Pd-Catalyzed Suzuki coupling reactions of aryl halides containing basic nitrogen centers with arylboronic acids in water in the absence of added base

Article abstract of DOI:10.1039/c7nj03567e

The Pd-catalyzed Suzuki coupling reactions of a series of aryl chlorides and aryl bromides containing basic nitrogen centers with arylboronic acids in water in the absence of added base are reported. The reactions proceed either partially or entirely under acidic conditions. After surveying twenty-two phosphorus ligands, high yields of products were obtained with aryl chlorides only when a bulky ligand, 2-(di-tert-butyl-phosphino)-1-phenyl-1H-pyrrole (cataCXiumPtB) was used. In contrast, aryl bromides produced high yields of products in the absence of both added base and added ligand. In order to explore the Suzuki coupling process entirely under acidic conditions, a series of reactions were conducted in buffered acidic media using several model substrates. 4-Chlorobenzylamine, in the presence of cataCXiumPtB, produced high yields of product at buffered pH 6.0; the yields dropped off precipitously at buffered pH 5.0 and lower. The fall-off in yield was attributed to the decomposition of the Pd-ligand complex due to the protonation of the ligand in the more acidic aqueous media. In contrast, in the absence of an added ligand, 4-amino-2-chloropyridine produced quantitative yields at buffered pH 3.5 and 4.5 while 4-amino-2-bromopyridine produced quantitative yields in a series of buffered media ranging from pH 4.5 to 1.5. These substrates are only partially protonated in acidic media and can behave as active Pd ligands in the Suzuki catalytic cycle.

Full text of DOI:10.1039/c7nj03567e

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Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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ARTICLE
Pd-Catalyzed Suzuki Coupling Reactions of Aryl Halides Containing
Basic Nitrogen Centers with Arylboronic Acids in Water in the
Absence of Added Base
Received 00th January 20xx,
Accepted 00th January 20xx
Zhao Li,a Carol Gelbaum,a Zachary S. Campbell,b Paul C Gould,a Jason S. Fisk,c Bruce Holden,c
Arvind Jaganathan,d Gregory T. Whiteker,d Pamela Pollet,a and Charles L. Liotta*,a,b
DOI: 10.1039/x0xx00000x
www.rsc.org/
The Pd-catalyzed Suzuki coupling reactions of a series of aryl chlorides and aryl bromides containing basic nitrogen centers
with arylboronic acids in water in the absence of added base are reported. The reactions proceed either partially or
entirely under acidic conditions. After surveying twenty-two phosphorus ligands, high yields of products were obtained
with aryl chlorides only when a bulky ligand, 2-(di-tert-butyl-phosphino)-1-phenyl-1H-pyrrole (cataCXium®PtB) was used. In
contrast, aryl bromides produced high yields of products in the absence of both added base and added ligand. In order to
explore the Suzuki coupling process entirely under acidic conditions, a series of reactions were conducted in buffered
acidic media using several model substrates. 4-Chlorobenzylamine, in the presence of cataCXium®PtB, produced high yields
of product at buffered pH 6.0; the yields dropped off precipitously at buffered pH 5.0 and lower. The fall-off in yield was
attributed to the decomposition of the Pd-ligand complex due to the protonation of the ligand in the more acidic aqueous
media. In contrast, in the absence of an added ligand, 4-amino-2-chloropyridine produced quantitative yields at buffered
pH 3.5 and 4.5 while 4-amino-2-bromopyridine produced quantitative yields in a series of buffered media ranging from pH
4.5 to 1.5. These substrates are only partially protonated in acidic media and can behave as active Pd ligands in the Suzuki
catalytic cycle.
atoms of aromatic amines and pyridines could play a positive
role under the aqueous, ligand-free conditions by stabilizing
the active Pd(0) species against deactivation, i.e. preventing
Introduction
The palladium-catalyzed Suzuki coupling reaction1,2 provides a
versatile synthetic strategy for the construction of biaryl
compounds.3-9 This is particularly important for those
substrates containing basic nitrogen centers,10-13 which are
present in many pharmaceutical and biologically active
molecules.14 However, the Suzuki reactions with substrates
containing basic nitrogen centers, such as amino groups and
pyridines, often suffer from the limitations of slow rates and
low yields of desired coupling products compared to the non-
basic neutral substrates under the same reaction conditions.15-
formation of insoluble Pd black.22 In these cases, quantitative
yields of desired products could be obtained without
protection of the basic nitrogen centers.22 This synthetic
protocol was further simplified; ligand-free/aqueous Suzuki
coupling reactions of phenylboronic acid with a series of aryl
bromides containing aliphatic amines and pyridines were
successfully coupled in the absence of added base.23 It should
be emphasized that these base-free Suzuki reactions were
found to be partially or entirely taking place under acidic
conditions.23
18
It has been suggested that the origin of the slow rates and
Encouraged by the success in the development of the
synthetic protocols for Suzuki couplings of aryl bromides,22,23
we expanded the scope of substrates for the aqueous, base-
free catalytic systems to aryl chlorides which are lower cost
substrates compared to bromide counterparts. However, it is
well-known that aryl chlorides exhibit much lower reactivity
than the corresponding aryl bromides and iodides.24 Reports in
the literature indicate that an effective way to enable the Pd
catalyzed Suzuki reactions of the less reactive aryl chlorides is
the use of bulky, electron-rich phosphorus ligands (P-
ligands).25,26 In addition to the commonly used
triphenylphosphine, the literature has reported several other
efficient P-ligands; these include the PCy3 and P(t-Bu)3 ligands
developed by the Fu group,27 the Buchwald ligands and pre-
low yields is the decreased activity of palladium catalyst due to
the coordination of the catalyst with the basic nitrogen center
of the substrates.18-21 We have, however, recently
demonstrated that this ligation effect of the basic nitrogen
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catalysts,28-30 and the cataCXium® ligand family.31,32 Recently, the reaction conditions in Table 1 constant but reducing the
the N-heterocyclic carbenes (NHC) and their transition metal amount of Pd catalyst to 2 mol% and reducing the time of
complexes have been demonstrated to have efficient catalytic reaction to 30 minutes resulted in yields of 100% for 4-amino-
activity toward the Suzuki couplings of aryl chlorides,33-35 and 2-bromopyridine and only a 62% yield for the chloro
the investigations in neat water were also reported during the counterpart (Table 1, Entry 6). Under these modified
past few years.36-38
conditions, where
Although the current literature contains a number of
reports describing Suzuki reactions of aryl chloride in water in
the presence of added ligand and base,9,26,36-42 to our
knowledge no successful reactions between aryl chlorides and
arylboronic acids have been reported in the absence of added
base. Herein, we report (1) a comparison between the
reactions of aryl bromides and chlorides containing basic
nitrogen centers in the absence of added ligand and added
base, (2) the screening of twenty-two phosphorus ligands to
optimize the cross-coupling of the aryl chlorides with a variety
of arylboronic acids in the absence of added base, (3) the
phase behavior of the reaction systems and the pH change of
the aqueous phase at the beginning and end of the coupling
process, (4) a yield comparison between the base-free
reactions of aryl bromides in the absence of added ligand with
the aryl chloride counterparts in the presence of an added
ligand, and (5) finally, using buffered aqueous media, the
demonstration that model substrates (4-chlorobenzylamine, 4-
amino-2-chloropyridine, and 4-amino-2-bromopyridine) can
undergo the coupling process entirely on the acidic side of the
pH scale.
Table 1. Suzuki Coupling Reactions of Aryl Bromides and Chlorides Containing Basic
Nitrogen Centers with PhB(OH)2 in the Absence of Added Base and Added Ligand.a
X = Br
X = Cl
Time
(h)
Entry
Ar-X
Yield Initial Final Yield Initial Final
(%)b
pH
pH
(%)b
pH
pH
NH2
1
2
4
4
92
9.2
2.5
15
9.3
7.6
X
92
94
9.2
9.3
3.1
1.5
12
28
9.4
9.0
7.4
7.2
3
4
4
5
6
7
4
4
1
4
40
70
7.9
7.4
6.5
5.6
6.0
4.1
2.3
4.4
13
3
7.8
7.0
6.3
6.6
6.4
4.7
2.5
5.4
100
100
(100)c
(62)c
81
4
Results and Discussion
8
9
4
4
4
56
82
94
5.8
4.8
4.6
3.1
2.6
2.7
5
5.5
5.3
5.1
4.7
2.5
3.1
(1) Comparison Between Suzuki Reactions of Aryl Bromides and
Chlorides in the Absence of Added Ligand and Added Base
25
27
Table 1 summarizes the results of the reaction of a variety of
aryl bromides and chlorides containing basic nitrogen centers
with phenylboronic acid (PhB(OH)2) using 4 mol% Pd(OAc)2 in
water at 100oC in the absence of both added ligand and added
base for a reaction period of 4 h. In addition, the initial and
final pH of the aqueous phase are also indicated. The aryl
halides listed in Table 1 include both aliphatic primary amine
substituents (Table 1, Entries 1-3) and aromatic basic nitrogen
centers (Table 1, Entries 4-11). It is clear that the yields
associated with the aryl bromides are, for the most part, good
to excellent while those of the aryl chloride counterparts are
extremely poor. These results are not unexpected. The
literature contains many examples reflecting the greater
reactivity of aryl bromides compared with their chloro
counterparts. There is, however, one notable exception. 4-
Amino-2-bromopyridine and 4-amino-2-chloropyridine (Table
1, Entry 6) both produce quantitative yields of coupled
products under the above conditions. This observation is
consistent with our previous report in which we observed that
these same two substrates produced quantitative yields of
coupled products with phenylboronic acid catalyzed by 4 mol%
Pd(PPh3)2Cl2 in acetonitrile/water (60/40, v/v) in the presence
of phosphate base.43 The only difference is the use of a mixed
solvent system and the presence of an added base. Keeping
10
11
4
44
4.6
2.7
5
5.1
3.5
a
Reaction conditions: Ar-X (10 mmol), PhB(OH)2 (15 mmol), Pd(OAc)2 (4 mol%),
H2O (25 mL), N2, 100 oC. Yields were determined by both GC and 1H NMR
(Supplemental Information S1-S5), GC yields were shown, and NMR yields were
b
summarized in Supplemental Information S6.
repetitions with an error < 5%. c 2 mol% Pd(OAc)2, 30 minutes.
GC yield, average of 2-3
turnover rates are reduced, the intrinsically higher reactivity of
4-amino-2-bromopyridine over 4-amino-2-chloropyridine is
observed. Finally, it is worth noting that Table 1, Entries 4-11
indicates that the pyridyl bromides undergo Suzuki coupling
either near neutral pH or completely on the acidic side of the
pH scale.
(2) Screening of Phosphorus Ligands
The poor reactivity of aryl chlorides prompted us to investigate
the effect of ligand structure on enhancing their reactivity
under aqueous conditions in the absence of added base. A
total of twenty-two phosphorus ligands and pre-catalysts were
surveyed. The base-free Suzuki coupling of 4-
chlorobenzylamine (4ClBnAm, 1a) and PhB(OH)2 (2) in water at
100 oC under N2 catalyzed by 4 mol% of Pd(OAc)2 over a 4 hour
2 | J. Name., 2017, 00, 1-12
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reaction period was selected as the model reaction for ligand was changed to 1:2, quantitative yield was obtained in 4 h in
screening. The ligands and the accompanying mol% used in the presence of 0.5 mol% of Pd(OAc)2 and 1 mol% of PtB ligand
these screening experiments are summarized in Fig. 1. In (Table 2, Entry 7). In all the experiments listed in Table 2 the
addition, the yield of coupled product 3a in the model reaction initial pH of the aqueous phase ranged from 8.8 to 9.1; the
is also indicated (in red). A 15% yield of product 3a was final pH ranged from 2.9 to 5.8. These results suggest that the
obtained without any added ligand. This yield is used as a Johnphos and PtB ligands might be active under both basic and
reference point for evaluating the effectiveness of the added acidic conditions.
ligands. It has been
Table 2. Optimization of Coupling Conditions for the Model Reaction Using JohnPhos or
PtB as Liganda
Ligand
Name
Pd(OAc)2 Time Yieldb
pH
Entry
(mol%)
(h)
4
(%)
91
72
92
91
91
90
mol%
initial Final
1
2
3
4
5
6
JohnPhos
JohnPhos
PtB
4
2
4
2
1
1
4
2
4
2
1
1
8.8
8.8
9.1
9.0
8.8
8.9
3.0
4.6
3.2
3.6
3.8
3.3
4
4
PtB
4
PtB
4
PtB
1
7
PtB
1
0.5
4
100
9.1
2.9
Fig. 1. Screening results of P-ligands for the model reaction between 4ClBnAm
(
8
9
PtB
PtB
PtB
PtB
1
1
0.5
0.5
0.5
0.5
2
1
92
65
54
72
8.8
8.8
8.9
8.8
3.2
5.6
5.8
4.5
1a) and PhB(OH)2 (2). Reaction conditions: 4ClBnAm (10 mmol), PhB(OH)2 (15
mmol), Pd(OAc)2 (4 mol%), H2O (25 mL), N2, 100 oC, 4 h. Yields of product 3a
were determined by GC.
10
11
1
0.5
4
0.5
reported that the hydrolysis of diorganophosphorus chlorides
a Reaction conditions: 4ClBnAm (10 mmol), PhB(OH)2 (15 mmol), H2O (25 mL), N2,
100 oC. b GC yield, average of 2-3 repetitions with an error < 5%.
(L1-L6) generates phosphine oxides and their less-stable
phosphinous acid tautomers which could act as suitable
ligands for Pd catalyzed coupling processes.44 As shown in Fig.
1, marginally improved yields were realized with these ligands.
A possible exception is di-tert-butylchlorophosphine (L4) which
resulted in a modest yield of 40%. This, however, is still an
unacceptably low yield. The addition of PPh3 (L7) or rac-BINAP
(4) Substrate Scope
In order to explore the scope of the Suzuki reactions of basic
nitrogen-containing aryl chlorides with PhB(OH)2 in water
catalyzed by Pd(OAc)2/PtB without added base, a variety of
aryl chlorides containing aliphatic amine substituents (1b-1f
)
(L9) showed no increase in yield compared to Pd(OAc)2 alone.
and aminopyridyl chlorides (1h-1n) were investigated. The
results are summarized in Table 3. Both the yields of coupled
products and the pH of the aqueous phase before and after
reaction are shown. Excellent yields were obtained for the first
A somewhat significant increase in yields (approximately 50-
60%) was realized with ligands L10-L16 and L22. It should be
noted that the pre-catalyst complexes, Pd(t-Bu3P)2 (L15) and
Pd(t-Bu2PhP)2Cl2
(L16) were directly used instead of the
and PPh(t-Bu)246. By far, the
27,45
nine substrates (1b-1f
to modest yields were realized for 3-amino-2-chloropyridine
1l) and 2-amino-6-chloropyidine (1m) (Table 3, Entries 18-22).
, 1h-1k, Table 3, Entries 1-17) while good
pyrophoric ligands P(t-Bu)3
best results in the ligand screening experiments were obtained
with Johnphos (2-(di-tert-butylphosphino)biphenyl, L18) and
cataCXium®PtB (PtB, 2-(di-tert-butyl-phosphino)-1-phenyl-1H-
pyrrole, L21); yields greater than of 90% were obtained.
(
Only a 25% yield was obtained for the reaction of 3-amino-6-
chloropyridine (1n, Table 3, Entries 23-24). While the result for
this substrate is only slightly better than the 5% yield obtained
without addition of PtB (Table 1, Entry 11), it is still much too
low to be of significant synthetic value. The results shown in
Table 3 also indicate that the effectiveness of PtB is substrate
dependent.
(3) Comparison and Optimization of Johnphos and PtB Ligands
Further comparison of the two most effective ligands,
Johnphos (L18) and cataCXium®PtB (L21) in the first round of
screening indicated that the latter is more effective in the
base-free Suzuki couplings of 4ClBnAm with PhB(OH)2 in water.
The results are shown in Table 2. When the 1:1 loading of the
catalyst/ligand pair Pd(OAc)2/JohnPhos is decreased from 4 to
2 mol% the yield of product decrease from 91% to 72% over a
four-hour reaction period (Table 2, Entry 2). In contrast, a yield
of approximately 90% could be maintained with cataCXiumPtB
It should be noted that in the reactions with the aliphatic
amine substrates (1b-1f, Table 3, Entries 1-7) and 4-amino-3-
chloropyridine (1h, Table 3, Entries 8-9) the pH of the aqueous
phase changes from basic to acidic suggesting that at least a
portion of these reactions may have taken place in an acidic
aqueous environment. In contrast, each of the remaining
reactions involving aminopyridyl chlorides (1i-1n, Table 3,
Entries 10-24) appear to have taken place entirely under acidic
aqueous conditions. The initial pH of the reaction solutions
(L21) even when the 1:1 catalyst/ligand loading was decreased
to 1 mol% (Table 2, Entries 4 and 5) and reaction time reduced
to 1 h (Table 2, Entry 6). In addition, if the catalyst/ligand ratio
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appear to be simply functions of the pKa of the amine- values and the observed yield for reactions in Table 3 that
substituted aryl chloride substrates calculated using the web- were conducted using ≤ 2 mol% Pd.
based acidity-basicity calculator available from the University
At this juncture, the correlations clearly indicate that the
of Kentucky.47 The pKa values are listed in Table 3, Column 3. aliphatic amino substrates (1a-1f) are completely protonated
Fig. 2 shows the relationship between the calculated pKa of the below pH 7. As a consequence, the amino functionality in
conjugate acids of amine-substituted aryl chlorides (pKa (Cl- these substrates would not be readily available to act as Pd
ArH+)) and the initial pH of the aqueous phase for the reactions ligands. However, the presence of the ammonium substituent
would increase the solubility of these substrates in the
Table 3. Pd(OAc)2–PtB Catalyzed Suzuki Reactions of Basic Nitrogen-Containing Aryl
Chlorides with PhB(OH)2 in Water in the Absence of Added Basea
aqueous phase
1b
1e
10
9
1c
1d
1f
1h
8
pH
pKa Pd(OAc)2 PtB Time Yield
Initial
pH
1j
7
Entry
1
Ar-Cl
(Cl-ArH+)47 (mol%) (mol%) (h)
(%)b
initial final
1k
6
1l
1i
1m
9.2
9.5
1
1
1
1
4
4
95
9.6 3.5
9.3 2.4
5
1n
(1b)
4
0
2
4
6
8
10
12
2
95
Calculated pKa (Cl-ArH+)
(1c)
(1d)
3
4
9.8
9.2
1
2
1
2
4
4
95
97
9.1 2.4
8.1 2.5
Fig. 2. Relationship between initial pH and calculated pKa of the conjugate acids
of amine-substituted aryl chlorides (pKa(Cl-ArH+)) based on the data in Table 3.
Reaction conditions: Ar-Cl (10 mmol), PhB(OH)2 (15 mmol), H2O (25 mL),
(1e)
NMe2
Pd(OAc)2 (0.1 mmol for 1b-1d; 0.2 mmol for 1e
,
1f
,
1h-1n), PtB (0.1 mmol for 1b-
1d; 0.2 mmol for 1e,1f,
1h-1n), N2, 100 oC, 4 h.
5
6
7
1
2
4
1
2
4
2
4
4
46
83
79
8.1 6.0
8.1 5.3
8.2 5.5
Cl
8.7
(1f)
1e 1c
100
80
8
9
2
4
2
4
4
4
74
95
7.8 5.4
7.8 4.1
1d
1b
7.2
4.8
1f
1i
1h
(1h)
(1i)
1k
1j
60
10
11
12
13
14
15
16
1
2
4
1
2
4
2
2
2
4
2
2
4
2
4
4
4
4
4
4
4
90
75
88
70
64
92
65
6.0 3.7
6.1 3.8
6.0 3.8
6.6 3.9
6.6 4.2
6.5 2.8
5.4 3.2
Yield
(%)
1m
40
1l
20
5.1
3.8
1.6
2.9
1.5
1n
(1j)
0
0
2
4
6
8
10
12
17
4
4
4
90
5.3 2.1
Calculated pKa (Cl-ArH+)
(1k)
18
19
20
21
2
2
4
2
2
2
4
2
4
24
4
28
44
38
41
5.3 1.9
5.3 1.8
5.3 2.1
4.8 2.8
Fig. 3. Relationship between Suzuki coupling yield and calculated pKa of the conjugate
acids amine-substituted aryl chlorides (pKa(Cl-ArH+)) based on the data in Table 3.
Reaction conditions: Ar-Cl (10 mmol), PhB(OH)2 (15 mmol), H2O (25 mL), Pd(OAc)2 (0.1
mmol for 1b-1d; 0.2 mmol for 1e,1f, 1h-1n), PtB (0.1 mmol for 1b-1d; 0.2 mmol for
1e,1f, 1h-1n), N2, 100 oC, 4 h.
(1l)
(1m)
(1n)
4
22
23
24
4
2
4
4
2
4
4
4
4
62
17
25
4.8 2.4
5.1 3.0
5.1 3.1
and also increase the electrophilic character, inductively
and/or electrostatically, of the ipso carbon facilitating the
oxidative insertion step in the catalytic cycle. In contrast, the
pyridyl
a Reaction conditions: Ar-Cl (10 mmol), PhB(OH)2 (15 mmol), H2O (25 mL), N2, 100
oC. Yields were determined by both GC and 1H NMR (Supplemental Information
S1-S5), GC Yields were shown, and NMR yields were summarized in Supplemental
Information S7. b GC Yield, average of 2-3 repetitions with an error < 5%.
substrates (1h-1n) would only be partially protonated. This, of
course, would also increase their aqueous solubility, enhance
the electrophilic character of the substrate’s ipso carbon, and
would allow them, in principle, to act as Pd ligands.
in Table 3. It is not surprising that the more basic amine
substrates result in a higher pH of the starting solution. Amine
basicity was also found to correlate with the yield of product.
Fig. 3 shows the relationship between the calculated pKa
4 | J. Name., 2017, 00, 1-12
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ARTICLE
(5) Yield Comparisons in the Base-Free Reactions of Aryl Bromides
The initial and final pH of the aqueous phase are also indicated.
in the Absence of Added Ligand and Aryl Chlorides in the Presence 1-Naphthylboronic acid, 4-methoxyphenylboronic acid, 4-
of the PtB Ligand
methylphenylboronic acid and 4-acetylphenylboronic acid
were the arylboronic acids employed in this study. All of the
coupling reactions proceeded smoothly regardless of the
electronic character of arylboronic acids and afforded
excellent yields for most of cases (Table 5, Entries 1-15).
Interestingly, all of the arylboronic acids successfully reacted
with 4-amino-2-chloropyridine under base-free conditions in
water without added ligand (Table 5, Entries 5-8). Moderate to
good yields were obtained in the reactions of 2-amino-6-
chloropyridine with 4-methoxy- and 4-methyl-phenylboronic
acids (Table 5, Entries 16 and 17). These results are similar to
those obtained with phenylboronic acid (Table 4, Entry 6).
Although only 41% yield was observed for the reaction
Table 4 represents a comparison of (a) the ligand-free/base-
free Suzuki coupling reactions of a series of aryl bromides with
(b) the base-free coupling reactions of the chloro counterparts
in the absence and in the presence of the PtB ligand. Each
reaction in these series used 4 mol% Pd(OAc)2 in water at
100oC for 4 h. As previously mentioned, the H2O/base-
free/ligand-free protocol in Suzuki couplings of aminopyridyl
bromides produces poor yields when applied to the chloro
counterparts (except for the 4-amino-2-halopyridines, Table 4,
Entry 3). However, the
Table 4. Comparison of (a) the Ligand-Free/Base-Free Suzuki Coupling Reactions of a
Series of Aryl Bromides with (b) the Base-Free Coupling Reactions of the Chloro
Counterparts in the Absence and in the Presence of the PtB Liganda
Table 5. Pd(OAc)2–PtB Catalyzed Suzuki Reactions of Basic Nitrogen-Containing Aryl
Chlorides with Arylboronic Acids in Water in the Absence of Added Basea
X = Br
X = Cl
Entry
Substrate
Initial
pH
Initial
pH
Yield (%)
ligand-free
Yield (%) Yield (%)
ligand-free 4 mol% PtB
1
2
3
40
7.9
7.4
6.5
13
3
95
88
-
7.8
6.0
6.4
70
100
100
4
5
6
7
8
81
56
82
93
44
5.6
5.8
4.8
4.7
4.6
4
5
92
90
38
62
25
6.6
5.3
5.3
4.8
5.1
23
27
4
a
Basing on the Data in Tables 1 and 3, GC yields were shown. Reaction
conditions: aminopyridyl halides (10 mmol), PhB(OH)2 (15 mmol), Pd(OAc)2 (4
mmol%), H2O (25 mL), N2, 100 oC, 4 h.
use of 4 mol% PtB ligand provides coupled products with the
aryl chlorides in excellent yields for several of these substrates
(Table 4, Entries 1, 2, 4 and 5). The yields for the aryl chlorides
compare favorably to the yields obtained for most of the
ligand-free/base free reactions used for aryl bromides.
(6) Survey of Arylboronic Acids in Base-Free Suzuki Coupling
Reactions of Aryl Chlorides Using the PtB Ligand.
Table 5 summarizes the yields and the reaction conditions for
the base-free
Suzuki
coupling
reactions of
4-
chlorobenzylamine and aminopyridyl chlorides with a variety
of electronically and structurally diverse arylboronic acids in
water at 100oC using the Pd(OAc)2/PtB catalyst/ligand system.
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Pd(OAc)2 PtB Time Yieldb
(mol%) (mol%) (h)
pH
Entry
1
Product
(%) initial Final
1
1
4
99
8.3 2.5
(4)
Scheme 2. Ligand-free and base-free Suzuki coupling reaction between bromobenzene
and 3-aminophenylbornic acid in water.
2
3
1
1
1
1
4
4
90c
88c
8.5 2.5
8.6 4.1
(5)
(7)
It is interesting to note that the ligand-free and base-free
Suzuki reactions of 4-bromobenzylamine with 3- and 4-
acetylphenylboronic acids produced excellent yields in 4 hours
(Scheme 1). It is also of interest to consider the question of
whether the base-free protocol reported here can be applied
to the Suzuki couplings between neutral aryl halides and the
arylboronic acids containing basic nitrogen center(s). In a
single preliminary experiment bromobenzene was reacted
with 3-aminophenylboronic acid in the absence of added base
and added ligand (Scheme 2). Although the reaction conditions
were not optimized, a modest 42% isolated yield of coupled
product was obtained after 24 hours.
(6)
4
5
1
4
1
0
4
2
96c
7.8 2.1
7.1 3.3
100
(8)
6
7
4
4
0
0
4
2
84
7.4 4.7
6.7 2.7
(9)
100
(10)
NH2
(7) Suzuki Reactions of Aryl Chlorides with PhB(OH)2 in Buffered
Acidic Solutions
O
8
4
0
2
100
6.6 2.3
H3C
N
(11)
At this juncture, it appears that the experimentally observed
initial and final pH of the aqueous phase suggest that the aryl
chlorides in the presence of PtB ligand (Tables 2-5) and aryl
bromides in the absence of added ligand (Tables 1 and 4,
previous work23), both in the absence of added base, undergo
the Suzuki coupling process either partially or entirely under
aqueous acidic conditions. A notable exception is 4-amino-2-
chloropyridine which produces a quantitative yield of coupled
product in the absence of added ligand and in the absence of
base (Table 1, Entry 6). The question was posed: “what
happens to the rate and yield of the reaction in buffered
solutions at fixed pH?” In order to address this question, we
conducted a series of coupling reactions in buffered aqueous
acidic media. In the first set of experiments 4-
chlorobenzylamine was chosen as a model substrate for PtB
ligand-promoted reactions and in second and third sets of
experiments 4-amino-2-chloropyridine and 4-amino-2-
bromopyridine, respectively, were chosen as the models for
the corresponding ligand-free reactions.
9
2
4
2
4
4
4
86
85
6.5 4.0
6.2 3.4
(12)
10
(13)
11
4
4
4
88c
7.9 3.6
(14)
12
13
14
15
16
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
88
92
82
90
65
7.9 4.1
6.6 3.3
6.3 3.5
5.5 2.2
5.6 2.5
(15)
(16)
(17)
(18)
(19)
(20)
17
18
4
4
4
4
4
4
67
41
5.4 2.1
5.4 2.9
Fig.
4 summarizes results for the reaction of 4-
chlorobenzylamine with phenylboronic acid at buffered pH 5.0
and 6.0 as a function of time employing 4 mol% PtB catalyst.
Maximum yields of approximately 82% are achieved at pH 6.0
in about two hours. In contrast, adjusting the pH to 5.0 results
in a much slower reaction; only a 30% yield is obtained after 4
hours of reaction. Under even more acidic condition the rates
of this reaction became extremely slow indicating that, for this
particular substrate, a strongly acidic aqueous phase retards
the coupling process. It is interesting to note that the same
reaction using an unbuffered aqueous phase (see Table 2,
Entry 3) produced a 92% yield in four hours. In this case,
however, the
(21)
a Reaction conditions: Ar-Cl (10 mmol), Ar’B(OH)2 (15 mmol), H2O (25 mL), N2, 100
oC. Yields were determined by both GC and 1H NMR (Supplemental Information
S1-S5), GC yields were shown, and NMR yields were summarized in Supplemental
Information S8. b GC yields, average of 2-3 repetitions with an error < 5%. c NMR
yield.
of 3-amino-6-chloropyridine with 4-methylphenylboronic acid
(Table 5, Entry 18), it is slightly better than the 25% yield of its
reaction with PhB(OH)2 (Table 4, Entry 8).
Scheme 1. Ligand-free and base-free Suzuki coupling reactions of 4-bromobenzylamine
with 3- and 4-acetylphenylbornic acids in water.
6 | J. Name., 2017, 00, 1-12
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100
80
60
40
20
0
82
82
23
82
64
53
10
GC Yield
(%)
120
30
100 100 100 100
100
99
89
1 h 3 h
24
93
79
100
80
12
78
75
70
70
63
57
60
GC Yield
(%)
55
60
40
20
0
42
0
1
2
3
4
5
35
time (h)
10
pH = 6.0
pH = 5.0
4
1
Fig. 4. Reaction yield as functions of time for the Pd(OAc)2/PtB catalyzed Suzuki
reaction of 4-chlorobenzyl amine (1a) with PhB(OH)2 (2) in buffered acidic solutions,
basing on the data in Supplemental Information S9. Reaction conditions: 1a (1.0 mmol),
2 (1.5 mmol), Pd(OAc)2 (0.04 mmol), PtB (0.04 mmol), acidic buffer (25 mL), N2, 100 oC.
7
6.5
6
5.6 5.2 4.5 3.5 3.1 2.6 1.5 1.3 1.1 0.7
buffer pH
Fig. 6. Reaction yields as a function of pH for the ligand-free Pd(OAc)2 catalyzed Suzuki
reaction of 4-amino-2-bromopyridine with PhB(OH)2 (2) in buffered acidic solutions,
basing on the data in Supplemental Information S11. Reaction conditions: 4-amino-2-
bromopyridine (1.0 mmol), 2 (1.1 mmol), Pd(OAc)2 (0.02 mmol), acidic buffer (25 mL),
N2, 100 oC.
periods of one and three hours in the absence of added ligand.
A very similar trend is observed. The yield of product steadily
increases as the pH of the aqueous phase decreases from 7.0
and becomes quantitative at pH 5.2 and remained quantitative
down to a pH of 1.5. The trends in yield were the same for
both the one-hour and three-hour experiments.
120
100 100
1 h 4 h
93
100
80
60
40
20
0
90
85
74
72 72
70
69
64
56
61
45
59 59
53
58
56
GC Yield
(%)
46
(8) Mechanistic Comments Concerning Suzuki Coupling Reactions
Conducted Under Acidic Aqueous Conditions
38
36
33
17
16
12
12
11
The palladium-catalyzed Suzuki cross-coupling reactions
presented in this report were conducted in water in the
absence of added base. The reactions were heterogeneous
and were experimentally observed to proceed partially or
entirely under acidic aqueous conditions. It was observed that
aryl bromides gave excellent yields of products in the absence
of added ligand. In contrast, aryl chlorides required the bulky
ligand PtB; the only exception was 4-amino-2-chloropyridine
which did not require a ligand to achieve a quantitative yield of
product. In order to unequivocally demonstrate that the
coupling process can take place under acidic aqueous
condition, a series of reactions were successfully conducted
with model substrates under buffered acidic conditions.
Excellent yields of coupled products were obtained when the
reactions were conducted entirely on the acidic side of the pH
scale (Fig. 4-6). Given these observations it is important to
address the relationship between the classical catalytic cycle
describing the Suzuki process (Fig. 7) conducted under basic
conditions and the catalytic cycle described here conducted in
the absence of added base.
7.0 6.5 6.0 5.6 5.2 4.5 3.5 3.1 2.6 2.0 1.5 1.3 1.1 0.7
buffer pH
Fig. 5. Reaction yields as functions of buffer pH for the ligand-free Pd(OAc)2 catalyzed
Suzuki reaction of 4-amino-2-chloropyridine (1g) with PhB(OH)2 (2) in buffered acidic
solutions, basing on the data in Supplemental Information S10. Reaction conditions: 1g
(1.0 mmol), 2a (1.5 mmol), Pd(OAc)2 (0.04 mmol), acidic buffer (25 mL), N2, 100 oC.
initial pH was 9.1 and the final pH 3.2. The results in the
buffered media strongly suggest that at least a portion of the
unbuffered reaction proceeds on the acidic side of the pH
scale.
Fig. 5 summarizes the reaction of 4-amino-2-chloropyridine
with phenylboronic acid using 4 mol% catalyst at buffered pH’s
ranging from 7.0 to 0.7 for reaction periods of one and four
hours; the two sets of reactions were conducted in the
absence of added ligand. Fig. 5 indicates that as reaction
proceeds from pH 7.0 to 3.5 the yields steadily increase from
61% to 100% over a period of four hours. Lowering the pH of
the buffered aqueous phase below 3.5, however, results in a
substantial decrease in yield. The trends in the yield profiles
for the one-hour and four-hour reaction times are quite
similar.
The generally accepted mechanistic pathway for the Suzuki
cross-coupling reaction is illustrated in Fig. 7.48-51 It has been
stated many times in the literature that the presence of base is
essential to achieve a successful reaction.48 For reactions
conducted in aqueous media (water-organic solvent systems),
the bases normally employed include K3PO4, K2CO3, KOH, or
KF. The initial step in the catalytic cycle is the oxidative
Fig. 6 summarizes the reaction of the bromo counterpart
over the same pH range using 2 mol% catalysts for reaction
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addition of the organohalide to the Pd(0) to form a Pd(II) Pd ligands in the Suzuki catalytic cycle- consistent with our
complex. A
previously published work.22 Further research is necessary to
establish the pertinent species involved under acidic
conditions as well as the phase location for each of the steps in
the overall process.
Conclusions
(1) The heterogeneous Pd(OAc)2 catalyzed aqueous Suzuki
couplings of relatively unreactive aryl chlorides containing
basic nitrogen centers with arylboronic acids in the absence of
added base produce excellent yields of coupled product by the
addition of bulky triorganophosphine ligands, such as
cataCXium®PtB. For the aryl chlorides containing aliphatic
amine substituents, the initial pH of the aqueous phase is basic
and the final pH is highly acidic. The pyridyl chloride substrates
undergo the coupling process almost entirely on the acidic side
of the pH scale.
Fig. 7. Mechanism of palladium-catalyzed Suzuki coupling reactions in aqueous media
molecule of the hydroxide (used as is or generated in water)
then replaces the halide on the palladium complex to form an
I
oxo-palladium intermediate (Ar1-PdIIL2-OH, Intermediate ).52-53
(2) The couplings of the corresponding aryl bromides produce
excellent yields in the absence of both added ligand and added
base. The initial and final aqueous phase pH are similar to the
chloride counterparts.
It has also been suggested that another hydroxide adds to the
organoborane to form the more nucleophilic boronate
-
intermediate (Ar2B(OH)3 , Intermediate II).54-57 Transmetalation
with the aryl boronic acid/boronate then follows where the Ar2
group replaces the hydroxide/halide anion on the palladium
complexes. Reductive elimination then gives the final coupled
product. The palladium catalyst is thus regenerates and the
catalytic cycle continues.
(3) At buffered pH 6.0 the reaction of 4-chlorobenzylamine in
the presence of the PtB ligand produces an excellent yield of
coupled product. At buffered pH 5.0 and below, very poor
yields are obtained. These observations are attributed to the
protonation of the phosphine ligand in the acidic aqueous
phase which disrupts the Pd-ligand interaction.
It is clear that in this classical representation of the
catalytic cycle hydroxide ion is critical for the formation of two
intermediates. However, for Suzuki coupling reactions
conducted in acidic aqueous media, the amount of hydroxide
ion is negligible- especially for those reactions conducted
below pH 6.0. We have shown that 4-chlorobenzylamine in the
presence of the PtB ligand produces very good yields (82%; Fig.
4) at pH 6.0 and poor yields (30%; Fig. 4) at pH 5.0 and below.
It has also been demonstrated that, in the absence of this
ligand, an extremely low yield (15%; Table 1, Entry 1) of
coupled product is produced; the presence of the ligand is
essential. At this juncture, it is conjectured that at pH 5.0 or
less, the Pd-ligand complex is not stable thus resulting in the
observed poor yield. We suggest that the origin of this
instability is the basicity of the phosphine ligand in acidic
media. The aqueous pKa values of a wide variety of tertiary
phosphines have been reported in the literature.58-60 Although
the pKa of PtB has not been determined, the pKa of
diethylphenyl phosphine, a structure somewhat similar to PtB,
has been reported to be 6.25.58 It is conjectured, therefore,
reasonable that in acidic aqueous media the complexation of
the ligand with Pd competes with the protonation of the
ligand. This would explain the decrease in yield from an
aqueous pH of 6.0 to 5.0 and below. In contrast, 4-amino-2-
chloropyridine and 4-amino-2-bromopyridine, the substrates
which do not require an added ligand, produce quantitative
yields of coupled product even under highly acidic conditions.
Since the calculated pKa values for these substrates indicate
that they are only partially protonated in acidic media, it is
suggested that the substrates themselves behave as the active
(4) The reactions of 4-amino-2-chloropyridine and 4-amino-2-
bromopyridine, in the absence of added ligand, produce
quantitative yields of product entirely under buffered acidic
conditions. Since these substrates are only partially protonated
in acidic aqueous media, it is suggested that they can act as Pd
ligands thus facilitating the Suzuki process.
Experimental
General Method
The commercially available solvents and reagents were
purchased from commercial providers in reagent grade and
were used without further purification. N,N-Dimethyl- and
N,N-diethyl 4-chlorobenzylamines
(
1f and 1e
)
were
synthesized following the published methods.61 The pure
products (except 5-7) used as standards for GC analysis were
isolated from the Suzuki reactions via column
chromatography. Pure compounds 5-7 have not been
successfully isolated due to the degradation during the drying
process
after
column
chromatographic
separation.
Spectroscopic data, however, are presented in the
Supplemental Information S14 consistent with the structure of
the products.
1
Reaction yields were determined by both GC and H NMR
following the reported method23,43 and are further discussed in
Supplemental Information S1-S5. The GC yields are reported in
the main text and NMR yields are summarized in Supplemental
Information S6-S8. For each reaction, 2 to 3 repetitions were
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usually conducted for consistent results with errors less than reflux at 100 oC in N2 for the requisite time. The initial and final
5%.
pH values of the aqueous phase were measured pre- and post-
A new compound, 4-amino-2-(4-acetophenyl)pyridine (11), reaction, once the temperature had stabilized at 25- 27 oC. The
was characterized by 1H NMR, 13C NMR, m.p. and HRMS. initial reaction time (t = 0) was taken when the reaction
Known compounds were characterized by H NMR, 13C NMR, mixture began to reflux; the time to reach this temperature
1
m.p. (for solids) and MS (EI), and compared with the literature was approximately 15- 20 minutes. For the reactions involving
value when available. Some of the m.p. values, and NMR/MS solid aryl halides, two phases were observed
—an aqueous
data for “known” compounds have not been previously phase and a solid phase composed of catalyst and substrate. In
reported. The “missing” analytical data are now documented the case of the liquid aryl halides, an additional liquid organic
in the Experimental Section and in the Supplemental phase was present. Once the reaction time was reached, the
Information.
reaction mixture was cooled, the pH was adjusted to pH ≥ 12
pH values of the aqueous phase were measured by a Cole- using 30% NaOH aqueous solution, and then was thoroughly
Parmer pH 20 m portable pH meter with an “all-in-one” extracted with organic solvents (chloroform for aliphatic
o
electrode at 25 ± 2 C. GC analyses were carried out on a amine-containing substrates, ethyl acetate or CH2Cl2 for
Shimazu GCMS-QP2010S (qualitative) and a Shimazu GC- aminopyridyl halides). The combined organic phase was dried
2010/FID (quantitative) gas chromatographs fitted with over anhydrous MgSO4 and filtered. The solvent was removed
Supelco PTA-5 capillary columns (30 m × 0.32 mm × 1.00 μm, under vacuum and the crude product was analyzed by GC and
length × inside diameter × film thickness). Melting points were 1H NMR following the published methods (Supplemental
measured on a Mel-Temp capillary melting point apparatus. 1H Information S1-S5).23,43 The pure products used as standard for
and 13C NMR spectra were recorded on a Varian Mercury Vx GC analysis were isolated from chromatography columns
400 and a Bruker Avance IIIHD 500 NMR spectrometers. packed with neutral alumina (for aliphatic amine-containing
Chemical shifts (δ) are reported in ppm and coupling constants substrates) or silica gel (for aminopyridyl halides) using CH2Cl2-
(J) are in Hz. MS analyses (EI-MS and an EI-HRMS) were methanol as eluent.
performed on a MicroMass AutoSpec M mass spectrometer.
4-Phenylbenzylamine (3a). CAS: 712-76-5. White solid,
m.p.: 51-53 C. (lit.64: 53-54 C) H NMR (500 MHz, CDCl3) δ
7.65 – 7.50 (m, 4H), 7.45 (t, J = 7.7 Hz, 2H), 7.42 – 7.37 (m, 2H),
7.37 – 7.30 (m, 1H), 3.93 (s, 2H). 13C NMR (126 MHz, CDCl3) δ
142.52, 141.07, 139.90, 128.87, 127.64, 127.42, 127.30,
127.17, 46.33. Agreed with literature data.65 MS (EI) m/z: Calcd
for [M] C13H13N 183.1; Found 183.1.
o
o
1
Synthesis of N,N-Dimethyl- and N,N-Diethyl-4-
Chlorobenzylamines61
3-Phenylbenzylamine (3b). CAS: 177976-49-7. White solid,
A mixture of 4-chlorobenzyl chloride (4.831 g, 30 mmol),
dimethylamine solution (40 wt.% in H2O) or diethylamine (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 GC), the white solid
was removed by filtration, the filtrate concentrated as much as
possible and residue 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 oil as product.
4-Chloro-N,N-dimethylbenzylamine (1f). CAS: 15184-98-2.
85%, slightly yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.14
(m, 1H), 3.36 (s, 1H), 2.21 (s, 2H). 13C NMR (101 MHz, CDCl3) δ
137.58, 132.80, 130.42, 128.46, 63.70, 45.40. Agreed with
literature data.62
o
1
m.p.: 157-159 C. H NMR (400 MHz, CD3OD) δ 7.74 (s, 1H),
7.73 – 7.60 (m, 3H), 7.54 (t, J = 7.7 Hz, 1H), 7.51 – 7.41 (m, 3H),
7.39 (dd, J = 4.7, 3.5 Hz, 1H), 4.20 (s, 2H). 13C NMR (126 MHz,
DMSO) δ 140.32, 139.71, 134.82, 129.15, 129.01, 128.10,
127.72, 127.60, 126.75, 126.53, 42.17. MS (EI) m/z: Calcd for
[M] C13H13N 183.1; Found 183.1.
1-Biphenyl-4-yl-ethylamine (3c). CAS: 86217-82-5. White
o
1
solid, m.p.: 218-219 C. H NMR (400 MHz, CD3OD) δ 7.77 –
7.67 (m, 2H), 7.63 (dd, J = 8.4, 1.3 Hz, 2H), 7.57 – 7.49 (m, 2H),
7.49 – 7.41 (m, 2H), 7.37 (dt, J = 9.4, 4.3 Hz, 1H), 4.51 (q, J = 6.9
Hz, 1H), 1.67 (d, J = 6.9 Hz, 3H). 13C NMR (126 MHz, DMSO) δ
140.11, 139.59, 138.78, 129.01, 127.66, 127.56, 126.89,
126.73, 49.76, 20.89. MS (EI) m/z: Calcd for [M] C13H13N 197.1;
Found 197.2.
2-Biphenyl-4-yl-ethylamine (3d). CAS: 17027-51-9. Yellow
4-Chloro-N,N-diethylbenzylamine (1e). CAS: 24619-87-2.
1
90%, slightly yellow oil. H NMR (400 MHz, CDCl3) δ 7.27 (s,
o
1
solid, m.p.: > 300 C. H NMR (400 MHz, CD3OD) δ 7.71 – 7.56
(m, 4H), 7.50 – 7.40 (m, 2H), 7.40 – 7.29 (m, 3H), 3.21 (t, J = 7.7
Hz, 2H), 3.06 – 2.93 (t, J = 7.7 Hz, 2H). 13C NMR (126 MHz,
DMSO) δ 139.89, 138.58, 136.84, 129.30, 128.96, 127.36,
126.87, 126.55, 39.95, 32.80. MS (EI) m/z: Calcd for [M]
C13H13N 197.1; Found 197.2.
1H), 3.52 (s, 1H), 2.50 (q, J = 7.1 Hz, 1H), 1.03 (t, J = 7.1 Hz, 2H).
13C NMR (101 MHz, CDCl3) δ 138.80, 132.38, 130.20, 128.34,
57.02, 46.87, 11.90. Agreed with literature data.63
General Experimental Procedure for Pd(OAc)2 Catalyzed Suzuki
Reactions of Basic Nitrogen-Containing Aryl Halides with
Arylboronic Acids in H2O without Added Base
4-Phenyl-N,N-diethylbenzylamine (3e). CAS: 294885-82-8.
Colorless oil. 1H NMR (500 MHz, DMSO) δ 7.65 (dd, J = 8.2, 1.0
Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.46 (dd, J = 10.7, 4.8 Hz, 2H),
7.39 (d, J = 8.1 Hz, 2H), 7.36 – 7.31 (m, 1H), 3.55 (s, 2H), 2.47
(q, J = 7.1 Hz, 4H), 0.99 (t, J = 7.1 Hz, 6H). 13C NMR (126 MHz,
A mixture of aryl halides (10 mmol), arylboronic acid (15
mmol), Pd(OAc)2, ligand (if used), and H2O (25 mL) in a 100-mL
3-neck round-bottom flask was stirred (600 – 800 rpm) under
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DMSO) δ 140.08, 139.33, 138.51, 129.03, 128.89, 127.22, 9.4, 4.3 Hz, 1H), 7.04 (dd, J = 7.4, 0.7 Hz, 1H), 6.42 (dd, J = 8.2,
126.54, 126.39, 56.53, 46.14, 11.70. MS (EI) m/z: Calcd for [M] 0.6 Hz, 1H), 5.97 (s, 1H). 13C NMR (126 MHz, DMSO) δ 159.50,
C17H21N 239.2; Found 239.1.
154.27, 139.39, 137.91, 128.37, 128.33, 126.25, 108.22,
4-Phenyl-N,N-dimethylbenzylamine (3f). CAS: 127292-60-8. 107.00. Agreed with literature data.18 MS (EI) m/z: Calcd for [M]
Colorless oil. 1H NMR (500 MHz, MeOD) δ 7.64 – 7.52 (m, 4H), C11H10N2 170.1; Found 170.1.
7.46 – 7.38 (m, 2H), 7.38 – 7.34 (m, 2H), 7.34 – 7.27 (m, 1H),
3-Amino-6-phenylpyridine (3n). CAS: 126370-67-0. Red
3.48 (s, 2H), 2.24 (s, 6H). 13C NMR (126 MHz, MeOD) δ 142.01, solid. m.p.: 102-103 C (lit.69: 105-106 C). H NMR (500 MHz,
141.69, 137.72, 131.19, 129.85, 128.34, 127.92, 127.90, 64.52, DMSO) δ 8.03 (d, J = 2.7 Hz, 1H), 7.91 (dd, J = 8.3, 1.2 Hz, 2H),
45.20. Agreed with literature data.66 MS (EI) m/z: Calcd for [M] 7.62 (d, J = 8.5 Hz, 1H), 7.39 (dd, J = 10.9, 4.6 Hz, 2H), 7.33 –
o
o
1
C15H17N 211.1; Found 211.1.
7.20 (m, 1H), 7.00 (dd, J = 8.5, 2.8 Hz, 1H), 5.47 (s, 2H). 13C
4-Amino-2-phenylpyridine (3g). CAS: 21203-86-1. Slightly NMR (126 MHz, DMSO) δ 144.11, 143.63, 139.38, 135.97,
yellow solid, m.p.: 127-128 oC. (lit.67: 129-130 oC) 1H NMR (400 128.48, 126.94, 124.97, 120.52, 120.21. Agreed with literature
MHz, CDCl3) δ 8.29 (d, J = 5.6 Hz, 1H), 7.95 – 7.82 (m, 2H), 7.50 data.18 MS (EI) m/z: Calcd for [M] C11H10N2 170.1; Found 170.1.
– 7.31 (m, 3H), 6.90 (d, J = 1.9 Hz, 1H), 6.45 (dd, J = 5.6, 2.3 Hz,
4-(1-Naphthalenyl)benzylamine (4). CAS: 1182977-17-8.
1H), 4.34 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 158.30, 153.60, Brown oil. H NMR (500 MHz, MeOD) δ 7.89 (dd, J = 8.2, 0.5
150.14, 139.86, 128.76, 128.63, 126.92, 108.47, 106.60. Hz, 1H), 7.87 – 7.74 (m, 2H), 7.54 – 7.30 (m, 8H), 3.87 (s, 2H).
Agreed with literature data.18 MS (EI) m/z: Calcd for [M] 13C NMR (126 MHz, MeOD) δ 142.74, 141.31, 140.74, 135.38,
1
C11H10N2 170.1; Found 170.1.
132.92, 131.19, 129.36, 128.65, 128.45, 127.86, 126.98, 126.79,
4-Amino-3-phenylpyridine (3h). CAS: 1211524-38-7. Yellow 126.74, 126.40, 46.47. MS (EI) m/z: Calcd for [M] C17H15N 233.1;
1
wax. H NMR (400 MHz, CDCl3) δ 8.25 – 8.10 (m, 2H), 7.62 – Found 233.1.
7.31 (m, 5H), 6.60 (dd, J = 5.6, 0.4 Hz, 1H), 4.27 (s, 2H). 13C
4-Amino-2-(1-naphthalenyl)pyridine (8). CAS: 937378-38-6.
o
NMR (101 MHz, CDCl3) δ 150.15, 150.11, 149.13, 135.82, Pink solid, m.p.: 120-121 C. H NMR (400 MHz, CDCl3) δ 8.32
1
129.25, 129.11, 128.00, 122.80, 109.70. MS (EI) m/z: Calcd for (d, J = 5.6 Hz, 1H), 8.18 – 7.97 (m, 1H), 7.86 (ddd, J = 6.6, 5.2,
[M] C11H10N2 170.1; Found 170.1.
1.8 Hz, 2H), 7.58 – 7.33 (m, 4H), 6.66 (d, J = 2.3 Hz, 1H), 6.46
2-Amino-5-phenylpyridine (3i). CAS: 33421-40-8. Slight (dd, J = 5.6, 2.3 Hz, 1H), 4.31 (s, 2H). 13C NMR (101 MHz, CDCl3)
yellow solid, m.p.: 132-133 oC (lit.68: 130-132 oC). 1H NMR (400 δ 159.74, 153.25, 149.82, 139.07, 133.84, 131.31, 128.56,
MHz, CDCl3) δ 8.33 (dd, J = 2.4, 0.7 Hz, 1H), 7.67 (dd, J = 8.5, 128.24, 126.93, 126.25, 125.98, 125.80, 125.27, 110.79,
2.5 Hz, 1H), 7.60 – 7.48 (m, 2H), 7.48 – 7.37 (m, 2H), 7.37 – 108.24. Agreed with literature data.70 MS (EI) m/z: Calcd for [M]
7.28 (m, 1H), 6.58 (dd, J = 8.5, 0.8 Hz, 1H), 4.53 (s, 2H). 13C C15H15N2 220.1; Found 220.1.
NMR (101 MHz, CDCl3) δ 157.72, 146.54, 138.42, 136.68,
4-Amino-2-(4-methoxyphenyl)pyridine (9). CAS: 1215072-
129.02, 127.50, 127.01, 126.40, 108.63 Agreed with literature 60-8. White solid, m.p.: 139 oC. H NMR (500 MHz, DMSO) δ
data.18 MS (EI) m/z: Calcd for [M] C11H10N2 170.1; Found 170.1. 8.04 (d, J = 5.5 Hz, 1H), 7.96 – 7.78 (m, 2H), 7.05 – 6.96 (m, 2H),
2-Amino-3-phenylpyridine (3j). CAS: 87109-10-2. Yellow 6.93 (d, J = 1.9 Hz, 1H), 6.40 (dd, J = 5.5, 2.1 Hz, 1H), 6.00 (s,
solid. m.p.: 107-108 oC. 1H NMR (500 MHz, CDCl3) δ 8.06 (dd, J 2H), 3.79 (s, 3H). 13C NMR (126 MHz, DMSO) δ 159.62, 155.92,
= 5.0, 1.8 Hz, 1H), 7.59 – 7.41 (m, 4H), 7.41 – 7.31 (m, 2H), 6.73 155.03, 149.37, 132.24, 127.43, 113.81, 107.37, 104.09, 55.13.
(dd, J = 7.3, 5.0 Hz, 1H), 4.85 – 4.40 (m, 2H). 13C NMR (126 MS (EI) m/z: Calcd for [M] C12H12N2O 200.1; Found 200.1.
1
MHz, CDCl3) δ 156.04, 147.37, 138.22, 137.88, 129.15, 128.76,
127.83, 121.90, 114.49. MS (EI) m/z: Calcd for [M] C11H10N2 63-4. White solid, m.p.: 118-119 oC. 1H NMR (500 MHz, DMSO)
170.1; Found 170.1. δ 8.06 (d, J = 5.5 Hz, 1H), 7.80 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.0
4-Amino-2-(4-methylphenyl)pyridine (10). CAS: 1010075-
3-Amino-5-phenylpyridine (3k). CAS: 31676-54-7. Brown Hz, 2H), 6.96 (d, J = 1.9 Hz, 1H), 6.42 (dd, J = 5.5, 2.1 Hz, 1H),
solid. m.p.: 136-137 oC. 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 6.02 (s, 2H), 2.33 (s, 3H). 13C NMR (126 MHz, DMSO) δ 156.16,
1.9 Hz, 1H), 8.07 (d, J = 2.6 Hz, 1H), 7.71 – 7.48 (m, 2H), 7.48 – 155.07, 149.43, 137.73, 137.00, 129.07, 126.07, 107.67,
7.40 (m, 2H), 7.40 – 7.28 (m, 1H), 7.18 – 7.06 (m, 1H), 3.85 (s, 104.59, 20.79. Agreed with literature data.70 MS (EI) m/z: Calcd
2H). 13C NMR (126 MHz, CDCl3) δ 142.54, 138.90, 138.21, for [M] C12H12N2 184.1; Found 184.1.
137.07, 136.43, 129.05, 128.09, 127.25, 120.02. MS (EI) m/z:
Calcd for [M] C11H10N2 170.1; Found 170.1.
4-Amino-2-(4-acetophenyl)pyridine (11): New Compound
.
White solid, m.p.: 207-209 oC. 1H NMR (500 MHz, CDCl3) δ 8.35
3-Amino-2-phenylpyridine (3l). CAS: 101601-80-3. Yellow (d, J = 5.5 Hz, 1H), 8.07 – 7.97 (m, 4H), 7.01 (dd, J = 2.2, 0.4 Hz,
o
1
solid. m.p.: 53-54 C. H NMR (500 MHz, DMSO) δ 7.92 (ddd, J 1H), 6.54 (dd, J = 5.5, 2.3 Hz, 1H), 4.23 (s, 2H), 2.64 (s, 3H). 13C
= 4.5, 1.3, 0.7 Hz, 1H), 7.67 (dd, J = 7.3, 0.8 Hz, 2H), 7.46 (dd, J NMR (126 MHz, DMSO) δ 197.67, 155.31, 154.97, 149.75,
= 10.4, 4.8 Hz, 2H), 7.42 – 7.33 (m, 1H), 7.27 – 7.11 (m, 1H), 144.00, 136.46, 128.58, 126.38, 108.44, 105.80, 26.84. HRMS
7.06 (dd, J = 8.1, 4.5 Hz, 1H), 5.06 (s, 2H). 13C NMR (126 MHz, (EI) m/z: Calcd for C13H12N2O, 212.0950; Found 212.0951.
DMSO) δ 142.91, 141.68, 139.17, 137.85, 128.39, 128.24,
127.59, 123.02, 122.24. Agreed with literature data.18 MS (EI) 75-2. Yellow solid, m.p.: 172-173 oC. 1H NMR (400 MHz, DMSO)
m/z: Calcd for [M] C11H10N2 170.1; Found 170.1. δ 8.17 (d, J = 2.4 Hz, 1H), 7.62 (dd, J = 8.6, 2.6 Hz, 1H), 7.56 –
2-Amino-5-(4-methoxyphenyl)pyridine (12). CAS: 503536-
2-Amino-6-phenylpyridine (3m). CAS: 39774-25-9. Yellow 7.38 (m, 2H), 7.08 – 6.89 (m, 2H), 6.51 (d, J = 8.6 Hz, 1H), 5.98
solid. m.p.: 69-71 oC (lit.68: 70-72 oC). 1H NMR (500 MHz, (s, 2H), 3.76 (s, 3H). 13C NMR (101 MHz, DMSO) δ 158.74,
DMSO) δ 7.99 – 7.89 (m, 1H), 7.54 – 7.39 (m, 2H), 7.36 (dt, J = 158.06, 145.18, 135.03, 130.67, 126.51, 123.76, 114.34,
10 | J. Name., 2017, 00, 1-12
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107.94, 55.12. Agreed with literature data.71 MS (EI) m/z: Calcd 2H), 2.33 (s, 3H).13C NMR (101 MHz, DMSO) δ 159.49, 154.35,
for [M] C12H12N2O 200.1; Found 200.1. 137.90, 137.73, 136.67, 129.04, 126.21, 107.96, 106.74, 20.83.
2-Amino-5-(4-acetophenyl)pyridine (13): CAS: 953420-73-0. MS (EI) m/z: Calcd for [M] C12H12N2 184.1; Found 184.1.
o
1
Yellow solid, m.p.: 172-174 C. H NMR (400 MHz, DMSO) δ
3-Amino-6-(4-methylphenyl)pyridine (21). CAS: 170850-45-
8.37 (d, J = 2.1 Hz, 1H), 7.96 (d, J = 8.5 Hz, 2H), 7.79 (dd, J = 8.7, 0. Red solid, m.p.: 104-105 oC. 1H NMR (400 MHz, CDCl3) δ 8.17
2.6 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 6.55 (dd, J = 8.7, 0.8 Hz, (dd, J = 2.9, 0.7 Hz, 1H), 7.85 – 7.65 (m, 2H), 7.51 (dd, J = 8.5,
1H), 6.28 (s, 2H), 2.57 (s, 3H). 13C NMR (101 MHz, DMSO) δ 0.7 Hz, 1H), 7.25 – 7.17 (m, 2H), 7.04 (dd, J = 8.5, 2.9 Hz, 1H),
197.24, 159.82, 146.43, 142.65, 135.49, 134.47, 128.97, 3.71 (s, 2H), 2.38 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 147.75,
125.03, 122.34, 108.04, 26.66. HRMS (EI) m/z: Calcd for 141.40, 137.40, 136.87, 136.70, 129.32, 125.77, 122.30, 120.44,
C13H12N2O, 212.1; Found 212.1.
21.13. MS (EI) m/z: Calcd for [M] C12H12N2 184.1; Found 184.1.
4-Amino-3-(4-methoxyphenyl)pyridine (14). CAS: 1258632-
56-2. slightly yellow wax. 1H NMR (400 MHz, CD3OD) δ 7.95 (d,
Preparation of Phosphate-Buffered Acidic Solutions
J = 5.9 Hz, 1H), 7.90 (s, 1H), 7.33 (d, J = 8.6 Hz, 2H), 7.05 (d, J = The phosphate-buffered acidic solutions were prepared by
8.6 Hz, 2H), 6.72 (d, J = 5.9 Hz, 1H), 3.84 (s, 3H). 13C NMR (101 adding varied amount of concentrated HCl or 10.0 M of KOH
MHz, CD3OD) δ 160.94, 154.33, 148.70, 147.45, 131.15, solution to the pH ~ 4.5 stock buffered solution (1.0 M,
128.71, 123.61, 115.63, 110.45, 55.75. MS (EI) m/z: Calcd for KH2PO4) and adjusting the pH to the requisite values.
[M] C12H12N2O 200.1; Found 200.1.
Procedure for Pd(OAc)2 Catalyzed Suzuki Reactions of Basic
4-Amino-3-(4-methylphenyl)pyridine (15). CAS: 1341149-
33-4. Yellow solid, m.p.: 90-93 oC. 1H NMR (500 MHz, DMSO) δ
Nitrogen-Containing Aryl Halides with Arylboronic Acids in
Phosphate-Buffered Acidic Solutions
8.18 – 7.70 (m, 2H), 7.52 – 7.03 (m, 4H), 6.65 (d, J = 5.5 Hz, 1H),
5.72 (s, 2H), 3.47 (s, 2H), 2.34 (s, 3H). 13C NMR (126 MHz, A mixture of aryl halides (1.0 mmol), arylboronic acid (1.5
DMSO) δ 151.14, 149.43, 148.15, 136.58, 133.25, 129.58, mmol), Pd(OAc)2, ligand (if used), and acidic buffer (25 mL, 1.0
128.62, 121.26, 109.40, 20.81. MS (EI) m/z: Calcd for [M] M) in a 100-mL 3-neck round-bottom flask was stirred (600 –
o
800 rpm) at 100 C in N2 for the requisite time. After being
C12H12N2 184.1; Found 184.1.
2-Amino-3-(4-methoxyphenyl)pyridine (16).CAS: 1258618- cooled to room temperature, the pH of the reaction mixture
76-6. Yellow solid, m.p.: 109-110 oC. 1H NMR (500 MHz, DMSO) was adjusted to pH ≥ 12 using 30% NaOH aqueous solution,
δ 7.92 (dd, J = 4.9, 1.8 Hz, 1H), 7.47 – 7.32 (m, 2H), 7.27 (dd, J = and then was thoroughly extracted with organic solvents
7.3, 1.8 Hz, 1H), 7.11 – 6.92 (m, 2H), 6.63 (dd, J = 7.3, 4.9 Hz, (chloroform for aliphatic 4-chlorobenzylamine, ethyl acetate
1H), 5.52 (s, 2H), 3.79 (s, 3H). 13C NMR (126 MHz, DMSO) δ for 4-amino-2-chloropyridine and 4-amino-2-bromopyridine).
158.53, 156.64, 146.60, 137.26, 130.35, 129.62, 120.32, The combined organic phase was dried over anhydrous MgSO4
114.36, 113.12, 55.13. MS (EI) m/z: Calcd for [M] C12H12N2O and filtered. The solvent was removed under vacuum and the
200.1; Found 200.1.
crude product was analyzed by GC.
2-Amino-3-(4-methylphenyl)pyridine (17). CAS: 1340103-
90-3. Yellow solid, m.p.: 127-128 oC. 1H NMR (500 MHz, DMSO)
δ 7.93 (dd, J = 4.9, 1.8 Hz, 1H), 7.48 – 7.15 (m, 5H), 6.64 (dd, J =
7.3, 4.9 Hz, 1H), 5.52 (s, 2H), 2.34 (s, 3H). 13C NMR (126 MHz,
DMSO) δ 156.51, 146.81, 137.32, 136.54, 135.27, 129.51,
128.29, 120.45, 113.10, 20.78. MS (EI) m/z: Calcd for [M]
C12H12N2 184.1; Found 184.1.
Conflicts of interest
There are no conflicts to declare
Acknowledgements
3-Amino-5-(4-methylphenyl)pyridine (18). CAS: 1226158-
35-5. Slightly yellow solid, m.p.: 141-143 oC. 1H NMR (500 MHz,
DMSO) δ 8.01 (d, J = 1.4 Hz, 1H), 7.91 (d, J = 1.5 Hz, 1H), 7.61 –
7.40 (m, 2H), 7.27 (d, J = 7.8 Hz, 2H), 7.12 (t, J = 2.0 Hz, 1H),
5.39 (s, 2H), 2.33 (s, 3H). 13C NMR (126 MHz, DMSO) δ 144.86,
137.13, 135.57, 135.25, 135.10, 129.60, 126.46, 117.36, 20.70.
MS (EI) m/z: Calcd for [M] C12H12N2 184.1; Found 184.1.
2-Amino-6-(4-methoxyphenyl)pyridine (19). CAS: 154479-
We thank The Dow Chemical Company for their collaboration
and financial support. We also thank Merranda Schmid (Ripon
College, WI, USA) for the help in product characterization
Notes and references
1
N. Miyaura and A. Suzuki, J. Chem. Soc.Chem. Commun.,
1979, 866-867.
o
1
27-3. Slightly brown solid, m.p.: 87-88 C. H NMR (500 MHz,
DMSO) δ 8.10 – 7.66 (m, 2H), 7.66 – 7.25 (m, 1H), 7.25 – 6.77
(m, 3H), 6.36 (dd, J = 8.1, 0.6 Hz, 1H), 5.92 (s, 2H), 3.79 (s, 3H).
13C NMR (126 MHz, DMSO) δ 159.60, 159.38, 154.07, 137.84,
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o
1
,
4. Yellow solid, m.p.: 79 C. H NMR (400 MHz, DMSO) δ 7.86
(d, J = 8.2 Hz, 2H), 7.42 (t, J = 7.8 Hz, 1H), 7.35 – 7.12 (m, 2H),
7.01 (dd, J = 7.5, 0.7 Hz, 1H), 6.38 (d, J = 8.1 Hz, 1H), 5.95 (s,
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New Journal of Chemistry
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DOI: 10.1039/C7NJ03567E
Successful Suzuki reactions of basic nitrogen containing aryl
chlorides/bromides with arylboronic acids in water without added base
partially or entirely under acidic conditions