Copper-catalyzed C-H acyloxylation of 2-phenylpyridine using oxygen as the oxidant

Article abstract of DOI:10.1039/c8ra01974f

An efficient copper-catalyzed direct o-acyloxylation of 2-phenylpyridine with carboxylic acids using oxygen as the oxidant has been developed. Various acids including aromatic acids, cinnamic acids and aliphatic acids are effective acyloxylation reagents

Full text of DOI:10.1039/c8ra01974f

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Copper-catalyzed C–H acyloxylation of 2-
phenylpyridine using oxygen as the oxidant†
Cite this: RSC Adv., 2018, 8, 16378
*
Feifan Wang, Zhiyang Lin, Weisheng Yu, Qingdong Hu, Chao Shu and Wu Zhang
Received 6th March 2018
Accepted 27th April 2018
An efficient copper-catalyzed direct o-acyloxylation of 2-phenylpyridine with carboxylic acids using oxygen
as the oxidant has been developed. Various acids including aromatic acids, cinnamic acids and aliphatic
acids are effective acyloxylation reagents and provide the desired products in moderate to excellent
yields. The reaction proceeds well under an oxygen atmosphere, making this method potentially practical.
DOI: 10.1039/c8ra01974f
rsc.li/rsc-advances
a clean terminal oxidant in copper-catalyzed reactions.9 Also,
different oxidation states of copper (Cu(I), Cu(II), and Cu(III))
could be mutually converted with the assistance of O2.10
Continuing our research efforts in the development of novel
copper-catalyzed C–H acyloxylation,11 we report now direct o-
acyloxylation of 2-phenylpyridine with carboxylic acids
including aromatic acids, cinnamic acids and aliphatic acids
using oxygen as terminal oxidant with inexpensive copper
catalysts, providing an operationally simple approach for the
synthesis of benzoate (Scheme 1).
Introduction
Transition-metal-catalyzed or -mediated C–H transformations
have been widely used to synthesize many multifunctional
molecules as a straightforward and atom economic method.1
The directing group assisted C–H bond activation and dehy-
drogenative cross-coupling are the most facile methods that
have gained considerable attention over traditional cross-
coupling methods.2,6a Copper complexes or salts have received
increased attention as highly efficient catalysts to promote
direct C–H bond functionalization for the construction of C–X,
C–O, C–S and C–N bonds due to their abundance and low cost
and toxicity over the past decades.3–5
Accordingly, the importance of ester functionality in natural
products, pharmaceuticals and functional materials has
prompted chemists to investigate the development of regiose-
lective C–O bond formation via C–H bond activation under
transition metal catalysis. Recently, 2-phenylpyridine was
elegantly identied as a versatile auxiliary in C–H trans-
formations.6 And a number of o-benzoxylation protocols of 2-
phenylpyridine have been developed with various acyloxyl
sources such as benzyl alcohols or benzyl amines,7a anhy-
drides,7b sodium carboxylates,7c carboxylic acid,7d,e benzylic
ethers,7f acyl chlorides,7g amides,7h aldehydes or methylarenes,7i
aryl alkenes and alkynes.7j Very recently, Li and co-workers re-
ported Rh(III)-catalyzed direct acyloxylation of sp2 C–H bonds
with various carboxylic acids.8 Although various valuable acy-
loxylated products were obtained, the transformation still
suffered from noble metal, and stoichiometric amount of silver
oxidants. It would be ideal that this o-benzoxylation can be
achieved under the oxidation of oxygen, which is oen used as
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. E-mail: zhangwu@mail.
ahnu.edu.cn
† Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
for ESI and details of instruments and experimental procedures. See DOI:
10.1039/c8ra01974f
Scheme 1 Copper-catalyzed direct acyloxylation of C(sp2)–H bonds.
16378 | RSC Adv., 2018, 8, 16378–16382
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Table 1 Optimization of the reaction conditionsa
Results and discussion
Initially, 3-methyl-2-phenylpyridine (1a, 1 equiv.) and benzoic
acid (2a, 1.5 equiv.) were chosen as model substrates to estab-
lish the best reaction conditions. The catalytic activity of various
copper sources, such as Cu(OAc)2$H2O, CuCl2$2H2O, CuBr2,
CuSO4$5H2O, Cu(OAc)2, CuCl, CuBr, and CuI were investigated.
Among them, CuBr was found to be superior and resulted in
88% yield (Table 1, entries 1–8). Decreasing the catalyst amount
from 10 to 5 mol% resulted in the obvious decrease of the yield
(Table 1, entry 9). In contrast, a little decrease of the yield was
observed by increasing the catalyst loading to 15 mol% (Table 1,
entry 10). The absence of copper catalyst fails to generate the
desired products, which indicated that the copper catalyst
played indispensable roles in this reaction (Table 1, entry 11).
Then different solvents like toluene, benzene, DMSO, and DMF
were screened, but they are not as effective as chlorobenzene
(Table 1, entries 12–16).
This transformation also proceeded well under air, but the
yield of 3aa was slightly lower (Table 1, entry 17). In contrast, the
reaction did not occur under argon, indicating that oxygen was
effective oxidant in the reaction.
With the optimized conditions in hand, we investigated the
substrate scope and generality of the copper-catalyzed C–H
acyloxylation of 2-phenylpyridine with carboxylic acids. As
shown in Scheme 2, a range of carboxylic acids were suitable for
this reaction, including aromatic acids, cinnamic acids and
Entry
Catalyst (mol%)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
Cu(OAc)2$H2O (10)
CuCl2$2H2O (10)
CuBr2 (10)
CuSO4$5H2O (10)
Cu(OAc)2 (10)
CuCl (10)
CuBr (10)
CuI (10)
CuBr (5)
CuBr (15)
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
Toluene
DMF
DMSO
1,2-DCB
THF
85
80
53
45
87
80
88
48
68
83
NR
38
57
NR
73
33
70c
9
10
11
12
13
14
15
16
17
18
—
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
PhCl
PhCl
d
—
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), solvent (2 mL)
under oxygen for 24 h. Isolated yield. c Under air. d Under Ar.
b
Scheme 2 ortho-Acyloxylation reaction of 3-methyl-2-phenylpyridine with acids. aReaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), PhCl (2
mL), 130 ꢀC, 24 h. bCu(OAc)2 (10 mol%).
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aliphatic acids. In general, benzoic acid bearing electron- using a halogen-bearing substrate, which can be used for
withdrawing groups exhibited higher reactivity than those further transformation.
bearing electron-donating groups. Although cinnamic acids
In a gram-scale experiment, a satisfactory yield of 81% was
and aliphatic acids exhibited lower reactivity than benzoic obtained in the model reaction. The present acyloxylation
acids, moderate to good yields could be obtained and the result provides an efficient and cost-effective approach for the
is superior to literature report using anhydrides as acyloxyl synthesis of benzoates.
source.7b Gratifyingly, it was found that the o-acyloxylation of 3-
To gain insights on the reaction pathway of copper-catalyzed
methyl-2-phenylpyridine occurred with excellent levels of aerobic oxidative acyloxylation of 2-phenylpyridine with
monosubstituted products, probably due to the steric carboxylic acid, a series of experiments were carried out, as
hindrance. This protocol was compatible with a wide range of shown in Scheme 4. First, the intermolecular competition
functional groups, such as alkyl, methoxy, chloro, bromo, aryl experiments between electronically differentiated substrates
and triuoromethyl groups.
were conducted.12 In the intermolecular competition reaction of
Then, we explored the viable substrate scope with variously 2-phenylpyridine with p-toluylic acid and p-chlorobenzoic acid
decorated 2-arylpyridines (Scheme 3). 2-Phenylpyridine bearing (2b and 2i) under the optimized conditions, the products 3ab
a methyl group (3ca, 3da, and 3ea) in different positions reacted and 3ai were obtained in 36% and 41% yield (Scheme 4a),
smoothly to afford the desired products in good yields. The indicating that the electron-decient aromatic carboxylic acids
methoxy and chloro groups at the ortho-position of the phenyl reacted preferentially. Additionally, a scrambling test of 2-aryl-
ring in 2-phenylpyridine did not exhibit a clear steric hindrance pyridines which bears an electron-donating and electron-
effect in this reaction (3ga and 3ha).
withdrawing group (1e and 1j) with benzoic acid was conduct-
Both electron-donating (OCH3, 3fa) and strong electron- ed, and 3ea was isolated in 22% yield along with 7% of 3ja,
withdrawing (CF3, 3la) functional groups on the phenyl ring indicating that the electron-rich arene proved to be inherently
of 2-phenylpyridine were well tolerated. We were pleased to nd more reactive than their electron-decient counterparts.
that the o-acyloxylation of 2-arylpyridines occurred with excel- Second, the desired product 3aa could be obtained in 74% or
lent levels of monoselectivity with methyl and chloro group at 82% yield when radical inhibitor 2,2,6,6-tetramethyl piperidine-
the meta-position (3da and 3ia). A good yield could be obtained N-oxide (TEMPO, 1 equiv.) or 2,6-di-tert-butyl-4-methylphenol
Scheme 3 Scope of 2-phenylpyridines. aReaction conditions: 1 (0.1 mmol), 2a (0.3 mmol), Cu(OAc)2 (20 mmol%), PhCl (1 mL), 130 ꢀC, 24 h. b11 h.
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It was found that treating [D5]-1b with benzoic acid under the
standard conditions afforded product [Dn]-3ba with a signicant
ortho-D/H exchange (see ESI†). The results conrmed that the
initial ortho-CAr–H metalation is reversible. Finally, the intermo-
lecular competition reaction between 1b and [D5]-1b with pivalic
acid 2r in one vessel, established a kinetic isotopic effect (KIE) of
KH/KD was 2.8. The results indicated that C–H bond cleavage in 2-
phenylpyridine was involved in the rate-limiting step.
Subsequently, sodium benzoate was used rather than benzoic
acid as acyloxyl sources. Trace of products was detected when
sodium benzoate was used (Scheme S3, eqn (2)†). Based on our
mechanistic studies and earlier precedent,7 a plausible mecha-
nism for the copper-catalyzed ortho-acyloxylation of 2-phenyl-
pyridine with benzoic acid is proposed in Scheme 5. Initially, Cu(I)
was oxidized by oxygen to the Cu(II), and Cu(II) reacted with benzoic
acids 2 affords cupric benzoate. Then, under the chelation assis-
tance of the azo group, ortho-C–H bond electrophilic metalation of
the phenyl ring of 2-arylpyridine with Cu(II) provides an active
cyclometallated Cu(II) intermediate A. The fact that the 2-arylpyr-
idine possessing electron-donating groups showed higher reac-
tivity is consistent with the C–H bond electrophilic metalation
regime. Subsequently, the intermediate A is oxidized to a Cu(III)
intermediate B in the presence of Cu(II).13 Finally, reductive elim-
ination from intermediate B delivered desired product 3b,
accompanying with the regeneration of Cu(I) for the next cycle.
Conclusions
In summary, we rst reported the copper-catalyzed C–H acy-
loxylation of 2-phenylpyridine with carboxylic acids under
oxygen atmosphere. Various acids including aromatic acids,
cinnamic acids and aliphatic acids are well compatible. This
methodology has the advantages of simple operation, mild
reaction condition with a broad substrate scope.
Scheme 4 Intermolecular competition and KIE experiments.
Experimental
General information
All starting materials and reagents were commercially available
and used directly without further purication. Most of 2-phe-
nylpyridines were synthesized by the reactions between the cor-
responding
2-bromopyridine
or
2-iodopyridine
and
phenylboronic acids according to the literature procedures.14 All
known products gave satisfactory analytical data by NMR spectra,
which corresponding to the reported literature values. Unknown
compounds were conrmed by HRMS additionally. NMR spectra
were determined at room temperature on Bruker Avance-300 or
Bruker Avance-500 at 300 MHz or 500 MHz with tetramethylsi-
lane (TMS) as an internal standard. Chemical shis are given in
d relative to TMS, the coupling constants J are given in Hz. High-
resolution mass spectra (HRMS) were recorded on Agilent 6200
LC/MS TOF using APCI or ESI in positive mode.
Scheme 5 Plausible reaction mechanism.
(BHT, 1 equiv.) was added to the standard reaction, and ruling
out the possibility of a radical pathway (Scheme 4-2). Third, the
ortho-acyloxylation of the isotopically labeled substrates was
investigated (Scheme 4-3).
Typical experimental procedure for the synthesis of 3
To a 10 mL reaction tube was added 3-methyl-2-phenylpyridine
1a (0.2 mmol), acid (0.3 mmol), CuBr (2.9 mg, 10 mol%), and
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chlorobenzene (2 mL) under oxygen atmosphere. The mixture
was stirred at 130 ꢀC for 24 h. The reaction mixture was then
cooled to room temperature, diluted with ethyl acetate and
quenched with saturated sodium chloride. The aqueous phase
was extracted with ethyl acetate (3 ꢁ 10 mL). The organic layer
was dried over Na2SO4. Aer concentration, the resulting residue
was puried by ash chromatography on silica gel (eluent:
petroleum ether/ethyl acetate ¼ 12/1) to afford the product.
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There are no conicts to declare.
Acknowledgements
We gratefully acknowledge the National Natural Science Foun-
dation of China (21272006), which provided nancial support.
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