Pd(II)-Catalyzed C3-Selective Arylation of Pyridine with (Hetero)arenes

Article abstract of DOI:10.1021/acs.orglett.5b03712

Palladium catalyzed, nondirected C3-selective arylation of pyridines with arenes and heteroarenes in the presence of 1,10-phenanthroline as the ligand has been developed. The optimized conditions allow for a highly C3-selective arylation of pyridines, affording various 3,3′-bipyridines and 3-arylpyridines. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.orglett.5b03712

Letter
pubs.acs.org/OrgLett
Pd(II)-Catalyzed C3-Selective Arylation of Pyridine with
(Hetero)arenes
Guo-Lin Gao,†,‡ Wujiong Xia,‡ Pankaj Jain,† and Jin-Quan Yu*,†
†Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
‡The Academy of Fundamental and Interdisciplinary Science, Harbin Institute of Technology, Harbin 150080, China
S
* Supporting Information
ABSTRACT: Palladium catalyzed, nondirected C3-selective
arylation of pyridines with arenes and heteroarenes in the
presence of 1,10-phenanthroline as the ligand has been
developed. The optimized conditions allow for a highly C3-
selective arylation of pyridines, affording various 3,3′-bipyridines and 3-arylpyridines.
a
Table 1. Optimization of Conditions
rylated pyridines are important structural motifs in many
natural products, pharmaceuticals, functional materials,
A
ligands, and biologically active compounds.1 The construction
of C−C bonds linking pyridine with arenes and heteroarenes
commonly utilizes transition-metal-catalyzed cross-coupling
reactions, such as Stille,2 Suzuki,3 Grignard,4 Negishi,5
Kumada,6 Hiyama,7 and Ullmann reductive coupling.8 While
these methods using arylboronic acids, aryl halides, or other
aryl organometallic compounds are remarkably efficient (eq 1),
1a
Ag2CO3
(mmol)
base
(mmol)
temp
(°C)
time
(h)
TON
2a (3a)
b
entry (mL)
1
2
1
1
0.5
0.5
none
120
120
24
24
1.0 (0.5)
1.5 (0.8)
Na2CO3
(1.0)
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
2
3
4
0.5
0.5
0.5
0.5
0.5
0.5
1.0
1.5
1.0
1.0
1.0
K2CO3
(1.0)
120
120
120
130
140
130
130
130
130
130
130
24
24
48
48
48
72
48
48
48
48
48
3.0 (1.0)
0.5 (0.3)
4.3 (1.3)
4.8 (1.3)
4.4 (0.8)
5.0 (1.1)
6.8 (2.0)
7.0 (1.5)
9.5 (2.8)
11.2 (2.8)
9.5 (2.5)
c
K2CO3
(1.0)
K2CO3
(1.0)
K2CO3
(1.0)
K2CO3
(1.0)
K2CO3
(1.0)
K2CO3
(1.0)
the development of direct arylation of unactivated pyridine with
activated or unactivated arenes has received growing attention
due to their potential for further improving efficiency in
synthesis (eq 2). Several reports have described progress in the
development of C−H arylation of pyridine with activated
arenes.9,10 Arylations of pyridine with unactivated arenes or
heteroarenes are less explored (eq 3). The absence of activating
groups on both of the coupling partners presents a challenge in
controlling regioselectivity. Recently, You et al. reported the
direct dehydrogenative C2 coupling of pyridine with electron-
rich arenes such as thiophenes and benzothiophenes.11 To the
best of ourknowledge, there are no examples of direct C3-
selective arylation of unactivated pyridines with simple
(hetero)arenes. Herein, we report a Pd-catalyzed C3-selective
arylation of pyridine with pyridines or simple arenes.
10
11
12
13
K2CO3
(1.0)
K2CO3
(1.0)
d
K2CO3
(1.0)
K2CO3
(1.0)
a
Reaction conditions: Pd(OAc)2 (0.05 mmol, 10 mol %), 1,10-
phenanthroline (0.05 mmol, 10 mol %), 1.0 mL of pyridine is 12
b
mmol of pyridine (12 equiv). TON (based on Pd) was determined
c
by 1H NMR using CH2Br2 as an internal standard. AgBF4 used
d
instead of Ag2CO3. Isolated TONs was 10.3 (2.2).
ligands and conditions, we found that 3,3′-bipyridine (2a)
was formed under the following reaction conditions: Pd(OAc)2
We started our investigation utilizing pyridine as the limiting
reagent (5 mmol) in various solvents and observed very low
TONs for the bipyridine products (see the Supporting
Information for details). Through extensive screening of
Received: December 31, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03712
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 2. Synthesis of C3 Bipyridines
Table 3. Synthesis of C3 Arylpyridines
a
Reaction conditions: pyridine substrate 1 (1.5 mL, 26−32 equiv,
based on density and formula weight of 1), arene 4 (1.5 mL, benzene
30 equiv, p-xylene 22 equiv), Pd(OAc)2 (0.05 mmol, 10 mol %), 1,10-
phenanthroline (0.05 mmol, 10 mol %), Ag2CO3 (1.0 mmol, 2 equiv),
b
K2CO3 (1.0 mmol, 2 equiv) at 130 °C for 48 h. TONs for 3-
arylpyridine (2-arylpyridine, 4-arylpyridine).
was found to be crucial for the product TON (Table 1, entries
10−13). When the amount of pyridine was increased from 1.0
to 3.0 mL, the TON of 2a was significantly improved to 11.2
(Table 1, entry 12).
With these optimized conditions in hand, we explored the
substrate scope with various pyridines (Table 2). Unfortu-
nately, under the standard reaction conditions, 2,6-dimethoxy-
pyridine (1b) only provided a TON of 1.7 for desired product
2b. Further investigation into the reaction conditions revealed
that the addition of 0.3 mL of pyridine as an additive along with
2.7 mL of 1b (see Supporting Information, 2,6-dimethoxy-3,3′-
bipyridine (2i) was found as the byproduct) significantly
enhanced the TON of 2b to 9.3. Similarly, other pyridine
substrates gave efficient TONs when pyridine was used as an
additive. We assume that pyridine might act as a comple-
mentary ligand to improve the reactivity of the catalyst. The
reaction worked efficiently for both electron-rich (1b, 1e) and
electron-deficient (1c, 1d, 1f, 1g) pyridine substrates, giving the
corresponding 3,3′-bipyridines with good TONs, and 2,3′-
bipyridines (3e, 3g) were isolated as minor products,
respectively. Surprisingly, when 2,5-difluoropyridine (1h) was
used as a substrate, 4,4′-bipyridine, instead of 3,3′-bipyridine,
was isolated as the main product with a high TON. A possible
explanation for the C4-coupling is that C−H activation occurs
through a CMD (Concerted Metalation−Deprotonation)
pathway,12 where the C3 fluoro atom enhances the acidity of
the already acidic C4 proton. Quinoline and isoquinoline
substrates provided a trace amount of products when subjected
to these reaction conditions.
a
Reaction conditions: 1 (2.7 mL, 20−32 equiv, dependent on density
and formula weight of 1), Pd(OAc)2 (0.05 mmol, 10 mol %), 1,10-
phenanthroline (0.05 mmol, 10 mol %), Ag2CO3 (1.0 mmol, 2 equiv),
K2CO3 (1.0 mmol, 2 equiv), pyridine (0.3 mL, 4 equiv) at 130 °C for
b
48 h. TON (based on isolated product) for 3,3′-bipyridine (2,3′-
c
bipyridine). 2,2′,5,5′-Tetrafluoro-4,4′-bipyridine was isolated as the
major product; 2,2′,5,5′-tetrafluoro-3,3′-bipyridine was also observed
1
by H NMR as minor product.
(0.05 mmol), 1,10-phenanthroline (Phen) (0.05 mmol), and
Ag2CO3 (0.5 mmol) in 1.0 mL of pyridine (1a) in a sealed
pressure tube at 120 °C for 24 h. However, the turnover
number (TON) of the product 2a was only 1.0. Along with the
desired product 2a, 2,3′-bipyridine (3a) was also obtained with
a 0.5 TON (Table 1, entry 1). Further optimization of reaction
conditions showed that the use of K2CO3 and Ag2CO3
improved the TON of 2a to 3.0; however, the formation of
3a was also increased (Table 1, entries 2−4). When the
reaction time was prolonged to 48 h, the TON of 2a was
improved to 4.3 (Table 1, entry 5). Increasing the temperature
from 120 to 130 °C gave a slight impovement in the TON
(Table 1, entry 6). Further raising the reaction temperature or
increasing the reaction time did not show any obvious
enhancement in the reactivity (Table 1, entries 7 and 8).
Increasing the loading of Ag2CO3 to 1.0 mmol resulted in the
apparent boost in the TON of 2a to 6.8 (Table 1, entry 9). A
further increase in the loading of Ag2CO3 showed minimal
effects in reactivity (Table 1, entry 10). The amount of pyridine
Next, we investigated the use of simple arenes as arylation
reagents for pyridine. Under the reaction conditions that were
used for pyridine−pyridine coupling, we screened the effect of
B
DOI: 10.1021/acs.orglett.5b03712
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
different ratios of arene and pyridine (see Supporting
Information; biphenyl (6a) was detected as a byproduct).
When 1.5 mL of benzene (4a) and 1.5 mL of pyridine (1a)
were used, 3-phenylpyridine (5a) was obtained as the major
product with a TON of 6.5 (Table 3). Both electron-rich (1e)
and electron-deficient (1c, 1f) pyridines were well tolerated.
para-Xylene also proved to be a good arylation reagent for
pyridine and gave the desired product 5b with a TON of 5.6.
However, when toluene was used as the substrate, the products
were formed in low TON with no regioselectivity.
ACKNOWLEDGMENTS
■
We gratefully acknowledge The Scripps Research Institute and
NIH (NIGMS, 1R01 GM102265) for financial support. This
work is also supported by the NSFC (21302029), the
Fundamental Research Funds for the Central Universities
(HIT.NSRIF.2014064), and Heilongjiang Postdoctoral Science
Foundation (No. LBH-Z14104).
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: yu200@scripps.edu.
Notes
The authors declare no competing financial interest.
C
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