Solvent-free one-pot oxidation of ethylarenes for the preparation of α-ketoamides under mild conditions

Article abstract of DOI:10.1039/c6ra26679g

Here we developed a highly efficient solvent-free, one-pot procedure for synthesizing α-ketoamides from ethylarenes and amines, by oxidizing a C-H bond sp³ center. A copper catalyst was employed, and the reactions proceeded smoothly at ambient temperatures. Most of the tested ethylarenes and amines were successfully converted to their corresponding α-ketoamides in moderate to excellent yields of up to 93% with three equivalents of the oxidant tert-butyl hydroperoxide.

Full text of DOI:10.1039/c6ra26679g

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Solvent-free one-pot oxidation of ethylarenes for
the preparation of a-ketoamides under mild
conditions†
Cite this: RSC Adv., 2017, 7, 7158
a
a
a
b
Fuyan Liu, Kuan Zhang, Yanfeng Liu, Shan Chen, Yiping Chen,a Dela Zhang,a
*
Chunfu Linab and Bo Wang
*
ab
Here we developed a highly efficient solvent-free, one-pot procedure for synthesizing a-ketoamides from
ethylarenes and amines, by oxidizing a C–H bond sp3 center. A copper catalyst was employed, and the
reactions proceeded smoothly at ambient temperatures. Most of the tested ethylarenes and amines were
successfully converted to their corresponding a-ketoamides in moderate to excellent yields of up to 93%
with three equivalents of the oxidant tert-butyl hydroperoxide.
Received 12th November 2016
Accepted 12th January 2017
DOI: 10.1039/c6ra26679g
www.rsc.org/advances
aryl acetaldehyde and aniline reactants.6 Some recently
developed one-pot approaches have included the direct
oxidative amidation of aryl methyl ketones,7c nBu4NI-catalyzed
Introduction
a-Ketoamides are key structural motifs in a variety of natural
products, biologically important compounds, and pharmaceu-
ticals, such as the immunosuppressant drug FK-506, rapamy-
cin, serine, cysteine proteases and other enzymes, and epoxide
hydrolase inhibitors.1 All of these compounds, as well as the
HIV replication inhibitors complestatin and chloropeptin I,2
include a-ketoamide frameworks. Furthermore, a-ketoamides
are also used as valuable precursors and synthetic intermedi-
ates in synthetic organic chemistry, for instance in the synthesis
of medicinally useful compounds tetrasubstituted 2-oxazolidin-
4-one and 2-oxindoles.3
Because of the signicance of the a-ketoamide scaffold, it is
of great interest and importance to develop efficient methods
to synthesize the many types of a-ketoamides that are in
demand. Over the past decades, several approaches have been
developed for synthesizing a-ketoamides.4–15 Most of these
procedures involved the direct amidation of a-keto acids and
a-keto acyl halides,4 but in most conditions hazardous
reagents were usually involved and harsh conditions were
required. Direct oxidations of a-hydroxyamides and a-amino-
amides have also been used to successfully produce the cor-
responding a-ketoamides.5 Recently, one-pot procedures for
synthesizing a-ketoamides have attracted the focus of
researchers worldwide. Jiao and his co-workers introduced
a one-pot procedure for synthesizing a-ketoamides by using
a copper catalyst to cleave Csp3–H, Csp2–H, and N–H bonds of
multiple sp3 C–H bond oxidation of ethylarenes and sequential
coupling with dialkylformamides,8 I2/IBX-catalyzed oxidative
amidation of terminal alkenes with amines in dimethyl sulf-
oxide (DMSO),9a oxidative amidation of terminal alkynes
catalyzed by copper(II) triate,10a iron-2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO)-catalyzed oxidative amidation of a-
keto alcohols,11a copper-catalyzed oxidative amidation of 1-
arylethanols with amines,12b amidation of halogen benzenes
promoted by palladium nanoparticles,13a DMSO-promoted
oxidative amidation of a-ketoaldehydes,14c and tert-butyl
hydroperoxide/I2 (TBHP/I2)-promoted tandem reactions of
b-diketones with amines.15 Most of these methods, however,
suffer from the need to carry out extra steps involving
the starting materials before the reactions for making the
a-ketoamides. They also suffer from low yields, harsh condi-
tions and toxic reagents, and the need to use large amounts
of oxidants that are considered to not be environmentally
benign.
Herein, we present a novel solvent-free and one-pot proce-
dure for the synthesis of a-ketoamides starting from commer-
cially available ethylarenes and amines. In this approach, we
used CuI as the catalyst and TBHP as the oxidant. No solvent
was required, and the reactions proceeded under mild condi-
tions (Scheme 1).
aState Key Lab of Marine Resource Utilisation in South China Sea, Hainan University,
Haikou 570228, PR China. E-mail: wangbo@hainu.edu.cn
bInstitute of Chemical Engineering, College of Materials and Chemical Engineering,
Hainan University, Haikou 570228, PR China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c6ra26679g
Scheme 1 Oxidative synthesis of a-ketoamides from ethylarenes and
amines.
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solvents evaluated, toluene was found to be the best one, having
afforded the desired product 3aa with a yield of 64% (entry 9,
Table 1), and was thus considered suitable for further investi-
gations. Nevertheless, for the purpose of adhering to at least
some of the principles of green chemistry, reactions without
organic solvent and with TBHP as the oxidant were also inves-
tigated. To our delight, when using three equivalents of TBHP in
the absence of organic solvent, great enhancements in the
yields of product 3aa were achieved (entry 1, 15–21, Table 1),
with yields of 88% for the reaction carried out at 70 ꢀC (entry 16,
Table 1), and 92% at 50 ꢀC (entry 10, Table 1). Therefore, in
the subsequent investigations, the reactions were performed
without organic solvent.
Results and discussion
Initial investigations for suitable reaction conditions were per-
formed on a 5 mL scale by employing ethylbenzene (1a) and
morpholine (2a) as the model substrates. Conditions such as
the identities of the catalyst, oxidants, and solvents, as well as
the amounts of loaded catalyst and oxidant, were evaluated, and
the results are summarized in Table 1. Carrying out the reaction
at 50 ꢀC in acetonitrile in the presence of the oxidant tert-butyl
hydroperoxide (TBHP) with copper iodide (CuI) as the catalyst
afforded the desired product 3aa in a 63% yield (entry 1, Table
1). CuI was shown to be the most suitable catalyst of all the
catalysts tested since this 63% yield of 3aa was better than the
yields afforded by the other tested catalysts (CuCl2, Cu2O, CuBr
and CuBr2) (see entries 1–5, Table 1). Therefore, in the subse-
quent investigations, all reactions were performed with CuI as
the catalyst.
A variety of oxidants, such as TBHP, DTBP, H2O2, DDQ, and
TEMPO, and their loadings were also tested to nd optimum
conditions for the designed reaction. As shown in Table 1,
TBHP performed the best of all the oxidants tested. As indicated
above, the desired product 3aa was obtained with yields of up to
92% (entry 10, Table 1) when using three equivalents of this
oxidant. Using more TBHP (four equivalents) or less of this
oxidant (one and two equivalents) resulted in somewhat lower
yields. Perhaps, more by-products were generated during the
reaction with the larger loading of TBHP, and the oxidation
actions were not great enough to convert substrate to product
when less of the oxidant was loaded (entry 21, Table 1).
Reaction temperatures were also evaluated to nd suitable
conditions for the reaction. As shown in Table 1, a temperature
The effects of the identity and presence of the solvent on the
yields were also evaluated for the purpose of nding suitable
conditions. Organic solvents such as tetrahydroꢀfuran (THF),
MeCN, 1,4-dioxane, and MeOH were tested at 50 C. Of all the
Table 1 Optimization of the model reaction conditionsa
ꢀ
of 50 C was best of all the temperatures evaluated (entry 10,
Table 1), with lower and higher temperatures (30 ꢀC and 70 ꢀC)
not leading to higher yields of the product 3aa. Therefore, 50 ꢀC
was chosen as the suitable reaction temperature for the subse-
quent reactions.
Entry
Catal.
Oxidant
Solvent
Temp. (ꢀC)
Yieldd (%)
1
2
3
4
5
6
7
8
CuI
TBHPb
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DTBP
MeCN
MeCN
MeCN
MeCN
MeCN
THF
Dioxane
MeOH
Toluene
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
50
50
50
50
50
50
50
50
50
50
50
50
50
50
30
70
50
50
50
50
50
63
With all of the optimized conditions in hand, a wide range of
ethylarenes and amines were then subjected to this reaction to
explore the scope of substrates. The results of this investigation
are summarized in Table 2. All reactions proceeded well in the
absence of solvent at ambient temperature. Yields of product
appeared to benet from the presence of electron-withdrawn
substituent(s) on the substrate. For example, the reaction of
an ethylarene substrate bearing a nitro group on the ring
resulted in the desired product with an excellent yield of 89%
(3ba, Table 2). In contrast, the presence instead of an electron-
donating ethyl group at the same position resulted in a poorer
yield of 70% (3fa, Table 2). Substituent groups on the substrate
could therefore either positively or negatively affect product
yield, and possibly the reaction rate as well. Note that the
reaction of substrates with more than one ethyl group, for
example, p-diethylbenzene, with amines resulted in mono-
oxidated amination products in relatively poor yields, possibly
due to more by-products having formed.
Based on some related publications,16 a possible mechanism
was proposed, as shown in Scheme 2. According to this mech-
anism, CuI catalyzed the breaking up of the oxidant TBHP into
a t-butoxyl radical and a hydroxyl anion (eqn (1) and (2)),17 with
the t-butoxyl radical in the following step releasing one
hydrogen from the C–H bond of ethylarene on the benzylic ring
1 to form the peroxide 5, which further decomposed to
CuCl2
Cu2O
CuBr
CuBr2
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
n.d.
n.d.
36
<5
6
<5
12
64
92
n.d.
n.d.
n.d.
n.d.
80
9
10
11
12
13
14
15
16
17
18
19
20
21
c
H2O2
DDQ
TEMPO
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
88
79e
90f
56g
78h
90i
CuI
CuI
CuI
Neat
Neat
Neat
a
Conditions: 1a (1.0 mmol), 2a (6.0 mmol), catalyst (20 mol%), and
oxidant (3 equiv.) under an air atmosphere for 24 h, n.d., not
detected; unless otherwise stated, all reaction were performed with 3
b
equiv. of oxidant. TBHP: tert-butyl hydroperoxide (TBHP), 70% in
water. Hydrogen peroxide, 30% in water. Unless otherwise stated,
all yields were determined by HPLC analysis. CuI (10 mol%). CuI
(30 mol%). Yields obtained from the reaction using 1 equivalent of
c
d
e
f
g
h
TBHP. Yields obtained from the reaction using 2 equivalents of
TBHP. i Yields obtained from the reaction using 4 equivalents of TBHP.
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Table 2 Copper-catalyzed oxidative synthesis of a-ketoamidesa
Scheme 2 Possible reaction pathway.
Scheme 3 Control experiments to test the proposed mechanism.
radical intermediates. When acetophenone was used instead of
ethylbenzene to react with morpholine, an excellent yield of the
product 3 was achieved (b). The reaction of experiment (c) was
carried out by employing phenylacetaldehyde instead of ethyl-
benzene, and this reaction produced the desired compound in
very low yield. These examples showed that the oxidation star-
ted from the benzylic C–H bond of ethylarene, and not from the
methyl group.
a
Conditions: 1 (1.0 mmol), 2 (6.0 mmol), CuI (20 mol%) and 3
equivalents of TBHP at 50 ꢀC under an air atmosphere for 24 h.
b
Yields were determined by HPLC analysis. Yields in the parentheses
are the yields of the isolated compounds.
acetophenone 6 with the assistance of TBHP.18 Then, according
to the proposed mechanism, acetophenone 6 reacted with
amine 2 to form the enamine 7,19 which then further reacted
with Cu(II) and t-butoxyl radicals from CuI and TBHP17 to form
Conclusions
aminodioxetane 8. Then, according to the mechanism, cleavage In summary, we have developed an efficient one-pot, solvent-
of the O–O bond of 8 produced the aryl glyoxal 9,20 which free procedure for the synthesis of a-ketoamides through
reacted with the introduced amine 2 to give the intermediate 10, a CuI-catalyzed sp3 C–H bond coupling process aided by aerobic
and then the reaction of 10 with the t-butoxyl radical from THBP oxidation using ethylarenes and amines. No harsh conditions
yielded compound 11 and nally the a-ketoamide 3 product.
were needed for this reaction. When using only three equiva-
To verify the mechanism proposed above, several control lents of TBHP, the desired a-ketoamide products were afforded
experiments were carried out, as are shown in Scheme 3. When with moderate to excellent yields of up to 93%. These results
the reaction was carried out in the presence of a radical scav- showed the promise of using this alternative and novel pathway
enger, for instance TEMPO, the oxidative coupling reaction did to synthesize a-ketoamides and to enrich the synthetic library
not work (a),21 indicating that this conversion likely involved for a-ketoamide preparations. This procedure can also be
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considered to adhere to some of the principles of green chem-
istry, as the reactions occurred without solvent. Overall, we
believe this procedure to have potential in large-scale prepara-
tions of a-ketoamides, especially for industrial purposes.
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Acknowledgements
Financial support from the National Natural Science Founda-
tion of China (21502036), Innovative research team project of
Hainan Natural Science Foundation (2016CXTD006), Hainan
Provincial Natural Science Foundation (213010) and Hainan
University (kyqd1408) are gratefully acknowledged.
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