A novel approach for the one-pot preparation of α-ketoamides by anodic oxidation

Article abstract of DOI:10.1039/c3cc43685c

The direct oxidative synthesis of α-ketoamides via anodic oxidation was developed by using dioxygen as a reactant under mild conditions. This methodology has a broad substrate scope (aromatic amines, aliphatic amines and ammonium acetate) and opens up an interesting and attractive avenue for the synthesis of α-ketoamide derivatives.

Full text of DOI:10.1039/c3cc43685c

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A novel approach for the one-pot preparation
of a-ketoamides by anodic oxidation†
Cite this: Chem. Commun., 2013,
49, 8982
a
b
Zhenlei Zhang,z Jihu Su,z Zhenggen Zha*a and Zhiyong Wang*a
Received 16th May 2013,
Accepted 26th July 2013
DOI: 10.1039/c3cc43685c
www.rsc.org/chemcomm
The direct oxidative synthesis of a-ketoamides via anodic oxidation the corresponding products with moderate to high yields while LiClO4
was developed by using dioxygen as a reactant under mild conditions. and n-Bu4NBr did not work for the reaction. Among various solvents
This methodology has a broad substrate scope (aromatic amines, examined, EtOH turned out to be the best choice, while others such as
aliphatic amines and ammonium acetate) and opens up an interesting THF, DMSO, CH2Cl2 and CH3OH were less effective (Table S1, ESI,†
and attractive avenue for the synthesis of a-ketoamide derivatives.
entries 7–10). When the reaction was performed under N2, no desired
product was observed (Table S1, ESI,† entry 11). Under the air atmo-
The a-ketoamides are important synthetic intermediates, and they sphere, the product could be obtained with a very low yield (o5%). On
exist as structural motifs in a variety of natural products.1 Traditionally the other hand, water had a significant influence on this reaction
a-ketoamides have been synthesized mainly by the following (Table S1, ESI,† entry 6). When 2 equivalents of H2O were added to the
strategies: (1) the amidation of a-ketoacids and a-keto acyl halides;2 reaction mixture, the yield dropped from 80% to minute quantity.
(2) the oxidation of a-hydroxyamides and a-aminoamides;3 (3) the After an extensive screening of the reaction parameters (Table 1), the
oxidation of acyl cyanophosphoranes followed by the amidation of optimal reaction conditions were obtained as follows: acetophenone
the resulting a,b-diketone nitrile;4 (4) the double carbonylative (0.5 mmol), n-butylamine (2 mmol), n-Bu4NI (1 mmol), EtOH (10 ml),
amidation of aryl halides catalyzed by transition-metal;5 and (5) and O2 (balloon) in an undivided cell equipped with a platinum anode
the reaction of isocyanides with aromatic acyl chlorides.3c,6 and a cathode at ambient temperature under a constant current of
Recently, a range of new approaches has been developed by using 20 mA for 3 hours.
O2,7 NIS8a or TBHP8b–d as an oxidant. In spite of the availability of
these synthetic methodologies, a more mild, convenient and was investigated with various combinations of acetophenones 1 and
efficient synthesis of a-ketoamides is still in high demand. amines 2 (Table 1). In general, when 1 was employed as the reaction
Under the optimized conditions, the scope of the reaction substrates
As far as we know, there has been no report on the synthesis substrate, both primary and secondary amines (including cyclic and
of a-ketoamides via electrochemical oxidation yet. The direct acyclic amines) could react with 1smoothly to afford the corresponding
formation of a-ketoamides from primary aliphatic amines has amides 3a–3z in moderate to high yields. As for the substrate aceto-
been hardly reported either. On the other hand, dioxygen is an phenones, both electron-rich and weak electron-deficient aromatic
ideal oxygen source for synthetic chemistry. However, oxidation ketones could be transformed into the desired products with the yields
involving both oxygen and electrochemistry is rare. Herein we from 56% to 90% (Table 1, entries 1–8). Nevertheless, 4-nitro aceto-
report a new method for the synthesis of a-ketoamides from phenone, a strong electron-deficient aromatic ketone, failed to afford
acetophenones and amines by using dioxygen as a reactant.
the corresponding a-ketoamide (Table 1, entry 9). As for the secondary
Initially, under an oxygen atmosphere, the reaction of aceto- amines, the reactions could be carried out smoothly to afford the
phenone with n-butylamine was performed to examine the different corresponding products with moderate to high yields (Table 1,
supporting electrolytes, including KI, NaI, n-Bu4NI, n-Bu4NBr and entries 20–23). As for the primary amines and benzylamines, which
LiClO4. As shown in ESI,† Table S1, among these electrolytes (Table S1, were hard to form a-ketoamides by the conventional method,5e the
ESI,† entries 1–5), all iodine salts could promote this reaction to give amidation reaction could also be carried out smoothly to give the
products with good yields (Table 1, entries 1–8, 14–19 and 24–28). It was
a 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. E-mail: zwang3@ustc.edu.cn; Fax: +86-551-3603185
b Hefei National Laboratory for Physical Sciences at Microscale and Department of
Modern Physics, Univ Sci & Technol China, Hefei, Anhui, 230026, P. R. China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3cc43685c
‡ These authors contributed equally.
noted that laurylamine, which was a weak nucleophile, could be
converted into the a-ketoamide with a moderate yield (Table 1, entry 25).
When the substrate amine was replaced by ammonium acetate,
to our delight, a-oxophenylacetamide derivatives can be obtained
with good reaction yields. As far as we know, a-oxophenylacetamide
is an important intermediate in organic synthesis with interesting
c
8982 Chem. Commun., 2013, 49, 8982--8984
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Table 1 Synthesis of a-ketoamidesa
Table 2 Synthesis of a-oxobenzeneacetamidea
Yieldb
[%] Entry a-Ketoamide
Yieldb
[%]
Entry a-Ketoamide
1
81
77
77
52
90
56
61
78
14c
15c
16c
17c
18c
19c
20c
21
65
53
76
65
56
85
52
52
70
2
3
4
5
6
7
8
9
a
Reaction conditions: 1 (0.5 mmol), 2 (2 mmol), Kl (1 mmol), tert-
butylamine (2 mmol), MeOH (10 ml), O2 (balloon), platinum sheets as
an anode and a cathode, at a constant current of 40 mA for 5 hours.
b
NH4OAc was added in batches, reaction time was prolonged to 10 hours.
Table 2, it was found that a variety of substituents on the phenyl ring
of acetophenone had little influence on the reaction, affording the
corresponding a-oxophenylacetamides with moderate to high yields
(Table 2). However, the strong electron-donating group, the methoxy
group, had a serious negative influence on this reaction. Only 5%
yield of the a-oxophenylacetamide can be obtained (Table 2, 6e).
When ammonium acetate was added in batches and the reaction
time was prolonged to 10 hours, the desired product could also be
obtained in 44% yield (Table 2, 6e).
To probe the mechanism of the reaction, a series of control
experiments were performed under electrochemical conditions. At
first, we thought that 1-phenyl-2-(piperidin-1-yl)ethanone (4a) was
the key intermediate, which was further oxidized to product 3v.
When 4a was employed as the reaction substrate, only a trace
amount of the product was observed, as shown in Scheme 1
[eqn (1)]. This showed that 4a was not the reaction intermediate.
2-Oxo-2-phenylacetaldehyde (5a) could be detected by GC-MS.
This implied that 5a could be the reaction intermediate. Further-
more, treatment of the isolated 5a with piperidine led to the
desired product 3v in 74% yield, as shown in Scheme 1 [eqn (2)].
Next, we investigated the precursor 4b. Initially we assumed that
Trace 22
10c
11c
12c
80
65
23
24
73
62
65
50
25
26
54
64
13c
a
Reaction conditions: 1 (0.5 mmol), 2 (2 mmol), n-Bu4Nl (1 mmol),
EtOH (10 ml), O2 (balloon), platinum sheet as an anode and a cathode,
b
c
at a constant current of 20 mA for 3 hours. Isolated yield. 1 mmol of
aniline and benzylamine were added.
biological properties.9 However the synthesis of the a-oxobenzene-
acetamide is rarely reported.10 Therefore this method is a useful
alternative method to synthesize a-oxophenylacetamide derivatives.
In order to increase the solubility of ammonium acetate, the solvent
ethanol was replaced with methanol. Among the various electrolytes
examined, potassium iodide was found to be the best choice in
methanol, as shown in Table S2 of ESI.† Besides, the basic environ-
ment of the reaction also played a crucial role in the reaction and the
amines were chosen as the additives to modulate the basic environ-
ment of the reaction. After optimizing the amines, it was found that
tert-butylamine was the best choice (see Table S2 of the ESI†). Also,
the scope of acetophenones was examined in this reaction. From Scheme 1 Control experiments for the reaction.
c
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new type of coupling of acetophenones with amines was realized,
affording a-ketoamides with good yields. This coupling features
high atom economy, easily available starting materials, a transition-
metal free process, and a wide scope of amines. Further investiga-
tions into the scope of the reaction and the synthetic applications
are ongoing in our laboratory.
The authors are grateful to the National Nature Science
Foundation of China (21272222, 21172205, 20972144, 20932002,
91213303 and J1030412) and the Ministry of Science and Technol-
ogy of China (2010CB912103).
Notes and references
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Scheme 2 The proposed reaction mechanism.
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Scheme 1 [eqn (4)]. This implied that 5a could come from 1a
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the key intermediate in the reaction.
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c
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8984 Chem. Commun., 2013, 49, 8982--8984