Metal-free oxidative esterification of acetophenones with alcohols: A facile one-pot approach to α-ketoesters

Article abstract of DOI:10.1039/c6ra19485k

A novel and efficient oxidative esterification method for the synthesis of α-ketoesters has been developed under mild and environmentally benign conditions, which is a facile one-pot approach to α-ketoesters from commercially available acetophenones with alcohols, especially under metal-free conditions, with broad substrate scope. A possible mechanism is proposed on the basis of a series of control experiments and DMSO¹⁸ isotopic labelling experiments.

Full text of DOI:10.1039/c6ra19485k

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Metal-free oxidative esterification of acetophenones with
alcohols: A facile one-pot approach to α-ketoesters
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
b
a
a
a
a
a
Shiyu Guo, Zhongxue Dai, Zhao Yang, Ning Zhu, Li Wan, Xin Li, Chengkou Liu, Zheng Fang, *
a,c,
Kai Guo
*
DOI: 10.1039/x0xx00000x
A novel and efficient oxidative esterification method for the synthesis of α-ketoesters has been developed under mild and
environment benign conditions, which is a facile one-pot approach to α-ketoesters from commercially available
acetophenones with alcohols, especially under metal-free conditions with broad substrate scope. Possible mechanism is
www.rsc.org/
1
8
proposed on the basis of a series of control experiments and DMSO isotopic labelling experiments.
Previous work
Ref. 11
O
O
O
O
O
Introduction
CuBr/TEMP
Toluene, O
R
R
Ar
Ar
R-OH
R-OH
Ar
Ar
2
O
O
The α-ketoesters as an important and prevalent structural
element of numerous biologically active molecules have
attracted considerable interests of chemists all over the
O
CuOTf/Pyr/TFA
Toluene, O
Ref. 12
1
2
world. In addition to this biological application, α-ketoesters
could also act as versatile synthetic precursors for further
2
transformations in organic synthesis.
This work
O
O
O
S
O
R
Owing to these useful characters of α-ketoesters, synthesis
of α-ketoesters is a significant work and more and more novel
synthetic methodologies have been developed. Traditionally,
the α-ketoesters could be generated from the esterification of
Ar
R-OH
Ar
O
I
2
2 3
Cs CO
Scheme 1 Facile one-pot approach to α-ketoesters from
acetophenes under metal-free conditions
3
α-ketoacyl halides and α-ketoacids, oxidation of α-hydroxy
4
ester, double carbopalladative esterification or some other
5
catalyzed aerobic oxidative esterification for the construction
of α-ketoesters from acetophenones has been reported
effectively in the last few years. For example, Jiao’s group
reported a TEMP and CuBr co-catalyzed oxygenation of
6
methods. Moreover, Jiao and co-workers reported two novel
methodologies to α-ketoesters: (1) Cu-catalyzed aerobic
oxidative dehydrogenative coupling of α-carbonyl aldehydes
1
1
7
with alcohols; (2) Cu-catalyzed aerobic oxidative C−C bond
acetophenones with O2 to construct α-ketoesters. Besides,
Song’s group reported a CuOTf catalyzed esterification of
8
cleavage of ketones. Sharada and co-workers developed an I -
2
1
2
acetophenones with alcohols to α-ketoesters. In the past
decades, reactions under metal-free conditions are very
popular and attract much attention in organic synthesis, such
promoted cross-dehydrogenative coupling of α-carbonyl
9
aldehydes with alcohols for the synthesis of α-ketoesters.
However, these methods mentioned above suffer from some
drawbacks, such as (1) the usage of expensive or impractical
starting materials; (2) harsh reaction conditions; (3) low atom
economy, which restrict the utility of these methods.
Relatively, acetophenones as commercially available and
cheaper starting materials were applied universally to further
1
3
as
I
2
/TBHP(tert-butyl peroxybenzoate) system,
NIS(N-
14
Iodosuccinimide)/TBHP system and I
2
/IBX (2-Iodoxybenzoic
1
5
acid) system, avoiding the usage of expensive, poisonous and
air-sensitive metals or organometallics. Iodine, a popular
available mild Lewis acid with less toxicity and low cost, is
often chosen as an alternative of toxic rare metals and
1
0
transformations. Transition-metal-catalyzed especially Cu-
1
6
transition-metal catalysts in organic synthesis. Previously, our
group has reported an I -promoted aerobic oxidative coupling
of acetophenes with amines to α-ketoamides under metal-free
2
1
7
conditions. Referring to relative literatures, there has no
reported work on the synthesis of α-ketoesters under metal-
free conditions from acetophenones so far. Herein, we wish to
develop a feasible, effective and mild method to α-ketoesters
from acetophenes, which is a novel methodology to α-
ketoesters from acetophenones with alcohols under metal-
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free conditions with broad substrate scope, employing DMSO solvent in the model reaction. Interestingly, a better yield of
as both important oxidant and solvent (Scheme 1).
product 3aa was obtained, demonstrating that it was actually
feasible (Table 1, entry 7). Subsequently, when the model
reaction was treated with a variety of bases, including
Results and discussion
2 3
inorganic and organic bases, Cs CO exhibited the most
positive effect with 68% yield of desired product isolated,
while organic bases performed a little bit worse (Table 1, entry
Initially, this investigation focused on the optimization of the
reaction conditions and a model reaction of acetophenone 1a
8
-12). To further improve the yield of product 3aa
temperature of the reaction was raised to higher gradients,
the best yield of 80% 3aa was obtained at 110 (Table 1,
entry 15). Next, different concentrations of iodine and Cs CO
,
(
0.5 mmol) and 2-phenylethanol 2a (1.5 mmol) was carried out
in the present of iodine as the promoter to screen a series of
parameters. As listed in Table 1, effects of different oxidants
on this reaction, such as tert-butyl hydroperoxide (TBHP), tert-
℃
2
3
were screened (Table1, entry 17-22), the optimized reaction
butyl perbenzoate (TBPB), H
PhI(OAc) and molecular oxygen were examined under the
model reaction in toluene at 50 , results showed that DMSO
2 2
O , dimethylsulfoxide (DMSO),
conditions were finally confirmed: 1a (0.5 mmol), 2a (1.5
2
2 3
mmol), 2.5 equivalents of iodine and 2.5 equivalents of Cs CO
℃
were dissolved in 3 mL DMSO and stirred at 110
℃
for 24h,
exhibited the highest reactivity to the reaction with 30% yield
of the desired product 3aa obtained (Table 1, entry 4). On this
base, DMSO was examined to serve as both oxidant and
affording 89% yield of product 3aa (Table 1, entry 21).
a
Table 1 Optimization studies of the model reaction conditions
b
Entry
Promoter(equiv.)
Base(equiv.)
Oxidant
TBHP
TBPB
H O
Solvent
Temp(℃)
50
Yield(%)
1
2
3
4
5
6
7
8
9
I
I
2
2
(2.0)
(2.0)
-
-
-
-
-
-
-
Toluene
13
15
Toluene
50
I2 (2.0)
I2 (2.0)
Toluene
50
<10
30
2
2
DMSO
Toluene
50
I
I
I
I
I
I
2
2
2
2
2
2
(2.0)
(2.0)
(2.0)
(2.0)
(2.0)
(2.0)
PhI(OAc)
2
Toluene
50
trace
<10
44
O
2
Toluene
50
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
50
K
2
CO
CO
N (2.0)
3
(2.0)
50
58
Cs
2
3
(2.0)
50
68
1
1
1
1
1
1
1
1
1
1
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
Et
3
50
Trace
49
I2 (2.0)
I2 (2.0)
DBU (2.0)
50
Pyridine (2.0)
50
52
I
I
I
I
I
I
2
2
2
2
2
2
(2.0)
(2.0)
(2.0)
(2.0)
(1.5)
(2.5)
Cs
Cs
Cs
Cs
Cs
Cs
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
(2.0)
(2.0)
(2.0)
(2.0)
(2.0)
(2.0)
70
70
90
74
110
130
110
110
110
110
110
110
80
75
Trace
84
I2 (2.7)
I2 (2.5)
Cs CO (2.0)
82
2
3
Cs CO (1.5)
57
2
2
2
3
3
3
I
I
2
(2.5)
(2.5)
Cs
Cs
CO
CO
(2.5)
(3.0)
89
2
33
a
Reaction conditions: 1a (0.5 mmol), 2a (1.5 mmol), promoter (2.0 equiv.), base (2.0 equiv.), oxidant (2.0 mmol) in 3 mL solvent, stirred
b
at 50 ℃ for 24 h in the sealed tube. Yields of the isolated product.
2
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a
Table 2 Substrate scope of acetophenes with alcohols
desired products were observed. In order to further expand
the universality under the optimized reaction conditions, the
substrate scope of alcohols was explored, including aromatic
and aliphatic alcohols. To our satisfaction, a range of 2-
phenylethanols and phenylmethanols bearing different
electronic variation substituents or substitution pattern were
all suitable to optimized reaction conditions and produced the
desired products in 69%-88% yields (Table 2, 3ab-3am).
Notably, 2-thiopheneethanol as heteroaromatic ethanol could
also be transformed to corresponding products 3ah in 66%
yield (Table 2, 3ah). Besides, a variety of aliphatic alcohols
were carried out under our optimized conditions. The results
suggest that both primary and second aliphatic alcohols, such
as cyclohexanol, n-butyl alcohol, ethanol and 3-methyl-3-
butenol were all feasible and tolerated under this oxidative
coupling reaction conditions with 60%-76% yields of
corresponding products obtained (Table 2, 3an-3aq).
According to the results of Table 2, this novel methodology to
α-ketoesters has a board substrate scope with good yields,
which implies its potential application in the last-stage
functionalization of natural alcohols or some ketones with
alcoholic hydroxyl group, such as cholesterol, androsterone,
1
8
testosterone and the like.
To gain deeper insight into the reaction mechanism and
investigate the special role of DMSO, a series of control
experiments were carried out between acetophenes 1a and 2-
phenylethanol 2a under optimized reaction conditions
(Scheme 2, Experiments 1-6). In the Experiment 1, no desired
product 3aa was obtained when iodine was removed from
optimized conditions. Meanwhile, the yield reduced greatly to
a
Reaction conditions: acetophenes 1 (0.5 mmol), alcohols 2
(1.5 mmol), I
DMSO (3 mL) were stirred at 110
2
(1.25 mmol) and Cs
2
CO
3
(1.25 mmol) solved in
℃
Yields given for isolated products after chromatography.
for 24h in the sealed tube.
With the optimized reaction conditions in hands, we next
probed the scope of synthesizing a series of α-ketoesters
3
applying optimized conditions and the results were
summarized in Table 2. Firstly, acetophenones bearing both
electron-deficient (-F, -Cl, -NO ) or electron-rich substituents (-
2
Me, -OMe) reacted well with 2-phenylethanol to produce
corresponding α-ketoesters in moderate to excellent yields
(Table 2, 3aa-3ia). In addition to this feature, the results
indicated that the position of these substituents on the
aromatic groups had no obvious differences on the yields of
corresponding products (Table 2, 3aa-3ia). Some other
aromatic rings and heterocyclic ring, such as 1-
acetonaphthone, 2-acetonaphthone and 2-acetylthiophene,
could also undergo the reaction with 2-phenylethanol to afford
desired α-ketoesters 3ja, 3ka and 3la in 92%, 82% and 65%
yields, respectively. Aliphatic methyl ketones, such as acetone,
cyclohexanone, and methylethylketone have been tested in
our optimized reaction conditions. However, none of the
Scheme 2 Control experiments under optimized conditions
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O
O
O
O
18O
I
2
Cs
2
CO
3
O
R
S
O
HO
HO
Ph
+
Ar
Ar
R
Ph
18O
O
S
O
I
2
Cs
CO
1
2
3
2
3
I
2
Base
1
a
2a
18O-3aa
Base
HI
HI
O
O
O
I
R
Ar
Ar
O
I
B
HI
DMSO
I
2
O
O
O
H
DMS
H
H
HO
O
I
R
R
Ar
Ar
Ar
O
O
OH
S
I
2
C
D
Scheme 4 Possible reaction mechanism
reaction conditions to further validate our conjecture (Scheme
1
). When this reaction were carried out in O-labeled DMSO
8
3
replacing the general one, the ESI-MS analysis of this
1
corresponding O-3aa product clearly assigned the presence
8
+
+
of the signal [M+Na] and [M+K] at 279.0906 and 295.0595 in
noticeable detection, proving that DMSO served as the
important oxidant in this transformation.
Based on the results above and the previous literatures
reported, a plausible mechanism is proposed as shown in
Scheme 4. To begin with, Compound
B is generated from the
iodination of arylmethylketone and then undergoes Kornblum
oxidation in the presence of DMSO, affording the key
intermediate arylglyoxal (Compound
C) with the release of
DMS. Next, alcoholic hydroxyl group attacks the aldehyde
group of α-carbonyl aldehyde that is activated by iodine to
generate the alcohol (Compound
D), which is finally oxidized
by the system of I2 and base to give desired product α-
ketoesters in good yields.
1
Scheme 3 O-labeled isotope experiment and ESI-MS analysis
8
5
1% in the absence of Cs
Experiment 3, the parallel reactions were performed under air, Conclusion
and argon environment, affording similar yields of products
2 3
CO (Scheme 2, Experiment 2). In the
O
2
In conclusion, we have developed a novel one-pot strategy for
the synthesis of functional and valuable α-ketoesters from
acetophenones with alcohols in moderate to excellent yields.
What’s more, this facile methodology takes advantage of
cheap and abundant starting materials under mildly metal-free
conditions and has wide functional group universality, implying
its potential value in industrialization and the last-stage
functionalization of natural alcohols. Plausible mechanism was
proposed based on a series of control experiments and
respectively, demonstrating that aerobic conditions are not
essential in this reaction process. Moreover, when the model
reaction was performed in other solvents instead of DMSO,
such as 1,4-Dioxane, Toluene, ACN and DMF, we failed to
isolated the products 3aa in an acceptable yield (Scheme 2,
Experiment 4). For the purpose of ruling out the possible effect
of water in the process, the same reaction was carried out in
relatively dry and inert conditions with anhydrous DMSO and
4Å MS added into the reaction conditions (experiment 5). In
18
DMSO isotopic labelling experiments. Further studies on the
this case also, comparable yields of desired product 3aa were
observed. Next, the reaction between phenylglyoxal
monohydrate 4a and 2-phenylethanol 2a were performed
under optimized conditions as shown in Experiment 6, the
results showed that it could also be transformed smoothly to
α-ketoesters 3aa in 88% yield under optimized reaction
conditions, indicating that phenylglyoxal monohydrate 4a
might act as the intermediate in this esterification process.
Meanwhile, the results above obviously imply the significant
applications of this strategy are ongoing in our group.
Acknowledgements
The research has been supported by the National Natural
Science Foundation of China (Grant No.21522604, U1463201
and 21402240); the youth in Jiangsu Province Natural Science
Fund (Grant No.BK20150031, BK20130913 and BY2014005-
03); a Project Funded by the Priority Academic Program
Development of Jiangsu Higher Education Institutions (PAPD).
1
8
role of DMSO in this reaction. Therefore, O-labeled isotope
experiment and ESI-MS analysis were conducted between
acetophenone 1a and 2-phenylethanol 2a under optimized
Notes and references
4
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A novel and efficient oxidative esterification method for the synthesis of α-ketoesters has
been developed under mild and environment benign conditions, which is a facile one-pot
approach to α-ketoesters from acetophenones with alcohols, especially under metal-free
conditions with broad substrate scope. Possible mechanism is proposed on the basis of a
1
8
series of control experiments and DMSO isotopic labelling experiments.