Electrochemical synthesis of the aryl α-ketoesters from acetophenones mediated by Ki

Article abstract of DOI:10.1002/chem.201302307

Two C-O bonds formed in one step: The oxidative coupling reaction of acetophenones with alcohol was developed by a dioxygen activation to afford α-ketoesters under electrochemical conditions. This novel transformation not only provides a simple and efficient approach to synthetize α-ketoester derivatives, but also invents a new strategy to construct a C-O bond by virtue of an anode oxidation (see scheme). Copyright

Full text of DOI:10.1002/chem.201302307

COMMUNICATION
DOI: 10.1002/chem.201302307
Electrochemical Synthesis of the Aryl a-Ketoesters from Acetophenones
Mediated by KI
Zhenlei Zhang,[a] Jihu Su,[b] Zhenggen Zha,*[a] and Zhiyong Wang*[a]
a-Ketoesters play an essential role in biological processes.
They serve as the backbones in some natural products,[1]
such as the 3-deoxy-2-ulosonic acids and their derivatives.[2]
In addition, a-ketoesters are also used as key intermediates
for the synthesis of highly valued substrates.[3]
currence of the haloform reaction without any chemical
waste.
Initially the reaction was carried out in an undivided cell,
while MeOH was employed as the solvent, acetophenone as
the model substrate, and amine as the additive under an
oxygen atmosphere. It was found that the acetophenone can
be oxidized into 2-oxo-2-phenylacetaldehyde (see Table S1
in the Supporting Information). Then we screened various
amines and tert-butylamine was found to be the most effec-
tive additive to afford the desired product with a yield of
64% (see Table S1 in the Supporting Information). To our
knowledge, the 2-oxo-2-phenylacetaldehyde could be an in-
termediate and further transformed into a hemiacetal in the
presence of alcohol. Then this hemiacetal can be converted
into the a-ketoester under electrochemical oxidation. To en-
hance the anode oxidation, we increased the electric current
from 20 to 40 mA. As expected, the a-ketoester was ob-
tained in 30% yield (Table 1, entry 1), which encouraged us
to further optimize the reaction conditions.
Over the past several decades, chemists have paid great
attention to the synthesis of a-ketoesters. Classical methods
include oxidation of a-hydroxy esters with various kinds of
oxidant,[4] oxidation of methyl 2-phenylacetate,[5] Friedel–
Crafts acylation,[6] hydrolysis and esterification of acyl cya-
nides,[7] hydrolysis of 2-aryl-2-nitroacetates,[8] and other
methods.[9] However, these protocols usually require stoi-
chiometric amounts of metal oxidants, and thus a large
amount of waste is formed in the reaction. It has been
known that electrochemistry is a green method for fine
chemical synthesis.[10] Recently the synthesis of esters from
aldehydes and the corresponding alcohols was realized by
virtue of an anode oxidation in the presence of N-heterocy-
clic
carbine
(NHC)/1,8-diazabicycloACTHUGNETRNNU[G 5.4.0]undec-7-ene
(DBU).[11] In our laboratory, we have been attempting to
prepare a-ketoesters from aryl ketones and the correspond-
ing alcohols by an anode oxidation. We conceive that this
oxidation of methyl ketones in the presence of potassium
iodide could avoid the waste pollution under electrochemi-
cal conditions.
Previously, the reaction of methyl ketones with iodine was
a typical haloform reaction, affording carboxylic acids or
esters with a loss of one carbon atom.[12] It is a challenge to
functionalize the methelene of methyl ketones without
losing the methyl carbon atom. Herein, we describe a novel
method to synthesize a-ketoesters via an anode oxidation
from acetophenones under mild conditions inhibiting the oc-
Under the electric current of 40 mA, the reaction base
amine was examined again. After examination of various
amines, 2,2,6,6-tetramethylpiperidine (TMP) was the best
choice for this reaction (see Table S2 in the Supporting In-
formation). From the result of Table S2, it was found that
only the amines with a large steric hindrance could catalyze
the reaction well. Perhaps the amines without steric hin-
drance could be converted into a-ketoamides.[13] Subse-
quently, we attempted to improve the hemiacetal yield by
the addition of some additive. At first, we assumed that this
additive could catalyze the formation of hemiacetal. This
meant that the additive should be an acidic compound. At
the same time, this additive could not protonize the amine
in the reaction mixture. Therefore ammonium acetate, nitro-
alkanes, and phenols were examined in the reaction. To our
delight, when two equivalents of nitromethane were added
to the reaction, a significant increase in yield was observed
(Table 1, entry 3). When more than two equivalents of nitro-
methane was added, the yield decreased a little. Inspired by
this result, other nitro compounds were examined and it was
found that the p-nitrophenol was the best additive for this
transformation, giving the a-ketoester with a high yield of
81% (entry 10). The dosage of p-nitrophenol in this reaction
was also very important. When the amount of p-nitrophenol
was increased from 0.5 to 1.0 equivalents, the reaction yield
was decreased to 78% although the reaction time was pro-
longed to 3 h (entry 11). When the p-nitrophenol was de-
[a] Z. Zhang,+ Z. Zha, Prof. Dr. Z. Wang
Hefei National Laboratory for Physical Sciences at Microscale
CAS Key Laboratory of Soft Matter Chemistry and
Department of Chemistry, Univ Sci & Technol China
Hefei, Anhui, 230026 (P.R. China)
Fax : (+86)551-3603185
E-mail: zgzha@ustc.edu.cn
zwang3@ustc.edu.cn
[b] Prof. Dr. J. Su+
Hefei National Laboratory for Physical Sciences at Microscale
and Department of Modern Physics, Univ Sci & Technol China
Hefei, Anhui, 230026 (P.R. China)
[+] These two authors have the equal contribution to this manuscript.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302307.
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Table 1. Optimization of the reaction conditions.[a]
Table 2. Synthesis of a-ketoesters.[a,b]
Entry
Additive
Equiv
Yield [%][b]
1
2
3
4
5
6
7
8
none
NH4OAc
CH3NO2
CH3CH2NO2
CH3CH2CH2NO2
CH3CH
PhNO2
4-Me-PhNO2
3,5-dinitrophenol
4-nitrophenol
4-nitrophenol
4-nitrophenol
4-tert-butylphenol
4-nitrophenol
4-nitrophenol
30
35
50
55
58
61
57
62
trace
81
78
42
45
76
80
ACHTUNGTRENNUNG(NO2)CH3
1
1
1
0.5
1
0.25
1
0.5
9
10
11[c]
12
13
14[d]
15[e]
[a] Reaction conditions: 1a (0.5 mmol), TMP (1 mmol), Kl (1 mmol), ad-
ditive (1 mmol), MeOH (10 mL), O2 (balloon), platinum sheet as the
anode and cathode, at a constant of 40 mA for 1.5 h. [b] Isolated yield.
[c] The reaction time prolonged to 3 h. [d] Electrolyte was Kl (0.1 mmol),
LiClO4 (1 mmol). [e] 1a (3 mmol), 4-nitrophenol (0.25 mmol), 1a was
added in 0.5 mmol per 1.5 h, the reaction was completed in 10 h.
creased to 0.25 equivalents, on the other hand, the yield of
a-ketoester was dropped remarkably (entry 12). The oxygen
was also very important to the reaction, only a trace of the
product was obtained when the reaction was carried out
under air or N2 atmosphere. When KI was decreased to
0.2 equivalents, the product was obtained in 76% yield
(entry 14). Upon increasing the amount of acetophenone to
3 mmol, the product was obtained with an enhanced yield of
80% (entry 15). After the optimization, the reaction condi-
tions were established, as shown in entry 10.
[a] Reaction conditions: 1 (0.5 mmol), TMP (1 mmol), Kl (1 mmol), 4-ni-
trophenol (0.25 mmol), MeOH (10 mL), O2 (balloon), platinum sheet as
the anode and cathode, at a constant of 40 mA for 1.5 h. [b] Isolated
yield. [c] Reaction time: 3 h.
tion of the products. When the reaction solvent was
switched to ethanol, the corresponding products were also
obtained with good yields (2q–t). Other alcohols, such as
propyl alcohol or butanol, could not be used in this reaction
to give the desired a-ketoesters, perhaps due to the low con-
ductivity and poor nucleophilicity of these alcohols.
With the optimal conditions in hand, we applied this elec-
À
trochemical oxidation to construct the C O bond between
acetophenones and alcohols, affording the desired a-ketoest-
ers. When methanol was employed as the solvent, the de-
sired products were obtained with moderate to high yields
(Table 2, 2a–o). As for the reaction substrates, a range of
substituents on the aryl ring of acetophenones were compat-
ible under the reaction conditions regardless of the variation
of electronic and steric effects. For instance, methyl, isobu-
tyl, methoxyl, and phenyl acetophenone could be employed
as the reaction substrates to afford the a-ketoesters with
comparable yields (2e–l). As for the electron-withdrawing
groups, the reactions could be also carried out smoothly to
give the products with moderate to high yields (2m–n). The
position of the substituent on the acetophenone had little in-
fluence on the reaction, as illustrated by the three isomers
of methyl-substituted acetophenone (2i–k). It was noted
To probe the mechanism of the reaction, a series of con-
trol experiments were performed. When 2-oxo-2-phenyl-
acetaldehyde was used as the substrate, the desired product
was obtained in 67% (Scheme 1A). When the reaction sub-
strate acetophenone was replaced with 2-iodo-1-phenyletha-
none, the desired product a-ketoester could be obtained in
56% yield (Scheme 1B). On the other hand, 2-hydroxy-1-
phenylethanone, which was a probable precursor of 2-oxo-2-
phenylacetaldehyde, was employed as the reaction substrate
but none of the desired product was obtained (Scheme 1C).
This implied that 2-oxo-2-phenylacetaldehyde did not come
from 2-hydroxy-1-phenylethan-one. 2-Methoxy-1-phenyl-
AHCTUNGTREGeNNNU thanone was also a hypothetical intermediate and we as-
sumed it could be oxidized further to afford a-ketoester.
However, the experimental result showed that 2-methoxy-1-
phenylethanone could not be oxidized to the product a-ke-
toester (Scheme 1D). These control experiments suggested
À
À
À
that C Cl, C Br, and C F bonds could survive the reaction
(2b–d, 2n), providing a versatile means for further elabora-
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Chem. Eur. J. 2013, 19, 17711 – 17714

Electrochemical Synthesis of the Aryl a-Ketoesters from Acetophenones
COMMUNICATION
signed to the oxidized DMPO with an A14N =17.1 G for the
nitrogen.[14] The DMPO was possibly oxidized by iodine rad-
ical or superoxide radical although the precise mechanism
was not clear. In the absence of acetophenone, we did not
observe the signal a (see Figure S1 in the Supporting Infor-
mation). As a result, the generation of hydroxyl radical
should involve the participation of acetophenone.
Based on the experimental results above, we proposed
a tentative reaction pathway as shown in Scheme 2. Firstly,
iodine anion is oxygenated into iodine free radical in the
anode, and then iodine free radical reacts with acetophe-
none (1a) to generate acetophenone radical 3. Another pos-
sible pathway is that the acetophenone is firstly transformed
Scheme 1. Control experiments for the reaction. ND=not detected.
that 2-iodo-1-phenylethanone was directly converted into 2-
oxo-2-phenylacetaldehyde instead of 2-methoxy-1-phenyl-
ACHTUNGTRENNUNGethanone under the electrochemical oxidation and then this
2-oxo-2-phenylacetaldehyde was further oxidized to the a-
ketoester. When two equivalents of 2,2,6,6-tetramethylpiper-
idinooxy (TEMPO) were added to the reaction
(Scheme 1E), it was completely suppressed. This implied
that the reaction involved a radical process. To verify this
radical mechanism, electron paramagnetic resonance (EPR)
spins trapping was applied to detect the possible radical in-
termediate. As shown in Figure 1, EPR spectra were moni-
tored by the addition of the radical trap 5,5-dimethyl-1-pro-
line-N-oxide (DMPO) and a complicated signal was ac-
quired. In the EPR spectra, a signal a corresponding to
DMPO-OH was identified, as shown in Figure 1. The hyper-
Scheme 2. Proposed reaction mechanism.
into 2-iodo-1-phenylethanone, which gains one electron and
then forms the radical 3. The radical 3 catches oxygen to
form 4.[15] Compound 4 is unstable and is transferred further
into 2-oxo-2-phenylacetaldehyde 5, accompanying the for-
mation of a hydroxyl radical 7 as a leaving group.[16] Radical
7 can be trapped by DMPO by a known Fentonꢁs reaction.
Radical 7 is a very active compound, which can be reduced
to a hydroxyl anion in the cathode. At the same time, meth-
anol is reduced in the cathode to give methoxide anion,
which attacks 5 to afford 6. Compound 6 can be oxidized to
the desired a-ketoester 2a in the anode.
fine constants for the nitrogen and proton in a were A14N
=
14.6 and A1H =14.6, respectively. Another signal b was as-
In conclusion, we have developed an anode oxidative re-
action of acetophenones with alcohol by a dioxygen activa-
tion under mild conditions, affording a-ketoesters with good
yields. This novel transformation not only provides a simple
and efficient approach to synthetize a-ketoester derivatives,
À
but also develops a new method to construct a C O bond
by an anode oxidation. The EPR experiment supports the
proposed mechanism strongly. Further investigations toward
the applications are ongoing in our laboratory.
Figure 1. EPR spectra (X band, 9.07 GHz, room temperature) for reac-
tion mixtures in the presence of the radical trap DMPO (2.5ꢂ10À2 m) and
the pure DMPO. In the spectra, a is assigned to the DMPO-OH radical
while b is assigned to oxidized DMPOX ( a: pure DMPO; c: ex-
periment).
Experimental Section
Representative procedures for the synthesis of a-ketoesters: An undivid-
ed cell was equipped with a magnet stirrer, platinum electrode as the
Chem. Eur. J. 2013, 19, 17711 – 17714
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17713

Z. Zha, Z. Wang et al.
working electrode, and counter-electrode. In the electrolytic cell a solu-
tion of acetophenone (0.5 mmol), TMP (1 mmol), KI (1 mmol), p-nitro-
phenol (0.25 mmol), O2 (balloon), and MeOH (10 mL) was allowed to
stir and electrolyze at a constant current of 40 mA for 1.5 h until the
quantity of the electricity 4.5 F/mol was passed at room temperature.
Upon completion of the reaction, the solvent was removed with the aid
of a rotary evaporator. The residue was purified by column chromatogra-
phy on silica gel, and the product was dried under high vacuum for at
least 0.5 h before it was weighed and characterized by NMR spectrosco-
py.
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China (21272222, 21172205, 20972144, 20932002, 91213303, 31070211, and
J1030412) and Ministry of Science and Technology of China
(2010CB912103).
Keywords: bond-forming reactions
·
electrochemistry
oxidation · esterification · iodine radical · oxygen
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Received: June 17, 2013
Published online: October 2, 2013
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Chem. Eur. J. 2013, 19, 17711 – 17714