Copper(II)-catalyzed ortho-benzoxylation of 2-arylpyridines with sodium carboxylates

Article abstract of DOI:10.1246/cl.2012.600

Copper-catalyzed ortho-benzoxylation of an sp² CH bond by sodium carboxylates is described. The procedure tolerates carbomethoxy, formyl, bromo, and chloro groups, providing the benzoxylated products in moderate to good yields.

Full text of DOI:10.1246/cl.2012.600

doi:10.1246/cl.2012.600
600
Published on the web May 26, 2012
Copper(II)-catalyzed ortho-Benzoxylation of 2-Arylpyridines with Sodium Carboxylates
Liping Li,1 Peng Yu,1 Jiang Cheng,1 Fan Chen,*1 and Changduo Pan*2
1College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, P. R. China
2Wenzhou Institute of Industry and Science, Wenzhou 325000, P. R. China
(Received February 28, 2012; CL-120162; E-mail: fanchen@wzu.edu.cn)
Copper-catalyzed ortho-benzoxylation of an sp2 C-H bond
ArCOOH (ref. 8)
by sodium carboxylates is described. The procedure tolerates
carbomethoxy, formyl, bromo, and chloro groups, providing the
benzoxylated products in moderate to good yields.
rhodium-catalyzed
N
ArCOOCOAr (ref. 9a)
ArCOCl (ref. 9b)
ArCHO (ref. 10)
N
O
Ar
O
copper-catalyzed
The ester functionality is a ubiquitous structural moiety in
natural products, pharmaceuticals, and functional materials.
Thus, the need for ester compounds will never lessen.1 Extensive
efforts in transition-metal-catalyzed esterification have shown
encouraging progress during the past decade.2 In the past few
years, selective functionalization of C-H bonds has emerged as a
powerful tool in modern organic synthesis.3 The C-H activation
strategy has also been applied in ester formation.4 Among them,
great interest has been focused on C-H acetoxylation of
pyridine- or imine-directing groups.5 For example, Sanford
discovered palladium-catalyzed ortho-acetoxylation of 2-aryl-
pyridines using PhI(OAc)2 as an oxidant.6 In 2005, Yu reported
Pd-catalyzed stereoselective oxidation of methyl groups in
2-oxazolines using lauroyl or benzoyl peroxide as the stoichio-
metric oxidant.7 Subsequently, Yu described the Cu(OAc)2-
catalyzed oxidative acetoxylation of arene C-H bonds in HOAc/
Ac2O using oxygen as a clean oxidant.8 However, most reports
on such transformations have been limited to acetoxylation. In
2009, we developed ortho-benzoxylation of 2-arylpyridines with
benzoic acid using expensive rhodium as the catalyst.9 Sub-
sequently, we demonstrated a copper-catalyzed ortho-benzox-
ylation reaction of an sp2 C-H bond with anhydride or acyl
chloride.10 However, the carboxylic anhydrides as benzoxylation
partner are not commercially available in most cases and acyl
chlorides are usually susceptible to moisture. More recently,
Huang developed a copper-catalyzed domino oxidation-acylox-
ylation reaction of 2-arylpyridines with aldehydes or methyl-
arenes affording relative lower yields.11 Thus, it is highly
desirable to develop a dependable benzoxylation partner.
Sodium carboxylates are widely used in traditional cross-
coupling reactions in ester synthesis due to their superior
features such as high air- and moisture-stability.12 Our interest in
transition-metal-catalyzed C-H functionalization spurred us to
explore the possibility of using readily available sodium
carboxylates as the benzoxylation partners for such transforma-
tions.9,10 Herein, we report the chelation-assisted copper(II)-
catalyzed ortho-benzoxylation of 2-arylpyridine with sodium
carboxylates (Scheme 1).
R
R
ArCOONa (this work)
copper-catalyzed
Scheme 1. ortho-Benzoxylation of 2-arylpyridine.
Table 1. Screening for the optimum conditionsa
N
N
copper source (20 mol%)
solvent, oxidant
PhCOONa
O
Ph
O
1a
2a
3aa
Entry Cu sources Oxidant
Solvent
Yield/%b
1
2
3
4
5
6
7
8
9
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
O2
DDQ
PhI(OAc)2 toluene
TBHP
toluene
toluene
15
<5
31
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
NMP
44
K2S2O8
82 (69)c, (28)d
Cu(OAc)2 K2S2O8
26
51
44
<5
47
49
CuCl2
CuF2
CuI
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
10 CuCl
11 CuBr2
12 CuBr
13 Cu(OTf)2
14 Cu(OTf)2
15 Cu(OTf)2
16 Cu(OTf)2
17 Cu(OTf)2
18 Cu(OTf)2
36
<5
<5
10
<5
50e
55f
DCE
DMF
1,4-dioxane
toluene
toluene
aAll reactions were run with 2-o-tolylpyridine (0.3 mmol), sodium
benzoate (0.2 mmol), copper source (20mol %), oxidant (2 equiv) in
2 mL of solvent under air at 130 °C for 24 h. See Supporting
Information (SI) for details.14 bIsolated yield. cK2S2O8 (1 equiv).
e
f
dUnder N2. 10 mol % Cu(OAc)2. 110 °C.
To begin our study, the effect of the various reaction
parameters on the reaction of 2-o-tolylpyridine (1a) with sodium
benzoate (2a) was examined using Cu(OTf)2 as the catalyst
(Table 1). The results suggested that the oxidant had a dramatic
effect on the reaction. Among the oxidants tested, only 15% of
3aa was obtained using O2, which had practical advantages in our
early reports9 (Table 1, Entry 1). No reaction was observed using
DDQ as oxidizing reagent (Table 1, Entry 2). The yield could be
improved when TBHP was employed in the reaction (Table 1,
Entry 4). To our delight, the reaction afforded the product 3aa
in 82% yield in the presence of K2S2O8 (Table 1, Entry 5).
Decreasing the amount of K2S2O8 to 1 equiv lowered the yield
Chem. Lett. 2012, 41, 600-602
© 2012 The Chemical Society of Japan
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601
Table 2. ortho-Benzoxylation reaction of 2-o-tolylpyridine with so-
dium carboxylatesa
Table 3. ortho-Benzoxylation reaction of arylpyridine with sodium
benzoatea
N
N
N
N
Cu(OTf)2 (20 mol%)
Cu(OTf)2 (20 mol%)
ArCOONa
PhCOONa
Ph
O
K2S2O8 (2 equiv), toluene
O
Ar
K2S2O8 (2 equiv), toluene
R
O
R
O
1
2a
3
2
1a
3
Entry
Substrate 1
Product 3
Yield/%b
65
Entry
1
Substrate 2
Product 3
Yield/%b
1
2
N
N
N
(3ba)
(3ca)
(1b)
(1c)
OCOPh
3aa
82
COONa
(2a)
(2b)
(2c)
75
N
OCOPh
2
3
3ab
3ac
75
60
COONa
62c
52
3
4
N
N
(1d)
(1e)
(1f)
(3da)
(3ea)
(3fa)
COONa
COONa
N
OCOPh
3ad
3ae
3af
50
(2d)
(2e)
4
5
MeO
MeO
5
6
52
85
N
N
OCOPh
86
60
MeO
COONa
OCOPh
N
(1g)
(1h)
(3ga)
(3ha)
OMe
Cl
N
OMe
(2f)
COONa
COONa
6
7
N
N
7
67
OCOPh
(2g)
3ag
36
N
8
9
(1i)
(3ia)
62
50
35
Cl
N
OCOPh
F
8
9
(2h)
(2i)
3ah
3ai
85
35
Br
COONa
COONa
F
N
(1j)
(3ja)
N
N
OCOPh
MeO
M
eOOC
OHC
(1k)
(3ka)
10
N
O
OCOPh
aAll reactions were run with 2-o-tolylpyridine (0.3 mmol), sodium
carboxylates (0.2 mmol), Cu(OTf)2 (20 mol %), K2S2O8 (2 equiv) in
2 mL of toluene under air at 130 °C for 24 h. See SI for details.14
bIsolated yield.
aAll reactions were run with 2-arylpyridine (0.3 mmol), sodium
benzoate (0.2 mmol), Cu(OTf)2 (20 mol %), K2S2O8 (2 equiv) in
2 mL of toluene under air at 130 °C for 24 h. See SI for details.14
bIsolated yield. cThe ratio of 2- and 6-benzoxylation product was 1:8.3,
1
determined by H NMR.
slightly, while 28% of 3aa was detected under nitrogen (Table 1,
Entry 5). Further study revealed that the source of copper had a
dramatic effect on the reaction and Cu(OTf)2 was the best
(Table 1, Entries 5-12). In addition, the amount of Cu(OTf)2 had
obvious effect on the reaction (Table 1, Entry 5 vs. 17). The yield
was decreased to 50% when using 10 mol % Cu(OTf)2 (Table 1,
Entry 17). Only 55% yield was obtained when the temperature
was decreased to 110 °C (Table 1, Entry 18). Replacing toluene
with other solvents such as NMP, DCE, DMF, and 1,4-dioxane
significantly decreased the yields (Table 1, Entries 13-16). Thus,
the best results were obtained in the presence of Cu(OTf)2
(20 mol %) in combination with two equivalents of K2S2O8 as
the oxidant in toluene at 130 °C for 24 h. The reaction conducted
on a 1 mmol scale provided 3aa in an acceptable 78% yield. It is
interesting that no product was detected when PhCOOH instead
of PhCOONa was used.
sodium carboxylates worked well under the reaction conditions.
It was found that this method was quite general, as diverse
substrates possessing methoxy, formyl, chloro, and bromo
groups were perfectly tolerated under these reaction conditions
and produced the corresponding products 3 in moderate to good
yields. However, steric hindrance affected the efficiency. For
example, 75% of 3ab was isolated, while the yield of 3ad
decreased to 50% (Table 2, Entries 2 and 4). In particular, when
sodium 4-bromobenzoate (2h) was subjected to the reaction, the
product 3ah was isolated in 85% yield, leaving the C-Br bond
intact (Table 2, Entry 8). Disappointingly, the feasibility of
accessing the acetoxylated product using sodium acetate failed.
Next, we promptly examined the scope of the arylpyridine
moiety in the ortho-benzoxylation process (Table 3). As
expected, the 2-phenylpyridine derivatives bearing various
substitutents at the para, meta, or ortho position on the phenyl
ring reacted smoothly to afford the desired monofunctionalized
With the optimized conditions in hand, the scope of sodium
carboxylates was next investigated (Table 2). As expected,
Chem. Lett. 2012, 41, 600-602
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

602
products in moderate to good yields. The reaction showed
remarkably broad substrate scope with good functional group
tolerance.
N
N
O
O
K2S2O8 (2 equiv)
Cu
+
O
Ph
Ph
O
O
Ph
O
We thank the National Natural Science Foundation of China
(No. 209072115) and the Natural Science Foundation of
Zhejiang Province (No. Y4110109).
70%
Scheme 2. Stoichiometric reactions of copper(II) benzoate with 2-o-
tolylpyridine.
References and Notes
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O
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Ph
Cu(OTf)2
ONa
(i)
2a
N
Cu(II)(OCOPh)2
2
3
H
K2S2O8
(v)
1a
(ii)
and/or O2
N
Cu(I)(OCOPh)
Cu(II)OCOPh
A
(iv)
N
Cu(I)
(iii)
O
O
Cu(II)
N
Ph
Cu(III)
(OCOPh)2
3aa
4
B
Scheme 3. Plausible mechanism.
products in 35-85% yields. Evidently, the regioselectivity of the
meta-substituted substrates was dominated by steric effects, and
the less hindered ortho-position of 2-arylpyridine was acyloxy-
lated with good selectivity (Table 3, Entry 3). Naphthalene
substrates were also successfully benzoxylated in good yields
and with excellent regioselectivity (Table 3, Entries 7 and 8).
The use of substrates containing strong electron-withdrawing
groups, such as ester was found to give the desired products in
35% yield (Table 3, Entry 10).
5
More experiments were carried out to gain a preliminary
insight into reaction mechanism. When the stoichiometric
reaction of 2-o-tolylpyridine (1a) with copper(II) benzoate was
conducted, 3-methyl-2-(pyridin-2-yl)phenyl benzoate (3aa) was
isolated in 70% yield (Scheme 2). This result showed copper(II)
benzoate may be the intermediate. A working mechanism was
proposed as outlined in Scheme 3. In step (i), the reaction of
copper(II) trifluoromethanesulfonate with sodium benzoate
forms copper(II) benzoate. Step (ii) involves the electrophilic
attack of copper(II) benzoate on the phenyl ring of 1a to afford a
cyclometallated Cu(II) intermediate A. Then, the Cu(II) inter-
mediate A is oxidized to a Cu(III) intermediate B in the presence
of Cu(II).13 In the final step, the reductive elimination of Cu(III)
intermediate B takes place immediately to deliver a Cu(I)
species, which is oxidized by K2S2O8 to regenerate the
copper(II) benzoate.
6
7
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In summary, we have developed the copper-catalyzed ortho-
benzoxylation of 2-arylpyridine C-H bonds employing the facile
prepared sodium carboxylates and afforded the benzoxylation
14 Supporting Information is available electronically on the CSJ-Journal
Web site, http://www.csj.jp/journals/chem-lett/index.html.
Chem. Lett. 2012, 41, 600-602
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/