TBAI-catalyzed synthesis of α-ketoamides via sp3 C-H radical/radical cross-coupling and domino aerobic oxidation

Article abstract of DOI:10.1016/j.tetlet.2015.06.021

A TBAI-catalyzed one-pot synthesis of α-ketoamides via sp³ C-H radical/radical cross-coupling and domino aerobic oxidation was developed. This synthesis is suitable for abroad range of substrates. The control experiments suggested a possible oxidative coupling mechanism.

Full text of DOI:10.1016/j.tetlet.2015.06.021

Tetrahedron Letters 56 (2015) 4638–4641
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
TBAI-catalyzed synthesis of a
-ketoamides via sp3 C–H radical/radical
cross-coupling and domino aerobic oxidation
⇑
Weizheng Fan , Dongyang Shi , Bainian Feng
School of Pharmaceutical Science, Jiangnan University, Wuxi 214122, China
a r t i c l e i n f o
a b s t r a c t
A TBAI-catalyzed one-pot synthesis of a
-ketoamides via sp3 C–H radical/radical cross-coupling and dom-
ino aerobic oxidation was developed. This synthesis is suitable for abroad range of substrates. The control
experiments suggested a possible oxidative coupling mechanism.
Ó 2015 Elsevier Ltd. All rights reserved.
Article history:
Received 13 May 2015
Revised 4 June 2015
Accepted 9 June 2015
Available online 14 June 2015
Keywords:
TBAI-catalyzed
a-Ketoamides
Radical/radical cross-coupling
Aerobic oxidation
sp3 C–H bond
a
-Ketoamides are key structural motifs in many natural prod-
aerobic oxidation, in which water was only by-product, without
CO or CO2 emissions (Scheme 1).
ucts, biological compounds, pharmaceuticals, and synthetic inter-
mediates.1,2 Traditionally, they are synthesized by condensation
Initially, we chose toluene (1a) and DMF (2a) as model sub-
strates to optimize the reaction conditions and the results are sum-
marized in Table 1. Firstly, the well-established nBu4NI/TBHP
catalytic system8 was chosen for this oxidative coupling.
Unexpectedly, the desired compound (3a) was isolated in very
poor yield (Table 1, entry 1). Further reaction attempts with other
oxidants (Table 1, entries 2–5), DTBP increased the yields to 21%
(Table 1, entry 2). However, when two equiv additive of K2CO3
was added, the yield of 3a increased to 43% (Table 1, entry 6).
Among the examined other bases, Cs2CO3 showed the best perfor-
mance, which increased the yield to 69% (Table 1, entries 7–10).
Upon elevating the temperature to 120 °C, the yields were remark-
ably increased to 83%. The use of other catalysts or increasing the
amount of loading catalyst, led no significant improvement on the
yield (Supporting information, SI-Tables 1 and 2).
Having optimized the conditions, we explored the utility of this
approach for this transformation. At the beginning of our investiga-
tion, most of the methylarenes were employed to react with DMF,
giving the corresponding products in moderate to good yields
(3a–3t). The reaction showed a good tolerance to many functional
groups, including electron-donating and electron-withdrawing
groups (e.g., OMe, Cl, Br, F, and CF3). However, the substrates with
electron-withdrawing groups gave some lower yields (3b > 3c and
3d, 3e > 3f, 3g and 3h, 3i > 3j and 3l). The connection position of
the substrates on the benzene ring had little significant influence
on the reaction (3b vs 3e and 3i, 3c vs 3h and 3j). O-tBu substitute
of their corresponding
amines.3 Recently, more convenient oxidation methods were
developed, including the direct oxidation of the corresponding
hydroxyamides,4 arylacetamides,5 or -cyanoketones,6
-amino-
the oxidative coupling of arylacetaldehydes, aryl methyl ketones,
b-diketones or terminal alkynes with amines,7 and decarboxylative
or decarbonylative acylation of formamides.8
a-keto acids or a-keto acyl halides with
a-
a
a
N,N-Dimethylformamide as a ubiquitous solvent and multipur-
pose reagent has widely been used in many organic reactions.9
With the development of green and sustainable chemistry, utiliza-
tion of DMF as a precursor may have important affection on the
practical transformations. Compared with the corresponding ami-
nes, DMF showed less pollution, odor, and toxicity. Recently, more
and more chemists focused on the research of using DMF as amine
or amide sources. Although a lot of successful syntheses of
a
-ketoamides using DMF8 were developed, these transformations
did not comply with the atom economy, in which at least one car-
bon atom was wasted in decarboxylation or decarbonylation.
Herein, we present a TBAI-catalyzed one-pot synthesis of
a-ke-
toamides via sp3 C–H radical/radical cross-coupling and domino
⇑
Corresponding author.
E-mail address: fengbainian@jiangnan.edu.cn (B. Feng).
The author contributed equally to this work.
http://dx.doi.org/10.1016/j.tetlet.2015.06.021
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

W. Fan et al. / Tetrahedron Letters 56 (2015) 4638–4641
4639
Scheme 1. Synthesis of a-ketoamides using formamides.
Table 1
Optimization of the conditions
O
O
TBAI (10 mol%)
Oxidant, Additive
N(CH )
3 2
H
N(CH )
3 2
O
2a
1a
3a
Entrya
Catalyst (mol %)
Oxidant (equiv)
Additive (equiv)
Yieldc (%)
1
2
3
4
5
6
7
8
TBAI (10)
TBAI (10)
TBAI (10)
TBAI (10)
TBAI (10)
TBAI (10)
TBAI (10)
TBAI (10)
TBAI (10)
TBAI (10)
TBAI (10)
TBHP (8)
DTBP (8)
DDQ (8)
—
—
—
—
4
21
0
0
0
43
69
13
0
62
83
K2S2O8 (8)
PhI(OAc)2 (8)
DTBP (8)
DTBP (8)
DTBP (8)
DTBP (8)
DTBP (8)
DTBP (8)
—
K2CO3 (2)
Cs2CO3 (2)
NaOH (2)
Et3N (2)
K3PO4 (2)
Cs2CO3 (2)
9
10
11b
a
b
c
Reaction conditions: 1a (0.5 mmol), 2a (4 mL), TBAI (10 mol %), oxidant, additive, at 80 °C, under Ar atmosphere for 12 h.
Reaction at 120 °C.
Isolated yield.
(3k) gave no product due to the big steric hindrance. Satisfactorily,
2-methylfuran and 2-methylthiophene also proceeded smoothly to
give the target products 3m and 3n in 48% and 53%, respectively.
However, non-aromatic substrates showed no activity (3o and
3p). Next a series of N,N-dialkylformamides were explored, but
the results did not show an evident difference with DMF (3m–
3p) (Scheme 2 and Table 2).
converted to 3a under standard conditions in 82% yield (Eq. 3),
which suggests 3a0 as an important intermediate for the transfor-
mation.5 Finally, 1a reacted under standard conditions with or
without Cs2CO3 not affording any phenylmethanol and benzalde-
hyde. Based upon the experimental and literatures’ results,5,7,8
a
plausible radical/radical cross-coupling and domino aerobic oxida-
tion mechanism is proposed in Scheme 3.
To understand the role of each compound in the formation of
In summary, we present a TBAI-catalyzed one-pot synthesis of
these
a
-ketoamides, control experiments were performed (see SI-
a
-ketoamides via sp3 C–H radical/radical cross-coupling and dom-
Scheme 1 in the Supporting Information). Firstly, 1a and 2a react-
ing under standard conditions in the absence of Cs2CO3 gave no 3a,
and 63% yield of N,N-dimethyl-2-phenyl-acetamide (3a0) was
afforded (Eqs. 1 and 2). Subsequently, addition of 1.5 equiv
TEMPO inhibited the reaction. These results suggest the formation
of 3a0 involving a radical process.7,8 Secondly, 3a0 could be
ino aerobic oxidation, in which water was only by-product, with-
out CO or CO2 emissions. This synthesis is suitable for a broad
range of substrates. The control experiments suggested a possible
oxidative coupling mechanism. Further studies concerning the
detailed mechanism and the broader scope of substrates are cur-
rently underway in our laboratory.

4640
W. Fan et al. / Tetrahedron Letters 56 (2015) 4638–4641
O
O
O
TBAI (10 mol%)
DTBP
(1)
(2)
H
H
N(CH )
3 2
N(CH )
3 2
No Cs CO
2
3
2a
O
1a
1a
3a', 63%
3a', 0
TBAI (10 mol%)
DTBP
N(CH )
3 2
N(CH )
3 2
No Cs CO
2
3
1.5 equiv TEMPO
2a
O
O
Standard
(3)
(4)
Conditions
N(CH )
3 2
N(CH )
3 2
3a'
1a
3a, 82%
OH
O
Standard
O
Conditions
With or without Cs CO
2
3
NO
NO
Scheme 2. Control experiments.
Table 2
Screening the utility of this approach
R
1
R
1
O
O
TBAI (10 mol%)
DTBP, Cs CO
2
3
H
NR'
2
NR'
2
2
1
3
O
F
MeO
Cl
O
O
O
O
O
N(CH )
N(CH )
3 2
N(CH )
3 2
N(CH )
3 2
3 2
O
O
O
O
O
3a, 83%
OMe
3b, 85%
Br
3d, 68%
Cl
3c, 71%
CF
3
O
O
O
N(CH )
3 2
N(CH )
N(CH )
N(CH )
3 2
3 2
3 2
O
O
O
3e, 81%
3f, 53%
3g, 59%
3k, 0
3h, 69%
3l, 55%
OMe
O
tBu
O
Cl
Cl
O
O
Cl
N(CH )
N(CH )
3 2
N(CH )
N(CH )
3 2
3 2
3 2
O
O
O
O
3i, 84%
O
3j, 67%
O
O
O
O
N(CH )
3 2
N(CH )
3 2
S
N(CH )
N(CH )
3 2
3 2
O
O
O
3m, 48%
O
O
3o, 0
O
3p, 0
3n, 53%
O
O
O
N(Et)
N
N
2
N
O
3q, 87%
O
O
O
3r, 78%
3t, 79%
3s, 82%

W. Fan et al. / Tetrahedron Letters 56 (2015) 4638–4641
4641
O
O
TBAI (10 mol%)
DTBP
N(CH )
3 2
H
N(CH )
3 2
2a
1a
radical/radical
cross-coupling
aerobic oxidation
O
O
Cs CO
2
3
DTBP
N(CH )
3 2
N(CH )
3 2
3a
3a'
O
Scheme 3. The possible mechanism.
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Acknowledgments
This work was supported financially by grants from the
National Natural Science Foundation of China (Grants 21302066)
and Young Program, SCF of Jiangsu Province (BK20130129).
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021.
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