Palladium-Catalyzed Suzuki Reactions in Water with No Added Ligand: Effects of Reaction Scale, Temperature, pH of Aqueous Phase, and Substrate Structure

Article abstract of DOI:10.1021/acs.oprd.6b00180

The heterogeneous palladium-catalyzed Suzuki reactions between model aryl bromides (4-bromoanisole, 4-bromoaniline, 4-amino-2-bromopyridine, and 2-bromopyridine) and phenylboronic acid have been successfully conducted in water with no added ligand at the 100 mL scale using 20-40 mmol of aryl bromide. The product yields associated with these substrates were optimized, and key reaction parameters affecting the yields were identified. The results clearly indicate that the reaction parameters necessary to achieve high yields are substrate-dependent. In addition, it is demonstrated that aqueous Suzuki reactions of substrates containing basic nitrogen centers can produce quantitative yields of desired products in the absence of added ligand.

Full text of DOI:10.1021/acs.oprd.6b00180

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Full Paper
Palladium-Catalyzed Suzuki Reactions in Water with no
Added Ligand: Effects of Reaction Scale, Temperature,
pH of Aqueous Phase, and Substrate Structure
Zhao Li, Carol Gelbaum, William L Heaner, Jason S. Fisk, Arvind
Jaganathan, Bruce Holden, Pamela Pollet, and Charles L. Liotta
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00180 • Publication Date (Web): 27 Jun 2016
Downloaded from http://pubs.acs.org on June 28, 2016
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PalladiumꢀCatalyzed Suzuki Reactions in Water with no
Added Ligand: Effects of Reaction Scale, Temperature,
pH of Aqueous Phase, and Substrate Structure
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Zhao Li, Carol Gelbaum, William L. Heaner IV, Jason Fisk, Arvind Jaganathan, Bruce Holden,
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,†,‡
Pamela Pollet, and Charles L. Liotta*
†
‡
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332
School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, Georgia
0332
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§
The Dow Chemical Company, Midland, Michigan 48674, USA
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TOC FIGURE
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ABSTRACT
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The heterogeneous palladiumꢀcatalyzed Suzuki reactions between model aryl bromides (4ꢀ
bromoanisole, 4ꢀbromoaniline, 4ꢀaminoꢀ2ꢀbromopyridine, and 2ꢀbromopyridine) and phenylboronic acid
have been successfully conducted in water with no added ligand at the 100ꢀmL scale using 20ꢀ40
millimoles of aryl bromide. The product yields associated with these substrates were optimized and key
reaction parameters affecting the yields were identified. The results clearly indicate that the reaction
parameters necessary to achieve high yields are substrate dependent. In addition, it is demonstrated that
aqueous Suzuki reactions of substrates containing basic nitrogen centers can produce quantitative yields
of desired products in the absence of added ligand.
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KEYWORDS: palladium catalysis without added ligand, Suzuki reactions in water, heterogeneous
catalysis, scaleꢀup, green and sustainable Suzuki reactions.
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INTRODUCTION
The palladiumꢀcatalyzed SuzukiꢀMiyaura coupling reaction has been extensively studied and
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widely used in both academia and industry. It is a particularly powerful synthetic strategy for the
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construction of numerous natural compounds, pharmaceuticals, agrochemicals, and polymers. Typical
systems for Suzuki coupling consist of an aryl bromide, an arylboronic acid or ester, catalytic quantities
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of Pd(0) or Pd(II) salts in the presence of a ligand, and the presence of added bases. The reactions are
usually conducted in an organic medium or in a biphasic organicꢀaqueous media. Ligand complexity can
vary greatly as a function of the application and reaction system requirement. For example, Suzuki
reactions with substrates that contain basic nitrogen centers, such as aromatic amines and pyridines,
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suffer from the limitations of slow rates and low yields
due to the competitive interaction between
However, the development of customized
ligands that strategically incorporate bulky and electronꢀrich groups enable high yields with reasonable
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the basic nitrogen center and the palladium catalyst.
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rates.
The increasing demand of modern chemical industry for green and sustainable processes calls for
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modifications of the Suzuki coupling conditions. These modifications include the development of
ligandꢀfree catalytic systems and the use of environmentally benign solvents such as water or ionic
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liquids. It is necessary to note that the terminologies of “ligandꢀfree” and “ligandless” commonly used
in literature specifically referred to a catalytic system with no added ligand. Although commercial or
designer ligands have been successfully employed in developing Suzuki coupling processes, the
economics associated with these ligands could be costꢀprohibitive in largeꢀscale production. As a
consequence, methodologies that do not require added customꢀdesigned or commercial ligands are
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desirable and have been explored.
In addition, compared to airꢀsensitive and expensive ligandꢀ
palladium complexes, ligandꢀfree palladium catalysts (e.g. Pd(OAc) and PdCl ) can be safely handled
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and easily removed from the reaction mixture. The literature contains many examples of aqueous Suzuki
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coupling reactions being conducted successfully in both the presence and the absence of added ligand.
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However, the limited solubility of the halogenated substrates and ligands in water often leads to slow
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rate and low yields. To overcome this limitation, alternative methodologies using waterꢀsoluble
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ligands,
organic coꢀsolvents,
phaseꢀtransfer catalysts
and inorganic salt promoters,
and
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heating with microwave or ultrasound were reported.
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In 1989, Bumagin et al. were the first to report a Pd(OAc) catalyzed Suzuki reaction of
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phenylboronic acid with aryl iodides containing a –OH or –COOH substituents; Na CO was employed
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as the base in neat water under an argon atmosphere. Later, a series of academic papers
reported
palladiumꢀcatalyzed Suzuki couplings of various aryl and allylic halides (I, Br, Cl) with no added ligand
or additives in hot water. Excellent yields (up to 99%) of crossꢀcoupling products were reported. As of
today, the ligandꢀfree catalytic systems in water have proven to be successful on milliliter scales (i.e. up
to 1 mmol of substrates with 1 ~ 5 mL of water). Few practical examples of larger scale Suzuki coupling
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reactions in water without any added ligand have been reported. Data on scales between small labꢀ
scale and commercialꢀscale reactions could have great importance for developing industrial processes. A
major reason could be that the Suzuki reactions in water are heterogeneous; the catalyst and substrate
have partial to minute solubility in water. Multiphasic systems are inherently difficult to scaleꢀup. Mass
transfer between phases and the possibility of interfacial reactions make the extrapolation of the results
from small to larger scale difficult.
Although the current literature reports encouraging results for aqueous Suzuki coupling reactions
without added ligand, the reported work has been limited to rather smallꢀscale reaction systems which
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limit the scope and applicability of ligandꢀfree processes.
In addition, a clear answer has not been
provided on whether the current ligandꢀfree/aqueous protocols are effective for the Suzuki couplings of
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unprotected basic nitrogen containing substrates at scales greater than a few milliliters. Herein, we report
00ꢀmL scale palladiumꢀcatalyzed Suzuki reactions with no added ligand in neat water involving four
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model substrates, three of which contain basic nitrogen centers. Pertinent reaction variables such as (a)
reaction scale, (b) the relative amounts of the substrate, base, and Pd catalyst, and (c) the initial and final
pH of the aqueous phase are reported.
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RESULTS AND DISCUSSION
(1) Reaction Protocol Development for Model Aryl Bromide Substrates
While Suzuki coupling reactions in water with no added ligand have been reported in the
literature, these reactions were conducted on a relatively small scale—usually 1 to 4 mL and sometimes
at 10 mL involving only 0.5 – 1 mmol of substrates. It is important to note that all of these reactions
were heterogeneous and, from a process point of view, mass transfer can become an issue as the scale of
heterogeneous reaction processes is increased. In order to determine the best protocols for aqueous,
ligandꢀfree Suzuki reactions on a substantially larger scale (20ꢀ40 millimoles aryl bromide in 100 mL
water), preliminary experiments were performed on a series of widely different aryl bromides with
phenylboronic acid (PhB(OH) ). The aryl bromides investigated were 4ꢀbromoanisole, 4ꢀbromoaniline,
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ꢀaminoꢀ2ꢀbromopyridine, and 2ꢀbromopyridine. It is important to note that the latter three substrates
possess basic nitrogen centers which, in the absence of added ligand, could possibly act as ligands for
the Pd catalyst and potentially retard or prevent successful coupling. This concern was an integral
component of our protocol development. At the 100 mL scale, 20 or 40 mmol of aryl bromide were
o
reacted with 1.1 equivalents of phenylboronic acid at 100 C for periods of time varying from 1 to 4
hours (Scheme 1). In order to minimize the number of variables in this investigation dealing with the
reaction scale, the pH of the aqueous phase, and the substrate structure, we chose to use an industrially
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attractive base: K PO . It is inexpensive and easily separated from the organic product postꢀreaction.
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Each of these reactions was conducted under a nitrogen atmosphere. The use of an inert atmosphere was
considered especially important for the substrates containing basic nitrogen centers which could be the
points of reaction with atmospheric oxygen. The results are summarized in Table 1. The yields for all
four model substrates are high and the isolated yields are consistent with the yields determined by GC
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and H NMR. As a consequence, GC and/or H NMR were employed for inꢀsitu determination of the
yields for the coupling reactions for a wide variety of aryl substrates presented later in this report.
Scheme 1. PalladiumꢀCatalyzed Suzuki Coupling Reactions in Water with no Added Ligand
Table 1. Comparison of Reaction Yields Determined by Various Analytic Methods
Time
Yield (%)
Entry
Aryl Bromide
Product
e
1
(
h)
Isolated
GC
H NMR
a
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75
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76
(
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2)
(5)
(6)
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(
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(
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4)
(7)
(8)
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(
a
Reaction conditions: 4ꢀbromoanisole (40 mmol), PhB(OH) (44 mmol), K PO (84 mmol), Pd(OAc) (5 mol%),
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4
2
o
H O (100 mL), N , 100 C.
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b
Reaction conditions: 4ꢀbromoaniline (40 mmol), PhB(OH) (44 mmol), K PO (40 mmol), Pd(OAc) (0.25 mol%),
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3
4
2
o
H O (100 mL), N , 100 C.
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c
Reaction conditions: 4ꢀaminoꢀ2ꢀbromopyridine (40 mmol), PhB(OH) (44 mmol), K PO (40 mmol), Pd(OAc) (2
2
3
4
2
o
mol%), H O (100 mL), N , 100 C.
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d
Reaction conditions: 2ꢀbromopyridine (20 mmol), PhB(OH) (22 mmol), K PO (22 mmol), Pd(OAc) (2 mol%),
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H O (100 mL), N , 100 C.
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e
by column chromatographic separation.
Several additional experimental observations are pertinent. (1) Visually the four model reactions
differed greatly (Table S1, Supporting Information (SI)). For the reactions involving solid aryl
bromides (4ꢀbromoaniline and 4ꢀaminoꢀ2ꢀbromopyridine), two phases were observed—a solid phase
composed of catalyst and substrate and an aqueous phase. In the case of the liquid aryl bromides (4ꢀ
bromoanisole and 2ꢀbromopyridine) an additional organic phase was present. (2) Under the conditions
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described in Table 1, PhB(OH) was completely dissolved in the aqueous phase in the presence of base.
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(
3) In all cases only small amounts (< 5%) of biphenyl were detected by both GC and H NMR which is
consistent with the homoꢀcoupling of the excess PhB(OH) . The homoꢀcoupling of aryl bromide
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substrates was only observed in the reaction of 2ꢀbromopyridine; approximately 10% of the substrate
was consumed with the formation of 2,2’ꢀbipyridyl. (4) With the exception of the 4ꢀbromoanisole
substrate, the formation of palladium black was not observed. It should be emphasized, however, that in
this case 5 mol% Pd catalyst was employed compared to 0.25 mol% for 4ꢀbromoaniline and 2 mol% for
4
ꢀaminoꢀ2ꢀbromopyridine and 2ꢀbromopyridine.
Using the above model reactions and accompanying protocols as points of reference the
following variables were investigated in order to determine how certain critical parameters influence the
yield of coupled product. These include (a) reaction scale, (b) the relative amounts of the substrate, base,
and Pd catalyst employed, and (c) the initial and final pH of the aqueous phase. Each of the model
substrates is addressed individually with respect to several of these reaction variables. The results of this
study illustrate that the conditions necessary for maximizing yields of product is clearly substrate
dependent.
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(
2) Suzuki Coupling Reactions of 4ꢀBromoanisole in Water with no Added Ligand
The results of the Suzuki crossꢀcoupling of 4ꢀbromoanisole with PhB(OH) in water was
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conducted at scales ranging from 1ꢀmL to 100ꢀmL. The results are summarized in Table 2. In each of
the experiments the ratio of substrate (1) to water was held constant. On 1ꢀmL scale, the product yield
obtained was only 37 % (Entry 1, Table 2) which is in agreement with the reported low yield (25%) by
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Liu et al obtained using the identical catalytic system (Pd(OAc) /K PO /H O) conducted on the same
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reaction scale. The yield, however, increased to 68 – 77% at scales of 10 to 100 mL. It is important to
note that the product yields were consistent regardless of the choice of reactor—glass tubes or roundꢀ
bottom flasks (Entry 2 and 3, Table 2). In order to minimize or eliminate the possible impact of mass
transfer on reaction rate and product yield all of these heterogeneous reactions were conducted with
magnetic stirring at rates varying from 600 – 800 rpm. The results in Table 2 suggest that with
controlled stirring rates the Suzuki coupling reaction of 4ꢀbromoanisole produces reasonably high yields
at scales of 10 mL and greater.
Table 2. ScaleꢀDependent Yields of Suzuki Coupling Reactions of 4ꢀBromoanisole with PhB(OH)
in Water
2
a
4ꢀBromoanisole (mmol)/H O (mL) = 0.4
2
Entry
4ꢀBromoanisole (mmol)
H O (mL)
GC Yield (%)
2
b
1
2
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4
0.4
4.0
4.0
20
1
10
10
50
100
37
68
69
77
74
b
c
c
c
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40
a
Reaction conditions: 4ꢀbromoanisole (0.4 mmol/1 mL H O, 1.0 equiv), PhB(OH) (1.1 equiv), K PO (2.1
2
2
3
4
o
equiv), Pd(OAc) (5 mol%), N , 100 C, 4 h.
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2
b
c
Reaction was run in a 20ꢀmL Carousel reaction tube with magnetic stirrer.
Reaction was run in a roundꢀbottom flask with magnetic stirrer.
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As indicated in Table 2 all reactions were conducted under an inert nitrogen atmosphere. The
question regarding the necessity for conducting this coupling reaction under an inert atmosphere was
also explored. Companion experiments for the reaction of 4ꢀbromoanisole were conducted in the
presence of air or under a blanket of nitrogen (Pd(OAc) , PhB(OH) , K PO , 4 hours). The results are
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
3
4
summarized in Table S2, SI. Similar product yields were obtained under both air and nitrogen and at
two palladium catalyst loadings.
The effects of several reaction variables (mole% Pd catalyst, equivalents of PhB(OH) and
2
K PO , and reaction time) on the yield of coupled product in the reaction of 40 mmol of 4ꢀbromoanisole
3
4
with PhB(OH) in 100 mL of water are summarized in Table 3. In addition, the measured initial and
2
final pH of the aqueous phase for each entry is also indicated. A 46% yield of 4ꢀmethoxybiphenyl (5)
was observed using 0.5 mol% of Pd(OAc) in the presence of 2.1 equivalents of K PO over a reaction
2
3
4
time of 4 hours (Entry 1, Table 3). This result is in stark contrast to the results obtained with 4ꢀ
bromoaniline where only 0.25 mol % Pd was employed to achieve a quantitative yield (Entry 2, Table
1
). Not surprisingly, the yields increase as the catalyst loading and the reaction time are increased
(Entries 2ꢀ5, Table 3). Indeed, after 24 hours a product yield of 90% is achieved. In each of these cases,
the initial and final pH of the aqueous phase varies less than 1 pH unit; the aqueous phase remained
highly basic (pH varies from 11.4 to 10.3) throughout the course of reaction.
The effect of varying the equivalents of base is also summarized in Table 3. As the equivalents
of base increases from 0.5 to 2.1 the yield steadily increases (Entries 4 and 6ꢀ8, Table 3). It appears,
however, to plateau above 2.1 equivalents (Entries 8 and 9, Table 3). It is interesting to note that, other
things being equal, reduced yields (25% and 49%, respectively) are obtained over the same period of
time, when the final pH of the aqueous phase drops to 9 and below (Entries 6 and 7, Table 3). In all the
other cases in Table 3 high yields are realized when the initial and final pH of the aqueous phase
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3
remains highly basic (pH above 10). The relationship between pH of aqueous phase and yield was
investigated by means of the comparison between a series of aqueous Suzuki reactions carried out with
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
various amounts of PhB(OH) . Theoretically, the crossꢀcouplings could be accelerated by increasing the
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
amount of PhB(OH) ; however, the decrease in pH caused by excess PhB(OH) was observed to be
2
2
detrimental. For instance, when the amount of PhB(OH) was increased from 1.1 to 2.0 equivalents, the
2
resulting initial pH decreased from 11.0 to 10.1. The yield of the corresponding reactions dropped from
7
4% (Entry 4, Table 3) to 46% (Entry 10, Table 3). By adding an additional equivalent of PhB(OH)2,
the detrimental effect of a lower pH was somewhat attenuated leading to a yield of 71% (Entry 11,
Table 3). The use of excess of boronic acids is not synthetically attractive.
Table 3. Screening Conditions for 100ꢀmL Scale Pd(OAc) Catalyzed Suzuki Reaction of 4ꢀ
2
a
Bromoanisole (1) and PhB(OH) in H O.
2
2
b
Pd(OAc)2
(mol%)
PhB(OH)2
(equiv)
1.1
K PO
(equiv)
2.1
2.1
2.1
2.1
2.1
0.5
1.0
1.5
3.0
2.1
Time
(h)
4
4
4
4
24
4
4
4
4
4
4
Yield
(%)
pH
3
4
Entry
initial
11.4
11.2
11.1
11.0
11.1
9.0
final
11.0
10.9
10.6
10.4
10.3
8.1
1
2
3
4
5
0.5
1
2
5
5
5
5
5
5
46
49
62
74
90
25
49
73
65
46
71
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
6
7
9.6
9.0
8
10.4
11.9
10.1
9.9
9.6
9
10
11
11.5
10.0
9.2
5
5
2.0
3.0
2.1
a
o
Reaction conditions: 4ꢀbromoanisole (40 mmol, 1 equiv), H O (100 mL), N , 100 C.
GC yield
2
2
b
The effect of the amounts (millimoles) of aryl bromide in 100 mL of water on the yield of
product was also investigated. The results are summarized in Table 4. In each of the experiments a
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
constant ratio of 4ꢀbromoanisole, PhB(OH) , K PO and Pd(OAc) was employed. The results show that
2
3
4
2
as the ratio of moles of aryl bromide to liters of water decreases the product yield increases from 74% to
the midꢀ90’s (Entries 1, 3ꢀ6, Table 4). Further decrease in this ratio resulted in a decrease in the yield to
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
4% (Entry 7, Table 4). No difference in yield was observed by just simply decreasing the scale of the
reaction by a factor of two (Entries 1 and 2, Table 4); a consistent yield in the midꢀ70’s was observed.
In all cases reported in Table 4 the initial pH of the aqueous phase was essentially constantꢀ
approximately 11 to 11.4. The final pH varied slightly from a pH of 10.7 to 9.8.
Table 4. Effect of the Amount of Aryl Bromide on the Heterogeneous Pd(OAc) Catalyzed Suzuki
2
a
Reaction of 4ꢀBromoanisole (1) and PhB(OH) in H O.
2
2
b
4
ꢀBromoanisole
H O
4ꢀbromoanisole/H O
Yield
(%)
74
77
92
96
93
95
74
pH
2
2
Entry
(mmol)
(mL)
100
50
100
100
100
100
100
(mol/L)
0.4
initial
11.0
11.1
11.2
11.4
11.4
11.4
11.4
final
10.4
10.7
10.6
10.2
10.1
9.9
1
2
3
4
5
6
7
40
20
30
20
10
4
0.4
0.3
0.2
0.1
0.04
0.01
1
9.8
a
Reaction conditions: 4ꢀbromoanisole (1.0 equiv), PhB(OH) (1.1 equiv), K PO (2.1 equiv), Pd(OAc) (5 mol%),
2
3
4
2
o
H O (100 mL), N , 100 C, 4 h.
2
2
b
GC yield
(
3) Suzuki Coupling Reactions of 4ꢀBromoaniline in Water with no Added Ligand
In contrast to 4ꢀbromoanisole, 4ꢀbromoaniline has a relatively basic nitrogen center. The effect
of the mol % catalyst loading and the number of equivalents of K PO are summarized in Table 5.
3
4
Quantitative yields of product were realized with a catalyst loading of 0.25 mol%. Indeed, a 98% yield
was achieved with 0.25 mol% catalyst in 30 minutes of reaction time (Entry 9, Table 5). These results
are in stark contrast to 4ꢀbromoanisole where 5 mol% catalyst was needed to achieve reasonable results.
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What was surprising was that the Suzuki coupling reaction of 4ꢀbromoaniline appears to be insensitive
to the pH of the aqueous phase. Indeed, in several of the experiments the product yield remained high
even though the pH dropped to the near neutral range (Entries 6ꢀ9, Table 5). It is noted that the
optimized reaction condition set (Entry 8, Table 5) was found to be scalable, which can be readily
applied to quantitatively produce the crossꢀcoupling product 6 on 50ꢀgram scale (Entry 10, Table 5).
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 5. Screening Conditions for 100 to 750 mLꢀScale Pd(OAc) Catalyzed Suzuki Reaction of 4ꢀ
2
a
Bromoaniline (2) and PhB(OH) in H O.
2
2
b
Pd(OAc)2
(mol%)
5
K PO
(equiv)
2.1
2.1
2.1
2.1
2.1
1.0
0.5
Time
(h)
4
4
4
4
4
4
4
Yield
(%)
100
100
100
100
99
pH
3
4
Entry
initial
11.2
11.3
11.5
11.5
11.8
10.3
9.2
final
9.9
1
2
3
4
5
6
7
8
2
0.5
10.2
10.2
10.2
10.4
7.3
0.25
0.10
0.25
0.25
0.25
0.25
0.25
100
86
100
98
6.5
7.4
1.0
1.0
1.0
1
0.5
1
10.3
10.1
10.3
9
7.4
7.4
c
1
0
99
a
Reaction conditions: 4ꢀbromoaniline (40 mmol, 1 equiv), PhB(OH) (44 mmol, 1.1 equiv), H O (100 mL), N ,
2
2
2
o
100 C.
b
GC yield
c
o
5
0ꢀgram scale reaction: 4ꢀbromoaniline (300 mmol), PhB(OH) (330 mmol), H O (750 mL), N , 100 C.
2 2 2
The coupling reaction of 4ꢀbromoaniline was investigated at five temperatures: 40, 60, 70, 80,
o
o
and 100 C. The results are tabulated and graphically illustrated in Table 6 and Figure 1. At 40 and 60 C
o
the measured yields after 1 hour were 10% and 52%, respectively. At 70 C and higher, the yields ranged
from 97 to 100%. Also note that at the higher temperatures the pH of the aqueous phase changed by
approximately 3 pH units; the final pH was near the neutral range (7.4ꢀ7.8).
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 6. Temperature Effects on the 100ꢀmL Scale Suzuki Reaction of 4ꢀBromoaniline (2) with
a
PhB(OH) in H O with no Added Ligand.
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
b
Temperature
Yield
(%)
10
52
97
pH
Final
9.9
9.2
7.8
7.6
7.4
o
c
Entry
( C)
40
60
70
80
initial
10.4
10.2
10.1
10.3
10.3
ꢁpH
0.5
1.0
2.3
2.7
2.9
1
2
3
4
5
98
100
100
a
Reaction conditions: 4ꢀbromoaniline (40 mmol), PhB(OH) (44 mmol), K PO (40 mmol), Pd(OAc) (0.25
2
3
4
2
mmol%), H O (100 mL), N , 1 h.
2
2
b
c
GC yield
ꢁ
pH = initial pH – final pH
1
20%
100%
9
7%
98%
100%
8
6
0%
0%
GC
Yield
5
2%
40%
0%
2
1
0%
50
0
%
3
0
40
60
70
80
90
100 110
o
Temperature ( C)
Figure 1. Temperature effects on the Suzuki reaction of 4ꢀbromoaniline with PhB(OH) in H O without
2
2
added ligand, also reported in Table 6.
The high yields associated with the reaction of 4ꢀbromoaniline with phenylboronic acid were
maintained when the source of Pd catalyst was varied (Table 7). In fact, all of the Pd (II) catalysts
(Entries 1 – 7, Table 7) exhibited very high catalytic activity in both the absence and the presence of a
ligand. Quantitative yields were realized with all the Pd catalysts initially in the +2 oxidation state. In
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contrast, Pd/C, a heterogeneous catalyst, did not give a good yield of product (Entry 8, Table 7) within
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
5
the one hour time frame used in this comparative investigation.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 7. The Effect of Palladium Catalysts on the 100ꢀmL Scale Suzuki Reaction of 4ꢀ
a
Bromoaniline (2) and PhB(OH) in H O.
2
2
b
Yield
(%)
100
98
pH
Entry
[Pd] Catalyst
Pd(OAc)2
Initial
10.3
10.3
10.1
10.4
10.5
10.4
10.4
10.3
final
7.4
7.6
7.5
7.7
7.6
7.6
7.8
9.7
1
2
3
4
5
6
7
8
Pd(CF COO)
3
2
PdCl2
98
95
K PdCl4
2
Pd(acac)2
100
99
Pd(PhCN) Cl
2
2
Pd(PPh ) Cl
96
25
3
2
2
Pd (10% wt on C )
a
Reaction conditions: 4ꢀbromoaniline (40 mmol), PhB(OH) (44 mmol), K PO (40 mmol), [Pd] (0.25 mol%),
2
3
4
o
H O (100 mL), N , 100 C, 1 h.
2
2
b
GC yield
The excellent results obtained with 4ꢀbromoaniline prompted employing the developed protocol
for several bromo anilines with a variety of aryl boronic acids and esters. The reactions were conducted
o
with 0.25 mol% Pd(OAc) and 1.0 equivalents of K PO at 100 C in water for one hour. The results are
2
3
4
summarized in Table 8. Arylboronic acids with electronꢀdonating and electronꢀwithdrawing groups
underwent reactions with 4ꢀbromoaniline efficiently to afford the desired products in good to excellent
yields (Entries 1 – 5, Table 8). High yields were also observed in the reactions of 3ꢀbromoaniline and
2
ꢀmethylꢀ4ꢀbromoaniline (Entries 6 – 8, Table 8). The reaction of 2ꢀbromoaniline, in contrast, resulted
in a somewhat lower yield (79%). This observation could be presumably due to the steric effects
6
9
between the amino group and the adjacent bromine atom (Entry 9, Table 8). The current protocol was
not as effective for the Suzuki couplings of 4ꢀbromobenzylamine (an aliphatic amine substrate), 2ꢀ
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
aminoꢀ5ꢀbromopyridine and 4ꢀaminoꢀ2ꢀbromopyridine (Entries 10ꢀ12, Table 8). Only a 13% yield was
achieved with 4ꢀbromobenzylamine while the yields associated with 2ꢀaminoꢀ5ꢀbromopyridine and 4ꢀ
aminoꢀ2ꢀbromopyridine were 37% and 29%, respectively.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 8. Pd(OAc) Catalyzed Suzuki Reactions of NH ꢀContaining Aryl Bromide and Aryl
2
2
Boronic Acids (Esters) in H O.
2
Yield
(%)
Entry
ArꢀBr
Ar’ꢀBX2
Product
a
c
1
100
a
c
2
97
a
d
3
98
b
c
4
95
b
c
5
88
a
d
6
99
a
c
7
100
a
d
8
97
a
c
9
79
a
c
1
1
0
1
13
a
a
c
37
c
1
2
29
a
40 mmol/100ꢀmL scale. Reaction conditions: aryl bromide (40 mmol), aryl boronic acid (ester) (44 mmol), K PO
3
4
o
(40 mmol), Pd(OAc) (0.25 mol%), H O (100 mL), N , 100 C, 1 h.
2
2
2
b
20 mmol/50ꢀmL scale. Reaction conditions: aryl bromide (20 mmol), aryl boronic acid (22 mmol), K PO (20
3
4
o
mmol), Pd(OAc) (0.25 mol%), H O (50 mL), N , 100 C, 1 h.
2
2
2
c
GC yield
Isolated yield
d
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6
7
(
4) Suzuki Coupling Reactions of Bromopyridines in Water with no Added Ligand.
Two typical bromopyridines (4ꢀaminoꢀ2ꢀbromopyridine and 2ꢀbromopyridine) were selected as
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
the substrates for the Suzuki crossꢀcouplings with PhB(OH) using Pd(OAc) /K PO in water under a N
2 2 3 4 2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
atmosphere with no added ligand. The results for 4ꢀaminoꢀ2ꢀbromopyridine (3) are reported in Table 9.
Increasing the Pd(OAc) loading from 0.25 to 2 mol% resulted in an increase in yield from 29 to 94%
2
(Entries 1 – 4, Table 9). Higher catalyst loading did not show significant effect (Entry 5, Table 9). The
reaction is relatively fast. In a time period of just 1 hour excellent yields were achieved. Longer reaction
times lead to marginal increases in yield (Entries 7 and 8, Table 9). Recalling Entry 3, Table 1, a
quantitative yield of product was isolated when 40 mmol of aryl bromide was reaction on a 100 mL
scale under the same conditions over a reaction period of one hour. Table 9 reveals interesting
information concerning the relationship of the change in pH during the course of reaction and the
product yield. It appears that when the pH is allowed to ultimately reach a value of approximately 8.4
during the course of reaction, the highest yields were achieved (Entries 4, 5, 7, and 8, Table 9). These
7
1
observations are consistent with those reported by Senter et al. who showed that in an acetonitrileꢀ
water solvent system the best yield for this reaction was realized at an aqueous pH of approximately 8.
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 9. Suzuki Reaction of 4ꢀAminoꢀ2ꢀbromopyridine (3) and PhB(OH) in H O.
2
2
Pd(OAc)2
(mol%)
Base
(equiv)
1.0
1.0
1.0
1.0
1.0
2.0
1.0
Time
(h)
1
1
1
1
1
1
2
GC
Yield (%)
pH
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Entry
1
initial
10.1
10.4
10.4
10.3
10.4
11.9
10.0
10.1
final
10.0
9.9
9.0
8.5
8.3
11.6
8.3
8.4
a
0.25
0.5
1
2
5
1
2
2
29
49
82
94
95
22
96
97
b
2
3
4
5
6
7
8
b
b
b
b
b
b
1.0
4
a
4
0 mmol/100ꢀmL scale, Reaction conditions: 4ꢀaminoꢀ2ꢀbromopyridine (40 mmol, 1 equiv), PhB(OH) (44
2
o
mmol, 1.1 equiv), H O (100 mL), N , 100 C.
2
2
b
2
0 mmol/50ꢀmL scale, Reaction conditions: 4ꢀaminoꢀ2ꢀbromopyridine (20 mmol, 1 equiv), PhB(OH) (22
2
o
mmol, 1.1 equiv), H O (50 mL), N , 100 C.
2
2
The results for the reaction of 2ꢀbromopyridine (4) with PhB(OH) in water are summarized in
2
Table 10. As the number of equivalents of catalyst is changed from 0.5 to 1.1ꢀ1.5 the yield of product
increases from 50% to 74% (Entries 1ꢀ4, Table 10). Increasing the amount of catalyst further results in
a reduction in the yield (Entries 5 and 6, Table 10). For comparison, it is noted that using the optimal
protocol for 4ꢀaminoꢀ2ꢀbromopyridine which produced a product yield of 96% (Entry 7, Table 9) only
a 74% yield was obtained in the reaction of 2ꢀbromopyridine accompanied by an 82% conversion
(Entry 3, Table 10). The difference between the yield and conversion was partially due to the formation
of 2,2’ꢀbipyridine formed via the homoꢀcoupling of 2ꢀbromopyridine (Table S1, SI). Our previous
report indicated that the crossꢀcoupling of 2ꢀbromopyridine (4) with PhB(OH)2 using
Pd(TPP) Cl /K PO in acetonitrileꢀwater required a pH of 12 or greater in the aqueous phase to reach the
2
2
3
4
1
7
quantitative yield. However, this reaction did not perform as well with the present catalytic system
(Pd(OAc) /K PO /H O) when the initial pH was greater than 12 (Entries 5 and 6, Table 10). The best
2
3
4
2
yields at 50 mLꢀscale reactions were observed at the initial pH range of 11 – 12, when 1.1 or 1.5
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3
equivalents of K PO were used. However, it seems that the yield plateaued at about 75% under these
3
4
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
conditions (Entries 3 and 8, Table 10). Interestingly, yields increased to 92% when the amount of
water increased by a factor of 2 (Compare Entries 3 and 9, Table 10).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Table 10. Suzuki Reaction of 2ꢀBromopyridine (4) and PhB(OH) in H O.
2
2
b
b
K PO
3 4
Time
Conversion of (4)
Yield of (8)
pH
H O
2
Entry
(mL)
50
50
50
50
50
50
50
(equiv)
0.5
0.75
1.1
1.5
2.1
3.0
1.1
1.1
1.1
(h)
4
4
4
4
4
4
2
24
(%)
57
64
82
82
59
42
76
87
(%)
50
57
74
74
45
28
69
77
92
87
initial
9.4
final
6.9
8.2
8.7
9.9
11.4
11.9
9.0
8.5
8.1
1
2
3
4
5
6
7
8
9
10.2
11.0
11.7
12.2
12.2
10.9
10.9
10.6
10.5
50
100
100
4
2
100
94
10
1.1
8.1
a
Reaction conditions: 2ꢀbromopyridine (20 mmol, 1 equiv), PhB(OH) (22 mmol, 1.1 equiv), Pd(OAc) (0.4
2
2
o
mmol, 2 mol%), N , 100 C.
2
b
Determined by GC
(5) Speciation of Palladium in Suzuki Coupling Reactions in Water with no Added Ligand.
Since 2000s, the use of Pd nanoparticles (Pd NPs) in the coupling reactions has attracted more
7
2ꢀ73
and more interest from both academia and industry.
These reusable catalysts do not only meet the
demand of modern chemical synthesis for sustainability, but can also further decrease the process cost
7
4
by lowering the loading of expensive Pd, sometimes as low as ppm level. In order to avoid the
deactivation by aggregating to low surfaceꢀarea bulk metal (such as Pd black) during the synthesis and
utilization of Pd NPs, two methods have been often employed: (1) using an electrostatic and/or steric
7
2
stabilizer and (2) immobilization of Pd NPs on a heterogeneous support. At this juncture the question
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8
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
arises as to whether Pd NPs can form in situ under our ligandꢀfree/water conditions and play an
important role therein.
Under the reaction conditions with no added ligand when water and PhB(OH) are present,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Pd(OAc) can rapidly generate catalytically active Pd(0) molecules, which undergo aggregation to form
2
7
5,76
nanoclusters, nanoparticles and, eventually, Pd black (Figure 2).
This process was confirmed by our
observation of Pd black formation in the reaction of 4ꢀbromoanisole with PhB(OH) using
Pd(OAc) /K PO /H O. However, in the other three model reactions, no Pd black formation was visually
2
3
4
2
observed throughout the course of reactions presumably due to the stabilization of Pd(0) by the basic
nitrogen atoms in 4ꢀbromoaniline, 2ꢀbromopyridine and 4ꢀaminoꢀ2ꢀbromopyridine, as well as their
coupled products. In contrast, Pd black formed rapidly at the initial stage of the reaction of 4ꢀ
bromoanisole, since nothing in the reaction system can act as an inꢀsitu ligand to stabilize the active
Pd(0) species against aggregation. That is why more Pd(OAc) (5 mol%) was required in this case to
2
maintain a reasonable reaction rate compared to the other three model reactions (0.25 mol% for 4ꢀ
bromoaniline and 2 mol% for 4ꢀaminoꢀ2ꢀbromopyridine and 2ꢀbromopyridine).
7
5
Figure 2. Process of catalyst activation and deactivation by aggregation.
The interactions between the basic nitrogen centers and Pd(0) can also be verified by the classic
mercury test, since the addition of excess of Hg(0) (relative to the Pd catalyst) will lead to the
7
7,78
amalgamation of the surface of a Pd particle, thus poisoning it.
The resulting deactivation effect is
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79
always obvious for a catalytic system containing heterogeneous and unprotected Pd(0) species. When
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
we added 150 – 400 equivalents of Hg (0) (relative to Pd(OAc) ) to the four model reactions at t = 0, the
2
catalytic deactivation effect was observed in all of reactions at varying levels (Table 11). Not
unexpectedly, the largest impact occurred in reaction of 4ꢀbromoanisole. The reaction yield was greatly
decreased from 76% to 22% by adding 200 equivalents of Hg(0) (Entry 1, Table 11). For the cases of
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
ꢀbromoaniline and 2ꢀbromopyrinde, the influence of Hg(0) on the coupling reactions was modest, since
their basic nitrogen centers can act as an inꢀsitu ligand to protect the catalytically active and waterꢀ
soluble Pd(0) species. About 30% and 20% lower yields were observed, respectively, compared with the
reactions conducted in the absence of Hg(0) (Entries 2 and 3, Table 11). Interestingly, the deactivation
effect by adding Hg(0) was not observed in the highꢀyield reaction of 4ꢀaminoꢀ2ꢀbromopyridine (Entry
4, Table 11). It indicated that the two nitrogen atoms act as effective ligands to favor the formation of
homogeneous catalytic species which allowed the reaction to complete. If the coupling rate was
decreased by lowering the catalyst loading and more Hg(0) was added, the deactivation effect of
amalgamation turned to more significant (Entry 5, Table 11).
Table 11. Mercury Test for the Pd(OAc) Catalyzed Suzuki Couplings of Model Aryl Bromides
2
with PhB(OH) in Water
2
without Hg (0)
GC Yield
with Hg(0)
Pd(OAc)2
Time
(h)
ArylꢀBr
GC Yield
Hg (equiv)
Entry
(mol%)
(
%)
(%)
relative to Pd
a,b
5
4
1
76
22
200
1
a,c
0
.25
2
100
67
67
50
400
2
a,d
4
300
3
a,c
2
1
1
100
47
100
37
150
400
4
a,c
0
.25
5
a
b
c
d
o
ArylꢀBr (4.0 mmol), PhB(OH) (4.4 mmol), H O (10 mL), N , 100 C.
2
2
2
K PO (8.4 mmol)
3
4
K PO (4.0 mmol)
3
4
K PO (4.4 mmol)
3
4
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
The catalytic deactivation observed from our mercury test (Table 11) confirms that there are
several competing catalytic pathways; both heterogeneous and homogeneous catalytic pathways are
occurring, as previously reported in literature. The active Pd(0) particles play an important role in the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1ꢀ17
mechanism of Suzuki couplings in water without added ligand. As early studies indicated,
the
coupling process can be retarded by the competitive interactions between the basic nitrogen centers and
Pd catalyst, meanwhile, the resulting complexes can also efficiently protect the Pd(0) from deactivation
by aggregation (or amalgamation in the mercury test) and stabilize the soluble catalytic species, enabling
homogeneous catalysis. The advantage of the latter effect probably overcame the negative influence of
the former one under our ligandꢀfree/water conditions. These two competitive effects can also be
employed to rationalize the high reactivity of 4ꢀbromoaniline. It is conjectured that the strength of the
ligation has to be balanced to favor stabilization of the Pdꢀspecies from aggregation over catalytic
inhibition
The influence of aromatic –NH on the aqueous Suzuki couplings in the absence of added ligand
2
was further investigated in the reaction of 4ꢀbromoanisole with 3ꢀaminophenylboronic acid, which
produced 86% yield of desired coupling product using only 0.25 mol% of Pd(OAc) and over a short
2
time period of 1 h (Figure 3). In contrast, a 49% yield (Entry 7, Table 3) was obtained from the
reaction between 4ꢀbromoanisole and phenylboronic acid using 5 mol% of catalyst and over 4 h.
Another important observation of the reaction in Figure 3 is that Pd black was not formed during the
entire reaction course. This has been interpreted to mean that the aromatic –NH in the aryl boronic acid
2
can still play a role in preventing the aggregation of the Pd(0) species, thus promoting the coupling
process.
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7
8
9
10
11
12
13
14
15
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17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. Suzuki reaction of 4ꢀbromoanisole with 3ꢀaminophenylboronic acid using
Pd(OAc) /K PO /H O in the absence of added ligand.
2
3
4
2
Lastly, the question still remains regarding the nature of the Pd catalyst under the ligandꢀ
free/H O conditions. It is probably a mixture of Pd(0) species with a wide range from molecular to
2
colloidal and fine particles, all possessing different reactivities and different contributions to the
coupling process. The basic nitrogen centers in the substrates and products appear to be conductive to
prevent the aggregation of catalyst and maintaining the activity of the Pd(0) species. However, for the
case with reaction partners without nitrogen coordinating centers, the aggregation of active Pd(0) cannot
be avoided; rapid formation of Pd black usually results.
CONCLUSIONS
In summary, the heterogeneous palladiumꢀcatalyzed Suzuki reactions between aryl bromides and
phenyl boronic acid in water with no added ligand have been successfully conducted at the 100ꢀmL
scale. The reaction of 4ꢀbromoaniline has been successfully scaled up to 50ꢀgram/750ꢀmL scale. The
product yields associated with four model substrates were optimized and key reaction parameters
affecting the yields were identified. The results clearly indicate that the reaction parameters necessary
to achieve high yields are substrate dependent. The results in Tables 5, 9 and 10 clearly indicated that
Suzuki reactions of basic nitrogen containing substrates in water without any added ligand can produce
quantitative yields of desired products. The basic nitrogen atoms were presumed to act as inꢀsitu ligands
and stabilize the active Pd(0) against deactivation such as aggregation. From a synthetic view point, the
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7
8
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
protection of the amino functionality in order to perform Suzuki coupling is not required, thus saving the
need for protectionꢀdeprotection steps. The scaleꢀup of the heterogeneous aqueous Suzuki reactions in
the absence of added ligand presented in this report offers an operational approach to the development of
green and sustainable Suzuki reaction processes.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
EXPERIMENTAL
General Method. All solvents and reagents were purchased from SigmaꢀAldrich in reagent
grade and were used without further purification. 50 to 100ꢀmL scale reactions were carried out in 3ꢀ
neck roundꢀbottom flasks equipped with a magnetic stirrer and heating mantle. Small scale (≤ 10 mL of
TM
solvent) reactions were performed in 20ꢀmL reaction tubes on a Radleys Carousel 12 Plus Reaction
Station. pH values of the aqueous phase were measured by a ColeꢀParmer pH 20 meter with “AllꢀinꢀOne”
o
electrode at 25 ± 2 C. All products were isolated by chromatography on a silica gel (40 – 60 ꢂm) or
neutral alumina (32 – 60 ꢂm) column using CH Cl – hexane as eluent.
2
2
1
Melting points were measured on a MelꢀTemp capillary melting point apparatus. H (400 MHz)
13
and C (100 MHz) NMR Spectra were recorded on a Varian Mercury Vx 400 spectrometer. Chemical
shifts (δ) are reported in ppm relative to TMS and coupling constants (J) are in Hz. GC analyses were
carried out on a Shimazu GCMSꢀQP2010S Gas Chromatograph (qualitative) and a Shimazu GCꢀ2010
w/FID Gas Chromatograph (quantitative).
General Procedure for the 50 and 100ꢀmL Scale Suzuki Reactions. A mixture of aryl
bromide, arylboronic acid, base, Pd catalyst and solvent in a 3ꢀneck roundꢀbottom flask was well stirred
under reflux for the requisite time. The initial and final pH values of the aqueous phase were measured
o
before and after the heating was enabled when the temperature was stabilized at 25 – 27 C. The cooled
reaction mixture was thoroughly extracted with CH Cl or ethyl acetate. The combined organic phase
2
2
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was dried over anhydrous MgSO filtered, and then concentrated in vacuo. The crude product was
4
,
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
71
analyzed by GC and H NMR following the published methods. The pure product was isolated from a
chromatography column packed with silica gel (for the reaction of 4ꢀbromoanisole) or neutral alumina
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
for reactions containing –NH group) using CH Cl – hexane as eluent. The isolated yields were
2 2 2
determined by mass.
General Procedure for the 1 and 10ꢀmL Scale Suzuki Reactions. This study was carried out
TM
in a Radleys Carousel 12 Plus Reaction Station under N with a reflux head connecting to Lauda E200
2
o
refrigerating circulator. The temperature of recirculating coolant is set at 10 C. In each 20ꢀmL
Carousel’s reaction tube, a mixture of aryl bromide, phenylboronic acid, Pd(OAc) , K PO and water
2
3
4
was stirred at the desired temperature for the indicated reaction time. The same methods as large labꢀ
scale reactions were used in the subsequent procedures of workꢀup and evaluation of reaction
performance.
Procedure for 50ꢀGram Scale Suzuki Reactions. In a 2ꢀL 3ꢀneck roundꢀbottom Morton flask
equipped with a condenser, a mechanical stirrer, and a thermometer, and maintained under nitrogen
atmosphere was charged with 4ꢀbromoaniline (51.61 g, 300 mmol), PhB(OH) (40.24 g, 330 mmol),
2
K PO (63.68 g, 300 mmol), Pd(OAc) (0.168 g, 0.25 mol%) and H O (750 mL). The reaction mixture
3
4
2
2
o
was well stirred (500 rpm) under reflux at 100 C for one hour. The initial and final pH values of the
aqueous phase were measured before and after the heating was enabled when the temperature was
stabilized at room temperature. The cooled reaction mixture was thoroughly extracted with CH Cl (3 ×
2
2
1
00 mL). The combined organic phase was washed with brine (200 mL) and water (2 × 200 mL), dried
over anhydrous MgSO , filtered, and then concentrated in vacuo. An almost quantitative yield of crude
4
product (dark brown solid) was obtained, which included more than 99% of target product analyzed by
GC.
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Procedure for Mercury Test. A mixture of aryl bromide (4 mmol, 1.0 equiv), PhB(OH) (4.4
2
mmol, 1.1 equiv), K PO , Pd(OAc) , mercury (99.9+%) and water (10 mL) in a 50ꢀmL 3ꢀneck roundꢀ
3
4
2
o
bottom flask was well stirred under reflux at 100 C in N for requisite time. The cooled reaction
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
mixture was thoroughly extracted with CH Cl (3 × 10 mL). The combined organic phase was dissolved
2
2
in methanol and measured in a 100 mL volumetric flask. An aliquot of the organic solution was taken
for GC analysis. A reference reaction in the absence of mercury was always conducted under the same
reaction conditions for the sake of comparison.
ASSOCIATED CONTENT
Supporting Information
1
13
Experimental details and copies of H and C NMR spectra of synthesized compounds.
AUTHOR INFORMATION
Corresponding Author
*
Eꢀmail: charles.liotta@chemistry.gatech.edu
Note
The authors declare no competing financial interest
ACKNOWLEDGMENTS
We thank The Dow Chemical Company for their collaboration and financial support.
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REFERENCE
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
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5
5
5
5
5
6
(
1) Miyaura, N.; Suzuki, A. Stereoselective Synthesis of Arylated (E)ꢀAlkenes by the Reaction of Alkꢀ1ꢀ
Enylboranes with Aryl Halides in the Presence of Palladium Catalyst. J. Chem. Soc. Chem. Comm. 1979,
66ꢀ867.
8
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
2) Miyaura, N.; Yamada, K.; Suzuki, A. New Stereospecific CrossꢀCoupling by the Palladiumꢀ
Catalyzed Reaction of 1ꢀAlkenylboranes with 1ꢀAlkenyl or 1ꢀAlkynyl Halides. Tetrahedron Lett. 1979,
0, 3437ꢀ3440.
2
(3) Miyaura, N.; Suzuki, A. PalladiumꢀCatalyzed CrossꢀCoupling Reactions of Organoboron
Compounds. Chem. Rev. 1995, 95, 2457ꢀ2483.
(4) Suzuki, A. Recent Advances in the CrossꢀCoupling Reactions of Organoboron Derivatives with
Organic Electrophiles, 1995ꢀ1998. J. Organomet. Chem. 1999, 576, 147ꢀ168.
(5) Kotha, S.; Lahiri, K.; Kashinath, D. Recent Applications of the SuzukiꢀMiyaura CrossꢀCoupling
Reaction in Organic Synthesis. Tetrahedron 2002, 58, 9633ꢀ9695.
(6) Bellina, F.; Carpita, A.; Rossi, R. Palladium Catalysts for the Suzuki CrossꢀCoupling Reaction: An
Overview of Recent Advances. SynthesisꢀStuttgart 2004, 2419ꢀ2440.
(7) Alonso, F.; Beletskaya, I. P.; Yus, M. NonꢀConventional Methodologies for TransitionꢀMetal
Catalysed CarbonꢀCarbon Coupling: a Critical Overview. Part 2: The Suzuki Reaction. Tetrahedron
2008, 64, 3047ꢀ3101.
(8) Magano, J.; Dunetz, J. R. LargeꢀScale Applications of Transition MetalꢀCatalyzed Couplings for the
Synthesis of Pharmaceuticals. Chem. Rev. 2011, 111, 2177ꢀ2250.
(9) Jiao, J.; Nishihara, Y.: Pharmaceuticals. In Applied CrossꢀCoupling Reactions; Nishihara, Y., Ed.;
SpringerꢀVerlag: Berlin Heidelberg, 2013; pp 85ꢀ109.
(10) Amatore, C.; Le Duc, G.; Jutand, A. Mechanism of PalladiumꢀCatalyzed SuzukiꢀMiyaura Reactions:
Multiple and Antagonistic Roles of Anionic "Bases" and Their Countercations. Chem.Eur. J. 2013, 19,
1
0082ꢀ10093.
(11) Thompson, A. E.; Hughes, G.; Batsanov, A. S.; Bryce, M. R.; Parry, P. R.; Tarbit, B. Palladiumꢀ
Catalyzed CrossꢀCoupling Reactions of Pyridylboronic Acids with Heteroaryl Halides Bearing a
Primary Amine Group: Synthesis of Highly Substituted Bipyridines and Pyrazinopyridines. J. Org.
Chem. 2005, 70, 388ꢀ90.
(12) Vagnini, M. T.; Smeigh, A. L.; Blakemore, J. D.; Eaton, S. W.; Schley, N. D.; D'Souza, F.;
Crabtree, R. H.; Brudvig, G. W.; Co, D. T.; Wasielewski, M. R. Ultrafast Photodriven Intramolecular
Electron Transfer from an IridiumꢀBased WaterꢀOxidation Catalyst to Perylene Diimide Derivatives.
PNAS 2012, 109, 15651ꢀ15656.
(13) Wang, K.; Fu, Q.; Zhou, R.; Zheng, X. L.; Fu, H. Y.; Chen, H.; Li, R. X.
Tetraphosphine/PalladiumꢀCatalyzed SuzukiꢀMiyaura Coupling of Heteroaryl Halides with 3ꢀPyridineꢀ
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1
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5
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5
5
5
5
5
5
5
5
6
and 3ꢀThiopheneboronic Acid: an Efficient Catalyst for the Formation of Biheteroaryls. Appl.
Organomet. Chem. 2013, 27, 232ꢀ238.
(
14) Itoh, T.; Mase, T. Direct Synthesis of HeteroꢀBiaryl Compounds Containing an Unprotected NH2
Group via SuzukiꢀMiyaura Reaction. Tetrahedron Lett. 2005, 46, 3573ꢀ3577.
0
1
2
3
4
5
6
7
8
9
0
1
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5
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0
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3
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5
6
7
8
9
0
(15) Hamann, B. C.; Hartwig, J. F. Sterically Hindered Chelating Alkyl Phosphines Provide Large Rate
Accelerations in PalladiumꢀCatalyzed Amination of Aryl Iodides, Bromides, and Chlorides, and the
First Amination of Aryl Tosylates. J. Am. Chem. Soc. 1998, 120, 7369ꢀ7370.
(16) Lee, D. H.; Choi, M.; Yu, B. W.; Ryoo, R.; Taher, A.; Hossain, S.; Jin, M. J. Expanded
Heterogeneous SuzukiꢀMiyaura Coupling Reactions of Aryl and Heteroaryl Chlorides under Mild
Conditions. Adv. Synth. Catal. 2009, 351, 2912ꢀ2920.
(17) Wagaw, S.; Buchwald, S. L. The Synthesis of Aminopyridines: A Method Employing Palladiumꢀ
Catalyzed CarbonꢀNitrogen Bond Formation. J. Org. Chem. 1996, 61, 7240ꢀ7241.
(18) Caron, S.; Massett, S. S.; Bogle, D. E.; Castaldi, M. J.; Braish, T. F. An Efficient and Costꢀ
Effective Synthesis of 2ꢀPhenylꢀ3ꢀaminopyridine. Org. Process Res. Dev. 2001, 5, 254ꢀ256.
(19) Bai, L.; Wang, J. X. Environmentally Friendly Suzuki ArylꢀAryl CrossꢀCoupling Reaction. Curr.
Org. Chem. 2005, 9, 535ꢀ553.
(20) Darses, S.; Jeffery, T.; Genet, J. P.; Brayer, J. L.; Demoute, J. P. CrossꢀCoupling of
Arenediazonium Tetrafluoroborates with Arylboronic Acids Catalysed by Palladium. Tetrahedron Lett.
1996, 37, 3857ꢀ3860.
(21) Chi, S. M.; Choi, J. K.; Yum, E. K.; Chi, D. Y. PalladiumꢀCatalyzed Functionalization of 5ꢀand 7ꢀ
Azaindoles. Tetrahedron Lett. 2000, 41, 919ꢀ922.
(
22) Yin, L.; Zhang, Z. H.; Wang, Y. M. PEG (300)ꢀPdCl Promoted Efficient and Convenient Suzukiꢀ
2
Miyaura Coupling of Aryl Chlorides with Arylboronic Acids. Tetrahedron 2006, 62, 9359ꢀ9364.
(23) Liu, C.; Wu, Y. H.; Han, N.; Qiu, J. S. Efficient Synthesis of 4ꢀHeteroarylꢀSubstituted
Triphenylamine Derivatives via a LigandꢀFree Suzuki Reaction. Appl. Organomet. Chem. 2011, 25,
8
62ꢀ866.
(24) Ding, G. D.; Wang, W. T.; Jiang, T.; Han, B. X. An Efficient Palladium Catalyst on Bentonite for
SuzukiꢀMiyaura Reaction at Room Temperature. Green Chem. 2013, 15, 3396ꢀ3403.
(25) Wallow, T. I.; Novak, B. M. Highly Efficient and Accelerated Suzuki Aryl Couplings Mediated by
PhosphineꢀFree Palladium Sources. J. Org. Chem. 1994, 59, 5034ꢀ5037.
(26) Liu, L. F.; Zhang, Y. H.; Xin, B. W. Synthesis of Biaryls and Polyaryls by LigandꢀFree Suzuki
Reaction in Aqueous Phase. J. Org. Chem. 2006, 71, 3994ꢀ3997.
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1
2
3
(27) Kitamura, Y.; Sako, S.; Udzu, T.; Tsutsui, A.; Maegawa, T.; Monguchi, Y.; Sajiki, H. LigandꢀFree
4
5
6
7
8
9
1
1
1
1
1
1
1
1
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5
5
5
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5
6
Pd/CꢀCatalyzed SuzukiꢀMiyaura Coupling Reaction for the Synthesis of Heterobiaryl Derivatives. Chem.
Commun. 2007, 5069ꢀ5071.
(28) Shi, S. Y.; Zhang, Y. H. SilicaꢀAssisted SuzukiꢀMiyaura Reactions of Heteroaryl Bromides in
Aqueous Media. Green Chem. 2008, 10, 868ꢀ872.
0
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5
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8
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0
(
29) Liu, C.; Ni, Q. J.; Hu, P. P.; Qiu, J. S.: OxygenꢀPromoted PdCl ꢀCatalyzed LigandꢀFree Suzuki
2
Reaction in Aqueous Media. Org. Biomol. Chem. 2011, 9, 1054ꢀ1060.
(
30) Qiu, J.; Wang, L. M.; Liu, M. T.; Shen, Q.; Tang, J. An Efficient and Simple Protocol for a PdCl2ꢀ
Ligandless and AdditiveꢀFree Suzuki Coupling Reaction of Aryl Bromides. Tetrahedron Lett. 2011, 52,
489ꢀ6491.
6
(
31) Wan, J. P.; Wang, C. P.; Zhou, R. H.; Liu, Y. Y. Sustainable H O/Ethyl Lactate System for Ligandꢀ
2
Free SuzukiꢀMiyaura Reaction. RSC Adv. 2012, 2, 8789ꢀ8792.
(
32) Liu, C.; Ni, Q. J.; Bao, F. Y.; Qiu, J. S.: A Simple and Efficient Protocol for a PalladiumꢀCatalyzed
LigandꢀFree Suzuki Reaction at Room Temperature in Aqueous DMF. Green Chem. 2011, 13, 1260ꢀ
266.
1
(
33) Rohlich, C.; Wirth, A. S.; Kohler, K. Suzuki Coupling Reactions in Neat Water as the Solvent:
Where in the Biphasic Reaction Mixture Do the Catalytic Reaction Steps Occur? Chem. Eur. J. 2012, 18,
5485ꢀ15494 and the references cited therein.
1
(34) Peng, Y. Y.; Liu, J. B.; Lei, X. L.; Yin, Z. L.: RoomꢀTemperature Highly Efficient SuzukiꢀMiyaura
Reactions in Water in the Presence of Stilbazo. Green Chem. 2010, 12, 1072ꢀ1075.
(35) Mondal, M.; Bora, U.: An Efficient Protocol for PalladiumꢀCatalyzed LigandꢀFree SuzukiꢀMiyaura
Coupling in Water. Green Chem. 2012, 14, 1873ꢀ1876.
(36) Polackova, V.; Hut'ka, M.; Toma, T. Ultrasound Effect on Suzuki Reactions. 1. Synthesis of
Unsymmetrical Biaryls. Ultrason. Sonochem. 2005, 12, 99ꢀ102.
(37) Dallinger, D.; Kappe, C. O.: MicrowaveꢀAssisted Synthesis in Water as Solvent. Chem. Rev. 2007,
1
07, 2563ꢀ2591 and the references cited therein.
(38) Kappe, C. O.: Microwave Dielectric Heating in Synthetic Organic Chemistry. Chem. Soc. Rev.
2
008, 37, 1127ꢀ1139 and the references cited therein.
(39) Zhang, J. L.; Yang, F.; Ren, G. R.; Mak, T. C. W.; Song, M. P.; Wu, Y. J. Ultrasonic Irradiation
Accelerated Cyclopalladated Ferrocenylimines Catalyzed Suzuki Reaction in Neat Water. Ultrason.
Sonochem. 2008, 15, 115ꢀ118.
(40) Schmidt, B.; Riemer, M. SuzukiꢀMiyaura Coupling of Halophenols and Phenol Boronic Acids:
Systematic Investigation of Positional Isomer Effects and Conclusions for the Synthesis of Phytoalexins
from Pyrinae. J. Org.c Chem. 2014, 79, 4104ꢀ4118.
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