Copper-catalyzed direct acyloxylation of C(sp2)-H bonds with Benzoic acids

Article abstract of DOI:10.1007/s11426-015-5376-z

A copper-catalyzed acyloxylation of C(sp₂)-H bond with sterically bulky benzoic acids was achieved. This protocol is compatible with a broad range of functional groups and could proceed in gram scale, providing an efficient and practical protoc

Full text of DOI:10.1007/s11426-015-5376-z

SCIENCE CHINA
Chemistry
June 2015 Vol.58 No.6: 1–10
doi: 10.1007/s11426-015-5376-z
• ARTICLES •
· SPECIAL ISSUE · CH bond activation
doi: 10.1007/s11426-015-5376-z
Copper-catalyzed direct acyloxylation of C(sp2)–H bonds with
Benzoic acids
Sheng Zhao, Fa-Jie Chen, Bin Liu & Bing-Feng Shi*
Department of Chemistry, Zhejiang University, Hangzhou 310027, China
Received November 29, 2014; accepted December 23, 2014
A copper-catalyzed acyloxylation of C(sp2)–H bond with sterically bulky benzoic acids was achieved. This protocol is com-
patible with a broad range of functional groups and could proceed in gram scale, providing an efficient and practical protocol
for the synthesis of aryl esters.
copper, C–H activation, acyloxylation, ester, bidentate
1 Introduction
Over the past decades, transition metal catalyzed C–H func-
tionalization has received great interest for the expeditious
synthesis of organic molecules [1–6]. Within this reaction
category, the use of first-row transition metals would be
beneficial compared with relatively expensive second- and
third-row transition metals [7]. In particular, the direct oxy-
genation of C–H bonds mediated by first-row transition
metals, such as copper, has been extensively investigated
(Scheme 1) [8]. In 2006, Yu et al. [9] reported a copper(II)
-cata-lyzed acetoxylation and hydroxylation of 2-arylpyri-
dine using O2 as terminal oxidant. Subsequently, Cheng et
al. [10] developed the copper-catalyzed acyloxylation of
2-arylpyridine with anhydride. Lei et al. [11,12] has also
shown that copper-catalyzed oxidation of electron-deficient
arenes is possible. Recently, Daugulis et al. [13] and Song
et al. [14] developed the copper-catalyzed etherification of
arenes with alcohols using different bidentate directing
groups. More recently, our group developed a copper medi-
ated C–H hydroxylation of arenes using our newly devel-
oped PIP auxiliary [15]. Besides, Kanai [16] and Ge [17]
groups have reported copper-catalyzed C(sp3)–H acetoxyla-
Scheme 1 Copper-catalyzed C–H acyloxylation.
tion by using a combination of stoichiometric amounts of
copper and silver salts. Despite of these significant ad-
vancements, copper-catalyzed acyloxylation of unactivated
C–H bonds with benzoic acids has never been achieved.
*Corresponding author (email: bfshi@zju.edu.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2015
chem.scichina.com link.springer.com

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Zhao et al. Sci China Chem June (2015) Vol.58 No.6
Esters play an important role in bioactive natural prod-
ucts, pharmaceuticals and organic synthesis. In addition,
esters are of great importance either as protecting groups of
carboxylic acids and alcohols or building blocks for further
transformation. Traditional strategies towards esters depend
on the reactions between the corresponding alcohols and
carboxylic acid derivates such as carboxylic halides and
anhydrides. Recently, transition-metal catalyzed esterifica-
tions, such as oxidative esterification of aldehydes, oxida-
tive esterification of alcohols with alkanes, esterification of
alcohols through oxidative carbonylation, and acyloxylation
of C–H bonds, have emerged as efficient and viable syn-
thetic alternatives to the traditional way [18]. To continue
our interest in direct functionalization of unactivated C–H
bonds, we herein reported a copper-catalyzed acyloxylation
of aryl C(sp2)–H with benzoic acids by employing our
newly developed PIP directing group [19,20].
A mixture of amine (5 mmol), acid (5 mmol), 3-(ethyli-
minomethyleneamino)-N,N-dimethyl-propan-1-amine (EDCI,
5.5 mmol) and HOBT (5.5 mmol) in anhydrous N,N-
dimethylformamide (DMF, 20 mL) was stirred at room
temperature overnight. Water was added and the mixture
was extracted with diethyl ether. The combined organic
layer was washed with brine, dried over MgSO4, filtered and
concentrated under reduced pressure. The residue was puri-
fied by flash chromatography to give the desired product.
Method C:
To a round bottom flask was added the acid (5 mmol)
and anhydrous CH2Cl2 (20 mL). Then the flask was sub-
merged in an ice bath, N-methylmorpholine (6 mmol) was
added via syringe and the solution stirred for 15 min. Iso-
butylchloroformate (5.5 mmol) was added dropwise over 20
min. After that, 20 mL anhydrous CH2Cl2 solution contain-
ing PIP–NH2 (5 mmol) and N-methylmorpholine (NMM, 5
mmol) was added to the solution, After stirring for 6 h at
ambient temperature, the resulting mixture was washed with
sat. Na2CO3, and brine, dried over MgSO4, filtered and
concentrated under reduced pressure. The residue was puri-
fied by flash chromatography to give the desired product.
2 Experimental
2.1 General experimental section
N,N-dimethylformamide was dried by CaH2, distilled under
reduced pressure and stored under nitrogen. The other ma-
terials and solvents were purchased from Adamas-beta and
other commercial suppliers and used without additional
purification. NMR spectra were recorded on a Bruke
Avance (Germany) operating for 1H NMR at 400 MHz, and
13C NMR at 100 MHz using TMS as internal standard.
Chemical shifts were given relative to CDCl3 (7.26 ppm for
1H NMR, 77.16 ppm for 13C NMR). The following abbrevi-
ations (or combinations thereof) were used to explain mul-
tiplicities: s=singlet, d=doublet, t=triplet, m=multiplet, br=
broad. Mass spectroscopy data of the products were col-
lected on an HRMS-TOF.
2.2.1 N-(2-(pyridin-2-yl)propan-2-yl)benzamide (1a)
The title compound 1a was prepared according to the gen-
1
eral procedure (Method A). H NMR (400 MHz, CDCl3) 
8.86 (s, 1H), 8.56 (ddd, J=4.8, 1.6, 0.8 Hz, 1H), 7.92–7.90
(m, 2H), 7.75 (td, J=8.0, 2.0 Hz, 1H), 7.50–7.43 (m, 4H),
7.23 (ddd, J=7.6, 4.8, 0.8 Hz, 1H), 1.88 (s, 6H). 13C NMR
(100 MHz, CDCl3)  166.35, 164.83, 147.70, 137.35,
136.15, 131.17, 128.55, 127.11, 122.06, 119.67, 56.76,
27.63. HRMS (EI-TOF) calcd for C15H16N2O (M+):
240.1263, found: 240.1259.
2.2 General procedures for the preparation of starting
materials
Method A:
2.2.2 2-Fluoro-N-(2-(pyridin-2-yl)propan-2-yl)benzamide
(1b)
The title compound 1b was prepared according to the
general procedure (Method A). 1H NMR (400 MHz, CDCl3)
 8.85 (d, J=11.0 Hz, 1H), 8.56 (d, J=4.4 Hz, 1H), 8.06 (td,
J=8.0, 1.6 Hz, 1H), 7.73 (td, J=7.6, 1.6 Hz, 1H), 7.49–7.40
(m, 2H), 7.25–7.17 (m, 2H), 7.14 (dd, J=11.6, 8.0 Hz, 1H),
1.88 (s, 6H).13C NMR (100 MHz, CDCl3)  164.63, 162.38
(d, JC–F=3.1 Hz), 160.77 (d, JC–F=247.1 Hz), 148.01, 137.14,
132.88 (d, JC–F=9.1 Hz), 131.86, 124.66 (d, JC–F=3.3 Hz),
122.88 (d, JC–F=12.2 Hz), 121.96, 119.55, 116.14 (d,
JC–F=24.7 Hz), 57.66, 27.80. HRMS (EI-TOF) calcd for
C15H15FN2O (M+): 258.1168, found: 258.1165.
A solution of acid (5 mmol) in SOCl2 (5 mL) was re-
fluxed for 2 h and cooled to r.t.. The excess of SOCl2 was
removed under vacuum to give the corresponding acid chlo-
ride. The acid chloride was then re-dissolved in 5 mL anhy-
drous CH2Cl2 and added dropwise to a 20 mL anhydrous
CH2Cl2 solution containing PIP-NH2 (5 mmol) and Et3N (10
mmol) at 0 °C. After stirring for 6 h at r.t., the resulting
mixture was washed with brine, dried over MgSO4, filtered
and concentrated under reduced pressure. The residue was
purified by flash chromatography to give the desired product.
Method B:

Zhao et al. Sci China Chem June (2015) Vol.58 No.6
3
2.2.3 2-Chloro-N-(2-(pyridin-2-yl)propan-2-yl)benzamide
(1c)
9.02 (s, 1H), 8.56 (dd, J=4.1, 0.8 Hz, 1H), 8.12 (d, J=8.4 Hz,
2H), 7.96 (d, J=8.4 Hz, 2H), 7.77 (td, J=8.0, 1.6 Hz, 1H),
7.47 (d, J=8.0 Hz, 1H), 7.26–7.20 (m, 1H), 3.95 (s, 3H),
1.89 (s, 6H). 13C NMR (100 MHz, CDCl3)  166.65, 165.43,
164.57, 147.70, 140.17, 137.50, 132.45, 129.90, 127.19,
122.21, 119.68, 56.92, 52.43, 27.53. HRMS (EI-TOF) calcd
for C17H18N2O3 (M+): 298.1317, found: 298.1320.
The title compound 1c was prepared according to the gen-
1
eral procedure (Method A). H NMR (400 MHz, CDCl3) 
8.49 (d, J=4.2 Hz, 1H), 8.36 (s, 1H), 7.73 (td, J=7.8, 1.8 Hz,
1H), 7.63 (dd, J=7.2, 2.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H),
7.41 (dd, J=7.6, 1.6 Hz, 1H), 7.36–7.28 (m, 2H), 7.19 (ddd,
J=7.4, 4.8, 0.8 Hz, 1H), 1.90 (s, 6H); 13C NMR (100 MHz,
CDCl3)  165.94, 164.34, 147.75, 137.15, 130.89, 130.24,
129.75, 127.02, 122.04, 119.58, 57.63, 27.64.
2.2.8 4-Methyl-N-(2-(pyridin-2-yl)propan-2-yl)benzamide
(1i)
The title compound 1i was prepared according to the gen-
1
2.2.4
N-(2-(pyridin-2-yl)propan-2-yl)-2-(trifluoromethyl)
eral procedure (Method A). H NMR (400 MHz, CDCl3) 
benzamide (1d)
8.77 (s, 1H), 8.56 (d, J=4.4 Hz, 1H), 7.80 (d, J=8.0 Hz, 2H),
7.75 (td, J=8.0, 1.6 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H),
7.26–7.22 (m, 3H), 2.40 (s, 3H), 1.88 (s, 6H). 13C NMR
(100 MHz, CDCl3)  166.37, 164.99, 147.74, 141.44,
137.31, 133.37, 129.22, 127.12, 122.02, 119.68, 56.74,
27.70, 21.55. HRMS (EI-TOF) calcd for C16H18N2O (M+):
254.1419, found: 254.1421.
The title compound 1d was prepared according to the
general procedure (Method B). 1H NMR (400 MHz, CDCl3)
 8.44–8.42 (m, 1H), 8.30 (s, 1H), 7.75–7.68 (m, 2H),
7.60–7.58 (m, 2H), 7.51 (t, J=6.8 Hz, 1H), 7.45 (dd, J=8.0,
0.8 Hz, 1H), 7.20–7.16 (m, 1H), 1.88 (d, J=2.4 Hz, 6H); 13C
NMR (100 MHz, CDCl3)  166.97, 164.15, 147.57, 137.46
(q, JC–F=2.0 Hz), 137.33, 132.03, 129.41, 128.67, 127.67 (q,
JC–F=31.7 Hz), 126.41 (q, JC–F=5.0 Hz), 123.91 (q,
JC–F=272.1 Hz), 122.09, 119.56, 57.42, 27.21; HRMS
(EI-TOF) calcd for C16H15F3N2O (M+): 308.1136, found:
308.1133.
2.3 General procedure for copper-catalyzed C(sp2)–H
esterification
2.2.5 3-Methoxy-N-(2-(pyridin-2-yl)propan-2-yl)benzamide
(1e)
The title compound 1e was prepared according to the gen-
eral procedure (Method B).1H NMR (400 MHz, CDCl3) 
8.81 (s, 1H), 8.56 (dd, J=4.8, 0.4 Hz, 1H), 7.75 (td, J=7.6,
1.6 Hz, 1H), 7.50–7.42 (m, 3H), 7.35 (t, J=8.0 Hz, 1H), 7.23
(ddd, J=7.6, 4.8, 0.8 Hz, 1H), 7.04–7.02 (m, 1H), 3.86 (s,
3H), 1.88 (s, 6H); 13C NMR (100 MHz, CDCl3)  166.15,
164.61, 159.82, 147.60, 137.43, 137.36, 129.41, 122.01,
119.62, 118.92, 117.47, 112.30, 56.71, 55.41, 27.55; HRMS
(EI-TOF) calcd for C16H18N2O2 (M+): 270.1368, found:
270.1371.
To a 50 mL sealed tube was added 1 (0.15 mmol), acid
(0.45 mmol), CuOAc (7.4 mg, 0.06 mmol), AgNO3 (101.9
mg, 0.6 mmol), Li2CO3 (33.3 mg, 0.45 mmol) and DMF (3
mL). The mixture was purged with N2 and stirred at 120 °C
for 24 h. The reaction mixture was then cooled to room
temperature, diluted with dichloromethane and quenched
with saturated sodium sulfide. The aqueous phase was ex-
tracted with dichloromethane (3×10 mL). The combined
organic phase was dried with anhydrous magnesium sulfate.
After concentration, the resulting residue was purified by
flash chromatography to afford the product.
2.2.6 3-Methyl-N-(2-(pyridin-2-yl)propan-2-yl)benzamide
(1g)
The title compound 1g was prepared according to the gen-
eral procedure (Method A).1H NMR (400 MHz, CDCl3): 
8.73 (s, 1H), 8.57 (d, J=4.8 Hz, 1H), 7.77–7.72 (m, 2H),
7.68 (d, J=7.2 Hz, 1H), 7.47 (d, J=8.0 Hz,1H), 7.35–7.29
(m, 2H), 7.22 (dd, J=7.2, 4.8 Hz, 1H) 2.42 (s, 3H), 1.88 (s,
6H); 13C NMR (100 MHz, CDCl3):  166.61, 164.88,147.33,
138.29, 137.32, 136.06, 131.86, 128.38, 127.89, 124.04,
122.00, 119.66, 56.77, 27.65, 21.49; HRMS (EI-TOF) calcd
for C16H18N2O (M+): 254.1419, found: 254.1418.
2.3.1 2-((2-(Pyridin-2-yl)propan-2-yl)carbamoyl)phenyl 2,
4,6-trimethylbenzoate (2a)
The title compound 2a was prepared according to the gen-
1
eral procedure. H NMR (400 MHz, CDCl3):  8.82 (brs,
1H), 8.04 (dd, J=7.6, 1.6 Hz, 1H), 7.93 (d, J=4.8 Hz, 1H),
7.60 (td, J=8.0, 1.6 Hz, 1H), 7.52 (td, J=8.0, 2.0 Hz, 1H),
7.38–7.29 (m, 3H), 7.00 (ddd, J=7.2, 5.2, 0.8 Hz, 1H), 6.82
(s, 2H), 2.40 (s, 6H), 2.28 (s, 3H), 1.75 (s, 6H); 13C NMR
(100 MHz, CDCl3):  167.68, 164.27, 164.03, 148.30,
147.58, 140.29, 136.89, 136.63, 131.60, 130.98, 129.31,
129.07, 128.92, 126.28, 123.19, 121.55, 119.13, 57.43,
27.51, 21.28, 20.56; HRMS (EI-TOF) calcd for C25H26N2O3
(M+): 402.1943, found: 402.1950.
2.2.7 Methyl 4-((2-(pyridin-2-yl)propan-2-yl)carbamoyl)
benzoate (1h)
The title compound 1h was prepared according to the gen-
1
eral procedure (Method C). H NMR (400 MHz, CDCl3) 

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Zhao et al. Sci China Chem June (2015) Vol.58 No.6
2.3.2 2-((2-(Pyridin-2-yl)propan-2-yl)carbamoyl)-1,3-phen-
2.3.6
2-Methoxy-6-((2-(pyridin-2-yl)propan-2-yl)carbam-
ylene bis(2,4,6-trimethylbenzoate) (2a′)
oyl)phenyl 2,4,6-trimethylbenzoate (2e)
The title compound 2a′ was prepared according to the gen-
eral procedure. H NMR (400 MHz, CDCl3):  8.33 (d,
The title compound 2e was prepared according to the gen-
eral procedure. 1H NMR (400 MHz, CDCl3):  8.75 (s, 1H),
7.96 (d, J=4.8 Hz, 1H), 7.61–7.55 (m, 2H), 7.33–7.28 (m,
2H), 7.12 (d, J=8.0 Hz, 1H), 6.99 (dd, J=6.4, 5.2 Hz, 1H),
6.82 (s, 2H), 3.89 (s, 3H), 2.45 (s, 6H), 2.27 (s, 3H), 1.74 (s,
6H); 13C NMR (100 MHz, CDCl3):  166.42, 164.28,
164.12, 151.73, 147.61, 140.27, 137.85, 136.83, 130.71,
129.07, 128.89, 126.63, 121.97, 121.54, 119.11, 114.52,
57.49, 56.20, 27.55, 21.27, 20.95; HRMS (EI-TOF) calcd
for C26H28N2O4 (M+): 432.2049, found: 432.2049.
1
J=4.0 Hz, 1H), 7.85 (brs, 1H), 7.52 (t, J=8.0 Hz, 1H),
7.36–7.22 (m, 4H), 7.04–7.00 (m, 1H), 6.84 (s, 4H), 2.37 (s,
12H), 2.28 (s, 6H), 1.56 (s, 6H); 13C NMR (100 MHz,
CDCl3):  167.69, 163.86, 162.17, 148.51, 147.68, 140.44,
137.04, 136.80, 129.86, 129.00, 128.80, 121.74, 120.35,
119.26, 57.68, 27.45, 21.31, 20.71; HRMS (ESI-TOF) calcd
for C35H36N2O5H+ (M+): 565.2697, found: 565.2700.
2.3.3 3-Fluoro-2-((2-(pyridin-2-yl)propan-2-yl)carbamoyl)-
phenyl 2,4,6-trimethylbenzoate (2b)
2.3.7 4-Methoxy-2-((2-(pyridin-2-yl)propan-2-yl)carbam-
oyl)phenyl 2,4,6-trimethylbenzoate (2f)
The title compound 2b was prepared according to the gen-
1
The title compound 2f was prepared according to the gen-
eral procedure. 1H NMR (400 MHz, CDCl3):  8.92 (s, 1H),
7.85 (d, J=4.0 Hz, 1H), 7.63–7.57 (m, 2H), 7.31 (d, J=8.0
Hz, 1H), 7.24 (d, J=9.2 Hz, 1H), 7.05 (dd, J=8.8, 2.8 Hz,
1H), 6.98 (dd, J=6.4, 4.8 Hz, 1H), 6.81 (s, 2H), 3.86 (s, 3H),
2.37 (s, 6H), 2.28 (s, 3H), 1.73 (s, 6H); 13C NMR (100 MHz,
CDCl3):  168.04, 164.25, 163.61, 157.47, 147.62, 141.85,
140.25, 136.85, 136.57, 129.44, 129.29, 128.91, 124.22,
121.52, 119.07, 118.40, 114.54, 57.53, 55.95, 27.50, 21.28,
20.56; HRMS (EI-TOF) calcd for C26H28N2O4 (M+):
432.2049, found: 432.2048.
eral procedure. H NMR (400 MHz, CDCl3):  8.42 (d,
J=4.0 Hz, 1H), 8.18 (brs, 1H), 7.61 (t, J=7.6 Hz), 7.46 –
7.36 (m , 2H), 7.15–7.10 (m, 2H), 7.06 (t, J=8.0 Hz), 6.85 (s,
2H), 2.39 (s, 6H), 2.28 (s, 3H), 1.78 (s, 6H); 13C NMR (100
MHz, CDCl3):  167.76, 163.97, 159.94 (JC–F=247.5 Hz),
158.70, 148.91 (JC–F=6.3 Hz), 147.68, 140.38, 137.11,
136.87, 130.54 (JC–F=9.5 Hz), 128.94, 128.87, 121.94,
121.19 (JC–F=20.9 Hz), 119.41, 118.88 (JC–F=3.4 Hz),
113.59 (JC–F=22.0 Hz), 57.74, 27.60, 21.28, 20.59; HRMS
(EI-TOF) calcd for C25H25FN2O3 (M+): 420.1849, found:
420.1846.
2.3.8 4-Methoxy-2-((2-(pyridin-2-yl)propan-2-yl)carbam-
oyl)-1,3-phenylene bis(2,4,6-trimethylbenzoate) (2f′)
2.3.4 3-Chloro-2-((2-(pyridin-2-yl)propan-2-yl)carbamoyl)-
phenyl 2,4,6-trimethylbenzoate (2c)
The title compound 2f′ was prepared according to the gen-
The title compound 2c was prepared according to the gen-
1
eral procedure. H NMR (400 MHz, CDCl3):  8.33 (d,
1
eral procedure. H NMR (400 MHz, CDCl3):  8.40 (d,
J=4.0 Hz, 1H), 7.82 (s, 1H), 7.32–7.22 (m, 3H), 7.08 (d,
J=8.8 Hz, 1H), 7.00 (t, J=5.2 Hz, 1H), 6.84 (s, 2H), 6.83 (s,
2H), 3.89 (s, 3H), 2.41 (s, 6H), 2.36 (s, 6H), 2.27 (s, 3H),
1.58 (s, 6H); 13C NMR (100 MHz, CDCl3):  168.13,
166.57, 163.86, 162.05, 149.56, 147.71, 140.86, 140.43,
140.27, 138.13, 137.39, 136.96, 136.73, 129.15, 129.01,
128.95, 128.31, 127.36, 121.69, 120.66, 119.23, 112.70,
57.71, 56.41, 27.53, 21.29, 21.00, 20.68; HRMS (EI-TOF)
calcd for C36H38N2O6 (M+): 594.2730, found: 594.2734.
J=4.0 Hz, 1H), 8.01 (brs, 1H), 7.56 (t, J=8.0 Hz, 1H),
7.41–7.32 (m, 3H), 7.27 (d, J=8.0 Hz, 1H), 7.12 (dd, J=7.2,
4.8 Hz, 1H), 6.83 (s, 2H), 2.35 (s, 6H), 2.27 (s, 3H), 1.77 (s,
6H); 13C NMR (100 MHz, CDCl3):  167.79, 163.94,
162.76, 148.45, 147.64, 140.45, 137.08, 136.91, 132.36,
131.76, 130.06, 128.96, 128.77, 127.25, 121.94, 121.48,
119.43, 57.75, 27.48, 21.29, 20.60; HRMS (EI-TOF) calcd
for C25H25ClN2O3 (M+): 436.1554, found: 436.1554.
2.3.5 2-((2-(Pyridin-2-yl)propan-2-yl)carbamoyl)-3-(trifluo-
romethyl)phenyl 2,4,6-trimethylbenzoate (2d)
2.3.9 4-Methyl-2-((2-(pyridin-2-yl)propan-2-yl)carbamoyl)
phenyl 2,4,6-trimethylbenzoate (2g)
The title compound 2d was prepared according to the gen-
The title compound 2g was prepared according to the gen-
eral procedure. 1H NMR (400 MHz, CDCl3):  8.78 (s, 1H),
7.91 (d, J=4.4 Hz, 1H), 7.85 (s, 1H), 7.60 (td, J=8.0, 1.6 Hz,
1H), 7.32 (d, J=8.0 Hz, 2H), 7.21 (d, J=8.0 Hz, 1H), 6.99
(dd, J=6.4, 4.8 Hz, 1H), 6.81 (s, 2H), 2.40 (s, 3H), 2.38
(s,6H), 2.28 (s, 3H), 1.73 (s, 6H); 13C NMR (100 MHz,
CDCl3):  167.88, 164.33, 164.14, 147.61, 146.06, 140.20,
136.83, 136.57, 136.08, 132.20, 131.34, 129.45, 128.88,
128.44, 122.92, 121.51, 119.12, 57.44, 27.51, 21.27, 20.96,
20.54; HRMS (EI-TOF) calcd for C26H28N2O3 (M+):
416.2100, found: 416.2102.
1
eral procedure. H NMR (400 MHz, CDCl3):  8.36 (d,
J=4.4 Hz, 1H), 8.18 (brs, 1H), 7.63–7.56 (m, 3H), 7.53 (td,
J=8.0, 1.2 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.10 (dd, J=7.2,
5.2 Hz, 1H), 6.83 (s, 2H), 2.34 (s, 6H), 2.27 (s, 3H), 1.71 (s,
6H); 13C NMR (100 MHz, CDCl3):  167.67, 163.82,
162.53, 148.42, 147.49, 140.55, 137.09, 137.03, 130.48,
129.76, 129.17, 129.00, 128.85, 128.49, 126.82, 123.69 (q,
JC–F=4.8 Hz), 123.45 (q, JC–F=272.5 Hz), 121.93, 119.38,
57.62, 27.04, 21.28, 20.59; HRMS (EI-TOF) calcd for
C26H25F3N2O3 (M+): 470.1817, found: 470.1821.

Zhao et al. Sci China Chem June (2015) Vol.58 No.6
5
2.3.10
4-Methoxy-2-((2-(pyridin-2-yl)propan-2-yl)carba-
2.3.14
2-((2-(Pyridin-2-yl)propan-2-yl)carbamoyl)phenyl
moyl)-1,3-phenylene bis(2,4,6-trimethylbenzoate) (2g′)
2,6-dimethylbenzoate (3)
The title compound 2g′ was prepared according to the gen-
eral procedure. H NMR (400 MHz, CDCl3):  8.34 (d,
The title compound 3 was prepared according to the general
procedure. H NMR (400 MHz, CDCl3):  8.85 (brs, 1H),
1
1
J=4.4 Hz, 1H), 7.75 (s, 1H), 7.36 (d, J=7.6 Hz, 1H),
7.26–7.19 (m, 3H), 6.99 (t, 5.6 Hz), 6.88 (s, 3H), 6.83 (s,
3H), 5.30 (s, 3H), 2.47 (s, 6H), 2.35 (s, 6H), 2.29 (s, 6H),
2.28 (s, 3H), 1.51 (s, 6H); 13C NMR (100 MHz, CDCl3):
 167.82, 166.66, 163.93, 162.74, 147.75, 146.87, 146.32,
141.09, 140.29, 139.17, 136.97, 136.65, 131.50, 129.81,
129.20, 128.95, 127.31, 126.51, 121.64, 120.45, 119.25,
57.68, 27.44, 22.07, 21.29, 20.64, 17.25; HRMS (EI-TOF)
calcd for C36H38N2O5 (M+): 578.2781, found: 578.2780.
8.03 (dd, J=8.0, 1.6 Hz, 1H), 7.90 (d, J=4.4 Hz, 1H), 7.60
(td, J=8.0, 1.6 Hz, 1H), 7.53 (td, J=8.0, 1.6 Hz, 1H),
7.40–7.31 (m, 3H), 7.20 (t, J=7.6 Hz, 1H), 7.04–6.98 (m,
3H), 2.43 (s, 6H), 1.75 (s, 6H); 13C NMR (100 MHz,
CDCl3):  167.63, 164.22, 164.04, 148.22, 147.58, 136.95,
136.27, 132.41, 131.60, 130.96, 130.18, 129.13, 128.05,
126.37, 123.15, 121.70, 119.16, 57.43, 27.51, 20.43; HRMS
(EI-TOF) calcd for C24H24N2O3 (M+): 388.1787, found:
388.1785.
2.3.11 5-(Methoxycarbonyl)-2-((2-(pyridin-2-yl)propan-2-
yl)carbamoyl)phenyl 2,4,6-trimethylbenzoate (2h)
2.3.15
2-((2-(Pyridin-2-yl)propan-2-yl)carbamoyl)-1,3-
phenylene bis(2,6-dimethylbenzoate) (3′)
The title compound 2h was prepared according to the gen-
eral procedure. 1H NMR (400 MHz, CDCl3):  8.95 (s, 1H),
8.08 (d, J=8.0 Hz, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.97 (s, 1H),
7.94 (d, J=4.0 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 7.33 (d,
J=8.0 Hz, 1H), 7.02 (dd, J=6.4, 5.2 Hz, 1H), 6.83 (s, 2H),
3.96 (s, 3H), 2.41 (s, 6H), 2.29 (s, 3H), 1.75 (s, 6H); 13C
NMR (100 MHz, CDCl3):  167.43, 165.84, 164.03, 163.32,
148.14, 147.55, 140.54, 137.02, 136.92, 133.32, 133.14,
131.01, 129.02, 128.87, 127.22, 124.57, 121.70, 119.15,
57.56, 52.66, 27.43, 21.30, 20.72; HRMS (EI-TOF) calcd
for C27H28N2O5 (M+): 460.1998, found: 460.2007.
The title compound 3′ was prepared according to the gen-
eral procedure. H NMR (400 MHz, CDCl3):  8.32 (d,
1
J=4.4 Hz, 1H), 7.93 (brs, 1H), 7.54 (t, J=8.4 Hz, 1H),
7.39–7.33 (m, 3H), 7.26–7.17 (m, 3H), 7.06–7.00 (m, 5H),
2.40 (s, 12H), 1.56 (s, 6H); 13C NMR (100 MHz, CDCl3): 
167.54, 163.81, 162.04, 148.43, 147.63, 136.87, 136.50,
131.96, 130.22, 129.85, 128.04, 125.83, 121.80, 120.30,
119.23, 57.65, 27.36, 20.49; HRMS (ESI-TOF) calcd for
C33H32N2O5H+ (M+): 537.2384, found: 537.2382.
2.3.16
2-((2-(Pyridin-2-yl)propan-2-yl)carbamoyl)phenyl
2,4,6-triisopropylbenzoate (4)
2.3.12 5-(Methoxycarbonyl)-2-((2-(pyridin-2-yl)propan-2-
yl)carbamoyl)-1,3-phenylene bis(2,4,6-trimethylbenzoate)
(2h′)
The title compound 4 was prepared according to the general
1
procedure. H NMR (400 MHz, CDCl3):  9.30 (s, 1H),
8.13 (dd, J=8.0, 1.6 Hz, 1H), 7.60–7.51 (m, 3H), 7.43 (d,
J=8.0 Hz, 1H), 7.39–7.30 (m, 2H), 7.03 (s, 2H), 6.93 (dd,
J=6.4, 4.8 Hz, 1H), 3.18–3.08 (m, 2H), 2.98–2.89 (m, 1H),
1.77 (s, 6H), 1.29 (d, J=7.2 Hz, 6H), 1.20 (d, J=6.8 Hz,
12H); 13C NMR (100 MHz, CDCl3):  168.19, 164.23,
163.78, 151.10, 148.49, 147.28, 146.27, 136.88, 131.57,
131.33, 129.25, 128.54, 126.05, 122.71, 121.48, 121.17,
119.21, 57.46, 34.67, 31.50, 27.58, 24.34, 24.13; HRMS
(ESI-TOF) calcd for C31H38N2O3H+ (M+): 487.2955, found:
487.2957.
The title compound 2h′ was prepared according to the gen-
eral procedure. H NMR (400 MHz, CDCl3):  8.33 (d,
1
J=4.0 Hz, 1H), 8.04 (s, 1H), 1.95 (s, 2H), 7.40 (td, J=8.0,
1.6 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.05 (dd, J=6.4, 4.8 Hz,
1H), 6.84 (s, 4H), 3.97 (s, 3H), 2.38 (s, 12H), 2.27 (s, 3H),
1.55 (s, 3H); 13C NMR (100 MHz, CDCl3):  167.39,
165.25, 163.62, 161.44, 148.46, 147.63, 140.66, 137.22,
136.91, 132.02, 130.02, 129.07, 128.36, 121.86, 121.66,
119.20, 57.73, 52.83, 27.35, 21.31, 20.79; HRMS (EI-TOF)
calcd for C37H38N2O7 (M+): 622.2679, found: 622.2653.
2.3.17
2-((2-(Pyridin-2-yl)propan-2-yl)carbamoyl)-1,3-
2.3.13 5-Methyl-2-((2-(pyridin-2-yl)propan-2-yl)carbamo-
yl)phenyl 2,4,6-trimethylbenzoate (2i)
phenylene bis(2,4,6-triisopropylbenzoate) (4′)
The title compound 4′ was prepared according to the gen-
eral procedure. H NMR (400 MHz, CDCl3):  8.29 (d,
The title compound 2i was prepared according to the gen-
eral procedure. 1H NMR (400 MHz, CDCl3):  8.78 (s, 1H),
7.95 (d, J=8.0 Hz, 1H), 7.89 (d, J=4.4 Hz, 1H), 7.59 (t,
J=7.6 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.16 (d, J=8.0 Hz,
1H), 7.12 (s, 1H), 6.99 (dd, J=6.0, 4.8 Hz, 1H), 6.82 (s, 2H),
2.43 (s, 3H), 2.40 (s, 6H), 2.28 (s, 3H), 1.73 (s, 6H); 13C
NMR (100 MHz, CDCl3):  167.68, 164.44, 164.02, 148.26,
147.62, 142.44, 140.27, 136.81, 136.69, 131.04, 129.40,
128.94, 127.16, 126.04, 123.55, 121.48, 119.11, 57.41,
27.56, 21.45, 21.28, 20.62; HRMS (EI-TOF) calcd for
C26H28N2O3 (M+): 416.2100, found: 416.2102.
1
J=4.0 Hz, 1H), 7.82 (s, 1H), 7.53 (dd, J=9.2, 7.2 Hz, 1H),
7.47–7.43 (m, 2H), 7.25–7.22 (m, 1H), 7.14 (td, J=7.2, 1.6
Hz, 1H), 7.03–6.95 (m, 5H), 3.12–3.03 (m, 4H), 2.93–2.84
(m, 2H), 1.55 (s, 6H), 1.24 (d, J=7.2 Hz, 12H), 1.19 (d,
J=6.8 Hz, 24H); 13C NMR (100 MHz, CDCl3):  168.25,
163.95, 162.03, 151.03, 148.68, 147.62, 146.06, 136.79,
129.71, 128.93, 125.42, 121.56, 121.11, 119.42, 119.26,
57.81, 34.59, 31.53, 27.68, 24.41, 24.04; HRMS (ESI-TOF)
calcd for C47H60N2O5H+ (M+): 733.4575, found: 733.4578.

6
Zhao et al. Sci China Chem June (2015) Vol.58 No.6
Table 1 Optimization of reaction condictions
2.3.18
2-((2-(Pyridin-2-yl)propan-2-yl)carbamoyl)phenyl
4-bromo-2,6-dimethylbenzoate (5)
The title compound 5 was prepared according to the general
1
procedure. H NMR (400 MHz, CDCl3)  8.88 (brs, 1H),
8.02 (dd, J=7.6, 1.2 Hz, 1H), 7.94 (d, J=4.4 Hz, 1H), 7.65
(td, J=7.6, 1.6 Hz, 1H), 7.53 (td, J=8.0, 1.6 Hz, 1H),
7.41–7.29 (m, 3H), 7.16 (s, 2H), 7.07 (dd, J=7.2, 5.2 Hz,
1H), 2.40 (s, 6H), 1.78 (s, 6H); 13C NMR (100 MHz, CDCl3)
 166.91, 164.19, 164.04, 148.02, 147.41, 138.49, 137.10,
131.62, 131.40, 130.89, 129.34, 126.56, 124.28, 123.09,
121.85, 119.19, 57.43, 27.46, 20.28. HRMS (EI-TOF) calcd
for C24H23BrN2O3 (M+): 466.0892, found: 466.0888.
[Ag] MesCOOH Li2CO3 DMF Yield
Entry [Cu] (equiv.)
(equiv.)
AgNO3
(4.0)
AgNO3
(4.0)
(equiv.)
(equiv.) (mL) (%) a)
51
1
2
3
4
5
6
7
8
9
CuOAc (0.1)
CuOAc (0.2)
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
–
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
3.0
(3.3:1)
63
(2.7:1)
44
(7.8:1)
61
(3.7:1)
51
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
Cu2(OH)2CO3 AgNO3
(0.2)
(4.0)
AgNO3
(4.0)
AgNO3
(4.0)
AgNO3
(4.0)
AgNO3
(4.0)
AgNO3
(4.0)
AgNO3
(4.0)
AgNO3
(4.0)
2.2.19 2-((2-(Pyridin-2-yl)propan-2-yl)carbamoyl)-1,3-phe-
nylene bis(4-bromo-2,6-dimethylbenzoate) (5′)
Cu(OAc)2 (0.2)
The title compound 5′ was prepared according to the gen-
CuBr2 (0.2)
CuO (0.2)
(2.6:1)
1
eral procedure. H NMR (400 MHz, CDCl3)  8.31 (d,
N.D.
J=4.0 Hz, 1H), 8.06 (brs, 1H), 7.56–7.46 (m, 2H), 7.32 (d,
J=8.4 Hz, 2H), 7.28–7.24 (m, 1H), 7.19 (s, 4H), 7.08 (ddd,
J=7.2, 4.8, 0.8 Hz, 1H), 2.37 (s, 12H), 1.57 (s, 6H). 13C
NMR (100 MHz, CDCl3)  166.78, 163.69, 161.88, 148.26,
147.55, 138.78, 137.04, 130.99, 130.84, 129.97, 125.80,
124.47, 122.00, 120.42, 119.28, 57.55, 27.34, 20.37. HRMS
(EI-TOF) calcd for C33H30Br2N2O5 (M+): 692.0521, found:
692.0516.
44
(3.9:1)
57
CuCN (0.2)
CuI (0.2)
(3.4:1)
CuOAc (0.2)
N.D.
70
(1.3:1)
10 b) CuOAc (0.4)
3.0
a) 1H NMR yield using CH2Br2 as the internal standard; b) isolated
yield.
3 Results and discussion
(2i). Notably, when meta-methylbenzamide 1g was empl-
oyed, the esterification occured predominantly at the steri-
cally more accessible site to avoid the steric congestion.
Interestingly, meta-methoxybenzamide 1e gave a mixture of
esterification at both of C6 and C2-position (2e and 2f),
probably due to the coordination effect of the methoxy sub-
stituten in stabilizing the aryl copper intermediate. Sub-
sequently, we further explored the scope of benzoic acids.
Generally, sterically bulky benzoic acids with 2,6-disubs-
tituents showed good reaction efficiency, thus affording the
desired esterification products in moderate to good yields
(3–5). However, simple benzoic acid did not provide the
desired product.
3.1 Optimization of reaction conditions
We started our study by investigating the optimal conditions
for copper-catalyzed C(sp2)–H esterification. PIP-NH2 was
employed as directing group and MesCOOH was chosen as
coupling partner. Our initial condition using CuOAc (10
mol%) as catalyst, Li2CO3 (3.0 equiv.) as base, AgNO3 (4.0
equiv.) as oxidant in DMF at 120 °C for 24 h afforded the
desired product in 51% overall yield (Table 1, Entry 1,
mono:di=3.3:1). The overall yield was improved to 63%
when when 20 mol% CuOAc was used (Entry 2). Subse-
quent screening of several copper salts revealed that CuOAc
and Cu(OAc)2 gave identical efficiency (Entries 3–8).
Li2CO3 was crucial for this transformation since no product
was observed in the absence of Li2CO3 (Entry 9). To our
delight, the yield could be increased by simply lowering the
concentration of the reaction and enhancing the amount of
copper salts (entry 10, 70% yield, mono:di=1.3:1).
3.3 Gram scale synthesis
To demonstrate the synthetic utility of this reaction, we
performed this reaction on gram scale (4.5 mmol) and the
desired product was obtained in 70% overall yield (Scheme
3, 1.46 g, mono:di=1.3:1).
3.2 Substrate scope
3.4 Plausible reaction mechansim
With the optimized reaction conditions in hand, we then
explored the amide substrate scope under the optimized
conditions. As shown in Scheme 2, a variety of functional
groups were well tolerated, such as fluoro (2b), chloro (2c),
trifluoromethyl (2d), methoxy (2e and 2f), methoxycarbonyl
On the basis of the experiments above and previous work on
copper-catalyzed C–H functionalized [21–25], the reaction
mechanism was tentatively proposed as shown in Schem 4.
The reaction starts with Cu(II)-catalyzed C–H activation to
generate C,N,N-Cu(II) intermediate A, which undergoes

Zhao et al. Sci China Chem June (2015) Vol.58 No.6
7
Scheme 4 Proposed reaction mechanism.
The reaction could tolerate various functional groups and
proceed in good yield even in gram scale, providing an effi-
cient and practical protocol for the synthesis of aryl esters.
This work was financially supported by the National Basic Research Pro-
gram of China (2015CB856600), the National Natural Science Foundation
of China (21422206, 21272206), the Fundamental Research Funds for the
Central Universities (2014QNA3008) and the Natural Science Foundation
of Zhejiang Province (Z12B02000).
Scheme 2 Copper-catalyzed acyloxylation of C(sp2)–H bonds. Reaction
conditions: benzamides 1 (0.15 mmol), CuOAc (0.06 mmol), acid (0.45
mmol), Li2CO3 (0.45 mmol), AgNO3 (0.6 mmol), DMF (3.0 mL), 120 °C,
N2.
1
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Baudoin O. Transition metal-catalyzed arylation of unactivated
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Scheme 3 Gram scale synthesis.
7
Kulkarni AA, Daugulis O. Direct conversion of carbon-hydrogen into
carbon-carbon bonds by first-row transition-metal catalysis. Synthesis,
2009, 24: 4087–4109
disproportion or oxidation to afford the C,N,N-Cu(III) spe-
cies B. Finally, ligand exchange and reductive elimination
from intermediate C delivered the desired product 2 with
Cu(I). Notably, when CuOAc was used as catalyst, the cat-
alytic cycle is both initiated and closed by the reoxidation of
Cu(I) to Cu(II) by silver salt.
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