A fast and oxygen-promoted protocol for the ligand-free Suzuki reaction of 2-halogenated pyridines in aqueous media

Article abstract of DOI:10.1039/b912364d

A fast protocol has been developed for the construction of 2-aryl-substituted pyridine derivatives by the oxygen-promoted, ligand-free, Pd(OAc)₂-catalyzed Suzuki reaction of 2-halogenated pyridines in aqueous isopropanol.

Full text of DOI:10.1039/b912364d

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
A fast and oxygen-promoted protocol for the ligand-free Suzuki reaction
of 2-halogenated pyridines in aqueous mediaw
Chun Liu* and Weibo Yang
Received (in Cambridge, UK) 24th June 2009, Accepted 17th August 2009
First published as an Advance Article on the web 3rd September 2009
DOI: 10.1039/b912364d
A fast protocol has been developed for the construction of
2-aryl-substituted pyridine derivatives by the oxygen-promoted,
ligand-free, Pd(OAc)2-catalyzed Suzuki reaction of 2-halogenated
pyridines in aqueous isopropanol.
2-phenylpyridine was obtained in the presence of 1.5 mol%
Pd(OAc)2 at 80 1C for 30 min in air (Table 1, entry 1). To the
best of our knowledge, this is the fastest cross-coupling of
2-bromopyridine with phenyl boronic acid under ligand-free
conditions.9a–e,h It is noteworthy that the reaction between
2-bromopyridine and 4-methylphenyl boronic acid could be
conducted with a 98% yield after 8 min, and a TOF up to
490 hÀ1 (Table 1, entry 2). Even when the catalyst loading was
decreased to 0.25 mol%, the cross-coupling was complete in
100 min (Table 1, entry 3). 2-Methoxyphenyl boronic acid was
coupled with 2-bromopyridine to afford the target product in
79% yield for 4 h (Table 1, entry 7), which was comparable
with the result using a thiourea ligand in aqueous isopropanol
at 80 1C for 5 h.10 The cross-coupling of 2-bromopyridine with
2-methylphenyl boronic acid gave the corresponding product
in 72% yield (Table 1, entry 5), as good as the result using
5 mol% PdCl2 in toluene at 100 1C for 8 h.9c In addition,
4-methoxyphenyl boronic acid was also successfully used in
the reaction with 2-bromopyridine to afford an excellent yield
in 12 min (Table 1, entry 6). More significantly, electron-poor
4-fluorophenyl boronic acid provided the corresponding
product in 94% yield in 45 min (Table 1, entry 8).
The construction of 2-aryl-substituted pyridine derivatives is
of great importance in the synthesis of natural products,
pharmaceuticals and advanced functional materials.1 Among
the methodologies described in the literature, the Suzuki
reaction is one of the most practical methods for the formation
of nitrogen-based heterobiaryls through two alternative
cross-coupling paths (Scheme 1).2 One synthetic path is the
cross-coupling of 2-pyridyl boronic acid/ester or borate with
aryl halides (Scheme 1, path I). In recent years, a variety of
activated boronates have been reported for the construction of
biaryl systems containing a 2-pyridyl moiety because of the
inactivity of 2-pyridylboronic acids.3 However, path I is
limited in terms of the accessibility and/or the stability of the
boron-containing reagents. Additionally, a phosphine ligand is
necessary for path I.3,4
Path II uses 2-halogenated pyridines as one of the coupling
partners. The groups of Buchwald,5 Fu,6 Plenio,7 and others8
have developed ligand-promoted approaches for the formation
of 2-aryl-substituted pyridine derivatives from 2-halopyridines.
Recently, ligand-free protocols for the synthesis of heterobiaryls
containing a 2-pyridyl moiety via path II have emerged
and attracted attention because they are the simplest and
cheapest protocols in comparison to the ligand-promoted
ones.9 Unfortunately, the ligand-free Suzuki reaction usually
proceeds with a low reactivity with respect to 2-halopyridines.
So far, a fast and efficient protocol for the palladium-catalyzed
ligand-free Suzuki reaction of 2-halopyridines has not been
reported.
To further investigate the scope and limitations of this
methodology, we carried out cross-couplings of different
nitrogen-based heteroaryl halides with various aryl boronic
acids under standard conditions. As shown in Table 2, the
coupling of 2-bromo-5-fluoropyridine with phenylboronic
acid exclusively gave 5-fluoro-2-phenylpyridine in 92% yield
after 10 min, showing high efficiency and good selectivity
(Table 2, entry 1). Using 4-methylphenyl boronic acid instead
of phenylboronic acid, the cross-coupling was completed in
5 min, resulting in a high TOF of 744 hÀ1 (Table 2, entry 2).
The Suzuki reaction of 2-bromo-5-methylpyridine with phenyl
boronic acid proceeded well to give the expected product in
excellent yield (Table 2, entry 4). In addition, 4-methylphenyl
boronic acid afforded a satisfactory 98% yield in 30 min
(Table 2, entry 5), while 4-methoxyphenyl boronic acid gave
85% yield due to the 4-MeO’s negative inductive effect,
resulting in a decrease of the nucleophilicity of 4-methoxyphenyl
In this paper, we report an oxygen-promoted protocol for
the fast and efficient Suzuki reaction of 2-halopyridines
and nitrogen-based heteroaryl halides using Pd(OAc)2 as a
precatalyst under ligand-free and aqueous conditions.
Initially, we explored the generality of the coupling reactions
between 2-bromopyridine and a variety of aryl boronic acids
under air in 50% aqueous isopropanol. The results are
summarized in Table 1. Both electron-rich and electron-poor
aryl boronic acids proceeded smoothly. A quantitative yield of
State Key Laboratory of Fine Chemicals, Dalian University of
Technology, Zhongshan Road 158, 116012, Dalian, China.
E-mail: chunliu70@yahoo.com; Fax: +86 41139893854;
Tel: +86 41139893854
w Electronic supplementary information (ESI) available: Experimental
details and characterization of cross-coupling products. See DOI:
10.1039/b912364d
Scheme 1 Alternative synthetic paths for 2-aryl-substituted pyridine
derivatives.
ꢀc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 6267–6269 | 6267

View Article Online
Table 1 Suzuki reactions of 2-bromopyridine with aryl boronic
acidsa
Table 2 Suzuki coupling of heteroaryl halides with aryl boronic
acidsa
Entry Ar–X
Product
Time/min Yield (%)b
Yield
Time/min (%)b
Entry Ar–B(OH)2
Product
1
10
92
1
30
8
96
2
3
4
5
5
120
180
30
93
35
87
98
2
3
98
100
96c
4
5
12
96
72
240
6
7
60
40
85
80
6
7
12
99
240
45
79
94
8
9
40
82
24
8
240
a
Reaction conditions: 2-bromopyridine (0.5 mmol), aryl boronic acid
(0.75 mmol), K3PO4Á7H2O (1 mmol), Pd(OAc)2 (1.5 mol%), 50%
isopropanol (4 mL), 80 1C, under air. The reaction was monitored by
b
c
TLC. Isolated yield. Pd(OAc)2 (0.25 mol%).
10
11
12
30
30
97
95
boronic acid (Table 2, entry 6). It is important to mention that,
in general, heteroaryl chlorides are less reactive than
heteroaryl bromides and require much more drastic reaction
conditions for arylation. However, the coupling of 2-chloro-
pyrazine with 4-methylphenyl boronic acid or phenylboronic
acid afforded high yields of the desired products in a short
reaction time without increasing the catalyst loading or
reaction temperature (Table 2, entries 7 and 8). Another note-
worthy result is the cross-coupling between 2-chloropyridine
and 4-methylphenyl boronic acid, resulting in 24% yield after
4 h (Table 2, entry 9). To the best of our knowledge,
2-chloropyridine has rarely been reported as a coupling
partner in the ligand-free Suzuki reaction. The cross-couplings
of 5-bromopyrimidine with aryl boronic acids were further
40
95
13
100
97c
a
Reaction conditions: heteroaryl halides (0.5 mmol), aryl boronic acid
(0.75 mmol), K3PO4Á7H2O (1 mmol), Pd(OAc)2 (1.5 mol%; 1.0 mol%
for entries 7 and 8), 50% isopropanol (4 mL), 80 1C, under air.
b
c
The reaction was monitored by TLC. Isolated yield. Pd(OAc)2
(0.05 mol%).
ꢀc
This journal is The Royal Society of Chemistry 2009
6268 | Chem. Commun., 2009, 6267–6269

View Article Online
Table 3 Effects of atmospheres on the Suzuki reactiona
or 2-bromo-5-methylpyridine with phenyl boronic acid, respec-
tively. Therefore, we can conclude that the oxygen serves as a
promoter in the Pd(OAc)2-catalyzed ligand-free Suzuki reaction
of 2-halopyridines and nitrogen-based heteroaryl halides in 50%
aqueous isopropanol. Although the nature of the oxygen in
the Suzuki reaction is unclear, we propose that a peroxo–
palladium complex might be formed in the presence of oxygen,12
which could accelerate the oxidative addition step in the catalytic
cycle due to the enhanced electron density of palladium.
In conclusion, we have developed a simple, ligand-free, oxygen-
promoted, and very fast protocol for the construction of
2-aryl-substituted pyridine derivatives via the Suzuki reaction
of 2-halopyridines in 50% aqueous isopropanol. Further
investigations on the mechanism and synthetic application of
this protocol are ongoing in our laboratory.
Isolated
yield (%)
Entry Ar–X
Product
Conditions Time
1a
1b
1c
Air
O2
N2
4 h
1 h
4 h
86b
96b
49bc
2a
2b
2c
Air
O2
N2
30 min 96
25 min 98
30 min 59c
3a
3b
Air
N2
40 min 80
40 min 43c
We thank the financial support from State Key Laboratory
of Fine Chemicals (KF0801), Science Research Foundation of
DUT, Graduate Student Education Reform Fund of DUT,
the National Science Funds for Distinguished Young Scholar
of China (20525620), and the Innovative Research Team in
University (IRT0711).
4a
4b
Air
N2
3 h
3 h
87
64c
a
Reaction conditions: heteroaryl halides (0.5 mmol), phenyl boronic
acid (0.75 mmol), K3PO4Á7H2O (1 mmol), Pd(OAc)2 (1.5 mol%;
1 mol% for 3a and 3b), 50% isopropanol (4 mL), 80 1C. The reaction
was monitored by TLC. K2CO3 (1 mmol). Isopropanol and H2O
were degassed.
Notes and references
1 (a) Y. Liu, K. Ye, Y. Fan, W. Song, Y. Wang and Z. Hou, Chem.
Commun., 2009, 3699; (b) E. K. Pefkianakis, N. P. Tzanetos and
J. K. Kallitsis, Chem. Mater., 2008, 20, 6254; (c) S. W. Thomas,
b
c
K. Venkatesan, P. Muller and T. M. Swager, J. Am. Chem. Soc.,
2006, 128, 16641.
¨
2 N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457.
3 (a) K. Billingsley and S. L. Buchwald, Angew. Chem., Int. Ed.,
2008, 47, 4695; (b) Y. Yamamoto, M. Takizawa, X. Yu and
N. Miyaura, Angew. Chem., Int. Ed., 2008, 47, 928; (c) K. Billingsley
and S. L. Buchwald, J. Am. Chem. Soc., 2007, 129, 3358;
(d) P. B. Hodgson and F. H. Salingue, Tetrahedron Lett., 2004, 45,
685; (e) P. Gros, A. Doudouh and Y. Fort, Tetrahedron Lett., 2004,
45, 6239.
4 (a) J. Z. Deng, D. V. Paone, A. T. Ginnetti, H. Kurihara,
S. D. Dreher, S. A. Weissman, S. R. Stauffer and C. S. Burgey,
Org. Lett., 2009, 11, 345; (b) D. X. Yang, S. L. Colletti, K. Wu,
M. Song, G. Y. Li and H. C. Shen, Org. Lett., 2009, 11, 381.
5 K. L. Billingsley, K. W. Anderson and S. L. Buchwald,
Angew. Chem., Int. Ed., 2006, 45, 3484.
investigated. It is remarkable that the electronic properties of
the substituent have little influence on the reactivity of the aryl
boronic acid. Both the electron-rich and the electron-deficient
aryl boronic acids delivered the products in high yields
(Table 2, entries 10, 11 and 12). Noticeably, an amount of
0.05 mol% Pd(OAc)2 was found to be sufficient to give a
complete conversion with 97% yield of the 5-phenylpyrimidine
after 100 min (Table 2, entry 13).
As we reported, the Suzuki reaction catalyzed by the
in situ-generated zero-valent palladium in PEG-400 was
promoted by oxygen,11 which inspired us to speculate whether
oxygen could also promote the Suzuki coupling reaction of
nitrogen-based heteroaryl halides in the Pd(OAc)2/i-PrOH(50%)
system. Consequently, the effects of different atmospheres on
the cross-coupling of various heteroaryl halides with phenyl
boronic acid were investigated. The results are provided in
Table 3. We noticed that all reactions carried out under
aerobic conditions worked well, affording the corresponding
cross-coupling products in good to excellent yields. For
example, the Suzuki reaction between 2-bromopyridine and
phenylboronic acid using K2CO3 as the base in open air
resulted in 86% isolated yield in 4 h (Table 3, entry 1a), while
the isolated yield was decreased to 49% in nitrogen (Table 3,
entry 1c). Excitingly, it took only 1 h to complete the same
cross-coupling in oxygen (Table 3, entry 1b).
6 N. Kudo, M. Perseghini and G. C. Fu, Angew. Chem., Int. Ed.,
2006, 45, 1282.
7 (a) C. A. Fleckenstein and H. Plenio, J. Org. Chem., 2008, 73, 3236;
(b) C. A. Fleckenstein and H. Plenio, Green Chem., 2007, 9, 1287.
8 (a) K. M. Clapham, A. S. Batsanov, M. R. Bryce and B. Tarbit,
Org. Biomol. Chem., 2009, 7, 2155; (b) C.-G. Dong, T.-P. Liu and
Q.-S. Hu, Synlett, 2009, 7, 1081; (c) I. Kondolff, H. Doucet and
M. Santelli, J. Mol. Catal. A: Chem., 2007, 269, 110.
9 (a) A. Del Zotto, F. Amoroso, W. Baratta and P. Rigo, Eur. J.
Org. Chem., 2009, 110; (b) S. Shi and Y. Zhang, Green Chem.,
2008, 10, 868; (c) C. Pan, M. Liu, L. Zhang, H. Wu, J. Ding and
J. Cheng, Catal. Commun., 2008, 9, 508; (d) Y. Kitamura, S. Sako,
T. Udzu, A. Tsutsui, T. Maegawa, Y. Monguchi and H. Sajiki,
Chem. Commun., 2007, 5069; (e) C.-L. Deng, S.-M. Guo, Y.-X. Xie
and J.-H. Li, Eur. J. Org. Chem., 2007, 1457; (f) A. Alimardanov,
L. S. de Vondervoort, A. H. M. de Vries and J. G. de Vries, Adv.
Synth. Catal., 2004, 346, 1812; (g) G. A. Molander and B. Biolatto,
J. Org. Chem., 2003, 68, 4302; (h) T. J. Colacot, E. S. Gore and
A. Kuber, Organometallics, 2002, 21, 3301.
Using K3PO4Á7H2O instead of K2CO3 for the same reaction,
it took 30 min to complete the coupling under aerobic
conditions (Table 3, entries 2a and 2b), faster than that in
nitrogen (Table 3, entry 2c). Evidence that the Suzuki reaction
proceeded with a higher yield in an aerobic atmosphere was also
observed in the cross-couplings between 2-chloropyrazine
10 D. Mingji, B. Liang, C. Wang, Z. You, J. Xiang, G. Dong, J. Chen
and Z. Yang, Adv. Synth. Catal., 2004, 346, 1669.
11 (a) W. Han, C. Liu and Z. L. Jin, Adv. Synth. Catal., 2008, 350,
501; (b) W. Han, C. Liu and Z.-L. Jin, Org. Lett., 2007, 9, 4005.
12 (a) G. J. T. Brink, I. W. C. E. Arends and R. A. Sheldon, Science,
2000, 287, 1636; (b) C. Adamo, C. Amatore, I. Ciofini, A. Jutand
and H. Lakmini, J. Am. Chem. Soc., 2006, 128, 6829.
ꢀc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 6267–6269 | 6269