An expeditious aqueous Suzuki-Miyaura method for the arylation of bromophenols

Article abstract of DOI:10.1016/j.tetlet.2006.04.027

The development of a novel Suzuki-Miyaura method has been achieved to allow the efficient arylation of bromophenols. A range of functionality is tolerated with regard to the boronic acid coupling partner and the reaction exhibits complete chemoselectivity for the C_aryl-Br bond versus the C_aryl-Cl bond in the aryl halide input. The experimental protocol features a short reaction time of 15 min, utilizes inexpensive Pd/C as a catalyst, and is conducted with water as the solvent.

Full text of DOI:10.1016/j.tetlet.2006.04.027

Tetrahedron Letters 47 (2006) 4275–4279
An expeditious aqueous Suzuki–Miyaura method
for the arylation of bromophenols
Joel S. Freundlicha,* and Howard E. Landisb
aJacobus Pharmaceutical Company, Department of Medicinal Chemistry, 37 Cleveland Lane, Princeton, NJ 08540, USA
bJacobus Pharmaceutical Company, Department of Analytical Chemistry, 37 Cleveland Lane, Princeton, NJ 08540, USA
Received 17 March 2006; revised 3 April 2006; accepted 5 April 2006
Abstract—The development of a novel Suzuki–Miyaura method has been achieved to allow the efficient arylation of bromophenols.
A range of functionality is tolerated with regard to the boronic acid coupling partner and the reaction exhibits complete chemo-
selectivity for the Caryl–Br bond versus the Caryl–Cl bond in the aryl halide input. The experimental protocol features a short
reaction time of 15 min, utilizes inexpensive Pd/C as a catalyst, and is conducted with water as the solvent.
Ó 2006 Elsevier Ltd. All rights reserved.
The venerable Suzuki–Miyaura reaction,1,2 along with
other palladium-mediated carbon–carbon bond forma-
tion reactions, has experienced an explosion in utiliza-
tion in the field of organic synthesis in recent years.3,4
Applications of this catalytic reaction firmly grounded
in the tenants of organometallic chemistry have been
supported by catalyst system improvements that have
allowed an expansion in the reaction scope and effi-
ciency.5–8 The Suzuki–Miyaura reaction may be found
as a key reaction step in a number of elegant total syn-
theses of natural products.9
Scheme 1. First generation routes to target arylated phenol. Reagents
and conditions: (a) BnBr, K2CO3, EtOH, 50 °C (91%); (b) Pd(PPh3)4,
PhB(OH)2, aq Na2CO3, DME, 80 °C (53%); (c) H2, Pd/C, MeOH
(96%).
Our interest in the Suzuki–Miyaura reaction began with
the optimization of a series of diaryl ether phenols based
Suzuki–Miyaura reaction, conducted under standard
conditions,13 of the intermediate benzyl ether proceeded
only in 53% yield and the overall desired transformation
occurred in three steps in 46% yield. Without protection
of the phenol, the aryl bromide cross-coupled in a
slightly decreased overall yield of 32%. Clearly, a more
optimal way of conducting the Suzuki–Miyaura reaction
was needed, and a one step transformation from 1 to
provide the target class of arylated phenols was deemed
most desirable.
on the promise of triclosan as an antimalarial.10
A
straightforward approach to the functionalization of 4-
bromo-2-methoxyphenol (1) to provide a small family
of m-arylphenols is shown in Scheme 1. To the best of
our knowledge, the literature provides little if any prec-
edent for the utilization of the Suzuki–Miyaura reaction
to functionalize this electron-rich bromophenol.11 Our
first inclination was to avoid the potentially complicat-
ing presence of the phenol12 in this metal-catalyzed
reaction by protecting it as the benzyl ether. The
At the outset of this effort, we were cognizant of
literature precedent for the Suzuki–Miyaura reaction
of the regioisomeric parent bromophenols8,14–18 and
bromosalicylaldehydes,19,20 which may exhibit different
reactivity due to the presence of an intramolecular
hydrogen bond masking the phenolic hydrogen. All
of these reported substrates are less electron-rich than
Keywords: Phenols; Suzuki–Miyaura coupling; Microwave chemistry;
Green chemistry.
*
Corresponding author at present address: Princeton University,
Department of Chemistry, USA. Tel.: +1 609 258 9804; fax: +1 609
258 1980; e-mail: joelf@princeton.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.027

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J. S. Freundlich, H. E. Landis / Tetrahedron Letters 47 (2006) 4275–4279
1. We contemplated an exhaustive survey of these
and other published protocols, but instead opted for
the development of a novel Suzuki–Miyaura method
that would offer short reaction times and high yields
of the desired coupling product while utilizing a catalyst
system that was inexpensive and environmentally-
benign.
solution. With regard to potassium carbonate, 0.5–
3.0 equiv afforded assay yields >90%, with 2.0 equiv
being optimal. Potassium hydroxide provides slightly
higher yields than potassium carbonate and sodium
hydroxide. Significantly lower HPLC assay yields were
determined when utilizing Na2CO3 (Leadbeater proto-
col),31 Cs2CO3, CsF, KF, and K3PO4. An overall reac-
tion volume of ca. 3 mL (2.0 mL 1 M aq base +
1.0 mL water) was optimal, compared to volumes of
1–4 mL. The assay yield and purity showed little depen-
dence on microwave power, but did decrease slightly,
due to the formation of small amounts of unidentifiable
by-products, as the reaction time was increased from 15
to 60 min.
We were fascinated by the report of Hirao that offered
the promise of a green protocol.14 Hirao demonstrated
the Pd/C catalyzed coupling of some arylboronic acids
with a series of iodophenols in the presence of 3 equiv
of aqueous potassium carbonate at room temperature
for 12 h. While the functionalizations of the iodophenols
were high-yielding, the one example of coupling a bromo-
phenol—4-bromophenol—with phenylboronic acid
afforded only 35% of the desired product at room tem-
perature over 12 h and a 76% yield at 50 °C over 12 h.
Also, the number of functionalized arylboronic acids ex-
plored was limited to five. Hirao’s method is a worth-
while extension of work in the literature examining the
Pd/C catalyzed Suzuki–Miyaura reaction dating back
to Buchecker’s 1994 publication.21 Clearly, this type of
Suzuki–Miyaura method has the benefits of using
Pd/C, an easily removed and cost-effective catalyst that
does not require a phosphine ligand,22 and water as an
inexpensive, environmentally-benign, and readily-avail-
able solvent.23
Experimental investigations, thus, afforded an optimized
protocol that differed from Hirao’s in terms of the reac-
tion time, temperature, catalyst loading, amount and
nature of base, and the use of microwave reactor tech-
nology. The optimum protocol was determined to be
as follows: 1 mol % 10 wt % Pd/C, 1.1 equiv PhB(OH)2,
2.0 equiv 1 M aq KOH, 1.0 mL H2O, 120 °C, and 150 W
for a reaction time of 15 min. This protocol afforded a
99% HPLC assay yield of 2 with a purity of 97%. The
reaction product upon typical extractive workup was
suitable for subsequent synthetic transformations or
could be further purified via silica gel chromatography
to afford spectroscopically pure material with a yield
of 83% (average of three independent runs). Interest-
ingly, when conducted under these optimum conditions
in a pre-equilibrated oil bath,33 the reaction was charac-
terized by a 96% HPLC assay yield of the desired prod-
uct with a purity of 98%. It appears reasonable that our
Suzuki–Miyaura method does not rely on non-thermal
microwave effects34 and is transferable between the
microwave and conventional oil bath.
We, thus, chose to explore a Pd/C catalyzed aqueous
method and were struck by the potential for an applica-
tion of microwave reactor technology24–26 to arrive at a
cleaner and more rapid reaction. The literature prece-
dents are highlighted by contributions from Leadbeater
where his system is characterized by a very low loading
of a Pd source, an excess of aqueous sodium carbonate,
and the use of a phase transfer catalyst such as tetrabu-
tylammonium bromide.27–31 Leadbeater, however, has
only reported the Suzuki–Miyaura coupling of 4-iodo-
and 4-bromophenol.29 Our approach was to explore a
variant of the Hirao method, incorporating the benefit
of microwave reactor technology, while expanding on
their substrate scope to include a variety of bromo-
phenols and arylboronic acids.
An investigation was conducted on the scope of aryl-
boronic acids tolerated by this novel Suzuki–Miyaura
protocol (Table 1). The method performed well for the
tolylboronic acids (o-, m-, p-; entries 2–4). It is interest-
ing to note that whereas the reaction with o-tolylboronic
acid (entry 2) proceeded in 91% yield, the reaction with
the more sterically-encumbered 2,6-dimethylphenyl-
boronic acid (entries 5 and 6) occurred in negligible
yield. The catalyst system allowed coupling of the 1-
and 2-naphthyl groups (entries 7 and 8, respectively)
to the phenol scaffold in moderate yields. The introduc-
tion of heteroatoms to the arylboronic acid resulted in
lower isolated yields of the desired Suzuki–Miyaura
product (entries 9–13 and 18–19). It is interesting to note
that utilization of both electron-rich (entry 9) and elec-
tron poor (entries 10–19) arylboronic acids led to lower
isolated yields than when using electron-neutral aryl-
boronic acids (entries 1–4). While by-products such as
a homocoupled bis(phenol) were not detected, we can-
not rule out the degradation of the boronic acids via
protodeboronation30,35,36 or homocoupling.37 These
types of arylboronic acid decomposition pathways could
occur in the presence of a strong base at elevated
temperatures. In the instances where the functional
group (i.e., cyano, carbomethoxy, and acetamide) on
the arylboronic acid itself could be hydrolyzed, the use
Our explorations began with an optimization of the
Suzuki–Miyaura coupling of commercially available 1
with phenylboronic acid in a CEM Discovery/Explorer
microwave system. It must be noted that all reactions
were performed in air with commercial grade solvents
and reagents used without further purification. The
reaction variables explored32 were reaction time
(10–60 min), temperature (80–170 °C), reactor wattage
(25–300 W), amount of commercially available 10 wt %
Pd/C catalyst (0–5 mol %), type of base added as a solid
or aqueous solution, number of equivalents of base
(0–4), and total reaction volume (1–4 mL). An HPLC
assay allowed the determination of the yield of desired
4-phenyl-2-methoxyphenol 2.32
Reaction temperatures of 110–170 °C afforded assay
yields above 90%. Base was necessary for the reaction
to occur and could be added as a solid or a 1 M aqueous

J. S. Freundlich, H. E. Landis / Tetrahedron Letters 47 (2006) 4275–4279
Table 1. Coupling of 1 with arylboronic acids
4277
method to include these intriguing salts. It should be
noted that Molander recently published Pd(OAc)2
catalyzed ligandless conditions for coupling the less
electron-rich 4-bromophenol with potassium phenyltri-
fluoroborate with an 82% overall yield.40 Kabalka and
Al-Masum are to be credited with the first examples of
microwave promoted Suzuki–Miyaura couplings with
potassium aryltrifluoroborates.41
Entry
Ar
% Yielda
1b
2
3
4
5c
6c,d
7
Ph
83
91
90
89
4
o-Tolyl
m-Tolyl
p-Tolyl
2,6-Me2C6H4
An examination of the reaction scope in terms of aryl
bromides is shown in Table 2 and serves to benchmark
our optimized protocol versus those previously reported
in the literature. As expected, the regioisomers of
bromophenol (entries 1–3) reacted in high yield with
phenylboronic acid under the standard reaction condi-
tions. It is noteworthy that the isolated yield of the
4-phenylphenol (entry 3) is comparable to those
obtained with the elegant, but more elaborate catalyst
systems of both Buchwald5,6 and Fu and co-workers.8
Selectivity for the Caryl–Br bond versus the Caryl–Cl
bond was achieved when reacting 2-bromo-4-chloro-
phenol (entries 4 and 5). A slight increase in the number
of equivalents of phenylboronic acid (1.1–>1.5) was
necessary to consume all of the starting material phenol.
It is interesting to note that 4-chloro-2-methoxyphenol
(entries 6–9) did not react to any significant extent as
judged by LC–MS analysis of the crude reaction mix-
ture. With this substrate, the temperature was increased
to 190 °C and the reactor power was elevated to 300 W,
7
1-Naphthyl
2-Naphthyl
p-MeOC6H4
4-ClC6H4
58
48
31
35
16
0
8
9
10
11e
12
13f,g
14
15e
16h
17e,i
18
19e
2,4-Cl2C6H4
3-CNC6H4
2
39
70
10
36
4
4-MeO2CC6H4
4-Ac(H)NC6H4
10
a Isolated yield obtained of chromatographically and spectroscopically
homogeneous material using standard conditions (1 mol % 10 wt %
Pd/C, 1.1 ArB(OH)2, 2.0 equiv 1 M aq KOH, 1.0 mL H2O, 120 °C,
150 W, 15 min, microwave), unless noted otherwise.
b Yield represents mean for three independent trials.
c Yield approximated by HPLC.
d Reaction time of 1 h.
Table 2. Coupling of aryl halides with phenylboronic acid
e Use of 1.0 equiv KOH (1 M aq soln).
f Yield determined by 1H NMR integration.
g 2.2 equiv boronic acid, 1.0 equiv K2CO3 (1 M aq soln), 50 W.
h 48% isolated yield of corresponding benzoic acid hydrolysis product.
i 12% isolated yield of corresponding benzoic acid hydrolysis product.
Entry
ArX
% Yielda
1
2
3
4b
5c
2-Bromophenol
3-Bromophenol
4-Bromophenol
2-Bromo-4-chlorophenol
96
88
94
40
88
0
0
0
0
of only 1 equiv of potassium hydroxide led to improved
yields.
Given the lower yields observed with heteroatom func-
tionalized arylboronic acids, we were interested in
exploring the use the corresponding potassium aryltri-
fluoroborates, which appear to be less susceptible to
protodeboronation than their boronic acid counter-
parts.38,39 We briefly examined the coupling of 1 with
potassium phenyltrifluoroborate (Scheme 2). Clearly,
the phenyltrifluoroborate salt is less reactive than phen-
ylboronic acid under our experimental conditions and
further optimization will be necessary to expand our
6
4-Chloro-2-methoxyphenol
7d
8e
9f
10g,h
11g,i,j
12
3-Bromoanisole
46
65
81
3-Bromobenzoic acid
a Isolated yield of chromatographically and spectroscopically homo-
geneous material obtained using standard conditions (1 mol %
10 wt % Pd/C, 1.1 equiv PhB(OH)2, 2.0 equiv 1 M aq KOH, 1.0 mL
H2O, 120 °C, 150 W, 15 min, microwave), unless noted otherwise.
b Yield approximated by HPLC, which demonstrated the presence of
68% desired product and 18% starting material phenol.
c Standard protocol except for use of 1.5 equiv PhB(OH)2.
d Standard protocol except for usage of 300 W power.
e Standard protocol except for usage of 300 W power with continuous
cool setting.
f Standard protocol except for use of 300 W power and T = 190 °C.
g Yield determined by 1H NMR integration.
h 29% starting material anisole recovered.
i Standard protocol except for use of 1.5 equiv PhB(OH)2 and
t = 30 min.
Scheme 2. Attempted Suzuki–Miyaura couplings with potassium
phenyltrifluoroborate.
j 25% starting material anisole recovered.

4278
J. S. Freundlich, H. E. Landis / Tetrahedron Letters 47 (2006) 4275–4279
with and without simultaneous cooling of the reaction
vessel with a stream of compressed air to allow for
increased levels of microwave irradiation. Consistent
with these results is the observation that 3-chlorophenol
did not react under our standard reaction conditions
with phenylboronic acid. During the preparation of this
manuscript, Leadbeater reported the productive Suzu-
ki–Miyaura reaction of aryl chlorides, but not chlor-
ophenols, using his standard phase-transfer protocol
with the alterations of 300 W of reactor power and
simultaneous cooling.42
Supplementary data
Experimental details and characterization data for all
new compounds reported. Supplementary data associ-
ated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2006.04.027.
References and notes
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In conclusion, we have reported a novel Suzuki–Miyaura
method that addresses the need for a facile and rapid syn-
thesis of arylated phenols from their bromophenol pre-
cursor. The method also accepts bromobenzoic acids as
substrates and holds promise for the implementation of
potassium aryltrifluoroborates. The protocol exhibits
complete chemoselectivity for arylbromides versus aryl-
chlorides and is thus complementary to Leadbeater’s
method. We believe the use of the cost-effective and sim-
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may necessitate the more complex, expensive, and
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coupling to prepare a range of biologically-active small
molecules that may serve as leads in the development of
next-generation antimalarials.
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Acknowledgments
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´

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