Cesium carbonate promoted aerobic oxidation of arylacetamides: an efficient access to N-substituted α-keto amides

Article abstract of DOI:10.1016/j.tetlet.2007.10.099

A novel cesium carbonate promoted aerobic oxidation reaction to prepare N-substituted α-keto amides in the presence of catalytic amount of tetra-n-butylammonium bromide was described. This reaction provides a very simple and convenient route from easily a

Full text of DOI:10.1016/j.tetlet.2007.10.099

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Tetrahedron Letters 48 (2007) 8982–8986
Cesium carbonate promoted aerobic oxidation of arylacetamides:
an efficient access to N-substituted a-keto amides
Bingrui Song,a, Siyuan Wang,a, Caiyun Sun,a Hongmei Dengb and Bin Xua,*
aDepartment of Chemistry, Shanghai University, Shanghai 20044, China
bInstrumental Analysis and Research Center, Shanghai University, Shanghai 200444, China
Received 27 August 2007; revised 17 October 2007; accepted 19 October 2007
Available online 24 October 2007
Abstract—A novel cesium carbonate promoted aerobic oxidation reaction to prepare N-substituted a-keto amides in the presence of
catalytic amount of tetra-n-butylammonium bromide was described. This reaction provides a very simple and convenient route from
easily available arylacetamides in good to high yields.
Ó 2007 Elsevier Ltd. All rights reserved.
a-Keto amides are valuable intermediates in organic
synthesis,1 have intriguing biological properties,2 and
are present in several natural products as main skele-
ton.3 A wide range of chemistry has been exploited for
the preparation of a-keto amides, including: (1) tradi-
tional amidation of a-keto acids;4 (2) oxidation of
hydroxyamides,5 cyanoketones,6 olefins7 or direct a-oxi-
a-keto amides were designed to be assembled into chem-
ical ligands. Herein, we wish to report a convenient
preparation of a-keto amides from readily available
arylacetamides in good yields (Scheme 1). The reactions
are effective in DMF at 120 °C in the presence of
Cs2CO3 and n-Bu4NBr under the atmosphere of air.
9
dation of amides mainly using SeO2,8 (NH4)2Ce(NO3)2
Pal and co-workers15 found 1,8-diazabicyclo-[5.4.0]-
undec-7-ene (DBU) could facilitate the oxidative cycliz-
ation of phenacylamides in acetonitrile under an
oxygen atmosphere at room temperature in good to
excellent yields. When we applied this reaction condition
to 2-phenyl-1-(piperidin-1-yl)ethanone 1a,16a however,
no desired a-oxidative product 2a was observed even
at 80 °C (Table 1, entry 1). Using Et3N or pyridine as
base in DMF, only a trace amount of 2a was detected
(Table 1, entries 2–3). Other inorganic bases such as
NaHCO3, K2CO3, K3PO4, or NaOH17 in DMF gave
slightly improved results (Table 1, entries 4–7). To our
delight, Cs2CO3 (2.0 equiv) turned out to be the base
of choice and 2a could be generated in 81% yield in
DMF, albeit with long reaction time to reach comple-
tion (Table 1, entry 8). DMSO was found to be equally
effective as DMF (Table 1, entry 9), while 1,4-dioxane
and toluene resulted in diminished yields with very low
10
or RuO2 as metal oxidants; (3) photooxygenation of
corresponding amides sensitized by Rose Bengal (RB)
or tetraphenyl-porphin (TPP);11 (4) double-carbonyl-
ation reaction of aryl halides catalyzed by palladium
complexes in the presence of carbon monoxide;12 and
(5) coupling reaction of acyl chloride with isonitrile
developed by Ugi in the 1960s.13 All these methods,
however, are either lack of effective procedure to prepare
starting materials, or incompatible with sensitive func-
tionalities due to the harsh conditions during these
transformations, or impractical because of the required
toxic or expensive reagents. It becomes a synthetic chal-
lenge to find an efficient and convenient way to access
a-keto amides without using any toxic or expensive
reagents, or to avoid harsh conditions.
For our continuous research interest to pursue selective
high affinity P2Y receptor antagonists,14 a series of
R1
N
O
R1
N
Cs2CO3/
n-Bu4NBr
Ar
R2
Ar
R2
Keywords: Oxidation; Atmospheric oxygen; Cesium carbonate; Aryl-
acetamides; a-Keto amides.
Corresponding author. Tel.: +86 21 66132065; fax: +86 21
66132797; e-mail: xubin@shu.edu.cn
DMF, air, 120 oC
O
O
*
2
1
With equal contribution to this work.
Scheme 1. Synthesis of a-keto arylacetamides.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.099

B. Song et al. / Tetrahedron Letters 48 (2007) 8982–8986
8983
a
Table 1. Optimization of bases, solvents, and temperature
Table 2. Screening of additives and amount of Cs2CO3
Entry
Base (equiv)
Additive (equiv)
Time
(h)
Yieldb
(%)
O
base, solvent
N
N
1
2
3
4
5
6
7
8
9
Cs2CO3 (2.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (0.5)
Cs2CO3 (0.1)
Cs2CO3 (1.1)
Cs2CO3 (1.1)
n-Bu4NBr (2.0)
n-Bu4NBr (1.0)
n-Bu4NBr (0.1)
n-Bu4NHSO4 (0.1)
n-Bu4NF (0.1)
n-Bu4NI (0.1)
n-Me4NCl (0.1)
n-Bu4NBr (0.1)
n-Bu4NBr (0.1)
n-Bu4NBr (0.5)
n-Bu4NBr (0.5)/N2
5
5
90
90
89
88
83
70
52c
86
85
93
0
O
O
air, temp., 24 h
1a
Entry Base (equiv)
2a
Temp Conv.a Yieldb
16
24
24
24
24
17
24
6
Solvent
(°C)
(%)
(%)
1
2
3
4
5
6
7
8
DBU (2.0)
Et3N (2.0)
C5H5N (2.0)
CH3CN
DMF
80
80
0
0
0
0
5
DMF
100
120
120
120
120
120
120
28
38
44
61
74
95
95
31
29
89
66
NaHCO3 (2.0) DMF
10
22
42
20
81
76
11
9
10
11
K2CO3 (2.0)
K3PO4 (2.0)
NaOH (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (1.2)
Cs2CO3 (0.1)
DMF
DMF
DMF
DMF
DMSO
24
a Reaction conditions: 1a (1.0 mmol) was reacted with Cs2CO3 and
additives in DMF (4 mL) at 120 °C under atmospheric air.
b Isolated yields.
9
c With conversion of 80% based on 1a.
10
11
12
13
Dioxane 100
Toluene
DMF
DMF
100
120
120
60
46
yields. Remarkably clean reactions were observed with
functionalized molecules bearing ortho, meta, and para
substitutions on aryl ring (entries 2–6 and 8), whereas
the substrate with nitro group gave a slightly compli-
cated reaction (entry 7). It should be noted that the
easily oxidizable amino group remained intact under
the reaction condition (entry 8). The steric and elec-
tronic effects of the substitution on the nitrogen atom
have also been examined. Compound 2i bearing two
bulky isopropyl groups was obtained in 82% yield (entry
9), while 2k with two bulky and electron-withdrawing
phenyl groups was obtained in only 28% yield (entry
11). For substrate 1j bearing one methyl and one phenyl
group at nitrogen atom, 2j was isolated as a mixture of
s-cis and s-trans isomers in a ratio of 9:1 which was in
agreement with the literature result reported by Takah-
ashi et al. (entry 10).6a This reaction was not limited to
simple benzene-containing aromatics, the pyridine-
containing substrate 1l also afforded 2l in good yield
(entry 12).
a Conversion was determined on the basis of 1a recovered.
b Isolated yields.
conversion rates (Table 1, entries 10 and 11). The reason
might be the poor solubility of Cs2CO3 in less polar sol-
vents. We were surprised to find, when the amount of
Cs2CO3 was decreased to 1.2 equiv and 0.1 equiv, the
reactions still gave 2a in 60% and 46% yield, respectively
(Table 1, entries 12 and 13), the latter clearly indicated
that the reaction proceeded in a catalytic manner.
Our further study demonstrated that introduction of
n-Bu4NBr18 as additive could significantly accelerate
the reaction (compare Table 2, entry 1 and Table 1,
entry 8). Reducing both n-Bu4NBr and Cs2CO3 loadings
to 1.0 equiv produced similar result (Table 2, entry 2),
and catalytic amounts of n-Bu4NBr (0.1 equiv) afforded
2a in 89% yield within 16 h (Table 2, entry 3). Other
quaternary ammonium salts such as n-Bu4NHSO4 and
n-Bu4NF gave satisfactory yields with longer reaction
time (entries 4 and 5), while n-Bu4NI and n-Me4NCl were
less effective to give lower yields (entries 6 and 7).
Furthermore, catalytic amounts of Cs2CO3 and
n-Bu4NBr still produced 2a in slightly lower yields (85–
86%) after longer reaction time (entries 8 and 9). Consid-
ering the reaction time and yield, the best condition was
optimized as: Cs2CO3 (1.1 equiv) and n-Bu4NBr
(0.5 equiv) in DMF at 120 °C under the atmosphere of
air, and 2a was obtained in 93% yield in only 6 h (Table
2, entry 10). It should be noted that when 1,4-hydroqui-
none (0.1 equiv) was used in the reaction, 2a was
obtained in 52% yield, which ruled out the free radical
mechanism.19 When the reaction was conducted under
nitrogen, no desired product was obtained (entry 11).
When attempted to oxidize one carbon homologated
derivative of 1a, 3-phenyl-1-(piperidin-1-yl)propan-1-
one 1m, no expected product was observed, and the
starting material was recovered quantitively. 2-Cycno
substituted reactant 1n16b failed to give corresponding
oxidation product 2n using our standard conditions
after 8.5 h. Instead, the isoindoline-1,3-dione 3 was iso-
lated in 50% yield (Scheme 2). The formation of 3 may
be attributed to a nitrile oxidation–hydrolysis–cycliz-
ation–elimination sequence.
The detailed mechanism is not clear at this stage. A pos-
sible reaction mechanism to account for the formation
of substituted a-keto amides using catalytic amount of
base is proposed in Scheme 3.15a,20 The mechanism
may involve deprotonation at the benzylic position of
amides 1 and to furnish the carbanions A, which then
could react with molecular oxygen to provide peroxy
anions B. After intramolecular abstraction of a proton
from the benzylic site20 by the peroxy anions B, products
2 could be formed through ionic pathway, and carba-
nions A could be regenerated from amide 1 and the
hydroxide ion released.
To explore the scope of this method, a variety of arylac-
etamides 1a–n16 were applied under the optimized con-
ditions (Table 2, entry 10). The results are summarized
in Table 3.
As shown in Table 3, the a-oxidation reaction proceeded
readily to give the corresponding a-keto amides in good

8984
B. Song et al. / Tetrahedron Letters 48 (2007) 8982–8986
Table 3. Synthesis of N-substituted a-keto amides by oxidation of corresponding amides
Cs2CO3 (1.1 equiv.)
R1
O
R1
N
n
-Bu4NBr (0.5 equiv.)
N
Ar
R2
Ar
R2
DMF, Air, 120 oC
O
O
Entry
1
Reactant
Product
Time (h)
6
Yielda (%)
93
O
N
N
N
1a
2a
O
O
Br
Br O
N
2
3
4
5
6
6.5
3
78
80
75
91
78
O
O
1b
1c
2b
2c
O
Br
N
Br
N
O
O
N
O
N
6
1d
1e
1f
O
O
2d
O
N
N
N
N
6
O
O
O
O
O
Cl
2e
2f
O
6
O
Cl
O
N
N
7
24
40
O
O
O
O2N
1g
1h
O2N
H2N
2g
O
N
N
8
9
9
10
6.5
3.5
5
75b
82
O
H2N
2h
2i
O
O
N
N
O
O
O
1i
1j
CH3
N
CH3
N
10
11
12
62c,d
28e
81
2j
O
O
Ph
N
O
O
Ph
N
Ph
Ph
1k
1l
2k
O
O
N
N
O
N
2l
N
a Isolated yields. Products were characterized by 1H and 13C NMR, MS, FT-IR data, and HRMS or elemental analysis was used for all new
compounds.
b Cs2CO3 (2.0 equiv) was used.
c Isolated as a mixture of s-cis and s-trans isomers in a ratio of 9:1.
d 13% of 1j was converted to the corresponding N-methylaniline.
e 29% of 1k was converted to the corresponding diphenylamine.

B. Song et al. / Tetrahedron Letters 48 (2007) 8982–8986
8985
Lett. 1999, 40; (d) Wong, M.-K.; Yu, C.-W.; Yuen, W.-H.;
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O
Cs2CO3 (1.1 equiv.)
-Bu4NBr (0.5 equiv.)
CN
n
N
NH
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O
O
3
1n
Scheme 2. Reaction of 1n under optimized conditions.
R1
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N
H2O
O2
Ar
R2
O
A
BH
B
R1
N
OH
Ar
R2
O
O
1
O
O
O
R1
R1
N
H
Ar
N
Ar
R2
R2
O
2
B
Scheme 3. Plausible mechanism of a-oxidation reaction.
In summary, we describe here a novel cesium carbonate
promoted aerobic oxidation reaction in the presence of
tetra-n-butylammonium bromide. Compared with other
reported methods, the current approach provides a very
simple and convenient route to a-keto amides from eas-
ily available arylacetamides in good to high yields, and
could potentially be carried out in industrial scales. This
reaction avoids using toxic reagents and harsh condi-
tions and could proceed catalytically.21 The scope of this
reaction and its applications for bioactive compounds
are currently under investigation in our laboratory and
will be reported in due course.
Acknowledgments
Financial support from the National Natural Science
Foundation of China (No. 20672071), Shanghai Pujiang
Program (No. 07pj14043) and Shanghai Municipal
Education Commission (No. 06AZ095) is gratefully
acknowledged. The authors thank Professor Qin Zhang
and Ms. Weiwei Rao for spectral support.
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.10.099.
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21. General procedure: To a solution of 1-(4-aminophenyl)-2-
(piperidin-1-yl)ethanone 1h (175 mg, 0.8 mmol) in DMF
(4 mL) was added Cs2CO3 (287 mg, 0.88 mmol) and
n-Bu4NBr (129 mg, 0.4 mmol). The reaction mixture was
stirred for 9 h at 120 °C under the atmosphere of air,
which was dried through a calcium chloride tube until 1h
was completely consumed. Ethyl acetate (15 mL) was then
added to the mixture after it was cooled to room
temperature, and the resulting mixture was filtered. The
filtrate was concentrated under reduced pressure. The
crude product was purified by column chromatography on
silica gel (elution with petroleum ether/ethyl acetate = 2:1)
to give 2h (139 mg, 75%) as a light yellow solid, mp 166–
168 °C. IR (KBr): 3428, 3347, 2924, 2853, 1644, 1610,
1593, 1558, 1446 cmꢀ1. 1H NMR (500 MHz, DMSO-d6): d
7.49 (AA0 of AA0BB0, J = 8.0 Hz, 2H), 6.58 (BB0 of
AA0BB0, J = 8.0 Hz, 2H), 6.43 (s, 2H), 3.60–3.40 (m, 2H),
3.20–3.10 (m, 2H), 1.65–1.45 (m, 4H), 1.40–1.30 (m, 2H).
13C NMR (125 MHz, DMSO-d6): d 189.52, 165.93,
155.33, 131.79, 120.24, 112.96, 46.27, 41.00, 25.82, 25.11,
23.84. MS (EI): m/z (%) = 232 (2) [M+], 120 (100), 112
(3), 92 (17). Anal. Calcd for C13H16N2O2: C, 67.22; H,
6.94; N, 12.06. Found: C, 67.01; H, 6.945; N, 11.96.
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