The syntheses of α-ketoamides vianBu4NI- catalyzed multiple sp3C-H bond oxidation of ethylarenes and sequential coupling with dialkylformamides

Article abstract of DOI:10.1039/c4ob00520a

The ⁿBu₄NI-catalyzed sequential C-O and C-N bond formation via multiple sp³C-H bond activation of ethylarenes, using N,N-dialkylformamide as the amino source, provided α-ketoamides with moderate yields. This journal is

Full text of DOI:10.1039/c4ob00520a

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The syntheses of α-ketoamides via nBu4NI-
catalyzed multiple sp3C–H bond oxidation of
ethylarenes and sequential coupling with
dialkylformamides†
Cite this: Org. Biomol. Chem., 2014,
12, 4586
Received 8th March 2014,
Accepted 9th May 2014
DOI: 10.1039/c4ob00520a
Bingnan Du,a Bo Jina and Peipei Sun*a,b
www.rsc.org/obc
The nBu4NI-catalyzed sequential C–O and C–N bond formation N-chloroamine,12 copper-catalyzed oxidative coupling of aryl
via multiple sp3C–H bond activation of ethylarenes, using N,N-di- methyl ketones or acetaldehydes with amines, and α-oxo-
alkylformamide as the amino source, provided α-ketoamides with carboxylic acids with formamides.13 Remarkably, a metal-free
moderate yields.
approach to α-ketoamides was recently developed by the
nBu4NI or I2-catalyzed oxidative coupling of aryl methyl
ketones with dialkylformamides or amines.14 To date, the acti-
vated methyl or methylene sp3C–H bond was centered on the
benzylic C–H bond or α-C–H bond of the carbonyl group. To
the best of our knowledge, the sequential dehydrogenation to
the five inert sp3C–H bonds of the ethyl group and coupling
were not reported. The continuing attention to the functionali-
zation of inert sp3C–H bonds inspired us to look into the acti-
vation of multiple C–H bonds of easily available and
unprefunctionalized ethylarenes. Herein, for the first time, we
present the nBu4NI-catalyzed sequential C–O and C–N bond
formation via multiple sp3C–H bond activation of ethylarenes,
providing an efficient approach to α-ketoamides.
The α-ketoamide functional group can be found in a number
of marketed and investigational drugs since it is recognized as
a key functional moiety for inhibitors of hydrolytic enzymes
such as serine and cysteine proteases.1 This moiety also exists
in several bioactive natural products such as in immuno-
suppressant drugs FK-506 and rapamycin.2 The compounds con-
taining the α-ketoamide scaffold such as chloropeptin I and
complestatin are proved to inhibit HIV replication.3 α-Keto-
amides are also valuable precursors in organic synthesis, for
example, to synthesize various heterocyclic compounds.4 Thus,
it is of great interest and important to develop efficient syn-
thetic methods for this type of compound. Synthetically,
α-ketoamides can be prepared by the oxidation of the corres-
ponding α-hydroxyamides,5 arylacetamides6 or α-amino-
α-cyanoketones,7 and by the amidation of α-ketoacids.8 Some
transition metal-catalyzed reactions were also successfully
used for the syntheses of α-ketoamides, e.g., palladium- or
copper-catalyzed double carbonylative amination of aryl
halides,9 and copper-catalyzed oxidative amidation/diketoniza-
tion of terminal alkynes.10
In recent years, nBu4NI in combination with the oxidant
TBHP, as an environmentally friendly and mild metal free cata-
lyst, was proved to be very efficient in a series of organic reac-
tions especially in C–H activation.15 Thus, this nBu4NI–TBHP
catalytic system was tried for the multiple oxidative coupling
reactions of ethylarenes with N,N-dialkylformamides. The reac-
tion of ethylbenzene (1a) and N,N-dimethylformamide (DMF)
(2a) was initially selected to study the reaction conditions
Recently, the oxidative carbonylation to sp3 C and sequen-
tial coupling has become an attractive strategy in organic syn-
thesis, especially for the syntheses of carbonyl compounds,
amides, including α-ketoamides. For example, the palladium
catalyzed chelation-assisted ortho-acylation using methylarenes
as the acylation reagents,11 Mn(IV) promoted syntheses of
amides via the oxidative coupling of methylarenes with urea or
n
(Table 1). Delightedly, in the presence of 10 mol% Bu4NI and
8 eq. TBHP, the reaction gave the product N,N-dimethyl-2-oxo-
2-phenylacetamide (3aa) in 23% isolated yield (entry 1).
Encouraged by this result, further optimization of the reaction
conditions was carried out. Without nBu4NI, the reaction could
n
not proceed at all. Increasing the amount of Bu4NI to 20 mol
%, and that of TBHP to 12 eq. led to the raised yield of 63%
(entries 2–4). Temperature had a significant effect on the reac-
tion. The appropriate reaction temperature was 80 °C. The
yield had no significant change when elevating the reaction
temperature to 100 °C, but reducing the temperature to 60 °C
resulted in a depressed yield of 48% (entries 5 and 6). Apart
from TBHP, other common oxidants, such as DTBP, DDQ,
H2O2, O2, K2S2O8 and PhI(OAc)2, were proved to be noneffec-
aJiangsu Key Laboratory of Biofunctional Materials, College of Chemistry and
Materials Science, Nanjing Normal University, Nanjing 210097, China
bJiangsu Collaborative Innovation Center of Biomedical Functional Materials,
Nanjing 210023, China. E-mail: sunpeipei@njnu.edu.cn; Fax: +86-25-85891767;
Tel: +86-25-85891767
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4ob00520a
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Table 1 Screening of reaction conditionsa
Table 2 nBu4NI-TBHP catalyzed synthesis of α-ketoamidesa
Entry Catalyst (mol%) Oxidant (equiv.) Temp. (°C) Yieldd (%)
1
2
3
4
5
6
7
8
nBu4NI (10)
nBu4NI (10)
nBu4NI (10)
nBu4NI (20)
nBu4NI (20)
nBu4NI (20)
nBu4NI (20)
nBu4NI (20)
nBu4NI (20)
nBu4NI (20)
nBu4NI (20)
nBu4NI (20)
KI (20)
TBHP (8)b
TBHP (10)
TBHP (12)
TBHP (12)
TBHP (12)
TBHP (12)
DTBP (12)
DDQ (4)c
H2O2 (12)
O2 (1 atm)
K2S2O8 (4)c
PhI(OAc)2 (4)c
TBHP (12)
TBHP (12)
TBHP (12)
TBHP (12)
80
80
80
80
60
100
80
80
80
80
80
80
80
80
80
80
23
42
52
63
48
57
0
0
0
0
0
9
10
11
12
13
14
15
16
0
16
Trace
Trace
Trace
I2 (20)
NIS (20)
CuI (20)
a Reaction conditions: 1a (1.0 mmol), 2a (6.0 mmol), catalyst, and
oxidant under an air atmosphere for 18 h. b TBHP: tert-butyl
hydroperoxide, 70% in water. c In DCE. d Isolated yield.
tive to this transformation (entries 7–12). When KI was used
instead of nBu4NI, the reaction only gave a low yield of 16%
(entry 13). Other iodides such as iodine, NIS and CuI showed
almost no activity towards the reaction (entries 14–16).
Under the optimized reaction conditions, the nBu4NI–TBHP
catalyzed multiple oxidative coupling reactions of various
ethylarenes with N,N-dialkylformamide were then studied
(Table 2). At the beginning of our investigation, DMF was
chosen as the amino source for this reaction. With most of the
ethylarenes we employed, the reaction gave the corresponding
products in moderate yields within a reaction time of 18 h.
The reaction showed a good tolerance to the chemically active
functional groups. The halogen (Cl, Br, I), ester and sulfonyl-
oxyl group on ethylarene remained after reaction (3ba–3ha),
and the connection position of the substituent on the benzene
ring had no significant influence on the reaction (3da–3fa).
Notably, in the case of ethylarenes with more than one ethyl
group such as p-diethylbenzene and 1,3,5-triethylbenzene, the
reaction could give monooxidation–amination products with
lower yields because of the formation of some oxidation bypro-
ducts (3ja, 3ka, 3jd). The presence of NO2 on the benzene ring
led to relatively low yields because of the strong electron-with-
drawing properties of the NO2 group (3ia, 3id). Next we
employed a series of N,N-dialkylformamides, including cyclic
and acyclic formamides (2b–2d), as the coupling partner; the
results did not show an evident difference compared with the
reaction of DMF (3ab–3id).
a Reaction conditions: 1 (1.0 mmol), 2 (6.0 mmol), nBu4NI (20 mol%),
TBHP (12 eq.), under an air atmosphere at 80 °C for 18 h. b Isolated
yield.
Scheme 1 Formation of N-isopropyl-2-oxo-2-arylacetamides.
To our surprise, when N,N-diisopropylformamide was
used as the amino source, instead of the general product N,N-
diisopropyl-2-oxo-2-arylacetamide, N-isopropyl-2-oxo-2-arylacet-
amides were generated (Scheme 1). Though the exact mechan-
ism is not clear, we presume that it may be related to the
relatively large steric hindrance of isopropyl. It also revealed
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ethanol was used instead of ethylbenzene to react with DMF,
a similar result was obtained under the same reaction con-
ditions. But from phenylacetaldehyde, no desired product was
separated. These results showed that the oxidation started
from the benzylic C–H bond of ethylarene, but not from
methyl. In addition, when dimethylamine was used instead of
DMF, the product 3aa was also not obtained, which implied
that dimethylamine was not the reaction intermediate.
Conclusions
In summary, we developed a convenient method for the syn-
thesis of α-ketoamides from cheap compounds, ethylarenes, in
aqueous media under metal-free conditions. And also, to the
best of our knowledge, it is the first example of formation of
C–O and C–N bonds sequentially via multiple inert sp3C–H
bond activation.
Acknowledgements
Scheme 2 Plausible reaction mechanism.
This work was supported by the National Natural Science
Foundation of China (project 21272117 and 20972068) and the
Priority Academic Program Development of Jiangsu Higher
Education Institutions.
that the cleavage of the alkyl C–N bond was possible in the
nBu4NI–TBHP catalytic system.
From the reaction mixture, acetophenones as the oxidation
products of ethylarenes could be found. In addition, the decar-
Notes and references
A
13C-isotope
bonylation of DMF has been well-documented.16
labeling experiment by Wan further proved that the cleavage
of the C–N bond of DMF was possible in the nBu4NI/TBHP
system.15a Based on the above results and the related
reports,14,15 a plausible catalytic mechanism is presented as
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t
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