 (s, 3H), 2.18 (s, 3H), 2.15 (s, 6H); 13C NMR (CDCl3, 125
MHz) δ 155.5, 151.5, 136.6, 131.4, 130.7, 128.9, 124.7, 122.8, 121.6,
112.4, 21.2, 16.2, 15.9; IR (neat, cm-1) 2923, 1507, 1192. Anal. Calcd
for C16H18O: C, 84.91; H, 8.02. Found: C, 84.99; H, 8.16.
Acknowledgment. The National Institutes of Health (GM
58160) and the National Cancer Institute (Training grant NCI
No. CI T32CA09112) provided financial support for this work
for which we are grateful. We also acknowledge Pfizer, Merck,
and Novartis for additional unrestricted support. J.P.W. is a
recipient of a fellowship from the Organic Division of the
American Chemical Society sponsored by Schering-Plough, and
A.A. is a Knut & Alice Wallenberg Foundation Postdoctoral
Fellow for which they are thankful. We are indebted to Dr. Ken
Kamikawa for developing the synthesis of 2-N,N-(dimethyl-
amino)-2′-bromo-1,1′-binaphthyl. We thank Professor John
Hartwig (Yale University) for informing us of related results
prior to publication.
4-Methoxy-2′-methyldiphenyl Ether (Table 2, Entry 11).38 General
procedure A (workup 1, ligand 6) was used to convert 4-chloroanisole
and o-cresol in 26 h to 156 mg (73%) of the title compound, which
1
was obtained as a colorless oil. H NMR (CDCl3, 300 MHz) δ 7.23
(broad d, 1H, J ) 7.2 Hz), 7.12 (broad t, 1H, J ) 7.8 Hz), 7.00 (broad
t, 1H, J ) 7.5 Hz), 6.92-6.83 (m, 4H), 6.79 (broad d, 1H, J ) 8.1
Hz), 3.89 (s, 3H), 2.23 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 155.8,
155.2, 151.0, 131.3, 129.0, 126.9, 123.0, 119.3, 118.0, 114.8, 55.7,
16.2; IR (neat, cm-1) 2952, 1503, 1225. Anal. Calcd for C14H14O2: C,
78.48; H, 6.59. Found: C, 78.43; H, 6.28.
Note Added in Proof. (1) Following the acceptance of this
manuscript, related studies by Hartwig have been published:
(37) Zeller, K.-P., Berger, S. J. Chem. Soc., Perkin Trans. 2 1977, 54-
58.
(38) Van Duzee, E. M.; Adkins, H. J. Am. Chem. Soc. 1935, 57, 7, 147-
150.
(39) Fujikawa, F.; Nakamura, I. J. Pharm. Soc. Jpn. 1944, 64, 274-
276; Chem. Abstr. 1951, 2906.

4378 J. Am. Chem. Soc., Vol. 121, No. 18, 1999
Aranyos et al.
Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am.
Chem. Soc. 1999, 121, 3224-3225. (2) Recent experiments in
our labs have demonstrated that under identical conditions,
reactions which employ 2-(di-tert-butylphosphino)-1,1′-binaph-
thyl (the desamino derivative of 4) provide results similar to
those which use 4.
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