Copper-Catalyzed Direct Acyloxylation of C(sp2)-H Bonds in Aromatic Amides

Article abstract of DOI:10.1021/acs.orglett.7b01559

Copper-catalyzed ortho-acyloxylation of the sp² C-H bond of aryl amides with carboxylic acids is reported. Benzoic acids, cinnamic acids, and aliphatic acids can be involved, and the desired products were obtained in moderate to good yields. This procedure is compatible with a wide range of functional groups and heteroarenes without the use of any ligands or additives. This method provides an operationally simple approach for the synthesis of benzoate and cinnamate.

Full text of DOI:10.1021/acs.orglett.7b01559

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Direct Acyloxylation of C(sp2)−H Bonds in
Aromatic Amides
Feifan Wang, Qiyan Hu, Chao Shu, Zhiyang Lin, Dewen Min, Tianchao Shi, and Wu Zhang*
Key Laboratory of Functional Molecular Solids, Ministry of Education, Anhui Laboratory of Molecule-Based Materials, College of
Chemistry and Materials Science, Anhui Normal University, Wuhu 241000, China
S
* Supporting Information
ABSTRACT: Copper-catalyzed ortho-acyloxylation of the sp2 C−H bond of aryl amides with carboxylic acids is reported.
Benzoic acids, cinnamic acids, and aliphatic acids can be involved, and the desired products were obtained in moderate to good
yields. This procedure is compatible with a wide range of functional groups and heteroarenes without the use of any ligands or
additives. This method provides an operationally simple approach for the synthesis of benzoate and cinnamate.
Scheme 1. Copper-Catalyzed Direct Acyloxylation of C(sp2)−
ver the last two decades, transition metal-catalyzed C−H
Obond activation has been extensively studied to enable the
direct conversion of ubiquitous C−H bonds of organic molecules
into diverse functional groups in a single synthetic operation.1
Much attention has been focused on the development of
regioselective C−O bond formation2 via C−H bond function-
alization because organic molecules containing C−O bonds have
been widely found in numerous natural products, agricultural
chemicals, drugs, and biologically active compounds.3 Among
these methods, directing group-assisted transition metal-
catalyzed direct acyloxylation of C−H bonds has emerged as a
powerful method for the synthesis of esters.4 For example,
Cheng5 demonstrated the Rh-catalyzed ortho-benzoxylation of
the sp2 C−H bond of 2-arylpyridines and the transformation
without any external oxidants. Xu,6 Zhong,7 Kantevari,8 Kuang,9
and Patel10 have independently developed Pd-catalyzed direct
acyloxylation of C(sp2)−H bonds. Ackermann reported the Ru-
catalyzed C−H oxygenation of reusable sulfoximine benza-
mides.11 However, these transformations required precious
metal catalysts, such as Rh, Pd, and Ru. Copper salts, which
are abundant, relatively inexpensive, and possess low toxicity,
have been the subject of extensive research.12
Although the 8-aminoquinoline-derived bidentate auxiliary
has been widely used in direct C−H amination, arylation, and
phenoxylation to facilitate the C−H bond activation and
cyclometalation process,13,14 8-aminoquinoline-assisted acylox-
ylation has not been extensively explored. Kanai15 and Ge16
developed the copper-mediated direct acyloxylation of C(sp3)−
H bonds using 8-aminoquinoline as the bidentate directing
group (Scheme 1). However, both reports are limited to
acetoxylation using a combination of stoichiometric amounts of
copper and silver salts. Herein, we report the copper-mediated
H bonds
direct acyloxylation of sp2 C−H bonds using 8-aminoquinoline
as the bidentate directing group (Scheme 1). This reaction
exhibits wide substrate scope and is compatible with a variety of
functional groups. More importantly, no external ligand or
additive was required in this procedure.
Our initial investigations started with the reaction of 2-methyl-
N-(quinolin-8-yl)benzamide (1a, 1 equiv) and benzoic acid (2a,
1.5 equiv) in the presence of 10 mol % of Cu(OAc)2·H2O and 2
Received: May 30, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01559
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Letter
equiv of Ag2CO3 in a mixed solvent consisting of toluene and
DMF at 130 °C under air for 20 h. The product (i.e., 3-methyl-2-
(quinolin-8-yl) phenyl benzoate (3aa)) was afforded in 57%
yield (Table 1, entry 1). Various catalysts, oxidants, and reaction
Scheme 2. ortho-Benzoxylation Reaction of 2-Methyl-N-
(quinolin-8-yl)benzamide with Aromatic Acids
a
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst (mol %)
oxidant
time (h)
yield (%)
1
Cu(OAc)2·H2O (10)
CuCl2·2H2O (10)
CuBr2 (10)
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
20
20
20
20
20
20
20
20
20
15
15
15
15
15
57
2
61
3
70
4
CuBr (10)
78
5
CuI (10)
56
6
NR
NR
81
7
CuBr (10)
CuBr (15)
CuBr (20)
CuBr (20)
CuBr (20)
CuBr (20)
CuBr (20)
CuBr (20)
8
Ag2CO3
Ag2CO3
Ag2CO3
AgOAc
BQ
9
89
10
11
12
13
14
89
39
NR
c
Ag2CO3
Ag2CO3
80
d
75
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), oxidant (2
b
equiv), toluene/DMF (1.5 mL/0.5 mL) in air. Isolated yield.
c
d
Ag2CO3 (1.5 equiv). 120 °C.
times were examined to determine the optimal reaction
conditions as summarized in Table 1. The catalytic activity of
the different copper sources, such as Cu(OAc)2, CuCl2, CuBr2,
CuBr, and CuI, was tested. Among these sources, CuBr was
superior and resulted in a 78% yield (entry 4). The absence of
either CuBr or Ag2CO3 failed to generate the desired products,
and all the starting materials were recovered from the reaction
system (entries 6 and 7), which indicated that both the copper
catalyst and oxidant played indispensable roles in this reaction.
The overall yield was improved to 89% when 20 mol % CuBr was
used (entry 9). We were pleased to find that the reaction
proceeded well when the reaction time was decreased from 20 to
15 h (entry 10). Various oxidants, such as Ag2CO3, AgOAc, and
BQ (p-benzoquinone), were tested, and Ag2CO3 was determined
to be especially effective (entries 11 and 12). A lower yield was
observed when the amount of Ag2CO3 was decreased from 2 to
1.5 equiv (entry 13). When the temperature was decreased from
130 to 120 °C, the product yield decreased to 75% (entry 14).
With the optimized conditions in hand, we tested their
versatility for C−H benzoxylation with diversely decorated
benzoic acids. As shown in Scheme 2, this protocol was
compatible with a wide range of functional groups, such as alkyl,
methoxy, fluoro, chloro, bromo, aryl, and trifluoromethyl groups.
No significant substitution effect was observed for the benzoic
acids. Good yields were obtained for benzoic acids with both
electron-donating and electron-withdrawing substituents on the
para-position of aryl ring. Benzoic acid with chloro group at the
para-position afforded better yields than those at the ortho- and
meta-positions. 3-(Trifluoromethyl) benzoic acid also worked
well and afforded product 3ak in 59% yield. A thiophene-derived
acid also reacted with 1a to afford 3an in good yield. More
importantly, the acyloxylation of 1a with isobutyric acid and 2-
phenyl butyric acid provided desired products 3ao and 3ap in
61% and 53% yields, respectively, revealing the broad adaptability
of this method.
Next, various benzamides 1 were used to further enrich the
structural diversity of the acyloxylation products (Scheme 3).
When meta-methylbenzamide 1c was employed, the benzox-
ylation occurred predominantly at the sterically more accessible
site to afford 3cb in 41% yield. However, when meta-
methoxybenzamide 1d was subjected to benzoxylation, a mixture
Scheme 3. Scope of Benzamides
B
DOI: 10.1021/acs.orglett.7b01559
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of 3db, 3db′, and 3db″ was obtained, which is most likely due to
the coordination effect of the methoxy substituent that stabilized
the aryl copper intermediate. Surprisingly, diacyloxylation
products were obtained in moderate yields when an extended
reaction time was used.
To further broaden the substrate scope of the copper-catalyzed
acyloxylation of C (sp2)−H, the reactions of cinnamic acids 4
with benzamide 1 were investigated, and the results are shown in
Scheme 4. As expected, a wide range of cinnamic acid substrates
the presence of a bidentate directing group is crucial for the C−H
bond activation and cyclometalation process. Additionally, 2-
phenyl-N-(quinolin-8-yl)acetamide 6b was not an effective
substrate for this reaction, indicating that the formation of a
six-membered ring intermediate is not favorable in the
cyclometalation step when the directing group is far away from
the benzene ring.
To gain additional insight into the mechanism of the C−H
acyloxylation reactions, a series of controlled experiments was
performed. The addition of 2,2,6,6-tetramethylpiperidine-N-
oxide (TEMPO) as a radical quencher slightly inhibited the
reaction (Scheme S2, eqs 1 and 2). The reaction proceeds well
when sodium benzoate was used rather than benzoic acid
(Scheme S2, eq 3), suggesting that the reaction does not involve
a radical pathway. The intermolecular isotope kinetic effects of
N-(quinolin-8-yl)benzamide and other experiments were studied
(Figure S3). The kinetic isotope effect value (kH/kD) was
calculated to be 1.4, indicating that the C−H cleavage was not
involved in the rate-determining step of the reaction.
a
Scheme 4. Reaction Scope with Respect to Cinnamic Acids
Based on these observations and earlier precedent,17
a
plausible mechanism for the current copper-catalyzed ortho-
acyloxylation of N-(quinolin-8-yl)benzamide with benzoic acid is
proposed in Scheme 6. The reaction was initiated by the
Scheme 6. Plausible Reaction Mechanism
a
Reaction time was extended to 30 h.
were compatible with this protocol. Products containing methyl,
methoxy, fluoro, chloro, and bromo groups were obtained in
good yields. As shown in Scheme 4, cinnamic acids exhibited
lower reactivity than most of the benzoic acids, and the C−H
acyloxylation of benzamides exhibited excellent monoselectivity
despite extending the reaction time.
Then, we investigated the effects of the directing group on the
efficiency of the acyloxylation reaction (Scheme 5). No reaction
occurred when amide 6a was used as the substrate, indicating that
complexation of benzamide 1b with copper using the N,N-
bidentate directing group to afford Cu(II)-complex A. Next, A
involved chelate-directed C−H activation of the substrate to
afford Cu(II) intermediate B. Then, intermediate C may be
produced by disproportionation or oxidation. Finally, ligand
exchange and reductive elimination from intermediate C
delivered desired product 3b with Cu(I). Based on this
mechanism, we rationalize that Ag2CO3 may not only act as an
oxidant but could also react with ArCOOH to generate
ArCOO−.
Scheme 5. Effects of the Directing Group
In summary, an efficient method for the ortho-acyloxylation of
benzamides with an inexpensive copper catalyst has been
developed to afford acyloxylation products in moderate to
good yields. This protocol exhibits wide substrate scope and
good functional group compatibility. The reaction can be
conducted without using any ligands or additives, resulting in
an operationally simple protocol for the synthesis of carboxylic
esters.
C
DOI: 10.1021/acs.orglett.7b01559
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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ASSOCIATED CONTENT
■
S
* Supporting Information
1278.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01559.
(12) Guo, X. X.; Gu, D. W.; Wu, Z. X.; Zhang, W. B. Chem. Rev. 2015,
115, 1622.
(13) Chen, Z. K.; Wang, B. J.; Zhang, J. T.; Yu, W. L.; Liu, Z. X.; Zhang,
Y. H. Org. Chem. Front. 2015, 2, 1107.
Experimental details, characterization data, and 1H NMR
and 13C NMR spectra of new compounds (PDF)
(14) (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 13154. (b) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: zhangwu@mail.ahnu.edu.cn.
ORCID
Wu Zhang: 0000-0002-8327-3957
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(15) Wang, Z.; Kuninobu, Y.; Kanai, M. Org. Lett. 2014, 16, 4790.
(16) Wu, X. S.; Zhao, Y.; Ge, H. B. Chem. - Asian J. 2014, 9, 2736.
(17) Li, X.; Liu, Y. H.; Gu, W. J.; Li, B.; Chen, F. J.; Shi, B. F. Org. Lett.
2014, 16, 3904.
We gratefully acknowledge the National Natural Science
Foundation of China (21272006), which provided financial
support.
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DOI: 10.1021/acs.orglett.7b01559
Org. Lett. XXXX, XXX, XXX−XXX