A new biarylphosphine ligand for the Pd-catalyzed synthesis of diaryl ethers under mild conditions

Article abstract of DOI:10.1021/ol202955h

A new bulky biarylphosphine ligand (L8) has been developed that allows the Pd-catalyzed C-O cross-coupling of a wide range of aryl halides and phenols under milder conditions than previously possible. A direct correlation between the size of the ligand substituents in the 2′, 4′, and 6′ positions of the nonphosphine containing ring and the reactivity of the derived catalyst system was observed. Specifically, the rate of coupling increased with the size of these substituents.

Full text of DOI:10.1021/ol202955h

ORGANIC
LETTERS
2012
Vol. 14, No. 1
170–173
A New Biarylphosphine Ligand for the
Pd-Catalyzed Synthesis of Diaryl Ethers
under Mild Conditions
Luca Salvi, Nicole R. Davis, Siraj Z. Ali, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139, United States
*sbuchwal@mit.edu
Received November 2, 2011
ABSTRACT
A new bulky biarylphosphine ligand (L8) has been developed that allows the Pd-catalyzed CꢀO cross-coupling of a wide range of aryl halides and
phenols under milder conditions than previously possible. A direct correlation between the size of the ligand substituents in the 20, 40, and 60
positions of the nonphosphine containing ring and the reactivity of the derived catalyst system was observed. Specifically, the rate of coupling
increased with the size of these substituents.
Diaryl ethers are routinely found as structural elements
in natural products and other biologically active com-
pounds.1 Traditionally, the synthesis of such ethers has
been accomplished via Ullmann cross-couplings, which
employ aryl halides and sodium or potassium aryloxides
in the presence of a stoichiometric (or greater) amount of
a copper species at elevated temperatures (125ꢀ220 °C).2
Unfortunately, these relatively harsh conditions are not
well tolerated for many synthetic applications. Conse-
quently, several modifications to the original Ullmann
conditions have been developed, allowing this reaction to
be run with a catalytic amount of copper and under
milder conditions.3
Alternatives to Cu-mediated or -catalyzed protocols
are Pd-catalyzed CꢀO cross-coupling methods, several of
which have been described employing a variety of
phosphine-based ligands suitable for Pd.4 In 2006 it was
demonstrated that the use of sterically hindered, electron-
rich biarylphosphine ligands, such as t-BuXPhos or
Me4t-BuXPhos (L1 and L2, Table 1), afforded catalyst
systems which could effectively promote the desired
(4) (a) Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi,
J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369–4378. (b)
Widenhoefer, R. A.; Zhong, H. A.; Buchwald, S. L. J. Am. Chem. Soc.
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Chem. Soc. 1998, 120, 6504–6511. (d) Mann, G.; Hartwig, J. F. Tetra-
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1997, 119, 10539–10540. (b) Palomo, C.; Oiarbide, M.; Lopez, R.;
Gomez-Bengoa, E. Chem. Commun. 1998, 2091–2092. (c) Gujadhur,
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r
10.1021/ol202955h
Published on Web 12/19/2011
2011 American Chemical Society

transformation under milder conditions and with a wider
substrate scope than was previously possible.5 How-
ever, the temperatures required were still >100 °C, and
most heteroaryl halides or heteroaromatic and electron-
deficient phenols were not competent substrates with this
system.
2-bromo-p-xylene and o-cresol at rt.10 Under these con-
ditions, none of our previously reported ligands bearing
i-Pr substituents on the nonphosphine containing ring
gave more than a 15% yield of the diaryl ether product
(Table 1, L1ꢀL6).9b,11
Prior to the current report, the only example of a Pd-
catalyzed intermolecular CꢀO coupling at rt was that of
the sodium salt of 4-methoxyphenol with 2-bromotoluene, a
reaction that required 5 mol % Pd and required 70 h
of reaction time using Ph5FcP(t-Bu)2 (QPhos) as the
ligand.4f Thus, the development of a method that allows
a general synthesis of diaryl ethers at rt and more gen-
erally under mild conditions, while increasing the scope of
applicable substrates, would be of significant interest.
Previous studies regarding the mechanism of this trans-
formation suggested reductive elimination as the prob-
able rate-limiting step in the catalytic cycle.6 Two
commonly used strategies for facilitating reductive elimi-
nation from Pd(II) centers are (1) to decrease the electron-
donating ability of the ligand4d,6e or (2) to increase
the steric bulk of the ligand around the phosphorus
center.4e,6d,7 Based on these considerations, we prepared
a new set of biarylphosphine ligands by modifying both
the phosphine and the biaryl backbone substituents.
Using these ligands, we sought to assess the effect of the
substituents in each position on the activity of the derived
catalyst in CꢀO bond-forming reactions.
Table 1. Study of the Relationship of Ligand Substituents to the
Activity of the Derived Catalyst
The synthesis of the ligands L7ꢀL12 commenced with
the preparation of the precursor to the bottom (non-
phosphine-containing) ring. Thus, 1,3,5-tricyclopentyl-,
1,3,5-tricyclohexyl-, and 1,3,5-tricycloheptyl-benzene
were prepared from benzene under conventional Friedelꢀ
Crafts conditions.8 These trisubstituted benzenes were
then converted to the corresponding bromides by treat-
ment with Br2. The overall yields from benzene were 68%,
50%, and 38%, respectively. These, along with commer-
cially available 1-bromo-2,4,6-tri-tert-butylbenzene, were
subsequently converted to L7ꢀL12 via procedures ana-
logous to those previously reported.9
a Yields were calculated by GC using dodecane as an internal
standard.
By employing ligand L7 under identical conditions, the
desired product could be obtained in 22% yield. Further-
more, catalyst systems derived from L8 and L10 (R1 = Cy)
furnished the diaryl ether product in 54% and 32%
yields, respectively. In contrast, the desired product was
obtained in only 19% yield when using L9 as the ligand,
suggesting that while a larger substituent is beneficial at
these positions, one that is too large may inhibit the
reaction. This effect was corroborated by the observation
that by using L12 as the ligand, which bears tert-butyl
groups at these positions, no product formation was
observed (Table 1, L12). The substitution pattern on the
phosphine-containing ring was also crucial to the reactiv-
ity of the catalyst system. For example, a catalyst derived
from L11, which lacks substituents on the upper ring,
provided the product in a yield similar to that observed
when L1 was employed. Thus, L8 was chosen as the
optimal ligand and was used in further studies.
The effectiveness of these new ligands in facilitating the
desired transformations was assessed as shown in Table 1.
As our starting point, we examined the coupling of
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6583.
We next examined the role of the solvent in this
transformation. We discovered that by employing 1,2-
dimethoxyethane (DME) as a more polar cosolvent in
addition to toluene, we were able to obtain the desired
(10) (a) We chose [(cinnamyl)PdCl]2 as our Pd source, since it has
been demonstrated to generate the active Pd(0) species at lower tem-
peratures than other commonly used precursors. (b) We were unable to
employ palladium precatalysts of the type we have recently reported as
we are unable to prepare them using tert-butylphosphino biaryls other
than t-BuXPhos.
(11) (a) Dooleweerdt, K.; Fors, B. P.; Buchwald, S. L. Org. Lett.
2010, 12, 2350–2353. (b) Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc.
2009, 131, 12898–12899. (c) Wu, X.; Fors, B. P.; Buchwald, S. L. Angew.
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Cuezva, A. M.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 16720–
16734.
Org. Lett., Vol. 14, No. 1, 2012
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product in consistently higher yields as compared to
reactions conducted in pure toluene.12 The proper choice
of base was also crucial for this transformation, and the
use of 1 equiv of K3PO4 proved to be optimal.12 Finally,
we examined various Pd sources. Not surprisingly, a
catalyst based on Pd(OAc)2 was completely inactive at
40 °C, as reduction to Pd(0) likely does not occur under
these conditions. We found [(cinnamyl)PdCl]2 to be the
most efficient Pd source, as it provided consistently
superior yields to those obtained when Pd(0) sources such
as Pd2dba3 were employed.12,13
Scheme 2. Example of a Low Catalyst Loading Application
in high yields (Scheme 1, 10ꢀ11). Both 3-Br- and 3-Cl-N,
N-dimethylaniline could be coupled to afford the desired
products in 87% and 83% yields, respectively (Scheme 1,
12, 13). Finally, an electron-rich aryl bromide, 4-Br-
anisole, could be coupled at 80 °C with both o-cresol
and 2-i-Pr-phenol in good yields (Scheme 1, 14, 15).
Scheme 1. Pd-Catalyzed CꢀO Bond Formation with a Catalyst
Based on L8 under Mild Conditionsa
Scheme 3. Pd-Catalyzed CꢀO Bond Formation Employing
Aryl or Heteroaryl Bromides and Aryl or Heteroaryl Phenols
with a Catalyst Based on L8a
a Reaction conditions: ArBr (1 mmol), phenol (1.5 mmol), K3PO4
(1.5 mmol), L8, [(cinnamyl)PdCl]2, toluene/DME (0.6/0.3 mL), rt, 16 h;
isolated yields, average of two runs. bL8 (2.25 mol %), [(cinnamyl)PdCl]2
(0.75 mol %). c40 °C. d80 °C. e100 °C.
a Reaction conditions: aryl bromide (1 mmol), phenol (1.5 mmol),
K3PO4 (1.5 mmol), L8 (1.5 mol %), [(cinnamyl)PdCl]2 (0.5 mol %),
toluene/DME (0.6/0.3 mL), 80 °C, 16 h; isolated yields, average of two
runs. bL8 (4.5 mol %), [(cinnamyl)PdCl]2 (1.5 mol %), 100 °C. cL8 (2.25
mol %), [(cinnamyl)PdCl]2 (0.75 mol %), 60 °C. dL8 (3.0 mol %),
[(cinnamyl)PdCl]2 (1.0 mol %).
We next probed the substrate scope using the optimal
L8/[(cinnamyl)PdCl]2 combination. We began our inves-
tigation by examing the rt coupling of electron-deficient
aryl bromides with electron-rich and -neutral phenols.
Both substrate combinations were efficient in this trans-
formation, providing the desired products in high yields
(Scheme 1, 1ꢀ9). These rt processes could be conducted
with moderate loadings of Pd (1ꢀ2%). It should be noted
that the product from the coupling of 4-chlorophenol and
p-cyanobromobenzene was obtained in 92% yield; there
was no evidence of products resulting from oxidative
addition of the CꢀCl bond (Scheme 1, 2).
Our focus then turned to the synthesis of diaryl ether
products derived from heteroaromatic substrates. Mol-
ecules containing 3-(aryloxy)pyridines have garnered sig-
nificant interest within the medicinal chemistry com-
munity over the past 10 years.14 However, methods for
the synthesis of this molecular fragment are still limited to
Cu-catalyzed processes, which require high temperatures
and often result in low product yields under conditions
with poor functional group tolerance.15 To test the limits
of our catalyst system based on L8, we thus chose to focus
on 3-hydroxypyridine, since it is electron-deficient and
possesses a heteroatom capable of coordinating to a
Pd(II) center. Nonetheless, by using our catalyst system
we found that it could be coupled effectively with an
electron-neutral aryl bromide at 100 °C (Scheme 3, 16) or
with electron-deficient aryl bromides at even milder
temperatures (Scheme 3, 17ꢀ20).
The increased activity of the catalyst based on L8
enabled us to demonstrate the utility of this system on a
large scale and with low catalyst loadings. By raising the
temperature to 100 °C, the synthesis of 3 could be carried
out on a 10 mmol scale employing 0.025 mol % of
[(cinnamyl)PdCl]2 and 0.075 mol % of L8. The isolated
yield in this case was 80% (Scheme 2).
We next focused our investigation on reactions of
electron-neutral and -rich aryl bromides. While these
coupling processes were not efficient at rt, at 40 °C
2-Br-p-xylene could be coupled with phenol and o-cresol
(14) See the Supporting Information for a list of patents related to
this class of compounds.
(15) (a) Renshaw, R. R.; Conn, R. C. J. Am. Chem. Soc. 1937, 59,
297–301. (b) Butler, D. E.; Poschel, B. P. H; Marriott, J. G. J. Med.
Chem. 1981, 24, 346–350. (c) Kawasuji, T.; Yoshinaga, T.; Sato, A.;
Yodo, M.; Fujiwara, T.; Kiyama, R. Biorg. Med. Chem. 2006, 14, 8430–
8445.
(12) See the Supporting Information for detailed experimental
information.
(13) Marion, N.; Navarro, O.; Mei, J.; Stevens, E. D.; Scott, N. M.;
Nolan, S. P. J. Am. Chem. Soc. 2006, 128, 4101–4111.
172
Org. Lett., Vol. 14, No. 1, 2012

A wide range of bromopyridine electrophiles were also
suitable substrates using lower catalytst loadings than
previously reported. For example, using our previous best
ligand the coupling of 3-bromopyridine with o-cresol
required 8 mol % Pd at 115 °C, while the coupling of
3-bromoquinoline required 4 mol % Pd at the same
temperature.5 Employing the current protocol, 1 mol %
Pd at 80 °C was sufficient to provide the product in 69%
yield in the case of 3-bromopyridine (Scheme 3, 21), while
1.5 mol % Pd and 60 °C were sufficient for the cross-
coupling of 3-bromoquinoline (Scheme 3, 22ꢀ23). All
other 3-bromopyridine substrates were coupled with
phenol, o-cresol, and 4-OH-anisole at 80 °C to provide
products in yields ranging from 75 to 88% (Scheme 3,
24ꢀ27). Finally, the coupling of 5-bromopyrimidine with
o-cresol provided the desired product in 72% yield
(Scheme 3, 28).
To test the limits of our new catalyst system further, we
applied it to traditionally recalcitrant substrates such as
five-membered-ring heteroaryl halides, as well as aryl
halides containing functional groups with acidic protons.
Those containing free carboxylic acids were not suitable
substrates; however, secondary amide-containing sub-
strates could be effectively coupled simply by including
an extra equivalent of base (Scheme 4, 29ꢀ31). Hetero-
aromatic amides were also suitable coupling partners
(Scheme 4, 31). Significantly, compounds similar to 31
have been studied extensively in both industry and aca-
demia as potential antidepressant/anxiolytic agents
(SB-243213).16 We also found N-protected 4- and 6-
bromoindoles to be suitable substrates (Scheme 4, 32,
33). Finally, a variety of thiophenes could also be readily
combined with phenols. For example, 3-bromo-2-thio-
phenecarbaldehyde reacted readily at 40 °C, and while
3-bromo-4-methylthiophene required 100 °C, the corre-
sponding products were obtained in good yields (Scheme 4,
34ꢀ36). Additionally, 3-bromo-1-benzothiophene was
coupled effectively with phenol and 4-OH-anisole,
though a higher Pd loading (3 mol %) was required
(Scheme 4, 37, 38).17
Scheme 4. Pd-Catalyzed CꢀO Bond Formation Using Amides
and Heteroaromatic Aryl Bromides with a Catalyst Based on
L8a
a Reaction conditions: aryl halide (1 mmol), phenol (1.5 mmol),
K3PO4 (1.5 mmol), L8 (3.0 mol %), [(cinnamyl)PdCl]2 (1.0 mol %),
toluene/DME (0.6/0.3 mL), 100 °C, 16 h; isolated yields, average of two
runs. bK3PO4 (3.0 mmol). cL8 (1.5 mol %), [(cinnamyl)PdCl]2 (0.5 mol
%). dL8 (1.5 mol %), [(cinnamyl)PdCl]2 (0.5 mol %), 40 °C. eL8 (4.5 mol
%), [(cinnamyl)PdCl]2 (1.5 mol %).
[(cinnamyl)PdCl]2, in combination with new ligand L8
that facilitates the synthesis of diaryl ethers under mild
conditions. The increased reactivity of the catalyst based
on L8 allows CꢀO cross-coupling to occur at rt in several
cases and further allows coupling to occur between pre-
viously unreactive coupling partners. Interestingly, the
ligands synthesized for this study demonstrate how a
seemingly small difference in the size of the substituents
of the lower (nonphosphine-containing) ring of biaryl-
phosphine ligands can significantly affect the reactivity of
the resulting catalysts. The structural features of the
catalysts derived from L7ꢀL12 and their mechanistic
implications are the object of ongoing study in our
laboratory.
Acknowledgment. We thank the National Institutes
of Health for financial support of this work (Grant
GM58160). This activity was also partially supported by
an educational donation provided by Amgen. We thank
FMC Lithium for a generous gift of tert-Bu2PCl. We also
In summary, we have developed a new catalytic sy-
stem which employs a more reactive Pd source,
´
thank Jorge Garcıa Fortanet (Novartis ꢀ Cambrige MA)
for first synthesizing L7 and L8.
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Duckworth, D. M.; Forbes, I. T.; Gaster, L. M.; Ham, P.; Jones,
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Supporting Information Available. Experimental pro-
cedures and characterization data for all new and known
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(17) For alternative synthesis of these diaryl ethers, see: (a) Palkowitz,
A. D.; Glasebrook, A. L.; Thrasher, K. J.; Hauser, K. L.; Short, L. L.;
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