'Ligand-free' palladium-catalyzed direct C-H bond oxidative acyloxylation of 2-arylpyridines with aromatic carboxylic acids

Article abstract of DOI:10.1016/j.tetlet.2012.03.022

A palladium-catalyzed direct C-H bond oxidative acyloxylation of 2-arylpyridines with aromatic carboxylic acids is described. Several 2-arylpyridines derivatives and aromatic carboxylic acids participate in the reaction, providing a series of mono-acyloxy

Full text of DOI:10.1016/j.tetlet.2012.03.022

Tetrahedron Letters 53 (2012) 2465–2468
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Tetrahedron Letters
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‘Ligand-free’ palladium-catalyzed direct C–H bond oxidative acyloxylation
of 2-arylpyridines with aromatic carboxylic acids
Chao-Jun Hu a, Xiao-Hong Zhang a, , Qiu-Ping Ding a,b, Ting Lv a, Shao-Peng Ge a, Ping Zhong a,c,
⇑
⇑
a College of Chemistry and Materials Science, Wenzhou University, Wenzhou 325035, China
b College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330027, China
c Oujiang College, Wenzhou University, Wenzhou 325035, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A palladium-catalyzed direct C–H bond oxidative acyloxylation of 2-arylpyridines with aromatic carbox-
ylic acids is described. Several 2-arylpyridines derivatives and aromatic carboxylic acids participate in the
reaction, providing a series of mono-acyloxylated products in moderate to good yields. Importantly, the
reaction can be conducted without using any ligands in a lower temperature.
Received 26 October 2011
Revised 28 February 2012
Accepted 6 March 2012
Available online 14 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
‘Ligand-free’
Palladium-catalyzed
Acyloxylation
2-Arylpyridines
Introduction
Yet, Cheng’s procedures required either expensive ligands
or high temperature and the carboxylic anhydrides are not
In the past decades, tremendous efforts have been paid to de-
velop mild methods for the direct functionalization of C–H in com-
plex organic substrates to construct C–C,1 C–N,2 C–O3 and C–S
bonds.4 Among them, transition-metal catalyzed acyloxylation of
the C–H bond is one of the most attractive processes. For example,
Sanford,5 Kwong,6 Pelcman7 and Chen8 illustrated acetoxylation of
sp2 C–H bond based on different aromatic substances using
PhI(OAc)2 as terminal oxidants. K2S2O8 and Cu(OAc)2 were also
employed as oxidants to achieve the similar reaction by Wu and
co-workers9 and Zhang and co-workers,10 respectively. However,
most of the reported acyloxylation is almost restricted to acetoxy-
lation9,11 and different oxidants are required to fulfill the catalytic
cycle. Additionally, the benzoxylation via transition-metal cata-
lyzed C–H bond is rarely reported. In view of this situation, Cheng’s
group12 had developed a rhodium-catalyzed ortho-benzoxylation
of sp2 C–H bond to afford the benzoxylated products without using
any oxidant in 2009. In an attempt to expand the diversity of the
available starting materials and the catalysts, copper(II)-catalyzed
ortho-benzoxylations of 2-arylpyridine with anhydride13 and acyl
chloride,14 respectively were reported by the same group.
commercially available. All of these limited the development of
C–H functionalization. We noted that Shi and co-workers has re-
cently developed a new method for the direct ortho-benzoxylation
of O-methyl oximes with various carboxylic acids using Pd as the
catalyst.15 So we envisioned that the direct ortho-benzoxylation
of 2-arylpyridine with carboxylic acids could proceed in mild
condition using Pd as the catalyst. Herein, we wish to demonstrate
a new process of direct C–H bond oxidative benzoxylation of
2-arylpyridines via the palladium-catalyzed reaction with
aromatic carboxylic acids. Importantly, the reaction can be
conducted without using any ligands at lower temperature.
Results and discussion
Our investigation started with the reaction of 2-phenylpyri-
dines and benzoic acid under air atmosphere to screen the optimal
reaction conditions (Table 1). First, in the presence of CuI, three
commonly used catalyst precursors for the oxidative acyloxylation
were surveyed when Ag2CO3 was used as the base and toluene as
the solvent. It was found that Pd(OAc)2 gave better yield of the
product than PdCl2 and Pd2(dba)3 (entries 1–3). The yield was
dropped sharply to less than 5% in the absence of Pd catalyst (entry
4). Notably, no product was formed in the absence of a Cu source
(entry 5), which showed that the Cu source played an indispens-
able role in the reaction. The behavior of the Cu source can be seen
in the possible mechanism (Scheme 1). Evaluation of additional Cu
⇑
Corresponding authors. Tel./fax:+86 0577 86689338.
E-mail addresses: kamenzxh@163.com (X.-H. Zhang), zhongp0512@163.com
(P. Zhong).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.022

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C.-J. Hu et al. / Tetrahedron Letters 53 (2012) 2465–2468
Table 1
Effects of Pd catalyst, Cu sources, bases, and solventsa
O
Pd, Cusource
COOH
O
Base, Solvent
N
80 °C
N
1a
2a
3aa
Entry
[Pd] (mol %)
[Cu] (equiv)
Base (equiv)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
PdCl2 (10)
CuI (2)
CuI (2)
CuI (2)
CuI (2)
—
CuBr (2)
CuCl (2)
Cu2O (2)
Cu(OAc)2 (2)
CuCl2 (2)
CuBr2 (2)
CuI (2)
CuI (0.5)
CuI (1)
CuI (1)
CuI (1)
CuI (1)
CuI (1)
CuI (1)
CuI (1)
CuI (1)
CuI (1)
CuI (1)
CuI (1)
CuI (1)
CuI (1)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (1)
Ag2CO3 (0.5)
—
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCE
26
31
43
<5
—
12
12
20
27
9
23
23
38
61
Pd2(dba)3 (10)
Pd(OAc)2 (10)
—
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (5)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
67 (45c, 70d)
49
23 (<5c)
37
K2CO3 (1)
NaHCO3 (1)
Na2CO3 (1)
K3PO4Á3H2O (1)
Ag2CO3 (1)
Ag2CO3 (1)
Ag2CO3 (1)
Ag2CO3 (1)
Ag2CO3 (1)
19
42 (<5c)
28
79
51
33
CH2Cl2
THF
DMSO
CH3COOH
12
17, (60e)
a
b
c
2-Phenylpyridine (0.2 mmol), benzoic acid (0.6 mmol) in a sealed tube, 80 °C, 17 h.
Isolated yields.
Under N2.
Under O2.
d
e
The yield of phenyl acetate.
When Ag2CO3 was replaced with K2CO3, NaHCO3, Na2CO3 and
K3PO4Á3H2O, lower yields of 3aa were obtained (entries 18–21).
In the absence of Ag2CO3, the desired product was obtained only
in 23% yield (entry 17). We envisioned that Ag2CO3 might play
more important roles than just a simple base. When the experi-
ments proceed under N2, the corresponding yields of entry 15
was decreased to 45%, while less than 5% yield of aimed product
was obtained in the absence of Ag2CO3 (entries 17 and 20). Replac-
ing air and N2 by O2 favored the benzoxylations slightly (entry 15).
Finally, different solvents were also screened, and DCE was shown
to be most suitable for this transformation (entries 22–26), while
phenyl acetate was generated in 60% yield when CH3COOH was
used as the solvent (entry 26).
Cu+/Ag+
Pd(OAc)2
N
1a
Pd(0)
N
HOAc
O
O
Ar
3
N
(A)
Pd
N
OAc
2
II
Pd
ArCOO
ArCOOAg
(B)
With the preliminary optimized reaction in hand, the scope of
aromatic acids was next discussed. The results were summarized
in Table 2. As expected, various aromatic acids worked well under
the reaction condition. A series of functional groups, such as
methyl, chloro and bromo groups, were tolerated in this process.
However, the yield can be affected by steric hindrance. For in-
stance, 78% 3ac and 75% 3ad were isolated, while the yield of
3ab was decreased to 53% (entries 1–3). It was also found that
the reaction seemed to be sensitive to electronic effects of the aro-
matic acids. The electron-donating group, such as methyl, was ben-
eficial for the transformation, but the electron-withdrawing group,
such as chloro and bromo, decreased the efficiency (entries 3–5),
while 4-nitro benzoic acid gave the benzoxylated product in less
Scheme 1. Plausible mechanism.
sources, including Cu(I) and Cu(II), such as CuBr, CuCl, Cu2O,
Cu(OAc)2, CuCl2 and CuBr2, provided conditions that gave a much
lower yield of the benzoxylated product relative to CuI (entries
6–11). Remarkably, among the amounts of Pd(OAc)2 and CuI
screened (entries 12–14), the combined amounts of 10 mol %
Pd(OAc)2 and 1 equiv CuI turned out to be the best (entry 14).
The amount of base affected the reaction: a higher yield was ob-
served when the amount of Ag2CO3 was decreased to 1 equiv than
2 equiv Ag2CO3, while lowering the amount of Ag2CO3 to 0.5 equiv
decreased the yield of 3aa to 49% (entries 15 and 16).

C.-J. Hu et al. / Tetrahedron Letters 53 (2012) 2465–2468
2467
Table 2
Ortho-benzoxylation reaction of 2-phenylpyridine with aromatic acids
R
Pd(OAc)2 (10 mol%)
CuI (1 equiv), Ag2CO3 (1 equiv)
O
O
COOH
DCE, 80 °C ,O2
R
N
N
1a
2
3
Entry
1
Aromatic acids 2
Products
Yielda (%)
2b
3ab
53
78
COOH
COOH
2
3ac
2c
3
4
5
3ad
3ae
3af
75
61
62
COOH
2d
Cl
Br
COOH 2e
COOH
COOH
2f
2g
O2N
6
7
—
<5
75
CH3COOH 2h
3ah
a
Isolated yields.
Table 3
Ortho-benzoxylation reaction of 2-arylpyridines with aromatic acids
R2
O
Pd(OAc)2 (10 mol%)
O
CuI (1 equiv), Ag2CO3 (1 equiv)
R1
COOH
R2
DCE, 80 °C, O2
R1
N
N
1b-1f
2
3
Entry
1
2-Arylpyridine 1
Aromatic acids 2
Products
Yielda (%)
77
COOH
2a
2b
1b
3ba
N
2
3
1b
3bb
3bc
55
69
COOH
COOH
1b
2c
2d
4
5
6
7
8
1b
1b
1b
1b
1b
Cl
COOH
3bd
3be
3bf
—
71
64
62
<5
69
Cl
COOH 2e
COOH 2f
COOH
Br
O2N
F
2g
COOH
3bi
2i
COOH
2a
2a
9
3ca
3da
3ea
53
59
65
N
1c
F
COOH
10
N
1d
H3CO
COOH 2a
11
N
1e
a
Isolated yields.

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C.-J. Hu et al. / Tetrahedron Letters 53 (2012) 2465–2468
than 5% yield (entry 6). The alkyl carboxylic acid, such as acetic
acid, can tolerate the reaction well (entry 7).
Supplementary data
Subsequently, promoted by the successful palladium-catalyzed
direct C–H bond oxidative acyloxylation of 2-phenylpyridine, we
explored the reaction of several 2-arylpyridines with aromatic
acids and the results were shown in Table 3.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.03.
022.
Initially, the substrate of 2-(4-methylphenyl)pyridine was trea-
ted with different aromatic acids, giving similar results with 2-
phenylpyridine. Steric hindrance and electronic effects of the aro-
matic acids both affected the reaction. For example, 2b gave a low-
er yield of 55% than 2c and d (entries 2–4). The electron-donating
group, such as methyl group, was also beneficial for the transfor-
mation, but the electron-withdrawing group, like chloro, bromo,
fluoro, and nitro, decreased the efficiency (entries 5–8). Moreover,
the yield of 3ba was nearly the same with 3aa, indicating that the
methyl group of the aryl ring had little influence on the reaction
(entry 1). Next, the reaction of a variety of 2-arylpyridines, such
as 2-(4-chlorophenyl)pyridine, 2-(4-fluorinphenyl)pyridine and
2-(4-methoxylphenyl)pyridine with benzoic acid were conducted
under the optimal conditions. The arenes possessing electron-
donating functional groups, like methyl and methoxyl, were found
to be more reactive and gave slightly higher yields than those of
electron-withdrawing groups, such as chloro and fluoro groups
(entries 1, 9–11).
A possible mechanism for the present palladium(II)-catalyzed
ortho-oxidative acyloxylation of 2-phenylpyridines (1a) with aro-
matic carboxylic acids is proposed in Scheme 1. First, the reaction
of Pd(OAc)2 with 2-phenylpyridine (1a) by removing HOAc affords
a cyclopalladated intermediate (A), which was actually confirmed
by many related reports16 and was also detected by HRMS in our
lab. This intermediate reacted with the in-situ generated silver car-
boxylate from the reaction of carboxylic acid with Ag2CO3 to give
the ligand exchanged product (B), in which occurs the reductive
elimination to release the acyloxylated product. The resulting Pd0
intermediate is then reoxidized by Ag(I) and Cu(I) salts to regener-
ate the Pd(II) catalyst.10,17
References and notes
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Acknowledgments
The authors thank the National Natural Science Foundation of
China (No. 20972114), the Zhejiang Provincial Natural Science
Foundation of China (Y4100578) and the Opening Foundations of
Zhejiang Provincial Top Key Discipline (100061200106 and
100061200140).
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