Metal-Free C=C Double Bond Cleavage on Enaminones for the Synthesis of α-Ketoamides by Free-Radical Aerobic Oxygenation

Article abstract of DOI:10.1002/ejoc.201900660

The tandem oxidation of the enaminone C=C double bond as well as subsequent C-N bond formation are realized under metal-free conditions by thermo-induced free radical transformation. In the presence of benzoyl peroxide (BPO) and N-iodosuccinimide (NIS), a

Full text of DOI:10.1002/ejoc.201900660

A Journal of
Accepted Article
Title: Metal-Free C=C Double Bond Cleavage on Enaminones for the
Synthesis of α-Ketoamides by Free-Radical Aerobic Oxygenation
Authors: Yiming Yang, Guofeng Zhong, Junfen Fan, and Yunyun Liu
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900660
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10.1002/ejoc.201900660
European Journal of Organic Chemistry
Metal-Free C=C Double Bond Cleavage on Enaminones for the
Synthesis of α-Ketoamides by Free-Radical Aerobic Oxygenation
Yiming Yang,[a] Guofeng Zhong,[a] Junfen Fan*[b] and Yunyun Liu*[a]
Abstract: The tandem oxidation of the enaminone C=C double bond
as well as subsequent C-N bond formation are realized under metal-
free conditions by thermo-induced free radical transformation. In the
presence of benzoyl peroxide (BPO) and N-iodosuccinimide (NIS), a
series of tertiary α-ketoamides are synthesized practically under
aerobic atmosphere. The 18O isotopic experiment confirms that air is
the source of oxygen in the newly generated carbonyl group.
C=C double bond cleavage wherein water acts as the source of
oxygen (Scheme 1A). Considering the current emphasis in
developing metal-free organic synthesis,16 especially the metal-
free C=C bond cleavage-based synthesis,17 it is highly desired to
discover alternative method for α-ketoamide synthesis without
employing metal reagent. Herein, we report a metal-free protocol
for the enaminone C=C double bond cleavage, leading to the
synthesis of α-ketoamides with broad scope (Scheme 1B).
Besides the operation free of metal reagent, isotopic experiment
using O18-oxygen gas confirms that unlike the previous work
absorbing the oxygen atom in water, the present method
employs the oxygen in air as the source of oxygen atom in the
newly generation C=O fragment.
Introduction
Amide is the fundamental structure in numerous clinical
medicines and bioactive lead compounds targeting the treatment
of various diseases, such as Alzheimer disease, tuberculosis,
nephropathy, cancer, and fever etc.1 As a class of special
amides, α-ketoamides are valuable scaffolds showing enriched
application in multiple disciplines.2 As substrates, they are used
to synthesize a variety of different organic products, such as
lactams, N,O-heterocycles, pyrrolidinones, functionalized
amides, fused aryls, chiral heterocycles, to name but a few.3 In
addition, the α-ketoamide fragment has been proved as crucial
substructure in a number of biologically active natural products
and lead compounds.4 To further disclose the application of α-
ketoamides, practical and diversity oriented synthesis toward α-
ketoamides is thus an issue of high significance. To date, a
plethora of synthetic methods have been reported to be capable
of affording α-ketoamide scaffolds. For instance, the oxidation
on pre-functionalized precursors such as hydroxyl amides,
haloamides or aminoamides;5 the amidation of α-ketoacids or
acyl chlorides,6 the C-H amidation of α-ketoaldehydes,7 the
oxoamidation of simple aldehydes and ketones,8 the
oxoamidation of α-hydroxyl or ester functionalized ketones,9 the
aminocarbonylation reaction using isocyanides,10 the oxidative
oxoamidation of α,α-dihaloketones,11 the oxoamination reactions
based on the cleavage of C-C single bonds,12 C=C double
bond13 and C≡C triple bonds,14 and others.15
A) Previous work:
copper-catalyed synthesis
O
R1
N
H2O18
PhI(OAc)2/CuI
O
R1
R2
N
R2
R
DMSO, 120 oC
R
18O
B) This work: metal-free synthesis
O
R'
N
O18 in air
NIS/BPO
O
R'
N
R'
R'
R
o
R
p-xylene, 60 C
18O
Aerobic ! Metal-free ! Mild conditions
Scheme 1 CuI-catalyzed, water-participated vs metal-free, air participated α-
ketoamide synthesis
Results and Discussion
To start the investigation, enaminone 1a was employed
together with NIS in p-xylene, and product 2a was formed with
38% yield by heating at 60 oC (entry 1, Table 1). Notably,
additionally employing BPO in the reaction led to significant
improvement on the product yield (entry 2, Table 1). However,
using only BPO gave the C-H acyloxyled product as in previous
literature,18 and 2a was not isolated (entry 3, Table 1).
Subsequently, several different iodo-reagents, including I2, KI
and Bu4NI were used as alternative additive, respectively. But no
improved result was observed (entries 4-6, Table 1).
Analogously, the parallel entries in the presence of different
peroxides such as TBHP, DTBP and H2O2 led to no improved
yield of 2a, either (entries 7-9, Table 1). In later study, the
loading of NIS and BPO were independently varied, but inferior
results were acquired in all these experiments (entries 10-12,
Table 1). Performing the reaction in different medium indicated
that p-xylene was amongst the most favorable one (entries 13-
16, Table 1). Moreover, heightening or lowering the reaction
temperature both afforded 2a with decreased yield (entries 17-
In previous work, Wan et al13a developed the method
synthesizing α-ketoamides by a copper-catalyzed enaminone
[a]
[b]
Prof. Dr. Y. Liu, Y. Yang, G. Zhong
College of Chemistry and Chemical Engineering
Jiangxi Normal University
Nanchang 330022, P. R. China
E-mail: chemliuyunyun@jxnu.edu.cn
Homepage: http://www.escience.cn/people/LiuYY/index.html
Dr. J. Fan
Department of Nephrology
First Affiliated Hospital of Zhejiang Chinese Medical University
Hangzhou 310006, P. R. China
Email: fan_13750847358@126.com
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900660
European Journal of Organic Chemistry
18, Table 1). Finally, a control experiment under nitrogen
atmosphere gave only tiny amount of 2a, illustrating the
indispensable role of air in the reaction (entry 19, Table 1).
pyrrolidine and morphorline functionalized enaminones took part
in the reactions to practically give corresponding products with
correspondingly diverse N,N-disubstitution (2r-2v, Table 2).
Generally, the products were acquired with moderate to good
yields under the metal-free conditions, and no clear impact of
the substituent in the enaminone substrates to the reaction
result was identified with the in hand data. However, the reaction
using an N-phenyl enaminone did not lead to the target product,
indicating that the present conditions might be not proper for the
reaction of NH-enaminone (2x, Table 2). In addition, an alkyl
based enaminone, the (E)-4-(dimethylamino)but-3-en-2-one was
also subjected to the present reaction conditions, but no
expected reaction forming similar α-ketoamide product was
observed therein.
Table 1 Optimization on reaction conditionsa
O
O
oxidant, addtive
solvent, T
N
Ph
Ph
N
O
2a
1a
Entry
Addtive
Oxidant
-
BPO
Solvent
T (oC)
Yield (%)b
1
NIS
NIS
-
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
toluene
DMSO
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
40
80
60
38
67
trace
35
27
23
30
33
59
27
35
35
31
23
46
15
50
45
<5
2
Table 2 Scope on the NIS-mediated α-ketoamide synthesisa
3
BPO
BPO
BPO
BPO
TBHP
DTBP
H2O2
BPO
BPO
BPO
BPO
BPO
BPO
BPO
BPO
BPO
BPO
O
O
R'
N
air
NIS/BPO
p-xylene, 60 oC
R'
N
R'
R'
4
I2
R
N
R
O
1
2
5
KI
O
O
O
O
6
Bu4NI
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
N
N
N
N
O
O
O
O
O2N
Cl
7
2a
, 67%
2d
2b
2c
, 63%
O
, 58%
O
, 61%
O
8
O
N
N
N
9
O
O
O
O
Br
F
NC
2e
10c
11d
12e
13
14
15
16
17
18
19f
, 60%
2h
2f
2g
, 60%
, 66%
, 59%
O
NO2
O
O
Br
O
MeO
N
N
Cl
N
N
N
O
, 62%
O
O
O
2j
2i
, 56%
, 55%
2l
2k
, 60%
O
O
O
O
Cl
Cl
N
N
N
N
O
O
O
O
2n
, 56%
2p
2o
, 57%
, 62%
MeCN
2m
, 70%
O
O
O
O
DMF
N
N
N
N
S
O
p-xylene
p-xylene
p-xylene
O
O
O
2q
2r
, 52%
, 59%
2s
, 58%
2t
, 61%
O
O
O
O
O
O
H
N
N
N
N
Ph
O
O
O
O
Cl
aGeneral conditions: 1a (0.3 mmol), oxidant (0.3 mmol), and additive (0.6
2u
, 58%
2x
2w
, not observed
, 61%
2v
, 53%
mmol) in 2 mL solvent, stirred at 60 oC for 12 h. bYield of isolated product.
aGeneral reaction conditions: 1 (0.3 mmol), NIS (0.6 mmol), BPO (0.3 mmol) in
p-xylene (2 mL), stirred at 60 oC for 12h under air atmosphere. bYield of
isolated product.
f
cWith NIS (0.3 mmol). dWith NIS (0.9 mmol). eWith BPO (0.6mmol). Reaction
under N2.
To examine the synthetic scope, a broad variety of N,N-
disubstituted enaminones 1 were employed to the optimized
reaction conditions. As expected, satisfactory tolerance of the
present method in the synthesis of α-ketoamides was implied.
When, the N,N-dimethyl functionalized enaminones were used,
the substrates containing alkyl-, halo-, nitro-, alkoxyl-, and
cyano-functionalized phenyl (2b-2l, Table 2), disubstituted
phenyl (2m, Table 2), fused aryl (2n-2o, Table 2) and heteroaryl
(2p-2q, Table 2) were generally tolerated. Moreover, in the
subsequent experiments, the enaminones with different N,N-
substituted amino group, such as diethylamino, pyperidine,
Notably, in a gram-scale (6 mmol) reaction synthesizing 1a, the
target product was obtained with 45% yield (Scheme 2),
suggesting the application potential of this method in the
synthesis of α-ketoamides with larger amount.
O
O
NIS (2.7 g)
BPO (1.45g)
N
N
O
p-xylene (20 mL)
60 oC, 12 h
1a
6 mmol (1.05g)
2a, 45% yield
0.48 g
Scheme 2 Scale-up synthesis of 2a
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10.1002/ejoc.201900660
European Journal of Organic Chemistry
In order to probe the possible reaction mechanism, several
control experiments were performed. First, the model reaction
carried out in the presence of 4 equiv TEMPO gave product 2a
with only trace amount (eq 1), illustrating that the reaction
proceeded via free radical mechanism. In addition, considering
the possible source of oxygen from both trace water or the
air,13a,19 the reaction of 1b under 18O2 was conducted, which
provided mixed 2b and 18O-labelled 2b wherein the 18O-2b was
the major product (eq 2) as observed in the HRMS spectra (See
SI). This result confirmed that the molecular oxygen in air was
the source of oxygen-atom in the synthesized product.
In conclusion, by combining BPO and NIS promotion, a
metal reagent-free method on enaminone C=C bond cleavage is
developed for the practical synthesis of α-ketoamides. Besides
the metal-free operation, the present method also benefits from
the feature employing air as the oxygen source. Therefore, this
method provides a valuable new route to complement those
previously reported methods employing metal reagent and/or
additional oxygen source for the synthesis of α-ketoamides.
Experimental Section
General procedure for the synthesis of α-ketoamides 2
To a 25 mL round-bottom flask equipped with stirring bar and condenser
were charged with enaminones 1 (0.3 mmol), NIS (0.6 mmol), BPO (0.3
mmol) and p-xylene (2 mL). The resulting mixture was stirred at 60 ℃ for
12 h under air atmosphere. Upon completion, the reaction mixture was
allowed to cool down to rt, and H2O (10 mL) was added to the vessel.
The resulting suspension was extracted with ethyl acetate (3 × 10 mL).
The organic phases were combined and dried over Na2SO4. After
filtration, the solvent was removed from the solution under reduced
pressure. The acquired residue was subjected to silica gel column
chromatography to provide pure product by using mixted petroleum ether
and ethyl acetate (v/v = 5:1) as the eluent.
Based on the results in hand, we proposed the possible
reaction mechanism (Scheme 3). At first, the BPO breaks to
provide carboxyl radical 3 by thermo-induced O-O bond homo-
cleavage. The reaction of 3 with NIS led to the production of
iodine radical. The coupling of the radical to oxygen then
promotes the free radical oxygenation on the α-site of the
enaminone 1 to give intermediate 4 by single electron transfer
(SET). Subsequently, the intramolecular free radical addition of
4 provides cyclic radical 5 which reacts with the in situ generated
HI to yield the 1,2-dioxetane intermediate 6. Under the driving
force of the dioxetane ring opening, the bond reorganization on
6 takes place to afford intermediate 7. The decomposition of 7
then provide products 2 and HCHO.
N,N-Dimethyl-2-oxo-2-phenylacetamide (3a).13a Yellow oil; 1H NMR
(400 MHz, CDCl3): δ 7.95 (d, J = 7.6 Hz, 2 H), 7.65 (d, J = 7.4 Hz, 1 H),
7.51 (d, J = 7.6 Hz, 2 H), 3.12 (s, 3 H), 2.96 (s, 3 H).
N,N-Dimethyl-2-oxo-2-(p-tolyl)acetamid (3b).13a Yellow oil; 1H NMR
(400 MHz, CDCl3): δ 7.84 (d, J = 8.0 Hz, 2 H), 7.31 (d, J = 8.0 Hz, 2 H),
3.11 (s, 1 H), 2.95 (s, 1 H), 2.43 (s, 1 H).
N,N-Dimethyl-2-(4-nitrophenyl)-2-oxoacetamide (3c).13a Yellow solid;
mp: 136-137 ℃; 1H NMR (400 MHz, CDCl3): δ 8.35 (d, J = 8.8 Hz, 2 H),
8.15 (d, J = 84.0 Hz, 2 H), 3.16 (s, 3 H), 3.02 (s, 3 H).
O2(air)
NIS
O
heat
2
I
BPO
Ph
O
O
2-(4-Chlorophenyl)-N, N-dimethyl-2-oxoacetamide (3d).13a Yellow oil;
1H NMR (400 MHz, CDCl3): δ 7.90 (d, J = 8.4 Hz, 2 H), 7.49 (d, J = 8.4
Hz, 2 H), 3.12 (s, 3 H), 2.97 (s, 3 H).
1
3
HI
N OCOPh
O
2-(4-Bromophenyl)-N,N-dimethyl-2-oxoacetamide (3e).8b Yellow oil; 1H
NMR (400 MHz, CDCl3): δ 7.82 (d, J = 8.0 Hz, 2 H), 7.66 (d, J = 8.4 Hz, 2
H), 3.11 (s, 3 H), 2.96 (s, 3 H).
HI
O
O
O
O
O
R'
R'
N
R'
N
R
R
R'
O
I
2-(4-Fluorophenyl)-N,N-dimethyl-2-oxoacetamide (3f).13a Yellow oil;
1H NMR (400 MHz, CDCl3): δ 8.01-7.98 (m, 2 H), 7.19 (d, J = 8.8 Hz, 2
H), 3.12 (s, 3 H), 2.97 (s, 3 H).
5
4
O
H
O
2
O
O
O
R'
O
2-(4-Cyanophenyl)-N,N-dimethyl-2-oxoacetamide (3g).13a White solid;
mp 132-133℃. 1H NMR (400 MHz, CDCl3): δ 8.07 (d, J = 8.4 Hz, 2 H),
7.82 (d, J = 8.4 Hz, 2 H), 3.14 (s, 3 H), 3.00 (s, 3 H).
R
N
R'
HCHO
N
R
R'
R'
H
6
7
N,N-Dimethyl-2-oxo-2-(o-tolyl)acetamide (3h).8b Yellow oil; 1H NMR
(400 MHz, CDCl3): δ 7.69 (d, J = 7.6 Hz, 1 H), 7.48 (d, J = 7.6 Hz, 1 H),
7.31 (t, J = 7.2 Hz, 2 H), 3.11 (s, 3 H), 2.97 (s, 3 H), 2.66 (s, 3 H).
Scheme 3 The proposed reaction mechanism
Conclusions
N,N-Dimethyl-2-(2-nitrophenyl)-2-oxoacetamide (3j). Yellow oil; 1H
NMR (400 MHz, CDCl3): δ 8.11 (d, J = 8.0 Hz, 1 H), 7.84-7.72 (m, 2 H),
7.68 (d, J = 7.6 Hz, 1 H), 3.35 (s, 3 H), 3.02 (s, 3 H); 13C NMR (100 MHz,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900660
European Journal of Organic Chemistry
CDCl3): 187.5, 163.8, 147.1, 134.4, 133.9, 132.1, 131.2, 123.8, 37.5,
35.7; ESI-HRMS cacld. for C10H11N2O4 [M+H]+: 223.0713, found:
223.0713.
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2-(3,4-Dichlorophenyl)-N,N-dimethyl-2-oxoacetamide (3m).13a White
solid; mp: 80-81℃; 1H NMR (400 MHz, CDCl3): δ 8.05 (s, 1 H), 7.80 (d, J
= 9.6 Hz, 1 H), 7.60 (d, J = 8.4 Hz, 1 H), 3.13 (s, 3 H), 2.98 (s, 3 H).
N,N-Dimethyl-2-(naphthalen-1-yl)-2-oxoacetamide (3n).13a Yellow oil;
1H NMR (400 MHz, CDCl3): δ 9.26 (d, J = 8.8 Hz, 1 H), 8.11 (d, J = 8.0
Hz, 1 H), 7.99 (d, J = 6.8 Hz, 1 H), 7.92 (d, J = 8.1 Hz, 1 H), 7.70 (d, J =
7.8 Hz, 1 H), 7.60 (d, J = 7.6 Hz, 1 H), 7.54 (d, J = 7.8 Hz, 1 H), 3.16 (s, 3
H), 3.02 (s, 3 H).
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1
N,N-Dimethyl-2-oxo-2-(thiophen-2-yl)acetamide (3q).13a Yellow oil;
H
NMR (400 MHz, CDCl3): δ 7.80 (t, J = 5.2 Hz, 2 H), 7.19 (t, J = 4.0 Hz, 1
H), 3.10 (s, 3 H), 3.05 (s, 3 H).
N,N-Diethyl-2-oxo-2-phenylacetamide (3r).13a Yellow oil; 1H NMR (400
MHz, CDCl3): δ 7.94 (d, J = 8.4 Hz, 2 H), 7.68-7.59 (m, 1 H), 7.51 (t, J =
7.6 Hz, 2 H), 3.57 (q, J = 7.2 Hz, 2 H), 3.25 (q, J = 7.2 Hz, 2 H), 1.29 (t, J
= 7.2 Hz, 3 H), 1.16 (t, J = 7.0 Hz, 3 H).
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(400 MHz, CDCl3): δ 7.95 (d, J = 7.6 Hz, 2 H), 7.64 (t, J = 7.4 Hz, 1 H),
7.51 (d, J = 7.6 Hz, 2 H), 3.71 (t, J = 4.4 Hz, 2 H), 3.29 (d, J = 5.4 Hz, 2
H), 1.71-1.68 (m, 4 H), 1.56-1.52 (m, 2 H).
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1-(4-chlorophenyl)-2-morpholinoethane-1,2-dione
(3v).13a
Yellow
gummy compound; 1H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 8.4 Hz, 2
H), 7.50 (d, J = 8.4 Hz, 1 H), 3.79 (s, 4 H), 3.66 (t, J = 4.6 Hz, 2 H), 3.39
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1-(pyrrolidin-1-yl)-2-(o-tolyl)ethane-1,2-dione (3w). Yellow oil; 1H NMR
(400 MHz, CDCl3): δ 7.73 (d, J = 7.6 Hz, 1 H), 7.47 (t, J = 7.6 Hz, 1 H),
7.47 (t, J = 7.6 Hz, 2 H), 3.79 (s, 4 H), 3.65 (t, J = 6.6 Hz, 2 H), 3.43 (t, J
= 6.4 Hz, 2 H), 2.64 (s, 3 H), 1.98-1.94 (m, 4 H); 13C NMR (100 MHz,
CDCl3): 193.7, 165.8, 141.4, 133.5, 132.6, 132.5, 131.6, 126.1, 46.6,
45.3, 25.9, 24.0, 21.6; ESI-HRMS cacld. for C13H16NO2 [M+H]+: 218.1176,
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Acknowledgments
This work is financially supported by National Natural Science
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Keywords: aerobic • metal-free • enaminone • C=C bond
cleavage • α-ketoamides
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European Journal of Organic Chemistry
Entry for the Table of Contents (Please choose one layout)
FULL PAPER
C=C bond activation*
Yiming Yang, Guofeng Zhong, Junfen
Fan,* Yunyun Liu*
Page No. – Page No.
Metal-Free
C=C
Double
Bond
The metal-free cleavage of the enaminone C=C double bond providing α-
ketoamides has been realized by the BPO/NIS-initiated free radical cascade
reactions. Isotopic labelling experiment confirms that air is the oxygen source in
these reactions involving new carbonyl group formation.
Cleavage on Enaminones for the
Synthesis of α-Ketoamides by Free-
Radical Aerobic Oxygenation
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