Cu-catalyzed aerobic oxygenation of 2-phenoxyacetophenones to alkyloxy acetophenones

Article abstract of DOI:10.1039/c5ra25734d

Cu-catalyzed aerobic oxygenation of 2-phenoxyacetophenones in the presence of alcohols was reported, and the corresponding alkyl benzoates, alkyloxy acetophenones and phenols were produced in high yields.

Full text of DOI:10.1039/c5ra25734d

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Cu-Catalyzed
Aerobic
Oxygenation
of
2-
Phenoxyacetophenones to Alkyloxy Acetophenones
Cite this: DOI: 10.1039/x0xx00000x
Xinwei Liu, Huanjun Xu, Zhishuang Ma, Hongye Zhang, Cailing Wu, and Zhimin Liu*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
Cu-catalyzed aerobic oxygenation of 2-phenoxyacetophenones in the compounds, which have been used as lignin model compounds
presence of alcohols was reported, and corresponding alkyl benzoates, to produce various aromatics.9 In this work, we used 2-
alkyloxy acetophenones and phenols were produced in high yields.
phenoxyacetophenones as feedstocks for the synthesis of
alkyloxy acetophenones via a novel approach, as illustrated in
Scheme 1. It was found that CuCl2 combined with pyridine as a
ligand and BF3·Et2O as an additive was effective for the aerobic
oxidation of 2-phenoxyacetophenones in the presence of
alcohols (e.g., methanol and ethanol) by refluxing the reaction
solution under open air conditions, producing alkyl benzoate
and alkyloxy acetophenones accompanied with phenols in high
yields.
Lignin that is the dominant aromatic biopolymer in nature can
be considered as natural aromatic resource, and the
production of aromatics from lignin-derived compounds has
been paid much attention in recent years.1,2 The cleavage of C-
O/C-C bond is the key to produce aromatics from lignin
platform compounds, which is usually achieved via hydrolysis,
thermal cracking, reduction and oxidation.3 Oxygen, hydrogen
peroxide or ozone as oxidants is one of the most efficient way.
Particularly, molecular oxygen is considered as an ideal oxidant
in view of green and sustainable chemistry, owing to its
abundant, natural and environmental friendly character.
Transition-metal catalysts including ruthenium complex4 and
vanadium complex5 have been applied in the production of
aromatics from lignin-derived compounds. For example, Loh
O
O
O
catalyst
ligand
O
R3
O
OH
O
R3
R3OH
R2
R1
R1
R1
R2
additive
reflux, 24 h
open air
O
R3
Scheme 1 Aerobic oxygenation of 2-phenoxyacetophenones.
2-Phenoxyacetophenone (1a) as a model substrate was
first examined to react with methanol under different
conditions, and the results are listed in Table 1. It was indicated
that 1a could not react with methanol in the
absence/presence of O2 without any catalyst and
ligand/additive. To our delight, as 1a (0.5 mmol) was treated in
methanol (2a, 1mL) catalyzed by CuCl2 (0.15 equiv.) with
pyridine (0.5 equiv.) as a ligand and BF3·Et2O (1 equiv.) as an
additive via refluxing the reaction solution under air
atmosphere, the reaction proceeded well, affording methyl
benzoate (3a), 2,2-dimethoxyacetophenone (4a) and phenol
and coworkers6 reported
a method for the chemical
conversion of β-O-4 linkage models through Cu-catalyzed
aerobic amide bond formation with secondary amines, and a
series of value-added aromatic nitrogen-containing
compounds were produced.
Alkyl benzoates and alkyloxy acetophenones are important
aromatics with many usages,7 generally produced from
petroleum-based
feedstocks.
Producing
alkyloxy
acetophenones suffer from complicated chemical processes
and high costs.8 The production from lignin platform
compounds can provide alternative route for the synthesis of
these chemicals. However, it has not been reported yet.
(5a) in 32.8%, 56.6% and 90.5% yields, respectively (Table 1,
entry 2). No reaction took place using argon instead of air
under the same other conditions (Table 1, entry 3), suggesting
that the oxidative cleavage of C-C/C-O bond occurred in the
reaction of 1a with methanol under air atmosphere. Other
copper salts including CuBr, CuCl, CuO, Cu2O, CuI, CuOAc,
CuCl2·2H2O instead of CuCl2 were examined for this reaction
(Table 1 and Table S1). It indicated that CuCl2 displayed the
2-Phenoxyacetophenones is
a kind of lignin platform
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DOI: 10.1039/C5RA25734D
best performance with high conversion of 1a and high yield of plot had a maximum at the BF3·Et2O amount of 0.5equiv. From
4a. In contrast, both CuCl and CuBr2 were less effective for Figure 1, it can be observed that the sum of the yields of 3a
catalysing the transformation, especially for the production of and 4a was almost identical to that of 5a, implying that 3a and
4a. We inferred that Cu(I) species was less oxidative than Cu(II) 4a might be produced from different reaction pathway, while
species, and under the experimental conditions Cu(I) might be 5a was produced at the both cases. With the less amount of
oxidized into Cu(II), which further catalysed the transformation. BF3·Et2O in the reaction system, more 3a was produced than
As for CuBr2, it might influence the role of BF3.Et2O in the 4a, while the situation became contrary as the amount of
reaction process, thus resulting in the declined activity of the BF3·Et2O gradually increased, suggesting that the presence of
catalytic system.10 Notably, for the conversion of 1a and for BF3·Et2O was more favourable to the formation of 4a. Thus, to
the production of 3a, 4a and 5a, the copper salts showed get more 4a, 1.0 equiv. BF3·Et2O was adopted in the following
unique ability in this transformation, and the yield of product reactions.
declined obviously without copper catalyst (Entry 6).
Table 1 Optimization of reaction conditions.a
O
O
O
catalyst
ligand
O
O
OH
O
MeOH
2a
O
additive
reflux, 24 h
open air
3a
1a
4a
5a
Yield (%)b
4a
Conv.
(%)
Entry
Cat.
Additive
Ligand
3a
5a
1
2
None
CuCl2
CuCl2
CuCl
None
None
Py
No reaction
BF3·Et2O
BF3·Et2O
BF3·Et2O
BF3·Et2O
BF3·Et2O
BF3·Et2O
BF3·Et2O
BF3·Et2O
None
32.8
56.6
90.5
99.9
Fig. 1 Dependence of the product GC yields on the amount of BF3·Et2O.
Conditions: 1a (0.5 mmol), methanol (1 mL), catalyst (0.15 equiv.),
ligand (0.5 equiv.), 24h.
3c
4
Py
No reaction
Py
21.4
27.1
13.2
13.0
52.9
59.5
trace
27.4
99.9
85.9
12.6
47.2
Fig. 2 shows the dependence of the product yields on the
reaction time, which indicates that all three products were
detected in the reaction process, and their yields had the
similar tendency with the reaction time. Especially, the sum of
the yields of 3a and 4a was close to that of 5a, and the yield
ratio of 4a to 3a was almost kept unchanged with the time. It
implies that 3a and 4a may be originated from different
reaction pathways.
5
CuBr2
None
CuCl2
CuCl2
CuCl2
CuCl2
Py
6
Py
trace trace
7
None
Pip
Pic
Py
18.1
16.1
8
No reaction
9
25.0
17.7
9.8
trace
46.3
46.8
76.7
54.0
10
aConditions: 2-phenoxyacetophenone (1a) (0.5 mmol), methanol (2a) (1 mL),
catalyst (0.15 equiv.), ligand (0.5 equiv.), BF3·Et2O (1.0 equiv.), 24h. bIsolated
yields. cThe reaction was performed under an argon atmosphere (1 atm). Py-
pyridine; Pic-4-picoline; Pip-Piperidine.
Ligand played a very important role in this copper-
catalyzed transformation. In the absence of ligand, the yields
of products plummeted (Entry 7). Of the tested ligand, pyridine
showed the best performance for this reaction. In this work,
the use of additive could make the reaction proceed in open
air system. BF3·Et2O as an additive had a great influence on the
conversion of 1a and the formation of 4a, as shown in Figure 1.
In the absence of BF3·Et2O, 4a was not detected in the reaction
solution, meanwhile both the 1a conversion and 3a yield were
low (Table 1, entry 10). Interestingly, the presence of BF3-Et2O
resulted in the formation of 4a and further promoted the
conversion of 1a and formation of 3a and 5a. Meanwhile, the
yields of 4a and 5a increased with the amount of BF3·Et2O in
the range of 0-1.0 equiv., and almost kept unchanged as the
amount of BF3·Et2O increased further. However, the 3a yield
Fig. 2 Dependence of the product GC yields on reaction time.
Conditions: 1a (0.5 mmol), methanol (1 mL), catalyst (0.15 equiv.),
ligand (0.5 equiv.), BF3·Et2O (1.0 equiv.).
Based on the above results, we selected the optimal
reaction conditions as listed in Table 1. Having optimized
reaction conditions in hand, we explored the substrate scope,
and the results are listed in Table 2. It was indicated that all
the tested substrates could react with methanol under the
experimental conditions, producing corresponding methyl
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C5RA25734D
benzoates, 2,2-dimethoxyacetophenones and phenols. The amount of TEMPO added (see SI, Scheme S1). This suggests
phenols were obtained in good to excellent yields, and the that the reaction was a radical mechanism. Moreover, this
yields of 2,2-dimethoxyacetophenones were much higher than reaction was electron paramagmetic resonance (EPR) active
those of the corresponding methyl benzoates in each case, (see Fig. S4). The reaction solution of 1a with methanol under
which was consistent with that observed for 2,2- the experimental conditions performed for 12h was examined
dimethoxyacetophenone as the substrate. This suggests that by GC-MS, and phenylglyoxal
I was detected (see SI).
the catalytic system could be extended to the tested Furthermore, phenylglyoxal was treated in methanol under
substrates with high performances.
the same experimental conditions, and 4a was produced,
suggesting that
formyloxybenzene
I
was an intermediate. In addition,
was treated as well under the
Table 2 Substrate scope of β-O-4a
D
experimental conditions, and phenol was obtained
accompanied with CO2, suggesting that formyloxybenzene
Entry
1
Substrate
Product &Yield (%)b
D
O
O
O
O
was also an intermediate though it was not detected in the
reaction process.
O
O
O
O
O
OH
22.5%
53.4%
90.1%
The oxidation states of the Cu species in the recovered
catalyst of Table 1 Entry 2 were examined by XPS, and the
Cu2p XPS spectrum is shown in Fig.S5. The band at the binding
O
O
O
O
O
O
O
O
2
3
4
5
6
O
31.9%
OH
OH
27.2%
Ⅰ
76.8%
energy of 932.3 eV was assigned to Cu , and the bands at the
O
O
O
O
binding energy of 935.0 eV, 937.2 eV, 941.9 eV, 944.6 eV, were
Ⅱ Ⅰ
assigned to Cu . These results indicated that Cu species were
F
O
O
O
O
F
14.7%
56.4%
78.6%
produced in the reaction process.
O
O
O
O
O
Br
O
46.7%
OH
Br
16.5%
80.2%
pathway a
OH
OH
O
O
O
O
O2
+ Py
OH
O
PyH
+
Cu
O
O
O
O
O
O
O
O
Cu
O
O
A
O
O
O
38.9%
O
OH
O
15.1%
O
61.8%
69.1%
OH
PyH
Py
Cu
+
Cu
+
B
C
O
O
O
O
O
O
O
O
O
CH3OH
OH
O
O
OH
O
13.4%
35.7%
+
+
CO2
O
O
O
aReaction condition: substrate (0.5 mmol), methanol (1 mL), CuCl2 (0.15
equiv.), pyridine (0.5 equiv.), BF3·Et2O (1.0 equiv.), reflux, 24h. bIsolated
yield.
O
D
1a
O
O
I
BF3·Et2O
Py
O
H
CH3OH
O
O
O
PyH
F
In addition, ethanol instead of methanol was used to
react with 2-phenoxyacetophenoneas illustrated in Scheme 2.
Excitingly, ethyl benzoate, 2,2-diethoxyacetophenone and
phenol were obtained under the experimental conditions. High
yield of 2,2-diethoxyacetophenone was achieved, suggesting
that this reaction can provide a new route to produce this
compound.
OH
F
O2
ꢀ
B
E
O
O
O
PyH
Cu
Cu
O
O
O
O
OH
Py
Cun
G
H
pathway b
Scheme 3 Possible reaction pathways.
On the basis of the experimental results and the previous
O
O
O
CuCl2 (0.15 eq)
Py (0.5 eq)
BF3·Et2O (1.0 eq)
reflux, 24 h
open air
O
reports, two possible pathways were proposed to produce 3a
O
OH
O
CH3CH2OH
2b
O
and 4a, respectively, as illustrated in Scheme 3. These two
1b
3b
4b
51.9%
5b
89.3%
pathways take place simultaneously. In pathway a, hemiketal A
is first formed by nucleophilic addition of ketone with
methanol in a reversible way before the aerobic oxidation
process,11 which is transformed to superoxide intermediate B
under the experimental conditions.12,13 Then, the single
electron transfer (SET) reduction and subsequent protonation
17.7%
Scheme 2 Aerobic oxygenation of 2-phenoxyacetophenones in
ethanol. Conditions: 1b (0.5 mmol), 2b (1 mL), CuCl2 (0.15 equiv.),
pyridine (0.5 equiv.), BF3·Et2O (1.0 equiv.), isolated yield.
Ⅰ
of B by Cu and [PyH]+ occurs to generate hydroperoxide C,14
To explore the reaction mechanism, several control
experiments were performed. 2,2,6,6-
which further rearranges, affording 3a along with the
intermediate formyloxybenzene D.15 D further transforms to
5a and CO2 under the experimental conditions. The carbonyl
group remains intact without the O atom incorporation in this
pathway. In pathway b, 1a first tautomerizes to its enolate,
Tetramethylpiperidinooxy (TEMPO) as a radical trapper was
added in the reaction solution of 2-phenoxyacetophenone
with methanol catalyzed by CuCl2 with pyridine and BF3⋅Et2O,
and the yield was suppressed to some extent based on the
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VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C5RA25734D
forming
peroxy radical and trapped by Cun species to produce copper
peroxide G 17
Fenton-like fragmentation of occurs to form
hemiacetal H 18
which eliminates phenol to provide
phenylglyoxal . Followed by further reaction with methanol,
4a is produced.
E E is oxidized to
by the addtion of BF3·Et2O.16 Then
.
G
,
I
In summary, we developed a new approach to produce
alkyl benzoates and alkyloxy acetophenones via aerobic
oxidative
cleavage
of
C-C/C-O
bond
in
2-
phenoxyacetophenones catalysed by CuCl2 with the assistance
of pyridine and BF3·Et2O in the presence of alcohols under
open air conditions. This work opens a novel and simple way
to produce aromatics, which may have promising applications
in the production of aromatics from lignin-derived compounds.
This work was financially supported by the National Natural
Science Foundation of China (Grants Nos. 21125314,
21321063, 21402208) and the Chinese Academy of Sciences.
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4 | J. Name., 2012, 00, 1-3
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Graphic Abstract
Cu-catalyzed aerobic oxygenation of 2-phenoxyacetophenones in alcohols was
achieved, producing alkyl benzoates, alkyloxy acetophenones and phenols in high
yields.