Copper(II)-catalyzed ortho-acyloxylation of the 2-arylpyridines sp 2 C-H bonds with anhydrides, using O2 as terminal oxidant

Article abstract of DOI:10.1021/jo1000719

(Figure Presented) A chelation-assisted copper(II)-catalyzed ortho-acyloxylation of the 2-arylpyridine sp₂ C-H bond with anhydride is described. The procedure tolerates various functional groups, such as carbomethoxyl, methoxyl, fluoro, bromo, chloro, and cyano groups, affording the mono- or diacyloxylated products in moderate to good yields. Importantly, this procedure uses O₂ as a clean terminal oxidant.

Full text of DOI:10.1021/jo1000719

pubs.acs.org/joc
C-H bond using transition metal catalysis.1 Notable pro-
Copper(II)-Catalyzed Ortho-Acyloxylation of the
2-Arylpyridines sp2 C-H Bonds with Anhydrides,
Using O2 as Terminal Oxidant
gress has been made predominantly with Pd,2 Ru,3 and Rh4
catalysts which allow atom-economical transformations of
the C-H bonds into C-C and C-heteroatom bonds. Re-
cently, the development of regioselective C-O bond formation
via C-H cleavage has attracted much attention.5 We also
have developed an efficient rhodium-catalyzed o-benzoxyla-
tion of the sp2 C-H bond.6 However, most reports on such
transformations have been limited to acetoxylation,7 and
have used relatively expensive palladium or rhodium catalysts.
From the synthetic point of view, it is more cost-efficient to
replace the expensive transition metal catalyst with a cheaper
one. Employing copper as the catalyst, which is not com-
monly used in C-H functionalization reactions,8 is particu-
larly attractive due to its low cost and toxicity. In 2006, Yu
described an elegant example of Cu(OAc)2-catalyzed oxida-
tive acetoxylation of arene C-H bonds in HOAc/Ac2O using
oxygen as a clean oxidant at an elevated temperature
(Scheme 1, eq 1).9 In 2005, Yu also reported a Pd-catalyzed
Wenhui Wang,† Fang Luo,† Shouhui Zhang,† and
Jiang Cheng*,†,‡
†College of Chemistry & Materials Engineering,
Wenzhou University, Wenzhou 325027, People’s Republic of
China, and ‡State Key Laboratory of Coordination
Chemistry, Nanjing University, Nanjing 210093,
People’s Republic of China
jiangcheng@wzu.edu.cn
Received January 16, 2010
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A chelation-assisted copper(II)-catalyzed ortho-acyloxy-
lation of the 2-arylpyridine sp2 C-H bond with anhy-
dride is described. The procedure tolerates various
functional groups, such as carbomethoxyl, methoxyl,
fluoro, bromo, chloro, and cyano groups, affording the
mono- or diacyloxylated products in moderate to good
yields. Importantly, this procedure uses O2 as a clean
terminal oxidant.
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DOI: 10.1021/jo1000719
r
Published on Web 03/10/2010
J. Org. Chem. 2010, 75, 2415–2418 2415
2010 American Chemical Society

Wang et al.
JOCNote
SCHEME 1. Copper-Catalyzed Acyloxylation of the
2-Phenylpyridine C-H Bond
Polar solvents such as NMP and DMF inhibited the reaction
(Table 1, entries 1 and 2). Among the low-polar solvents
screened, toluene was the best, affording the diacyloxylated
product in 85% yield (Table 1, entry 7). Several copper
sources were also examined. Cu(OAc)2 and CuCl2 showed
better catalytic reactivity. In addition, the amount of Cu-
(OAc)2 had little effect on the reaction (Table 1, entries
7-10). To reduce the catalyst loading, we finally chose
10 mol % of Cu(OAc)2 as the catalyst. Increasing or decreasing
the amount of benzoic anhydride slightly decreased the yield
(Table 1, entry 9).
Under air, the yield of 3aa sharply decreased to 53%
(Table 1, entry 11). Under N2, only a trace of the product
was formed (Table 1, entry 12), which indicated that O2
may act as the terminal oxidant in the procedure. Particularly,
the use of O2 as an oxidant in C-H bond functionalization
showed practical advantages compared to other oxidants,
such as PhI(OAc)2, Oxone, K2S2O8, BQ, and TBHP.
Benzoic acid was subjected to the reaction, and the yield of
3aa decreased to 34%. Replacing Ac2O with benzoic anhy-
dride in Yu’s protocol resulted in the formation of acetoxy-
lated product along with a trace of the benzoxylated product.
The reaction temperature was also crucial for the reaction,
with lower yields obtained at temperatures below 145 °C.
stereoselective oxidation of methyl groups by carboxylic
anhydrides.10 Our interest in C-H functionalization6,11 led
us to explore the possibility of using readily available anhy-
drides as the reaction partners catalyzed by copper for such
transformations. Herein, we report a chelation-assisted
copper(II)-catalyzed ortho-acyloxylation of the sp2 C-H
bond of 2-arylpyridine employing O2 as the terminal oxidant
(Scheme 1, eq 2).
TABLE 1. Selected Results of Screening the Optimal Conditionsa
TABLE 2. Ortho-Acyloxylation of 2-Arylpyridines with Benzoic
Anhydridea
entry
Cu source (mol %)
solvent
NMP
DMF
DCE
xylene
1,4-dioxane
CH3CN
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
yield (%)
<5
<5
36
77
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Cu(OAc)2(30)
Cu(OAc)2(30)
Cu(OAc)2(30)
Cu(OAc)2(30)
Cu(OAc)2(30)
Cu(OAc)2(30)
Cu(OAc)2(30)
Cu(OAc)2(20)
Cu(OAc)2(10)
Cu(OAc)2(5)
Cu(OAc)2(10)
Cu(OAc)2(10)
Cu(OTf)2(10)
CuBr2(10)
<5
12
85
85
84 (79b, 73c)
78
53d
<5e
<5
<5
49
Cu(acac)2(10)
CuO(10)
CuCl2(10)
11
75
a2-Phenylpyridine (0.2 mmol), benzoic anhydride (0.6 mmol), Cu
source in dry solvent in a sealed tube, 145 °C, 24 h, under O2. bBenzoic
anhydride (0.5 mmol). cBenzoic anhydride (0.7 mmol). dUnder air.
eUnder N2.
We initiated our investigation by examining the reaction
of benzoic anhydride and 2-phenylpyridine using Cu(OAc)2
as the catalyst in a sealed tube (Table 1). The results sug-
gested that the solvent was crucial for this transformation.
(10) Giri, R.; Liang, J.; Lei, J.-G.; Li, J.-J.; Wang, D.-H.; Chen, X.;
Naggar, I. C.; Guo, C.; Foxman, B. M.; Yu, J.-Q. Angew. Chem., Int. Ed.
2005, 44, 7420.
(11) (a) Jia, X.; Zhang, S.; Wang, W.; Luo, F.; Cheng, J. Org. Lett. 2009,
11, 3120. (b) Jia, X.; Yang, D.; Zhang, S.; Cheng, J. Org. Lett. 2009, 11, 4716.
(c) Jia, X.; Yang, D.; Wang, W.; Luo, F.; Cheng, J. J. Org. Chem. 2009, 74,
9470.
a2-Arylpyridine (0.2 mmol), benzoic anhydride (0.6 mmol), Cu(OAc)2
(10 mol %) in dry toluene (2 mL) in a sealed tube, O2, 145 °C, 24 h.
b48 h.
2416 J. Org. Chem. Vol. 75, No. 7, 2010

Wang et al.
JOCNote
Finally, the optimized conditions were defined as follows:
under O2, 10 mol % of Cu(OAc)2 as the catalyst, and a
1:3 mol ratio of 2-arylpyridine and anhydride in dry toluene
at 145 °C.
anhydrides had little effect on the transformation (Table 3,
entry 1 vs entry 3). Acetic anhydride produced the monoace-
toxylated product 4af as a major product in moderate yield. In
particular, trans-cinnamic anhydride 2g was subjected to the
reaction, affording the product 3ag in 40% yield with longer
reaction time (Table 3, entry 6). Disappointingly, the feasibility
of access to trifluoromethanesulfonated product by use of
trifluoromethanesulfonic anhydride failed.
A competition reaction was conducted under the standard
conditions, and 3aa was isolated in 58% yield along with
38% of 30aa, indicating that it was the benzoyloxyl that
preferably transferred to the ortho-acyloxylation product
(Scheme 2).
With the optimized reaction conditions in hand, the scope
of 2-arylpyridines was investigated (Table 2). The electronic
property of the substituent significantly affected the reac-
tion. The electron-donating functional groups attached to
the aryl ring gave higher yields than those with electron-
withdrawing groups (Table 2, entries 2, 3, 4, 10, 11 vs 6, 7, 8,
9). Notably, the procedure tolerated a range of functional
groups, such as cyano, chloro, bromo, and carbomethoxyl
groups. Importantly, the selectivity of mono- and diacyloxy-
lation may be dominated by the hindrance on the aryl ring.
For example, the meta-substituted substrates 1c and 1e solely
produced the monoacyloxylated product in moderate yields
(Table 2, entries 3 and 5). Furthermore, the monoacyloxy-
lated product was obtained when one ortho-position of
phenyl was blocked. For example, 2-o-tolylpyridine 1j and
2-(2-methoxyphenyl)pyridine 1k provided monoacyloxy-
lated products in 85% and 91% yields, respectively
(Table 2, entries 10 and 11). Aryl bromide was also a reaction
partner, albeit the acyloxylation product 4la was isolated in
33% yield, along with the recovery of starting material. This
was notable as on one hand the aryl bromide substrates are
often very reactive in Pd0/II catalytic cycles, and on the other
hand the bromo products could be easily further modifiable
(Table 2, entry 12).
SCHEME 2. Competition Reaction of Anhydride with 2-Phe-
nylpyridine
Radical inhibitor 2,6-di-tert-butyl-4-methylphenol (BHT,
2 mol %) and 2,2,6,6-tetramethylpiperidinooxy (TEMPO, 2
mol %) were added to the standard procedure, respectively.
However, product 3aa was isolated in 81% and 85% yields,
respectively. This result ruled out the possibility of a radical-
mediated mechanism.9
Next, we explored the reaction of a variety of anhydrides
with 2-phenylpyridine as shown in Table 3. These results
indicated that steric hindrance on the aryl ring of the
SCHEME 3. Plausible Mechanism
TABLE 3. Ortho-Acyloxylation of 2-Phenylpyridine with Anhydridesa
On the basis of the experimental results and Stahl’s
seminal work on mechanistic study of copper-catalyzed
aerobic oxidative coupling of arylboronic esters and methanol,12
a plausible mechanism for this transformation is outlined in
Scheme 3. In step i, the reation of Cu(OAc)2 with benzoic
anhydride 2 affords Cu(II) benzoate and acetic anhydride as
a byproduct. Step ii involves the electrophilic attack of Cu(II)
on phenyl ring of 2-arylpyridine to afford a cyclometalated
Cu(II) intermediate A. The fact that the 2-arylpyridine
possessing electron-donating groups showed higher reacti-
vity is consistent with this step. Then, the Cu(II) intermediate
A is oxidized to a Cu(III) intermediate B in the presence of
Cu(II). In the final step, the reductive elimination of Cu(III)
intermediate B takes place immediately to deliver the pro-
duct 4 along with a Cu(I) species, which is oxidized by O2 to
a2-Phenylpyridine (0.2 mmol), anhydride (0.6 mmol), Cu(OAc)2
(10 mol %) in dry toluene (2 mL) in a sealed tube, O2, 145 °C, 24 h.
b48 h.
(12) King, A. E.; Brunold, T. C.; Stahl, S. S. J. Am. Chem. Soc. 2009, 131,
5044.
J. Org. Chem. Vol. 75, No. 7, 2010 2417

Wang et al.
JOCNote
regenerate the Cu(II) benzoate in the presence of benzoic
anhydride 2.
2-(Pyridin-2-yl)-1,3-phenylene bis(3-methylbenzoate) (3ac):
1H NMR (CDCl3, 300 MHz) δ 8.58 (d, J = 3.9 Hz, 1H), 7.73
(d, J = 9.9 Hz, 4H),7.58-7.52 (m, 2H), 7.42 (d, J = 7.8 Hz, 1H),
7.36-7.24 (m, 6H), 7.10 (m, 1H), 2.34 (s, 6H); 13C NMR
(CDCl3, 75 MHz) δ 164.8, 152.0, 149.4, 149.2, 138.2, 136.2,
134.3, 133.7, 130.6, 129.5, 128.9, 128.3, 127.2, 125.3, 122.5,
120.6, 21.2; IR (prism, cm-1) ν 3061, 2923, 1735, 1457, 1426,
1269; HRMS (EI) calcd for C27H21NNaO4 (MþNa)þ 446.1368,
found 446.1348.
In conclusion, we have developed an efficient chelation-
assisted copper-catalyzed ortho-acyloxylation reaction of
the 2-arylpyridine sp2 C-H bond, affording mono- or
diacyloxylation products in moderate to good yields. The
use of inexpensive copper catalysts and O2 as the terminal
oxidant provides a significant practical advantage for this
transformation. The reaction showed remarkably broad
substrate scope and good functional group tolerance.
Acknowledgment. We thank the National Natural Science
Foundation of China (No. 20972115), the Key Project of
Chinese Ministry of Education (No. 209054), and State Key
Laboratory of Coordination Chemistry of Nanjing Univer-
sity for financial support.
Experimental Section
General Procedure for Ortho-Acyloxylation of the 2-Arylpyr-
idines. Under O2 atmosphere, a sealed tube was charged with 2-
arylpyridine (0.2 mmol), anhydrides (0.6 mmol), Cu(OAc)2
(10 mol %), and dry toluene (2 mL). The mixture was stirred
at 145 °C for 24 h. Then the solvent was concentrated in vacuo
and the residue was purified by flash column chromatography on a
silica gel to give the desired product.
Supporting Information Available: Experimental proce-
dures along with copies of spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
2418 J. Org. Chem. Vol. 75, No. 7, 2010