A simple and efficient approach to realize difunctionalization of arylketones with malonate esters via electrochemical oxidation

Article abstract of DOI:10.1039/c4cc01277a

A facile difunctionalization of arylketones with malonate esters via electrochemical oxidation was achieved under mild conditions. A variety of difunctionalized products were obtained in good to excellent yields.

Full text of DOI:10.1039/c4cc01277a

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A simple and efficient approach to realize
difunctionalization of arylketones with malonate
esters via electrochemical oxidation†
Cite this: Chem. Commun., 2014,
50, 5034
Received 18th February 2014,
Accepted 23rd March 2014
Huihui Gao, Zhenggen Zha,* Zhenlei Zhang, Huanyue Ma and Zhiyong Wang*
DOI: 10.1039/c4cc01277a
www.rsc.org/chemcomm
Table 1 Optimization of the reaction conditionsa
A facile difunctionalization of arylketones with malonate esters via
electrochemical oxidation was achieved under mild conditions.
A variety of difunctionalized products were obtained in good to
excellent yields.
sp3 C–H functionalization of arylketones has attracted considerable
attention because of their wide applications, especially in organic
synthesis.1 Consequently, considerable efforts have been devoted to
develop this kind of reaction under mild reaction conditions, includ-
ing a-oximation of arylketones,2 synthesis of a-diazo ketones,3 a-azido
ketones,4 aryl a-keto esters,5 a-ketoamides6 and a,b-unsaturated
carbonyl compounds,7 direct a-hydroxylation,8 a-acidification9
and a-halogenation10 of arylketones. Compared with these direct
functionalization reactions, arylketone difunctionalization reac-
tions are less developed, which can provide an efficient method to
access multisubstituted arylketones. Bis(b-dimethoxycarbonyl)
derivatives have the potential to serve as bone affinity agents in
the treatment of bone disease.11 More importantly, these deriva-
tives are usually employed as the precursors for the synthesis of
glutaric acid,12 which is very useful in industrial chemistry.
Electrochemical synthesis makes use of electrons directly with-
out assistance from transition-metal-catalysts or toxic oxidants;
therefore it is much more environmentally friendly and sustainable
in comparison with the conventional redox process.13 Our group
has recently developed a series of useful electrochemical reactions
for different transformations.14–19 Encouraged by these successful
transformations, we developed an arylketone difunctionalization
reaction via electrochemical oxidation. This strategy provides a
facile access to the preparation of multisubstituted arylketones.
The initial optimization was performed using a model reaction of
acetophenone 1a with dimethyl malonate 2a. The reaction was con-
ducted in an undivided cell when KI was employed as the electrolyte
and MeOH as the solvent with a constant current of 20 mA.
Entry
Base
Electrolyte
Solvent
Yieldb (%)
1c
2
3
4
5
6
7
8
9
10
11
12
13
14
15
—
KI
KI
KI
KI
KI
KI
KI
KI
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
DMSO
CH2CI2
CH3CN
40
75
42
57
76
51
7
82
63
0
0
72
0
0
0
Na2CO3
K2CO3
Ca(OH)2
LiOHÁH2O
K3PO4Á3H2O
Et3N
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
NaI
LiCIO4
Bu4NBr
Bu4NI
Bu4NI
Bu4NI
Bu4Nl
a
Reaction conditions: acetophenone (0.5 mmol), dimethyl malonate
(2 mmol), base (1 mmol), electrolyte (1 mmol), solvent (8 mL), two
platinum electrodes, was electrolyzed at a constant current of 20 mA
b
c
for 3 h in an undivided cell. Isolated yields. The reaction was
electrolyzed for 7 h.
To our delight, the difunctionalized product 3aa was obtained in 40%
yield (Table 1, entry 1). However, the electrolytic process was too slow
and it took more than 7 hours to get this poor yield. To promote the
reaction, base was added to the reaction. When Na2CO3 was chosen
as the base, the yield of 3aa increased to 75% (Table 1, entry 2) and
the reaction time was shortened to 3 h. Then other kinds of bases
were examined. The results showed that KOH was the best choice
for the electrochemical reaction (Table 1, entries 2–8). Afterwards,
different kinds of electrolytes were examined. It was found that the
iodide ion was necessary for this transformation. In the absence of
iodide ions, the reaction did not occur (Table 1, entries 8–12). After
optimization of various iodide salts, KI proved to be the most efficient
for this reaction (Table 1, entries 8 and 9 vs. 12). Finally, different
Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory
of Soft Matter Chemistry & Collaborative Innovation Center of Suzhou Nano
Science and Technology, University of Science and Technology of China, Hefei,
230026, P. R. China. E-mail: zwang3@ustc.edu.cn; Fax: +86-551-3603185
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4cc01277a solvents were also optimized (Table 1, entries 12–15). It was found
5034 | Chem. Commun., 2014, 50, 5034--5036
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that MeOH was the best choice, while other solvents could not
promote the reaction at all. Therefore, the optimal conditions were
described as follows: KOH as the base, KI as the electrolyte, MeOH as
the solvent and the reaction being electrolyzed at a constant current
of 20 mA for 3 h with two platinum electrodes in an undivided cell at
room temperature.
With the optimal conditions in hand, the scope of arylketone
was investigated first. The results were summarized in Table 2.
Both electron-rich and electron-deficient aryl methyl ketones
could be smoothly transformed into the desired products with
high yields (Table 2, 3aa–3am). In general, the electron-rich
methyl ketones were more reactive than electron-deficient ones.
It was found that p-CF3 substitution on the aromatic ring of the
arylketone led to a poor yield (Table 2, 3ah). Besides, a notable
steric effect was observed: ortho substitution resulted in a lower
yield compared with para and meta substitutions (Table 2, 3ab,
Scheme 1 The process of transesterification.
solvent MeOH, 3aa was generated in 73% yield. These experi-
ment results clearly revealed that transesterification occurred
easily in the reaction (Scheme 1).
In order to gain insight into the mechanism, several control
3an and 3aq; 3ad and 3ao; 3af and 3ap). Furthermore, when experiments were carried out (Scheme 2). First, the reaction of
multisubstituted ketones were employed as the substrates, the 2-iodo-1-phenylethanone with 2a under standard conditions
corresponding products could still be obtained with good yields
(Table 2, 3as–3at). Interestingly, when the reaction substrate was
dimethyl malonate (2a) with the solvent EtOH, the product 3ba
was obtained with the yield of 58%. In contrast, when the
substrate was switched to diethyl malonate (2b) with the
without electrolysis did not produce the desired product
(Scheme 2a) and the reactants were completely recovered. However,
when the reaction mixture was electrolyzed, the desired product
was obtained in 73% yield (Scheme 2b). This indicated that the
electrolysis is necessary for this reaction. When 2-hydroxy-1-
phenylethanone reacted with 2a under standard conditions, on
the other hand, we could not get the desired product (Scheme 2c).
Subsequently, 2-oxo-2-phenylacetaldehyde was mixed with 2a
Table 2 Substrate scope of acetophenonesa,b
a
Reaction conditions: 1a (0.5 mmol). 2a (2 mmol). KI (1 mmol). KOH
(1 mmol). MeOH (8 mL). two platinum electrolytes, at a constant
current of 20 mA for 3 h in an undivided cell. Isolated yields.
b
Scheme 2 Control experiments for the reaction.
Chem. Commun., 2014, 50, 5034--5036 | 5035
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We are grateful for financial support from the Natural Science
Foundation of China (2127222, 91213303, 21172205, J1030412).
Notes and references
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In summary, we have developed a new method to realize sp3
C–H difunctionalization of arylketones under mild conditions.
A series of multisubstituted arylketones were synthesized effici-
ently by virtue of environmentally friendly electrochemistry.
Further studies on C–H functionalization via the electrochemical
method are underway in our lab.
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5036 | Chem. Commun., 2014, 50, 5034--5036
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