Aqueous Suzuki Coupling Reactions of Basic Nitrogen-Containing Substrates in the Absence of Added Base and Ligand: Observation of High Yields under Acidic Conditions

Article abstract of DOI:10.1021/acs.joc.6b01683

A series of aqueous heterogeneous Suzuki coupling reactions of substrates containing basic nitrogen centers with phenylboronic acid in the absence of added base and ligand is presented. High yields of products were obtained by employing aryl bromides containing aliphatic 1°, 2°, and 3° amine substituents, and good to high yields were obtained by employing a variety of substituted bromopyridines. In the former series, the pH of the aqueous phase changed from basic to acidic during the course of the reaction, while in the latter series the aqueous phase was on the acidic side of the pH scale throughout the entire course of reaction. A mechanistic interpretation for these observations, which generally preserves the oxo palladium catalytic cycle widely accepted in the literature, is presented.

Full text of DOI:10.1021/acs.joc.6b01683

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Article
Aqueous Suzuki Coupling Reactions of Basic Nitrogen-
Containing Substrates in the Absence of Added Base and
Ligand: Observation of High Yields under Acidic Conditions
Zhao Li, Carol Gelbaum, Jason S. Fisk, Bruce Holden, Arvind
Jaganathan, Gregory T Whiteker, Pamela Pollet, and Charles L. Liotta
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01683 • Publication Date (Web): 25 Aug 2016
Downloaded from http://pubs.acs.org on August 28, 2016
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Aqueous Suzuki Coupling Reactions of Basic
NitrogenꢀContaining Substrates in the Absence of
Added Base and Ligand: Observation of High Yields
under Acidic Conditions
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Zhao Li†, Carol Gelbaum†, Jason S. Fisk§, Bruce Holden§, Arvind Jaganathan§, Gregory T.
Whiteker£, Pamela Pollet†, and Charles L. Liotta*†‡
†School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia
30332, USA
‡School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta,
Georgia 30332, USA
§The Dow Chemical Company, Midland, Michigan 48674, USA
£Dow AgroSciences, Indianapolis, Indiana 46268, USA
KEYWORDS: aqueous Suzuki reactions, ligandꢀfree, baseꢀfree, acidic conditions, oxo
palladium mechanism
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ABSTRACT
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A series of aqueous heterogeneous Suzuki coupling reactions of substrates containing
basic nitrogen centers with phenylboronic acid in the absence of added base and ligand is
presented. High yields of products were obtained employing aryl bromides containing aliphatic
1o, 2o, and 3o amine substituents and good to high yields were obtained employing a variety of
substituted bromopyridines. In the former series, the pH of the aqueous phase changed from
basic to acidic during the course of reaction while in the latter series the aqueous phase was on
the acidic side of the pH scale throughout the entire course of reaction. A mechanistic
interpretation for these observations, which generally preserves the oxo palladium catalytic cycle
widely accepted in the literature, is presented.
INTRODUCTION
Heterocyclic biaryl compounds, particularly those containing nitrogen, are components in
many pharmaceutical and biologically active molecules.1 While many synthetic methods have
been employed for coupling aromatic reaction partners to form biaryl products, the Suzuki
coupling reaction has emerged as the most versatile of the synthetic protocols.2ꢀ11 These Pdꢀ
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catalyzed reactions are usually conducted in an organicꢀaqueous coꢀsolvent in the presence of a
suitable ligand.12,13 In addition, the presence of base (e.g., K3PO4) is considered to be crucial for
the success of the reaction.2ꢀ4,14 Indeed, in his Nobel address, Professor Suzuki emphasized that
no coupling reaction occurs without base.4 While there has been great success in a wide range of
Suzuki coupling processes, reaction partners containing basic nitrogen centers often react more
slowly and/or produce the desired coupled products in lower yields compared to the neutral
substrates under the same reaction conditions.15ꢀ18 In these cases, the basic nitrogen centers are
postulated to coordinate with the palladium catalyst, reducing or poisoning its catalytic
activity.18ꢀ21 As a consequence, the use of additional protection/deprotection steps or expensive
designer ligands is often necessary to achieve reasonable reaction rates and high yields.18,21,22
Herein, we report the surprising observation that aqueous heterogeneous Suzuki coupling
reactions of a wide variety of aryl bromides containing aliphatic 1o, 2o, and 3o amine substituents
and substituted bromopyridines produce excellent yields in the absence of added base and
ligand. In the former cases, it will be shown that the 1o, 2o, and 3o amines are basic enough to
produce hydroxide ions in the aqueous phase such that at least the initial stages of the reaction
take place in the presence of a basic aqueous phase. In contrast, it will also be shown that the less
basic substituted bromopyridines undergo the coupling process under acidic aqueous conditions
throughout the entire course of reaction. The observed changes in pH of the aqueous phase at the
beginning and at the end of each reaction and, in several cases, throughout the course of reaction
are presented. A mechanistic interpretation for these results, which generally preserves the
literature accepted catalytic cycle, is presented.
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Previously, we reported that the outcome of Suzuki coupling reactions of 4ꢀaminoꢀ2ꢀ
halopyridines with phenylboronic acid using PdCl2 and triphenylphosphine ligand in
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acetonitrile/water medium (60/40, v/v) is highly dependent on the buffered pH of the aqueous
phase of the reaction mixture.23 For example, buffering the reaction mixture at pH 8 provided the
desired product in near quantitative yield, whereas conducting the same reaction at a buffered pH
of 13 resulted in only a 30% yield (Figure 1a). In contrast, however, the opposite effect of pH
was observed with 2ꢀhalopyridines. The highest yields were obtained at a pH buffered at 11
while the yields fell precipitously at a buffered pH of 8 (Figure 1b). These results strongly
suggested that the pH of the acetonitrileꢀwater phase is an important parameter in developing a
successful Suzuki crossꢀcoupling process for substrates containing basic nitrogen centers—at
least in mixed solvent systems in the presence of a ligand. In addition, these results suggest that
the optimum pH of the aqueous phase may be substrate dependent.23
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Figure 1. Effect of aqueous buffered pH on the Suzuki coupling of substrates containing basic
nitrogen centers.23
The literature contains a number of reports describing Suzuki reactions of heterocyclic
molecules in the absence of added ligand (so called “ligandꢀfree”) using only water as a
solvent.24ꢀ37 In general, good to high yields of coupled products are reported. Based upon our
observations that the buffered pH of the acetonitrileꢀwater phase appears to be playing an
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important role in the success of the Suzuki coupling process,23 we elected to investigate this by
simplifying the reaction system still further. The coꢀsolvent and the ligand were removed, and
the reactions were conducted in pure water in the absence of added base. In order to ascertain the
effects of the “no added base” Suzuki reactions, additional experiments were performed in which
varying quantities of base (K3PO4) were added to the reaction mixture. Two different nitrogenꢀ
containing substrates were used in this study: 4ꢀbromobenzylamine and 4ꢀaminoꢀ2ꢀ
bromopyridine. Each of these substrates was reacted with phenylboronic acid using 2 and 4
mol% Pd(OAc)2. In addition to the yields of the coupled products, specific attention was paid to
the phase behavior of the reaction system and the initial and final pH of the aqueous phase.
Finally, the results described for 4ꢀbromobenzylamine and 4ꢀaminoꢀ2ꢀbromopyridine were
extended to a series of aryl bromides containing aliphatic 1o, 2o, and 3o amine substituents and
substituted bromopyridines.
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RESULTS AND DISCUSSION
Reaction of 4-Bromobenzylamine with Phenylboronic Acid
Table 1 summarizes reaction conversions and product yields as a function of time and
catalyst loading for the ligandꢀfree reaction of 4ꢀbromobenzylamine with phenylboronic acid
(PhB(OH)2) in water in the absence of added base (eq 1). With a catalyst loading of 2 mol%, a
78% yield of product was obtained after 4 hours of reaction (Entry 4, Table 1). Increasing the
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reaction time to 24 hours produced a 94% yield (Entry 5, Table 1). Doubling the amount of
catalyst to 4 mol% produced a 93 % yield in just 4 hours (Entry 9, Table 1). In all the
experiments listed in Table 1 the initial pH of the aqueous phase ranged from 9.1 to 9.5. The
final pH, however, was highly acidic for the high conversion cases (Entries 5, 9 and 10, Table 1).
Table 2 summarizes the yields of products as a function of amounts of added base. Employing 2
mol% catalyst loading, the yields appear to be largely independent of the amount of added base.
Within a reaction period of 4 hours, the yield varies from 73 to 83% (Entries 1 – 3, and 7 – 9,
Table 2) and the final pH ranges from neutral to highly basic—especially when large quantities
of added base are employed (Entries 8 and 9, Table 2). The 2 mol% catalyst data summarized in
Tables 1 and 2 are graphically displayed in Figure 2. The yield of coupled product appears to be
largely independent of the absence or presence of base added to the system.
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Table 1. Reaction of 4ꢀBromobenzylamine with PhB(OH)2 in Water in the Absence of Added
Base Following the Reaction Conditions in Eq 1
pH
Pd(OAc)2
(equiv)
2.0%
Time
(h)
0.5
1
2
4
24
0.5
1
GC Yield
(%)
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Entry
initial
9.2
9.4
9.3
9.1
9.5
9.4
9.5
9.4
9.4
9.5
final
7.4
7.1
7.2
6.8
3.2
7.7
7.7
6.1
2.1
2.8
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8
9
2.0%
2.0%
2.0%
2.0%
4.0%
4.0%
4.0%
4.0%
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68
78
94
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65
83
93
2
4
6
10
4.0%
92
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Table 2. Reaction of 4ꢀBromobenzylamine with PhB(OH)2 in Water in the Presence of Varying
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Amounts of Added K3PO4 Following the Reaction Conditions in Eq 1
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Pd(OAc)2
(equiv)
2.0%
2.0%
2.0%
2.0%
2.0%
2.0%
2.0%
2.0%
2.0%
4.0%
4.0%
4.0%
4.0%
4.0%
K3PO4
(equiv)
0.10
0.25
0.50
1.0
Time
(h)
4
GC Yield
(%)
78
pH
Entry
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initial
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final
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10.4
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90
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11.5
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1.0
1.0
1.5
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0.10
1.0
1.0
1.0
0.5
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2
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9.8
9.8
9.8
1.0
4
90
Figure 2. The effect of initial pH on product yield in the ligandꢀfree Suzuki reactions of 4ꢀ
bromobenzylamine in H2O; reaction conditions: 4ꢀbromobenzylamine (10 mmol), PhB(OH)2 (11
mmol), Pd(OAc)2 (2 mol%), H2O (25 mL), N2, 100 oC, 4 h.
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Reaction of 4-Amino-2-Bromopyridine with Phenylboronic Acid
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Table 3 summarizes the product yields as a function of time and catalyst loading for the
ligandꢀfree reaction of 4ꢀaminoꢀ2ꢀbromopyridine with PhB(OH)2 in water in the absence of
added base (eq 2). With a catalyst loading of 2 mol% a near quantitative yield was obtained in
one hour. An increased catalyst loading of 4 mol% did very little in improving the rate of
reaction; a quantitative yield was obtained in one hour. In all the experiments listed in Table 3,
the initial pH of the aqueous phase ranged from 6.2 to 6.5. The final pH was even more acidic,
reaching as low as 2.2. These results clearly demonstrate a Suzuki coupling process taking place
entirely on the acidic side of the pH scale.
Table 3. Reaction of 4ꢀAminoꢀ2ꢀbromopyridine with PhB(OH)2 in Water in the Absence of
Added Base Following the Reaction Conditions in Eq 2
pH
Pd(OAc)2
(equiv)
2.0%
Time
(h)
0.5
0.75
1
GC Yield
(%)
82
Entry
initial
6.4
6.5
final
4.8
4.6
4.2
4.2
2.2
4.1
2.3
2.6
1
2
3
2.0%
2.0%
89
96
6.6
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5
2.0%
2.0%
4.0%
4.0%
2
4
0.5
1
4
95
100
93
100
100
6.4
6.2
6.4
6.5
6
7 a
8
4.0%
6.5
aGC yield is independent of stirring rate, 100% for 60, 100, 150, 200, 400, 600 rpm or greater.
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Table 4 summarizes the results for the same reaction conducted in the presence of
varying quantities of added base as a function of time. As the amount of added base increases,
the yield of product remains relatively constant (Entries 1ꢀ7, Table 4). However, when 1.5 to 2.0
equivalents of added base were employed, the yield decreases significantly (Entries 8 and 9,
Table 4). It is also interesting to note that the final pH for these latter entries remained highly
basic in contrast to the reactions conducted with 0.25 to 1.0 equivalents of added base. The 2
mol% catalyst results are graphically summarized in Figure 3. It was quite surprising to observe
that a 95% yield of coupled product was achieved in the absence of added base and where the
reaction proceeded entirely on the acidic side of the pH scale.
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Table 4. Reaction of 4ꢀAminoꢀ2ꢀbromobenzylamine with PhB(OH)2 in Water in the Presence of
Varying Amounts of Added K3PO4 Following the Reaction Conditions in Eq (2) (2.0 mol%
Pd(OAc)2)
K3PO4
(equiv)
0.25
0.50
0.75
1.0
Time
(h)
2
GC Yield
pH
Entry
(%)
90
91
92
78
94
96
97
83
49
initial
9.1
final
7.1
7.6
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8.9
8.5
8.3
8.4
9.9
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0.5
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2
9.5
9.9
10.8
10.3
10.0
10.1
11.8
12.4
1.0
1.0
1.0
1.5
2.0
11.4
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Figure 3. The effect of initial pH on product yield in the ligandꢀfree Suzuki reactions of 4ꢀ
aminoꢀ2ꢀbromopyridine in H2O; reaction conditions: 4ꢀaminoꢀ2ꢀbromopyridine (10 mmol),
PhB(OH)2 (11 mmol), Pd(OAc)2 (2 mol%), H2O (25 mL), N2, 100 oC, 2 h
Reaction of Aryl Bromides Containing 1o, 2o, and 3o Amine Substituents with
Phenylboronic Acid
In order to explore the scope of the aqueous, baseꢀfree and ligandꢀfree conditions for
conducting Suzuki reactions, a variety of aryl bromides containing 1o, 2o, and 3o aliphatic amine
substituents in pure water was investigated. The results are shown in Table 5. The substrate
conversions, the yields of coupled products, and the pH values of the aqueous phase before and
after reaction are indicated. All of these aryl bromides (Table 5, Entries 1ꢀ11) underwent smooth
crossꢀcoupling in the absence of added base to afford the products in excellent yields. It is
interesting to note that the reactions with the primary and secondary amine substrates (Table 5,
Entries 1ꢀ7) had initial pH values of approximate 9.0 and a final pH of 1.5ꢀ3.6. In contrast, for
the tertiary amines (Table 5, Entries 8ꢀ11), the initial pH was approximately 7.0 and decreased to
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a final pH which ranged from 2.0 to 2.7. These results indicate that at least a portion of the
reactions took place on the acidic side of the pH scale.
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Table 5. Pd(OAc)2 Catalyzed Suzuki Reactions of Aryl Bromides Containing 1o, 2o, and 3o
Aliphatic Amine Substituents with PhB(OH)2 in Water in the Absence of Added Base and
Ligand a
Conversion Yield of
pH
Time
(h)
Entry
Ar-Br
of Ar-Br
(%)c
93
Product
(%)
93c
Initial Final
1b
2b
3b
4
5
6
7
8
9
4ꢀBrC6H4CH2NH2
3ꢀBrC6H4CH2NH2
4
4
4
6
4
4
4
4
4
4
4
9.5
9.2
9.3
9.6
9.0
9.0
8.7
7.2
7.5
6.9
6.6
2.8
3.1
1.5
3.1
3.4
3.0
3.6
2.6
2.3
2.7
2.0
92
94
99
94
94
97
95
95
92c
4ꢀBrC6H4CH(CH3)NH2
4ꢀBrC6H4CH2CH2NH2
4ꢀBrC6H4CH2NHCH3
3ꢀBrC6H4CH2NHCH3
4ꢀBrC6H4CH2NHiꢀPr
4ꢀBrC6H4CH2N(CH3)2
4ꢀBrC6H4CH2NEt2
94c
99c
96d
98d
92d
92d
98d
10
11
4ꢀBrC6H4CH2NPr2
4ꢀBrC6H4CH2N(iꢀPr)2
96
96d
86
87d
a
Reaction conditions: ArꢀBr (10 mmol), PhB(OH)2 (15 mmol), Pd(OAc)2 (4 mol%), H2O (25
mL), N2, 100 oC.
b PhB(OH)2 (11 mmol)
c Determined by GC
d Determined by 1H NMR
Reaction of Pyridyl Bromides with Phenylboronic Acid
A study similar to that involving the amineꢀcontaining aryl bromides was conducted with
a variety of pyridyl bromides. The results are summarized in Table 6. The substrate conversions,
the yields of coupled products, and pH values of the aqueous phase before and after reaction are
shown; 4 mol% Pd(OAc)2 was employed. For this series of reactions the initial pH varied from
6.5 to 3.2 and the final pH from 1.1 to 4.4. Each of the reactions appears to have taken place
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entirely on the acid side of the pH scale. Excellent yields were obtained for the first six substrates
(Table 6, Entries 1ꢀ8) while good to modest yields were realized for the remaining five substrates
(Table 6, Entries 9ꢀ15). It is interesting to note that in the latter cases the yields of coupled
products and the corresponding conversions were within a few percent of each other.
Table 6. Pd(OAc)2 Catalyzed Suzuki Reactions of Substituted Pyridyl Bromides with PhB(OH)2
in Water in the Absence of Added Base and Ligand a
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pH
Time
(h)
Conversion
Yield of Product
(%)
Ar-Br
Entry
of Ar-Br (%)c
Initial Final
1b
1
100
100c
6.5
2.3
2
3
4
24
81
97
83d
97d
5.7
5.6
4.4
2.1
4
5
6
4
4
4
96
94
94
96c
91d
93d
5.2
4.8
4.6
2.0
2.6
2.7
7
8
4
89
97
75c
82c
59c
69c
34c
43c
4.0
3.9
1.4
1.5
24
9
4
24
4
64
73
41
50
3.8
3.7
3.6
3.7
1.9
1.9
1.7
1.8
10
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12
24
13
14
4
4
39
35
35d
3.5
3.3
1.3
1.3
29d
15
4
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29d
3.2
1.1
a
Reaction conditions: ArꢀBr (10 mmol), PhB(OH)2 (15 mmol), Pd(OAc)2 (4 mol%), H2O (25
mL), N2, 100 oC.
b PhB(OH)2 (11 mmol)
c Determined by GC
d Determined by 1H NMR
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pH Changes During the Course of Reaction of 4-Bromobenzylamine and 4-Amino-2-
Bromopyridine with Phenylboronic Acid.
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The issue regarding the pH change during the course of reaction was also investigated.
The results for 4ꢀbromobenzylamine and 4ꢀaminoꢀ2ꢀbromopyridine are summarized in Figure 4.
Figure 4a shows the product yield and the pH of the aqueous phase vs. time for the Pd(OAc)2
catalyzed reaction of 4ꢀbromobenzylamine with PhB(OH)2 in water in the absence of base and in
the presence of 1.0 equivalent of K3PO4. During the first 1.5 hours both reactions proceeded
smoothly in a system in which the aqueous phase was in the basic pH region. At this point in
time the yields of products were approximately 85% and 75% in the presence and absence of
added base, respectively. After 1.5 hours of reaction, the pH of the baseꢀfree system dropped
below 7. Nevertheless, the reaction proceeded to produce an identical yield as that obtained in
the presence of K3PO4. Figure 4b shows the corresponding product yield and the pH of the
aqueous phase vs. time for the reaction of 4ꢀaminoꢀ2ꢀbromopyridine in the absence and presence
of 1.0 equivalent of K3PO4. In this case, the rate profiles are almost identical for the two reaction
conditions. Quantitative yields are obtained under both sets of conditions. The major difference
is the pH profiles. In the presence of base, the entire reaction experiences a basic aqueous phase,
while in the absence of base the entire reaction takes place within a pH range substantially below
7.
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Figure 4. Reaction yield and pH as functions of time for the ligandꢀfree Suzuki reactions of (a)
4ꢀbromobenzylamine and (b) 4ꢀaminoꢀ2ꢀbromopyridine with PhB(OH)2 in water in the presence
of 1.0 equivalent of K3PO4 or without added bases. Reaction conditions: aryl bromide (10
mmol), PhB(OH)2 (11 mmol), Pd(OAc)2 [(a) 4 mol%, (b) 2 mol%], H2O (25 mL), N2.
4ꢀAminoꢀ2ꢀbromopyridine is a weaker base than 4ꢀbromobenzylamine due to
delocalization of its nitrogen lone pairs. The initial pH of the Suzuki reaction of 4ꢀaminoꢀ2ꢀ
bromopyridine is lower due to its lower basicity. Reaction mixtures with 4ꢀaminoꢀ2ꢀ
bromopyridine were, in fact, acidic, presumably due to the known hydrolysis equilibrium
ꢀ
between PhB(OH)2 and trihydroxyphenylborate (PhB(OH)3 , eq 3). In the absence of added
K3PO4, the pH of both reaction mixtures decreased with increasing conversion due to generation
of B(OH)3 and HBr (buffered by the basic nitrogen centers of products) by the Suzuki
coupling.14
B(OH)3 + H3O
(3)
B(OH)2 + 2H2O
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Mechanistic Interpretation of Aqueous Suzuki Coupling in the Absence of Added Base and
Ligand
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9
At this juncture the question arises as to whether the generally accepted Suzuki
mechanism (Scheme 1)14,38,39 is operating in the absence of added base and ligand when dealing
with substrates containing basic nitrogen centers—especially in situations where the entire
reaction readily takes place within an acidic pH range as is the case for the 4ꢀaminoꢀ2ꢀ
bromopyridine substrate. The Suzuki coupling of aryl bromides is widely accepted to proceed via
a mechanism which involves oxidative addition of Pd(0) species, transmetallation and reductive
elimination of the biaryl product to regenerate the catalytically active Pd(0) (Scheme 1).14
Following oxidative addition, the resulting LnPd(Ar)Br intermediate can undergo substitution of
the bromide ligand by hydroxide ion (use as is or generated by ionization of water) to form oxo
palladium intermediate, LnPd(Ar)OH. The transmetallation step is less understood and has been
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ꢀ
proposed to occur via reaction with either PhB(OH)3 (boronate pathway) or PhB(OH)2 (oxo
palladium mechanism).40 Hartwig41 has demonstrated that in the absence of added base, the
stoichiometric reaction of LnPd(Ar)OH with ArB(OH)2 is orders of magnitude faster than
ꢀ
reaction of LnPd(Ar)Br with ArB(OH)3 . At high pH, the equilibrium between boronic acid and
ꢀ 14
trihydroxyborate strongly favors ArB(OH)3 . However, the acidic pH would be expected to
decelerate either potential pathways for transmetallation by decreasing the concentration of
ꢀ
ArB(OH)3 or LnPd(Ar)OH, and leads to low catalytic activity.
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Scheme 1. Mechanism of Ligand-Free Palladium-Catalyzed Suzuki Coupling Reactions in
H2O (Oxo Palladium Intermediate Pathway)14
6
7
8
Pd(OAc)2
Ar2 B(OH)2
+
OH
Ar1 Ar2
Ar1 Br
+
+ B(OH)3
Pd Black
+
Br
H2O
9
PdII(OAc)2
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Ar1 Br
Ar Ar2
Pd0
Reductive
Elimination
Oxidative Addition
added base
PO43- or CO3
H2O
Ar1 PdII Br
OH-
2-
Ar PdII
Ar2
Metathesis
B(OH)3
Ar1 PdII
OH
Transmetallation
Br-
oxo palladium
intermediate
Ar2B(OH)2
Our observation of highꢀyielding Suzuki couplings at acidic pH is unusual in light of the
vast literature which typically demonstrates the requirement of base for catalytic activity. The
observation that the nitrogenꢀcontaining substrates in Figure 4 undergo Suzuki coupling at rates
which are essentially insensitive to added base suggests that the pH of the aqueous phase may
not be a critical parameter in these reaction processes.
Under the reaction conditions in the presence of water and PhB(OH)2, but in the absence
of added ligand, Pd(OAc)2 can rapidly generate catalytically active Pd(0) molecules, which
undergo aggregation to form clusters, nanoparticles and, eventually, Pd black.42,43 We observed
the formation of Pd black in these reaction mixtures, and the mercury drop test44,45 showed an
partial catalytic deactivation caused by adding an excess of Hg(0) (Supporting Information (SI),
Section 1). These observations are consistent with literature and support that there are
competitive catalytic pathways operating including active Pd(0) particles (highly likely a mixture
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of Pd(0) clusters and nanoparticles) and waterꢀsoluble oxoꢀPd catalytic species.46 The
contribution of each pathway most likely changes from reaction to reaction based upon
conditions such as the ability of substrate to be an effective ligand and the pH of aqueous phase.
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The limited solubility of the substrates in Figure 4 in water leads to the presence of two
or more phases at the reaction temperature. In both cases there is an aqueous liquid phase. In the
case of 4ꢀbromobenzylamine there is an additional liquid organic phase, and in the case of 4ꢀ
aminoꢀ2ꢀbromopyridine there is an additional solid organic phase. Due to the heterogeneity of
these reaction mixtures, it is uncertain in which phase the catalytic steps occur. It is important to
note, however, that the basic nitrogen centers can act as both ligands for Pd(0) (Figure 5b) and
effective hydrogen bonding centers with water to create incipient hydroxide ions (Figure 5a).
Thus, it is conjectured that both the oxidative addition of Pd(0) and the metathesis step to
generate the oxo palladium intermediate take place primarily at the organicꢀaqueous interface
where the substrate behaves as both the ligand and the source of incipient hydroxide.
δ−
O H
δ−
O H
Pd
NH2
Pd
NH2
N
H
H
NH2
δ+
N
δ+
NH2
δ+
NH2
H2N
N
Br
Br
H
N
Br
Pd
H O
δ−
Br
Br
Br
a
b
Figure 5. Basic nitrogenꢀcontaining substrates acting as (a) the source of incipient hydroxide
ions and (b) Pd(0) ligands.
In order to test our hypothesis, we compared the Suzuki reactivity of 4ꢀ
bromobenzylamine with analogues which did not contain a nitrogen lone pair (Table 7).
Experiments with 4ꢀbromoanisole confirmed that essentially no Suzuki coupled product was
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observed at acidic pH (3.3 – 2.5) with PhB(OH)2 (Entry 11, Table 7). In the absence of added
base, there is apparently insufficient concentration of hydroxide ion to convert the LnPd(Ar)Br
species to LnPd(Ar)OH. Under these same reaction conditions, 4ꢀbromobenzylamine (Entry 1,
Table 7) gave 90% yield of coupled product with no added base. Protonation of the benzylamine
in 4ꢀbromoꢀbenzylammonium bromide (Entry 9, Table 7) sequestered this internal basic nitrogen
atom and drastically decreased conversion. Similarly, the quaterized amine substituent in 4ꢀ
bromobenzyltriethylꢀammonium bromide lacks a basic nitrogen atom and was essentially
unreactive in the absence of added base (Entry 10, Table 7). In the case of 4ꢀaminoꢀ2ꢀ
bromopyridine, the quantitative yields (Entries 7 and 8, Table 3) can be attributed to the
cooperation of the aromatic amino and pyridyl nitrogen atoms (Figure 5), although both of them
are less basic than the benzylic amines, and neither of which can produce a high yield of crossꢀ
coupling product alone (Entries 12 and 13, Table 7) under the same reaction conditions
accompanied by the excellent yield when they work together (Entries 7 and 8, Table 3).
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In addition, the importance of the presence of substantial quantities of water in the
reaction system was addressed. 4ꢀBromobenzylamine was reacted with PhB(OH)2 in water and a
variety of mixed and pure organic solvent systems using 4 mol% Pd(OAc)2 for 4 hours in the
absence of added base at reflux temperatures (Entries 1ꢀ8, Table 7). While the reflux temperature
varied approximately 24 degrees over the solvent systems investigated, the general conclusion
from this series of reactions is still qualitatively instructive. All of the reaction systems were
heterogeneous. The observed yield in water was greater than 90%. The corresponding yields in
ethanol, acetonitrile and tertꢀbutanol were extremely poor (approximately 21%). In the mixed
solvent systems, it is clear that as the quantity of water increases, the corresponding yields
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increase. Water, the source of hydroxide ion for the metathesis step in the catalytic cycle, is
essential for successful coupling.
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9
Table 7 Control Reactions for the Pd(OAc)2 Catalyzed Suzuki Reactions in Water in the
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Absence of Added Base and Ligand a
Temperature
(oC)
GC Yield
(%)
Substrate
Entry
1
Solvent
H2O
(pH: 9.4 → 2.1)
EtOH
100
93
2
3
4
5
6
7
8
76
82
82
80
80
86
79
21
21
22
38
69
86
50
CH3CN
tBuOH
EtOH (20% H2O)
EtOH (40% H2O)
EtOH (60% H2O)
CH3CN (40% H2O)
H2O
9
100
14
(pH: 4.7 → 1.5)
H2O
(pH: 4.0 → 1.3)
10
11
12
100
100
100
11b
1
H2O
(pH: 3.3 → 2.5)
H2O
(pH: 3.8 → 2.0)
39
H2O
(pH: 4.4 → 2.6)
13
100
21
a Reaction conditions: ArꢀBr (10 mmol), PhB(OH)2 (11 mmol), Pd(OAc)2 (4 mol%), solvent (25 mL), N2,
reflux, 4 h.
b Determined by 1H NMR
Lastly, the question still remains as to the mechanism by which the oxo palladium
intermediate is presumably generated at the organicꢀaqueous interface. Differences in the initial
pH of the Suzuki reaction mixtures are likely due to differences in the pKb of the amine moiety in
the aryl bromide. In the absence of added base, reaction mixtures of 4ꢀbromobenzylamine had an
initial pH of 9.1 – 9.5 (Table 1). We hypothesized that 4ꢀbromobenzylamine is, therefore,
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sufficiently basic to cause ionization of water to generate hydroxide ion required for producing
the oxo palladium intermediate. This mechanism is conceptually similar to the existing “baseꢀ
free” approaches using boronate reagents that can liberate inꢀsitu base species.47ꢀ52
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Conversely, bromopyridine substrates are less mechanistically straightforward due to
their lower basicity. Suzuki coupling reaction mixtures of 4ꢀaminoꢀ2ꢀbromopyridine had a much
lower initial pH (6.2 – 6.5, Table 3) due to the lower basicity of the aromatic amino and pyridyl
nitrogen atoms in comparison to benzylic amines. For the less basic bromopyridine substrates,
we hypothesize that the oxo palladium species may be generated via the deprotonation of a
cationic aqua palladium intermediate (Figure 6). Following oxidative addition, the resulting
LnPd(Ar)Br intermediate may be solvated by the aqueous media, resulting in the formation of a
cationic aqua palladium complex, LnPd(Ar)(OH2)+.53 Deprotonation of the cationic aqua ligand
complex by the weakly basic pyridine and amino substituent of 4ꢀaminoꢀ2ꢀbromopyridine would
ultimately afford the desired oxo palladium intermediate, LnPd(ArH)+(OH), required for the
catalytic cycle (Figure 6).
Figure 6. Generation of oxo palladium species via cationic aqua palladium complexes
Structurally characterized palladacyclic aqua complexes have been found to be highly
active Suzuki catalyst precursors at basic pH ranges below the pKa (10.9) of the Pd hydroxide
species.54 However, it is likely that the aqua ligands in this reported example serve primarily as
weakly bound ligands which easily dissociate and facilitate entry into the catalytic cycle.
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Consequently, the aqua complex does not seem to be responsible for the surprising reactivity of
our Suzuki coupling catalyst system under acidic pH conditions since aryl bromides which lack
nitrogen lone pairs should also be expected to undergo cross coupling under acidic conditions.
One possible explanation for the unusual reactivity of bromopyridines at low pH is that the
weakly basic amine moiety stabilizes the oxo palladium intermediate (Figure 6). It has been
reported that the cationic aqua palladium complexes are quite acidic even with aliphatic amine
ligands.55 Although the relative basicities of the pyridyl nitrogen atoms and PdꢀOH groups are
not exactly known, we propose that protonation of the pyridines would increase the acidity of the
aqua ligand and favor LnPd(ArH)+(OH), thereby allowing the oxo palladium mechanism to
proceed under acidic conditions. The mechanistic details of ligandꢀfree and aqueous Suzuki
couplings under acidic conditions will be addressed in future investigations.
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CONCLUSIONS
It is concluded that these pHꢀindependent Suzuki couplings of basic nitrogen containing
substrates proceed by the widely accepted oxo palladium and Pd(0) catalysis mechanisms. The
reactions are heterogeneous and results are consistent with the reaction taking place primarily at
the organicꢀaqueous interface where the substrate behaves as both the ligand and the source of
incipient hydroxide for generating the oxo palladium intermediate. In the case of relatively basic
benzylic amines, the amino substituent is able to generate hydroxide ion for oxo palladium
intermediate that undergoes transmetallation. For less basic bromopyridines, the deprotonation of
a cationic aqua intermediate is proposed to allow the oxo palladium intermediate to form under
acidic conditions.
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EXPERIMENTAL
General Method
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The commercially available solvents, reagents and standard products for GC analysis
were purchased from commercial providers in reagent grade and were used without further
purification. Some aryl bromides substrates, such as some of Nꢀsubstituted 4ꢀ
bromobenzylamines56 and Nꢀ(4ꢀbromobenzyl)ꢀN,N,Nꢀtriethylammonium bromide57 were
synthesized following the published methods.
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o
pH values of the aqueous phase were measured by a portable pH meter at 25 ± 2 C.
1
Melting points were measured on a capillary melting point apparatus. H (400 MHz) and 13C
(100 MHz) NMR spectra were recorded on a 400 MHz NMR 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 GCꢀMS (qualitative) and a GCꢀFID (quantitative) fitted with a capillary column
(30 m × 0.32 mm × 1.00 ꢁm, length × inside diameter × film thickness).
General Experimental Procedure for Suzuki Reactions
A mixture of aryl bromide, arylboronic acid, base (if used), Pd(OAc)2 and solvent in a 3ꢀ
neck roundꢀbottom flask was stirred (600 – 800 rpm) under reflux for the requisite time. The
initial and final pH values of the aqueous phase were measured pre and postꢀ reaction, once the
o
temperature had stabilized at 25 – 27 C. The initial reaction time (t = 0) was taken when the
reaction mixture began to reflux; the time to reach this temperature was approximately 20 – 30
minutes. The cooled reaction mixture was extracted with organic solvents (chloroform for
benzylamines, ethyl acetate for aminopyridines, and dichloromethane for the rest). The combined
organic phase was dried over anhydrous MgSO4 and filtered. The solvent was removed under
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vacuum and the crude product was analyzed by GC and H NMR following the published
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methods (SI, Section 2).23
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Procedure for the Reactions of 4-Bromobenzylamine with Phenylboronic Acid in Water in
the Absence of Added Base (Table 1)
A mixture of 4ꢀbromobenzylamine (1.861 g, 10 mmol, 1.0 equiv), PhB(OH)2 (1.341 g,
1.1 equiv), Pd(OAc)2 (0.0449 g, 2 mol%; or 0.0898 g, 4 mol%) and H2O (25 mL) in a 3ꢀneck
o
roundꢀbottom flask (100ꢀmL) was stirred under reflux at 100 C in N2. The reactions were triꢀ
phasic: an aqueous phase, an organic phase and a solid phase (catalyst). Palladium black
o
gradually formed when 100 C was reached. Once the reaction time was reached, the reaction
mixture was cooled, basified to pH ≥ 12 using 30% NaOH aqueous solution, and then was
thoroughly extracted with chloroform. The combined organic phase was dried over anhydrous
MgSO4 and filtered. The solvent was removed under vacuum. The crude product was analyzed
by GC and 1H NMR.
Procedure for the Reactions of 4-Bromobenzylamine with Phenylboronic Acid in Water in
the Presence of Varying Amount s of Added Base (Table 2)
A mixture of 4ꢀ bromobenzylamine (1.861 g, 10 mmol, 1.0 equiv), PhB(OH)2 (1.341 g,
1.1 equiv), K3PO4, Pd(OAc)2 (0.0449 g, 2 mol%; or 0.0898 g, 4 mol%) and H2O (25 mL) in a 3ꢀ
o
neck roundꢀbottom flask (100ꢀmL) was stirred under reflux at 100 C in N2. The reactions were
triphasic: an aqueous phase, an organic phase and a solid phase (catalyst). Formation of
palladium black was not observed. After cooling to room temperature, the reaction was
thoroughly extracted with chloroform. The combined organic phase was dried over anhydrous
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MgSO4 and filtered. The solvent was removed under vacuum. The crude product was analyzed
by GC and 1H NMR.
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Procedure for the Reactions of 4-Amino-2-bromopyridine with Phenylboronic Acid in
Water in the Absence of Added Base (Table 3)
A mixture of 4ꢀaminoꢀ2ꢀbromopyridine (1.730 g, 10 mmol, 1.0 equiv), phenylboronic
acid (PhB(OH)2,1.341 g, 1.1 equiv), Pd(OAc)2 (0.0449 g, 2 mol%; or 0.0898 g, 4 mol%) and
H2O (25 mL) in a 3ꢀneck roundꢀbottom flask (100ꢀmL) was stirred under reflux at 100 oC in N2.
The reactions were biphasic: an aqueous phase and a solid phase (catalyst and substrate).
Palladium black gradually formed when 100 oC was reached. After cooling to room temperature,
the reaction mixture was basified to pH ≥ 12 using 30% NaOH aqueous solution, and then was
thoroughly extracted with ethyl acetate. The combined organic phase was dried over anhydrous
MgSO4 and filtered. The solvent was removed under vacuum. The crude product was analyzed
by GC and 1H NMR.
Procedure for the Reactions of 4-Amino-2-bromopyridine with Phenylboronic Acid in
Water in the Presence of Varying Amounts of Added Base (Table 4)
A mixture of 4ꢀaminoꢀ2ꢀbromopyridine (1.730 g, 10 mmol, 1.0 equiv), PhB(OH)2 (1.341
g, 1.1 equiv), K3PO4, Pd(OAc)2 (0.0449 g, 2 mol%) and H2O (25 mL) in a 3ꢀneck roundꢀbottom
flask (100ꢀmL) was stirred under reflux at 100 oC in N2. The reactions were biphasic: an aqueous
phase and a solid phase (catalyst and substrate). The formation of palladium black was not
observed. The cooled reaction mixture was thoroughly extracted with ethyl acetate. The
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combined organic phase was dried over anhydrous MgSO4, and filtered. The solvent was
removed under vacuum. The crude product was analyzed by GC and 1H NMR.
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Procedure for the Reactions of Aryl Bromides Containing 1o, 2o, and 3o Amine Substituents
with Phenylboronic Acid in Water in the Absence of Added Base (Table 5)
A mixture of aryl bromides (10 mmol, 1.0 equiv), phenylboronic acid (1.829 g, 1.5
equiv), Pd(OAc)2 (0.0899 g, 4 mol%) and H2O (25 mL) in a 3ꢀneck roundꢀbottom flask (100ꢀ
mL) was stirred under reflux at 100 oC in N2. The reactions were triꢀphasic: an aqueous phase, an
organic phase (substrate) and a solid phase (catalyst). Palladium black gradually formed when
100 oC was reached. After cooling to room temperature, the reaction mixture was basified to pH
≥ 12 using 30% NaOH aqueous solution, and then was thoroughly extracted with chloroform.
The combined organic phase was dried over anhydrous MgSO4 and filtered. The solvent was
removed under vacuum. The crude product was analyzed by GC and 1H NMR.
Procedure for the Reactions of Pyridyl Bromides with Phenylboronic Acid in Water in the
Absence of Added Base (Table 6)
A mixture of bromopyridine substrate (10 mmol, 1.0 equiv), PhB(OH)2 (1.829 g, 1.5
equiv), Pd(OAc)2 (0.0898 g, 4 mol%) and H2O (25 mL) in a 3ꢀneck roundꢀbottom flask (100ꢀ
o
mL) was well stirred under reflux at 100 C in N2. The reactions with solid substrates were
biphasic: an aqueous phase and a solid phase (catalyst and substrate). If the substrate was a
liquid, there was an additional liquid organic phase. The gradual formation of palladium black
was observed when the reaction temperature reached 100 oC. After cooling to room temperature,
the reaction mixture was basified to pH ≥ 12 using 30% NaOH aqueous solution, and then was
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thoroughly extracted with ethyl acetate (for aminopyridines) or dichloromethane (for the rest).
The combined organic phase was dried over anhydrous MgSO4 and filtered. The solvent was
removed under vacuum. The crude product was analyzed by GC and 1H NMR.
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Procedure for the Reaction of 4-Bromoanisole with Phenylboronic Acid in Water in the
Absence of Added Base (Entry 11, Table 7)
A mixture of 4ꢀ bromoanisole (1.870 g, 10 mmol, 1.0 equiv), PhB(OH)2 (1.341 g, 1.1
equiv), Pd(OAc)2 (0.0898 g, 4 mol%) and H2O (25 mL) in a 3ꢀneck roundꢀbottom flask (100ꢀ
o
mL)was well stirred under reflux at 100 C in N2 for 4 h. The reactions were triꢀphasic: an
aqueous phase, an organic phase and a solid phase (catalyst). Palladium black formed
immediately upon addition of Pd(OAc)2 to the reaction mixture. After cooling to room
temperature, the reaction mixture was thoroughly extracted with dichloromethane. The combined
organic phase was dried over anhydrous MgSO4 and filtered. The solvent was removed under
vacuum. The crude product was analyzed by GC and 1H NMR.
Procedure for the Control Reactions of 4-Bromobenzylamine with Phenylboronic Acid in
Varying Solvents in the Absence of Added Base (Entries 2 – 8, Table 7)
A mixture of 4ꢀbromobenzylamine (1.861 g, 10 mmol, 1.0 equiv), PhB(OH)2 (1.341 g,
1.1 equiv), Pd(OAc)2 (0.0898 g, 4 mol%) and solvent (25 mL) in a 3ꢀneck roundꢀbottom flask
(100ꢀmL) was stirred under reflux in N2 for 4 h. The reactions were triꢀphasic: an aqueous phase,
an organic phase and a solid phase (catalyst). After cooling to room temperature, the reaction
mixture was basified to pH ≥ 12 using 30% NaOH aqueous solution, and was thoroughly
extracted with chloroform. The combined organic phase was dried over anhydrous MgSO4,
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NMR.
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Procedure for the Control Reactions of Varing Aryl Bromides with Phenylboronic Acid in
Water in the Absence of Added Base (Entries 9, 10, 12, 13, Table 7)
A mixture of aryl bromide (10 mmol, 1.0 equiv), PhB(OH)2 (1.341 g, 1.1 equiv),
Pd(OAc)2 (0.0898 g, 4 mol%) and H2O (25 mL) in a 3ꢀneck roundꢀbottom flask (100ꢀmL) was
stirred under reflux at 100 oC in N2. After cooling to room temperature, the reaction mixture was
basified to pH ≥ 12 using 30% NaOH aqueous solution, and then was thoroughly extracted with
dichloromethane. The combined organic phase was dried over anhydrous MgSO4, filtered. The
solvent was removed under vacuum. The crude product was analyzed by GC and 1H NMR.
Procedure for Mercury Test
A mixture of aryl bromide (4 mmol, 1.0 equiv), PhB(OH)2 (4.4 mmol, 1.1 equiv),
Pd(OAc)2 (2 mol% for 4ꢀaminoꢀ2ꢀbromopyridine, 4 mol% for 4ꢀbromobenzylamine), mercury
(99.9+%) and water (10 mL) in a 3ꢀneck roundꢀbottom flask (50ꢀmL) was stirred under reflux at
o
100 C in N2. After cooling to room temperature, the reaction mixture was basified using 30%
NaOH aqueous solution (2 mL). The resulting reaction mixture was diluted with methanol and
measured in a 100 mL volumetric flask. An aliquot of the organic solution was taken for GC
analysis. In parallel, a control reaction in the absence of mercury was carried out under the
identical reaction conditions for comparison.
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Synthesis of N-Substituted 4-Bromobenzylamines56
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A mixture of 4ꢀbromombenzyl bromide (7.498 g, 30 mmol), amine (35 mmol), K2CO3
(6.346 g, 35 mmol) and THF (50.0 mL) was stirred under a N2 atmosphere at room temperature
overnight. When reaction completed (monitored by GCꢀFID), the white solid was removed by
filtration, while the filtrate was concentrated as much as possible and then dissolved in
dichloromethane (~50.0 mL). The resulting organic solution was thoroughly washed with cold
water, dried over MgSO4 and filtered. The solvent was removed under vacuum to afford slightly
yellow to yellow oil.
1
4-Bromo-N-isopropylbenzylamine (substrate for Entry 7, Table 5), 90%, yellow oil. H NMR
(400 MHz, CDCl3) δ (ppm): 7.37 – 7.40 (m, 2H), 7.14 – 7.18 (m, 2H), 3.69 (s, 2H), 2.79 (heptet,
J = 6.2 Hz, 1H), 1.05 (d, J = 6.2 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ (ppm): 139.8, 131.4,
129.8, 120.5, 50.9, 48.1, 22.9.
4-Bromo-N,N-dimethylbenzylamine (substrate for Entry 8, Table 5), 97%, yellow oil. 1H NMR
(400 MHz, CDCl3) δ (ppm): 7.37 – 7.40 (m, 2H), 7.11 – 7.16 (m, 2H), 3.31 (s, 2H), 2.17 (s, 6H).
13C NMR (100 MHz, CDCl3) δ (ppm): 137.9, 131.1, 130.7, 120.8, 63.6, 45.3.
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4-Bromo-N,N-diethylbenzylamine (substrate for Entry 9, Table 5), 96%, yellow oil. H NMR
(400 MHz, CDCl3) δ (ppm): 7.40 – 7.43 (m, 2H), 7.20 – 7.23 (m, 2H), 3.50 (s, 2H), 2.50 (q, J =
7.1 Hz, 4H), 1.03 (t, J = 7.1 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ (ppm): 139.1, 131.2, 130.5,
56.9, 46.7, 11.8.
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4-Bromo-N,N-dipropylbenzylamine (substrate for Entry 10, Table 5), 92%, yellow oil. H
NMR (400 MHz, CDCl3) δ (ppm): 7.41 – 7.45 (m, 2H), 7.22 – 7.26 (m, 2H), 3.50 (s, 2H), 2.38
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(t, J = 7.4 Hz, 4H), 2.79 (sextet, J = 7.3 Hz, 4H), 0.89 (t, J = 7.4 Hz, 6H). C NMR (100 MHz,
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CDCl3) δ (ppm): 139.6, 131.1, 130.4, 120.2, 58.1, 55.9, 20.2, 11.9.
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4-Bromo-N,N-diisopropylbenzylamine (substrate for Entry 11, Table 5), 93%, slightly yellow
oil. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.41 – 7.44 (m, 2H), 7.27 – 7.31 (m, 2H), 3.60 (s, 2H),
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2.79 (heptet, J = 6.6 Hz, 2H), 1.04 (d, J = 6.6 Hz, 12H). C NMR (100 MHz, CDCl3) δ (ppm):
142.4, 131.0, 129.6, 119.6, 48.4, 48.0, 20.8.
Synthesis of N-(4-Bromobenzyl)-N,N,N-triethylammonium Bromide (Substrate for Entry
10, Table 7)57
A mixture of 4ꢀbromombenzyl bromide (12.497 g, 50 mmol), triethylamine (7.589 g, 75
mmol), dry Et2O (100 mL) was stirred under a N2 atmosphere at room temperature overnight,
while a white solid gradually precipitated. The precipitated solid was collected by filtration,
washed with dry Et2O, and dried in a vacuum overnight to afford Nꢀ(4ꢀBromobenzyl)ꢀN,N,Nꢀ
1
triethylammonium bromide (8.778 g, yield: 50%) as white fluffy solid. H NMR (400 MHz,
CDCl3) δ (ppm): 7.36 – 7.50 (m, 4H), 4.76 (s, 2H), 3.32 (q, J = 6.8 Hz, 6H), 1.34 (t, J = 6.8 Hz,
9H). 13C NMR (100 MHz, CDCl3) δ (ppm): 134.3, 132.4, 126.2, 125.2, 60.6, 53.2, 8.7.
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: charles.liotta@chemistry.gatech.edu
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