Cu-Catalysed oxidative amidation of cinnamic acids/arylacetic acids with 2° amines: An efficient synthesis of α-ketoamides

Article abstract of DOI:10.1039/c9ob02045d

A new and convenient copper-catalysed synthesis of α-ketoamides has been accomplished using readily available cinnamic acids/arylacetic acids and 2° amines in an open atmosphere. The reaction between cinnamic acid and amine involves the formation of enamine followed by its aerobic oxidation, whereas the reaction of arylacetic acid with amine involves amide formation followed by benzylic methylene oxidation.

Full text of DOI:10.1039/c9ob02045d

Organic &
Biomolecular Chemistry
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Cu-Catalysed oxidative amidation of cinnamic
acids/arylacetic acids with 2° amines: an efficient
synthesis of α-ketoamides†
Cite this: Org. Biomol. Chem., 2019,
17, 9348
Anup Kumar Sharma, Anjali Jaiswal and Krishna Nand Singh
*
A new and convenient copper-catalysed synthesis of α-ketoamides has been accomplished using readily
available cinnamic acids/arylacetic acids and 2° amines in an open atmosphere. The reaction between
cinnamic acid and amine involves the formation of enamine followed by its aerobic oxidation, whereas
the reaction of arylacetic acid with amine involves amide formation followed by benzylic methylene
oxidation.
Received 19th September 2019,
Accepted 7th October 2019
DOI: 10.1039/c9ob02045d
rsc.li/obc
reagents. Zhao et al. have described a metal-free oxidative aryl
migration and C–C bond cleavage for the synthesis of
Introduction
α-Ketoamides are key structural motifs of a variety of natural pro- α-ketoamides from acrylic derivatives, whereas Liu et al. have
ducts, bio-active molecules and pharmaceuticals such as anti- reported a carbon degradation-based amidation to form
HIV, anti-tumor, anti-IBD, anti-bacterial, immunosuppressant pyridyl benzamides using phenylacetic acids and 2-aminopyri-
and enzyme inhibitors.1 They also act as valuable intermediates dine.8 Therefore, the development of fresh strategies for the
and synthons in a number of functional group transformations synthesis of α-ketoamides employing easily available materials
and total synthesis. Due to their potential significance, several is in high demand. In view of the above, and as part of our
methods have been explored for the synthesis of α-ketoamides ongoing research on decarboxylative coupling reactions,9 we
using transition-metal catalysts based on Pd, Cu, Ag, Au, and Fe, describe herein a new and efficient one-pot approach to
as well as metal-free catalysts, especially iodine based.2,3
α-ketoamides by the reaction of cinnamic/arylacetic acids with
The synthesis of α-ketoamide scaffolds has been accom- secondary amines under aerobic conditions (Scheme 1).
plished using diverse substrates such as ethylarenes, terminal
alkenes, terminal alkynes, aryl methyl ketones, aryl acet-
aldehydes, 2-oxo aldehydes, 1-arylethanols, 2-arylethanols,
2-oxo alcohols, and phenylglyoxylic acids.4 MW/UV-assisted
oxidative synthesis of α-ketoamides is also reported using acet-
ophenones and secondary amines.5 Among various catalytic
methods of α-ketoamide formation, the strategies involving
oxidative amidation4 and double aminocarbonylation6 have
received much more attention using carbon monoxide (CO) as
a direct source of carbonyl functionality, and molecular oxygen
(O2)/air as a terminal oxidant and/or reactant (Scheme 1).
Decarboxylative reactions have recently cropped up as a
powerful method to form carbon–carbon or carbon–hetero-
atom bonds in organic synthesis.7 Carboxylic acids are stable,
nontoxic, easy to store/handle, readily available at low costs in
great structural diversity, and far less air and moisture sensi-
tive in comparison with typical cross-coupling organometallic
Department of Chemistry, Institute of Science, Banaras Hindu University,
Varanasi 221005, India. E-mail: knsingh@bhu.ac.in, knsinghbhu@yahoo.co.in
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9ob02045d
Scheme 1 Previous reports and the present strategy.
9348 | Org. Biomol. Chem., 2019, 17, 9348–9351
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remained unproductive (entries 19 & 20). Then we screened
the molar ratio of the reactants and catalyst at different tem-
Results and discussion
In order to optimize the reaction conditions, a model reaction peratures and times (entry 21), which revealed a 1 : 2 molar
employing cinnamic acid (1a) and morpholine (2a) was investi- ratio of 1a and 2a in the presence of 40 mol% of Cu(OAc)2
gated in detail by varying different parameters such as catalyst, in p-xylene at 110 °C in an open atmosphere as the best fit
solvent, oxidant, base and temperature (Table 1).
(entry 4).
Under the optimized set of conditions, the scope and versa-
The reaction commenced with 40 mol% Cu(OAc)2 in DMSO
in an open air atmosphere at 110 °C for 24 h, which gave rise tility of the reaction were then thoroughly examined using
to the product 1-morpholino-2-phenylethane-1,2-dione (3a) in different sets of cinnamic acids/arylacetic acids and amines
61% yield (entry 1). Upon changing the solvent from DMSO having various substitution patterns, which readily delivered
to DMF, 1,4-dioxane, p-xylene, toluene, ethanol, CH3CN and the desired products 3a–t in moderate to good yields (Table 2).
PEG-600 (entries 2–8), only p-xylene could make some
Unsubstituted as well as substituted cinnamic acids
enhancement in the product yield (64%, entry 4). Notably the bearing both electron-donating (OMe and Me) and electron-
reaction remained completely futile in the absence of the cata- withdrawing substituents (Cl, F, Br, and NO2) on the
lyst (entry 9). Thereafter, the use of some other Cu salts such aromatic ring smoothly underwent the reaction to afford the
as CuI, CuBr, CuCl2 and Cu(OTf)2 was tried (entries 10–13), α-ketoamides (3). The position of the substituent on the
but none of them could surpass the efficacy of Cu(OAc)2. The aromatic ring was noticed to have some effect on the product
combination of Cu(OAc)2 with other oxidants such as K2S2O8 yield. ortho-Substitution provided somewhat inferior product
and TBHP also stayed worthless (entries 14 & 15). The role of yield as compared to meta- and para-substitution, which may
base was also found to be insignificant with no increase in the be attributed to the steric effect (3a–f). To expand the adapta-
product yield (entry 16), while replacing Cu(OAc)2 by Ag2CO3 bility of the reaction, investigations were also carried out using
in the reaction rather decreased the product yield considerably a number of arylacetic acids viz. phenylacetic acid, 3-methoxy-
(entry 17). The Cu(OAc)2/Ag2CO3 combination also could not
improve the product yield further (entry 18). The use of I2 and
DIB in combination with TBHP in acetonitrile at 80 °C also
Table 2 Scope of the reactiona,b
Table 1 Optimization of the reaction conditionsa
Entry
Catalyst
Oxidant
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
—
CuI
CuBr
CuCl2
Cu(OTf)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Ag2CO3
Cu(OAc)2/Ag2CO3
I2
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
DMSO
DMF
1,4-Dioxane
p-Xylene
Toluene
EtOH
61
54
Trace
64
62
20c
CH3CN
32c
PEG-600
p-Xylene
p-Xylene
p-Xylene
p-Xylene
p-Xylene
p-Xylene
p-Xylene
p-Xylene
p-Xylene
p-Xylene
CH3CN
28
Trace
35
43
48
28
9
10
11
12
13
14
15
16
17
18
19
20
21
Air
K2S2O8
TBHP
Air
Air
Air
TBHP
TBHP
Air
Trace
15
54d, 15e
21
64
21c
DIB
Cu(OAc)2
CH3CN
p-Xylene
23c
37c, 63f, 61g,
58h, 64i, j
a Reaction conditions: 1a (1.0 mmol), 2a (2.0 mmol), catalyst
(40 mol%), oxidant (2.0 equiv.), solvent (1.0 mL), 110 °C, 24 h.
b Isolated yield after column chromatography. c At 80 °C. d Using a Reaction conditions:
1 (1.0 mmol), 2 (2.0 mmol), Cu(OAc)2
K2CO3. e Using KOtBu. f At 130 °C. g Catalyst (20 mol%). h 2a (40 mol%), p-xylene (1.0 mL), 110 °C, 24 h. b Isolated yield after
(1.0 mmol). i 2a (4.0 mmol). j Under O2.
column chromatography. c Using arylacetic acids.
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phenylacetic acid, 2-methylphenylacetic acid, and 3-thio-
pheneacetic acid, which underwent transformation adequately
to give the products in good yields (3a–3c, 3g). To increase the
usefulness of the reaction, some other secondary amines such
as piperidine, pyrrolidine, diethylamine and dipropylamine
were also made to react with different cinnamic acids, which
led to the formation of products 3h–3t in fairly good yields.
Piperidine and pyrrolidine gave better yields as compared to
diethylamine and dipropylamine, which is perhaps controlled
by the basicity and steric nature of the amines. In place of sec-
ondary amines, the reaction was also carried using primary
amines such as benzylamine and 2-aminopyridine with cin-
namic acid, which however furnished only a trace amount of
the desired product, with a good yield of α,β-unsaturated
amides. Furthermore, the reaction of primary amines with
arylacetic acids led to one carbon degraded amides as the only
isolable product, which is in close conformity with the obser-
vation of Liu’s group.8b
To demonstrate the synthetic utility of the method, a gram
scale reaction using 1.184 g of 1a (8 mmol) with 1.5 mL of
morpholine was carried out under the standard conditions
(Scheme 2), which led to the formation of the desired product
1-morpholino-2-phenylethane-1,2-dione (3a) in 51% (0.893 g)
yield.
Scheme 3 Control experiments.
To gain insight into the reaction mechanism, various
control experiments were carried out (Scheme 3). The standard
reaction in the presence of radical scavengers such as TEMPO
and BHT was fully suppressed implying a radical pathway
(Scheme 3, eqn (1)). The reaction also remained futile when
carried out under an N2 atmosphere (Scheme 3, eqn (1)),
which implicates the role of atmospheric oxygen in the reac-
tion. In order to ascertain the intermediacy of (E)-1-morpho-
lino-3-phenylprop-2-en-1-one (A), the reaction of the proposed
intermediate A was separately carried out under the standard
conditions, which did not afford the product at all (eqn (2))
thereby excluding the possibility of intermediate A. Assuming
the involvement of phenylglyoxal (B) as an intermediate, a
control experiment involving B with 2a under established con-
ditions was also carried out which gave rise to the product in
89% yield (eqn (3)). An additional experiment involving 1′a
and 2a in the presence of Cu(OAc)2 was also performed
under an N2 atmosphere to afford the corresponding amide C
(eqn (4)). The isolated amide C, when made to react under the
standard conditions, also gave rise to the desired product 3a.
Based on control experiments, isolation of products, and
the existing literature,3,4,8,9 a plausible mechanism is outlined
in Scheme 4. The reaction of cinnamic acid (1a) in the pres-
Scheme 4 Plausible mechanism.
ence of 2a and Cu(II) is assumed to pass through copper cinna- mate to give the enamine, which on subsequent reaction with
Cu/O2 forms aminodioxetane. The O–O bond cleavage of the
aminodioxetane then leads to the formation of aryl glyoxal.
The reaction of the amine 2a with aryl glyoxal affords a
hemiaminal intermediate which is then oxidized by Cu/O2 to
produce product 3a. Conversely, phenylacetic acid (1′a) reacts
with 2a in the presence of a copper catalyst to form the amide
first followed by copper catalysed aerobic oxidation of the
Scheme 2 Gram scale synthesis of α-ketoamide 3a.
9350 | Org. Biomol. Chem., 2019, 17, 9348–9351
benzylic methylene to afford product 3a.
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Conclusions
In summary, a new and simple method for the synthesis of
α-ketoamides has been developed via oxidative amidation of
bench stable and readily available cinnamic acids/arylacetic
acids with 2° amines in an open atmosphere in the presence
of Cu(OAc)2. The strategy involves in situ decarboxylation as
well as oxidative amidation of cinnamic acids. The method-
ology is versatile and provides a useful alternative to access
α-ketoamides.
Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
We are thankful to the SERB, New Delhi for financial support
(file no. EMR/2016/000750). One of the authors (AKS) thanks
the UGC, New Delhi for a Senior Research Fellowship.
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